Drugs for the Management of Rheumatoid Arthritis: - CADTH

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Drugs for the

Management of

Rheumatoid Arthritis:

Clinical Evaluation

December 2017

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Cite as: Drugs for the management of rheumatoid arthritis: clinical evaluation. Ottawa: 3

CADTH; 2017 Dec. 4

This report is prepared by the Cardiovascular Research Methods Centre (CRMC) for the 5

Canadian Agency for Drugs and Technologies in Health (CADTH) in collaboration with the 6

Canadian Institutes of Health Research (CIHR) Drug Safety and Effectiveness Network 7

(DSEN). This report contains a comprehensive review of existing public literature, studies, 8

materials, and other information and documentation (collectively the “source 9

documentation”) available to CADTH at the time it was prepared, and its creation was 10

guided by expert input and advice throughout its preparation. 11

The information in this report is intended to help health care decision-makers, patients, 12

health care professionals, health systems leaders and policy-makers make well-informed 13

decisions and thereby improve the quality of health care services. The information in this 14

report should not be used as a substitute for the application of clinical judgment in respect 15

of the care of a particular patient or other professional judgment in any decision-making 16

process, nor is it intended to replace professional medical advice. While CADTH has 17

taken care in the preparation of the report to ensure that its contents are accurate, 18

complete, and up-to-date, CADTH does not make any guarantee to that effect. CADTH is 19

not responsible for any errors or omissions or injury, loss, or damage arising from or as a 20

result of the use (or misuse) of any information contained in or implied by the information 21

in this report. 22

CADTH takes sole responsibility for the final form and content of this report. The 23

statements, conclusions, and views expressed herein do not necessarily represent the 24

view of Health Canada or any provincial or territorial government. 25

Production of this report is made possible through a financial contribution from the Health 26

Canada and CIHR-DSEN. 27

Copyright © 2017 CADTH. This report may be reproduced for non-commercial purposes 28

only and provided that appropriate credit is given to CADTH. 29

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ABBREVIATIONS AND DEFINITIONS 31

32 Abbreviations 33 ABA abatacept

ABP501 biosimilar adalimumab

ADA adalimumab

ANA anakinra

AnBaiNuo biosimilar etanercept

BAR4 baricitinib 4mg

bid twice daily

biw twice weekly

CAPA Canadian Arthritis Patient Alliance

CERTO certolizumab pegol

csDMARD conventional synthetic disease modifying anti-rheumatic drug

CT-P13 biosimilar infliximab

ETN etanercept

F/P/T Federal, Provincial, Territorial

FDA Food and Drug Administration

GOL golimumab

HCQ hydroxychloroquine

HD203 biosimilar etanercept

IL interleukin INF infliximab

IV intravenous

LEF leflunomide

MA meta analysis

MD mean difference

MTX methotrexate

NMA network meta-analysis

OR odds ratio

P.O. orally

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

qw every week

q2w every two weeks

q4w every four weeks

q8w every eight weeks

RA rheumatoid arthritis

RD risk difference

RIT rituximab

RR relative risk

SAR_200 sarilumab 200mg every two weeks

SB2 biosimilar infliximab

SB4 biosimilar etanercept

SC subcutaneous

SEB subsequent entry biologic

SIR_100 sirukumab 100mg every two weeks

SIR_50 sirukumab 50mg every two weeks

SMD standardized mean difference

SSZ sulfasalazine

STD standard dose

TOC_4 tocilizumab 4mg/kg

TOC_8 tocilizumab 8mg/kg

TOF tofacitinib

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tsDMARD targeted synthetic disease-modifying anti-rheumatic drug

ZRC-3197 biosimilar adalimumab

34 35 Definitions 36 Moderate rheumatoid

arthritis

Patients with moderate disease activity as defined by the American College

of Rheumatology guidelines 20151.

Severe rheumatoid arthritis Patients with high disease activity as defined by the American College of

Rheumatology guidelines 20151.

Treatment-experienced Patients previously treated for rheumatoid arthritis. Example of previous

treatments include: traditional DMARD; combination DMARDs (double or

triple DMARDs); biologic drug alone; biologic drug in combination with

methotrexate, tofacitinib, or any of the emerging drugs for rheumatoid

arthritis.

Treatment intolerance Intolerance to treatment due to an adverse event or contraindication to

treatment.

Treatment failure Less than optimal response to treatment due to a lack of efficacy (i.e., patient

does not attain low disease activity).

Inadequate treatment Patients with treatment intolerance or treatment failure.

DMARD monotherapy methotrexate, sulfasalazine, hydroxychloroquine, or leflunomide.

Double DMARD therapy any two of methotrexate, sulfasalazine, hydroxychloroquine, or leflunomide.

Triple DMARD therapy methotrexate with sulfasalazine and hydroxychloroquine.

DMARD combination

therapy

double or triple DMARD therapy.

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EXECUTIVE SUMMARY 39

Context and Policy Issues 40

An important group of patients that have been researched in rheumatoid arthritis (RA) are 41

those with an inadequate response to methotrexate. These patients are often treated with 42

biologics or with double or triple conventional synthetic disease-modifying anti-rheumatic 43

drug (csDMARD) therapy. Newer treatment options include targeted synthetic DMARDs 44

(tsDMARDs; e.g., as tofacitinib, bariticinib) and biosimilars. Comparative efficacy and 45

safety including, for example, direct comparisons of one biologic to another, as well as 46

between double and triple csDMARD therapy and csDMARD combination therapy to 47

biologics, are lacking and it is important for patients, clinicians and policy makers to know 48

of any differences in the benefits and harms of the different treatment options. Assessing 49

the available direct and indirect evidence using a network meta-analysis can provide 50

evidence to address this question. 51

Objective and Research Question 52

The objective of this review is to assess the benefits and harms of drugs used in adult 53

patients with moderate to severe rheumatoid arthritis who have failed or are intolerant to 54

methotrexate (MTX). 55

56

The research question was: What is the comparative clinical efficacy and safety of 57

csDMARD therapies (alone or in combination), biologics (including biosimilars), and 58

tsDMARDs in adult patients with moderate to severe rheumatoid arthritis who have failed 59

or are intolerant to MTX? 60

Methods 61

A literature search was performed May 3, 2016 in MEDLINE, Embase, the Cochrane 62

Library (Wiley), Cochrane CENTRAL, and PubMed. Regular database search alerts were 63

established to update the search until March 1, 2017. References of three Cochrane 64

reviews were also considered. Two reviewers independently selected included studies; 65

data extraction and Cochrane Risk of Bias assessments were performed by one reviewer 66

and verified by a second reviewer. The primary outcome is the ACR50. ACR response 67

rates are binary composite outcomes consisting of the following outcomes on disease 68

activity: tender and swollen joint counts, patient’s assessment of pain, patient and 69

physician’s global assessments of disease activity and an acute-phase reactant value 70

(either the erythrocyte sedimentation rate or a C-reactive protein level). Secondary 71

efficacy outcomes are as follows: ACR20 and ACR70, disease severity (DAS28), disability 72

(HAQ-DI), remission (DAS28<2.6), health-related quality of life (SF-36 physical and 73

mental component scores, fatigue, pain, and radiographic progression. The primary safety 74

outcome is withdrawals due to adverse events. Secondary safety outcomes included 75

serious adverse events and mortality, as well as the notable harms of serious infections, 76

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tuberculosis, cancer, leukemia, lymphoma, congestive heart failure, major adverse 77

cardiac events, and herpes zoster. 78

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Bayesian network meta-analyses (NMA) were conducted on the outcomes listed above 80

when there were more than three studies and odds ratios (OR) and 95% credible intervals 81

(CrI) were calculated. Meta-analyses (MAs) were conducted when only direct pairwise 82

comparisons were possible. Descriptive analyses were performed when there was 83

insufficient data to conduct NMAs or MAs. 84

Key Findings 85

This report included 98 unique studies and 91 had usable data for analysis. Risk of bias 86

assessments only revealed elevated proportions of high risk of bias for incomplete 87

efficacy and safety outcome data and half of included studies reported vaguely on random 88

sequence generation and allocation concealment. Overall, half of studies were judged to 89

be high risk of bias. 90

91

Methotrexate as a Common Comparator 92

Triple csDMARD therapy [MTX, sulfasalazine (SSZ) and hydroxychloroquine (HCQ)] was 93

favoured over double csDMARD therapy and was also found to be comparable to 94

biologics/biosimilars and tsDMARDs in terms of disease response (ACR50). In general, 95

most biologic monotherapies had lower odds of benefits based on disease response 96

(ACR50), remission, and health-related quality of life (for certain biologics only) than 97

biologics in combination with methotrexate (MTX), but biologics in combination with MTX 98

had higher odds of serious adverse events (SAEs) and withdrawal due to adverse events 99

(WDAEs). Several of the biologics in combination with MTX were found to be effective. 100

Discussions between clinicians and patients about treatment goals, preferences and cost 101

must be considered in selecting an appropriate biologic/biosimilar in combination with 102

MTX. 103

104

Patients intolerant to MTX are likely to benefit from 8 mg/kg tocilizumab monotherapy 105

because of the benefits compared to other biologics in terms of disease response, 106

remission, disease severity, and disability. 107

There were insufficient data to detect a difference between treatments for mortality and 108

the following notable harms: serious infections, tuberculosis, cancer, leukemia, 109

lymphoma, congestive heart failure, major adverse cardiac events and herpes zoster. 110

Abatacept in combination with MTX had lower odds of SAEs compared to several biologic 111

monotherapies and combination therapies with MTX, tofacitinib in combination with MTX, 112

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and a few biosimilar etanercepts (SB4 and HD203). Etanercept and one of its biosimilars 113

(SB4), both in combination with MTX had lower odds of WDAEs compared to csDMARD 114

dual therapy and tofacitinib. Double csDMARD therapy of SSZ and HCQ also had lower 115

odds of WDAEs compared to tofacitinib in combination with MTX. Among biosimilars, 116

MTX combination therapy with SB4 (biosimilar etanercept) or SB5 (biosimilar 117

adalimumab) are good options for safety based on results of the WDAE. 118

119

Conventional Synthetic DMARD as a Common Comparator 120

When a csDMARD other than MTX is administered concomitantly to a biologic, tsDMARD, 121

or biosimilar, there is insufficient evidence to draw conclusions on the comparative 122

benefits of the treatments (based on disease severity, disability, physical and mental 123

HRQOL, pain, and fatigue) and harms of the treatments (mortality, tuberculosis, cancer, 124

leukemia, lymphoma, congestive heart failure, major adverse cardiac events, and herpes 125

zoster). 126

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While etanercept monotherapy demonstrated lower odds of WDAEs compared to 128

csDMARD monotherapy, there was also one study that reported a higher number of 129

participants with a serious infection also compared to csDMARD monotherapy. 130

Strengths and Limitations 131

Strengths of this review include the method of accounting for the impact of various study 132

designs (e.g., adaptive design studies, older versus newer studies), differing patient 133

characteristics, differing background therapy (i.e., MTX or another csDMARD), and data 134

quality through sensitivity analyses planned a priori. In addition, validity of the NMAs was 135

assessed by testing the assumptions of homogeneity, consistency, and similarity. 136

Through the use of NMAs, it was possible to compare treatments that had not been 137

directly compared to one another in any studies through mixed- and indirect-treatment 138

comparisons. The literature search was comprehensive and executed in accordance with 139

the protocol specified a priori; it also included grey literature to reduce the impact of 140

publication bias. 141

142

Limitations of the included studies involved differences in study design (e.g., around one 143

third of trials used an adaptive design), treatment doses, and background therapies. We 144

attempted to reduce the impact of these differences by limiting the analysis to data at the 145

time of adaptation for adaptive design trials. Analysis was restricted to standard doses 146

only, which may not be generalizable to what patients are prescribed (or adhere to) in 147

practice, but allowed for greater homogeneity in the analysis. Patients in RCTs may not 148

be representative of patients in clinical practice, thus results from this review are not 149

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generalizable to all patients. NMAs were separated based on use of MTX or a different 150

csDMARD as a comparator for insight into the effect of the background therapy. Included 151

studies also did not always report on all of the outcomes of interest, so comparisons of 152

benefits or harms across several outcomes were not possible for all treatments (e.g., 153

csDMARD double and triple therapy did not have data for many outcomes). Lastly, data 154

conversions and imputations were required at times to include studies in analysis, which 155

may have introduced bias. 156

Conclusions and Implications for Decision- or Policy-Making 157

To the authors’ knowledge, this was the first comprehensive systematic review and NMA 158

that included csDMARD mono-, double and triple therapies, as well as biologics, 159

tsDMARDs, and biosimilars as monotherapy and in combination with csDMARDs. Among 160

all the treatment comparisons considered for patients with moderate to severe RA and an 161

inadequate response to MTX, various treatment strategies were found to be effective. In 162

selecting a treatment, it is important to balance the benefits and harms of treatments 163

based on patient preference, access to treatment (e.g., infusion clinics), and affordability. 164

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Table of Contents 167

DSEN CORE REVIEW TEAM ............................... ERROR! BOOKMARK NOT DEFINED. 168

CONTRIBUTORS FROM CADTH ......................... ERROR! BOOKMARK NOT DEFINED. 169

EXTERNAL EXPERTS ......................................... ERROR! BOOKMARK NOT DEFINED. 170

ABBREVIATIONS AND DEFINITIONS ............................................................................ III 171

EXECUTIVE SUMMARY .................................................................................................. V 172

Context and Policy Issues ............................................................................................. v 173

Objective and Research Question ................................................................................. v 174

Methods......................................................................................................................... v 175

Key Findings ................................................................................................................. vi 176

Strengths and Limitations ............................................................................................. vii 177

Conclusions and Implications for Decision- or Policy-Making ....................................... viii 178

TABLES .......................................................................................................................... XII 179

FIGURES ....................................................................................................................... XV 180

1 RATIONALE ............................................................................................................. 19 181

2 POLICY QUESTIONS .............................................................................................. 24 182

3 OBJECTIVE ............................................................................................................. 25 183

4 RESEARCH QUESTION .......................................................................................... 25 184

5 METHODS ............................................................................................................... 25 185

5.1 Scope and Protocol ........................................................................................... 25 186

5.2 Literature Search Strategy ................................................................................. 25 187

5.3 Patient Group Input ........................................................................................... 26 188

5.4 Selection Criteria ............................................................................................... 27 189

5.5 Data Extraction .................................................................................................. 30 190

5.6 Quality of Evidence ............................................................................................ 32 191

5.7 Data Conversion and Imputation ....................................................................... 32 192

5.8 Data Analysis .................................................................................................... 33 193

5.8.1 Network Meta-Analysis ............................................................................... 33 194

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5.8.2 Meta-Analysis ............................................................................................. 35 195

6 RESULTS ................................................................................................................ 36 196

6.1 Selection of Primary Studies .............................................................................. 36 197

6.2 Study Characteristics ......................................................................................... 37 198

6.3 Risk of Bias ....................................................................................................... 39 199

6.4 Data Synthesis .................................................................................................. 41 200

6.4.1 Disease Severity ......................................................................................... 43 201

6.4.2 Disease Activity Score ................................................................................ 74 202

6.4.3 Disability ..................................................................................................... 97 203

6.4.4 Remission ................................................................................................. 110 204

6.4.5 Health-Related Quality of Life ................................................................... 117 205

6.4.6 Pain .......................................................................................................... 124 206

6.4.7 Fatigue ..................................................................................................... 132 207

6.4.8 Radiographic Progression ......................................................................... 137 208

6.4.9 Serious Adverse Events ............................................................................ 140 209

6.4.10 Withdrawal due to Adverse Events ........................................................... 152 210

6.4.11 Mortality .................................................................................................... 177 211

6.4.12 Serious Infections ..................................................................................... 183 212

6.4.13 Tuberculosis ............................................................................................. 191 213

6.4.14 Cancer ...................................................................................................... 197 214

6.4.15 Leukemia .................................................................................................. 202 215

6.4.16 Lymphoma ................................................................................................ 204 216

6.4.17 Congestive Heart Failure .......................................................................... 205 217

6.4.18 Major Adverse Cardiac Events .................................................................. 207 218

6.4.19 Herpes Zoster ........................................................................................... 207 219

6.4.20 Heterogeneity ........................................................................................... 210 220

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6.4.21 Publication Bias ........................................................................................ 210 221

6.4.22 Sensitivity Analyses .................................................................................. 210 222

7 DISCUSSION ......................................................................................................... 212 223

7.1 Policy Implications ........................................................................................... 213 224

7.2 Interpretation of Systematic Review Results .................................................... 214 225

7.2.1 Methotrexate as a Common Comparator .................................................. 214 226

7.2.2 Conventional Synthetic DMARD as a Common Comparator ..................... 225 227

7.2.3 Sensitivity Analyses .................................................................................. 227 228

7.3 Strengths and Limitations ................................................................................ 230 229

7.4 Conclusion....................................................................................................... 232 230

8 REFERENCES ....................................................................................................... 235 231

9 APPENDICES ........................................................................................................ 255 232

APPENDIX 1: LITERATURE SEARCH STRATEGY ..................................................... 255 233

APPENDIX 2: STATISTICAL ANALYSIS PLAN ............................................................ 267 234

APPENDIX 3: LIST OF INCLUDED STUDIES (AND COMPANION PUBLICATIONS) .. 280 235

APPENDIX 4: LIST OF EXCLUDED STUDIES (WITH REASONS) .............................. 295 236

APPENDIX 5: STUDY CHARACTERISTICS OF INCLUDED ADAPTIVE DESIGN 237

STUDIES ...................................................................................................................... 327 238

APPENDIX 6: STUDY AND PATIENT CHARACTERISTICS OF INCLUDED STUDIES 340 239

APPENDIX 7: RISK OF BIAS ASSESSMENT............................................................... 371 240

APPENDIX 8: SENSITIVITY ANALYSES ...................................................................... 379 241

APPENDIX 9: DETAILED NMA RESULTS FOR THE OUTCOMES ACR20 AND ACR70 242

AMONG PATIENTS WITH INADEQUATE RESPONSE TO METHOTREXATE ............ 581 243

APPENDIX 10: RESULTS PRESENTED IN THE FORM OF STAIRCASE TABLES ..... 635 244

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TABLES 247

Table 1: Approved Doses of Biologics, Small Molecules and Biosimilars Included in the 248

Clinical Review................................................................................................................ 21 249

Table 2: Population, Intervention, Comparator, Outcome, and Study Designs of Interest 27 250

Table 3: Definition of Adaptive Design Trials ................................................................... 31 251

Table 4: Summary of Trial Characteristics ....................................................................... 38 252

Table 5: Summary of Patient Characteristics .................................................................. 39 253

Table 7: Americal College of Rheumatology 50 (Placebo+MTX): Odds Ratios, Relative 254

Risks and Risk Differences for All Treatment Comparisons – Random Effects Model ..... 46 255

Table 8: American College of Rheumatology 50 (Placebo+csDMARD): Odds Ratios, 256

Relative Risks and Risk Differences for All Treatment Comparisons – Random Effects 257

Model .............................................................................................................................. 72 258

Table 9: Disease Activity Score 28-Joint Count (Placebo+MTX): Standardized Mean 259

Differences for All Treatment Comparisons – Random Effects Model ............................. 76 260

Table 10: Disease Activity Score 28-Joint Count (Placebo+csDMARD): Standardized 261

Mean Differences for All Treatment Comparisons – Random Effects Model ................... 95 262

Table 11: Health Assessment Questionnaire Disability Index (Placebo+MTX): Mean 263

Differences for All Treatment Comparisons – Random Effects Model ............................. 99 264

Table 12: Health Assessment Questionnaire Disability Index (Placebo+csDMARD): Mean 265

Differences for All Treatment Comparisons – Random Effects Model ........................... 108 266

Table 13: Remission (Placebo+MTX): Odds Ratios, Relative Risks and Risk Differences 267

for All Treatment Comparisons – Random Effects Model .............................................. 111 268

Table 14: Remission Events, Concomitant Conventional Synthetic DMARD ................. 116 269

Table 15: Health-Related Quality of Life, SF-36 Physical Component Score 270

(Placebo+MTX): Mean Differences for All Treatment Comparisons – Random Effects 271

Model ............................................................................................................................ 118 272

Table 16: Health-Related Quality of Life, SF-36 Mental Component Score 273

(Placebo+MTX): Mean Differences for All Treatment Comparisons – Random Effects 274

Model ............................................................................................................................ 121 275

Table 17. Health-Related Quality of Life, SF-36 PCS Mean Change from Baseline Data, 276

Concomitant Conventional Synthetic DMARD ............................................................... 124 277

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Table 18. Health-Related Quality of Life, SF-36 MCS Mean Change from Baseline Data, 278

Concomitant Conventional Synthetic DMARD ............................................................... 124 279

Table 19: Pain (Placebo+MTX): Standardized Mean Differences for All Treatment 280

Comparisons – Random Effects Model ......................................................................... 126 281

Table 20: Pain, Standardized Mean Change from Baseline Data, Concomitant 282

Conventional Synthetic DMARD ................................................................................... 131 283

Table 21: Fatigue (Placebo+MTX): Standardized Mean Differences for All Treatment 284

Comparisons – Random Effects Model ......................................................................... 133 285

Table 22: Fatigue, Standardized Mean Difference Data, Concomitant Conventional 286

Synthetic DMARD ......................................................................................................... 137 287

Table 23: Radiographic Progression (Placebo+MTX): Standardized Mean Differences for 288

All Treatment Comparisons – Random Effects Model ................................................... 138 289

Table 24: Serious Adverse Events: Odds Ratios, Relative Risks and Risk Differences for 290

All Treatment Comparisons – Random Effects Model ................................................... 141 291

Table 25: Serious Adverse Events (Placebo+csDMARD): Odds Ratios, Relative Risks and 292

Risk Differences for All Treatment Comparisons – Random Effects Model ................... 151 293

Table 27: Withdrawal Due to Adverse Events (Placebo+csDMARD): Odds Ratios, 294

Relative Risks and Risk Differences for All Treatment Comparisons – Random Effects 295

Model ............................................................................................................................ 175 296

Table 28. Mortality Events, Concomitant Methotrexate ................................................. 179 297

Table 29. Mortality Events, Concomitant Conventional Synthetic DMARD .................... 182 298

Table 30: Serious Infections Events, Concomitant Methotrexate ................................... 185 299

Table 31: Serious Infection Events, Concomitant Conventional Synthetic DMARD ....... 190 300

Table 32. Tuberculosis Events, Concomitant Methotrexate ........................................... 193 301

Table 33. Tuberculosis Events, Concomitant Conventional Synthetic DMARD ............. 196 302

Table 34. Cancer Events, Concomitant Methotrexate ................................................... 198 303

Table 35. Cancer Event Data, Concomitant Conventional Synthetic DMARD ............... 201 304

Table 36. Leukemia Event Data, Concomitant Methotrexate ......................................... 202 305

Table 37. Leukemia Event Data, Concomitant Conventional Synthetic DMARD ........... 203 306

Table 38. Lymphoma Event Data .................................................................................. 204 307

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Table 39. Congestive Heart Failure Events, Concomitant Methotrexate ........................ 206 308

Table 40. Herpes Zoster Events, Concomitant Methotrexate ........................................ 208 309

Table 41. Herpes Zoster Events, Concomitant Conventional Synthetic DMARD ........... 209 310

Table 42. Table of Study Characteristics of Included Adaptive Design Studies ............. 327 311

Table 43. Table of Study Characteristics of Included Studies ........................................ 340 312

Table 44. Table of Patient Characteristics of Included Studies ...................................... 348 313

Table 45. Full Results of Risk of Bias Assessment ........................................................ 371 314

Table 46. ACR50 Sensitivity Analysis Results Compared to the Reference Case (A Priori 315

Table) ........................................................................................................................... 379 316

Table 47. ACR50 Sensitivity Analysis Results Compared to the Reference Case (Post 317

Hoc Table) .................................................................................................................... 428 318

Table 48. DAS28 Sensitivity Analysis Results Compared to the Reference Case ......... 478 319

Table 49. HAQ-DI Sensitivity Analysis Results Compared to the Reference Case ........ 499 320

Table 50. Pain Sensitivity Analysis Results Compared to the Reference Case ............. 508 321

Table 51. Fatigue Sensitivity Analysis Results Compared to the Reference Case ......... 514 322

Table 52. SF-36 PCS and MCS Sensitivity Analysis Results Compared to the Reference 323

Case ............................................................................................................................. 518 324

Table 53. WDAE Sensitivity Analysis Results Compared to the Reference Case (A Priori 325

Table) ........................................................................................................................... 520 326

Table 54. WDAE Sensitivity Analysis Results Compared to the Reference Case (Post Hoc 327

Table) ........................................................................................................................... 546 328

Table 55. ACR50 Sensitivity Analysis Results Compared to the Reference Case – 329

Conventional Synthetic DMARD as the Common Comparator ...................................... 572 330

Table 56. DAS28 Sensitivity Analysis Results Compared to the Reference Case – 331

Conventional Synthetic DMARD as a Common Comparator ......................................... 576 332

Table 57. HAQ-DI Sensitivity Analysis Results Compared to the Reference Case – 333


Table 58. WDAE Sensitivity Analysis Results Compared to the Reference Case – 335


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Table 59. ACR20, Methotrexate as a Common Comparator: Odds Ratios, Relative Risks 337

and Risk Difference for All Treatment Comparisons – Random Effects Model .............. 581 338

Table 60. ACR70, Methotrexate as a Common Comparator: Odds Ratios, Relative Risks 339

and Risk Difference for All Treatment Comparisons – Random Effects Model .............. 605 340

Table 61. ACR20, Conventional Synthetic DMARD as a Common Comparator: Odds 341

Ratios, Relative Risks and Risk Difference for All Treatment Comparisons – Random 342

Effects Model ................................................................................................................ 628 343

Table 62. ACR70, Conventional Synthetic DMARD as a Common Comparator: Odds 344

Ratios, Relative Risks and Risk Difference for All Treatment Comparisons – Random 345

Effects Model ................................................................................................................ 631 346

Table 63. Staircase Table, ACR20 (Placebo+csDMARD) – Random Effects Model ...... 635 347



Table 66. Staircase Table, DAS28 (Placebo+csDMARD) – Random Effects Model ...... 638 350

Table 67. Staircase Table, HAQ-DI (Placebo+csDMARD) – Random Effects Model ..... 639 351

Table 68. Staircase Table, SF-36, Physical Component Score (Placebo+MTX) – Random 352

Effects Model ................................................................................................................ 640 353

Table 69. Staircase Table, SF-36, Mental Component Score (Placebo+MTX) – Random 354

Effects Model ................................................................................................................ 641 355

Table 70. Staircase Table, Fatigue (Placebo+MTX) – Random Effects Model .............. 642 356

Table 71. Staircase Table, Radiographic Progression (Placebo+MTX) – Random Effects 357

Model ............................................................................................................................ 644 358

Table 72. Staircase Table, Serious Adverse Events (Placebo+csDMARD) – Random 359

Effects Model ................................................................................................................ 645 360

Table 73. Staircase Table, Withdrawals due to Adverse Events (Placebo+csDMARD) – 361

Random Effects Model .................................................................................................. 646 362

363

FIGURES 364

Figure 1: PRISMA Flow Diagram241 ................................................................................. 37 365

Figure 2: Summary of Risk of Bias Assessment .............................................................. 41 366

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Figure 3. Evidence Network: ACR50 (Placebo+MTX) ..................................................... 44 367

Figure 4. Evidence Network: American College of Rheumatology 50 (Placebo+csDMARD)368

....................................................................................................................................... 72 369

Figure 5. Evidence Network: Disease Activity Score 28-Joint Count (Placebo+MTX) ...... 75 370

Figure 6. Evidence Network: Disease Activity Score 28-Joint Count (Placebo+csDMARD)371

....................................................................................................................................... 95 372

Figure 7. Evidence Network: Health Assessment Questionnaire Disability Index 373

(Placebo+MTX) ............................................................................................................... 98 374

Figure 8. Evidence Network: Health Assessment Questionnaire, Disability Index 375

(Placebo+csDMARD) .................................................................................................... 108 376

Figure 9. Evidence Network: Remission (Placebo+MTX) .............................................. 110 377

Figure 10: Evidence Network: Remission (Placebo+csDMARD) ................................... 116 378

Figure 11. Evidence Network: Health-Related Quality of Life, SF-36 Physical Component 379

Score (Placebo+MTX) ................................................................................................... 117 380

Figure 12. Evidence Network: Health-Related Quality of Life, SF-36 Mental Component 381

Score (Placebo+MTX) ................................................................................................... 120 382

Figure 13. Evidence Network: Health-Related Quality of Life, SF-36 Physical Component 383

Score (Placebo+csDMARD) .......................................................................................... 123 384

Figure 14. Evidence Network: Pain (Placebo+MTX) ...................................................... 125 385

Figure 15. Evidence Network: Pain (Placebo+csDMARD) ............................................. 131 386

Figure 16. Evidence Network: Fatigue (Placebo+MTX) ................................................. 133 387

Figure 17. Evidence Network: Fatigue (Placebo+csDMARD) ........................................ 137 388

Figure 18. Evidence Network: Radiographic Progression (Placebo+MTX) .................... 138 389

Figure 19. Evidence Network: Serious Adverse Events (Placebo+MTX) ....................... 140 390

Figure 20. Evidence Network: Serious Adverse Events (Placebo+csDMARD) .............. 151 391

Figure 21. Evidence Network: Withdrawal due to Adverse Events (Placebo+MTX) ....... 153 392

Figure 22. Evidence Network: Withdrawal due to Adverse Events (Placebo+csDMARD)393

..................................................................................................................................... 175 394

Figure 23. Evidence Network: Mortality (Placebo+MTX) ............................................... 178 395

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Figure 24. Mortality (Infliximab with MTX versus MTX Monotherapy): Meta-Analysis – 396

Peto Odds Ratio ............................................................................................................ 181 397

Figure 25. Mortality (Etanercept with MTX versus Etanercept Monotherapy): Meta-398

Analysis – Peto Odds Ratio........................................................................................... 181 399

Figure 26. Evidence Network: Mortality (Placebo+csDMARD) ...................................... 182 400

Figure 27. Evidence Network: Serious Infections (Placebo+MTX) ................................. 184 401

Figure 28. Serious Infections (Infliximab with MTX versus MTX Monotherapy): Meta-402


Figure 29. Serious Infections (Tofacitinib with MTX versus MTX Monotherapy): Meta-404


Figure 30. Serious Infections (Golimumab (SC) with MTX versus MTX Monotherapy): 406

Meta-Analysis – Peto Odds Ratio.................................................................................. 188 407

Figure 31. Serious Infections (Etanercept with MTX versus MTX Monotherapy): Meta-408


Figure 32. Serious Infections (Adalimumab with MTX versus MTX Monotherpay): Meta-410


Figure 33. Serious Infections (Etanercept with MTX versus Etanercept Monotherapy): 412

Meta-Analysis – Peto Odds Ratio.................................................................................. 189 413

Figure 34. Serious Infections (8 mg/kg Tocilizumab (IV) with MTX versus 8 mg/kg 414

Tocilizumab (IV) Monotherapy): Meta-Analysis – Peto Odds Ratio ............................... 189 415

Figure 35. Evidence Network: Serious Infections (Placebo+csDMARD) ........................ 190 416

Figure 36. Evidence Network: Tuberculosis (Placebo+MTX) ......................................... 192 417

Figure 37. Tuberculosis (Adalimumab with MTX versus MTX Monotherapy): Meta-418


Figure 38. Evidence Network: Tuberculosis (Placebo+csDMARD) ................................ 196 420

Figure 39. Evidence Network: Cancer (Placebo+MTX) ................................................. 197 421

Figure 40. Cancer (Etanercept MTX versus Etanercept Monotherapy): Meta-Analysis – 422

Peto Odds Ratio ............................................................................................................ 199 423

Figure 41. Cancer (Infliximab with MTX versus MTX Monotherapy): Meta-Analysis – Peto 424

Odds Ratio .................................................................................................................... 200 425

Figure 42. Evidence Network: Cancer (Placebo+csDMARD) ........................................ 201 426

xviii

Figure 43. Evidence Network: Leukemia (Placebo+MTX) ............................................. 202 427

Figure 44. Evidence Network: Leukemia (Placebo+csDMARD) .................................... 203 428

Figure 45. Evidence Network: Lymphoma (Placebo+MTX) ........................................... 204 429

Figure 46. Evidence Network: Congestive Heart Failure (Concomitant MTX) ................ 206 430

Figure 47. Evidence Network: Herpes Zoster (Placebo+MTX) ...................................... 208 431

Figure 48. Herpes Zoster (CT-P13 (Biosimilar Etanercept) with MTX versus Infliximab with 432

MTX): Meta-Analysis – Peto Odds Ratio ....................................................................... 209 433

Figure 49. Consistency Plot for ACR20 Inadequate Response to Methotrexate ............ 605 434

Figure 50. Consistency Plot for ACR70 Inadequate Response to Methotrexate ............ 628 435

Figure 51. Consistency Plot for ACR20 Concomitant Conventional synthetic DMARD .. 631 436

Figure 52. Consistency Plot for ACR70 Concomitant Conventional synthetic DMARD .. 634 437

438

439

19

1 RATIONALE 440

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease characterized by 441

inflammation of the synovial lining of the joints, tendons and periarticular structures.1 RA affects 442

0.5% to 1.0% of the population in Western countries,2 with the prevalence being lower closer to 443

the equator or in more rural areas.3 Untreated, RA leads to joint destruction, functional limitation 444

and severe disability,4, 5 and has a significant impact on health-related quality of life (HRQOL).6, 7 445

Those with RA would like to achieve total disease remission without significant joint damage 446

and impact on their lives, but recognize that this might not be possible. For whom total 447

remission may be unrealistic, their goal is to have as low disease activity as possible to be able 448

to live a life that is as productive and pain free as possible. 449

Definitive treatments that have disease-modifying potential include glucocorticoids, conventional 450

synthetic disease-modifying anti-rheumatic drugs (csDMARDs, such as methotrexate, 451

sulfasalazine, hydroxychloroquine, leflunomide, cyclosporine etc.), biologic DMARDs (referred 452

to henceforth as biologics) or targeted synthetic DMARDs (tsDMARDs, such as tofacitinib and 453

baricitinib). The use of csDMARDs leads to an improvement in pain and function with diability 454

for patients with RA, as well as more long-term outcomes such as reduced radiographic 455

progression8, 9 and disability.10, 11 456

Conventional synthetic DMARDs, including methotrexate (MTX), are usually the first drug of 457

choice for people with RA.12-14 When csDMARDs, including MTX, have either been ineffective or 458

partially effective15 or have had associated side effects, treatment options include other 459

csDMARDs, biologics, tsDMARDs or biosimilars.12-14 The patient population with inadequate 460

response to MTX (IR MTX) is one of the most commonly studied RA patient populations.16-18 461

The European League of Associations in Rheumatology (EULAR) clinical practice guideline 462

(CPG) recommends that these patients with IR MTX and moderate to severe disease activity 463

should receive a biologic or tsDMARD, with current practice being to start a biologic.19 The 464

American College of Rheumatology (ACR) CPG is more general in its recommendation in that 465

these patients could receive a combination of csDMARDs, or receive a biologic (tumor necrosis 466

factor (TNF) inhibitor or non-TNF inhibitor) or the tsDMARD tofacitinib as monotherapy or in 467

combination with a csDMARD.20 In contrast, NICE recommends that patients who are IR MTX 468

with moderate to severe disease activity receive two six-month trials of csDMARDs (either MTX 469

monotherapy or a combination therapy of two csDMARDs) in combination with low-dose 470

glucocorticoids before trying a biologic. Moreover, the provincial drug plans in Canada differ in 471

their coverage for this patient group with IR MTX. After an inadequate response to MTX, some 472

permit patients to receive a biologic as second line after a trial of triple csDMARD therapy while 473

others require non-response in patients on as many as three different csDMARDs (monotherapy 474

and/or combination therapy).21-32 Given the uncertainty about which treatment has the most 475

benefits and a good safety profile among patients with moderate to severe RA who have failed 476

or are intolerant to MTX, it is an important area of research. Thus, this patient population is the 477

20

focus of this review; it will be referred to as IR MTX, indicating that they were inadequate 478

responders to MTX due to lack of efficacy, the occurrence of adverse events, or other reasons. 479

The Arthritis Society asked their membership of their lived experience with MTX and received 133 responses. For some, it is well tolerated: “Ten years on methotrexate, and still taking it. No serious side effects to date”; “No side effects from methotrexate except weight gain.” As a side effect, severe nausea was commonly reported: “I vomited for days after taking the medicine (bi-weekly)”. Some individuals found subcutaneous methotrexate was easier than oral to tolerate: “Pill form methotrexate made me extremely ill. Injectable was fine.” Not so for others: “The nausea was extreme taking both pills and injections.” Also described were “brain fog”, a “hangover feeling” or fatigue and headaches post weekly or monthly injections. Several individuals described spending “at least one day” or “24 – 48 hours” in bed after injection. For others, feeling unwell was constant: “horrible the entire time”; “mood changed constantly”.

Hair and teeth loss were reported: ‘loss of hair all over the body”; “lost all hair, lost ten teeth” and a resulting “loss of identity”. Also noted were mouth sores, food sensitivities, loss of appetite, a metallic taste, racing heart, rise in blood pressure, profuse sweating, and bruising on stomach and legs. Others described other health complications following methotrexate treatment: fatty liver hepatitis, lymphoma, pneumonia requiring hospitalization, chronic ulcerative colitis, and bladder problems.

The introduction of biologics has revolutionized the management of RA. Biologics provide 480

clinically important and statistically significant improvements in pain and function in patients not 481

responding to csDMARDs such as MTX. While biologics appear to have fewer side-effects and 482

much greater success in slowing structural joint destruction than MTX, they are much more 483

costly than csDMARDs.33, 34 484

Affordability of treatment was a concern for many Arthritis Society respondents. “The drugs are so expensive. It is crazy to think there are drugs out there that can help control, not cure, the rheumatoid arthritis and yet a lot of us can't afford them.” Some respondents had private health insurance through family members or their own employment. “Even with health insurance and annual renewal of government coverage, it's still hundreds of dollars each month until I reach my deductible.” “I've had challenges every time I've changed jobs. The time it takes to get my insurance coverage in place is never fast enough, and I end up having to pay for at least one-month worth of medication without any coverage. If I didn't have insurance coverage through work, there is no question that I could afford this medication.”

The Canadian Arthritis Patients Alliance (CAPA) described that for patients receiving a diagnosis of RA and then finding an appropriate therapy is a multiple year process. CAPA explained for those relying on publicly funded drug plans, patients must fail to respond to two disease-modifying drugs before receiving coverage for a biologic, which can result in a substantial delay in getting their disease under control and consequently experiencing permanent joint damage. A respondent to the Arthritis Society described: “I have encountered irreversible damage to my joints because I was not diagnosed early enough. Once I became sick, it took me over a year to get someone to refer me to a rheumatologist. Then I had to fail on

21

all the first line treatments before I could qualify for a biologic. Once I finally could access biologics, my life improved immensely.”

Biologics are commonly used for patients with suboptimal response or intolerance to 485

csDMARDs, such as MTX. In these patients with IR csDMARD or IR MTX, biologics or other 486

csDMARDs (including use of two csDMARDs) are used in combination with MTX. 487

In addition, more recently, the tsDMARD, tofacitinib (XELJANZ®),35 was approved in 2012 for 488

use in RA patients in the U.S. Most biologics and tofacitinib are approved for use in RA 489

internationally, although the indications for use differ slightly between countries. Table 1 490

provides an overview of the standard doses of biologics, tsDMARDs and biosimilars approved 491

by Health Canada for the treatment of RA. 492

493

Table 1: Approved Doses of Biologics, Small Molecules and Biosimilars Included in the Clinical Review 494

Drug Class Drug (Generic Name)

Trade Name Year First Approved

Health Canada Approved Dose

TNF Inhibitors

TNF inhibitors Etanercept Enbrel 1998 (FDA);36 (Health Canada in

2000)37

25 mg SC, twice weekly, or

50 mg every week

Infliximab Remicade 1998 (FDA);38 (Health Canada in

2001)39

3 mg/kg IV, initial dose at 0, 2 and 6

weeks then every 8 weeks

Adalimumab Humira 2002 (FDA);40 (Health Canada in

2004)41

40 mg SC, every 2 weeks

Certolizumab pegol

Cimzia 2008 (FDA);42 (Health Canada in

2009)43

400 mg SC (divided in two injections)

initially and at weeks 2 and 4 then 200 mg

every 2 weeksa

Golimumab Simponi

2009 (FDA);44 (Health Canada in

2011)45

50 mg SC every 4 weeks (monthly)

2 mg/kg IV, initial dose at 0 and 4


Non-TNF Inhibitors

IL-1 inhibitor Anakinrab Kineret 2001 (FDA)46

2002 (Health

Canada)47

100 mg SC, every day

B lymphocyte- Rituximab Rituxan 1997 for 2 doses of 1000 mg

22

depleting drug (anti-CD20 therapy)

lymphoma;48

2006 for RA (Health

Canada, FDA)49, 50

IV, every 2 weeks

T cell costimulatory inhibitor

Abatacept Orencia

IV: 200551

(Health Canada in 2006)

52

SC: 201153

(Health Canada in 2013)

54


weeks then every 4 weeks (<60 kg:

500mg; 60-100 kg: 750mg; >100 kg: 1000mg dose)

125 mg SC, initial loading dose and

second dose within 1 day then once weekly

IL-6 inhibitor Tocilizumab Actemra (RoActemra in Europe)

2010 (FDA)55; (Health Canada in

2010)56

4 mg/kg IV, every 4 weeks; increase to 8

mg/kg based on clinical response

162 mg SC, every 2 weeks; increase to every week based

on clinical response

Sarilumab Kevzara 2017 (Health Canada)57

200 mg every 2 weeks SC; reduction

to 150 mg every 2 weeks SC to

manage neutropenia,

thrombocytopenia and elevated liver

enzymes

Sirukumabc Plivensia (CNTO-136)

All applications for approval have

been withdrawn58 NA

Targeted Synthetic DMARDs

Janus-associated kinase inhibitor

Tofacitinib XELJANZ® 201235 (Health Canada in 2014)59

5 mg PO, twice daily

Baricitinibb Olumiant 2017 (EMA);60 under review

(Health Canada)61

EMA approved dose: 4 mg once daily oral, can be reduced to 2 mg

once daily if disease under control60

Subsequent Entry Biologics (Biosimilars)

Biosimilar of infliximab

CT-P13 Remsimad/ Inflectra

2013 (EMA),62 2014 (Health Canada)63, 64



23

SB2 Flixabi 2016 (EMA)65 EMA approved dose: 3 mg/kg at 9, 2 and 6 weeks, then

every 8 weeks (IV);66 has not

received Health Canada notice of

compliance

Biosimilar of etanercept

HD203 Davictrel 2014 (South Korea)67

25 mg twice weekly (SC)

SB4 Benepali Brenzys

2015 (EMA)68 2015 (South

Korea);69 2016 (Health Canada)70

50 mg/week (SC); 25 mg twice weekly

(SC)

Unknown AnBaiNuo® Unknown Has not received Health Canada

notice of compliance

Biosimilar of adalimumab

ABP501 Amjevita 2016 (FDA)71 40 mg every two weeks (SC)

ZRC-3197 Exemptia Unknown Has not received Health Canada

notice of compliance

SB5 Unknown Under review by EMA

Has not received Health Canada

notice of compliance a400 mg every 4 weeks can be used for a maintenance dose 495

bAlmost never used to treat adult RA according to the clinical expert 496

cApplications for approval have been withdrawn globally after sirukumab was not approved by the U.S. Food and Drug Agency 497

dManufacturer has suspended sale

72 498

bid = twice weekly; DMARD = disease-modifying anti-rheumatic drug; EMA = European Medicines Agency; FDA = U.S. Federal 499 Drug Administration; IV = intravenously; PO = orally; SC = subcutaneously 500

The systemic and joint inflammation in RA is mediated by activation of T-cells,73 B-cells, 501

macrophages,74 and other immune cells.75 These interactions lead to expression of chemokines, 502

metalloproteinases and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-503

alpha) and various interleukins (IL).76, 77 Interaction of lymphocytes and inflammatory cytokines 504

with host cells such as fibroblasts, osteoclasts and chondrocytes leads to bone and cartilage 505

destruction, a hallmark of RA.76, 78 As briefly mentioned in Table 1, the mechanism of action 506

differs between the biologics (i.e., inhibition of TNF-alpha versus interleukin-1 versus interleukin-507

6 versus B-cells versus T-cell co-stimulatory molecule, CD28). It is possible that, due to different 508

contributions of these cytokines and processes to the disease expression, the use of therapy 509

targeting one cytokine may be more efficacious or safer than therapy targeting another 510

cytokine/mechanism. 511

24

As shown in Cochrane systematic reviews of the biologics and tofacitinib published in The 512

Cochrane Library, these medications provide clinically important improvements in pain and 513

disability in treating RA compared to MTX/csDMARD/placebo.79-88 The existing Cochrane 514

systematic reviews, however, only reviewed each agent individually, that is they are systematic 515

reviews of each of the biologics.34, 89 Treatment guidelines published recently12-14, 90 as well as 516

consensus statements91-93 have also conducted systematic reviews of these interventions, but 517

most are outdated and none performed indirect comparisons, to our knowledge. This was 518

primarily due to the relative lack of head-to-head comparative effectiveness trials, which has 519

been a barrier in comparing effectiveness of one biologic to another. Therefore, a review 520

summarizing all evidence to date is needed. 521

Patients, clinicians, and policy-makers need to know if there are any important differences 522

between the various biologics in terms of benefits and harms. Ideally, this requires head-to-head 523

comparison studies. Few studies to date have compared two biologics94-101 other than those 524

comparing a biosimilar to its reference product, as is required for regulatory approval.102 In the 525

absence of head-to-head studies, indirect comparisons provide the best evidence for 526

demonstrating any differences between the available biologics.103, 104 When randomized 527

controlled trials fail to make head-to-head comparisons, a common comparator can be used to 528

make an indirect comparison.105 For ethical reasons, it is not possible to conduct a trial with a 529

placebo arm for more than 12 to 16 weeks as after that time efficacy of the biologic compared to 530

placebo is established.106, 107 Thus, the common comparator across many trials is MTX 531

monotherapy because the study personnel provide participants in the control arm with placebo 532

of the experimental drug as well as MTX in order to extend the trial length.107 A major limitation 533

of previous systematic reviews was the lack of use of indirect comparisons, which precluded the 534

possibility of assessing the comparative benefits and harms of treatments to help identify the 535

most appropriate treatment for patients with RA. 536

Using both direct and indirect comparisons is the essence of network meta-analysis (NMA) and 537

the resulting review differs from the usual review, such that it is not intended to examine only 538

one intervention for RA but aims to systematically review and simultaneously compare the 539

existing randomized controlled trials of biologics (including biosimilars), tsDMARDs, and 540

csDMARD combination therapies for RA.108, 109 541

2 POLICY QUESTIONS 542

The policy question for this project, which was developed by CADTH’s jurisdictional clients, is: 543

In patients with moderate to severe rheumatoid arthritis who have failed or are intolerant to 544

methotrexate, what is the optimal drug therapy? 545

25

3 OBJECTIVE 546

The objective of this review is to assess the benefits and harms of drugs used in adult patients 547

with moderate to severe rheumatoid arthritis who have failed or are intolerant to methotrexate. 548

4 RESEARCH QUESTION 549

There is one research question for this review. This was developed to address the 550

aforementioned policy issues: 551

What is the comparative clinical efficacy and safety of csDMARD therapies (alone or in 552

combination), biologics (including biosimilars), and tsDMARDs in adult patients with 553

moderate to severe rheumatoid arthritis who have failed or are intolerant to MTX? 554

5 METHODS 555

5.1 Scope and Protocol 556

The CADTH clinical evaluation will bring together, and build upon, existing systematic reviews 557

and network meta-analyses conducted by Cochrane.88, 89, 110 To inform the final scope of the 558

therapeutic review, a proposed scope was developed with the assistance of clinical experts and 559

CADTH’s F/P/T customers. In addition, targeted stakeholder feedback from patient groups and 560

industry was solicited. 561

562

The protocol was written a priori and was registered with the International Prospective Register 563

of Systematic Reviews (PROSPERO) prior to the completion of screening and study selection: 564

CRD42016041498. An update to the protocol was made in July 2017 to indicate that this review 565

is focused on a subset of the population identified in the protocol in order to address the specific 566

policy questions of interest in a timely manner. 567

5.2 Literature Search Strategy 568

The literature searches were performed by information specialists using a peer-reviewed search 569

strategy. 570

Published literature was identified by searching the following bibliographic databases: MEDLINE 571

(1946- ) with in-process records & daily updates via Ovid; Embase (1974- ) via Ovid; The 572

Cochrane Library via Wiley; EBM Reviews - Cochrane Central Register of Controlled Trials via 573

Ovid; and PubMed. The search strategy was comprised of both controlled vocabulary, such as 574

the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main 575

search concepts were Traditional DMARDs (methotrexate, hydroxychloroquine, sulfasalazine, 576

leflunomide); Biologic DMARDs (adalimumab, certolizumab pegol, etanercept, golimumab, 577

infliximab, anakinra, tocilizumab, abatacept, rituximab); Small Molecules (tofacitinib); 578

26

Subsequent Entry Biologics (infliximab SEB); Products under development (adalimumab SEB, 579

etanercept SEB, baricitinib, sarilumab, sirukumab) and rheumatoid arthritis. 580

581

Methodological filters were applied to limit retrieval to randomized controlled trials, controlled 582

clinical trials. Where possible, retrieval was limited to the human population. Retrieval was 583

limited to English language, and by publication year (for certain drugs only). Conference 584

abstracts were excluded from the search results. See Appendix 1 for the detailed search 585

strategies. 586

587

Due to the use of existing systematic reviews as a baseline,88, 89, 110 searches and retrieval were 588

limited by various publication years (adalimumab, certolizumab pegol, etanercept, golimumab, 589

infliximab, anakinra, tocilizumab, abatacept, rituximab published between January 1, 2015 to 590

present; methotrexate published between January 1, 2014 to present; hydroxychloroquine, 591

sulfasalazine, leflunomide, infliximab SEB, adalimumab SEB, etanercept SEB, tofacitinib, 592

baricitinib, sarilumab, sirukumab no publication date limit). 593

594

The searches were completed on May 3, 2016. Regular alerts were established to update the 595

search until March 1, 2017. Regular search updates were performed on databases that do not 596

provide alert services. 597

Grey literature (literature that is not commercially published) was identified by searching the 598

Grey Matters checklist (https://www.cadth.ca/grey-matters), which includes the websites of 599

regulatory agencies, health technology assessment agencies, clinical guideline repositories, and 600

professional associations. Google and other Internet search engines were used to search for 601

additional web-based materials. See Appendix 1 for more information on the grey literature 602

search strategy. 603

5.3 Patient Group Input 604

CADTH received patient input specific to this project in August 2016 from The Arthritis Society 605

and The Canadian Arthritis Patient Alliance (CAPA). To collect information for the purpose of 606

this project, the Arthritis Society surveyed its membership, promoted the survey via their social 607

media channels and received 149 responses. CAPA’s board prepared their group’s submission 608

drawing on the knowledge and experience of five board members with rheumatoid arthritis and 609

its network of members. 610

611

The input was used to help inform the protocol and the groups’ comments are integrated into 612

the report where applicable. 613

27

5.4 Selection Criteria 614

Studies were eligible for inclusion if they met the study design, population, intervention and 615

comparator criteria, and were eligible for inclusion in analysis if they met the outcomes of 616

interest (Table 2). RCTs were considered for efficacy outcomes. RCTs, controlled clinical trials, 617

clinical trial registries, and US Food and Drug Administration (FDA), Health Canada, European 618

Medicines Agency reports, labels and warnings were considered for inclusion for safety 619

outcomes. Further details on the biologics and biosimilars are available in Table 1; a list of the 620

interventions of interest, including tumour necrosis factor blockers, IL-1 and IL-6 agonists, T cell 621

costimulatory inhibitor, B lymphocyte-depleting drug, tsDMARDs, subsequent entry biologics 622

(SEBs now termed biosimilars), products under development, and combinations of csDMARDs 623

is also available in Table 2. Only standard doses approved by Health Canada were eligible for 624

analysis. In the event that a drug had two dosing strategies in which the total dose remained the 625

same (e.g., etanercept 25 mg twice weekly or 50 mg every week) were included as part of the 626

same treatment node. Drugs that involved different routes of administration (e.g., abatacept 627

intravenous and subcutaneous routes are both approved by Health Canada) were considered 628

as separate treatment nodes. In the event of more than one biosimilar for the same reference 629

product, each biosimilar was considered a separate node because they may not have the same 630

modification in molecular structure than the reference product (e.g., Remsima and Flixabi as 631

biosimilar infliximabs). Patient groups of interest were those who had intolerance to or failure of 632

methotrexate (inadequate responders to MTX or IR MTX). 633

634

The primary efficacy outcome for this report is the ACR50. While the ACR20 is often used in 635

clinical trials, the ACR50 provides a more stable comparison between the placebo and 636

treatment arms because the placebo arm response does not fluctuate as much as for the 637

ACR20. Moreover, results of the ACR50 are also in line with the ACR20, as they use the same 638

scale. 639

640

Table 2: Population, Intervention, Comparator, Outcome, and Study Designs of Interest 641

Inclusion Criteria

28

Population Inclusion:

Treatment-experienced adults with moderate to severe, active RA who have failed or are intolerant to methotrexate (inadequate responders)a

Exclusion:

Patients who are methotrexate naïve

Patients who are treatment experienced, but only inadequate responders to

sulfasalazine


leflunomide


hydroxychloroquine

Patients who are inadequate responders to a biologic DMARD (biologic)

Patients who are in clinical remission, have low disease activity, or early RA

Interventions Inclusion:

csDMARD monotherapy, double therapy or triple therapy (eligible csDMARDs:

methotrexate, hydroxychloroquine, sulfasalazine, leflunomide)

Any of the nine biologics alone or in combination with csDMARDs (i.e.,

adalimumab, certolizumab pegol, etanercept, anakinra, golimumab, infliximab,

tocilizumab, abatacept, and rituximab)

tsDMARDs (i.e., tofacitinib) alone or in combination with csDMARDs

Biosimilars (i.e., biosimilars of etanercept, infliximab, and adalimumab) alone or in

combination with csDMARDs

Newly developed drugs (i.e., baricitinib, sarilumab and sirukumabb)

Exclusion:

Doses of any of the eligible drugs that are above or below the standard dose approved

by Health Canadac

Methotrexate compared to itself, placebo, or a drug that is not of interest

Older csDMARDs (i.e., auranofin, intramuscular gold, azathioprine, cyclosporine,

and chloroquine)

Combination biologics (i.e., two or more biologics given concurrently)

Comparators Inclusion:

Any of the drugs of interest or placebo

Exclusion:

Studies with only one arm that is eligible

Studies comparing multiple doses of the same drug without a comparator

Studies comparing different routes of administration of the same drug without a

comparator

29

Outcomes Efficacy

ACR 20, 50, 70d

Disease Activity Score (DAS/DAS 28)

Disability (Health Assessment Questionnaire Disability Index [HAQ-DI])

Remission (DAS 28 remission [<2.6])

Radiographic progression

Health-related quality of life (SF-36 Physical and Mental Component Scores)

Fatigue

Pain

Harms

Serious adverse events

Withdrawal due to adverse events

Mortality

Notable harms

Serious infections

Tuberculosis

Cancer

Leukemia

Lymphoma

Congestive heart failure

Major adverse cardiac events

Herpes zoster

Study Design Inclusion:

Efficacy

Randomized controlled trials

Safetye

Randomized controlled trials

Controlled clinical trials

Exclusion:

Non-controlled studies (i.e., observational designs)

Single arm studies

Trials with a randomization phase of <12 weeks’ duration

Additional Exclusion Criteria

Exclusions Non-English publications Conference abstracts

ACR = American College of Rheumatology; csDMARD = conventional synthetic disease modifying antirheumatic drugs; EULAR 642 = European League Against Rheumatism; MTX = methotrexate; RA = rheumatoid arthritis; TNF = tumour necrosis factor; 643 tsDMARD = targeted synthetic disease-modifying anti-rheumatic drug. 644 aStudies where it is unclear whether patients were inadequate responders to methotrexate or a different csDMARD will be included 645 in the reference case and removed in a sensitivity analysis. 646 bApplications for approval have been withdrawn globally after sirukumab was not approved by the U.S. Food and Drug Agency 647 cAll doses will be considered for drugs that are under development at the time of the review 648 dACR 50 will be the primary ACR response outcome reported in the main text of the results 649 eSafety data as found in grey literature sources (i.e., clinical trial registries, US Food and Drug Administration, Health Canada, and 650 European Medicines Agency reports, labels and warnings) were also included 651 652

653

30

Duplicates of studies identified across databases and from within the existing Cochrane 654

systematic reviews were removed. Two reviewers then independently screened titles and 655

abstracts for relevance to the clinical research questions. Full texts of potentially relevant 656

articles were retrieved and independently assessed for possible inclusion based on the 657

predetermined selection criteria (Table 2). The two reviewers compared their chosen included 658

and excluded studies and discussed any disagreements until a consensus was reached. The 659

selection process was standardized using DistillerSR, which is an online systematic review 660

software tool (https://distillercer.com/products/distillersr-systematic-review-software/). This was 661

done in order to maintain consistency across reporting from reviewers for the process of 662

selecting studies and extracting data. 663

664

The study selection process is presented in a Preferred Reporting Items for Systematic Reviews 665

and Meta-Analyses (PRISMA) flowchart (Figure 1). 666

5.5 Data Extraction 667

Any published studies, as well as grey literature sources (e.g., studies registered and that had 668

data reported in clinical trial registries) were eligible to have data extracted. One reviewer 669

performed data extraction and this was checked for accuracy by a second independent 670

reviewer. A standardized data extraction form designed a priori in DistillerSR was used. Data 671

extraction included: characteristics of included studies including trial design, eligibility criteria, 672

location, funding source, and trial registry number; characteristics of trial participants including 673

type of intervention, dose, duration and concomitant medication; risk of bias assessment; and 674

results of the clinical efficacy/effectiveness and safety outcomes. Any disagreements were 675

resolved by consensus when possible; otherwise, the judgment of a third reviewer was 676

considered final. 677

678

The original, primary publication for each unique study was used for data extraction. However, 679

in the event of multiple publications for a single primary study, the original article published was 680

identified as the parent article and any subsequent publications (reporting specific outcomes or 681

sub-populations from the original study) were identified as companions for the study. 682

Supplemental online appendices contributing additional information for the parent and/or 683

companion articles were also compiled. Data extraction (in the presence of multiple publications 684

for a single primary study as described above) was handled by extracting the most recently 685

adjudicated data for each outcome specified a priori in the protocol. Data were extracted from 686

figures using WebPlotDigitizer (www.arohatgi.info/WebPlotDigitizer) if not reported in tables or 687

the text of the publication. When data on an outcome of interest were missing from the 688

published article(s), data from clinical trial registry records were extracted. 689

690

https://distillercer.com/products/distillersr-systematic-review-software/

31

Studies included from the previous Cochrane reviews went through the same de novo data 691

extraction process for outcomes and baseline characteristics as for newly identified studies in 692

the literature search. 693

694

In the event that a study reported multiple time-points for an outcome of interest, the end of 695

treatment time-point was extracted for analysis except in the case of trials involving an adaptive 696

design. Adaptive design trials have become more common in research for RA as they allow a 697

study to plan for modifications to trial design and/or dose modifications with the use of a pre-698

defined interim analysis.111, 112 In this report, we distinguish between four major types of 699

adaptive designs: 1) early escape trials, 2) rescue therapy trials, 3) treatment switching trials 700

based on non-response criteria, and 4) planned treatment switching trials (Table 3). For studies 701

involving an adaptive design, we extracted the data up until the time of adaptation to ensure that 702

treatment effects could be attributed to a specific treatment. This was done to ensure that data 703

included for analysis represented results with patients receiving the originally randomized 704

treatment. 705

706

Event data was extracted and analyzed as the number of participants with an event, rather than 707

the number of events. While it is possible for participants to experience an event more than 708

once, this was not often reported in the studies and would not be appropriate to combine with 709

the number of patients with an event in an analysis. When a study reported the DAS or DAS28 710

erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), the scale using the ESR 711

was selected. 712

713

Table 3: Definition of Adaptive Design Trials 714

Adaptive Design Description Early escape trial After a pre-determined period (e.g. 12 or 16 weeks) receiving treatment, patients

who do not attain a pre-defined level of disease response are withdrawn from the trial and may enter an open-label extension phase.

Rescue therapy trial After a pre-determined period of receiving treatment, patients who do not attain a pre-defined level of disease response are permitted to receive rescue therapy (e.g. dose adjustment or addition of a DMARD or corticosteroid, receipt of one or more doses of active treatment for those in the comparator arm, increased dose of active drug).

Treatment switching trial (based on non-response)

After a pre-determined period (e.g. 12 or 16 weeks) receiving treatment, patients who do not attain a pre-defined level of disease response are switched to another treatment arm for the remainder of the study.

Treatment switching trial (planned)

Investigators plan a priori to have patients (e.g. in a control group) either switch

to another arm or re-randomize patients to switch to one of a few possible treatment arms. The planned treatment switch could occur either:

a) as the only adaptation in the study duration, or b) as the second adaptation after an initial adaptation (typically involving

patients who had an inadequate response).

715

32

5.6 Quality of Evidence 716

We assessed all unique studies included in this review using the Cochrane Risk of Bias (ROB) 717

tool. The ROB assessment was comprised of the following domains: sequence generation, 718

allocation concealment, blinding of participants, personnel and outcome assessors, incomplete 719

outcome data, and “other risks of bias”. The assessment for each domain is made in a “risk of 720

bias” table that first describes what was reported to have occurred in the study and then 721

involves a judgment by the ROB reviewer as to whether the study adequately met the 722

requirements of the domain (“LOW” risk of bias) or not (“HIGH” risk of bias), or if there was 723

insufficient information to make a decision (“UNCLEAR” or unknown risk of bias). The domain 724

“blinding of outcome assessors” was assessed separately for subjective and objective outcomes 725

because subjective outcomes would be strongly influenced by a lack of proper blinding.113 In 726

addition, a separate consideration was made for the domain ‘incomplete outcome reporting’ for 727

efficacy and safety data. 728

729

Where multiple publications were present for a single primary study (i.e. parent and companion 730

study publications, design and rationale documents, protocols, clinical trial registry records, and 731

supplementary appendices), the original primary publication was assessed and the other 732

available sources were also considered to inform the ROB assessment. 733

734

Assessments were performed by a reviewer and verified by a second reviewer. Disagreements 735

were resolved through consensus, or by a third reviewer if consensus could not be reached. 736

737

Grey literature sources (regulatory agencies, websites of regulatory agencies, clinical trial 738

registries) were searched and any eligible sources were included in the review in order to 739

reduce the risk of publication bias. Publication bias was also assessed using funnel plots and 740

Egger’s test on outcomes with at least ten studies to aid in interpreting the review findings. 741

5.7 Data Conversion and Imputation 742

For continuous outcomes, the selected measure for analysis was the mean difference from 743

baseline to end of treatment. When mean change from baseline results were not available, 744

other available data was extracted with an aim to calculate a mean change. In the event that a 745

measure of dispersion (e.g., standard deviation, standard error) was not reported for the mean 746

change from baseline, all efforts were made to find a measure of dispersion reported at baseline 747

and/or end of treatment in the published study or within the clinical trial registry. When the 748

measure of dispersion (e.g., standard deviation, standard error) was not available for the 749

change from baseline data, we assumed that the measure of dispersion was the same between 750

baseline and the end of treatment in order to calculate the measure of dispersion for the mean 751

change from baseline. If no measure of dispersion was found for a primary study among any of 752

33

its published and unpublished materials, the standard error was imputed by taking the median 753

standard error across other studies of similar patient populations. Since it is difficult to ensure 754

that the populations are the same across studies, any studies requiring such imputation were 755

excluded from the reference case analysis and included only in a sensitivity analysis. 756

757

Calculations were required to obtain standard deviations and 95% confidence intervals into 758

standard errors for the mean change from baseline. In the event that a study reported the 759

median and range, the mean and standard error were calculated using the methods outlined by 760

Hozo et al.114 If the median and interquartile range was presented, the median was assumed to 761

be equivalent to the mean and the interquartile range was divided by 1.35 based on guidance in 762

the Cochrane Handbook (Version 5.1.0).115 763

5.8 Data Analysis 764

The study and patient characteristics for the included studies are presented narratively and 765

summarized to accompany synthesized data. 766

767

A network meta-analysis (NMA) was conducted when there were more than three studies 768

contributing data to an outcome. If the NMA model did not properly converge, due to a large 769

proportion of studies with all-arm zero events for binary data, a continuity correction was 770

applied. If model convergence was not robust following continuity correction,116 pairwise meta-771

analysis (MA) was used to analyze the outcome if there were at least two treatments being 772

compared. A pairwise MA could not be conducted when all but one of the eligible studies had 773

all-arm zero events. A descriptive analysis was performed when both MA and NMA were not 774

feasible or appropriate (due to studies with all-arm zero events for binary outcomes, for which 775

the effect cannot be estimated, or when there were less than two studies eligible for a pairwise 776

comparison). 777

778

Data from studies with adaptive designs could only be included up to the time of adaptation, and 779

any study in which the adaptation occurred before 12 weeks was excluded from analysis based 780

on the review selection criteria. Additionally, studies without the standard dose of a treatment or 781

that had only one arm with eligible data were excluded from analysis. 782

783

Additional details on the statistical analysis plan are available in Appendix 2. 784

5.8.1 Network Meta-Analysis 785

Bayesian NMAs were conducted for outcomes pre-specified in the protocol, following 786

assessment of heterogeneity across trials in terms of patient characteristics, trial methodologies, 787

34

and treatment protocols.117 The minimum required length of treatment for analysis was three 788

months. The effect estimate depended on the outcome of interest and availability of data. Only 789

the standard doses approved by Health Canada were included for analysis; if Health Canada 790

had not yet approved a treatment, the approved dose of another regulatory agency (i.e., FDA, 791

EMA) was selected or, if not approved anywhere, the phase III trial doses being investigated for 792

approval were analyzed. Both fixed and random-effects models were conducted; model 793

selection was based on the Deviance Information Criterion (DIC) and residual deviance. R (R 794

Foundation for Statistical Computing, Vienna, Austria) and WinBUGS (MRC Biostatistics Unit, 795

Cambridge, UK) were used for Bayesian NMA according to the routing that accommodates 796

evidence structures, which may consist of multi-arm trials as developed at the Universities of 797

Bristol and Leicester (http://www.bristol.ac.uk/population-health-798

sciences/centres/cresyda/mpes/). A generalized linear model was used with a logit link function 799

for binary outcomes and a generalized linear model with an identity link function was used for 800

continuous outcomes. 801

802

Given that it is unethical to conduct a RCT with a placebo arm for more than 12 to 16 weeks in 803

RA (due to a lack of clinical equipoise and sufficient time to demonstrate clinical efficacy during 804

that period),106, 107 trials often provide those receiving placebo of the experiemental drug with 805

concomitant MTX (or other csDMARD) monotherapy in order to extend the trial length for 806

longer-term outcomes (e.g., radiographic progression, quality of life, safety).107 MTX 807

monotherapy with a placebo of another drug (Placebo+MTX) was identified as the common 808

comparator (i.e., index node about which all other treatments are anchored) for the Bayesian 809

NMAs. In most studies, concomitant MTX was permitted for participants, but all other 810

csDMARDs were not. However, certain studies did not specifically indicate if participants were 811

receiving MTX due to either 1) unclear reporting (e.g., only indicating a csDMARD was 812

permitted for concomitant use) or 2) the study permitted participants to receive their choice of 813

one of several csDMARDs that may have included MTX). To ensure greater homogeneity of the 814

evidence network, analyses were conducted by subgroups: with studies permitting concomitant 815

treatment with MTX (common comparator: Placebo+MTX) in one evidence network and studies 816

permitting concomitant treatment with any csDMARD (common comparator: 817

Placebo+csDMARD) in a separate evidence network. 818

819

Posterior densities for unknown parameters were estimated using Markov Chain Monte Carlo 820

(MCMC) methods. Basic parameters were assigned informative prior distributions for the 821

between-study variance, following Turner et al.118; non-informative or vague priors were 822

considered when there were issues of model convergence. Findings are summarized as the 823

point estimates and 95% credible intervals. Point estimates were reported as the odds ratio for 824

binary outcomes; for continuous outcomes the mean difference was reported or the 825

standardized mean difference was reported when more than one scale was used across 826

included studies. Consistency between direct and indirect evidence was formally assessed 827

using back-calculation and node splitting techniques. Model diagnostics also included trace 828

http://www.bristol.ac.uk/population-health-sciences/centres/cresyda/mpes/

http://www.bristol.ac.uk/population-health-sciences/centres/cresyda/mpes/

35

plots and the Gelman-Rubin-Brooks statistic to assess and ensure model convergence. Three 829

chains were fit in WinBUGS for each analysis, each employing approximately 20,000 iterations, 830

with a burn in of approximately 20,000 iterations. 831

832

Graphical methods of displaying the geometry for each evidence network were used to 833

investigate the shape, symmetry and complexity of the evidence networks being analyzed.119, 120 834

The nodes represent specific treatments and the lines connecting nodes represent a direct 835

comparison between two treatments within included studies. Nodes are proportional to the total 836

number of participants who had received a particular treatment and contributed data; line 837

thickness is proportional to the number of studies involving a particular direct comparison. For 838

each evidence network, we presented the total number of participants, treatments, and direct 839

comparisons. 840

841

For sensitivity analyses, studies that were of poor methodological quality (i.e., unclear or high 842

risk of bias overall) were removed from the network. Inclusion of treatment doses above and 843

below the standard dose was another sensitivity analysis. Moreoever, the following sensitivity 844

analyses were also conducted: 1) imputed standard errors for studies with no measure of 845

dispersion (e.g., standard deviation, standard error) available; it was imputed by taking the 846

median standard error from other studies included in the evidence network; 2) publication date 847

before 2007 versus 2007 onwards; 3) end of treatment data from adaptive design trials; and 4) 848

including only studies that explicitly mentioned patients had IR MTX rather than any csDMARD. 849

Sensitivity analyses planned post hoc included: 1) a restricted time-point analysis including only 850

studies with adaptive or end of treatment data between 12 and 16 weeks; 2) only studies that 851

clearly stated patients were IR MTX and also had never received biologic treatment; and 3) an 852

analysis without Asian-only trials or including only Asian-only trials because they may have 853

different characteristics, including a lower dose of concomitant MTX. Results of the outcome 854

sensitivity analyses are reported as the difference in log OR with 95% confidence intervals for 855

binary outcomes and the difference in mean difference (or difference in standardized mean 856

difference) with 95% confidence intervals. When the sensitivity analysis estimate was higher 857

than the reference case, the difference in log OR or difference in mean difference was greater 858

than zero and if it was lower the difference in log OR or difference in mean difference was less 859

than zero. When the confidence interval was fully above or below zero, this indicated a 860

statistically significantly different result between the sensitivity analysis and reference case. 861

5.8.2 Meta-Analysis 862

When a NMA was not possible, use of pairwise MAs was explored. If no pairwise comparisons 863

were present in two or more trials, the results were analyzed descriptively. Meta-analyses were 864

undertaken using fixed or random-effects models when data were available, sufficiently similar 865

and of sufficient quality. The effect sizes for the identified binary outcomes were expressed in 866

terms of the odds ratio (OR). In cases when events were rare, the Peto OR was used.121 867

36

868

Results were assessed for both clinical heterogeneity and methodological heterogeneity. 869

Clinical heterogeneity was assessed by checking that the populations, interventions, and 870

comparators were not too different from each other, such that combining them would be 871

inappropriate. Methodological diversity was assessed by checking that the studies were similar 872

in terms of study design and risk of bias. Once satisfied that the studies were minimally diverse 873

and that it was appropriate to pool them together in a meta-analysis, an assessment of the 874

statistical heterogeneity was undertaken by examining the forest plot and result of the I2 statistic; 875

the forest plots providing a visual sense of heterogeneity and the I2 statistic indicating the 876

presence of statistical heterogeneity. If the effects observed across trials were inconsistent, and 877

varied to a large extent (e.g., I2 > 50%), the results were explored again to assess whether the 878

differences could be explained by some clinical or methodological feature. 879

6 RESULTS 880

6.1 Selection of Primary Studies 881

The literature search yielded 4,656 citations; 373 records were additionally retrieved from 882

existing systematic reviews (n = 364), grey literature (n = 4) and a hand search (n = 5). 883

Altogether, 4809 citations were identified after removal of 220 duplicate records. Screening of 884

titles and/or abstracts led to an exclusion of 4396 of these records. The full-texts of the 413 885

remaining records were assessed and 98 unique studies and 41 companion publications were 886

included in the systematic review.94-101, 122-252 There were 91 unique RCTs and 40 companion 887

publications eligible for analysis.94-101, 122-126, 128-156, 158-163, 165-174, 176-198, 200-207, 209-222, 224-229, 231-252 888

One clinical controlled trial was included in the systematic review, but did not report any safety 889

outcomes, thus was not eligible for the analysis.127 Three studies were not included in the 890

analysis because they involved an adaptive design at eight weeks,199, 223, 230 which meant the 891

data eligible for analysis in our review was less than the pre-specified 12-week duration. A 892

minimum of 12 weeks was determined based on it being the shortest time frame for 893

demonstrating efficacy of a drug versus placebo in RA.106 Three studies and one companion 894

publication were not analyzed with the other studies because all participants received the 895

experimental drug (a biologic in these cases) in an open-label lead-in phase and those who 896

responded to biologic were randomized to one of the study arms; this represents a different 897

population than the other studies because participants had already been shown to respond to 898

the biologic prior to the randomization phase.157, 164, 175, 208 The PRISMA flowchart for the study 899

selection process is found in Figure 1. A full list of included studies is available in Appendix 3 900

and excluded studies (with reasons) in Appendix 4. 901

37

Figure 1. PRISMA Flow Diagram 902

903

6.2 Study Characteristics 904

Detailed trial characteristics of the included studies that reported on the outcomes of interest are 905

available in Table 3. Forty-one RCTs,94, 95, 97, 100, 133, 141, 149, 151, 156, 158, 160, 161, 169, 172-174, 176, 178, 182-186, 906 191, 205, 206, 209, 212-215, 221, 227, 229, 233, 239, 242, 244, 246-248 along with 18 companion publications used an 907

adaptive design that involved one of the following adaptations when participants did not reach a 908

pre-defined level of disease response: 909

Figure 1: PRISMA Flow Diagram

253

38

1) Early escape from the trial; 910

2) Rescue therapy; 911

3) Treatment switch based on non-response criteria defined a priori; or 912

4) Planned treatment switch. 913

Data available up to the time of first trial adaptation was analyzed for these RCTs, which 914

occurred most often between 12 and 16 weeks after initiation of treatment (see Appendix 5 for 915

details on each adaptive design trial). 916

The 91 RCTs included for analysis had their data extracted and analyzed at the end of 917

treatment period, except for the 41 adaptive design trials that were analyzed at the time of 918

adaptation. Treatment duration varied greatly across studies from three to 36 months. Due to 919

the presence of adaptive design trials, the treatment duration eligible for analysis ranged from 920

three months to 24 months, with the most common treatment durations being four, three and six 921

months, respectively. 922

923

In the included studies, the proportion of women comprised an average of 80.6% of the total 924

number of participants (range 43.3% to 100%). Patients enrolled in the RCTs were adults 925

diagnosed with RA who had failed or were intolerant to at least one csDMARD. The majority of 926

included studies enrolled participants who had an inadequate response to MTX, while 14 927

studies permitted the concomitant use of an unspecified csDMARD (i.e., either the report did not 928

specify which csDMARD participants could take or investigators permitted participants a choice 929

to take MTX or another csDMARD). Sample sizes of RCTs ranged from 28 to 1220 participants 930

with a median of 313 participants. More specifically, 10 studies had a sample size <100, six 931

studies had a sample size >1000, and the rest had a sample size between 100 to 1000 932

participants. A summary of patient characteristics of included studies is available in Table 4. 933

Appendix 6 provides further details on study characteristics (Table 43) and patient 934

characteristics (Table 44) of included studies. 935

936

Table 4: Summary of Trial Characteristics 937

Trial Characteristics Categories Number of Unique Included Studies

Publication Status Unique studies 98 Unique studies reporting outcomes of interest

91

Study Design (Unique studies)

Parallel RCT 52 Adaptive design RCT 41 Open-label lead-in phasea RCT 4 Controlled clinical trial 1

Intervention Comparison (Unique studies reporting outcomes of interest)

Placebo Control 6 Active Control (MTX monotherapy) 49 Active Control (csDMARD monotherapy) 13

39

Trial Characteristics Categories Number of Unique Included Studies

Active Control (csDMARD combination therapy)

4

Active Control (Biologic) 19

Publication Year (Unique studies) Range: 1995 to

2017

Randomizedb Sample Size (Unique studies)

Small (<100 participants) 11 Medium (100-500 participants) 55 Large (>500 participants) 32

Duration of Study (Unique studies)

<3 monthsc 2 3 to 6 months 79 >6 months to one year 12 >1 year 5

Treatment Duration Eligible for Analysis (Unique studies)

3 to 6 months 65 >6 months to one year 22 >1 year 11

aPatients who respond during the open-label lead-in phase are eligible to enter the randomization phase

938 bSample size at baseline in the case of the one included clinical controlled trial 939

cStudies with an adaptive design before 3 months 940

csDMARD = conventional synthetic disease-modifying antirheumatic drug; MTX = methotrexate; RCT = randomized controlled trial 941 942

Table 5: Summary of Patient Characteristics 943

Baseline Characteristics Pooled Baseline Estimates, Mean (Range)

Mean age (years) 52.5 (43.9, 58.1)

Gender (% female) 80.6 (43.3, 100)

Mean duration of RA (years) 7.72 (0.34, 13.0)

Caucasian (%) 35.2 (0, 99.4)

Total mean of Tender Joint Count 23.43 (7.1, 37.2)

Total mean of Swollen Joint Count 15.91 (6.3, 31.0)

944

6.3 Risk of Bias 945

A risk of bias assessment was performed for all unique studies using the Cochrane 946

Collaboration’s Risk of Bias tool. Figure 2 provides an overall summary of the results for all 947

included RCTs. More detailed results at the study level are reported in Appendix 7. 948

949

40

Three of the studies included in analysis did not have their risk of bias assessed because they 950

were grey literature sources.128, 209, 211 Of the 88 assessed, just over half of included studies 951

inadequately reported on random sequence generation and allocation concealment, resulting in 952

unclear risk of bias. The remaining studies all had low risk of bias in these domains, except for 953

one study.190 All studies reporting objective outcomes had low risk of bias for blinding. For 954

studies reporting subjective outcomes, about half (52%) were considered unclear risk of bias 955

because there were no details on how blinding was maintained for participants. About one third 956

of studies (38%) had low risk of bias because they provided sufficient details on how blinding 957

was maintained for participants, personnel and outcome assessors. While a majority of studies 958

had low risk of bias for incomplete outcome data for efficacy and safety, 42% and 28% of 959

studies had high risk of bias for incomplete outcome data for efficacy outcomes and safety 960

outcomes, respectively. For this review, the domain “Other Bias” was predominantly used to 961

assess whether outcome data was reported at the time of adaptation in adaptive design trials 962

(see Table 3 for definitions). Thirteen adaptive design trials had low risk of bias because they 963

reported on outcome data at the time of adaptation; 26 adaptive design trials had high risk of 964

bias because they did not adequately report on outcome data at the time of adaptation (two 965

adaptive design trials did not have risk of bias assessed because they were from grey literature 966

sources). There were two conventional design trials that had unclear risk of bias because of 967

small sample sizes that impacted either the ability to demonstrate non-inferiority167 or resulted in 968

baseline imbalances, but the impact on the results was unclear.168 One other conventional 969

design trial had high risk of bias due to imbalanced randomization.225 Among all studies 970

assessed for risk of bias, half were judged to have high risk of bias and only 10 studies were 971

considered to have low risk of bias overall; the rest (39%) had unclear risk of bias overall. 972

973

Studies also poorly reported the definitions of study outcomes (e.g., DAS28 using ESR or CRP, 974

HAQ or HAQ-DI), and did not conduct true intention-to-treat analyses (i.e., all randomized 975

patients are analyzed according to their original assignment) for reported outcomes. The use of 976

adaptive designs also limited the ability to incorporate data from later time-points from studies in 977

this review because the true treatment effect was unclear with changes to therapy or high 978

attrition after the point of adaptation. Eleven studies, while they reported outcomes of interest, 979

failed to report measures of dispersion along with mean change from baseline values in at least 980

one outcome of interest.129, 154, 169, 170, 176, 184, 189, 232, 235, 240, 243 This required either imputation using 981

baseline or end of study standard deviations or standard errors if available, or exclusion of 982

studies from the reference case analysis (missing standard errors for these were imputed in a 983

sensitivity analysis). 984

41

Figure 2: Summary of Risk of Bias Assessment

985

6.4 Data Synthesis 986

Thirteen NMAs were conducted for 12 outcomes (the SF-36 Physical and Mental Component 987

Scales were assessed separately for HRQOL) for the reference case where the common 988

comparator was MTX monotherapy. Seven NMAs were conducted on seven outcomes for the 989

reference case where the common comparator was a csDMARD (i.e., not necessarily MTX). 990

These outcomes had sufficient data for network models (Table 6). 991

992

For each outcome, the mean differences or odds ratios from the NMA of the reference case are 993

provided comparing the standard approved dose of each drug with either MTX monotherapy 994

(Placebo+MTX) or csDMARD monotherapy (Placebo+csDMARD). For tocilizumab, both the 4 995

mg/kg and 8 mg/kg standard doses were included. Baricitinib has not yet been approved in 996

Canada, but the dose of 4 mg daily (orally) was selected given its approval in the European 997

Union.254 Sirukumab was under review with Health Canada at the time of analysis, thus the 998

phase 3 trial doses (50 mg every four weeks and 100 mg every two weeks, subcutaneously) 999

were used in this review.255 1000

1001

For continuous outcome measures that used a standardized mean difference (i.e., DAS28, pain, 1002

and fatigue), the results were interpreted using the rule of thumb as defined by Cohen256 that 1003

identifies a small effect size (SMD = 0.2 to <0.5), medium effect size (SMD = 0.5 to <0.8) and 1004

large effect size (SMD ≥0.8). 1005

0% 20% 40% 60% 80% 100%

Overall quality

Other risk of bias

Incomplete outcome data (safety)

Incomplete outcome data (efficacy)

Blinding (subjective outcomes)

Blinding (objective outcomes)

Allocation concealment

Random sequence generation

Low

Unclear

High

42

1006

Fifty-seven studies did not clearly report on the route of administration of MTX (i.e., oral or 1007

subcutaneous) and 14 studies permitted participants to take concomitant MTX orally or 1008

subcutaneously. Thirteen studies only permitted oral MTX use and eleven studies included in 1009

analysis did not permit the participants to receive MTX. In most cases, it was not clear whether 1010

participants of included studies were receiving oral or subcutaneous MTX, and since this was 1011

often the background therapy, the route of administration may have differed. 1012

1013

Table 6 provides an overview of each analysis by outcome and patient group. Results for 1014

sensitivity analyses are available in Appendix 8. 1015

1016

Table 6. Overview of Evidence and Analyses Performed 1017

Method of Analysis Methotrexate as a Common

Comparator

Conventional Synthetic

DMARD as a Common

Comparator

Efficacy Outcomes

Network Meta-

Analysis

- ACR20, 50, 70;

- DAS28;

- Disability (HAQ-DI);

- Remission;

- Radiographic progression;

- Pain;

- Fatigue;

- Health-related quality of life

(Physical and Mental

Component Scores)

- ACR20, 50, 70;

- DAS28;

- Disability (HAQ-DI);

Meta-Analysis NA NA

Descriptive Analysis NA - Health-related quality of life

(SF-36 Physical and Mental

Component Scores);

- Remission;

- Pain;

- Fatigue

43

Safety Outcomes

Network Meta-

Analysis

- Withdrawal due to adverse

events;

- Serious adverse events

- Withdrawal due to adverse

events;

- Serious adverse events

Meta-Analysis - Serious infections;

- Mortality;

- Tuberculosis;

- Cancer;

- Herpes zoster

NA

Descriptive Analysis - Mortality;

- Serious infections;

- Tuberculosis;

- Cancer;

- Leukemia;

- Lymphoma;

- Congestive heart failure;

- Herpes zoster

- Mortality;

- Serious infections;

- Tuberculosis;

- Cancer;

- Leukemia;

- Major adverse cardiac event;

- Herpes zoster

ACR = American College of Rheumatology; csDMARD = conventional disease-modifying anti-rhuematic drug; DAS28 = Disease 1018 Activity Score, 28 joint count; HAQ-DI = Health Assessment Questionnaire, Disability Index; NA = not applicable; SF-36 = 36-item 1019 short-form survey 1020 N.B.: Certain outcomes are listed in both the meta-analysis and descriptive analysis. This is when there were one or more pairwise 1021 meta-analyses that could be performed. The remaining treatment comparisons that did not appear in more than one study were 1022 reported in a descriptive analysis. 1023

1024

6.4.1 Disease Severity 1025

The results for disease severity based on the ACR50 are presented below. Full results for the 1026

ACR20 and ACR70 are presented in Appendix 9. 1027

6.4.1.1 Methotrexate as a Common Comparator 1028

There were 63 RCTs (53 2-arm studies, nine 3-arm studies, and one 5-arm study) reporting 1029

ACR50 that were included in the reference case NMA.95, 97, 100, 126, 128, 130, 131, 133-137, 148, 153, 154, 163, 1030 165, 167, 169, 172-174, 176-178, 183, 184, 186, 188, 189, 191-193, 197, 201-205, 211-214, 216, 221, 222, 224, 225, 227-229, 231, 233, 235, 236, 1031 239, 242-244, 246, 247, 250, 252 The evidence network involved 19,782 participants and 36 treatments 1032

forming 90 direct comparisons. Assessment for consistency demonstrated that the model was 1033

consistent. A geometric illustration of the evidence network is presented in Figure 3 and the 1034

odds ratios for all treatment comparisons with MTX monotherapy as the common comparator 1035

are available in Table 7. 1036

44

1037

Figure 3. Evidence Network: ACR50 (Placebo+MTX) 1038

1039

Compared to MTX monotherapy, participants receiving the following treatments had statistically 1040

significantly higher odds of achieving the ACR50 disease response, by treatment category: 1) 1041

csDMARD double therapy with MTX and hydroxychloroquine (HCQ) and csDMARD triple 1042

therapy with MTX, HCQ, and sulfasalazine (SSZ); 2) the TNF inhibitors etanercept 1043

(monotherapy), etanercept in combination with MTX, infliximab in combination with MTX, 1044

adalimumab in combination with MTX, golimumab in combination with MTX (IV and SC routes), 1045

and certolizumab pegol in combination with MTX; 3) the non-TNF inhibitors abatacept (IV) in 1046

combination with MTX, 8 mg/kg tocilizumab monotherapy, 8 mg/kg tocilizumab combination 1047

therapy with MTX, 4 mg/kg tocilizumab in combination with MTX, and rituximab in combination 1048

with MTX; 4) the tsDMARDs tofacitinib in combination with MTX and 4 mg baricitinib in 1049

combination with MTX; and 5) the biosimilars HD203 (biosimilar etanercept) in combination with 1050

MTX, SB4 (biosimilar etanercept) in combination with MTX, ANBAI (AnBaiNuo, biosimilar 1051

45

etanercept) in combination with MTX, CT-P13 (biosimilar infliximab) in combination with MTX, 1052

SB5 (biosimilar adalimumab) in combination with MTX, ZRC-3197 (biosimilar adalimumab) in 1053

combination with MTX, and ABP501 (biosimilar adalimumab) in combination with MTX (Table 1054

7). Most of the biologic and tsDMARD monotherapy treatment arms did not have a statistically 1055

significant ACR50 response compared to MTX monotherapy (Table 7). 1056

1057

When the treatments were compared against placebo, the same treatments listed above had 1058

statistically significant ACR50 in addition to: csDMARD double therapy with SSZ and HCQ, 1059

tofacitinib monotherapy, 4 mg/kg tocilizumab monotherapy, golimumab (SC) monotherapy, 1060

certolizumab pegol monotherapy, rituximab monotherapy, and SB2 (biosimilar infliximab) in 1061

combination with MTX. Most of these additional treatments were monotherapies, except the 1062

biosimilar infliximab and the csDMARD double therapy (Table 7). 1063

1064

Several treatments were found to have statistically significantly higher odds of reaching the 1065

ACR50 disease response compared to double csDMARD therapy with MTX and any other 1066

csDMARD. The only csDMARD combination that was better compared to csDMARD+MTX was 1067

csDMARD triple therapy with MTX, SSZ and HCQ (OR = 7.67, [95% CrI: 1.76, 33.88]). The 1068

other treatments with statistically significant odds of achieving the ACR50 compared to a 1069

csDMARD in combination with MTX include: 1) the TNF inhibitors etanercept in combination 1070

with MTX, adalimumab in combination with MTX, golimumab (SC) in combination with MTX, and 1071

certolizumab pegol in combination with MTX; 2) the non-TNF inhibitors abatacept (IV) in 1072

combination with MTX, 8 mg/kg tocilizumab (monotherapy), and 8 mg/kg tocilizumab in 1073

combination with MTX; 3) the tsDMARDs tofacitinib in combination with MTX and 4 mg 1074

baricitinib in combination with MTX; 4) the biosimilars HD203 (biosimilar etanercept) in 1075

combination with MTX, SB4 (biosimilar etanercept) in combination with MTX, and AnBaiNuo 1076

(biosimilar etanercept) in combination with MTX. Interestingly, only participants receiving MTX in 1077

combination with HCQ and csDMARD triple therapy with MTX, SSZ and HCQ had statistically 1078

significantly higher odds of achiving the ACR50 response compared to double csDMARD 1079

therapy with MTX and SSZ (OR = 4.36 [1.05, 24.04] and OR = 4.90 [1.19, 25.20], respectively). 1080

When the double csDMARD combination therapy of SSZ and HCQ was the comparator, it was 1081

found that two biosimilar etanercepts (HD203 and AnBaiNuo) had greater odds of achieving the 1082

ACR50 (OR = 3.67 [1.08, 13.20] and OR = 4.00 [1.08, 16.20], respectively). 1083

1084

Seven treatments in combination with MTX had higher odds of meeting the ACR50 response 1085

criteria compared with etanercept monotherapy, including all three biosimilar etanercepts 1086

(HD203, SB4, and AnBaiNuo). The other treatments were etanercept, tofacitinib, golimumab 1087

(SC), and certolizumab pegol, all in combination with MTX (Table 7). However, when these 1088

three biosimilar etanercepts were compared against etanercept in combination with MTX there 1089

was no statistically significant difference in the ACR50 disease response. 1090

46

1091

Patients with inadequate response to MTX in most treatment arms had higher odds of reaching 1092

the ACR50 response criteria compared to adalimumab monotherapy. These included 1093

monotherapy with 8 mg/kg tocilizumab (IV), or MTX combination therapy with: tofacitinib, 4 1094

mg/kg or 8 mg/kg tocilizumab (IV), golimumab (SC and IV routes), infliximab, certolizumab 1095

pegol, rituximab, 4 mg baricitnib, HD203 (biosimilar etanercept), SB4 (biosimilar etanercept), 1096

AnBaiNuo (biosimilar etanercept), SB5 (biosimilar adalimumab), ZRC-3197 (biosimilar 1097

adalimumab), and ABP501 (biosimilar adalimumab). Yet there was no statistically significant 1098

difference when the two biosimilar adalimumabs were compared against adalimumab in 1099

combination with MTX. Compared to tofacitinib monotherapy, only two of the etanercept 1100

biosimilars (HD203 and AnBaiNuo) had statistically significantly higher odds of achieving the 1101

ACR50, though the 95% credible intervals are wide (Table 7). 1102

1103

Compared to 4 mg/kg tocilizumab (IV) monotherapy, patients receiving MTX combination 1104

therapy with 8 mg/kg tocilizumab (IV), golimumab (SC), certolizumab pegol, 4 mg baricitinib, 1105

HD203 (biosimilar etanercept), and AnBaiNuo (biosimilar etanercept) had a higher odds of 1106

achieving the ACR50 response criteria (Table 7). Two biosimilar etanercepts (HD203 and 1107

AnBaiNuo) had statistically significant odds ratios with 200 mg sarilumab monotherapy as the 1108

comparator, but these had wide 95% credible intervals (Table 7). 1109

1110

There were no statistically significant comparisons between treatments when the common 1111

comparator was the combination of MTX with etanercept, abatacept (IV), adalimumab, 4 mg/kg 1112

and 8 mg/kg tocilizumab (IV), golimumab (SC and IV routes), infliximab, certolizumab pegol, 1113

rituximab, 4 mg baricitinib, HD203 (biosimilar etanercept), SB4 (biosimilar etanercept), 1114

AnBaiNuo (biosimilar etanercept), CT-P13 (biosimilar infliximab), SB2 (biosimilar infliximab), 1115

SB5 (biosimilar adalimumab), and ZRC-3197 (biosimilar adalimumab). There were also no 1116

statistically significant findings with the comparator as monotherapy of certolizumab pegol, 1117

golimumab, 8 mg/kg tocilizumab (IV), or rituximab (Table 7). 1118

1119

Table 7: Americal College of Rheumatology 50 (Placebo+MTX): Odds Ratios, Relative Risks and Risk 1120 Differences for All Treatment Comparisons – Random Effects Model 1121

Treatment Reference OR (95% CrI) RR (95% CrI) RD (95% Crl)

Placebo Placebo+MTX 0.15 (0.03, 0.71) 0.16 (0.04, 0.73) -0.09 (-0.12, -0.03)

csDMARD+MTX

1.21 (0.54, 3.07) 1.19 (0.57, 2.49) 0.02 (-0.05, 0.17)

MTX+SSZ

1.89 (0.25, 13.56) 1.71 (0.28, 5.64) 0.08 (-0.08, 0.52)

47


MTX+HCQ

8.47 (1.41, 50.46) 4.57 (1.35, 7.76) 0.41 (0.04, 0.75)

SSZ+HCQ

2.21 (1.00, 5.10) 1.94 (1.00, 3.50) 0.11 (0.0002, 0.28)

MTX+SSZ+HCQ

9.34 (2.74, 35.07) 4.77 (2.28, 7.33) 0.43 (0.15, 0.70)

ETN_STD

1.95 (1.05, 4.02) 1.76 (1.04, 3.00) 0.09 (0.005, 0.22)

ETN_STD+MTX

4.52 (2.69, 8.59) 3.23 (2.24, 4.68) 0.25 (0.15, 0.41)

ABA_STD

(IV)+MTX

4.13 (2.57, 6.82) 3.04 (2.17, 4.13) 0.23 (0.14, 0.35)

ADA_STD+MTX

4.00 (2.82, 5.65) 2.97 (2.32, 3.75) 0.23 (0.15, 0.30)

ADA_STD

0.31 (0.04, 2.39) 0.33 (0.05, 2.06) -0.08 (-0.11, 0.12)

TOF_STD+MTX

5.79 (3.41, 9.86) 3.74 (2.66, 4.98) 0.31 (0.19, 0.44)

TOF_STD

0.78 (0.11, 5.85) 0.80 (0.12, 3.78) -0.02 (-0.10, 0.31)

TOC_4 (IV)

1.55 (0.57, 4.04) 1.46 (0.60, 3.01) 0.05 (-0.05, 0.23)

TOC_8 (IV)

3.82 (2.15, 7.03) 2.89 (1.90, 4.21) 0.22 (0.10, 0.36)

TOC_4 (IV)+MTX

2.72 (1.42, 5.10) 2.27 (1.35, 3.50) 0.15 (0.04, 0.28)

TOC_8 (IV)+MTX

4.33 (2.64, 7.22) 3.13 (2.22, 4.26) 0.24 (0.14, 0.37)

GOL_STD (SC)

1.05 (0.15, 7.72) 1.04 (0.17, 4.40) 0.005 (-0.10, 0.38)

GOL_STD

(SC)+MTX

5.96 (3.24, 11.45) 3.81 (2.57, 5.30) 0.32 (0.18, 0.48)

GOL_STD

(IV)+MTX

2.92 (1.19, 7.35) 2.39 (1.17, 4.30) 0.16 (0.02, 0.37)

INF_STD+MTX

3.02 (1.80, 5.14) 2.45 (1.65, 3.51) 0.17 (0.07, 0.28)

CERTO_STD+MTX

5.39 (3.45, 8.75) 3.59 (2.67, 4.72) 0.30 (0.20, 0.41)

CERTO_STD

1.35 (0.22, 8.46) 1.30 (0.25, 4.63) 0.03 (-0.09, 0.41)

RIT_STD

3.44 (0.87, 14.47) 2.69 (0.88, 5.80) 0.19 (-0.01, 0.53)

RIT_STD+MTX

5.33 (1.37, 22.72) 3.56 (1.31, 6.68) 0.29 (0.04, 0.63)

SAR_200

0.62 (0.07, 5.90) 0.64 (0.08, 3.78) -0.04 (-0.11, 0.31)

BAR_4+MTX

5.49 (3.20, 10.01) 3.62 (2.55, 5.02) 0.30 (0.18, 0.45)

HD203+MTX

8.06 (2.75, 26.02) 4.47 (2.29, 6.90) 0.40 (0.15, 0.65)

48


SB4+MTX

5.26 (2.02, 15.41) 3.54 (1.81, 5.91) 0.29 (0.09, 0.55)

ANBAI+MTX

8.81 (3.15, 27.54) 4.65 (2.53, 6.96) 0.42 (0.17, 0.66)

CT-P13+MTX

4.14 (1.82, 9.92) 3.05 (1.66, 4.96) 0.23 (0.08, 0.44)

SB2+MTX

2.59 (0.98, 7.14) 2.19 (0.98, 4.23) 0.14 (-0.002, 0.37)

SB5+MTX

3.73 (1.44, 9.36) 2.84 (1.37, 4.84) 0.21 (0.04, 0.43)

ZRC-3197+MTX

3.88 (1.26, 11.95) 2.92 (1.22, 5.36) 0.22 (0.03, 0.49)

ABP501+MTX

3.59 (1.45, 8.77) 2.77 (1.38, 4.70) 0.20 (0.04, 0.41)

csDMARD+MTX Placebo 8.18 (1.73, 42.96) 7.15 (1.65, 35.39) 0.11 (0.04, 0.25)

MTX+SSZ

13.24 (0.98, 152.30) 10.35 (0.98, 73.44) 0.17 (-0.001, 0.61)

MTX+HCQ

58.18 (5.49, 600.20) 26.17 (4.16, 135.30) 0.50 (0.13, 0.84)

SSZ+HCQ

15.09 (2.97, 76.56) 11.78 (2.60, 54.49) 0.20 (0.08, 0.37)

MTX+SSZ+HCQ

65.07 (8.93, 470.60) 28.36 (5.68, 136.00) 0.52 (0.23, 0.79)

ETN_STD

13.27 (3.55, 54.39) 10.68 (2.96, 43.46) 0.18 (0.10, 0.30)

ETN_STD+MTX

30.60 (7.34, 142.20) 19.49 (4.89, 87.68) 0.35 (0.24, 0.49)

ABA_STD

(IV)+MTX

28.40 (5.41, 143.30) 18.70 (4.00, 88.41) 0.32 (0.21, 0.44)

ADA_STD+MTX

27.57 (5.44, 129.90) 18.50 (4.00, 84.86) 0.32 (0.22, 0.40)

ADA_STD

2.06 (0.58, 7.89) 2.01 (0.59, 6.73) 0.02 (-0.01, 0.17)

TOF_STD+MTX

39.70

(7.37, 198.30)

23.00 (4.83, 107.40) 0.40 (0.27, 0.53)

TOF_STD

5.22 (1.48, 19.76) 4.70 (1.46, 14.79) 0.07 (0.01, 0.37)

TOC_4 (IV)

10.51 (1.59, 65.16) 8.84 (1.53, 48.82) 0.14 (0.03, 0.32)

TOC_8 (IV)

26.11 (4.95, 135.80) 17.71 (3.74, 85.52) 0.31 (0.18, 0.45)

TOC_4 (IV)+MTX

18.45 (3.37, 97.24) 13.80 (2.85, 67.86) 0.24 (0.12, 0.38)

TOC_8 (IV)+MTX

29.60 (5.79, 148.80) 19.27 (4.18, 90.89) 0.34 (0.21, 0.46)

GOL_STD (SC)

7.14 (2.17, 24.41) 6.19 (2.10, 17.41) 0.10 (0.01, 0.43)

GOL_STD

(SC)+MTX

41.17 (7.60, 212.10) 23.44 (4.99, 109.30) 0.41 (0.26, 0.57)

49


GOL_STD

(IV)+MTX

19.94 (3.31, 118.40) 14.51 (2.83, 75.59) 0.25 (0.10, 0.46)

INF_STD+MTX

20.40 (3.85, 105.60) 14.92 (3.14, 72.62) 0.26 (0.15, 0.38)

CERTO_STD+MTX

36.96 (7.04, 189.50) 22.13 (4.75, 106.40) 0.39 (0.27, 0.51)

CERTO_STD

9.27 (3.93, 22.79) 7.69 (3.60, 16.47) 0.13 (0.02, 0.45)

RIT_STD

23.67 (2.85, 194.80) 16.08 (2.54, 94.90) 0.28 (0.07, 0.62)

RIT_STD+MTX

36.81 (4.50, 288.30) 21.17 (3.60, 114.10) 0.38 (0.12, 0.72)

SAR_200

4.17 (0.89, 20.52) 3.85 (0.90, 14.59) 0.05 (-0.001, 0.37)

BAR_4+MTX

37.68 (7.21, 194.00) 22.13 (4.83, 105.20) 0.39 (0.26, 0.54)

HD203+MTX

55.00 (9.86, 342.10) 26.30 (5.93, 125.70) 0.49 (0.24, 0.74)

SB4+MTX

35.90 (6.87, 201.80) 21.11 (4.66, 100.80) 0.38 (0.18, 0.63)

ANBAI+MTX

60.66 (9.62, 381.60) 27.92 (5.80, 133.50) 0.51 (0.26, 0.76)

CT-P13+MTX

28.12 (4.77, 168.40) 18.36 (3.68, 93.96) 0.32 (0.15, 0.54)

SB2+MTX

17.52 (2.72, 111.90) 13.26 (2.39, 72.50) 0.23 (0.08, 0.46)

SB5+MTX

25.31 (4.08, 146.40) 17.00 (3.32, 84.53) 0.30 (0.12, 0.52)

ZRC-3197+MTX

26.01 (3.75, 175.90) 17.41 (3.12, 93.94) 0.31 (0.11, 0.58)

ABP501+MTX

24.78 (3.70, 137.20) 17.00 (3.11, 81.74) 0.29 (0.12, 0.51)

MTX+SSZ csDMARD+MTX 1.55 (0.17, 12.40) 1.44 (0.21, 5.61) 0.06 (-0.16, 0.49)

MTX+HCQ

6.99 (0.95, 45.98) 3.69 (0.96, 9.26) 0.38 (-0.01, 0.73)

SSZ+HCQ

1.83 (0.64, 4.82) 1.64 (0.70, 3.58) 0.08 (-0.07, 0.25)

MTX+SSZ+HCQ

7.67 (1.76, 33.88) 3.93 (1.50, 8.93) 0.40 (0.10, 0.69)

ETN_STD

1.61 (0.70, 3.67) 1.49 (0.75, 2.99) 0.06 (-0.06, 0.18)

ETN_STD+MTX

3.74 (1.96, 7.02) 2.71 (1.58, 4.82) 0.23 (0.13, 0.33)

ABA_STD

(IV)+MTX

3.41 (1.22, 8.82) 2.56 (1.15, 5.64) 0.21 (0.04, 0.35)

ADA_STD+MTX

3.30 (1.19, 7.94) 2.51 (1.13, 5.39) 0.20 (0.03, 0.31)

ADA_STD

0.25 (0.03, 1.91) 0.29 (0.04, 1.71) -0.09 (-0.23, 0.08)

TOF_STD+MTX

4.78 (1.62, 12.67) 3.14 (1.39, 6.91) 0.29 (0.10, 0.44)

50


TOF_STD

0.65 (0.08, 4.75) 0.68 (0.10, 3.28) -0.04 (-0.19, 0.27)

TOC_4 (IV)

1.27 (0.32, 4.47) 1.22 (0.38, 3.46) 0.03 (-0.15, 0.22)

TOC_8 (IV)

3.15 (1.09, 8.67) 2.42 (1.06, 5.51) 0.19 (0.02, 0.35)

TOC_4 (IV)+MTX

2.24 (0.71, 6.22) 1.91 (0.76, 4.45) 0.12 (-0.06, 0.28)

TOC_8 (IV)+MTX

3.57 (1.24, 9.35) 2.64 (1.16, 5.85) 0.22 (0.04, 0.36)

GOL_STD (SC)

0.87 (0.11, 6.03) 0.89 (0.13, 3.71) -0.01 (-0.18, 0.34)

GOL_STD

(SC)+MTX

4.91 (1.62, 14.00) 3.19 (1.39, 7.12) 0.30 (0.10, 0.47)

GOL_STD

(IV)+MTX

2.44 (0.64, 7.95) 2.03 (0.70, 5.03) 0.14 (-0.07, 0.36)

INF_STD+MTX

2.47 (0.86, 6.56) 2.06 (0.89, 4.67) 0.14 (-0.03, 0.28)

CERTO_STD+MTX

4.46 (1.56, 11.23) 3.02 (1.36, 6.50) 0.27 (0.09, 0.41)

CERTO_STD

1.12 (0.17, 6.86) 1.10 (0.19, 4.08) 0.01 (-0.16, 0.36)

RIT_STD

2.83 (0.53, 14.63) 2.25 (0.58, 6.52) 0.17 (-0.09, 0.51)

RIT_STD+MTX

4.38 (0.83, 22.00) 2.95 (0.86, 7.81) 0.27 (-0.03, 0.61)

SAR_200

0.51 (0.05, 4.73) 0.55 (0.06, 3.16) -0.06 (-0.21, 0.27)

BAR_4+MTX

4.55 (1.54, 12.21) 3.05 (1.35, 6.71) 0.28 (0.09, 0.44)

HD203+MTX

6.67 (2.09, 20.81) 3.67 (1.70, 7.59) 0.37 (0.13, 0.61)

SB4+MTX

4.34 (1.50, 12.65) 2.94 (1.35, 6.15) 0.26 (0.07, 0.50)

ANBAI+MTX

7.28 (1.77, 30.17) 3.86 (1.49, 9.10) 0.39 (0.11, 0.66)

CT-P13+MTX

3.39 (0.98, 11.26) 2.55 (0.99, 6.19) 0.21 (-0.002, 0.43)

SB2+MTX

2.15 (0.54, 7.69) 1.85 (0.60, 4.93) 0.11 (-0.09, 0.35)

SB5+MTX

3.09 (0.79, 10.16) 2.39 (0.84, 5.82) 0.19 (-0.04, 0.41)

ZRC-3197+MTX

3.20 (0.75, 12.21) 2.44 (0.79, 6.26) 0.19 (-0.04, 0.48)

ABP501+MTX

2.97 (0.78, 9.80) 2.32 (0.82, 5.76) 0.18 (-0.04, 0.40)

MTX+HCQ MTX+SSZ 4.36 (1.05, 24.04) 2.44 (1.03, 10.58) 0.28 (0.01, 0.60)

SSZ+HCQ

1.18 (0.17, 8.73) 1.13 (0.33, 6.70) 0.03 (-0.39, 0.25)

MTX+SSZ+HCQ

4.90 (1.19, 25.20) 2.68 (1.07, 12.18) 0.31 (0.04, 0.56)

51


ETN_STD

1.04 (0.14, 8.45) 1.03 (0.29, 6.58) 0.01 (-0.43, 0.22)

ETN_STD+MTX

2.41 (0.34, 18.90) 1.89 (0.57, 11.77) 0.17 (-0.26, 0.40)

ABA_STD

(IV)+MTX

2.19 (0.30, 17.49) 1.78 (0.52, 11.33) 0.15 (-0.29, 0.37)

ADA_STD+MTX

2.10 (0.29, 16.35) 1.72 (0.53, 10.81) 0.14 (-0.29, 0.33)

ADA_STD

0.16 (0.01, 2.96) 0.20 (0.02, 2.65) -0.15 (-0.58, 0.09)

TOF_STD+MTX

3.05 (0.40, 24.59) 2.17 (0.63, 13.72) 0.23 (-0.22, 0.45)

TOF_STD

0.41 (0.03, 6.99) 0.48 (0.05, 5.17) -0.09 (-0.54, 0.25)

TOC_4 (IV)

0.81 (0.09, 7.38) 0.85 (0.19, 5.90) -0.03 (-0.47, 0.22)

TOC_8 (IV)

2.01 (0.26, 16.44) 1.67 (0.48, 10.78) 0.13 (-0.31, 0.36)

TOC_4 (IV)+MTX

1.43 (0.18, 11.82) 1.32 (0.36, 8.45) 0.06 (-0.39, 0.29)

TOC_8 (IV)+MTX

2.28 (0.30, 18.01) 1.82 (0.53, 11.44) 0.16 (-0.28, 0.38)

GOL_STD (SC)

0.55 (0.03, 9.03) 0.61 (0.07, 6.07) -0.07 (-0.51, 0.33)

GOL_STD

(SC)+MTX

3.13 (0.42, 25.66) 2.19 (0.65, 13.90) 0.23 (-0.21, 0.48)

GOL_STD

(IV)+MTX

1.54 (0.18, 13.63) 1.38 (0.34, 9.27) 0.07 (-0.38, 0.36)

INF_STD+MTX

1.59 (0.21, 13.13) 1.42 (0.41, 9.35) 0.08 (-0.36, 0.30)

CERTO_STD+MTX

2.87 (0.39, 22.25) 2.09 (0.63, 13.14) 0.21 (-0.23, 0.42)

CERTO_STD

0.71 (0.05, 11.38) 0.76 (0.10, 7.43) -0.04 (-0.49, 0.36)

RIT_STD

1.82 (0.16, 23.05) 1.55 (0.29, 12.45) 0.10 (-0.38, 0.50)

RIT_STD+MTX

2.82 (0.27, 33.75) 2.01 (0.45, 14.31) 0.19 (-0.29, 0.59)

SAR_200

0.32 (0.02, 6.64) 0.38 (0.03, 4.86) -0.11 (-0.55, 0.26)

BAR_4+MTX

2.93 (0.39, 22.60) 2.11 (0.62, 13.21) 0.21 (-0.23, 0.45)

HD203+MTX

4.31 (0.49, 42.37) 2.56 (0.70, 16.64) 0.29 (-0.16, 0.63)

SB4+MTX

2.80 (0.34, 26.51) 2.04 (0.55, 13.45) 0.20 (-0.25, 0.52)

ANBAI+MTX

4.60 (0.52, 49.04) 2.64 (0.73, 17.72) 0.31 (-0.16, 0.65)

CT-P13+MTX

2.20 (0.26, 20.08) 1.76 (0.46, 12.00) 0.14 (-0.31, 0.44)

52


SB2+MTX

1.37 (0.15, 13.55) 1.28 (0.30, 9.03) 0.05 (-0.40, 0.35)

SB5+MTX

1.96 (0.23, 16.97) 1.63 (0.42, 10.66) 0.12 (-0.33, 0.41)

ZRC-3197+MTX

2.04 (0.22, 19.90) 1.66 (0.40, 11.61) 0.13 (-0.33, 0.47)

ABP501+MTX

1.90 (0.21, 17.06) 1.60 (0.40, 10.74) 0.11 (-0.34, 0.40)

SSZ+HCQ MTX+HCQ 0.26 (0.04, 1.63) 0.44 (0.20, 1.46) -0.30 (-0.64, 0.08)

MTX+SSZ+HCQ

1.11 (0.32, 3.99) 1.04 (0.64, 2.45) 0.02 (-0.24, 0.30)

ETN_STD

0.23 (0.04, 1.50) 0.40 (0.18, 1.38) -0.31 (-0.67, 0.06)

ETN_STD+MTX

0.54 (0.09, 3.45) 0.71 (0.38, 2.46) -0.15 (-0.51, 0.24)

ABA_STD

(IV)+MTX

0.49 (0.08, 3.18) 0.67 (0.36, 2.34) -0.17 (-0.53, 0.21)

ADA_STD+MTX

0.47 (0.08, 2.93) 0.65 (0.36, 2.26) -0.18 (-0.54, 0.19)

ADA_STD

0.04 (0.003, 0.55) 0.08 (0.01, 0.64) -0.47 (-0.82, -0.07)

TOF_STD+MTX

0.69 (0.10, 4.47) 0.82 (0.43, 2.86) -0.09 (-0.47, 0.30)

TOF_STD

0.09 (0.01, 1.33) 0.19 (0.03, 1.22) -0.40 (-0.79, 0.05)

TOC_4 (IV)

0.18 (0.02, 1.37) 0.33 (0.11, 1.27) -0.35 (-0.72, 0.05)

TOC_8 (IV)

0.45 (0.07, 3.04) 0.64 (0.32, 2.24) -0.19 (-0.56, 0.21)

TOC_4 (IV)+MTX

0.32 (0.05, 2.12) 0.50 (0.23, 1.78) -0.26 (-0.63, 0.13)

TOC_8 (IV)+MTX

0.51 (0.08, 3.33) 0.69 (0.36, 2.41) -0.16 (-0.53, 0.23)

GOL_STD (SC)

0.12 (0.01, 1.73) 0.24 (0.03, 1.43) -0.37 (-0.77, 0.10)

GOL_STD

(SC)+MTX

0.70 (0.11, 4.76) 0.83 (0.44, 2.95) -0.09 (-0.46, 0.32)

GOL_STD

(IV)+MTX

0.35 (0.05, 2.45) 0.54 (0.21, 1.91) -0.24 (-0.63, 0.17)

INF_STD+MTX

0.35 (0.05, 2.32) 0.54 (0.27, 1.90) -0.24 (-0.61, 0.15)

CERTO_STD+MTX

0.64 (0.10, 4.16) 0.79 (0.43, 2.74) -0.11 (-0.48, 0.28)

CERTO_STD

0.16 (0.01, 2.06) 0.30 (0.05, 1.60) -0.35 (-0.75, 0.14)

RIT_STD

0.41 (0.04, 3.96) 0.61 (0.17, 2.45) -0.20 (-0.64, 0.29)

RIT_STD+MTX

0.62 (0.07, 6.07) 0.79 (0.25, 2.97) -0.11 (-0.56, 0.39)

53


SAR_200

0.07 (0.004, 1.24) 0.15 (0.02, 1.16) -0.42 (-0.80, 0.04)

BAR_4+MTX

0.65 (0.10, 4.27) 0.80 (0.42, 2.78) -0.11 (-0.48, 0.29)

HD203+MTX

0.96 (0.12, 7.85) 0.98 (0.43, 3.47) -0.01 (-0.44, 0.44)

SB4+MTX

0.63 (0.09, 4.86) 0.79 (0.34, 2.84) -0.11 (-0.52, 0.33)

ANBAI+MTX

1.04 (0.14, 8.92) 1.02 (0.46, 3.60) 0.01 (-0.42, 0.47)

CT-P13+MTX

0.49 (0.07, 3.66) 0.68 (0.29, 2.44) -0.17 (-0.56, 0.26)

SB2+MTX

0.30 (0.04, 2.43) 0.49 (0.18, 1.91) -0.26 (-0.65, 0.17)

SB5+MTX

0.44 (0.06, 3.20) 0.63 (0.25, 2.29) -0.19 (-0.59, 0.23)

ZRC-3197+MTX

0.45 (0.06, 3.70) 0.65 (0.23, 2.43) -0.18 (-0.59, 0.27)

ABP501+MTX

0.42 (0.06, 3.14) 0.62 (0.25, 2.26) -0.20 (-0.60, 0.22)

MTX+SSZ+HCQ SSZ+HCQ 4.23 (1.24, 15.78) 2.39 (1.15, 4.72) 0.32 (0.04, 0.59)

ETN_STD

0.89 (0.37, 2.22) 0.91 (0.47, 1.87) -0.02 (-0.18, 0.13)

ETN_STD+MTX

2.05 (0.97, 4.61) 1.66 (0.98, 3.14) 0.14 (-0.01, 0.29)

ABA_STD

(IV)+MTX

1.87 (0.73, 4.79) 1.57 (0.81, 3.26) 0.12 (-0.07, 0.29)

ADA_STD+MTX

1.81 (0.72, 4.26) 1.53 (0.81, 3.07) 0.12 (-0.07, 0.25)

ADA_STD

0.14 (0.02, 1.18) 0.17 (0.02, 1.14) -0.17 (-0.35, 0.03)

TOF_STD+MTX

2.63 (0.97, 6.79) 1.92 (0.98, 3.95) 0.20 (-0.01, 0.38)

TOF_STD

0.35 (0.05, 2.81) 0.42 (0.06, 2.05) -0.12 (-0.31, 0.20)

TOC_4 (IV)

0.70 (0.19, 2.45) 0.75 (0.26, 2.02) -0.06 (-0.25, 0.15)

TOC_8 (IV)

1.72 (0.63, 4.77) 1.48 (0.73, 3.21) 0.11 (-0.10, 0.30)

TOC_4 (IV)+MTX

1.23 (0.42, 3.35) 1.17 (0.53, 2.55) 0.04 (-0.16, 0.21)

TOC_8 (IV)+MTX

1.95 (0.76, 5.02) 1.61 (0.83, 3.34) 0.13 (-0.06, 0.30)

GOL_STD (SC)

0.48 (0.06, 3.62) 0.54 (0.09, 2.40) -0.10 (-0.30, 0.27)

GOL_STD

(SC)+MTX

2.72 (0.94, 7.56) 1.96 (0.96, 4.12) 0.21 (-0.01, 0.41)

GOL_STD

(IV)+MTX

1.32 (0.39, 4.40) 1.23 (0.49, 2.95) 0.05 (-0.17, 0.29)

54


INF_STD+MTX

1.36 (0.50, 3.57) 1.26 (0.62, 2.68) 0.06 (-0.14, 0.22)

CERTO_STD+MTX

2.47 (0.95, 6.21) 1.86 (0.97, 3.75) 0.19 (-0.01, 0.35)

CERTO_STD

0.61 (0.09, 4.17) 0.67 (0.12, 2.64) -0.07 (-0.27, 0.29)

RIT_STD

1.56 (0.30, 8.32) 1.38 (0.38, 3.91) 0.08 (-0.19, 0.45)

RIT_STD+MTX

2.41 (0.48, 12.39) 1.81 (0.58, 4.51) 0.18 (-0.13, 0.53)

SAR_200

0.28 (0.03, 2.81) 0.34 (0.04, 2.06) -0.14 (-0.32, 0.20)

BAR_4+MTX

2.49 (0.91, 6.65) 1.86 (0.95, 3.85) 0.19 (-0.02, 0.38)

HD203+MTX

3.67 (1.08, 13.20) 2.26 (1.05, 4.72) 0.28 (0.01, 0.55)

SB4+MTX

2.38 (0.79, 7.75) 1.80 (0.85, 3.83) 0.18 (-0.05, 0.44)

ANBAI+MTX

4.00 (1.08, 16.20) 2.37 (1.05, 5.22) 0.30 (0.02, 0.59)

CT-P13+MTX

1.88 (0.56, 6.18) 1.57 (0.66, 3.58) 0.12 (-0.11, 0.37)

SB2+MTX

1.18 (0.32, 4.29) 1.14 (0.41, 2.87) 0.03 (-0.20, 0.28)

SB5+MTX

1.68 (0.47, 5.54) 1.46 (0.57, 3.40) 0.10 (-0.14, 0.34)

ZRC-3197+MTX

1.75 (0.44, 6.89) 1.49 (0.54, 3.67) 0.11 (-0.14, 0.40)

ABP501+MTX

1.62 (0.47, 5.30) 1.42 (0.57, 3.30) 0.09 (-0.14, 0.33)

ETN_STD MTX+SSZ+HCQ 0.21 (0.05, 0.83) 0.38 (0.19, 0.88) -0.34 (-0.62, -0.04)

ETN_STD+MTX

0.49 (0.12, 1.81) 0.68 (0.41, 1.45) -0.17 (-0.46, 0.13)

ABA_STD

(IV)+MTX

0.44 (0.10, 1.68) 0.64 (0.37, 1.41) -0.20 (-0.50, 0.11)

ADA_STD+MTX

0.43 (0.11, 1.51) 0.62 (0.38, 1.33) -0.21 (-0.49, 0.09)

ADA_STD

0.03 (0.003, 0.36) 0.07 (0.01, 0.50) -0.49 (-0.78, -0.16)

TOF_STD+MTX

0.62 (0.15, 2.39) 0.79 (0.45, 1.72) -0.12 (-0.43, 0.20)

TOF_STD

0.08 (0.01, 0.89) 0.17 (0.02, 0.93) -0.43 (-0.74, -0.03)

TOC_4 (IV)

0.17 (0.03, 0.77) 0.31 (0.11, 0.84) -0.37 (-0.67, -0.05)

TOC_8 (IV)

0.41 (0.10, 1.60) 0.61 (0.33, 1.37) -0.21 (-0.51, 0.11)

TOC_4 (IV)+MTX

0.29 (0.06, 1.16) 0.48 (0.24, 1.11) -0.28 (-0.58, 0.03)

TOC_8 (IV)+MTX

0.46 (0.11, 1.73) 0.66 (0.38, 1.43) -0.19 (-0.48, 0.12)

55


GOL_STD (SC)

0.11 (0.01, 1.08) 0.23 (0.03, 1.04) -0.40 (-0.73, 0.02)

GOL_STD

(SC)+MTX

0.64 (0.16, 2.56) 0.80 (0.46, 1.77) -0.11 (-0.41, 0.22)

GOL_STD

(IV)+MTX

0.31 (0.06, 1.42) 0.51 (0.22, 1.25) -0.26 (-0.58, 0.08)

INF_STD+MTX

0.32 (0.08, 1.24) 0.52 (0.28, 1.16) -0.26 (-0.56, 0.05)

CERTO_STD+MTX

0.58 (0.14, 2.17) 0.76 (0.45, 1.63) -0.13 (-0.43, 0.18)

CERTO_STD

0.14 (0.02, 1.28) 0.28 (0.05, 1.16) -0.38 (-0.70, 0.06)

RIT_STD

0.37 (0.05, 2.51) 0.57 (0.17, 1.64) -0.23 (-0.60, 0.22)

RIT_STD+MTX

0.56 (0.09, 3.63) 0.75 (0.26, 1.89) -0.13 (-0.51, 0.30)

SAR_200

0.06 (0.01, 0.86) 0.14 (0.02, 0.92) -0.45 (-0.76, -0.03)

BAR_4+MTX

0.59 (0.14, 2.29) 0.77 (0.44, 1.67) -0.13 (-0.43, 0.19)

HD203+MTX

0.86 (0.17, 4.31) 0.94 (0.44, 2.10) -0.03 (-0.40, 0.34)

SB4+MTX

0.57 (0.12, 2.70) 0.75 (0.35, 1.73) -0.13 (-0.48, 0.23)

ANBAI+MTX

0.94 (0.18, 5.03) 0.97 (0.47, 2.21) -0.02 (-0.38, 0.37)

CT-P13+MTX

0.44 (0.09, 2.04) 0.65 (0.30, 1.55) -0.19 (-0.52, 0.16)

SB2+MTX

0.28 (0.05, 1.37) 0.47 (0.18, 1.22) -0.29 (-0.61, 0.07)

SB5+MTX

0.40 (0.08, 1.82) 0.60 (0.26, 1.45) -0.22 (-0.55, 0.13)

ZRC-3197+MTX

0.41 (0.07, 2.12) 0.62 (0.24, 1.53) -0.20 (-0.55, 0.17)

ABP501+MTX

0.39 (0.08, 1.75) 0.59 (0.26, 1.42) -0.22 (-0.55, 0.13)

ETN_STD+MTX ETN_STD 2.32 (1.39, 4.01) 1.82 (1.25, 2.80) 0.16 (0.07, 0.28)

ABA_STD

(IV)+MTX

2.12 (0.88, 4.70) 1.72 (0.92, 3.17) 0.14 (-0.03, 0.29)

ADA_STD+MTX

2.05 (0.91, 4.19) 1.69 (0.93, 3.01) 0.14 (-0.02, 0.25)

ADA_STD

0.16 (0.02, 1.03) 0.19 (0.03, 1.02) -0.15 (-0.27, 0.01)

TOF_STD+MTX

2.96 (1.19, 6.82) 2.12 (1.12, 3.87) 0.22 (0.04, 0.38)

TOF_STD

0.40 (0.06, 2.46) 0.46 (0.07, 1.86) -0.10 (-0.24, 0.18)

TOC_4 (IV)

0.79 (0.23, 2.47) 0.82 (0.29, 2.02) -0.03 (-0.21, 0.16)

56


TOC_8 (IV)

1.96 (0.79, 4.63) 1.64 (0.85, 3.10) 0.13 (-0.05, 0.29)

TOC_4 (IV)+MTX

1.39 (0.52, 3.30) 1.29 (0.61, 2.51) 0.06 (-0.12, 0.22)

TOC_8 (IV)+MTX

2.22 (0.91, 4.94) 1.78 (0.94, 3.25) 0.16 (-0.02, 0.30)

GOL_STD (SC)

0.54 (0.08, 3.22) 0.60 (0.11, 2.18) -0.08 (-0.22, 0.25)

GOL_STD

(SC)+MTX

3.04 (1.19, 7.65) 2.15 (1.13, 4.04) 0.23 (0.04, 0.42)

GOL_STD

(IV)+MTX

1.50 (0.48, 4.47) 1.36 (0.56, 2.94) 0.07 (-0.12, 0.30)

INF_STD+MTX

1.55 (0.62, 3.53) 1.39 (0.71, 2.65) 0.08 (-0.09, 0.22)

CERTO_STD+MTX

2.77 (1.18, 6.15) 2.04 (1.12, 3.68) 0.21 (0.04, 0.35)

CERTO_STD

0.70 (0.13, 3.47) 0.74 (0.16, 2.27) -0.05 (-0.20, 0.27)

RIT_STD

1.74 (0.37, 8.24) 1.51 (0.44, 3.84) 0.10 (-0.14, 0.45)

RIT_STD+MTX

2.73 (0.59, 12.57) 2.00 (0.66, 4.47) 0.20 (-0.09, 0.54)

SAR_200

0.31 (0.04, 2.56) 0.37 (0.05, 1.88) -0.12 (-0.25, 0.19)

BAR_4+MTX

2.82 (1.13, 6.60) 2.06 (1.08, 3.77) 0.21 (0.03, 0.38)

HD203+MTX

4.15 (1.37, 12.57) 2.48 (1.25, 4.49) 0.30 (0.06, 0.54)

SB4+MTX

2.69 (1.01, 7.42) 1.99 (1.01, 3.60) 0.20 (0.001, 0.44)

ANBAI+MTX

4.52 (1.27, 16.48) 2.61 (1.17, 5.06) 0.33 (0.05, 0.59)

CT-P13+MTX

2.13 (0.70, 6.16) 1.72 (0.77, 3.56) 0.14 (-0.06, 0.37)

SB2+MTX

1.33 (0.39, 4.34) 1.25 (0.47, 2.88) 0.05 (-0.15, 0.29)

SB5+MTX

1.91 (0.57, 5.64) 1.61 (0.65, 3.36) 0.12 (-0.10, 0.35)

ZRC-3197+MTX

1.98 (0.53, 7.04) 1.65 (0.60, 3.71) 0.13 (-0.11, 0.41)

ABP501+MTX

1.86 (0.55, 5.36) 1.57 (0.64, 3.29) 0.11 (-0.10, 0.34)

ABA_STD

(IV)+MTX ETN_STD+MTX 0.91 (0.41, 1.86) 0.94 (0.57, 1.50) -0.02 (-0.21, 0.14)

ADA_STD+MTX

0.88 (0.42, 1.66) 0.92 (0.59, 1.40) -0.03 (-0.21, 0.11)

ADA_STD

0.07 (0.01, 0.46) 0.10 (0.01, 0.59) -0.32 (-0.47, -0.15)

TOF_STD+MTX

1.29 (0.55, 2.64) 1.16 (0.70, 1.80) 0.06 (-0.14, 0.23)

57


TOF_STD

0.17 (0.02, 1.13) 0.25 (0.04, 1.08) -0.26 (-0.43, 0.03)

TOC_4 (IV)

0.34 (0.10, 1.01) 0.45 (0.17, 1.01) -0.20 (-0.39, 0.003)

TOC_8 (IV)

0.84 (0.36, 1.87) 0.89 (0.51, 1.49) -0.04 (-0.23, 0.14)

TOC_4 (IV)+MTX

0.60 (0.24, 1.34) 0.71 (0.37, 1.22) -0.11 (-0.30, 0.06)

TOC_8 (IV)+MTX

0.96 (0.42, 1.97) 0.97 (0.59, 1.55) -0.01 (-0.20, 0.15)

GOL_STD (SC)

0.23 (0.03, 1.55) 0.33 (0.05, 1.28) -0.24 (-0.42, 0.10)

GOL_STD

(SC)+MTX

1.32 (0.54, 3.07) 1.18 (0.69, 1.92) 0.07 (-0.15, 0.27)

GOL_STD

(IV)+MTX

0.65 (0.21, 1.78) 0.75 (0.33, 1.44) -0.09 (-0.31, 0.13)

INF_STD+MTX

0.66 (0.29, 1.40) 0.76 (0.44, 1.25) -0.09 (-0.27, 0.07)

CERTO_STD+MTX

1.20 (0.54, 2.40) 1.12 (0.70, 1.72) 0.04 (-0.15, 0.20)

CERTO_STD

0.30 (0.05, 1.65) 0.41 (0.08, 1.32) -0.21 (-0.40, 0.12)

RIT_STD

0.76 (0.16, 3.43) 0.83 (0.25, 1.91) -0.06 (-0.33, 0.29)

RIT_STD+MTX

1.18 (0.26, 5.23) 1.11 (0.38, 2.22) 0.04 (-0.27, 0.39)

SAR_200

0.14 (0.02, 1.17) 0.20 (0.02, 1.09) -0.28 (-0.44, 0.04)

BAR_4+MTX

1.22 (0.51, 2.62) 1.13 (0.67, 1.78) 0.05 (-0.16, 0.23)

HD203+MTX

1.78 (0.67, 4.62) 1.37 (0.77, 2.05) 0.14 (-0.08, 0.35)

SB4+MTX

1.17 (0.50, 2.69) 1.10 (0.62, 1.65) 0.04 (-0.14, 0.24)

ANBAI+MTX

1.94 (0.56, 6.81) 1.43 (0.70, 2.47) 0.16 (-0.13, 0.44)

CT-P13+MTX

0.92 (0.32, 2.50) 0.95 (0.46, 1.71) -0.02 (-0.25, 0.22)

SB2+MTX

0.57 (0.17, 1.76) 0.68 (0.28, 1.42) -0.12 (-0.33, 0.13)

SB5+MTX

0.82 (0.26, 2.29) 0.88 (0.38, 1.64) -0.04 (-0.28, 0.20)

ZRC-3197+MTX

0.86 (0.24, 2.88) 0.91 (0.35, 1.81) -0.03 (-0.28, 0.25)

ABP501+MTX

0.80 (0.25, 2.17) 0.86 (0.38, 1.60) -0.05 (-0.28, 0.18)

ADA_STD+MTX ABA_STD (IV)+MTX 0.97 (0.52, 1.74) 0.98 (0.66, 1.46) -0.01 (-0.15, 0.12)

ADA_STD

0.07 (0.01, 0.63) 0.11 (0.01, 0.72) -0.30 (-0.43, -0.09)

TOF_STD+MTX

1.39 (0.68, 2.84) 1.22 (0.78, 1.89) 0.08 (-0.09, 0.24)

58


TOF_STD

0.19 (0.02, 1.48) 0.27 (0.04, 1.28) -0.25 (-0.40, 0.09)

TOC_4 (IV)

0.37 (0.12, 1.09) 0.48 (0.19, 1.06) -0.18 (-0.34, 0.02)

TOC_8 (IV)

0.93 (0.44, 1.99) 0.95 (0.57, 1.56) -0.02 (-0.18, 0.16)

TOC_4 (IV)+MTX

0.66 (0.29, 1.43) 0.75 (0.40, 1.27) -0.09 (-0.25, 0.08)

TOC_8 (IV)+MTX

1.05 (0.52, 2.09) 1.03 (0.65, 1.61) 0.01 (-0.15, 0.17)

GOL_STD (SC)

0.25 (0.03, 1.93) 0.34 (0.05, 1.49) -0.22 (-0.39, 0.15)

GOL_STD

(SC)+MTX

1.44 (0.65, 3.23) 1.25 (0.76, 2.00) 0.09 (-0.10, 0.27)

GOL_STD

(IV)+MTX

0.71 (0.25, 1.96) 0.79 (0.36, 1.51) -0.07 (-0.26, 0.16)

INF_STD+MTX

0.73 (0.39, 1.37) 0.80 (0.52, 1.23) -0.07 (-0.20, 0.07)

CERTO_STD+MTX

1.30 (0.66, 2.58) 1.18 (0.78, 1.81) 0.06 (-0.10, 0.22)

CERTO_STD

0.32 (0.05, 2.16) 0.43 (0.08, 1.57) -0.19 (-0.37, 0.18)

RIT_STD

0.83 (0.19, 3.83) 0.89 (0.28, 2.05) -0.04 (-0.29, 0.32)

RIT_STD+MTX

1.28 (0.30, 5.78) 1.16 (0.41, 2.37) 0.06 (-0.23, 0.41)

SAR_200

0.15 (0.02, 1.50) 0.21 (0.02, 1.29) -0.26 (-0.41, 0.09)

BAR_4+MTX

1.33 (0.64, 2.84) 1.19 (0.75, 1.88) 0.07 (-0.10, 0.24)

HD203+MTX

1.95 (0.59, 7.03) 1.46 (0.70, 2.55) 0.16 (-0.12, 0.44)

SB4+MTX

1.27 (0.43, 4.16) 1.16 (0.56, 2.15) 0.06 (-0.18, 0.34)

ANBAI+MTX

2.14 (0.67, 7.29) 1.53 (0.77, 2.57) 0.18 (-0.09, 0.45)

CT-P13+MTX

1.00 (0.40, 2.53) 1.00 (0.52, 1.73) 0.001 (-0.19, 0.22)

SB2+MTX

0.62 (0.22, 1.79) 0.72 (0.32, 1.43) -0.10 (-0.27, 0.14)

SB5+MTX

0.90 (0.30, 2.53) 0.93 (0.42, 1.74) -0.02 (-0.23, 0.22)

ZRC-3197+MTX

0.94 (0.27, 3.20) 0.96 (0.38, 1.92) -0.01 (-0.24, 0.28)

ABP501+MTX

0.87 (0.30, 2.38) 0.91 (0.42, 1.69) -0.03 (-0.24, 0.20)

ADA_STD ADA_STD+MTX 0.08 (0.01, 0.63) 0.11 (0.01, 0.72) -0.30 (-0.39, -0.09)

TOF_STD+MTX

1.45 (0.82, 2.62) 1.26 (0.88, 1.77) 0.09 (-0.04, 0.23)

TOF_STD

0.19 (0.03, 1.52) 0.27 (0.04, 1.31) -0.24 (-0.36, 0.10)

59


TOC_4 (IV)

0.39 (0.14, 1.05) 0.49 (0.20, 1.04) -0.17 (-0.30, 0.01)

TOC_8 (IV)

0.96 (0.49, 1.94) 0.97 (0.61, 1.51) -0.01 (-0.15, 0.15)

TOC_4 (IV)+MTX

0.68 (0.32, 1.39) 0.77 (0.43, 1.24) -0.08 (-0.21, 0.07)

TOC_8 (IV)+MTX

1.09 (0.59, 2.02) 1.06 (0.70, 1.55) 0.02 (-0.11, 0.16)

GOL_STD (SC)

0.26 (0.04, 1.98) 0.35 (0.06, 1.50) -0.22 (-0.35, 0.16)

GOL_STD

(SC)+MTX

1.50 (0.73, 3.12) 1.28 (0.82, 1.91) 0.10 (-0.07, 0.27)

GOL_STD

(IV)+MTX

0.73 (0.28, 1.96) 0.81 (0.38, 1.51) -0.07 (-0.23, 0.16)

INF_STD+MTX

0.75 (0.41, 1.45) 0.82 (0.52, 1.28) -0.06 (-0.18, 0.08)

CERTO_STD+MTX

1.35 (0.83, 2.31) 1.21 (0.89, 1.66) 0.07 (-0.04, 0.20)

CERTO_STD

0.34 (0.05, 2.23) 0.44 (0.08, 1.59) -0.19 (-0.34, 0.19)

RIT_STD

0.86 (0.21, 3.74) 0.91 (0.29, 2.01) -0.03 (-0.26, 0.32)

RIT_STD+MTX

1.34 (0.34, 5.84) 1.20 (0.44, 2.31) 0.07 (-0.20, 0.41)

SAR_200

0.15 (0.02, 1.56) 0.22 (0.03, 1.32) -0.26 (-0.37, 0.10)

BAR_4+MTX

1.38 (0.77, 2.62) 1.22 (0.84, 1.75) 0.07 (-0.06, 0.23)

HD203+MTX

2.02 (0.66, 6.97) 1.49 (0.75, 2.45) 0.17 (-0.09, 0.44)

SB4+MTX

1.31 (0.48, 4.16) 1.18 (0.59, 2.11) 0.06 (-0.15, 0.34)

ANBAI+MTX

2.22 (0.75, 7.30) 1.57 (0.82, 2.49) 0.19 (-0.06, 0.45)

CT-P13+MTX

1.03 (0.43, 2.67) 1.02 (0.54, 1.77) 0.01 (-0.17, 0.23)

SB2+MTX

0.65 (0.23, 1.91) 0.73 (0.32, 1.49) -0.09 (-0.25, 0.15)

SB5+MTX

0.93 (0.39, 2.18) 0.95 (0.49, 1.56) -0.02 (-0.17, 0.19)

ZRC-3197+MTX

0.97 (0.33, 2.85) 0.98 (0.43, 1.76) -0.01 (-0.19, 0.25)

ABP501+MTX

0.90 (0.38, 2.06) 0.93 (0.49, 1.52) -0.02 (-0.17, 0.17)

TOF_STD+MTX ADA_STD 18.71 (2.25, 154.00) 11.02 (1.75, 84.20) 0.38 (0.16, 0.52)

TOF_STD

2.54 (0.78, 8.31) 2.34 (0.80, 7.00) 0.05 (-0.01, 0.26)

TOC_4 (IV)

5.02 (0.49, 46.89) 4.31 (0.56, 35.69) 0.12 (-0.09, 0.30)

TOC_8 (IV)

12.44 (1.47, 103.40) 8.59 (1.33, 65.34) 0.28 (0.07, 0.44)

60


TOC_4 (IV)+MTX

8.79 (1.03, 75.19) 6.72 (1.02, 52.05) 0.21 (0.01, 0.36)

TOC_8 (IV)+MTX

14.07 (1.70, 115.70) 9.30 (1.46, 70.89) 0.31 (0.10, 0.44)

GOL_STD (SC)

3.42 (0.59, 20.51) 3.03 (0.63, 15.58) 0.07 (-0.04, 0.37)

GOL_STD

(SC)+MTX

19.41 (2.20, 161.20) 11.29 (1.73, 86.52) 0.39 (0.16, 0.56)

GOL_STD

(IV)+MTX

9.53 (1.01, 85.72) 7.08 (1.01, 55.94) 0.22 (0.001, 0.44)

INF_STD+MTX

9.87 (1.13, 81.99) 7.32 (1.10, 56.89) 0.23 (0.02, 0.36)

CERTO_STD+MTX

17.42 (2.16, 144.60) 10.62 (1.69, 82.54) 0.36 (0.16, 0.49)

CERTO_STD

4.47 (0.88, 20.15) 3.79 (0.90, 15.58) 0.10 (-0.01, 0.39)

RIT_STD

11.47 (0.94, 136.40) 7.91 (0.95, 69.96) 0.25 (-0.01, 0.60)

RIT_STD+MTX

17.67 (1.50, 201.60) 10.29 (1.35, 84.28) 0.35 (0.06, 0.69)

SAR_200

2.00 (0.82, 4.97) 1.89 (0.83, 4.18) 0.03 (-0.01, 0.23)

BAR_4+MTX

17.75 (2.08, 150.60) 10.75 (1.67, 82.34) 0.37 (0.15, 0.52)

HD203+MTX

26.24 (3.06, 256.80) 12.88 (2.12, 98.57) 0.46 (0.18, 0.72)

SB4+MTX

17.26 (2.11, 146.70) 10.42 (1.69, 76.66) 0.35 (0.12, 0.61)

ANBAI+MTX

29.01 (2.95, 280.00) 13.56 (2.06, 104.20) 0.48 (0.19, 0.74)

CT-P13+MTX

13.70 (1.42, 122.60) 9.05 (1.31, 70.88) 0.30 (0.06, 0.52)

SB2+MTX

8.35 (0.88, 85.50) 6.42 (0.91, 55.78) 0.20 (-0.02, 0.44)

SB5+MTX

11.96 (1.31, 108.70) 8.26 (1.22, 65.37) 0.27 (0.04, 0.50)

ZRC-3197+MTX

12.54 (1.20, 130.40) 8.48 (1.16, 72.55) 0.28 (0.03, 0.56)

ABP501+MTX

11.69 (1.17, 103.70) 8.20 (1.13, 64.55) 0.27 (0.02, 0.49)

TOF_STD TOF_STD+MTX 0.13 (0.02, 1.12) 0.21 (0.03, 1.06) -0.32 (-0.49, 0.03)

TOC_4 (IV)

0.27 (0.09, 0.79) 0.39 (0.15, 0.86) -0.26 (-0.43, -0.05)

TOC_8 (IV)

0.66 (0.30, 1.48) 0.78 (0.47, 1.27) -0.09 (-0.27, 0.09)

TOC_4 (IV)+MTX

0.47 (0.20, 1.06) 0.61 (0.33, 1.04) -0.17 (-0.34, 0.01)

TOC_8 (IV)+MTX

0.75 (0.36, 1.57) 0.84 (0.53, 1.32) -0.07 (-0.24, 0.11)

GOL_STD (SC)

0.18 (0.02, 1.43) 0.28 (0.04, 1.22) -0.30 (-0.48, 0.09)

61


GOL_STD

(SC)+MTX

1.03 (0.46, 2.40) 1.02 (0.63, 1.62) 0.01 (-0.19, 0.21)

GOL_STD

(IV)+MTX

0.50 (0.18, 1.45) 0.64 (0.30, 1.25) -0.15 (-0.35, 0.09)

INF_STD+MTX

0.52 (0.25, 1.08) 0.66 (0.40, 1.05) -0.15 (-0.31, 0.02)

CERTO_STD+MTX

0.93 (0.48, 1.88) 0.96 (0.66, 1.45) -0.02 (-0.18, 0.15)

CERTO_STD

0.23 (0.04, 1.63) 0.35 (0.06, 1.31) -0.27 (-0.46, 0.12)

RIT_STD

0.60 (0.14, 2.71) 0.72 (0.23, 1.64) -0.12 (-0.37, 0.24)

RIT_STD+MTX

0.92 (0.22, 4.27) 0.95 (0.34, 1.91) -0.02 (-0.31, 0.34)

SAR_200

0.11 (0.01, 1.10) 0.17 (0.02, 1.06) -0.34 (-0.50, 0.02)

BAR_4+MTX

0.95 (0.45, 2.08) 0.97 (0.63, 1.51) -0.01 (-0.19, 0.18)

HD203+MTX

1.40 (0.42, 5.09) 1.19 (0.59, 2.05) 0.08 (-0.20, 0.37)

SB4+MTX

0.91 (0.30, 3.04) 0.95 (0.46, 1.74) -0.02 (-0.26, 0.27)

ANBAI+MTX

1.53 (0.48, 5.38) 1.25 (0.64, 2.09) 0.10 (-0.17, 0.39)

CT-P13+MTX

0.71 (0.27, 1.97) 0.81 (0.42, 1.46) -0.08 (-0.29, 0.16)

SB2+MTX

0.45 (0.15, 1.40) 0.59 (0.25, 1.22) -0.17 (-0.37, 0.08)

SB5+MTX

0.65 (0.22, 1.80) 0.76 (0.36, 1.39) -0.10 (-0.31, 0.14)

ZRC-3197+MTX

0.67 (0.20, 2.30) 0.78 (0.32, 1.53) -0.09 (-0.33, 0.20)

ABP501+MTX

0.62 (0.22, 1.69) 0.74 (0.35, 1.35) -0.11 (-0.31, 0.13)

TOC_4 (IV) TOF_STD 1.95 (0.20, 18.01) 1.79 (0.29, 13.79) 0.07 (-0.28, 0.27)

TOC_8 (IV)

4.89 (0.60, 38.09) 3.58 (0.72, 24.41) 0.23 (-0.12, 0.41)

TOC_4 (IV)+MTX

3.47 (0.43, 28.18) 2.81 (0.56, 19.76) 0.16 (-0.17, 0.33)

TOC_8 (IV)+MTX

5.56 (0.69, 44.03) 3.91 (0.79, 26.87) 0.26 (-0.09, 0.42)

GOL_STD (SC)

1.35 (0.23, 7.95) 1.29 (0.29, 6.15) 0.02 (-0.20, 0.28)

GOL_STD

(SC)+MTX

7.76 (0.90, 60.97) 4.75 (0.94, 32.46) 0.33 (-0.02, 0.53)

GOL_STD

(IV)+MTX

3.80 (0.41, 33.29) 2.98 (0.55, 21.86) 0.17 (-0.18, 0.41)

INF_STD+MTX

3.86 (0.47, 31.37) 3.04 (0.61, 21.51) 0.18 (-0.16, 0.33)

62


CERTO_STD+MTX

6.92 (0.89, 52.87) 4.46 (0.93, 30.08) 0.31 (-0.03, 0.46)

CERTO_STD

1.76 (0.35, 8.02) 1.61 (0.43, 6.26) 0.05 (-0.15, 0.29)

RIT_STD

4.44 (0.38, 50.30) 3.26 (0.50, 25.84) 0.20 (-0.17, 0.56)

RIT_STD+MTX

6.88 (0.58, 73.93) 4.30 (0.70, 31.54) 0.29 (-0.10, 0.65)

SAR_200

0.78 (0.18, 3.44) 0.81 (0.21, 2.87) -0.01 (-0.19, 0.16)

BAR_4+MTX

7.07 (0.84, 56.01) 4.50 (0.91, 30.95) 0.31 (-0.04, 0.49)

HD203+MTX

10.41 (1.27, 91.95) 5.42 (1.15, 36.74) 0.39 (0.05, 0.68)

SB4+MTX

6.82 (0.85, 57.81) 4.32 (0.90, 29.50) 0.29 (-0.03, 0.56)

ANBAI+MTX

11.52 (1.19, 104.40) 5.73 (1.11, 39.44) 0.42 (0.04, 0.70)

CT-P13+MTX

5.30 (0.60, 47.67) 3.75 (0.72, 27.30) 0.24 (-0.11, 0.48)

SB2+MTX

3.29 (0.36, 32.09) 2.68 (0.48, 21.26) 0.15 (-0.20, 0.40)

SB5+MTX

4.74 (0.53, 42.14) 3.47 (0.66, 25.19) 0.22 (-0.13, 0.46)

ZRC-3197+MTX

4.97 (0.48, 48.11) 3.54 (0.61, 26.76) 0.23 (-0.14, 0.52)

ABP501+MTX

4.60 (0.49, 39.59) 3.40 (0.61, 24.36) 0.21 (-0.15, 0.45)

TOC_8 (IV) TOC_4 (IV) 2.49 (0.95, 6.80) 1.98 (0.97, 4.67) 0.16 (-0.01, 0.31)

TOC_4 (IV)+MTX

1.76 (0.64, 4.84) 1.55 (0.72, 3.68) 0.09 (-0.08, 0.24)

TOC_8 (IV)+MTX

2.79 (1.10, 7.39) 2.13 (1.06, 4.97) 0.19 (0.02, 0.32)

GOL_STD (SC)

0.68 (0.08, 6.49) 0.72 (0.10, 3.91) -0.04 (-0.25, 0.34)

GOL_STD

(SC)+MTX

3.87 (1.24, 12.57) 2.60 (1.15, 6.68) 0.26 (0.05, 0.46)

GOL_STD

(IV)+MTX

1.90 (0.50, 7.46) 1.64 (0.59, 4.80) 0.10 (-0.12, 0.34)

INF_STD+MTX

1.94 (0.67, 6.09) 1.67 (0.74, 4.40) 0.11 (-0.08, 0.27)

CERTO_STD+MTX

3.49 (1.25, 10.72) 2.46 (1.16, 6.27) 0.24 (0.05, 0.40)

CERTO_STD

0.89 (0.11, 7.18) 0.91 (0.14, 4.27) -0.01 (-0.24, 0.37)

RIT_STD

2.25 (0.41, 12.62) 1.83 (0.49, 5.94) 0.14 (-0.13, 0.49)

RIT_STD+MTX

3.46 (0.65, 19.65) 2.40 (0.72, 7.28) 0.24 (-0.07, 0.59)

SAR_200

0.40 (0.04, 4.92) 0.45 (0.05, 3.29) -0.08 (-0.28, 0.27)

63


BAR_4+MTX

3.58 (1.18, 11.54) 2.48 (1.11, 6.41) 0.25 (0.04, 0.43)

HD203+MTX

5.28 (1.23, 24.72) 3.02 (1.15, 8.56) 0.34 (0.04, 0.63)

SB4+MTX

3.43 (0.88, 15.10) 2.40 (0.91, 6.89) 0.23 (-0.02, 0.52)

ANBAI+MTX

5.78 (1.41, 26.56) 3.14 (1.25, 8.59) 0.36 (0.07, 0.64)

CT-P13+MTX

2.69 (0.76, 10.22) 2.08 (0.82, 5.81) 0.18 (-0.05, 0.41)

SB2+MTX

1.66 (0.44, 7.10) 1.49 (0.53, 4.63) 0.08 (-0.14, 0.33)

SB5+MTX

2.38 (0.64, 9.10) 1.92 (0.72, 5.39) 0.15 (-0.08, 0.39)

ZRC-3197+MTX

2.49 (0.58, 11.80) 1.97 (0.65, 5.92) 0.16 (-0.09, 0.46)

ABP501+MTX

2.32 (0.61, 8.69) 1.88 (0.70, 5.30) 0.15 (-0.09, 0.38)

TOC_4 (IV)+MTX TOC_8 (IV) 0.71 (0.34, 1.41) 0.79 (0.46, 1.27) -0.07 (-0.22, 0.07)

TOC_8 (IV)+MTX

1.13 (0.68, 1.84) 1.08 (0.78, 1.51) 0.03 (-0.09, 0.13)

GOL_STD (SC)

0.28 (0.04, 2.16) 0.36 (0.06, 1.60) -0.20 (-0.40, 0.17)

GOL_STD

(SC)+MTX

1.55 (0.67, 3.68) 1.31 (0.78, 2.23) 0.10 (-0.10, 0.30)

GOL_STD

(IV)+MTX

0.77 (0.25, 2.25) 0.83 (0.37, 1.68) -0.06 (-0.26, 0.18)

INF_STD+MTX

0.78 (0.35, 1.75) 0.85 (0.49, 1.48) -0.05 (-0.22, 0.11)

CERTO_STD+MTX

1.41 (0.67, 3.01) 1.24 (0.79, 2.04) 0.08 (-0.09, 0.25)

CERTO_STD

0.35 (0.05, 2.35) 0.45 (0.08, 1.67) -0.18 (-0.38, 0.20)

RIT_STD

0.90 (0.20, 4.13) 0.93 (0.29, 2.21) -0.02 (-0.28, 0.33)

RIT_STD+MTX

1.39 (0.31, 6.46) 1.23 (0.42, 2.59) 0.08 (-0.22, 0.43)

SAR_200

0.16 (0.02, 1.62) 0.22 (0.03, 1.37) -0.24 (-0.42, 0.11)

BAR_4+MTX

1.44 (0.63, 3.26) 1.25 (0.76, 2.10) 0.08 (-0.11, 0.27)

HD203+MTX

2.11 (0.62, 7.58) 1.53 (0.73, 2.82) 0.18 (-0.11, 0.46)

SB4+MTX

1.38 (0.44, 4.66) 1.22 (0.57, 2.37) 0.07 (-0.17, 0.36)

ANBAI+MTX

2.32 (0.71, 8.18) 1.60 (0.80, 2.85) 0.20 (-0.08, 0.48)

CT-P13+MTX

1.08 (0.38, 3.09) 1.05 (0.52, 2.01) 0.02 (-0.20, 0.26)

SB2+MTX

0.68 (0.22, 2.22) 0.76 (0.31, 1.66) -0.08 (-0.28, 0.18)

64


SB5+MTX

0.97 (0.32, 2.84) 0.98 (0.44, 1.91) -0.01 (-0.23, 0.24)

ZRC-3197+MTX

1.01 (0.28, 3.48) 1.01 (0.39, 2.09) 0.002 (-0.24, 0.29)

ABP501+MTX

0.94 (0.31, 2.70) 0.96 (0.43, 1.87) -0.01 (-0.23, 0.22)

TOC_8 (IV)+MTX TOC_4 (IV)+MTX 1.59 (0.87, 3.03) 1.38 (0.91, 2.23) 0.10 (-0.03, 0.22)

GOL_STD (SC)

0.39 (0.05, 3.11) 0.47 (0.07, 2.08) -0.13 (-0.32, 0.25)

GOL_STD

(SC)+MTX

2.21 (0.91, 5.59) 1.68 (0.94, 3.10) 0.18 (-0.02, 0.37)

GOL_STD

(IV)+MTX

1.08 (0.36, 3.30) 1.06 (0.46, 2.30) 0.01 (-0.18, 0.25)

INF_STD+MTX

1.11 (0.49, 2.58) 1.08 (0.60, 2.02) 0.02 (-0.14, 0.18)

CERTO_STD+MTX

1.99 (0.92, 4.46) 1.58 (0.95, 2.84) 0.15 (-0.02, 0.31)

CERTO_STD

0.50 (0.07, 3.47) 0.58 (0.10, 2.21) -0.11 (-0.30, 0.27)

RIT_STD

1.26 (0.28, 6.07) 1.18 (0.36, 2.98) 0.05 (-0.20, 0.40)

RIT_STD+MTX

1.97 (0.45, 9.52) 1.56 (0.54, 3.55) 0.15 (-0.15, 0.50)

SAR_200

0.23 (0.02, 2.34) 0.29 (0.03, 1.77) -0.18 (-0.34, 0.17)

BAR_4+MTX

2.02 (0.89, 4.85) 1.59 (0.93, 2.94) 0.15 (-0.03, 0.34)

HD203+MTX

2.96 (0.86, 11.54) 1.95 (0.90, 3.94) 0.25 (-0.03, 0.54)

SB4+MTX

1.94 (0.63, 6.90) 1.55 (0.72, 3.28) 0.14 (-0.09, 0.43)

ANBAI+MTX

3.26 (1.00, 12.30) 2.03 (1.00, 4.00) 0.27 (-0.001, 0.55)

CT-P13+MTX

1.53 (0.53, 4.57) 1.34 (0.64, 2.73) 0.09 (-0.12, 0.33)

SB2+MTX

0.95 (0.30, 3.32) 0.97 (0.39, 2.28) -0.01 (-0.21, 0.25)

SB5+MTX

1.36 (0.45, 4.20) 1.24 (0.55, 2.62) 0.06 (-0.15, 0.31)

ZRC-3197+MTX

1.42 (0.39, 5.21) 1.28 (0.49, 2.87) 0.07 (-0.16, 0.37)

ABP501+MTX

1.32 (0.43, 3.98) 1.22 (0.53, 2.56) 0.06 (-0.15, 0.29)

GOL_STD (SC) TOC_8 (IV)+MTX 0.24 (0.03, 1.86) 0.34 (0.05, 1.45) -0.23 (-0.41, 0.15)

GOL_STD

(SC)+MTX

1.38 (0.62, 3.13) 1.21 (0.74, 1.95) 0.08 (-0.11, 0.27)

GOL_STD

(IV)+MTX

0.68 (0.24, 1.92) 0.77 (0.35, 1.50) -0.08 (-0.27, 0.15)

65


INF_STD+MTX

0.69 (0.33, 1.46) 0.78 (0.47, 1.29) -0.08 (-0.24, 0.08)

CERTO_STD+MTX

1.24 (0.64, 2.51) 1.14 (0.77, 1.78) 0.05 (-0.10, 0.21)

CERTO_STD

0.31 (0.05, 2.10) 0.42 (0.08, 1.54) -0.20 (-0.39, 0.18)

RIT_STD

0.80 (0.18, 3.56) 0.86 (0.27, 1.96) -0.05 (-0.29, 0.30)

RIT_STD+MTX

1.23 (0.29, 5.65) 1.14 (0.41, 2.30) 0.05 (-0.24, 0.40)

SAR_200

0.14 (0.01, 1.39) 0.21 (0.02, 1.24) -0.27 (-0.43, 0.08)

BAR_4+MTX

1.27 (0.61, 2.75) 1.16 (0.73, 1.84) 0.06 (-0.12, 0.24)

HD203+MTX

1.86 (0.57, 6.74) 1.41 (0.69, 2.47) 0.15 (-0.13, 0.44)

SB4+MTX

1.22 (0.41, 4.06) 1.13 (0.55, 2.13) 0.05 (-0.19, 0.33)

ANBAI+MTX

2.06 (0.65, 7.08) 1.49 (0.75, 2.53) 0.17 (-0.10, 0.45)

CT-P13+MTX

0.96 (0.36, 2.63) 0.97 (0.50, 1.77) -0.01 (-0.21, 0.23)

SB2+MTX

0.60 (0.20, 1.90) 0.70 (0.30, 1.48) -0.11 (-0.29, 0.15)

SB5+MTX

0.86 (0.29, 2.44) 0.91 (0.41, 1.69) -0.03 (-0.24, 0.21)

ZRC-3197+MTX

0.89 (0.26, 3.04) 0.93 (0.37, 1.87) -0.03 (-0.26, 0.26)

ABP501+MTX

0.83 (0.29, 2.28) 0.89 (0.41, 1.65) -0.04 (-0.25, 0.19)

GOL_STD

(SC)+MTX GOL_STD (SC) 5.79 (0.67, 42.95) 3.65 (0.80, 22.97) 0.31 (-0.09, 0.51)

GOL_STD

(IV)+MTX

2.79 (0.32, 23.37) 2.27 (0.47, 15.52) 0.14 (-0.24, 0.39)

INF_STD+MTX

2.87 (0.37, 21.93) 2.34 (0.53, 15.27) 0.16 (-0.23, 0.32)

CERTO_STD+MTX

5.15 (0.67, 37.46) 3.42 (0.80, 21.52) 0.28 (-0.09, 0.45)

CERTO_STD

1.29 (0.29, 5.86) 1.24 (0.36, 4.58) 0.02 (-0.19, 0.26)

RIT_STD

3.30 (0.28, 35.10) 2.52 (0.41, 18.20) 0.17 (-0.24, 0.54)

RIT_STD+MTX

5.12 (0.46, 52.66) 3.30 (0.60, 22.22) 0.27 (-0.16, 0.64)

SAR_200

0.59 (0.08, 4.13) 0.63 (0.10, 3.26) -0.03 (-0.31, 0.19)

BAR_4+MTX

5.27 (0.67, 38.87) 3.47 (0.80, 21.76) 0.29 (-0.09, 0.48)

HD203+MTX

7.67 (0.94, 64.44) 4.15 (0.97, 25.73) 0.37 (-0.01, 0.66)

SB4+MTX

4.99 (0.65, 40.84) 3.31 (0.77, 20.61) 0.27 (-0.09, 0.55)

66


ANBAI+MTX

8.52 (0.95, 73.34) 4.36 (0.97, 27.23) 0.39 (-0.01, 0.68)

CT-P13+MTX

3.94 (0.46, 34.22) 2.86 (0.61, 19.82) 0.22 (-0.17, 0.47)

SB2+MTX

2.46 (0.27, 22.20) 2.08 (0.40, 14.72) 0.12 (-0.27, 0.38)

SB5+MTX

3.54 (0.40, 29.04) 2.68 (0.55, 17.32) 0.19 (-0.20, 0.45)

ZRC-3197+MTX

3.71 (0.37, 34.56) 2.74 (0.52, 18.97) 0.20 (-0.20, 0.51)

ABP501+MTX

3.42 (0.37, 27.40) 2.62 (0.52, 17.23) 0.19 (-0.21, 0.43)

GOL_STD

(IV)+MTX GOL_STD (SC)+MTX 0.49 (0.16, 1.47) 0.63 (0.28, 1.26) -0.16 (-0.38, 0.09)

INF_STD+MTX

0.50 (0.22, 1.14) 0.65 (0.38, 1.09) -0.15 (-0.34, 0.03)

CERTO_STD+MTX

0.91 (0.41, 1.96) 0.95 (0.61, 1.50) -0.02 (-0.22, 0.16)

CERTO_STD

0.22 (0.03, 1.62) 0.34 (0.06, 1.31) -0.28 (-0.49, 0.12)

RIT_STD

0.57 (0.12, 2.71) 0.71 (0.22, 1.65) -0.13 (-0.40, 0.24)

RIT_STD+MTX

0.89 (0.19, 4.22) 0.94 (0.33, 1.93) -0.03 (-0.34, 0.34)

SAR_200

0.10 (0.01, 1.08) 0.17 (0.02, 1.04) -0.35 (-0.54, 0.02)

BAR_4+MTX

0.92 (0.40, 2.17) 0.95 (0.59, 1.57) -0.02 (-0.22, 0.19)

HD203+MTX

1.35 (0.39, 5.07) 1.17 (0.57, 2.11) 0.07 (-0.22, 0.38)

SB4+MTX

0.88 (0.27, 3.08) 0.93 (0.44, 1.77) -0.03 (-0.29, 0.27)

ANBAI+MTX

1.49 (0.43, 5.36) 1.22 (0.62, 2.13) 0.10 (-0.20, 0.38)

CT-P13+MTX

0.70 (0.24, 1.99) 0.80 (0.40, 1.47) -0.08 (-0.32, 0.17)

SB2+MTX

0.44 (0.13, 1.41) 0.58 (0.24, 1.23) -0.18 (-0.40, 0.08)

SB5+MTX

0.62 (0.20, 1.86) 0.75 (0.33, 1.41) -0.11 (-0.35, 0.15)

ZRC-3197+MTX

0.65 (0.18, 2.39) 0.77 (0.30, 1.58) -0.10 (-0.36, 0.21)

ABP501+MTX

0.60 (0.20, 1.75) 0.73 (0.34, 1.38) -0.12 (-0.35, 0.13)

INF_STD+MTX GOL_STD (IV)+MTX 1.03 (0.37, 2.96) 1.02 (0.51, 2.30) 0.01 (-0.22, 0.20)

CERTO_STD+MTX

1.84 (0.68, 5.14) 1.49 (0.80, 3.26) 0.13 (-0.09, 0.32)

CERTO_STD

0.46 (0.06, 3.49) 0.55 (0.09, 2.31) -0.12 (-0.37, 0.26)

RIT_STD

1.18 (0.23, 6.28) 1.12 (0.32, 3.21) 0.03 (-0.27, 0.40)

67


RIT_STD+MTX

1.82 (0.36, 9.70) 1.48 (0.48, 3.85) 0.13 (-0.20, 0.50)

SAR_200

0.21 (0.02, 2.32) 0.27 (0.03, 1.79) -0.19 (-0.41, 0.17)

BAR_4+MTX

1.87 (0.65, 5.49) 1.50 (0.77, 3.33) 0.14 (-0.10, 0.34)

HD203+MTX

2.72 (0.70, 12.55) 1.83 (0.79, 4.37) 0.23 (-0.08, 0.54)

SB4+MTX

1.80 (0.49, 7.46) 1.46 (0.62, 3.63) 0.13 (-0.15, 0.43)

ANBAI+MTX

3.04 (0.76, 12.89) 1.92 (0.85, 4.46) 0.25 (-0.06, 0.55)

CT-P13+MTX

1.41 (0.41, 5.00) 1.26 (0.55, 3.06) 0.07 (-0.19, 0.33)

SB2+MTX

0.88 (0.23, 3.48) 0.91 (0.34, 2.42) -0.02 (-0.27, 0.24)

SB5+MTX

1.28 (0.35, 4.53) 1.19 (0.47, 2.86) 0.05 (-0.22, 0.31)

ZRC-3197+MTX

1.32 (0.32, 5.40) 1.21 (0.44, 3.10) 0.06 (-0.23, 0.36)

ABP501+MTX

1.22 (0.33, 4.43) 1.15 (0.47, 2.83) 0.04 (-0.23, 0.30)

CERTO_STD+MTX INF_STD+MTX 1.79 (0.89, 3.62) 1.47 (0.93, 2.36) 0.13 (-0.03, 0.28)

CERTO_STD

0.45 (0.07, 3.06) 0.53 (0.10, 2.02) -0.13 (-0.31, 0.26)

RIT_STD

1.14 (0.26, 5.18) 1.10 (0.33, 2.61) 0.03 (-0.22, 0.38)

RIT_STD+MTX

1.77 (0.41, 7.89) 1.45 (0.51, 3.01) 0.13 (-0.16, 0.47)

SAR_200

0.21 (0.02, 2.10) 0.27 (0.03, 1.63) -0.20 (-0.34, 0.16)

BAR_4+MTX

1.83 (0.84, 4.00) 1.48 (0.90, 2.46) 0.13 (-0.04, 0.31)

HD203+MTX

2.69 (0.80, 9.78) 1.81 (0.86, 3.32) 0.23 (-0.05, 0.51)

SB4+MTX

1.74 (0.59, 5.76) 1.44 (0.68, 2.78) 0.12 (-0.11, 0.40)

ANBAI+MTX

2.95 (0.90, 10.02) 1.90 (0.93, 3.34) 0.25 (-0.02, 0.51)

CT-P13+MTX

1.38 (0.71, 2.77) 1.24 (0.77, 1.89) 0.07 (-0.07, 0.24)

SB2+MTX

0.86 (0.38, 2.03) 0.90 (0.46, 1.56) -0.03 (-0.16, 0.16)

SB5+MTX

1.23 (0.42, 3.59) 1.16 (0.52, 2.28) 0.04 (-0.16, 0.29)

ZRC-3197+MTX

1.29 (0.36, 4.44) 1.19 (0.46, 2.49) 0.05 (-0.18, 0.34)

ABP501+MTX

1.19 (0.41, 3.37) 1.13 (0.51, 2.19) 0.04 (-0.17, 0.27)

CERTO_STD CERTO_STD+MTX 0.25 (0.04, 1.67) 0.36 (0.07, 1.33) -0.26 (-0.44, 0.13)

RIT_STD

0.63 (0.15, 2.86) 0.75 (0.24, 1.70) -0.10 (-0.34, 0.26)

68


RIT_STD+MTX

0.98 (0.23, 4.52) 0.99 (0.36, 1.97) -0.004 (-0.29, 0.35)

SAR_200

0.12 (0.01, 1.14) 0.18 (0.02, 1.08) -0.33 (-0.48, 0.03)

BAR_4+MTX

1.02 (0.50, 2.08) 1.01 (0.66, 1.52) 0.004 (-0.16, 0.18)

HD203+MTX

1.49 (0.46, 5.30) 1.24 (0.61, 2.09) 0.10 (-0.18, 0.38)

SB4+MTX

0.97 (0.34, 3.15) 0.98 (0.49, 1.77) -0.01 (-0.23, 0.28)

ANBAI+MTX

1.64 (0.52, 5.54) 1.30 (0.67, 2.12) 0.12 (-0.15, 0.39)

CT-P13+MTX

0.77 (0.29, 2.05) 0.85 (0.44, 1.49) -0.06 (-0.26, 0.17)

SB2+MTX

0.48 (0.16, 1.47) 0.61 (0.26, 1.26) -0.16 (-0.35, 0.09)

SB5+MTX

0.69 (0.24, 1.84) 0.79 (0.37, 1.41) -0.09 (-0.29, 0.15)

ZRC-3197+MTX

0.72 (0.22, 2.30) 0.82 (0.33, 1.55) -0.08 (-0.30, 0.20)

ABP501+MTX

0.67 (0.24, 1.74) 0.78 (0.37, 1.37) -0.09 (-0.29, 0.13)

RIT_STD CERTO_STD 2.57 (0.25, 25.44) 2.03 (0.38, 12.78) 0.15 (-0.26, 0.52)

RIT_STD+MTX

3.95 (0.41, 37.57) 2.67 (0.55, 15.96) 0.24 (-0.18, 0.61)

SAR_200

0.45 (0.08, 2.84) 0.51 (0.10, 2.30) -0.06 (-0.32, 0.15)

BAR_4+MTX

4.09 (0.60, 26.98) 2.79 (0.75, 15.33) 0.26 (-0.12, 0.46)

HD203+MTX

5.94 (0.83, 46.10) 3.33 (0.90, 18.07) 0.34 (-0.04, 0.64)

SB4+MTX

3.89 (0.57, 28.51) 2.65 (0.73, 14.79) 0.24 (-0.13, 0.52)

ANBAI+MTX

6.62 (0.80, 50.21) 3.51 (0.89, 18.98) 0.37 (-0.05, 0.66)

CT-P13+MTX

3.07 (0.41, 23.44) 2.32 (0.57, 13.42) 0.19 (-0.20, 0.45)

SB2+MTX

1.91 (0.24, 14.92) 1.67 (0.37, 10.16) 0.09 (-0.28, 0.37)

SB5+MTX

2.73 (0.35, 19.86) 2.14 (0.51, 11.95) 0.16 (-0.23, 0.43)

ZRC-3197+MTX

2.81 (0.33, 24.23) 2.17 (0.48, 13.41) 0.17 (-0.23, 0.49)

ABP501+MTX

2.66 (0.33, 19.10) 2.11 (0.48, 11.86) 0.16 (-0.24, 0.41)

RIT_STD+MTX RIT_STD 1.55 (0.46, 5.11) 1.30 (0.61, 3.01) 0.09 (-0.17, 0.35)

SAR_200

0.18 (0.01, 2.49) 0.25 (0.02, 1.91) -0.21 (-0.57, 0.17)

BAR_4+MTX

1.61 (0.35, 7.25) 1.35 (0.59, 4.34) 0.11 (-0.25, 0.37)

HD203+MTX

2.33 (0.40, 15.10) 1.63 (0.61, 5.55) 0.19 (-0.22, 0.56)

69


SB4+MTX

1.52 (0.28, 9.16) 1.30 (0.49, 4.61) 0.09 (-0.29, 0.44)

ANBAI+MTX

2.57 (0.46, 15.20) 1.71 (0.67, 5.59) 0.22 (-0.18, 0.56)

CT-P13+MTX

1.21 (0.24, 6.21) 1.13 (0.43, 3.87) 0.04 (-0.33, 0.35)

SB2+MTX

0.76 (0.14, 4.22) 0.82 (0.27, 3.00) -0.05 (-0.42, 0.26)

SB5+MTX

1.08 (0.20, 5.54) 1.05 (0.37, 3.53) 0.02 (-0.36, 0.32)

ZRC-3197+MTX

1.13 (0.18, 6.73) 1.08 (0.34, 3.90) 0.03 (-0.38, 0.38)

ABP501+MTX

1.04 (0.19, 5.28) 1.03 (0.36, 3.46) 0.01 (-0.36, 0.31)

SAR_200 RIT_STD+MTX 0.11 (0.01, 1.60) 0.19 (0.02, 1.36) -0.31 (-0.67, 0.09)

BAR_4+MTX

1.03 (0.23, 4.56) 1.02 (0.51, 2.89) 0.01 (-0.34, 0.31)

HD203+MTX

1.51 (0.26, 9.42) 1.24 (0.51, 3.75) 0.10 (-0.31, 0.49)

SB4+MTX

0.98 (0.18, 5.71) 0.99 (0.41, 3.03) -0.005 (-0.39, 0.37)

ANBAI+MTX

1.67 (0.29, 9.85) 1.30 (0.56, 3.78) 0.12 (-0.29, 0.50)

CT-P13+MTX

0.78 (0.15, 3.97) 0.86 (0.36, 2.61) -0.06 (-0.42, 0.29)

SB2+MTX

0.49 (0.09, 2.69) 0.62 (0.22, 2.00) -0.15 (-0.52, 0.19)

SB5+MTX

0.70 (0.13, 3.47) 0.80 (0.32, 2.41) -0.08 (-0.45, 0.25)

ZRC-3197+MTX

0.73 (0.12, 4.34) 0.82 (0.28, 2.66) -0.07 (-0.47, 0.31)

ABP501+MTX

0.67 (0.12, 3.39) 0.78 (0.30, 2.31) -0.09 (-0.47, 0.24)

BAR_4+MTX SAR_200 8.92 (0.85, 86.82) 5.57 (0.90, 48.46) 0.33 (-0.04, 0.50)

HD203+MTX

13.10 (1.29, 143.90) 6.62 (1.15, 58.29) 0.41 (0.06, 0.69)

SB4+MTX

8.60 (0.85, 87.15) 5.34 (0.91, 45.49) 0.31 (-0.03, 0.58)

ANBAI+MTX

14.55 (1.26, 168.30) 7.07 (1.13, 63.49) 0.43 (0.05, 0.71)

CT-P13+MTX

6.70 (0.60, 74.15) 4.67 (0.73, 42.16) 0.26 (-0.11, 0.49)

SB2+MTX

4.20 (0.37, 50.38) 3.34 (0.49, 32.55) 0.16 (-0.19, 0.41)

SB5+MTX

6.00 (0.54, 63.58) 4.30 (0.65, 39.11) 0.23 (-0.13, 0.48)

ZRC-3197+MTX

6.22 (0.49, 75.25) 4.39 (0.62, 41.62) 0.24 (-0.14, 0.53)

ABP501+MTX

5.86 (0.50, 62.79) 4.23 (0.63, 38.28) 0.23 (-0.14, 0.46)

HD203+MTX BAR_4+MTX 1.46 (0.43, 5.28) 1.23 (0.59, 2.15) 0.09 (-0.19, 0.38)

70


SB4+MTX

0.96 (0.31, 3.19) 0.98 (0.47, 1.82) -0.01 (-0.26, 0.28)

ANBAI+MTX

1.61 (0.49, 5.52) 1.28 (0.65, 2.17) 0.12 (-0.17, 0.39)

CT-P13+MTX

0.75 (0.27, 2.14) 0.84 (0.42, 1.54) -0.07 (-0.28, 0.18)

SB2+MTX

0.47 (0.15, 1.50) 0.61 (0.25, 1.27) -0.16 (-0.37, 0.09)

SB5+MTX

0.68 (0.23, 1.91) 0.79 (0.36, 1.44) -0.09 (-0.31, 0.15)

ZRC-3197+MTX

0.71 (0.20, 2.34) 0.81 (0.33, 1.59) -0.08 (-0.32, 0.21)

ABP501+MTX

0.65 (0.22, 1.79) 0.77 (0.36, 1.41) -0.10 (-0.31, 0.14)

SB4+MTX HD203+MTX 0.65 (0.18, 2.36) 0.80 (0.40, 1.62) -0.10 (-0.39, 0.20)

ANBAI+MTX

1.10 (0.23, 5.16) 1.05 (0.49, 2.23) 0.02 (-0.34, 0.38)

CT-P13+MTX

0.52 (0.12, 2.06) 0.69 (0.32, 1.56) -0.16 (-0.47, 0.17)

SB2+MTX

0.32 (0.07, 1.42) 0.50 (0.19, 1.24) -0.25 (-0.57, 0.08)

SB5+MTX

0.47 (0.10, 1.84) 0.65 (0.27, 1.45) -0.18 (-0.50, 0.14)

ZRC-3197+MTX

0.48 (0.10, 2.16) 0.66 (0.25, 1.55) -0.17 (-0.51, 0.18)

ABP501+MTX

0.44 (0.10, 1.74) 0.63 (0.27, 1.41) -0.19 (-0.51, 0.13)

ANBAI+MTX SB4+MTX 1.69 (0.37, 7.51) 1.31 (0.60, 2.88) 0.13 (-0.23, 0.45)

CT-P13+MTX

0.79 (0.20, 2.86) 0.86 (0.39, 1.96) -0.05 (-0.36, 0.24)

SB2+MTX

0.49 (0.11, 1.98) 0.63 (0.23, 1.58) -0.15 (-0.45, 0.15)

SB5+MTX

0.71 (0.16, 2.60) 0.81 (0.32, 1.85) -0.08 (-0.40, 0.21)

ZRC-3197+MTX

0.73 (0.16, 3.17) 0.83 (0.30, 2.01) -0.07 (-0.40, 0.26)

ABP501+MTX

0.68 (0.16, 2.51) 0.79 (0.32, 1.83) -0.09 (-0.40, 0.20)

CT-P13+MTX ANBAI+MTX 0.47 (0.12, 1.86) 0.66 (0.31, 1.44) -0.18 (-0.48, 0.15)

SB2+MTX

0.29 (0.06, 1.28) 0.48 (0.19, 1.17) -0.27 (-0.57, 0.06)

SB5+MTX

0.42 (0.10, 1.67) 0.61 (0.27, 1.35) -0.20 (-0.51, 0.12)

ZRC-3197+MTX

0.44 (0.09, 2.00) 0.64 (0.24, 1.47) -0.19 (-0.52, 0.16)

ABP501+MTX

0.40 (0.09, 1.60) 0.60 (0.26, 1.32) -0.21 (-0.51, 0.11)

SB2+MTX CT-P13+MTX 0.63 (0.21, 1.84) 0.73 (0.32, 1.50) -0.09 (-0.31, 0.13)

SB5+MTX

0.89 (0.24, 3.08) 0.93 (0.39, 2.09) -0.02 (-0.30, 0.25)

71


ZRC-3197+MTX

0.93 (0.22, 3.78) 0.95 (0.35, 2.26) -0.02 (-0.31, 0.30)

ABP501+MTX

0.86 (0.24, 2.93) 0.91 (0.38, 2.04) -0.03 (-0.31, 0.23)

SB5+MTX SB2+MTX 1.44 (0.36, 5.42) 1.29 (0.49, 3.36) 0.07 (-0.21, 0.33)

ZRC-3197+MTX

1.48 (0.32, 6.66) 1.32 (0.44, 3.70) 0.08 (-0.22, 0.39)

ABP501+MTX

1.37 (0.35, 5.22) 1.25 (0.48, 3.34) 0.06 (-0.21, 0.32)

ZRC-3197+MTX SB5+MTX 1.05 (0.27, 4.17) 1.03 (0.40, 2.49) 0.01 (-0.27, 0.31)

ABP501+MTX

0.96 (0.30, 3.21) 0.98 (0.44, 2.22) -0.01 (-0.25, 0.24)

ABP501+MTX ZRC-3197+MTX 0.92 (0.23, 3.56) 0.95 (0.39, 2.46) -0.02 (-0.32, 0.25)

Random-Effect

Model Residual Deviance 142 vs 138 datapoints

Deviance Information

Criteria 907.492

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1122 and favour the comparator. 1123 ABA = abatacept; ABP501 = biosimilar adalimumab; ADA = adalimumab; ANBAI = AnBaiNuo (biosimilar adalimumab); BAR_4 = 1124 4mg baricitinib; CERTO = certolizumab pegol; CrI = credible interval; csDMARD = conventional synthetic disease-modifying anti-1125 rheumatic drug; CT-P13 = biosimilar of infliximab; ETN=etanercept; GOL = golimumab; HCQ = hydroxychloroquine; HD203 = 1126 etanercept biosimilar; INF = infliximab; IV = intravenous; MTX = methotrexate; OR = odds ratio; RD = risk difference; RIT = 1127 rituximab; RR = relative risk; SAR_200 = 200mg sarilumab; SB2= biosimilar infliximab 3mg/kg; SB4 = biosimilar etanercept 50mg; 1128 SB5=biosimilar adalimumab; SC = subcutaneous; SSZ = sulfasalazine; STD = standard dose; TOC_4 = tocilizumab 4mg/kg; TOC_8 1129 = 8mg/kg tocilizumab; TOF = tofacitinib; ZRC-3197 = biosimilar of adalimumab. 1130

1131

6.4.1.2 Conventional Synthetic DMARD Background Therapy 1132

Nine studies (seven 2-arm studies and two 3-arm studies)141, 149, 156, 160, 161, 170, 215, 240, 248 were 1133

included that used a csDMARD as the common comparator. The evidence network involved 1134

4264 participants and ten treatments forming 13 direct comparisons. Assessment for 1135

consistency demonstrated that the model was consistent. A geometric illustration of the 1136

evidence network is presented in Figure 4 and the odds ratios for all treatment comparisons with 1137

csDMARD monotherapy as the common comparator are available in Table 8. A staircase table 1138

of the results for odds ratios is also presented in Appendix 10. 1139

72

Figure 4. Evidence Network: American College of Rheumatology 50 (Placebo+csDMARD)

1140

Participants receiving a combination of csDMARD with adalimumab, 8 mg/kg tocilizumab, and 1141

50 mg or 100 mg sirukumab had statistically significantly higher odds of achieving ACR50 1142

disease response compared to those receiving csDMARD monotherapy (Table 8). However, the 1143

95% credible intervals for the comparisons of both 50 mg and 100 mg of sirukumab were very 1144

wide. There were no other statistically significant results when comparing any biologic or JAK 1145

inhibitor to one another. 1146

1147

Table 8: American College of Rheumatology 50 (Placebo+csDMARD): Odds Ratios, Relative Risks and Risk 1148 Differences for All Treatment Comparisons – Random Effects Model 1149


ETN_STD

PLACEBO

+csDMARD 4.10 (0.89, 23.63) 3.14 (0.90, 7.66) 0.21 (-0.01, 0.62)

73


ETN_STD+csDMARD 4.72 (1.40, 16.87) 3.45 (1.34, 6.87) 0.24 (0.03, 0.54)

ADA_STD+csDMARD 4.05 (1.24, 13.53) 3.11 (1.21, 6.25) 0.21 (0.02, 0.50)

TOC_8 (IV)+csDMARD 3.59 (1.13, 10.97) 2.85 (1.11, 5.67) 0.18 (0.01, 0.45)

CERTO_STD

+csDMARD

4.32 (0.82, 23.02) 3.25 (0.84, 7.53) 0.22 (-0.02, 0.61)

BAR_4+csDMARD 3.09 (0.61, 15.65) 2.56 (0.64, 6.52) 0.15 (-0.04, 0.53)

SIR_100+csDMARD 13.12 (1.10, 465.50) 5.90 (1.08, 13.66) 0.49 (0.01, 0.90)

SIR_50+csDMARD

15.90

(1.28, 571.60) 6.36 (1.24, 13.78) 0.54 (0.03, 0.90)

ETN_STD+csDMARD ETN_STD 1.15 (0.23, 5.12) 1.10 (0.42, 3.28) 0.03 (-0.32, 0.31)

ADA_STD+csDMARD 0.99 (0.12, 6.76) 0.99 (0.27, 4.01) 0.00 (-0.45, 0.35)

TOC_8 (IV)+csDMARD 0.88 (0.11, 5.67) 0.91 (0.25, 3.67) -0.03 (-0.46, 0.31)

CERTO_STD

+csDMARD

1.06 (0.09, 9.83) 1.04 (0.21, 4.53) 0.01 (-0.46, 0.45)

BAR_4+csDMARD 0.76 (0.07, 6.71) 0.82 (0.16, 3.71) -0.05 (-0.50, 0.36)

SIR_100+csDMARD 3.26 (0.15, 145.90) 1.83 (0.29, 8.20) 0.26 (-0.38, 0.79)

SIR_50+csDMARD 3.95 (0.17, 179.00) 1.95 (0.34, 8.45) 0.30 (-0.35, 0.80)

ADA_STD+csDMARD

ETN_STD

+csDMARD 0.86 (0.15, 4.64) 0.90 (0.28, 2.80) -0.03 (-0.39, 0.32)

TOC_8 (IV)+csDMARD 0.76 (0.13, 3.93) 0.83 (0.26, 2.56) -0.06 (-0.41, 0.27)

CERTO_STD

+csDMARD

0.92 (0.11, 7.14) 0.95 (0.21, 3.25) -0.02 (-0.41, 0.42)

BAR_4+csDMARD 0.66 (0.08, 4.86) 0.75 (0.16, 2.69) -0.08 (-0.44, 0.33)

SIR_100+csDMARD 2.82 (0.17, 114.70) 1.69 (0.29, 5.76) 0.24 (-0.35, 0.75)

SIR_50+csDMARD 3.42 (0.20, 143.00) 1.80 (0.34, 5.95) 0.28 (-0.32, 0.76)

TOC_8 (IV)+csDMARD

ADA_STD

+csDMARD 0.88 (0.16, 4.54) 0.92 (0.29, 2.88) -0.02 (-0.36, 0.30)

74


CERTO_STD

+csDMARD

1.07 (0.14, 8.28) 1.04 (0.24, 3.64) 0.01 (-0.36, 0.44)

BAR_4+csDMARD 0.76 (0.10, 5.70) 0.83 (0.18, 3.06) -0.05 (-0.39, 0.36)

SIR_100+csDMARD 3.28 (0.21, 137.00) 1.87 (0.32, 6.56) 0.27 (-0.30, 0.77)

SIR_50+csDMARD 4.00 (0.24, 168.10) 2.00 (0.37, 6.70) 0.32 (-0.28, 0.78)

CERTO_STD

+csDMARD

TOC_8 (IV)

+csDMARD 1.21 (0.16, 9.39) 1.14 (0.26, 4.00) 0.04 (-0.32, 0.46)

BAR_4+csDMARD 0.86 (0.12, 6.35) 0.89 (0.20, 3.36) -0.03 (-0.35, 0.38)

SIR_100+csDMARD 3.72 (0.23, 159.40) 2.03 (0.35, 7.25) 0.30 (-0.26, 0.79)

SIR_50+csDMARD 4.47 (0.28, 190.60) 2.18 (0.41, 7.43) 0.34 (-0.24, 0.80)

BAR_4+csDMARD

CERTO_STD

+csDMARD 0.71 (0.07, 7.36) 0.79 (0.16, 4.02) -0.06 (-0.50, 0.37)

SIR_100+csDMARD 3.10 (0.16, 151.60) 1.76 (0.30, 8.63) 0.25 (-0.38, 0.79)

SIR_50+csDMARD 3.75 (0.18, 186.00) 1.89 (0.34, 8.93) 0.29 (-0.35, 0.80)

SIR_100+csDMARD BAR_4+csDMARD 4.32 (0.21, 211.90) 2.23 (0.36, 11.46) 0.32 (-0.29, 0.83)

SIR_50+csDMARD 5.26 (0.26, 260.60) 2.39 (0.41, 11.88) 0.36 (-0.26, 0.83)

SIR_50+csDMARD

SIR_100

+csDMARD 1.20 (0.17, 8.47) 1.04 (0.42, 3.01) 0.03 (-0.34, 0.41)

Random-Effect Model Residual Deviance 21.4 vs 20 datapoints

Deviance

Information Criteria 137.79

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1150 and favour the comparator. 1151 ADA = adalimumab; BAR_4 =baricitinib 4mg; CERTO = certolizumab pegol; CrI = credible interval; csDMARD = disease-modifying anti-1152 rheumatic drug; ETN = etanercept; IV = intravenous; OR=odds ratio; RD = risk difference; RR = relative risk; SIR_100 = 100mg sirukumab; 1153 SIR_50 = 50mg sirukumab; STD = standard dose; TOC_8 = tocilizumab 8mg/kg 1154 1155

6.4.2 Disease Activity Score 1156

The DAS-28 was analyzed using the standardized mean difference to account for differences in 1157

scales (i.e., DAS28-ESR and DAS28-CRP). 1158

75


Thirty-three studies94, 95, 97, 100, 128, 130, 133, 135, 136, 143, 150, 151, 153, 163, 165, 167, 186, 193, 205, 212, 213, 221, 222, 224, 1160 227-229, 231, 233, 239, 246, 247, 250 were included for the evidence network of DAS28 with methotrexate 1161

monotherapy as the common comparator (Placebo+MTX). The DAS28 ESR and CRP scales 1162

were both included and standardized mean differences were calculated. There were 47 direct 1163

comparisons in the evidence network based on 30 treatments with 26 2-arm studies and seven 1164

3-arm studies. The total number of participants contributing to the evidence network was 1165

12,376. Assessment for consistency demonstrated that the model was consistent. A geometric 1166

illustration of the evidence network is presented in Figure 5. The standardized mean differences 1167

for all treatment comparisons with placebo as the common comparator are available in Table 9. 1168

Figure 5. Evidence Network: Disease Activity Score 28-Joint Count (Placebo+MTX)

1169

Compared to MTX monotherapy, abatacept (IV), certolizumab pegol and rituximab, all in 1170

combination with MTX, had statistically significant improvements in the DAS28. In addition, 1171

tocilizumab at a dose of 8 mg/kg (IV) both as monotherapy and in combination with MTX 1172

76

statistically significantly improved in DAS28 scores compared to MTX monotherapy (-3.70, [95% 1173

CrI: -7.40, -0.21] and -3.70 [-6.30, -1.18], respectively). Of the head-to-head comparisons of 1174

drugs, the odds of an improvement in DAS28 was higher for 8 mg/kg tocilizumab compared to 1175

etanercept monotherapy (OR = -3.58 [-6.93, -0.38]). None of the remaining comparisons of one 1176

drug to another had any statistically significant results. 1177

1178

Table 9: Disease Activity Score 28-Joint Count (Placebo+MTX): Standardized Mean Differences for All 1179 Treatment Comparisons – Random Effects Model 1180

Treatment Reference SMD (95% CrI)

Placebo Placebo+MTX -1.12 (-6.27, 3.92)

SSZ+HCQ -0.79 (-3.82, 2.28)

ETN_STD -0.11 (-2.13, 1.97)

ETN_STD+MTX -1.00 (-2.69, 0.69)

ABA_STD (IV)+MTX -1.42 (-2.70, -0.15)

ADA_STD -1.83 (-6.31, 2.44)

ADA_STD+MTX -1.06 (-2.74, 0.67)

TOF_STD -1.26 (-6.51, 3.76)

TOF_STD+MTX -1.27 (-2.72, 0.13)

TOC_8 (IV) -3.70 (-7.40, -0.21)

TOC_4 (IV)+MTX -2.18 (-4.68, 0.29)

TOC_8 (IV)+MTX -3.70 (-6.30, -1.18)

GOL_STD (SC) -2.10 (-7.79, 3.61)

GOL_STD (SC)+MTX -1.27 (-3.80, 1.26)

GOL_STD (IV)+MTX -1.03 (-3.53, 1.47)

INF_STD+MTX -0.76 (-2.97, 1.54)

CERTO_STD -2.71 (-8.52, 2.94)

CERTO_STD+MTX -2.23 (-4.02, -0.45)

77


RIT_STD -1.50 (-3.87, 0.88)

RIT_STD+MTX -2.65 (-4.46, -0.85)

SAR_200 -1.32 (-6.49, 3.67)

BAR_4+MTX -0.84 (-3.18, 1.51)

HD203+MTX -1.13 (-4.22, 1.95)

SB4+MTX -1.16 (-4.18, 1.80)

ANBAI+MTX -1.38 (-3.88, 1.15)

CT-P13+MTX -0.98 (-3.84, 1.93)

SB2+MTX -0.77 (-4.11, 2.64)

ZRC-3197+MTX -0.94 (-4.05, 2.13)

ABP501+MTX -1.04 (-4.06, 1.97)

SSZ+HCQ Placebo 0.35 (-5.59, 6.39)

ETN_STD 1.03 (-4.49, 6.61)

ETN_STD+MTX 0.12 (-5.24, 5.52)

ABA_STD (IV)+MTX -0.30 (-5.53, 4.97)

ADA_STD -0.74 (-3.28, 1.82)

ADA_STD+MTX 0.08 (-5.25, 5.44)

TOF_STD -0.14 (-2.67, 2.37)

TOF_STD+MTX -0.16 (-5.43, 5.17)

TOC_8 (IV) -2.59 (-6.18, 1.04)

TOC_4 (IV)+MTX -1.07 (-6.13, 4.09)

TOC_8 (IV)+MTX -2.58 (-6.97, 1.80)

GOL_STD (SC) -0.95 (-3.43, 1.57)

GOL_STD (SC)+MTX -0.14 (-5.82, 5.61)

78


GOL_STD (IV)+MTX 0.10 (-5.47, 5.84)

INF_STD+MTX 0.39 (-5.19, 5.99)

CERTO_STD -1.60 (-4.13, 0.92)

CERTO_STD+MTX -1.13 (-6.46, 4.37)

RIT_STD -0.37 (-5.95, 5.34)

RIT_STD+MTX -1.54 (-6.84, 3.98)

SAR_200 -0.21 (-3.83, 3.38)

BAR_4+MTX 0.29 (-5.30, 5.93)

HD203+MTX -0.03 (-6.01, 5.96)

SB4+MTX -0.05 (-6.04, 5.91)

ANBAI+MTX -0.25 (-5.95, 5.58)

CT-P13+MTX 0.14 (-5.70, 6.07)

SB2+MTX 0.35 (-5.71, 6.58)

ZRC-3197+MTX 0.16 (-5.69, 6.15)

ABP501+MTX 0.08 (-5.83, 6.00)

ETN_STD SSZ+HCQ 0.67 (-2.35, 3.68)

ETN_STD+MTX -0.22 (-2.74, 2.30)

ABA_STD (IV)+MTX -0.64 (-3.93, 2.62)

ADA_STD -1.06 (-6.55, 4.21)

ADA_STD+MTX -0.26 (-3.74, 3.18)

TOF_STD -0.47 (-6.53, 5.38)

TOF_STD+MTX -0.48 (-3.86, 2.81)

TOC_8 (IV) -2.93 (-7.75, 1.76)

TOC_4 (IV)+MTX -1.40 (-5.32, 2.55)

79


TOC_8 (IV)+MTX -2.92 (-6.87, 0.99)

GOL_STD (SC) -1.29 (-7.80, 5.11)

GOL_STD (SC)+MTX -0.49 (-4.47, 3.47)

GOL_STD (IV)+MTX -0.24 (-4.21, 3.63)

INF_STD+MTX 0.03 (-3.72, 3.82)

CERTO_STD -1.92 (-8.55, 4.50)

CERTO_STD+MTX -1.45 (-4.96, 2.04)

RIT_STD -0.71 (-4.55, 3.09)

RIT_STD+MTX -1.86 (-5.39, 1.62)

SAR_200 -0.54 (-6.54, 5.37)

BAR_4+MTX -0.07 (-3.80, 3.77)

HD203+MTX -0.36 (-3.92, 3.22)

SB4+MTX -0.39 (-3.93, 3.13)

ANBAI+MTX -0.59 (-4.53, 3.32)

CT-P13+MTX -0.20 (-4.38, 3.99)

SB2+MTX 0.02 (-4.46, 4.56)

ZRC-3197+MTX -0.16 (-4.48, 4.09)

ABP501+MTX -0.27 (-4.46, 4.03)

ETN_STD+MTX ETN_STD -0.89 (-2.59, 0.83)

ABA_STD (IV)+MTX -1.31 (-3.76, 1.06)

ADA_STD -1.73 (-6.74, 3.04)

ADA_STD+MTX -0.93 (-3.60, 1.67)

TOF_STD -1.14 (-6.81, 4.27)

TOF_STD+MTX -1.16 (-3.70, 1.28)

80


TOC_8 (IV) -3.60 (-7.90, 0.45)

TOC_4 (IV)+MTX -2.07 (-5.36, 1.12)

TOC_8 (IV)+MTX -3.58 (-6.93, -0.38)

GOL_STD (SC) -1.98 (-8.10, 4.08)

GOL_STD (SC)+MTX -1.16 (-4.46, 2.09)

GOL_STD (IV)+MTX -0.92 (-4.22, 2.31)

INF_STD+MTX -0.65 (-3.67, 2.36)

CERTO_STD -2.60 (-8.84, 3.41)

CERTO_STD+MTX -2.12 (-4.83, 0.60)

RIT_STD -1.38 (-4.53, 1.77)

RIT_STD+MTX -2.54 (-5.27, 0.20)

SAR_200 -1.21 (-6.78, 4.28)

BAR_4+MTX -0.72 (-3.87, 2.38)

HD203+MTX -1.02 (-4.11, 2.00)

SB4+MTX -1.06 (-4.10, 1.96)

ANBAI+MTX -1.28 (-4.47, 2.02)

CT-P13+MTX -0.87 (-4.39, 2.66)

SB2+MTX -0.65 (-4.53, 3.34)

ZRC-3197+MTX -0.84 (-4.53, 2.85)

ABP501+MTX -0.94 (-4.61, 2.73)

ABA_STD (IV)+MTX ETN_STD+MTX -0.43 (-2.56, 1.67)

ADA_STD -0.84 (-5.65, 3.81)

ADA_STD+MTX -0.05 (-2.45, 2.34)

TOF_STD -0.25 (-5.72, 5.08)

81


TOF_STD+MTX -0.28 (-2.49, 1.90)

TOC_8 (IV) -2.71 (-6.73, 1.20)

TOC_4 (IV)+MTX -1.19 (-4.23, 1.82)

TOC_8 (IV)+MTX -2.70 (-5.79, 0.32)

GOL_STD (SC) -1.09 (-7.11, 4.85)

GOL_STD (SC)+MTX -0.27 (-3.33, 2.78)

GOL_STD (IV)+MTX -0.03 (-3.06, 3.00)

INF_STD+MTX 0.24 (-2.54, 3.06)

CERTO_STD -1.70 (-7.83, 4.19)

CERTO_STD+MTX -1.24 (-3.70, 1.22)

RIT_STD -0.50 (-3.40, 2.42)

RIT_STD+MTX -1.66 (-4.14, 0.84)

SAR_200 -0.32 (-5.77, 4.97)

BAR_4+MTX 0.15 (-2.72, 3.02)

HD203+MTX -0.14 (-2.66, 2.39)

SB4+MTX -0.17 (-2.71, 2.32)

ANBAI+MTX -0.38 (-3.40, 2.67)

CT-P13+MTX -0.002 (-3.32, 3.37)

SB2+MTX 0.25 (-3.47, 3.99)

ZRC-3197+MTX 0.05 (-3.47, 3.52)

ABP501+MTX -0.05 (-3.51, 3.44)

ADA_STD ABA_STD (IV)+MTX -0.41 (-5.09, 4.11)

ADA_STD+MTX 0.37 (-1.75, 2.55)

TOF_STD 0.17 (-5.18, 5.37)

82


TOF_STD+MTX 0.15 (-1.76, 2.05)

TOC_8 (IV) -2.27 (-6.16, 1.45)

TOC_4 (IV)+MTX -0.77 (-3.59, 2.03)

TOC_8 (IV)+MTX -2.27 (-5.16, 0.58)

GOL_STD (SC) -0.67 (-6.51, 5.22)

GOL_STD (SC)+MTX 0.15 (-2.66, 3.00)

GOL_STD (IV)+MTX 0.40 (-2.39, 3.22)

INF_STD+MTX 0.67 (-1.51, 2.94)

CERTO_STD -1.27 (-7.23, 4.51)

CERTO_STD+MTX -0.81 (-2.96, 1.37)

RIT_STD -0.07 (-2.76, 2.63)

RIT_STD+MTX -1.22 (-3.40, 0.98)

SAR_200 0.11 (-5.23, 5.29)

BAR_4+MTX 0.58 (-2.06, 3.29)

HD203+MTX 0.29 (-3.02, 3.63)

SB4+MTX 0.26 (-3.01, 3.56)

ANBAI+MTX 0.05 (-2.77, 2.89)

CT-P13+MTX 0.44 (-2.43, 3.36)

SB2+MTX 0.66 (-2.65, 4.08)

ZRC-3197+MTX 0.48 (-2.82, 3.81)

ABP501+MTX 0.38 (-2.87, 3.69)

ADA_STD+MTX ADA_STD 0.79 (-3.84, 5.57)

TOF_STD 0.60 (-1.96, 3.10)

TOF_STD+MTX 0.56 (-3.96, 5.18)

83


TOC_8 (IV) -1.86 (-4.36, 0.69)

TOC_4 (IV)+MTX -0.34 (-4.62, 4.15)

TOC_8 (IV)+MTX -1.85 (-5.37, 1.77)

GOL_STD (SC) -0.22 (-3.86, 3.40)

GOL_STD (SC)+MTX 0.58 (-4.46, 5.77)

GOL_STD (IV)+MTX 0.81 (-4.13, 6.00)

INF_STD+MTX 1.09 (-3.77, 6.09)

CERTO_STD -0.85 (-4.46, 2.72)

CERTO_STD+MTX -0.40 (-5.01, 4.44)

RIT_STD 0.35 (-4.58, 5.45)

RIT_STD+MTX -0.82 (-5.45, 4.11)

SAR_200 0.53 (-1.99, 3.01)

BAR_4+MTX 1.00 (-3.92, 6.10)

HD203+MTX 0.71 (-4.60, 6.13)

SB4+MTX 0.67 (-4.65, 6.07)

ANBAI+MTX 0.48 (-4.54, 5.67)

CT-P13+MTX 0.87 (-4.36, 6.26)

SB2+MTX 1.09 (-4.37, 6.71)

ZRC-3197+MTX 0.89 (-4.40, 6.36)

ABP501+MTX 0.82 (-4.47, 6.17)

TOF_STD ADA_STD+MTX -0.22 (-5.66, 5.06)

TOF_STD+MTX -0.23 (-2.18, 1.69)

TOC_8 (IV) -2.66 (-6.71, 1.23)

TOC_4 (IV)+MTX -1.14 (-4.13, 1.84)

84


TOC_8 (IV)+MTX -2.66 (-5.71, 0.36)

GOL_STD (SC) -1.05 (-6.94, 4.89)

GOL_STD (SC)+MTX -0.22 (-3.28, 2.80)

GOL_STD (IV)+MTX 0.02 (-3.03, 3.08)

INF_STD+MTX 0.28 (-2.51, 3.16)

CERTO_STD -1.67 (-7.71, 4.20)

CERTO_STD+MTX -1.18 (-3.68, 1.29)

RIT_STD -0.45 (-3.33, 2.51)

RIT_STD+MTX -1.61 (-4.06, 0.86)

SAR_200 -0.27 (-5.66, 4.96)

BAR_4+MTX 0.20 (-2.12, 2.53)

HD203+MTX -0.09 (-3.59, 3.42)

SB4+MTX -0.13 (-3.58, 3.35)

ANBAI+MTX -0.33 (-3.35, 2.73)

CT-P13+MTX 0.06 (-3.26, 3.44)

SB2+MTX 0.28 (-3.49, 4.08)

ZRC-3197+MTX 0.10 (-2.44, 2.65)

ABP501+MTX -0.001 (-2.51, 2.51)

TOF_STD+MTX TOF_STD -0.01 (-5.25, 5.29)

TOC_8 (IV) -2.45 (-6.03, 1.14)

TOC_4 (IV)+MTX -0.92 (-5.93, 4.19)

TOC_8 (IV)+MTX -2.44 (-6.78, 2.02)

GOL_STD (SC) -0.82 (-4.37, 2.76)

GOL_STD (SC)+MTX -0.001 (-5.65, 5.77)

85


GOL_STD (IV)+MTX 0.23 (-5.35, 6.05)

INF_STD+MTX 0.52 (-4.97, 6.17)

CERTO_STD -1.45 (-5.00, 2.08)

CERTO_STD+MTX -0.97 (-6.29, 4.54)

RIT_STD -0.23 (-5.82, 5.53)

RIT_STD+MTX -1.40 (-6.71, 4.28)

SAR_200 -0.08 (-3.64, 3.48)

BAR_4+MTX 0.42 (-5.13, 6.16)

HD203+MTX 0.11 (-5.84, 6.16)

SB4+MTX 0.10 (-5.84, 6.09)

ANBAI+MTX -0.10 (-5.76, 5.68)

CT-P13+MTX 0.30 (-5.56, 6.22)

SB2+MTX 0.51 (-5.52, 6.67)

ZRC-3197+MTX 0.32 (-5.60, 6.37)

ABP501+MTX 0.23 (-5.70, 6.17)

TOC_8 (IV) TOF_STD+MTX -2.43 (-6.38, 1.39)

TOC_4 (IV)+MTX -0.90 (-3.78, 1.95)

TOC_8 (IV)+MTX -2.42 (-5.36, 0.49)

GOL_STD (SC) -0.81 (-6.69, 5.09)

GOL_STD (SC)+MTX -0.01 (-2.85, 2.94)

GOL_STD (IV)+MTX 0.24 (-2.59, 3.14)

INF_STD+MTX 0.52 (-2.09, 3.24)

CERTO_STD -1.44 (-7.40, 4.39)

CERTO_STD+MTX -0.96 (-3.20, 1.36)

86


RIT_STD -0.22 (-2.96, 2.58)

RIT_STD+MTX -1.37 (-3.64, 0.94)

SAR_200 -0.04 (-5.38, 5.17)

BAR_4+MTX 0.44 (-2.16, 3.07)

HD203+MTX 0.14 (-3.24, 3.51)

SB4+MTX 0.11 (-3.23, 3.42)

ANBAI+MTX -0.11 (-2.94, 2.82)

CT-P13+MTX 0.29 (-2.89, 3.55)

SB2+MTX 0.52 (-3.12, 4.23)

ZRC-3197+MTX 0.33 (-2.88, 3.55)

ABP501+MTX 0.22 (-2.91, 3.42)

TOC_4 (IV)+MTX TOC_8 (IV) 1.54 (-1.98, 5.10)

TOC_8 (IV)+MTX 0.02 (-2.49, 2.56)

GOL_STD (SC) 1.62 (-2.76, 6.04)

GOL_STD (SC)+MTX 2.45 (-1.84, 6.91)

GOL_STD (IV)+MTX 2.68 (-1.65, 7.12)

INF_STD+MTX 2.97 (-1.21, 7.29)

CERTO_STD 1.02 (-3.46, 5.34)

CERTO_STD+MTX 1.46 (-2.43, 5.57)

RIT_STD 2.21 (-2.01, 6.59)

RIT_STD+MTX 1.06 (-2.89, 5.19)

SAR_200 2.38 (-1.16, 5.96)

BAR_4+MTX 2.85 (-1.36, 7.22)

HD203+MTX 2.57 (-2.05, 7.34)

87


SB4+MTX 2.55 (-2.13, 7.26)

ANBAI+MTX 2.33 (-1.96, 6.81)

CT-P13+MTX 2.75 (-1.86, 7.43)

SB2+MTX 2.97 (-1.91, 7.97)

ZRC-3197+MTX 2.77 (-1.92, 7.54)

ABP501+MTX 2.68 (-1.99, 7.37)

TOC_8 (IV)+MTX TOC_4 (IV)+MTX -1.52 (-4.02, 1.01)

GOL_STD (SC) 0.10 (-5.61, 5.79)

GOL_STD (SC)+MTX 0.91 (-2.58, 4.47)

GOL_STD (IV)+MTX 1.16 (-2.32, 4.63)

INF_STD+MTX 1.42 (-1.91, 4.81)

CERTO_STD -0.52 (-6.29, 5.08)

CERTO_STD+MTX -0.06 (-3.10, 3.05)

RIT_STD 0.69 (-2.75, 4.14)

RIT_STD+MTX -0.48 (-3.55, 2.66)

SAR_200 0.87 (-4.22, 5.86)

BAR_4+MTX 1.35 (-2.06, 4.79)

HD203+MTX 1.05 (-2.89, 5.04)

SB4+MTX 1.01 (-2.91, 4.92)

ANBAI+MTX 0.81 (-2.74, 4.37)

CT-P13+MTX 1.20 (-2.61, 5.05)

SB2+MTX 1.42 (-2.68, 5.64)

ZRC-3197+MTX 1.24 (-2.71, 5.17)

ABP501+MTX 1.15 (-2.75, 4.99)

88


GOL_STD (SC) TOC_8 (IV)+MTX 1.61 (-3.50, 6.69)

GOL_STD (SC)+MTX 2.42 (-1.12, 6.04)

GOL_STD (IV)+MTX 2.68 (-0.89, 6.23)

INF_STD+MTX 2.94 (-0.41, 6.38)

CERTO_STD 0.99 (-4.17, 6.04)

CERTO_STD+MTX 1.46 (-1.57, 4.60)

RIT_STD 2.20 (-1.27, 5.71)

RIT_STD+MTX 1.05 (-2.01, 4.18)

SAR_200 2.38 (-2.03, 6.68)

BAR_4+MTX 2.86 (-0.57, 6.31)

HD203+MTX 2.56 (-1.36, 6.59)

SB4+MTX 2.54 (-1.39, 6.46)

ANBAI+MTX 2.32 (-1.24, 5.98)

CT-P13+MTX 2.72 (-1.09, 6.60)

SB2+MTX 2.94 (-1.20, 7.18)

ZRC-3197+MTX 2.76 (-1.20, 6.80)

ABP501+MTX 2.66 (-1.22, 6.58)

GOL_STD (SC)+MTX GOL_STD (SC) 0.81 (-5.40, 7.08)

GOL_STD (IV)+MTX 1.07 (-5.10, 7.31)

INF_STD+MTX 1.34 (-4.82, 7.49)

CERTO_STD -0.64 (-4.24, 2.89)

CERTO_STD+MTX -0.16 (-6.12, 5.90)

RIT_STD 0.59 (-5.56, 6.81)

RIT_STD+MTX -0.57 (-6.49, 5.38)

89


SAR_200 0.74 (-3.65, 5.14)

BAR_4+MTX 1.26 (-4.96, 7.42)

HD203+MTX 0.93 (-5.53, 7.41)

SB4+MTX 0.90 (-5.58, 7.35)

ANBAI+MTX 0.71 (-5.51, 7.01)

CT-P13+MTX 1.11 (-5.34, 7.49)

SB2+MTX 1.34 (-5.30, 8.04)

ZRC-3197+MTX 1.14 (-5.38, 7.63)

ABP501+MTX 1.04 (-5.44, 7.46)

GOL_STD (IV)+MTX GOL_STD (SC)+MTX 0.23 (-3.28, 3.74)

INF_STD+MTX 0.51 (-2.86, 3.92)

CERTO_STD -1.44 (-7.81, 4.79)

CERTO_STD+MTX -0.96 (-4.06, 2.09)

RIT_STD -0.22 (-3.69, 3.24)

RIT_STD+MTX -1.37 (-4.46, 1.71)

SAR_200 -0.06 (-5.81, 5.59)

BAR_4+MTX 0.43 (-3.02, 3.88)

HD203+MTX 0.14 (-3.86, 4.13)

SB4+MTX 0.11 (-3.87, 4.02)

ANBAI+MTX -0.10 (-3.68, 3.46)

CT-P13+MTX 0.29 (-3.54, 4.12)

SB2+MTX 0.50 (-3.67, 4.75)

ZRC-3197+MTX 0.32 (-3.67, 4.32)

ABP501+MTX 0.22 (-3.69, 4.14)

90


INF_STD+MTX GOL_STD (IV)+MTX 0.28 (-3.04, 3.65)

CERTO_STD -1.68 (-8.04, 4.43)

CERTO_STD+MTX -1.21 (-4.26, 1.85)

RIT_STD -0.46 (-3.90, 2.99)

RIT_STD+MTX -1.61 (-4.73, 1.44)

SAR_200 -0.29 (-6.04, 5.33)

BAR_4+MTX 0.19 (-3.23, 3.70)

HD203+MTX -0.09 (-4.08, 3.82)

SB4+MTX -0.13 (-4.09, 3.76)

ANBAI+MTX -0.35 (-3.87, 3.22)

CT-P13+MTX 0.06 (-3.78, 3.87)

SB2+MTX 0.28 (-3.88, 4.47)

ZRC-3197+MTX 0.07 (-3.91, 4.07)

ABP501+MTX -0.001 (-3.94, 3.93)

CERTO_STD INF_STD+MTX -1.96 (-8.26, 4.12)

CERTO_STD+MTX -1.47 (-4.37, 1.35)

RIT_STD -0.74 (-4.04, 2.56)

RIT_STD+MTX -1.89 (-4.78, 0.97)

SAR_200 -0.59 (-6.17, 4.88)

BAR_4+MTX -0.08 (-3.37, 3.15)

HD203+MTX -0.39 (-4.15, 3.39)

SB4+MTX -0.40 (-4.18, 3.27)

ANBAI+MTX -0.62 (-4.00, 2.71)

CT-P13+MTX -0.23 (-2.00, 1.54)

91


SB2+MTX -0.001 (-2.49, 2.51)

ZRC-3197+MTX -0.19 (-4.06, 3.60)

ABP501+MTX -0.27 (-4.12, 3.41)

CERTO_STD+MTX CERTO_STD 0.48 (-5.42, 6.60)

RIT_STD 1.22 (-4.87, 7.53)

RIT_STD+MTX 0.05 (-5.87, 6.20)

SAR_200 1.39 (-2.98, 5.81)

BAR_4+MTX 1.88 (-4.28, 8.15)

HD203+MTX 1.58 (-4.88, 8.17)

SB4+MTX 1.55 (-4.90, 8.09)

ANBAI+MTX 1.34 (-4.87, 7.67)

CT-P13+MTX 1.72 (-4.60, 8.20)

SB2+MTX 1.95 (-4.54, 8.73)

ZRC-3197+MTX 1.76 (-4.66, 8.30)

ABP501+MTX 1.66 (-4.72, 8.17)

RIT_STD CERTO_STD+MTX 0.74 (-2.22, 3.72)

RIT_STD+MTX -0.42 (-2.92, 2.08)

SAR_200 0.92 (-4.54, 6.20)

BAR_4+MTX 1.39 (-1.51, 4.36)

HD203+MTX 1.10 (-2.45, 4.63)

SB4+MTX 1.07 (-2.47, 4.54)

ANBAI+MTX 0.86 (-2.19, 3.95)

CT-P13+MTX 1.25 (-2.16, 4.65)

SB2+MTX 1.48 (-2.32, 5.31)

92


ZRC-3197+MTX 1.28 (-2.29, 4.81)

ABP501+MTX 1.18 (-2.36, 4.74)

RIT_STD+MTX RIT_STD -1.16 (-3.58, 1.23)

SAR_200 0.18 (-5.49, 5.67)

BAR_4+MTX 0.66 (-2.68, 3.98)

HD203+MTX 0.35 (-3.51, 4.19)

SB4+MTX 0.32 (-3.52, 4.18)

ANBAI+MTX 0.12 (-3.33, 3.56)

CT-P13+MTX 0.51 (-3.22, 4.25)

SB2+MTX 0.74 (-3.40, 4.87)

ZRC-3197+MTX 0.56 (-3.42, 4.41)

ABP501+MTX 0.45 (-3.43, 4.26)

SAR_200 RIT_STD+MTX 1.34 (-4.19, 6.64)

BAR_4+MTX 1.81 (-1.12, 4.72)

HD203+MTX 1.51 (-2.08, 5.09)

SB4+MTX 1.48 (-2.06, 4.98)

ANBAI+MTX 1.28 (-1.80, 4.34)

CT-P13+MTX 1.67 (-1.69, 5.04)

SB2+MTX 1.89 (-1.90, 5.69)

ZRC-3197+MTX 1.71 (-1.83, 5.26)

ABP501+MTX 1.61 (-1.90, 5.06)

BAR_4+MTX SAR_200 0.48 (-5.01, 6.12)

HD203+MTX 0.17 (-5.75, 6.14)

SB4+MTX 0.15 (-5.68, 6.13)

93


ANBAI+MTX -0.05 (-5.60, 5.66)

CT-P13+MTX 0.36 (-5.43, 6.25)

SB2+MTX 0.58 (-5.46, 6.71)

ZRC-3197+MTX 0.37 (-5.49, 6.41)

ABP501+MTX 0.29 (-5.54, 6.19)

HD203+MTX BAR_4+MTX -0.30 (-4.14, 3.54)

SB4+MTX -0.32 (-4.15, 3.44)

ANBAI+MTX -0.54 (-3.96, 2.90)

CT-P13+MTX -0.15 (-3.81, 3.57)

SB2+MTX 0.08 (-3.93, 4.23)

ZRC-3197+MTX -0.10 (-3.57, 3.32)

ABP501+MTX -0.20 (-3.63, 3.18)

SB4+MTX HD203+MTX -0.04 (-3.62, 3.59)

ANBAI+MTX -0.25 (-4.18, 3.77)

CT-P13+MTX 0.16 (-4.04, 4.37)

SB2+MTX 0.36 (-4.16, 4.88)

ZRC-3197+MTX 0.19 (-4.14, 4.54)

ABP501+MTX 0.09 (-4.20, 4.39)

ANBAI+MTX SB4+MTX -0.22 (-4.09, 3.77)

CT-P13+MTX 0.17 (-3.94, 4.36)

SB2+MTX 0.41 (-4.01, 4.92)

ZRC-3197+MTX 0.23 (-4.08, 4.51)

ABP501+MTX 0.12 (-4.13, 4.40)

CT-P13+MTX ANBAI+MTX 0.39 (-3.38, 4.19)

94


SB2+MTX 0.62 (-3.50, 4.84)

ZRC-3197+MTX 0.44 (-3.58, 4.39)

ABP501+MTX 0.34 (-3.58, 4.29)

SB2+MTX CT-P13+MTX 0.23 (-2.79, 3.30)

ZRC-3197+MTX 0.05 (-4.20, 4.26)

ABP501+MTX -0.05 (-4.24, 4.06)

ZRC-3197+MTX SB2+MTX -0.18 (-4.82, 4.37)

ABP501+MTX -0.29 (-4.85, 4.19)

ABP501+MTX ZRC-3197+MTX -0.10 (-3.63, 3.49)



Criteria -7.925

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1181 and favour the comparator. Bold results represent large effect sizes. 1182 ABA = abatacept; ABP501 = biosimilar of adalimumab; ANBAI = anbainuo (biosimilar of etanercept); BAR_4 = 4 mg baricitinib once 1183 daily (oral); CERTO = certolizumab pegol; CrI = credible interval; csDMARD = conventional synthetic disease modifying 1184 antirheumatic drug; CT-P13 = biosimilar of infliximab; GOL = golimumab; HCQ = hydroxychloroquine; INF = infliximab; LFN = 1185 leflunomide; MTX=methotrexate; RIT = rituximab; SAR_200 = 200 mg sarilumab; SB2 = biosimilar of infliximab; SMD = standardized 1186 mean difference; SSZ = sulfasalazine; STD = standard dose; TOC_4 = 4 mg/kg tocilizumab; TOC_8 = 8 mg/kg tocilizumab; TOF= 1187 tofacitinib; ZRC-3197 = biosimilar adalimumab. 1188

1189

6.4.2.2 Conventional Synthetic DMARD as a Common Comparator 1190

A total of nine RCTs101, 141, 149, 161, 170, 182, 209, 215, 248 were included for the evidence network of 1191

DAS28 with monotherapy of a csDMARD other than MTX as the common comparator 1192

(Placebo+csDMARD). The DAS28 ESR and CRP scales were both included and standardized 1193

mean differences were calculated. Thirteen direct comparisons from nine treatments were 1194

available in the evidence network; there were seven 2-arm studies and two 3-arm studies. The 1195

total number of participants contributing to the evidence network was 2131. Assessment for 1196


evidence network is presented in Figure 6. The standardized mean differences for all treatment 1198

comparisons with placebo as the common comparator are available in Table 10. A staircase 1199

table of the results as standardized mean differences is also presented in Appendix 10. 1200

95

Figure 6. Evidence Network: Disease Activity Score 28-Joint Count (Placebo+csDMARD)

1201

1202

There were no statistically significant differences between treatments and csDMARD 1203

monotherapy or any head-to-head comparisons of biologics or tsDMARDs. 1204

1205

Table 10: Disease Activity Score 28-Joint Count (Placebo+csDMARD): Standardized Mean 1206

Differences for All Treatment Comparisons – Random Effects Model 1207


ETN_STD Placebo+csDMARD -1.88 (-5.79, 1.98)

ETN_STD+ csDMARD -1.53 (-4.20, 1.14)

ADA_STD+ csDMARD -1.05 (-4.34, 2.20)

TOC_8 (IV)+ csDMARD -1.50 (-4.47, 1.46)

96


INF_STD+ csDMARD -0.95 (-5.16, 3.27)

BAR_4+ csDMARD -1.49 (-5.68, 2.73)

SIR_100+ csDMARD -0.93 (-5.15, 3.25)

SIR_50+ csDMARD -1.14 (-5.40, 3.04)

ETN_STD+ csDMARD ETN_STD 0.34 (-3.54, 4.21)

ADA_STD+ csDMARD 0.82 (-3.88, 5.52)

TOC_8 (IV)+ csDMARD 0.38 (-4.49, 5.25)

INF_STD+ csDMARD 0.93 (-4.82, 6.71)

BAR_4+ csDMARD 0.39 (-5.34, 6.09)

SIR_100+ csDMARD 0.94 (-4.83, 6.63)

SIR_50+ csDMARD 0.73 (-5.01, 6.46)

ADA_STD+ csDMARD ETN_STD+ csDMARD 0.47 (-2.78, 3.70)

TOC_8 (IV)+ csDMARD 0.03 (-3.94, 4.02)

INF_STD+ csDMARD 0.58 (-4.41, 5.57)

BAR_4+ csDMARD 0.04 (-4.94, 5.00)

SIR_100+ csDMARD 0.60 (-4.37, 5.59)

SIR_50+ csDMARD 0.40 (-4.59, 5.36)

TOC_8 (IV)+ csDMARD ADA_STD+ csDMARD -0.45 (-4.86, 4.01)

INF_STD+ csDMARD 0.10 (-5.25, 5.45)

BAR_4+ csDMARD -0.44 (-5.75, 4.89)

SIR_100+ csDMARD 0.12 (-5.12, 5.43)

SIR_50+ csDMARD -0.09 (-5.42, 5.23)

INF_STD+ csDMARD TOC_8 (IV)+ csDMARD 0.55 (-4.64, 5.73)

BAR_4+ csDMARD -0.001 (-5.11, 5.16)

97


SIR_100+ csDMARD 0.57 (-4.61, 5.74)

SIR_50+ csDMARD 0.36 (-4.84, 5.47)

BAR_4+ csDMARD INF_STD+ csDMARD -0.54 (-6.48, 5.42)

SIR_100+ csDMARD 0.01 (-5.93, 5.91)

SIR_50+ csDMARD -0.19 (-6.14, 5.76)

SIR_100+ csDMARD BAR_4+ csDMARD 0.57 (-5.40, 6.48)

SIR_50+ csDMARD 0.35 (-5.58, 6.29)

SIR_50+ csDMARD SIR_100+ csDMARD -0.20 (-4.47, 3.95)

Random-Effect Model Total Residual Deviance 11.03 vs 20 datapoints

Deviance Information Criteria 6.368

Fixed-Effect Model Total Residual Deviance 89.19 vs 20 datapoints


Total Patients

2131

Total Studies

9

2-arm 7

3-arm 2

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1208 and favour the comparator. Bold results represent large effect sizes. 1209 ADA = adalimumab; BAR_4 = 4 mg baricitinib; CrI = credible interval; csDMARD = conventional synthetic disease-modifying anti-1210 rheumatic drug; ETN = etanercept; GOL=golimumab; INF = infliximab; SIR_100 = 100 mg sirukumab; SMD = standardized mean 1211 difference; STD = standard dose; TOC_4 = 4 mg/kg tocilizumab; TOC_8 = 8 mg/kg tocilizumab; TOF = tofacitinib. 1212

1213

6.4.3 Disability 1214

Disability was extracted and analyzed in terms of the Health Assessment Questionnaire (HAQ-1215

DI). 1216

98


A total of 27 studies95, 132, 134-136, 148, 158, 163, 167, 173, 174, 176, 184, 186, 191, 213, 216, 218, 220, 222, 224, 227-229, 233, 244, 1218 247 reported the change from baseline data for disability in the evidence network with MTX 1219

monotherapy as the common comparator (Placebo+MTX) and were included in the reference 1220

case NMA. The evidence network had 19 treatments, 37 treatment comparisons, 22 2-arm 1221

studies and five 3-arm studies. The total number of participants contributing to the evidence 1222

network was 10,010. Assessment for consistency demonstrated that the model was consistent. 1223

A geometric illustration of the evidence network is presented in Figure 7. The mean differences 1224

for all treatment comparisons with placebo as the common comparator are available in Table 1225

11. 1226

Figure 7. Evidence Network: Health Assessment Questionnaire Disability Index (Placebo+MTX)

1227

1228

Overall, 15 of the 18 treatments were found to have a reduction in disability that was statistically 1229

significant compared to MTX monotherapy. The 15 treatments were as follows: abatacept (IV), 1230

99

adalimumab, tofacitinib, 4 mg/kg tocilizumab (IV), 8 mg/kg tocilizumab, golimumab (SC), 1231

golimumab (IV), infliximab, certolizumab pegol, sarilumab, baricitinib, AnBaiNuo (biosimilar 1232

etanercept), CT-P13 (biosimilar inflixmab), all in combination with MTX, and monotherapy with 8 1233

mg/kg tocilizumab (IV) and rituximab. There was insufficient evidence to determine whether 1234

rituximab, SB2 (biosimilar infliximab) and ZRC-3197 (biosimilar adalimumab), all in combination 1235

with MTX, had statistically significant reductions in disability compared with MTX monotherapy. 1236

1237

AnBaiNuo (biosimilar etanercept) in combination with MTX had a statistically significant 1238

reduction in disability compared to: 4 mg/kg of tocilizumab (IV) in combination with MTX (-0.32 [-1239

0.60, -0.04]), golimumab (SC) in combination with MTX (-0.32 [-0.57, -0.08]), golimumab (IV) in 1240

combination with MTX (-0.35 [-0.63, -0.07]), infliximab in combination with MTX (-0.38 [-0.67, -1241

0.09]), certolizumab pegol in combination with MTX (-0.27 [-0.52, -0.02]), rituximab in 1242

combination with MTX (-0.43 [-0.74, -0.12]), 200 mg sarilumab in combination with MTX (-0.37 [-1243

0.65, -0.09]) and 4 mg baricitinib in combination with MTX (-0.33 [-0.58, -0.09]). However, no 1244

comparison could be made between AnBaiNuo in combination with MTX and its reference 1245

product etanercept (either as monotherapy or in combination with MTX) because none of the 1246

included studies with HAQ-DI data involved eternercept. Both SB2 (biosimilar infliximab) in 1247

combination with MTX and ZRC-3197 (biosimilar adalimumab) in combination with MTX 1248

demonstrated worsening in disability compared to AnBaiNuo in combination with MTX (0.38 1249

[0.03, 0.73] and 0.38 [0.03, 0.74], respectively). 1250

CT-P13 (biosimilar infliximab) in combination with MTX had a greater reduction in disability 1251

compared to infliximab in combination with MTX (-0.29 [-0.55, -0.03]). 1252

1253

Table 11: Health Assessment Questionnaire Disability Index (Placebo+MTX): Mean Differences for All 1254 Treatment Comparisons – Random Effects Model 1255

Treatment Reference MD (95% CrI)

ABA_STD (IV)+MTX Placebo+MTX -0.28 (-0.40, -0.16)

ADA_STD+MTX -0.25 (-0.33, -0.15)

TOF_STD+MTX -0.31 (-0.42, -0.20)

TOC_8 (IV) -0.47 (-0.72, -0.23)

TOC_4 (IV)+MTX -0.31 (-0.50, -0.12)

TOC_8 (IV)+MTX -0.44 (-0.64, -0.25)

GOL_STD (SC)+MTX -0.31 (-0.43, -0.19)

100


GOL_STD (IV)+MTX -0.28 (-0.47, -0.09)

INF_STD+MTX -0.25 (-0.45, -0.05)

CERTO_STD+MTX -0.36 (-0.49, -0.22)

RIT_STD -0.40 (-0.63, -0.17)

RIT_STD+MTX -0.20 (-0.42, 0.03)

SAR_200+MTX -0.26 (-0.44, -0.08)

BAR_4+MTX -0.30 (-0.42, -0.17)

ANBAI+MTX -0.63 (-0.84, -0.42)

CT-P13+MTX -0.54 (-0.87, -0.21)

SB2+MTX -0.25 (-0.52, 0.03)

ZRC-3197+MTX -0.25 (-0.53, 0.04)

ADA_STD+MTX ABA_STD (IV)+MTX 0.03 (-0.12, 0.19)

TOF_STD+MTX -0.03 (-0.19, 0.13)

TOC_8 (IV) -0.20 (-0.47, 0.08)

TOC_4 (IV)+MTX -0.03 (-0.26, 0.20)

TOC_8 (IV)+MTX -0.16 (-0.39, 0.07)

GOL_STD (SC)+MTX -0.03 (-0.20, 0.15)

GOL_STD (IV)+MTX -0.003 (-0.22, 0.23)

INF_STD+MTX 0.03 (-0.16, 0.23)

CERTO_STD+MTX -0.09 (-0.26, 0.11)

RIT_STD -0.12 (-0.38, 0.14)

RIT_STD+MTX 0.08 (-0.17, 0.34)

SAR_200+MTX 0.02 (-0.20, 0.24)

BAR_4+MTX -0.02 (-0.19, 0.16)

101


ANBAI+MTX -0.35 (-0.59, -0.10)

CT-P13+MTX -0.26 (-0.58, 0.07)

SB2+MTX 0.03 (-0.24, 0.31)

ZRC-3197+MTX 0.03 (-0.28, 0.34)

TOF_STD+MTX ADA_STD+MTX -0.06 (-0.20, 0.06)

TOC_8 (IV) -0.23 (-0.50, 0.03)

TOC_4 (IV)+MTX -0.07 (-0.28, 0.14)

TOC_8 (IV)+MTX -0.20 (-0.42, 0.02)

GOL_STD (SC)+MTX -0.06 (-0.22, 0.09)

GOL_STD (IV)+MTX -0.03 (-0.25, 0.17)

INF_STD+MTX -0.001 (-0.22, 0.21)

CERTO_STD+MTX -0.12 (-0.28, 0.05)

RIT_STD -0.15 (-0.40, 0.09)

RIT_STD+MTX 0.04 (-0.20, 0.29)

SAR_200+MTX -0.02 (-0.22, 0.19)

BAR_4+MTX -0.06 (-0.19, 0.09)

ANBAI+MTX -0.38 (-0.62, -0.16)

CT-P13+MTX -0.29 (-0.63, 0.04)

SB2+MTX -0.001 (-0.30, 0.28)

ZRC-3197+MTX -0.001 (-0.27, 0.27)

TOC_8 (IV) TOF_STD+MTX -0.17 (-0.43, 0.10)

TOC_4 (IV)+MTX -0.005 (-0.22, 0.22)

TOC_8 (IV)+MTX -0.13 (-0.35, 0.09)

GOL_STD (SC)+MTX 0.001 (-0.16, 0.16)

102


GOL_STD (IV)+MTX 0.03 (-0.19, 0.25)

INF_STD+MTX 0.06 (-0.16, 0.29)

CERTO_STD+MTX -0.06 (-0.22, 0.13)

RIT_STD -0.09 (-0.34, 0.16)

RIT_STD+MTX 0.11 (-0.14, 0.36)

SAR_200+MTX 0.05 (-0.16, 0.26)

BAR_4+MTX 0.01 (-0.15, 0.18)

ANBAI+MTX -0.32 (-0.55, -0.08)

CT-P13+MTX -0.23 (-0.57, 0.12)

SB2+MTX 0.06 (-0.23, 0.36)

ZRC-3197+MTX 0.06 (-0.24, 0.36)

TOC_4 (IV)+MTX TOC_8 (IV) 0.16 (-0.08, 0.41)

TOC_8 (IV)+MTX 0.03 (-0.11, 0.19)

GOL_STD (SC)+MTX 0.17 (-0.10, 0.44)

GOL_STD (IV)+MTX 0.19 (-0.12, 0.51)

INF_STD+MTX 0.23 (-0.09, 0.55)

CERTO_STD+MTX 0.11 (-0.16, 0.40)

RIT_STD 0.07 (-0.26, 0.41)

RIT_STD+MTX 0.27 (-0.05, 0.61)

SAR_200+MTX 0.21 (-0.09, 0.53)

BAR_4+MTX 0.17 (-0.10, 0.46)

ANBAI+MTX -0.16 (-0.48, 0.17)

CT-P13+MTX -0.06 (-0.47, 0.35)

SB2+MTX 0.23 (-0.14, 0.60)

103


ZRC-3197+MTX 0.23 (-0.14, 0.61)


GOL_STD (SC)+MTX 0.004 (-0.22, 0.23)

GOL_STD (IV)+MTX 0.03 (-0.24, 0.30)

INF_STD+MTX 0.07 (-0.21, 0.34)

CERTO_STD+MTX -0.05 (-0.28, 0.19)

RIT_STD -0.09 (-0.38, 0.21)

RIT_STD+MTX 0.11 (-0.18, 0.40)

SAR_200+MTX 0.05 (-0.22, 0.32)

BAR_4+MTX 0.01 (-0.21, 0.25)

ANBAI+MTX -0.32 (-0.60, -0.04)

CT-P13+MTX -0.23 (-0.61, 0.15)

SB2+MTX 0.06 (-0.27, 0.40)

ZRC-3197+MTX 0.06 (-0.28, 0.41)

GOL_STD (SC)+MTX TOC_8 (IV)+MTX 0.13 (-0.10, 0.36)

GOL_STD (IV)+MTX 0.16 (-0.12, 0.43)

INF_STD+MTX 0.20 (-0.09, 0.47)

CERTO_STD+MTX 0.08 (-0.16, 0.32)

RIT_STD 0.04 (-0.26, 0.34)

RIT_STD+MTX 0.24 (-0.06, 0.54)

SAR_200+MTX 0.18 (-0.09, 0.45)

BAR_4+MTX 0.14 (-0.09, 0.38)

ANBAI+MTX -0.19 (-0.48, 0.10)

CT-P13+MTX -0.10 (-0.48, 0.28)

104


SB2+MTX 0.20 (-0.15, 0.53)

ZRC-3197+MTX 0.19 (-0.15, 0.54)


INF_STD+MTX 0.06 (-0.17, 0.29)

CERTO_STD+MTX -0.06 (-0.23, 0.13)

RIT_STD -0.09 (-0.35, 0.16)

RIT_STD+MTX 0.11 (-0.15, 0.36)

SAR_200+MTX 0.05 (-0.17, 0.27)

BAR_4+MTX 0.01 (-0.16, 0.19)

ANBAI+MTX -0.32 (-0.57, -0.08)

CT-P13+MTX -0.23 (-0.58, 0.12)

SB2+MTX 0.06 (-0.24, 0.36)

ZRC-3197+MTX 0.06 (-0.25, 0.37)


CERTO_STD+MTX -0.08 (-0.31, 0.16)

RIT_STD -0.12 (-0.42, 0.18)

RIT_STD+MTX 0.08 (-0.21, 0.38)

SAR_200+MTX 0.02 (-0.25, 0.28)

BAR_4+MTX -0.02 (-0.25, 0.22)

ANBAI+MTX -0.35 (-0.63, -0.07)

CT-P13+MTX -0.26 (-0.64, 0.12)

SB2+MTX 0.03 (-0.30, 0.37)

ZRC-3197+MTX 0.03 (-0.31, 0.38)

CERTO_STD+MTX INF_STD+MTX -0.12 (-0.35, 0.13)

105


RIT_STD -0.15 (-0.45, 0.15)

RIT_STD+MTX 0.05 (-0.25, 0.35)

SAR_200+MTX -0.01 (-0.28, 0.26)

BAR_4+MTX -0.05 (-0.29, 0.19)

ANBAI+MTX -0.38 (-0.67, -0.09)

CT-P13+MTX -0.29 (-0.55, -0.03)

SB2+MTX -0.001 (-0.19, 0.19)

ZRC-3197+MTX -0.002 (-0.34, 0.35)

RIT_STD CERTO_STD+MTX -0.04 (-0.30, 0.22)

RIT_STD+MTX 0.16 (-0.10, 0.42)

SAR_200+MTX 0.10 (-0.13, 0.33)

BAR_4+MTX 0.06 (-0.13, 0.25)

ANBAI+MTX -0.27 (-0.52, -0.02)

CT-P13+MTX -0.17 (-0.53, 0.18)

SB2+MTX 0.12 (-0.20, 0.42)

ZRC-3197+MTX 0.11 (-0.20, 0.43)

RIT_STD+MTX RIT_STD 0.20 (-0.04, 0.43)

SAR_200+MTX 0.14 (-0.15, 0.43)

BAR_4+MTX 0.10 (-0.16, 0.36)

ANBAI+MTX -0.23 (-0.54, 0.08)

CT-P13+MTX -0.14 (-0.54, 0.26)

SB2+MTX 0.15 (-0.21, 0.51)

ZRC-3197+MTX 0.15 (-0.21, 0.52)

SAR_200+MTX RIT_STD+MTX -0.06 (-0.35, 0.23)

106


BAR_4+MTX

-0.10 (-0.36, 0.16)

ANBAI+MTX -0.43 (-0.74, -0.12)

CT-P13+MTX -0.34 (-0.74, 0.06)

SB2+MTX -0.05 (-0.41, 0.31)

ZRC-3197+MTX -0.05 (-0.41, 0.31)

BAR_4+MTX SAR_200+MTX -0.04 (-0.26, 0.19)

ANBAI+MTX -0.37 (-0.65, -0.09)

CT-P13+MTX -0.28 (-0.65, 0.10)

SB2+MTX 0.01 (-0.32, 0.34)

ZRC-3197+MTX 0.01 (-0.32, 0.35)

ANBAI+MTX BAR_4+MTX -0.33 (-0.58, -0.09)

CT-P13+MTX -0.24 (-0.59, 0.11)

SB2+MTX 0.05 (-0.26, 0.35)

ZRC-3197+MTX 0.05 (-0.25, 0.35)

CT-P13+MTX ANBAI+MTX 0.09 (-0.30, 0.48)

SB2+MTX 0.38 (0.03, 0.73)

ZRC-3197+MTX 0.38 (0.03, 0.74)

SB2+MTX CT-P13+MTX 0.29 (-0.04, 0.61)

ZRC-3197+MTX 0.29 (-0.14, 0.73)

ZRC-3197+MTX SB2+MTX -0.0002 (-0.39, 0.40)



Criteria -142.134

107

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1256 and favour the comparator. 1257 ABA = abatacept; ADA = adalimumab; ANBAI = Anbainuo (biosimilar of etanercept); BAR_4 = 4 mg baricitinib; CERTO = 1258 certolizumab pegol; CrI = credible interval; CT-P13 = biosimilar infliximab; ETN = etanercept; GOL = golimumab; HCQ = 1259 hydroxychloroquine; INF = infliximab; LFN = leflunomide; MD = mean difference; MTX = methotrexate; RIT = rituximab; SAR_200 = 1260 200 mg sarilumab; SB2 = biosimilar infliximab; SSZ = sulfasalazine; STD = standard dose; TOC_4 = 4 mg/kg tocilizumab; TOC_8 = 1261 8 mg/kg tocilizumab; TOF= tofacitinib; ZRC-3197 = biosimilar adalimumab. 1262

1263


Four studies149, 161, 209, 215 were included in the evidence network for the HAQ-DI outcome with 1265

monotherapy of a csDMARD other than MTX as the common comparator (Placebo+csDMARD). 1266

There were six direct comparisons in the evidence network based on six treatments with two 2-1267

arm studies, one 3-arm study and one 5-arm study. The total number of participants contributing 1268

to the evidence network was 1086 (Figure 8). Assessment for consistency demonstrated that 1269

the model was consistent. The mean differences for all treatment comparisons with placebo as 1270

the common comparator are available in Table 12. A staircase table of the results as mean 1271

differences is also presented in Appendix 10. 1272

108

Figure 8. Evidence Network: Health Assessment Questionnaire, Disability Index (Placebo+csDMARD) 1273

There were no statistically significant results for any of the treatment comparisons. 1274

1275

Table 12: Health Assessment Questionnaire Disability Index (Placebo+csDMARD): Mean Differences for All 1276 Treatment Comparisons – Random Effects Model 1277


ETN_STD+

csDMARD Placebo+csDMARD -0.19 (-6.44, 6.13)

TOC_8

(IV)+csDMARD -0.63 (-6.91, 5.62)

BAR_4+csDMARD -0.24 (-6.53, 6.05)

SIR_100+csDMARD -0.14 (-6.35, 6.12)

109


SIR_50+csDMARD -0.37 (-6.67, 5.85)

TOC_8

(IV)+csDMARD ETN_STD+csDMARD -0.44 (-9.34, 8.44)

BAR_4+csDMARD -0.05 (-8.91, 8.72)

SIR_100+csDMARD 0.05 (-8.84, 8.85)

SIR_50+csDMARD -0.19 (-9.02, 8.69)

BAR_4+csDMARD TOC_8 (IV)+csDMARD 0.40 (-8.55, 9.30)

SIR_100+csDMARD 0.49 (-8.29, 9.47)

SIR_50+csDMARD 0.26 (-8.61, 9.07)

SIR_100+csDMARD BAR_4+csDMARD 0.10 (-8.76, 9.02)

SIR_50+csDMARD -0.13 (-9.10, 8.79)

SIR_50+csDMARD SIR_100+csDMARD -0.24 (-6.51, 6.07)


Deviance Information Criteria -17.679

Fixed-Effect Model Residual Deviance 9.017 vs 9 datapoints


Total Patients

1086

Total Studies

4

2-arm 2

3-arm 1

4-arm 0

5-arm 1

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1278 and favour the comparator. 1279

110

BAR_4 = 4 mg baricitinib; CrI = credible interval; MD = mean difference; SIR_100 = 100 mg sirukumab; SIR_50 = 50 mg sirukumab; 1280 STD = standard dose; TOC_4 = 4 mg/kg tocilizumab; TOC_8 = 8 mg/kg tocilizumab 1281

1282

6.4.4 Remission 1283


There were 23 studies (20 2-arm studies and three 3-arm studies)95, 130, 136, 137, 143, 148, 153, 165, 167, 1285 169, 173, 184-186, 191, 197, 202, 222, 227, 232, 235, 247, 249 included with methotrexate monotherapy as the 1286

common comparator and that reported on remission outcomes using DAS28 scores less than 1287

2.6. The evidence network involved 6882 participants and 15 treatments forming 29 direct 1288

comparisons. Assessment for consistency demonstrated that the model was fairly consistent. A 1289

geometric illustration of the evidence network is presented in Figure 9 and the odds ratios for all 1290

treatment comparisons with MTX monotherapy as the common comparator are available in 1291

Table 13. 1292

1293

Figure 9. Evidence Network: Remission (Placebo+MTX)

1294

Compared with MTX monotherapy, there was a statistically significantly higher odds of going 1295

111

into remission for participants receiving combination therapy with MTX and either etanercept, 1296

abatacept (IV), tocilizumab (4 mg/kg or 8 mg/kg), golimumab (SC), infliximab, certolizumab 1297

pegol, CT-P13 (infliximab biosimilar), or SB2 (infliximab biosimilar) and also 8 mg/kg tocilizumab 1298

monotherapy (Table 13). 1299

1300

When the comparator was etanercept monotherapy, the following biologics in combination with 1301

MTX resulted in higher odds of disease remission: etanercept, tocilizumab (4 mg/kg or 8 mg/kg), 1302

golimumab, infliximab, and certolizumab pegol (Table 13). Monotherapy with 8 mg/kg 1303

tocilizumab was also statistically significant compared with etanercept monotherapy (Table 13). 1304

1305

Three treatments demonstrated higher odds of remission compared with etanercept in 1306

combination with MTX: 8 mg/kg tocilizumab monotherapy, 8 mg/kg tocilizumab in combination 1307

with MTX, and golimumab (SC) in combination with MTX (Table 13). There were no other 1308

statistically significant results for the remaining comparisons of biologics and biosimilars to one 1309

another. 1310

1311

Table 13: Remission (Placebo+MTX): Odds Ratios, Relative Risks and Risk Differences for All Treatment 1312 Comparisons – Random Effects Model 1313


ETN_STD Placebo+MTX 1.40 (0.65, 3.02) 1.39 (0.66, 2.86) 0.01 (-0.01, 0.05)

ETN_STD+MTX

2.88 (1.31, 6.00) 2.74 (1.30, 5.30) 0.05 (0.01, 0.12)

ABA_STD (IV)+MTX

5.72 (3.29, 11.20) 5.07 (3.08, 9.09) 0.11 (0.06, 0.20)

TOF_STD+MTX

3.49 (0.91, 15.48) 3.27 (0.91, 11.38) 0.06 (-0.002, 0.27)

TOC_8 (IV)

10.71 (3.77, 35.61) 8.49 (3.48, 19.77) 0.20 (0.07, 0.45)

TOC_4 (IV)+MTX

11.77 (2.92, 51.30) 9.12 (2.77, 23.40) 0.21 (0.05, 0.54)

TOC_8 (IV)+MTX

14.68 (4.70, 52.71) 10.72 (4.23, 24.00) 0.26 (0.09, 0.55)

GOL_STD

(SC)+MTX

11.28 (4.67, 32.94) 8.84 (4.19, 19.76) 0.21 (0.09, 0.40)

INF_STD+MTX

6.13 (2.30, 17.64) 5.38 (2.22, 12.60) 0.12 (0.03, 0.29)

CERTO_STD+MTX

9.50 (2.55, 55.25) 7.72 (2.44, 25.32) 0.18 (0.04, 0.54)

HD203+MTX

3.23 (0.98, 10.30) 3.05 (0.98, 8.29) 0.05 (-0.001, 0.20)

SB4+MTX

3.02 (0.97, 8.98) 2.86 (0.97, 7.44) 0.05 (-0.001, 0.17)

112


CT-P13+MTX

8.60 (2.33, 33.70) 7.14 (2.25, 18.81) 0.16 (0.03, 0.44)

SB2+MTX

5.44 (1.50, 20.65) 4.86 (1.47, 13.89) 0.10 (0.01, 0.33)


ABA_STD (IV)+MTX

4.07 (1.64, 11.28) 3.65 (1.56, 9.38) 0.10 (0.03, 0.19)

TOF_STD+MTX

2.49 (0.53, 13.12) 2.36 (0.54, 9.89) 0.05 (-0.02, 0.25)

TOC_8 (IV)

7.62 (2.11, 30.76) 6.08 (1.97, 18.26) 0.19 (0.05, 0.44)

TOC_4 (IV)+MTX

8.38 (1.73, 42.81) 6.51 (1.66, 21.50) 0.20 (0.03, 0.53)

TOC_8 (IV)+MTX

10.47 (2.70, 45.47) 7.69 (2.43, 22.63) 0.25 (0.07, 0.53)

GOL_STD

(SC)+MTX

8.09 (2.48, 29.86) 6.39 (2.25, 18.83) 0.20 (0.07, 0.39)

INF_STD+MTX

4.38 (1.29, 15.95) 3.88 (1.26, 11.94) 0.10 (0.01, 0.28)

CERTO_STD+MTX

6.84 (1.46, 45.85) 5.58 (1.42, 22.32) 0.17 (0.02, 0.53)

HD203+MTX

2.31 (0.80, 6.42) 2.20 (0.81, 5.41) 0.04 (-0.01, 0.17)

SB4+MTX

2.15 (0.80, 5.52) 2.06 (0.80, 4.79) 0.04 (-0.01, 0.14)

CT-P13+MTX

6.14 (1.37, 29.05) 5.11 (1.34, 17.21) 0.15 (0.02, 0.43)

SB2+MTX

3.89 (0.87, 17.82) 3.50 (0.88, 12.63) 0.09 (-0.01, 0.31)

ABA_STD (IV)+MTX ETN_STD+MTX 1.98 (0.81, 5.66) 1.85 (0.83, 4.79) 0.06 (-0.02, 0.16)

TOF_STD+MTX

1.21 (0.26, 6.47) 1.20 (0.28, 5.03) 0.01 (-0.08, 0.22)

TOC_8 (IV)

3.73 (1.04, 15.11) 3.10 (1.03, 9.17) 0.15 (0.004, 0.40)

TOC_4 (IV)+MTX

4.10 (0.85, 21.06) 3.32 (0.87, 10.78) 0.17 (-0.01, 0.49)

TOC_8 (IV)+MTX

5.11 (1.35, 22.57) 3.91 (1.29, 11.41) 0.21 (0.03, 0.50)

GOL_STD

(SC)+MTX

3.96 (1.23, 14.57) 3.24 (1.20, 9.44) 0.16 (0.02, 0.36)

INF_STD+MTX

2.14 (0.64, 7.98) 1.97 (0.67, 6.07) 0.07 (-0.04, 0.24)

CERTO_STD+MTX

3.33 (0.72, 22.32) 2.83 (0.75, 11.25) 0.13 (-0.03, 0.50)

HD203+MTX

1.12 (0.46, 2.79) 1.11 (0.48, 2.45) 0.01 (-0.04, 0.11)

SB4+MTX

1.05 (0.46, 2.39) 1.04 (0.48, 2.16) 0.003 (-0.04, 0.09)

CT-P13+MTX

2.99 (0.68, 14.50) 2.60 (0.70, 8.80) 0.11 (-0.03, 0.40)

113


SB2+MTX

1.90 (0.44, 8.97) 1.78 (0.47, 6.43) 0.05 (-0.06, 0.28)

TOF_STD+MTX ABA_STD (IV)+MTX 0.61 (0.13, 2.97) 0.64 (0.16, 2.43) -0.05 (-0.16, 0.16)

TOC_8 (IV)

1.86 (0.53, 6.96) 1.67 (0.58, 4.30) 0.09 (-0.08, 0.35)

TOC_4 (IV)+MTX

2.05 (0.42, 9.79) 1.79 (0.47, 5.07) 0.11 (-0.09, 0.44)

TOC_8 (IV)+MTX

2.57 (0.68, 10.29) 2.11 (0.72, 5.26) 0.15 (-0.05, 0.45)

GOL_STD

(SC)+MTX

1.98 (0.65, 6.44) 1.75 (0.70, 4.26) 0.10 (-0.06, 0.31)

INF_STD+MTX

1.07 (0.42, 2.63) 1.06 (0.46, 2.18) 0.01 (-0.08, 0.15)

CERTO_STD+MTX

1.67 (0.38, 10.17) 1.53 (0.43, 5.21) 0.07 (-0.11, 0.44)

HD203+MTX

0.56 (0.14, 1.98) 0.60 (0.16, 1.77) -0.05 (-0.16, 0.09)

SB4+MTX

0.53 (0.14, 1.73) 0.56 (0.16, 1.59) -0.06 (-0.16, 0.07)

CT-P13+MTX

1.51 (0.42, 5.21) 1.41 (0.46, 3.36) 0.05 (-0.08, 0.31)

SB2+MTX

0.95 (0.27, 3.17) 0.95 (0.30, 2.46) -0.01 (-0.11, 0.19)

TOC_8 (IV) TOF_STD+MTX 3.07 (0.49, 18.21) 2.57 (0.56, 11.69) 0.13 (-0.11, 0.40)

TOC_4 (IV)+MTX

3.36 (0.44, 24.91) 2.75 (0.50, 13.55) 0.15 (-0.11, 0.49)

TOC_8 (IV)+MTX

4.21 (0.63, 26.55) 3.24 (0.70, 14.55) 0.19 (-0.07, 0.49)

GOL_STD

(SC)+MTX

3.28 (0.58, 17.98) 2.72 (0.65, 12.14) 0.14 (-0.09, 0.36)

INF_STD+MTX

1.76 (0.30, 9.70) 1.65 (0.37, 7.57) 0.05 (-0.16, 0.24)

CERTO_STD+MTX

2.76 (0.37, 24.07) 2.37 (0.44, 13.29) 0.11 (-0.14, 0.48)

HD203+MTX

0.93 (0.14, 5.45) 0.93 (0.17, 4.67) -0.01 (-0.21, 0.15)

SB4+MTX

0.86 (0.13, 4.86) 0.87 (0.17, 4.26) -0.01 (-0.22, 0.12)

CT-P13+MTX

2.46 (0.35, 16.45) 2.16 (0.41, 10.64) 0.10 (-0.14, 0.38)

SB2+MTX

1.55 (0.22, 10.17) 1.48 (0.27, 7.66) 0.04 (-0.18, 0.27)

TOC_4 (IV)+MTX TOC_8 (IV) 1.09 (0.45, 2.72) 1.06 (0.51, 1.99) 0.01 (-0.12, 0.21)

TOC_8 (IV)+MTX

1.37 (0.74, 2.57) 1.25 (0.80, 1.99) 0.06 (-0.05, 0.19)

GOL_STD

(SC)+MTX

1.06 (0.24, 4.60) 1.04 (0.36, 3.26) 0.01 (-0.28, 0.26)

114


INF_STD+MTX

0.57 (0.12, 2.59) 0.64 (0.20, 2.15) -0.08 (-0.35, 0.14)

CERTO_STD+MTX

0.90 (0.15, 6.35) 0.92 (0.23, 3.66) -0.02 (-0.32, 0.37)

HD203+MTX

0.30 (0.06, 1.45) 0.36 (0.09, 1.36) -0.14 (-0.40, 0.05)

SB4+MTX

0.28 (0.06, 1.29) 0.34 (0.09, 1.24) -0.14 (-0.40, 0.03)

CT-P13+MTX

0.79 (0.14, 4.58) 0.83 (0.21, 3.07) -0.04 (-0.32, 0.28)

SB2+MTX

0.50 (0.09, 2.84) 0.57 (0.14, 2.26) -0.09 (-0.36, 0.17)


GOL_STD

(SC)+MTX

0.98 (0.17, 5.45) 0.98 (0.31, 3.90) -0.004 (-0.37, 0.27)

INF_STD+MTX

0.52 (0.09, 3.07) 0.59 (0.17, 2.55) -0.10 (-0.43, 0.15)

CERTO_STD+MTX

0.83 (0.11, 6.89) 0.87 (0.20, 4.14) -0.03 (-0.41, 0.36)

HD203+MTX

0.27 (0.04, 1.69) 0.34 (0.08, 1.56) -0.15 (-0.49, 0.06)

SB4+MTX

0.25 (0.04, 1.49) 0.31 (0.08, 1.42) -0.16 (-0.49, 0.04)

CT-P13+MTX

0.73 (0.11, 5.22) 0.78 (0.18, 3.59) -0.05 (-0.40, 0.28)

SB2+MTX

0.46 (0.07, 3.28) 0.53 (0.12, 2.62) -0.11 (-0.45, 0.17)

GOL_STD

(SC)+MTX TOC_8 (IV)+MTX 0.77 (0.16, 3.55) 0.83 (0.29, 2.62) -0.05 (-0.38, 0.23)

INF_STD+MTX

0.42 (0.09, 1.99) 0.50 (0.16, 1.72) -0.14 (-0.44, 0.11)

CERTO_STD+MTX

0.66 (0.10, 4.83) 0.73 (0.19, 2.92) -0.07 (-0.42, 0.32)

HD203+MTX

0.22 (0.04, 1.11) 0.28 (0.07, 1.09) -0.20 (-0.49, 0.01)

SB4+MTX

0.20 (0.04, 0.99) 0.27 (0.07, 0.99) -0.20 (-0.50, -0.001)

CT-P13+MTX

0.58 (0.10, 3.51) 0.66 (0.17, 2.47) -0.09 (-0.41, 0.24)

SB2+MTX

0.37 (0.06, 2.16) 0.46 (0.11, 1.81) -0.15 (-0.46, 0.13)

INF_STD+MTX GOL_STD (SC)+MTX 0.54 (0.13, 2.15) 0.61 (0.19, 1.81) -0.09 (-0.32, 0.13)

CERTO_STD+MTX

0.84 (0.16, 6.00) 0.88 (0.23, 3.35) -0.03 (-0.30, 0.37)

HD203+MTX

0.28 (0.06, 1.23) 0.34 (0.09, 1.18) -0.15 (-0.36, 0.03)

SB4+MTX

0.26 (0.06, 1.09) 0.32 (0.09, 1.08) -0.16 (-0.36, 0.01)

CT-P13+MTX

0.75 (0.14, 3.81) 0.80 (0.20, 2.60) -0.05 (-0.29, 0.26)

115


SB2+MTX

0.48 (0.09, 2.36) 0.55 (0.13, 1.92) -0.10 (-0.33, 0.15)


HD203+MTX

0.53 (0.10, 2.39) 0.57 (0.13, 2.12) -0.06 (-0.24, 0.10)

SB4+MTX

0.49 (0.10, 2.11) 0.53 (0.13, 1.92) -0.06 (-0.24, 0.08)

CT-P13+MTX

1.40 (0.58, 3.30) 1.32 (0.63, 2.48) 0.04 (-0.06, 0.22)

SB2+MTX

0.88 (0.38, 2.01) 0.90 (0.42, 1.73) -0.01 (-0.10, 0.11)

HD203+MTX CERTO_STD+MTX 0.33 (0.04, 2.00) 0.39 (0.08, 1.81) -0.12 (-0.49, 0.08)

SB4+MTX

0.31 (0.04, 1.75) 0.37 (0.08, 1.64) -0.13 (-0.49, 0.06)

CT-P13+MTX

0.88 (0.10, 6.07) 0.91 (0.18, 4.05) -0.02 (-0.40, 0.31)

SB2+MTX

0.56 (0.07, 3.74) 0.62 (0.12, 2.93) -0.08 (-0.45, 0.19)

SB4+MTX HD203+MTX 0.93 (0.27, 3.16) 0.94 (0.31, 2.86) -0.005 (-0.12, 0.09)

CT-P13+MTX

2.66 (0.47, 16.56) 2.32 (0.52, 10.43) 0.10 (-0.08, 0.39)

SB2+MTX

1.68 (0.30, 10.21) 1.59 (0.34, 7.53) 0.04 (-0.11, 0.27)

CT-P13+MTX SB4+MTX 2.86 (0.52, 17.04) 2.48 (0.56, 10.79) 0.11 (-0.06, 0.39)

SB2+MTX

1.81 (0.34, 10.56) 1.70 (0.38, 7.77) 0.05 (-0.10, 0.28)

SB2+MTX CT-P13+MTX 0.63 (0.19, 2.08) 0.69 (0.25, 1.82) -0.05 (-0.26, 0.10)

Random-Effect

Model Residual Deviance 52.51 vs 47 datapoints


Criteria 295.404

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1314 and favour the comparator. 1315 ABA = abatacept; CERTO = certolizumab pegol; CrI = credible interval; CT-P13 = biosimilar infliximab; ETN = etanercept; GOL = 1316 golimumab; HD203 = etanercept biosimilar; INF = infliximab; IV = intravenous; MTX = methotrexate; OR = odds ratio; RD = risk 1317 difference; RR = relative risk; SB2 = biosimilar infliximab; SB4 = biosimilar etanercept; STD = standard dose; TOC_4 = 4mg/kg 1318 tocilizumab; TOC_8 = 8mg/kg tocilizumab; TOF = tofacitinib. 1319

1320


There were two RCTs215, 248 that permitted concomitant treatment with a csDMARD that 1322

reported data on remission outcomes. A NMA could not be conducted since there were too few 1323

116

studies and each study presented different treatment comparisons (Figure 10). Thus, a 1324

descriptive analysis is presented below, along with the event data in Table 14. 1325

1326

Figure 10: Evidence Network: Remission (Placebo+csDMARD) 1327

In the study by Yacizi and colleagues,248 many more participants receiving 8 mg/kg tocilizumab 1328

in combination with a csDMARD achieved disease remission during the 16 weeks of treatment 1329

prior to study adaptation compared to participants receiving csDMARD monotherapy. There was 1330

not a noticeable difference in the number of participants achieving disease remission in the 1331

study comparing 100 mg and 50 mg sirukumab in combination with a csDMARD to csDMARD 1332

monotherapy during the 12 weeks of treatment prior to the adaptation in treatment (Table 14).215 1333

1334

Table 14: Remission Events, Concomitant Conventional Synthetic DMARD 1335

Author Treatment 1 n N Treatment 2 n N Treatment 3 n N

Yazici 2012 Placebo+csDMARD 4 205 TOC_8 (IV)+csDMARD 98 409

Smolen 2014 Placebo+csDMARD 0 30 SIR_100+csDMARD 1 30 SIR_50+csDMARD 4 30

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 1336 csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; IV = intravenous; SIR_100 = 100mg sirukumab; SIR_50 1337 = 50mg sirukumab; TOC_8 = 8mg/kg tocilizumab 1338

1339

117

6.4.5 Health-Related Quality of Life 1340

6.4.5.1 Methotrexate Monotherapy as a Comparator 1341

In terms of HRQOL as measured by the SF-36 Physical Component Score (PCS), eleven 1342

studies95, 132, 159, 179, 191, 210, 218-220, 247, 250 were included in the evidence network with MTX 1343

monotherapy as the common comparator (Placebo+MTX). There were 15 direct comparisons in 1344

the evidence network based on nine treatments with nine 2-arm studies and two 3-arm studies. 1345

A total of 4347 participants contributed to the evidence network (Figure 11). Assessment for 1346

consistency demonstrated that the model was consistent. The mean differences for all treatment 1347


table of the results as mean differences is also presented in Appendix 10. 1349

Figure 11. Evidence Network: Health-Related Quality of Life, SF-36 Physical Component Score (Placebo+MTX)

1350

A statistically significant improvement in physical HRQOL was observed for each of the 1351

biologics compared to methotrexate monotherapy. No significant results were found for any of 1352

the head-to-head comparisons of biologics, small molecules, and biosimilars. 1353

1354

118

Table 15: Health-Related Quality of Life, SF-36 Physical Component Score (Placebo+MTX): Mean Differences 1355 for All Treatment Comparisons – Random Effects Model 1356


ABA_STD (IV)+MTX Placebo+MTX 4.15 (2.64, 5.75)

TOF_STD+MTX 3.78 (1.22, 6.20)

ADA_STD+MTX 3.12 (0.60, 5.49)

GOL_STD (SC)+MTX 4.84 (3.09, 6.69)

GOL_STD (IV)+MTX 3.62 (1.42, 5.93)

INF_STD+MTX 4.59 (2.83, 5.95)

CERTO_STD+MTX 5.06 (3.72, 6.42)

CT-P13+MTX 5.37 (2.39, 7.99)

TOF_STD+MTX ABA_STD (IV)+MTX -0.36 (-3.38, 2.48)

ADA_STD+MTX -1.02 (-4.03, 1.79)

GOL_STD (SC)+MTX 0.67 (-1.64, 3.10)

GOL_STD (IV)+MTX -0.50 (-3.27, 2.26)

INF_STD+MTX 0.43 (-1.78, 2.18)

CERTO_STD+MTX 0.91 (-1.20, 2.93)

CT-P13+MTX 1.22 (-2.06, 4.05)

ADA_STD+MTX TOF_STD+MTX -0.68 (-3.01, 1.64)

GOL_STD (SC)+MTX 1.05 (-1.93, 4.27)

GOL_STD (IV)+MTX -0.13 (-3.41, 3.29)

INF_STD+MTX 0.80 (-2.24, 3.62)

CERTO_STD+MTX 1.27 (-1.49, 4.12)

CT-P13+MTX 1.58 (-2.29, 5.18)

GOL_STD (SC)+MTX ADA_STD+MTX 1.73 (-1.18, 4.89)

119


GOL_STD (IV)+MTX 0.54 (-2.72, 3.96)

INF_STD+MTX 1.48 (-1.59, 4.26)

CERTO_STD+MTX 1.92 (-0.76, 4.81)

CT-P13+MTX 2.27 (-1.66, 5.85)

GOL_STD (IV)+MTX GOL_STD (SC)+MTX -1.19 (-4.05, 1.57)

INF_STD+MTX -0.26 (-2.89, 1.90)

CERTO_STD+MTX 0.21 (-2.06, 2.36)

CT-P13+MTX 0.51 (-3.07, 3.64)


CERTO_STD+MTX 1.42 (-1.23, 4.02)

CT-P13+MTX 1.73 (-2.07, 5.16)

CERTO_STD+MTX INF_STD+MTX 0.45 (-1.39, 2.76)

CT-P13+MTX 0.78 (-1.60, 3.15)

CT-P13+MTX CERTO_STD+MTX 0.32 (-3.02, 3.23)





Total Patients

4347

Total Studies

11

2-arm 9

3-arm 2

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1357 and favour the comparator. 1358

120

ABA = abatacept; ADA = adalimumab; CERTO = certolizumab pegol; CrI = credible interval; CT-P13 = biosimilar infliximab; GOL = 1359 golimumab; INF = infliximab; MD = mean difference; STD = standard dose; TOF = tofacitinib. 1360

1361

The Mental Component Score (MCS) of the SF-36 was also assessed for HRQOL and 10 1362

studies were included.95, 132, 159, 191, 210, 218-220, 247, 250 There were 14 direct comparisons in the 1363

evidence network based on nine treatments with eight 2-arm studies and two 3-arm studies. A 1364

total of 4204 participants contributed to the evidence network (Figure 12). Assessment for 1365

consistency demonstrated that the model was consistent. The mean differences for all treatment 1366


table of the results as mean differences is also presented in Appendix 10. 1368

Figure 12. Evidence Network: Health-Related Quality of Life, SF-36 Mental Component Score (Placebo+MTX) 1369

Compared to MTX monotherapy, abatacept (IV), golimumab (SC) and golimumab (IV), all in combination 1370

with MTX, demonstrated a statistically significant improvement in mental HRQOL. No significant results 1371

were found for any of the head-to-head comparisons of biologics, tsDMARDs, and biosimilars. 1372

121

Table 16: Health-Related Quality of Life, SF-36 Mental Component Score (Placebo+MTX): Mean Differences 1373 for All Treatment Comparisons – Random Effects Model 1374


ABA_STD (IV)+MTX Placebo+MTX 2.77 (0.04, 6.26)

TOF_STD+MTX 1.38 (-3.09, 5.77)

ADA_STD+MTX 1.61 (-2.93, 6.02)

GOL_STD (SC)+MTX 1.87 (-1.48, 5.16)

GOL_STD (IV)+MTX 5.91 (1.52, 10.23)

INF_STD+MTX 2.15 (-1.91, 6.77)

CERTO_STD+MTX 3.60 (1.11, 6.13)

CT-P13+MTX 2.00 (-3.88, 8.56)

TOF_STD+MTX ABA_STD (IV)+MTX -1.42 (-7.26, 3.61)

ADA_STD+MTX -1.18 (-7.02, 3.93)

GOL_STD (SC)+MTX -0.95 (-5.89, 3.27)

GOL_STD (IV)+MTX 3.12 (-2.67, 8.11)

INF_STD+MTX -0.67 (-4.95, 3.53)

CERTO_STD+MTX 0.85 (-3.63, 4.49)

CT-P13+MTX -0.79 (-7.01, 5.31)

ADA_STD+MTX TOF_STD+MTX 0.23 (-4.09, 4.49)

GOL_STD (SC)+MTX 0.47 (-5.14, 6.03)

GOL_STD (IV)+MTX 4.56 (-1.67, 10.76)

INF_STD+MTX 0.78 (-5.21, 7.16)

CERTO_STD+MTX 2.21 (-2.86, 7.38)

CT-P13+MTX 0.66 (-6.63, 8.57)

GOL_STD (SC)+MTX ADA_STD+MTX 0.27 (-5.35, 5.81)

GOL_STD (IV)+MTX 4.29 (-1.94, 10.52)

122

INF_STD+MTX 0.54 (-5.45, 7.10)

CERTO_STD+MTX 1.97 (-3.05, 7.20)

CT-P13+MTX 0.40 (-6.93, 8.48)


INF_STD+MTX 0.31 (-4.87, 6.01)

CERTO_STD+MTX 1.73 (-2.40, 5.99)

CT-P13+MTX 0.15 (-6.55, 7.49)

INF_STD+MTX GOL_STD (IV)+MTX -3.78 (-9.53, 2.73)

CERTO_STD+MTX

-2.32 (-7.20, 2.79)

CT-P13+MTX -3.92 (-11.20, 4.03)

CERTO_STD+MTX INF_STD+MTX 1.46 (-3.82, 6.21)

CT-P13+MTX -0.14 (-4.43, 4.35)

CT-P13+MTX CERTO_STD+MTX -1.61 (-8.01, 5.45)





Total Patients

4204

Total Studies

10

2-arm 8

3-arm 2

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1375 and favour the comparator. 1376 ABA = abatacept; ADA = adalimumab; CERTO = certolizumab pegol; CrI = credible interval; CT-P13 = biosimilar infliximab; GOL = 1377 golimumab; INF = infliximab; MD = mean difference; STD = standard dose; TOF = tofacitinib. 1378

1379

123

6.4.5.2 Conventional Synthetic DMARD as a Comparator 1380

Only two studies with csDMARD as the common comparator had data on the SF-36 PCS and 1381

MCS based on a total of 633 participants.215, 248 The included studies were the same for the SF-1382

36 PCS and MCS, thus a single geometric illustration of the evidence network is presented for 1383

both outcomes in Figure 13. The mean changes from baseline values for the SF-36 PCS were 1384

reported in Table 17 and the values for the SF-36 MCS are reported in Table 18. 1385

Figure 13. Evidence Network: Health-Related Quality of Life, SF-36 Physical Component Score (Placebo+csDMARD)

1386

Tocilizumab at 8 mg/kg in combination with csDMARD had a greater mean improvement from 1387

baseline in terms of physical HRQOL compared to csDMARD monotherapy (MD = 4.72 [3.11, 1388

6.33]); neither treatment had greater improvement than the other for mental HRQOL (MD = 1.03 1389

[-0.85, 2.91]).248 Likewise, sirukumab at 100 mg in combination with csDMARD had greater 1390

mean improvement from baseline versus csDMARD monotherapy in terms of physical HRQOL 1391

(MD = 3.80 [0.08, 7.52]), but in terms of mental HRQOL there was no statistically significant 1392

difference (-1.10 [-6.31, 4.11]).215 When comparing 50 mg/kg of sirukumab in combination with 1393

csDMARD to csDMARD monotherapy, sirukumab also demonstrated a statistically significant 1394

improvement from baseline for physical HRQOL (MD = 3.80 [0.19, 7.41]), but not for mental 1395

HRQOL (MD = 2.80 [-2.74, 8.34]).215 1396

124

1397 Table 17. Health-Related Quality of Life, SF-36 PCS Mean Change from Baseline Data, Concomitant 1398 Conventional Synthetic DMARD 1399

Author,

Year Treatment 1 N

Mean

(SE) Treatment 2 N

Mean

(SE) Treatment 3 N

Mean

(SE)

Yazici 2012

Placebo

+csDMARD

185 2.4 (0.66) TOC_8 (IV)

+csDMARD 358

7.12

(0.49)

Smolen

2014

Placebo

+csDMARD

30 2.6 (1.50)

SIR_100

+csDMARD

30 6.4 (1.17)

SIR_50

+csDMARD

30 6.4

(1.08)

Results are presented as the mean change from baseline, with larger numbers indicating greater improvement in the mental 1400 component of health-related quality of life. 1401 csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; IV = intravenous; SIR_100 = 100mg sirukuman; SIR_50 1402 = 50mg sirukumab; TOC_8 = 8mg/kg tocilizumab. 1403

1404 1405

Table 18. Health-Related Quality of Life, SF-36 MCS Mean Change from Baseline Data, Concomitant 1406 Conventional Synthetic DMARD 1407

Author,

Year Treatment 1 N

Mean

(SE) Treatment 2 N

Mean

(SE) Treatment 3 N

Mean

(SE)

Yazici 2012

Placebo

+csDMARD

185 2.23

(0.77)

TOC_8 (IV)

+csDMARD 358

3.26

(0.57)

Smolen

2014

Placebo

+csDMARD

30 5.1 (1.94)

SIR_100

+csDMARD

30

4.0

(1.83)

SIR_50

+csDMARD

30 7.9

(2.06)

Results are presented as the mean change from baseline, with larger numbers indicating greater improvement in the mental 1408 component of health-related quality of life. 1409 csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; IV = intravenous; SIR_100 = 100mg sirukuman; SIR_50 1410 = 50mg sirukumab; TOC_8 = 8mg/kg tocilizumab. 1411

1412

6.4.6 Pain 1413


Eighteen studies97, 134, 154, 163, 184, 186, 193, 200, 203, 205, 217, 218, 220, 228, 229, 244, 246, 247 were included for pain 1415

in the evidence network with MTX monotherapy as the common comparator. The evidence 1416

network involved 6558 participants and 18 treatments (18 2-arm studies, four 3-arm studies, 1417

and one 4-arm study) forming 31 direct comparisons. Assessment for consistency demonstrated 1418

that the model was consistent. A geometric illustration of the evidence network is presented in 1419

Figure 14. Two different VAS scales were reported in the included studies, so the results are 1420

reported as standardized mean differences in Table 19 for all treatment comparisons. 1421

125

Figure 14. Evidence Network: Pain (Placebo+MTX)

1422

Compared to MTX monotherapy, the following treatments demonstrated a statistically significant 1423

reduction in pain: etanercept, abatacept (IV), adalimumab, tofacitinib, certolizumab pegol, 200 1424

mg sarilumab, and 4 mg baricitinib, all in combination with MTX. Compared to no treatment 1425

(placebo), the same treatments listed above – as well as 10 mg leflunomide, and certolizumab 1426

pegol monotherapy – demonstrated a statistically significant reduction in pain. Most of these 1427

comparisons had large effect sizes that may represent clinically important reductions in pain. 1428

Certolizumab pegol and 200 mg sarilumab (both in combination with MTX) had statistically 1429

significant reductions in pain compared to double csDMARD therapy with sulfasalazine and 1430

hydroxychloroquine (SMD = -1.70 [-2.93, -0.41] and SMD = -1.44 [-2.67, -0.16], respectively), 1431

representing a large effect size. Certolizumab pegol in combination with MTX and monotherapy 1432

both also had greater reductions in pain compared to adalimumab monotherapy (SMD = -2.00 1433

[-3.55, -0.43] and SMD = -1.22 [-2.25, -0.16], respectively); tofacitinib monotherapy also had a 1434

reduction in pain compared to adalimumab monotherapy (-1.74 [-3.29, -0.17]). These results 1435

126

had large effect sizes. In addition, certolizumab in combination with MTX demonstrated greater 1436

reduction in pain compared to tofacitinib monotherapy (-1.59, [-3.14, -0.02]) with a large effect 1437

size based on the point estimate, but minimal statistical significance. 1438

1439

Table 19: Pain (Placebo+MTX): Standardized Mean Differences for All Treatment Comparisons – Random 1440 Effects Model 1441


Placebo Placebo+MTX 0.60 (-0.44, 1.63)

LEF_10 -0.67 (-1.98, 0.65)

SSZ+HCQ 0.12 (-0.88, 1.07)

MTX+SSZ+HCQ -0.58 (-1.37, 0.13)

ETN_STD+MTX -0.72 (-1.42, -0.06)

ABA_STD (IV)+MTX -0.91 (-1.71, -0.11)

ADA_STD 0.42 (-0.92, 1.74)

ADA_STD+MTX -0.66 (-1.15, -0.30)

TOF_STD 0.01 (-1.34, 1.33)

TOF_STD+MTX -0.81 (-1.31, -0.35)

CERTO_STD -0.79 (-1.65, 0.05)

CERTO_STD+MTX -1.58 (-2.38, -0.79)

SAR_200+MTX -1.32 (-2.12, -0.52)

BAR_4+MTX -0.68 (-1.44, -0.01)

ZRC-3197+MTX -0.71 (-1.72, 0.17)

LEF_10 Placebo -1.27 (-2.10, -0.43)

SSZ+HCQ -0.48 (-1.92, 0.91)

MTX+SSZ+HCQ -1.18 (-2.50, 0.07)

ETN_STD+MTX -1.32 (-2.58, -0.10)

ABA_STD (IV)+MTX -1.51 (-2.81, -0.20)

127

ADA_STD -0.18 (-1.05, 0.67)

ADA_STD+MTX -1.26 (-2.45, -0.22)

TOF_STD -0.60 (-1.46, 0.26)

TOF_STD+MTX -1.41 (-2.57, -0.30)

CERTO_STD -1.40 (-1.98, -0.81)

CERTO_STD+MTX -2.18 (-3.49, -0.88)

SAR_200+MTX -1.92 (-3.22, -0.60)

BAR_4+MTX -1.29 (-2.59, -0.07)

ZRC-3197+MTX -1.31 (-2.78, 0.03)

SSZ+HCQ LEF_10 0.78 (-0.89, 2.40)

MTX+SSZ+HCQ 0.09 (-1.48, 1.57)

ETN_STD+MTX -0.05 (-1.56, 1.42)

ABA_STD (IV)+MTX -0.25 (-1.79, 1.30)

ADA_STD 1.09 (-0.12, 2.27)

ADA_STD+MTX 0.01 (-1.45, 1.32)

TOF_STD 0.67 (-0.53, 1.86)

TOF_STD+MTX -0.14 (-1.57, 1.23)

CERTO_STD -0.13 (-1.15, 0.87)

CERTO_STD+MTX -0.92 (-2.45, 0.62)

SAR_200+MTX -0.65 (-2.20, 0.89)

BAR_4+MTX -0.02 (-1.56, 1.44)

ZRC-3197+MTX -0.04 (-1.75, 1.51)

MTX+SSZ+HCQ SSZ+HCQ -0.70 (-1.65, 0.23)

ETN_STD+MTX -0.84 (-1.88, 0.21)

ABA_STD (IV)+MTX -1.03 (-2.26, 0.24)

128

ADA_STD 0.30 (-1.34, 1.97)

ADA_STD+MTX -0.78 (-1.88, 0.25)

TOF_STD -0.12 (-1.75, 1.56)

TOF_STD+MTX -0.93 (-2.01, 0.15)

CERTO_STD -0.92 (-2.18, 0.41)

CERTO_STD+MTX -1.70 (-2.93, -0.41)

SAR_200+MTX -1.44 (-2.67, -0.16)

BAR_4+MTX -0.81 (-2.03, 0.39)

ZRC-3197+MTX -0.83 (-2.24, 0.48)

ETN_STD+MTX MTX+SSZ+HCQ -0.14 (-0.81, 0.57)

ABA_STD (IV)+MTX -0.33 (-1.38, 0.81)

ADA_STD 1.00 (-0.51, 2.58)

ADA_STD+MTX -0.07 (-0.97, 0.75)

TOF_STD 0.58 (-0.91, 2.16)

TOF_STD+MTX -0.23 (-1.11, 0.67)

CERTO_STD -0.21 (-1.32, 0.96)

CERTO_STD+MTX -1.00 (-2.05, 0.14)

SAR_200+MTX -0.74 (-1.79, 0.40)

BAR_4+MTX -0.11 (-1.14, 0.95)

ZRC-3197+MTX -0.13 (-1.36, 1.05)


ADA_STD 1.14 (-0.35, 2.65)

ADA_STD+MTX 0.07 (-0.79, 0.81)

TOF_STD 0.72 (-0.76, 2.25)

TOF_STD+MTX -0.09 (-0.93, 0.73)

129

CERTO_STD -0.08 (-1.15, 1.03)

CERTO_STD+MTX -0.87 (-1.90, 0.21)

SAR_200+MTX -0.60 (-1.62, 0.48)

BAR_4+MTX 0.03 (-0.97, 1.00)

ZRC-3197+MTX 0.01 (-1.19, 1.12)

ADA_STD ABA_STD (IV)+MTX 1.34 (-0.24, 2.88)

ADA_STD+MTX 0.26 (-0.72, 1.09)

TOF_STD 0.92 (-0.64, 2.47)

TOF_STD+MTX 0.11 (-0.85, 1.01)

CERTO_STD 0.12 (-1.05, 1.27)

CERTO_STD+MTX -0.67 (-1.81, 0.46)

SAR_200+MTX -0.40 (-1.54, 0.72)

BAR_4+MTX 0.23 (-0.89, 1.26)

ZRC-3197+MTX 0.21 (-1.11, 1.37)

ADA_STD+MTX ADA_STD -1.08 (-2.54, 0.26)

TOF_STD -0.42 (-1.28, 0.45)

TOF_STD+MTX -1.23 (-2.66, 0.17)

CERTO_STD -1.22 (-2.25, -0.16)

CERTO_STD+MTX -2.00 (-3.55, -0.43)

SAR_200+MTX -1.74 (-3.29, -0.17)

BAR_4+MTX -1.11 (-2.65, 0.37)

ZRC-3197+MTX -1.13 (-2.83, 0.44)

TOF_STD ADA_STD+MTX 0.66 (-0.68, 2.12)

TOF_STD+MTX -0.15 (-0.68, 0.46)

CERTO_STD -0.14 (-1.02, 0.87)

130

CERTO_STD+MTX -0.93 (-1.76, 0.06)

SAR_200+MTX -0.67 (-1.49, 0.31)

BAR_4+MTX -0.04 (-0.72, 0.72)

ZRC-3197+MTX -0.05 (-0.90, 0.79)


CERTO_STD -0.80 (-1.84, 0.25)

CERTO_STD+MTX -1.59 (-3.14, -0.02)

SAR_200+MTX -1.32 (-2.88, 0.24)

BAR_4+MTX -0.69 (-2.25, 0.79)

ZRC-3197+MTX -0.71 (-2.41, 0.87)

CERTO_STD TOF_STD+MTX 0.01 (-0.93, 1.01)

CERTO_STD+MTX -0.78 (-1.67, 0.19)

SAR_200+MTX -0.51 (-1.41, 0.45)

BAR_4+MTX 0.12 (-0.73, 0.96)

ZRC-3197+MTX 0.10 (-0.96, 1.09)

CERTO_STD+MTX CERTO_STD -0.79 (-1.96, 0.38)

SAR_200+MTX -0.52 (-1.68, 0.65)

BAR_4+MTX 0.11 (-1.05, 1.17)

ZRC-3197+MTX 0.08 (-1.25, 1.29)

SAR_200+MTX CERTO_STD+MTX 0.26 (-0.88, 1.39)

BAR_4+MTX 0.90 (-0.22, 1.93)

ZRC-3197+MTX 0.87 (-0.44, 2.04)

BAR_4+MTX SAR_200+MTX 0.63 (-0.48, 1.66)

ZRC-3197+MTX 0.61 (-0.70, 1.76)

ZRC-3197+MTX BAR_4+MTX -0.02 (-1.17, 1.06)

131

Random-Effect Model Total Residual Deviance 25.62 vs 42 datapoints


Fixed-Effect Model Total Residual Deviance 39.91 vs 42 datapoints


Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1442 and favour the comparator. Bold results represent large effect sizes. 1443 ABA = abatacept; ADA = adalimumab; BAR_4 = 4 mg baricitinib 4mg; CERTO = certolizumab pegol; CrI = credible interval; ETN = 1444 etanercept; HCQ = hydroxychloroquine; IV = intravenous; LEF_10 = 10 mg leflunomide; MTX = methotrexate; SAR_200 = 200 mg 1445 sarilumab; SMD = standardized mean difference; SSZ = sulfasalazine; STD = standard dose; TOF = tofacitinib; ZRC-3197 = 1446 biosimilar adalimumab. 1447

1448


There were three studies that reported on pain outcomes with a total of 712 participants 1450

contributing data.149, 161, 209 It was not possible to conduct an NMA due to the limited number of 1451

trials. No two studies investigated the same treatment comparison, so a descriptive analysis is 1452

presented. The comparator in all cases was csDMARD monotherapy and the treatments of 1453

interest were etanercept, 8 mg/kg tocilizumab and 4 mg baricitinib, all in combination with a 1454

csDMARD (Figure 15). In all three studies, the treatments of interest had a statistically 1455

significant reduction in pain from baseline compared to csDMARD monotherapy (Table 20). 1456

Figure 15. Evidence Network: Pain (Placebo+csDMARD)

1457

1458

Table 20: Pain, Standardized Mean Change from Baseline Data, Concomitant Conventional Synthetic DMARD 1459

132

Author, Year Treatment 1 Treatment 2 SMD (95% CI) SE

Hobbs 2015 Placebo+csDMARD ETN_STD+csDMARD -0.65 (-0.93, -0.38) 0.14

Hoffmann-La Roche 2015 Placebo+csDMARD TOC_8 (IV)+csDMARD -0.76 (-1.36, -0.15) 0.31

Dougados 2017 Placebo+csDMARD BAR_4+csDMARD -0.60 (-0.79, -0.41) 0.096

Results are presented as the standardized mean difference, with negative numbers indicating greater reduction in pain 1460 BAR_4 = 4mg baricitinib; CI = confidence interval; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN 1461 = etanercept; IV = intravenous; SE = standard error; SMD = standardized mean difference; TOC_8 = 8mg/kg tocilizumab. 1462

1463

6.4.7 Fatigue 1464


Twelve RCTs published in 11 articles130, 132, 159, 191, 193, 210, 213, 217, 218, 220, 251 were included for the 1466

reference case NMA of fatigue in the evidence network with MTX monotherapy as the common 1467

comparator. The evidence network involved 5910 participants and 12 treatments (10 2-arm 1468

studies and two 3-arm studies) forming 16 direct comparisons. More than one scale was used to 1469

measure fatigue, thus standardized mean differences were calculated. Assessment for 1470


evidence network is presented in Figure 16 and the standardized mean differences for all 1472

treatment comparisons with MTX monotherapy as the common comparator are available in 1473

Table 21. A staircase table of the results as standardized mean differences is also presented in 1474

Appendix 10. 1475

133

Figure 16. Evidence Network: Fatigue (Placebo+MTX)

1476

Only the standard dose of certolizumab pegol in combination with MTX had a statistically 1477

significantly greater reduction in fatigue compared to MTX monotherapy (OR = 1.25 [0.30, 1478

2.22]). There were no statistically significant results when comparing the biologics, tsDMARDs, 1479

and biosimilars to one another. 1480

1481 Table 21: Fatigue (Placebo+MTX): Standardized Mean Differences for All Treatment Comparisons – Random 1482 Effects Model 1483


ETN_STD+MTX Placebo+MTX 0.47 (-0.48, 1.42)

ABA_STD (IV)+MTX 0.43 (-0.54, 1.40)

TOF_STD+MTX 0.48 (-0.35, 1.41)

ADA_STD+MTX 0.35 (-0.18, 0.96)

TOC_4 (IV)+MTX 0.28 (-0.73, 1.28)

TOC_8 (IV)+MTX 0.37 (-0.61, 1.34)

134


GOL_STD (SC)+MTX 0.54 (-0.15, 1.23)

GOL_STD (IV)+MTX 0.52 (-0.46, 1.49)

CERTO_STD+MTX 1.25 (0.30, 2.22)

SAR_200+MTX 0.54 (-0.44, 1.51)

HD203+MTX 0.55 (-0.82, 1.86)


TOF_STD+MTX 0.01 (-1.24, 1.38)

ADA_STD+MTX -0.13 (-1.17, 1.05)

TOC_4 (IV)+MTX -0.19 (-1.57, 1.23)

TOC_8 (IV)+MTX -0.11 (-1.47, 1.28)

GOL_STD (SC)+MTX 0.07 (-1.10, 1.27)

GOL_STD (IV)+MTX 0.04 (-1.30, 1.44)

CERTO_STD+MTX 0.78 (-0.56, 2.13)

SAR_200+MTX 0.07 (-1.28, 1.44)

HD203+MTX 0.08 (-0.89, 1.07)

TOF_STD+MTX ABA_STD (IV)+MTX 0.05 (-1.22, 1.43)

ADA_STD+MTX -0.09 (-1.15, 1.11)

TOC_4 (IV)+MTX -0.15 (-1.54, 1.23)

TOC_8 (IV)+MTX -0.07 (-1.44, 1.31)

GOL_STD (SC)+MTX 0.11 (-1.06, 1.31)

GOL_STD (IV)+MTX 0.08 (-1.28, 1.45)

CERTO_STD+MTX 0.81 (-0.55, 2.22)

SAR_200+MTX 0.11 (-1.25, 1.50)

HD203+MTX 0.12 (-1.57, 1.76)

135


ADA_STD+MTX TOF_STD+MTX -0.14 (-1.00, 0.76)

TOC_4 (IV)+MTX -0.20 (-1.57, 1.08)

TOC_8 (IV)+MTX -0.11 (-1.49, 1.16)

GOL_STD (SC)+MTX 0.06 (-1.10, 1.13)

GOL_STD (IV)+MTX 0.03 (-1.34, 1.33)

CERTO_STD+MTX 0.77 (-0.58, 2.06)

SAR_200+MTX 0.06 (-1.28, 1.29)

HD203+MTX 0.07 (-1.60, 1.64)

TOC_4 (IV)+MTX ADA_STD+MTX -0.06 (-1.26, 1.02)

TOC_8 (IV)+MTX 0.02 (-1.18, 1.10)

GOL_STD (SC)+MTX 0.19 (-0.75, 1.04)

GOL_STD (IV)+MTX 0.18 (-1.00, 1.23)

CERTO_STD+MTX 0.91 (-0.26, 1.96)

SAR_200+MTX 0.20 (-0.98, 1.27)

HD203+MTX 0.20 (-1.30, 1.60)

TOC_8 (IV)+MTX TOC_4 (IV)+MTX 0.08 (-0.90, 1.06)

GOL_STD (SC)+MTX 0.26 (-0.94, 1.45)

GOL_STD (IV)+MTX 0.24 (-1.12, 1.60)

CERTO_STD+MTX 0.97 (-0.37, 2.39)

SAR_200+MTX 0.26 (-1.09, 1.64)

HD203+MTX 0.27 (-1.42, 1.95)


GOL_STD (IV)+MTX 0.15 (-1.23, 1.52)

CERTO_STD+MTX 0.88 (-0.46, 2.26)

136


SAR_200+MTX 0.18 (-1.17, 1.55)

HD203+MTX 0.19 (-1.52, 1.85)


CERTO_STD+MTX 0.71 (-0.46, 1.90)

SAR_200+MTX 0.00 (-1.16, 1.19)

HD203+MTX 0.01 (-1.51, 1.51)

CERTO_STD+MTX GOL_STD (IV)+MTX 0.73 (-0.60, 2.08)

SAR_200+MTX 0.03 (-1.35, 1.40)

HD203+MTX 0.03 (-1.65, 1.69)

SAR_200+MTX CERTO_STD+MTX -0.71 (-2.08, 0.67)

HD203+MTX -0.69 (-2.42, 0.93)

HD203+MTX SAR_200+MTX 0.01 (-1.67, 1.63)



Criteria -9.466

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1484 and favour the comparator. 1485 ADA = adalimumab; CERTO = certolizumab pegol; CrI = credible interval; ETN = etanercept; GOL = golimumab; HD203 = biosimilar 1486 etanercept; IV = intravenous; MTX = methotrexate; SAR_200 = 200 mg sarilumab; SC = subcutaneous; SMD = standardized mean 1487 difference; STD = standard dose; TOF = tofacitinib; TOC_4 = 4 mg/kg tocilizumab; TOC_8 = 8 mg/kg tocilizumab. 1488

1489


A total of three RCTs reported on fatigue outcomes, with 1817 participants contributing data.161, 1491 248, 251 No NMA was conducted because there were not enough studies for the model to run. In 1492

addition, none of the three studies compared the same two treatments for a pairwise MA, thus a 1493

descriptive analysis is presented below. The common comparator in all studies was csDMARD 1494

monotherapy; active treatments were 8 mg/kg tocilizumab, etanercept and adalimumab (Figure 1495

17). 1496

137

Figure 17. Evidence Network: Fatigue (Placebo+csDMARD)

1497

The standardized mean difference was calculated because not all the studies presented the 1498

same fatigue scale. All three biologics in combination with csDMARD (8 mg/kg tocilizumab, 1499

etanercept and adalimumab) demonstrated a statistically significant improvement in fatigue (i.e., 1500

less fatigue) compared to csDMARD monotherapy (Table 22). 1501

1502

1503 Table 22: Fatigue, Standardized Mean Difference Data, Concomitant Conventional Synthetic DMARD 1504

Author Treatment 1 Treatment 2 Mean (95% CI) SE

Yazici 2012 Placebo+csDMARD TOC_8 (IV)+csDMARD 0.27 (0.09, 0.45) 0.091

Hobbs 2015 Placebo+csDMARD ETN_STD+csDMARD 0.28 (0.007, 0.55) 0.14

Yount 2007 Placebo+csDMARD ADA_STD+csDMARD 0.45 (0.29, 0.61) 0.083

Results are presented as the standardized mean difference, with positive numbers indicating greater improvement in fatigue 1505 ADA = adalimumab; CI = confidence interval; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN = 1506 etanercept; IV = intravenous; SE = standard error; TOC_8 = 8mg/kg tocilizumab. 1507

1508

6.4.8 Radiographic Progression 1509


There were six studies165, 192, 193, 205, 231, 250 included in the reference case NMA for radiographic 1511

progression in which MTX monotherapy is the common comparator. The evidence network 1512

involved 2244 participants and seven treatments (within five 2-arm studies and one 3-arm 1513

study) forming eight direct comparisons. Assessment for consistency demonstrated that the 1514

model was consistent. A geometric illustration of the evidence network is presented in Figure 18 1515

138

and the standardized mean differences for all treatment comparisons are available in Table 23. 1516

A staircase table of the results as standardized mean differences is also presented in Appendix 1517

10. 1518

Figure 18. Evidence Network: Radiographic Progression (Placebo+MTX)

1519

1520

There were no statistically significant differences in radiographic progression for the treatments 1521

compared to placebo or for any head-to-head comparisons of double or triple csDMARD 1522

therapy, biologics, or biosimilars. 1523

1524

Table 23: Radiographic Progression (Placebo+MTX): Standardized Mean Differences for All Treatment 1525 Comparisons – Random Effects Model 1526


csDMARD+MTX Placebo+MTX -0.25 (-6.03, 5.52)

MTX+SSZ+HCQ -0.27 (-6.02, 5.48)

ETN_STD -0.23 (-4.15, 3.67)

ETN_STD+MTX -0.41 (-4.33, 3.53)

INF_STD+MTX -0.68 (-4.85, 3.46)

CT-P13+MTX -0.61 (-6.56, 5.26)

139


MTX+SSZ+HCQ csDMARD+MTX -0.01 (-5.85, 5.90)

ETN_STD 0.03 (-5.15, 5.18)

ETN_STD+MTX -0.16 (-4.36, 4.09)

INF_STD+MTX -0.43 (-7.56, 6.71)

CT-P13+MTX -0.36 (-8.54, 7.88)

ETN_STD MTX+SSZ+HCQ 0.04 (-5.11, 5.22)

ETN_STD+MTX -0.14 (-4.32, 4.00)

INF_STD+MTX -0.41 (-7.48, 6.62)

CT-P13+MTX -0.35 (-8.57, 7.88)

ETN_STD+MTX ETN_STD -0.18 (-3.15, 2.81)

INF_STD+MTX -0.45 (-6.13, 5.23)

CT-P13+MTX -0.39 (-7.42, 6.64)

INF_STD+MTX ETN_STD+MTX -0.27 (-5.99, 5.46)

CT-P13+MTX -0.20 (-7.25, 6.85)

CT-P13+MTX INF_STD+MTX 0.07 (-4.14, 4.26)



Criteria -3.873

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1527 and favour the comparator. Bold results represent large effect sizes. 1528 CrI = credible interval; CT-P13 = biosimilar infliximab; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; 1529 ETN = etanercept; HCQ = hydroxychloroquine; INF = infliximab; MTX = methotrexate; SMD = standardized mean difference; SSZ = 1530 sulfasalazine; STD = standard dose. 1531

1532


There were no studies reporting on radiographic progression outcomes that involved a 1534

csDMARD (other than MTX) as the common comparator. 1535

1536

140

6.4.9 Serious Adverse Events 1537


A total of 33 studies (28 2-arm studies, four 3-arm studies and one 5-arm study) with MTX 1539

monotherapy as the common comparator were included for the number of participants with a 1540

serious adverse event.95, 100, 126, 128, 130, 134, 136, 137, 143, 148, 150, 153, 165, 167, 169, 173, 177, 179, 180, 188, 192, 193, 197, 1541 202, 222, 224, 227, 228, 231, 233, 235, 250, 252 The evidence network involved 9239 participants and 21 1542

treatments forming 50 direct comparisons. Assessment for consistency demonstrated that the 1543

model was consistent. A geometric illustration of the evidence network is presented in Figure 1544

19. The odds ratios for all treatment comparisons with MTX monotherapy as the common 1545

comparator are available in Table 24. 1546

Figure 19. Evidence Network: Serious Adverse Events (Placebo+MTX)

1547

Participants receiving a combination of abatacept (IV) and MTX had statistically significantly 1548

lower odds of developing a SAE compared to participants receiving MTX monotherapy (OR = 1549

0.35 [0.18, 0.66]), etanercept monotherapy (OR = 0.33 [0.14, 0.76]), or etanercept in 1550

141

combination with MTX (OR = 0.28 [0.12, 0.65]). When abatacept (IV) in combination with MTX 1551

was the common comparator, the following treatments had higher odds of SAEs in comparison: 1552

combination therapy of MTX and tofacitinib, adalimumab, 8 mg/kg tocilizumab, golimumab (SC), 1553

certolizumab pegol, HD203 (biosimilar etanercept) or SB4 (biosimilar etanercept) and also 4 1554

mg/kg and 8 mg/kg tocilizumab monotherapy (Table 24). 1555

1556

Compared to tofacitinib in combination with MTX, participants who received infliximab in 1557

combination with MTX had statistically significantly lower odds of developing a SAE (OR = 0.29 1558

[0.11, 0.78]). In the comparison of 8 mg/kg tocilizumab to 4 mg/kg tocilizumab (both in 1559

combination with MTX), the 8 mg/kg dose had higher odds of SAEs, though the 95% credible 1560

interval was very wide (Table 24). The odds of SAEs were found to be lower for infliximab in 1561

combination with MTX compared to 8 mg/kg tocilizumab in combination with MTX (OR = 0.24 1562

[0.06, 0.81]) and compared to golimumab (SC) in combination with MTX (OR = 0.31 [0.09, 1563

0.96]). There were no other statistically significant comparisons for SAE outcomes (Table 24). 1564

1565

1566

Table 24: Serious Adverse Events: Odds Ratios, Relative Risks and Risk Differences for All Treatment 1567 Comparisons – Random Effects Model 1568


csDMARD+MTX Placebo+MTX 0.73 (0.20, 2.24) 0.74 (0.21, 2.10) -0.01 (-0.04, 0.06)

ETN_STD

1.08 (0.62, 1.85) 1.08 (0.63, 1.77) 0.004 (-0.02, 0.04)

ETN_STD+MTX

1.24 (0.73, 2.17) 1.22 (0.74, 2.04) 0.01 (-0.01, 0.05)

ABA_STD (IV)+MTX

0.35 (0.18, 0.66) 0.37 (0.19, 0.67) -0.03 (-0.05, -0.02)

TOF_STD+MTX

2.19 (0.94, 5.34) 2.06 (0.95, 4.46) 0.05 (-0.003, 0.16)

ADA_STD+MTX

1.17 (0.45, 3.09) 1.16 (0.47, 2.83) 0.01 (-0.03, 0.08)

TOC_4 (IV)

2.14 (0.50, 9.99) 2.02 (0.51, 7.00) 0.05 (-0.03, 0.29)

TOC_8 (IV)

1.80 (0.61, 6.47) 1.73 (0.63, 5.12) 0.04 (-0.02, 0.20)

TOC_4 (IV)+MTX

0.32 (0.01, 3.14) 0.33 (0.01, 2.83) -0.03 (-0.06, 0.09)

TOC_8 (IV)+MTX

2.72 (0.87, 10.20) 2.49 (0.88, 7.07) 0.08 (-0.01, 0.29)

GOL_STD (SC)

+MTX

2.09 (0.73, 6.29) 1.98 (0.74, 5.07) 0.05 (-0.01, 0.19)

INF_STD+MTX

0.65 (0.39, 1.05) 0.66 (0.40, 1.05) -0.02 (-0.03, 0.002)

142


CERTO_STD+MTX

1.33 (0.55, 3.34) 1.30 (0.56, 2.98) 0.02 (-0.02, 0.10)

RIT_STD

0.58 (0.06, 3.95) 0.60 (0.06, 3.44) -0.02 (-0.05, 0.12)

RIT_STD+MTX

0.98 (0.15, 5.87) 0.98 (0.16, 4.74) -0.001 (-0.05, 0.18)

HD203+MTX

1.32 (0.50, 3.47) 1.30 (0.52, 3.08) 0.02 (-0.03, 0.11)

SB4+MTX

1.25 (0.44, 3.69) 1.23 (0.46, 3.24) 0.01 (-0.03, 0.12)

CT-P13+MTX

0.85 (0.40, 1.75) 0.85 (0.41, 1.68) -0.01 (-0.03, 0.03)

SB2+MTX

0.66 (0.27, 1.55) 0.67 (0.28, 1.51) -0.02 (-0.04, 0.03)

ABP501+MTX

0.84 (0.23, 3.35) 0.85 (0.24, 3.01) -0.01 (-0.04, 0.10)

ETN_STD csDMARD+MTX 1.48 (0.49, 5.22) 1.45 (0.52, 4.97) 0.02 (-0.05, 0.06)

ETN_STD+MTX

1.71 (0.63, 5.56) 1.66 (0.65, 5.28) 0.02 (-0.03, 0.06)

ABA_STD (IV)+MTX

0.49 (0.13, 2.01) 0.50 (0.14, 1.99) -0.02 (-0.09, 0.01)

TOF_STD+MTX

3.03 (0.72, 14.62) 2.81 (0.74, 12.39) 0.07 (-0.02, 0.18)

ADA_STD+MTX

1.60 (0.36, 7.81) 1.56 (0.38, 7.15) 0.02 (-0.06, 0.10)

TOC_4 (IV)

2.94 (0.48, 21.44) 2.72 (0.50, 15.82) 0.06 (-0.04, 0.30)

TOC_8 (IV)

2.49 (0.55, 15.29) 2.35 (0.57, 12.41) 0.05 (-0.04, 0.21)

TOC_4 (IV)+MTX

0.43 (0.01, 6.42) 0.45 (0.01, 5.74) -0.02 (-0.09, 0.10)

TOC_8 (IV)+MTX

3.79 (0.77, 23.67) 3.39 (0.79, 17.49) 0.09 (-0.02, 0.30)

GOL_STD (SC)

+MTX

2.92 (0.59, 15.88) 2.71 (0.61, 13.01) 0.06 (-0.03, 0.20)

INF_STD+MTX

0.89 (0.25, 3.47) 0.90 (0.27, 3.37) -0.004 (-0.08, 0.03)

CERTO_STD+MTX

1.83 (0.43, 8.82) 1.77 (0.46, 7.92) 0.03 (-0.05, 0.12)

RIT_STD

0.80 (0.06, 7.97) 0.81 (0.06, 6.91) -0.01 (-0.09, 0.14)

RIT_STD+MTX

1.34 (0.16, 12.40) 1.32 (0.17, 10.10) 0.01 (-0.07, 0.20)

HD203+MTX

1.81 (0.50, 7.59) 1.75 (0.52, 6.87) 0.03 (-0.04, 0.11)

SB4+MTX

1.71 (0.45, 7.54) 1.66 (0.48, 6.79) 0.02 (-0.04, 0.12)

CT-P13+MTX

1.17 (0.30, 5.12) 1.17 (0.32, 4.86) 0.01 (-0.07, 0.06)

SB2+MTX

0.91 (0.21, 4.18) 0.91 (0.23, 4.00) -0.003 (-0.08, 0.05)

143


ABP501+MTX

1.18 (0.20, 7.51) 1.17 (0.22, 6.76) 0.01 (-0.07, 0.11)

ETN_STD+MTX ETN_STD 1.15 (0.73, 1.87) 1.14 (0.74, 1.80) 0.01 (-0.02, 0.04)

ABA_STD (IV)+MTX

0.33 (0.14, 0.76) 0.34 (0.15, 0.77) -0.04 (-0.08, -0.01)

TOF_STD+MTX

2.03 (0.75, 5.86) 1.92 (0.76, 4.95) 0.05 (-0.02, 0.16)

ADA_STD+MTX

1.07 (0.36, 3.33) 1.07 (0.38, 3.05) 0.004 (-0.05, 0.08)

TOC_4 (IV)

1.98 (0.42, 10.49) 1.88 (0.44, 7.43) 0.05 (-0.04, 0.29)

TOC_8 (IV)

1.68 (0.49, 6.58) 1.61 (0.51, 5.33) 0.03 (-0.04, 0.20)

TOC_4 (IV)+MTX

0.29 (0.01, 3.12) 0.31 (0.01, 2.83) -0.04 (-0.08, 0.09)

TOC_8 (IV)+MTX

2.52 (0.72, 10.40) 2.32 (0.74, 7.46) 0.07 (-0.02, 0.29)

GOL_STD (SC)

+MTX

1.94 (0.59, 6.83) 1.84 (0.61, 5.52) 0.05 (-0.03, 0.19)

INF_STD+MTX

0.60 (0.29, 1.24) 0.61 (0.30, 1.23) -0.02 (-0.06, 0.01)

CERTO_STD+MTX

1.23 (0.44, 3.62) 1.22 (0.46, 3.25) 0.01 (-0.04, 0.10)

RIT_STD

0.54 (0.05, 3.96) 0.56 (0.05, 3.47) -0.02 (-0.07, 0.12)

RIT_STD+MTX

0.91 (0.13, 5.99) 0.91 (0.14, 4.84) -0.005 (-0.06, 0.18)

HD203+MTX

1.21 (0.49, 3.11) 1.20 (0.50, 2.80) 0.01 (-0.03, 0.09)

SB4+MTX

1.15 (0.43, 3.26) 1.14 (0.44, 2.92) 0.01 (-0.04, 0.10)

CT-P13+MTX

0.79 (0.31, 1.95) 0.80 (0.33, 1.88) -0.01 (-0.06, 0.04)

SB2+MTX

0.60 (0.22, 1.67) 0.62 (0.23, 1.63) -0.02 (-0.06, 0.03)

ABP501+MTX

0.78 (0.19, 3.48) 0.79 (0.20, 3.14) -0.01 (-0.06, 0.09)

ABA_STD (IV)+MTX ETN_STD+MTX 0.28 (0.12, 0.65) 0.30 (0.13, 0.66) -0.04 (-0.09, -0.01)

TOF_STD+MTX

1.78 (0.63, 5.00) 1.69 (0.65, 4.25) 0.04 (-0.03, 0.15)

ADA_STD+MTX

0.94 (0.31, 2.81) 0.94 (0.33, 2.60) -0.003 (-0.06, 0.08)

TOC_4 (IV)

1.72 (0.37, 8.98) 1.65 (0.39, 6.37) 0.04 (-0.05, 0.28)

TOC_8 (IV)

1.45 (0.43, 5.60) 1.41 (0.45, 4.55) 0.03 (-0.05, 0.19)

TOC_4 (IV)+MTX

0.25 (0.01, 2.74) 0.27 (0.01, 2.50) -0.04 (-0.10, 0.08)

TOC_8 (IV)+MTX

2.19 (0.62, 8.82) 2.03 (0.65, 6.37) 0.06 (-0.03, 0.28)

144


GOL_STD (SC)

+MTX

1.69 (0.52, 5.84) 1.62 (0.54, 4.77) 0.04 (-0.04, 0.18)

INF_STD+MTX

0.52 (0.24, 1.06) 0.54 (0.26, 1.06) -0.03 (-0.08, 0.002)

CERTO_STD+MTX

1.07 (0.38, 3.09) 1.07 (0.40, 2.80) 0.004 (-0.05, 0.09)

RIT_STD

0.47 (0.04, 3.41) 0.49 (0.05, 3.00) -0.03 (-0.09, 0.11)

RIT_STD+MTX

0.79 (0.11, 5.26) 0.80 (0.12, 4.27) -0.01 (-0.08, 0.18)

HD203+MTX

1.06 (0.48, 2.36) 1.05 (0.50, 2.17) 0.003 (-0.04, 0.08)

SB4+MTX

1.00 (0.41, 2.53) 1.00 (0.43, 2.31)

0.0003

(-0.04, 0.09)

CT-P13+MTX

0.69 (0.26, 1.66) 0.70 (0.28, 1.61) -0.02 (-0.07, 0.03)

SB2+MTX

0.53 (0.18, 1.41) 0.54 (0.20, 1.39) -0.03 (-0.08, 0.02)

ABP501+MTX

0.68 (0.16, 2.96) 0.70 (0.17, 2.69) -0.02 (-0.08, 0.09)

TOF_STD+MTX ABA_STD (IV)+MTX 6.22 (2.20, 19.28) 5.66 (2.13, 15.75) 0.09 (0.03, 0.19)

ADA_STD+MTX

3.31 (1.06, 10.50) 3.17 (1.06, 9.40) 0.04 (0.002, 0.11)

TOC_4 (IV)

6.04 (1.25, 31.66) 5.49 (1.24, 21.81) 0.08 (0.01, 0.32)

TOC_8 (IV)

5.09 (1.49, 21.71) 4.72 (1.47, 16.92) 0.07 (0.01, 0.23)

TOC_4 (IV)+MTX

0.89 (0.03, 9.98) 0.90 (0.03, 8.84) -0.002 (-0.03, 0.12)

TOC_8 (IV)+MTX

7.76 (2.12, 34.40) 6.86 (2.06, 23.55) 0.11 (0.02, 0.33)

GOL_STD (SC)

+MTX

5.96 (1.74, 21.30) 5.44 (1.70, 17.01) 0.08 (0.02, 0.22)

INF_STD+MTX

1.83 (0.89, 3.78) 1.80 (0.90, 3.66) 0.01 (-0.003, 0.03)

CERTO_STD+MTX

3.78 (1.31, 11.51) 3.58 (1.30, 10.05) 0.05 (0.01, 0.13)

RIT_STD

1.67 (0.15, 12.41) 1.64 (0.15, 10.52) 0.01 (-0.02, 0.15)

RIT_STD+MTX

2.79 (0.40, 18.21) 2.69 (0.41, 14.44) 0.03 (-0.01, 0.22)

HD203+MTX

3.73 (1.19, 11.90) 3.54 (1.19, 10.32) 0.05 (0.004, 0.14)

SB4+MTX

3.54 (1.05, 12.47) 3.38 (1.05, 10.68) 0.04 (0.001, 0.15)

CT-P13+MTX

2.41 (0.97, 5.89) 2.34 (0.97, 5.54) 0.02 (-0.001, 0.07)

145


SB2+MTX

1.86 (0.67, 5.10) 1.83 (0.68, 4.82) 0.02 (-0.01, 0.06)

ABP501+MTX

2.42 (0.56, 10.64) 2.35 (0.57, 9.36) 0.02 (-0.01, 0.13)

ADA_STD+MTX TOF_STD+MTX 0.53 (0.20, 1.35) 0.56 (0.23, 1.31) -0.05 (-0.14, 0.02)

TOC_4 (IV)

0.97 (0.18, 5.75) 0.97 (0.20, 4.27) -0.003 (-0.14, 0.25)

TOC_8 (IV)

0.82 (0.20, 3.86) 0.84 (0.23, 3.22) -0.02 (-0.14, 0.16)

TOC_4 (IV)+MTX

0.14 (0.004, 1.66) 0.16 (0.005, 1.57) -0.08 (-0.19, 0.05)

TOC_8 (IV)+MTX

1.25 (0.29, 6.22) 1.21 (0.33, 4.55) 0.02 (-0.12, 0.25)

GOL_STD (SC)

+MTX

0.95 (0.24, 3.78) 0.96 (0.28, 3.19) -0.004 (-0.13, 0.15)

INF_STD+MTX

0.29 (0.11, 0.78) 0.32 (0.13, 0.79) -0.07 (-0.18, -0.01)

CERTO_STD+MTX

0.61 (0.17, 2.06) 0.64 (0.20, 1.92) -0.04 (-0.15, 0.06)

RIT_STD

0.26 (0.02, 2.12) 0.28 (0.03, 1.94) -0.07 (-0.18, 0.08)

RIT_STD+MTX

0.45 (0.06, 3.21) 0.48 (0.07, 2.72) -0.05 (-0.17, 0.14)

HD203+MTX

0.59 (0.16, 2.14) 0.62 (0.19, 1.99) -0.04 (-0.15, 0.07)

SB4+MTX

0.56 (0.15, 2.26) 0.59 (0.17, 2.07) -0.04 (-0.15, 0.08)

CT-P13+MTX

0.38 (0.12, 1.19) 0.41 (0.15, 1.17) -0.06 (-0.17, 0.01)

SB2+MTX

0.30 (0.09, 0.97) 0.32 (0.10, 0.97)

-0.07

(-0.18, -0.002)

ABP501+MTX

0.38 (0.10, 1.46) 0.41 (0.11, 1.41) -0.06 (-0.16, 0.03)

TOC_4 (IV) ADA_STD+MTX 1.86 (0.33, 11.39) 1.76 (0.35, 8.24) 0.04 (-0.07, 0.29)

TOC_8 (IV)

1.57 (0.37, 7.79) 1.52 (0.39, 6.27) 0.03 (-0.07, 0.20)

TOC_4 (IV)+MTX

0.27 (0.01, 3.27) 0.28 (0.01, 2.99) -0.04 (-0.11, 0.08)

TOC_8 (IV)+MTX

2.39 (0.54, 12.21) 2.20 (0.57, 8.73) 0.07 (-0.04, 0.29)

GOL_STD (SC)

+MTX

1.83 (0.43, 7.57) 1.74 (0.46, 6.19) 0.04 (-0.06, 0.19)

INF_STD+MTX

0.55 (0.19, 1.62) 0.57 (0.21, 1.60) -0.03 (-0.10, 0.02)

CERTO_STD+MTX

1.14 (0.30, 4.29) 1.13 (0.33, 3.88) 0.01 (-0.08, 0.10)

146


RIT_STD

0.50 (0.04, 4.27) 0.51 (0.05, 3.75) -0.03 (-0.10, 0.12)

RIT_STD+MTX

0.86 (0.11, 6.55) 0.86 (0.11, 5.35) -0.01 (-0.09, 0.18)

HD203+MTX

1.12 (0.29, 4.36) 1.11 (0.32, 3.91) 0.01 (-0.08, 0.11)

SB4+MTX

1.08 (0.26, 4.46) 1.07 (0.28, 3.97) 0.004 (-0.08, 0.12)

CT-P13+MTX

0.73 (0.21, 2.40) 0.74 (0.23, 2.29) -0.02 (-0.09, 0.04)

SB2+MTX

0.56 (0.15, 2.03) 0.58 (0.17, 1.96) -0.02 (-0.10, 0.03)

ABP501+MTX

0.74 (0.29, 1.88) 0.75 (0.30, 1.78) -0.01 (-0.06, 0.05)

TOC_8 (IV) TOC_4 (IV) 0.84 (0.26, 3.16) 0.85 (0.31, 2.86) -0.01 (-0.18, 0.09)

TOC_4 (IV)+MTX

0.15 (0.004, 1.26) 0.17 (0.01, 1.23) -0.08 (-0.29, 0.01)

TOC_8 (IV)+MTX

1.26 (0.39, 4.71) 1.22 (0.45, 4.00) 0.02 (-0.13, 0.17)

GOL_STD (SC)

+MTX

0.99 (0.15, 6.10) 0.99 (0.20, 5.19) -0.001 (-0.25, 0.16)

INF_STD+MTX

0.30 (0.06, 1.41) 0.33 (0.09, 1.39) -0.07 (-0.31, 0.01)

CERTO_STD+MTX

0.62 (0.11, 3.52) 0.64 (0.15, 3.23) -0.04 (-0.27, 0.08)

RIT_STD

0.26 (0.02, 2.98) 0.29 (0.02, 2.70) -0.07 (-0.31, 0.08)

RIT_STD+MTX

0.46 (0.04, 4.57) 0.49 (0.06, 3.86) -0.05 (-0.29, 0.14)

HD203+MTX

0.61 (0.10, 3.51) 0.64 (0.14, 3.22) -0.04 (-0.28, 0.08)

SB4+MTX

0.58 (0.09, 3.52) 0.61 (0.12, 3.22) -0.04 (-0.28, 0.09)

CT-P13+MTX

0.39 (0.07, 2.04) 0.42 (0.10, 1.97) -0.06 (-0.30, 0.03)

SB2+MTX

0.30 (0.05, 1.66) 0.33 (0.07, 1.62) -0.07 (-0.31, 0.02)

ABP501+MTX

0.40 (0.05, 2.88) 0.43 (0.07, 2.68) -0.06 (-0.30, 0.07)

TOC_4 (IV)+MTX TOC_8 (IV) 0.18 (0.01, 1.32) 0.20 (0.01, 1.28) -0.06 (-0.20, 0.02)

TOC_8 (IV)+MTX

1.51 (0.86, 2.70) 1.43 (0.88, 2.39) 0.04 (-0.01, 0.14)

GOL_STD (SC)

+MTX

1.16 (0.22, 5.49) 1.14 (0.26, 4.56) 0.01 (-0.16, 0.17)

INF_STD+MTX

0.36 (0.09, 1.15) 0.38 (0.12, 1.14) -0.05 (-0.22, 0.01)

CERTO_STD+MTX

0.73 (0.16, 3.10) 0.75 (0.19, 2.84) -0.02 (-0.19, 0.08)

147


RIT_STD

0.32 (0.02, 2.74) 0.34 (0.03, 2.48) -0.05 (-0.22, 0.09)

RIT_STD+MTX

0.55 (0.06, 4.44) 0.57 (0.07, 3.72) -0.03 (-0.21, 0.15)

HD203+MTX

0.72 (0.15, 3.10) 0.74 (0.18, 2.83) -0.02 (-0.18, 0.09)

SB4+MTX

0.69 (0.14, 3.11) 0.71 (0.16, 2.83) -0.02 (-0.19, 0.09)

CT-P13+MTX

0.47 (0.11, 1.69) 0.49 (0.14, 1.64) -0.04 (-0.21, 0.03)

SB2+MTX

0.36 (0.08, 1.43) 0.38 (0.10, 1.40) -0.05 (-0.22, 0.02)

ABP501+MTX

0.46 (0.08, 2.80) 0.49 (0.10, 2.57) -0.04 (-0.21, 0.07)

TOC_8 (IV)+MTX TOC_4 (IV)+MTX 8.38 (1.19, 285.50)

7.29

(1.17, 241.10)

0.10 (0.01, 0.29)

GOL_STD (SC)

+MTX

6.65 (0.51, 278.30)

6.00

(0.54, 239.00)

0.08 (-0.06, 0.22)

INF_STD+MTX

2.03 (0.20, 67.43) 1.99 (0.22, 64.89) 0.02 (-0.11, 0.05)

CERTO_STD+MTX

4.19 (0.36, 139.00) 3.95 (0.39, 127.50) 0.05 (-0.08, 0.14)

RIT_STD

1.90 (0.07, 86.72) 1.86 (0.07, 79.95) 0.01 (-0.11, 0.15)

RIT_STD+MTX

3.27 (0.16, 118.40) 3.11 (0.17, 103.90) 0.03 (-0.10, 0.21)

HD203+MTX

4.18 (0.35, 144.70)

3.94

(0.38, 133.00)

0.04 (-0.08, 0.14)

SB4+MTX

3.99 (0.32, 144.30)

3.77

(0.35, 130.20)

0.04 (-0.08, 0.15)

CT-P13+MTX

2.64 (0.24, 91.70) 2.57 (0.27, 87.17) 0.02 (-0.10, 0.07)

SB2+MTX

2.06 (0.18, 76.96) 2.02 (0.20, 73.23) 0.02 (-0.11, 0.06)

ABP501+MTX

2.77 (0.19, 103.20) 2.67 (0.21, 95.55) 0.02 (-0.10, 0.12)

GOL_STD (SC)

+MTX

TOC_8 (IV)+MTX 0.76 (0.14, 3.71) 0.79 (0.19, 3.16) -0.03 (-0.26, 0.14)

INF_STD+MTX

0.24 (0.06, 0.81) 0.26 (0.08, 0.82) -0.09 (-0.31, -0.01)

CERTO_STD+MTX

0.48 (0.10, 2.08) 0.52 (0.14, 1.95) -0.06 (-0.28, 0.06)

RIT_STD

0.21 (0.01, 1.88) 0.24 (0.02, 1.75) -0.09 (-0.31, 0.06)

148


RIT_STD+MTX

0.36 (0.04, 2.95) 0.40 (0.05, 2.54) -0.07 (-0.30, 0.12)

HD203+MTX

0.48 (0.09, 2.10) 0.51 (0.13, 1.96) -0.06 (-0.28, 0.06)

SB4+MTX

0.46 (0.09, 2.05) 0.49 (0.12, 1.92) -0.06 (-0.28, 0.06)

CT-P13+MTX

0.31 (0.07, 1.19) 0.34 (0.10, 1.17) -0.08 (-0.30, 0.01)

SB2+MTX

0.24 (0.05, 1.01) 0.27 (0.07, 1.01)

-0.09

(-0.31, 0.0003)

ABP501+MTX

0.31 (0.05, 1.80) 0.34 (0.07, 1.70) -0.08 (-0.30, 0.05)

INF_STD+MTX GOL_STD

(SC)+MTX 0.31 (0.09, 0.96) 0.33 (0.12, 0.96)

-0.07

(-0.21, -0.002)

CERTO_STD+MTX

0.63 (0.15, 2.58) 0.66 (0.19, 2.38) -0.03 (-0.18, 0.07)

RIT_STD

0.27 (0.02, 2.43) 0.30 (0.03, 2.21) -0.07 (-0.21, 0.08)

RIT_STD+MTX

0.46 (0.05, 3.77) 0.49 (0.06, 3.21) -0.05 (-0.20, 0.14)

HD203+MTX

0.62 (0.15, 2.61) 0.65 (0.18, 2.39) -0.03 (-0.18, 0.08)

SB4+MTX

0.59 (0.13, 2.70) 0.62 (0.16, 2.45) -0.04 (-0.18, 0.09)

CT-P13+MTX

0.40 (0.11, 1.42) 0.43 (0.13, 1.40) -0.06 (-0.20, 0.02)

SB2+MTX

0.31 (0.08, 1.17) 0.34 (0.09, 1.16) -0.07 (-0.21, 0.01)

ABP501+MTX

0.40 (0.08, 2.25) 0.43 (0.09, 2.10) -0.06 (-0.20, 0.06)


RIT_STD

0.90 (0.08, 6.65) 0.91 (0.08, 5.72) -0.003 (-0.04, 0.14)

RIT_STD+MTX

1.52 (0.22, 10.07) 1.49 (0.22, 7.99) 0.02 (-0.03, 0.20)

HD203+MTX

2.03 (0.71, 6.14) 1.96 (0.72, 5.37) 0.03 (-0.01, 0.13)

SB4+MTX

1.92 (0.62, 6.49) 1.86 (0.63, 5.63) 0.03 (-0.02, 0.14)

CT-P13+MTX

1.32 (0.76, 2.25) 1.30 (0.76, 2.16) 0.01 (-0.01, 0.04)

SB2+MTX

1.01 (0.50, 2.05) 1.01 (0.51, 1.98)

0.0004

(-0.02, 0.03)

ABP501+MTX

1.31 (0.33, 5.56) 1.30 (0.34, 4.94) 0.01 (-0.03, 0.11)

RIT_STD CERTO_STD+MTX 0.44 (0.03, 3.55) 0.46 (0.04, 3.15) -0.03 (-0.13, 0.11)

149


RIT_STD+MTX

0.74 (0.10, 5.19) 0.76 (0.11, 4.31) -0.02 (-0.11, 0.17)

HD203+MTX

0.98 (0.26, 3.65) 0.98 (0.29, 3.30) -0.001 (-0.09, 0.10)

SB4+MTX

0.94 (0.23, 3.84) 0.94 (0.25, 3.43) -0.004 (-0.10, 0.11)

CT-P13+MTX

0.64 (0.19, 2.01) 0.65 (0.22, 1.94) -0.02 (-0.11, 0.03)

SB2+MTX

0.49 (0.14, 1.68) 0.51 (0.16, 1.64) -0.03 (-0.12, 0.02)

ABP501+MTX

0.63 (0.13, 3.24) 0.65 (0.14, 2.96) -0.02 (-0.11, 0.09)


HD203+MTX

2.25 (0.26, 29.46) 2.16 (0.30, 26.29) 0.03 (-0.11, 0.13)

SB4+MTX

2.17 (0.25, 26.29) 2.09 (0.28, 23.65) 0.03 (-0.11, 0.14)

CT-P13+MTX

1.46 (0.18, 16.36) 1.44 (0.21, 15.52) 0.01 (-0.13, 0.07)

SB2+MTX

1.12 (0.14, 14.00) 1.11 (0.16, 13.36) 0.003 (-0.14, 0.06)

ABP501+MTX

1.46 (0.15, 19.38) 1.44 (0.17, 17.88) 0.01 (-0.13, 0.12)

HD203+MTX RIT_STD+MTX 1.34 (0.17, 10.50) 1.31 (0.20, 9.47) 0.01 (-0.17, 0.12)

SB4+MTX

1.28 (0.16, 10.44) 1.26 (0.20, 9.40) 0.01 (-0.17, 0.13)

CT-P13+MTX

0.86 (0.12, 6.80) 0.87 (0.15, 6.46) -0.01 (-0.19, 0.06)

SB2+MTX

0.66 (0.09, 5.22) 0.67 (0.11, 5.00) -0.02 (-0.20, 0.05)

ABP501+MTX

0.86 (0.09, 8.40) 0.87 (0.11, 7.69) -0.01 (-0.19, 0.10)

SB4+MTX HD203+MTX 0.95 (0.29, 3.25) 0.96 (0.31, 2.96) -0.003 (-0.09, 0.09)

CT-P13+MTX

0.65 (0.19, 2.09) 0.67 (0.21, 2.01) -0.02 (-0.12, 0.03)

SB2+MTX

0.50 (0.13, 1.77) 0.52 (0.15, 1.73) -0.03 (-0.13, 0.03)

ABP501+MTX

0.65 (0.13, 3.38) 0.66 (0.14, 3.09) -0.02 (-0.12, 0.08)

CT-P13+MTX SB4+MTX 0.69 (0.18, 2.39) 0.70 (0.20, 2.30) -0.02 (-0.13, 0.04)

SB2+MTX

0.53 (0.13, 1.97) 0.55 (0.14, 1.91) -0.03 (-0.14, 0.03)

ABP501+MTX

0.68 (0.12, 3.78) 0.70 (0.14, 3.47) -0.02 (-0.13, 0.09)

SB2+MTX CT-P13+MTX 0.77 (0.32, 1.89) 0.77 (0.34, 1.83) -0.01 (-0.05, 0.03)

ABP501+MTX

1.00 (0.22, 4.72) 1.00 (0.24, 4.25)

0.0001

(-0.05, 0.10)

150


ABP501+MTX SB2+MTX 1.31 (0.26, 6.53) 1.29 (0.27, 5.86) 0.01 (-0.05, 0.11)

Random-Effect


Deviance



Deviance


Total Patients

9,239

Total Studies

33

2-arm 28

3-arm 4

4-arm 0

5-arm 1

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1569 and favour the comparator. 1570 ABA = abatacept; ABP501 = biosimilar adalimumab; ADA = adalimumab; CERTO = certolizumab pegol; CrI = credible interval; CT-1571 P13 = biosimilar infliximab; csDMARD = conventional synthetic disease modifying antirheumatic drug; ETN = etanercept; GOL = 1572 golimumab; HD203 = etanercept biosimilar; INF = infliximab; IV = intravenous; MTX = methotrexate; OR = odds ratio; RD = risk 1573 difference; RIT = rituximab; RR = relative risk; SB2 = biosimilar infliximab; SB4 = biosimilar etanercept; SC = subcutaneous; STD = 1574 standard dose; TOC_4 = 4mg/kg tocilizumab; TOC_8 = 8mg/kg tocilizumab; TOF = tofacitinib. 1575

1576


Six studies (five 2-arm studies and one 3-arm study)101, 142, 149, 161, 170, 248 were included that 1578

reported on the number of participants who developed serious adverse events (SAEs). The 1579

evidence network involved 1780 participants and six treatments forming eight direct 1580

comparisons. Assessment for consistency demonstrated that the model was consistent. A 1581

geometric illustration of the evidence network is presented in Figure 20 and the odds ratios for 1582

all treatment comparisons with csDMARD monotherapy as the common comparator are 1583

available in Table 25. 1584

1585

151

Figure 20. Evidence Network: Serious Adverse Events (Placebo+csDMARD)

1586

1587

Participants receiving 4 mg of baricitinib in combination with csDMARD had a statistically 1588

significantly lower odds of developing a SAE when compared to participants receiving 1589

adalimumab in combination with csDMARD (OR = 0.10 [0.01, 0.87]) and compared with 1590

etanercept in combination with csDMARD (OR = 0.09 [0.01, 0.75]). There were no other 1591

statistically significant comparisons of any treatments compared to one another or to csDMARD 1592

monotherapy (Table 25). A staircase table of the results as odds ratios is also presented in 1593

Appendix 10. 1594

1595

Table 25: Serious Adverse Events (Placebo+csDMARD): Odds Ratios, Relative Risks and Risk Differences for 1596 All Treatment Comparisons – Random Effects Model 1597


ADA_STD+csDMARD Placebo+csDMARD 2.17 (0.55, 11.04) 2.10 (0.56, 9.57) 0.03 (-0.02, 0.14)

ETN_STD 1.26 (0.19, 8.74) 1.25 (0.20, 7.74) 0.01 (-0.03, 0.12)

ETN_STD+csDMARD 2.35 (0.67, 9.82) 2.27 (0.68, 8.70) 0.03 (-0.01, 0.12)

TOC_8 (IV)+csDMARD 1.44 (0.53, 4.06) 1.43 (0.54, 3.77) 0.01 (-0.01, 0.07)

152


BAR_4+csDMARD 0.22 (0.02, 1.13) 0.22 (0.03, 1.13) -0.02 (-0.04, 0.003)

ETN_STD

ADA_STD

+csDMARD 0.58 (0.07, 3.89) 0.59 (0.08, 3.58) -0.02 (-0.12, 0.08)

ETN_STD+csDMARD 1.07 (0.32, 3.61) 1.07 (0.35, 3.37) 0.00 (-0.08, 0.07)

TOC_8 (IV)+csDMARD 0.67 (0.10, 3.79) 0.68 (0.11, 3.55) -0.02 (-0.13, 0.06)

BAR_4+csDMARD 0.10 (0.01, 0.87) 0.10 (0.01, 0.87) -0.05 (-0.15, -0.003)


TOC_8 (IV)+csDMARD 1.15 (0.13, 10.24) 1.15 (0.15, 9.50) 0.004 (-0.11, 0.08)

BAR_4+csDMARD 0.16 (0.01, 2.26) 0.17 (0.01, 2.23) -0.02 (-0.13, 0.01)

TOC_8 (IV)+csDMARD

ETN_STD

+csDMARD 0.62 (0.11, 3.09) 0.63 (0.12, 2.90) -0.02 (-0.11, 0.06)

BAR_4+csDMARD 0.09 (0.01, 0.75) 0.09 (0.01, 0.76) -0.05 (-0.13, -0.01)

BAR_4+csDMARD

TOC_8 (IV)

+csDMARD 0.15 (0.01, 1.02) 0.15 (0.01, 1.02)

-0.03

(-0.10, 0.0004)



Criteria 64.912

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1598 and favour the comparator. 1599 ADA = adalimumab; BAR_4 = 4 mg baricitinib; CrI = credible interval; csDMARD = conventional synthetic disease-modifying anti-1600 rheumatic drug; ETN = etanercept; IV = intravenous; OR = odds ratio; RD = risk difference; RR = relative risk; STD = standard dose; 1601 TOC_8 = 8mg/kg tocilizumab. 1602

1603

6.4.10 Withdrawal due to Adverse Events 1604


A total of 42 studies95, 100, 126, 128, 130, 131, 134, 136, 137, 143, 148, 153, 165, 169, 173, 176, 177, 184, 186, 188, 189, 192, 193, 196, 1606 197, 202, 203, 211, 214, 216, 222, 224, 225, 227, 228, 232, 233, 235, 236, 243, 250, 252 were included in the reference case 1607

NMA for the number of withdrawals due to adverse events among inadequate responders to 1608

MTX. There were 63 direct comparisons in the evidence network based on 26 treatments. The 1609

studies consisted of 35 2-arm studies, six 3-arm studies and one 5-arm study. The total number 1610

of participants contributing to the evidence network was 11,731. Assessment for consistency 1611

153

demonstrated that the model was consistent. A geometric illustration of the evidence network is 1612

presented in Figure 21. The odds ratios for all treatment comparisons with placebo as the 1613

common comparator are available in Table 26. 1614

1615

1616

Figure 21. Evidence Network: Withdrawal due to Adverse Events (Placebo+MTX)

1617

There was insufficient evidence to detect a statistically significant difference in the odds of 1618

WDAEs for any treatment compared to MTX monotherapy, though tofacitinib in combination 1619

with MTX was trending toward higher odds of WDAEs in comparison (OR = 1.93 [95% CrI: 0.99, 1620

4.01]), as well as SB2 (biosimilar infliximab) in combination with MTX compared to MTX 1621

monotherapy (3.16 [0.98, 9.98]). 1622

1623

154

Among the direct treatment comparisons, both etanercept in combination with MTX and a 1624

biosimilar etanercept in combination with MTX (SB4) had lower odds of WDAEs compared to 1625

any csDMARD in combination with MTX. Tofacitinib in combination with MTX had higher odds 1626

of WDAEs compared to double csDMARD therapy with SSZ and HCQ, etanercept in 1627

combination with MTX, SB4 (biosimilar etanercept) in combination with MTX, and the newer 1628

tsDMARD baricitinib at 4 mg in combination with MTX. 1629

1630

SB2 (biosimilar infliximab) in combination with MTX had higher odds of WDAEs compared to 1631

SSZ and HCQ, triple csDMARD therapy with MTX, SSZ and HCQ, etanercept monotherapy and 1632

combination therapy with MTX, abatacept (IV) in combination with MTX, HD203 (biosimilar 1633

etanercept) in combination with MTX, and SB5 (biosimilar adalimumab) in combination with 1634

MTX. Another biosimilar that appeared to have a worse safety profile was ABP501 (biosimilar 1635

adalimumab) in combination with MTX when compared to double csDMARD therapy with SSZ 1636

and HCQ, SB4 (biosimilar etanercept) in combination with MTX and a different biosimilar 1637

adalimumab (SB5) in combination with MTX. Interestingly, SB5 (biosimilar adalimumab) in 1638

combination with MTX demonstrated a statistically significantly lower odds of WDAE compared 1639

to adalimumab in combination with MTX (0.20 [.02, 0.90]). 1640

1641

Table 26: Withdrawal Due to Adverse Events (Placebo+MTX): Odds Ratios, Relative Risks and Risk 1642 Differences for All Treatment Comparisons – Random Effects Model 1643

Treatment Reference OR (95% CrI) RR (95% CrI) RD % (95% Crl)

csDMARD+MTX Placebo+MTX 2.15 (0.70, 6.73) 2.07 (0.71, 5.64) 0.04 (-0.01, 0.16)

SSZ+HCQ 0.37 (0.06, 1.45) 0.38 (0.06, 1.43) -0.02 (-0.04, 0.01)

MTX+SSZ+HC

Q 0.40 (0.08, 1.78) 0.41 (0.08, 1.73) -0.02 (-0.04, 0.02)

ETN_STD 0.79 (0.45, 1.49) 0.80 (0.46, 1.47) -0.01 (-0.02, 0.02)

ETN_STD+MTX 0.70 (0.40, 1.21) 0.70 (0.41, 1.21) -0.01 (-0.02, 0.01)

ABA_STD

(IV)+MTX 0.75 (0.36, 1.64) 0.76 (0.37, 1.60) -0.01 (-0.02, 0.02)

ADA_STD+MTX 1.47 (0.67, 3.19) 1.45 (0.68, 2.99) 0.02 (-0.01, 0.06)

TOF_STD+MTX 1.93 (0.99, 4.01) 1.87 (0.99, 3.67)

0.03 (-0.0004,

0.08)

TOC_4 (IV) 1.31 (0.35, 5.14) 1.29 (0.36, 4.53) 0.01 (-0.02, 0.12)

155


TOC_8 (IV) 0.98 (0.33, 2.91) 0.98 (0.34, 2.73)

-0.001 (-0.02,

0.06)

TOC_4

(IV)+MTX 1.43 (0.38, 5.46) 1.41 (0.39, 4.76) 0.01 (-0.02, 0.12)

TOC_8

(IV)+MTX 1.45 (0.45, 4.44) 1.43 (0.46, 3.98) 0.01 (-0.02, 0.10)

GOL_STD

(SC)+MTX 1.03 (0.32, 3.04) 1.02 (0.33, 2.85)

0.001 (-0.02,

0.06)

INF_STD+MTX 1.41 (0.67, 2.92) 1.39 (0.68, 2.75) 0.01 (-0.01, 0.06)

INF_STD 2.40 (0.05, 73.12)

2.29 (0.06,

22.08) 0.04 (-0.03, 0.68)

CERTO_STD

+MTX 1.20 (0.46, 3.02) 1.20 (0.47, 2.84) 0.01 (-0.02, 0.06)

RIT_STD 2.50 (0.16, 77.06)

2.37 (0.17,

22.92) 0.05 (-0.03, 0.68)

RIT_STD+MTX 0.98 (0.02, 30.43)

0.98 (0.03,

15.66)

-0.001 (-0.04,

0.47)

BAR_4+MTX 0.31 (0.02, 1.67) 0.32 (0.02, 1.63) -0.02 (-0.04, 0.02)

HD203+MTX 0.62 (0.20, 1.96) 0.63 (0.21, 1.90) -0.01 (-0.03, 0.03)

SB4+MTX 0.54 (0.19, 1.44) 0.54 (0.20, 1.42) -0.02 (-0.03, 0.01)

CT-P13+MTX 1.22 (0.48, 3.06) 1.21 (0.49, 2.87) 0.01 (-0.02, 0.06)

SB2+MTX 3.16 (0.98, 9.98) 2.94 (0.98, 7.73)

0.07 (-0.001,

0.22)

SB5+MTX 0.29 (0.02, 1.59) 0.30 (0.02, 1.56) -0.02 (-0.04, 0.02)

ABP501+MTX 3.71 (0.70, 25.72)

3.39 (0.71,

14.16) 0.08 (-0.01, 0.44)

SSZ+HCQ csDMARD+MTX 0.17 (0.02, 1.07) 0.18 (0.02, 1.06)

-0.06 (-0.18,

0.002)

156


MTX+SSZ+HC

Q 0.19 (0.03, 1.14) 0.20 (0.03, 1.13)

-0.05 (-0.17,

0.005)

ETN_STD 0.37 (0.12, 1.15) 0.39 (0.14, 1.14)

-0.04 (-0.16,

0.004)

ETN_STD

+MTX 0.32 (0.12, 0.86) 0.34 (0.14, 0.87)

-0.05

(-0.16, -0.003)

ABA_STD

(IV)+MTX 0.35 (0.09, 1.32) 0.37 (0.10, 1.31) -0.04 (-0.17, 0.01)

ADA_STD+MTX 0.67 (0.17, 2.61) 0.69 (0.20, 2.49) -0.02 (-0.14, 0.05)

TOF_STD+MTX 0.89 (0.24, 3.44) 0.90 (0.28, 3.22) -0.01 (-0.13, 0.07)

TOC_4 (IV) 0.60 (0.10, 3.68) 0.62 (0.12, 3.34) -0.03 (-0.15, 0.09)

TOC_8 (IV) 0.46 (0.10, 2.29) 0.48 (0.11, 2.20) -0.04 (-0.16, 0.04)

TOC_4

(IV)+MTX 0.66 (0.11, 3.98) 0.67 (0.13, 3.57) -0.02 (-0.15, 0.10)

TOC_8

(IV)+MTX 0.67 (0.13, 3.39) 0.69 (0.15, 3.14) -0.02 (-0.15, 0.07)

GOL_STD

(SC)+MTX 0.47 (0.10, 2.21) 0.49 (0.11, 2.12) -0.03 (-0.16, 0.04)

INF_STD+MTX 0.65 (0.17, 2.45) 0.67 (0.20, 2.34) -0.02 (-0.15, 0.04)

INF_STD 1.12 (0.02, 38.89)

1.11 (0.02,

13.64) 0.01 (-0.14, 0.63)

CERTO_STD

+MTX 0.55 (0.13, 2.33) 0.57 (0.15, 2.24) -0.03 (-0.15, 0.04)

RIT_STD 1.16 (0.06, 44.10)

1.14 (0.07,

13.93) 0.01 (-0.14, 0.64)

RIT_STD+MTX 0.46 (0.01, 15.66) 0.48 (0.01, 8.33) -0.03 (-0.16, 0.42)

BAR_4+MTX 0.14 (0.01, 1.13) 0.15 (0.01, 1.12)

-0.06 (-0.18,

0.005)

157


HD203+MTX 0.29 (0.07, 1.16) 0.30 (0.08, 1.15)

-0.05 (-0.16,

0.005)

SB4+MTX 0.25 (0.06, 0.89) 0.26 (0.07, 0.89)

-0.05

(-0.17, -0.003)

CT-P13+MTX 0.56 (0.13, 2.40) 0.58 (0.15, 2.30) -0.03 (-0.15, 0.04)

SB2+MTX 1.46 (0.28, 7.22) 1.41 (0.31, 5.94) 0.03 (-0.11, 0.19)

SB5+MTX 0.13 (0.01, 1.02) 0.14 (0.01, 1.02)

-0.06 (-0.18,

0.001)

ABP501+MTX 1.69 (0.24, 15.64) 1.60 (0.27, 9.45) 0.04 (-0.11, 0.40)

MTX+SSZ+HC

Q SSZ+HCQ 1.12 (0.18, 7.30) 1.12 (0.18, 7.07)

0.001 (-0.03,

0.04)

ETN_STD 2.14 (0.49, 13.86)

2.11 (0.51,

13.44) 0.01 (-0.02, 0.04)

ETN_STD+MTX 1.87 (0.42, 12.67)

1.85 (0.43,

12.36) 0.01 (-0.03, 0.03)

ABA_STD

(IV)+MTX 2.06 (0.41, 12.83)

2.03 (0.43,

12.43) 0.01 (-0.03, 0.04)

ADA_STD+MTX 3.97 (0.81, 25.83)

3.81 (0.81,

24.33) 0.03 (-0.01, 0.09)

TOF_STD+MTX 5.24 (1.15, 34.55)

4.96 (1.14,

31.65) 0.05 (0.01, 0.11)

TOC_4 (IV) 3.59 (0.51, 32.24)

3.46 (0.52,

29.00) 0.03 (-0.02, 0.14)

TOC_8 (IV) 2.65 (0.47, 22.81)

2.59 (0.48,

21.38) 0.02 (-0.02, 0.08)

TOC_4

(IV)+MTX 3.98 (0.56, 35.28)

3.81 (0.57,

31.55) 0.03 (-0.02, 0.15)

TOC_8

(IV)+MTX 3.98 (0.62, 32.91)

3.81 (0.63,

29.89) 0.03 (-0.01, 0.12)

158


GOL_STD

(SC)+MTX 2.82 (0.44, 21.66)

2.75 (0.45,

20.43) 0.02 (-0.02, 0.08)

INF_STD+MTX 3.81 (0.78, 25.03)

3.67 (0.79,

23.63) 0.03 (-0.01, 0.08)

INF_STD 6.66 (0.11, 288.80)

6.09 (0.12,

109.20) 0.06 (-0.02, 0.69)

CERTO_STD

+MTX 3.30 (0.61, 23.28)

3.20 (0.62,

21.86) 0.03 (-0.02, 0.08)

RIT_STD 6.99 (0.31, 310.60)

6.38

(0.32, 114.30) 0.07 (-0.02, 0.70)

RIT_STD+MTX 2.73 (0.06, 129.20)

2.65 (0.06,

68.95) 0.02 (-0.03, 0.49)

BAR_4+MTX 0.87 (0.04, 10.05) 0.87 (0.04, 9.71)

-0.001 (-0.04,

0.04)

HD203+MTX 1.70 (0.28, 13.90)

1.69 (0.29,

13.38) 0.01 (-0.03, 0.05)

SB4+MTX 1.47 (0.25, 11.23)

1.46 (0.26,

10.91) 0.01 (-0.03, 0.04)

CT-P13+MTX 3.29 (0.62, 23.18)

3.19 (0.63,

21.81) 0.03 (-0.02, 0.08)

SB2+MTX 8.57 (1.38, 70.51)

7.73 (1.36,

57.95) 0.08 (0.01, 0.24)

SB5+MTX 0.78 (0.04, 8.74) 0.78 (0.04, 8.46)

-0.002 (-0.04,

0.04)

ABP501+MTX

10.60 (1.12,

134.20)

9.26 (1.12,

86.23) 0.10 (0.003, 0.46)

ETN_STD

MTX+SSZ+HC

Q 1.98 (0.41, 11.58)

1.95 (0.42,

11.19) 0.01 (-0.03, 0.04)

ETN_STD+MTX 1.74 (0.36, 9.70) 1.72 (0.38, 9.45) 0.01 (-0.03, 0.03)

159


ABA_STD

(IV)+MTX 1.87 (0.35, 11.23)

1.84 (0.36,

10.88) 0.01 (-0.03, 0.04)

ADA_STD+MTX 3.58 (0.66, 23.52)

3.45 (0.68,

22.00) 0.03 (-0.02, 0.08)

TOF_STD+MTX 4.84 (0.92, 29.79)

4.58 (0.93,

27.24)

0.05 (-0.004,

0.11)

TOC_4 (IV) 3.32 (0.43, 25.92)

3.20 (0.45,

23.43) 0.03 (-0.02, 0.14)

TOC_8 (IV) 2.49 (0.39, 17.05)

2.43 (0.40,

16.10) 0.02 (-0.03, 0.08)

TOC_4

(IV)+MTX 3.61 (0.47, 28.35)

3.46 (0.48,

25.36) 0.03 (-0.02, 0.14)

TOC_8

(IV)+MTX 3.65 (0.53, 25.49)

3.50 (0.54,

23.25) 0.03 (-0.02, 0.12)

GOL_STD

(SC)+MTX 2.55 (0.40, 17.51)

2.49 (0.41,

16.40) 0.02 (-0.03, 0.08)

INF_STD+MTX 3.53 (0.65, 20.77)

3.41 (0.66,

19.56) 0.03 (-0.02, 0.08)

INF_STD 6.17 (0.10, 262.90)

5.67 (0.10,

90.27) 0.06 (-0.03, 0.69)

CERTO_STD

+MTX 2.94 (0.53, 19.50)

2.85 (0.54,

18.32) 0.02 (-0.02, 0.08)

RIT_STD 6.35 (0.29, 258.30)

5.81 (0.30,

91.13) 0.06 (-0.02, 0.70)

RIT_STD+MTX 2.44 (0.05, 103.80)

2.37 (0.06,

54.12) 0.02 (-0.04, 0.49)

BAR_4+MTX 0.76 (0.03, 8.18) 0.77 (0.04, 7.90)

-0.003 (-0.05,

0.04)

HD203+MTX 1.55 (0.24, 11.02)

1.54 (0.25,

10.57) 0.01 (-0.04, 0.05)

160


SB4+MTX 1.33 (0.22, 8.85) 1.32 (0.23, 8.59)

0.004 (-0.04,

0.04)

CT-P13+MTX 3.04 (0.51, 20.12)

2.95 (0.53,

18.84) 0.03 (-0.02, 0.08)

SB2+MTX 7.95 (1.15, 57.50)

7.19 (1.14,

47.22) 0.08 (0.01, 0.24)

SB5+MTX 0.69 (0.04, 8.50) 0.70 (0.04, 8.17)

-0.004 (-0.05,

0.04)

ABP501+MTX 9.38 (0.98, 111.90)

8.26 (0.98,

72.68)

0.10 (-0.001,

0.45)

ETN_STD+MTX ETN_STD 0.88 (0.50, 1.45) 0.88 (0.51, 1.43)

-0.003 (-0.02,

0.01)

ABA_STD

(IV)+MTX 0.94 (0.36, 2.48) 0.95 (0.37, 2.42)

-0.001 (-0.03,

0.03)

ADA_STD+MTX 1.82 (0.69, 4.87) 1.78 (0.70, 4.54) 0.02 (-0.01, 0.07)

TOF_STD+MTX 2.45 (0.97, 6.15) 2.35 (0.97, 5.61)

0.04 (-0.001,

0.09)

TOC_4 (IV) 1.66 (0.37, 7.10) 1.63 (0.38, 6.24) 0.02 (-0.02, 0.12)

TOC_8 (IV) 1.25 (0.35, 4.13) 1.24 (0.36, 3.88) 0.01 (-0.03, 0.06)

TOC_4

(IV)+MTX 1.79 (0.42, 7.76) 1.75 (0.43, 6.76) 0.02 (-0.02, 0.13)

TOC_8

(IV)+MTX 1.84 (0.47, 6.29) 1.80 (0.48, 5.65) 0.02 (-0.02, 0.11)

GOL_STD

(SC)+MTX 1.29 (0.34, 4.36) 1.28 (0.35, 4.07) 0.01 (-0.03, 0.07)

INF_STD+MTX 1.77 (0.68, 4.33) 1.73 (0.69, 4.07) 0.02 (-0.01, 0.06)

INF_STD 3.00 (0.06, 95.62)

2.83 (0.06,

29.48) 0.05 (-0.03, 0.68)

CERTO_STD 1.51 (0.48, 4.48) 1.49 (0.49, 4.17) 0.01 (-0.02, 0.07)

161


+MTX

RIT_STD 3.13 (0.19, 100.10)

2.95 (0.19,

30.06) 0.05 (-0.03, 0.69)

RIT_STD+MTX 1.22 (0.03, 42.79)

1.21 (0.03,

21.48) 0.01 (-0.04, 0.48)

BAR_4+MTX 0.39 (0.03, 2.37) 0.39 (0.03, 2.29) -0.02 (-0.04, 0.03)

HD203+MTX 0.78 (0.25, 2.39) 0.79 (0.26, 2.31) -0.01 (-0.03, 0.03)

SB4+MTX 0.67 (0.24, 1.74) 0.68 (0.25, 1.71) -0.01 (-0.03, 0.02)

CT-P13+MTX 1.53 (0.51, 4.38) 1.50 (0.52, 4.10) 0.01 (-0.02, 0.07)

SB2+MTX 3.96 (1.06, 14.37)

3.66 (1.05,

11.18) 0.07 (0.002, 0.23)

SB5+MTX 0.36 (0.03, 2.16) 0.37 (0.03, 2.11) -0.02 (-0.04, 0.03)

ABP501+MTX 4.67 (0.79, 34.59)

4.23 (0.80,

19.21) 0.09 (-0.01, 0.44)

ABA_STD

(IV)+MTX ETN_STD+MTX 1.09 (0.42, 2.74) 1.08 (0.43, 2.66)

0.002 (-0.02,

0.03)

ADA_STD+MTX 2.09 (0.83, 5.49) 2.03 (0.84, 5.10) 0.02 (-0.01, 0.07)

TOF_STD+MTX 2.76 (1.19, 7.02) 2.64 (1.18, 6.37) 0.04 (0.01, 0.10)

TOC_4 (IV) 1.89 (0.44, 7.86) 1.85 (0.45, 6.89) 0.02 (-0.02, 0.13)

TOC_8 (IV) 1.43 (0.42, 4.66) 1.42 (0.43, 4.36) 0.01 (-0.02, 0.07)

TOC_4

(IV)+MTX 2.06 (0.50, 8.53) 2.00 (0.50, 7.40) 0.02 (-0.01, 0.13)

TOC_8

(IV)+MTX 2.10 (0.57, 7.07) 2.04 (0.58, 6.34) 0.02 (-0.01, 0.11)

GOL_STD

(SC)+MTX 1.48 (0.40, 4.92) 1.46 (0.41, 4.59) 0.01 (-0.02, 0.07)

INF_STD+MTX 2.01 (0.80, 4.99) 1.96 (0.81, 4.68) 0.02 (-0.01, 0.07)

162


INF_STD 3.49 (0.07, 110.40)

3.29 (0.07,

33.46) 0.05 (-0.03, 0.68)

CERTO_STD

+MTX 1.72 (0.58, 5.05) 1.69 (0.59, 4.72) 0.02 (-0.01, 0.07)

RIT_STD 3.55 (0.22, 115.50)

3.34 (0.22,

34.74) 0.06 (-0.02, 0.69)

RIT_STD+MTX 1.40 (0.04, 45.74)

1.38 (0.04,

23.96) 0.01 (-0.03, 0.48)

BAR_4+MTX 0.44 (0.03, 2.71) 0.45 (0.03, 2.62) -0.01 (-0.03, 0.03)

HD203+MTX 0.90 (0.32, 2.43) 0.90 (0.33, 2.35)

-0.002 (-0.02,

0.03)

SB4+MTX 0.77 (0.33, 1.74) 0.77 (0.33, 1.70) -0.01 (-0.02, 0.02)

CT-P13+MTX 1.73 (0.60, 5.11) 1.70 (0.61, 4.76) 0.02 (-0.01, 0.07)

SB2+MTX 4.54 (1.23, 16.41)

4.17 (1.22,

12.75) 0.08 (0.01, 0.23)

SB5+MTX 0.42 (0.03, 2.49) 0.42 (0.03, 2.41) -0.01 (-0.03, 0.03)

ABP501+MTX 5.32 (0.95, 40.03)

4.80 (0.95,

21.96)

0.09 (-0.001,

0.45)

ADA_STD+MTX

ABA_STD

(IV)+MTX 1.94 (0.64, 5.80) 1.89 (0.65, 5.40) 0.02 (-0.02, 0.07)

TOF_STD+MTX 2.59 (0.90, 7.32) 2.49 (0.91, 6.67)

0.04 (-0.004,

0.10)

TOC_4 (IV) 1.75 (0.38, 7.99) 1.71 (0.39, 7.05) 0.02 (-0.02, 0.13)

TOC_8 (IV) 1.33 (0.34, 5.02) 1.32 (0.35, 4.69) 0.01 (-0.03, 0.07)

TOC_4

(IV)+MTX 1.92 (0.41, 8.62) 1.87 (0.42, 7.58) 0.02 (-0.02, 0.13)

TOC_8

(IV)+MTX 1.95 (0.48, 7.71) 1.90 (0.48, 6.87) 0.02 (-0.02, 0.11)

163


GOL_STD

(SC)+MTX 1.35 (0.34, 5.02) 1.34 (0.35, 4.70) 0.01 (-0.03, 0.07)

INF_STD

+MTX 1.86 (0.73, 4.92) 1.82 (0.74, 4.64) 0.02 (-0.01, 0.06)

INF_STD 3.16 (0.07, 113.30)

2.98 (0.07,

36.20) 0.05 (-0.03, 0.69)

CERTO_STD

+MTX 1.60 (0.46, 5.40) 1.57 (0.47, 5.04) 0.01 (-0.02, 0.07)

RIT_STD 3.32 (0.21, 105.10)

3.13 (0.22,

32.08) 0.05 (-0.03, 0.68)

RIT_STD+MTX 1.30 (0.03, 41.21)

1.29 (0.03,

21.29) 0.01 (-0.04, 0.47)

BAR_4+MTX 0.41 (0.03, 2.74) 0.41 (0.03, 2.65) -0.01 (-0.04, 0.03)

HD203+MTX 0.83 (0.21, 3.32) 0.83 (0.22, 3.18)

-0.004 (-0.04,

0.04)

SB4+MTX 0.71 (0.20, 2.51) 0.71 (0.21, 2.45) -0.01 (-0.04, 0.03)

CT-P13+MTX 1.61 (0.55, 5.02) 1.58 (0.56, 4.68) 0.01 (-0.02, 0.07)

SB2+MTX 4.14 (1.16, 16.11)

3.81 (1.15,

12.74) 0.07 (0.01, 0.23)

SB5+MTX 0.39 (0.03, 2.51) 0.39 (0.03, 2.43) -0.01 (-0.04, 0.03)

ABP501+MTX 4.94 (0.82, 37.69)

4.47 (0.82,

21.11) 0.09 (-0.01, 0.44)

TOF_STD+MTX ADA_STD+MTX 1.34 (0.61, 2.93) 1.31 (0.62, 2.76) 0.01 (-0.03, 0.06)

TOC_4 (IV)

0.89 (0.19, 4.56) 0.89 (0.20, 4.10)

-0.005 (-0.07,

0.11)

TOC_8 (IV) 0.67 (0.18, 2.66) 0.68 (0.19, 2.52) -0.01 (-0.07, 0.05)

TOC_4

(IV)+MTX 0.97 (0.22, 4.74) 0.98 (0.23, 4.23)

-0.001 (-0.06,

0.11)

164


TOC_8

(IV)+MTX 0.99 (0.25, 4.06) 0.99 (0.26, 3.68)

-0.001 (-0.06,

0.09)

GOL_STD

(SC)+MTX 0.69 (0.18, 2.70) 0.70 (0.19, 2.56) -0.01 (-0.07, 0.05)

INF_STD+MTX 0.97 (0.33, 2.84) 0.97 (0.35, 2.69)

-0.001 (-0.06,

0.05)

INF_STD 1.62 (0.03, 57.44)

1.57 (0.04,

17.68) 0.03 (-0.07, 0.66)

CERTO_STD

+MTX 0.83 (0.32, 1.95) 0.83 (0.34, 1.88) -0.01 (-0.05, 0.04)

RIT_STD 1.72 (0.10, 49.82)

1.66 (0.11,

16.60) 0.03 (-0.07, 0.66)

RIT_STD+MTX 0.68 (0.02, 22.99)

0.69 (0.02,

11.81) -0.01 (-0.08, 0.45)

BAR_4+MTX 0.22 (0.01, 1.39) 0.23 (0.01, 1.37) -0.04 (-0.09, 0.01)

HD203+MTX 0.42 (0.11, 1.67) 0.44 (0.12, 1.63) -0.03 (-0.08, 0.02)

SB4+MTX 0.37 (0.10, 1.30) 0.38 (0.11, 1.29) -0.03 (-0.08, 0.01)

CT-P13+MTX 0.84 (0.25, 2.80) 0.84 (0.26, 2.65) -0.01 (-0.06, 0.05)

SB2+MTX 2.16 (0.53, 8.73) 2.04 (0.55, 6.95) 0.05 (-0.03, 0.21)

SB5+MTX 0.20 (0.02, 0.90) 0.21 (0.02, 0.90)

-0.04

(-0.08, -0.004)

ABP501+MTX 2.51 (0.61, 14.97) 2.33 (0.62, 8.72) 0.06 (-0.02, 0.40)

TOC_4 (IV) TOF_STD+MTX 0.67 (0.15, 3.09) 0.68 (0.16, 2.79) -0.02 (-0.08, 0.09)

TOC_8 (IV) 0.51 (0.14, 1.84) 0.53 (0.15, 1.77) -0.03 (-0.09, 0.03)

TOC_4

(IV)+MTX 0.73 (0.17, 3.33) 0.75 (0.18, 2.99) -0.02 (-0.08, 0.10)

TOC_8 0.75 (0.19, 2.73) 0.76 (0.21, 2.52) -0.01 (-0.08, 0.07)

165


(IV)+MTX

GOL_STD

(SC)+MTX 0.52 (0.14, 1.90) 0.54 (0.15, 1.82) -0.03 (-0.09, 0.04)

INF_STD+MTX 0.73 (0.26, 1.93) 0.74 (0.28, 1.86) -0.02 (-0.08, 0.04)

INF_STD 1.22 (0.02, 38.93)

1.20 (0.03,

12.36) 0.01 (-0.09, 0.65)

CERTO_STD

+MTX 0.62 (0.21, 1.77) 0.64 (0.22, 1.71) -0.02 (-0.08, 0.03)

RIT_STD 1.31 (0.08, 41.49)

1.28 (0.08,

13.11) 0.02 (-0.09, 0.65)

RIT_STD+MTX 0.51 (0.01, 17.19) 0.53 (0.01, 9.23) -0.03 (-0.10, 0.44)

BAR_4+MTX 0.16 (0.01, 0.96) 0.17 (0.01, 0.96)

-0.05

(-0.11, -0.002)

HD203+MTX 0.32 (0.08, 1.22) 0.34 (0.09, 1.21) -0.04 (-0.10, 0.01)

SB4+MTX 0.28 (0.08, 0.93) 0.29 (0.08, 0.93)

-0.04

(-0.10, -0.003)

CT-P13+MTX 0.63 (0.20, 1.97) 0.64 (0.22, 1.89) -0.02 (-0.08, 0.04)

SB2+MTX 1.62 (0.41, 6.17) 1.56 (0.44, 4.97) 0.03 (-0.05, 0.20)

SB5+MTX 0.15 (0.01, 0.83) 0.16 (0.01, 0.84)

-0.05 (-0.11, -

0.01)

ABP501+MTX 1.90 (0.38, 12.91) 1.79 (0.39, 7.57) 0.05 (-0.05, 0.40)

TOC_8 (IV) TOC_4 (IV) 0.76 (0.23, 2.56) 0.77 (0.25, 2.48) -0.01 (-0.09, 0.03)

TOC_4

(IV)+MTX 1.11 (0.29, 4.09) 1.10 (0.31, 3.79)

0.004 (-0.07,

0.08)

TOC_8

(IV)+MTX 1.09 (0.33, 3.84) 1.08 (0.36, 3.62)

0.003 (-0.07,

0.07)

166


GOL_STD

(SC)+MTX 0.78 (0.13, 4.35) 0.79 (0.15, 4.12) -0.01 (-0.11, 0.06)

INF_STD+MTX 1.08 (0.23, 4.89) 1.07 (0.26, 4.63)

0.003 (-0.11,

0.06)

INF_STD 1.82 (0.03, 66.77)

1.74 (0.04,

23.77) 0.03 (-0.10, 0.66)

CERTO_STD

+MTX 0.92 (0.17, 4.56) 0.93 (0.19, 4.30)

-0.003 (-0.11,

0.06)

RIT_STD 1.97 (0.08, 77.98)

1.88 (0.09,

27.00) 0.04 (-0.10, 0.67)

RIT_STD+MTX 0.73 (0.02, 33.34)

0.74 (0.02,

18.23) -0.01 (-0.13, 0.46)

BAR_4+MTX 0.23 (0.01, 2.19) 0.24 (0.02, 2.14) -0.03 (-0.14, 0.02)

HD203+MTX 0.47 (0.08, 2.74) 0.49 (0.09, 2.65) -0.02 (-0.13, 0.03)

SB4+MTX 0.41 (0.08, 2.20) 0.42 (0.09, 2.15) -0.02 (-0.13, 0.02)

CT-P13+MTX 0.93 (0.18, 4.74) 0.93 (0.20, 4.47)

-0.003 (-0.11,

0.06)

SB2+MTX 2.41 (0.40, 13.76)

2.26 (0.43,

11.25) 0.05 (-0.07, 0.21)

SB5+MTX 0.22 (0.01, 1.88) 0.23 (0.01, 1.85) -0.03 (-0.14, 0.02)

ABP501+MTX 2.86 (0.34, 29.43)

2.62 (0.36,

18.20) 0.07 (-0.07, 0.42)

TOC_4

(IV)+MTX TOC_8 (IV) 1.47 (0.41, 4.88) 1.44 (0.43, 4.46) 0.01 (-0.03, 0.10)

TOC_8

(IV)+MTX 1.46 (0.63, 3.41) 1.43 (0.64, 3.20) 0.01 (-0.02, 0.07)

GOL_STD

(SC)+MTX 1.04 (0.21, 4.75) 1.04 (0.22, 4.46)

0.001 (-0.06,

0.06)

167


INF_STD+MTX 1.42 (0.38, 5.30) 1.40 (0.40, 4.99) 0.01 (-0.05, 0.06)

INF_STD 2.40 (0.05, 87.78)

2.27 (0.05,

28.01) 0.04 (-0.06, 0.68)

CERTO_STD

+MTX 1.21 (0.28, 4.96) 1.20 (0.29, 4.66) 0.01 (-0.06, 0.06)

RIT_STD 2.57 (0.13, 90.43)

2.43 (0.14,

30.93) 0.05 (-0.06, 0.68)

RIT_STD+MTX 0.98 (0.03, 41.73)

0.98 (0.03,

21.39)

-0.001 (-0.07,

0.47)

BAR_4+MTX 0.31 (0.02, 2.39) 0.32 (0.02, 2.32) -0.02 (-0.08, 0.03)

HD203+MTX 0.63 (0.13, 3.22) 0.64 (0.14, 3.09) -0.01 (-0.07, 0.04)

SB4+MTX 0.54 (0.12, 2.36) 0.55 (0.13, 2.31) -0.01 (-0.07, 0.02)

CT-P13+MTX 1.24 (0.29, 4.97) 1.23 (0.31, 4.69) 0.01 (-0.06, 0.06)

SB2+MTX 3.20 (0.63, 15.37)

2.96 (0.65,

12.47) 0.06 (-0.02, 0.22)

SB5+MTX 0.29 (0.02, 2.36) 0.30 (0.02, 2.30) -0.02 (-0.08, 0.03)

ABP501+MTX 3.76 (0.55, 34.48)

3.41 (0.56,

20.60) 0.08 (-0.03, 0.44)

TOC_8

(IV)+MTX

TOC_4

(IV)+MTX 0.99 (0.30, 3.50) 0.99 (0.33, 3.31)

-0.0003

(-0.08, 0.06)

GOL_STD

(SC)+MTX 0.73 (0.12, 3.82) 0.74 (0.13, 3.63) -0.01 (-0.13, 0.05)

INF_STD+MTX 0.98 (0.21, 4.41) 0.98 (0.24, 4.18)

-0.001 (-0.11,

0.06)

INF_STD 1.65 (0.03, 62.28)

1.59 (0.03,

21.39) 0.03 (-0.11, 0.65)

CERTO_STD 0.83 (0.16, 4.19) 0.84 (0.18, 3.97) -0.01 (-0.12, 0.06)

168


+MTX

RIT_STD 1.72 (0.08, 79.27)

1.66 (0.09,

25.15) 0.03 (-0.11, 0.67)

RIT_STD+MTX 0.68 (0.02, 33.97)

0.69 (0.02,

17.25) -0.01 (-0.13, 0.46)

BAR_4+MTX 0.21 (0.01, 1.98) 0.22 (0.01, 1.94) -0.04 (-0.14, 0.02)

HD203+MTX 0.42 (0.08, 2.57) 0.44 (0.09, 2.49) -0.03 (-0.14, 0.03)

SB4+MTX 0.37 (0.07, 1.94) 0.38 (0.08, 1.91) -0.03 (-0.14, 0.02)

CT-P13+MTX 0.84 (0.16, 4.27) 0.85 (0.18, 4.04) -0.01 (-0.12, 0.06)

SB2+MTX 2.18 (0.38, 12.78)

2.05 (0.42,

10.44) 0.05 (-0.08, 0.21)

SB5+MTX 0.20 (0.01, 1.87) 0.21 (0.01, 1.83) -0.04 (-0.15, 0.02)

ABP501+MTX 2.65 (0.31, 26.32)

2.44 (0.34,

15.63) 0.06 (-0.08, 0.42)

GOL_STD

(SC)+MTX

TOC_8

(IV)+MTX 0.71 (0.14, 3.36) 0.73 (0.15, 3.20) -0.01 (-0.10, 0.05)

INF_STD+MTX 0.96 (0.26, 3.93) 0.96 (0.28, 3.72)

-0.002 (-0.09,

0.06)

INF_STD 1.64 (0.03, 57.26)

1.58 (0.04,

19.38) 0.03 (-0.09, 0.66)

CERTO_STD

+MTX 0.83 (0.18, 3.74) 0.84 (0.20, 3.53) -0.01 (-0.10, 0.06)

RIT_STD 1.72 (0.09, 66.17)

1.66 (0.10,

22.27) 0.03 (-0.09, 0.66)

RIT_STD+MTX 0.66 (0.02, 30.66)

0.67 (0.02,

15.63) -0.01 (-0.11, 0.46)

BAR_4+MTX 0.21 (0.01, 1.71) 0.22 (0.01, 1.67) -0.04 (-0.12, 0.02)

HD203+MTX 0.43 (0.09, 2.25) 0.44 (0.10, 2.19) -0.03 (-0.11, 0.03)

169


SB4+MTX 0.36 (0.08, 1.71) 0.38 (0.09, 1.68) -0.03 (-0.11, 0.01)

CT-P13+MTX 0.84 (0.19, 3.80) 0.84 (0.21, 3.58) -0.01 (-0.10, 0.06)

SB2+MTX 2.14 (0.44, 11.67) 2.02 (0.47, 9.46) 0.05 (-0.06, 0.21)

SB5+MTX 0.20 (0.01, 1.64) 0.21 (0.01, 1.61) -0.04 (-0.12, 0.02)

ABP501+MTX 2.53 (0.35, 24.51)

2.34 (0.38,

14.56) 0.06 (-0.06, 0.42)

INF_STD+MTX

GOL_STD

(SC)+MTX 1.37 (0.38, 5.41) 1.35 (0.40, 5.10) 0.01 (-0.05, 0.06)

INF_STD 2.31 (0.05, 94.06)

2.20 (0.05,

32.09) 0.04 (-0.06, 0.68)

CERTO_STD

+MTX 1.18 (0.27, 5.20) 1.17 (0.29, 4.90) 0.01 (-0.06, 0.07)

RIT_STD 2.39 (0.15, 82.15)

2.27 (0.15,

27.94) 0.04 (-0.05, 0.67)

RIT_STD+MTX 0.96 (0.02, 35.21)

0.96 (0.03,

18.37)

-0.001 (-0.07,

0.47)

BAR_4+MTX 0.30 (0.02, 2.41) 0.31 (0.02, 2.35) -0.02 (-0.08, 0.03)

HD203+MTX 0.61 (0.13, 3.08) 0.62 (0.14, 2.97) -0.01 (-0.07, 0.04)

SB4+MTX 0.52 (0.12, 2.45) 0.53 (0.13, 2.39) -0.02 (-0.07, 0.02)

CT-P13+MTX 1.20 (0.29, 5.29) 1.19 (0.31, 4.98) 0.01 (-0.06, 0.07)

SB2+MTX 3.08 (0.63, 16.11)

2.85 (0.65,

13.00) 0.06 (-0.02, 0.22)

SB5+MTX 0.29 (0.02, 2.19) 0.30 (0.02, 2.14) -0.02 (-0.08, 0.02)

ABP501+MTX 3.68 (0.52, 33.14)

3.35 (0.54,

20.22) 0.08 (-0.03, 0.43)

INF_STD INF_STD+MTX 1.69 (0.04, 55.81)

1.63 (0.04,

17.11) 0.03 (-0.06, 0.66)

170


CERTO_STD

+MTX 0.85 (0.26, 2.79) 0.85 (0.27, 2.64) -0.01 (-0.06, 0.05)

RIT_STD 1.80 (0.11, 54.86)

1.73 (0.12,

18.04) 0.03 (-0.06, 0.66)

RIT_STD+MTX 0.68 (0.02, 22.38)

0.69 (0.02,

11.74) -0.01 (-0.07, 0.45)

BAR_4+MTX 0.22 (0.01, 1.47) 0.23 (0.01, 1.44) -0.03 (-0.08, 0.02)

HD203+MTX 0.44 (0.12, 1.70) 0.45 (0.13, 1.66) -0.02 (-0.07, 0.02)

SB4+MTX 0.38 (0.11, 1.28) 0.39 (0.12, 1.27) -0.03 (-0.07, 0.01)

CT-P13+MTX 0.86 (0.51, 1.53) 0.87 (0.52, 1.49) -0.01 (-0.03, 0.02)

SB2+MTX 2.22 (0.93, 5.53) 2.09 (0.94, 4.55)

0.05 (-0.003,

0.19)

SB5+MTX 0.20 (0.01, 1.39) 0.21 (0.01, 1.37) -0.04 (-0.08, 0.01)

ABP501+MTX 2.65 (0.45, 19.98)

2.46 (0.46,

11.57) 0.07 (-0.04, 0.42)

CERTO_STD

+MTX INF_STD 0.51 (0.02, 25.07)

0.53 (0.05,

23.77) -0.04 (-0.67, 0.06)

RIT_STD 1.08 (0.01, 156.20)

1.07 (0.03,

74.50)

0.003 (-0.61,

0.64)

RIT_STD+MTX 0.40 (0.003, 68.86)

0.43 (0.01,

40.15) -0.03 (-0.66, 0.44)

BAR_4+MTX 0.12 (0.002, 8.21)

0.13 (0.004,

8.03) -0.06 (-0.69, 0.03)

HD203+MTX 0.26 (0.01, 13.80)

0.28 (0.02,

13.40) -0.05 (-0.68, 0.04)

SB4+MTX 0.22 (0.01, 11.63)

0.24 (0.02,

11.38) -0.06 (-0.69, 0.03)

CT-P13+MTX 0.51 (0.02, 22.45) 0.53 (0.05,

-0.04 (-0.66, 0.06)

171


21.38)

SB2+MTX 1.31 (0.04, 57.77)

1.28 (0.11,

50.50) 0.02 (-0.60, 0.20)

SB5+MTX 0.11 (0.002, 7.80)

0.13 (0.004,

7.62) -0.06 (-0.70, 0.02)

ABP501+MTX 1.65 (0.03, 92.59)

1.56 (0.09,

70.49) 0.03 (-0.59, 0.40)

RIT_STD

CERTO_STD

+MTX 2.14 (0.12, 58.68)

2.04 (0.12,

21.42) 0.04 (-0.06, 0.66)

RIT_STD+MTX 0.83 (0.02, 26.50)

0.84 (0.02,

14.00) -0.01 (-0.08, 0.46)

BAR_4+MTX 0.26 (0.02, 1.93) 0.27 (0.02, 1.88) -0.03 (-0.08, 0.02)

HD203+MTX 0.52 (0.12, 2.27) 0.53 (0.13, 2.20) -0.02 (-0.07, 0.03)

SB4+MTX 0.45 (0.11, 1.76) 0.46 (0.12, 1.73) -0.02 (-0.08, 0.02)

CT-P13+MTX 1.02 (0.27, 3.79) 1.02 (0.29, 3.58)

0.001 (-0.06,

0.06)

SB2+MTX 2.65 (0.59, 11.76) 2.47 (0.61, 9.38) 0.06 (-0.03, 0.22)

SB5+MTX 0.24 (0.02, 1.41) 0.25 (0.02, 1.39) -0.03 (-0.08, 0.01)

ABP501+MTX 3.05 (0.57, 23.15)

2.79 (0.59,

14.08) 0.07 (-0.02, 0.42)

RIT_STD+MTX RIT_STD 0.39 (0.02, 5.44) 0.44 (0.02, 4.82) -0.03 (-0.42, 0.13)

BAR_4+MTX 0.11 (0.002, 3.23)

0.13 (0.004,

3.16) -0.07 (-0.69, 0.02)

HD203+MTX 0.25 (0.01, 4.94) 0.27 (0.02, 4.78) -0.06 (-0.69, 0.03)

SB4+MTX 0.21 (0.01, 3.91) 0.23 (0.02, 3.82) -0.06 (-0.69, 0.02)

CT-P13+MTX 0.48 (0.02, 8.39) 0.50 (0.05, 7.94) -0.04 (-0.67, 0.06)

SB2+MTX 1.21 (0.04, 24.95) 1.19 (0.10,

0.01 (-0.60, 0.20)

172


21.18)

SB5+MTX 0.11 (0.002, 3.11)

0.12 (0.005,

3.04) -0.07 (-0.70, 0.02)

ABP501+MTX 1.54 (0.04, 40.25)

1.47 (0.10,

29.21) 0.03 (-0.57, 0.38)

BAR_4+MTX RIT_STD+MTX 0.30 (0.003, 19.03)

0.31 (0.01,

18.51) -0.02 (-0.49, 0.04)

HD203+MTX 0.64 (0.02, 29.80)

0.65 (0.03,

28.83) -0.01 (-0.47, 0.05)

SB4+MTX 0.55 (0.02, 22.39)

0.56 (0.03,

21.85) -0.01 (-0.48, 0.03)

CT-P13+MTX 1.27 (0.04, 53.09)

1.26 (0.07,

50.36) 0.01 (-0.46, 0.08)

SB2+MTX 3.24 (0.09, 142.60)

2.98

(0.16, 122.20) 0.06 (-0.40, 0.22)

SB5+MTX 0.27 (0.004, 14.76)

0.28 (0.01,

14.23) -0.02 (-0.49, 0.03)

ABP501+MTX 3.93 (0.09, 205.00)

3.50

(0.16, 137.90) 0.07 (-0.38, 0.42)

HD203+MTX BAR_4+MTX 2.06 (0.27, 34.78)

2.04 (0.28,

33.52) 0.01 (-0.04, 0.05)

SB4+MTX 1.73 (0.24, 31.34)

1.71 (0.25,

30.39) 0.01 (-0.04, 0.04)

CT-P13+MTX 3.94 (0.54, 66.72)

3.80 (0.55,

62.77) 0.03 (-0.02, 0.08)

SB2+MTX

10.32 (1.21,

180.40)

9.26

(1.20, 152.30) 0.09 (0.01, 0.25)

SB5+MTX 0.93 (0.04, 22.20)

0.93 (0.04,

21.45)

-0.001 (-0.05,

0.04)

173


ABP501+MTX

12.58 (1.10,

316.40)

10.96

(1.09, 212.40) 0.10 (0.003, 0.46)

SB4+MTX HD203+MTX 0.85 (0.23, 3.22) 0.85 (0.24, 3.14)

-0.003 (-0.04,

0.03)

CT-P13+MTX 1.95 (0.46, 8.32) 1.90 (0.47, 7.77) 0.02 (-0.03, 0.07)

SB2+MTX 5.03 (1.01, 25.73)

4.60 (1.01,

20.61)

0.08 (0.0003,

0.24)

SB5+MTX 0.46 (0.03, 3.57) 0.47 (0.03, 3.47) -0.01 (-0.06, 0.03)

ABP501+MTX 6.02 (0.80, 54.28)

5.39 (0.81,

32.41) 0.09 (-0.01, 0.45)

CT-P13+MTX SB4+MTX 2.26 (0.60, 9.06) 2.20 (0.60, 8.48) 0.02 (-0.01, 0.08)

SB2+MTX 5.92 (1.29, 27.37)

5.40 (1.27,

21.67) 0.08 (0.01, 0.24)

SB5+MTX 0.53 (0.04, 3.88) 0.54 (0.04, 3.76) -0.01 (-0.04, 0.03)

ABP501+MTX 6.94 (1.03, 62.03)

6.19 (1.02,

36.07) 0.09 (0.001, 0.45)

SB2+MTX CT-P13+MTX 2.58 (0.89, 7.42) 2.41 (0.90, 6.19) 0.06 (-0.01, 0.20)

SB5+MTX 0.23 (0.01, 1.74) 0.24 (0.02, 1.70) -0.03 (-0.08, 0.02)

ABP501+MTX 3.08 (0.47, 25.62)

2.82 (0.48,

15.01) 0.07 (-0.03, 0.43)

SB5+MTX SB2+MTX 0.09 (0.01, 0.76) 0.10 (0.01, 0.77)

-0.09 (-0.24, -

0.01)

ABP501+MTX 1.18 (0.16, 11.07) 1.16 (0.19, 6.87) 0.01 (-0.17, 0.37)

ABP501+MTX SB5+MTX

13.50 (1.62,

240.20)

11.68

(1.58, 171.10) 0.10 (0.01, 0.45)

Random-Effect Residual 86.05 vs 93 datapoints

174


Model Deviance

Deviance

Information

Criteria 445.185

Fixed-Effect

Model

Residual

Deviance 87.16 vs 93 datapoints

Deviance

Information

Criteria 444.419

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1644 and favour the comparator. Italicized results indicate a very wide credible interval. 1645 ABA = abatacept; ABP501 = biosimilar adalimumab; ADA = adalimumab; CERTO = certolizumab pegol; CrI = credible interval; CT-1646 P13 = biosimilar infliximab; csDMARD = conventional synthetic disease modifying antirheumatic drug; ETN = etanercept; GOL = 1647 golimumab; HCQ = hydroxychloroquine; HD203 = etanercept biosimilar; INF = infliximab; IV = intravenous; MTX = methotrexate; OR 1648 = odds ratio; RD = risk difference; RR = relative risk; SB2 = biosimilar infliximab; SB4 = biosimilar of etanercept 50mg; SC = 1649 subcutaneous; SSZ = sulfasalazine; STD = standard dose; TOC_4 = 4 mg/kg tocilizumab; TOC_8 = 8 mg/kg tocilizumab; TOF = 1650 tofacitinib. 1651

1652


Seven studies (six 2-arm studies and one 3-arm study) were included for the reference case 1654

NMA with csDMARD monotherapy as the common comparator.101, 141, 149, 160, 161, 240, 248 The 1655

evidence network involved 3936 participants and seven treatments forming nine direct 1656

comparisons. Assessment for consistency demonstrated that the model was consistent. A 1657

geometric illustration of the evidence network is presented in Figure 22 and the odds ratios for 1658

all treatment comparisons with placebo as the common comparator are available in Table 27. A 1659

staircase table of the results as odds ratios is also presented in Appendix 10. 1660

1661

175

Figure 22. Evidence Network: Withdrawal due to Adverse Events (Placebo+csDMARD)

1662

1663

Only etanercept monotherapy had statistically significantly higher odds of WDAE compared with 1664

csDMARD monotherapy (OR = 3.46 [95% CrI: 1.07, 13.18]). There were no other statistically 1665

significant results for any of the comparisons of biologics and 4 mg baricitinib in terms of 1666

WDAEs (Table 27). 1667

1668

1669

Table 27: Withdrawal Due to Adverse Events (Placebo+csDMARD): Odds Ratios, Relative Risks and Risk 1670 Differences for All Treatment Comparisons – Random Effects Model 1671


ETN_STD Placebo+csDMARD 3.46 (1.07, 13.18) 3.11 (1.07, 9.08) 0.10 (0.004, 0.31)

ETN_STD+csDMARD

1.65 (0.53, 6.03) 1.60 (0.54, 5.11) 0.03 (-0.03, 0.15)

ADA_STD+csDMARD

1.16 (0.24, 6.08) 1.15 (0.25, 5.10) 0.01 (-0.04, 0.16)

176


TOC_8 (IV)+csDMARD

1.95 (0.98, 4.05) 1.87 (0.98, 3.60) 0.04 (-0.001, 0.11)

CERTO_STD

+csDMARD

1.47 (0.52, 4.78) 1.44 (0.53, 4.14) 0.02 (-0.02, 0.13)

BAR_4+csDMARD

1.00 (0.30, 3.28) 1.00 (0.31, 2.99)

-0.0002

(-0.03, 0.09)

ETN_STD+csDMARD ETN_STD 0.48 (0.18, 1.29) 0.52 (0.22, 1.26) -0.07 (-0.22, 0.02)

ADA_STD+csDMARD

0.33 (0.08, 1.39) 0.37 (0.10, 1.33) -0.08 (-0.26, 0.03)

TOC_8 (IV)+csDMARD

0.56 (0.12, 2.25) 0.60 (0.17, 2.08) -0.06 (-0.27, 0.07)

CERTO_STD

+csDMARD

0.43 (0.08, 2.21) 0.47 (0.11, 2.03) -0.07 (-0.29, 0.07)

BAR_4+csDMARD

0.28 (0.05, 1.53) 0.32 (0.07, 1.47) -0.09 (-0.30, 0.03)

ADA_STD+csDMARD ETN_STD+csDMARD 0.70 (0.24, 1.95) 0.72 (0.26, 1.81) -0.02 (-0.08, 0.07)

TOC_8 (IV)+csDMARD

1.18 (0.27, 4.64) 1.17 (0.31, 4.15) 0.01 (-0.12, 0.11)

CERTO_STD

+csDMARD

0.90 (0.17, 4.37) 0.91 (0.19, 3.87) -0.01 (-0.14, 0.12)

BAR_4+csDMARD

0.59 (0.10, 3.04) 0.61 (0.12, 2.80) -0.03 (-0.15, 0.07)

TOC_8 (IV)+csDMARD

ADA_STD

+csDMARD

1.68 (0.28, 9.60) 1.62 (0.32, 8.52) 0.03 (-0.13, 0.12)

CERTO_STD

+csDMARD

1.29 (0.18, 8.45) 1.27 (0.21, 7.44) 0.01 (-0.14, 0.13)

BAR_4+csDMARD

0.86 (0.11, 5.98) 0.86 (0.13, 5.48) -0.01 (-0.16, 0.09)

CERTO_STD

+csDMARD

TOC_8 (IV)

+csDMARD

0.75 (0.21, 2.96) 0.77 (0.23, 2.64) -0.02 (-0.11, 0.10)

BAR_4+csDMARD

0.51 (0.12, 2.00) 0.53 (0.14, 1.88) -0.04 (-0.12, 0.05)

BAR_4+csDMARD

CERTO_STD

+csDMARD

0.67 (0.13, 3.34) 0.69 (0.14, 3.08) -0.02 (-0.14, 0.08)

177




Criteria 87.491

Results highlighted in green are statistically significant and favour the treatment. Results highlighted in red are statistically significant 1672 and favour the comparator. 1673 ADA = adalimumab; BAR_4 = 4mg baricitinib; CrI = credible interval; CERTO = certolizumab pegol; csDMARD = conventional 1674 synthetic disease-modifying anti-rheumatic drug; ETN = etanercept; IV = intravenous; OR = odds ratio; RD = risk difference; RR = 1675 relative risk; STD = standard dose; TOC_8 = 8mg/kg tocilizumab. 1676

1677

6.4.11 Mortality 1678


A total of 30 studies reported mortality outcomes.95, 126, 130, 134, 136, 137, 143, 150, 151, 153, 169, 173, 176, 177, 185, 1680 191, 195, 205, 222, 225, 227, 228, 231, 233, 235, 236, 243, 244, 247, 250 Of these, 19 reported no deaths in any 1681

treatment arm for the duration of the treatment period that was eligible for this analysis.126, 134, 137, 1682 143, 150, 151, 169, 173, 176, 185, 191, 205, 222, 225, 227, 228, 236, 243, 244, 247 The mortality studies are graphically 1683

represented in Figure 23 and outcome data on all eligible studies is represented graphically in 1684

reported in Table 28. 1685

178

Figure 23. Evidence Network: Mortality (Placebo+MTX)

1686

A pairwise MA of two studies that compared infliximab in combination with MTX to MTX 1687

monotherapy had no statistically significant difference in the occurrence of mortality (Peto OR = 1688

0.62 [0.11, 3.67]) (Figure 24). A third comparison arm in the trial by Schiff and colleagues was of 1689

standard dose abatacept in combination with MTX, which reported one death among 156 1690

participants.95 A second pairwise comparison was available based on two studies of etanercept 1691

in combination with MTX or etanercept alone and found no statistically significant difference 1692

between these two active treatments in terms of deaths (Peto OR = 1.93 [0.39, 9.59]) (Figure 1693

25). 1694

1695

Two studies compared a biosimilar etanercept to etanercept in combination with MTX; the first 1696

compared SB4 in combination with MTX to etanercept combination therapy and one death 1697

occurred in the biosimilar arm and none in the etanercept arm.153 The second was of HD203 in 1698

179

combination with MTX and in that study two deaths occurred in the etanercept combination arm 1699

and none in the biosimilar arm.130 1700

1701

Infliximab in combination with MTX was the comparator for two studies of different biosimilar 1702

infliximabs. Choe and colleagues reported one death in the infliximab combination arm and zero 1703

deaths in the SB2 in combination with MTX arm.136 Yoo and colleagues reported one death in 1704

the infliximab combination arm and no deaths in the CT-P13 arm.250 Neither study demonstrated 1705

any statistically significant difference in mortality between the treatment arms. 1706

1707

Another study compared etanercept in combination with MTX to a csDMARD combination 1708

therapy involving MTX and another csDMARD; there was one patient in the etanercept arm who 1709

died, but no participants died in the csDMARD combination arm.177 A three-arm trial comparing 1710

rituximab combination therapy with MTX, rituximab monotherapy and MTX monotherapy 1711

reported one death in the rituximab monotherapy arm and no deaths in the other treatment 1712

arms.150 None of these treatments were statistically significantly different from one another. 1713

1714

Table 28. Mortality Events, Concomitant Methotrexate 1715

Author, Year Treatment 1 n N Treatment 2 n N Treatment 3 n N

Bae, 2016 ETN_STD+MTX 2 146 HD203+MTX 0 147

Tanaka, 2016 Placebo+MTX 0 49 BAR_4+MTX 0 24

Choe, 2015 INF_STD+MTX 1 293 SB2+MTX 0 290

Emery, 2015 ETN_STD+MTX 0 297 SB4+MTX 1 298

Keystone, 2015 Placebo+MTX 0 98 BAR_4+MTX 0 52

Li, 2015 Placebo+MTX 0 132 GOL_STD (SC)+MTX 0 131

Weinblatt, 2015 Placebo+MTX 0 61 ADA_STD+MTX 0 59

Yoo, 2016 INF_STD+MTX 1 300 CT-P13+MTX 0 302

Yamamoto, 2014 Placebo+MTX 0 77 CERTO_STD+MTX 0 82

Choy, 2012 Placebo+MTX 0 119 CERTO_STD+MTX 0 124

Abe, 2006 Placebo+MTX 0 47 INF_STD+MTX 0 49

Conaghan, 2013 Placebo+MTX 0 23 ABA_STD (IV)+MTX 0 27

Emery, 2010 Placebo+MTX 0 172 RIT_STD+MTX 0 170

180


Kim, 2012 csDMARD+MTX 0 103 ETN_STD+MTX 1 197

O'Dell, 2013 MTX+SSZ+HCQ 0 222 ETN_STD+MTX 0 219

Takeuchi, 2013 Placebo+MTX 0 66 ABA_STD (IV)+MTX 0 61

Tanaka, 2011 Placebo+MTX 0 28 TOF_STD+MTX 0 27

Tanaka, 2012 Placebo+MTX 0 88 GOL_STD (SC)+MTX 0 86

Chen, 2009 Placebo+MTX 0 12 ADA_STD+MTX 0 35

Kay, 2008 Placebo+MTX 0 34 GOL_STD (SC)+MTX 0 37

Keystone, 2009 Placebo+MTX 0 133 GOL_STD (SC)+MTX 0 89

Kremer, 2005 Placebo+MTX 0 119 ABA_STD (IV)+MTX 0 115

Maini, 1999 Placebo+MTX 3 88 INF_STD+MTX 1 86

Weinblatt, 1999 Placebo+MTX 0 30 ETN_STD+MTX 0 59

van Vollenhoven,

2011 Placebo+MTX 0 76 ADA_STD+MTX 0 79

van der Heijde,

2013 Placebo+MTX 0 160 TOF_STD+MTX 2 321

Van Riel, 2006 ETN_STD 0 159 ETN_STD+MTX 2 155

Edwards, 2004 Placebo+MTX 0 40 RIT_STD 1 40 RIT_STD+MTX 0 40

Schiff, 2008 Placebo+MTX 0 110 ABA_STD (IV)+MTX 1 156 INF_STD+MTX 1 165

van der Heijde,

2007 Placebo+MTX 1 228 ETN_STD 2 223 ETN_STD+MTX 2 231

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 1716 ABA = abatacept; ADA = adalimumab; BAR_4 = 4 mg baricitinib; CERTO = certolizumab pegol; csDMARD = conventional synthetic 1717 disease-modifying anti-rheumatic drug; ETN = etanercept; GOL = golimumab; HD203 = biosimilar etanercept; INF = infliximab; IV = 1718 intravenous; MTX = methotrexate; RIT = rituximab; SB2 = biosimilar infliximab; SB4 = biosimilar etanercept; SC = subcutaneous; 1719 STD = standard dose; TOF = tofacitinib. 1720

1721

181

Figure 24. Mortality (Infliximab with MTX versus MTX Monotherapy): Meta-Analysis – Peto Odds Ratio

1722

1723

Figure 25. Mortality (Etanercept with MTX versus Etanercept Monotherapy): Meta-Analysis – Peto Odds Ratio

1724

1725


Seven trials treating 1398 participants with concomitant csDMARD (either MTX or another 1727

csDMARD) reported on mortality.101, 141, 156, 161, 170, 194, 215 Four of these trials had zero events for 1728

all treatment arms.161, 170, 194, 215 One participant receiving adalimumab in combination with a 1729

csDMARD died in a study where csDMARD monotherapy was the comparator.156 Another study 1730

reported two deaths in the adalimumab in combination with csDMARD arm and no deaths in the 1731

etanercept in combination with csDMARD arm.101 A three-arm trial compared etanercept in 1732

combination with sulfasalazine, etanercept monotherapy and sulfasalazine monotherapy; during 1733

the eligible treatment period, one participant in the etanercept monotherapy arm died and no 1734

other deaths were reported in the other treatment arms.141 A geometric illustration of the 1735

evidence network is available in Figure 26. Full mortality data on the included studies is 1736

presented in Table 29. 1737

Study or Subgroup

Maini 1999

Schiff 2008

Total (95% CI)

Total events

Heterogeneity: Chi² = 1.37, df = 1 (P = 0.24); I² = 27%

Test for overall effect: Z = 0.52 (P = 0.60)

Events

1

1

2

Total

86

165

251

Events

3

0

3

Total

88

110

198

Weight

80.4%

19.6%

100.0%

Peto, Fixed, 95% CI

0.37 [0.05, 2.67]

5.29 [0.10, 289.29]

0.62 [0.11, 3.67]

INF_STD+MTX Placebo+MTX Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.001 0.1 1 10 1000

Favours INF_STD+MTX Favours Placebo+MTX

Study or Subgroup

van der Heijde 2007

van Riel 2006

Total (95% CI)

Total events



Events

2

2

4

Total

231

155

386

Events

2

0

2

Total

223

159

382

Weight

66.6%

33.4%

100.0%

Peto, Fixed, 95% CI

0.97 [0.14, 6.90]

7.63 [0.48, 122.58]

1.93 [0.39, 9.59]

ETN_STD+MTX ETN_STD Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.001 0.1 1 10 1000

Favours ETN_STD+MTX Favours ETN_STD

182

Figure 26. Evidence Network: Mortality (Placebo+csDMARD)

1738

1739

Table 29. Mortality Events, Concomitant Conventional Synthetic DMARD 1740


Furst, 2003 Placebo+csDMARD 0 318

ADA_STD

+csDMARD

1 318

Hobbs, 2015 Placebo+csDMARD 0 104 ETN_STD+csDMARD 0 106

Jobanputra, 2012

ADA_STD

+csDMARD

2 60 ETN_STD+csDMARD 0 60

Kennedy, 2014

Placebo

+csDMARD

0 43 ADA_STD+csDMARD 0 85

MacIsaac, 2014

Placebo

+csDMARD

0 31 INF_STD+csDMARD 0 30

183

Combe, 2009 Placebo+SSZ 0 50 ETN_STD 1 103 ETN_STD+SSZ 0 101

Smolen, 2014

Placebo

+csDMARD

0 30 SIR_100+csDMARD 0 30

SIR_50

+csDMARD

0 30

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 1741 ADA = adalimumab; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN = etanercept; INF = infliximab; 1742 SIR_100 = sirukumab 100mg; SIR_50 = sirukumab 50mg; SSZ = sulfasalazine; STD = standard dose. 1743

1744

6.4.12 Serious Infections 1745


Twenty-four studies consisting of 6624 participants reported on the number of participants 1747

experiencing serious infections and involved MTX as the common comparator.95, 100, 128, 136, 137, 1748 143, 148, 150, 153, 167, 169, 173, 176, 188, 189, 192, 197, 225, 227, 228, 231, 233, 235, 236 A geometric illustration of the 1749

evidence network is available in Figure 27. Full event data for these studies is reported in Table 1750

30. 1751

1752

184

Figure 27. Evidence Network: Serious Infections (Placebo+MTX)

1753

Six of the studies reported no serious infections among participants in all treatment arms.143, 176, 1754 188, 225, 227, 228 In the five-arm CHARISMA trial, no participants developed a serious infection in 1755

any treatment arm, except the 8 mg/kg tocilizumab in combination with MTX arm in which three 1756

participants out of 50 developed one or more serious infections.197 Another study reported zero 1757

events in the MTX monotherapy arm, but two participants with serious infections in the 1758

tofacitinib in combination with MTX arm.233 1759

1760

A pairwise MA of two trials of combination infliximab therapy with MTX compared to MTX 1761

monotherapy did not have a statistically significant result (Peto OR = 0.71 [0.28, 1.79]) (Figure 1762

28).95, 192 Two trials compared the combination therapy of tofacitinib with MTX to MTX alone, 1763

and the pooled results indicate there is no difference in the number of participants developing 1764

serious infections (Peto OR = 2.19 [0.40, 11.91]) (Figure 29).100, 233 Another pairwise MA 1765

conducted with MTX monotherapy as the comparator involved two studies of subcutaneous 1766

185

golimumab in combination with MTX and no difference in the number of participants with serious 1767

infections was found (Peto OR = 1.87 [0.31, 11.14]) (Figure 30).169, 173 There was no statistically 1768

significant difference in the number of serious infections based on the pairwise MA of etanercept 1769

in combination with MTX compared to MTX alone (Peto OR = 0.88 [0.45, 1.17]) (Figure 31).189, 1770 231 Two studies of adalimumab in combination with MTX compared to MTX monotherapy 1771

combined in a pairwise MA had insufficient evidence to demonstrate one treatment to have 1772

fewer participants with serious infections over another (Peto OR = 1.29 [0.22, 7.68]) (Figure 1773

32).100, 236 1774

There were two pairwise MAs that involved direct comparisons of biologic monotherapy versus 1775

combination therapy (Figures 33 and 34). The first involved two studies with etanercept in 1776

combination with MTX and etanercept monotherapy as the two treatments of interest; there was 1777

no statistically significant difference in the number of participants developing serious infections 1778

(Peto OR = 1.03 [0.52, 2.04]) (Figure 33).231, 235 The second pairwise MA compared 8 mg/kg 1779

tocilizumab monotherapy and combination therapy with MTX among three studies, but there 1780

was no statistically significant difference between the treatments in terms of the number of 1781

participants with serious infections (Peto OR = 1.14 [0.54, 2.43]) (Figure 34).148, 167, 197 1782

1783

Choy et al. conducted a study comparing certolizumab pegol in combination with MTX to MTX 1784

monotherapy; three (2.4%) participants in the certolizumab arm and two (1.7%) in the MTX arm 1785

developed a serious adverse event.137 The number of participants with a serious infection in a 1786

three-arm study by Edwards and colleagues were as follows: zero events in the rituximab in 1787

combination with MTX arm, two (5.0%) events in the rituximab monotherapy arm, and one 1788

(2.5%) event in the MTX monotherapy arm.150 1789

1790

Another study that reported cases of serious infection compared SB2 in combination with MTX 1791

to its reference product infliximab in combination with MTX. There were nine (3.1%) participants 1792

who developed a serious infection in the biosimilar infliximab with MTX arm and six (2.0%) 1793

participants who developed a serious infection in the infliximab in combination with MTX arm.136 1794

Emery and colleagues conducted a study of a head-to-head comparison between a biologic and 1795

a biosimilar, both in combination with MTX. They reported one (0.3%) participant with a serious 1796

infection in the SB4 (biosimilar etanercept) arm and four (1.3%) participants with serious 1797

infections in the etanercept arm.153 Lastly, one study sponsored by Amgen reported five (1.9%) 1798

participants with serious infection in the biosimilar adalimumab in combination with MTX arm 1799

and three (1.1%) in the adalimumab in combination with MTX arm.128 Despite the trials 1800

mentioned above reporting cases of serious infection during the study period, the proportions in 1801

each treatment arm remained low and comparable from one trial to another. 1802

1803

Table 30: Serious Infections Events, Concomitant Methotrexate 1804

186

Author, Year Trt 1 n N Trt 2 n N Trt 3 n N Trt 4 n N Trt 5 n N

Tanaka, 2016

Placebo

+MTX

0 49

BAR_4

+MTX

0 24

Keystone,

2015

Placebo

+MTX

0 98

BAR_4

+MTX

0 52

Conaghan,

2013

Placebo

+MTX

0 23 ABA_STD

(IV)+MTX 0 27

Kermer, 2003

Placebo

+MTX

0 119 ABA_STD

(IV)+MTX 0 115

Tanaka, 2011

Placebo

+MTX

0 28

TOF_STD

+MTX

0 27

Tanaka, 2012

Placebo

+MTX

0 88 GOL_STD

(SC)+MTX 0 86

van der

Heijde, 2013t

Placebo

+MTX

0 160

TOF_STD

+MTX

2 321

Kay, 2008

Placebo

+MTX

1 34 GOL_STD

(SC)+MTX 1 37

Keystone,

2009

Placebo

+MTX

1 133 GOL_STD

(SC)+MTX 2 89

Lan, 2004

Placebo

+MTX

1 29

ETN_STD

+MTX

1 29

van

Vollenhoven,

2011

Placebo

+MTX

1 76

ADA_STD

+MTX

3 79

Choy, 2012

Placebo

+MTX

2 119

CERTO

_STD+MTX

3 124

Van Riel, 2006 ETN_STD 2 159

ETN_STD

+MTX

1 155

Amgen

(Sponsor),

2016

ADA_STD

+MTX

3 262

ABP501

+MTX

5 264

Emery, 2015 ETN_STD 4 297 SB4+MTX 1 298

187

Author, Year Trt 1 n N Trt 2 n N Trt 3 n N Trt 4 n N Trt 5 n N

+MTX

Choe, 2015

INF_STD

+MTX

6 293 SB2+MTX 9 290

Dougados,

2013

TOC_8

(IV) 6 276

TOC_8

(IV)+MTX 6 277

Lipsky, 2000

Placebo

+MTX

7 86

INF_STD

+MTX

2 88

Kaneko, 2015 TOC_8

(IV) 7 111

TOC_8

(IV)+MTX 6 115

van

Vollenhoven,

2012

Placebo

+MTX

1 108

TOF_STD

+MTX

3 204

ADA_STD

+MTX

0 204

Edwards, 2004

Placebo

+MTX

1 40 RIT_STD 2 40

RIT_STD

+MTX

0 40

Schiff, 2008

Placebo

+MTX

3 110 ABA_STD

(IV)+MTX 2 156

INF_STD

+MTX

7 165

van der

Heijde, 2007

Placebo

+MTX

19 228 ETN_STD 15 223

ETN_STD

+MTX

17 231

Maini, 2006

Placebo

+MTX

0 49 TOC_4 (IV) 0 54 TOC_8 (IV) 0 52 TOC_4

(IV)+MTX 0 49

TOC_8

(IV)+MTX 3 50

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 1805 ABA = abatacept; ABP501 = adalimumab biosimilar; ADA = adalimumab; BAR_4 = baricitinib 4mg; CERTO = certolizumab pegol; 1806 ETN = etanercept; GOL = golimumab; INF = infliximab; IV = intravenous; MTX = methotrexate; RIT = rituximab; SB2 = biosimilar 1807 infliximab; SB4 = biosimilar etanercept; SC = subcutaneous; STD = standard dose; TOC_4 = tocilizumab 4mg/kg; TOC_8 = 1808 tocilizumab 8mg/kg; TOF = tofacitinib; Trt = treatment. 1809 1810

Figure 28. Serious Infections (Infliximab with MTX versus MTX Monotherapy): Meta-Analysis – Peto Odds Ratio

1811

Study or Subgroup

Lipsky 2000

Schiff 2008

Total (95% CI)

Total events



Events

2

7

9

Total

88

165

253

Events

7

3

10

Total

86

110

196

Weight

48.0%

52.0%

100.0%

Peto, Fixed, 95% CI

0.30 [0.08, 1.16]

1.54 [0.43, 5.57]

0.71 [0.28, 1.79]


Peto, Fixed, 95% CI

0.01 0.1 1 10 100


188

1812

Figure 29. Serious Infections (Tofacitinib with MTX versus MTX Monotherapy): Meta-Analysis – Peto Odds Ratio

1813

1814

Figure 30. Serious Infections (Golimumab (SC) with MTX versus MTX Monotherapy): Meta-Analysis – Peto Odds Ratio

1815

1816

Figure 31. Serious Infections (Etanercept with MTX versus MTX Monotherapy): Meta-Analysis – Peto Odds Ratio

1817

1818

Study or Subgroup

van der Heijde 2013

van Vollenhoven 2012

Total (95% CI)

Total events



Events

2

3

5

Total

321

204

525

Events

0

1

1

Total

160

108

268

Weight

33.1%

66.9%

100.0%

Peto, Fixed, 95% CI

4.49 [0.24, 85.30]

1.54 [0.19, 12.17]

2.19 [0.40, 11.91]

TOF_STD+MTX Placebo+MTX Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.01 0.1 1 10 100

Favours TOF_STD+MTX Favours Placebo+MTX

Study or Subgroup

Kay 2008

Keystone 2009

Total (95% CI)

Total events



Events

1

2

3

Total

37

89

126

Events

1

1

2

Total

34

133

167

Weight

40.8%

59.2%

100.0%

Peto, Fixed, 95% CI

0.92 [0.06, 15.01]

3.05 [0.30, 31.07]

1.87 [0.31, 11.14]

GOL_STD (SC)+MTX Placebo+MTX Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.01 0.1 1 10 100

Favours GOL_STD (SC)+MTX Favours Placebo+MTX

Study or Subgroup

Lan 2004

van der Heijde 2007

Total (95% CI)

Total events



Events

1

17

18

Total

29

231

260

Events

1

19

20

Total

29

228

257

Weight

5.6%

94.4%

100.0%

Peto, Fixed, 95% CI

1.00 [0.06, 16.39]

0.87 [0.44, 1.73]

0.88 [0.45, 1.71]

ETN_STD+MTX Placebo+MTX Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.01 0.1 1 10 100

Favours ETN_STD+MTX Favours Placebo+MTX

189

Figure 32. Serious Infections (Adalimumab with MTX versus MTX Monotherpay): Meta-Analysis – Peto Odds Ratio

1819

1820

Figure 33. Serious Infections (Etanercept with MTX versus Etanercept Monotherapy): Meta-Analysis – Peto Odds Ratio

1821

1822

Figure 34. Serious Infections (8 mg/kg Tocilizumab (IV) with MTX versus 8 mg/kg Tocilizumab (IV) Monotherapy): Meta-Analysis – Peto Odds Ratio

1823


There were four studies with a total of 1047 participants with csDMARD as a common 1825

comparator that reported on serious infection outcomes.141, 149, 161, 170 It was not possible to 1826

conduct a NMA because there were too many zero events. Pairwise MAs were also not possible 1827

Study or Subgroup



Total (95% CI)

Total events



Events

3

0

3

Total

79

204

283

Events

1

1

2

Total

76

108

184

Weight

81.2%

18.8%

100.0%

Peto, Fixed, 95% CI

2.67 [0.37, 19.31]

0.06 [0.00, 3.42]

1.29 [0.22, 7.68]

ADA_STD+MTX Placebo+MTX Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.001 0.1 1 10 1000

Favours ADA_STD+MTX Favours Placebo+MTX

Study or Subgroup

van der Heijde 2007

van Riel 2006

Total (95% CI)

Total events



Events

17

1

18

Total

231

155

386

Events

15

2

17

Total

223

159

382

Weight

90.9%

9.1%

100.0%

Peto, Fixed, 95% CI

1.10 [0.54, 2.26]

0.52 [0.05, 5.08]

1.03 [0.52, 2.04]


Peto, Fixed, 95% CI

0.01 0.1 1 10 100


Study or Subgroup

Dougados 2013

Kaneko 2015

Maini 2006

Total (95% CI)

Total events



Events

6

6

3

15

Total

277

115

50

442

Events

6

7

0

13

Total

276

111

52

439

Weight

43.6%

45.6%

10.9%

100.0%

Peto, Fixed, 95% CI

1.00 [0.32, 3.12]

0.82 [0.27, 2.50]

8.01 [0.81, 78.85]

1.14 [0.54, 2.43]

TOC_8 (IV)+MTX TOC_8 (IV) Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.01 0.1 1 10 100

Favours TOC_8(IV)+MTX Favours TOC_8(IV)

190

because no two studies had the same comparison. Figure 35 presents the evidence network 1828

and the event data for the available studies is reported in Table 31. 1829

Figure 35. Evidence Network: Serious Infections (Placebo+csDMARD)

1830

1831

One of the studies compared etanercept in combination with csDMARD to csDMARD 1832

monotherapy reported zero events in either treatment arm.161 Etanercept was also an 1833

intervention of interest in a three-arm trial, which compared etanercept in combination with 1834

csDMARD, etanercept monotherapy, and csDMARD monotherapy.141 In this trial there were five 1835

(5.0%) participants in the etanercept combination arm, 11 (10.7%) in the etanercept 1836

monotherapy arm, and zero in the csDMARD monotherapy arm who developed a serious 1837

infection.141 Participants in the etanercept monotherapy arm had a statistically significantly 1838

higher odds of developing a serious infection compared to participants in the csDMARD 1839

monotherapy arm (Peto OR = 4.90 [1.33, 18.06]).141 A study comparing adalimumab in 1840

combination with csDMARD to csDMARD alone reported that only adalimumab arm had cases 1841

of serious infection (n = 2, 2.4%).170 Finally, the recent RA-BUILD trial of the oral tsDMARD 1842

baricitinib in combination with csDMARD versus csDMARD monotherapy reported a low number 1843

of cases, with two (0.9%) participants in the 4 mg baricitinib arm and three (1.3%) participants in 1844

the csDMARD monotherpay arm having a serious infection.149 1845

1846

Table 31: Serious Infection Events, Concomitant Conventional Synthetic DMARD 1847


Hobbs, 2015

Placebo

+csDMARD

0 104 ETN_STD+csDMARD 0 106

191


Kennedy, 2014

Placebo

+csDMARD

0 43 ADA_STD+csDMARD 2 85

Dougados, 2017

Placebo

+csDMARD

3 228 BAR_4+csDMARD 2 227

Combe, 2009

Placebo

+csDMARD

0 50 ETN_STD 11 103 ETN_STD+csDMARD 5 101

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 1848 ADA = adalimumab; BAR_4 = baricitinib 4mg; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN = 1849 etanercept; STD = standard dose. 1850

1851

1852

6.4.13 Tuberculosis 1853


Twenty-nine studies with MTX as a common comparator reported on tuberculosis (active and 1855

latent) outcomes among a total of 8614 participants.98, 126, 130, 134, 135, 137, 153, 166, 169, 173, 176, 177, 179, 183, 1856 191, 193, 197, 202, 212, 225, 227, 231, 235, 236, 239, 244, 247, 250, 252 Twenty-one of these studies reported zero 1857

cases of tuberculosis (TB) in all treatment arms.98, 126, 135, 137, 166, 169, 173, 176, 177, 179, 183, 191, 193, 197, 202, 1858 225, 227, 235, 239, 244, 247 With so many zero events, it was not possible to conduct a NMA. A 1859

geometric illustration of the evidence network is available in Figure 36. Descriptive analyses 1860

were used for the remaining studies and the event data for all studies reporting TB outcomes 1861

are reported in Table 32. One pairwise MA was possible based on two studies that compared 1862

adalimumab in combination with MTX to MTX monotherapy. The 95% confidence interval was 1863

very wide because both arms had zero events in the MTX monotherapy arm and it was not 1864

possible to detect any statistically significant difference in the number of cases of TB (Peto OR 1865

= 5.44 [0.28, 104.49]) (Figure 37).134, 236 1866

192

Figure 36. Evidence Network: Tuberculosis (Placebo+MTX)

1867

One study of infliximab combination therapy with MTX versus MTX monotherapy found that one 1868

participant developed TB in the infliximab arm and no participants had TB in the MTX arm.252 1869

Infliximab was also the comparator in another study for CT-P13 (biosimilar infliximab); the 1870

number of participants with TB (latent and active) was high with 22 cases (7.3%) in the CT-P13 1871

arm and 20 (6.7%) in the infliximab arm,250 yet there was no statistically significant difference in 1872

the number of cases between arms. Smolen and colleagues compared certolizumab pegol in 1873

combination with MTX to MTX monotherapy and reported three and zero participants with TB in 1874

each arm, respectively.212 1875

1876

Three studies included etanercept, with different comparators. One was a three-arm study 1877

comparing etanercept in combination with MTX, etanercept monotherapy, and MTX 1878

monotherapy. The only case of TB that occurred in that study was in the etanercept combination 1879

193

arm.231 A study by Emery et al. on SB4 (biosimilar etanercept) versus etanercept, both in 1880

combination with MTX, reported a somewhat high number of cases of TB in both arms: 13 1881

cases (4.4%) in the biosimilar arm and 12 cases (4.0%) in the etanercept arm, respectively.153 1882

Bae and colleagues conducted a study of a different biosimilar etanercept (HD203) in 1883

combination with MTX compared to etanercept in combination with MTX; the number of 1884

participants who developed TB during the study was 14 (9.5%) and 8 (5.5%) in the HD203 and 1885

etanercept arms, respectively.130 In both trials of a biosimilar eternercept there was no 1886

statistically significant difference in the number of TB cases between the biosimilar and the 1887

reference product. 1888

1889

Table 32. Tuberculosis Events, Concomitant Methotrexate 1890

Author, Year Trt1 n N Trt2 n N Trt3 n N Trt4 n N Trt5 n N

Li, 2015

Placebo

+MTX

0 132 GOL_STD

(SC)+MTX 0 131

Tanaka, 2016

Placebo

+MTX

0 49

BAR_4

+MTX

0 24

Keystone,

2015

Placebo

+MTX

0 98

BAR_4

+MTX

0 52

Weinblatt,

2015

Placebo

+MTX

0 61

ADA_STD

+MTX

0 59

Yamamoto,

2014

Placebo

+MTX

0 77

CERTO

_STD+MTX

0 82

Choy, 2012

Placebo

+MTX

0 119

CERTO

_STD+MTX

0 124

Weinblatt,

2013

Placebo

+MTX

0 197 GOL_STD

(IV)+MTX 0 395

Abe, 2006

Placebo

+MTX

0 47

INF_STD

+MTX

0 49

Kim, 2013

Placebo

+MTX

0 72

INF_STD

+MTX

0 71

Nishimoto, Placebo 0 64 TOC_8 (IV) 0 61

194


2009 +MTX

Tanaka, 2012

Placebo

+MTX

0 88 GOL_STD

(SC)+MTX 0 86

Kay, 2008

Placebo

+MTX

0 34 GOL_STD

(SC)+MTX 0 37

Keystone,

2009

Placebo

+MTX

0 133 GOL_STD

(SC)+MTX 0 89

Chen, 2016

Placebo

+MTX

0 200

ANBAI

+MTX

0 400

Kim, 2012

csDMARD

+MTX

0 103

ETN_STD

+MTX

0 197

Machado, 2014

csDMARD

+MTX

0 142

ETN_STD

+MTX

0 279

Kameda, 2010 ETN_STD 0 74

ETN_STD

+MTX

0 77

Van Riel, 2006 ETN_STD 0 159

ETN_STD

+MTX

0 155

Gashi, 2014 ETN_STD

+MTX 0 13

RIT_STD

+MTX

0 20

Kremer, 2011

Placebo

+MTX

0 393 TOC_4

(IV)+MTX 0 399

TOC_8

(IV)+MTX 0 398

Maini, 2006

Placebo

+MTX

0 49 TOC_4 (IV) 0 54 TOC_8

(IV) 0 52

TOC_4

(IV)

+MTX

0 49

TOC_8

(IV)

+MTX

0 50

Chen, 2009

Placebo

+MTX

0 12

ADA_STD

+MTX

1 35

Smolen, 2009

Placebo

+MTX

0 127

CERTO

_STD+MTX

3 246

195


van

Vollenhoven,

2011

Placebo

+MTX

0 76

ADA_STD

+MTX

1 79

Zhang, 2006

Placebo

+MTX

0 86

INF_STD

+MTX

1 87

Bae, 2016 ETN_STD

+MTX 8 146

HD203

+MTX

14 147

Emery, 2015 ETN_STD

+MTX 12 297 SB4+MTX 13 298

Yoo, 2016

INF_STD

+MTX

20 300

CT-P13

+MTX

22 302

Klareskog,

2004

Placebo

+MTX

0 228 ETN_STD 0 223 ETN_STD

+MTX 1 231

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 1891 ABP501 = adalimumab biosimilar; ADA = adalimumab; ANBAI = AnBaiNuo (biosimilar etanercept); BAR_4 = baricitinib 4mg; 1892 CERTO = certolizumab pegol; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; CT-P13 = biosimilar 1893 infliximab; ETN = etanercept; GOL = golimumab; INF = infliximab; IV = intravenous; MTX = methotrexate; RIT = rituximab; SB4 = 1894 biosimilar etanercept; SC = subcutaneous; STD = standard dose; TOC_4 = tocilizumab 4mg/kg; TOC_8 = tocilizumab 8mg/kg; Trt = 1895 treatment. 1896

1897

1898

Figure 37. Tuberculosis (Adalimumab with MTX versus MTX Monotherapy): Meta-Analysis – Peto Odds Ratio

1899


Four trials involving csDMARD as the common comparator and 2556 total participants reported 1901

on TB outcomes.156, 160, 215, 248 There were no cases of TB reported in any treatment of these 1902

trials. A geometric illustration of the evidence network is available in Figure 38 and event data is 1903

available in Table 33. 1904

Study or Subgroup

Chen 2009


Total (95% CI)

Total events



Events

1

1

2

Total

35

79

114

Events

0

0

0

Total

12

76

88

Weight

43.2%

56.8%

100.0%

Peto, Fixed, 95% CI

3.83 [0.04, 343.01]

7.11 [0.14, 358.77]

5.44 [0.28, 104.49]

ADA_STD+MTX Placebo+MTX Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.001 0.1 1 10 1000

Favours ADA_STD+MTX Favours Placebo+MTX

196

Figure 38. Evidence Network: Tuberculosis (Placebo+csDMARD)

1905

1906

Table 33. Tuberculosis Events, Concomitant Conventional Synthetic DMARD 1907


Yazici 2012 Placebo+csDMARD 0 205 TOC_8 (IV)+csDMARD 0 409

Furst 2003 Placebo+csDMARD 0 318 ADA_STD+csDMARD 0 318

Genovese 2008 Placebo+csDMARD 0 414 TOC_8 (IV)+csDMARD 0 802

Smolen 2014 Placebo+csDMARD 0 30 SIR_100+csDMARD 0 30 SIR_50+csDMARD 0 30

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 1908 ADA = adalimumab; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; IV = intravenous; SIR_100 = 1909 100mg sirukumab; SIR_50 = 50mg sirukumab; STD = standard dose; TOC_8 = tocilizumab 8mg/kg. 1910

1911

197

6.4.14 Cancer 1912


A total of 27 RCTs in which MTX monotherapy was the common comparator reported on cancer 1914

outcomes with 6728 participants contributing data.95, 134-137, 143, 153, 154, 165, 169, 173, 178, 179, 191, 193, 195, 1915 196, 221, 225, 227, 232, 236, 244, 247, 249, 252 Nineteen of these trials had zero events in all treatment arms for 1916

the duration of the treatment period eligible for our analysis.134, 135, 137, 143, 154, 169, 173, 178, 191, 193, 195, 1917 196, 221, 225, 227, 236, 244, 247, 252 A geometric illustration of the evidence network is presented in Figure 1918

39. The number of cancer events in each study is reported in Table 34. 1919

Figure 39. Evidence Network: Cancer (Placebo+MTX)

1920

Two trials compared etanercept monotherapy and combination therapy with MTX. A pooled 1921

estimate of the treatment effects indicates that there is no statistically significant difference 1922

between etanercept monotherapy and combination therapy (95% CI: 0.69, 11.22)165, 232 (Figure 1923

40). A direct comparison of SB4 (biosimilar etanercept) to etanercept, both in combination with 1924

MTX, the etanercept arm had one case of cancer and the biosimilar arm reported three cases 1925

198

(Emery 2015).153 The 3-arm trial by van der Heijde and colleagues from 2006 reported five 1926

cases of cancer in the etanercept monotherapy and etanarecept combination therapy with MTX 1927

arms (2.2% each) and two cases in the MTX monotherapy arm (0.9%). 1928

1929

A pairwise MA was conducted on two trials that compared infliximab in combination with MTX to 1930

MTX monotherapy and the results were not statistically significant (95% CI: 0.10, 5.41)95, 179 1931

(Figure 41). The study by Schiff and colleagues published in 2008 was a three-arm trial and the 1932

third arm was of the treatment abatacept, which had one participant develop cancer.95 Two 1933

participants in a study by Choe and colleagues (2015) in the SB2 (biosimilar infliximab) in 1934

combination with MTX arm developed cancer during the study period but none of the 1935

participants in the infliximab in combination with MTX arm had cancer. In a study that directly 1936

compared infliximab to CT-P13 (biosimilar infliximab), both in combination with MTX, the 1937

infliximab arm reported 2 cases of cancer.249 1938

1939

Overall, the number of participants who developed cancer was very low across all trials. Even 1940

those trials where there were cases, the proportion was low and did not differ between the 1941

treatment and control arms. 1942

1943

Table 34. Cancer Events, Concomitant Methotrexate 1944

Author, Year Treatment n N Treatment 2 n N Treatment 3 n N

Choe 2015 INF_STD+MTX 0 293 SB2+MTX 2 290

Tanaka 2016 Placebo+MTX 0 49 BAR_4+MTX 0 24

Li 2015 Placebo+MTX 0 132 GOL_STD (SC)+MTX 0 131

Weinblatt 2015 Placebo+MTX 0 61 ADA_STD+MTX 0 59

Kim 2007 Placebo+MTX 0 63 ADA_STD+MTX 0 65

Yamamoto 2014 Placebo+MTX 0 77 CERTO_STD+MTX 0 82

Choy 2012 Placebo+MTX 0 119 CERTO_STD+MTX 0 124

Conaghan 2013 Placebo+MTX 0 23 ABA_STD (IV)+MTX 0 27

Kim 2013 Placebo+MTX 1 72 INF_STD+MTX 0 71

Tanaka 2012 Placebo+MTX 0 88 GOL_STD (SC)+MTX 0 86

Chen 2009 Placebo+MTX 0 12 ADA_STD+MTX 0 35

199

Author, Year Treatment n N Treatment 2 n N Treatment 3 n N

Kay 2008 Placebo+MTX 0 34 GOL_STD (SC)+MTX 0 37

Keystone 2009 Placebo+MTX 0 133 GOL_STD (SC)+MTX 0 89

Maini 1999 Placebo+MTX 0 88 INF_STD+MTX 0 86

van Vollenhoven 2011 Placebo+MTX 0 76 ADA_STD+MTX 0 79

Zhang 2006 Placebo+MTX 0 86 INF_STD+MTX 0 87

Chen 2016 Placebo+MTX 0 200 ANBAI+MTX 0 400

Machado 2014 csDMARD+MTX 0 143 ETN_STD+MTX 0 281

Kameda 2010 ETN_STD 0 71 ETN_STD+MTX 1 76

Emery 2015 ETN_STD+MTX 1 297 SB4+MTX 3 298

Yoo 2013 INF_STD+MTX 2 301 CT-P13+MTX 0 301

Takeuchi 2013 Placebo 0 105 GOL_STD (SC) 0 101

Fleischmann 2009 Placebo 0 109 CERTO_STD 0 111

Maini 1998 Placebo+MTX 0 14 INF_STD 0 14 INF_STD+MTX 0 15

Schiff 2008 Placebo+MTX 1 110 ABA_STD (IV)+MTX 1 156 INF_STD+MTX 2 165

Heijde 2006 Placebo+MTX 2 228 ETN_STD 5 223 ETN_STD+MTX 5 231

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 1945 ABA = abatacept; ADA = adalimumab; ANBAI = AnBaiNuo (biosimilar etanercept); BAR_4 = 4 mg baricitinib; CERTO = 1946 certolizumab pegol; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN = etanercept; GOL = 1947 golimumab; INF = infliximab; IV = intravenous; MTX = methotrexate; SB2 = biosimilar infliximab; SB4 = biosimilar etanercept; SC = 1948 subcutaneous; SSZ = sulfasalazine; STD = standard dose. 1949

Figure 40. Cancer (Etanercept MTX versus Etanercept Monotherapy): Meta-Analysis – Peto Odds Ratio

1950

Study or Subgroup

Kameda 2010

van der Heijde 2006

Total (95% CI)

Total events



Events

1

5

6

Total

76

223

299

Events

0

2

2

Total

71

228

299

Weight

12.6%

87.4%

100.0%

Peto, Fixed, 95% CI

6.92 [0.14, 349.47]

2.44 [0.55, 10.84]

2.78 [0.69, 11.22]


Peto, Fixed, 95% CI

0.001 0.1 1 10 1000


200

Figure 41. Cancer (Infliximab with MTX versus MTX Monotherapy): Meta-Analysis – Peto Odds Ratio

1951


There were three trials with a total of 785 participants that reported on cancer outcomes with 1953

csDMARDs as the common comparator.101, 149, 161 One study reported zero events in both the 1954

etanercept with csDMARD monotherapy arm and the csDMARD monotherapy arm.161 Another 1955

study that used csDMARD monotherapy as the comparator reported one case of cancer in the 4 1956

mg baricitinib in combination with csDMARD arm.149 In the RED SEA trial, one participant 1957

developed cancer each in the etanercept in combination with csDMARD and adalimumab in 1958

combination with csDMARD arms.101 A geometric illustration of the evidence network is 1959

available in Figure 42. Results for the number of cancer events in these studies are reported in 1960

Table 35. 1961

Study or Subgroup

Kim 2013

Schiff 2008

Total (95% CI)

Total events



Events

0

2

2

Total

71

165

236

Events

1

1

2

Total

72

110

182

Weight

25.9%

74.1%

100.0%

Peto, Fixed, 95% CI

0.14 [0.00, 6.92]

1.32 [0.13, 13.44]

0.74 [0.10, 5.41]


Peto, Fixed, 95% CI

0.001 0.1 1 10 1000


201

Figure 42. Evidence Network: Cancer (Placebo+csDMARD)

1962

Table 35. Cancer Event Data, Concomitant Conventional Synthetic DMARD 1963

Author Year Treatment 1 n N Treatment 2 n N

Jobanputra 2012 ETN_STD+csDMARD 1 60 ADA_STD+csDMARD 1 60

Hobbs 2015 Placebo+csDMARD 0 104 ETN_STD+csDMARD 0 106

Dougados 2017 Placebo+csDMARD 0 228 BAR_4+csDMARD 1 227

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 1964 ADA = adalimumab; BAR_4 = 4mg baricitinib; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN = 1965 etanercept. 1966

1967

202

6.4.15 Leukemia 1968


A total of eight RCTs135, 143, 172, 178, 191, 244, 245, 247 permitted concomitant treatment with MTX and 1970

reported leukemia outcomes, with 2504 participants contributing data. Two studies compared 1971

certolizumab pegol in combination with MTX to MTX monotherapy. Two studies also compared 1972

adalimumab in combination with MTX to MTX monotherapy. One study each of golimumab 1973

(SC), golimumab (IV), abatacept (IV) and AnBaiNuo (biosimilar etanercept) all in combination 1974

with MTX were compared to MTX monotherapy. A geometric illustration of the evidence network 1975

is available in Figure 43. All of these studies reported no leukemia events for the eligible time 1976

period for analysis (Table 36). 1977

Figure 43. Evidence Network: Leukemia (Placebo+MTX)

1978

1979

Table 36. Leukemia Event Data, Concomitant Methotrexate 1980

Author, Year Treatment 1 n N Treatment 2 n N

Li 2015 Placebo+MTX 0 132 GOL_STD (SC)+MTX 0 131

Weinblatt 2015 Placebo+MTX 0 61 ADA_STD+MTX 0 59

Weinblatt 2014 Placebo+MTX 0 197 GOL_STD (IV)+MTX 0 395

Kim 2007 Placebo+MTX 0 63 ADA_STD+MTX 0 65

Yamamoto 2014 Placebo+MTX 0 77 CERTO_STD+MTX 0 82

Conaghan 2013 Placebo+MTX 0 23 ABA_STD (IV)+MTX 0 27

203

Keystone 2008 Placebo+MTX 0 199 CERTO_STD+MTX 0 393

Chen 2016 Placebo+MTX 0 200 ANBAI+MTX 0 400

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 1981 ABA = abatacept; ADA = adalimumab; ANBAI = AnBaiNuo (biosimilar etanercept); CERTO = certolizumab pegol; IV = intravenous; 1982 MTX = methotrexate; SC = subcutaneous; SSZ = sulfasalazine; STD = standard dose. 1983

1984


A total of three RCTs101, 141, 149 permitted concomitant treatment with a csDMARD and reported 1986

leukemia outcomes. A geometric illustration of the evidence network is available in Figure 44. 1987

One study comparing 4 mg baricitinib in combination with a csDMARD to csDMARD 1988

monotherapy reported no leukemia events during the treatment period eligible for analysis.149 In 1989

a direct comparison of etanercept and adalimumab both in combination with a csDMARD, the 1990

etanercept arm reported one case of leukemia out of 60 participants.101 In a three-arm trial of 1991

etanercept monotherapy, etanercept in combination with sulfasalazine, and sulfasalazine 1992

monotherapy, one patient in the etanercept monotherapy arm out of 103 participants developed 1993

leukemia during the study141 (Table 37). 1994

Figure 44. Evidence Network: Leukemia (Placebo+csDMARD)

1995

1996

Table 37. Leukemia Event Data, Concomitant Conventional Synthetic DMARD 1997


Jobanputra 2012 ETN_STD+csDMARD 1 60 ADA_STD+csDMARD 0 60

204


Combe 2009 Placebo+SSZ 0 50 ETN_STD 1 103 ETN_STD+SSZ 0 101

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 1998 ADA = adalimumab; BAR_4 = 4mg baricitinib; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN = 1999 etanercept; SSZ = sulfasalazine; STD = standard dose. 2000

2001

6.4.16 Lymphoma 2002


There were four RCTs in total that reported on lymphoma outcomes,154, 169, 195, 239 with three 2004

being combination therapy with MTX and one investigating monotherapy of certolizumab pegol 2005

compared to no treatment. A total of 1057 participants contributed data. A geometric illustration 2006

of the evidence network is available in Figure 45. There were no cases of lymphoma in any of 2007

the studies during the treatment period analyzed (Table 38). 2008

Figure 45. Evidence Network: Lymphoma (Placebo+MTX)

2009

2010

Table 38. Lymphoma Event Data 2011

Author Treatment 1 n N Treatment 2 n N

Weinblatt 2013 Placebo+MTX 0 197 GOL_STD (IV)+MTX 0 395

Kay 2998 Placebo+MTX 0 34 GOL_STD (SC)+MTX 0 37

Maini 1999 Placebo+MTX 0 88 INF_STD+MTX 0 86

Fleischmann 2009 Placebo 0 109 CERTO_STD 0 111

205

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 2012 CERTO = certolizumab pegol; GOL = golimumab; INF = infliximab; MTX = methotrexate; SC = subcutaneous; STD = standard dose. 2013


There were no included studies with csDMARD as a common comparator that reported 2015

lymphoma outcomes. 2016

6.4.17 Congestive Heart Failure 2017


A total of eight RCTs reported on congestive heart failure with 2329 participants contributing 2019

data.99, 100, 128, 153, 165, 169, 193, 252 Three of these studies reported no events in any treatment 2020

arm.100, 193, 252 Etanercept in combination with MTX was compared to eternercept monotherapy 2021

in one study and the combination therapy arm had one event during the study.165 A different 2022

study also reported one event in the arm of etanercept in combination with MTX while the SB4 2023

(biosimilar etanercept) arm had no reports of congestive heart failure.153 Golimumab (SC) in 2024

combination with MTX had one event in a study that compared it to MTX monotherapy.169 In a 2025

head-to-head comparison trial of adalimumab and ABP501 (biosimilar adalimumab) both in 2026

combination with MTX, there was one case of congestive heart failure in the adalimumab 2027

arm.128 One study comparing the standard dose of adalimumab in combination with MTX to 2028

abatacept at 125 mg/wee (SC) in combination with MTX reported one case of congestive heart 2029

failure in each treatment arm.99 Figure 46 provides a geometric illustration of the evidence 2030

network and Table 39 reports the event data. 2031

206

Figure 46. Evidence Network: Congestive Heart Failure (Concomitant MTX)

2032

2033

2034

Table 39. Congestive Heart Failure Events, Concomitant Methotrexate 2035


Machado 2014 csDMARD+MTX 0 143 ETN_STD+MTX 0 281


Emery 2015 ETN_STD+MTX 1 297 SB4+MTX 0 299

Kay 2008

Placebo+MTX 0 34

GOL_STD (SC)

+MTX 1 37

Zhang 2006 Placebo+MTX 0 86 INF_STD+MTX 0 87

Amgen (Sponsor) 2016 ADA_STD+MTX 1 262 ABP501+MTX 0 264

Schiff 2013 ADA_STD+MTX 1 328 ABA_STD (SC) 1 318

207


+MTX

Van Vollenhoven 2012 Placebo+MTX 0 108 TOF_STD+MTX 0 204

ADA_STD

+MTX

0 204

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 2036 ABA = abatacept; ABP501 = biosimilar adalimumab; ADA = adalimumab; csDMARD = conventional synthetic disease-modifying 2037 anti-rheumatic drug; ETN = etanercept; GOL = golimumab; HD = high dose; INF = infliximab; MTX = methotrexate; SB4 = biosimilar 2038 etanercept; SC = subcutaneous; STD = standard dose. 2039


There were no included studies with csDMARD as a common comparator that reported 2041

congestive heart failure data. 2042

6.4.18 Major Adverse Cardiac Events 2043


There were no included studies with MTX as a common comparator that reported MACE 2045

outcomes. 2046

6.4.18.2 Conventional Synthetic DMARD as Common Comparator 2047

Only one study reported on major adverse cardiac event outcomes and it included 455 2048

participants for this outcome.149 The study compared 4 mg baricitinib in combination with a 2049

csDMARD to csDMARD monotherapy. Two participants out of 228 in the csDMARD 2050

monotherapy arm and zero participants out of 227 in the 4 mg baricitinib combination arm 2051

experienced a MACE, but there was no statistically significant difference.149 2052

6.4.19 Herpes Zoster 2053


A total of 10 trials100, 165, 176, 177, 221, 224, 225, 227, 233, 249 reported herpes zoster outcomes that involved 2055

MTX as the common comparator (Figure 47). Table 40 reports the full event data for herpes 2056

zoster. There were 4073 participants contributing data to this outcome. The studies by Takeuchi 2057

and colleagues (2015) and Yoo and colleagues (2013) were able to be analyzed in a pairwise 2058

MA because they both compared infliximab and CT-P13 (infliximab biosimilar) both in 2059

combination with MTX.224, 249 In this comparison, there was no statistically significant difference 2060

between the treatments in terms of the number of herpes zoster cases (1.02 [95% CI = 0.25, 2061

4.13]) (Figure 48). 2062

208

Figure 47. Evidence Network: Herpes Zoster (Placebo+MTX)

2063

Four trials had zero events in both arms.100, 176, 225, 227 There were two cases of herpes zoster in 2064

a trial of etanercept in combination with methotrexate and a combination of a csDMARD with 2065

MTX,177 as well as one case of herpes zoster when it was compared to etarnercept 2066

monotherapy.165 In a comparison against MTX monotherapy, three participants receiving 2067

tofacitinib in combination with MTX developed herpes zoster during the 12 week period prior to 2068

the treatment switch adaptation.233 In another trial, one participant receiving no treatment 2069

developed herpes zoster while there were no cases in the golimumab (SC) monotherapy arm 2070

(Table 40).221 2071

2072

Table 40. Herpes Zoster Events, Concomitant Methotrexate 2073

Author Treatment 1 n N Treatment 2 n N Treatment 3 n N

Tanaka 2012 Placebo+MTX 0 88 GOL_STD (SC)+MTX 0 86

van der Heijde 2013 Placebo+MTX 0 160 TOF_STD+MTX 3 321

209

Tanaka 2016 Placebo+MTX 0 49 BAR_4+MTX 0 24

Keystone 2015 Placebo+MTX 0 98 BAR_4+MTX 0 52

Takeuchi 2015 INF_STD+MTX 1 53 CT-P13+MTX 3 51

Yoo 2013 INF_STD+MTX 3 301 CT-P13+MTX 1 301

Kim 2012 csDMARD+MTX 0 103 ETN_STD+MTX 2 197

Takeuchi 2013 Placebo 1 105 GOL_STD (SC) 0 101


van Vollenhoven 2012 Placebo+MTX 0 108 ADA_STD+MTX 0 204 TOF_STD+MTX 0 204

Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 2074 ADA = adalimumab; BAR_4 = 4 mg baricitinib; CT-P13 = biosimilar infliximab; csDMARD = conventional synthetic disease-2075 modifying anti-rheumatic drug; ETN = etanercept; MTX = methotrexate; SC = subcutaneous; STD = standard dose; TOC_8 = 2076 tocilizumab 8mg/kg; TOF = tofacitinib. 2077

2078

Figure 48. Herpes Zoster (CT-P13 (Biosimilar Etanercept) with MTX versus Infliximab with MTX): Meta-Analysis – Peto Odds Ratio

2079


A total of two trials149, 156 had data available for herpes zoster outcomes with csDMARD 2081

monotherapy as the comparator. There were 1091 participants contributing data to herpes 2082

zoster outcomes. One case of herpes zoster occurred among a participant receiving 2083

adalimumab in combination with a csDMARD versus zero events in the comparator arm.156 The 2084

other study reported three cases of the outcome among participants receiving 4 mg baricitinib 2085

versus zero events in the csDMARD monotherapy arm149 (Table 41). 2086

2087

Table 41. Herpes Zoster Events, Concomitant Conventional Synthetic DMARD 2088

Author Treatment 1 n N Treatment 2 n N

Furst 2003 Placebo+csDMARD 0 318 ADA_STD+csDMARD 1 318

Study or Subgroup

Yoo 2013

Takeuchi 2015

Total (95% CI)

Total events



Events

1

3

4

Total

301

51

352

Events

3

1

4

Total

301

53

354

Weight

50.6%

49.4%

100.0%

Peto, Fixed, 95% CI

0.37 [0.05, 2.61]

2.92 [0.40, 21.32]

1.02 [0.25, 4.13]

CT-P13+MTX INF_STD+MTX Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.01 0.1 1 10 100

Favours experimental Favours control

210


Data is reported as the number of events (n) and the number of participants in each treatment arm (N) 2089 ADA = adalimumab; BAR_4 = 4mg baricitinib; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; STD = 2090 standard dose. 2091

2092

6.4.20 Heterogeneity 2093

Statistical heterogeneity was assessed for individual pairwise comparisons from studies forming 2094

each NMA. For NMAs with MTX as the common comparator, ACR20, 50, 70, DAS28, HAQ-DI, 2095

remission, SF-36 PCS and MCS, pain and fatigue all had moderate to substantial heterogeneity 2096

present that could impact the mixed treatment comparisons in each NMA. Thus, results should 2097

be interpreted with caution. However, there was minimal risk of heterogeneity for the WDAE and 2098

SAE outcomes. 2099

2100

Among NMAs with csDMARD as the common comparator, there was moderate to substantial 2101

heterogeneity present in a majority of direct comparisons for the outcomes ACR20 and 50 and 2102

DAS28. There was minimal risk of heterogeneity for the ACR70, WDAE and SAE NMA results. 2103

6.4.21 Publication Bias 2104

A total of 10 NMAs could be assessed for publication bias because there were at least 10 trials 2105

available for the funnel plot. Of these, the ACR20, 50 and 70 and remission in the NMAs with 2106

MTX as the common comparator had asymmetry in the funnel plots. These outcomes were also 2107

found to have moderate to substantial heterogeneity in some of their direct pairwise 2108

comparisons (with at least two studies reporting the same pairwise comparison). It is possible 2109

that the asymmetry present is due to the heterogeneity that was detected among the included 2110

studies or it could be due to publication bias. 2111

2112

There was no asymmetry for the outcomes DAS28, HAQ-DI, fatigue, pain, WDAE and SAE with 2113

MTX as the common comparator and ACR20 with csDMARDs as a common comparator. Thus, 2114

there is unlikely to be publication bias impacting the results of these NMAs. 2115

6.4.22 Sensitivity Analyses 2116

A total of six sensitivity analyses were planned a priori. The majority were conducted on the 2117

primary outcomes of the ACR50 and WDAE, while continuous outcomes had median standard 2118

errors across studies imputed and used for studies without any measure of dispersion. All 2119

sensitivity analyses were assessed for the NMAs with MTX as the common comparator and any 2120

csDMARD as the common comparator. Full comparisons of the sensitivity analyses to the 2121

reference case are presented in Appendix 8. 2122

2123

211

Methotrexate as a Common Comparator 2124

The reference case for the ACR50 model was robust based on three of the nine sensitivity 2125

analyses assessed (studies of only patients who were IR MTX and biologic naïve, including only 2126

studies published 2007 and onwards, and excluding Asian-only trials). The proportion of 2127

differences was small between the reference case model and the sensitivity analysis on all 2128

doses (including low, standard and high doses) and the sensitivity analysis with end of 2129

treatment data used for adaptive design studies. Around a third of the comparisons were 2130

different for the reference case versus the sensitivity analysis of: including only Asian-only 2131

studies, including only studies published before 2007, including only studies that specifically 2132

mentioned whether patients were IR MTX and not IR to another csDMARD, and using a 2133

restricted time point analysis of end of treatment data from 12 to 16 weeks. Given that in all 2134

sensitivity analyses the majority of comparisons were the same in comparison to the reference 2135

case, the model used for this report is fairly robust. 2136

2137

Overall, only one sensitivity analysis (including only Asian-only studies) for WDAE showed any 2138

statistically significant differences in the effect estimates of treatment comparisons that were 2139

similar between the sensitivity analysis and reference case. The other eight sensitivity analyses 2140

had no differences from the reference case. Therefore, the model used for WDAE is robust. 2141

2142

DAS28, HAQ-DI, pain, fatigue, and SF-36 PCS and MCS had a sensitivity analysis for imputing 2143

missing standard errors from studies that reported no measure of dispersion. DAS28, pain, 2144

fatigue, and SF-36 PCS and MCS had no statistically significant differences between the 2145

sensitivity analysis and reference case. This indicates that the model from the reference case 2146

was robust. In contrast, for HAQ-DI there were some differences between the models. However, 2147

this represents only a quarter of comparisons. It is probable that there were differences in the 2148

HAQ-DI imputation results and not the other outcomes because the studies with imputations 2149

represented a quarter of the total studies in the NMA, whereas the other outcomes had 10% or 2150

fewer studies with imputations, and this could have had an important influence on the sensitivity 2151

results. For this reason, the reference case model is robust in comparison to the sensitivity 2152

analysis model. The results indicated that the sensitivity analysis and reference case results 2153

were similar, thus the reference case model is robust. 2154

2155

Conventional Synthetic DMARD as a Common Comparator 2156

Five sensitivity analyses could be assessed for ACR50: inclusion of all drug doses, studies 2157

published from 2007 onwards, inclusion of end of treatment data for adaptive design trials, use 2158

of a restricted time point analysis with 12- to 16-week data, and studies that included only 2159

patients who were IR MTX and were also biologic naïve. There were no statistically significant 2160

212

differences between any of these sensitivity analyses and the reference case, which indicates 2161

that the reference case model is robust. 2162

2163

All three sensitivity analyses assessed for WDAE had no statistically significant differences 2164

compared to the reference case, which indicates that the reference case model is robust. The 2165

sensitivity analyses that were assessed were: inclusion of all drug doses, inclusion of end of 2166

treatment data for adaptive design trials, and use of a restricted time point analysis with 12- to 2167

16-week data. 2168

7 DISCUSSION 2169

The objective of this report was to investigate the comparative benefits and harms of drugs for 2170

the treatment of RA in individuals with an inadequate response to MTX. Results for NMAs, 2171

pairwise MAs and descriptive analyses are reported for any comparison of biologics to each 2172

other (including biosimilars), to csDMARD combination therapy (double or triple), to tsDMARDs 2173

or to either MTX monotherapy or csDMARD monotherapy. To the authors’ knowledge, this was 2174

the first comprehensive systematic review and NMA that included csDMARD mono-, double and 2175

triple therapies, as well as biologics, tsDMARDs, and biosimilars as monotherapy and in 2176

combination with csDMARDs. 2177

2178

A total of 98 unique studies were included in this CADTH review, along with 41 companion 2179

publications. A majority of included studies permitted concomitant therapy with MTX and had 12 2180

outcomes that could be analyzed by NMA. The largest of these NMAs were for ACR 20, 50 and 2181

70 with over 38, 36, and 34 treatments included respectively, HAQ-DI with 30 treatments, 2182

DAS28 with 30 treatments and WDAE with 26 treatments included. Other outcomes had about 2183

20 or fewer treatments. There were much fewer studies (and treatments) with csDMARDs as 2184

the concomitant therapy. Therefore, not as many NMAs could be conducted on the outcomes of 2185

interest and those that could be analyzed were much smaller, with less than 10 treatments, and 2186

lacking power to detect statistically significant differences among treatments being compared. 2187

2188

No studies in which participants could receive concomitant treatment with MTX reported on the 2189

outcome of major adverse cardiac events. No studies permitting concomitant treatment with a 2190

csDMARD reported on the outcomes of radiographic progression, lymphoma, and congestive 2191

heart failure. 2192

2193

Assessment of the risk of bias of included studies revealed that over half of studies poorly 2194

reported random sequence generation and allocation concealment and were thus considered to 2195

213

have unclear risk of bias. In addition, high risk of bias was most prevalent within the domains of 2196

incomplete outcome data for efficacy (42%) followed by incomplete outcome data for safety 2197

(28%). Blinding of subjective outcomes mostly had unclear risk of bias (53%) because the 2198

methods used to maintain blinding were not adequately reported. In terms of overall quality 2199

when considering all domains, only 10 were assessed to have low risk of bias. 2200

2201

After analysis for this review was completed, the company that makes sirukumab withdrew all 2202

applications to regulatory agencies after the FDA requested further clinical data on sirukumab.58 2203

Therefore, the results on sirukumab from this review may no longer be relevant to clinical 2204

practice since it will not go through the approval process. 2205

7.1 Policy Implications 2206

Questions of interest were gathered from the F/P/T drug plans regarding the use of drugs for 2207

treating RA. Specifically the drug plans were interested in the following: 2208

1. For patients whose response to MTX is less than optimal, should a biologic be added to MTX, should a biologic 2209 be prescribed alone, or should other csDMARDs be added or substituted for MTX? 2210

2. For patients who cannot tolerate MTX due to an adverse event or a contraindication, should csDMARDs, alone 2211 or in combination, be tried ahead of a biologic? 2212

3. What is the relative efficacy of double csDMARD therapy compared with triple csDMARD therapy? 2213 4. For patients who are inadequately treated with a biologic (alone or with MTX), what should be tried next? 2214 5. What is the place in therapy of tofacitinib and other JAK inhibitors? 2215 6. What are the benefits and harms of innovator biologics and subsequent entry biologics (biosimilars)? 2216 2217 To make this project manageable, the scope was limited to patients who have failed or are 2218

intolerant to MTX. This review excluded patients with early or mild disease, csDMARD-naïve 2219

patients, patients with comorbidities, or patients with a poor prognosis. Treatments of interest 2220

were identified through consultation with the F/P/T jurisdictions and had been approved by 2221

Health Canada or were advanced in the development process. 2222

The overarching policy question was determined to be: In patients with moderate to severe 2223

rheumatoid arthritis who have failed or are intolerant to methotrexate, what is the optimal drug 2224

therapy? 2225

2226

We have addressed the questions related to the most effective treatment for patients with 2227

moderate to severe RA who are inadequately treated due to treatment failure or intolerance with 2228

MTX or who are intolerant to MTX due to an adverse event or a contraindication. We were able 2229

to partially address the questions on the comparative efficacy of double and triple csDMARD 2230

therapy, as well as the comparative evidence for double and triple csDMARD therapy versus a 2231

biologic alone or in combination with MTX among treatment-experienced patients with moderate 2232

to severe rheumatoid arthritis. 2233

2234

214

The question on the most effective treatment for patients with moderate to severe rheumatoid 2235

arthritis who are inadequately treated due to treatment failure or intolerance with a biologic 2236

(alone or with MTX) was out of scope of the current review. We were also unable to address the 2237

question pertaining to whether csDMARD monotherapy or double csDMARD therapy should be 2238

second-line therapy following MTX failure as first-line therapy; this is because the available 2239

studies were not clear on whether patients entering the study were starting second-line therapy 2240

or if they were on third- or even fourth-line therapy. 2241

2242

7.2 Interpretation of Systematic Review Results 2243

7.2.1 Methotrexate as a Common Comparator 2244

Sufficient data was available for NMAs of the following outcomes: disease response (ACR 20, 2245

50, 70), disease activity (DAS28), disability (HAQ-DI), remission (DAS28 <2.6), radiographic 2246

progression, HRQOL (SF-36 Physical and Mental Component Scores), fatigue, pain, and SAEs, 2247

and WDAEs. Studies of double and triple csDMARD therapies only had data available for ACR 2248

20, 50, 70, pain, radiographic progression, and WDAE. 2249

7.2.1.1 Efficacy Outcomes 2250

CADTH asked what would those with RA and their families like drug therapies to achieve. Total disease remission without significant joint damage and impact on their lives is a key outcome; with the recognition that this might not be possible: “Remission, but I’m not keeping my hopes up, as I know that's not always how it works out.” For whom total remission may be unrealistic, the goal is as low disease activity as possible to be able to live a life that is as productive and pain free as possible. Specifically, improvements to fatigue, reduced inflammation, lessened joint damage and disfigurement, lessened frequency of major flares, decreased pain, increased mobility, less stiffness, increased cognitive function, and less depression were desired outcomes.

2251

ACR50 2252

Thirty-five treatments, including csDMARD combinations (any csDMARD+MTX, MTX+SSZ, 2253

MTX+HCQ, SSZ+HCQ, and MTX+SSZ+HCQ), all biologics, tofacitinib, baricitinib, sarilumab, 2254

and all biosimilars for this review, were compared in the NMA for the primary outcome (ACR50). 2255

Triple csDMARD therapy (MTX, HCQ, SSZ) was favoured over double csDMARD therapy (MTX 2256

and SSZ or any csDMARD with MTX) for achieving disease response. Results from one of the 2257

previous NMAs indicated there was more evidence to support triple csDMARD therapy over the 2258

biologics abatacept (IV), infliximab and 4 mg/kg tocilizumab all in combination with MTX.88 In our 2259

review, we found no statistically significant difference between csDMARD triple therapy and 2260

MTX combination therapy with abatacept (IV), infliximab, or 4 mg/kg tocilizumab (OR = 0.44 2261

[95% CrI: 0.10, 1.68], OR = 0.32 [0.08, 1.24] and OR = 0.29 [0.06, 1.16]) or any of the other 2262

215

biologics, biosimilars or tsDMARDs in the analysis. However, results for all of these 2263

comparisons did slightly favour csDMARD triple therapy based on the point estimates. In our 2264

review, we included 63 studies to their 45 studies and we had different eligibility criteria for 2265

included studies, which may have influenced the difference in results of the network. 2266

Additionally, of the 63 trials in our ACR50 NMA, there were only two csDMARD therapy trials 2267

with eligible data,203, 204 which means the evidence comparing csDMARD triple therapy to 2268

biologics is limited. The NICE guidelines recommend use of csDMARD combination therapy and 2269

the ACR guidelines recommend it as one option for patients with IR MTX.20, 257 Based on the 2270

results from our review and the previous review as well as guideline recommendations, 2271

csDMARD triple therapy has greater benefit for disease response compared to csDMARD dual 2272

therapy (any csDMARD with MTX or MTX with SSZ). Triple therapy with csDMARD is also likely 2273

comparable in achieving disease response compared to other biologics, biosimilars or 2274

tsDMARDs in combination with MTX. 2275

2276

When comparing the efficacy of biologic monotherapy to combination therapy with a biologic or 2277

biosimilar and MTX, most biologics as monotherapy included in the analysis (i.e. adalimumab, 2278

etanercept) had lower odds for patients to achieve disease response, except for 8 mg/kg 2279

tocilizumab. Biologic combinations with MTX that were better than biologic monotherapies 2280

included etanercept, golimumab (SC), and certolizumab pegol, as well as the tsDMARD 2281

tofacitinib in combination with MTX. However, there was insufficient evidence to identify which 2282

biologic, biosimilar or tsDMARD in combination with MTX had the most efficacy compared to the 2283

other biologics, biosimilars or tsDMARDs. Another NMA in patients with inadequate response to 2284

MTX found no statistically significant results in the head-to-head comparisons of biologics in 2285

combination with MTX.258 The ACR guidelines recommend either biologic monotherapy or 2286

combination therapy with MTX for patients with IR MTX;20 the results from this review for the 2287

ACR 50 may indicate that a biologic in combination with MTX may be more effective than 2288

biologics as monotherapy. Some of the credible intervals for comparisons for disease response 2289

were wide. While the NMA by Hazelwood and colleagues also reported wide credible intervals 2290

for ACR50 results,88 the results for this analysis should be interpreted with caution. 2291

2292

Biosimilars etanercept (HD203 or AnBaiNuo) in combination with MTX demonstrated better 2293

disease response compared to double csDMARD therapy (csDMARD+MTX and HCQ+SSZ) 2294

and etanercept monotherapy or tofacitinib monotherapy (but not etanercept in combination with 2295

MTX or tofacitinib in combination with MTX). SB4, another biosimilar etanercept, may be a third 2296

option if the first two fail based on it having weaker evidence for its efficacy compared to HD203 2297

in combination with MTX and AnBaiNuo in combination with MTX. 2298

2299

Disease Severity (DAS28) 2300

216

Thirty treatments were included for the NMA of DAS28; this represented most of the eligible 2301

treatments for this review (some being included as monotherapy and/or combination therapy 2302

with MTX). Four biologics in combination with MTX (abatacept [IV], 8 mg/kg tocilizumab, 2303

certolizumab pegol and rituximab) and 8 mg/kg tocilizumab monotherapy demonstrated greater 2304

improvement in disease severity based on the DAS28 scale versus the comparator MTX 2305

monotherapy to which patients had an inadequate response. There was insufficient evidence 2306

based on statistical significance to detect a difference on the efficacy of the other biologics 2307

combined with MTX compared to MTX monotherapy, but there was a trend toward statistical 2308

significance. The Cochrane review by Hazelwood and colleagues also reported statistically 2309

significant reductions in disease severity for these treatments, but did not include certolizumab 2310

pegol in combination with MTX in the NMA due to concerns about risk of bias.259 Their review 2311

additionally found statistically significant results for infliximab in combination with MTX, 4 mg/kg 2312

tocilizumab in combination with MTX, and adalimumab in combination with MTX all compared to 2313

MTX monotherapy. The difference of statistically significant results compared to our review 2314

(which did not find any statistically significant difference for these comparisons) may be due to 2315

the variations in the treatments included for each network. 2316

2317

Of all the comparisons of one biologic, biosimilar or tsDMARD to another, 8 mg/kg tocilizumab 2318

in combination with MTX had greater benefits in terms of reducing disease severity than 2319

etanercerpt monotherapy and had nearly favourable results compared to etanercept in 2320

combination with MTX, adalimumab in combination with MTX, infliximab in combination with 2321

MTX, and tofacitinib in combination with MTX. Rituximab in combination with MTX was nearly 2322

favoured over etanercept monotherapy. There were no other statistically significant or 2323

potentially clinically important differences between biologics, biosimilars and tsDMARDs as 2324

monotherapy or as combination therapy with MTX. No evidence was available for double and 2325

triple csDMARD therapies as there were no included studies with DAS28 data for these 2326

treatments. 2327

2328

Disability (HAQ-DI) 2329

Some Arthritis Society respondents explained to CADTH that they had modest hopes for improvement: “a few days a week that the pain would be controlled” or “to sleep soundly through an entire night” or “walking farther than one aisle in the supermarket” or “allow pain free use of my hands”.

2330

Nineteen treatments had data available for the NMA on HAQ-DI. Treatments that were not 2331

present were: all csDMARD double and triple therapies, etanercept (monotherapy and 2332

combination therapy), adalimumab monotherapy, infliximab monotherapy, certolizumab pegol 2333

monotherapy, 4 mg/kg tocilizumab monotherapy, tofacitinib monotherapy, golimumab (SC) 2334

217

monotherapy, two biosimilar etanercepts in combination with MTX (HD203 and SB4), and 2335

biosimilar adalimumabs in combination with MTX (SB5 and ABP501). 2336

2337

Results for the HAQ-DI, demonstrated that most treatments were better than MTX 2338

monotherapy, including monotherapy with 8 mg/kg tocilizumab and rituximab, and MTX in 2339

combination with the following: abatacept (IV), adalimumab, tofacitinib, 4 mg/kg tocilizumab, 8 2340

mg/kg tocilizumab, golimumab (SC and IV), infliximab, certolizumab pegol, 200 mg sarilumab, 4 2341

mg baricitinib, AnBaiNuo (biosimilar etanercept), and CT-P13 (biosimilar infliximab). These 2342

results are expected since patients in these studies were IR MTX and the findings are similar to 2343

the results of the Cochrane review by Singh and colleagues in which any biologic in combination 2344

with MTX had a statististically significant improvement in function compared to MTX 2345

monotherapy.20 The Cochrane review by Hazelwood and colleagues also reported statistically 2346

significant results that match the ones above, except for 4 mg/kg tocilizumab (MD = -0.18 [95% 2347

CrI: -0.37, 0.01] versus MD = -0.31 [-0.50, -0.12] in our review).259 The discrepancy may be 2348

related to the different treatments included in each NMA; for example, our NMA included 2349

biosimilars and biologic monotherapies where the Cochrane review did not but instead included 2350

gold and cyclosporine (both in combination with MTX). 2351

2352

When comparing biologics, biosimilars and tsDMARDs to one another, there were no 2353

statistically significant differences between them. However, 8 mg/kg tocilizumab monotherapy 2354

probably has greater benefit than adalimumab in combination with MTX, infliximab in 2355

combination with MTX, rituximab in combination with MTX, SB2 (biosimilar infliximab) in 2356

combination with MTX, and ZRC-3197 (biosimilar adalimumab) in combination with MTX based 2357

on clinically important differences (mean difference point estimates were larger than the MCID 2358

of 0.22). Combination therapy of 8 mg/kg tocilizumab and MTX is also probably more beneficial 2359

than combination therapy of rituximab and MTX based on clinical importance. 2360

2361

AnBaiNuo (biosimilar etanercept) in combination with MTX demonstrated greater benefit in 2362

terms of disability compared to several other biologics (4 mg/kg tocilimumab in combination with 2363

MTX, golimumab [SC and IV routes] in combination with MTX, infliximab in combination with 2364

MTX, certolizumab pegol in combination with MTX, rituximab in combination with MTX, and 4 2365

mg baricitinib in combination with MTX) and the biosimilars SB2 (biosimilar infliximab) and ZRC-2366

3197 (biosimilar adalimumab), both in combination with MTX. One study published in 2016 2367

compared AnBaiNuo against MTX monotherapy and it had unclear risk of bias overall.135 To the 2368

authors’ knowledge, there were no other NMAs that included this treatment in their evidence 2369

networks. Since the quality of the study providing this evidence is unclear, results for the 2370

benefits of AnBaiNuo in combination with MTX should be interpreted with caution. 2371

2372

218

Mixed treatment comparison evidence for CT-P13 demonstrated its superiority in terms of 2373

disability compared to its reference product (i.e. infliximab in combination with MTX). While 2374

biosimilars are designed to be non-inferior to the reference product, it is likely that an outcome 2375

such as the ACR20 was used to test efficacy, so it is possible that the biosimilar may have more 2376

(or less) benefit in other efficacy outcomes compared to the reference product. Treatment 2377

comparisons between double or triple csDMARD therapy and compared to biologics, biosimilars 2378

or tsDMARDs were not statistically significant. 2379

2380

While the Cochrane review found there were statistically significant comparisons between 2381

biologic drug classes,20 it is likely that our results were not statistically significant because the 2382

power is decreased with fewer patients in each individual treatment node. In either case, there 2383

is insufficient evidence based on statistical significance to identify one biologic, biosimilar or 2384

tsDMARD as a preferred option improving disability over another biologic, biosimilar or 2385

tsDMARD. However, looking at the clinical importance of the results may indicate that 8 mg/kg 2386

tocilizumab monotherapy probably has greater benefit than several biologics and biosimilars, as 2387

mentioned above. 2388

2389

Remission 2390

A total of 15 treatments had eligible data for the NMA of remission. Missing treatments were: all 2391

csDMARD double and triple therapies, adalimumab (monotherapy and combination therapy with 2392

MTX), infliximab monotherapy, certolizumab pegol monotherapy, golimumab (SC) monotherapy, 2393

golimumab (IV) in combination with MTX, tofacitinib monotherapy, 4 mg/kg tocilizumab 2394

monotherapy, AnBaiNuo (biosimilar etanercept) in combination with MTX, and biosimilars 2395

adalimumab (SB5, ZRC-3107 and ABP501) in combination with MTX. 2396

2397

As expected for studies of patients who had failed or were intolerant to MTX, most treatments 2398

had higher odds of remission compared to MTX monotherapy. Most of the results of the 2399

comparative efficacy amongst biologics and biosimilars were not statistically significant and 2400

were also unlikely to be clinically different from one another. One recent NMA reported on 2401

remission outcomes (using DAS28<2.6). In contrast to this review, they investigated the 2402

comparative efficacy of all TNF inhibitors in combination with MTX to triple csDMARD therapy. 2403

Their results indicate no statistically significant difference between the treatment categories.260 2404

Another NMA that included just four studies in their NMA of remission (DAS28<2.6) reported 2405

similar results to our review with golimumab in combination with MTX and infliximab in 2406

combination with MTX having higher odds of remission compared to MTX monotherapy (OR = 2407

14.40 [95% CI: 5.34, 38.79] and OR = 5.20 [1.51, 17.89], respectively).258 The authors also 2408

reported no statistically significant difference in any head-to-head comparisons of the three 2409

included treatments (golimumab monotherapy, golimumab in combination with MTX, and 2410

219

infliximab in combination with MTX).258 These same head-to-head comparisons were also not 2411

found to be statistically significant in our review, except for golimumab monotherapy, which was 2412

not in this outcome because none of the included studies with this treatment reported remission 2413

data. 2414

2415

It is likely that 8 mg/kg tocilizumab in combination with MTX and golimumab (SC) in combination 2416

with MTX provide higher odds of remission compared to abatacept (IV) in combination with MTX 2417

and tofacitinib in combination with MTX. While the results were not statistically significant, they 2418

is a trend toward significance. Both 8 mg/kg tocilizumab and golimumab (SC) combination 2419

therapies with MTX had higher odds of remission than etanercept monotherapy. Furthermore, 2420

etanercept monotherapy and combination therapy with MTX had lower odds of remission 2421

compared to other treatments, including 8 mg/kg tocilizumab monotherapy and combination 2422

therapy with MTX and golimumab (SC) in combination with MTX. These results indicate that 8 2423

mg/kg tocilizumab as either monotherapy or combination therapy and golimumab (SC) in 2424

combination with MTX may be good treatment options for achieving remission. 2425

2426

Comparisons against etanercept monotherapy revealed that several biologics in combination 2427

with MTX were favoured in terms of remission: etanercept, abatacept (IV), 4 mg/kg tocilizumab, 2428

8 mg/kg tocilizumab, and golimumab (SC), and certolizumab pegol. Monotherapy with 8 mg/kg 2429

tocilizumab also demonstrated higher odds of remission compared to etanercept monotherapy. 2430

Compared to etanercept combination therapy with MTX, only golimumab (SC) in combination 2431

with MTX and 8 mg/kg tocilizumab monotherapy or 8 mg/kg tocilizumab combination therapy 2432

with MTX had higher odds of remission. 2433

2434

With improvements in their health, respondents to the Arthritis Society hoped to continue working, to start or raise families, to be more active parents, employees and members of society. “I was so sick with arthritis that I was not the mom I wanted to be and this had a long term effect on my kids and my husband.” “Pain free life would equal different job opportunities for me.” Others had difficulty even imagining such a future: “Such a far off goal. I can barely comprehend. It would mean more than anything.”

2435

HRQOL 2436

Both the physical and mental NMAs for HRQOL had only nine treatments: MTX monotherapy, 2437

biologics in combination with MTX (adalimumab, golimumab (SC and IV), infliximab, 2438

certolizumab pegol, abatacept [IV]), tofacitinib in combination with MTX, and biosimilar 2439

220

infliximab (CT-P13) in combination with MTX. There was no evidence to assess the comparative 2440

efficacy of double and triple csDMARD therapy because no included studies with these 2441

treatments had data for the SF-36 PCS or MCS. 2442

2443

As expected, the SF-36 PCS results indicated that all treatments in the NMA (i.e., MTX 2444

combination therapy with abatacept (IV), tofacitinib, adalimumab, golimumab (SC and IV), 2445

infliximab, certolizumab pegol, and CT-P13 [biosimilar infliximab]) were better than MTX 2446

monotherapy. However, in terms of the SF-36 MCS only the combination of MTX with either 2447

abatacept (IV), golimumab or certolizumab pegol demonstrated greater benefit than MTX 2448

monotherapy. Comparisons of the biologics, biosimilars and tsDMARD to one another did not 2449

clearly indicate one treatment to have greater benefit in terms of either physical or mental 2450

HRQOL. To the authors’ knowledge, there were no other NMAs that reported on HRQOL 2451

outcomes to which these findings can be compared 2452

. 2453

Improved ability to complete simple daily activities could allow individuals with RA to participate in social activities and lead to a better state of mental health. “I would not be angry all the time. Living in a chronic state of pain and exhaustion causes a state of little patience. I would love to be able to exercise and enjoy the outdoors without it taking away valuable energy levels and causing even more pain.”

2454

Pain 2455

Sixteen treatments of interest had eligible data for the NMA for pain, but none of the csDMARD 2456

double or triple therapies had eligible data. Treatments that were included were: 10 mg 2457

leflunomide monotherapy, adalimumab monotherapy, certolizumab pegol monotherapy, 2458

biologics in combination with MTX (etanercept, adalimumab, certolizumab pegol, abatacept IV, 2459

and 200 mg sarilumab), tofacitinib monotherapy, tofacitinib in combination with MTX, 4 mg 2460

baricitinib in combination with MTX, and biosimilar adalimumab (ZRC-3197) in combination with 2461

MTX. 2462

2463

In terms of pain reduction, both certolizumab pegol and 200 mg sarilumab in combination with 2464

MTX demonstrated higher odds of pain reduction compared to double csDMARD therapy with 2465

SSZ and HCQ. Certolizumab pegol in combination with MTX was also found to have greater 2466

benefit than MTX in combination with adalimumab and tofacitinib. Another NMA that compared 2467

the drug class of TNF inhibitors to triple csDMARD therapy found no statistically significant 2468

differences in pain reduction.260 In contrast, our results are on the individual drug level and 2469

indicate that one TNF inhibitor (certolizumab pegol in combination with MTX) had greater pain 2470

reductions than another TNF inhibitor (adalimumab in combination with MTX). These findings 2471

221

should be interpreted with caution, however, because three of the studies involving certolizumab 2472

had high risk of bias overall218, 246, 247 and one had unclear risk of bias overall.154 To the authors’ 2473

knowledge, there were no other NMAs that included 200 mg sarilumab in combination with MTX 2474

or tofacitinib in combination with MTX in a NMA on pain outcomes. 2475

2476

With reduced pain and/or fatigue, those with RA hoped to continue normal activities: “to do things without suffering later on for your efforts”, and “to be independent”. “It would mean not budgeting my energy so I can complete necessary tasks. It would mean not scheduling my week around a day of being sick from my methotrexate dose.”

2477

Fatigue 2478

There were 12 treatments in the NMA for fatigue that were all combination therapies with MTX: 2479

etanercept, adalimumab, certolizumab pegol, golimumab (SC and IV), abatacept (IV), 200 mg 2480

sarilumab, tofacitinib, and biosimilar etanercept (HD203). 2481

2482

Only certolizumab pegol in combination with MTX was found to have a statistically significant 2483

improvement in fatigue compared with MTX monotherapy, with a large effect size. This differed 2484

from the Cochrane review by Hazelwood and colleagues, in which their NMA demonstrated 2485

statistically significant results over MTX monotherapy for golimumab (SC and IV) in combination 2486

with MTX, 4 mg/kg tocilizumab in combination with MTX, 8 mg/kg tocilizumab in combination 2487

with MTX and rituximab in combination with MTX (none of the included studies of rituximab had 2488

eligible data for this review). These differences are likely a result of the variation in treatments 2489

included in the evidence networks; only our NMA involved 200 mg sarilumab, HD203 (biosimilar 2490

etanercept), and certolizumab pegol, whereas only their NMA included abatacept (SC) in 2491

combination with MTX.259 In both their NMA and ours, tofacitinib in combination with MTX 2492

demonstrated no statistically significant difference compared with MTX monotherapy (MD = -2493

3.67 [95% CrI: -8.95, 1.32] versus SMD = 0.48 [95% CrI: -0.35, 1.41], respectively).259 2494

2495

Results for fatigue did not demonstrate any difference in benefit between biologics, biosimilars, 2496

or tsDMARDs. There was no evidence available on double or triple csDMARD therapies, which 2497

was also the case for the other review.259 Additionally, no biologic monotherapies were present 2498

in the eligible data, thus assessment of treatment options for patients who have an intolerance 2499

to MTX could not be made. 2500

2501

Radiographic progression 2502

222

Only seven treatments were represented in the NMA for radiographic progression, likely 2503

because longer studies were not as common and we analyzed adaptive design trials based on 2504

data at the time of adaptation. Included treatments were: any csDMARD in combination with 2505

MTX, csDMARD triple therapy (MTX, SSZ, HCQ), etanercept monotherapy, etanercept in 2506

combination with MTX, infliximab in combination with MTX, and biosimilar infliximab (CT-P13) in 2507

combination with MTX. 2508

2509

There were no statistically significant results for any comparisons in the evidence network on 2510

radiographic progression and none of the results indicated any clear trend in favour of one 2511

treatment compared to another. A review that assessed the modified Total Sharp Scale for 2512

radiographic progression among patients with IR MTX found that TNF inhibitors in combination 2513

with MTX had greater reduction (i.e., improvement) (MD = 2.61 [95% CI: -4.08, -1.14]) on the 2514

Sharp and modified total Sharp Score scale at two years than MTX or csDMARD therapy.260 2515

This difference may be in part due to this review analyzing adaptive design trials at the time of 2516

adaptation (e.g., 12 or 16 weeks), and thus having a limited quantity of included data with longer 2517

time points for an outcome that requires more long-term follow-up to detect differences. It may 2518

also be due to their review including a mixed population of patients who were naïve to MTX and 2519

patients with an inadequate response to MTX,260 whereas our review focused specifically on 2520

patients who had an inadequate response to MTX. 2521

7.2.1.2 Safety Outcomes 2522

One respondent to the Arthritis Society summarized her experience with RA drugs as “if it gave me two heads, I would have taken it”. Several respondents describe the fear and necessity of balancing benefits and harms of treatment. “The side effects we do suffer, we do so willingly, because life without medication is not a life to wish on your worst enemy.” Expressed by another respondent: “The cost and the way I feel don’t seem worth it. Unfortunately, I have no alternative.” Canadian Arthritis Patient Alliance (CAPA) noted that many patients live with multiple co-morbidities and take medications for other diseases along with those for RA. As described by one respondent, RA therapies “frequently result in the need to take other medications (which have their own side effects) for side effects. I am now also on a PPI, stool softener, laxative and folic acid all because of side effects from RA drugs. However, I am sincerely grateful for the progress in RA disease control achieved because of the RA medications.” Several individuals expressed deep concern over long-term risks of treatment. Although out of scope for this project, CAPA emphasized the need to include existing Canadian biologic registries and RA cohort data for CADTH to better appreciate risks and benefits of RA treatments. CAPA also highlight the need for greater research regarding the safety of RA medications for those trying to get pregnant, during pregnancy and while breastfeeding.

2523

223

Among safety outcomes, there was insufficient evidence to detect a difference for any treatment 2524

comparisons for mortality or the notable harms identified in the protocol, namely serious 2525

infections, TB, cancer, leukemia, lymphoma, congestive heart failure, major adverse cardiac 2526

events, and herpes zoster. Of note, among the studies reporting TB outcomes, three studies 2527

reported high percentages of events ranging from about 4% to 10%. For two of the studies, they 2528

reported latent TB outcomes, which would explain the higher number of TB cases as compared 2529

to most studies that report only active TB cases.130, 250 2530

2531

Serious Adverse Events (SAEs) 2532

The NMA for serious adverse events was fairly large with 22 treatments. Missing treatments 2533

were: most csDMARD double and triple therapies (MTX and SSZ, MTX and HCQ, SSZ and 2534

HCQ, and MTX, SSZ and HCQ), biologic monotherapies (adalimumab, golimumab (SC), 2535

infliximab, certolizumab pegol, and 200 mg sarilumab), tofacitinib monotherapy, golimumab (IV) 2536

in combination with MTX, 200 mg sarilumab in combination with MTX, 4 mg baricitinib in 2537

combination with MTX, AnBaiNuo (biosimilar etanercept) in combination with MTX, and two 2538

biosimilar adalimumabs (SB5 and ABP501) in combination with MTX. 2539

2540

In terms of SAEs, abatacept (IV) in combination with MTX was the only treatment that had lower 2541

odds of SAEs when compared against MTX monotherapy. The Cochrane review by Hazelwood 2542

and colleagues reported no statistically significant results for treatments compared to MTX 2543

monotherapy;259 our results only indicated abatacept (IV) in combination with MTX to have lower 2544

odds of SAEs compared to MTX monotherapy (OR = 0.35 [95% CrI: 0.18, 0.66]). The remaining 2545

treatments from the NMA were shown to have no difference in the odds of SAEs compared to 2546

MTX monotherapy. However, etanercept in combination with MTX, golimumab (SC) in 2547

combination with MTX, tofacitinib in combination with MTX, and 8 mg/kg tocilizumab in 2548

combination with MTX were trending toward having higher odds of SAEs compared to MTX 2549

monotherapy without a statistically significant difference. 2550

Abatacept (IV) in combination with MTX also demonstrated lower odds of SAEs versus 2551

etanercept monotherapy and combination therapy with MTX, tofacitinib in combination with 2552

MTX, adalimumab in combination with MTX, 4 mg/kg or 8 mg/kg tocilizumab monotherapy, 8 2553

mg/kg tocilizumab in combination with MTX, certolizumab pegol in combination with MTX, 2554

HD203 (biosimilar etanercept) in combination with MTX, and SB4 (biosimilar etanercept) in 2555

combination with MTX. 2556

2557

There were more SAEs with 8 mg/kg tocilizumab in combination with MTX than 4 mg/kg in 2558

combination with MTX, but these results should be interpreted with caution due to the very wide 2559

credible interval (95% CrI: 1.19, 285.5). Infliximab in combination with MTX also had lower odds 2560

of SAEs than 8 mg/kg tocilizumab in combination with MTX, tofacitinib in combination with MTX, 2561

224

or golimumab (SC) in combination with MTX. There was insufficient evidence to detect a 2562

difference in safety among the other comparisons of biologics, biosimilars and tsDMARDs 2563

against one another. A 2011 Cochrane review by Singh and colleagues on the harms of 2564

biologics found one statistically significant result in the NMA for certolizumab pegol in 2565

comparison to adalimumab,110 but this was not statistically significant in our NMA. These 2566

differences may be due to the new studies published since 2011 that were included for this 2567

review. 2568

2569

Withdrawals due to Adverse Events (WDAEs) 2570

Most treatments were included in the NMA for WDAEs, except for: two csDMARD double 2571

therapies (MTX and SSZ and MTX and HCQ), adalimumab monotherapy, tofacitinib 2572

monotherapy, golimumab (SC) monotherapy, golimumab (IV) in combination with MTX, 2573

certolizumab pegol monotherapy, 200 mg sarilumab (monotherapy or in combination with MTX), 2574

and ZRC-3197 (biosimilar adalimumab) in combination with MTX. 2575

2576

Etanercept in combination with MTX as well as one of its biosimilars (SB4 in combination with 2577

MTX) had lower odds of WDAEs compared to any csDMARD in combination with MTX and 2578

tofacitinib in combination with MTX. SB4 in combination with MTX also had lower odds of 2579

WDAEs compared to ABP501 (biosimilar adalimumab) in combination with MTX. Double 2580

csDMARD therapy with SSZ and HCQ had lower odds of WDAEs compared to tofacitinib in 2581

combination with MTX. Baricitinib (4 mg) in combination with MTX also had lower odds of 2582

WDAEs compared to tofacitinib in combination with MTX. More long-term data on safety events 2583

for tofacitinib and baricitinib are needed based on these results and due to their more recent 2584

entry into the market. 2585

2586

There is some evidence to suggest that SB2 (biosimilar infliximab) and ABP501 (biosimilar 2587

adalimumab) in combination with MTX have higher odds of WDAEs compared to other 2588

treatments. In contrast, among the biosimilars investigated, SB4 (biosimilar etanercept) in 2589

combination with MTX and SB5 (biosimilar adalimumab) in combination with MTX may be better 2590

options in terms of safety. 2591

2592

Several credible intervals were very wide in this analysis so caution should be taken in drawing 2593

conclusions on these results. 2594

2595

As gathered by the Arthritis Society of their membership, individuals shared their lived

225

experience with side effects of hydroxychloroquine as: stomach bleeding, severe constipation and gastric problems, dry itchy skin and rash on face and scalp, and fear of potential damage to the kidneys, liver and eyes. CAPA described a shortage of specialists in Canada able to provide the on-going vision monitoring necessary for hydroxychloroquine. Shared side effects of sulfasalazine were: nausea, hives, fever, light sensitivity, massive headaches, painful rash, weight gain, impaired menstruation, excessive urination and discomfort, and urine discoloration. Side effects shared by individuals receiving leflunomide were: severe nausea, weight loss, serious diarrhea “that prevented me from working” or loose stools, metallic taste, raised blood pressure, headaches, chest pain, hot tingling on feet, high anxiety and disorientation, extreme exhaustion, difficulty breathing, low white blood cell count, rash, and hair loss. With regards to biologics, injection site reactions or skin issues were reported for adalimumab, etanercept and certolizumab pegol. Self-injection of therapy is not without challenges: “when I am in a flare my hands are so painful, I have trouble inserting the needle and then depressing the plunger.” CAPA noted that repeated, weekly injections can result in scarring, making future injections difficult and painful. This is also experienced with the repeated, routine laboratory tests required with multiple drugs for RA. With adalimumab, one individual noted tremors and another “numbness and tingling throughout body then subsided after about a day.” Infection while on a biologic was a concern for patients. One individual noted a delay in the healing process with abatacept: “I have a scar from a joint replacement. It took two years for it to heal.” Anaphylactic reactions were experienced with rituximab and infliximab. Major adverse events were pancreatitis (etanercept), blood clot that went to brain (adalimumab), slow cardiac failure (adalimumab), and lymphadenopathy (respondent taking anakinra and methotrexate). Other events noted were raised cholesterol (tocilizumab) and gastroparesis (tofacitinib). It is not known if patients continued therapy with these side effects, or withdrew from treatment. Instead of tradeoffs, a respondent expressed:” I don't want to have to ask myself if I want to deal with nausea, vomiting and diarrhea in place of my arthritis. I just want manageability without so many consequences.” 2596

2597

7.2.2 Conventional Synthetic DMARD as a Common Comparator 2598

The following outcomes were assessed using NMAs: disease response (ACR 20, 50, 70), 2599

disease activity (DAS28), disability (HAQ-DI), SAEs, and WDAEs. No evidence was available 2600

on double or triple csDMARD therapies in any of the outcomes. 2601

7.2.2.1 Efficacy Outcomes 2602

Compared to csDMARD monotherapy, the following biologics in combination with a csDMARD 2603

had higher odds of achieving ACR50: etanercept, adalimumab, 8 mg/kg tocilizumab, 100 mg 2604

sirukumab, and 50 mg sirukumab. However, the results for both doses of sirukumab should be 2605

interpreted with caution because the 95% credible intervals were very wide. Current practice as 2606

reported by the NICE and EULAR guidelines is to prescribe TNF inhibibtors as the first biologic 2607

226

for patients with IR MTX to receive.19, 257 These results indicate that if a patient is receiving 2608

concomitant treatment with any csDMARD (i.e., not necessarily MTX), two TNF inhibitors do 2609

demonstrate greater efficacy compared to csDMARD monotherapy. In addition, an IL-6 inhibitor 2610

(8 mg/kg tocilizumab) may be just as good of an option for patients to take as TNF inhibitors, 2611

given that there is currently no evidence to indicate a difference in treatment effect between 2612

etanercept, adalimumab and tocilizumab in combination with a csDMARD. 2613

2614

There was insufficient evidence to detect a difference in benefit among treatments in terms of 2615

disease severity (DAS28) and disability (HAQ-DI). To the authors’ knowledge, there were no 2616

other reviews using NMAs that compared only studies with csDMARD as the concomitant 2617

treatment in a NMA, thus it is challenging to compare the results. 2618

2619

An NMA could not be conducted for physical and mental HRQOL, pain and fatigue, so it was not 2620

possible to assess head-to-head comparisons of treatments. As stated above, none of these 2621

patient-reported outcomes had any included studies with double or triple csDMARD therapy as 2622

one of the treatment arms. 2623

7.2.2.2 Safety Outcomes 2624

Serious Adverse Events 2625

Baricitinib at a dose of 4mg in combination with csDMARD had lower odds of SAEs compared 2626

with csDMARD in combination with adalimumab or etanercept. These results could indicate that 2627

treatment options once biologics are the next choice for patients with IR MTX should be 2628

broadened to allow tsDMARDs as one option rather than strictly TNF inhibitors.19, 257 There were 2629

no other statistically significant comparisons of the biologics and tsDMARD (baricitinib) to one 2630

another. There was also no indication of a clinically important difference based on the 2631

comparisons of etanercept monotherapy to etanercept in combination with a csDMARD, 8 2632

mg/kg tocilizumab in combination with a csDMARD, or 4 mg baricitinib in combination with 2633

csDMARD. To the authors’ knowledge, there were no other reviews that considered the studies 2634

with csDMARD as a common comparator in separate NMAs. Only a few studies were included 2635

in the NMA for SAEs, hence there is a possibility of type II error (i.e., considering there is no 2636

difference between treatments when there is). 2637

2638

Withdrawals due to Adverse Events 2639

Treatments included in the NMA for WDAE with csDMARD as the common comparator were: 2640

etanercept monotherapy, etanercept in combination with a csDMARD, adalimumab in 2641

combination with a csDMARD, 8 mg/kg tocilizumab in combination with a csDMARD, 2642

certolizumab pegol in combination with a csDMARD, and 4 mg baricitinib in combination with a 2643

csDMARD. 2644

227

2645

Only etanercept monotherapy was found to have lower odds of WDAEs compared to csDMARD 2646

monotherapy. This result is in line with what is recommended by the NICE and EULAR 2647

guidelines as the first option for treatment with a biologic after patients are IR MTX.19, 257 2648

However, there was one study in which participants receiving etanercept monotherapy had 2649

more serious infections than those receiving csDMARD monotherapy, thus it is important for 2650

clinicians and patients to discuss the benefits and harms of the available treatments to make a 2651

decision that fits with their treatment goals and tolerability. There were no statistically significant 2652

or clinically important comparisons of the biologics against one another based on the results. To 2653

the authors’ knowledge, there were no other reviews that considered the studies with csDMARD 2654

as a common comparator in separate NMAs. Given the small number of studies included, there 2655

is a possibility of type II error. 2656

2657

Notable Harms 2658

Among studies reporting on serious infections, one reported a higher number of participants 2659

developing a serious infection who were receiving etanercept monotherapy compared to 2660

participants receiving csDMARD monotherapy. Typically patients are prescribed a TNF inhibitor 2661

in combination with a csDMARD such as MTX due to the synergy between the two 2662

treatments.261 Taken together, for patients with moderate to severe RA that have an inadequate 2663

response to MTX (and that MTX is not contraindicated), it may be a better option to avoid 2664

etanercept monotherapy for greater benefits and to avoid potential side effects such as serious 2665

infections. 2666

2667

There was insufficient evidence to identify any difference in the comparative harms of 2668

treatments with csDMARD concomitant therapy for the outcomes of mortality, TB, cancer, 2669

leukemia, lymphoma, congestive heart failure, major adverse cardiac events, and herpes zoster. 2670

This is likely due to the small number of included studies that were in this NMA category (i.e., 2671

Placebo+csDMARD as the common comparator), which resulted in either a smaller NMA with 2672

weaker connections and lower power to detect any difference or no NMA at all. 2673

7.2.3 Sensitivity Analyses 2674

Planned sensitivity analyses included: 1) removing studies of low methodological quality (i.e., 2675

unclear or high risk of bias overall); 2) including doses above and below the standard dose; 3) 2676

imputing missing standard errors; 4) analyzing studies published before 2007 separately from 2677

studies published in 2007 or later; 5) using end of treatment data for adaptive design trials; and 2678

6) including studies that clearly incidated patients were IR MTX rather than IR to a different 2679

csDMARD. It was not possible to conduct the sensitivity analysis removing low methodological 2680

quality studies because there were not enough remaining studies with low risk of bias overall to 2681

run the NMA models. 2682

228

Post hoc sensitivity analyses included: 1) a restricted time-point analysis; 2) studies that clearly 2683

stated patients were IR MTX and also had never received biologic treatment; and 3) an analysis 2684

without Asian-only trials or including only Asian-only trials to determine whether differences in 2685

characteristics, including a lower dose of concomitant MTX, would influence the results. 2686


Disease Response (ACR50) 2688

For ACR50, there were no differences between the reference case and a sensitivity analysis of 2689

only studies that clearly stated patients were IR MTX and had never taken a biologic. This result 2690

provides greater confidence that this report is able to provide insight into treatment options right 2691

after patients have failed or are intolerant to MTX because the results were comparable 2692

between the two. Our decision to analyze adaptive design trial data had minimal impact on the 2693

results due to only a small proportion of results changing in the sensitivity analysis when 2694

analyzing end of treatment data for adaptive design trials. Furthermore, the method we chose 2695

(i.e., including the latest time-point prior to adaptation in the analysis) made it possible to clearly 2696

identify which treatment was responsible for a particular treatment effect. 2697

2698

There were some differences for the sensitivity analysis of studies published before 2007 to the 2699

reference case, but none compared to the newer studies (2007 onward). One explanation may 2700

be that the reference case had a larger proportion of studies published from 2007 onwards, so 2701

the weight of the evidence is based on the results of the newer studies. Eligibility criteria for 2702

more recent trials may not be the same as older trials because the patient characteristics that 2703

are likely to result in good treatment responses are more well-known. Therefore, patients 2704

included in this review may have a very particular set of disease characteristics (e.g., 2705

seropositivity, elevated levels of acute phase reactants) that is not applicable to all patients with 2706

RA. 2707

2708

Since there were some differences between the reference case and a sensitivity analysis of 2709

studies that clearly included only patients who were inadequate responders to MTX and not a 2710

different csDMARD, interpretations of this review may be more broadly applicable to patients 2711

with an inadequate response to a csDMARD, rather than specifically MTX (though MTX is the 2712

most common). 2713

2714

Results for the restricted time point analysis compared to the reference case were fairly robust. 2715

In addition, use of the end of treatment data permits more studies to be included in the analysis 2716

rather than having to exclude a study that fits the eligibility criteria, but does not report data at 2717

the same time point. Studies are also designed with a treatment duration that is appropriate for 2718

the patient population of interest. Thus, the reference case model is a good choice for analysis. 2719

229

2720

There were some differences between the Asian-only sensitivity analysis compared to the 2721

reference case. It is possible that differences in the results were observed because there are 2722

fewer Asian-only trials than trials of only one other race/ethnicity or trials including patients from 2723

a variety of races and ethnicities. There is also a possibility that patient characteristics differ 2724

based on race, particularly since Asian countries recommend a much lower dose of MTX 2725

compared to what is recommended for other races or ethnicities. Therefore, the results of this 2726

review may not be generalizable to Asian patients. 2727

2728

Altogether, while the results of the reference case model for ACR50 are fairly robust, it is 2729

important to carefully consider whether the results are applicable to specific patients with RA, 2730

such as Asian patients or patients with laboratory measures that would not fit eligibility criteria of 2731

more recent studies. 2732

2733

Continuous Outcomes 2734

There were no differences between the sensitivity analysis imputing missing standard errors 2735

and the reference case for DAS28, pain, fatigue, and HRQOL (SF-36 PCS and MCS). 2736

Therefore, our decision to exclude studies from the reference case that had no measure of 2737

dispersion (e.g., standard deviation, standard error) reported anywhere in the study is unlikely to 2738

have changed the results. HAQ-DI had some differences between the sensitivity analysis and 2739

reference case; this is most likely because a quarter of the studies required an imputation. 2740

Using an imputed standard error for that many studies in the NMA means the estimates were 2741

made to be more similar to the studies that did provide standard errors (i.e., these studies with 2742

standard errors are weighted more) rather than accurately representing the results of the 2743

studies missing standard errors. Therefore, we find the reference case is still a good choice for 2744

reporting the results of the HAQ-DI. 2745

2746

Withdrawals due to Adverse Events (WDAE) 2747

As with the ACR50, there were some differences in the results of the sensitivity analysis of 2748

Asian-only patients compared to the reference case for WDAE. Results may differ based on 2749

there being fewer studies of Asian-only participants than studies with other races included or 2750

due to the possibility of patient characteristics specific to race or ethnicity influencing the results. 2751

Thus, results from this review may not be generabilizable to Asian patients with RA. 2752

2753

230

The reference case model for WDAEs was robust across all other sensitivity analyses, 2754

indicating that the results are likely to be reliable, although results with wide CrIs for this 2755

outcome should be considered with caution. 2756


None of the sensitivity analyses for ACR50, DAS28, HAQ-DI, or WDAE showed any statistically 2758

significant differences between any of the sensitivity analyses and the reference case. 2759

7.3 Strengths and Limitations 2760

2761

Our review has several strengths. First, the use of a NMA allowed for a comprehensive 2762

assessment of the comparative benefits and harms of double and triple csDMARD therapies, 2763

biologics, biosimilars, and tsDMARDs that would not have been possible with pairwise MAs 2764

alone. In addition, the validity of the NMAs was assessed by testing the assumptions of 2765

homogeneity, consistency and similarity. Second, the literature search also followed 2766

comprehensive methods and was executed in accordance with the protocol that was specified a 2767

priori; it also included grey literature to reduce the impact of publication bias. We also accounted 2768

for adaptive design trials by analyzing their data at the time of adaptation and conducted a 2769

sensitivity analysis using end of treatment results to test the robustness of the reference case 2770

and found no major difference. Publication date of included studies was also considered through 2771

a sensitivity analysis to determine if older and more recent studies differ in their results. In 2772

addition, the impact of differences in patients characteristics were explored in planned and post 2773

hoc sensitivity analyses. The restriction of the scope to patients with moderate to severe RA and 2774

an inadequate response to MTX allowed for more homogeneity in the included studies. 2775

Analyses were conducted separately for evidence networks in which the common comparator 2776

was MTX monotherapy and evidence networks in which the common comparator was any 2777

csDMARD. This was to ensure that results could be more clinically relevant since many 2778

physicians and patients would be interested in knowing the treatment effects when MTX is used 2779

as background therapy because it is the most commonly used csDMARD.20 Furthermore, the 2780

results of the NMAs with csDMARD as a common comparator permitted the investigation of the 2781

benefits and harms of treatments that patients with intolerance to MTX could receive. 2782

2783

A few limitations were present in this review. In terms of included studies, due to the use of 2784

adaptive design trials in about one third of included studies, it was not possible to use data from 2785

the full length of these studies because of dose modifications or changes to treatments. Thus, 2786

the results for this review reflect mostly short-term efficacy/effectiveness and safety findings 2787

rather than the durability of response to the treatments in the longer-term. Another limitation is 2788

that the majority of included studies that permitted patients to take MTX either did not clearly 2789

report which route of administration was permitted (57 studies) or allowed participants to receive 2790

oral or subcutaneous MTX (14 studies). There were also 14 studies that permitted concomitant 2791

treatment with any csDMARD without specifying which one. While analyzing these studies in a 2792

separate NMA (i.e., MTX as a common comparator and csDMARD as a common comparator) 2793

231

may have reduced the power of the NMAs to detect a difference between treatments, we felt it 2794

was important to maintain homogeneity. 2795

2796

An additional limitation in the included studies involved the choice of outcome measures. 2797

DAS28 was selected to report disease activity because it is the most commonly used scale and 2798

is reported in a majority of trials262 (particularly those from before the ACR/EULAR criteria were 2799

developed). However, the DAS28 has been criticized because the development and validation 2800

of the scale were sub-optimal.262 Furthermore, clinical remission does not equate with a pain-2801

free state; in fact, many patients in remission still experience pain, which is a key patient-2802

reported outcome. Our review attempted to address the issue of clinical outcome measures that 2803

do not adequately address what is most important to patients by also including patient-reported 2804

outcomes (pain, fatigue, HRQOL); however, many of the included studies did not report on 2805

these. In addition, certain outcomes commonly reported in RA trials are generic, such as the 2806

HAQ-DI for disability and the SF-36 for HRQOL, which are less responsive to clinically relevant 2807

changes than disease-specific outcome measures. Furthermore, not all included studies 2808

reported results on all of the outcomes of interest for this review, which means that certain 2809

treatments are underrepresented in the NMAs, such as csDMARD double and triple therapies 2810

and certain biologic monotherapies. As a result, it was necessary to interpret the relative 2811

benefits and harms of treatments by outcome rather than across several outcomes as once. 2812

2813

Analysis of included studies was restricted to the standard approved doses; for baricitinib, a 2814

dose approved in Europe was selected and for sirukumab the phase 3 trial doses were selected 2815

as these were up for review with the FDA at the time of analysis. In the case of tocilizumab, 2816

there are two approved doses (i.e., 4 mg/kg and 8 mg/kg), which were both included. As a 2817

result, eligible studies with treatment arms involving lower or higher doses of drugs were 2818

excluded from analysis, or at times an entire study was excluded from analysis because it was 2819

reduced to one eligible treatment arm or less. Moreover, this limits the generalizability of the 2820

results to clinical practice, since the standard dose is not always what is actually prescribed and 2821

used by patients with RA. To address this limitation, a sensitivity analysis including the lower 2822

and higher doses of treatments was performed and indicated the results of the report are robust 2823

that use the standard doses alone. Another limitation was for treatments that had a small 2824

number of participants (e.g., due to only one or two included studies contributing to the 2825

treatment node) and/or low event rates. The results for these treatments may not be as reliable, 2826

as evidenced by very wide credible intervals for some treatment comparisons in ACR 20, 50, 2827

70, WDAEs and SAEs. Therefore, the level of confidence based on results with wide credible 2828

intervals is low. 2829

2830

Patients in RCTs must meet strict eligibility criteria (e.g., no comorbidities, non-pregnant 2831

women, strict treatment doses) and thus may not represent all patients in clinical practice; RCTs 2832

232

are also conducted in a highly controlled manner that may not reflect typical patient behavior 2833

(e.g., higher than normal adherence). Thus, results from this review are not generalizable to all 2834

patients. 2835

2836

Median and range or interquartile range data were converted into the mean and standard error, 2837

which could lead to bias. While this is commonly used practice in conducting SRs, it is possible 2838

that the results are biased in favour of a biologic when the true effect is additive based on, for 2839

example, the combination of MTX and a biologic. 2840

2841

Lastly, when no measure of dispersion was reported, the baseline value was used to impute the 2842

standard error for the mean change from baseline. It was assumed that the variance does not 2843

change significantly from baseline to the end of the study as it is a representation of the patient 2844

population. Since the imputation was within the same study it is likely that any resulting error 2845

from these assumptions is low because the patient population is the same. However, in the 2846

event there were no baseline data available, the study was excluded from the reference case 2847

because imputation of the standard error from other studies was considered to be more biased. 2848

7.4 Conclusion 2849

The patient groups who provided input into this review indicated that the ultimate goal of therapy 2850

should be disease remission or achieving low disease activity. Improved fatigue and decreased 2851

pain were also important. The outcomes most often evaluated in the studies included disease 2852

response (measured with ACR20, 50, 70), disease activity (measured with DAS28), function 2853

(measured with HAQ-DI), and remission, as well as the safety outcomes of WDAEs and SAEs. 2854

There were less data to inform the outcomes of pain, fatigue, and HRQOL. Mortality, serious 2855

infections, cancer, tuberculosis, and herpes zoster could not be assessed in a NMA due to 2856

many all-arm zero event studies; very little data was available on leukemia, lymphoma, 2857

congestive heart failure and major adverse cardiac events. In general, most treatments were 2858

shown to have greater benefits compared to MTX, but there was often insufficient evidence to 2859

detect a difference between csDMARD monotherapy and the treatments (in NMAs with 2860

csDMARD as the common compartor). Results on sirukumab in this review may no longer be 2861

relevant due to the company’s recent withdrawal of applications to regulatory agencies 2862

globally.58 2863

2864 For patients whose response to MTX is less than optimal, there are a number of treatment strategies to choose from. 2865 Triple csDMARD therapy offered statistically significantly greater benefit than double csDMARD therapy for 2866 disease response (measured with ACR50) but had similar efficacy for function (measured with HAQ-DI). Triple 2867 csDMARD therapy is also likely to have comparable disease response (ACR50) to biologics in combination with 2868 MTX. There were no included studies of double or triple csDMARD therapy with data for the outcomes of disability 2869 (HAQ-DI), remission, fatigue, serious infections, TB, cancer (including leukemia and lymphoma as separate 2870 outcomes), and MACE. Combining MTX with a biologic, biosimilar or tsDMARD was another treatment option for 2871 patients with a less than optimal response to MTX because it demonstrated greater benefits compared to 2872 monotherapy with a biologic or tsDMARD. In terms of which biologic, biosimilar or tsDMARD to use in 2873

233

combination with MTX, the evidence from this review does not indicate one treatment that stands out as having 2874 greater benefits than the others because 1) not all treatments had data available for each of the outcomes and 2) there 2875 were often no important differences in the head-to-head comparison results of these treatments. If safety is a concern 2876 for patients, however, there is some evidence to indicate that abatacept (IV) in combination with MTX has lower 2877 harms than other treatments based on SAE data. Clinicians should discuss with patients about their treatment goals 2878 and their level of tolerability to side effects (and risks of side effects) to identify an appropriate treatment strategy. 2879 Other important factors to consider that are important for patients include the cost of the treatment, accessibility to 2880 treatment (e.g., travelling to a clinic to receive the treatment), and route of administration (i.e., IV, SC or oral). 2881 2882 For patients who are intolerant to MTX, the evidence indicates that monotherapy with TNF inhibitors may not be the 2883 preferred option due to lower benefits compared to TNF inhibitors in combination with MTX. Therapy with 2884 csDMARDs may not be the best option either because the double and triple csDMARD therapies that demonstrated 2885 greater benefits involved MTX as one component of therapy. Tocilizumab monotherapy at a dose of 8 mg/kg 2886 demonstrated benefits compared to a few treatments (any csDMARD in combination with MTX and adalimumab 2887 monotherapy [though the credible intervals were wide] for ACR50 and etanercept monotherapy and etanercept in 2888 combination with MTX for remission). When there were no statistically significant differences for comparisons of 8 2889 mg/kg tocilizumab to other treatments for ACR50 and remission, as well as for DAS28 and HAQ-DI (no data was 2890 available for HRQOL, pain, fatigue and radiographic progression), 8 mg/kg tocilizumab had a favourable point 2891 estimate compared to biologic monotherapies and biologics in combination with MTX. Additionally, there was 2892 insufficient evidence for SAEs and WDAEs to indicate 8 mg/kg tocilizumab was worse than other treatments, 2893 including the comparator MTX monotherapy. There was also insufficient evidence to detect a difference between 8 2894 mg/kg tocilizumab monotherapy and other treatments in terms of notable harms with data available for tocilizumab, 2895 namely serious infections and tuberculosis. Therefore, 8 mg/kg tocilizumab may represent a good treatment option 2896 for patients who are intolerant to MTX. Another possibility for these patients is to receive a biologic in combination 2897 with a csDMARD other than MTX. Based on results for the NMAs with csDMARD as the common comparator, 2898 there was no clinical difference that was found between the TNF inhibitors etanercept, adalimumab and 2899 certolizumab pegol and the IL-6 inhibitor tocilizumab (8 mg/kg) for achieving disease response (ACR50). 2900 2901 While many studies have been conducted in patients with IR MTX with moderate to severe 2902

disease activity, there are still unanswered questions regarding the comparative benefits and 2903

harms of treatments used for this patient population: 2904

There was insufficient data to draw conclusions on the benefits and harms of the 2905

combination of a csDMARD (MTX or another) with a biologic, biosimilar or tsDMARD 2906

compared to csDMARD monotherapy and to other biologics, biosimilars or tsDMARDs 2907

in combination with a csDMARD. 2908

There was insufficient evidence to detect a difference between treatments for 2909

radiographic progression for any comparisons. This may have been in part due to the 2910

limited quantity of studies with longer-term data in the analysis since many studies 2911

involved an adaptive design as early as 12 or 16 weeks. 2912

There was limited evidence available to compare the benefits and harms of double and 2913

triple csDMARD therapies against one another and against biologics, biosimilars and 2914

tsDMARDs. The outcomes of HAQ-DI, remission, HRQOL, fatigue, serious infections, 2915

cancer (including leukemia and lymphoma as separate outcomes), and major adverse 2916

cardiac events did not have data from any studies of double or triple csDMARD 2917

therapies. With csDMARD as a common comparator, there were no studies of double 2918

and triple csDMARD therapies available. 2919

234

There was limited evidence to determine which biologic or biosimilar (combined with 2920

MTX) was the most effective compared to another biologic or biosimilar (combined with 2921

MTX). This may be due to either a lack of power or too short of a treatment duration to 2922

detect a difference or that there is no important difference in the benefits of biologics, 2923

biosimilars and tsDMARDs. 2924

2925

The results of this review must be interpreted in light of the limitations of the data. Namely one 2926

third of the studies used an adaptive design which meant that only the data before the 2927

adaptation could be used in the analyses. Hence the long-term benefits and harms as well as 2928

durability of the interventions were not captured. Furthermore, some of the results yielded wide 2929

credible intervals, which means those treatment comparisons are less reliable. Results from the 2930

sensitivity analyses indicated that the findings in this review may not be generalizable to Asian 2931

patients, but that the models remained robust when compared to another sensitivity analysis of 2932

studies including a variety of races. Many studies had unclear or high risk of bias overall, thus 2933

new findings from this review that could not be compared to other reviews or mentioned in 2934

clinical practice guidelines (because the comparisons have never been made) should be 2935

interpreted with caution until more research is available. 2936

2937

Finally, in answer to the original policy question on what is the optimal treatment for patients 2938

with moderate to severe RA who have had an inadequate response to MTX, various treatment 2939

strategies were found to be effective. Whether one treatment is prescribed over another will 2940

depend on goals of therapy and tolerability to the treatment, taking into consideration patient 2941

preference on the balance between benefits and harms, access to treatment, and affordability. 2942

2943

235

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193. Machado DA, Guzman RM, Xavier RM, et al. Open-label observation of addition of 3452 etanercept versus a conventional disease-modifying antirheumatic drug in subjects with active 3453 rheumatoid arthritis despite methotrexate therapy in the Latin American region. Journal of 3454 clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2014; 20: 25-3455 33. 3456

194. MacIsaac KD, Baumgartner R, Kang J, et al. Pre-treatment whole blood gene 3457 expression is associated with 14-week response assessed by dynamic contrast enhanced 3458 magnetic resonance imaging in infliximab-treated rheumatoid arthritis patients. PLoS ONE. 3459 2014; 9: e113937, 2014. 3460

195. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor 3461 alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving 3462 concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet. 1999; 3463 354: 1932-9. 3464

196. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous 3465 infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose 3466 weekly methotrexate in rheumatoid arthritis. Arthritis and rheumatism. 1998; 41: 1552-63. 3467

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249

198. Mathias SD, Colwell HH, Miller DP, Moreland LW, Buatti M and Wanke L. Health-related 3472 quality of life and functional status of patients with rheumatoid arthritis randomly assigned to 3473 receive etanercept or placebo. Clinical therapeutics. 2000; 22: 128-39. 3474

199. Miyasaka N and Investigators CS. Clinical investigation in highly disease-affected 3475 rheumatoid arthritis patients in Japan with adalimumab applying standard and general 3476 evaluation: the CHANGE study. Mod Rheumatol. 2008; 18: 252-62. 3477

200. Mladenovic V, Domljan Z, Rozman B, et al. Safety and effectiveness of leflunomide in 3478 the treatment of patients with active rheumatoid arthritis. Results of a randomized, placebo-3479 controlled, phase II study. Arthritis and rheumatism. 1995; 38: 1595-603. 3480

201. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid 3481 arthritis. A randomized, controlled trial. Annals of internal medicine. 1999; 130: 478-86. 3482

202. Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of active controlled tocilizumab 3483 monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate 3484 (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor 3485 by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009; 19: 12-9. 3486

203. O'Dell JR, Haire CE, Erikson N, et al. Treatment of rheumatoid arthritis with 3487 methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three 3488 medications. The New England journal of medicine. 1996; 334: 1287-91. 3489

204. O'Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with methotrexate 3490 and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three 3491 medications: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis 3492 and rheumatism. 2002; 46: 1164-70. 3493

205. O'Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after 3494 methotrexate failure. N Engl J Med. 2013; 369: 307-18. 3495

206. Peterfy C, Emery P, Tak PP, et al. MRI assessment of suppression of structural damage 3496 in patients with rheumatoid arthritis receiving rituximab: results from the randomised, placebo-3497 controlled, double-blind RA-SCORE study. Ann Rheum Dis. 2016; 75: 170-7. 3498

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208. Pope JE, Haraoui B, Thorne JC, Vieira A, Poulin-Costello M and Keystone EC. The 3502 Canadian methotrexate and etanercept outcome study: a randomised trial of discontinuing 3503 versus continuing methotrexate after 6 months of etanercept and methotrexate therapy in 3504 rheumatoid arthritis. Ann Rheum Dis. 2014; 73: 2144-51. 3505

209. Roche H-L. A Study of Tocilizumab Plus Non-biological DMARD in Patients With 3506 Moderate to Severe Rheumatoid Arthritis and an Inadequate Response to Non-biological 3507 DMARDs. p. NCT01034397. 3508

210. Russell AS, Wallenstein GV, Li T, et al. Abatacept improves both the physical and 3509 mental health of patients with rheumatoid arthritis who have inadequate response to 3510 methotrexate treatment. Annals of the rheumatic diseases. 2007; 66: 189-94. 3511

250

211. Samsung Bioepis Co L. A Study Comparing SB5 to Humira® in Subjects With Moderate 3512 to Severe Rheumatoid Arthritis Despite Methotrexate Therapy. p. NCT02167139. 3513

212. Smolen J, Landewe RB, Mease P, et al. Efficacy and safety of certolizumab pegol plus 3514 methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. 3515 Annals of the rheumatic diseases. 2009; 68: 797-804. 3516

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219. Strand V, Smolen JS, van Vollenhoven RF, et al. Certolizumab pegol plus methotrexate 3537 provides broad relief from the burden of rheumatoid arthritis: analysis of patient-reported 3538 outcomes from the RAPID 2 trial. Annals of the rheumatic diseases. 2011; 70: 996-1002. 3539

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223. Takeuchi T, Miyasaka N, Zang C, et al. A phase 3 randomized, double-blind, multicenter 3550 comparative study evaluating the effect of etanercept versus methotrexate on radiographic 3551

251

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225. Tanaka Y, Emoto K, Cai Z, et al. Efficacy and Safety of Baricitinib in Japanese Patients 3557 with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, 3558 Double-blind, Randomized Placebo-controlled Study. J Rheumatol. 2016; 43: 504-11. 3559

226. Tanaka Y, Harigai M, Takeuchi T, et al. Clinical efficacy, radiographic progression, and 3560 safety through 156 weeks of therapy with subcutaneous golimumab in combination with 3561 methotrexate in Japanese patients with active rheumatoid arthritis despite prior methotrexate 3562 therapy: final results of the randomized GO-FORTH trial. Mod Rheumatol. 2016; 26: 481-90. 3563

227. Tanaka Y, Harigai M, Takeuchi T, et al. Golimumab in combination with methotrexate in 3564 Japanese patients with active rheumatoid arthritis: results of the GO-FORTH study. Annals of 3565 the rheumatic diseases. 2012; 71: 817-24. 3566

228. Tanaka Y, Suzuki M, Nakamura H, Toyoizumi S, Zwillich SH and Tofacitinib Study I. 3567 Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with 3568 rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken). 3569 2011; 63: 1150-8. 3570

229. Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus Placebo or 3571 Adalimumab in Rheumatoid Arthritis. The New England journal of medicine. 2017; 376: 652-62. 3572

230. Van De Putte LBA, Rau R, Breedveld FC, et al. Efficacy and safety of the fully human 3573 anti-tumour necrosis factor alpha monoclonal antibody adalimumab (D2E7) in DMARD 3574 refractory patients with rheumatoid arthritis: A 12 week, phase II study. Ann Rheum Dis. 2003; 3575 62: 1168-77. 3576

231. van der Heijde D, Klareskog L, Landewe R, et al. Disease remission and sustained 3577 halting of radiographic progression with combination etanercept and methotrexate in patients 3578 with rheumatoid arthritis. Arthritis and rheumatism. 2007; 56: 3928-39. 3579

232. van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al. Comparison of etanercept 3580 and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical 3581 and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis and 3582 rheumatism. 2006; 54: 1063-74. 3583

233. van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients 3584 with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month 3585 phase III randomized radiographic study. Arthritis and rheumatism. 2013; 65: 559-70. 3586

234. van Riel PL, Freundlich B, MacPeek D, Pedersen R, Foehl JR and Singh A. Patient-3587 reported health outcomes in a trial of etanercept monotherapy versus combination therapy with 3588 etanercept and methotrexate for rheumatoid arthritis: the ADORE trial. Annals of the rheumatic 3589 diseases. 2008; 67: 1104-10. 3590

252

235. van Riel PL, Taggart AJ, Sany J, et al. Efficacy and safety of combination etanercept 3591 and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an 3592 inadequate response to methotrexate: the ADORE study. Annals of the rheumatic diseases. 3593 2006; 65: 1478-83. 3594

236. van Vollenhoven RF, Kinnman N, Vincent E, Wax S and Bathon J. Atacicept in patients 3595 with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, 3596 randomized, placebo-controlled trial. Arthritis and rheumatism. 2011; 63: 1782-92. 3597

237. Visvanathan S, Rahman MU, Keystone E, et al. Association of serum markers with 3598 improvement in clinical response measures after treatment with golimumab in patients with 3599 active rheumatoid arthritis despite receiving methotrexate: results from the GO-FORWARD 3600 study. Arthritis Res Ther. 2010; 12: R211. 3601

238. Wallenstein GV, Kanik KS, Wilkinson B, et al. Effects of the oral Janus kinase inhibitor 3602 tofacitinib on patient-reported outcomes in patients with active rheumatoid arthritis: results of 3603 two Phase 2 randomised controlled trials. Clinical and experimental rheumatology. 2016; 34: 3604 430-42. 3605

239. Weinblatt ME, Bingham CO, 3rd, Mendelsohn AM, et al. Intravenous golimumab is 3606 effective in patients with active rheumatoid arthritis despite methotrexate therapy with responses 3607 as early as week 2: results of the phase 3, randomised, multicentre, double-blind, placebo-3608 controlled GO-FURTHER trial. Annals of the rheumatic diseases. 2013; 72: 381-9. 3609

240. Weinblatt ME, Fleischmann R, Huizinga TW, et al. Efficacy and safety of certolizumab 3610 pegol in a broad population of patients with active rheumatoid arthritis: results from the 3611 REALISTIC phase IIIb study. Rheumatology (Oxford). 2012; 51: 2204-14. 3612

241. Weinblatt ME, Fleischmann R, van Vollenhoven RF, et al. Twenty-eight-week results 3613 from the REALISTIC phase IIIb randomized trial: efficacy, safety and predictability of response 3614 to certolizumab pegol in a diverse rheumatoid arthritis population. Arthritis Res Ther. 2015; 17: 3615 325. 3616

242. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor 3617 necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients 3618 taking concomitant methotrexate: the ARMADA trial. Arthritis and rheumatism. 2003; 48: 35-45. 3619

243. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant 3620 tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving 3621 methotrexate. The New England journal of medicine. 1999; 340: 253-9. 3622

244. Weinblatt ME, Mease P, Mysler E, et al. The efficacy and safety of subcutaneous 3623 clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate 3624 response to methotrexate: results from a multinational, phase IIb, randomized, double-blind, 3625 placebo/active-controlled, dose-ranging study. Arthritis Rheumatol. 2015; 67: 2591-600. 3626

245. Weinblatt ME, Westhovens R, Mendelsohn AM, et al. Radiographic benefit and 3627 maintenance of clinical benefit with intravenous golimumab therapy in patients with active 3628 rheumatoid arthritis despite methotrexate therapy: results up to 1 year of the phase 3, 3629 randomised, multicentre, double blind, placebo controlled GO-FURTHER trial. Ann Rheum Dis. 3630 2014; 73: 2152-9. 3631

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246. Yamamoto K, Takeuchi T, Yamanaka H, et al. Efficacy and safety of certolizumab pegol 3632 without methotrexate co-administration in Japanese patients with active rheumatoid arthritis: the 3633 HIKARI randomized, placebo-controlled trial. Mod Rheumatol. 2014; 24: 552-60. 3634

247. Yamamoto K, Takeuchi T, Yamanaka H, et al. Efficacy and safety of certolizumab pegol 3635 plus methotrexate in Japanese rheumatoid arthritis patients with an inadequate response to 3636 methotrexate: the J-RAPID randomized, placebo-controlled trial. Mod Rheumatol. 2014; 24: 3637 715-24. 3638

248. Yazici Y, Curtis JR, Ince A, et al. Efficacy of tocilizumab in patients with moderate to 3639 severe active rheumatoid arthritis and a previous inadequate response to disease-modifying 3640 antirheumatic drugs: The ROSE study. Ann Rheum Dis. 2012; 71: 198-205. 3641

249. Yoo DH, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to 3642 demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab 3643 when coadministered with methotrexate in patients with active rheumatoid arthritis: the 3644 PLANETRA study. Ann Rheum Dis. 2013; 72: 1613-20. 3645

250. Yoo DH, Racewicz A, Brzezicki J, et al. A phase III randomized study to evaluate the 3646 efficacy and safety of CT-P13 compared with reference infliximab in patients with active 3647 rheumatoid arthritis: 54-week results from the PLANETRA study. Arthritis Res Ther. 2015; 18: 3648 82, 2015. 3649

251. Yount S, Sorensen MV, Cella D, Sengupta N, Grober J and Chartash EK. Adalimumab 3650 plus methotrexate or standard therapy is more effective than methotrexate or standard therapies 3651 alone in the treatment of fatigue in patients with active, inadequately treated rheumatoid 3652 arthritis. Clinical and experimental rheumatology. 2007; 25: 838-46. 3653

252. Zhang F, Hou Y, Huang F, et al. Inflixiamab versus placebo in rheumatoid arthritis 3654 patients receiving concomitant methotrexate: a preliminary study from China. APLAR J 3655 Rheumatol. 2006; 9: 127-30. 3656

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3685

255

9 APPENDICES 3686

APPENDIX 1: LITERATURE SEARCH STRATEGY 3687

OVERVIEW

Interface: Ovid

Databases: EBM Reviews - Cochrane Central Register of Controlled Trials <April

2016>

Embase

Ovid MEDLINE

Ovid MEDLINE In-Process & Other Non-Indexed Citations

Note: Subject headings have been customized for each database.

Duplicates between databases were removed in Ovid.

Date of

Search:

May 3, 2016

Alerts: Monthly search updates began May 4 and ran until March 1, 2017.

Study Types: randomized controlled trials; controlled clinical trials

Limits: Publication years: see multi-database strategie

Humans

SYNTAX GUIDE

/ At the end of a phrase, searches the phrase as a subject heading

MeSH Medical Subject Heading

exp Explode a subject heading

* Before a word, indicates that the marked subject heading is a primary topic;

or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying

endings

ADJ Requires words are adjacent to each other (in any order)

ADJ# Adjacency within # number of words (in any order)

.ti Title

.ab Abstract

.hw Heading Word; usually includes subject headings and controlled vocabulary

.kf Author keyword heading word (MEDLINE)

.kw Author keyword (Embase)

.pt Publication type

256

3688

3689

3690

MULTI-DATABASE STRATEGIES

biologic DMARDs – 2015 to present

# Searches

1 Adalimumab/

2 Certolizumab Pegol/

3 Etanercept/

4 golimumab/ use oemezd

5 Infliximab/

6 tocilizumab/ use oemezd

7 Abatacept/

8 Rituximab/

9 (adalimumab or Humira or Trudexa or certolizumab pegol or Cimzia or Perstymab

or etanercept or Enbrel or golimumab or Simponi or infliximab or Inflectra or

Remicade or Remsima or Reemsima or Remmicade or Remykeyd or Revellex or

anakinra or Kineret or Antril or tocilizumab or Actemra or Aktemra or RoActemra or

atlizumab or abatacept or Orencia or Belatacept or Nulojix or rituximab or Rituxan

or Mabtera or Mabthera or Reditux or Relito or Rituxim).ti,ab,kw,kf.

10 or/1-9

11 exp Arthritis, Rheumatoid/ use pmez

12 exp rheumatoid arthritis/ use oemezd

13 (rheumatic* or rheumatoid* or rheumatis*).ti,ab,kf,kw.

14 ((Caplan* or Felty* or Sjogren* or Sicca*) adj3 syndrome*).ti,ab,kf,kw.

257

15 Still* Disease*.ti,ab,kf,kw.

16 or/11-15

17 10 and 16

18 (Randomized Controlled Trial or Controlled Clinical Trial or Pragmatic Clinical

Trial).pt.

19 Randomized Controlled Trial/

20 exp Randomized Controlled Trials as Topic/

21 "Randomized Controlled Trial (topic)"/

22 Controlled Clinical Trial/

23 exp Controlled Clinical Trials as Topic/

24 "Controlled Clinical Trial (topic)"/

25 Randomization/

26 Random Allocation/

27 Double-Blind Method/

28 Double Blind Procedure/

29 Double-Blind Studies/

30 Single-Blind Method/

31 Single Blind Procedure/

32 Single-Blind Studies/

33 Placebos/

34 Placebo/

35 Control Groups/

36 Control Group/

37 (random* or sham or placebo*).ti,ab,hw,kf,kw.

38 ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf,kw.

258

39 ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf,kw.

40 (control* adj3 (study or studies or trial*)).ti,ab,kf,kw.

41 (Nonrandom* or non random* or non-random* or quasi-random* or

quasirandom*).ti,ab,hw,kf,kw.

42 allocated.ti,ab,hw.

43 ((open label or open-label) adj5 (study or studies or trial*)).ti,ab,hw,kf,kw.

44 or/18-43

45 17 and 44

46 exp animals/

47 exp animal experimentation/ or exp animal experiment/

48 exp models animal/

49 nonhuman/

50 exp vertebrate/ or exp vertebrates/

51 or/46-50

52 exp humans/

53 exp human experimentation/ or exp human experiment/

54 or/52-53

55 51 not 54

56 45 not 55

57 56 not conference abstract.pt.

58 limit 57 to english language

59 limit 58 to yr="2015 -Current"

60 remove duplicates from 59

Methotrexate – 2014 to present

259

# Searches

1 Methotrexate/

2 (abitrexate or amethopterin* or amethpterin* or ametopterin* or antifolan or Artrait

or Atrexal or Bertanel or Biotrexate or brimexate or canceren or cytotrex or ebetrex

or ebetrexat* or emtexate or emthexat* or Emthrxate or emtrexate or enthexate or

farmitrexat* or farmotrex or Hytas or Imutrex or ifamet or imeth or fermitrexat* or

fauldexato or folex or hdmtx or lantarel or ledertrexate or lumexon or maxtrex or

medsatrexate or Meisusheng or merox or metatrexan or metex or Metrex or

Methoblastin or methohexate or methotrate or Methox or meticil or Metodik or

methotrexat* or Methylaminopterin* or methrotrexate or methopterin* or

methpterin* or metopterin* or Metotressato or Metotrexato or Metotreksat or

metoject or Metrotex or mexate or MTX or Novatrex or Otrexup or Rasuvo or

Rheumatrex or texate or tremetex or trexeron or Trexall or trixilem or Midu or Mtrex

or Neotrexat* or Onkomet or Otaxem or Pterin or Quinux or Reumatrex or

Sanotrexat* or Texorate or Trexan or Trexate or Trexol or Trexonate or Trexxol or

Unitrexates or Viztreksat or Xantromid or Zexate).ti,ab,kw,kf.

3 1 or 2






9 or/4-8

10 3 and 9


Trial).pt.






260


18 Randomization/








26 Placebos/

27 Placebo/

28 Control Groups/

29 Control Group/









37 or/11-36

38 10 and 37

39 exp animals/


261


42 nonhuman/


44 or/39-43

45 exp humans/


47 or/45-46

48 44 not 47

49 38 not 48



52 limit 51 to yr="2014 -Current"


Subsequent Entry Biologics (SEBs), products under development, small molecules,

traditional DMARDs (hydroxychloroquine, sulfasalazine, leflunomide) – no date limit

# Searches






6 or/1-5

7 Infliximab/ or Adalimumab/ or Etanercept/

262

8 (adalimumab or Humira or Trudexa or infliximab or Inflectra or Remicade or

Remsima or Reemsima or Remmicade or Remykeyd or Revellex or etanercept or

Enbrel).ti,ab,kw,kf.

9 7 or 8

10 (reference or innovator or originator or generic or generics or biosimilar or bio-

similar or biosimilars or bio-similars or follow-on or subsequent-entry or SEB or

SEBs or biobetter or biobetters or bio-better or bio-betters or biosuperior or

biosuperiors or bio-superior or bio-superiors or next generation or second-

generation or third-generation or next-gen).ti,ab.

11 (biologic* or biological*).ti,kw,kf.

12 exp *Biological Products/ use pmez

13 exp *biological product/ use oemezd

14 or/10-13

15 9 and 14

16 Hydroxychloroquine/

17 (Hydroxychloroquin* or Oxychlorochin* or Oxychloroquin* or Hydroxychlorochin* or

Plaquenil or Idrossiclorochina or Oxichlorochinum or Hydroxyquine or Advaquenil

or Arthroquin or Axokine or Chloguin or Diclor or Dimard or Dolquine or Duloc or

Duroc or Ercoquin or Evoquin or Fen Le or Geniquin or Haloxin or HCQS or

Hydroquin or Hydroquine or Hyquin or Ilinol or Immard or Metirel or Oxcq or

Oxiklorin or Plakvenil or Plaquinol or Quensyl or Quinoric or Reconil or Reuquinol

or Roquin or Supretic or Winflam or Yuma or Zyq or chloroquinol).ti,ab,kf,kw.

18 Sulfasalazine/ use pmez

19 salazosulfapyridine/ use oemezd

20 (Salicylazosulfapyridin* or salazosulfpyridin* or salazopyrin* or salazopyridin* or

Sulphasalazin* or Salazosulfapyridin* or Pleon or azopyrin* or azosulfidin* or

benzosulfa or colopleon or Ulcol or Ucine or Azulfidin* or azlufidin* or Azulfadin* or

pyralin or Asulfidine or Azulfin or azulfid* or Bomecon or Disalazin or Falazine or

Gastropyrin or Lazafin or Lazo or rorasul or Rosulfant or SAAZ or Salazex or

Salazine or Salazo or Salazodin or Salivon or salisulf or Salopyr or Salopyrine or

Saridin* or Sazo or Sulcolon or Sulfasalazin or Sulfasalizin* or sulfosalazin* or

Sulfitis or Sulzin or Zopyrin).ti,ab,kw,kf.

21 leflunomide/

263

22 (leflunomid* or arava or Airuohua or Arabloc or Arastad or Aravida or Arheuma or

Arolef or Arresto* or Artrilab or Cartina or Imaxetil or Inflaxen or Kinetos or Lara or

Leflu or Lefluar or Lefluartil or Leflyutab or Lefno or Lefora or Lefra-20 or Motoral or

Movelef or Nodia or Repso or Rheufact or Rheumide or Rualba or Synomid or

Youtong).ti,ab,kw,kf.

23 tofacitinib/

24 (Tofacitinib* or tasocitinib* or Xeljanz* or Kselyanz*).ti,ab,kw,kf.

25 baricitinib/

26 (Baricitinib* or ISP4442I3Y or LY3009104 or INCB028050 or ISP 4442I3Y or LY

3009104 or INCB 28050 or "INCB 028050").ti,ab,kf,kw.

27 sarilumab/

28 (Sarilumab* or NU90V55F8I or SAR153191 or REGN88 or SAR 153191 or REGN

88).ti,ab,kw,kf.

29 sirukumab/

30 (sirukumab* or 640443FU93 or CNTO136 or CNTO 136).ti,ab,kw,kf.

31 or/16-30

32 6 and (15 or 31)


Trial).pt.







40 Randomization/



264






48 Placebos/

49 Placebo/

50 Control Groups/

51 Control Group/









59 or/33-58

60 32 and 59

61 exp animals/



64 nonhuman/


66 or/61-65

265

67 exp humans/


69 or/67-68

70 66 not 69

71 60 not 70




3691

3692

OTHER DATABASES

PubMed A limited PubMed search was performed to capture records not

found in MEDLINE. Same MeSH, keywords, limits, and study types

used as per Ovid search, with appropriate syntax used.

The Cochrane

Library

Same MeSH, keywords, and date limits used as per Ovid search,

excluding study types and Human restrictions. Syntax adjusted for

Cochrane Library databases.

3693

3694

Grey Literature 3695

Dates for

Search:

May to June 2016

Keywords: Traditional DMARDs (methotrexate, hydroxychloroquine,

sulfasalazine, leflunomide); Biologic DMARDs (adalimumab,

certolizumab pegol, etanercept, golimumab, infliximab, anakinra,

tocilizumab, abatacept, rituximab); Small Molecules (tofacitinib);

Subsequent Entry Biologics (infliximab SEB); Products under

development (adalimumab SEB, etanercept SEB, baricitinib,

sarilumab, sirukumab) and rheumatoid arthritis

Limits: Date limits used as per Ovid search

3696

266

Relevant websites from the following sections of the CADTH grey literature checklist Grey 3697

Matters: a practical tool for searching health-related grey literature (https://www.cadth.ca/grey-3698

matters) were searched: 3699

3700

Advisories & Warnings 3701

Clinical Practice Guidelines 3702

HTA Agency -- Standard 3703

HTA Agency -- International 3704

Databases 3705

Internet 3706

https://www.cadth.ca/grey-matters

https://www.cadth.ca/grey-matters

267

APPENDIX 2: STATISTICAL ANALYSIS PLAN 3707

3708

STATISTICAL PLAN - CADTH RA PROJECT 3709

Objectives 3710

The objective of this project is to determine the comparative efficacy and safety of conventional 3711

disease-modifying anti-rheumatic (DMARD) therapies (alone or in combination), biologics 3712

(including biosimilars), and JAK inhibitors in patients with moderate to severe rheumatoid 3713

arthritis (RA) who have failed or are intolerant to methotrexate (MTX). 3714

More specifically, we are comparing all treatment effects to one another on each outcome of 3715

interest. The hypothesis is that all treatments have an equal effect on each outcome. 3716

Study Population 3717

The population of interest is patients with moderate to severe RA who have failed or are 3718

intolerant to MTX. 3719

Studies may not clearly indicate if patients were inadequate responders to MTX (IR MTX) or 3720

DMARDs (IR DMARD). We anticipate that dividing data into further groups by previous 3721

DMARD-experience vs. MTX-experience would likely lead to low power and the analyses would 3722

likely miss important differences, especially regarding harms. Therefore, we will analyze 3723

patients with IR MTX and IR DMARD together for this systematic review and NMA in the main 3724

analysis. A sensitivity analysis will be conducted in which we remove any studies that do not 3725

clearly indicate if patients were inadequate responders to MTX. 3726

Interventions and Comparators 3727

Interventions of interest include monotherapy, double therapy, or triple therapy with the following 3728

conventional DMARDs: methotrexate (any dose, oral or parenteral), hydroxychloroquine (any 3729

dose, oral), sulfasalazine (any dose, oral), and leflunomide (any dose, oral). 3730

Biologic DMARDs (biologics) that are eligible include: 3731

1. adalimumab (40 mg every two weeks, subcutaneous [SC]), 3732

2. certolizumab pegol (400 mg in two injections on day 0, 200 mg at weeks 2 and 4, 3733

then 200 mg every two weeks, SC), 3734

3. etanercept (25 mg twice weekly, SC), 3735

4. anakinra (100 mg/day, SC), 3736

5. golimumab (2 mg/kg at baseline, week 4 and then every eight weeks, 3737

intravenous [IV] or 50 mg every four weeks, SC), 3738

268

6. infliximab (3 mg/kg at baseline, weeks 2 and 6 and every eight weeks, IV), 3739

7. tocilizumab (4 mg/kg every four weeks or increased to 8 mg/kg if lack of clinical 3740

response, IV or 162 mg every two weeks or increased to every week if lack of 3741

clinical response, SC), 3742

8. abatacept (10 mg/kg every four weeks with initial infusions at baseline, weeks 2 3743

and 4, IV or 125 mg once weekly after an initial loading dose and one more 3744

injection within a day, SC) and 3745

9. rituximab (two 1000 mg doses two weeks apart, IV). 3746

3747

Oral inhibitors of Janus kinases that are eligible include: tofacitinib (5 mg twice daily, oral) and 3748

baricitinib (dose not yet approved, oral). 3749

The biosimilars of interest for this project include: etanercept biosimilars (SC), infliximab 3750

biosimilars (SC) and adalimumab biosimilars (SC). Different biosimilars for the same biologic 3751

will be analyzed separately, since they may not be identical to one another. 3752

All biologics, Janus kinase inhibitors and biosimilars are eligible as monotherapy or in 3753

combination with one of the above mentioned conventional DMARDs. There will be no class 3754

analyses conducted for this review. 3755

Treatment Dose 3756

Only the standard doses of the biologics and Janus kinase inhibitors approved by Health 3757

Canada will be considered for analysis as either interventions or comparators. The dose of 3758

biosimilars that will be analyzed will follow the standard dose of the biologic that it is attempting 3759

to replicate (e.g. 40 mg/kg subcutaneously every two weeks for adalimumab biosimilar). Any 3760

intervention or comparator that has not yet received approval by Health Canada at the time of 3761

analysis will have all available doses included. Different routes of administration for the same 3762

intervention or comparator (e.g. intravenous and subcutaneous) will be considered separately in 3763

the analysis as there may be differences in terms of adherence between intravenous and 3764

subcutaneous routes of administration for the same intervention. 3765

Treatment Duration 3766

Duration of treatment must be a minimum of 12 weeks to be eligible for analysis. There is no 3767

upper limit on the length of the intervention. Analysis will be done on the controlled period of 3768

randomized controlled trials and clinical controlled trials while the intervention is being 3769

administered. Any follow-up period post-intervention or open-label extension phase (i.e. where 3770

all participants receive the same intervention) will not be eligible for analysis. 3771

Outcomes 3772

American College of Rheumatology (ACR) 20, 50, 70 3773

269

The ACR response rates are binary composite outcomes consisting of the following outcomes 3774

on disease activity: tender and swollen joint counts, patient’s assessment of pain, patient and 3775

physician’s global assessments of disease activity and an acute-phase reactant value (either 3776

the erythrocyte sedimentation rate of a C-reactive protein level).1 3777

A patient attains an ACR20 response when they have at least a 20% improvement in tender and 3778

swollen joint counts as well as three of the five remaining core set outcomes listed.1 The same 3779

can be applied for the ACR50 and ACR70, only the response that must be achieved is 50% and 3780

70%, respectively. The primary efficacy outcome for this analysis is the ACR50. 3781

Disease Activity Score and Disease Activity Score with 28-Joint Counts (DAS/DAS28) 3782

The DAS is a continuous composite outcome that consists of: 1) the number of painful joints 3783

(Ritchie Articular Index, 0-78 joints), 44-joint count for swollen joints, erythrocyte sedimentation 3784

rate (ESR) and patient global assessment of disease activity or general health using a visual 3785

analogue scale.2 The DAS28 is similar to the DAS, but instead uses 28-joint counts for both 3786

tender and swollen joint counts. A reduction in the DAS or DAS28 indicates improvement. A 3787

change of 1.2 is clinically important for the DAS or DAS28.2 The C-reactive protein can be used 3788

instead of the ESR; the DAS28-ESR will be the main version of the DAS28 considered, but the 3789

DAS28-CRP will be included in the analysis when the DAS28-ESR is not reported. 3790

Results on the change from baseline to the end of treatment data will be analyzed; for adaptive 3791

design trials, results on the change from baseline to the time of adaptation will be analyzed as 3792

the reference case. 3793

3794

Health Assessment Questionnaire, Disability Index (HAQ-DI) 3795

Functional ability will be measured using the Health Assessment Questionnaire disability index 3796

(HAQ-DI), which is the gold standard outcome measure to use.3 The scoring system ranges 3797

from 0 (no impairment of functional ability) to 3.0 (full impairment of functional ability). The 3798

minimal clinically important difference is 0.22 units.3 3799




Remission 3803

Remission will be assessed based on a DAS28 score of <2.6.2 As with the DAS28, the version 3804

using CRP will be selected for analysis when ESR is not available. More recent measures of 3805

remission are available, but the DAS28 remission criteria have been available for a longer 3806

period of time and thus are more likely to be captured in older studies. 3807

Radiographic Progression 3808

270

There will be no restrictions on the type of radiographic progression measures eligible for 3809

analysis because there are several scores and modifications of those scores available. Two of 3810

the more common scores are described below. 3811

The total Sharp score (TSS) assesses erosions (scale from 0 to 5) and joint space narrowing 3812

(scale from 0 to 4) in joints of the hand and wrist.4 The modified total Sharp score (mTSS) uses 3813

the original Sharp score and adds joints of the feet to the assessment (scale from 0 to 10).4 The 3814

minimal clinically important difference for patients with a longer disease duration and high 3815

disease activity is 4.5 units for the mTSS.5 3816




Health-Related Quality of Life 3820

Health-related quality of life will be measured using the Short Form-36 (SF-36) questionnaire. 3821

The SF-36 is a generic health measure and is commonly used in rheumatology.6 For this 3822

review, the two summary (physical component summary [PCS] and mental component 3823

summary [MCS]) scores will be analyzed separately. Both component scores use a range from 3824

0 (worse health) to 100 (better health). The minimal clinically important difference for the SF-36 3825

is a change of 5 points, though this applies broadly rather than specifically to patients with RA.6 3826


design trials results on the change from baseline to the time of adaptation will be analyzed as 3828


Fatigue 3830

No restrictions will be made on which fatigue scales or instruments are eligible for this review. 3831

We anticipate studies may report fatigue using the FACIT-F or FAS scales and thus details on 3832

these instruments are provided below. 3833

The Functional Assessment Chronic Illness Therapy (FACIT-F) scale assesses various types of 3834

fatigue (physical, functional, and emotional), as well as the impacts fatigue has on the individual 3835

in terms of social interactions.7 It involves a type of 5-point Likert scale; overall scores are from 3836

0 (more fatigue) to 52 (less fatigue). The minimal clinically important difference is a change of 3 3837

to 4 points.7 The Fatigue Assessment Scale (FAS) involves ten questions on fatigue and how 3838

the individual feels they rate on a type of 5-point Likert scale in which higher scores indicating 3839

more fatigue.8 3840

3841




271

Pain 3845

As with fatigue, there will be no restrictions on the scales or instruments accepted for pain in this 3846

review. Common adult pain scales include the Visual Analog Scale for Pain (VAS Pain) and 3847

Numeric Rating Scale for Pain (NRS Pain), which are described below. 3848

Pain VAS uses a continuous 100 mm scale from 0 (“no pain”) to 100 (“worst imaginable pain”).9 3849

An individual marks their level of pain on the scale, which is then measured. The MCID is a 3850

change of 11 mm on the 100 mm scale.9 Pain NRS is well correlated with the pain VAS. An 3851

individual will verbally rate their pain using the integers from 0 (“no pain”) to 10 (“worst 3852

imaginable pain”). A clinically important difference for the pain NRS is a reduction in pain by 2 3853

points for various conditions.9 3854




Serious Adverse Events 3858

Serious adverse events are defined by the Food and Drug Administration when a patient: dies, 3859

has a life-threatening event, is hospitalized, experiences disability or permanent damage, 3860

experiences a congenital anomaly or birth defect as a result of exposure to an intervention 3861

before conception or during pregnancy, requires a device as an intervention to prevent 3862

permanent impairment or damage, or experiences a different medical event that is important 3863

and serious (e.g. drug dependence).10 3864

Withdrawal due to adverse events 3865

Any adverse event that results in a patient discontinuing the treatment and leaving the study is 3866

considered a withdrawal due to an adverse event (WDAE). This is the primary safety outcome 3867

for this analysis. 3868

Cancer 3869

Overall numbers of cancer events will be analyzed. Leukemia and lymphoma will be analyzed 3870

separately as they have been identified as notable harms by the clinical expert. 3871

Other safety outcomes include: mortality, serious infections, tuberculosis, congestive heart 3872

failure, major adverse cardiac events, and herpes zoster. 3873

Time Points for Analysis 3874

Analyses will be conducted on the end of treatment time points for each of the above outcomes. 3875

The exception is for adaptive design trials. Adaptive design trials have been used in RA more 3876

recently to allow for planned modifications to participant treatment in the study at a pre-defined 3877

interim analysis.11, 12 In this report, we distinguish between four major types of adaptive designs: 3878

1) early escape trials, 2) rescue therapy trials, 3) treatment switching trials based on non-3879

response criteria; and 4) planned treatment switching trials (Table 1). 3880

272

Table 1. Definition of Adaptive Design Trials 3881

Adaptive Design Description Early escape trial After a pre-determined period (e.g. 12 or 16 weeks) receiving treatment, patients

who do not attain a pre-defined level of disease response are withdrawn from the trial and may enter an open-label extension phase.

Rescue therapy trial After a pre-determined period of receiving treatment, patients who do not attain a pre-defined level of disease response are permitted to receive rescue therapy (e.g. dose adjustment or addition of a DMARD or corticosteroid, receipt of one or more doses of active treatment for those in the comparator arm, increased dose of active drug).

Treatment switching trial (based on non-response)

After a pre-determined period (e.g. 12 or 16 weeks) receiving treatment, patients who do not attain a pre-defined level of disease response are switched to another treatment arm for the remainder of the study.

Treatment switching trial (planned)

Investigators plan a priori to have patients (e.g. in a control group) either switch to another arm or re-randomize patients to switch to one of a few possible treatment arms. The planned treatment switch could occur either:

c) as the only adaptation in the study duration, or d) as the second adaptation after an initial adaptation (typically involving

patients who had an inadequate response).

3882

For studies that involve an adaptive design, we plan to analyze the end of treatment data using 3883

rate ratios adjusted for the length of exposure of participants to intervention who had an 3884

adaptation to their treatment course. This would account for each patient’s actual treatment 3885

length and amount and improve accuracy of the effect estimate. For example, in early escape 3886

trials, the end of treatment data for an outcome would be weighted based on a participant’s 3887

length of exposure to the treatment before discontinuation from the trial. In rescue therapy trials, 3888

an adjustment would be made to account for the amount and length of time rescue therapy was 3889

received by a participant. If patient-level data is not reported in the study, we will consider the 3890

data up until the time of adaptation for the main analysis. This will provide greater confidence in 3891

identifying if the results are due to the treatments rather than a combination of the treatments 3892

under investigation, a specific treatment sequence, cross-over effect, or any adaptations made 3893

to the treatment during the study. 3894

In addition, it is common for early phase studies to report data at three months to demonstrate 3895

the treatment’s efficacy compared to placebo13 and three months has been shown to be a good 3896

predictor of long-term efficacy.14 Nevertheless, to address concerns about losing data on more 3897

long-term outcomes such as radiographic progression, health-related quality of life and safety, a 3898

sensitivity analysis will be conducted on the primary efficacy (ACR50) and safety (WDAE) 3899

outcomes using the end of treatment data for the adaptive designs. Figure 1 outlines in general 3900

the four major adaptations and how we plan to analyze these types of studies in the main and 3901

sensitivity analyses. 3902

3903

273

3904

Figure 1. Analysis time points for adaptive design trials. Red lines indicate the main analysis 3905

and blue lines indicate sensitivity analyses. A represents any treatment eligible for the review 3906

and B represents either a comparator group or another treatment. For multi-arm planned 3907

treatment switch trials, PL is added to distinguish between the active treatments (A and B) and 3908

the comparator group (PL). 3909

For a sensitivity analysis on the end of treatment, data for rescue therapy studies will have data 3910

where treatments A and B are modified slightly since patients may have had a change in 3911

background therapy or received a rescue dose of a biologic. Data for early escape studies will 3912

have data where the number of patients contributing data for treatments A and B will be smaller 3913

because of patients escaping the study. 3914

In terms of treatment switch trials, we will analyze end of treatment data (for the sensitivity 3915

analysis) that is uncontaminated (i.e. patients who switched treatments have data reported 3916

separately from those who did not switch). If this is not reported, we will analyze contaminated 3917

data that maintains an intention to treat reporting and then contaminated data that is reported as 3918

per protocol. In the event that more than one adaptation occurs in a study (e.g. a planned 3919

treatment switch followed by early escape for those who are still not responding), data up until 3920

the end of the treatment switch phase of the trial will be considered because we anticipate the 3921

data after the second adaptation will lose its meaning and ability to address the objective of our 3922

review. 3923

274

Parameter Estimates 3924

Binary outcomes will be analyzed using odds ratios. Based on a prevalence estimate, relative 3925

risks and risk differences will be derived. 3926

For continuous outcomes, data for the mean change from baseline to end of the treatment 3927

period will be used in all analyses. Any studies that do not report in this format will have the 3928

change scores calculated using the baseline and end of treatment data. If measure of 3929

dispersion data (e.g., standard deviation, standard error, 95% confidence interval) is missing for 3930

either baseline or end of treatment, we will use the value that is available and assume it remains 3931

unchanged for the duration of the study in order to calculate the change score standard error. If 3932

a measure of dispersion data is missing for both baseline and end of treatment, the study will be 3933

excluded from the main analysis and a sensitivity analysis will be conducted in which the 3934

standard error is imputed using the median standard error reported in all studies from the 3935

evidence network. Certain continuous outcomes may be reported using different scales or 3936

instruments, which will require analysis using a standardized mean difference. Otherwise, the 3937

mean difference will be the parameter estimate used for continuous outcomes. Wherever 3938

possible, the raw data (i.e. that has not been adjusted for any baseline characteristics) reported 3939

in the included studies will be extracted and used for analysis. 3940

Quality of Evidence 3941

The Cochrane Risk of Bias tool will be used to assess the internal validity of each included 3942

study and identify studies of low methodological quality (i.e. high risk of bias overall) and high 3943

methodological quality (i.e. low risk of bias overall). A sensitivity analysis will be conducted in 3944

which only studies of high methodological quality will be analyzed. If the results differ, then the 3945

results will be reported based on only the studies of high methodological quality. 3946

Attempts at reducing publication bias will be made through searching the grey literature, such as 3947

websites of regulatory agencies and clinical trial registries; any source that fits the selection 3948

criteria will be included in the review. In addition, publication bias will be assessed using a 3949

funnel plot if at least ten studies are available within an evidence network. Results from the 3950

funnel plot will be used in interpreting and reporting the findings for this review. 3951

Evidence Network Diagrams 3952

The evidence network for each outcome will be displayed graphically in the form of a diagram. 3953

The lines will indicate direct comparisons of one intervention to another intervention (or 3954

comparator) and the thickness of the line will reflect the number of studies with this particular 3955

comparison. The vertices (“nodes”) will represent individual interventions. Sizes of nodes will be 3956

directly proportional to the total sample size of participants contributing data to the node across 3957

all studies involving that intervention. 3958

Datasets 3959

275

Data extraction forms will capture information on the general study characteristics (e.g. first 3960

author’s last name, year of publication, trial name, title, trial registry number, etc.), patient 3961

characteristics (e.g. age, sex, race, disease duration, methotrexate dose, etc.), and intervention 3962

characteristics (e.g. name of intervention, dose, frequency, route, etc.). In addition, each 3963

outcome will have its own form and will capture information on the time point, statistical power, 3964

dataset analyzed (e.g. intention to treat, per protocol, safety set, etc.), group names, sample 3965

size and either: 1) the mean (or median) change from baseline and measure of dispersion (or 3966

the interquartile range or range) for continuous outcomes, or 2) the number of participants with 3967

an event for binary outcomes. The intention to treat analysis will be extracted and analyzed in 3968

priority, followed by a modified intention to treat analysis and then a per protocol analysis for 3969

efficacy outcomes; for safety outcomes the safety set will be analyzed. Adaptive design trials 3970

will have data extracted either for individual patient data or, if not available, for the latest time 3971

point before adaptation (for the main analysis) and the end of treatment (for the sensitivity 3972

analysis). 3973

Feasibility Assessment 3974

Prior to commencing the network meta-analysis (NMA), baseline characteristics of studies 3975

included in the same evidence network will be compared to identify any potentially 3976

heterogeneous trials (e.g. based on differences in baseline characteristics or study design) to be 3977

excluded from analysis or, given a sufficient number of trials (e.g. ten trials for every outcome 3978

adjusted),15 a meta-regression adjusting for the variable that is the source of heterogeneity. 3979

In the event that any treatment has values of zero (e.g. for binary outcomes) or a very wide 3980

credible interval, we will exclude that trial so long as it is clinically feasible to do so. If it is not 3981

feasible to conduct a NMA for any of the following reasons: 1) heterogeneity, 2) a lack of trials 3982

(i.e. fewer than three or four trials), 3) a large number of zero events for binary data, or 4) outlier 3983

trials, then a meta-analysis will be attempted. If that is also not feasible, a descriptive analysis 3984

will be completed. 3985

Statistical Models: Network Meta-Analysis (NMA) 3986

A NMA will be conducted in order to assess the comparative efficacy and safety of DMARD 3987

therapies (alone or in combination), biologics (including biosimilars), and JAK inhibitors in 3988

patients with moderate to severe RA who have failed or are intolerant to methotrexate. Given 3989

the large number of interventions available to patients combined with the paucity of evidence 3990

from head-to-head comparison trials, it is not possible to directly compare the biologics and 3991

conventional DMARDs through pairwise meta-analysis. A NMA is capable of using mixed 3992

treatment comparisons wherein direct evidence (from actual comparisons made within trials) 3993

and indirect evidence (estimated through the model) are combined to increase the robustness of 3994

the effect estimates when there is consistency in the evidence network.16 Due to the anticipated 3995

complexity of the evidence networks, a NMA will be used, since it has the capacity to analyze a 3996

variety of network structures.17 3997

276

Bayesian NMAs will be conducted for outcomes pre-specified in the protocol, after careful 3998

assessment of heterogeneity across trials in terms of subject characteristics, trial methodologies 3999

and treatment protocols. The effect estimate will depend on the outcome of interest and 4000

availability of data. For reference case NMAs, appropriate comparators will be considered. Both 4001

fixed and random effects models will be conducted; model selection will be based on the 4002

Deviance Information Criterion (DIC) and residual deviance. WinBUGS (MRC Biostatistics Unit, 4003

Cambridge, UK) will be used for Bayesian NMA using scripts developed at the Universities of 4004

Bristol and Leicester (www.bris.ac.uk/cobm/research/mpes/) that are appropriate for evidence 4005

structures under consideration. 4006

Specific therapies will be identified as the reference group for all Bayesian network meta-4007

analyses. Posterior densities for unknown parameters will be estimated using Markov Chain 4008

Monte Carlo (MCMC) methods. Basic parameters will be assigned non-informative or vague 4009

prior distributions; more informative priors will be considered; for example, an informative prior 4010

for the between-study variance will be considered following Turner et al.18 Point estimates and 4011

95% credible intervals will be used to summarize findings. The probability of a comparator being 4012

optimal will be estimated for each outcome based on the proportion of MCMC simulations in 4013

which its relative measure of effect was best. 4014

Consistency between direct and indirect evidence will be formally assessed using back-4015

calculation and node splitting techniques. Model diagnostics will also include trace plots and the 4016

Brooks-Gelman-Rubin statistic to assess and ensure model convergence. Three chains will be 4017

fit in WinBUGS for each analysis, each usually employing ~ 20,000 iterations, with a burn in of ~ 4018

20,000 iterations. Provided sufficient data is available to inform the evidence network, meta-4019

regression and/or subgroup analysis will be conducted for key demographic, medical and study 4020

design characteristics to test the robustness of reference case analyses. Investigation for 4021

potential outliers will be conducted by looking at point estimates that differ greatly from the 4022

others. 4023

Statistical Models: Meta-Analysis 4024

Meta-analysis will be conducted when an NMA is not feasible (see Feasibility Assessment 4025

section). The data will first be summarized descriptively. A meta-analysis will be undertaken 4026

using fixed or random-effects models when data are available, sufficiently similar and of 4027

sufficient quality. The effect sizes for the identified dichotomous outcomes will be expressed in 4028

terms of the risk ratio (RR) or odds ratio (OR). In cases when events are rare, the Peto odds 4029

ratio will be used. For continuous outcomes, the mean differences will be used; if the data is not 4030

normally distributed the median differences will be used. If the included data are presented 4031

using more than one scale or instrument the standardized mean difference (SMD) will be used. 4032

It is essential to know both estimated relative and absolute differences in the important benefits 4033

and harms, absolute mean difference and relative percent change from baseline will be included 4034

in the summary of findings table. 4035

Results will be assessed for both clinical diversity and methodological diversity. Clinical diversity 4036

will be assessed by checking that the populations, interventions, and comparators are not too 4037

http://www.bris.ac.uk/cobm/research/mpes/

277

different from each other such that combining them is not appropriate. Methodological diversity 4038

will be assessed by checking that the studies are similar in terms of study design and risk of 4039

bias. Once satisfied that the studies are minimally diverse and that it makes sense to pool them 4040

together in a meta-analysis, an assessment of the statistical heterogeneity will be undertaken by 4041

examining the forest plot and result of the I2 statistic; the forest plots providing a visual sense of 4042

heterogeneity and the I2 statistic indicating the presence of statistical heterogeneity. If the effects 4043

observed across trials are inconsistent, and vary to a large extent (e.g., I2>50%), the results will 4044

again be explored to assess whether the differences can be explained by some clinical or 4045

methodological feature. Heterogeneity that cannot be reduced by pre-specified subgroup or 4046

meta-regression analyses will lead to an overall estimate with less confidence when interpreting 4047

the inference from the meta-analysis. In this case, a more conservative random-effects model 4048

approach would be used so that the uncertainty of the single effect estimate is reflected in wider 4049

confidence intervals. Investigation for potential outliers will be conducted by looking at point 4050

estimates that differ greatly from the others. 4051

Summary of Sensitivity Analyses 4052

Sensitivity analyses will be conducted by: 4053

Removing studies of poor methodological quality 4054

Analyzing the end of treatment data for adaptive design trials if patient-level data is not 4055

available 4056

Analyzing old and new publications (i.e. studies published before 2007 and from 2007 4057

onward) separately 4058

Removing studies that do not clearly indicate if patients were inadequate responders to 4059

MTX (i.e. it is only stated that they did not respond to one or more conventional 4060

DMARDs) 4061

Imputing the median standard error across all studies in an evidence network to get a 4062

standard error for the mean change from baseline in a study that does not report it or the 4063

baseline values 4064

Subgroup Analyses and Meta-Regressions 4065

There are currently no planned subgroup analyses or meta-regressions. For the outcomes 4066

where NMA is appropriate and feasible and sufficient data is available, meta-regression 4067

analyses may be carried out for the primary efficacy and safety outcomes (i.e. ACR50 and 4068

WDAE). 4069

278

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2. Anderson JK, Zimmerman L, Caplan L and Michaud K. Measures of rheumatoid arthritis 4073 disease activity: Patient (PtGA) and Provider (PrGA) Global Assessment of Disease Activity, 4074 Disease Activity Score (DAS) and Disease Activity Score With 28-Joint Counts (DAS28), 4075 Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Patient Activity 4076 Score (PAS) and Patient Activity Score-II (PASII), Routine Assessment of Patient Index Data 4077 (RAPID), Rheumatoid Arthritis Disease Activity Index (RADAI) and Rheumatoid Arthritis 4078 Disease Activity Index-5 (RADAI-5), Chronic Arthritis Systemic Index (CASI), Patient-Based 4079 Disease Activity Score With ESR (PDAS1) and Patient-Based Disease Activity Score Without 4080 ESR (PDAS2), and Mean Overall Index for Rheumatoid Arthritis (MOI-RA). Arthritis Care & 4081 Research. 2011; 63: S14-S36. 4082

3. Maska L, Anderson J and Michaud K. Measures of functional status and quality of life in 4083 rheumatoid arthritis: Health Assessment Questionnaire Disability Index (HAQ), Modified Health 4084 Assessment Questionnaire (MHAQ), Multidimensional Health Assessment Questionnaire 4085 (MDHAQ), Health Assessment Questionnaire II (HAQ-II), Improved Health Assessment 4086 Questionnaire (Improved HAQ), and Rheumatoid Arthritis Quality of Life (RAQoL). Arthritis Care 4087 & Research. 2011; 63: S4-S13. 4088

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5. Bruynesteyn K, van der Heijde D, Boers M, et al. Determination of the minimal clinically 4091 important difference in rheumatoid arthritis joint damage of the Sharp/van der Heijde and 4092 Larsen/Scott scoring methods by clinical experts and comparison with the smallest detectable 4093 difference. Arthritis Rheum. 2002; 46: 913-20. 4094

6. Busija L, Pausenberger E, Haines TP, Haymes S, Buchbinder R and Osborne RH. Adult 4095 measures of general health and health-related quality of life: Medical Outcomes Study Short 4096 Form 36-Item (SF-36) and Short Form 12-Item (SF-12) Health Surveys, Nottingham Health 4097 Profile (NHP), Sickness Impact Profile (SIP), Medical Outcomes Study Short Form 6D (SF-6D), 4098 Health Utilities Index Mark 3 (HUI3), Quality of Well-Being Scale (QWB), and Assessment of 4099 Quality of Life (AQOL). Arthritis Care & Research. 2011; 63: S383-S412. 4100

7. Hewlett S, Dures E and Almeida C. Measures of fatigue: Bristol Rheumatoid Arthritis 4101 Fatigue Multi-Dimensional Questionnaire (BRAF MDQ), Bristol Rheumatoid Arthritis Fatigue 4102 Numerical Rating Scales (BRAF NRS) for Severity, Effect, and Coping, Chalder Fatigue 4103 Questionnaire (CFQ), Checklist Individual Strength (CIS20R and CIS8R), Fatigue Severity 4104 Scale (FSS), Functional Assessment Chronic Illness Therapy (Fatigue) (FACIT-F), Multi-4105 Dimensional Assessment of Fatigue (MAF), Multi-Dimensional Fatigue Inventory (MFI), 4106 Pediatric Quality Of Life (PedsQL) Multi-Dimensional Fatigue Scale, Profile of Fatigue (ProF), 4107 Short Form 36 Vitality Subscale (SF-36 VT), and Visual Analog Scales (VAS). Arthritis Care & 4108 Research. 2011; 63: S263-S86. 4109

8. Michielsen HJ, De Vries J and Van Heck GL. Psychometric qualities of a brief self-rated 4110 fatigue measure: The Fatigue Assessment Scale. J Psychosom Res. 2003; 54: 345-52. 4111

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9. Hawker GA, Mian S, Kendzerska T and French M. Measures of adult pain: Visual 4112 Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain 4113 Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade 4114 Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and 4115 Constant Osteoarthritis Pain (ICOAP). Arthritis Care & Research. 2011; 63: S240-S52. 4116

10. Food & Drug Administration. What is a Serious Adverse Event? 2016. 4117

11. Cornu C, Kassai B, Fisch R, et al. Experimental designs for small randomised clinical 4118 trials: an algorithm for choice. Orphanet J Rare Dis. 2013; 8: 48. 4119

12. Gupta S, Faughnan ME, Tomlinson GA and Bayoumi AM. A framework for applying 4120 unfamiliar trial designs in studies of rare diseases. J Clin Epidemiol. 2011; 64: 1085-94. 4121

13. Boers M. The time has come to limit the placebo period in rheumatoid arthritis trials to 3 4122 months: a systematic comparison of 3- and 6-month response rates in trials of biological agents. 4123 Ann Rheum Dis. 2010; 69: 186-92. 4124

14. Wang Y, Zhu R, Xiao J, et al. Short-Term Efficacy Reliably Predicts Long-Term Clinical 4125 Benefit in Rheumatoid Arthritis Clinical Trials as Demonstrated by Model-Based Meta-Analysis. 4126 J Clin Pharmacol. 2016; 56: 835-44. 4127

15. Gagnier JJ, Morgenstern H, Altman DG, et al. Consensus-based recommendations for 4128 investigating clinical heterogeneity in systematic reviews. BMC Med Res Methodol. 2013; 13: 4129 106. 4130

16. Jansen JP, Fleurence R, Devine B, et al. Interpreting indirect treatment comparisons and 4131 network meta-analysis for health-care decision making: report of the ISPOR Task Force on 4132 Indirect Treatment Comparisons Good Research Practices: part 1. Value Health. 2011; 14: 417-4133 28. 4134

17. Wells G, Sultan S, Chen L, Khan M and Coyle D. Indirect Evidence: Indirect Treatment 4135 Comparisons in Meta-Analysis. Ottawa: Canadian Agency for Drugs and Technologies in 4136 Health, 2009. 4137

18. Turner RM, Davey J, Clarke MJ, Thompson SG and Higgins JP. Predicting the extent of 4138 heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic 4139 Reviews. Int J Epidemiol. 2012; 41: 818-27. 4140

4141

4142

280

APPENDIX 3: LIST OF INCLUDED STUDIES (AND COMPANION 4143

PUBLICATIONS) 4144

1. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis (New England Journal 4145

of Medicine (2012) 367, (508-519)). N Engl J Med. 2013;369:293. 4146

2. Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis 4147

Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-4148

controlled Study. The Journal of rheumatology. 2016;43(5):998. 4149

3. Erratum: Head-to-head comparison of certolizumab pegol versus adalimumab in 4150

rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE 4151

study (The Lancet (2016) 388(10061) (2763-2774) (S0140673616316518) (10.1016/S0140-4152

6736(16)31651-8)). The Lancet. 2016;388:2742. 4153

4. Erratum: Head-to-head comparison of certolizumab pegol versus adalimumab in 4154

rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE 4155

study (The Lancet (2016) 388(10061) (2763-2774)(S0140673616316518)(10.1016/S0140-4156

6736(16)31651-8)). The Lancet. 2017;389:e2. 4157

5. Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, et al. A multicenter, 4158

double-blind, randomized, placebo controlled trial of infliximab combined with low dose 4159

methotrexate in Japanese patients with rheumatoid arthritis. The Journal of rheumatology. 4160

2006;33:37-44. 4161

6. Alzaidy AH, Numan IT, Jassim NA. Effects of adalimumab on bones 4162

destruction/repairing marker (CTX-I & preptin) in iraqi patients with rheumatoid arthritis. 4163

Pharmacie Globale. 2016;7. 4164

7. Amgen. Efficacy and Safety Study of ABP 501 Compared to Adalimumab in Subjects 4165

With Moderate to Severe Rheumatoid Arthritis. [Gery Lit]. In press. 4166

8. Bae SC, Gun SC, Mok CC, Khandker R, Nab HW, Koenig AS, et al. Improved health 4167

outcomes with Etanercept versus usual DMARD therapy in an Asian population with established 4168

rheumatoid arthritis. BMC Musculoskelet Disord. 2013;14. 4169

9. Bae SC, Kim J, Choe JY, Park W, Lee SH, Park YB, et al. A phase III, multicentre, 4170

randomised, double-blind, active-controlled, parallel-group trial comparing safety and efficacy of 4171

HD203, with innovator etanercept, in combination with methotrexate, in patients with rheumatoid 4172

arthritis: the HERA study. Ann Rheum Dis. 2016. 4173

10. Bankhurst AD. Etanercept and methotrexate combination therapy. Clinical and 4174

experimental rheumatology. 1999;17(6 Suppl 18):S69-72. 4175

281

11. Bingham CO, III, Weinblatt M, Han C, Gathany TA, Kim L, Lo KH, et al. The effect of 4176

intravenous golimumab on health-related quality of life in rheumatoid arthritis: 24-week results of 4177

the phase III GO-FURTHER trial. J Rheumatol. 2014;41:1067-76. 4178

12. Burmester GR, Lin Y, Patel R, van Adelsberg J, Mangan EK, Graham NM, et al. Efficacy 4179

and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of 4180

patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-4181

group phase III trial. Annals of the rheumatic diseases. 2017;76(5):840-7. 4182

13. Chen DY, Chou SJ, Hsieh TY, Chen YH, Chen HH, Hsieh CW, et al. Randomized, 4183

double-blind, placebo-controlled, comparative study of human anti-TNF antibody adalimumab in 4184

combination with methotrexate and methotrexate alone in Taiwanese patients with active 4185

rheumatoid arthritis. Journal of the Formosan Medical Association = Taiwan yi zhi. 4186

2009;108:310-9. 4187

14. Chen XX, Li ZG, Wu HX, Zhao DB, Li XF, Xu JH, et al. A randomized, controlled trial of 4188

efficacy and safety of Anbainuo, a bio-similar etanercept, for moderate to severe rheumatoid 4189

arthritis inadequately responding to methotrexate. Clinical rheumatology. 2016;35(9):2175-83. 4190

15. Choe JY, Prodanovic N, Niebrzydowski J, Staykov I, Dokoupilova E, Baranauskaite A, et 4191

al. A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the 4192

infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis 4193

despite methotrexate therapy. Ann Rheum Dis. 2015. 4194

16. Choy E, McKenna F, Vencovsky J, Valente R, Goel N, Vanlunen B, et al. Certolizumab 4195

pegol plus MTX administered every 4 weeks is effective in patients with RA who are partial 4196

responders to MTX. Rheumatology (Oxford). 2012;51:1226-34. 4197

17. Ciconelli RM, Ferraz MB, Visioni RA, Oliveira LM, Atra E. A randomized double-blind 4198

controlled trial of sulphasalazine combined with pulses of methylprednisolone or placebo in the 4199

treatment of rheumatoid arthritis. British journal of rheumatology. 1996;35(2):150-4. 4200

18. Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, et al. Treatment of 4201

rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in 4202

combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-4203

blind, placebo-controlled trial. Arthritis and rheumatism. 2002;46:614-24. 4204

19. Cohen SB, Moreland LW, Cush JJ, Greenwald MW, Block S, Shergy WJ, et al. A 4205

multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a 4206

recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with 4207

background methotrexate. Annals of the rheumatic diseases. 2004;63:1062-8. 4208

20. Combe B, Codreanu C, Fiocco U, Gaubitz M, Geusens PP, Kvien TK, et al. Efficacy, 4209

safety and patient-reported outcomes of combination etanercept and sulfasalazine versus 4210

etanercept alone in patients with rheumatoid arthritis: a double-blind randomised 2-year study. 4211

Annals of the rheumatic diseases. 2009;68:1146-52. 4212

282

21. Combe B, Codreanu C, Fiocco U, Gaubitz M, Geusens PP, Kvien TK, et al. Etanercept 4213

and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite 4214

receiving sulfasalazine: a double-blind comparison. Annals of the rheumatic diseases. 4215

2006;65:1357-62. 4216

22. Conaghan PG, Durez P, Alten RE, Burmester GR, Tak PP, Klareskog L, et al. Impact of 4217

intravenous abatacept on synovitis, osteitis and structural damage in patients with rheumatoid 4218

arthritis and an inadequate response to methotrexate: the ASSET randomised controlled trial. 4219


23. Conaghan PG, Emery P, Ostergaard M, Keystone EC, Genovese MC, Hsia EC, et al. 4221

Assessment by MRI of inflammation and damage in rheumatoid arthritis patients with 4222

methotrexate inadequate response receiving golimumab: results of the GO-FORWARD trial. 4223

Annals of the rheumatic diseases. 2011;70(11):1968-74. 4224

24. Conaghan PG, Peterfy C, Olech E, Kaine J, Ridley D, Dicarlo J, et al. The effects of 4225

tocilizumab on osteitis, synovitis and erosion progression in rheumatoid arthritis: results from the 4226

ACT-RAY MRI substudy. Annals of the rheumatic diseases. 2014;73(5):810-6. 4227

25. Deodhar A, Bitman B, Yang Y, Collier DH. The effect of etanercept on traditional 4228

metabolic risk factors for cardiovascular disease in patients with rheumatoid arthritis. Clinical 4229

rheumatology. 2016;35(12):3045-52. 4230

26. Dougados M, Kissel K, Conaghan PG, Mola EM, Schett G, Gerli R, et al. Clinical, 4231

radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in 4232

rheumatoid arthritis: the ACT-RAY study. Annals of the rheumatic diseases. 2014;73(5):803-9. 4233

27. Dougados M, Kissel K, Sheeran T, Tak PP, Conaghan PG, Mola EM, et al. Adding 4234

tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 4235

24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in 4236

rheumatoid arthritis (ACT-RAY). Annals of the rheumatic diseases. 2013;72:43-50. 4237

28. Dougados M, van der Heijde D, Chen YC, Greenwald M, Drescher E, Liu J, et al. 4238

Baricitinib in patients with inadequate response or intolerance to conventional synthetic 4239

DMARDs: results from the RA-BUILD study. Annals of the rheumatic diseases. 2017;76(1):88-4240

95. 4241

29. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close 4242

DR, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. 4243

The New England journal of medicine. 2004;350(25):2572-81. 4244

30. Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ, et al. Efficacy and 4245

safety of different doses and retreatment of rituximab: A randomised, placebo-controlled trial in 4246

patients who are biological naive with active rheumatoid arthritis and an inadequate response to 4247

methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders 4248

(SERENE)). Ann Rheum Dis. 2010;69:1629-35. 4249

283

31. Emery P, Kosinski M, Li T, Martin M, Williams GR, Becker JC, et al. Treatment of 4250

rheumatoid arthritis patients with abatacept and methotrexate significantly improved health-4251

related quality of life. The Journal of rheumatology. 2006;33(4):681-9. 4252

32. Emery P, Vencovsky J, Sylwestrzak A, Leszczynski P, Porawska W, Baranauskaite A, et 4253

al. A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept 4254

reference product in patients with active rheumatoid arthritis despite methotrexate therapy. Ann 4255

Rheum Dis. 2015. 4256

33. Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, et al. Phase IIb 4257

dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab 4258

monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate 4259

response to disease-modifying antirheumatic drugs. Arthritis and rheumatism. 2012;64:617-29. 4260

34. Fleischmann R, Vencovsky J, van Vollenhoven RF, Borenstein D, Box J, Coteur G, et al. 4261

Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with 4262

rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD 4263

study. Annals of the rheumatic diseases. 2009;68:805-11. 4264

35. Fleischmann R, Weinblatt ME, Schiff M, Khanna D, Maldonado MA, Nadkarni A, et al. 4265

Patient-Reported Outcomes from a 2-year Head-to-Head Comparison of Subcutaneous 4266

Abatacept versus Adalimumab for Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2015. 4267

36. Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara CA, Compagnone D, et al. 4268

Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and 4269

concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of 4270

STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). The Journal of rheumatology. 4271

2003;30:2563-71. 4272

37. Furst DE, Shaikh SA, Greenwald M, Bennett B, Davies O, Luijtens K, et al. Two dosing 4273

regimens of certolizumab pegol in patients with active rheumatoid arthritis. Arthritis Care Res 4274

(Hoboken). 2015;67:151-60. 4275

38. Gabay C, Emery P, van Vollenhoven R, Dikranian A, Alten R, Pavelka K, et al. 4276

Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis 4277

(ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381:1541-50. 4278

39. Gashi AA, Rexhepi S, Berisha I, Kryeziu A, Ismaili J, Krasniqi G. Treatment of 4279

rheumatoid arthritis with biologic DMARDS (Rituximab and Etanercept). Med Arh. 2014;68:51-3. 4280

40. Genovese MC, Fleischmann R, Kivitz AJ, Rell-Bakalarska M, Martincova R, Fiore S, et 4281

al. Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate 4282

Response to Methotrexate: Results of a Phase III Study. Arthritis rheumatol. 2015;67:1424-37. 4283

284

41. Genovese MC, Han C, Keystone EC, Hsia EC, Buchanan J, Gathany T, et al. Effect of 4284

golimumab on patient-reported outcomes in rheumatoid arthritis: results from the GO-4285

FORWARD study. The Journal of rheumatology. 2012;39(6):1185-91. 4286

42. Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, et al. 4287

Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis 4288

with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in 4289

combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis and 4290

rheumatism. 2008;58:2968-80. 4291

43. Hobbs K, Deodhar A, Wang B, Bitman B, Nussbaum J, Chung J, et al. Randomized, 4292

double-blind, placebo-controlled study to evaluate the efficacy and safety of etanercept in 4293

patients with moderately active rheumatoid arthritis despite DMARD therapy. SpringerPlus. 4294

2015;4:113. 4295

44. Huizinga TW, Fleischmann RM, Jasson M, Radin AR, van AJ, Fiore S, et al. Sarilumab, 4296

a fully human monoclonal antibody against IL-6Ralpha in patients with rheumatoid arthritis and 4297

an inadequate response to methotrexate: efficacy and safety results from the randomised 4298

SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 2014;73:1626-34. 4299

45. Jani RH, Gupta R, Bhatia G, Rathi G, Ashok KP, Sharma R, et al. A prospective, 4300

randomized, double-blind, multicentre, parallel-group, active controlled study to compare 4301

efficacy and safety of biosimilar adalimumab (Exemptia; ZRC-3197) and adalimumab (Humira) 4302

in patients with rheumatoid arthritis. Int J Rheum Dis. 2015. 4303

46. Jobanputra P, Maggs F, Deeming A, Carruthers D, Rankin E, Jordan AC, et al. A 4304

randomised efficacy and discontinuation study of etanercept versus adalimumab (RED SEA) for 4305

rheumatoid arthritis: a pragmatic, unblinded, non-inferiority study of first TNF inhibitor use: 4306

outcomes over 2 years. BMJ open. 2012;2(6). 4307

47. Kaine J, Gladstein G, Strusberg I, Robles M, Louw I, Gujrathi S, et al. Evaluation of 4308

abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of 4309

withdrawal and reintroduction on immunogenicity, efficacy and safety (phase Iiib ALLOW study). 4310


48. Kameda H, Kanbe K, Sato E, Ueki Y, Saito K, Nagaoka S, et al. Continuation of 4312

methotrexate resulted in better clinical and radiographic outcomes than discontinuation upon 4313

starting etanercept in patients with rheumatoid arthritis: 52-week results from the JESMR study. 4314

The Journal of rheumatology. 2011;38:1585-92. 4315

49. Kameda H, Ueki Y, Saito K, Nagaoka S, Hidaka T, Atsumi T, et al. Etanercept (ETN) 4316

with methotrexate (MTX) is better than ETN monotherapy in patients with active rheumatoid 4317

arthritis despite MTX therapy: a randomized trial. Mod Rheumatol. 2010;20:531-8. 4318

50. Kaneko Y, Atsumi T, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, et al. 4319

Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with 4320

285

rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a 4321

prospective, randomised, controlled study (SURPRISE study). Ann Rheum Dis. 2016. 4322

51. Kavanaugh A, St Clair EW, McCune WJ, Braakman T, Lipsky P. Chimeric anti-tumor 4323

necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis 4324

receiving methotrexate therapy. The Journal of rheumatology. 2000;27:841-50. 4325

52. Kay J, Matteson EL, Dasgupta B, Nash P, Durez P, Hall S, et al. Golimumab in patients 4326

with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-4327

blind, placebo-controlled, dose-ranging study. Arthritis and rheumatism. 2008;58:964-75. 4328

53. Kennedy WP, Simon JA, Offutt C, Horn P, Herman A, Townsend MJ, et al. Efficacy and 4329

safety of pateclizumab (anti-lymphotoxin-alpha) compared to adalimumab in rheumatoid 4330

arthritis: a head-to-head phase 2 randomized controlled study (The ALTARA Study). Arthritis 4331

Res Ther. 2014;16(5):467. 4332

54. Keystone E, Genovese MC, Klareskog L, Hsia EC, Hall S, Miranda PC, et al. 4333

Golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: 52-week 4334

results of the GO-FORWARD study. Annals of the rheumatic diseases. 2010;69(6):1129-35. 4335

55. Keystone E, Heijde D, Mason D, Jr., Landewe R, Vollenhoven RV, Combe B, et al. 4336

Certolizumab pegol plus methotrexate is significantly more effective than placebo plus 4337

methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, 4338

randomized, double-blind, placebo-controlled, parallel-group study. Arthritis and rheumatism. 4339

2008;58:3319-29. 4340

56. Keystone EC, Genovese MC, Klareskog L, Hsia EC, Hall ST, Miranda PC, et al. 4341

Golimumab, a human antibody to tumour necrosis factor 263 given by monthly subcutaneous 4342

injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD 4343

Study. Annals of the rheumatic diseases. 2009;68:789-96. 4344

57. Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, et al. 4345

Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-4346

tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving 4347

concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis 4348

and rheumatism. 2004;50:1400-11. 4349

58. Keystone EC, Pope JE, Thorne JC, Poulin-Costello M, Phan-Chronis K, Vieira A, et al. 4350

Two-year radiographic and clinical outcomes from the Canadian Methotrexate and Etanercept 4351

Outcome study in patients with rheumatoid arthritis. Rheumatology (Oxford). 2016;55:327-34. 4352

59. Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, et al. 4353

Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had 4354

an inadequate response to methotrexate. Ann Rheum Dis. 2015;74:333-40. 4355

286

60. Kim HY, Hsu PN, Barba M, Sulaiman W, Robertson D, Vlahos B, et al. Randomized 4356

comparison of etanercept with usual therapy in an Asian population with active rheumatoid 4357

arthritis: The APPEAL trial. Int J Rheum Dis. 2012;15:188-96. 4358

61. Kim HY, Lee SK, Song YW, Yoo DH, Koh EM, Yoo B, et al. A randomized, double-blind, 4359

placebo-controlled, phase III study of the human anti-tumor necrosis factor antibody 4360

adalimumab administered as subcutaneous injections in Korean rheumatoid arthritis patients 4361

treated with methotrexate. APLAR Journal of Rheumatology. 2007;10:9-16. 4362

62. Kim J, Ryu H, Yoo DH, Park SH, Song GG, Park W, et al. A clinical trial and extension 4363

study of infliximab in Korean patients with active rheumatoid arthritis despite methotrexate 4364

treatment. Journal of Korean medical science. 2013;28:1716-22. 4365

63. Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. 4366

Therapeutic effect of the combination of etanercept and methotrexate compared with each 4367

treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. 4368

Lancet. 2004;363:675-81. 4369

64. Knudsen LS, Hetland ML, Johansen JS, Skjodt H, Peters ND, Colic A, et al. Changes in 4370

plasma IL-6, plasma VEGF and serum YKL-40 during Treatment with Etanercept and 4371

Methotrexate or Etanercept alone in Patients with Active Rheumatoid Arthritis Despite 4372

Methotrexate Therapy. Biomark Insights. 2009;4:91-5. 4373

65. Kremer J, Ritchlin C, Mendelsohn A, Baker D, Kim L, Xu Z, et al. Golimumab, a new 4374

human anti-tumor necrosis factor alpha antibody, administered intravenously in patients with 4375

active rheumatoid arthritis: Forty-eight-week efficacy and safety results of a phase III 4376

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66. Kremer JM, Blanco R, Brzosko M, Burgos-Vargas R, Halland AM, Vernon E, et al. 4378

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4658

4659

295

APPENDIX 4: LIST OF EXCLUDED STUDIES (WITH REASONS)

First Author Year Reference Reason for Exclusion

Alam 2012 Alam MK, Sutradhar SR, Pandit H, Ahmed S, Bhattacharjee M, Miah AH, et al. Comparative study on methotrexate and hydroxychloroquine in the treatment of rheumatoid arthritis. Mymensingh Med J. 2012;21:391-8.

Wrong population

Aletaha 2017 Aletaha D, Bingham CO, Tanaka Y, Agarwal P, Kurrasch R, Tak PP, et al. Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): A randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3 study. The Lancet. 2017;(no.

Wrong population

Alten 2010 Alten RE, Zerbini C, Jeka S, Irazoque F, Khatib F, Emery P, et al. Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy. Ann Rheum Dis. 2010;69:364-7.

Wrong intervention

Alten 2011 Alten R, Gomez-Reino J, Durez P, Beaulieu A, Sebba A, Krammer G, et al. Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, Phase II, dose-finding study. BMC Musculoskelet Disord. 2011;12:153, 2011 Jul 07.

Wrong intervention

Andersen 1985 Andersen PA, West SG, Dell JRO, Via CS, Claypool RG, Kotzin BL. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Annals of internal medicine. 1985;103:489-96.

Wrong population

Asahina 2016 Asahina A, Etoh T, Igarashi A, Imafuku S, Saeki H, Shibasaki Y, et al. Oral tofacitinib efficacy, safety and tolerability in Japanese patients with moderate to severe plaque psoriasis and psoriatic arthritis: A randomized, double-blind, phase 3 study. J Dermatol. 2016.

Wrong population

Atsumi 2016 Atsumi T, Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro N, Tanaka Y, et al. The first double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naive early rheumatoid arthritis patients with poor prognostic factors, C-OPERA, shows inhibition of radiographic progression. Ann Rheum Dis. 2016;75:75-83.

Wrong population

Atsumi 2017 Atsumi T, Tanaka Y, Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro N, et al. Clinical benefit of 1-year certolizumab pegol (CZP) add-on therapy to methotrexate treatment in patients with early rheumatoid arthritis was observed following CZP discontinuation: 2-year results of the C-OPERA study, a phase III randomised trial.

Wrong population

296


Ann Rheum Dis. 2017.

Bao 2003 Bao C, Chen S, Gu Y, Lao Z, Ni L, Yu Q, et al. Leflunomide, a new disease-modifying drug for treating active rheumatoid arthritis in methotrexate-controlled phase II clinical trial. Chinese medical journal. 2003;116:1228-34.

Wrong population

Bathon 2003 Bathon JM, Genovese MC. The Early Rheumatoid Arthritis (ERA) trial comparing the efficacy and safety of etanercept and methotrexate. Clin Exp Rheumatol. 2003;21:S195-S7.

Wrong population

Bay-Jensen 2014 Bay-Jensen AC, Platt A, Byrjalsen I, Vergnoud P, Christiansen C, Karsdal MA. Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium, cartilage, and bone in the LITHE study. Semin Arthritis Rheum. 2014;43:470-8.

Wrong study design

Bijlsma 2016 Bijlsma JW, Welsing PM, Woodworth TG, Middelink LM, Petho-Schramm A, Bernasconi C, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016.

Wrong population

Bissell 2016 Bissell LA, Hensor EM, Kozera L, Mackie SL, Burska AN, Nam JL, et al. Improvement in insulin resistance is greater when infliximab is added to methotrexate during intensive treatment of early rheumatoid arthritis-results from the IDEA study. Rheumatology (Oxford). 2016.

Wrong population

Blanco 2017 Blanco FJ, Moricke R, Dokoupilova E, Codding C, Neal J, Andersson M, et al. Secukinumab in active rheumatoid arthritis: A randomized, double-blind placebo and active comparator controlled phase 3 study. Arthritis Rheumatol. 2017.

Wrong population

Braun 2008 Braun J, Kastner P, Flaxenberg P, Wahrisch J, Hanke P, Demary W, et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis and rheumatism. 2008;58:73-81.

Wrong population

Bresnihan 1998 Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis and rheumatism. 1998;41:2196-204.

Wrong population

Burmester 2016 Burmester GR, Rubbert-Roth A, Cantagrel A, Hall S, Leszczynski P, Feldman D, et al. Efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA). Ann Rheum Dis. 2016;75:68-74.

Wrong comparator

297


Burmester 2013 Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda B, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381:451-60.

Wrong population

Burmester 2011 Burmester GR, Feist E, Kellner H, Braun J, Iking-Konert C, Rubbert-Roth A. Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: The first phase IIIb real-life study (TAMARA). Ann Rheum Dis. 2011;70:755-9.

Wrong study design

Burmester 2014 Burmester GR, Rubbert-Roth A, Cantagrel A, Hall S, Leszczynski P, Feldman D, et al. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Annals of the rheumatic diseases. 2014;73:69-74.

Wrong intervention

Burmester 2013 Burmester GR, Weinblatt ME, McInnes IB, Porter D, Barbarash O, Vatutin M, et al. Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis. Ann Rheum Dis. 2013;72:1445-52.

Wrong intervention

Burmester 2017 Burmester GR, McInnes IB, Kremer J, Miranda P, Korkosz M, Vencovsky J, et al. A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2017.

Wrong intervention

Buttgereit 2013 Buttgereit F, Mehta D, Kirwan J, Szechinski J, Boers M, Alten RE, et al. Low-dose prednisone chronotherapy for rheumatoid arthritis: A randomised clinical trial (CAPRA-2). Ann Rheum Dis. 2013;72:204-10.

Wrong intervention

Calguneri 1999 Calguneri M, Pay S, Caliskaner Z, Apras S, Kiraz S, Ertenli I, et al. Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. Clin Exp Rheumatol. 1999;17:699-704.

Wrong population

Capell 2007 Capell HA, Madhok R, Porter DR, Munro RA, McInnes IB, Hunter JA, et al. Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study. Ann Rheum Dis. 2007;66:235-41.

Wrong population

Cardiel 2010 Cardiel MH, Tak PP, Bensen W, Burch FX, Forejtova S, Badurski JE, et al. A phase 2 randomized, double-blind study of AMG 108, a fully human monoclonal antibody to IL-

Wrong intervention

298


1R, in patients with rheumatoid arthritis. Arthritis Res Ther. 2010;12:R192, 2010.

Carubbi 2015 Carubbi F, Zugaro L, Cipriani P, Conchiglia A, Gregori L, Danniballe C, et al. Safety and efficacy of intra-articular anti-tumor necrosis factor alpha agents compared to corticosteroids in a treat-to-target strategy in patients with inflammatory arthritis and monoarthritis flare. International Journal of Immunopathology and Pharmacology. 2015;29:252-66.

Wrong intervention

Charles-Schoeman

2016 Charles-Schoeman C, Wang X, Lee YY, Shahbazian A, Navarro-Millan I, Yang S, et al. Association of Triple Therapy With Improvement in Cholesterol Profiles Over Two-Year Followup in the Treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis rheumatol. 2016;68:577-86.

Wrong population

Charles-Schoeman

2015 Charles-Schoeman C, Burmester G, Nash P, Zerbini CA, Soma K, Kwok K, et al. Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2015.

Wrong study design

Charles-Schoeman

2017 Charles-Schoeman C, Yin LY, Shahbazian A, Wang X, Elashoff D, Curtis JR, et al. Improvement of High-Density Lipoprotein Function in Patients With Early Rheumatoid Arthritis Treated With Methotrexate Monotherapy or Combination Therapies in a Randomized Controlled Trial. Arthritis rheumatol. 2017;69:46-57.

Wrong population

Chatzidionysiou

2016 Chatzidionysiou K, Turesson C, Teleman A, Knight A, Lindqvist E, Larsson P, et al. A multicentre, randomised, controlled, open-label pilot study on the feasibility of discontinuation of adalimumab in established patients with rheumatoid arthritis in stable clinical remission. Rmd open. 2016;2:e000133, 2016.

Wrong population

Chopra 2016 Chopra A, Chandrashekara S, Iyer R, Rajasekhar L, Shetty N, Veeravalli SM, et al. Itolizumab in combination with methotrexate modulates active rheumatoid arthritis: safety and efficacy from a phase 2, randomized, open-label, parallel-group, dose-ranging study. Clin Rheumatol. 2016;35:1059-64.

Wrong intervention

Choy 2013 Choy EH, Bendit M, McAleer D, Liu F, Feeney M, Brett S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of an anti- oncostatin M monoclonal antibody in rheumatoid arthritis: results from phase II randomized, placebo-controlled trials. Arthritis Res Ther. 2013;15:R132, 2013.

Wrong intervention

Clegg 1997 Clegg DO, Dietz F, Duffy J, Willkens RF, Hurd E, Germain BF, et al. Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine. J Rheumatol. 1997;24:1896-902.

Wrong population

299


Cohen 2016 Cohen SB, Koenig A, Wang L, Kwok K, Mebus CA, Riese R, et al. Efficacy and safety of tofacitinib in US and non-US rheumatoid arthritis patients: pooled analyses of phase II and III. Clin Exp Rheumatol. 2016;34:32-6.

Wrong study design

Cohen 2006 Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis and rheumatism. 2006;54:2793-806.

Wrong population

Cohen 2010 Cohen SB, Keystone E, Genovese MC, Emery P, Peterfy C, Tak PP, et al. Continued inhibition of structural damage over 2 years in patients with rheumatoid arthritis treated with rituximab in combination with methotrexate. Ann Rheum Dis. 2010;69:1158-61.

Wrong study design

Combe 2016 Combe B, Furst DE, Keystone EC, Heijde Dvd, Luijtens K, Ionescu L, et al. Certolizumab Pegol Efficacy Across Methotrexate Regimens: A Pre-Specified Analysis of Two Phase III Trials. Arthritis Care Res (Hoboken). 2016;68:299-307.

Wrong population

Combe 2014 Combe B, Dasgupta B, Louw I, Pal S, Wollenhaupt J, Zerbini CA, et al. Efficacy and safety of golimumab as add-on therapy to disease-modifying antirheumatic drugs: results of the GO-MORE study. Ann Rheum Dis. 2014;73:1477-86.

Wrong population

Coombs 2010 Coombs JH, Bloom BJ, Breedveld FC, Fletcher MP, Gruben D, Kremer JM, et al. Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial. Annals of the rheumatic diseases. 2010;69:413-6.

<12 weeks

Cuomo 2006 Cuomo G, Molinaro G, La Montagna G, Migliaresi S, Valentini G. [A comparison between the Simplified Disease Activity Index (SDAI) and the Disease Activity Score (DAS28) as measure of response to treatment in patients undergoing different therapeutic regimens]. Reumatismo. 2006;58:22-5.

Non-English

Curtis 2016 Curtis JR, Lee EB, Kaplan IV, Kwok K, Geier J, Benda B, et al. Tofacitinib, an oral Janus kinase inhibitor: Analysis of malignancies across the rheumatoid arthritis clinical development programme. Ann Rheum Dis. 2016;75:831-41.

Wrong study design

Curtis 2015 Curtis JR, Churchill M, Kivitz A, Samad A, Gauer L, Gervitz L, et al. A Randomized Trial Comparing Disease Activity Measures for the Assessment and Prediction of Response in Rheumatoid Arthritis Patients Initiating Certolizumab Pegol. Arthritis

Wrong intervention

300


rheumatol. 2015;67:3104-12.

Dale 2016 Dale J, Stirling A, Zhang R, Purves D, Foley J, Sambrook M, et al. Targeting ultrasound remission in early rheumatoid arthritis: the results of the TaSER study, a randomised clinical trial. Ann Rheum Dis. 2016.

Wrong population

Damjanov 2016 Damjanov N, Tlustochowicz M, Aelion J, Greenwald M, Diehl A, Bhattacharya I, et al. Safety and Efficacy of SBI-087, a Subcutaneous Agent for B Cell Depletion, in Patients with Active Rheumatoid Arthritis: Results from a Phase II Randomized, Double-blind, Placebo-controlled Study. J Rheumatol. 2016;43:2094-100.

Wrong intervention

Das 2007 Das SK, Pareek A, Mathur DS, Wanchu A, Srivastava R, Agarwal GG, et al. Efficacy and safety of hydroxychloroquine sulphate in rheumatoid arthritis: a randomized, double-blind, placebo controlled clinical trial--an Indian experience. Curr Med Res Opin. 2007;23:2227-34.

Wrong population

Das 2014 Das S, Vital EM, Horton S, Bryer D, El-Sherbiny Y, Rawstron AC, et al. Abatacept or tocilizumab after rituximab in rheumatoid arthritis? An exploratory study suggests non-response to rituximab is associated with persistently high IL-6 and better clinical response to IL-6 blocking therapy. Ann Rheum Dis. 2014;73:909-12.

Wrong study design

de Jong 2013 de Jong PH, Hazes JM, Barendregt PJ, Huisman M, van ZD, van der Lubbe PA, et al. Induction therapy with a combination of DMARDs is better than methotrexate monotherapy: first results of the tREACH trial. Ann Rheum Dis. 2013;72:72-8.

Wrong population

De Stefano 2010 De Stephano R, Frati E, Nargi F, Baldi C, Menza L, Hammoud M, et al. Comparison of combination therapies in the treatment of rheumatoid arthritis: leflunomide-anti-TNF-alpha versus methotrexate-anti-TNF-alpha. Clin Rheumatol. 2010;29:517-24.

Wrong intervention

den Broeder 2002 den Broeder A, van de Putte L, Rau R, Schattenkirchner M, Van Riel P, Sander O, et al. A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis. The Journal of rheumatology. 2002;29:2288-98.

<12 weeks

Dhaon 2016 Dhaon P, Das SK, Srivastava R, Agarwal G, Asthana A. Oral Methotrexate in split dose weekly versus oral or parenteral Methotrexate once weekly in Rheumatoid Arthritis: a short-term study. Int J Rheum Dis. 2016.

Wrong comparator

Dhir 2014 Dhir V, Singla M, Gupta N, Goyal P, Sagar V, Sharma A, et al. Randomized controlled trial comparing 2 different starting doses of methotrexate in rheumatoid arthritis. Clin Ther. 2014;36:1005-15.

Wrong intervention

Dougados 2015 Dougados M, Huizinga TW, Choy EH, Bingham CO, Aassi M, Bernasconi C. Wrong study

301


Evaluation of the Disease Activity Score in Twenty-Eight Joints-Based Flare Definitions in Rheumatoid Arthritis: Data From a Three-Year Clinical Trial. Arthritis Care Res (Hoboken). 2015;67:1762-6.

design

Dougados 2014 Dougados MR, Heijde DMvd, Brault Y, Koenig AS, Logeart IS. When to adjust therapy in patients with rheumatoid arthritis after initiation of etanercept plus methotrexate or methotrexate alone: findings from a randomized study (COMET). J Rheumatol. 2014;41:1922-34.

Wrong population

Dougados 2005 Dougados M, Emery P, Lemmel EM, Zerbini CA, Brin S, van RP. When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide? Ann Rheum Dis. 2005;64:44-51.

Wrong population

Dumitru 2016 Dumitru RB, Horton S, Hodgson R, Wakefield RJ, Hensor EM, Emery P, et al. A prospective, single-centre, randomised study evaluating the clinical, imaging and immunological depth of remission achieved by very early versus delayed Etanercept in patients with Rheumatoid Arthritis (VEDERA). BMC Musculoskelet Disord. 2016;17:61, 2016.

Wrong population

Durez 2004 Durez P, Toukap AN, Lauwerys BR, Manicourt DH, Verschueren P, Westhovens R, et al. A randomised comparative study of the short term clinical and biological effects of intravenous pulse methylprednisolone and infliximab in patients with active rheumatoid arthritis despite methotrexate treatment. Ann Rheum Dis. 2004;63:1069-74.

Wrong intervention

Elmuntaser 2014 Elmuntaser K. Efficacy of leflunomide 100mg weekly compared to 10mg methotrexate weekly in patients with active rheumatoid arthritis. Clinical and experimental rheumatology. 2014;83:S43.

Conference abstract

Emery 2015 Emery P, Fleischmann RM, Strusberg I, Durez P, Nash P, Amante E, et al. Efficacy and safety of subcutaneous golimumab in methotrexate-naive patients with rheumatoid arthritis: 5-year results of the GO-BEFORE trial. Arthritis Care Res (Hoboken). 2015.

Wrong population

Emery 2015 Emery P, Bingham C, Burmester GR, Bykerk VP, Furst D, Mariette X, et al. Improvements in Workplace and Household Productivity Following 52 Weeks of Treatment with Certolizumab Pegol in Combination with Methotrexate in Dmard-Naive Patients with Severe, Active and Progressive Rheumatoid Arthritis: Results from the C-Early Randomized, Double-Blind, Controlled Phase 3 Study. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

Wrong population

302


2015;18:A710, 2015.

Emery 2015 Emery P, Bingham C, Burmester G, Bykerk V, Furst D, Mariette X, et al. Improvements in Patient-Reported outcomes Following 52 Weeks of Treatment with Certolizumab Pegol in Combination with Methotrexate in Dmard-Naive Patients with Severe, Active and Progressive Rheumatoid Arthritis: Results from the C-Early Randomized, Double-Blind, Controlled Phase 3 Study. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2015;18:A707-A8.

Wrong population

Emery 2014 Emery P, Fleischmann RM, Hsia EC, Xu S, Zhou Y, Baker D. Efficacy of golimumab plus methotrexate in methotrexate-naive patients with severe active rheumatoid arthritis. Clin Rheumatol. 2014;33:1239-46.

Wrong population

Emery 2014 Emery P, Hammoudeh M, FitzGerald O, Combe B, Martin-Mola E, Buch MH, et al. Sustained remission with etanercept tapering in early rheumatoid arthritis. N Engl J Med. 2014;371:1781-92.

Wrong population

Emery 2013 Emery P, Fleischmann RM, Doyle MK, Strusberg I, Durez P, Nash P, et al. Golimumab, a human anti-tumor necrosis factor monoclonal antibody, injected subcutaneously every 4 weeks in patients with active rheumatoid arthritis who had never taken methotrexate: 1-year and 2-year clinical, radiologic, and physical function findings of a phase III, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Care Res (Hoboken). 2013;65:1732-42.

Wrong population

Emery 2000 Emery P, Breedveld FC, Lemmel EM, Kaltwasser JP, Dawes PT, Gomor B, et al. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology. 2000;39:655-65.

Wrong population

Emery 2006 Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIb randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis and Rheumatism. 2006;54:1390-400.

Wrong population

Emery 2008 Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008;372:375-82.

Wrong population

Emery 2008 Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, et al. Wrong

303


IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Annals of the rheumatic diseases. 2008;67:1516-23.

population

Emery 2009 Emery P, Fleischmann RM, Moreland LW, Hsia EC, Strusberg I, Durez P, et al. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis and rheumatism. 2009;60:2272-83.

Wrong population

Emery 2010 Emery P, Breedveld F, van der HD, Ferraccioli G, Dougados M, Robertson D, et al. Two-year clinical and radiographic results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid arthritis: a two-year, double-blind, randomized study. Arthritis and Rheumatism. 2010;62:674-82.

Wrong population

Emery 2017 Emery P, Bingham CO, III, Burmester GR, Bykerk VP, Furst DE, Mariette X, et al. Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naive patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study. Ann Rheum Dis. 2017;76:96-104.

Wrong population

Eriksson 2016 Eriksson JK, Wallman JK, Miller H, Petersson IF, Ernestam S, Vivar N, et al. Infliximab versus Conventional Combination Treatment and 7-Year Work Loss in Early RA: Results of the Randomized Swefot Trial. Arthritis Care Res (Hoboken). 2016.

Wrong population

Esdaile 1995 Esdaile JM, Suissa S, Shiroky JB, Lamping D, Tsakonas E, Anderson D, et al. A randomized trial of hydroxychloroquine in early rheumatoid arthritis: The HERA study. Am J Med. 1995;98:156-68.

Wrong population

Faarvang 1993 Faarvang KL, Egsmose C, Kryger P, Podenphant J, Ingeman-Nielsen M, Hansen TM. Hydroxychloroquine and sulphasalazine alone and in combination in rheumatoid arthritis: a randomised double blind trial. Ann Rheum Dis. 1993;52:711-5.

Wrong population

Farr 1995 Farr M, Waterhouse L, Johnson AE, Kitas GD, Jubb RW, Bacon PA. A Double-blind controlled study comparing sulphasalazine with placebo in rheumatoid factor (RF)-negative rheumatoid arthritis. Clin Rheumatol. 1995;14:531-6.

Wrong population

Fautrel 2016 Fautrel B, Pham T, Alfaiate T, Gandjbakhch F, Foltz V, Morel J, et al. Step-down Wrong

304


strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study). Ann Rheum Dis. 2016;75:59-67.

population

Ferraccioli 2002 Ferraccioli GF, Gremese E, Tomietto P, Favret G, Damato R, Poi ED. Analysis of improvements, full responses, remission and toxicity in rheumatoid patients treated with step-up combination therapy (methotrexate, cyclosporin A, sulphasalazine) or monotherapy for three years. Rheumatology. 2002;41:892-8.

Wrong population

Ferraz 1994 Ferraz MB, Pinheiro GR, Helfenstein M, Albuquerque E, Rezende C, Roimicher L, et al. Combination therapy with methotrexate and chloroquine in rheumatoid arthritis. A multicenter randomized placebo-controlled trial. Scandinavian journal of rheumatology. 1994;23:231-6.

Wrong intervention

Fiehn 2007 Fiehn C, Jacki S, Heilig B, Lampe M, Wiesmuller G, Richter C, et al. Eight versus 16-week re-evaluation period in rheumatoid arthritis patients treated with leflunomide or methotrexate accompanied by moderate dose prednisone. Rheumatology international. 2007;27:975-9.

Wrong population

Fleicshmann 2006 Fleischmann RM, Tesser J, Schiff MH, Schechtman J, Burmester GR, Bennett R, et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Annals of the rheumatic diseases. 2006;65:1006-12.

Wrong study design

Fleischmann 2016 Fleischmann R, Connolly SE, Maldonado MA, Schiff M. Estimating disease activity using multi-biomarker disease activity scores in patients with rheumatoid arthritis treated with abatacept or adalimumab. Arthritis Rheumatol. 2016.

Wrong study design

Fleischmann 2014 Fleischmann R, Goldman JA, Leirisalo-Repo M, Zanetakis E, El-Kadi H, Kellner H, et al. Infliximab efficacy in rheumatoid arthritis after an inadequate response to etanercept or adalimumab: results of a target-driven active switch study. Curr Med Res Opin. 2014;30:2139-49.

Wrong population

Fleischmann 2012 Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. The New England journal of medicine. 2012;367:495-507.

Wrong population

Fleischmann 2003 Fleischmann RM, Schechtman J, Bennett R, Handel ML, Burmester GR, Tesser J, et al. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis and rheumatism. 2003;48:927-34.

Wrong population

305


Fleischmann 2016 Fleischmann R, Strand V, Wilkinson B, Kwok K, Bananis E. Relationship between clinical and patient-reported outcomes in a phase 3 trial of tofacitinib or MTX in MTX-naive patients with rheumatoid arthritis. Rmd open. 2016;2:e000232.

Wrong population

Fleischmann 2016 Fleischmann R, van AJ, Lin Y, Castelar-Pinheiro GD, Brzezicki J, Hrycaj P, et al. Sarilumab and Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis and Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors. Arthritis rheumatol. 2017;69:277-90.

Wrong population

Fleischmann 2017 Fleischmann R, van AJ, Lin Y, Castelar-Pinheiro GD, Brzezicki J, Hrycaj P, et al. Sarilumab and Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis and Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors. Arthritis rheumatol. 2017;69:277-90.

Wrong population

Fleischmann 2017 Fleischmann R, Schiff M, van der HD, Ramos-Remus C, Spindler A, Stanislav M, et al. Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment. Arthritis rheumatol. 2017;69:506-17.

Wrong population

Fleishaker 2012 Fleishaker DL, Garcia Meijide JA, Petrov A, Kohen MD, Wang X, Menon S, et al. Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial. Arthritis Res Ther. 2012;14:R11, 2012.

Wrong intervention

Furst 1989 Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill I. Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. The Journal of rheumatology. 1989;16:313-20.

Wrong population

Furst 2007 Furst DE, Gaylis N, Bray V, Olech E, Yocum D, Ritter J, et al. Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept: the opposite study. Annals of the rheumatic diseases. 2007;66:893-9.

Wrong population

Genovese 2016 Genovese MC, Braun DK, Erickson JS, Berclaz PY, Banerjee S, Heffernan MP, et al. Safety and efficacy of open-label subcutaneous ixekizumab treatment for 48 weeks in a phase II study in biologic-naive and TNF-IR patients with rheumatoid arthritis. J Rheumatol. 2016;43:289-97.

Wrong intervention

Genovese 2016 Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016;374:1243-52.

Wrong population

Genovese 2016 Genovese MC, Vollenhoven RFv, Pacheco-Tena C, Zhang Y, Kinnman N. VX-509 Wrong

306


(Decernotinib), an Oral Selective JAK-3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis. Arthritis rheumatol. 2016;68:46-55.

intervention

Genovese 2004 Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis and rheumatism. 2004;50:1412-9.

Wrong intervention

Genovese 2011 Genovese MC, Covarrubias A, Leon G, Mysler E, Keiserman M, Valente R, et al. Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate. Arthritis and rheumatism. 2011;63:2854-64.

Wrong intervention

Genovese 2005 Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. The New England journal of medicine. 2005;353:1114-23.

Wrong population

Genovese 2008 Genovese MC, Schiff M, Luggen M, Becker JC, Aranda R, Teng J, et al. Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy. Annals of the rheumatic diseases. 2008;67:547-54.

Wrong population

Genovese 2016 Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, et al. Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate. Arthritis rheumatol. 2016;68:2857-66.

Wrong intervention

Genovese 2014 Genovese MC, Fleischmann R, Furst D, Janssen N, Carter J, Dasgupta B, et al. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study. Ann Rheum Dis. 2014;73:1607-15.

Wrong population

Gherghe 2016 Gherghe AM, Ramiro S, Landewe R, Mihai C, Heijde Dvd. Association of the different types of radiographic damage with physical function in patients with rheumatoid arthritis: analysis of the RAPID trials. Rmd open. 2016;2:e000219, 2016.

Wrong study design

Gottenberg 2016 Gottenberg JE, Brocq O, Perdriger A, Lassoued S, Berthelot JM, Wendling D, et al. NonTNF-targeted biologic vs a second anti-TNF drug to treat rheumatoid arthritis in patients with insufficient response to a first anti-TNF drug: A randomized clinical trial. JAMA - Journal of the American Medical Association. 2016;316:1172-80.

Wrong population

Greenwald 2011 Greenwald MW, Shergy WJ, Kaine JL, Sweetser MT, Gilder K, Linnik MD. Evaluation Wrong

307


of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: Results from a randomized controlled trial. Arthritis and Rheumatism. 2011;63:622-32.

intervention

Gubar 2008 Gubar EE, Bochkova AG, Bunchuk NV. [Comparison of efficacy and tolerability of triple combination therapy (methotrexate + sulfasalazine + hydroxychloroquine) with methotrexate monotherapy in patients with rheumatoid arthritis]. Terapevticheskii arkhiv. 2008;80:25-30.

Non-English

Haagsma 1994 Haagsma CJ, van Riel PL, de Rooij DJ, Vree TB, Russel FJ, van't Hof MA, et al. Combination of methotrexate and sulphasalazine vs methotrexate alone: a randomized open clinical trial in rheumatoid arthritis patients resistant to sulphasalazine therapy. Br J Rheumatol. 1994;33:1049-55.

Wrong population

Halland 2012 Halland AM. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate at one year - The LITHE study. European Musculoskeletal Review. 2012;7:108-11.

No PDF

Hanyu 1999 Hanyu T, Arai K, Ishikawa H. Long-term methotrexate (MTX) combination therapy versus MTX alone for active rheumatoid arthritis. Japanese Journal of Rheumatology. 1999;9:31-44.

Wrong population

Haschka 2016 Haschka J, Englbrecht M, Hueber AJ, Manger B, Kleyer A, Reiser M, et al. Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study. Ann Rheum Dis. 2016;75:45-51.

Wrong intervention

Hashimoto 2011 Hashimoto J, Garnero P, van der HD, Miyasaka N, Yamamoto K, Kawai S, et al. Humanized anti-interleukin-6-receptor antibody (tocilizumab) monotherapy is more effective in slowing radiographic progression in patients with rheumatoid arthritis at high baseline risk for structural damage evaluated with levels of biomarkers, radiography, and BMI: data from the SAMURAI study. Mod Rheumatol. 2011;21:10-5.

Wrong population

Heimans 2016 Heimans L, Akdemir G, Boer KV, Goekoop-Ruiterman YP, Molenaar ET, Groenendael JHv, et al. Two-year results of disease activity score (DAS)-remission-steered treatment strategies aiming at drug-free remission in early arthritis patients (the IMPROVED-study). Arthritis Res Ther. 2016;18:23, 2016.

Wrong population

Herwaarden 2015 Herwaarden Nv, Maas Avd, Minten MJ, Hoogen FHvd, Kievit W, Vollenhoven RFv, et al. Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised

Wrong population

308


controlled, non-inferiority trial. BMJ. 2015;350:h1389, 2015.

Hu 2001 Hu Y, Tu S, Liu P. A randomized, controlled, single-blind trial of leflunomide in the treatment of rheumatoid arthritis. Journal of Tongji Medical University = Tong ji yi ke da xue xue bao. 2001;21:72-4.

Wrong population

Huang 2012 Huang Z, Yang B, Shi Y, Cai B, Li Y, Feng W, et al. Anti-TNF-alpha therapy improves Treg and suppresses Teff in patients with rheumatoid arthritis. Cellular immunology. 2012;279:25-9.

Wrong population

Huang 2000 Bao C, Huang WSLC, Gu Y. Treatment of rheumatoid arthritis with leflunomide: a double blind, randomised controlled study. Clinical Journal of Rheumatology. 2000;4:44-6.

Non-English

Huffstutter 2017 Huffstutter JE, Kafka S, Brent LH, Matucci-Cerinic M, Tang KL, Chevrier M, et al. Clinical response to golimumab in rheumatoid arthritis patients who were receiving etanercept or adalimumab: results of a multicenter active treatment study. Curr Med Res Opin. 2017;()(pp:1-10.

Wrong population

Huizinga 2015 Huizinga TW, Conaghan PG, Martin-Mola E, Schett G, Amital H, Xavier RM, et al. Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study. Annals of the rheumatic diseases. 2015;74:35-43.

Wrong study design

Iannone 2014 Iannone F, La MG, Bagnato G, Gremese E, Giardina A, Lapadula G. Safety of etanercept and methotrexate in patients with rheumatoid arthritis and hepatitis C virus infection: a multicenter randomized clinical trial. J Rheumatol. 2014;41:286-92.

Wrong population

Ichikawa 2005 Ichikawa Y, Saito T, Yamanaka H, Akizuki M, Kondo H, Kobayashi S, et al. Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study. Mod Rheumatol. 2005;15:323-8.

Wrong intervention

Ishaq 2011 Ishaq M, Muhammad JS, Hameed K, Mirza AI. Leflunomide or methotrexate? Comparison of clinical efficacy and safety in low socio-economic rheumatoid arthritis patients. Mod Rheumatol. 2011;21:375-80.

Wrong population

Ishiguro 2013 Ishiguro N, Yamamoto K, Katayama K, Kondo M, Sumida T, Mimori T, et al. Concomitant iguratimod therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trial. Mod Rheumatol. 2013;23:430-9.

Wrong intervention

Islam 2000 Islam MN, Alam MN, Haq SA, Moyenuzzaman M, Patwary MI, Rahman MH. Efficacy Wrong

309


of sulphasalazine plus methotrexate in rheumatoid arthritis. Bangladesh Med Res Counc Bull. 2000;26:1-7.

population

Iwahashi 2014 Iwahashi M, Inoue H, Matsubara T, Tanaka T, Amano K, Kanamono T, et al. Efficacy, safety, pharmacokinetics and immunogenicity of abatacept administered subcutaneously or intravenously in Japanese patients with rheumatoid arthritis and inadequate response to methotrexate: a Phase II/III, randomized study. Mod Rheumatol. 2014;24:885-91.

Wrong comparator

Jaimes-Hernandez

2012 Jaimes-Hernandez J, Melendez-Mercado CI, Mendoza-Fuentes A, randa-Pereira P, Castaneda-Hernandez G. Efficacy of leflunomide 100mg weekly compared to low dose methotrexate in patients with active rheumatoid arthritis. Double blind, randomized clinical trial. Reumatol. 2012;clin.. 8:243-9.

Wrong population

Johnsen 2006 Johnsen AK, Schiff MH, Mease PJ, Moreland LW, Maier AL, Coblyn JS, et al. Comparison of 2 doses of etanercept (50 vs 100 mg) in active rheumatoid arthritis: a randomized double blind study. The Journal of rheumatology. 2006;33:659-64.

Wrong intervention

Jones 2010 Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Annals of the rheumatic diseases. 2009;69:88-96.

Wrong population

Joo 2012 Joo K, Heejung K, Lim MJ, Kwon SR, Park W. Safety and efficacy of TNFa inhibitor versus leflunomide in patients with rheumatoid arthritis inadequately responding to methotrexate in Korea. Int J Rheum Dis. 2012;15:53-4.

Conference abstract

Kaeley 2016 Kaeley GS, Evangelisto AM, Nishio MJ, Goss SL, Liu S, Kalabic J, et al. Methotrexate Dosage Reduction Upon Adalimumab Initiation: Clinical and Ultrasonographic Outcomes from the Randomized Noninferiority MUSICA Trial. J Rheumatol. 2016.

Wrong intervention

Kalden 2008 Kalden JR, Nusslein HG, Wollenhaupt J, Burmester GR, Kruger K, Antoni C. Combination treatment with infliximab and leflunomide in patients with active rheumatoid arthritis: safety and efficacy in an open-label clinical trial. Clin Exp Rheumatol. 2008;26:834-40.

Wrong study design

Kang 2012 Kang Ym Pw, Park YE, Choe JY, Bae SC, Cho CS, Shim SC, Lee SK, Suh CH, Cha HS, Song YW, You B, Lee SS, Lee SH, Park MC. Efficacy and safety of certolizumab pegol (CZP) with concomitant methotrexate (MTX) in Korean rheumatoid arthritis (RA) patients (pts) with an inadequate response to MTX. Ann Rheum Dis. 2012;71:666.

Conference abstract

Kavanaugh 2016 Kavanaugh A, Kremer J, Ponce L, Cseuz R, Reshetko OV, Stanislavchuk M, et al. Wrong

310


Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis. 2016.

intervention

Kay 2015 Kay J, Fleischmann R, Keystone E, Hsia EC, Hsu B, Mack M, et al. Golimumab 3-year safety update: an analysis of pooled data from the long-term extensions of randomised, double-blind, placebo-controlled trials conducted in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. Ann Rheum Dis. 2015;74:538-46.

Wrong study design

Kekow 2010 Kekow J, Moots RJ, Emery P, Durez P, Koenig A, Singh A, et al. Patient-reported outcomes improve with etanercept plus methotrexate in active early rheumatoid arthritis and the improvement is strongly associated with remission: the COMET trial. Ann Rheum Dis. 2010;69:222-5.

Wrong population

Keystone 2016 Keystone EC, Genovese MC, Hall S, Bae SC, Han C, Gathany TA, et al. Safety and Efficacy of Subcutaneous Golimumab in Patients with Active Rheumatoid Arthritis despite Methotrexate Therapy: Final 5-year Results of the GO-FORWARD Trial. J Rheumatol. 2016;43:298-306.

Wrong study design

Keystone 2014 Keystone E, Landewe R, Vollenhoven Rv, Combe B, Strand V, Mease P, et al. Long-term safety and efficacy of certolizumab pegol in combination with methotrexate in the treatment of rheumatoid arthritis: 5-year results from the RAPID 1 trial and open-label extension. Ann Rheum Dis. 2014;73:2094-100.

Wrong study design

Keystone 2014 Keystone EC, Anisfeld A, Ogale S, Devenport JN, Curtis JR. Continued benefit of tocilizumab plus disease-modifying antirheumatic drug therapy in patients with rheumatoid arthritis and inadequate clinical responses by week 8 of treatment. J Rheumatol. 2014;41:216-26.

Wrong population

Keystone 2004 Keystone EC, Schiff MH, Kremer JM, Kafka S, Lovy M, DeVries T, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis and rheumatism. 2004;50:353-63.

<12 weeks

Keystone 2007 Keystone E, Fleischmann R, Emery P, Furst DE, Vollenhoven Rv, Bathon J, et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis. Arthritis and rheumatism. 2007;56:3896-908.

Wrong study design

Keystone 2008 Keystone E, Burmester GR, Furie R, Loveless JE, Emery P, Kremer J, et al. Wrong

311


Improvement in patient-reported outcomes in a rituximab trial in patients with severe rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. Arthritis and rheumatism. 2008;59:785-93.

population

Keystone 2009 Keystone E, Emery P, Peterfy CG, Tak PP, Cohen S, Genovese MC, et al. Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies. Ann Rheum Dis. 2009;68:216-21.

Wrong population

Kivitz 2014 Kivitz A, Olech E, Borofsky M, Zazueta BM, Navarro-Sarabia F, Radominski SC, et al. Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2014;66:1653-61.

Wrong population

Kivitz 2016 Kivitz AJ, Gutierrez-Urena SR, Poiley J, Genovese MC, Kristy R, Shay K, et al. Peficitinib, a JAK inhibitor, in the treatment of moderate-to-severe rheumatoid arthritis in methotrexate-inadequate responders. Arthritis Rheumatol. 2016.

Wrong intervention

Klarenbeek 2011 Klarenbeek NB, Guler-Yuksel M, Kooij SMVD, Han KH, Ronday HK, Kerstens PJSM, et al. The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study. Ann Rheum Dis. 2011;70:1039-46.

Wrong population

Klareskog 2006 Klareskog L, Gaubitz M, Rodriguez-Valverde V, Malaise M, Dougados M, Wajdula J, et al. A long-term, open-label trial of the safety and efficacy of etanercept (Enbrel) in patients with rheumatoid arthritis not treated with other disease-modifying antirheumatic drugs. Annals of the rheumatic diseases. 2006;65:1578-84.

Wrong study design

Konijn 2016 Konijn NP, van Tuyl LH, Boers M, van dV, den UD, ter Wee MM, et al. The short-term effects of two high-dose, step-down prednisolone regimens on body composition in early rheumatoid arthritis. Rheumatology (Oxford). 2016.

Wrong population

Kraan 2000 Kraan MC, Reece RJ, Barg EC, Smeets TJ, Farnell J, Rosenburg R, et al. Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers. Arthritis and Rheumatism. 2000;43:1820-30.

Wrong population

Kremer 2016 Kremer JM, Blanco R, Halland AM, Brzosko M, Burgos-Vargas R, Mela CM, et al. Clinical efficacy and safety maintained up to 5 years in patients with rheumatoid arthritis treated with tocilizumab in a randomised trial. Clin Exp Rheumatol. 2016.

Wrong study design

312


Kremer 2015 Kremer JM, Kivitz AJ, Simon-Campos JA, Nasonov EL, Tony HP, Lee SK, et al. Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial. Arthritis Res Ther. 2015;17:95, 2015.

<12 weeks

Kremer 2002 Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2002;137:726-33.

<12 weeks

Kremer 2009 Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis and rheumatism. 2009;60:1895-905.

<12 weeks

Kremer 2013 Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Annals of internal medicine. 2013;159:253-61.

Wrong population

Kremer 2003 Kremer JM, Weinblatt ME, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Jackson CG, et al. Etanercept added to background methotrexate therapy in patients with rheumatoid arthritis: continued observations. Arthritis and rheumatism. 2003;48:1493-9.

Wrong study design

Kremer 2016 Kremer JM, Emery P, Camp HS, Friedman A, Wang L, Othman AA, et al. A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy. Arthritis rheumatol. 2016;68:2867-77.

Wrong intervention

Lazzerini 2008 Lazzerini PE, Acampa M, Hammoud M, Maffei S, Capecchi PL, Selvi E, et al. Arrhythmic risk during acute infusion of infliximab: A prospective, single-blind, placebo-controlled, crossover study in patients with chronic arthritis. J Rheumatol. 2008;35:1958-65.

Wrong population

Lee 2014 Lee EB, Fleischmann R, Hall S, Wilkinson B, Bradley JD, Gruben D, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370:2377-86.

Wrong population

Li 2013 Li Z, Zhang F. Kay J. et al. Safety and efficacy of subcutaneous golimumab in Chinese patients with active rheumatoid arthritis despite MTX therapy: Results from a randomized, placebo-

Conference abstract

313


controlled, phase 3 trial. Ann Rheum Dis. 2013;72.

Li 2016 Li R, Zhao JX, Su Y, He J, Chen LN, Gu F, et al. High remission and low relapse with prolonged intensive DMARD therapy in rheumatoid arthritis (PRINT): A multicenter randomized clinical trial. Medicine (Baltimore). 2016;95:e3968, 2016.

Wrong population

Lindegaard 2016 Lindegaard HM, Johansen P, Grondal G, Jensen EC, Juul L, Schlemmer AM, et al. Doubling the single-dose infusion rate of tocilizumab in rheumatoid arthritis is safe and efficacious. Scand J Rheumatol. 2016:1-5.

Wrong comparator

Lisbona 2010 Lisbona MP, Maymo J, Perich J, Almirall M, Carbonell J. Rapid reduction in tenosynovitis of the wrist and fingers evaluated by MRI in patients with rheumatoid arthritis after treatment with etanercept. Annals of the rheumatic diseases. 2010;69:1117-22.

<12 weeks

Lunzer 2016 Lunzer R. Baricitinib, methotrexate, or baricitinib plus methotrexate in patients with early rheumatoid arthritis who had received limited or no treatment with disease-modifying anti-rheumatic drugs (DMARDs): Phase 3 trial results: Kommentar. Journal fur Mineralstoffwechsel. 2016;23:28.

Non-English

Machado 2016 Machado DA, Guzman R, Xavier RM, Simon JA, Mele L, Shen Q, et al. Two-Year Safety and Efficacy Experience in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Treated with Etanercept and Conventional Disease-Modifying Anti-rheumatic Drugs in the Latin American Region. Open Rheumatol J. 2016;10:13-25, 2016.:25.

Wrong study design

Mariette 2014 Mariette X, Rouanet S, Sibilia J, Combe B, Loet XL, Tebib J, et al. Evaluation of low-dose rituximab for the retreatment of patients with active rheumatoid arthritis: a non-inferiority randomised controlled trial. Ann Rheum Dis. 2014;73:1508-14.

Wrong comparator

Markusse 2016 Markusse IM, Akdemir G, Dirven L, Goekoop-Ruiterman YP, Groenendael JHv, Han KH, et al. Long-Term Outcomes of Patients With Recent-Onset Rheumatoid Arthritis After 10 Years of Tight Controlled Treatment: A Randomized Trial. Ann Intern Med. 2016;164:523-31.

Wrong population

Martin 2013 Martin DA, Churchill M, Flores-Suarez L, Cardiel MH, Wallace D, Martin R, et al. A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis. Arthritis Res Ther. 2013;15:R164, 2013.

Wrong intervention

Mathur 2016 Mathur R, Singh H, Arya S, Singh V. Comparative evaluation of efficacy of leflunomide versus combination of methotrexate and hydroxychloroquine in patients of

Wrong population

314


rheumatoid arthritis - An Indian experience. Indian Journal of Rheumatology. 2016;11:86-90.

Matsubara 2012 Matsubara T Ih, Iwahashi M, Yamazaki A, Takeuchi T, the Japan Abatacept Study Group. A multi-center, double-dummy, double-blind study of subcutaneous (sc) abatacept (aba) compared with intravenous (iv) aba in Japanese rheumatoid arthritis patients with inadequate response to methotrexate. Ann Rheum Dis. 2012;71:197.

Conference abstract

Matsubara 2013 Matsubara T, Yamana S, Tohma S, Takeuchi T, Kondo H, Kohsaka H, et al. Tolerability and efficacy of abatacept in Japanese patients with rheumatoid arthritis: a phase I study. Mod Rheumatol. 2013;23:634-45.

Wrong comparator

McInnes 2015 McInnes IB, Thompson L, Giles JT, Bathon JM, Salmon JE, Beaulieu AD, et al. Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Ann Rheum Dis. 2015;74:694-702.

Wrong population

Mease 2016 Mease P, Gottlieb AB, Berman A, Drescher E, Xing J, Wong R, et al. The Efficacy and Safety of Clazakizumab, an Anti-Interleukin-6 Monoclonal Antibody, in a Phase 2b Study of Adults with Active Psoriatic Arthritis. Arthritis Rheumatol. 2016.

Wrong population

Modi 2017 Modi JV, Patel KR, Patel ZM, Patel HR, Dhanani SS, Shah BH. Dose response relationship of hydroxychloroquine sulphate in the treatment of rheumatoid arthritis: A randomised control study. International Journal of Pharmaceutical Sciences and Research. 2017;8:856-8.

<12 weeks

Nash 2016 Nash P, Vanhoof J, Hall S, Arulmani U, Tarzynski-Potempa R, Unnebrink K, et al. Randomized Crossover Comparison of Injection Site Pain with 40 mg/0.4 or 0.8 mL Formulations of Adalimumab in Patients with Rheumatoid Arthritis. Rheumatol Ther. 2016.

<12 weeks

Navarro Coy 2014 Navarro Coy NC, Brown S, Bosworth A, Davies CT, Emery P, Everett CC, et al. The 'Switch' study protocol: A randomised-controlled trial of switching to an alternative tumour-necrosis factor (TNF)-inhibitor drug or abatacept or rituximab in patients with rheumatoid arthritis who have failed an initial TNF-inhibitor drug. BMC Musculoskelet Disord. 2014;15.

Wrong population

Ni 2001 Ni LLZ. Leflunomide in treating rheumatoid arthritis: a double-blind study. Chinese Journal of New Drugs and Clinical Remedies. 2001;20:94-7.

Non-English

Nikas 2006 Nikas SN, Voulgari PV, Alamanos Y, Papadopoulos CG, Venetsanopoulou AI, Wrong study

315


Georgiadis AN, et al. Efficacy and safety of switching from infliximab to adalimumab: A comparative controlled study. Ann Rheum Dis. 2006;65:257-60.

design

Nishimoto 2004 Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis and rheumatism. 2004;50:1761-9.

Wrong population

Nishimoto 2007 Nishimoto N, Hashimoto J, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Annals of the rheumatic diseases. 2007;66:1162-7.

Wrong population

Nishimoto 2009 Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J. Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study. Annals of the rheumatic diseases. 2009;68:1580-4.

Wrong study design

O'Dell 1996 O'Dell JR, Haire C, Erikson N, Drymalski W, Palmer W, Maloley P, et al. Efficacy of triple DMARD therapy in patients with RA with suboptimal response to methotrexate. J Rheumatol Suppl. 1996;44:72-4, 1996 Mar.:4.

Wrong study design

Ostergaard 2015 Ostergaard M, Jacobsson LT, Schaufelberger C, Hansen MS, Bijlsma JW, Dudek A, et al. MRI assessment of early response to certolizumab pegol in rheumatoid arthritis: a randomised, double-blind, placebo-controlled phase IIIb study applying MRI at weeks 0, 1, 2, 4, 8 and 16. Annals of the rheumatic diseases. 2015;74:1156-63.

<12 weeks

Ostergaard 2011 Ostergaard M, Emery P, Conaghan PG, Fleischmann R, Hsia EC, Xu W, et al. Significant improvement in synovitis, osteitis, and bone erosion following golimumab and methotrexate combination therapy as compared with methotrexate alone: a magnetic resonance imaging study of 318 methotrexate-naive rheumatoid arthritis patients. Arthritis and Rheumatism. 2011;63:3712-22.

Wrong population

Pal 2016 Pal S, Veeravalli SCM, Das SK, Shobha V, Uppuluri RR, Dharmanand BG, et al. Efficacy and safety of golimumab in Indian patients with rheumatoid arthritis: Subgroup data from GO-MORE study. Int J Rheum Dis. 2016;(no.

<12 weeks

Papp 2016 Papp K, Menter MA, Raman M, Disch D, Schlichting DE, Gaich C, et al. A Randomized Phase 2b Trial of Baricitinib, an Oral JAK1/JAK2 Inhibitor, in Patients

Wrong population

316


with Moderate-to-Severe Psoriasis. Br J Dermatol. 2016.

Pavelka 2014 Pavelka K, Burgos-Vargas R, Miranda P, Guzman R, Yen JH, Izzi MA, et al. Etanercept in moderate rheumatoid arthritis: PRESERVE study results from central/eastern Europe, Latin America and Asia. International Journal of Clinical Rheumatology. 2014;9:415-30.

Wrong population

Pavelka 2009 Pavelka K, Jarosova K, Suchy D, Senolt L, Chroust K, Dusek L, et al. Increasing the infliximab dose in rheumatoid arthritis patients: a randomised, double blind study failed to confirm its efficacy. Annals of the rheumatic diseases. 2009;68:1285-9.

Wrong comparator

Pescovitz 2009 Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. The New England journal of medicine. 2009;361:2143-52.

Wrong population

Peterfy 2016 Peterfy C, Burmester GR, Bykerk VP, Combe BG, DiCarlo JC, Furst DE, et al. Sustained improvements in MRI outcomes with abatacept following the withdrawal of all treatments in patients with early, progressive rheumatoid arthritis. Ann Rheum Dis. 2016.

Wrong population

Peterfy 2013 Peterfy CG, Olech E, DiCarlo JC, Merrill JT, Countryman PJ, Gaylis NB. Monitoring cartilage loss in the hands and wrists in rheumatoid arthritis with magnetic resonance imaging in a multi-center clinical trial: IMPRESS (NCT00425932). Arthritis Res Ther. 2013;15:R44, 2013.

Wrong study design

Pinals 1986 Pinals RS, Kaplan SB, Lawson JG, Hepburn B. Sulfasalazine in rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis and Rheumatism. 1986;29:1427-34.

Wrong population

Pincus 2003 Pincus T, Strand V, Koch G, Amara I, Crawford B, Wolfe F, et al. An index of the three core data set patient questionnaire measures distinguishes efficacy of active treatment from that of placebo as effectively as the American College of Rheumatology 20% response criteria (ACR20) or the Disease Activity Score (DAS) in a rheumatoid arthritis clinical trial. Arthritis and Rheumatism. 2003;48:625-30.

Wrong study design

Pinheiro 1993 Pinheiro GR, Helfenstein Junior M, Ferraz MB, Atra E. [A short-term randomized controlled study with methotrexate in rheumatoid arthritis]. Revista da Associacao Medica Brasileira. 1993;39:91-4.

Non-English

Poor 2004 Poor G, Strand V, Leflunomide Multinational Study G. Efficacy and safety of leflunomide 10 mg versus 20 mg once daily in patients with active rheumatoid arthritis: multinational double-blind, randomized trial. Rheumatology (Oxford). 2004;43:744-9.

Wrong study design

Porter 2016 Porter D, van MJ, Dale J, Messow CM, McConnachie A, Walker A, et al. Tumour Wrong

317


necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial. Lancet. 2016.

intervention

Quach 2016 Quach LT, Chang BH, Brophy MT, Soe TS, Hannagan K, O'Dell JR. Rheumatoid arthritis triple therapy compared with etanercept: difference in infectious and gastrointestinal adverse events. Rheumatology (Oxford). 2016.

Wrong population

Raffeiner 2015 Raffeiner B, Botsios C, Ometto F, Bernardi L, Stramare R, Todesco S, et al. Effects of half dose etanercept (25 mg once a week) on clinical remission and radiographic progression in patients with rheumatoid arthritis in clinical remission achieved with standard dose. Clin Exp Rheumatol. 2015;33:63-8.

Wrong study design

Ramirez-Lafita

2015 Ramirez-Lafita F. Disease activity- guided TNF inhibitor dose reduction was noninferior to continuing TNF inhibitors for RA flares. Ann Intern Med. 2015;163:JC9.

Conference abstract

Rau 2004 Rau R, Simianer S, van Riel PL, van de Putte LB, Kruger K, Schattenkirchner M, et al. Rapid alleviation of signs and symptoms of rheumatoid arthritis with intravenous or subcutaneous administration of adalimumab in combination with methotrexate. Scand J Rheumatol. 2004;33:145-53.

Wrong intervention

Reece 2002 Reece RJ, Kraan MC, Radjenovic A, Veale DJ, Connor PJO, Ridgway JP, et al. Comparative assessment of leflunomide and methotrexate for the treatment of rheumatoid arthritis, by dynamic enhanced magnetic resonance imaging. Arthritis and rheumatism. 2002;46:366-72.

Wrong population

Rubbert-Roth 2010 Rubbert-Roth A, Tak PP, Zerbini C, Tremblay JL, Carreno L, Armstrong G, et al. Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR). Rheumatology. 2010;49:1683-93.

Wrong comparator

Salaffi 1995 Salaffi F, Carotti M, Cervini C. Serum soluble interleukin-2 receptor levels in rheumatoid arthritis: effect of methotrexate, sulphasalazine and hydroxychloroquine therapy. Clinical rheumatology. 1995;14:458-63.

Wrong population

Salgado 2013 Salgado E, Gomez-Reino JJ. The JAK inhibitor tofacitinib for active rheumatoid arthritis: Results from Phase III trials. International Journal of Clinical Rheumatology. 2013;8:315-26.

Wrong study design

Santhanam 2015 Santhanam S, Sankaralingam R, Natesan TT, Mani M. Rituximab in biologically naive rheumatoid arthritis patients and methotrexate non-responders - An Indian experience. Indian Journal of Rheumatology. 2015;10:177-8.

Wrong intervention

318


Schiff 2016 Schiff M, Weinblatt ME, Valente R, Citera G, Maldonado M, Massarotti E, et al. Reductions in disease activity in the AMPLE trial: clinical response by baseline disease duration. Rmd open. 2016;2:e000210, 2016.

Wrong study design

Schiff 2004 Schiff MH, DiVittorio G, Tesser J, Fleischmann R, Schechtman J, Hartman S, et al. The safety of anakinra in high-risk patients with active rheumatoid arthritis: six-month observations of patients with comorbid conditions. Arthritis and rheumatism. 2004;50:1752-60.

Wrong study design

Schiff 2014 Schiff MH, von KJ, Goldblum R, Tesser JR, Mueller RB. Rheumatoid arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol: A phase IV, randomised, multicentre, double-blind, 12-week study, followed by a 12-week open-label phase. Ann Rheum Dis. 2014;73:2174-7.

Wrong population

Schiff 2009 Schiff M, Pritchard C, Huffstutter JE, Rodriguez-Valverde V, Durez P, Zhou X, et al. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. Ann Rheum Dis. 2009;68:1708-14.

Wrong population

Scott 2015 Scott DL, Ibrahim F, Farewell V, Keeffe AGO, Walker D, Kelly C, et al. Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial. BMJ. 2015;350:h1046, 2015.

Wrong intervention

Scott 2014 Scott DL, Ibrahim F, Farewell V, Keeffe AGO, Ma M, Walker D, et al. Randomised controlled trial of tumour necrosis factor inhibitors against combination intensive therapy with conventional disease-modifying antirheumatic drugs in established rheumatoid arthritis: the TACIT trial and associated systematic reviews. Health Technol Assess. 2014;18:i-xxiv.

Wrong intervention

Scott 2001 Scott DL, Smolen JS, Kalden JR, van de Putte LB, Larsen A, Kvien TK, et al. Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine. Ann Rheum Dis. 2001;60:913-23.

Wrong population

Shashikumar 2010 Shashikumar NS, Shivamurthy MC, Chandrashekara S. Evaluation of efficacy of combination of methotrexate and hydroxychloroquine with leflunomide in active rheumatoid arthritis. Indian journal of pharmacology. 2010;42:358-61.

Wrong population

Shim 2010 Shim S PSHBSC, et al. Efficacy and safety of abatacept in Korean patients with active Conference

319


rheumatoid arthritis and inadequate response to methotrexate: A phase III, multicenter, randomized, double-blind, placebocontrolled bridging study. Int J Rheum Dis. 2010;13:101.

abstract

Shuai 2002 Shuai Z, Liu S, Shun G, Xue J, Xue S. The phase II clinical trial of leflunomide in treatment of rheumatoid arthritis. Acta Universitatis Medicinalis Anhui. 2002;37:41-4.

Non-English

Singh 2012 Singh H, Mathur R, Arya S, et al. Comparison of efficacy of combination of methotrexate and hydroxychloroquine with leflunomide alone in patients of rheumatoid arthritis. Indian Journal of Rheumatology. 2012;7:S31.

Conference abstract

Smolen 2015 Smolen JS, Kay J, Doyle M, Landewe R, Matteson EL, Gaylis N, et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumor necrosis factor alpha inhibitors: findings with up to five years of treatment in the multicenter, randomized, double-blind, placebo-controlled, phase 3 GO-AFTER study. Arthritis Res Ther. 2015;17:14, 2015.

Wrong study design

Smolen 2014 Smolen JS, Kay J, Matteson EL, Landewe R, Hsia EC, Xu S, et al. Insights into the efficacy of golimumab plus methotrexate in patients with active rheumatoid arthritis who discontinued prior anti-tumour necrosis factor therapy: post-hoc analyses from the GO-AFTER study. Ann Rheum Dis. 2014;73:1811-8.

Wrong study design

Smolen 1999 Smolen JS. Efficacy and safety of the new DMARD leflunomide: comparison to placebo and sulfasalazine in active rheumatoid arthritis. Scand J Rheumatol Suppl. 1999;112:15-21, 1999.:21.

Wrong population

Smolen 1999 Smolen JS, Kalden JR, Scott DL, Rozman B, Kvien TK, Larsen A, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet. 1999;353:259-66.

Wrong population

Smolen 2013 Smolen JS, Nash P, Durez P, Hall S, Ilivanova E, Irazoque-Palazuelos F, et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet. 2013;381:918-29.

Wrong population

Smolen 2015 Smolen JS, Emery P, Ferraccioli GF, Samborski W, Berenbaum F, Davies OR, et al. Certolizumab pegol in rheumatoid arthritis patients with low to moderate activity: the CERTAIN double-blind, randomised, placebo-controlled trial. Annals of the rheumatic diseases. 2015;74:843-50.

Wrong population

320


Smolen 2009 Smolen JS, Kay J, Doyle MK, Landewe R, Matteson EL, Wollenhaupt J, et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet. 2009;374:210-21.

Wrong population

Smolen 2016 Smolen JS, Kremer JM, Gaich CL, DeLozier AM, Schlichting DE, Xie L, et al. Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON). Ann Rheum Dis. 2016.

Wrong population

Smolen 2013 Smolen JS, van der Heijde DM, Keystone EC, van Vollenhoven RF, Goldring MB, Guerette B, et al. Association of joint space narrowing with impairment of physical function and work ability in patients with early rheumatoid arthritis: protection beyond disease control by adalimumab plus methotrexate. Ann Rheum Dis. 2013;72:1156-62.

Wrong population

Smolen 2009 Smolen JS, Han C, van der Heijde DM, Emery P, Bathon JM, Keystone E, et al. Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade. Ann Rheum Dis. 2009;68:823-7.

Wrong population

Smolen 2017 Smolen JS, Agarwal SK, Ilivanova E, Xu XL, Miao Y, Zhuang Y, et al. A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. Ann Rheum Dis. 2017.

Wrong intervention

Stohl 2012 Stohl W, Gomez-Reino J, Olech E, Dudler J, Fleischmann RM, Zerbini CA, et al. Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: the phase III FILM trial. Ann Rheum Dis. 2012;71:1289-96.

Wrong intervention

Strand 2015 Strand V, Kremer J, Wallenstein G, Kanik KS, Connell C, Gruben D, et al. Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDs. Arthritis Res Ther. 2015;17:307, 2015.

Wrong population

Strand 2015 Strand V, Burmester GR, Zerbini CA, Mebus CA, Zwillich SH, Gruben D, et al. Tofacitinib with methotrexate in third-line treatment of patients with active rheumatoid arthritis: patient-reported outcomes from a phase III trial. Arthritis Care Res (Hoboken). 2015;67:475-83.

Wrong population

321


Strand 2005 Strand V, Scott DL, Emery P, Kalden JR, Smolen JS, Cannon GW, et al. Physical function and health related quality of life: analysis of 2-year data from randomized, controlled studies of leflunomide, sulfasalazine, or methotrexate in patients with active rheumatoid arthritis. J Rheumatol. 2005;32:590-601.

Wrong population

Strand 1999 Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G, et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Archives of internal medicine. 1999;159:2542-50.

Wrong population

Strand 2012 Strand V, Burmester GR, Ogale S, Devenport J, John A, Emery P. Improvements in health-related quality of life after treatment with tocilizumab in patients with rheumatoid arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week randomized controlled RADIATE study. Rheumatology (Oxford). 2012;51:1860-9.

Wrong population

Strand 2012 Strand V, Rentz AM, Cifaldi MA, Chen N, Roy S, Revicki D. Health-related quality of life outcomes of adalimumab for patients with early rheumatoid arthritis: results from a randomized multicenter study. J Rheumatol. 2012;39:63-72.

Wrong population

Strand 2016 Strand V, Lee EB, Fleischmann R, Alten RE, Koncz T, Zwillich SH, et al. Tofacitinib versus methotrexate in rheumatoid arthritis: patient-reported outcomes from the randomised phase III ORAL Start trial. Rmd open. 2016;2:e000308, 2016.

Wrong population

Strand 2016 Strand V, Kremer JM, Gruben D, Krishnaswami S, Zwillich SH, Wallenstein GV. Tofacitinib in Combination with Conventional synthetic DMARDs in Patients with Active Rheumatoid Arthritis: PROs from a Phase 3 Randomized Controlled Trial. Arthritis Care Res (Hoboken). 2016.

Wrong population

Tada 2012 Tada M, Koike T, Okano T, Sugioka Y, Wakitani S, Fukushima K, et al. Comparison of joint destruction between standard- and low-dose etanercept in rheumatoid arthritis from the Prevention of Cartilage Destruction by Etanercept (PRECEPT) study. Rheumatology. 2012;51:2164-9.

Wrong comparator

Takeuchi 2009 Takeuchi T, Miyasaka N, Inoue K, Abe T, Koike T, Rising s. Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study. Mod Rheumatol. 2009;19:478-87.

Wrong comparator

Tanaka 2016 Tanaka Y, Yamanaka H, Ishiguro N, Miyasaka N, Kawana K, Hiramatsu K, et al. Adalimumab discontinuation in patients with early rheumatoid arthritis who were

Wrong population

322


initially treated with methotrexate alone or in combination with adalimumab: 1 year outcomes of the HOPEFUL-2 study. Rmd open. 2016;2:e000189, 2016.

Tanaka 2016 Tanaka Y, Harigai M, Takeuchi T, Yamanaka H, Ishiguro N, Yamamoto K, et al. Prevention of joint destruction in patients with high disease activity or high C-reactive protein levels: Post hoc analysis of the GO-FORTH study. Mod Rheumatol. 2016;26:323-30.

Wrong study design

Tanaka 2015 Tanaka Y, Takeuchi T, Yamanaka H, Nakamura H, Toyoizumi S, Zwillich S. Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study. Mod Rheumatol. 2015;25:514-21.

Wrong population

Taylor 2011 Taylor PC, Quattrocchi E, Mallett S, Kurrasch R, Petersen J, Chang DJ. Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial. Ann Rheum Dis. 2011;70:2119-25.

Wrong intervention

Tesser 2004 Tesser J, Fleischmann R, Dore R, Bennett R, Solinger A, Joh T, et al. Concomitant Medication Use in a Large, International, Multicenter, Placebo Controlled Trial of Anakinra, a Recombinant Interleukin 1 Receptor Antagonist, in Patients with Rheumatoid Arthritis. J Rheumatol. 2004;31:649-54.

Wrong population

Thurmond 2016 Thurmond RL, Greenspan A, Radziszewski W, Xu XL, Miao Y, Chen B, et al. Toreforant, A Histamine H4 Receptor Antagonist, in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy: Results of 2 Phase II Studies. J Rheumatol. 2016.

Wrong intervention

Trnavsky 1993 Trnavsky K, Gatterova J, Linduskova M, Peliskova Z. Combination therapy with hydroxychloroquine and methotrexate in rheumatoid arthritis. Z Rheumatol. 1993;52:292-6.

Non-English

Ummarino 2016 Ummarino D. Rheumatoid arthritis: RA-BEACON illuminates baricitinib. Nature Reviews Rheumatology. 2016;12.

Wrong study design

Van De Putte 2004 Van De Putte LBA, Atkins C, Malaise M, Sany J, Russell AS, van Riel PLCM, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis. 2004;63:508-16.

<12 weeks

van der Heijde

1989 van der Heijde DM, van Riel PL, Nuver-Zwart IH, Gribnau FW, vad de Putte LB. Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet. 1989;1:1036-8.

Wrong population

323


van der Heijde

2007 van der Heijde D, Burmester G, Melo-Gomes J, Codreanu C, Mola EM, Pedersen R, et al. The safety and efficacy of adding etanercept to methotrexate or methotrexate to etanercept in moderately active rheumatoid arthritis patients previously treated with monotherapy. Annals of the rheumatic diseases. 2007;67:182-8.

Wrong study design

van Vollenhoven

2016 Vollenhoven RFv, Ostergaard M, Leirisalo-Repo M, Uhlig T, Jansson M, Larsson E, et al. Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis. Ann Rheum Dis. 2016;75:52-8.

Wrong population

van Vollenhoven

2011 van Vollenhoven RF, Kinnman N, Vincent E, Wax S, Bathon J. Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial. Arthritis and rheumatism. 2011;63:1782-92.

Wrong intervention

Verschueren 2015 Verschueren P, Cock DD, Corluy L, Joos R, Langenaken C, Taelman V, et al. Patients lacking classical poor prognostic markers might also benefit from a step-down glucocorticoid bridging scheme in early rheumatoid arthritis: week 16 results from the randomized multicenter CareRA trial. Arthritis Res Ther. 2015;17:97, 2015.

Wrong population

Verschueren 2017 Verschueren P, De CD, Corluy L, Joos R, Langenaken C, Taelman V, et al. Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial. Ann Rheum Dis. 2017;76:511-20.

Wrong population

Wada 2012 Wada T, Son Y, Ozaki Y, Nomura S, Iida H. Clinical and radiographic results from a 2-year comparison of once-weekly versus twice-weekly administration of etanercept in biologics-naive patients with rheumatoid arthritis. Mod Rheumatol. 2012;22:824-30.

Wrong comparator

Wagner 2013 Wagner C, Chen D, Fan H, Hsia EC, Mack M, Emery P, et al. Evaluation of serum biomarkers associated with radiographic progression in methotrexate-naive rheumatoid arthritis patients treated with methotrexate or golimumab. J Rheumatol. 2013;40:590-8.

Wrong population

Weinblatt 2014 Weinblatt ME, Genovese MC, Ho M, Hollis S, Rosiak-Jedrychowicz K, Kavanaugh A, et al. Effects of fostamatinib, an oral spleen tyrosine kinase inhibitor, in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis rheumatol. 2014;66:3255-64.

Wrong intervention

Weinblatt 1985 Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, et al. Wrong

324


Efficacy of low-dose methotrexate in rheumatoid arthritis. The New England journal of medicine. 1985;312:818-22.

population

Weinblatt 2006 Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E. Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study. Arthritis and rheumatism. 2006;54:2807-16.

Wrong intervention

Weinblatt 2006 Weinblatt ME, Keystone EC, Furst DE, Kavanaugh AF, Chartash EK, Segurado OG. Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study. Annals of the rheumatic diseases. 2006;65:753-9.

Wrong study design

Weinblatt 2007 Weinblatt M, Schiff M, Goldman A, Kremer J, Luggen M, Li T, et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Annals of the rheumatic diseases. 2007;66:228-34.

Wrong intervention

Weinblatt 2008 Weinblatt ME, Schiff MH, Ruderman EM, Bingham CO, 3rd, Li J, Louie J, et al. Efficacy and safety of etanercept 50 mg twice a week in patients with rheumatoid arthritis who had a suboptimal response to etanercept 50 mg once a week: results of a multicenter, randomized, double-blind, active drug-controlled study. Arthritis and rheumatism. 2008;58:1921-30.

Wrong comparator

Weisman 2003 Weisman MH, Moreland LW, Furst DE, Weinblatt ME, Keystone EC, Paulus HE, et al. Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study. Clinical therapeutics. 2003;25:1700-21.

<12 weeks

Weisman 2007 Weisman MH, Paulus HE, Burch FX, Kivitz AJ, Fierer J, Dunn M, et al. A placebo-controlled, randomized, double-blinded study evaluating the safety of etanercept in patients with rheumatoid arthritis and concomitant comorbid diseases. Rheumatology. 2007;46:1122-5.

Wrong population

Westhovens 2014 Westhovens R, Kremer JM, Emery P, Russell AS, Alten R, Barre E, et al. Long-term safety and efficacy of abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: a 7-year extended study. Clin Exp Rheumatol. 2014;32:553-62.

Wrong study design

325


Westhovens 2006 Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, et al. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis and rheumatism. 2006;54:1075-86.

Wrong population

Westhovens 2009 Westhovens R, Kremer JM, Moreland LW, Emery P, Russell AS, Li T, et al. Safety and efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: a 5-year extended phase IIB study. The Journal of rheumatology. 2009;36:736-42.

Wrong intervention

Westhovens 2016 Westhovens R, Taylor PC, Alten R, Pavlova D, Enriquez-Sosa F, Mazur M, et al. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis. 2016.

Wrong intervention

Wiland 2016 Wiland P, Dudler J, Veale D, Tahir H, Pedersen R, Bukowski J, et al. The Effect of Reduced or Withdrawn Etanercept-methotrexate Therapy on Patient-reported Outcomes in Patients with Early Rheumatoid Arthritis. J Rheumatol. 2016.

Wrong population

Williams 1985 Williams HJ, Willkens RF, Samuelson CO, Alarcon GS, Guttadauria M, Yarboro C, et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis and rheumatism. 1985;28:721-30.

Wrong population

Williams 2016 Williams JH, Hutmacher MM, Zierhut ML, Becker JC, Gumbiner B, Spencer-Green G, et al. Comparative assessment of clinical response in patients with rheumatoid arthritis between PF-05280586, a proposed rituximab biosimilar, and rituximab. Br J Clin Pharmacol. 2016.

Wrong intervention

Xia 2011 Xia L, Lu J, Xiao W. Blockage of TNF-alpha by infliximab reduces CCL2 and CCR2 levels in patients with rheumatoid arthritis. Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2011;59:961-3.

Wrong population

Yamanaka 2015 Yamanaka H, Nagaoka S, Lee SK, Bae SC, Kasama T, Kobayashi H, et al. Discontinuation of etanercept after achievement of sustained remission in patients with rheumatoid arthritis who initially had moderate disease activity-results from the ENCOURAGE study, a prospective, international, multicenter randomized study. Mod Rheumatol. 2015:1-11.

Wrong population

Yazici 2013 Yazici Y, Curtis JR, Ince A, Baraf HS, Lepley DM, Devenport JN, et al. Early effects of Wrong study

326


tocilizumab in the treatment of moderate to severe active rheumatoid arthritis: a one-week sub-study of a randomised controlled trial (Rapid Onset and Systemic Efficacy [ROSE] Study). Clin Exp Rheumatol. 2013;31:358-64.

design

Yoo 2016 Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis. 2016.

Wrong study design

Yoo 2017 Yoo DH, Suh CH, Shim SC, Jeka S, Cons-Molina FF, Hrycaj P, et al. A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76:566-70.

Wrong intervention

Zeb 2016 Zeb S, Wazir N, Waqas M, Taqweem A. Comparison of short-term efficacy of leflunomide and methotrexate in active rheumatoid arthritis. Journal of Postgraduate Medical Institute. 2016;30:177-80.

Wrong population

Zhang 2004 Zhang X, Cui Y, r QL, Yao RY, Zhou H. [Methotrexate combined with leflunomide or hydroxychloroquine in the treatment of rheumatoid arteritis]. Zhonghua yi xue za zhi. 2004;84:1038-40.

Non-English

Zhou 2007 Zhou H, Jang H, Fleischmann RM, Bouman-Thio E, Xu Z, Marini JC, et al. Pharmacokinetics and safety of golimumab, a fully human anti-TNF-alpha monoclonal antibody, in subjects with rheumatoid arthritis. Journal of clinical pharmacology. 2007;47:383-96.

Wrong intervention

Zhu 2016 Zhu T, Keirns J, Howieson C, Kaibara A, Goldwater R, Kivitz AJ, et al. Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of ASP2408, a Potent Selective T-Cell Costimulation Modulator After Single and Multiple Ascending Doses in Healthy Volunteers and RA Patients. Clinical Pharmacology in Drug Development. 2016;5:408-25.

Wrong intervention

327

APPENDIX 5: STUDY CHARACTERISTICS OF INCLUDED ADAPTIVE DESIGN STUDIES

Table 42. Table of Study Characteristics of Included Adaptive Design Studies

Author, Year Type of

Adaptive Design

Details Measure used to determine

"non-response"

Time Point Useda

Study Dura-tion

Arm 1b Arm 2b Arm 3b Arm 4b Arm 5b Arm 6b Arm 7b

Burmester (2016), MONARCH

Rescue therapy

Non-responders in the ADA arm would receive qw (instead of q2w) admin of ADA (or matching placebo for SAR arm)

# TJC and SJC <20% from baseline to week 16

16 weeks

24 weeks

ADA 40mg q2w (SC)

SAR 200mg q2w (SC)

Dougados (2017), RA-BUILD

Rescue therapy

Non-responders received BAR 4mg

# TJC and SJC <20% from baseline to weeks 12 and 14 or at investigator discretion after week 16

16 weeks

24 weeks

Placebo +

csDMARD

BAR 2mg/day

(P.O.) +

csDMARD

BAR 4mg/day

(P.O.) +

csDMARD

Emery (2010), SERENE

Rescue therapy

Non-biological DMARD for rest of study

# TJC and SJC <20% from baseline to between week 16 and 23

16 weeks

24 weeks

Placebo +MTX

RIT 500mg at 1 and 15

days (IV)+MTX

RIT 1000mg infusions at

1 and 15 days

(IV)+MTX

Fleischmann (2012)

Treatment switch

Patients in placebo, TOF 1mg or 3mg arms blindly reassigned to TOF 5mg bid


12 weeks

24 weeks

Placebo TOF 5mg bid (P.O.)

TOF 10mg bid (P.O.)

TOF 15mg bid (P.O.)

ADA 40mg q2w (SC)

TOF 1mg bid (P.O.)

TOF 3mg bid (P.O.)

328


Adaptive Design


"non-response"

Time Point Useda

Study Dura-tion


Furst (2003), STAR

Rescue therapy

Any non-responders could receive a single increase in dose of csDMARD and/or corticosteroid therapy (max 10 mg/day) or receive treatment with a different csDMARD

ACR20 <20% at week 12

12 weeks

24 weeks

Placebo +

csDMARD

ADA 40mg q2w (SC)

+ csDMARD

Gabay (2013), ADACTA

Early escape

Non-responders received weekly SC injections (ADA and placebo)

# TJC and SJC <20% from baseline to week 16 or any time after

16 weeks

24 weeks

ADA 40mg q2w (SC)

TOC 8mg/kg q4w (IV)

Genovese (2015), MOBILITY

Early escape

Any non-responder could receive "rescue therapy" with open-label SAR 200mg q2w

# TJC and SJC <20% at 2 consecutive assessments from week 16 onwards

16 weeks

52 weeks

Placebo +MTX

SAR 150mg q2w

(SC)+MTX

SAR 200mg q2w

(SC)+MTX

329


Adaptive Design


"non-response"

Time Point Useda

Study Dura-tion


Genovese (2008), TOWARD

Rescue therapy

Any non-responders could: adjust background DMARD dose and/or receive different DMARD and/or receive IA or oral GCs


16 weeks

24 weeks

Placebo +

csDMARD

TOC 8mg/kg q4w (IV)

+ csDMARD

Hobbs (2015) Treatment switch

All patients in placebo arm switched to receive ETN 50mg

NA - planned switch

12 weeks

24 weeks

Placebo +

csDMARD

ETN 50mg qw (SC)

+ csDMARD

Hoffman-La Roche (Sponsor) (2015)

Rescue therapy

Any nonresponder received TOC 8 mg/kg IV q4w from week 12 through to week 24

# TJC and SJC <20% improvement from baseline to week 12

12 weeks

24 weeks

Placebo + csDMARD

TOC 8 mg/kg IV

q4w +

csDMARD

Kay (2008) Treatment switch

Placebo arm was switched to receive INF 3 mg/kg every 8 weeks (after induction at 0, 2 and 6 weeks from start of switch)

NA - planned switch

16 weeks

52 weeks

Placebo +MTX

GOL 50 mg SC

q4w+MTX

GOL 50 mg SC

q2w+MTX

GOL 100 mg SC

q4w+MTX

GOL 100 mg SC

q2w+MTX

Keystone (2015), I4V-MC-JADA

Treatment switch

Placebo and BAR 1mg groups only were re-randomized to either BAR 2mg bid or BAR 4mg qd

NA - planned switch

12 weeks

24 weeks

Placebo +MTX

BAR 1mg/day

(P.O.) +MTX

BAR 2mg/day

(P.O.) +MTX

BAR 4mg/day

(P.O.) +MTX

BAR 8mg/day

(P.O.) +MTX

330


Adaptive Design


"non-response"

Time Point Useda

Study Dura-tion


Keystone (2004)

Rescue therapy

Any non-responder could receive csDMARD

ACR20 <20% at weeks 16 and onwards

16 weeks

52 weeks

Placebo +MTX

ADA 40mg q2w

(SC)+MTX

ADA 20mg qw

(SC)+MTX

Keystone (2008), RAPID1

Early escape

Any non-responder was withdrawn into an open-label extension study to receive CERTO 400mg q2w

ACR20 <20% at weeks 12 and 14

16 weeks

52 weeks

Placebo +MTX

CERTO 200mg q2w after loading

dose of 400mg at 0,

2 and 4 weeks

(SC)+MTX


dose of 400mg at 0,

2 and 4 weeks

(SC)+MTX

Keystone (2009), GO-FOWARD

Treatment switch

Patients from any arm other than the GOL100mg + MTX arm could switch; those in Placebo+MTX arm received GOL50mg; GOL100mg arm received MTX; GOL50mg + MTX arm received GOL100mg + MTX


16 weeks

52 weeks

Placebo +MTX

GOL 100mg qw (SC)

GOL 50mg qw

(SC)+MTX

GOL 100mg qw

(SC)+MTX

331


Adaptive Design


"non-response"

Time Point Useda

Study Dura-tion


Kim 2007 Early escape

Any non-responder could enter open-label phase and receive ADA 40mg q2w

# TJC and SJC <20% for at least 2 consecutive weeks from week 12 to week 22

18 weeks

24 weeks

Placebo +MTX

ADA 40mg q2w

(SC)+MTX

Kremer (2011), LITHE

Rescue therapy

1st-step rescue: Placebo+MTX, TOC4mg, TOC8mg arms received rescue therapy of TOC4mg, TOC8mg and TOC8mg, respectively. GCs were also given if needed; 2nd-step rescue: All arms received TOC8mg through week 52; early escape was permitted only if non-response after 3 doses of 2nd-step rescue

# TJC and SJC <20% from baseline to week 16 (same criteria used to assess response after 3 doses of 1st- and 2nd-step rescue)

16 weeks

52 weeks

Placebo +MTX

TOC 4mg/kg q4w

(IV)+MTX

TOC 8 mg/kg q4w (IV)+MTX

332


Adaptive Design


"non-response"

Time Point Useda

Study Dura-tion


Kremer (2010) Early escape

Any non-responders could enter early escape in a blinded manner

# TJC and SJC <20% from baseline to week 16 (and week 24 for dose adjustment portion)

16 weeks

48 weeks

Placebo +MTX

GOL 2mg/kg q12w (IV)


GOL 2mg/kg q12w

(IV)+MTX

GOL 4mg/kg q12w

(IV)+MTX

Kremer (2012) Treatment switch

Placebo arm reassigned to TOF 5mg bid for remaining 12 weeks (blinding remained)


12 weeks

24 weeks

Placebo +MTX

TOF 1mg/day

(P.O.) +MTX

TOF 3mg/day

(P.O.) +MTX

TOF 5mg/day

(P.O.) +MTX

TOF 10mg/day

(P.O.) +MTX

TOF 15mg /day (P.O.) +MTX

TOF 20mg /day (P.O.) +MTX

Kremer (2003) Rescue therapy

Patients were allowed to receive any of the following: 1) changes to MTX dose; 2) addition of another csDMARD; 3) changes to dose of GCs (up to 10mg/day of GCs)

Clinician or investigator judgment

24 weeks

52 weeks

Placebo +MTX

ABA 2mg/kg (IV)+MTX

ABA 10mg/kg (IV)+MTX

333


Adaptive Design


"non-response"

Time Point Useda

Study Dura-tion


Kremer (2006), AIM

Rescue therapy

Any non-responders were allowed to receive any of the following: 1) changes to MTX dose; 2) addition of another csDMARD; 3) changes to dose of GCs (up to 10mg/day of GCs)

Investigator judgment

24 weeks

52 weeks

Placebo +MTX

ABA 10mg/kg q4w after

loading at 1, 15 and 30

days (IV)+MTX

Li (2015) Treatment switch

Placebo arm only - entered blinded "early escape" to GOL 50mg

# TJC and SJC <20% from baseline to week 16; Planned switch at week 24 for remaining placebo patients

16 weeks

52 weeks

Placebo +MTX

GOL 50mg q4w

(SC)+MTX

O'Dell (2013), RACAT

Treatment switch

Any non-responder would be switched to the other treatment arm

Reduction (i.e. improvement) in DAS28 <1.2 by week 24

24 weeks

48 weeks

SSZ 1g/day for 6 weeks, increased to

2g/day +HCQ

400mg qd

ETN 50mg qw (SC)+SSZ

334


Adaptive Design


"non-response"

Time Point Useda

Study Dura-tion


Peterfy (2016), RA-SCORE

Rescue therapy

Increased MTX or received non-biologic DMARDs


16 weeks

52 weeks

Placebo +MTX

RIT 500mg on day 1 and 15

(IV)+MTX


(IV)+MTX

Schiff (2008), ATTEST

Treatment switch, then MTX dose adjust-ments allowed after day 198 if needed

Placebo arm reallocated (day 198) to ABA with blinding maintained; ABA 10mg/kg and INF 3mg/kg arms continued their treatment

NA - planned switch

26 weeks

26 weeks

Placebo +MTX

ABA 10mg/kg q4w (IV)

after initial infusions on days 1, 15

and 29 (IV)+MTX

INF 3mg/kg q8w after

initial infusions on days 1, 15, 43 and 85 (IV)+MTX

Smolen (2008), OPTION

Rescue therapy

Non-responders could receive TOC 8mg/kg and/or IA steroids or an increase in dose of oral GCs (max 10mg/day)


16 weeks

24 Weeks

Placebo +MTX

TOC 4mg/kg q4w

(IV)+MTX

TOC 8mg/kg q4w

(IV)+MTX

Smolen (2009), RAPID2

Early escape

Non-responders were withdrawn and could enter an open-label extension phase with CERTO 400mg q2w


16 weeks

24 weeks

Placebo +MTX

CERTO 200mg q2w after initial

dose of 400mg at 0,

2 and 4 weeks

(SC)+MTX


dose of 400mg at 0,

2 and 4 weeks

(SC)+MTX

335


Adaptive Design


"non-response"

Time Point Useda

Study Dura-tion


Smolen (2014, Part A)

Treatment switch

Planned cross-over design from weeks 12-22

NA - planned switch

12 weeks

22 weeks

Placebo +

csDMARD

SIR 100 mg SC q2w

+ csDMARD

Smolen (2014, Part B)

Treatment switch

Placebo arm was switched to receive SIR 100 mg q2w+csDMARD from weeks 12 through to 24

NA - planned switch

12 weeks

24 weeks

Placebo +

csDMARD

SIR 100 mg SC q2w

+ csDMARD

SIR 100 mg SC q4w

+ csDMARD

SIR 50 mg SC q4w

+ csDMARD

SIR 25 mg SC q4w

+ csDMARD

Smolen (2016), EXXELERATE

Treatment switch then withdrawn if still non-responders at week 24

CERTO arm non-responders switched to ADA 40mg q2w; ADA arm non-responders switched to CERTO 400mg (wks 12, 14, 16 loading dose) then 200mg q2w; if still non-responders at week 24 (even after switching) they were deemed TNF inhibitor non-responders and withdrawn from study

DAS28-ESR ≥3.2 or a DAS28-ESR reduction from baseline of ≤1.2 at week 12

12 weeks

104 weeks

ADA 40mg q2w

(SC)+MTX

CERTO 200mg q2w after initial 400mg at 0,

2 and 4 weeks

(SC)+MTX

336


Adaptive Design


"non-response"

Time Point Useda

Study Dura-tion


Takeuchi (2013), GO-MONO

Treatment switch

Placebo arm reassigned to GOL 50mg in a double-blind fashion

NA - planned switch

24 weeks

16 weeks

Placebo GOL 50mg q4w (SC)

GOL 100mg q4w (SC)

Tanaka (2012), GO-FORTH

Early escape

Any non-responder could enter double-blind early escape


16 weeks

24 weeks

Placebo +MTX

GOL 50mg q4w

(SC)+MTX

GOL 100mg q4w

(SC)+MTX

Taylor (2017), RA BEAM

Rescue therapy

Any non-responder received BAR 2mg; after 24 weeks those in placebo arm were switched blindly to BAR 4mg

# TJC and SJC <20% from baseline to weeks 12 and 14 or at investigator discretion (based on joint count) afterwards

16 weeks

52 weeks

Placebo +MTX

ADA 40mg q2w

(SC)+MTX

BAR 4mg qd (P.O.) +MTX

van der Heijde (2013), ORAL scan

Treatment switch

Early escape at week 12; Planned switch at 6 months -- patients still in placebo arm blindly switched to pre-determined dose of TOF


12 weeks

52 weeks

Placebo +MTX

TOF 5mg bid (P.O.) +MTX

TOF 10mg bid (P.O.)

+MTX

337


Adaptive Design


"non-response"

Time Point Useda

Study Dura-tion


van Vollenhoven (2012), ORAL Standard

Treatment switch

Placebo arm only was reassigned randomly to TOF 5mg or 10mg

# TJC and SJC <20% from baseline to week 12; at 6 months all remaining placebo patients were switched

12 weeks

52 weeks

Placebo +MTX

TOF 5mg bid (P.O.) +MTX

TOF 10mg bid (P.O.)

+MTX

ADA 40mg q2w

(SC)+MTX

Weinblatt (2015)

Rescue therapy

No restrictions on who could receive rescue therapy; non-responders could early escape to open-label treatment with CLZ 200 mg q4w+MTX

Rescue therapy allowed after week 12 and not within 4 weeks of the week 24 assessment; early escape: # TJC and SJC <20% reduction from baseline to week 12

12 weeks

24 weeks

Placebo +MTX

ADA 40 mg SC

q2w+MTX

CLZ 25 mg SC

q4w+MTX

CLZ 100 mg SC

q4w+MTX

CLZ 200 mg SC

q4w+MTX

CLZ 100 mg SC q4w

CLZ 200 mg SC q4w

Weinblatt 2013

Treatment switch

Placebo arm non-responders could switch to GOL 2mg/kg (induction at 16 and 20 weeks then q8w)


16 weeks

24 weeks

Placebo +MTX

GOL 2mg/kg q8w after

initial dosing at 0 and 4

weeks (IV)+MTX

338


Adaptive Design


"non-response"

Time Point Useda

Study Dura-tion


Weinblatt (2003), ARMADA

Early escape

Any non-responders could enter the open-label continuation study or remain in the study (those who left were considered non-responders in primary and secondary analyses of week 24 data)

ACR20 <20% at week 16

16 weeks

24 weeks

Placebo +MTX

ADA 20mg q2w

(SC)+MTX

ADA 40mg q2w

(SC)+MTX

ADA 80mg q2w

(SC)+MTX

Yamamoto (2014), HIKARI

Early escape

Any non-responders could enter open-label extension


16 weeks

24 weeks

Placebo CERTO 200mg q2w after 400mg at 0, 2 and 4 weeks (SC)

Yamamoto (2014), J-RAPID

Early escape

Any non-responders could enter open-label extension study


16 weeks

24 weeks

Placebo +MTX

CERTO 100mg q2w after 200mg at 0, 2 and 4

weeks (SC)+MTX


weeks (SC)+MTX


weeks (SC)+MTX

Yazici (2012), ROSE

Rescue therapy

Any non-responders received two courses of TOC 8mg/kg q4w in place of assigned study drug


16 weeks

24 weeks

Placebo +

csDMARD

TOC 8mg/kg q4w (IV)

+ csDMARD

aRepresents the study duration that was analyzed (i.e. shorter than full study length for adaptive design studies)

339

bCertain studies included both standard and non-standard doses of treatments; this table lists all treatments as they appear in the study. However, only the included treatments listed in Table 2 are

standard doses were included in the analysis. ABA = abatacept; ADA = adalimumab; BAR = baricitinib; bid = twice daily; biw = twice weekly; CERTO = certolizumab pegol; CT-P13 = biosimilar of infliximab; csDMARD = conventional

synthetic disease modifying anti-rheumatic drug; ETN = etanercept; GC = glucocorticoid; GOL = golimumab; HCQ = hydroxychloroquine; HD203 = biosimilar of etanercept; IA = intra-articular; INF =

infliximab; IV = intravenous; MTX = methotrexate; NA = not applicable; P.O. = orally; qw = every week; q2w = every two weeks; q4w = every four weeks; q8w = every eight weeks; qd = every day; RIT = rituximab; SAR = sarilumab; SB2 = biosimilar of infliximab; SB4 = biosimilar of etanercept; SC = subcutaneous; SIR = sirukumab; SJC = swollen joint count; SSZ = sulfasalazine; TJC = tender

joint count; TNF = tumour necrosis factor; TOC = tocilizumab; TOF = tofacitinib; ZRC-3197 = biosimilar of adalimumab

340

APPENDIX 6: STUDY AND PATIENT CHARACTERISTICS OF INCLUDED STUDIES

Table 43. Table of Study Characteristics of Included Studies

Author, Year RCT

Design

Time Point Used

a

Study Dura-tion

No. random

-ized Arm 1

b Arm 2

b Arm 3

b Arm 4

b Arm 5

b Arm 6

b Arm 7

b

Abe (2006) Parallel 14

weeks 14

weeks 151 Placebo+MTX

INF 3mg/kg at 0, 2 and 6

weeks (IV)+MTX

INF 10mg/kg (IV)+MTX

Alzaidy (2016) Parallel 48

weeks 48


ADA+MTX (dose not described)

Amgen (Sponsor) (2016)

Parallel 24

weeks 24

weeks 526

ADA 40mg q2w

(SC)+MTX

ABP501 40mg q2w

(SC)+MTX

Bae (2016), HERA

Parallel 48

weeks 48

weeks 233

ETN 25mg biw

(SC)+MTX

HD203 25mg+MTX

Burmester (2016), MONARCH

Adaptive 16

weeks 24

weeks 369

ADA 40mg q2w (SC)

SAR 200mg q2w (SC)

Chen (2009) Parallel 12

weeks 12


ADA 40mg q2w

(SC)+MTX

Chen (2016) Parallel 12

weeks 12


Anbainuo 25mg q2w

(SC)

Choe (2015) Parallel 30

weeks 54

weeks 584

INF 3mg/kg q8w (IV)+MTX

SB2 3mg/kg q8w (IV)+MTX

Choy (2012) Parallel 24

weeks 24


CERTO 400mg q4w (SC)+MTX

Ciconelli (1996)

Parallel 24

weeks 24

weeks 38

Placebo+SSZ 2g/day

Methylpred-nisone

5mg/kg (IV pulses)+SSZ

2g/day

Cohen (2002) Parallel 24

weeks 24


ANA 0.04mg/kg qd

(SC)+MTX

ANA 0.1mg/kg qd (SC)+MTX



ANA 2.0mg/kg qd (SC) +MTX

341

Author, Year RCT

Design

Time Point Used

a

Study Dura-tion

No. random

-ized Arm 1

b Arm 2

b Arm 3

b Arm 4

b Arm 5

b Arm 6

b Arm 7

b

Cohen (2004) Parallel 24

weeks 24


ANA 100mg qd (SC)+MTX

Combe (2006) Parallel 104

weeks 104

week 260

Placebo+SSZ 2-3g/day

(P.O.)

ETN 25mg biw (SC)

ETN 25mg biw (SC)+SSZ

2-3g/day (P.O.)

Conaghan (2013), ASSET

Parallel 16

weeks 16


ABA 10mg/kg q4w (IV)+MTX

Dougados (2013), ACT-RAY

Parallel 24

weeks 24

weeks 556

TOC 8mg/kg q4w (IV)

TOC 8mg/kg q4w (IV)+MTX

Dougados (2017), RA-BUILD

Adaptive 16

weeks 24

weeks 684

Placebo +csDMARD

BAR 2mg/day (P.O.)

+csDMARD

BAR 4mg/day (P.O.)

+csDMARD

Edwards (2004)

Parallel 48

weeks

104 weeks 161 Placebo+MTX

RIT 1000mg at 1 and 15 days (IV)

RIT 1000 mg at 1 and 15

days (IV)+CTX

RIT 1000mg at 1 and 15 days (IV)+

MTX

Emery (2015) Parallel 24

weeks 24

weeks 596

ETN 50mg qw (SC)+MTX

SB4 50mg qw (SC)+MTX

Emery (2010), SERENE

Adaptive 16

weeks 24


RIT 500mg at 1 and 15 days

(IV)+MTX

RIT 1000mg infusions at 1 and 15 days

(IV)+MTX

Fleischmann (2012)

Adaptive 12

weeks 24

weeks 386 Placebo

TOF 5mg bid (P.O.)

TOF 10mg bid (P.O.)

TOF 15mg bid (P.O.)

ADA 40mg q2w (SC)

TOF 1mg bid (P.O.)

TOF 3mg bid (P.O.)

Fleischmann (2009), FAST4WARD

Parallel 24

weeks 24

weeks 220 Placebo

CERTO 400mg q4w

(SC)

Furst (2015), DOSEFLEX

Withdrawal 16 weeks

16 weeks

333 Placebo+MTX CERTO

200mg q2w (SC)

CERTO 400mg q2w

(SC)

Furst (2003), STAR

Adaptive 12

weeks 24

weeks 636

Placebo +csDMARD

ADA 40mg q2w (SC)

+csDMARD

Gabay (2013), ADACTA

Adaptive 16

weeks 24

weeks 326

ADA 40mg q2w (SC)

TOC 8mg/kg q4w (IV)

Gashi (2014) Parallel 24

weeks 24

weeks 33

ETN 25mg biw

(SC)+MTX

RIT 1000mg at week 0 and 2 (IV)+MTX

342

Author, Year RCT

Design

Time Point Used

a

Study Dura-tion

No. random

-ized Arm 1

b Arm 2

b Arm 3

b Arm 4

b Arm 5

b Arm 6

b Arm 7

b

Genovese (2008), TOWARD

Adaptive 16

weeks 24

weeks 1220

Placebo +csDMARD

TOC 8mg/kg q4w (IV)

+csDMARD

Genovese (2015), MOBILITY

Adaptive 16

weeks 52


SAR 150mg q2w

(SC)+MTX

SAR 200mg q2w

(SC)+MTX

Hobbs (2015) Adaptive 12

weeks 24

weeks 210

Placebo +csDMARD

ETN 50mg qw (SC)

+csDMARD

Hoffmann-La Roche (Sponsor) (2015)

Adaptive 12

weeks 24

weeks 54

Placebo +csDMARD

TOC 8mg/kg q4w (IV)

+csDMARD

Jani (2015) Parallel 12

weeks 12

weeks 120

ADA 40 q2w (SC)+MTX

ZRC-3197 40mg q2w (SC)+MTX

Jobanputra (2012), RED SEA

Parallel 52

weeks 52

weeks 125

ETN 50mg qw (SC)

+csDMARD

ADA 40mg q2w (SC)

+csDMARD

Kaine (2012) Withdrawal 12

weeks 36


ABA 125mg qw (SC)+MTX

Kameda (2010), JESMR

Parallel 24

weeks 24

weeks 151

ETN 25mg biw (SC)

ETN 25mg biw

(SC)+MTX

Kaneko (2015), SURPRISE

Parallel 52

weeks 52

weeks 233


TOC 8mg/kg q4w (IV)

Kavanaugh (2000)

Parallel 12

weeks 12





Kay (2008) Parallel 16

weeks 16


GOL 50mg q4w

(SC)+MTX

GOL 50mg q2w

(SC)+MTX

GOL 100mg q4w

(SC)+MTX

GOL 100mg q2w

(SC)+MTX

Kennedy (2014), ALTARA

Parallel 12

weeks 12

weeks 214

Placebo +csDMARD

ADA 40mg q2w (SC)

+csDMARD

Pateclizumab 360mg

+csDMARD

Keystone (2015), I4V-MC-JADA

Adaptive 12

weeks 24


BAR 1mg/day (P.O.)+MTX




Keystone (2004)

Adaptive 16

weeks 52


ADA 40mg q2w

(SC)+MTX

ADA 20mg qw (SC)+MTX

343

Author, Year RCT

Design

Time Point Used

a

Study Dura-tion

No. random

-ized Arm 1

b Arm 2

b Arm 3

b Arm 4

b Arm 5

b Arm 6

b Arm 7

b

Keystone (2008), RAPID1

Adaptive 16

weeks 52



dose of 400mg at 0, 2 and 4 weeks (SC)+MTX



Keystone (2009), GO-FORWARD

Adaptive 16

weeks


GOL 100mg qw (SC)

GOL 50mg qw (SC)+MTX

GOL 100mg qw (SC)+MTX

Kim (2012), APPEAL

Parallel 16

weeks 16

weeks 300

csDMARD +MTX

ETN 25mg biw

(SC)+MTX

Kim (2007) Adaptive 18

weeks 24


ADA 40mg q2w

(SC)+MTX

Kim (2013) Parallel 30

weeks 30


INF 3mg/kg at 0, 2, 6, 14 and

22 weeks (SC)+MTX

Klareskog (2004), TEMPO

Parallel 52

weeks 52


ETN 25mg biw (SC)

ETN 25mg biw

(SC)+MTX

Kremer (2003)

Parallel 24

weeks


ABA 2mg/kg (IV)+MTX


Kremer (2012)

Adaptive 12

weeks 24


TOF 1mg/day (P.O.)+MTX



TOF 10mg/day

(P.O.)+MTX

TOF 15mg/day

(P.O.) +MTX

TOF 20mg/day

(P.O.) +MTX

Kremer (2010)

Adaptive 16

weeks 48




GOL 2mg/kg q12w

(IV)+MTX

GOL 4mg/kg q12w

(IV)+MTX

Kremer (2011), LITHE

Adaptive 16

weeks 52



TOC 8 mg/kg q4w (IV)+MTX

Kremer (2006), AIM

Adaptive 24

weeks 52


ABA 10mg/kg q4w after

loading at 1, 15 and 30

days (IV)+MTX

344

Author, Year RCT

Design

Time Point Used

a

Study Dura-tion

No. random

-ized Arm 1

b Arm 2

b Arm 3

b Arm 4

b Arm 5

b Arm 6

b Arm 7

b

Lan (2004) Parallel 12

weeks 12


ETN 25mg biw

(SC)+MTX

Li (2015) Adaptive 16

weeks 24


GOL 50mg q4w

(SC)+MTX

Loet (2008), OMEGA

Parallel 36

weeks 36

weeks 1207

ANA 100mg/day (SC)+MTX

ANA 100mg/day (SC)+SSZ

ANA 100mg/day (SC)+HCQ

Machado (2014)

Parallel 24

weeks 24

weeks 429

csDMARD +MTX


MacIssac (2014)

Parallel 14

weeks 14

weeks 61

Placebo +csDMARD

INF 3mg/kg at 0, 2, 6 and 14

weeks (IV) +csDMARD

Maini (2006), CHARISMA

Parallel 16

weeks 16


TOC 4mg/kg q4w (IV)

TOC 8mg/kg q4w (IV)



TOC 2mg/kg q4w (IV)

TOC 2mg/kg

q4w (IV)+MTX

Maini (1998) Parallel 26

weeks 26


INF 3mg/kg at 0, 2, 6, 10 and

14 days (IV)+MTX

INF 3mg/kg at 0, 2, 6, 10 and 14 days (IV)

INF 10mg/kg at 0, 2, 6, 10 and 14 days

(IV)+MTX

INF 10mg/kg at 0, 2, 6, 10 and 14 days

(IV)

INF 1mg/kg at 0, 2, 6, 10

and 14 days

(IV)+MTX

INF 1mg/kg at 0, 2, 6, 10 and 14 days (IV)

Maini (1999), ATTRACT

Parallel 30

weeks



infusions at 0, 2 and 6

weeks+MTX



weeks+MTX



weeks+MTX



weeks+MTX

Miyasaka (2008), CHANGE

Adaptive 8

weeks 24

weeks 352 Placebo

ADA 20mg q2w (SC)

ADA 40mg q2w (SC)

ADA 80mg q2w (SC)

Mladenovic (1995)

Parallel 24

weeks 24

weeks 402 Placebo

LEF 5mg after 50mg loading

dose

LEF 10mg after 100mg loading dose

LEF 25mg after 100mg loading dose

Moreland (1999)

Parallel 26

weeks 26

weeks 246 Placebo

ETN 10mg q2w (SC)

ETN 25mg q2w (SC)

Nishimoto (2009), SATORI

Parallel 24

weeks 24


TOC 8mg/kg q4w (IV)

345

Author, Year RCT

Design

Time Point Used

a

Study Dura-tion

No. random

-ized Arm 1

b Arm 2

b Arm 3

b Arm 4

b Arm 5

b Arm 6

b Arm 7

b

O'Dell (2002) Parallel 104

weeks 104

weeks 171

MTX17.5mg qw+HCQ

200mg bid

MTX 17.5mg qw+SSZ

500mg bid then 1g bid at

6 mo

MTX 17.5mg qw+HCQ 200mg

bid+SSZ 500mg bid

then 1g bid at 6 mo

O'Dell (1996) Parallel 104

weeks 104


HCQ 200mg bid+SSZ

500mg bid

MTX+HCQ 200mg

bid+SSZ 500mg bid

O'Dell (2013), RACAT

Adaptive 24

weeks 48

weeks 353

SSZ 1g/day for 6 weeks, increased to 2g/day+HCQ

400mg qd

ETN 50mg qw (SC)+SSZ

Peterfy (2016), RA-SCORE

Adaptive 16

weeks 52



(IV)+MTX

RIT 1000mg on day 1 and 15 (IV)+MTX

Pope (2014), CAMEO

Withdrawal 24

weeks 76

weeks 205


ETN 50mg qw (SC)

Samsung Bioepis Co (Sponsor) (2016)

Parallel 24

weeks 24

weeks 544

ADA 40mg q2w

(SC)+MTX

SB5 40mg q2w

(SC)+MTX

Schiff (2013), AMPLE

Parallel 104

weeks 104

week 646

ABA 125mg qw (SC)

ADA 40mg q2w

(SC)+MTX

Schiff (2008), ATTEST

Adaptive 26

weeks 26


ABA 10mg/kg q4w (IV) after

initial infusions on days 1, 15

and 29 (IV)+MTX


initial infusions on days 1, 15,

43 and 85 (IV)+MTX

Smolen (2016), EXXELERATE

Adaptive 12

weeks 104

weeks 915

ADA 40mg q2w

(SC)+MTX


400mg at 0, 2 and 4 weeks (SC)+MTX

Smolen Adaptive 12 22 36 Placebo SIR 100mg

346

Author, Year RCT

Design

Time Point Used

a

Study Dura-tion

No. random

-ized Arm 1

b Arm 2

b Arm 3

b Arm 4

b Arm 5

b Arm 6

b Arm 7

b

(2014) weeks weeks +csDMARD q2w (SC) +csDMARD

Smolen (2008), OPTION

Adaptive 16

weeks 24

Weeks 623 Placebo+MTX



Smolen (2009), RAPID2

Adaptive 16

weeks 24






Smolen (2014)

Adaptive 12

weeks 24

weeks 151

Placebo +csDMARD

SIR 100mg q2w (SC)

+csDMARD

SIR 100mg q4w (SC)

+csDMARD

SIR 50mg q4w (SC)

+csDMARD

SIR 25mg q4w (SC)

+csDMARD

Takeuchi (2013)

Parallel 24

weeks 24


ABA 2mg/kg (IV)+MTX


Takeuchi (2012), GO-MONO

Parallel 16

weeks 24

weeks 316 Placebo

GOL 50mg q4w (SC)

GOL 100mg q4w (SC)

Takeuchi (2013)

Adaptive 52

weeks 52

weeks 550 MTX

ETN 10mg biw (SC)

ETN 25 mg biw (SC)

Takeuchi (2015)

Parallel 54

weeks 54

weeks 108


initial dosing at 0, 2 and 6

weeks (IV)+MTX

CT-P13 3mg/kg q8w after initial

dosing at 0, 2 and 6 weeks

(IV)+MTX

Tanaka (2016)

Parallel 12

weeks 12






Tanaka (2011)

Parallel 12

weeks 12


TOF 1mg bid (P.O.)+MTX




Tanaka (2012), GO-FORTH

Adaptive 16

weeks 24


GOL 50mg q4w

(SC)+MTX

GOL 100mg q4w

(SC)+MTX

Taylor (2017), RA BEAM

Adaptive 16

weeks 52


ADA 40mg q2w

(SC)+MTX

BAR 4mg qd (P.O.)+MTX

Van de Putte (2003)

Adaptive 8

weeks 12

weeks 284 Placebo

ADA 20mg qw (SC)

ADA 40mg qw (SC)

ADA 80mg qw (SC)

van der Heijde (2013),

Adaptive 12

weeks 52




347

Author, Year RCT

Design

Time Point Used

a

Study Dura-tion

No. random

-ized Arm 1

b Arm 2

b Arm 3

b Arm 4

b Arm 5

b Arm 6

b Arm 7

b

ORAL Standard

Van Riel (2006)

Parallel 16

weeks 16

weeks 315

ETN 25mg biw (SC)

ETN 25mg biw

(SC)+MTX

van Vollenhoven (2011), AUGUST II

Parallel 26

weeks 26


ADA 40mg q2w

(SC)+MTX

Atacicept 150mg biw for 4 weeks then 150mg SC qw for 21 weeks (SC)+MTX

Atacicept 150mg biw for

25 weeks (SC)+MTX

van Vollenhoven (2012)

Adaptive 12

weeks 52




ADA 40mg q2w

(SC)+MTX

Weinblatt (2012)

Parallel 12

weeks 12

weeks 1063

Placebo +csDMARD

CERTO 200mg q2w

after 400mg at 0, 2 and 4

weeks (SC) +csDMARD

Weinblatt (2015)

Adaptive 12

weeks 24


ADA 40mg (SC)

q2w+MTX

CLZ 25mg q4w

(SC)+MTX

CLZ 100mg q4w

(SC)+MTX

CLZ 200mg q4w

(SC)+MTX

CLZ 100mg

q4w (SC)

CLZ 200mg q4w (SC)

Weinblatt (2013), GO-FURTHER

Adaptive 16

weeks 24


GOL 2mg/kg q8w after

initial dosing at 0 and 4

weeks (IV)+MTX

Weinblatt (2003), ARMADA

Adaptive 16

weeks 24


ADA 20mg q2w

(SC)+MTX

ADA 40mg q2w

(SC)+MTX

ADA 80mg q2w

(SC)+MTX

Weinblatt (1999)

Parallel 24

weeks 24


ETN 25mg biw

(SC)+MTX

Yamamoto (2014), HIKARI

Adaptive 16

weeks 24

weeks 230 Placebo

CERTO 200mg q2w


weeks (SC)

Yamamoto (2014), J-

Adaptive 16

weeks 24


CERTO 100mg q2w

CERTO 200mg q2w

CERTO 400mg q2w

348

Author, Year RCT

Design

Time Point Used

a

Study Dura-tion

No. random

-ized Arm 1

b Arm 2

b Arm 3

b Arm 4

b Arm 5

b Arm 6

b Arm 7

b

RAPID after 200mg at 0, 2 and 4

weeks (SC)+MTX


weeks (SC)+MTX


weeks (SC)+MTX

Yazici (2012), ROSE

Adaptive 16

weeks 24

weeks 619

Placebo +csDMARD

TOC 8mg/kg q4w (IV)

+csDMARD

Yoo (2013), PLANETRA

Parallel 30

weeks 30

weeks 606

INF 3mg/kg q8w (IV) after initial dosing at 0, 2 and 6 weeks+MTX

CT-P13 3mg/kg q8w after initial

dosing at 0, 2 and 6

weeks+MTX

Zhang (2006) Parallel 18

weeks 18


INF 3 mg/kg at 0, 2, 6 and

14 weeks (IV)+MTX

aRepresents the study duration that was analyzed (at times shorter than full study length if an adaptive design was present or if only interim data has was reported to date)

bCertain studies included treatments that are and treatments that are not eligible for the review or used both standard and non-standard doses; this table lists all treatments as they

appear in the study. However, only the included treatments listed in Table 2 are standard doses were included in the analysis.

ABA = abatacept; ABP501 = biosimilar adalimumab; ABNAI = AnBaiNuo (biosimilar etanercept); ADA = adalimumab; BAR = baricitinib; bid = twice daily; biw = twice weekly; CERTO =

certolizumab pegol; csDMARD = conventional synthetic disease modifying anti-rheumatic drug; CT-P13 = biosimilar infliximab; ETN = etanercept; GOL = golimumab; HCQ =

hydroxychloroquine; HD203 = biosimilar etanercept; INF = infliximab; IV = intravenous; MTX = methotrexate; P.O. = orally; qw = every week; q2w = every two weeks; q4w = every four

weeks; q8w = every eight weeks; qd = every day; RIT = rituximab; SAR = sarilumab; SB2 = biosimilar of infliximab; SB4 = biosimilar of etanercept; SB5 = biosimilar adalimumab; SC =

subcutaneous; SIR = sirukumab; SSZ = sulfasalazine; TOC = tocilizumab; TOF = tofacitinib; ZRC-3197 = biosimilar of adalimumab

Table 44. Table of Patient Characteristics of Included Studies

Author Year, Trial

name (if known) Treatment Groups

a

No. of

participants

Age, mean

(SD/range) years Female, n (%)

Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

349

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

Bae 2016, HERA

Study

ETN 25mg biw (SC)+MTX 115 51.3 (12.4) 101 (85.6) 0 (0) 8.05 (7.43)

HD203 25mg+MTX 118 51.0 (12.0) 101 (87.8) 0 (0) 7.19 (7.39)

Peterfy 2016, RA-

SCORE

Placebo + MTX 63 50.3 (11.9) 48 (76.2) NR 4.4 (3.1)

RIT 500mg on day 1 and 15 (IV) + MTX 62 48.7 (11.1) 45 (72.6) NR 4.5 (2.9)

RIT 1000mg on day 1 and 15 (IV) + MTX 60 50.7 (11.7) 50 (83.3) NR 4.9 (2.9)

Tanaka 2016

Placebo + MTX 49 51.1 (12.0) 39 (80) 0 (0) 5.06 (3.96)

BAR 1mg/day (P.O.) + MTX 24 52.7 (12.8) 22 (92) 0 (0) 6.22 (3.27)

BAR 2mg/day (P.O.) + MTX 24 56.1 (11.5) 21 (88) 0 (0) 6.32 (4.18)

BAR 4mg/day (P.O.) + MTX 24 57.5 (10.4) 19 (79) 0 (0) 5.86 (3.95)

BAR 8mg/day (P.O.) + MTX 24 53.6 (11.3) 17 (71) 0 (0) 5.55 (4.62)

Choe 2015, NR

INF 3mg/kg q8w (IV) + MTX 293 52.6(11.7) 236 (80.5) 254 (86.7) 6.6 (6.0)

SB2 3mg/kg q8w (IV) + MTX 291 51.6(11.9) 232 (79.7) 252 (86.6) 6.3 (5.9)

Emery 2015, NR

ETN 50mg qw (SC) + MTX 297 51.6 (11.63) 253 (85.2) 273 (91.9) 6.20 (4.41)

SB4 50mg qw (SC) + MTX 299 52.1 (11.72) 249 (83.3) 279 (93.3) 6.0 (4.20)

Furst 2015,

DOSEFLEX

Placebo + MTX 69 51.5 (13.2) 56 (81.2) NR 6.5 (4.6)

CERTO 200mg q2w (SC) 70 55.6 (10.7) 49 (70.0) NR 5.9 (4.20)

350

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

CERTO 400mg q2w (SC) 70 53.1 (13.8) 58 (82.9) NR 6.4 (4.7)

Genovese 2015,

MOBILITY

Placebo + MTX 398 50.9 (11.2) 322 (81) 343 (86.2)

9.1

(0.3-44.0)

SAR 150mg q2w (SC) + MTX 400 50.1 (11.9) 320 (80) 345 (86.3)

9.5

(0.3-44.7)

SAR 200mg q2w (SC) + MTX 399 50.8 (11.8) 339 (85) 343 (86.0)

8.6

(0.3-34.2)

Jani 2015, NR

ADA 40 q2w (SC) + MTX 60 45 (10.92) 48 (80.0) NR 4.0 (4.98)

ZRC-3197 40mg q2w (SC) + MTX 60 45 (11.06) 51 (85.0) NR 3.3 (4.19)

Keystone 2015,

I4V-MC-JADA

MTX 98 49 (12) 85 (87) NR 5.4 (4.3)

BAR 1mg/day (P.O.) + MTX 49 53 (11) 42 (86) NR 5.5 (3.9)




Li 2015, NR

MTX 132 46.7 (12.2) 104 (78.8) 0 (0) 8.0 (7.3)

GOL 50mg q4w (SC) + MTX 132 47.7 (11.5) 110 (83.3) 0 (0) 7.6 (7.1)

Takeuchi 2015, NR INF 3mg/kg q8w after initial dosing at 0, 2 and 6

51 53.8 (13.4) 41 (80.4) 0 (0) 8.0 (7.3)

351

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

weeks (IV) + MTX

CT-P13 3mg/kg q8w after initial dosing at 0, 2

and 6 weeks (IV) + MTX 50 54.5 (13.0) 40 (80.0) 0 (0) 7.1 (7.3)

Placebo + MTX 61 51.4 (11.0) 46 (75.4) 43 (70.5) 6.4 (8.1)

Weinblatt 2015, NR

ADA 40mg (SC) q2w + MTX 59 52.8 (11.4) 48 (81.4) 47 (79.7) 6.1 (7.5)

CLZ 25mg q4w (SC) + MTX 59 47.4 (11.0) 46 (78.0) 43 (72.9) 5.0 (5.6)

CLZ 100mg q4w (SC) + MTX 60 49.9 (14.0) 53 (88.3) 46 (76.7) 5.6 (6.1)

CLZ 200mg q4w (SC) + MTX 60 46.4 (11.9) 49 (81.7) 50 (83.3) 6.0 (7.2)

CLZ 100mg q4w (SC) 60 55.0 (12.2) 52 (86.7) 47 (78.3) 7.4 (6.8)

CLZ 200mg q4w (SC) 59 50.0 (12.5) 49 (83.1) 46 (78.0) 5.0 (5.5)

Dougados 2013,

ACT-RAY

Placebo + TOC 8mg/kg q4w (IV) 32 55.8 (10.46) 21 (65.6) NR NR

TOC 8mg/kg q4w (IV) + MTX 31 55.2 (14.12) 24 (77.4) NR NR

Gashi 2014, NR

RIT 2mg + MTX 20 47 (37-69) 15 NR NR

ETN 25mg BID + MTX 13 44 (19-69) 8 NR NR

Smolen 2014, NR

Placebo + csDMARD 19 46.2 (10.2) 11 (57.9) 18 (94.7) 7.5 (6.9)

SIR 100mg q2w (SC) + csDMARD 17 50.1 (10.7) 14 (82.4) 16 (94.1) 7.3 (6.7)

Yoo 2013, INF 3mg/kg q8w (IV) after initial dosing at 0, 2 304 50 (21-74) 256 (84.2) 222 (73.0) NR

352

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

PLANETRA and 6 weeks + MTX

CT-P13 3mg/kg q8w after initial dosing at 0, 2

and 6 weeks + MTX 302 50 (18-75) 245 (81.1) 220 (72.8) NR

Loet 2008, OMEGA

ANA 100mg/day (SC) + MTX 957 56 (20-86) 757 (79.1) 934 (97.6) 7.3 (0-50.5)

ANA 100mg/day (SC) + SSZ 102 57 (23-80) 79 (77.5) 98 (96.1) 6.1 (0.4-48.6)

ANA 100mg/day (SC) + HCQ 127 57 (24-80) 113 (89.0) 126 (99.2) 9.0 (0-51.9)

Ciconelli 1996, NR

Placebo + SSZ 2g/day 18 43.9 (9.7) 18 (100) NR 6.9 (6.9)

Methylprednisone 5mg/kg (IV pulses)

+ SSZ 2g/day

20 43.2 (11.9) 20 (100) NR 6.1 (4.6)

Mladenovic 1995,

NR

Placebo 102 52.8 (28-73) 77 NR 8.3 (0.8-26.3)

LEF 5mg after 50mg loading dose 95 50.3 (24-74) 79 NR 7.7 (0.8-31.3)



Yamamoto 2014,

HIKARI

Placebo 114 55.4 (9.8) 88 (77.2) 0 (0) 5.8 (4.3)


weeks (SC) 116 56.0 (10.2) 83 (71.6) 0 (0) 5.4 (4.0)

Yazici 2012, ROSE Placebo + csDMARD 205 55.8 (12.42) 172 (83.9) 170 (82.9) 8.52 (9.05)

353

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

study TOC 8mg/kg q4w (IV) + csDMARD 409 55.2 (12.06) 325 (79.5) 328 (80.2) 8.62 (8.93)

Van de Putte 2004,

NR

Placebo 70 50.2 (11.9) 57 (81) NR 9.4 (6.6)

ADA 20mg qw (SC) 72 53.7 (13.3) 61 (85) NR 10.4 (7.3)

ADA 40mg qw (SC) 70 52.6 (11.6) 57 (81) NR 10.0 (7.0)

ADA 80mg qw (SC) 72 53.2 (12.3) 50 (69) NR 10.1 (7.9)

O’Dell 2002, NR

MTX17.5mg qw + HCQ 200mg bid 58 50.9 (28-68) 45 (78) NR 7.9 (10.0)

MTX 17.5mg qw + SSZ 500mg bid then 1g bid

at 6 mo 55 52.5 (25-71) 46 (84) NR 5.8 (5.9)

MTX 17.5mg qw + HCQ 200mg bid + SSZ

500mg bid then 1g bid at 6 mo 58 48.9 (26-66) 44 (76) NR 6.9 (8.4)

Kim 2007, NR

Placebo + MTX 63 49.8 (10.5) 54 (85.7) 0 (0) 6.9 (4.5)

ADA 40mg q2w (SC) + MTX 65 48.5 (10.2) 62 (95.4) 0 (0) 6.8 (4.2)

Yamamoto 2014, J-

RAPID

Placebo + MTX 77 51.9 (11.1) 66 (85.7) 0 (0) 5.8 (4.1)


weeks (SC) + MTX 72 54.3 (10.6) 58 (80.6) 0 (0) 6.0 (4.1)


weeks (SC) + MTX 82 50.6 (11.4) 69 (84.1) 0 (0) 5.6 (4.2)


weeks (SC) + MTX 85 55.4 (10.3) 69 (81.2) 0 (0) 6.0 (3.9)

354

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

Choy 2012, NR

Placebo + MTX 121 55.6 (11.7) 80 (66.1) (99.2) 9.9 (7.8)

CERTO 400mg q4w (SC) + MTX 126 53.0 (12.3) 91 (72.2) (99.2) 9.4 (7.5)

Weinblatt 2013,

GO-FURTHER

Placebo + MTX 197 51.4 (11.26) 157 (79.7) (80.4) 7.0 (7.24)

GOL 2mg/kg q8w after initial dosing at 0 and 4

weeks (IV) + MTX 395 51.9 (12.55) 326 (82.5) (80.4) 6.9 (7.00)

MacIssac 2014, NR

Placebo + csDMARD 31 50 (11) 27 (90) NR NR

INF 3mg/kg at 0, 2, 6 and 14 weeks (IV) +

csDMARD 30 50 (10) 28 (93) NR NR

Abe 2006, NR

Placebo + MTX 47 55.1 (7.6) 35 (74.5) 0 (0) 7.5 (5.0)

INF 3mg/kg at 0, 2 and 6 weeks (IV) + MTX 49 55.2 (10.9) 40 (81.6) 0 (0) 9.1 (7.4)

INF 10mg/kg (IV) + MTX 51 56.8 (10.5) 40 (78.4) 0 (0) 7.1 (5.1)

Kaneko 2015,

SURPRISE

MTX + TOC 8 mg/kg q4w (IV) 118 55.8 (11.7) 100 (87.0) NR 3.6 (3.2)

TOC 8 mg/kg q4w (IV) 115 56.3 (2.7) 96 (86.5) NR 3.8 (3.1)

Dougados 2013,

ACT-RAY

TOC 8mg/kg q4w (IV) + Placebo (of MTX) 276 53.6 (11.9) 217 (78.6) NR 8.3 (8.4)

TOC 8mg/kg q4w (IV) + MTX 277 53.0 (13.4) 227 (81.9) NR 8.2 (8.0)

Kremer 2011,

LITHE Placebo + MTX 393 51.3 (12.4) (83) NR

9.0

(0.5-44.3)

355

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

TOC 4mg/kg q4w (IV) + MTX 399 51.4 (12.6) (84) NR

9.4

(0.5-43.2)

TOC 8 mg/kg q4w (IV) + MTX 398 53.4 (11.7) (82) NR

9.3

(0.6-48.8)

van Vollenhoven

2012, ORAL

Standard

Placebo to TOF 5mg bid (P.O.) + MTX 56 55.5 (13.7) 43 (76.8) 40 (71.4) 6.9

Placebo to TOF 10mg bid (P.O.) + MTX 52 51.9 (13.7) 39 (75.0) 35 (67.3) 9.0

TOF 5mg bid (P.O.) + MTX 204 53.0 (11.9) 174 (85.3) 151 (74.0) 7.6

TOF 10mg bid (P.O.) + MTX 201 52.9 (11.8) 168 (83.6) 143 (71.1) 7.4

ADA 40mg q2w (SC) + MTX 204 52.5 (11.7) 162 (79.4) 148 (72.5) 8.1

Combe 2006, NR

Placebo + SSZ 2-3g/day (P.O.) 50 53.3 (12.8) 41.0 (82.0) NR 5.6 (4.4)

ETN 25mg biw (SC) 103 51.3 (13.5) 81.0 (78.6) NR 7.1 (5.2)

ETN 25mg biw (SC) + SSZ 2-3g/day (P.O.) 101 50.6 (12.3) 81.0 (80.2) NR 6.5 (5.1)

Conaghan 2013,

ASSET

Placebo + MTX 23 52.5 (11.5) 16 (69.6) 19 (82.6) 2.35 (1.42)

ABA 10mg/kg q4w (IV) + MTX 27 51.7 (11.2) 16 (59.3) 26 (96.3) 2.14 (1.50)

Emery 2010,

SERENE

Placebo + MTX 172 52.16 (12.390) 147 (85.5) 142 (82.6) 7.48 (7.64)

RIT 500mg at 1 and 15 days (IV) + MTX 168 51.91 (12.926) 133 (79.6) 134 (80.2) 7.10 (6.97)

RIT 1000mg infusions at 1 and 15 days (IV) + 172 51.30 (12.644) 138 (81.2) 137 (80.6) 6.61 (7.29)

356

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

MTX

Fleischmann 2012,

NR

Placebo 59 53 (13.7) 52 (88.1) 43 (72.9)

10.8

(0.7-44.0)

TOF 5mg bid (P.O.) 49 54 (13.5) 43 (87.8) 36 (73.5)

8.1

(0.5-38.0)

TOF 10mg bid (P.O.) 61 52 (10.9) 53 (86.9) 44 (72.1)

8.6

(0.5-38.0)

TOF 15mg bid (P.O.) 57 53 (13.0) 50 (87.7) 46 (80.7)

8.7

(0.8-38.0)

ADA 40mg q2w (SC) 53 54 (11.9) 45 (84.9) 43 (81.1)

7.7

(0.8-50.0)

TOF 1mg bid (P.O.) 54 55 (13.3) 46 (85.2) 44 (81.5)

9.4

(0.6-38.0)

TOF 3mg bid (P.O.) 51 53 (12.2) 44 (86.3) 38 (74.5)

9.9

(0.8-30.0)

Furst 2003, STAR

Placebo + Standard Therapy 318 55.8 (12.4) 252 (79.2) 273 (85.8) 11.5 (9.7)

ADA 40mg q2w (SC) + csDMARD 318 55.0 (12.8) 253 (79.6) 283 (89.0) 9.3 (8.8)

357

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

Gabay 2013,

ADACTA

ADA 40mg q2w (SC) 163 53.3 (12.4) 133 (82) 133 (82) 6.3 (6.9)

TOC 8mg/kg q4w (IV) 163 54.4 (13.0) 129 (79) 145 (89) 7.3 (8.1)

Hobbs 2015, NR

Placebo + Standard Therapy 104 55.5 (12.8) 86 (82.7) 90 (86.5) 7.4 (8.1)

ETN 50mg qw (SC) + Standard Therapy 106 56.5 (12.1) 75 (70.8) 91 (85.8) 8.3 (11.2)

Jobanputra 2012,

RED SEA

ADA 40mg q2w (SC) + csDMARD 60 55.0 (12.5) 45 (75) NR 7.0 (3.3-13.0)

ETN 50mg qw (SC) + csDMARD 60 53.2 (13.4) 42 (70) NR 5.5 (2.0-14.5)

Kaine 2012,

ALLOW

Placebo + MTX 80 49.1 (12.8) 67 (83.8) 75 (93.8) 6.2 (5.8)

ABA 125mg qw (SC)+MTX 40 48.9 (14.2) 34 (85.0) 38 (95.0) 7.4 (7.7)

Kameda 2010,

JESMR

ETN 25mg biw (SC) 74 58.1 (12.6) 62 (87.3) 0 (0) 10.6 (10.5)

ETN 25mg biw (SC)+MTX 77 56.5 (11.1) 60 (80.0) 0 (0) 8.1 (7.7)

Kim 2012, APPEAL

csDMARD + MTX 103 48.5 (11.3) 91 (88.4) 0 (0) 6.9 (8.5)

ETN 25mg biw (SC)+MTX 197 48.4 (12.0) 180 (91.4) 0 (0) 6.5 (7.3)

Kim 2013, NR

Placebo + MTX 72 51.4 (11.4) 64 (88.9) 0 (0)

9.8

(0.7-45.7)

INF 3mg/kg at 0, 2, 6, 14 and 22 weeks (SC) +

MTX 71 49.3 (10.1) 64 (90.1) 0 (0)

7.4

(0.6-35.7)

Kremer 2003, NR Placebo + MTX 119 54.7 79 (66) 104 (87) 8.9 (8.3)

358

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

(23-80)

ABA 2mg/kg (IV) + MTX 105

54.4

(23-80)

66 (63) 91 (87) 9.7 (8.1)

ABA 10mg/kg (IV) + MTX 115

55.8

(17-83)

87 (75) 100 (87) 9.7 (9.8)

Kremer 2010, NR

Placebo + MTX 129 50.2 (51.0) 103 (79.8) 92 (71.3) 7.4 (5.6)

GOL 2mg/kg q12w (IV) 128 49.9 (51.0) 107 (83.6) 93 (72.7) 7.4 (4.9)

GOL 4mg/kg q12w (IV) 129 48.4 (50.0) 105 (81.4) 86 (66.7) 8.4 (6.6)

GOL 2mg/kg q12w (IV)+MTX 129 49.7 (51.0) 99 (76.7) 88 (68.2) 8.1 (5.2)

GOL 4mg/kg q12w (IV)+MTX 128 49.6 (52.0) 103 (80.5) 88 (68.8) 9.4 (7.4)

Kremer 2012, NR

Placebo 69 53 (13.4) 56 (81.2) 58 (84.1)

9.2

(0.5-39.0)

TOF 5mg/day (P.O.) + MTX 71 52 (12.8) 57 (80.3) 63 (88.7)

9.0

(0.5-46.0)

TOF 10mg/day (P.O.) + MTX 74 56 (10.4) 55 (74.3) 64 (86.5)

7.5

(0.5-30.0)

TOF 15mg/day (P.O.) + MTX 75 54 (11.1) 66 (88.0) 65 (86.7) 10.8

359

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

(0.6-65.0)

TOF 20mg/day (P.O.) + MTX 80 54 (10.8) 63 (78.8) 72 (90.0)

9.8

(0.6-46.0)

TOF 1mg/day (P.O.) + MTX 70 52 (11.6) 57 (81.4) 61 (87.1)

11.8

(0.5-40.8)

TOF 3mg/day (P.O.) + MTX 68 51 (14.9) 52 (76.5) 54 (79.4)

9.4

(0.5-43.3)

Nishimoto 2009,

SATORI

Placebo + MTX 64 50.8 (12.2) 48 (75.0) 0 (0) 8.7 (7.1)

TOC 8mg/kg q4w (IV) + Placebo (of MTX) 61 52.6 (10.6) 55 (90.2) 0 (0) 8.5 (8.4)

O'Dell 2013, NR

SSZ 1g/day for 6 weeks, increased to 2g/day +

HCQ 400mg qd 178 57.8 (13.0) 77 (43.3) 161 (90.4) 5.5 (9.3)

ETN 50mg qw (SC) + SSZ 175 56.0 (13.2) 85 (48.6) 146 (83.4) 4.9 (8.0)

Pope 2014,

CAMEO

ETN 50mg qw (SC) + MTX 107 54.4 (12.7) 84.0 (78.5) 103 (96.3) 9.3 (9.1)

ETN 50mg qw (SC) 98 54.3 (11.9) 72.0 (73.5) 96 (98.0) 9.0 (8.2)

Schiff 2013,

AMPLE

ABA 125mg qw (SC) 318 NR NR NR NR

ADA 40mg q2w (SC) + MTX 328 NR NR NR NR

Takeuchi 2013, NR Placebo + MTX 66 53.4 (12.0) 52 (78.8) 0 (0) NR

360

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

ABA 2mg/kg (IV) + MTX 67 52.5 (11.1) 57 (85.1) 0 (0) NR

ABA 10mg/kg (IV) + MTX 62 53.4 (11.3) 49 (80.3) 0 (0) NR

Takeuchi 2013, NR

Placebo + MTX 176 50.4 (11.9) 140 (79.9) 0 (0) 3.0 (2.7)

ETN 10mg biw (SC) 192 51.5 (12.2) 154 (80.2) 0 (0) 2.9 (2.7)

ETN 25mg biw (SC) 182 51.8 (11.1) 145 (79.7) 0 (0) 3.0 (2.6)

Takeuchi 2012,

GO-MONO

Placebo 105 52.4 (11.1) 86 (81.9) 0 (0) 9.2 (8.6)

GOL 50mg q4w (SC) 101 52.9 (11.3) 81 (80.2) 0 (0) 8.1 (8.4)

GOL 100mg q4w (SC) 102 51.6 (11.9) 85 (83.3) 0 (0) 9.4 (8.5)

Tanaka 2011, NR

Placebo + MTX 28 50.6 (12.4) 25 (89.3) 0 (0)

8.4

(0.6-24.0)

TOF 1mg bid (P.O.) + MTX 28 52.0 (9.4) 21 (75.0) 0 (0)

5.7

(0.4-31.0)

TOF 3mg bid (P.O.) + MTX 28 53.3 (12.1) 24 (88.9) 0 (0)

8.7

(0.6-23.0)

TOF 5mg bid (P.O.) + MTX 28 50.0 (9.8) 22 (81.5) 0 (0)

8.3

(1.1-26.0)

TOF 10mg bid (P.O.) + MTX 28 50.6 (10.0) 25 (96.2) 0 (0) 7.1

361

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

(0.5-20.1)

Tanaka 2012, GO-

FORTH

Placebo + MTX 88 51.1 (11.6) 73 (83.0) 0 (0) 8.7 (8.2)

GOL 50mg q4w (SC) + MTX 86 50.4 (9.9) 73 (84.9) 0 (0) 8.8 (8.8)

GOL 100mg q4w (SC) + MTX 87 50.0 (12.2) 78 (89.7) 0 (0) 8.1 (6.5)

Weinblatt 2003,

ARMADA

Placebo + MTX 62 56.0 (10.8) 51 (82.3) NR 11.1 (8.0)

ADA 20mg q2w (SC) + MTX 69 53.5 (12.4) 52 (75.4) NR 13.1 (8.1)

ADA 40mg q2w (SC) + MTX 67 57.2 (11.4) 50 (74.6) NR 12.2 (11.1)

ADA 80mg q2w (SC) + MTX 73 55.5 (11.7) 55 (75.3) NR 12.8 (9.9)

Weinblatt 2012,

REALISTIC

Placebo + Standard Therapy 212 53.9 (12.7) 169 (79.7) NR 8.9 (9.1)


weeks (SC) + Standard Therapy 851 55.4 (12.4) 660 (77.6) NR 8.6 (8.8)

Chen 2009, NR

Placebo + MTX 12

53.0

(35.0-73.0)

11 (91.7) 0 (0)

8.3

(1.3-15.6)

ADA 40mg q2w (SC) + MTX 35

53.0

(29.0-75.0)

26 (74.3) 0 (0)

6.2

(0.3-19.1)

Cohen 2002, NR

Placebo + MTX 74 53.0 (85.1) 67 (90.5) 7.8

ANA 0.1mg/kg qd (SC) + MTX 74 53.0 (79.7) 67 (90.5) 8.8

362

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

ANA 0.4mg/kg qd (SC) + MTX 77 52.8 (76.6) 64 (83.1) 7.0

ANA 1.0mg/kg qd (SC) + MTX 59 49.0 (84.7) 51 (86.4) 6.5

ANA 2.0mg/kg qd (SC) + MTX 72 54.1 45 (62.5) 66 (91.7) 8

ANA 0.04mg/kg qd (SC) + MTX 63 52.6 49 (77.8) 56 (88.9) 6.3

Cohen 2004, NR

Placebo + MTX 251 57 188 (75) 218 (87) 10

ANA 100mg qd (SC) + MTX 250 56 198 (79) 215 (86) 11

Edwards 2004, NR

Placebo + MTX 40 54 (11) 32 (80.0) NR 11.0 (7.1)

RIT 1000mg at 1 and 15 days (IV) 40 54 (10) 29 (72.5) NR 9.3 (5.5)

RIT 1000 mg at 1 and 15 days (IV) + CTX 41 53 (10) 34 (82.9) NR 9.8 (6.1)

RIT 1000mg at 1 and 15 days (IV) + MTX 40 54 (12) 30 (75.0) NR 11.5 (7.3)

Fleischmann 2009,

FAST4WARD

Placebo 109 54.9 (11.6) 97 (89.0) NR 10.4 (9.6)

CERTO 400mg q4w (SC) 111 52.7 (12.7) 87 (78.4) NR 8.7 (8.2)

Genovese 2008,

TOWARD

Placebo + csDMARD 415 54 (13) 349 (84) 299 (72) 9.8 (9.1)

TOC 8mg/kg q4w (IV) + csDMARD 805 53 (13) 652 (81) 580 (72) 9.8 (8.8)

Kavanaugh 2000,

NR

Placebo + MTX 7 44.6 (12.5) 6 (86) NR 4.9 (3.9)

INF 5mg/kg q8w (IV) + MTX 7 47.0 (6.9) 5 (71) NR 7.4 (2.7)

363

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years



Kay 2008, NR

Placebo + MTX 35

52.0

(46.0-66.0)

26 (74.3) NR

5.6

(1.4-10.9)

GOL 50mg q4w (SC) + MTX 35

57.0

(50.0-64.0)

30 (85.7) NR

8.2

(4.1-14.3)


48.0

(41.0-63.0)

23 (67.6) NR

8.2

(2.9-12.8)


57.5

(47.0-66.0)

26 (76.5) NR

6.3

(3.4-14.1)


53.5

(45.0-65.0)

27 (79.4) NR

9.0

(4.1-14.2)

Keystone 2004, NR

Placebo + MTX 200 56.1 (12.0) 146 (73.0) 166 (83.0) 10.9 (8.8)

ADA 40mg q2w (SC) + MTX 207 56.1 (13.5) 158 (76.3) 173 (83.6) 11.0 (9.2)

ADA 20mg qw (SC) + MTX 212 57.3 (10.5) 160 (75.5) 181 (85.4) 11.0 (9.4)

Keystone 2008,

RAPID1

Placebo + MTX 199 52.2 (11.2) (83.9) NR 6.2 (4.4)

CERTO 200mg q2w after loading dose of 400mg 393 51.4 (11.6) (82.4) NR 6.1 (4.2)

364

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

at 0, 2 and 4 weeks (SC) + MTX

CERTO 400mg q2w after loading dose of 400mg

at 0, 2 and 4 weeks (SC) + MTX 390 52.4 (11.7) (83.6) NR 6.2 (4.4)

Keystone 2009,

GO-FORWARD

Placebo + MTX 133

52

(42-58)

109 (82.0) NR

6.5

(3.1-11.9)

GOL 100mg qw (SC) 133

51

(42-59)

105 (78.9) NR

5.9

(2.4-12.2)

GOL 50mg qw (SC) + MTX 89

52

(43-57)

72 (80.9) NR

4.5

(2.1-9.7)

GOL 100mg qw (SC) + MTX 89 50 (45-56) 72 (80.9) NR

6.7

(2.4-14.3)

Klareskog 2004,

TEMPO

Placebo + MTX 228 53.0 (12.8) 180 (79) NR 6.8 (5.5)

ETN 25mg biw (SC) 223 53.2 (13.8) 171 (77) NR 6.3 (5.1)

ETN 25mg biw (SC) + MTX 231 52.5 (12.4) 171 (74) NR 6.8 (5.4)

Kremer 2006, AIM

Placebo + MTX 219 50.4 (12.4) 179 (81.7) 193 (88.1) 8.9 (7.1)

ABA 10mg/kg q4w after loading at 1, 15 and 30

days (IV) + MTX 433 51.5 (12.9) 337 (77.8) 379 (87.5) 8.5 (7.3)

Lan 2004, NR Placebo + MTX 29 50.79 26 (90) 0 (0) NR

365

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

ETN 25mg biw (SC) + MTX 29 47.55 24 (83) 0 (0) NR

Maini 1998, NR

Placebo + MTX 14 48.8 (12.3) 10 (71) 13 (93) 7.6 (4.0)

INF 3mg/kg at 0, 2, 6, 10 and 14 days (IV) +

MTX 15 58.9 (10.0) 10 (67) 14 (93) 12.1 (9.0)

INF 3mg/kg at 0, 2, 6, 10 and 14 days (IV) 14 47.0 (15.0) 12 (86) 14 (100) 7.8 (4.3)


MTX 14 50.4 (13.4) 11 (79) 15 (100) 11.1 (7.4)



MTX 14 53.6 (14.0) 10 (71) 13 (93) 14.3 (12.1)


Maini 1999,

ATTRACT

Placebo + MTX 88

51

(19.0-75.0)

70 (80) 78 (89)

8.9

(0.8–35.0)

INF 3mg/kg q8w after infusions at 0, 2 and 6

weeks + MTX 86

56

(25.0-74.0)

70 (81) 80 (93)

8.4

(0.7–45.0)


weeks + MTX 86

51

(19.0-78.0)

66 (77) 76 (88)

7.2

(0.5–33.8)

INF 10mg/kg q8w after infusions at 0, 2 and 6 87 55 67 (77) 79 (91) 9.0

366

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

weeks + MTX (19.0-80.0) (0.5–49.9)


weeks + MTX 81

52

(23.0-74.0)

59 (73) 76 (94)

8.7

(0.6–47.0)

Maini 2006,

CHARISMA

MTX 49 50.9 38 (78) NR 0.94

TOC 4mg/kg q4w (IV) 54 49.3 41 (76) NR 0.82

TOC 8mg/kg q4w (IV) 52 50.1 38 (73) NR 0.77

TOC 4mg/kg q4w (IV) + MTX 49 50.2 37 (76) NR 0.65


TOC 2mg/kg q4w (IV) 53 52.2 44 (83) NR 0.77


Miyasaka 2008,

CHANGE

Placebo 87 53.4 (12.8) 67 (77.0) 0 (0) 8.4 (8.2)

ADA 20mg q2w (SC) 87 54.8 (12.5) 69 (79.3) 0 (0) 10.0 (7.7)

ADA 40mg q2w (SC) 91 56.9 (10.3) 72 (79.1) 0 (0) 9.9 (7.9)

ADA 80mg q2w (SC) 87 54.3 (10.9) 72 (82.8) 0 (0) 9.5 (8.3)

Moreland 1999, NR

Placebo 80 51 (76) (89) 12

ETN 10mg q2w (SC) 76 53 (84) (96) 13

367

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

ETN 25mg q2w (SC) 78 53 (74) (94) 11

Schiff 2008,

ATTEST

Placebo + MTX 110 49.4 (11.5) (87.3) (76.4) 8.4 (8.6)

ABA 10mg/kg q4w (IV) after initial infusions on

days 1, 15 and 29 (IV) + MTX 156 49.0 (12.5) (83.3) (80.8) 7.9 (8.5)

INF 3mg/kg q8w after initial infusions on days 1,

15, 43 and 85 (IV) + MTX 165 49.1 (12.0) (82.4) (80.6) 7.3 (6.2)

Smolen 2008,

OPTION

Placebo + MTX 204 50.6 (12.1) 159 (77.9) NR 7·8 (7·2)

TOC 4mg/kg q4w (IV) + MTX 214 51·4 (12·8) 175 (82.2) NR 7·4 (7·4)

TOC 8mg/kg q4w (IV) + MTX 205 50·8 (11·8) 175 (85.4) NR 7·5 (7·3)

Smolen 2009,

RAPID2

Placebo + MTX 127 51.5 (11.8) 107 (84.3) NR 5.6 (3.9)

CERTO 200mg q2w after initial dose of 400mg

at 0, 2 and 4 weeks (SC) + MTX 246 52.2 (11.1) 206 (83.7) NR 6.1 (4.1)

CERTO 400mg q2w after initial dose of 400mg

at 0, 2 and 4 weeks (SC) + MTX 246 51.9 (11.8) 192 (78.0) NR 6.5 (4.3)

Weinblatt 1999, NR

Placebo + MTX 30 53 22 (73) 25 (83) 13

ETN 25mg biw (SC) + MTX 59 48 53 (90) 45 (76) 13

O'Dell 1996, NR

MTX 36 50 (21-69) 25 (69) NR 10 (8)

HCQ 200mg bid + SSZ 500mg bid 35 49 (36-63) 26 (74) NR 6 (6)

368

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

MTX + HCQ 200mg bid + SSZ 500mg bid 31 50 (27-67) 20 (65) NR 10 (10)

Van Vollenhoven

2011,

AUGUST II

Placebo + MTX 76 54 (10.3) 64 (84) NR 8.4 (7.4)

Atacicept 150mg biw for 4 weeks then 150mg

SC qw for 21 weeks (SC) + MTX 78 53 (11.3) 65 (83) NR 7.8 (7.3)

Atacicept 150mg biw for 25 weeks (SC) + MTX 78 53 (13.2) 66 (85) NR 7.3 (6.5)

ADA 40mg q2w (SC) + MTX 79 53 (11.5) 64 (81) NR 8.8 (7.4)

van der Heijde

2013, ORAL scan

(PLACEBO to TOF 5mg bid (P.O.) + MTX) +

MTX 81 53.2 (11.5) 65 (80.2) 36 (44.4)

8.8

(0.6-30.8)

(PLACEBO to TOF 10mg bid (P.O.) + MTX) +

MTX 79 52.1 (11.8) 72 (91.1) 36 (45.6)

9.5

(0.4-43.5)

TOF 5mg bid (P.O.) + MTX 321 53.7 (11.6) 269 (83.8) 152 (47.4)

8.9

(0.3-43.0)

TOF 10mg bid (P.O.) + MTX 316 52.0 (11.4) 273 (86.4) 144 (45.6)

9.0

(0.3-42.0)

Van Riel 2006,

ADORE

ETN 25mg biw (SC) 159 53 126 (79.2) 158 (99.4) 10.0

ETN 25mg biw (SC) + MTX 155 54 119 (76.8) 153 (98.7) 9.8

Zhang 2006, NR PLACEBO + MTX 86 48.9 (8.0) 73 (84.9) 0 (0) 8.0 (6.2)

369

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

INF 3 mg/kg at 0, 2, 6 and 14 weeks (IV) + MTX 87 47.9 (10.1) 74 (85.1) 0 (0) 7.1 (6.2)

Dougados 2017,

RA-BUILD

PBO + csDMARD 228 51 (13) 189 (83) NR 7 (8)

BAR 2mg/day (P.O.) + csDMARD 229 52 (12) 184 (80) NR 8 (8)

BAR 4mg/day (P.O.) + csDMARD 227 52 (12) 187 (82) NR 8 (8)

Machado 2014, NR DMARD + MTX 142 48.6 (11.3) 128 (90.1) 65 (45.8) 9.0 (7.5)

ETN 50mg qw (SC) + MTX 281 48.4 (12.0) 248 (88.3) 134 (47.7) 7.9 (7.0)

Chen 2016, NR

Placebo 119 48.10 (9.84) 107 (89.9) 0 (0) NR

Anbainuo 25mg q2w (SC) 239 49.89 (9.98) 213 (89.1) 0 (0) NR

Smolen 2016,

EXXELERATE

ADA 40mg q2w (SC) + MTX

safety (457);

efficacy

(454)

52.9 (12.8) 362 (79) NR 5.8 (6.9)

CERTO 200mg q2w after initial 400mg at 0, 2

and 4 weeks (SC) + MTX

safety (457);

efficacy

(454)

53.5 (12.3) 360 (79) NR 6.0 (6.9)

Burmester 2016,

MONARCH SAR 200mg q2w (SC) 184 50.9 (12.6) 157 (85.3) 171 (92.9) 8.1 (8.1)

ADA 40mg q2w (SC) 185 53.6 (11.9) 150 (81.1) 164 (88.6) 6.6 (7.8)

Kennedy 2014,

ALTARA Study

Placebo 44 48.8 (14.0) 37 (84.1) 29 (65.9) 7.2 to 9.3

(overall)

ADA 40mg q2w (SC) + csDMARD 85 50.6 (13.3) 68 (80.0) 48 (56.5) 7.2 to 9.3

(overall)

Pateclizumab 360mg

+ csDMARD

85 50.2 (13.1) 78 (91.8) 53 (62.4) 7.2 to 9.3

(overall)

Taylor 2017, RA Placebo 488 53 (2) 382 (78) NR 10 (9)

370

Author Year, Trial


a

No. of

participants

Age, mean


Caucasian,

n (%)

Disease

duration, mean

(SD/range)

years

BEAM BAR 4mg qd (P.O.) + MTX 487 54 (2) 375 (77) NR 10 (9)

ADA 40mg q2w (SC) + MTX 330 53 (12) 251 (76) NR 10 (9)

Weinblatt 1999, NR Placebo + MTX 30 53 22 (73) 25 (83) 13

ETN 25mg biw (SC) + MTX 59 48 53 (90) 45 (76) 13

Smolen 2014, NR

Placebo + csDMARD 30 54.1 (12.7) 25 (83.3) 19 (63.3) 7.7 (6.8)





Samsung Bioepisb

Co. 2016 ADA 40mg q2w (SC) + MTX 273 52.5 (11.91) 224 (82.1) NR NR

SB5 40mg q2w (SC) + MTX 271 49.8 (12.67) 217 (80.1) NR NR

Hoffmann-La

Rocheb 2015

Placebo + csDMARD 19 54 (45 to 69) 17 (89.5) NR NR

TOC 8mg/kg q4w (IV) + csDMARD 35 54 (28 to 79) 29 (82.9) NR NR

Amgenb 2016 ADA 40mg q2w (SC) + MTX 262 56.3 (11.47) 212 (80.92) 249 (95.04) 9.37 (8.047)

ABP501 40mg q2w (SC) + MTX 264 55.4 (11.88) 214 (81.06) 251 (95.08) 9.41 (8.076) aCertain studies included treatments that are and treatments that are not eligible for the review or used both standard and non-standard doses; this table lists all treatments as they

appear in the study. However, only the included treatments listed in Table 2 are standard doses were included in the analysis. bStudy sponsor; trial authors were not listed as this was an NCT record

ABA = abatacept; ABP501 = biosimilar adalimumab; ANBAI = AnBaiNuo (biosimilar etanercept); ADA = adalimumab; BAR = baricitinib; bid = twice daily; biw = twice weekly; CERTO =

certolizumab pegol; csDMARD = conventional synthetic disease modifying anti-rheumatic drug; CT-P13 = biosimilar infliximab; ETN = etanercept; GOL = golimumab; HCQ =

hydroxychloroquine; HD203 = biosimilar etanercept; INF = infliximab; IV = intravenous; MTX = methotrexate; P.O. = orally; qw = every week; q2w = every two weeks; q4w = every four

weeks; q8w = every eight weeks; qd = every day; RIT = rituximab; SAR = sarilumab; SB2 = biosimilar of infliximab; SB4 = biosimilar of etanercept; SB5 = biosimilar adalimumab; SC =

subcutaneous; SIR = sirukumab; SSZ = sulfasalazine; TOC = tocilizumab; TOF = tofacitinib; ZRC-3197 = biosimilar of adalimumab

371

APPENDIX 7: RISK OF BIAS ASSESSMENT

Table 45. Full Results of Risk of Bias Assessment

Author, Year Sequence

Generation

Allocation

Concealment

Blinding

(Objective

outcomes)

Blinding

(Subjective

outcomes)

Incomplete

Outcome Data

for Efficacy

Incomplete

Outcome Data

for Safety

Other Risk of

Bias

Overall

Quality

Abe 2006 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear

Bae 2016 Low risk of bias Low risk of bias Low risk of bias Low risk of bias High risk of

bias Low risk of bias Low risk of bias High risk

Burmester 2016 Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias High risk of

bias Low risk

Chen 2009 Unclear Unclear Low risk of bias Unclear Unclear Unclear Low risk of bias Unclear

Chen 2016 Unclear Unclear Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Unclear

Choe 2015 Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk

Choy 2012 Low risk of bias Low risk of bias Low risk of bias Low risk of bias High risk of

bias Unclear Low risk of bias High risk

Ciconelli 1996 Unclear Unclear Low risk of bias Low risk of bias Low risk of bias Unclear Low risk of bias Unclear

Cohen 2002 Unclear Unclear Low risk of bias Unclear High risk of

bias

High risk of

bias Low risk of bias High risk

Cohen 2004 Unclear Unclear Low risk of bias Unclear Unclear Unclear Low risk of bias Unclear

Combe 2006 Unclear Unclear Low risk of bias Low risk of bias High risk of


Conaghan 2013 Unclear Low risk of bias Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear

372


Generation

Allocation

Concealment

Blinding

(Objective

outcomes)

Blinding

(Subjective

outcomes)

Incomplete

Outcome Data

for Efficacy

Incomplete

Outcome Data

for Safety

Other Risk of

Bias

Overall

Quality

Dougados 2013 Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Unclear

Dougados 2017 Unclear Unclear Low risk of bias Unclear High risk of

bias

High risk of


Edwards 2004 Unclear Unclear Low risk of bias Low risk of bias High risk of


Emery 2015 Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk

Emery 2010 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias High risk of

bias Unclear

Fleischmann

2012 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias

High risk of

bias Unclear

Fleischmann

2009 Low risk of bias Low risk of bias Low risk of bias Unclear

High risk of

bias

High risk of


Furst 2003 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias High risk of

bias Unclear

Gabay 2013 Low risk of bias Low risk of bias Low risk of bias Low risk of bias High risk of

bias Unclear

High risk of

bias High risk

Genovese 2015 Unclear Low risk of bias Low risk of bias Unclear High risk of

bias

High risk of

bias

High risk of

bias High risk

Genovese 2008 Unclear Unclear Low risk of bias Unclear High risk of

bias Unclear

High risk of

bias High risk

Hobbs 2015 Low risk of bias Low risk of bias Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear

Jani 2015 Low risk of bias Unclear Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear

373


Generation

Allocation

Concealment

Blinding

(Objective

outcomes)

Blinding

(Subjective

outcomes)

Incomplete

Outcome Data

for Efficacy

Incomplete

Outcome Data

for Safety

Other Risk of

Bias

Overall

Quality

Jobanputra

2012 Low risk of bias Low risk of bias Low risk of bias

High risk of

bias

High risk of

bias

High risk of


Kameda 2010 Low risk of bias Low risk of bias Low risk of bias High risk of

bias

High risk of

bias

High risk of


Kaneko 2015 Low risk of bias Low risk of bias Low risk of bias High risk of

bias Low risk of bias Low risk of bias Unclear High risk

Kavanaugh

2000 Unclear Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Unclear Low risk

Kay 2008 Unclear Unclear Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Unclear

Kennedy 2014 Unclear Unclear Low risk of bias Unclear High risk of

bias

High risk of


Kermer 2003 Unclear Low risk of bias Low risk of bias Unclear High risk of


Keystone 2015 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear

Keystone 2004 Unclear Unclear Low risk of bias Low risk of bias High risk of

bias

High risk of

bias

High risk of

bias High risk

Keystone 2008 Unclear Unclear Low risk of bias Low risk of bias High risk of

bias

High risk of

bias

High risk of

bias High risk

Keystone 2009 Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk

Kim 2007 Unclear Unclear Low risk of bias Unclear High risk of

bias

High risk of

bias

High risk of

bias High risk

Kim 2012 Low risk of bias Low risk of bias Low risk of bias High risk of

Low risk of bias Low risk of bias Low risk of bias High risk

374


Generation

Allocation

Concealment

Blinding

(Objective

outcomes)

Blinding

(Subjective

outcomes)

Incomplete

Outcome Data

for Efficacy

Incomplete

Outcome Data

for Safety

Other Risk of

Bias

Overall

Quality

bias

Kim 2013 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear

Klareskog 2004 Unclear Low risk of bias Low risk of bias Unclear High risk of

bias

High risk of


Kremer 2011 Unclear Unclear Low risk of bias Unclear High risk of

bias Unclear

High risk of

bias High risk

Kremer 2010 Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk

Kremer 2012 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear

Kremer 2006 Low risk of bias Low risk of bias Low risk of bias Unclear High risk of

bias

High risk of

bias

High risk of

bias High risk

Lan 2004 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear

Le Loet 2008 High risk of

bias

High risk of

bias Low risk of bias

High risk of

bias

High risk of

bias

High risk of


Li 2015 Unclear Unclear Low risk of bias Unclear High risk of

bias

High risk of

bias

High risk of

bias High risk

Machado 2014 Low risk of bias Unclear Low risk of bias High risk of

bias Low risk of bias Low risk of bias Low risk of bias High risk

MacIssac 2014 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear

Maini 1998 Unclear Low risk of bias Low risk of bias Low risk of bias High risk of

bias

High risk of


Maini 1999 Unclear Low risk of bias Low risk of bias Low risk of bias High risk of High risk of

Low risk of bias High risk

375


Generation

Allocation

Concealment

Blinding

(Objective

outcomes)

Blinding

(Subjective

outcomes)

Incomplete

Outcome Data

for Efficacy

Incomplete

Outcome Data

for Safety

Other Risk of

Bias

Overall

Quality

bias bias

Maini 2006 Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk

Mladenovic

1995 Unclear Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk

Moreland 1999 Low risk of bias Low risk of bias Low risk of bias Low risk of bias High risk of

bias

High risk of


Nishimoto 2009 Unclear Low risk of bias Low risk of bias Low risk of bias High risk of

bias

High risk of


O’Dell 2002 Low risk of bias Low risk of bias Low risk of bias Low risk of bias High risk of

bias

High risk of


O'Dell 2013 Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk

O'Dell 1996 Low risk of bias Unclear Low risk of bias Low risk of bias Unclear Unclear Low risk of bias Unclear

Peterfy 2016 Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias High risk of

bias Low risk

Schiff 2013 Unclear Unclear Low risk of bias High risk of


Schiff 2008 Unclear Unclear Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Unclear

Smolen 2014 Low risk of bias Low risk of bias Low risk of bias Unclear Low risk of bias Low risk of bias High risk of

bias Unclear

Smolen 2008 Low risk of bias Low risk of bias Low risk of bias Unclear High risk of

bias

High risk of

bias

High risk of

bias High risk

376


Generation

Allocation

Concealment

Blinding

(Objective

outcomes)

Blinding

(Subjective

outcomes)

Incomplete

Outcome Data

for Efficacy

Incomplete

Outcome Data

for Safety

Other Risk of

Bias

Overall

Quality

Smolen 2009 Unclear Unclear Low risk of bias Unclear High risk of

bias

High risk of

bias

High risk of

bias High risk


bias Unclear

Smolen 2017 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias High risk of

bias Unclear


bias Unclear

Takeuchi 2015 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear



Tanaka 2016 Low risk of bias Low risk of bias Low risk of bias Unclear Low risk of bias Low risk of bias High risk of

bias Unclear

Tanaka 2011 Unclear Unclear Low risk of bias Unclear High risk of


Tanaka 2012 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear

van der Heijde

2013 Low risk of bias Low risk of bias Low risk of bias Unclear

High risk of

bias

High risk of

bias

High risk of

bias High risk

Van Riel 2006 Unclear Unclear Low risk of bias High risk of


van

Vollenhoven

Low risk of bias Low risk of bias Low risk of bias Low risk of bias High risk of


377


Generation

Allocation

Concealment

Blinding

(Objective

outcomes)

Blinding

(Subjective

outcomes)

Incomplete

Outcome Data

for Efficacy

Incomplete

Outcome Data

for Safety

Other Risk of

Bias

Overall

Quality

2012

van

Vollenhoven

2011

Low risk of bias Low risk of bias Low risk of bias High risk of


Weinblatt 2015 Unclear Unclear Low risk of bias Low risk of bias Unclear Low risk of bias High risk of

bias Unclear

Weinblatt 2015 Unclear Unclear Low risk of bias Unclear Unclear Unclear Low risk of bias Unclear

Weinblatt 2013 Low risk of bias Low risk of bias Low risk of bias Unclear High risk of

bias Unclear

High risk of

bias High risk

Weinblatt 2003 Unclear Unclear Low risk of bias Unclear Low risk of bias Low risk of bias High risk of

bias Unclear

Weinblatt 2012 Low risk of bias Low risk of bias Low risk of bias Unclear Low risk of bias Low risk of bias Low risk of bias Unclear

Weinblatt 1999 Low risk of bias Unclear Low risk of bias Low risk of bias Unclear Unclear Low risk of bias Unclear

Yamamoto

2014 Low risk of bias Low risk of bias Low risk of bias Low risk of bias

High risk of

bias

High risk of

bias

High risk of

bias High risk

Yamamoto

2014 Low risk of bias Low risk of bias Low risk of bias Low risk of bias

High risk of

bias

High risk of

bias

High risk of

bias High risk

Yazici 2012 Unclear Unclear Low risk of bias Unclear High risk of

bias

High risk of

bias

High risk of

bias High risk

Yoo 2013 Low risk of bias Low risk of bias Low risk of bias Unclear High risk of


Zhang 2006 Unclear Unclear Low risk of bias Unclear Unclear Unclear Low risk of bias Unclear

378

379

APPENDIX 8: SENSITIVITY ANALYSES

Table 46. ACR50 Sensitivity Analysis Results Compared to the Reference Case (A Priori Table)

Treatment Comparator

Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

Placebo Placebo

+MTX

1.60 (0.44, 2.75) 2.31 (0.73, 3.90) - -0.21 (-1.85, 1.43) -

csDMARD

+MTX

0.45 (-0.44, 1.33) - -0.43 (-1.34, 0.48) - 1.49 (0.41, 2.57)

MTX+SSZ

-0.65 (-2.57, 1.26) -0.19 (-2.16, 1.77) - 0.001 (-1.57, 1.57) -

MTX+HCQ

-0.60 (-2.27, 1.08) -0.28 (-2.04, 1.49) - -1.92 (-3.77, -0.06) -

SSZ+HCQ

-0.64 (-1.65, 0.38) -0.51 (-1.36, 0.35) -0.19 (-1.15, 0.77) 0.87 (-0.48, 2.22) 1.74 (0.61, 2.87)

MTX+SSZ +HCQ

-0.61 (-1.68, 0.46) -0.27 (-1.53, 0.99) - -2.05 (-3.32, -0.78) -

ETN_STD

0.51 (-0.16, 1.17) 2.34 (1.56, 3.12) -0.69 (-1.40, 0.01) 1.09 (0.26, 1.92) 1.79 (0.78, 2.80)

ETN_STD+MTX

0.44 (-0.16, 1.04) 1.43 (0.75, 2.10) -0.44 (-1.09, 0.22) -0.98 (-1.72, -0.25) 1.48 (0.60, 2.37)

ABA_STD

(IV)+MTX

-0.001 (-0.50, 0.50) -0.13 (-0.62, 0.35) 0.12 (-0.48, 0.73) 0.52 (-0.07, 1.12) -0.02 (-0.49, 0.45)

ADA_STD +MTX

-0.05 (-0.42, 0.31) 0.29 (-0.10, 0.67) -0.08 (-0.44, 0.28) - -0.001 (-0.33, 0.33)

380


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

ADA_STD

1.66 (-0.12, 3.44) - - 2.94 (1.48, 4.41) -

TOF_STD+MTX

-0.05 (-0.57, 0.48) - -0.03 (-0.54, 0.49) -1.12 (-2.09, -0.15) -0.004 (-0.51, 0.50)

TOF_STD

1.66 (-0.07, 3.39) - - 1.87 (0.38, 3.35) -

TOC_4 (IV)

-0.04 (-1.04, 0.95) -0.49 (-1.46, 0.49) - -0.97 (-2.69, 0.75) -0.02 (-0.96, 0.93)

TOC_8 (IV)

0.004 (-0.61, 0.61) -0.82 (-1.47, -0.16) 0.23 (-0.40, 0.86) -0.80 (-1.68, 0.08) -0.02 (-0.59, 0.56)

TOC_4 (IV)+MTX

-0.01 (-0.66, 0.65) -0.63 (-1.33, 0.06) 0.18 (-0.50, 0.86) 0.48 (-0.18, 1.14) 0.005 (-0.61, 0.62)

TOC_8 (IV)+MTX

-0.0004 (-0.53, 0.53) -0.38 (-0.97, 0.21) 0.10 (-0.42, 0.62) -0.30 (-0.88, 0.28) -0.02 (-0.50, 0.47)

GOL_STD (SC)

1.24 (-0.31, 2.80) - - 1.60 (0.17, 3.03) -

GOL_STD

(SC)+MTX

0.08 (-0.55, 0.71) - 0.00 (-0.62, 0.62) -2.34 (-3.92, -0.75) 0.01 (-0.60, 0.61)

GOL_STD

(IV)+MTX

-0.01 (-0.94, 0.92) - -0.01 (-0.89, 0.86) 0.40 (-0.39, 1.19) 0.001 (-0.86, 0.86)

INF_STD+MTX

0.01 (-0.53, 0.55) -0.05 (-0.58, 0.48) 0.08 (-0.61, 0.77) 0.17 (-0.69, 1.03) -0.02 (-0.52, 0.49)

CERTO_STD

+MTX

-0.01 (-0.48, 0.46) - -0.06 (-0.51, 0.40) -0.98 (-1.51, -0.45) -0.03 (-0.47, 0.42)

CERTO_STD

1.58 (0.10, 3.05) - - 1.58 (0.25, 2.91) -

381


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

RIT_STD

0.03 (-1.40, 1.45) 0.05 (-1.34, 1.44) - -0.94 (-2.68, 0.80) 0.04 (-1.34, 1.42)

RIT_STD+MTX

-0.01 (-1.40, 1.38) 0.06 (-1.33, 1.44) - -1.89 (-3.46, -0.32) 0.04 (-1.33, 1.41)

SAR_200

1.66 (-0.34, 3.67) - - 1.62 (-0.03, 3.28) -

BAR_4+MTX

-0.09 (-0.69, 0.51) - -0.06 (-0.61, 0.50) -0.38 (-1.63, 0.87) -0.02 (-0.57, 0.52)

HD203+MTX

0.45 (-0.70, 1.59) - -0.42 (-1.56, 0.72) 0.19 (-0.83, 1.22) 1.50 (0.23, 2.78)

SB4+MTX

0.44 (-0.61, 1.49) - -0.42 (-1.46, 0.61) 0.86 (-0.31, 2.03) 1.50 (0.31, 2.68)

ANBAI+MTX

-0.03 (-1.12, 1.06) - -0.03 (-1.09, 1.03) -0.07 (-1.23, 1.10) -0.04 (-1.08, 1.00)

CT-P13+MTX

0.01 (-0.86, 0.88) - 0.06 (-0.89, 1.01) 0.74 (-0.32, 1.80) -0.03 (-0.85, 0.78)

SB2+MTX

0.01 (-1.03, 1.05) - 0.10 (-0.97, 1.16) 0.11 (-0.87, 1.10) -0.01 (-0.96, 0.94)

SB5+MTX

-0.05 (-1.02, 0.91) - -0.08 (-0.99, 0.83) -0.75 (-1.82, 0.32) 0.002 (-0.88, 0.89)

ZRC-3197+MTX

-0.07 (-1.20, 1.06) - -0.08 (-1.18, 1.03) 0.32 (-0.81, 1.46) -0.001 (-1.08, 1.08)

ABP501+MTX

-0.05 (-1.00, 0.91) - -0.09 (-0.97, 0.79) 0.47 (-0.65, 1.58) -0.002 (-0.87, 0.86)

csDMARD +MTX Placebo -1.13 (-2.48, 0.21) - - -0.45 (-1.82, 0.93) -

382


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

MTX+SSZ

-2.27 (-4.49, -0.05) -2.56 (-5.09, -0.04) - 0.18 (-2.02, 2.39) -

MTX+HCQ

-2.20 (-4.23, -0.16) -2.61 (-4.96, -0.26) - -1.73 (-4.16, 0.70) -

SSZ+HCQ

-2.22 (-3.68, -0.75) -2.84 (-4.53, -1.14) - 1.08 (-0.95, 3.10) -

MTX+SSZ+HCQ

-2.21 (-3.76, -0.66) -2.60 (-4.61, -0.60) - -1.85 (-3.87, 0.18) -

ETN_STD

-1.08 (-2.18, 0.02) 0.03 (-1.31, 1.38) - 1.30 (-0.33, 2.93) -

ETN_STD+MTX

-1.15 (-2.33, 0.02) -0.87 (-2.34, 0.60) - -0.77 (-2.27, 0.73) -

ABA_STD

(IV)+MTX

-1.61 (-2.87, -0.34) -2.45 (-4.11, -0.78) - 0.72 (-0.94, 2.38) -

ADA_STD+MTX

-1.66 (-2.83, -0.48) -2.03 (-3.65, -0.40) - 0.59 (-1.11, 2.29) -

ADA_STD

0.07 (-1.26, 1.39) - - 2.04 (0.25, 3.83) -

TOF_STD+MTX

-1.65 (-2.92, -0.38) - - 0.08 (-1.69, 1.86) -

TOF_STD

0.07 (-1.22, 1.35) - - -0.05 (-1.41, 1.31) -

TOC_4 (IV)

-1.61 (-3.14, -0.08) -2.80 (-4.68, -0.92) - 0.33 (-1.64, 2.29) -

TOC_8 (IV)

-1.59 (-2.89, -0.30) -3.13 (-4.84, -1.43) - 0.35 (-1.42, 2.12) -

383


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

TOC_4 (IV)+MTX

-1.60 (-2.93, -0.26) -2.95 (-4.68, -1.22) - 0.38 (-1.39, 2.15) -

TOC_8 (IV)+MTX

-1.59 (-2.85, -0.33) -2.70 (-4.39, -1.02) - 0.40 (-1.34, 2.14) -

GOL_STD (SC)

-0.34 (-1.48, 0.79) - - -0.38 (-1.62, 0.85) -

GOL_STD

(SC)+MTX

-1.51 (-2.80, -0.23) - - -0.11 (-1.88, 1.66) -

GOL_STD

(IV)+MTX

-1.60 (-3.07, -0.12) - - 0.42 (-1.50, 2.34) -

INF_STD+MTX

-1.57 (-2.84, -0.29) -2.35 (-4.03, -0.67) - -0.18 (-1.91, 1.55) -

CERTO_STD

+MTX

-1.61 (-2.87, -0.35) - - 0.42 (-1.32, 2.15) -

CERTO_STD

-0.03 (-0.91, 0.84) - - 0.20 (-0.73, 1.12) -

RIT_STD

-1.58 (-3.43, 0.28) -2.26 (-4.37, -0.14) - -1.24 (-3.51, 1.03) -

RIT_STD+MTX

-1.61 (-3.41, 0.19) -2.26 (-4.35, -0.17) - -0.33 (-2.31, 1.65) -

SAR_200

0.06 (-1.54, 1.67) - - 2.04 (0.01, 4.07) -

BAR_4+MTX

-1.70 (-2.92, -0.47) - - 0.80 (-1.02, 2.62) -

HD203+MTX

-1.13 (-2.65, 0.39) - - 0.64 (-1.27, 2.55) -

384


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

SB4+MTX

-1.14 (-2.59, 0.31) - - 0.66 (-1.19, 2.50) -

ANBAI+MTX

-1.64 (-3.19, -0.08) - - 0.20 (-1.79, 2.19) -

CT-P13+MTX

-1.59 (-3.03, -0.14) - - -0.15 (-2.02, 1.72) -

SB2+MTX

-1.58 (-3.13, -0.03) - - -0.18 (-2.14, 1.78) -

SB5+MTX

-1.65 (-3.11, -0.19) - - 0.58 (-1.34, 2.51) -

ZRC-3197+MTX

-1.64 (-3.24, -0.03) - - 0.64 (-1.42, 2.69) -

ABP501+MTX

-1.66 (-3.14, -0.17) - - 0.60 (-1.34, 2.54) -

MTX+SSZ csDMARD +MTX -1.07 (-3.10, 0.95) - - - -

MTX+HCQ

-1.05 (-2.88, 0.77) - - - -

SSZ+HCQ

-1.09 (-2.35, 0.18) - 0.25 (-0.78, 1.27) -1.02 (-2.62, 0.57) 0.24 (-0.76, 1.25)

MTX+SSZ +HCQ

-1.05 (-2.30, 0.20) - - -1.01 (-2.68, 0.65) -

ETN_STD

0.06 (-0.79, 0.91) - -0.26 (-1.10, 0.58) -0.92 (-2.15, 0.32) 0.31 (-0.53, 1.14)

ETN_STD+MTX

-0.01 (-0.67, 0.65) - -0.004 (-0.62, 0.62) -0.187 (-1.13, 0.76) -0.004 (-0.61, 0.61)

385


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

ABA_STD

(IV)+MTX

-0.44 (-1.43, 0.55) - 0.56 (-0.52, 1.64) -1.33 (-2.36, -0.30) -1.51 (-2.68, -0.34)

ADA_STD +MTX

-0.51 (-1.47, 0.46) - 0.35 (-0.63, 1.33) 0.11 (-0.74, 0.97) -1.49 (-2.61, -0.36)

ADA_STD

1.19 (-0.69, 3.08) - - 2.51 (0.86, 4.16) -

TOF_STD+MTX

-0.50 (-1.54, 0.54) - 0.41 (-0.64, 1.45) -1.56 (-2.94, -0.18) -1.49 (-2.68, -0.31)

TOF_STD

1.19 (-0.65, 3.03) - - 1.43 (-0.25, 3.11) -

TOC_4 (IV)

-0.48 (-1.79, 0.82) - - -1.40 (-3.31, 0.51) -1.51 (-2.94, -0.07)

TOC_8 (IV)

-0.45 (-1.52, 0.62) - 0.66 (-0.43, 1.75) -1.25 (-2.53, 0.04) -1.51 (-2.72, -0.30)

TOC_4 (IV)+MTX

-0.44 (-1.55, 0.67) - 0.61 (-0.52, 1.75) 0.05 (-1.10, 1.20) -1.49 (-2.73, -0.24)

TOC_8 (IV)+MTX

-0.44 (-1.47, 0.60) - 0.54 (-0.51, 1.58) -0.74 (-1.86, 0.37) -1.51 (-2.69, -0.32)

GOL_STD (SC)

0.78 (-0.91, 2.48) - - 1.15 (-0.47, 2.77) -

GOL_STD

(SC)+MTX

-0.35 (-1.42, 0.73) - 0.43 (-0.67, 1.53) -2.78 (-4.54, -1.02) -1.48 (-2.72, -0.25)

GOL_STD

(IV)+MTX

-0.45 (-1.75, 0.85) - 0.42 (-0.85, 1.68) -0.05 (-1.29, 1.18) -1.51 (-2.88, -0.13)

INF_STD+MTX

-0.43 (-1.46, 0.61) - 0.52 (-0.62, 1.66) -0.27 (-1.55, 1.01) -1.51 (-2.69, -0.32)

386


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

CERTO_STD

+MTX

-0.45 (-1.44, 0.55) - 0.37 (-0.64, 1.39) -1.42 (-2.50, -0.34) -1.51 (-2.67, -0.35)

CERTO_STD

1.10 (-0.53, 2.74) - - 1.14 (-0.40, 2.68) -

RIT_STD

-0.43 (-2.13, 1.27) - - -1.38 (-3.29, 0.52) -1.46 (-3.22, 0.31)

RIT_STD+MTX

-0.45 (-2.13, 1.23) - - -2.34 (-4.17, -0.50) -1.45 (-3.20, 0.29)

SAR_200

1.18 (-0.91, 3.28) - - 1.17 (-0.64, 2.99) -

BAR_4+MTX

-0.54 (-1.61, 0.53) - 0.37 (-0.69, 1.43) -0.82 (-2.40, 0.75) -1.52 (-2.72, -0.32)

HD203+MTX

0.01 (-1.16, 1.19) - 0.01 (-1.10, 1.12) -0.24 (-1.50, 1.02) 0.003 (-1.09, 1.10)

SB4+MTX

0.004 (-1.08, 1.09) - 0.01 (-1.02, 1.04) 0.42 (-0.80, 1.65) 0.01 (-1.00, 1.02)

ANBAI+MTX

-0.47 (-1.87, 0.94) - 0.40 (-1.00, 1.81) -0.52 (-1.87, 0.82) -1.54 (-3.05, -0.04)

CT-P13+MTX

-0.42 (-1.66, 0.82) - 0.50 (-0.81, 1.81) 0.31 (-1.11, 1.73) -1.53 (-2.88, -0.18)

SB2+MTX

-0.43 (-1.79, 0.92) - 0.52 (-0.88, 1.93) -0.33 (-1.69, 1.03) -1.51 (-2.95, -0.08)

SB5+MTX

-0.50 (-1.80, 0.80) - 0.35 (-0.93, 1.63) -1.20 (-2.62, 0.22) -1.50 (-2.89, -0.11)

ZRC-3197+MTX

-0.52 (-1.95, 0.91) - 0.36 (-1.06, 1.77) -0.12 (-1.59, 1.35) -1.51 (-3.02, 0.001)

387


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

ABP501+MTX

-0.49 (-1.80, 0.82) - 0.34 (-0.94, 1.62) 0.03 (-1.44, 1.49) -1.50 (-2.88, -0.12)

MTX+HCQ MTX+SSZ 0.05 (-1.53, 1.63) -0.05 (-1.59, 1.49) - -0.43 (-1.97, 1.11) -

SSZ+HCQ

-0.01 (-2.05, 2.03) -0.32 (-2.28, 1.63) - 1.28 (-0.53, 3.10) -

MTX+SSZ +HCQ

0.03 (-1.52, 1.59) -0.07 (-1.57, 1.44) - -1.61 (-3.47, 0.24) -

ETN_STD

1.14 (-0.78, 3.07) 2.57 (0.49, 4.64) - 1.52 (-0.34, 3.38) -

ETN_STD+MTX

1.06 (-0.84, 2.96) 1.65 (-0.38, 3.68) - -0.56 (-2.56, 1.43) -

ABA_STD

(IV)+MTX

0.64 (-1.32, 2.60) 0.06 (-1.96, 2.07) - 0.94 (-1.00, 2.89) -

ADA_STD +MTX

0.60 (-1.34, 2.55) 0.50 (-1.50, 2.49) - 0.22 (-1.78, 2.22) -

ADA_STD

2.29 (-0.28, 4.86) - - 3.38 (0.97, 5.80) -

TOF_STD+MTX

0.61 (-1.38, 2.60) - - -0.69 (-2.89, 1.51) -

TOF_STD

2.29 (-0.28, 4.86) - - 2.29 (-0.15, 4.74) -

TOC_4 (IV)

0.60 (-1.53, 2.73) -0.29 (-2.47, 1.88) - -0.50 (-3.05, 2.05) -

TOC_8 (IV)

0.64 (-1.37, 2.65) -0.62 (-2.68, 1.44) - -0.36 (-2.50, 1.77) -

388


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

TOC_4 (IV)+MTX

0.63 (-1.39, 2.66) -0.43 (-2.53, 1.66) - 0.91 (-1.16, 2.97) -

TOC_8 (IV)+MTX

0.66 (-1.31, 2.63) -0.17 (-2.21, 1.86) - 0.13 (-1.90, 2.16) -

GOL_STD (SC)

1.90 (-0.53, 4.33) - - 2.04 (-0.38, 4.45) -

GOL_STD

(SC)+MTX

0.76 (-1.24, 2.75) - - -1.87 (-4.35, 0.62) -

GOL_STD

(IV)+MTX

0.66 (-1.43, 2.75) - - 0.83 (-1.26, 2.93) -

INF_STD+MTX

0.65 (-1.33, 2.64) 0.16 (-1.89, 2.20) - 0.60 (-1.54, 2.74) -

CERTO_STD

+MTX

0.63 (-1.34, 2.60) - - -0.56 (-2.56, 1.44) -

CERTO_STD

2.26 (-0.14, 4.66) - - 2.02 (-0.35, 4.39) -

RIT_STD

0.65 (-1.78, 3.09) 0.25 (-2.19, 2.69) - -0.51 (-3.11, 2.09) -

RIT_STD+MTX

0.63 (-1.73, 2.99) 0.27 (-2.12, 2.66) - -1.47 (-3.96, 1.03) -

SAR_200

2.28 (-0.42, 4.98) - - 2.06 (-0.48, 4.60) -

BAR_4+MTX

0.58 (-1.40, 2.56) - - 0.04 (-2.28, 2.36) -

HD203+MTX

1.08 (-1.03, 3.19) - - 0.61 (-1.56, 2.79) -

389


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

SB4+MTX

1.09 (-0.99, 3.17) - - 1.30 (-0.87, 3.47) -

ANBAI+MTX

0.61 (-1.58, 2.81) - - 0.37 (-1.82, 2.57) -

CT-P13+MTX

0.62 (-1.46, 2.71) - - 1.19 (-1.02, 3.40) -

SB2+MTX

0.65 (-1.53, 2.83) - - 0.55 (-1.63, 2.72) -

SB5+MTX

0.61 (-1.51, 2.73) - - -0.32 (-2.51, 1.88) -

ZRC-3197+MTX

0.57 (-1.64, 2.78) - - 0.76 (-1.49, 3.01) -

ABP501+MTX

0.58 (-1.56, 2.73) - - 0.89 (-1.34, 3.13) -

SSZ+HCQ MTX+HCQ -0.01 (-1.82, 1.80) -0.24 (-2.02, 1.53) - 2.81 (0.79, 4.82) -

MTX+SSZ +HCQ

-0.004 (-1.31, 1.30) 0.01 (-1.23, 1.25) - -1.57 (-3.23, 0.08) -

ETN_STD

1.11 (-0.63, 2.84) 2.65 (0.76, 4.53) - 1.57 (-0.07, 3.21) -

ETN_STD+MTX

1.04 (-0.65, 2.73) 1.73 (-0.12, 3.57) - -0.51 (-2.32, 1.31) -

ABA_STD

(IV)+MTX

0.61 (-1.14, 2.36) 0.15 (-1.68, 1.97) - 0.99 (-0.75, 2.74) -

ADA_STD +MTX

0.54 (-1.17, 2.25) 0.58 (-1.23, 2.39) - 0.27 (-1.53, 2.08) -

390


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

ADA_STD

2.23 (-0.18, 4.65) - - 3.41 (1.14, 5.68) -

TOF_STD+MTX

0.56 (-1.21, 2.32) - - -0.66 (-2.69, 1.37) -

TOF_STD

2.25 (-0.15, 4.66) - - 2.34 (0.06, 4.63) -

TOC_4 (IV)

0.57 (-1.39, 2.52) -0.21 (-2.23, 1.81) - -0.47 (-2.90, 1.96) -

TOC_8 (IV)

0.61 (-1.19, 2.41) -0.54 (-2.43, 1.34) - -0.33 (-2.30, 1.64) -

TOC_4 (IV)+MTX

0.61 (-1.18, 2.40) -0.36 (-2.25, 1.53) - 0.96 (-0.92, 2.83) -

TOC_8 (IV)+MTX

0.61 (-1.15, 2.37) -0.12 (-1.98, 1.75) - 0.17 (-1.69, 2.03) -

GOL_STD (SC)

1.82 (-0.43, 4.07) - - 2.07 (-0.19, 4.32) -

GOL_STD

(SC)+MTX

0.70 (-1.09, 2.48) - - -1.84 (-4.16, 0.49) -

GOL_STD

(IV)+MTX

0.58 (-1.32, 2.49) - - 0.86 (-1.04, 2.77) -

INF_STD+MTX

0.62 (-1.15, 2.39) 0.24 (-1.62, 2.10) - 0.64 (-1.32, 2.61) -

CERTO_STD

+MTX

0.60 (-1.14, 2.34) - - -0.49 (-2.31, 1.33) -

CERTO_STD

2.20 (-0.03, 4.42) - - 2.07 (-0.11, 4.25) -

391


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

RIT_STD

0.64 (-1.57, 2.85) 0.34 (-1.91, 2.58) - -0.46 (-2.90, 1.98) -

RIT_STD+MTX

0.62 (-1.56, 2.79) 0.36 (-1.85, 2.56) - -1.40 (-3.73, 0.92) -

SAR_200

2.23 (-0.34, 4.79) - - 2.10 (-0.28, 4.49) -

BAR_4+MTX

0.52 (-1.26, 2.31) - - 0.08 (-2.10, 2.27) -

HD203+MTX

1.06 (-0.89, 3.01) - - 0.66 (-1.35, 2.68) -

SB4+MTX

1.05 (-0.85, 2.95) - - 1.34 (-0.67, 3.34) -

ANBAI+MTX

0.57 (-1.43, 2.58) - - 0.41 (-1.61, 2.43) -

CT-P13+MTX

0.60 (-1.29, 2.48) - - 1.21 (-0.83, 3.26) -

SB2+MTX

0.63 (-1.35, 2.61) - - 0.61 (-1.38, 2.60) -

SB5+MTX

0.56 (-1.37, 2.49) - - -0.27 (-2.29, 1.75) -

ZRC-3197+MTX

0.54 (-1.46, 2.55) - - 0.80 (-1.26, 2.87) -

ABP501+MTX

0.53 (-1.40, 2.46) - - 0.95 (-1.12, 3.03) -

MTX+SSZ +HCQ SSZ+HCQ 0.03 (-1.21, 1.28) 0.26 (-1.00, 1.52) - -1.45 (-3.17, 0.28) -

392


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

ETN_STD

1.15 (0.01, 2.28) 2.86 (1.82, 3.91) -0.52 (-1.48, 0.45) 1.70 (0.56, 2.83) 0.06 (-0.90, 1.02)

ETN_STD+MTX

1.08 (0.02, 2.13) 1.95 (1.03, 2.88) -0.26 (-1.06, 0.55) -0.38 (-1.55, 0.80) -0.25 (-1.04, 0.54)

ABA_STD

(IV)+MTX

0.63 (-0.50, 1.76) 0.38 (-0.59, 1.36) 0.31 (-0.82, 1.43) 1.13 (-0.04, 2.29) -1.76 (-2.98, -0.55)

ADA_STD +MTX

0.58 (-0.50, 1.65) 0.80 (-0.14, 1.74) 0.10 (-0.92, 1.13) 0.40 (-0.78, 1.57) -1.74 (-2.91, -0.57)

ADA_STD

2.26 (0.29, 4.23) - - 3.56 (1.80, 5.32) -

TOF_STD+MTX

0.58 (-0.58, 1.73) - 0.15 (-0.93, 1.24) -0.52 (-1.97, 0.94) -1.75 (-2.98, -0.52)

TOF_STD

2.27 (0.35, 4.19) - - 2.48 (0.70, 4.26) -

TOC_4 (IV)

0.59 (-0.83, 2.01) 0.02 (-1.28, 1.32) - -0.37 (-2.36, 1.63) -1.75 (-3.23, -0.28)

TOC_8 (IV)

0.63 (-0.57, 1.83) -0.31 (-1.38, 0.77) 0.42 (-0.73, 1.57) -0.19 (-1.58, 1.19) -1.75 (-3.02, -0.49)

TOC_4 (IV)+MTX

0.63 (-0.59, 1.86) -0.12 (-1.22, 0.97) 0.36 (-0.82, 1.54) 1.09 (-0.18, 2.35) -1.73 (-3.01, -0.46)

TOC_8 (IV)+MTX

0.64 (-0.50, 1.78) 0.13 (-0.90, 1.16) 0.28 (-0.80, 1.37) 0.31 (-0.91, 1.53) -1.75 (-2.97, -0.53)

GOL_STD (SC)

1.86 (0.07, 3.65) - - 2.20 (0.47, 3.92) -

GOL_STD

(SC)+MTX

0.71 (-0.46, 1.89) - 0.18 (-0.97, 1.32) -1.74 (-3.63, 0.15) -1.75 (-3.03, -0.46)

393


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

GOL_STD

(IV)+MTX

0.62 (-0.75, 2.00) - 0.18 (-1.12, 1.48) 1.01 (-0.33, 2.34) -1.74 (-3.15, -0.33)

INF_STD+MTX

0.65 (-0.50, 1.80) 0.47 (-0.54, 1.48) 0.27 (-0.92, 1.46) 0.77 (-0.60, 2.15) -1.76 (-2.99, -0.52)

CERTO_STD

+MTX

0.62 (-0.51, 1.75) - 0.12 (-0.94, 1.18) -0.38 (-1.59, 0.83) -1.77 (-2.99, -0.56)

CERTO_STD

2.19 (0.45, 3.93) - - 2.19 (0.53, 3.85) -

RIT_STD

0.66 (-1.10, 2.42) 0.57 (-1.09, 2.23) - -0.35 (-2.36, 1.66) -1.71 (-3.51, 0.09)

RIT_STD+MTX

0.61 (-1.13, 2.35) 0.58 (-1.04, 2.20) - -1.27 (-3.17, 0.63) -1.70 (-3.48, 0.08)

SAR_200

2.27 (0.11, 4.44) - - 2.23 (0.31, 4.15) -

BAR_4+MTX

0.55 (-0.63, 1.73) - 0.13 (-0.99, 1.24) 0.22 (-1.43, 1.87) -1.76 (-3.01, -0.52)

HD203+MTX

1.09 (-0.33, 2.51) - -0.25 (-1.49, 0.99) 0.80 (-0.63, 2.23) -0.24 (-1.46, 0.98)

SB4+MTX

1.10 (-0.27, 2.47) - -0.25 (-1.38, 0.89) 1.46 (-0.02, 2.94) -0.23 (-1.36, 0.89)

ANBAI+MTX

0.60 (-0.90, 2.10) - 0.15 (-1.27, 1.58) 0.53 (-1.01, 2.07) -1.78 (-3.31, -0.25)

CT-P13+MTX

0.65 (-0.68, 1.98) - 0.24 (-1.13, 1.61) 1.34 (-0.18, 2.86) -1.78 (-3.18, -0.38)

SB2+MTX

0.64 (-0.82, 2.11) - 0.27 (-1.18, 1.71) 0.71 (-0.76, 2.17) -1.76 (-3.23, -0.29)

394


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

SB5+MTX

0.57 (-0.81, 1.96) - 0.10 (-1.22, 1.43) -0.15 (-1.67, 1.37) -1.74 (-3.17, -0.31)

ZRC-3197+MTX

0.56 (-0.97, 2.08) - 0.11 (-1.36, 1.57) 0.93 (-0.64, 2.50) -1.75 (-3.30, -0.20)

ABP501+MTX

0.57 (-0.80, 1.94) - 0.10 (-1.21, 1.41) 1.08 (-0.46, 2.61) -1.74 (-3.15, -0.34)

ETN_STD MTX+SSZ+HCQ 1.12 (-0.04, 2.28) 2.62 (1.16, 4.07) - 3.03 (1.48, 4.59) -

ETN_STD+MTX

1.03 (-0.04, 2.11) 1.71 (0.32, 3.09) - -0.52 (-1.74, 0.70) -

ABA_STD

(IV)+MTX

0.60 (-0.59, 1.79) 0.13 (-1.24, 1.50) - 0.99 (-0.16, 2.15) -

ADA_STD +MTX

0.55 (-0.58, 1.68) 0.56 (-0.75, 1.88) - 0.27 (-0.94, 1.48) -

ADA_STD

2.27 (0.25, 4.28) - - 3.44 (1.63, 5.25) -

TOF_STD+MTX

0.56 (-0.64, 1.76) - - -0.64 (-2.15, 0.87) -

TOF_STD

2.27 (0.25, 4.29) - - 2.36 (0.50, 4.23) -

TOC_4 (IV)

0.56 (-0.88, 2.00) -0.23 (-1.82, 1.35) - -0.49 (-2.51, 1.52) -

TOC_8 (IV)

0.61 (-0.62, 1.85) -0.55 (-1.96, 0.86) - -0.32 (-1.75, 1.10) -

TOC_4 (IV)+MTX

0.61 (-0.66, 1.88) -0.36 (-1.82, 1.10) - 0.96 (-0.36, 2.29) -

395


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

TOC_8 (IV)+MTX

0.61 (-0.57, 1.80) -0.12 (-1.51, 1.27) - 0.17 (-1.09, 1.44) -

GOL_STD (SC)

1.84 (-0.03, 3.70) - - 2.07 (0.27, 3.87) -

GOL_STD

(SC)+MTX

0.70 (-0.53, 1.94) - - -1.84 (-3.72, 0.04) -

GOL_STD

(IV)+MTX

0.60 (-0.82, 2.02) - - 0.87 (-0.49, 2.24) -

INF_STD+MTX

0.62 (-0.58, 1.82) 0.23 (-1.15, 1.61) - 0.65 (-0.77, 2.07) -

CERTO_STD

+MTX

0.60 (-0.57, 1.78) - - -0.51 (-1.74, 0.73) -

CERTO_STD

2.19 (0.40, 3.99) - - 2.07 (0.36, 3.79) -

RIT_STD

0.64 (-1.17, 2.44) 0.33 (-1.56, 2.22) - -0.46 (-2.49, 1.57) -

RIT_STD+MTX

0.61 (-1.14, 2.35) 0.33 (-1.50, 2.16) - -1.41 (-3.32, 0.50) -

SAR_200

2.26 (0.04, 4.49) - - 2.12 (0.13, 4.10) -

BAR_4+MTX

0.50 (-0.73, 1.74) - - 0.09 (-1.61, 1.79) -

HD203+MTX

1.06 (-0.37, 2.48) - - 0.67 (-0.81, 2.15) -

SB4+MTX

1.05 (-0.32, 2.43) - - 1.33 (-0.17, 2.84) -

396


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

ANBAI+MTX

0.59 (-0.93, 2.11) - - 0.40 (-1.10, 1.91) -

CT-P13+MTX

0.62 (-0.75, 2.00) - - 1.22 (-0.34, 2.77) -

SB2+MTX

0.61 (-0.88, 2.11) - - 0.59 (-0.89, 2.07) -

SB5+MTX

0.55 (-0.89, 1.99) - - -0.27 (-1.80, 1.27) -

ZRC-3197+MTX

0.55 (-1.02, 2.12) - - 0.80 (-0.78, 2.38) -

ABP501+MTX

0.54 (-0.89, 1.98) - - 0.95 (-0.62, 2.53) -

ETN_STD+MTX ETN_STD -0.07 (-0.60, 0.46) -0.91 (-1.46, -0.37) 0.26 (-0.31, 0.83) -0.93 (-2.06, 0.19) -0.31 (-0.88, 0.26)

ABA_STD

(IV)+MTX

-0.51 (-1.33, 0.32) -2.48 (-3.40, -1.56) 0.81 (-0.11, 1.74) 0.66 (-0.13, 1.45) -1.81 (-2.93, -0.70)

ADA_STD +MTX

-0.56 (-1.32, 0.20) -2.06 (-2.93, -1.18) 0.61 (-0.18, 1.40) -0.07 (-0.97, 0.83) -1.80 (-2.86, -0.73)

ADA_STD

1.14 (-0.60, 2.87) - - 3.09 (1.58, 4.59) -

TOF_STD+MTX

-0.55 (-1.41, 0.30) - 0.67 (-0.21, 1.55) -0.97 (-2.24, 0.29) -1.80 (-2.93, -0.67)

TOF_STD

1.11 (-0.56, 2.79) - - 2.01 (0.48, 3.53) -

TOC_4 (IV)

-0.54 (-1.73, 0.65) -2.83 (-4.09, -1.58) - -0.81 (-2.51, 0.88) -1.81 (-3.20, -0.42)

397


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

TOC_8 (IV)

-0.51 (-1.40, 0.38) -3.17 (-4.19, -2.16) 0.92 (-0.02, 1.86) -0.66 (-1.83, 0.51) -1.81 (-2.97, -0.66)

TOC_4 (IV)+MTX

-0.52 (-1.45, 0.42) -3.00 (-4.04, -1.96) 0.87 (-0.10, 1.84) 0.62 (-0.39, 1.64) -1.80 (-2.98, -0.61)

TOC_8 (IV)+MTX

-0.50 (-1.34, 0.33) -2.73 (-3.72, -1.75) 0.80 (-0.08, 1.68) -0.16 (-1.12, 0.80) -1.81 (-2.94, -0.69)

GOL_STD (SC)

0.72 (-0.80, 2.24) - - 1.73 (0.26, 3.20) -

GOL_STD

(SC)+MTX

-0.41 (-1.33, 0.50) - 0.70 (-0.24, 1.64) -2.18 (-3.72, -0.63) -1.78 (-2.97, -0.60)

GOL_STD

(IV)+MTX

-0.52 (-1.65, 0.62) - 0.68 (-0.43, 1.80) 0.54 (-0.56, 1.64) -1.80 (-3.12, -0.48)

INF_STD+MTX

-0.49 (-1.35, 0.36) -2.39 (-3.34, -1.44) 0.77 (-0.22, 1.77) 0.31 (-0.85, 1.46) -1.81 (-2.95, -0.68)

CERTO_STD+MTX

-0.51 (-1.33, 0.30) - 0.63 (-0.22, 1.48) -0.84 (-1.77, 0.09) -1.82 (-2.93, -0.71)

CERTO_STD

1.05 (-0.37, 2.48) - - 1.72 (0.36, 3.08) -

RIT_STD

-0.47 (-2.06, 1.12) -2.29 (-3.87, -0.71) - -0.80 (-2.50, 0.90) -1.75 (-3.46, -0.04)

RIT_STD+MTX

-0.51 (-2.05, 1.03) -2.29 (-3.85, -0.72) - -1.75 (-3.47, -0.02) -1.75 (-3.45, -0.06)

SAR_200

1.14 (-0.82, 3.09) - - 1.77 (0.08, 3.46) -

BAR_4+MTX

-0.60 (-1.48, 0.28) - 0.63 (-0.27, 1.53) -0.23 (-1.71, 1.24) -1.81 (-2.96, -0.66)

398


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

HD203+MTX

-0.06 (-1.16, 1.05) - 0.27 (-0.82, 1.35) 0.34 (-0.85, 1.52) -0.31 (-1.39, 0.77)

SB4+MTX

-0.06 (-1.08, 0.95) - 0.27 (-0.72, 1.26) 1.00 (-0.18, 2.19) -0.30 (-1.28, 0.69)

ANBAI+MTX

-0.56 (-1.83, 0.72) - 0.67 (-0.60, 1.94) 0.06 (-1.21, 1.34) -1.84 (-3.29, -0.39)

CT-P13+MTX

-0.50 (-1.60, 0.60) - 0.74 (-0.45, 1.93) 0.88 (-0.44, 2.19) -1.84 (-3.14, -0.53)

SB2+MTX

-0.50 (-1.72, 0.73) - 0.78 (-0.50, 2.06) 0.24 (-1.00, 1.49) -1.82 (-3.20, -0.43)

SB5+MTX

-0.56 (-1.72, 0.60) - 0.61 (-0.53, 1.75) -0.62 (-1.93, 0.69) -1.80 (-3.14, -0.46)

ZRC-3197+MTX

-0.59 (-1.90, 0.73) - 0.62 (-0.69, 1.93) 0.46 (-0.90, 1.82) -1.81 (-3.28, -0.33)

ABP501+MTX

-0.57 (-1.73, 0.59) - 0.59 (-0.55, 1.73) 0.61 (-0.74, 1.96) -1.81 (-3.14, -0.48)

ABA_STD

(IV)+MTX ETN_STD+MTX -0.43 (-1.19, 0.33) -1.56 (-2.39, -0.73) 0.56 (-0.32, 1.45) 1.22 (0.08, 2.36) -1.50 (-2.50, -0.50)

ADA_STD+MTX

-0.49 (-1.18, 0.21) -1.14 (-1.92, -0.35) 0.36 (-0.39, 1.11) -0.05 (-0.81, 0.70) -1.48 (-2.42, -0.53)

ADA_STD

1.20 (-0.57, 2.97) - - 1.39 (-0.33, 3.10) -

TOF_STD+MTX

-0.49 (-1.28, 0.31) - 0.40 (-0.43, 1.23) -0.56 (-1.46, 0.33) -1.50 (-2.51, -0.49)

TOF_STD

1.19 (-0.52, 2.90) - - -0.71 (-2.78, 1.36) -

399


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

TOC_4 (IV)

-0.47 (-1.62, 0.68) -1.92 (-3.12, -0.73) - -0.33 (-1.55, 0.90) -1.50 (-2.81, -0.19)

TOC_8 (IV)

-0.43 (-1.28, 0.41) -2.25 (-3.19, -1.31) 0.67 (-0.23, 1.58) -0.29 (-1.19, 0.60) -1.50 (-2.55, -0.45)

TOC_4 (IV)+MTX

-0.44 (-1.32, 0.45) -2.08 (-3.05, -1.11) 0.61 (-0.33, 1.56) -0.26 (-1.17, 0.64) -1.49 (-2.56, -0.41)

TOC_8 (IV)+MTX

-0.43 (-1.22, 0.35) -1.82 (-2.72, -0.92) 0.54 (-0.29, 1.37) -0.25 (-1.09, 0.59) -1.50 (-2.51, -0.49)

GOL_STD (SC)

0.79 (-0.79, 2.37) - - -1.02 (-3.03, 0.99) -

GOL_STD

(SC)+MTX

-0.35 (-1.23, 0.52) - 0.44 (-0.47, 1.34) -0.75 (-1.66, 0.16) -1.48 (-2.55, -0.40)

GOL_STD

(IV)+MTX

-0.44 (-1.54, 0.67) - 0.42 (-0.67, 1.52) -0.24 (-1.42, 0.95) -1.49 (-2.72, -0.26)

INF_STD+MTX

-0.42 (-1.22, 0.38) -1.47 (-2.33, -0.61) 0.52 (-0.43, 1.48) -0.82 (-1.66, 0.02) -1.50 (-2.52, -0.48)

CERTO_STD+MTX

-0.44 (-1.19, 0.32) - 0.37 (-0.43, 1.17) -0.24 (-1.05, 0.58) -1.51 (-2.50, -0.51)

CERTO_STD

1.13 (-0.35, 2.60) - - -0.44 (-2.30, 1.42) -

RIT_STD

-0.41 (-1.99, 1.18) -1.39 (-2.94, 0.17) - -1.89 (-3.59, -0.19) -1.45 (-3.10, 0.20)

RIT_STD+MTX

-0.45 (-1.98, 1.07) -1.38 (-2.90, 0.15) - -0.98 (-2.26, 0.30) -1.46 (-3.09, 0.17)

SAR_200

1.20 (-0.78, 3.18) - - 1.38 (-0.61, 3.37) -

400


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

BAR_4+MTX

-0.53 (-1.37, 0.32) - 0.38 (-0.48, 1.23) 0.15 (-0.84, 1.14) -1.50 (-2.54, -0.46)

HD203+MTX

0.01 (-0.96, 0.99) - 0.01 (-0.91, 0.94) 0.003 (-1.04, 1.04) 0.01 (-0.90, 0.92)

SB4+MTX

0.01 (-0.86, 0.87) - 0.004 (-0.80, 0.81) -0.0003 (-0.94,

0.94) 0.01 (-0.79, 0.81)

ANBAI+MTX

-0.46 (-1.69, 0.78) - 0.41 (-0.84, 1.66) -0.45 (-1.78, 0.89) -1.53 (-2.90, -0.15)

CT-P13+MTX

-0.42 (-1.46, 0.62) - 0.49 (-0.67, 1.65) -0.80 (-1.90, 0.30) -1.53 (-2.73, -0.33)

SB2+MTX

-0.43 (-1.63, 0.76) - 0.52 (-0.73, 1.78) -0.82 (-2.09, 0.44) -1.50 (-2.80, -0.21)

SB5+MTX

-0.49 (-1.62, 0.64) - 0.36 (-0.76, 1.47) -0.07 (-1.30, 1.16) -1.49 (-2.73, -0.24)

ZRC-3197+MTX

-0.51 (-1.78, 0.76) - 0.37 (-0.91, 1.65) -0.03 (-1.38, 1.31) -1.50 (-2.89, -0.11)

ABP501+MTX

-0.49 (-1.60, 0.63) - 0.34 (-0.78, 1.45) -0.06 (-1.27, 1.14) -1.49 (-2.73, -0.26)

ADA_STD+MTX ABA_STD

(IV)+MTX -0.06 (-0.68, 0.56) 0.42 (-0.20, 1.05) -0.20 (-0.90, 0.49) 0.62 (-0.03, 1.27) 0.02 (-0.56, 0.60)

ADA_STD

1.66 (-0.19, 3.51) - - 2.06 (0.28, 3.84) -

TOF_STD+MTX

-0.04 (-0.77, 0.69) - -0.15 (-0.94, 0.64) 0.11 (-0.70, 0.93) 0.02 (-0.66, 0.71)

TOF_STD

1.66 (-0.14, 3.45) - - -0.05 (-2.22, 2.12) -

401


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

TOC_4 (IV)

-0.03 (-1.16, 1.09) -0.35 (-1.45, 0.74) - 0.35 (-0.82, 1.52) 0.01 (-1.05, 1.07)

TOC_8 (IV)

0.003 (-0.78, 0.79) -0.69 (-1.49, 0.12) 0.11 (-0.75, 0.96) 0.38 (-0.44, 1.20) 0.005 (-0.73, 0.74)

TOC_4 (IV)+MTX

-0.01 (-0.84, 0.81) -0.50 (-1.35, 0.34) 0.05 (-0.85, 0.96) 0.41 (-0.41, 1.22) 0.02 (-0.75, 0.79)

TOC_8 (IV)+MTX

0.01 (-0.71, 0.73) -0.25 (-1.01, 0.51) -0.02 (-0.81, 0.77) 0.42 (-0.33, 1.17) 0.01 (-0.66, 0.68)

GOL_STD (SC)

1.25 (-0.39, 2.88) - - -0.35 (-2.46, 1.76) -

GOL_STD

(SC)+MTX

0.08 (-0.72, 0.89) - -0.13 (-0.99, 0.73) -0.07 (-0.90, 0.75) 0.03 (-0.74, 0.80)

GOL_STD

(IV)+MTX

-0.003 (-1.05, 1.04) - -0.13 (-1.18, 0.92) 0.44 (-0.69, 1.56) 0.02 (-0.96, 0.99)

INF_STD+MTX

0.02 (-0.62, 0.66) 0.09 (-0.56, 0.73) -0.04 (-0.75, 0.67) -0.16 (-0.84, 0.53) 0.01 (-0.60, 0.61)

CERTO_STD+MTX

-0.28 (-1.19, 0.64) - -0.18 (-0.93, 0.57) 0.43 (-0.29, 1.16) -0.004 (-0.65, 0.65)

CERTO_STD

1.40 (0.05, 2.75) - - 0.24 (-1.73, 2.20) -

RIT_STD

0.64 (-0.72, 2.01) 0.18 (-1.30, 1.66) - -1.20 (-2.87, 0.46) 0.06 (-1.40, 1.53)

RIT_STD+MTX

-0.41 (-1.91, 1.10) 0.19 (-1.26, 1.65) - -0.29 (-1.52, 0.94) 0.07 (-1.37, 1.51)

SAR_200

1.66 (-0.40, 3.71) - - 2.05 (0.01, 4.08) -

402


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

BAR_4+MTX

-0.09 (-0.86, 0.68) - -0.18 (-0.99, 0.63) 0.82 (-0.10, 1.74) -0.001 (-0.71, 0.71)

HD203+MTX

0.46 (-0.79, 1.71) - -0.55 (-1.84, 0.74) 0.67 (-0.66, 2.01) 1.52 (0.16, 2.89)

SB4+MTX

0.46 (-0.70, 1.61) - -0.54 (-1.75, 0.66) 0.69 (-0.56, 1.93) 1.52 (0.25, 2.80)

ANBAI+MTX

-0.04 (-1.24, 1.17) - -0.16 (-1.38, 1.06) 0.22 (-1.06, 1.49) -0.02 (-1.17, 1.12)

CT-P13+MTX

0.01 (-0.93, 0.96) - -0.07 (-1.03, 0.90) -0.12 (-1.13, 0.89) -0.02 (-0.90, 0.87)

SB2+MTX

0.02 (-1.08, 1.11) - -0.03 (-1.10, 1.05) -0.14 (-1.30, 1.03) 0.02 (-0.98, 1.02)

SB5+MTX

-0.05 (-1.13, 1.03) - -0.20 (-1.29, 0.88) 0.60 (-0.57, 1.78) 0.02 (-0.98, 1.03)

ZRC-3197+MTX

-0.06 (-1.29, 1.17) - -0.21 (-1.47, 1.05) 0.63 (-0.68, 1.95) 0.02 (-1.17, 1.20)

ABP501+MTX

-0.04 (-1.12, 1.05) - -0.21 (-1.29, 0.86) 0.62 (-0.53, 1.77) 0.02 (-0.97, 1.01)

ADA_STD ADA_STD+MTX 1.72 (-0.07, 3.52) - - 1.43 (-0.31, 3.17) -

TOF_STD+MTX

-0.0001 (-0.59, 0.59) - 0.05 (-0.51, 0.62) -0.52 (-1.18, 0.15) -0.01 (-0.56, 0.55)

TOF_STD

1.72 (-0.03, 3.46) - - -0.66 (-2.82, 1.49) -

TOC_4 (IV)

0.01 (-1.04, 1.06) -0.78 (-1.82, 0.26) - -0.28 (-1.38, 0.83) -0.02 (-1.02, 0.98)

403


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

TOC_8 (IV)

0.06 (-0.64, 0.77) -1.11 (-1.86, -0.35) 0.31 (-0.41, 1.03) -0.25 (-1.00, 0.51) -0.02 (-0.68, 0.64)

TOC_4 (IV)+MTX

0.05 (-0.70, 0.80) -0.93 (-1.73, -0.13) 0.26 (-0.51, 1.02) -0.22 (-0.97, 0.54) 0.001 (-0.70, 0.70)

TOC_8 (IV)+MTX

0.06 (-0.58, 0.69) -0.67 (-1.38, 0.03) 0.18 (-0.45, 0.81) -0.20 (-0.88, 0.48) -0.02 (-0.60, 0.57)

GOL_STD (SC)

1.30 (-0.28, 2.88) - - -0.98 (-3.08, 1.12) -

GOL_STD

(SC)+MTX

0.13 (-0.59, 0.85) - 0.08 (-0.64, 0.79) -0.70 (-1.46, 0.06) 0.001 (-0.70, 0.70)

GOL_STD

(IV)+MTX

0.05 (-0.95, 1.05) - 0.07 (-0.87, 1.02) -0.19 (-1.26, 0.89) 0.001 (-0.92, 0.93)

INF_STD+MTX

0.08 (-0.57, 0.72) -0.33 (-0.99, 0.33) 0.17 (-0.61, 0.94) -0.770 (-1.46, -

0.08) -0.01 (-0.63, 0.60)

CERTO_STD+MTX

0.05 (-0.48, 0.57) - 0.02 (-0.48, 0.53) -0.18 (-0.75, 0.39) -0.03 (-0.52, 0.47)

CERTO_STD

1.63 (0.13, 3.13) - - -0.41 (-2.37, 1.56) -

RIT_STD

0.07 (-1.39, 1.53) -0.24 (-1.67, 1.19) - -1.83 (-3.44, -0.22) 0.04 (-1.37, 1.46)

RIT_STD+MTX

0.04 (-1.39, 1.46) -0.23 (-1.65, 1.19) - -0.91 (-2.10, 0.27) 0.04 (-1.36, 1.45)

SAR_200

1.73 (-0.28, 3.74) - - 1.43 (-0.57, 3.43) -

BAR_4+MTX

-0.04 (-0.67, 0.60) - 0.02 (-0.57, 0.61) 0.20 (-0.56, 0.95) -0.02 (-0.60, 0.56)

404


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

HD203+MTX

0.51 (-0.68, 1.70) - -0.34 (-1.53, 0.85) 0.05 (-1.23, 1.33) 1.50 (0.19, 2.82)

SB4+MTX

0.50 (-0.62, 1.62) - -0.34 (-1.44, 0.77) 0.07 (-1.13, 1.28) 1.50 (0.27, 2.74)

ANBAI+MTX

0.02 (-1.13, 1.17) - 0.05 (-1.07, 1.17) -0.40 (-1.63, 0.83) -0.04 (-1.14, 1.05)

CT-P13+MTX

0.07 (-0.87, 1.02) - 0.14 (-0.87, 1.15) -0.73 (-1.73, 0.26) -0.03 (-0.92, 0.85)

SB2+MTX

0.07 (-1.02, 1.17) - 0.18 (-0.95, 1.32) -0.77 (-1.93, 0.40) -0.004 (-1.02, 1.01)

SB5+MTX

-0.01 (-0.89, 0.88) - 0.003 (-0.82, 0.83) -0.016 (-0.98, 0.95) 0.002 (-0.81, 0.82)

ZRC-3197+MTX

-0.02 (-1.11, 1.07) - 0.004 (-1.04, 1.05) 0.01 (-1.13, 1.16) -0.01 (-1.04, 1.03)

ABP501+MTX

-0.0001 (-0.89, 0.89) - -0.01 (-0.82, 0.80) -0.003 (-0.94, 0.93) -0.01 (-0.81, 0.79)

TOF_STD+MTX ADA_STD -1.70 (-3.55, 0.15) - - -1.94 (-3.75, -0.13) -

TOF_STD

0.001 (-1.22, 1.22) - - -2.10 (-4.10, -0.11) -

TOC_4 (IV)

-1.70 (-3.75, 0.36) - - -1.71 (-3.64, 0.23) -

TOC_8 (IV)

-1.66 (-3.55, 0.22) - - -1.68 (-3.35, -0.02) -

TOC_4 (IV)+MTX

-1.66 (-3.58, 0.25) - - -1.64 (-3.41, 0.12) -

405


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

TOC_8 (IV)+MTX

-1.67 (-3.53, 0.20) - - -1.64 (-3.35, 0.07) -

GOL_STD (SC)

-0.41 (-2.16, 1.34) - - -2.42 (-4.59, -0.25) -

GOL_STD

(SC)+MTX

-1.58 (-3.46, 0.30) - - -2.13 (-3.95, -0.32) -

GOL_STD

(IV)+MTX

-1.65 (-3.66, 0.35) - - -1.62 (-3.57, 0.32) -

INF_STD+MTX

-1.64 (-3.51, 0.23) - - -2.21 (-4.01, -0.42) -

CERTO_STD+MTX

-1.67 (-3.52, 0.17) - - -1.61 (-3.39, 0.16) -

CERTO_STD

-0.08 (-1.67, 1.50) - - -1.84 (-3.88, 0.20) -

RIT_STD

-1.67 (-3.96, 0.62) - - -3.30 (-5.60, -0.99) -

RIT_STD+MTX

-1.68 (-3.92, 0.55) - - -2.37 (-4.38, -0.36) -

SAR_200

0.01 (-0.90, 0.93) - - -0.01 (-0.99, 0.98) -

BAR_4+MTX

-1.74 (-3.58, 0.09) - - -1.23 (-3.10, 0.63) -

HD203+MTX

-1.19 (-3.20, 0.82) - - -1.38 (-3.41, 0.64) -

SB4+MTX

-1.19 (-3.15, 0.76) - - -1.37 (-3.33, 0.58) -

406


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

ANBAI+MTX

-1.68 (-3.76, 0.39) - - -1.82 (-3.86, 0.21) -

CT-P13+MTX

-1.65 (-3.63, 0.34) - - -2.19 (-4.13, -0.26) -

SB2+MTX

-1.63 (-3.67, 0.42) - - -2.19 (-4.20, -0.17) -

SB5+MTX

-1.71 (-3.68, 0.25) - - -1.44 (-3.40, 0.52) -

ZRC-3197+MTX

-1.71 (-3.83, 0.41) - - -1.42 (-3.50, 0.66) -

ABP501+MTX

-1.71 (-3.71, 0.29) - - -1.43 (-3.41, 0.54) -

TOF_STD TOF_STD+MTX 1.71 (-0.10, 3.53) - - -0.14 (-2.36, 2.08) -

TOC_4 (IV)

0.02 (-1.11, 1.14) - - 0.24 (-0.98, 1.46) -0.01 (-1.08, 1.06)

TOC_8 (IV)

0.04 (-0.76, 0.84) - 0.25 (-0.56, 1.06) 0.26 (-0.65, 1.17) -0.02 (-0.78, 0.74)

TOC_4 (IV)+MTX

0.04 (-0.80, 0.88) - 0.20 (-0.65, 1.05) 0.29 (-0.61, 1.19) 0.01 (-0.79, 0.80)

TOC_8 (IV)+MTX

0.05 (-0.69, 0.79) - 0.13 (-0.61, 0.86) 0.31 (-0.54, 1.16) -0.01 (-0.72, 0.69)

GOL_STD (SC)

1.29 (-0.35, 2.93) - - -0.46 (-2.62, 1.70) -

GOL_STD

(SC)+MTX

0.12 (-0.70, 0.95) - 0.03 (-0.78, 0.83) -0.19 (-1.09, 0.71) 0.01 (-0.79, 0.80)

407


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

GOL_STD

(IV)+MTX

0.06 (-1.02, 1.13) - 0.02 (-0.99, 1.04) 0.32 (-0.87, 1.52) 0.003 (-1.00, 1.00)

INF_STD+MTX

0.06 (-0.69, 0.82) - 0.11 (-0.74, 0.97) -0.26 (-1.10, 0.58) -0.01 (-0.73, 0.70)

CERTO_STD+MTX

0.04 (-0.66, 0.73) - -0.03 (-0.69, 0.64) 0.33 (-0.46, 1.12) -0.02 (-0.67, 0.64)

CERTO_STD

1.63 (0.06, 3.21) - - 0.13 (-1.89, 2.14) -

RIT_STD

0.06 (-1.46, 1.58) - - -1.32 (-3.02, 0.37) 0.04 (-1.42, 1.51)

RIT_STD+MTX

0.04 (-1.45, 1.52) - - -0.40 (-1.69, 0.89) 0.05 (-1.40, 1.51)

SAR_200

1.70 (-0.36, 3.76) - - 1.93 (-0.12, 3.98) -

BAR_4+MTX

-0.05 (-0.83, 0.74) - -0.03 (-0.76, 0.70) 0.70 (-0.25, 1.66) -0.02 (-0.75, 0.70)

HD203+MTX

0.50 (-0.75, 1.75) - -0.39 (-1.64, 0.85) 0.57 (-0.81, 1.94) 1.51 (0.13, 2.88)

SB4+MTX

0.49 (-0.70, 1.68) - -0.40 (-1.56, 0.76) 0.57 (-0.73, 1.87) 1.50 (0.21, 2.79)

ANBAI+MTX

0.01 (-1.20, 1.22) - -0.01 (-1.18, 1.17) 0.12 (-1.21, 1.44) -0.04 (-1.20, 1.12)

CT-P13+MTX

0.06 (-0.97, 1.08) - 0.09 (-0.99, 1.17) -0.23 (-1.34, 0.89) -0.03 (-0.99, 0.93)

SB2+MTX

0.06 (-1.10, 1.22) - 0.13 (-1.06, 1.32) -0.26 (-1.52, 1.00) -0.01 (-1.08, 1.07)

408


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

SB5+MTX

-0.01 (-1.08, 1.05) - -0.05 (-1.06, 0.95) 0.50 (-0.68, 1.67) 0.002 (-0.99, 0.99)

ZRC-3197+MTX

-0.03 (-1.26, 1.20) - -0.05 (-1.25, 1.15) 0.53 (-0.79, 1.85) 0.002 (-1.17, 1.17)

ABP501+MTX

-0.01 (-1.07, 1.06) - -0.06 (-1.05, 0.93) 0.52 (-0.64, 1.67) 0.003 (-0.97, 0.98)

TOC_4 (IV) TOF_STD -1.67 (-3.67, 0.33) - - 0.40 (-1.97, 2.77) -

TOC_8 (IV)

-1.64 (-3.47, 0.19) - - 0.42 (-1.79, 2.64) -

TOC_4 (IV)+MTX

-1.66 (-3.52, 0.20) - - 0.45 (-1.75, 2.66) -

TOC_8 (IV)+MTX

-1.65 (-3.48, 0.17) - - 0.47 (-1.72, 2.66) -

GOL_STD (SC)

-0.40 (-2.11, 1.31) - - -0.32 (-2.17, 1.52) -

GOL_STD

(SC)+MTX

-1.57 (-3.40, 0.26) - - -0.04 (-2.25, 2.17) -

GOL_STD

(IV)+MTX

-1.66 (-3.62, 0.30) - - 0.47 (-1.87, 2.81) -

INF_STD+MTX

-1.64 (-3.45, 0.18) - - -0.12 (-2.30, 2.06) -

CERTO_STD+MTX

-1.66 (-3.47, 0.14) - - 0.48 (-1.68, 2.65) -

CERTO_STD

-0.07 (-1.62, 1.49) - - 0.24 (-1.41, 1.90) -

409


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

RIT_STD

-1.66 (-3.91, 0.60) - - -1.18 (-3.79, 1.44) -

RIT_STD+MTX

-1.68 (-3.91, 0.56) - - -0.26 (-2.64, 2.13) -

SAR_200

0.01 (-1.50, 1.53) - - 2.10 (-0.11, 4.32) -

BAR_4+MTX

-1.73 (-3.52, 0.05) - - 0.86 (-1.39, 3.12) -

HD203+MTX

-1.20 (-3.16, 0.76) - - 0.70 (-1.62, 3.01) -

SB4+MTX

-1.20 (-3.14, 0.74) - - 0.71 (-1.55, 2.97) -

ANBAI+MTX

-1.69 (-3.73, 0.34) - - 0.25 (-2.14, 2.64) -

CT-P13+MTX

-1.66 (-3.57, 0.26) - - -0.09 (-2.38, 2.20) -

SB2+MTX

-1.61 (-3.62, 0.39) - - -0.10 (-2.47, 2.28) -

SB5+MTX

-1.71 (-3.65, 0.23) - - 0.66 (-1.68, 2.99) -

ZRC-3197+MTX

-1.72 (-3.79, 0.35) - - 0.68 (-1.75, 3.12) -

ABP501+MTX

-1.70 (-3.67, 0.26) - - 0.67 (-1.67, 3.01) -

TOC_8 (IV) TOC_4 (IV) 0.02 (-0.98, 1.02) -0.34 (-1.31, 0.64) - 0.02 (-1.02, 1.07) -0.01 (-0.96, 0.94)

410


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

TOC_4 (IV)+MTX

0.02 (-1.02, 1.06) -0.15 (-1.16, 0.85) - 0.06 (-1.00, 1.11) 0.02 (-0.96, 1.00)

TOC_8 (IV)+MTX

0.04 (-0.94, 1.02) 0.11 (-0.84, 1.06) - 0.08 (-0.92, 1.09) 0.003 (-0.92, 0.93)

GOL_STD (SC)

1.28 (-0.55, 3.12) - - -0.70 (-3.02, 1.61) -

GOL_STD

(SC)+MTX

0.13 (-1.05, 1.30) - - -0.41 (-1.62, 0.79) 0.02 (-1.10, 1.14)

GOL_STD

(IV)+MTX

0.03 (-1.33, 1.39) - - 0.09 (-1.37, 1.54) 0.01 (-1.28, 1.31)

INF_STD+MTX

0.05 (-1.08, 1.18) 0.44 (-0.66, 1.55) - -0.49 (-1.66, 0.68) 0.003 (-1.07, 1.07)

CERTO_STD+MTX

0.04 (-1.07, 1.14) - - 0.09 (-1.06, 1.24) -0.01 (-1.05, 1.03)

CERTO_STD

1.58 (-0.20, 3.36) - - -0.14 (-2.34, 2.06) -

RIT_STD

0.06 (-1.67, 1.80) 0.52 (-1.17, 2.22) - -1.56 (-3.45, 0.32) 0.05 (-1.62, 1.72)

RIT_STD+MTX

0.03 (-1.69, 1.75) 0.52 (-1.17, 2.21) - -0.64 (-2.16, 0.89) 0.06 (-1.60, 1.71)

SAR_200

1.68 (-0.56, 3.92) - - 1.70 (-0.48, 3.87) -

BAR_4+MTX

-0.06 (-1.23, 1.10) - - 0.47 (-0.82, 1.76) -0.02 (-1.11, 1.08)

HD203+MTX

0.48 (-1.04, 2.01) - - 0.31 (-1.30, 1.92) 1.51 (-0.08, 3.11)

411


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

SB4+MTX

0.48 (-0.96, 1.92) - - 0.33 (-1.22, 1.88) 1.52 (-0.01, 3.04)

ANBAI+MTX

-0.01 (-1.49, 1.47) - - -0.13 (-1.67, 1.42) -0.03 (-1.45, 1.38)

CT-P13+MTX

0.03 (-1.30, 1.37) - - -0.47 (-1.86, 0.92) -0.02 (-1.28, 1.23)

SB2+MTX

0.06 (-1.38, 1.50) - - -0.49 (-1.99, 1.02) 0.02 (-1.32, 1.35)

SB5+MTX

0.001 (-1.36, 1.36) - - 0.27 (-1.18, 1.73) 0.03 (-1.25, 1.31)

ZRC-3197+MTX

-0.04 (-1.54, 1.47) - - 0.30 (-1.30, 1.90) 0.02 (-1.43, 1.46)

ABP501+MTX

-0.01 (-1.40, 1.37) - - 0.28 (-1.17, 1.72) 0.01 (-1.26, 1.29)

TOC_4 (IV)+MTX TOC_8 (IV) -0.001 (-0.73, 0.72) 0.18 (-0.56, 0.92) -0.05 (-0.82, 0.73) 0.02 (-0.70, 0.75) 0.03 (-0.65, 0.70)

TOC_8 (IV)+MTX

0.004 (-0.50, 0.51) 0.44 (-0.14, 1.01) -0.13 (-0.64, 0.38) 0.04 (-0.49, 0.58) 0.003 (-0.47, 0.48)

GOL_STD (SC)

1.23 (-0.42, 2.88) - - -0.74 (-2.89, 1.40) -

GOL_STD

(SC)+MTX

0.08 (-0.79, 0.95) - -0.23 (-1.10, 0.64) -0.45 (-1.36, 0.46) 0.03 (-0.80, 0.86)

GOL_STD

(IV)+MTX

-0.01 (-1.13, 1.10) - -0.24 (-1.31, 0.84) 0.05 (-1.14, 1.24) 0.01 (-1.02, 1.05)

INF_STD+MTX

0.02 (-0.80, 0.83) 0.78 (-0.07, 1.63) -0.13 (-1.06, 0.79) -0.52 (-1.37, 0.33) 0.01 (-0.76, 0.78)

412


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

CERTO_STD+MTX

-0.005 (-0.76, 0.76) - -0.28 (-1.04, 0.48) 0.06 (-0.76, 0.88) -0.01 (-0.73, 0.72)

CERTO_STD

1.57 (-0.01, 3.15) - - -0.15 (-2.18, 1.89) -

RIT_STD

0.04 (-1.52, 1.59) 0.87 (-0.66, 2.39) - -1.59 (-3.28, 0.11) 0.06 (-1.42, 1.55)

RIT_STD+MTX

0.002 (-1.52, 1.53) 0.87 (-0.65, 2.40) - -0.67 (-1.96, 0.63) 0.06 (-1.42, 1.54)

SAR_200

1.65 (-0.44, 3.74) - - 1.67 (-0.26, 3.60) -

BAR_4+MTX

-0.09 (-0.96, 0.77) - -0.29 (-1.11, 0.54) 0.44 (-0.56, 1.44) -0.005 (-0.79, 0.78)

HD203+MTX

0.45 (-0.84, 1.74) - -0.65 (-1.95, 0.64) 0.29 (-1.08, 1.67) 1.52 (0.13, 2.91)

SB4+MTX

0.46 (-0.76, 1.67) - -0.65 (-1.86, 0.56) 0.30 (-1.00, 1.61) 1.52 (0.21, 2.83)

ANBAI+MTX

-0.04 (-1.29, 1.22) - -0.27 (-1.49, 0.95) -0.16 (-1.49, 1.17) -0.03 (-1.21, 1.15)

CT-P13+MTX

0.01 (-1.07, 1.09) - -0.17 (-1.30, 0.96) -0.49 (-1.61, 0.63) -0.02 (-1.02, 0.98)

SB2+MTX

0.01 (-1.19, 1.21) - -0.13 (-1.37, 1.10) -0.52 (-1.79, 0.75) 0.01 (-1.10, 1.13)

SB5+MTX

-0.05 (-1.18, 1.08) - -0.30 (-1.39, 0.79) 0.23 (-0.99, 1.45) 0.03 (-1.02, 1.07)

ZRC-3197+MTX

-0.07 (-1.34, 1.21) - -0.31 (-1.57, 0.96) 0.26 (-1.08, 1.61) 0.02 (-1.19, 1.23)

413


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

ABP501+MTX

-0.05 (-1.19, 1.08) - -0.31 (-1.39, 0.77) 0.24 (-0.95, 1.44) 0.01 (-1.02, 1.05)

TOC_8 (IV)+MTX TOC_4

(IV)+MTX 0.01 (-0.62, 0.64) 0.25 (-0.42, 0.93) -0.08 (-0.74, 0.58) 0.02 (-0.60, 0.64) -0.02 (-0.61, 0.57)

GOL_STD (SC)

1.24 (-0.43, 2.91) - - -0.77 (-2.91, 1.37) -

GOL_STD

(SC)+MTX

0.08 (-0.84, 1.00) - -0.19 (-1.11, 0.73) -0.49 (-1.40, 0.42) -0.003 (-0.87, 0.86)

GOL_STD

(IV)+MTX

0.003 (-1.14, 1.15) - -0.19 (-1.30, 0.91) 0.02 (-1.17, 1.21) -0.01 (-1.06, 1.04)

INF_STD+MTX

0.02 (-0.83, 0.88) 0.60 (-0.28, 1.47) -0.09 (-1.06, 0.87) -0.55 (-1.41, 0.30) -0.02 (-0.82, 0.78)

CERTO_STD+MTX

-0.005 (-0.82, 0.81) - -0.24 (-1.06, 0.58) 0.04 (-0.79, 0.86) -0.03 (-0.79, 0.73)

CERTO_STD

1.59 (-0.03, 3.20) - - -0.18 (-2.22, 1.85) -

RIT_STD

0.04 (-1.53, 1.61) 0.68 (-0.86, 2.22) - -1.61 (-3.30, 0.08) 0.05 (-1.46, 1.55)

RIT_STD+MTX

0.004 (-1.52, 1.53) 0.68 (-0.85, 2.22) - -0.70 (-1.99, 0.58) 0.04 (-1.45, 1.53)

SAR_200

1.66 (-0.46, 3.78) - - 1.64 (-0.38, 3.66) -

BAR_4+MTX

-0.09 (-0.98, 0.80) - -0.24 (-1.11, 0.63) 0.42 (-0.58, 1.42) -0.03 (-0.84, 0.79)

HD203+MTX

0.45 (-0.86, 1.77) - -0.60 (-1.92, 0.73) 0.27 (-1.10, 1.64) 1.51 (0.09, 2.92)

414


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

SB4+MTX

0.45 (-0.80, 1.70) - -0.61 (-1.85, 0.64) 0.28 (-1.02, 1.58) 1.50 (0.17, 2.84)

ANBAI+MTX

-0.02 (-1.29, 1.26) - -0.21 (-1.46, 1.04) -0.18 (-1.51, 1.15) -0.05 (-1.25, 1.16)

CT-P13+MTX

0.01 (-1.08, 1.10) - -0.13 (-1.30, 1.04) -0.53 (-1.65, 0.60) -0.04 (-1.07, 0.99)

SB2+MTX

0.03 (-1.22, 1.27) - -0.09 (-1.36, 1.19) -0.56 (-1.83, 0.72) -0.01 (-1.16, 1.13)

SB5+MTX

-0.04 (-1.20, 1.12) - -0.25 (-1.37, 0.87) 0.21 (-1.01, 1.42) 0.01 (-1.06, 1.07)

ZRC-3197+MTX

-0.06 (-1.38, 1.25) - -0.25 (-1.54, 1.04) 0.23 (-1.13, 1.60) -0.001 (-1.24, 1.24)

ABP501+MTX

-0.04 (-1.20, 1.12) - -0.27 (-1.38, 0.84) 0.21 (-0.99, 1.42) -0.01 (-1.07, 1.05)

GOL_STD (SC) TOC_8

(IV)+MTX 1.24 (-0.40, 2.88) - - -0.80 (-2.92, 1.33) -

GOL_STD

(SC)+MTX

0.08 (-0.73, 0.90) - -0.10 (-0.91, 0.71) -0.49 (-1.34, 0.36) 0.02 (-0.76, 0.81)

GOL_STD

(IV)+MTX

-0.02 (-1.10, 1.06) - -0.11 (-1.13, 0.91) 0.01 (-1.14, 1.16) 0.01 (-0.98, 1.00)

INF_STD+MTX

0.02 (-0.74, 0.77) 0.34 (-0.46, 1.14) -0.01 (-0.88, 0.85) -0.57 (-1.36, 0.21) 0.002 (-0.71, 0.71)

CERTO_STD+MTX

-0.005 (-0.70, 0.69) - -0.15 (-0.84, 0.53) 0.02 (-0.72, 0.76) -0.01 (-0.67, 0.65)

CERTO_STD

1.57 (0.01, 3.14) - - -0.19 (-2.20, 1.81) -

415


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

RIT_STD

0.02 (-1.50, 1.54) 0.43 (-1.08, 1.93) - -1.63 (-3.28, 0.02) 0.06 (-1.40, 1.52)

RIT_STD+MTX

-0.002 (-1.49, 1.48) 0.44 (-1.06, 1.94) - -0.72 (-1.96, 0.53) 0.06 (-1.39, 1.50)

SAR_200

1.65 (-0.41, 3.71) - - 1.63 (-0.34, 3.59) -

BAR_4+MTX

-0.09 (-0.89, 0.70) - -0.16 (-0.91, 0.60) 0.40 (-0.55, 1.35) -0.01 (-0.73, 0.72)

HD203+MTX

0.45 (-0.81, 1.71) - -0.52 (-1.77, 0.73) 0.25 (-1.08, 1.59) 1.52 (0.15, 2.89)

SB4+MTX

0.44 (-0.73, 1.61) - -0.52 (-1.68, 0.63) 0.26 (-1.01, 1.53) 1.52 (0.24, 2.80)

ANBAI+MTX

-0.05 (-1.26, 1.16) - -0.14 (-1.32, 1.03) -0.21 (-1.50, 1.09) -0.04 (-1.19, 1.11)

CT-P13+MTX

-0.01 (-1.04, 1.03) - -0.04 (-1.12, 1.04) -0.54 (-1.61, 0.54) -0.02 (-0.98, 0.94)

SB2+MTX

0.01 (-1.14, 1.17) - -0.001 (-1.19, 1.18) -0.56 (-1.79, 0.67) 0.01 (-1.06, 1.08)

SB5+MTX

-0.06 (-1.14, 1.03) - -0.18 (-1.22, 0.86) 0.17 (-1.00, 1.35) 0.02 (-0.99, 1.02)

ZRC-3197+MTX

-0.07 (-1.32, 1.17) - -0.17 (-1.39, 1.04) 0.22 (-1.09, 1.54) 0.02 (-1.16, 1.19)

ABP501+MTX

-0.06 (-1.15, 1.03) - -0.19 (-1.21, 0.84) 0.20 (-0.96, 1.35) 0.01 (-0.98, 1.00)

GOL_STD

(SC)+MTX GOL_STD (SC) -1.17 (-2.81, 0.47) - - 0.27 (-1.91, 2.44) -

416


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

GOL_STD

(IV)+MTX

-1.24 (-3.03, 0.56) - - 0.80 (-1.48, 3.08) -

INF_STD+MTX

-1.23 (-2.87, 0.42) - - 0.20 (-1.93, 2.32) -

CERTO_STD+MTX

-1.25 (-2.88, 0.37) - - 0.80 (-1.31, 2.90) -

CERTO_STD

0.33 (-1.10, 1.76) - - 0.59 (-0.96, 2.14) -

RIT_STD

-1.23 (-3.34, 0.87) - - -0.84 (-3.42, 1.73) -

RIT_STD+MTX

-1.24 (-3.30, 0.81) - - 0.05 (-2.26, 2.36) -

SAR_200

0.42 (-1.56, 2.39) - - 2.42 (0.04, 4.79) -

BAR_4+MTX

-1.33 (-2.96, 0.29) - - 1.17 (-1.01, 3.36) -

HD203+MTX

-0.79 (-2.63, 1.05) - - 1.03 (-1.24, 3.30) -

SB4+MTX

-0.79 (-2.59, 1.00) - - 1.04 (-1.17, 3.25) -

ANBAI+MTX

-1.29 (-3.15, 0.58) - - 0.60 (-1.74, 2.93) -

CT-P13+MTX

-1.23 (-3.02, 0.56) - - 0.22 (-2.03, 2.47) -

SB2+MTX

-1.22 (-3.09, 0.64) - - 0.21 (-2.11, 2.52) -

417


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

SB5+MTX

-1.30 (-3.11, 0.51) - - 0.96 (-1.32, 3.24) -

ZRC-3197+MTX

-1.31 (-3.23, 0.62) - - 1.00 (-1.40, 3.39) -

ABP501+MTX

-1.29 (-3.09, 0.52) - - 0.99 (-1.32, 3.29) -

GOL_STD

(IV)+MTX

GOL_STD

(SC)+MTX -0.09 (-1.22, 1.04) - -0.0004 (-1.08, 1.08) 0.51 (-0.69, 1.71) -0.003 (-1.07, 1.06)

INF_STD+MTX

-0.07 (-0.91, 0.76) - 0.09 (-0.83, 1.02) -0.08 (-0.94, 0.78) -0.02 (-0.82, 0.78)

CERTO_STD+MTX

-0.09 (-0.88, 0.70) - -0.05 (-0.82, 0.71) 0.51 (-0.31, 1.32) -0.03 (-0.79, 0.72)

CERTO_STD

1.49 (-0.10, 3.08) - - 0.32 (-1.70, 2.33) -

RIT_STD

-0.07 (-1.64, 1.49) - - -1.13 (-2.82, 0.56) 0.04 (-1.47, 1.56)

RIT_STD+MTX

-0.08 (-1.61, 1.45) - - -0.21 (-1.51, 1.09) 0.04 (-1.46, 1.55)

SAR_200

1.55 (-0.53, 3.63) - - 2.12 (0.06, 4.18) -

BAR_4+MTX

-0.17 (-1.03, 0.69) - -0.06 (-0.88, 0.77) 0.89 (-0.11, 1.88) -0.03 (-0.84, 0.79)

HD203+MTX

0.36 (-0.96, 1.67) - -0.43 (-1.71, 0.86) 0.75 (-0.62, 2.13) 1.50 (0.10, 2.91)

SB4+MTX

0.36 (-0.86, 1.58) - -0.43 (-1.65, 0.79) 0.76 (-0.55, 2.07) 1.50 (0.16, 2.84)

418


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

ANBAI+MTX

-0.12 (-1.39, 1.16) - -0.04 (-1.27, 1.19) 0.30 (-1.03, 1.63) -0.05 (-1.27, 1.16)

CT-P13+MTX

-0.08 (-1.16, 1.00) - 0.05 (-1.07, 1.18) -0.05 (-1.17, 1.07) -0.04 (-1.06, 0.98)

SB2+MTX

-0.08 (-1.29, 1.13) - 0.09 (-1.14, 1.32) -0.09 (-1.36, 1.19) -0.02 (-1.16, 1.12)

SB5+MTX

-0.15 (-1.29, 1.00) - -0.07 (-1.16, 1.02) 0.68 (-0.55, 1.91) -0.002 (-1.08, 1.07)

ZRC-3197+MTX

-0.15 (-1.46, 1.15) - -0.07 (-1.35, 1.20) 0.70 (-0.67, 2.08) -0.01 (-1.26, 1.24)

ABP501+MTX

-0.13 (-1.26, 0.99) - -0.09 (-1.17, 0.99) 0.70 (-0.51, 1.90) -0.01 (-1.06, 1.04)

INF_STD+MTX GOL_STD

(IV)+MTX 0.03 (-1.03, 1.09) - 0.10 (-1.01, 1.21) -0.59 (-1.72, 0.55) -0.01 (-1.01, 0.99)

CERTO_STD+MTX

0.001 (-1.03, 1.03) - -0.05 (-1.02, 0.93) 0.01 (-1.10, 1.12) -0.03 (-0.99, 0.94)

CERTO_STD

1.59 (-0.14, 3.31) - - -0.21 (-2.36, 1.93) -

RIT_STD

0.02 (-1.69, 1.73) - - -1.64 (-3.49, 0.21) 0.05 (-1.57, 1.67)

RIT_STD+MTX

-0.01 (-1.68, 1.67) - - -0.73 (-2.22, 0.75) 0.05 (-1.56, 1.65)

SAR_200

1.66 (-0.53, 3.84) - - 1.62 (-0.57, 3.80) -

BAR_4+MTX

-0.10 (-1.21, 1.02) - -0.05 (-1.07, 0.98) 0.39 (-0.87, 1.65) -0.02 (-1.03, 1.00)

419


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

HD203+MTX

0.47 (-1.01, 1.95) - -0.40 (-1.84, 1.03) 0.25 (-1.33, 1.83) 1.52 (-0.02, 3.06)

SB4+MTX

0.44 (-0.96, 1.85) - -0.42 (-1.78, 0.94) 0.24 (-1.26, 1.75) 1.51 (0.05, 2.97)

ANBAI+MTX

-0.03 (-1.47, 1.40) - -0.03 (-1.40, 1.35) -0.21 (-1.74, 1.32) -0.05 (-1.40, 1.31)

CT-P13+MTX

0.01 (-1.26, 1.29) - 0.07 (-1.23, 1.36) -0.56 (-1.90, 0.79) -0.04 (-1.22, 1.15)

SB2+MTX

0.02 (-1.37, 1.40) - 0.11 (-1.28, 1.49) -0.59 (-2.07, 0.90) -0.005 (-1.29, 1.28)

SB5+MTX

-0.06 (-1.39, 1.28) - -0.08 (-1.32, 1.17) 0.17 (-1.27, 1.62) -0.001 (-1.23, 1.22)

ZRC-3197+MTX

-0.07 (-1.53, 1.40) - -0.07 (-1.46, 1.32) 0.20 (-1.36, 1.76) 0.0004 (-1.37, 1.37)

ABP501+MTX

-0.05 (-1.40, 1.30) - -0.08 (-1.32, 1.17) 0.20 (-1.24, 1.64) 0.001 (-1.23, 1.23)

CERTO_STD+MTX INF_STD+MTX -0.02 (-0.74, 0.69) - -0.14 (-0.96, 0.68) 0.59 (-0.16, 1.34) -0.01 (-0.69, 0.67)

CERTO_STD

1.55 (-0.03, 3.14) - - 0.39 (-1.60, 2.38) -

RIT_STD

0.02 (-1.50, 1.54) 0.10 (-1.38, 1.59) - -1.05 (-2.71, 0.62) 0.06 (-1.41, 1.54)

RIT_STD+MTX

-0.01 (-1.49, 1.46) 0.10 (-1.36, 1.56) - -0.14 (-1.39, 1.10) 0.06 (-1.40, 1.52)

SAR_200

1.62 (-0.46, 3.69) - - 2.20 (0.15, 4.25) -

420


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

BAR_4+MTX

-0.11 (-0.91, 0.69) - -0.14 (-1.02, 0.74) 0.97 (0.03, 1.91) -0.01 (-0.75, 0.73)

HD203+MTX

0.43 (-0.83, 1.69) - -0.51 (-1.84, 0.82) 0.82 (-0.52, 2.16) 1.51 (0.14, 2.89)

SB4+MTX

0.43 (-0.75, 1.61) - -0.51 (-1.75, 0.74) 0.84 (-0.41, 2.09) 1.53 (0.24, 2.81)

ANBAI+MTX

-0.06 (-1.27, 1.15) - -0.12 (-1.38, 1.15) 0.38 (-0.90, 1.66) -0.03 (-1.19, 1.13)

CT-P13+MTX

-0.001 (-0.70, 0.70) - -0.03 (-0.68, 0.63) 0.03 (-0.71, 0.78) -0.02 (-0.67, 0.62)

SB2+MTX

-0.01 (-0.90, 0.88) - 0.01 (-0.81, 0.82) -0.002 (-0.94, 0.93) 0.005 (-0.80, 0.81)

SB5+MTX

-0.07 (-1.15, 1.02) - -0.16 (-1.30, 0.97) 0.76 (-0.42, 1.94) 0.02 (-1.00, 1.04)

ZRC-3197+MTX

-0.09 (-1.33, 1.15) - -0.16 (-1.47, 1.14) 0.781 (-0.56, 2.12) 0.01 (-1.19, 1.21)

ABP501+MTX

-0.06 (-1.14, 1.03) - -0.17 (-1.29, 0.95) 0.78 (-0.39, 1.94) 0.02 (-1.00, 1.03)

CERTO_STD CERTO_STD+M

TX 1.58 (0.03, 3.14) - - -0.21 (-2.20, 1.78) -

RIT_STD

0.04 (-1.44, 1.52) - - -1.63 (-3.29, 0.02) 0.07 (-1.37, 1.52)

RIT_STD+MTX

0.002 (-1.45, 1.45) - - -0.73 (-1.97, 0.51) 0.07 (-1.38, 1.51)

SAR_200

1.66 (-0.39, 3.72) - - 1.61 (-0.42, 3.63) -

421


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

BAR_4+MTX

-0.09 (-0.83, 0.66) - 0.0003 (-0.69, 0.69) 0.39 (-0.49, 1.27) 0.01 (-0.68, 0.69)

HD203+MTX

0.46 (-0.77, 1.69) - -0.36 (-1.59, 0.87) 0.25 (-1.07, 1.56) 1.53 (0.18, 2.89)

SB4+MTX

0.45 (-0.71, 1.61) - -0.36 (-1.49, 0.76) 0.25 (-0.99, 1.49) 1.52 (0.26, 2.79)

ANBAI+MTX

-0.03 (-1.21, 1.15) - 0.02 (-1.14, 1.18) -0.22 (-1.48, 1.04) -0.02 (-1.15, 1.12)

CT-P13+MTX

0.02 (-0.97, 1.02) - 0.12 (-0.93, 1.17) -0.55 (-1.59, 0.49) -0.01 (-0.94, 0.92)

SB2+MTX

0.03 (-1.11, 1.17) - 0.16 (-1.00, 1.32) -0.58 (-1.80, 0.63) 0.02 (-1.04, 1.08)

SB5+MTX

-0.05 (-1.08, 0.99) - -0.02 (-0.99, 0.95) 0.16 (-0.96, 1.28) 0.03 (-0.93, 0.99)

ZRC-3197+MTX

-0.06 (-1.27, 1.15) - -0.03 (-1.19, 1.13) 0.20 (-1.08, 1.47) 0.02 (-1.12, 1.16)

ABP501+MTX

-0.04 (-1.07, 0.99) - -0.03 (-0.99, 0.92) 0.18 (-0.91, 1.28) 0.02 (-0.92, 0.96)

RIT_STD CERTO_STD -1.55 (-3.62, 0.51) - - -1.44 (-3.90, 1.03) -

RIT_STD+MTX

-1.57 (-3.59, 0.45) - - -0.52 (-2.72, 1.69) -

SAR_200

0.09 (-1.72, 1.91) - - 1.83 (-0.42, 4.08) -

BAR_4+MTX

-1.67 (-3.21, -0.14) - - 0.60 (-1.49, 2.68) -

422


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

HD203+MTX

-1.10 (-2.88, 0.68) - - 0.44 (-1.70, 2.59) -

SB4+MTX

-1.12 (-2.85, 0.61) - - 0.45 (-1.64, 2.54) -

ANBAI+MTX

-1.63 (-3.44, 0.18) - - 0.001 (-2.19, 2.20) -

CT-P13+MTX

-1.57 (-3.31, 0.16) - - -0.35 (-2.47, 1.77) -

SB2+MTX

-1.56 (-3.36, 0.23) - - -0.39 (-2.57, 1.79) -

SB5+MTX

-1.62 (-3.36, 0.11) - - 0.40 (-1.77, 2.56) -

ZRC-3197+MTX

-1.61 (-3.46, 0.24) - - 0.43 (-1.84, 2.71) -

ABP501+MTX

-1.64 (-3.37, 0.10) - - 0.39 (-1.77, 2.55) -

RIT_STD+MTX RIT_STD -0.03 (-1.24, 1.18) 0.004 (-1.17, 1.18) - 0.92 (-0.54, 2.38) 0.01 (-1.16, 1.17)

SAR_200

1.63 (-0.82, 4.09) - - 3.27 (0.77, 5.76) -

BAR_4+MTX

-0.11 (-1.64, 1.42) - - 2.02 (0.27, 3.76) -0.07 (-1.55, 1.41)

HD203+MTX

0.42 (-1.44, 2.28) - - 1.90 (-0.10, 3.90) 1.47 (-0.42, 3.36)

SB4+MTX

0.44 (-1.34, 2.23) - - 1.91 (-0.02, 3.84) 1.47 (-0.35, 3.30)

423


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

ANBAI+MTX

-0.06 (-1.84, 1.72) - - 1.42 (-0.52, 3.37) -0.09 (-1.80, 1.63)

CT-P13+MTX

-0.02 (-1.69, 1.65) - - 1.09 (-0.72, 2.91) -0.08 (-1.68, 1.51)

SB2+MTX

-0.02 (-1.77, 1.73) - - 1.06 (-0.86, 2.98) -0.06 (-1.74, 1.61)

SB5+MTX

-0.08 (-1.79, 1.63) - - 1.82 (-0.05, 3.68) -0.04 (-1.67, 1.59)

ZRC-3197+MTX

-0.10 (-1.94, 1.74) - - 1.84 (-0.16, 3.84) -0.05 (-1.81, 1.71)

ABP501+MTX

-0.07 (-1.77, 1.64) - - 1.84 (-0.02, 3.70) -0.05 (-1.67, 1.57)

SAR_200 RIT_STD+MTX 1.67 (-0.78, 4.12) - - 2.36 (0.11, 4.62) -

BAR_4+MTX

-0.07 (-1.57, 1.43) - - 1.12 (-0.24, 2.47) -0.06 (-1.53, 1.40)

HD203+MTX

0.46 (-1.35, 2.28) - - 0.97 (-0.68, 2.62) 1.47 (-0.40, 3.34)

SB4+MTX

0.45 (-1.30, 2.20) - - 0.99 (-0.59, 2.58) 1.47 (-0.33, 3.28)

ANBAI+MTX

-0.05 (-1.83, 1.73) - - 0.51 (-1.10, 2.13) -0.10 (-1.81, 1.62)

CT-P13+MTX

0.003 (-1.63, 1.64) - - 0.17 (-1.27, 1.61) -0.09 (-1.68, 1.51)

SB2+MTX

0.01 (-1.70, 1.73) - - 0.14 (-1.43, 1.71) -0.06 (-1.73, 1.60)

424


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

SB5+MTX

-0.05 (-1.73, 1.63) - - 0.90 (-0.62, 2.41) -0.04 (-1.65, 1.56)

ZRC-3197+MTX

-0.07 (-1.88, 1.74) - - 0.94 (-0.72, 2.59) -0.05 (-1.80, 1.70)

ABP501+MTX

-0.03 (-1.72, 1.65) - - 0.92 (-0.60, 2.44) -0.05 (-1.67, 1.56)

BAR_4+MTX SAR_200 -1.74 (-3.79, 0.31) - - -1.22 (-3.34, 0.89) -

HD203+MTX

-1.19 (-3.38, 1.01) - - -1.38 (-3.62, 0.87) -

SB4+MTX

-1.19 (-3.36, 0.97) - - -1.37 (-3.56, 0.82) -

ANBAI+MTX

-1.71 (-3.97, 0.56) - - -1.83 (-4.10, 0.44) -

CT-P13+MTX

-1.62 (-3.81, 0.57) - - -2.16 (-4.33, 0.01) -

SB2+MTX

-1.64 (-3.90, 0.63) - - -2.19 (-4.45, 0.07) -

SB5+MTX

-1.70 (-3.86, 0.46) - - -1.43 (-3.62, 0.76) -

ZRC-3197+MTX

-1.70 (-4.01, 0.60) - - -1.40 (-3.72, 0.91) -

ABP501+MTX

-1.70 (-3.91, 0.52) - - -1.42 (-3.62, 0.78) -

HD203+MTX BAR_4+MTX 0.55 (-0.72, 1.82) - -0.36 (-1.62, 0.90) -0.14 (-1.57, 1.28) 1.52 (0.14, 2.91)

425


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

SB4+MTX

0.53 (-0.68, 1.75) - -0.37 (-1.54, 0.80) -0.13 (-1.48, 1.21) 1.52 (0.22, 2.82)

ANBAI+MTX

0.05 (-1.18, 1.28) - 0.03 (-1.16, 1.21) -0.59 (-1.99, 0.81) -0.02 (-1.19, 1.15)

CT-P13+MTX

0.10 (-0.96, 1.16) - 0.11 (-0.99, 1.22) -0.93 (-2.12, 0.26) -0.01 (-0.99, 0.97)

SB2+MTX

0.11 (-1.10, 1.31) - 0.15 (-1.06, 1.36) -0.96 (-2.29, 0.37) 0.02 (-1.09, 1.12)

SB5+MTX

0.03 (-1.07, 1.14) - -0.02 (-1.05, 1.01) -0.22 (-1.45, 1.01) 0.02 (-0.99, 1.03)

ZRC-3197+MTX

0.01 (-1.23, 1.26) - -0.02 (-1.21, 1.18) -0.17 (-1.54, 1.19) 0.02 (-1.16, 1.20)

ABP501+MTX

0.05 (-1.05, 1.14) - -0.03 (-1.03, 0.98) -0.19 (-1.40, 1.01) 0.02 (-0.97, 1.01)

SB4+MTX HD203+MTX -0.01 (-1.35, 1.32) - 0.001 (-1.23, 1.23) 0.004 (-1.40, 1.40) 0.001 (-1.21, 1.21)

ANBAI+MTX

-0.49 (-2.07, 1.09) - 0.39 (-1.16, 1.94) -0.45 (-2.14, 1.24) -1.55 (-3.19, 0.09)

CT-P13+MTX

-0.44 (-1.88, 1.00) - 0.48 (-1.01, 1.97) -0.78 (-2.29, 0.73) -1.54 (-3.06, -0.03)

SB2+MTX

-0.45 (-2.00, 1.10) - 0.52 (-1.07, 2.10) -0.83 (-2.47, 0.82) -1.52 (-3.12, 0.07)

SB5+MTX

-0.52 (-2.03, 0.99) - 0.33 (-1.11, 1.78) -0.08 (-1.69, 1.53) -1.51 (-3.06, 0.04)

ZRC-3197+MTX

-0.53 (-2.12, 1.07) - 0.35 (-1.22, 1.91) -0.03 (-1.73, 1.67) -1.51 (-3.17, 0.14)

426


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

ABP501+MTX

-0.51 (-1.98, 0.96) - 0.34 (-1.10, 1.77) -0.05 (-1.64, 1.53) -1.51 (-3.03, 0.02)

ANBAI+MTX SB4+MTX -0.48 (-2.01, 1.05) - 0.40 (-1.09, 1.89) -0.46 (-2.09, 1.17) -1.55 (-3.13, 0.02)

CT-P13+MTX

-0.43 (-1.80, 0.94) - 0.48 (-0.93, 1.89) -0.81 (-2.25, 0.64) -1.55 (-2.98, -0.11)

SB2+MTX

-0.44 (-1.93, 1.06) - 0.52 (-0.97, 2.02) -0.82 (-2.39, 0.75) -1.52 (-3.03, -

0.003)

SB5+MTX

-0.48 (-1.93, 0.96) - 0.35 (-1.04, 1.73) -0.09 (-1.64, 1.47) -1.50 (-2.98, -0.02)

ZRC-3197+MTX

-0.51 (-2.05, 1.02) - 0.36 (-1.15, 1.86) -0.05 (-1.69, 1.58) -1.51 (-3.11, 0.09)

ABP501+MTX

-0.50 (-1.92, 0.92) - 0.33 (-1.05, 1.71) -0.06 (-1.59, 1.47) -1.50 (-2.97, -0.03)

CT-P13+MTX ANBAI+MTX 0.05 (-1.34, 1.44) - 0.09 (-1.33, 1.51) -0.34 (-1.82, 1.13) 0.01 (-1.32, 1.33)

SB2+MTX

0.05 (-1.46, 1.56) - 0.14 (-1.37, 1.65) -0.36 (-1.96, 1.25) 0.04 (-1.38, 1.46)

SB5+MTX

-0.01 (-1.48, 1.46) - -0.04 (-1.44, 1.35) 0.38 (-1.18, 1.94) 0.05 (-1.31, 1.42)

ZRC-3197+MTX

-0.04 (-1.60, 1.52) - -0.06 (-1.58, 1.47) 0.41 (-1.25, 2.07) 0.03 (-1.47, 1.53)

ABP501+MTX

-0.03 (-1.48, 1.42) - -0.05 (-1.44, 1.34) 0.40 (-1.14, 1.95) 0.04 (-1.32, 1.40)

SB2+MTX CT-P13+MTX 0.003 (-1.12, 1.12) - 0.04 (-1.01, 1.09) -0.03 (-1.22, 1.17) 0.03 (-1.01, 1.06)

427


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies Published

Before 2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including

IR MTX Patients

SB5+MTX

-0.05 (-1.34, 1.23) - -0.13 (-1.44, 1.17) 0.73 (-0.65, 2.11) 0.05 (-1.16, 1.25)

ZRC-3197+MTX

-0.06 (-1.47, 1.35) - -0.13 (-1.59, 1.33) 0.77 (-0.75, 2.28) 0.04 (-1.32, 1.41)

ABP501+MTX

-0.05 (-1.35, 1.25) - -0.14 (-1.45, 1.16) 0.74 (-0.63, 2.12) 0.04 (-1.16, 1.24)

SB5+MTX SB2+MTX -0.08 (-1.48, 1.32) - -0.18 (-1.58, 1.22) 0.75 (-0.77, 2.26) 0.01 (-1.29, 1.31)

ZRC-3197+MTX

-0.08 (-1.61, 1.45) - -0.16 (-1.71, 1.38) 0.78 (-0.85, 2.41) 0.01 (-1.44, 1.47)

ABP501+MTX

-0.05 (-1.46, 1.36) - -0.18 (-1.56, 1.20) 0.77 (-0.72, 2.26) 0.01 (-1.28, 1.30)

ZRC-3197+MTX SB5+MTX -0.03 (-1.42, 1.36) - 0.001 (-1.33, 1.33) 0.02 (-1.48, 1.52) -0.01 (-1.33, 1.30)

ABP501+MTX

-0.004 (-1.24, 1.23) - -0.01 (-1.15, 1.13) 0.02 (-1.32, 1.36) -0.01 (-1.14, 1.12)

ABP501+MTX ZRC-3197+MTX 0.02 (-1.36, 1.39) - -0.01 (-1.33, 1.30) -0.02 (-1.50, 1.47) -0.001 (-1.30, 1.30)

Difference in log odds ratios represents the comparison of the sensitivity analysis to the reference case. Each column presents the comparison of one sensitivity analysis to the

reference case. Only treatment comparisons from the sensitivity analysis that were also present in the reference case were compared; dashes indicate where the treatment

comparison was not present in the sensitivity analysis. Pink cells indicate the sensitivity analysis has a lower effect estimate than the reference case. Green cells indicate the sensitivity

analysis has a higher effect estimate than the reference case.

ABA = abatacept; ABP501 = biosimilar adalimumab; ADA = adalimumab; ANBAI = AnBaiNuo (biosimilar adalimumab); BAR_4 = 4mg baricitinib; CERTO = certolizumab pegol; CI =

confidence interval; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; CT-P13 = biosimilar of infliximab; ETN = etanercept; GOL= golimumab; HCQ =

hydroxychloroquine; HD203=etanercept biosimilar; INF = infliximab; IV = intravenous; MTX = methotrexate; log OR = log odds ratio; RIT = rituximab; SAR_200 = 200mg sarilumab;

SB2 = biosimilar infliximab 3mg/kg; SB4 = biosimilar etanercept 50mg; SB5 = biosimilar adalimumab; SC = subcutaneous; SSZ = sulfasalazine; STD = standard dose; TOC_4 =

tocilizumab 4mg/kg; TOC_8 = 8mg/kg tocilizumab; TOF = tofacitinib; ZRC-3197 = biosimilar of adalimumab

428

Table 47. ACR50 Sensitivity Analysis Results Compared to the Reference Case (Post Hoc Table)


Difference of log OR

(95% CI) - Restricted

Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR

(95% CI) of SA vs REF

- Exclude Asian-Only

Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

Placebo Placebo

+MTX

- 0.15 (-1.49, 1.78) -0.20 (-1.71, 1.31) 3.97 (2.38, 5.56)

csDMARD

+MTX

1.87 (0.65, 3.08) 0.24 (-0.72, 1.19) -0.61 (-1.54, 0.32) -

MTX+SSZ

- -0.18 (-2.24, 1.89) -0.02 (-1.96, 1.91) -

MTX+HCQ

- -0.23 (-2.09, 1.64) -0.12 (-1.84, 1.60) -

SSZ+HCQ

- -0.50 (-1.54, 0.54) -0.15 (-0.95, 0.64) -

MTX+SSZ +HCQ

- -0.25 (-1.58, 1.09) -0.09 (-1.33, 1.14) -

ETN_STD

2.37 (1.24, 3.50) 0.17 (-0.57, 0.91) -0.17 (-0.82, 0.47) 2.28 (1.43, 3.13)

ETN_STD+MTX

1.45 (0.43, 2.47) 0.24 (-0.41, 0.89) -0.23 (-0.80, 0.34) 1.16 (0.45, 1.88)

ABA_STD

(IV)+MTX

- -0.34 (-1.08, 0.40) -0.20 (-0.68, 0.29) -0.09 (-0.65, 0.47)

429




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

ADA_STD +MTX

0.02 (-0.32, 0.35) -0.12 (-0.52, 0.29) -0.04 (-0.39, 0.30) -

ADA_STD

- - -0.23 (-2.25, 1.79) 4.15 (2.16, 6.14)

TOF_STD+MTX

0.001 (-0.50, 0.50) - -0.15 (-0.67, 0.38) -

TOF_STD

- - -0.24 (-2.21, 1.74) -

TOC_4 (IV)

-0.21 (-1.15, 0.74) - -0.13 (-1.09, 0.83) 1.67 (0.67, 2.67)

TOC_8 (IV)

-0.52 (-1.22, 0.17) - -0.25 (-0.88, 0.37) -

TOC_4 (IV)+MTX

-0.08 (-0.69, 0.53) - -0.09 (-0.71, 0.54) -

TOC_8 (IV)+MTX

-0.10 (-0.59, 0.39) - -0.14 (-0.64, 0.37) -

GOL_STD (SC)

- - - 1.73 (-0.13, 3.59)

GOL_STD

(SC)+MTX

-0.01 (-0.62, 0.60) -0.10 (-0.81, 0.61) 0.05 (-0.67, 0.78) -

GOL_STD

(IV)+MTX

-0.001 (-0.86, 0.85) -0.01 (-0.99, 0.98) 0.01 (-0.86, 0.89) -0.02 (-0.92, 0.87)

INF_STD+MTX

0.51 (-0.40, 1.41) -0.13 (-0.80, 0.54) -0.06 (-0.65, 0.52) 1.08 (0.45, 1.72)

CERTO_STD

+MTX

0.005 (-0.45, 0.46) -0.46 (-1.09, 0.18) -0.12 (-0.58, 0.35) -

430




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

CERTO_STD

- - -0.31 (-2.24, 1.61) -

RIT_STD

- - 0.04 (-1.35, 1.43) -

RIT_STD+MTX

- - 0.03 (-1.33, 1.38) -

SAR_200

- - -0.24 (-2.43, 1.96) 3.16 (1.00, 5.32)

BAR_4+MTX

-0.04 (-0.58, 0.50) -0.19 (-0.83, 0.45) -0.16 (-0.73, 0.40) 1.84 (1.01, 2.67)

HD203+MTX

- - - -

SB4+MTX

- 0.25 (-0.88, 1.37) -0.23 (-1.21, 0.76) 0.49 (-0.52, 1.50)

ANBAI+MTX

-0.02 (-1.05, 1.01) - - -0.32 (-1.43, 0.78)

CT-P13+MTX

- -0.38 (-1.44, 0.68) -0.32 (-1.24, 0.60) -

SB2+MTX

- - -0.06 (-1.06, 0.95) -

SB5+MTX

- -0.11 (-1.14, 0.92) -0.05 (-0.95, 0.85) -

ZRC-3197+MTX

0.02 (-1.05, 1.10) -0.12 (-1.32, 1.07) -0.07 (-1.16, 1.03) -

ABP501+MTX

- - -0.04 (-0.92, 0.83) -

431




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

csDMARD +MTX Placebo - 0.11 (-1.58, 1.80) -0.38 (-1.99, 1.23) -

MTX+SSZ

- -0.33 (-2.96, 2.29) 0.16 (-2.30, 2.61) -

MTX+HCQ

- -0.37 (-2.83, 2.09) 0.09 (-2.17, 2.36) -

SSZ+HCQ

- -0.64 (-2.49, 1.21) 0.06 (-1.54, 1.65) -

MTX+SSZ+HCQ

- -0.41 (-2.49, 1.68) 0.11 (-1.84, 2.05) -

ETN_STD

- 0.04 (-1.38, 1.46) 0.04 (-1.30, 1.38) -

ETN_STD+MTX

- 0.10 (-1.44, 1.65) -0.02 (-1.46, 1.43) -

ABA_STD

(IV)+MTX

- -0.49 (-2.28, 1.31) -0.001 (-1.59, 1.59) -

ADA_STD+MTX

- -0.27 (-1.95, 1.41) 0.14 (-1.39, 1.68) -

ADA_STD

- - 0.002 (-1.32, 1.32) -

TOF_STD+MTX

- - 0.06 (-1.54, 1.66) -

TOF_STD

- - 0.01 (-1.28, 1.30) -

TOC_4 (IV)

- - 0.07 (-1.73, 1.87) -

432




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

TOC_8 (IV)

- - -0.06 (-1.69, 1.58) -

TOC_4 (IV)+MTX

- - 0.13 (-1.50, 1.75) -

TOC_8 (IV)+MTX

- - 0.06 (-1.51, 1.64) -

GOL_STD (SC)

- - - -

GOL_STD

(SC)+MTX

- -0.25 (-2.02, 1.52) 0.24 (-1.44, 1.91) -

GOL_STD

(IV)+MTX

- -0.15 (-2.04, 1.75) 0.22 (-1.51, 1.95) -

INF_STD+MTX

- -0.24 (-2.01, 1.53) 0.15 (-1.47, 1.78) -

CERTO_STD

+MTX

- -0.61 (-2.37, 1.16) 0.08 (-1.51, 1.67) -

CERTO_STD

- - -0.13 (-1.28, 1.02) -

RIT_STD

- - 0.26 (-1.79, 2.31) -

RIT_STD+MTX

- - 0.25 (-1.77, 2.28) -

SAR_200

- - -0.003 (-1.56, 1.55) -

BAR_4+MTX

- -0.33 (-2.07, 1.42) 0.04 (-1.56, 1.64) -

433




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

HD203+MTX

- - - -

SB4+MTX

- 0.12 (-1.66, 1.91) -0.005 (-1.66, 1.65) -

ANBAI+MTX

- - - -

CT-P13+MTX

- -0.49 (-2.44, 1.46) -0.10 (-1.87, 1.67) -

SB2+MTX

- - 0.17 (-1.65, 1.99) -

SB5+MTX

- -0.24 (-2.15, 1.68) 0.17 (-1.55, 1.90) -

ZRC-3197+MTX

- -0.24 (-2.27, 1.79) 0.16 (-1.72, 2.05) -

ABP501+MTX

- - 0.15 (-1.59, 1.89) -

MTX+SSZ csDMARD +MTX - -0.42 (-2.66, 1.83) 0.58 (-1.55, 2.70) -

MTX+HCQ

- -0.47 (-2.53, 1.58) 0.49 (-1.43, 2.42) -

SSZ+HCQ

- -0.75 (-2.06, 0.56) 0.45 (-0.60, 1.50) -

MTX+SSZ +HCQ

- -0.48 (-2.07, 1.12) 0.52 (-0.99, 2.02) -

ETN_STD

0.51 (-0.40, 1.41) -0.06 (-0.96, 0.84) 0.43 (-0.45, 1.32) 0.43 (-0.40, 1.25)

434




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

ETN_STD+MTX

-0.41 (-1.09, 0.26) -0.004 (-0.70, 0.69) 0.37 (-0.35, 1.09) -0.70 (-1.68, 0.28)

ABA_STD

(IV)+MTX

- -0.58 (-1.78, 0.62) 0.41 (-0.62, 1.45) -1.94 (-3.10, -0.77)

ADA_STD +MTX

-1.85 (-3.12, -0.57) -0.35 (-1.40, 0.69) 0.56 (-0.43, 1.56) -

ADA_STD

- - 0.39 (-1.72, 2.49) 2.31 (0.20, 4.42)

TOF_STD+MTX

-1.87 (-3.19, -0.55) - 0.46 (-0.61, 1.54) -

TOF_STD

- - 0.37 (-1.69, 2.43) -

TOC_4 (IV)

-2.07 (-3.61, -0.53) - 0.48 (-0.86, 1.82) -0.18 (-1.62, 1.26)

TOC_8 (IV)

-2.40 (-3.79, -1.01) - 0.36 (-0.75, 1.46) -

TOC_4 (IV)+MTX

-1.95 (-3.32, -0.59) - 0.53 (-0.60, 1.65) -

TOC_8 (IV)+MTX

-1.97 (-3.28, -0.65) - 0.47 (-0.59, 1.53) -

GOL_STD (SC)

- - - -0.13 (-2.12, 1.85)

GOL_STD

(SC)+MTX

-1.88 (-3.25, -0.52) -0.34 (-1.52, 0.84) 0.66 (-0.53, 1.84) -

GOL_STD

(IV)+MTX

-1.89 (-3.39, -0.40) -0.25 (-1.62, 1.11) 0.61 (-0.66, 1.88) -1.89 (-3.25, -0.53)

435




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

INF_STD+MTX

-1.38 (-2.91, 0.16) -0.36 (-1.53, 0.81) 0.55 (-0.55, 1.65) -0.77 (-1.99, 0.44)

CERTO_STD

+MTX

-1.85 (-3.16, -0.55) -0.69 (-1.84, 0.46) 0.49 (-0.54, 1.53) -

CERTO_STD

- - 0.29 (-1.71, 2.28) -

RIT_STD

- - 0.64 (-1.05, 2.33) -

RIT_STD+MTX

- - 0.64 (-1.01, 2.29) -

SAR_200

- - 0.38 (-1.89, 2.65) 1.29 (-0.97, 3.55)

BAR_4+MTX

-1.91 (-3.24, -0.58) -0.43 (-1.57, 0.71) 0.44 (-0.64, 1.52) -0.02 (-1.07, 1.03)

HD203+MTX

- - - -

SB4+MTX

- 0.02 (-1.14, 1.17) 0.39 (-0.69, 1.47) -1.36 (-2.60, -0.13)

ANBAI+MTX

-1.88 (-3.48, -0.27) - - -2.19 (-3.72, -0.66)

CT-P13+MTX

- -0.60 (-2.04, 0.83) 0.31 (-1.00, 1.62) -

SB2+MTX

- - 0.54 (-0.82, 1.91) -

SB5+MTX

- -0.35 (-1.75, 1.04) 0.56 (-0.72, 1.84) -

436




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

ZRC-3197+MTX

-1.85 (-3.46, -0.25) -0.37 (-1.88, 1.15) 0.54 (-0.87, 1.95) -

ABP501+MTX

- - 0.57 (-0.71, 1.84) -

MTX+HCQ MTX+SSZ - -0.04 (-1.64, 1.56) -0.05 (-1.59, 1.48) -

SSZ+HCQ

- -0.32 (-2.39, 1.75) -0.14 (-2.08, 1.80) -

MTX+SSZ +HCQ

- -0.06 (-1.64, 1.52) -0.03 (-1.54, 1.47) -

ETN_STD

- 0.36 (-1.81, 2.52) -0.15 (-2.16, 1.86) -

ETN_STD+MTX

- 0.41 (-1.72, 2.54) -0.21 (-2.18, 1.76) -

ABA_STD

(IV)+MTX

- -0.17 (-2.36, 2.02) -0.18 (-2.16, 1.81) -

ADA_STD +MTX

- 0.08 (-2.02, 2.17) -0.02 (-1.98, 1.94) -

ADA_STD

- - -0.16 (-2.94, 2.62) -

TOF_STD+MTX

- - -0.11 (-2.11, 1.89) -

TOF_STD

- - -0.16 (-2.93, 2.61) -

TOC_4 (IV)

- - -0.10 (-2.24, 2.04) -

437




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

TOC_8 (IV)

- - -0.23 (-2.26, 1.79) -

TOC_4 (IV)+MTX

- - -0.06 (-2.10, 1.98) -

TOC_8 (IV)+MTX

- - -0.11 (-2.11, 1.88) -

GOL_STD (SC)

- - - -

GOL_STD

(SC)+MTX

- 0.09 (-2.08, 2.25) 0.09 (-1.97, 2.14) -

GOL_STD

(IV)+MTX

- 0.18 (-2.10, 2.47) 0.05 (-2.07, 2.16) -

INF_STD+MTX

- 0.06 (-2.13, 2.24) -0.05 (-2.08, 1.99) -

CERTO_STD

+MTX

- -0.29 (-2.44, 1.87) -0.10 (-2.07, 1.86) -

CERTO_STD

- - -0.25 (-2.96, 2.46) -

RIT_STD

- - 0.07 (-2.36, 2.49) -

RIT_STD+MTX

- - 0.08 (-2.30, 2.45) -

SAR_200

- - -0.17 (-3.07, 2.73) -

BAR_4+MTX

- -0.02 (-2.15, 2.12) -0.15 (-2.14, 1.85) -

438




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

HD203+MTX

- - - -

SB4+MTX

- 0.44 (-1.87, 2.75) -0.19 (-2.32, 1.93) -

ANBAI+MTX

- - - -

CT-P13+MTX

- -0.21 (-2.54, 2.13) -0.28 (-2.43, 1.86) -

SB2+MTX

- - -0.03 (-2.23, 2.16) -

SB5+MTX

- 0.09 (-2.18, 2.37) -0.004 (-2.12, 2.11) -

ZRC-3197+MTX

- 0.07 (-2.29, 2.42) -0.04 (-2.26, 2.19) -

ABP501+MTX

- - -0.02 (-2.14, 2.10) -

SSZ+HCQ MTX+HCQ - -0.26 (-2.15, 1.63) -0.03 (-1.78, 1.71) -

MTX+SSZ +HCQ

- -0.01 (-1.33, 1.31) 0.02 (-1.21, 1.24) -

ETN_STD

- 0.42 (-1.55, 2.39) -0.05 (-1.85, 1.75) -

ETN_STD+MTX

- 0.46 (-1.48, 2.40) -0.12 (-1.88, 1.65) -

ABA_STD

(IV)+MTX

- -0.12 (-2.13, 1.88) -0.09 (-1.88, 1.69) -

439




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

ADA_STD +MTX

- 0.11 (-1.80, 2.02) 0.08 (-1.67, 1.84) -

ADA_STD

- - -0.10 (-2.73, 2.53) -

TOF_STD+MTX

- - -0.03 (-1.84, 1.78) -

TOF_STD

- - -0.12 (-2.72, 2.49) -

TOC_4 (IV)

- - -0.01 (-1.98, 1.96) -

TOC_8 (IV)

- - -0.15 (-1.99, 1.69) -

TOC_4 (IV)+MTX

- - 0.04 (-1.79, 1.87) -

TOC_8 (IV)+MTX

- - -0.03 (-1.83, 1.78) -

GOL_STD (SC)

- - - -

GOL_STD

(SC)+MTX

- 0.14 (-1.86, 2.13) 0.18 (-1.68, 2.04) -

GOL_STD

(IV)+MTX

- 0.21 (-1.89, 2.32) 0.12 (-1.80, 2.03) -

INF_STD+MTX

- 0.11 (-1.88, 2.09) 0.05 (-1.79, 1.89) -

CERTO_STD

+MTX

- -0.22 (-2.20, 1.76) 0.01 (-1.78, 1.80) -

440




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

CERTO_STD

- - -0.16 (-2.70, 2.39) -

RIT_STD

- - 0.15 (-2.05, 2.34) -

RIT_STD+MTX

- - 0.17 (-1.99, 2.33) -

SAR_200

- - -0.11 (-2.87, 2.64) -

BAR_4+MTX

- 0.04 (-1.93, 2.01) -0.05 (-1.86, 1.76) -

HD203+MTX

- - - -

SB4+MTX

- 0.48 (-1.67, 2.63) -0.11 (-2.06, 1.84) -

ANBAI+MTX

- - - -

CT-P13+MTX

- -0.15 (-2.31, 2.01) -0.20 (-2.18, 1.77) -

SB2+MTX

- - 0.06 (-1.94, 2.06) -

SB5+MTX

- 0.13 (-2.00, 2.25) 0.08 (-1.86, 2.01) -

ZRC-3197+MTX

- 0.12 (-2.07, 2.31) 0.07 (-1.95, 2.08) -

ABP501+MTX

- - 0.07 (-1.87, 2.01) -

441




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

MTX+SSZ +HCQ SSZ+HCQ - 0.26 (-1.09, 1.61) 0.07 (-1.16, 1.31) -

ETN_STD

- 0.68 (-0.51, 1.86) -0.02 (-0.88, 0.85) -

ETN_STD+MTX

- 0.74 (-0.37, 1.85) -0.08 (-0.83, 0.67) -

ABA_STD

(IV)+MTX

- 0.16 (-1.11, 1.43) -0.04 (-0.97, 0.88) -

ADA_STD +MTX

- 0.39 (-0.73, 1.51) 0.11 (-0.76, 0.98) -

ADA_STD

- - -0.06 (-2.17, 2.04) -

TOF_STD+MTX

- - 0.004 (-0.95, 0.96) -

TOF_STD

- - -0.08 (-2.16, 1.99) -

TOC_4 (IV)

- - 0.04 (-1.21, 1.28) -

TOC_8 (IV)

- - -0.09 (-1.11, 0.92) -

TOC_4 (IV)+MTX

- - 0.07 (-0.95, 1.09) -

TOC_8 (IV)+MTX

- - 0.02 (-0.91, 0.96) -

GOL_STD (SC)

- - - -

442




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

GOL_STD

(SC)+MTX

- 0.39 (-0.87, 1.66) 0.20 (-0.89, 1.29) -

GOL_STD

(IV)+MTX

- 0.51 (-0.92, 1.93) 0.18 (-0.99, 1.35) -

INF_STD+MTX

- 0.39 (-0.86, 1.63) 0.09 (-0.90, 1.08) -

CERTO_STD

+MTX

- 0.04 (-1.18, 1.26) 0.03 (-0.88, 0.95) -

CERTO_STD

- - -0.15 (-2.15, 1.85) -

RIT_STD

- - 0.19 (-1.43, 1.81) -

RIT_STD+MTX

- - 0.20 (-1.37, 1.78) -

SAR_200

- - -0.07 (-2.33, 2.18) -

BAR_4+MTX

- 0.32 (-0.90, 1.53) -0.004 (-0.98, 0.97) -

HD203+MTX

- - - -

SB4+MTX

- 0.76 (-0.68, 2.20) -0.07 (-1.16, 1.02) -

ANBAI+MTX

- - - -

CT-P13+MTX

- 0.13 (-1.37, 1.63) -0.16 (-1.38, 1.06) -

443




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SB2+MTX

- - 0.09 (-1.20, 1.38) -

SB5+MTX

- 0.39 (-1.06, 1.85) 0.11 (-1.09, 1.31) -

ZRC-3197+MTX

- 0.38 (-1.19, 1.96) 0.09 (-1.24, 1.43) -

ABP501+MTX

- - 0.12 (-1.05, 1.29) -

ETN_STD MTX+SSZ+HCQ - 0.42 (-1.08, 1.93) -0.09 (-1.44, 1.26) -

ETN_STD+MTX

- 0.48 (-0.97, 1.92) -0.14 (-1.45, 1.16) -

ABA_STD

(IV)+MTX

- -0.11 (-1.64, 1.43) -0.12 (-1.46, 1.22) -

ADA_STD +MTX

- 0.12 (-1.27, 1.51) 0.04 (-1.24, 1.31) -

ADA_STD

- - -0.13 (-2.47, 2.20) -

TOF_STD+MTX

- - -0.06 (-1.40, 1.29) -

TOF_STD

- - -0.11 (-2.45, 2.23) -

TOC_4 (IV)

- - -0.06 (-1.60, 1.49) -

TOC_8 (IV)

- - -0.17 (-1.54, 1.20) -

444




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

TOC_4 (IV)+MTX

- - 0.00 (-1.39, 1.39) -

TOC_8 (IV)+MTX

- - -0.05 (-1.38, 1.28) -

GOL_STD (SC)

- - - -

GOL_STD

(SC)+MTX

- 0.14 (-1.36, 1.64) 0.13 (-1.29, 1.55) -

GOL_STD

(IV)+MTX

- 0.24 (-1.41, 1.88) 0.09 (-1.41, 1.59) -

INF_STD+MTX

- 0.12 (-1.38, 1.61) 0.02 (-1.36, 1.40) -

CERTO_STD

+MTX

- -0.22 (-1.70, 1.25) -0.03 (-1.35, 1.28) -

CERTO_STD

- - -0.21 (-2.49, 2.08) -

RIT_STD

- - 0.11 (-1.76, 1.99) -

RIT_STD+MTX

- - 0.14 (-1.67, 1.95) -

SAR_200

- - -0.14 (-2.63, 2.36) -

BAR_4+MTX

- 0.04 (-1.43, 1.52) -0.09 (-1.45, 1.27) -

HD203+MTX

- - - -

445




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SB4+MTX

- 0.49 (-1.22, 2.19) -0.14 (-1.65, 1.38) -

ANBAI+MTX

- - - -

CT-P13+MTX

- -0.14 (-1.86, 1.58) -0.23 (-1.77, 1.32) -

SB2+MTX

- - 0.03 (-1.57, 1.63) -

SB5+MTX

- 0.14 (-1.54, 1.83) 0.04 (-1.48, 1.56) -

ZRC-3197+MTX

- 0.14 (-1.64, 1.91) 0.02 (-1.62, 1.65) -

ABP501+MTX

- - 0.03 (-1.47, 1.53) -

ETN_STD+MTX ETN_STD -0.92 (-1.52, -0.32) 0.06 (-0.51, 0.63) -0.06 (-0.57, 0.45) -

ABA_STD

(IV)+MTX

- -0.52 (-1.57, 0.53) -0.02 (-0.83, 0.79) -

ADA_STD +MTX

-2.35 (-3.54, -1.17) -0.29 (-1.13, 0.56) 0.13 (-0.60, 0.87) -

ADA_STD

- - -0.05 (-1.98, 1.87) -

TOF_STD+MTX

-2.38 (-3.63, -1.14) - 0.03 (-0.81, 0.87) -

TOF_STD

- - -0.08 (-1.96, 1.80) -

446




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

TOC_4 (IV)

-2.58 (-4.06, -1.10) - 0.06 (-1.11, 1.22) -

TOC_8 (IV)

-2.91 (-4.23, -1.59) - -0.08 (-0.97, 0.82) -

TOC_4 (IV)+MTX

-2.45 (-3.74, -1.16) - 0.09 (-0.81, 1.00) -

TOC_8 (IV)+MTX

-2.46 (-3.69, -1.23) - 0.04 (-0.79, 0.86) -

GOL_STD (SC)

- - - -

GOL_STD

(SC)+MTX

-2.37 (-3.66, -1.09) -0.27 (-1.29, 0.76) 0.23 (-0.75, 1.21) -

GOL_STD

(IV)+MTX

-2.38 (-3.79, -0.96) -0.18 (-1.40, 1.04) 0.19 (-0.89, 1.26) -

INF_STD+MTX

-1.87 (-3.34, -0.39) -0.30 (-1.30, 0.70) 0.11 (-0.77, 0.98) -

CERTO_STD+MTX

-2.36 (-3.59, -1.14) -0.63 (-1.61, 0.35) 0.05 (-0.74, 0.85) -

CERTO_STD

- - -0.15 (-1.95, 1.65) -

RIT_STD

- - 0.22 (-1.31, 1.75) -

RIT_STD+MTX

- - 0.21 (-1.28, 1.70) -

SAR_200

- - -0.06 (-2.16, 2.05) -

447




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

BAR_4+MTX

-2.41 (-3.67, -1.16) -0.36 (-1.33, 0.62) 0.01 (-0.85, 0.87) -

HD203+MTX

- - - -

SB4+MTX

- 0.08 (-1.01, 1.17) -0.04 (-1.00, 0.91) -

ANBAI+MTX

-2.39 (-3.91, -0.87) - - -

CT-P13+MTX

- -0.55 (-1.86, 0.75) -0.14 (-1.27, 0.98) -

SB2+MTX

- - 0.12 (-1.07, 1.31) -

SB5+MTX

- -0.28 (-1.55, 0.98) 0.12 (-0.97, 1.22) -

ZRC-3197+MTX

-2.36 (-3.91, -0.81) -0.29 (-1.69, 1.10) 0.11 (-1.16, 1.37) -

ABP501+MTX

- - 0.13 (-0.96, 1.21) -0.90 (-2.19, 0.39)

ABA_STD

(IV)+MTX ETN_STD+MTX - -0.57 (-1.56, 0.41) 0.04 (-0.71, 0.79) -1.52 (-2.49, -0.56)

ADA_STD+MTX

-1.43 (-2.50, -0.35) -0.35 (-1.12, 0.42) 0.19 (-0.47, 0.86) -

ADA_STD

- - 0.01 (-1.97, 1.99) 2.72 (0.72, 4.72)

TOF_STD+MTX

-1.46 (-2.58, -0.33) - 0.08 (-0.70, 0.86) -

448




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

TOF_STD

- - 0.004 (-1.93, 1.94) -

TOC_4 (IV)

-1.66 (-3.05, -0.27) - 0.10 (-1.02, 1.23) 0.23 (-1.05, 1.51)

TOC_8 (IV)

-1.98 (-3.21, -0.74) - -0.01 (-0.86, 0.83) -

TOC_4 (IV)+MTX

-1.53 (-2.72, -0.34) - 0.15 (-0.70, 1.01) -

TOC_8 (IV)+MTX

-1.54 (-2.66, -0.42) - 0.10 (-0.66, 0.86) -

GOL_STD (SC)

- - - 0.28 (-1.61, 2.18)

GOL_STD

(SC)+MTX

-1.46 (-2.64, -0.27) -0.34 (-1.30, 0.63) 0.28 (-0.65, 1.21) -

GOL_STD

(IV)+MTX

-1.46 (-2.78, -0.14) -0.24 (-1.40, 0.92) 0.25 (-0.79, 1.29) -1.46 (-2.64, -0.28)

INF_STD+MTX

-0.96 (-2.34, 0.43) -0.36 (-1.30, 0.57) 0.17 (-0.65, 0.99) -0.35 (-1.37, 0.66)

CERTO_STD+MTX

-1.44 (-2.56, -0.32) -0.69 (-1.60, 0.22) 0.12 (-0.61, 0.85) -

CERTO_STD

- - -0.09 (-1.96, 1.78) -

RIT_STD

- - 0.27 (-1.24, 1.78) -

RIT_STD+MTX

- - 0.26 (-1.22, 1.74) -

449




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SAR_200

- - -0.001 (-2.16, 2.15) 1.71 (-0.46, 3.87)

BAR_4+MTX

-1.48 (-2.64, -0.33) -0.42 (-1.33, 0.49) 0.07 (-0.73, 0.87) 0.40 (-0.42, 1.21)

HD203+MTX

- - - -

SB4+MTX

- 0.01 (-0.91, 0.93) 0.01 (-0.79, 0.81) -0.96 (-2.00, 0.08)

ANBAI+MTX

-1.46 (-2.91, -0.004) - - -1.77 (-3.14, -0.40)

CT-P13+MTX

- -0.61 (-1.86, 0.64) -0.08 (-1.16, 1.00) -

SB2+MTX

- - 0.18 (-0.97, 1.33) -

SB5+MTX

- -0.35 (-1.56, 0.87) 0.19 (-0.87, 1.25) -

ZRC-3197+MTX

-1.44 (-2.90, 0.03) -0.36 (-1.71, 0.99) 0.16 (-1.06, 1.39) -

ABP501+MTX

- - 0.19 (-0.85, 1.24) -1.12 (-2.29, 0.05)

ADA_STD+MTX ABA_STD

(IV)+MTX - 0.23 (-0.62, 1.08) 0.15 (-0.45, 0.76) -

ADA_STD

- - -0.04 (-2.13, 2.05) 2.90 (0.79, 5.00)

TOF_STD+MTX

- - 0.05 (-0.66, 0.77) -

450




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

TOF_STD

- - -0.04 (-2.07, 2.00) -

TOC_4 (IV)

- - 0.06 (-1.02, 1.15) 0.42 (-0.78, 1.61)

TOC_8 (IV)

- - -0.06 (-0.85, 0.73) -

TOC_4 (IV)+MTX

- - 0.10 (-0.69, 0.90) -

TOC_8 (IV)+MTX

- - 0.06 (-0.64, 0.75) -

GOL_STD (SC)

- - - 0.47 (-1.50, 2.45)

GOL_STD

(SC)+MTX

- 0.24 (-0.79, 1.26) 0.24 (-0.64, 1.13) -

GOL_STD

(IV)+MTX

- 0.33 (-0.91, 1.56) 0.20 (-0.80, 1.20) -1.29 (-2.39, -0.19)

INF_STD+MTX

- 0.22 (-0.58, 1.02) 0.13 (-0.52, 0.78) -0.18 (-1.03, 0.68)

CERTO_STD+MTX

- -0.11 (-1.10, 0.87) 0.08 (-0.59, 0.76) -

CERTO_STD

- - -0.12 (-2.11, 1.88) -

RIT_STD

- - 0.24 (-1.24, 1.72) -

RIT_STD+MTX

- - 0.24 (-1.21, 1.68) -

451




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SAR_200

- - -0.04 (-2.28, 2.21) 1.90 (-0.36, 4.15)

BAR_4+MTX

- 0.16 (-0.82, 1.13) 0.04 (-0.70, 0.78) 0.59 (-0.45, 1.64)

HD203+MTX

- - - -

SB4+MTX

- 0.60 (-0.75, 1.95) -0.03 (-1.13, 1.07) -0.76 (-1.97, 0.45)

ANBAI+MTX

- - - -1.59 (-2.88, -0.31)

CT-P13+MTX

- -0.04 (-1.19, 1.12) -0.12 (-1.09, 0.85) -

SB2+MTX

- - 0.14 (-0.90, 1.19) -

SB5+MTX

- 0.23 (-1.04, 1.50) 0.14 (-0.89, 1.18) -

ZRC-3197+MTX

- 0.22 (-1.20, 1.64) 0.13 (-1.07, 1.33) -

ABP501+MTX

- - 0.15 (-0.85, 1.15) -

ADA_STD ADA_STD+MTX - - -0.19 (-2.26, 1.87) 4.20 (2.16, 6.25)

TOF_STD+MTX

-0.02 (-0.57, 0.53) - -0.10 (-0.67, 0.47) -

TOF_STD

- - -0.19 (-2.20, 1.83) -

452




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

TOC_4 (IV)

-0.23 (-1.22, 0.77) - -0.09 (-1.10, 0.92) 1.72 (0.63, 2.81)

TOC_8 (IV)

-0.54 (-1.31, 0.22) - -0.22 (-0.93, 0.50) -

TOC_4 (IV)+MTX

-0.10 (-0.79, 0.60) - -0.04 (-0.76, 0.68) -

TOC_8 (IV)+MTX

-0.12 (-0.71, 0.47) - -0.10 (-0.71, 0.52) -

GOL_STD (SC)

- - - 1.79 (-0.12, 3.70)

GOL_STD

(SC)+MTX

-0.03 (-0.73, 0.66) 0.01 (-0.81, 0.83) 0.09 (-0.72, 0.91) -

GOL_STD

(IV)+MTX

-0.02 (-0.94, 0.90) 0.11 (-0.95, 1.18) 0.06 (-0.89, 1.00) 0.03 (-0.97, 1.04)

INF_STD+MTX

0.49 (-0.47, 1.46) -0.003 (-0.79, 0.78) -0.02 (-0.71, 0.68) 1.14 (0.34, 1.93)

CERTO_STD+MTX

-0.02 (-0.51, 0.47) -0.34 (-0.99, 0.30) -0.07 (-0.58, 0.43) -

CERTO_STD

- - -0.28 (-2.24, 1.69) -

RIT_STD

- - 0.08 (-1.35, 1.51) -

RIT_STD+MTX

- - 0.07 (-1.33, 1.47) -

SAR_200

- - -0.20 (-2.43, 2.03) 3.21 (1.00, 5.41)

453




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

BAR_4+MTX

-0.06 (-0.64, 0.51) -0.07 (-0.76, 0.61) -0.12 (-0.73, 0.48) 1.89 (0.98, 2.81)

HD203+MTX

- - - -

SB4+MTX

- 0.37 (-0.83, 1.57) -0.18 (-1.22, 0.87) 0.55 (-0.57, 1.67)

ANBAI+MTX

-0.04 (-1.13, 1.04) - - -0.28 (-1.48, 0.92)

CT-P13+MTX

- -0.26 (-1.39, 0.88) -0.27 (-1.26, 0.72) -

SB2+MTX

- - -0.01 (-1.08, 1.07) -

SB5+MTX

- 0.004 (-0.93, 0.94) -0.003 (-0.82, 0.82) -

ZRC-3197+MTX

0.002 (-1.02, 1.03) -0.01 (-1.14, 1.12) -0.02 (-1.07, 1.02) -

ABP501+MTX

- - -0.01 (-0.81, 0.80) -

TOF_STD+MTX ADA_STD - - 0.10 (-2.00, 2.19) -

TOF_STD

- - 0.0002 (-1.18, 1.18) -

TOC_4 (IV)

- - 0.10 (-2.16, 2.36) -

TOC_8 (IV)

- - -0.02 (-2.15, 2.10) -

454




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

TOC_4 (IV)+MTX

- - 0.15 (-1.96, 2.27) -

TOC_8 (IV)+MTX

- - 0.09 (-2.00, 2.19) -

GOL_STD (SC)

- - - -

GOL_STD

(SC)+MTX

- - 0.27 (-1.89, 2.43) -

GOL_STD

(IV)+MTX

- - 0.25 (-1.96, 2.45) -

INF_STD+MTX

- - 0.16 (-1.96, 2.28) -

CERTO_STD+MTX

- - 0.13 (-1.95, 2.22) -

CERTO_STD

- - -0.11 (-1.85, 1.63) -

RIT_STD

- - 0.26 (-2.18, 2.70) -

RIT_STD+MTX

- - 0.29 (-2.14, 2.72) -

SAR_200

- - -0.0003 (-0.86, 0.86) -

BAR_4+MTX

- - 0.08 (-2.03, 2.18) -

HD203+MTX

- - - -

455




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SB4+MTX

- - -0.003 (-2.14, 2.13) -

ANBAI+MTX

- - - -

CT-P13+MTX

- - -0.09 (-2.32, 2.14) -

SB2+MTX

- - 0.20 (-2.07, 2.47) -

SB5+MTX

- - 0.20 (-1.99, 2.38) -

ZRC-3197+MTX

- - 0.17 (-2.14, 2.48) -

ABP501+MTX

- - 0.18 (-2.03, 2.39) -

TOF_STD TOF_STD+MTX - - -0.09 (-2.16, 1.98) -

TOC_4 (IV)

-0.20 (-1.27, 0.87) - 0.02 (-1.08, 1.12) 0.46 (-0.77, 1.70)

TOC_8 (IV)

-0.53 (-1.39, 0.32) - -0.11 (-0.93, 0.70) -

TOC_4 (IV)+MTX

-0.08 (-0.87, 0.71) - 0.05 (-0.76, 0.87) -

TOC_8 (IV)+MTX

-0.10 (-0.81, 0.61) - 0.01 (-0.72, 0.74) -

GOL_STD (SC)

- - - 0.51 (-1.49, 2.51)

456




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

GOL_STD

(SC)+MTX

-0.01 (-0.80, 0.77) - 0.19 (-0.70, 1.09) -

GOL_STD

(IV)+MTX

0.003 (-0.98, 0.99) - 0.16 (-0.86, 1.18) -1.24 (-2.39, -0.09)

INF_STD+MTX

0.51 (-0.52, 1.53) - 0.08 (-0.70, 0.86) -0.13 (-1.09, 0.82)

CERTO_STD+MTX

0.01 (-0.64, 0.66) - 0.03 (-0.65, 0.71) -

CERTO_STD

- - -0.16 (-2.18, 1.86) -

RIT_STD

- - 0.17 (-1.31, 1.65) -

RIT_STD+MTX

- - 0.18 (-1.28, 1.64) -

SAR_200

- - -0.10 (-2.36, 2.16) 1.93 (-0.34, 4.21)

BAR_4+MTX

-0.05 (-0.77, 0.67) - -0.03 (-0.78, 0.73) 0.63 (-0.47, 1.72)

HD203+MTX

- - - -

SB4+MTX

- - -0.09 (-1.21, 1.04) -0.72 (-1.97, 0.53)

ANBAI+MTX

-0.02 (-1.17, 1.13) - - -1.55 (-2.88, -0.22)

CT-P13+MTX

- - -0.17 (-1.23, 0.89) -

457




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SB2+MTX

- - 0.09 (-1.05, 1.22) -

SB5+MTX

- - 0.09 (-0.92, 1.10) -

ZRC-3197+MTX

0.02 (-1.14, 1.19) - 0.08 (-1.11, 1.27) -

ABP501+MTX

- - 0.10 (-0.89, 1.09) -

TOC_4 (IV) TOF_STD - - 0.10 (-2.10, 2.31) -

TOC_8 (IV)

- - -0.03 (-2.11, 2.06) -

TOC_4 (IV)+MTX

- - 0.15 (-1.92, 2.21) -

TOC_8 (IV)+MTX

- - 0.09 (-1.97, 2.14) -

GOL_STD (SC)

- - - -

GOL_STD

(SC)+MTX

- - 0.26 (-1.86, 2.38) -

GOL_STD

(IV)+MTX

- - 0.23 (-1.93, 2.39) -

INF_STD+MTX

- - 0.17 (-1.90, 2.25) -

CERTO_STD+MTX

- - 0.12 (-1.91, 2.16) -

458




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

CERTO_STD

- - -0.12 (-1.84, 1.60) -

RIT_STD

- - 0.27 (-2.11, 2.66) -

RIT_STD+MTX

- - 0.29 (-2.09, 2.67) -

SAR_200

- - 0.002 (-1.45, 1.46) -

BAR_4+MTX

- - 0.06 (-2.02, 2.13) -

HD203+MTX

- - - -

SB4+MTX

- - 0.01 (-2.10, 2.12) -

ANBAI+MTX

- - - -

CT-P13+MTX

- - -0.08 (-2.27, 2.11) -

SB2+MTX

- - 0.18 (-2.03, 2.40) -

SB5+MTX

- - 0.19 (-1.97, 2.35) -

ZRC-3197+MTX

- - 0.16 (-2.12, 2.43) -

ABP501+MTX

- - 0.19 (-1.98, 2.35) -

459




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

TOC_8 (IV) TOC_4 (IV) -0.33 (-1.31, 0.66) - -0.13 (-1.09, 0.83) -

TOC_4 (IV)+MTX

0.12 (-0.85, 1.09) - 0.04 (-0.95, 1.03) -

TOC_8 (IV)+MTX

0.11 (-0.82, 1.03) - -0.004 (-0.93, 0.92) -

GOL_STD (SC)

- - - -

GOL_STD

(SC)+MTX

0.19 (-0.93, 1.31) - 0.18 (-1.03, 1.39) -

GOL_STD

(IV)+MTX

0.20 (-1.08, 1.49) - 0.14 (-1.15, 1.44) -

INF_STD+MTX

0.73 (-0.57, 2.03) - 0.07 (-1.06, 1.20) -

CERTO_STD+MTX

0.21 (-0.83, 1.25) - 0.01 (-1.04, 1.07) -

CERTO_STD

- - -0.20 (-2.35, 1.96) -

RIT_STD

- - 0.16 (-1.53, 1.85) -

RIT_STD+MTX

- - 0.16 (-1.51, 1.83) -

SAR_200

- - -0.11 (-2.51, 2.28) -

BAR_4+MTX

0.16 (-0.93, 1.25) - -0.04 (-1.16, 1.08) -

460




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

HD203+MTX

- - - -

SB4+MTX

- - -0.10 (-1.47, 1.28) -

ANBAI+MTX

0.17 (-1.23, 1.56) - - -

CT-P13+MTX

- - -0.18 (-1.52, 1.15) -

SB2+MTX

- - 0.09 (-1.29, 1.47) -

SB5+MTX

- - 0.10 (-1.21, 1.40) -

ZRC-3197+MTX

0.23 (-1.21, 1.67) - 0.08 (-1.39, 1.54) -

ABP501+MTX

- - 0.08 (-1.21, 1.37) -

TOC_4 (IV)+MTX TOC_8 (IV) 0.45 (-0.32, 1.21) - 0.17 (-0.53, 0.87) -

TOC_8 (IV)+MTX

0.42 (-0.22, 1.06) - 0.12 (-0.38, 0.62) -

GOL_STD (SC)

- - - 0.96 (-1.01, 2.93)

GOL_STD

(SC)+MTX

0.52 (-0.39, 1.43) - 0.30 (-0.65, 1.25) -

GOL_STD

(IV)+MTX

0.52 (-0.58, 1.63) - 0.27 (-0.80, 1.34) -0.79 (-1.91, 0.34)

461




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

INF_STD+MTX

1.05 (-0.09, 2.20) - 0.19 (-0.67, 1.05) 0.32 (-0.62, 1.26)

CERTO_STD+MTX

0.54 (-0.29, 1.36) - 0.14 (-0.63, 0.92) -

CERTO_STD

- - -0.07 (-2.08, 1.94) -

RIT_STD

- - 0.29 (-1.23, 1.82) -

RIT_STD+MTX

- - 0.29 (-1.22, 1.79) -

SAR_200

- - 0.01 (-2.27, 2.30) 2.41 (0.16, 4.65)

BAR_4+MTX

0.48 (-0.40, 1.36) - 0.09 (-0.75, 0.94) 1.08 (0.01, 2.15)

HD203+MTX

- - - -

SB4+MTX

- - 0.03 (-1.13, 1.20) -0.27 (-1.50, 0.95)

ANBAI+MTX

0.50 (-0.73, 1.74) - - -1.10 (-2.39, 0.19)

CT-P13+MTX

- - -0.06 (-1.18, 1.06) -

SB2+MTX

- - 0.20 (-0.99, 1.39) -

SB5+MTX

- - 0.21 (-0.88, 1.30) -

462




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

ZRC-3197+MTX

0.55 (-0.71, 1.82) - 0.20 (-1.06, 1.45) -

ABP501+MTX

- - 0.21 (-0.87, 1.29) -


(IV)+MTX -0.02 (-0.61, 0.57) - -0.05 (-0.64, 0.55) -

GOL_STD (SC)

- - - -

GOL_STD

(SC)+MTX

0.06 (-0.80, 0.93) - 0.14 (-0.82, 1.10) -

GOL_STD

(IV)+MTX

0.07 (-0.97, 1.12) - 0.09 (-0.97, 1.16) -

INF_STD+MTX

0.59 (-0.50, 1.69) - 0.02 (-0.85, 0.88) -

CERTO_STD+MTX

0.08 (-0.68, 0.84) - -0.03 (-0.80, 0.74) -

CERTO_STD

- - -0.24 (-2.26, 1.77) -

RIT_STD

- - 0.12 (-1.39, 1.63) -

RIT_STD+MTX

- - 0.12 (-1.37, 1.61) -

SAR_200

- - -0.17 (-2.44, 2.11) -

BAR_4+MTX

0.04 (-0.77, 0.85) - -0.08 (-0.92, 0.77) -

463




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

HD203+MTX

- - - -

SB4+MTX

- - -0.14 (-1.30, 1.03) -

ANBAI+MTX

0.06 (-1.14, 1.25) - - -

CT-P13+MTX

- - -0.24 (-1.36, 0.88) -

SB2+MTX

- - 0.02 (-1.17, 1.22) -

SB5+MTX

- - 0.04 (-1.06, 1.13) -

ZRC-3197+MTX

0.11 (-1.12, 1.34) - 0.03 (-1.23, 1.29) -

ABP501+MTX

- - 0.04 (-1.04, 1.12) -

GOL_STD (SC) TOC_8

(IV)+MTX - - - -

GOL_STD

(SC)+MTX

0.09 (-0.69, 0.88) - 0.19 (-0.69, 1.08) -

GOL_STD

(IV)+MTX

0.10 (-0.89, 1.08) - 0.14 (-0.86, 1.15) -

INF_STD+MTX

0.61 (-0.42, 1.65) - 0.07 (-0.72, 0.86) -

CERTO_STD+MTX

0.11 (-0.55, 0.77) - 0.02 (-0.66, 0.70) -

464




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

CERTO_STD

- - -0.19 (-2.17, 1.79) -

RIT_STD

- - 0.17 (-1.31, 1.64) -

RIT_STD+MTX

- - 0.17 (-1.28, 1.61) -

SAR_200

- - -0.11 (-2.36, 2.14) -

BAR_4+MTX

0.06 (-0.67, 0.78) - -0.03 (-0.79, 0.72) -

HD203+MTX

- - - -

SB4+MTX

- - -0.09 (-1.20, 1.02) -

ANBAI+MTX

0.07 (-1.07, 1.20) - - -

CT-P13+MTX

- - -0.18 (-1.24, 0.88) -

SB2+MTX

- - 0.08 (-1.04, 1.21) -

SB5+MTX

- - 0.09 (-0.94, 1.12) -

ZRC-3197+MTX

0.12 (-1.05, 1.30) - 0.08 (-1.12, 1.28) -

ABP501+MTX

- - 0.09 (-0.93, 1.10) -

465




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

GOL_STD

(SC)+MTX GOL_STD (SC) - - - -

GOL_STD

(IV)+MTX

- - - -

INF_STD+MTX

- - - -

CERTO_STD+MTX

- - - -

CERTO_STD

- - - -

RIT_STD

- - - -

RIT_STD+MTX

- - - -

SAR_200

- - - -

BAR_4+MTX

- - - -

HD203+MTX

- - - -

SB4+MTX

- - - -

ANBAI+MTX

- - - -

CT-P13+MTX

- - - -

466




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SB2+MTX

- - - -

SB5+MTX

- - - -

ZRC-3197+MTX

- - - -

ABP501+MTX

- - - -

GOL_STD

(IV)+MTX

GOL_STD

(SC)+MTX 0.01 (-1.05, 1.07) 0.11 (-1.11, 1.33) -0.04 (-1.18, 1.11) -0.01 (-1.13, 1.10)

INF_STD+MTX

0.53 (-0.57, 1.62) -0.02 (-1.00, 0.96) -0.11 (-1.05, 0.83) 1.09 (0.17, 2.01)

CERTO_STD+MTX

0.01 (-0.74, 0.77) -0.36 (-1.31, 0.59) -0.17 (-1.04, 0.70) -

CERTO_STD

- - -0.35 (-2.41, 1.71) -

RIT_STD

- - -0.01 (-1.59, 1.57) -

RIT_STD+MTX

- - -0.002 (-1.56, 1.55) -

SAR_200

- - -0.28 (-2.59, 2.03) 3.16 (0.91, 5.41)

BAR_4+MTX

-0.03 (-0.83, 0.77) -0.08 (-1.04, 0.87) -0.22 (-1.13, 0.70) 1.85 (0.80, 2.90)

HD203+MTX

- - - -

467




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SB4+MTX

- 0.36 (-0.98, 1.70) -0.27 (-1.50, 0.96) 0.49 (-0.73, 1.71)

ANBAI+MTX

-0.02 (-1.22, 1.18) - - -0.32 (-1.61, 0.97)

CT-P13+MTX

- -0.28 (-1.55, 1.00) -0.37 (-1.54, 0.81) -

SB2+MTX

- - -0.11 (-1.35, 1.14) -

SB5+MTX

- -0.01 (-1.25, 1.23) -0.10 (-1.26, 1.07) -

ZRC-3197+MTX

0.03 (-1.22, 1.27) -0.03 (-1.42, 1.37) -0.11 (-1.44, 1.22) -

ABP501+MTX

- - -0.10 (-1.24, 1.04) -

INF_STD+MTX GOL_STD

(IV)+MTX 0.52 (-0.72, 1.77) -0.12 (-1.30, 1.07) -0.07 (-1.12, 0.98) -

CERTO_STD+MTX

0.004 (-0.96, 0.96) -0.46 (-1.62, 0.71) -0.13 (-1.11, 0.85) -

CERTO_STD

- - -0.32 (-2.41, 1.77) -

RIT_STD

- - 0.03 (-1.61, 1.67) -

RIT_STD+MTX

- - 0.02 (-1.58, 1.62) -

SAR_200

- - -0.24 (-2.60, 2.12) -

468




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

BAR_4+MTX

-0.04 (-1.04, 0.96) -0.17 (-1.35, 1.00) -0.17 (-1.21, 0.87) -

HD203+MTX

- - - -

SB4+MTX

- 0.25 (-1.24, 1.73) -0.24 (-1.55, 1.07) -

ANBAI+MTX

-0.03 (-1.36, 1.31) - - -

CT-P13+MTX

- -0.37 (-1.82, 1.09) -0.33 (-1.60, 0.94) -

SB2+MTX

- - -0.07 (-1.39, 1.26) -

SB5+MTX

- -0.11 (-1.51, 1.30) -0.06 (-1.30, 1.19) -

ZRC-3197+MTX

0.03 (-1.33, 1.38) -0.12 (-1.65, 1.42) -0.08 (-1.47, 1.30) -

ABP501+MTX

- - -0.04 (-1.28, 1.19) 0.94 (-0.37, 2.24)

CERTO_STD+MTX INF_STD+MTX -0.50 (-1.51, 0.51) -0.33 (-1.26, 0.59) -0.05 (-0.81, 0.70) -

CERTO_STD

- - -0.25 (-2.26, 1.77) -

RIT_STD

- - 0.11 (-1.39, 1.61) -

RIT_STD+MTX

- - 0.10 (-1.35, 1.55) -

469




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SAR_200

- - -0.18 (-2.45, 2.10) 3.20 (0.96, 5.45)

BAR_4+MTX

-0.55 (-1.60, 0.50) -0.06 (-1.00, 0.87) -0.10 (-0.91, 0.71) 1.90 (0.90, 2.90)

HD203+MTX

- - - -

SB4+MTX

- 0.38 (-0.92, 1.68) -0.14 (-1.28, 0.99) 0.55 (-0.60, 1.70)

ANBAI+MTX

-0.54 (-1.91, 0.83) - - -0.28 (-1.46, 0.90)

CT-P13+MTX

- -0.25 (-1.08, 0.58) -0.26 (-0.98, 0.46) -

SB2+MTX

- - 0.01 (-0.80, 0.81) -

SB5+MTX

- 0.01 (-1.21, 1.24) 0.02 (-1.06, 1.10) -

ZRC-3197+MTX

-0.50 (-1.90, 0.91) 0.005 (-1.38, 1.39) -0.001 (-1.25, 1.25) -

ABP501+MTX

- - 0.03 (-1.03, 1.08) -

CERTO_STD CERTO_STD+M

TX - - -0.20 (-2.19, 1.79) -

RIT_STD

- - 0.15 (-1.31, 1.62) -

RIT_STD+MTX

- - 0.15 (-1.29, 1.59) -

470




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SAR_200

- - -0.13 (-2.38, 2.12) 2.65 (0.41, 4.89)

BAR_4+MTX

-0.04 (-0.72, 0.63) 0.27 (-0.60, 1.14) -0.05 (-0.76, 0.66) 1.34 (0.34, 2.35)

HD203+MTX

- - - -

SB4+MTX

- 0.70 (-0.59, 1.99) -0.11 (-1.18, 0.97) -0.01 (-1.18, 1.16)

ANBAI+MTX

-0.03 (-1.16, 1.10) - - -0.83 (-2.09, 0.43)

CT-P13+MTX

- 0.08 (-1.16, 1.32) -0.20 (-1.24, 0.84) -

SB2+MTX

- - 0.06 (-1.06, 1.18) -

SB5+MTX

- 0.35 (-0.79, 1.49) 0.07 (-0.90, 1.05) -

ZRC-3197+MTX

0.01 (-1.12, 1.14) 0.34 (-0.96, 1.64) 0.05 (-1.11, 1.20) -

ABP501+MTX

- - 0.07 (-0.89, 1.02) -

RIT_STD CERTO_STD - - 0.34 (-2.02, 2.70) -

RIT_STD+MTX

- - 0.35 (-1.98, 2.68) -

SAR_200

- - 0.10 (-1.83, 2.04) -

471




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

BAR_4+MTX

- - 0.15 (-1.85, 2.16) -

HD203+MTX

- - - -

SB4+MTX

- - 0.09 (-1.94, 2.13) -

ANBAI+MTX

- - - -

CT-P13+MTX

- - -0.01 (-2.13, 2.12) -

SB2+MTX

- - 0.26 (-1.90, 2.42) -

SB5+MTX

- - 0.28 (-1.84, 2.39) -

ZRC-3197+MTX

- - 0.28 (-1.95, 2.50) -

ABP501+MTX

- - 0.27 (-1.85, 2.38) -

RIT_STD+MTX RIT_STD - - 0.01 (-1.17, 1.18) -

SAR_200

- - -0.30 (-2.89, 2.29) -

BAR_4+MTX

- - -0.20 (-1.70, 1.30) -

HD203+MTX

- - - -

472




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SB4+MTX

- - -0.25 (-1.95, 1.45) -

ANBAI+MTX

- - - -

CT-P13+MTX

- - -0.35 (-2.00, 1.30) -

SB2+MTX

- - -0.10 (-1.80, 1.60) -

SB5+MTX

- - -0.08 (-1.72, 1.57) -

ZRC-3197+MTX

- - -0.11 (-1.88, 1.65) -

ABP501+MTX

- - -0.08 (-1.73, 1.56) -

SAR_200 RIT_STD+MTX - - -0.29 (-2.87, 2.28) -

BAR_4+MTX

- - -0.19 (-1.66, 1.29) -

HD203+MTX

- - - -

SB4+MTX

- - -0.25 (-1.92, 1.43) -

ANBAI+MTX

- - - -

CT-P13+MTX

- - -0.35 (-1.98, 1.27) -

473




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SB2+MTX

- - -0.10 (-1.77, 1.57) -

SB5+MTX

- - -0.08 (-1.69, 1.54) -

ZRC-3197+MTX

- - -0.11 (-1.86, 1.65) -

ABP501+MTX

- - -0.08 (-1.70, 1.54) -

BAR_4+MTX SAR_200 - - 0.08 (-2.19, 2.35) -

HD203+MTX

- - - -

SB4+MTX

- - 0.004 (-2.30, 2.31) -

ANBAI+MTX

- - - -

CT-P13+MTX

- - -0.08 (-2.47, 2.32) -

SB2+MTX

- - 0.19 (-2.24, 2.61) -

SB5+MTX

- - 0.20 (-2.15, 2.55) -

ZRC-3197+MTX

- - 0.18 (-2.29, 2.65) -

ABP501+MTX

- - 0.18 (-2.18, 2.54) -0.89 (-3.30, 1.52)

474




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

HD203+MTX BAR_4+MTX - - - -

SB4+MTX

- 0.43 (-0.85, 1.72) -0.06 (-1.19, 1.06) -0.48 (-1.72, 0.77)

ANBAI+MTX

0.02 (-1.13, 1.18) - - -1.30 (-2.62, 0.02)

CT-P13+MTX

- -0.18 (-1.43, 1.06) -0.14 (-1.23, 0.94) -

SB2+MTX

- - 0.10 (-1.06, 1.26) -

SB5+MTX

- 0.07 (-1.10, 1.24) 0.12 (-0.91, 1.14) -

ZRC-3197+MTX

0.06 (-1.11, 1.23) 0.06 (-1.25, 1.38) 0.09 (-1.10, 1.29) -

ABP501+MTX

- - 0.12 (-0.88, 1.13) -

SB4+MTX HD203+MTX - - - -0.97 (-2.38, 0.43)

ANBAI+MTX

- - - -1.80 (-3.46, -0.14)

CT-P13+MTX

- - - -

SB2+MTX

- - - -

SB5+MTX

- - - -

475




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

ZRC-3197+MTX

- - - -

ABP501+MTX

- - - -

ANBAI+MTX SB4+MTX - - - -

CT-P13+MTX

- -0.63 (-2.17, 0.91) -0.09 (-1.43, 1.25) -

SB2+MTX

- - 0.17 (-1.24, 1.58) -

SB5+MTX

- -0.36 (-1.88, 1.17) 0.18 (-1.15, 1.51) -

ZRC-3197+MTX

- -0.37 (-2.01, 1.27) 0.16 (-1.31, 1.62) -

ABP501+MTX

- - 0.18 (-1.15, 1.51) 0.08 (-1.33, 1.49)

CT-P13+MTX ANBAI+MTX - - - -

SB2+MTX

- - - -

SB5+MTX

- - - -

ZRC-3197+MTX

0.04 (-1.44, 1.52) - - -

ABP501+MTX

- - - -

476




Time Point Analysis

(12 to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

Difference log OR



Studies

Difference log OR

(95% CI) of SA vs

REF - Include Only

Asian-Only Studies

SB2+MTX CT-P13+MTX - - 0.25 (-0.83, 1.34) -

SB5+MTX

- 0.27 (-1.21, 1.75) 0.27 (-1.02, 1.56) -

ZRC-3197+MTX

- 0.26 (-1.35, 1.87) 0.25 (-1.18, 1.68) -

ABP501+MTX

- - 0.28 (-1.00, 1.56) -

SB5+MTX SB2+MTX - - 0.01 (-1.34, 1.36) -

ZRC-3197+MTX

- - -0.0002 (-1.50, 1.50) -

ABP501+MTX

- - 0.02 (-1.31, 1.35) -

ZRC-3197+MTX SB5+MTX - -0.02 (-1.49, 1.45) -0.03 (-1.35, 1.30) -

ABP501+MTX

- - -0.001 (-1.14, 1.14) -

ABP501+MTX ZRC-3197+MTX - - 0.02 (-1.29, 1.34) 0.08 (-1.20, 1.35)





ABA = abatacept; ABP501 = biosimilar adalimumab; ADA = adalimumab; ANBAI = AnBaiNuo (biosimilar adalimumab); BAR_4 = 4mg baricitinib; CERTO = certolizumab pegol; CI =

confidence interval; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; CT-P13 = biosimilar of infliximab; ETN = etanercept; GOL= golimumab; HCQ =

hydroxychloroquine; HD203=etanercept biosimilar; INF = infliximab; IV = intravenous; MTX = methotrexate; log OR = log odds ratio; RIT = rituximab; SAR_200 = 200mg sarilumab;

477

SB2 = biosimilar infliximab 3mg/kg; SB4 = biosimilar etanercept 50mg; SB5 = biosimilar adalimumab; SC = subcutaneous; SSZ = sulfasalazine; STD = standard dose; TOC_4 =

tocilizumab 4mg/kg; TOC_8 = 8mg/kg tocilizumab; TOF = tofacitinib; ZRC-3197 = biosimilar of adalimumab

478

Table 48. DAS28 Sensitivity Analysis Results Compared to the Reference Case

Treatment Comparator Difference of SMD (95% CI) - Impute Missing SE

Placebo Placebo+MTX 1.20 (-3.05, 5.45)

SSZ+HCQ

0.07 (-2.66, 2.81)

ETN_STD

-0.16 (-1.96, 1.65)

ETN_STD+MTX

0.08 (-1.45, 1.60)

ABA_STD (IV)+MTX

0.01 (-1.14, 1.16)

ADA_STD

1.18 (-2.38, 4.74)

ADA_STD+MTX

0.03 (-1.49, 1.56)

TOF_STD

1.21 (-3.07, 5.49)

TOF_STD+MTX

0.03 (-1.18, 1.25)

TOC_8 (IV)

1.19 (-1.56, 3.93)

TOC_4 (IV)+MTX

0.60 (-1.41, 2.60)

TOC_8 (IV)+MTX

0.63 (-1.40, 2.67)

GOL_STD (SC)

1.21 (-3.61, 6.03)

GOL_STD (SC)+MTX

-0.28 (-2.32, 1.75)

GOL_STD (IV)+MTX

0.01 (-2.24, 2.25)

INF_STD+MTX

-0.02 (-2.06, 2.03)

CERTO_STD

1.19 (-3.65, 6.03)

CERTO_STD +MTX

-0.01 (-1.62, 1.60)

RIT_STD

0.01 (-2.14, 2.16)

RIT_STD+MTX

-0.01 (-1.63, 1.61)

479


SAR_200

1.21 (-3.02, 5.45)

BAR_4+MTX

0.04 (-2.06, 2.14)

HD203+MTX

0.06 (-2.71, 2.82)

SB4+MTX

0.07 (-2.64, 2.78)

ANBAI+MTX

0.003 (-2.26, 2.27)

CT-P13+MTX

-0.03 (-2.62, 2.56)

SB2+MTX

0.01 (-3.03, 3.04)

ZRC-3197+MTX

0.003 (-2.77, 2.77)

ABP501+MTX

0.03 (-2.67, 2.74)

SSZ+HCQ Placebo -1.13 (-6.23, 3.97)

ETN_STD

-1.38 (-6.02, 3.27)

ETN_STD+MTX

-1.12 (-5.64, 3.39)

ABA_STD (IV)+MTX

-1.18 (-5.58, 3.21)

ADA_STD

0.02 (-2.26, 2.31)

ADA_STD+MTX

-1.17 (-5.67, 3.32)

TOF_STD

0.01 (-2.27, 2.29)

TOF_STD+MTX

-1.15 (-5.57, 3.27)

TOC_8 (IV)

-0.001 (-3.25, 3.25)

TOC_4 (IV)+MTX

-0.60 (-4.86, 3.66)

TOC_8 (IV)+MTX

-0.57 (-4.37, 3.23)

GOL_STD (SC)

-0.02 (-2.27, 2.24)

480


GOL_STD (SC)+MTX

-1.48 (-6.21, 3.25)

GOL_STD (IV)+MTX

-1.19 (-6.00, 3.61)

INF_STD+MTX

-1.25 (-5.97, 3.48)

CERTO_STD

0.002 (-2.27, 2.27)

CERTO_STD +MTX

-1.17 (-5.74, 3.40)

RIT_STD

-1.19 (-5.96, 3.58)

RIT_STD+MTX

-1.20 (-5.75, 3.35)

SAR_200

0.03 (-3.20, 3.25)

BAR_4+MTX

-1.17 (-5.92, 3.58)

HD203+MTX

-1.11 (-6.20, 3.97)

SB4+MTX

-1.12 (-6.21, 3.96)

ANBAI+MTX

-1.20 (-6.06, 3.67)

CT-P13+MTX

-1.23 (-6.23, 3.77)

SB2+MTX

-1.20 (-6.46, 4.06)

ZRC-3197+MTX

-1.17 (-6.21, 3.87)

ABP501+MTX

-1.18 (-6.22, 3.86)

ETN_STD SSZ+HCQ -0.22 (-2.89, 2.44)

ETN_STD+MTX

0.01 (-2.27, 2.28)

ABA_STD (IV)+MTX

-0.07 (-3.01, 2.87)

ADA_STD

1.12 (-3.41, 5.65)

ADA_STD+MTX

-0.04 (-3.16, 3.07)

481


TOF_STD

1.13 (-3.94, 6.19)

TOF_STD+MTX

-0.04 (-3.02, 2.95)

TOC_8 (IV)

1.14 (-2.77, 5.05)

TOC_4 (IV)+MTX

0.53 (-2.86, 3.92)

TOC_8 (IV)+MTX

0.57 (-2.82, 3.95)

GOL_STD (SC)

1.11 (-4.44, 6.65)

GOL_STD (SC)+MTX

-0.34 (-3.76, 3.08)

GOL_STD (IV)+MTX

-0.08 (-3.61, 3.45)

INF_STD+MTX

-0.08 (-3.48, 3.31)

CERTO_STD

1.12 (-4.48, 6.73)

CERTO_STD +MTX

-0.07 (-3.24, 3.09)

RIT_STD

-0.07 (-3.53, 3.39)

RIT_STD+MTX

-0.08 (-3.24, 3.08)

SAR_200

1.15 (-3.92, 6.22)

BAR_4+MTX

-0.03 (-3.45, 3.40)

HD203+MTX

0.01 (-3.22, 3.24)

SB4+MTX

0.01 (-3.18, 3.19)

ANBAI+MTX

-0.07 (-3.60, 3.46)

CT-P13+MTX

-0.07 (-3.83, 3.68)

SB2+MTX

-0.07 (-4.13, 3.99)

ZRC-3197+MTX

-0.07 (-3.95, 3.81)

482


ABP501+MTX

-0.03 (-3.87, 3.81)

ETN_STD+MTX ETN_STD 0.23 (-1.21, 1.67)

ABA_STD (IV)+MTX

0.16 (-1.98, 2.30)

ADA_STD

1.36 (-2.68, 5.39)

ADA_STD+MTX

0.17 (-2.17, 2.52)

TOF_STD

1.36 (-3.30, 6.02)

TOF_STD+MTX

0.19 (-1.98, 2.36)

TOC_8 (IV)

1.37 (-1.94, 4.67)

TOC_4 (IV)+MTX

0.75 (-1.96, 3.45)

TOC_8 (IV)+MTX

0.78 (-1.94, 3.50)

GOL_STD (SC)

1.35 (-3.82, 6.52)

GOL_STD (SC)+MTX

-0.13 (-2.86, 2.60)

GOL_STD (IV)+MTX

0.16 (-2.74, 3.06)

INF_STD+MTX

0.14 (-2.56, 2.84)

CERTO_STD

1.35 (-3.85, 6.56)

CERTO_STD +MTX

0.15 (-2.26, 2.57)

RIT_STD

0.16 (-2.66, 2.97)

RIT_STD+MTX

0.15 (-2.29, 2.59)

SAR_200

1.38 (-3.25, 6.01)

BAR_4+MTX

0.18 (-2.60, 2.96)

HD203+MTX

0.23 (-2.46, 2.92)

483


SB4+MTX

0.23 (-2.44, 2.90)

ANBAI+MTX

0.18 (-2.72, 3.07)

CT-P13+MTX

0.14 (-3.01, 3.29)

SB2+MTX

0.15 (-3.38, 3.68)

ZRC-3197+MTX

0.17 (-3.12, 3.46)

ABP501+MTX

0.19 (-3.08, 3.45)


ADA_STD

1.12 (-2.77, 5.02)

ADA_STD+MTX

-0.05 (-2.20, 2.11)

TOF_STD

1.13 (-3.42, 5.67)

TOF_STD+MTX

-0.03 (-1.99, 1.92)

TOC_8 (IV)

1.13 (-2.01, 4.28)

TOC_4 (IV)+MTX

0.53 (-2.00, 3.05)

TOC_8 (IV)+MTX

0.56 (-1.98, 3.09)

GOL_STD (SC)

1.12 (-3.95, 6.19)

GOL_STD (SC)+MTX

-0.36 (-2.91, 2.19)

GOL_STD (IV)+MTX

-0.07 (-2.80, 2.65)

INF_STD+MTX

-0.09 (-2.63, 2.44)

CERTO_STD

1.11 (-4.00, 6.22)

CERTO_STD +MTX

-0.08 (-2.29, 2.14)

RIT_STD

-0.08 (-2.72, 2.57)

484


RIT_STD+MTX

-0.08 (-2.32, 2.16)

SAR_200

1.15 (-3.36, 5.66)

BAR_4+MTX

-0.03 (-2.63, 2.57)

HD203+MTX

0.01 (-2.26, 2.28)

SB4+MTX

0.005 (-2.25, 2.26)

ANBAI+MTX

-0.07 (-2.80, 2.66)

CT-P13+MTX

-0.08 (-3.09, 2.93)

SB2+MTX

-0.10 (-3.48, 3.29)

ZRC-3197+MTX

-0.08 (-3.22, 3.07)

ABP501+MTX

-0.04 (-3.17, 3.08)

ADA_STD ABA_STD (IV)+MTX 1.18 (-2.59, 4.96)

ADA_STD+MTX

0.03 (-1.90, 1.95)

TOF_STD

1.20 (-3.22, 5.62)

TOF_STD+MTX

0.03 (-1.64, 1.70)

TOC_8 (IV)

1.19 (-1.79, 4.16)

TOC_4 (IV)+MTX

0.60 (-1.73, 2.92)

TOC_8 (IV)+MTX

0.63 (-1.71, 2.97)

GOL_STD (SC)

1.20 (-3.77, 6.16)

GOL_STD (SC)+MTX

-0.29 (-2.62, 2.05)

GOL_STD (IV)+MTX

-0.02 (-2.55, 2.51)

INF_STD+MTX

-0.02 (-2.05, 2.00)

485


CERTO_STD

1.17 (-3.81, 6.15)

CERTO_STD +MTX

-0.02 (-1.98, 1.94)

RIT_STD

-0.01 (-2.45, 2.43)

RIT_STD+MTX

-0.01 (-1.99, 1.96)

SAR_200

1.21 (-3.20, 5.61)

BAR_4+MTX

0.03 (-2.37, 2.43)

HD203+MTX

0.06 (-2.93, 3.05)

SB4+MTX

0.06 (-2.89, 3.02)

ANBAI+MTX

-0.02 (-2.56, 2.53)

CT-P13+MTX

-0.03 (-2.64, 2.57)

SB2+MTX

-0.01 (-3.04, 3.02)

ZRC-3197+MTX

0.002 (-2.98, 2.99)

ABP501+MTX

0.03 (-2.92, 2.97)

ADA_STD+MTX ADA_STD -1.17 (-5.05, 2.71)

TOF_STD

-0.001 (-2.28, 2.27)

TOF_STD+MTX

-1.15 (-4.91, 2.60)

TOC_8 (IV)

-0.003 (-2.28, 2.28)

TOC_4 (IV)+MTX

-0.60 (-4.18, 2.97)

TOC_8 (IV)+MTX

-0.57 (-3.62, 2.48)

GOL_STD (SC)

-0.02 (-3.26, 3.23)

GOL_STD (SC)+MTX

-1.49 (-5.63, 2.65)

486


GOL_STD (IV)+MTX

-1.19 (-5.43, 3.05)

INF_STD+MTX

-1.22 (-5.33, 2.88)

CERTO_STD

-0.02 (-3.25, 3.21)

CERTO_STD +MTX

-1.18 (-5.11, 2.74)

RIT_STD

-1.19 (-5.37, 2.99)

RIT_STD+MTX

-1.20 (-5.15, 2.75)

SAR_200

0.005 (-2.24, 2.25)

BAR_4+MTX

-1.16 (-5.32, 3.01)

HD203+MTX

-1.12 (-5.65, 3.40)

SB4+MTX

-1.12 (-5.65, 3.40)

ANBAI+MTX

-1.21 (-5.48, 3.05)

CT-P13+MTX

-1.25 (-5.70, 3.20)

SB2+MTX

-1.22 (-5.92, 3.49)

ZRC-3197+MTX

-1.18 (-5.70, 3.35)

ABP501+MTX

-1.19 (-5.68, 3.29)

TOF_STD ADA_STD +MTX 1.20 (-3.32, 5.71)

TOF_STD+MTX

0.01 (-1.71, 1.73)

TOC_8 (IV)

1.18 (-1.96, 4.31)

TOC_4 (IV)+MTX

0.57 (-1.93, 3.07)

TOC_8 (IV)+MTX

0.62 (-1.90, 3.14)

GOL_STD (SC)

1.18 (-3.87, 6.23)

487


GOL_STD (SC)+MTX

-0.31 (-2.86, 2.23)

GOL_STD (IV)+MTX

-0.02 (-2.75, 2.70)

INF_STD+MTX

-0.03 (-2.58, 2.51)

CERTO_STD

1.17 (-3.89, 6.24)

CERTO_STD +MTX

-0.03 (-2.27, 2.20)

RIT_STD

-0.03 (-2.66, 2.60)

RIT_STD+MTX

-0.03 (-2.24, 2.18)

SAR_200

1.19 (-3.29, 5.66)

BAR_4+MTX

0.01 (-2.09, 2.10)

HD203+MTX

0.04 (-3.10, 3.18)

SB4+MTX

0.05 (-3.06, 3.17)

ANBAI+MTX

-0.02 (-2.75, 2.71)

CT-P13+MTX

-0.05 (-3.06, 2.96)

SB2+MTX

-0.02 (-3.43, 3.38)

ZRC-3197+MTX

-0.01 (-2.29, 2.27)

ABP501+MTX

0.01 (-2.23, 2.26)


TOC_8 (IV)

-0.01 (-3.25, 3.22)

TOC_4 (IV)+MTX

-0.61 (-4.83, 3.61)

TOC_8 (IV)+MTX

-0.59 (-4.40, 3.22)

GOL_STD (SC)

-0.01 (-3.23, 3.20)

488


GOL_STD (SC)+MTX

-1.51 (-6.22, 3.21)

GOL_STD (IV)+MTX

-1.20 (-6.03, 3.63)

INF_STD+MTX

-1.24 (-5.96, 3.48)

CERTO_STD

-0.01 (-3.21, 3.19)

CERTO_STD +MTX

-1.20 (-5.78, 3.37)

RIT_STD

-1.21 (-6.01, 3.59)

RIT_STD+MTX

-1.21 (-5.82, 3.40)

SAR_200

0.02 (-3.20, 3.23)

BAR_4+MTX

-1.17 (-5.94, 3.59)

HD203+MTX

-1.13 (-6.23, 3.97)

SB4+MTX

-1.15 (-6.23, 3.94)

ANBAI+MTX

-1.23 (-6.08, 3.61)

CT-P13+MTX

-1.26 (-6.27, 3.75)

SB2+MTX

-1.22 (-6.46, 4.01)

ZRC-3197+MTX

-1.20 (-6.29, 3.89)

ABP501+MTX

-1.20 (-6.25, 3.84)

TOC_8 (IV) TOF_STD+MTX 1.16 (-1.86, 4.19)

TOC_4 (IV)+MTX

0.56 (-1.78, 2.91)

TOC_8 (IV)+MTX

0.60 (-1.77, 2.96)

GOL_STD (SC)

1.15 (-3.83, 6.13)

GOL_STD (SC)+MTX

-0.31 (-2.68, 2.06)

489


GOL_STD (IV)+MTX

-0.04 (-2.59, 2.52)

INF_STD+MTX

-0.06 (-2.43, 2.32)

CERTO_STD

1.15 (-3.84, 6.15)

CERTO_STD +MTX

-0.04 (-2.07, 1.98)

RIT_STD

-0.04 (-2.50, 2.42)

RIT_STD+MTX

-0.05 (-2.07, 1.97)

SAR_200

1.18 (-3.23, 5.59)

BAR_4+MTX

-0.01 (-2.33, 2.32)

HD203+MTX

0.03 (-2.97, 3.04)

SB4+MTX

0.03 (-2.94, 3.00)

ANBAI+MTX

-0.03 (-2.59, 2.53)

CT-P13+MTX

-0.06 (-2.94, 2.81)

SB2+MTX

-0.05 (-3.34, 3.24)

ZRC-3197+MTX

-0.02 (-2.90, 2.85)

ABP501+MTX

0.002 (-2.83, 2.83)

TOC_4 (IV)+MTX TOC_8 (IV) -0.62 (-3.34, 2.10)

TOC_8 (IV)+MTX

-0.57 (-2.58, 1.43)

GOL_STD (SC)

0.01 (-3.96, 3.97)

GOL_STD (SC)+MTX

-1.49 (-4.90, 1.92)

GOL_STD (IV)+MTX

-1.21 (-4.77, 2.36)

INF_STD+MTX

-1.24 (-4.66, 2.18)

490


CERTO_STD

-0.02 (-3.96, 3.93)

CERTO_STD +MTX

-1.19 (-4.38, 2.00)

RIT_STD

-1.19 (-4.67, 2.29)

RIT_STD+MTX

-1.20 (-4.41, 2.00)

SAR_200

0.01 (-3.19, 3.22)

BAR_4+MTX

-1.14 (-4.60, 2.31)

HD203+MTX

-1.12 (-4.98, 2.74)

SB4+MTX

-1.15 (-5.02, 2.72)

ANBAI+MTX

-1.20 (-4.76, 2.36)

CT-P13+MTX

-1.26 (-5.05, 2.54)

SB2+MTX

-1.23 (-5.33, 2.88)

ZRC-3197+MTX

-1.21 (-5.10, 2.69)

ABP501+MTX

-1.18 (-5.03, 2.68)


GOL_STD (SC)

0.61 (-4.22, 5.43)

GOL_STD (SC)+MTX

-0.88 (-3.73, 1.97)

GOL_STD (IV)+MTX

-0.61 (-3.59, 2.37)

INF_STD+MTX

-0.61 (-3.46, 2.24)

CERTO_STD

0.59 (-4.23, 5.42)

CERTO_STD +MTX

-0.60 (-3.19, 1.99)

RIT_STD

-0.60 (-3.53, 2.34)

491


RIT_STD+MTX

-0.59 (-3.18, 2.00)

SAR_200

0.62 (-3.59, 4.83)

BAR_4+MTX

-0.57 (-3.48, 2.34)

HD203+MTX

-0.52 (-3.91, 2.87)

SB4+MTX

-0.52 (-3.90, 2.86)

ANBAI+MTX

-0.59 (-3.64, 2.45)

CT-P13+MTX

-0.61 (-3.90, 2.67)

SB2+MTX

-0.60 (-4.21, 3.02)

ZRC-3197+MTX

-0.59 (-3.98, 2.81)

ABP501+MTX

-0.57 (-3.91, 2.76)

GOL_STD (SC) TOC_8 (IV)+MTX 0.58 (-3.87, 5.02)

GOL_STD (SC)+MTX

-0.90 (-3.77, 1.97)

GOL_STD (IV)+MTX

-0.66 (-3.68, 2.37)

INF_STD+MTX

-0.65 (-3.52, 2.21)

CERTO_STD

0.57 (-3.90, 5.04)

CERTO_STD +MTX

-0.63 (-3.21, 1.95)

RIT_STD

-0.63 (-3.58, 2.33)

RIT_STD+MTX

-0.64 (-3.22, 1.95)

SAR_200

0.59 (-3.18, 4.36)

BAR_4+MTX

-0.60 (-3.51, 2.31)

HD203+MTX

-0.55 (-3.95, 2.84)

492


SB4+MTX

-0.56 (-3.93, 2.82)

ANBAI+MTX

-0.63 (-3.69, 2.43)

CT-P13+MTX

-0.66 (-3.95, 2.62)

SB2+MTX

-0.65 (-4.28, 2.99)

ZRC-3197+MTX

-0.63 (-4.05, 2.79)

ABP501+MTX

-0.61 (-3.97, 2.76)

GOL_STD (SC)+MTX GOL_STD (SC) -1.47 (-6.70, 3.76)

GOL_STD (IV)+MTX

-1.20 (-6.50, 4.10)

INF_STD+MTX

-1.23 (-6.48, 4.03)

CERTO_STD

0.01 (-3.19, 3.22)

CERTO_STD +MTX

-1.18 (-6.27, 3.92)

RIT_STD

-1.19 (-6.48, 4.09)

RIT_STD+MTX

-1.20 (-6.27, 3.86)

SAR_200

0.06 (-3.89, 4.00)

BAR_4+MTX

-1.17 (-6.44, 4.10)

HD203+MTX

-1.09 (-6.63, 4.44)

SB4+MTX

-1.10 (-6.64, 4.43)

ANBAI+MTX

-1.19 (-6.54, 4.16)

CT-P13+MTX

-1.23 (-6.71, 4.26)

SB2+MTX

-1.22 (-6.95, 4.51)

ZRC-3197+MTX

-1.18 (-6.74, 4.39)

493


ABP501+MTX

-1.18 (-6.72, 4.35)


INF_STD+MTX

0.26 (-2.63, 3.14)

CERTO_STD

1.47 (-3.81, 6.75)

CERTO_STD +MTX

0.27 (-2.32, 2.86)

RIT_STD

0.29 (-2.66, 3.24)

RIT_STD+MTX

0.27 (-2.32, 2.87)

SAR_200

1.50 (-3.21, 6.22)

BAR_4+MTX

0.33 (-2.60, 3.26)

HD203+MTX

0.35 (-3.08, 3.78)

SB4+MTX

0.35 (-3.05, 3.76)

ANBAI+MTX

0.28 (-2.78, 3.33)

CT-P13+MTX

0.25 (-3.05, 3.56)

SB2+MTX

0.28 (-3.38, 3.94)

ZRC-3197+MTX

0.30 (-3.14, 3.73)

ABP501+MTX

0.33 (-3.06, 3.71)

INF_STD+MTX GOL_STD (IV)+MTX -0.02 (-3.03, 3.00)

CERTO_STD

1.17 (-4.18, 6.52)

CERTO_STD +MTX

-0.01 (-2.76, 2.75)

RIT_STD

-0.002 (-3.11, 3.10)

RIT_STD+MTX

-0.02 (-2.79, 2.75)

494


SAR_200

1.22 (-3.58, 6.03)

BAR_4+MTX

0.03 (-3.06, 3.13)

HD203+MTX

0.05 (-3.49, 3.59)

SB4+MTX

0.06 (-3.47, 3.59)

ANBAI+MTX

0.004 (-3.18, 3.19)

CT-P13+MTX

-0.04 (-3.48, 3.40)

SB2+MTX

-0.02 (-3.78, 3.75)

ZRC-3197+MTX

0.01 (-3.55, 3.58)

ABP501+MTX

0.02 (-3.51, 3.55)

CERTO_STD INF_STD+MTX 1.23 (-4.05, 6.51)

CERTO_STD +MTX

0.01 (-2.58, 2.60)

RIT_STD

0.02 (-2.95, 2.99)

RIT_STD+MTX

0.01 (-2.58, 2.60)

SAR_200

1.25 (-3.43, 5.94)

BAR_4+MTX

0.04 (-2.89, 2.97)

HD203+MTX

0.10 (-3.31, 3.51)

SB4+MTX

0.09 (-3.28, 3.46)

ANBAI+MTX

0.02 (-3.01, 3.05)

CT-P13+MTX

-0.001 (-1.60, 1.60)

SB2+MTX

0.01 (-2.25, 2.27)

ZRC-3197+MTX

0.01 (-3.42, 3.44)

495


ABP501+MTX

0.04 (-3.34, 3.42)

CERTO_STD+MTX CERTO_STD -1.20 (-6.31, 3.92)

RIT_STD

-1.19 (-6.49, 4.11)

RIT_STD+MTX

-1.19 (-6.32, 3.94)

SAR_200

0.02 (-3.92, 3.96)

BAR_4+MTX

-1.16 (-6.46, 4.15)

HD203+MTX

-1.12 (-6.70, 4.46)

SB4+MTX

-1.11 (-6.70, 4.48)

ANBAI+MTX

-1.19 (-6.55, 4.17)

CT-P13+MTX

-1.23 (-6.72, 4.26)

SB2+MTX

-1.20 (-6.92, 4.52)

ZRC-3197+MTX

-1.18 (-6.74, 4.38)

ABP501+MTX

-1.16 (-6.70, 4.38)

RIT_STD CERTO_STD+MTX 0.001 (-2.68, 2.69)

RIT_STD+MTX

-0.01 (-2.27, 2.26)

SAR_200

1.21 (-3.32, 5.75)

BAR_4+MTX

0.05 (-2.59, 2.70)

HD203+MTX

0.07 (-3.12, 3.25)

SB4+MTX

0.08 (-3.08, 3.23)

ANBAI+MTX

0.01 (-2.77, 2.78)

CT-P13+MTX

-0.02 (-3.08, 3.04)

496


SB2+MTX

-0.002 (-3.45, 3.44)

ZRC-3197+MTX

0.03 (-3.17, 3.22)

ABP501+MTX

0.04 (-3.14, 3.22)

RIT_STD+MTX RIT_STD -0.01 (-2.17, 2.14)

SAR_200

1.21 (-3.53, 5.96)

BAR_4+MTX

0.04 (-2.96, 3.03)

HD203+MTX

0.09 (-3.39, 3.56)

SB4+MTX

0.08 (-3.40, 3.57)

ANBAI+MTX

0.001 (-3.10, 3.11)

CT-P13+MTX

-0.02 (-3.39, 3.35)

SB2+MTX

-0.01 (-3.74, 3.72)

ZRC-3197+MTX

0.01 (-3.49, 3.50)

ABP501+MTX

0.03 (-3.43, 3.48)

SAR_200 RIT_STD+MTX 1.22 (-3.32, 5.77)

BAR_4+MTX

0.05 (-2.58, 2.67)

HD203+MTX

0.08 (-3.13, 3.29)

SB4+MTX

0.08 (-3.09, 3.24)

ANBAI+MTX

0.003 (-2.76, 2.77)

CT-P13+MTX -0.03 (-3.07, 3.02)

SB2+MTX 0.00 (-3.44, 3.44)

ZRC-3197+MTX 0.01 (-3.17, 3.20)

497


ABP501+MTX 0.04 (-3.10, 3.18)

BAR_4+MTX SAR_200 -1.18 (-5.90, 3.54)

HD203+MTX -1.15 (-6.19, 3.89)

SB4+MTX -1.14 (-6.18, 3.89)

ANBAI+MTX -1.24 (-6.03, 3.55)

CT-P13+MTX -1.26 (-6.24, 3.71)

SB2+MTX -1.24 (-6.45, 3.98)

ZRC-3197+MTX -1.19 (-6.28, 3.89)

ABP501+MTX -1.21 (-6.21, 3.79)

HD203+MTX BAR_4+MTX 0.04 (-3.42, 3.50)

SB4+MTX 0.04 (-3.40, 3.47)

ANBAI+MTX -0.03 (-3.11, 3.06)

CT-P13+MTX -0.03 (-3.35, 3.28)

SB2+MTX -0.04 (-3.72, 3.63)

ZRC-3197+MTX -0.02 (-3.13, 3.08)

ABP501+MTX -0.003 (-3.06, 3.06)

SB4+MTX HD203+MTX 0.01 (-3.20, 3.22)

ANBAI+MTX -0.06 (-3.63, 3.50)

CT-P13+MTX -0.09 (-3.88, 3.69)

SB2+MTX -0.07 (-4.15, 4.01)

ZRC-3197+MTX -0.08 (-3.98, 3.82)

498


ABP501+MTX -0.05 (-3.90, 3.80)

ANBAI+MTX SB4+MTX -0.07 (-3.60, 3.46)

CT-P13+MTX -0.08 (-3.82, 3.66)

SB2+MTX -0.08 (-4.10, 3.94)

ZRC-3197+MTX -0.08 (-3.94, 3.77)

ABP501+MTX -0.03 (-3.88, 3.81)

CT-P13+MTX ANBAI+MTX -0.03 (-3.45, 3.40)

SB2+MTX -0.01 (-3.78, 3.75)

ZRC-3197+MTX 0.01 (-3.56, 3.57)

ABP501+MTX 0.03 (-3.50, 3.55)

SB2+MTX CT-P13+MTX 0.01 (-2.75, 2.76)

ZRC-3197+MTX 0.003 (-3.79, 3.80)

ABP501+MTX 0.04 (-3.70, 3.79)

ZRC-3197+MTX SB2+MTX -0.003 (-4.12, 4.11)

ABP501+MTX 0.03 (-4.03, 4.09)

ABP501+MTX ZRC-3197+MTX 0.03 (-3.17, 3.22)

Difference in Standardized Mean Difference represents the comparison of the sensitivity analysis to the reference case. Each

column presents the comparison of one sensitivity analysis to the reference case. Only treatment comparisons from the sensitivity

analysis that were also present in the reference case were compared; dashes indicate where the treatment comparison was not

present in the sensitivity analysis. Pink cells indicate the sensitivity analysis has a lower effect estimate than the reference case.

Green cells indicate the sensitivity analysis has a higher effect estimate than the reference case.

ABA = abatacept; ABP501 = biosimilar adalimumab; ADA = adalimumab; ANBAI = AnBaiNuo (biosimilar adalimumab); BAR_4 =

4mg baricitinib; CERTO = certolizumab pegol; CI = confidence interval; CT-P13 = biosimilar of infliximab; ETN = etanercept; GOL=

golimumab; HCQ = hydroxychloroquine; HD203=etanercept biosimilar; INF = infliximab; IV = intravenous; MTX = methotrexate; RIT

= rituximab; SAR_200 = 200mg sarilumab; SB2 = biosimilar infliximab 3mg/kg; SB4 = biosimilar etanercept 50mg; SB5 = biosimilar

adalimumab; SC = subcutaneous; SSZ = sulfasalazine; STD = standard dose; TOC_4 = tocilizumab 4mg/kg; TOC_8 = 8mg/kg

tocilizumab; TOF = tofacitinib; ZRC-3197 = biosimilar of adalimumab

499

Table 49. HAQ-DI Sensitivity Analysis Results Compared to the Reference Case

Treatment Comparator Difference of MD (95% CI) - Impute Missing SE

ABA_STD (IV)+MTX Placebo+MTX -0.22 (-0.38, -0.06)

ADA_STD+MTX

0.16 (0.05, 0.27)

TOF_STD+MTX

-0.03 (-0.15, 0.08)

TOC_8 (IV)

-0.23 (-0.41, -0.05)

TOC_4 (IV)+MTX

-0.004 (-0.16, 0.15)

TOC_8 (IV)+MTX

0.03 (-0.18, 0.25)

GOL_STD (SC)+MTX

0.005 (-0.15, 0.16)

GOL_STD (IV)+MTX

0.16 (-0.03, 0.35)

INF_STD+MTX

0.06 (-0.10, 0.23)

CERTO_STD+MTX

-0.08 (-0.24, 0.08)

RIT_STD

-0.16 (-0.37, 0.05)

RIT_STD+MTX

0.16 (-0.03, 0.35)

SAR_200+MTX

0.14 (-0.06, 0.34)

BAR_4+MTX

-0.10 (-0.28, 0.08)

ANBAI+MTX

-0.37 (-0.57, -0.17)

CT-P13+MTX

-0.24 (-0.49, 0.02)

SB2+MTX

0.39 (0.15, 0.63)

ZRC-3197+MTX

0.29 (-0.01, 0.59)

ADA_STD+MTX ABA_STD (IV)+MTX 0.27 (0.06, 0.49)

500


TOF_STD+MTX

0.21 (-0.01, 0.44)

TOC_8 (IV)

0.15 (-0.08, 0.38)

TOC_4 (IV)+MTX

0.19 (-0.04, 0.41)

TOC_8 (IV)+MTX

0.03 (-0.19, 0.25)

GOL_STD (SC)+MTX

0.22 (0.03, 0.42)

GOL_STD (IV)+MTX

0.42 (0.15, 0.68)

INF_STD+MTX

0.29 (0.05, 0.53)

CERTO_STD+MTX

0.30 (0.07, 0.53)

RIT_STD

0.13 (-0.12, 0.37)

RIT_STD+MTX

0.30 (0.04, 0.57)

SAR_200+MTX

0.20 (-0.04, 0.45)

BAR_4+MTX

0.28 (0.08, 0.49)

ANBAI+MTX

-0.01 (-0.27, 0.26)

CT-P13+MTX

-0.11 (-0.42, 0.20)

SB2+MTX

0.24 (-0.03, 0.51)

ZRC-3197+MTX

0.28 (0.005, 0.55)

TOF_STD+MTX ADA_STD+MTX 0.52 (0.30, 0.74)

TOC_8 (IV)

0.25 (-0.07, 0.57)

TOC_4 (IV)+MTX

0.13 (-0.15, 0.40)

TOC_8 (IV)+MTX

-0.004 (-0.28, 0.28)

GOL_STD (SC)+MTX

-0.19 (-0.35, -0.03)

501


GOL_STD (IV)+MTX

-0.20 (-0.38, -0.01)

INF_STD+MTX

-0.10 (-0.29, 0.10)

CERTO_STD+MTX

-0.04 (-0.26, 0.18)

RIT_STD

-0.25 (-0.48, -0.02)

RIT_STD+MTX

0.08 (-0.15, 0.31)

SAR_200+MTX

-0.11 (-0.30, 0.07)

BAR_4+MTX

-0.18 (-0.36, 0.01)

ANBAI+MTX

-0.55 (-0.78, -0.32)

CT-P13+MTX

-0.33 (-0.61, -0.06)

SB2+MTX

0.002 (-0.27, 0.27)

ZRC-3197+MTX

-0.20 (-0.46, 0.06)

TOC_8 (IV) TOF_STD+MTX -0.31 (-0.55, -0.07)

TOC_4 (IV)+MTX

-0.11 (-0.31, 0.09)

TOC_8 (IV)+MTX

0.09 (-0.13, 0.32)

GOL_STD (SC)+MTX

0.13 (-0.14, 0.40)

GOL_STD (IV)+MTX

-0.14 (-0.40, 0.12)

INF_STD+MTX

-0.09 (-0.36, 0.17)

CERTO_STD+MTX

-0.09 (-0.25, 0.08)

RIT_STD

-0.07 (-0.28, 0.14)

RIT_STD+MTX

0.31 (0.05, 0.56)

SAR_200+MTX

0.08 (-0.14, 0.30)

502


BAR_4+MTX

0.17 (-0.02, 0.37)

ANBAI+MTX

-0.29 (-0.50, -0.09)

CT-P13+MTX

-0.22 (-0.52, 0.07)

SB2+MTX

0.03 (-0.22, 0.28)

ZRC-3197+MTX

0.15 (-0.10, 0.40)

TOC_4 (IV)+MTX TOC_8 (IV) 0.29 (0.04, 0.54)

TOC_8 (IV)+MTX

-0.04 (-0.24, 0.17)

GOL_STD (SC)+MTX

0.16 (-0.08, 0.40)

GOL_STD (IV)+MTX

0.22 (-0.03, 0.47)

INF_STD+MTX

0.59 (0.32, 0.87)

CERTO_STD+MTX

0.38 (0.07, 0.68)

RIT_STD

0.04 (-0.26, 0.34)

RIT_STD+MTX

0.25 (-0.07, 0.56)

SAR_200+MTX

0.28 (0.04, 0.51)

BAR_4+MTX

0.41 (0.15, 0.67)

ANBAI+MTX

-0.09 (-0.36, 0.18)

CT-P13+MTX

0.14 (-0.19, 0.46)

SB2+MTX

0.30 (0.02, 0.57)

ZRC-3197+MTX

0.27 (-0.03, 0.57)


GOL_STD (SC)+MTX

0.12 (-0.07, 0.32)

503


GOL_STD (IV)+MTX

0.19 (-0.07, 0.44)

INF_STD+MTX

0.03 (-0.23, 0.28)

CERTO_STD+MTX

-0.03 (-0.25, 0.18)

RIT_STD

-0.04 (-0.27, 0.19)

RIT_STD+MTX

0.50 (0.23, 0.76)

SAR_200+MTX

0.34 (0.04, 0.64)

BAR_4+MTX

0.01 (-0.25, 0.26)

ANBAI+MTX

-0.32 (-0.59, -0.05)

CT-P13+MTX

-0.05 (-0.38, 0.27)

SB2+MTX

0.07 (-0.21, 0.35)

ZRC-3197+MTX

0.20 (-0.08, 0.49)


GOL_STD (IV)+MTX

0.13 (-0.11, 0.38)

INF_STD+MTX

0.14 (-0.11, 0.38)

CERTO_STD+MTX

0.14 (-0.07, 0.34)

RIT_STD

0.14 (-0.13, 0.41)

RIT_STD+MTX

0.14 (-0.14, 0.41)

SAR_200+MTX

0.14 (-0.10, 0.37)

BAR_4+MTX

0.14 (-0.06, 0.34)

ANBAI+MTX

0.14 (-0.13, 0.40)

CT-P13+MTX

0.13 (-0.23, 0.50)

504


SB2+MTX

0.13 (-0.18, 0.45)

ZRC-3197+MTX

0.14 (-0.18, 0.46)


INF_STD+MTX

0.03 (-0.17, 0.22)

CERTO_STD+MTX

-0.23 (-0.45, -0.002)

RIT_STD

-0.29 (-0.57, -0.01)

RIT_STD+MTX

-0.13 (-0.41, 0.15)

SAR_200+MTX

-0.07 (-0.32, 0.18)

BAR_4+MTX

-0.07 (-0.33, 0.19)

ANBAI+MTX

-0.60 (-0.89, -0.32)

CT-P13+MTX

-0.44 (-0.77, -0.12)

SB2+MTX

-0.11 (-0.40, 0.17)

ZRC-3197+MTX

0.22 (-0.09, 0.53)


CERTO_STD+MTX

-0.32 (-0.61, -0.02)

RIT_STD

-0.35 (-0.68, -0.02)

RIT_STD+MTX

0.21 (-0.04, 0.46)

SAR_200+MTX

0.01 (-0.23, 0.26)

BAR_4+MTX

-0.05 (-0.29, 0.20)

ANBAI+MTX

-0.42 (-0.69, -0.14)

CT-P13+MTX

-0.20 (-0.52, 0.11)

505


SB2+MTX

0.13 (-0.18, 0.45)

ZRC-3197+MTX

-0.07 (-0.39, 0.24)

CERTO_STD+MTX INF_STD+MTX -0.17 (-0.41, 0.08)

RIT_STD

-0.17 (-0.44, 0.09)

RIT_STD+MTX

0.36 (0.07, 0.65)

SAR_200+MTX

0.20 (-0.12, 0.53)

BAR_4+MTX

-0.13 (-0.41, 0.16)

ANBAI+MTX -0.46 (-0.77, -0.15)

CT-P13+MTX -0.43 (-0.67, -0.19)

SB2+MTX -0.16 (-0.39, 0.07)

ZRC-3197+MTX -0.20 (-0.51, 0.10)

RIT_STD CERTO_STD+MTX -0.12 (-0.37, 0.13)

RIT_STD+MTX 0.12 (-0.16, 0.40)

SAR_200+MTX -0.14 (-0.40, 0.12)

BAR_4+MTX -0.12 (-0.34, 0.11)

ANBAI+MTX -0.41 (-0.65, -0.17)

CT-P13+MTX 0.02 (-0.31, 0.34)

SB2+MTX 0.21 (-0.13, 0.55)

ZRC-3197+MTX -0.08 (-0.40, 0.24)

RIT_STD+MTX RIT_STD 0.004 (-0.29, 0.29)

SAR_200+MTX 0.12 (-0.14, 0.38)

506


BAR_4+MTX 0.04 (-0.20, 0.28)

ANBAI+MTX -0.17 (-0.43, 0.08)

CT-P13+MTX -0.04 (-0.37, 0.30)

SB2+MTX 0.06 (-0.25, 0.36)

ZRC-3197+MTX 0.12 (-0.18, 0.41)

SAR_200+MTX RIT_STD+MTX -0.06 (-0.31, 0.18)

BAR_4+MTX 0.23 (-0.02, 0.48)

ANBAI+MTX -0.20 (-0.53, 0.13)

CT-P13+MTX -0.40 (-0.75, -0.05)

SB2+MTX -0.10 (-0.43, 0.23)

ZRC-3197+MTX -0.08 (-0.40, 0.24)

BAR_4+MTX SAR_200+MTX 0.04 (-0.19, 0.27)

ANBAI+MTX -0.25 (-0.54, 0.04)

CT-P13+MTX -0.35 (-0.69, -0.01)

SB2+MTX -0.001 (-0.30, 0.29)

ZRC-3197+MTX 0.03 (-0.25, 0.32)

ANBAI+MTX BAR_4+MTX 0.02 (-0.25, 0.28)

CT-P13+MTX 0.02 (-0.35, 0.38)

SB2+MTX 0.02 (-0.30, 0.33)

ZRC-3197+MTX 0.02 (-0.30, 0.34)

CT-P13+MTX ANBAI+MTX 0.21 (-0.11, 0.54)

507


SB2+MTX 0.55 (0.23, 0.87)

ZRC-3197+MTX 0.35 (0.02, 0.68)

SB2+MTX CT-P13+MTX 0.31 (0.02, 0.61)

ZRC-3197+MTX 0.35 (-0.001, 0.70)

ZRC-3197+MTX SB2+MTX 0.39 (0.05, 0.73)

Difference in Mean Difference represents the comparison of the sensitivity analysis to the reference case. Each column presents the

comparison of one sensitivity analysis to the reference case. Only treatment comparisons from the sensitivity analysis that were also

present in the reference case were compared; dashes indicate where the treatment comparison was not present in the sensitivity

analysis. Pink cells indicate the sensitivity analysis has a lower effect estimate than the reference case. Green cells indicate the

sensitivity analysis has a higher effect estimate than the reference case.

ABA = abatacept; ADA = adalimumab; ANBAI = AnBaiNuo (biosimilar adalimumab); BAR_4 = 4mg baricitinib; CERTO =

certolizumab pegol; CI = confidence interval; CT-P13 = biosimilar of infliximab; GOL= golimumab; INF = infliximab; IV = intravenous;

MTX = methotrexate; RIT = rituximab; SAR_200 = 200mg sarilumab; SB2 = biosimilar infliximab 3mg/kg; SC = subcutaneous; STD

= standard dose; TOC_4 = tocilizumab 4mg/kg; TOC_8 = 8mg/kg tocilizumab; TOF = tofacitinib; ZRC-3197 = biosimilar of

adalimumab

508

Table 50. Pain Sensitivity Analysis Results Compared to the Reference Case


Placebo Placebo+MTX -0.01 (-1.63, 1.61)

LEF_10

-0.01 (-2.10, 2.08)

SSZ+HCQ

-0.16 (-1.54, 1.21)

MTX+SSZ+HCQ

-0.26 (-1.32, 0.79)

ETN_STD+MTX

-0.38 (-1.19, 0.43)

ABA_STD (IV)+MTX

0.001 (-1.29, 1.29)

ADA_STD

-0.43 (-2.53, 1.67)

ADA_STD+MTX

-0.10 (-0.75, 0.55)

TOF_STD

-0.01 (-2.13, 2.10)

TOF_STD+MTX

-0.05 (-0.80, 0.70)

CERTO_STD

-0.02 (-1.35, 1.31)

CERTO_STD+MTX

0.004 (-1.28, 1.29)

SAR_200+MTX

-0.002 (-1.30, 1.30)

BAR_4+MTX

-0.05 (-1.21, 1.10)

ZRC-3197+MTX

-0.09 (-1.57, 1.38)

LEF_10 Placebo -0.004 (-1.33, 1.32)

SSZ+HCQ

-0.15 (-2.28, 1.99)

MTX+SSZ+HCQ

-0.25 (-2.19, 1.70)

ETN_STD+MTX

-0.37 (-2.17, 1.44)

ABA_STD (IV)+MTX

0.01 (-2.07, 2.08)

509


ADA_STD

-0.41 (-1.75, 0.92)

ADA_STD+MTX

-0.09 (-1.83, 1.64)

TOF_STD

0.002 (-1.33, 1.34)

TOF_STD+MTX

-0.03 (-1.82, 1.75)

CERTO_STD

-0.001 (-0.93, 0.93)

CERTO_STD+MTX

0.02 (-2.05, 2.09)

SAR_200+MTX

0.02 (-2.07, 2.11)

BAR_4+MTX

-0.03 (-2.03, 1.97)

ZRC-3197+MTX

-0.08 (-2.27, 2.11)

LEF_25 LEF_10 -0.001 (-1.33, 1.32)

SSZ+HCQ

-0.15 (-2.66, 2.36)

MTX+SSZ+HCQ

-0.25 (-2.58, 2.08)

ETN_STD+MTX

-0.37 (-2.61, 1.87)

ABA_STD (IV)+MTX

0.01 (-2.46, 2.47)

ADA_STD

-0.42 (-2.30, 1.47)

ADA_STD+MTX

-0.10 (-2.27, 2.07)

TOF_STD

-0.01 (-1.87, 1.86)

TOF_STD+MTX

-0.04 (-2.26, 2.18)

CERTO_STD

-0.004 (-1.62, 1.61)

CERTO_STD+MTX

0.02 (-2.43, 2.47)

SAR_200+MTX

0.01 (-2.44, 2.47)

510


BAR_4+MTX

-0.04 (-2.43, 2.35)

ZRC-3197+MTX

-0.09 (-2.64, 2.45)

MTX+SSZ+HCQ SSZ+HCQ -0.10 (-1.43, 1.24)

ETN_STD+MTX

-0.21 (-1.66, 1.24)

ABA_STD (IV)+MTX

0.16 (-1.72, 2.04)

ADA_STD

-0.26 (-2.77, 2.24)

ADA_STD+MTX

0.06 (-1.45, 1.58)

TOF_STD

0.15 (-2.36, 2.67)

TOF_STD+MTX

0.11 (-1.45, 1.67)

CERTO_STD

0.16 (-1.76, 2.07)

CERTO_STD+MTX

0.16 (-1.71, 2.04)

SAR_200+MTX

0.16 (-1.73, 2.06)

BAR_4+MTX

0.11 (-1.69, 1.91)

ZRC-3197+MTX

0.07 (-1.93, 2.08)

ETN_STD+MTX MTX+SSZ+HCQ -0.12 (-1.16, 0.91)

ABA_STD (IV)+MTX

0.26 (-1.41, 1.93)

ADA_STD

-0.18 (-2.53, 2.18)

ADA_STD+MTX

0.16 (-1.08, 1.41)

TOF_STD

0.25 (-2.12, 2.62)

TOF_STD+MTX

0.22 (-1.08, 1.51)

CERTO_STD

0.25 (-1.45, 1.95)

511


CERTO_STD+MTX

0.27 (-1.40, 1.93)

SAR_200+MTX

0.26 (-1.42, 1.93)

BAR_4+MTX

0.21 (-1.37, 1.79)

ZRC-3197+MTX

0.17 (-1.66, 1.99)

ABA_STD (IV)+MTX ETN_STD+MTX 0.39 (-1.13, 1.91)

ADA_STD

-0.04 (-2.29, 2.21)

ADA_STD+MTX

0.28 (-0.76, 1.32)

TOF_STD

0.37 (-1.88, 2.62)

TOF_STD+MTX

0.34 (-0.77, 1.44)

CERTO_STD

0.36 (-1.20, 1.92)

CERTO_STD+MTX

0.39 (-1.14, 1.91)

SAR_200+MTX

0.39 (-1.15, 1.92)

BAR_4+MTX

0.33 (-1.09, 1.75)

ZRC-3197+MTX

0.28 (-1.41, 1.96)

ADA_STD ABA_STD (IV)+MTX -0.43 (-2.89, 2.03)

ADA_STD+MTX

-0.11 (-1.56, 1.34)

TOF_STD

-0.01 (-2.48, 2.45)

TOF_STD+MTX

-0.05 (-1.54, 1.43)

CERTO_STD

-0.01 (-1.85, 1.83)

CERTO_STD+MTX 0.01 (-1.83, 1.84)

SAR_200+MTX 0.004 (-1.83, 1.84)

512


BAR_4+MTX -0.06 (-1.80, 1.69)

ZRC-3197+MTX -0.11 (-2.08, 1.86)

ADA_STD+MTX ADA_STD 0.33 (-1.86, 2.51)

TOF_STD 0.41 (-0.92, 1.75)

TOF_STD+MTX 0.39 (-1.85, 2.62)

CERTO_STD 0.42 (-1.21, 2.04)

CERTO_STD+MTX 0.44 (-2.03, 2.90)

SAR_200+MTX 0.43 (-2.04, 2.90)

BAR_4+MTX 0.37 (-2.01, 2.76)

ZRC-3197+MTX 0.33 (-2.23, 2.89)

TOF_STD ADA_STD+MTX 0.08 (-2.11, 2.27)

TOF_STD+MTX 0.05 (-0.85, 0.96)

CERTO_STD 0.09 (-1.40, 1.58)

CERTO_STD+MTX 0.11 (-1.33, 1.55)

SAR_200+MTX 0.11 (-1.35, 1.56)

BAR_4+MTX 0.06 (-1.10, 1.22)

ZRC-3197+MTX 0.003 (-1.33, 1.33)


CERTO_STD -0.004 (-1.63, 1.62)

CERTO_STD+MTX 0.03 (-2.44, 2.50)

SAR_200+MTX 0.02 (-2.46, 2.49)

513


BAR_4+MTX -0.03 (-2.44, 2.37)

ZRC-3197+MTX -0.09 (-2.67, 2.48)

CERTO_STD TOF_STD+MTX 0.03 (-1.48, 1.55)

CERTO_STD+MTX 0.05 (-1.44, 1.55)

SAR_200+MTX 0.05 (-1.45, 1.55)

BAR_4+MTX -0.01 (-1.36, 1.35)

ZRC-3197+MTX -0.06 (-1.65, 1.54)

CERTO_STD+MTX CERTO_STD 0.02 (-1.82, 1.87)

SAR_200+MTX 0.02 (-1.83, 1.86)

BAR_4+MTX -0.04 (-1.80, 1.73)

ZRC-3197+MTX -0.10 (-2.08, 1.89)

SAR_200+MTX CERTO_STD+MTX 0.001 (-1.83, 1.83)

BAR_4+MTX -0.05 (-1.78, 1.67)

ZRC-3197+MTX -0.10 (-2.08, 1.87)

BAR_4+MTX SAR_200+MTX -0.05 (-1.79, 1.69)

ZRC-3197+MTX -0.11 (-2.08, 1.86)

ZRC-3197+MTX BAR_4+MTX -0.05 (-1.81, 1.72)






ABA = abatacept; ADA = adalimumab; BAR_4 = 4mg baricitinib; CERTO = certolizumab pegol; CI = confidence interval; ETN =

etanercept; HCQ = hydroxychloroquine; LEF = Leflunomide; MTX = methotrexate; SAR_200 = 200mg sarilumab; SSZ =

sulfasalazine; STD = standard dose; TOF = tofacitinib; ZRC-3197 = biosimilar of adalimumab

514

Table 51. Fatigue Sensitivity Analysis Results Compared to the Reference Case


ETN_STD+MTX Placebo+MTX -0.01 (-2.63, 2.62)

ABA_STD (IV)+MTX

-0.0001 (-2.60, 2.60)

TOF_STD+MTX

0.003 (-2.39, 2.40)

ADA_STD+MTX

0.002 (-1.51, 1.51)

TOC_4 (IV)+MTX

0.004 (-2.65, 2.65)

TOC_8 (IV)+MTX

0.003 (-2.58, 2.59)

GOL_STD (SC)+MTX

-0.004 (-1.87, 1.86)

GOL_STD (IV)+MTX

0.01 (-2.62, 2.63)

CERTO_STD+MTX

-0.001 (-2.60, 2.60)

SAR_200+MTX

-0.003 (-2.56, 2.56)

HD203+MTX

-0.004 (-3.68, 3.67)

ABA_STD (IV)+MTX ETN_STD+MTX 0.003 (-3.74, 3.74)

TOF_STD+MTX

0.004 (-3.55, 3.56)

ADA_STD+MTX

0.004 (-3.02, 3.03)

TOC_4 (IV)+MTX

0.01 (-3.71, 3.72)

TOC_8 (IV)+MTX

0.01 (-3.66, 3.68)

GOL_STD (SC)+MTX

0.001 (-3.22, 3.22)

GOL_STD (IV)+MTX

0.01 (-3.72, 3.74)

CERTO_STD+MTX

0.01 (-3.72, 3.73)

515


SAR_200+MTX

0.001 (-3.71, 3.71)

HD203+MTX -0.002 (-2.60, 2.60)

TOF_STD+MTX ABA_STD (IV)+MTX 0.01 (-3.53, 3.54)

ADA_STD+MTX 0.01 (-3.04, 3.06)

TOC_4 (IV)+MTX 0.01 (-3.71, 3.73)

TOC_8 (IV)+MTX 0.01 (-3.71, 3.73)

GOL_STD (SC)+MTX -0.002 (-3.20, 3.19)

GOL_STD (IV)+MTX 0.01 (-3.64, 3.66)

CERTO_STD+MTX 0.01 (-3.72, 3.73)

SAR_200+MTX -0.001 (-3.66, 3.66)

HD203+MTX -0.002 (-4.48, 4.48)

ADA_STD+MTX TOF_STD+MTX 0.0002 (-2.40, 2.40)

TOC_4 (IV)+MTX -0.001 (-3.60, 3.60)

TOC_8 (IV)+MTX 0.001 (-3.60, 3.60)

GOL_STD (SC)+MTX -0.004 (-3.03, 3.03)

GOL_STD (IV)+MTX 0.01 (-3.51, 3.52)

CERTO_STD+MTX 0.0001 (-3.61, 3.61)

SAR_200+MTX -0.004 (-3.55, 3.54)

HD203+MTX -0.004 (-4.43, 4.42)

TOC_4 (IV)+MTX ADA_STD+MTX 0.0002 (-3.07, 3.07)

TOC_8 (IV)+MTX -0.001 (-3.04, 3.04)

516


GOL_STD (SC)+MTX -0.01 (-2.41, 2.39)

GOL_STD (IV)+MTX 0.005 (-2.99, 3.00)

CERTO_STD+MTX -0.002 (-3.05, 3.05)

SAR_200+MTX -0.01 (-2.96, 2.95)

HD203+MTX -0.004 (-3.95, 3.94)


GOL_STD (SC)+MTX -0.005 (-3.23, 3.22)

GOL_STD (IV)+MTX 0.01 (-3.69, 3.70)

CERTO_STD+MTX 0.003 (-3.68, 3.69)

SAR_200+MTX -0.01 (-3.70, 3.68)

HD203+MTX -0.01 (-4.49, 4.48)

GOL_STD (SC)+MTX TOC_8 (IV)+MTX -0.01 (-3.18, 3.16)

GOL_STD (IV)+MTX 0.001 (-3.73, 3.74)

CERTO_STD+MTX -0.005 (-3.72, 3.71)

SAR_200+MTX -0.005 (-3.64, 3.63)

HD203+MTX -0.02 (-4.55, 4.52)


CERTO_STD+MTX 0.004 (-3.22, 3.23)

SAR_200+MTX -0.001 (-3.17, 3.17)

HD203+MTX 0.003 (-4.07, 4.08)

CERTO_STD+MTX GOL_STD (IV)+MTX -0.004 (-3.72, 3.71)

517


SAR_200+MTX -0.01 (-3.68, 3.66)

HD203+MTX -0.01 (-4.53, 4.50)

SAR_200+MTX CERTO_STD+MTX -0.01 (-3.67, 3.66)

HD203+MTX -0.01 (-4.50, 4.48)

HD203+MTX SAR_200+MTX -0.001 (-4.50, 4.49)






ABA = abatacept; ADA = adalimumab; CERTO = certolizumab pegol; CI = confidence interval; ETN = etanercept; GOL= golimumab

; HD203=etanercept biosimilar; MTX = methotrexate; SAR_200 = 200mg sarilumab; STD = standard dose; TOC_4 = tocilizumab

4mg/kg; TOC_8 = 8mg/kg tocilizumab;TOF = tofacitinib

518

Table 52. SF-36 PCS and MCS Sensitivity Analysis Results Compared to the Reference Case


SF-36 PCS Difference of MD (95% CI) -

Impute Missing SE

SF-35 MCS Difference

of MD (95% CI) -

Impute Missing SE

ABA_STD (IV)+MTX Placebo+MTX -0.01 (-1.63, 1.61) -0.07 (-3.00, 2.87)

TOF_STD+MTX -1.08 (-3.30, 1.14) 0.66 (-3.07, 4.39)

ADA_STD+MTX -0.69 (-3.12, 1.75) 0.38 (-3.73, 4.49)

GOL_STD (SC)+MTX -0.01 (-1.85, 1.84) -0.03 (-3.23, 3.17)

GOL_STD (IV)+MTX 0.02 (-2.32, 2.35) -0.004 (-4.10, 4.09)

INF_STD+MTX -0.02 (-1.64, 1.60) 0.01 (-4.13, 4.14)

CERTO_STD+MTX -0.001 (-1.39, 1.39) 0.003 (-2.37, 2.37)

CT-P13+MTX -0.01 (-2.93, 2.91) 0.03 (-5.87, 5.93)

TOF_STD+MTX ABA_STD (IV)+MTX -1.08 (-3.82, 1.66) 0.72 (-4.04, 5.48)

ADA_STD+MTX -0.69 (-3.62, 2.24) 0.46 (-4.61, 5.53)

GOL_STD (SC)+MTX 0.03 (-2.41, 2.47) 0.05 (-4.32, 4.41)

GOL_STD (IV)+MTX 0.002 (-2.86, 2.87) 0.06 (-5.00, 5.12)

INF_STD+MTX 0.01 (-2.03, 2.04) 0.08 (-3.98, 4.15)

CERTO_STD+MTX 0.02 (-2.13, 2.16) 0.07 (-3.74, 3.88)

CT-P13+MTX -0.003 (-3.18, 3.17) 0.08 (-5.76, 5.92)

ADA_STD+MTX TOF_STD+MTX 0.41 (-1.91, 2.74) -0.27 (-4.24, 3.71)

GOL_STD (SC)+MTX 1.09 (-1.81, 3.99) -0.68 (-5.64, 4.28)

GOL_STD (IV)+MTX 1.09 (-2.13, 4.31) -0.69 (-6.23, 4.85)

INF_STD+MTX 1.05 (-1.69, 3.79) -0.67 (-6.23, 4.89)

519


SF-36 PCS Difference of MD (95% CI) -

Impute Missing SE

SF-35 MCS Difference

of MD (95% CI) -

Impute Missing SE

CERTO_STD+MTX 1.07 (-1.53, 3.66) -0.63 (-5.06, 3.79)

CT-P13+MTX 1.07 (-2.59, 4.73) -0.68 (-7.62, 6.26)

GOL_STD (SC)+MTX ADA_STD+MTX 0.67 (-2.38, 3.72) -0.42 (-5.64, 4.79)

GOL_STD (IV)+MTX 0.67 (-2.70, 4.04) -0.38 (-6.16, 5.41)

INF_STD+MTX 0.64 (-2.30, 3.59) -0.39 (-6.24, 5.47)

CERTO_STD+MTX 0.69 (-2.11, 3.49) -0.36 (-5.11, 4.40)

CT-P13+MTX 0.64 (-3.19, 4.46) -0.38 (-7.58, 6.82)

GOL_STD (IV)+MTX GOL_STD (SC)+MTX -0.02 (-2.95, 2.92) 0.03 (-5.19, 5.25)

INF_STD+MTX -0.02 (-2.48, 2.45) -0.01 (-5.25, 5.23)

CERTO_STD+MTX 0.004 (-2.27, 2.28) 0.03 (-3.96, 4.03)

CT-P13+MTX 0.004 (-3.45, 3.46) 0.04 (-6.66, 6.74)

INF_STD+MTX GOL_STD (IV)+MTX -0.01 (-2.86, 2.83) 0.03 (-5.78, 5.84)

CERTO_STD+MTX -0.02 (-2.74, 2.70) 0.01 (-4.71, 4.73)

CT-P13+MTX -0.02 (-3.76, 3.73) 0.02 (-7.17, 7.21)

CERTO_STD+MTX INF_STD+MTX 0.01 (-2.13, 2.15) -0.02 (-4.80, 4.76)

CT-P13+MTX 0.02 (-2.44, 2.47) -0.0001 (-4.16, 4.16)

CT-P13+MTX CERTO_STD+MTX -0.01 (-3.25, 3.24) 0.03 (-6.34, 6.40)

Difference in Mean Difference represents the comparison of the sensitivity analysis to the reference case. Each column presents the





ABA = abatacept; ADA = adalimumab; CERTO = certolizumab pegol; CI = confidence interval; CT-P13 = biosimilar of infliximab;

GOL= golimumab ; INF = infliximab; IV = intravenous; MTX = methotrexate; SC = subcutaneous; STD = standard dose;TOF =

tofacitinib

520

Table 53. WDAE Sensitivity Analysis Results Compared to the Reference Case (A Priori Table)


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies

Clearly Including IR

MTX Patients

csDMARD+MTX Placebo+MTX -0.03 (-1.23, 1.17) - - -0.02 (-1.18, 1.15) 0.45 (-1.05, 1.94)

SSZ+HCQ

0.10 (-1.37, 1.58) -0.06 (-1.65, 1.54) - 0.02 (-1.59, 1.63) -

MTX+SSZ+HCQ

-0.01 (-1.48, 1.47) 0.01 (-1.58, 1.60) - -0.01 (-1.62, 1.60) -

ETN_STD

0.01 (-0.58, 0.60) -0.03 (-0.65, 0.59) - 0.05 (-0.59, 0.70) 0.94 (-0.42, 2.30)

ETN_STD+MTX

-0.04 (-0.60, 0.53) 0.05 (-0.53, 0.62) - 0.02 (-0.58, 0.62) 0.46 (-0.73, 1.64)

ABA_STD

(IV)+MTX

-0.01 (-0.74, 0.71) 0.12 (-0.69, 0.93) 0.10 (-1.02, 1.22) 0.03 (-0.72, 0.77) -0.001 (-0.75, 0.74)

ADA_STD+MTX

0.05 (-0.69, 0.79) - -0.03 (-0.82, 0.75) 0.41 (-0.38, 1.20) 0.01 (-0.78, 0.79)

TOF_STD+MTX

0.04 (-0.65, 0.72) - -0.01 (-0.71, 0.70) 0.41 (-0.30, 1.12) 0.02 (-0.68, 0.72)

TOC_4 (IV)

-0.15 (-1.46, 1.16) 0.08 (-1.31, 1.47) - -0.01 (-1.35, 1.34) -0.05 (-1.40, 1.30)

TOC_8 (IV)

-0.07 (-1.05, 0.91) 0.20 (-1.00, 1.40) -0.37 (-1.93, 1.18) 0.002 (-1.11, 1.12) 0.001 (-1.10, 1.10)

TOC_4 (IV)+MTX

-0.08 (-1.44, 1.28) 0.10 (-1.28, 1.47) - 0.02 (-1.31, 1.35) -0.04 (-1.38, 1.30)

521


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

TOC_8 (IV)+MTX

-0.09 (-1.20, 1.02) 0.07 (-1.17, 1.30) -0.41 (-2.16, 1.33) -0.03 (-1.21, 1.15) -0.04 (-1.19, 1.11)

GOL_STD

(SC)+MTX

0.19 (-1.02, 1.40) - 0.01 (-1.11, 1.14) -0.09 (-1.19, 1.01) 0.01 (-1.11, 1.12)

INF_STD+MTX

0.01 (-0.67, 0.69) -0.33 (-1.10, 0.45) 0.84 (-0.27, 1.95) -0.10 (-0.86, 0.67) 0.01 (-0.73, 0.76)

INF_STD

-0.33 (-3.58, 2.92) -0.02 (-3.64, 3.60) - 0.01 (-3.67, 3.69) 0.17 (-3.63, 3.97)

CERTO_STD

+MTX

-0.01 (-1.01, 0.99) - -0.01 (-0.95, 0.93) 0.50 (-0.41, 1.42) 0.02 (-0.92, 0.97)

RIT_STD

-0.77 (-3.42, 1.89) -0.01 (-3.08, 3.06) - -0.16 (-3.14, 2.82) 0.04 (-3.17, 3.24)

RIT_STD+MTX

-0.93 (-4.19, 2.33) -0.02 (-3.58, 3.54) - -0.07 (-3.55, 3.41) 0.14 (-3.53, 3.80)

BAR_4+MTX

-0.02 (-2.30, 2.26) - -0.11 (-2.32, 2.10) -1.03 (-5.20, 3.14) 0.01 (-2.14, 2.16)

HD203+MTX

-0.01 (-1.12, 1.10) - - 0.04 (-1.17, 1.25) 0.40 (-1.13, 1.93)

SB4+MTX

-0.02 (-1.01, 0.98) - - 0.03 (-1.05, 1.10) 0.44 (-1.00, 1.88)

CT-P13+MTX

0.001 (-0.89, 0.90) - 0.85 (-0.41, 2.10) -0.09 (-1.07, 0.89) 0.002 (-0.94, 0.94)

SB2+MTX

0.03 (-1.09, 1.15) - 0.86 (-0.59, 2.31) -0.11 (-1.33, 1.11) -0.01 (-1.17, 1.16)

SB5+MTX

-0.19 (-2.36, 1.98) - -0.08 (-2.15, 1.99) 0.35 (-1.67, 2.36) -0.08 (-2.10, 1.93)

522


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

ABP501+MTX

0.17 (-1.62, 1.97) - -0.02 (-1.80, 1.76) 0.46 (-1.36, 2.27) -0.003 (-1.78, 1.78)

SSZ+HCQ csDMARD

+MTX 0.08 (-1.83, 1.99) - - 0.03 (-1.96, 2.02) -

MTX+SSZ+HCQ

-0.03 (-1.86, 1.81) - - 0.003 (-1.96, 1.97) -

ETN_STD

0.05 (-1.06, 1.17) - - 0.07 (-1.09, 1.23) 0.46 (-0.77, 1.69)

ETN_STD+MTX

0.01 (-0.99, 1.01) - - 0.04 (-0.97, 1.05) -0.01 (-1.00, 0.98)

ABA_STD

(IV)+MTX

-0.04 (-1.44, 1.36) - - 0.03 (-1.34, 1.41) -0.47 (-2.17, 1.22)

ADA_STD+MTX

0.07 (-1.35, 1.50) - - 0.43 (-0.99, 1.86) -0.42 (-2.15, 1.31)

TOF_STD+MTX

0.05 (-1.37, 1.46) - - 0.43 (-0.95, 1.80) -0.43 (-2.10, 1.24)

TOC_4 (IV)

-0.13 (-1.89, 1.63) - - -0.003 (-1.81, 1.81) -0.48 (-2.52, 1.57)

TOC_8 (IV)

-0.08 (-1.63, 1.47) - - 0.01 (-1.62, 1.64) -0.43 (-2.31, 1.45)

TOC_4 (IV)+MTX

-0.06 (-1.82, 1.71) - - 0.05 (-1.75, 1.86) -0.45 (-2.51, 1.61)

TOC_8 (IV)+MTX

-0.06 (-1.66, 1.55) - - -0.01 (-1.68, 1.65) -0.47 (-2.41, 1.46)

GOL_STD

(SC)+MTX

0.30 (-1.36, 1.97) - - -0.04 (-1.61, 1.54) -0.43 (-2.30, 1.45)

523


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

INF_STD+MTX

0.01 (-1.37, 1.38) - - -0.09 (-1.45, 1.28) -0.46 (-2.11, 1.19)

INF_STD

-0.26 (-3.52, 3.00) - - 0.02 (-3.79, 3.84) -0.33 (-4.40, 3.73)

CERTO_STD

+MTX

0.02 (-1.53, 1.56) - - 0.53 (-0.97, 2.02) -0.40 (-2.19, 1.38)

RIT_STD

-0.83 (-3.75, 2.08) - - -0.12 (-3.30, 3.06) -0.34 (-3.83, 3.14)

RIT_STD+MTX

-0.99 (-4.36, 2.37) - - -0.02 (-3.61, 3.57) -0.35 (-4.18, 3.47)

BAR_4+MTX

0.09 (-2.45, 2.63) - - -1.08 (-5.40, 3.25) -0.42 (-3.08, 2.24)

HD203+MTX

-0.01 (-1.39, 1.38) - - 0.06 (-1.38, 1.51) -0.03 (-1.42, 1.37)

SB4+MTX

-0.01 (-1.33, 1.30) - - 0.05 (-1.30, 1.39) -0.01 (-1.32, 1.29)

CT-P13+MTX

0.01 (-1.46, 1.48) - - -0.07 (-1.58, 1.44) -0.45 (-2.20, 1.30)

SB2+MTX

0.03 (-1.63, 1.70) - - -0.09 (-1.77, 1.59) -0.46 (-2.33, 1.41)

SB5+MTX

-0.20 (-2.90, 2.49) - - 0.39 (-1.95, 2.72) -0.53 (-3.07, 2.01)

ABP501+MTX

0.13 (-1.96, 2.22) - - 0.49 (-1.66, 2.64) -0.40 (-2.74, 1.94)

MTX+SSZ+HCQ SSZ+HCQ -0.15 (-1.90, 1.59) 0.02 (-1.85, 1.89) - -0.06 (-1.94, 1.82) -

524


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

ETN_STD

-0.12 (-1.72, 1.49) 0.04 (-1.65, 1.72) - 0.04 (-1.67, 1.75) -

ETN_STD+MTX

-0.17 (-1.77, 1.42) 0.12 (-1.60, 1.83) - 0.02 (-1.69, 1.73) -

ABA_STD

(IV)+MTX

-0.11 (-1.76, 1.53) 0.17 (-1.58, 1.93) - -0.002 (-1.77, 1.77) -

ADA_STD+MTX

-0.08 (-1.71, 1.56) - - 0.37 (-1.38, 2.13) -

TOF_STD+MTX

-0.06 (-1.66, 1.53) - - 0.39 (-1.35, 2.13) -

TOC_4 (IV)

-0.34 (-2.30, 1.62) 0.12 (-1.99, 2.24) - -0.05 (-2.21, 2.11) -

TOC_8 (IV)

-0.20 (-2.03, 1.62) 0.25 (-1.76, 2.26) - -0.04 (-2.07, 2.00) -

TOC_4 (IV)+MTX

-0.31 (-2.30, 1.69) 0.12 (-1.99, 2.23) - -0.02 (-2.17, 2.13) -

TOC_8 (IV)+MTX

-0.23 (-2.10, 1.65) 0.12 (-1.92, 2.16) - -0.09 (-2.15, 1.98) -

GOL_STD

(SC)+MTX

0.08 (-1.74, 1.90) - - -0.13 (-2.06, 1.81) -

INF_STD+MTX

-0.09 (-1.72, 1.54) -0.27 (-2.04, 1.49) - -0.11 (-1.85, 1.63) -

INF_STD

-0.37 (-3.85, 3.11) 0.04 (-3.90, 3.98) - -0.05 (-4.06, 3.96) -

CERTO_STD

+MTX

-0.10 (-1.87, 1.67) - - 0.47 (-1.36, 2.29) -

525


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

RIT_STD

-0.97 (-3.91, 1.97) 0.09 (-3.36, 3.54) - -0.18 (-3.55, 3.20) -

RIT_STD+MTX

-1.05 (-4.57, 2.47) 0.04 (-3.79, 3.86) - -0.08 (-3.86, 3.69) -

BAR_4+MTX

-0.21 (-2.95, 2.52) - - -1.18 (-5.73, 3.38) -

HD203+MTX

-0.12 (-1.97, 1.72) - - 0.01 (-1.99, 2.01) -

SB4+MTX

-0.18 (-1.96, 1.61) - - -0.02 (-1.95, 1.92) -

CT-P13+MTX

-0.10 (-1.85, 1.64) - - -0.12 (-1.97, 1.73) -

SB2+MTX

-0.07 (-1.93, 1.78) - - -0.14 (-2.15, 1.88) -

SB5+MTX

-0.29 (-2.86, 2.28) - - 0.33 (-2.26, 2.92) -

ABP501+MTX

-0.04 (-2.38, 2.30) - - 0.42 (-1.98, 2.81) -

ETN_STD MTX+SSZ

+HCQ 0.01 (-1.58, 1.59) -0.04 (-1.74, 1.66) - 0.06 (-1.68, 1.79) -

ETN_STD+MTX

-0.03 (-1.61, 1.55) 0.03 (-1.63, 1.70) - 0.03 (-1.67, 1.72) -

ABA_STD

(IV)+MTX

0.003 (-1.68, 1.68) 0.12 (-1.65, 1.89) - 0.04 (-1.73, 1.81) -

ADA_STD+MTX

0.10 (-1.56, 1.76) - - 0.45 (-1.36, 2.26) -

526


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

TOF_STD+MTX

0.11 (-1.53, 1.74) - - 0.42 (-1.35, 2.19) -

TOC_4 (IV)

-0.18 (-2.21, 1.86) 0.07 (-2.02, 2.16) - -0.02 (-2.14, 2.10) -

TOC_8 (IV)

0.02 (-1.78, 1.81) 0.17 (-1.82, 2.16) - -0.01 (-1.99, 1.97) -

TOC_4 (IV)+MTX

0.01 (-1.98, 2.00) 0.08 (-2.01, 2.18) - 0.03 (-2.07, 2.12) -

TOC_8 (IV)+MTX

-0.08 (-1.98, 1.83) 0.05 (-1.96, 2.06) - -0.02 (-2.05, 2.01) -

GOL_STD

(SC)+MTX

0.23 (-1.57, 2.04) - - -0.04 (-1.94, 1.86) -

INF_STD+MTX

0.02 (-1.57, 1.61) -0.33 (-2.09, 1.43) - -0.10 (-1.87, 1.67) -

INF_STD

-0.38 (-3.90, 3.13) -0.02 (-3.97, 3.92) - 0.01 (-3.99, 4.00) -

CERTO_STD

+MTX

0.07 (-1.69, 1.83) - - 0.53 (-1.32, 2.38) -

RIT_STD

-0.73 (-3.68, 2.23) 0.01 (-3.41, 3.42) - -0.10 (-3.45, 3.25) -

RIT_STD+MTX

-0.86 (-4.38, 2.65) -0.02 (-3.82, 3.77) - -0.06 (-3.85, 3.73) -

BAR_4+MTX

0.11 (-2.64, 2.86) - - -1.09 (-5.63, 3.45) -

HD203+MTX

-0.03 (-1.83, 1.77) - - 0.04 (-1.94, 2.03) -

527


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

SB4+MTX

-0.02 (-1.81, 1.77) - - 0.05 (-1.87, 1.96) -

CT-P13+MTX

0.01 (-1.70, 1.73) - - -0.10 (-1.98, 1.78) -

SB2+MTX

0.05 (-1.79, 1.90) - - -0.13 (-2.17, 1.91) -

SB5+MTX

-0.08 (-2.76, 2.60) - - 0.42 (-2.17, 3.01) -

ABP501+MTX

0.15 (-2.09, 2.40) - - 0.49 (-1.94, 2.91) -

ETN_STD+MTX ETN_STD -0.06 (-0.59, 0.48) 0.08 (-0.46, 0.63) - -0.04 (-0.59, 0.52) -0.46 (-1.20, 0.27)

ABA_STD

(IV)+MTX

-0.03 (-0.96, 0.90) 0.15 (-0.87, 1.17) - -0.02 (-1.00, 0.96) -0.95 (-2.51, 0.62)

ADA_STD+MTX

0.04 (-0.92, 0.99) - - 0.37 (-0.65, 1.40) -0.89 (-2.50, 0.72)

TOF_STD+MTX

0.05 (-0.89, 0.98) - - 0.36 (-0.61, 1.32) -0.91 (-2.45, 0.64)

TOC_4 (IV)

-0.19 (-1.66, 1.28) 0.10 (-1.42, 1.63) - -0.07 (-1.56, 1.42) -0.96 (-2.89, 0.97)

TOC_8 (IV)

-0.08 (-1.25, 1.09) 0.22 (-1.14, 1.57) - -0.07 (-1.36, 1.22) -0.88 (-2.64, 0.88)

TOC_4 (IV)+MTX

-0.08 (-1.59, 1.43) 0.13 (-1.38, 1.65) - -0.03 (-1.51, 1.45) -0.93 (-2.87, 1.01)

TOC_8 (IV)+MTX

-0.09 (-1.37, 1.20) 0.09 (-1.29, 1.47) - -0.09 (-1.44, 1.25) -0.92 (-2.74, 0.89)

528


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

GOL_STD

(SC)+MTX

0.20 (-1.08, 1.48) - - -0.14 (-1.40, 1.13) -0.91 (-2.65, 0.82)

INF_STD+MTX -0.01 (-0.89, 0.86) -0.29 (-1.26, 0.69) - -0.14 (-1.13, 0.85) -0.92 (-2.43, 0.60)

INF_STD -0.34 (-3.56, 2.87) 0.01 (-3.68, 3.70) - -0.04 (-3.77, 3.69) -0.79 (-4.86, 3.27)

CERTO_STD

+MTX -0.004 (-1.12, 1.11) - - 0.46 (-0.67, 1.59) -0.90 (-2.59, 0.79)

RIT_STD -0.80 (-3.49, 1.88) 0.03 (-3.11, 3.16) - -0.22 (-3.25, 2.81) -0.80 (-4.21, 2.60)

RIT_STD+MTX -0.92 (-4.17, 2.33) 0.02 (-3.61, 3.65) - -0.09 (-3.66, 3.47) -0.84 (-4.66, 2.97)

BAR_4+MTX 0.01 (-2.39, 2.41) - - -1.11 (-5.32, 3.11) -0.88 (-3.43, 1.68)

HD203+MTX -0.04 (-1.11, 1.04) - - -0.02 (-1.20, 1.16) -0.50 (-1.74, 0.73)

SB4+MTX -0.03 (-1.02, 0.96) - - -0.02 (-1.07, 1.02) -0.47 (-1.59, 0.65)

CT-P13+MTX -0.003 (-1.02, 1.02) - - -0.13 (-1.29, 1.03) -0.91 (-2.54, 0.71)

SB2+MTX 0.05 (-1.22, 1.33) - - -0.16 (-1.55, 1.22) -0.91 (-2.68, 0.85)

SB5+MTX -0.20 (-2.53, 2.13) - - 0.30 (-1.80, 2.40) -1.02 (-3.47, 1.43)

ABP501+MTX 0.14 (-1.69, 1.96) - - 0.40 (-1.53, 2.34) -0.92 (-3.18, 1.33)

529


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

ABA_STD

(IV)+MTX

ETN_STD

+MTX -0.004 (-0.93, 0.93) 0.06 (-0.93, 1.05) - -0.005 (-0.95, 0.94) -0.47 (-1.89, 0.96)

ADA_STD+MTX 0.07 (-0.86, 1.00) - - 0.40 (-0.59, 1.39) -0.41 (-1.85, 1.04)

TOF_STD+MTX 0.09 (-0.83, 1.01) - - 0.39 (-0.54, 1.32) -0.39 (-1.78, 0.99)

TOC_4 (IV) -0.13 (-1.56, 1.30) 0.02 (-1.47, 1.52) - -0.03 (-1.50, 1.43) -0.49 (-2.29, 1.31)

TOC_8 (IV) -0.07 (-1.21, 1.07) 0.13 (-1.19, 1.45) - -0.04 (-1.30, 1.22) -0.43 (-2.07, 1.21)

TOC_4 (IV)+MTX -0.04 (-1.49, 1.42) 0.05 (-1.43, 1.53) - -0.01 (-1.46, 1.45) -0.46 (-2.26, 1.34)

TOC_8 (IV)+MTX -0.07 (-1.30, 1.16) 0.01 (-1.34, 1.35) - -0.06 (-1.38, 1.26) -0.45 (-2.15, 1.24)

GOL_STD

(SC)+MTX 0.22 (-1.09, 1.54) - - -0.11 (-1.35, 1.13) -0.43 (-2.04, 1.19)

INF_STD+MTX 0.04 (-0.83, 0.92) -0.37 (-1.33, 0.59) - -0.12 (-1.09, 0.86) -0.45 (-1.83, 0.93)

INF_STD -0.33 (-3.55, 2.89) -0.09 (-3.79, 3.60) - -0.02 (-3.77, 3.72) -0.31 (-4.32, 3.70)

CERTO_STD

+MTX 0.03 (-1.08, 1.14) - - 0.49 (-0.61, 1.58) -0.40 (-1.95, 1.14)

RIT_STD -0.74 (-3.43, 1.94) -0.06 (-3.19, 3.07) - -0.18 (-3.20, 2.85) -0.33 (-3.69, 3.03)

RIT_STD+MTX -0.87 (-4.10, 2.35) -0.07 (-3.65, 3.50) - -0.05 (-3.58, 3.47) -0.34 (-4.09, 3.41)

530


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

BAR_4+MTX 0.07 (-2.31, 2.44) - - -1.06 (-5.26, 3.14) -0.40 (-2.86, 2.06)

HD203+MTX 0.01 (-0.95, 0.96) - - 0.001 (-1.05, 1.05) -0.02 (-1.03, 0.98)

SB4+MTX 0.004 (-0.82, 0.83) - - 0.02 (-0.87, 0.90) -0.002 (-0.84, 0.84)

CT-P13+MTX 0.04 (-0.97, 1.06) - - -0.10 (-1.25, 1.04) -0.44 (-1.92, 1.03)

SB2+MTX 0.05 (-1.23, 1.33) - - -0.14 (-1.51, 1.23) -0.45 (-2.09, 1.19)

SB5+MTX -0.18 (-2.47, 2.12) - - 0.33 (-1.77, 2.43) -0.53 (-2.91, 1.85)

ABP501+MTX 0.17 (-1.64, 1.97) - - 0.43 (-1.49, 2.35) -0.43 (-2.59, 1.73)

ADA_STD+MTX ABA_STD

(IV)+MTX 0.12 (-0.93, 1.17) - -0.11 (-1.48, 1.26) 0.38 (-0.72, 1.49) 0.02 (-1.07, 1.10)

TOF_STD+MTX 0.06 (-0.93, 1.06) - -0.11 (-1.43, 1.21) 0.38 (-0.67, 1.43) 0.004 (-1.03, 1.04)

TOC_4 (IV) -0.15 (-1.65, 1.35) -0.04 (-1.63, 1.55) - -0.05 (-1.57, 1.46) -0.05 (-1.59, 1.49)

TOC_8 (IV) -0.09 (-1.38, 1.20) 0.07 (-1.39, 1.53) -0.50 (-2.40, 1.40) -0.05 (-1.38, 1.28) -0.003 (-1.35, 1.34)

TOC_4 (IV)+MTX -0.07 (-1.53, 1.40) -0.03 (-1.61, 1.56) - -0.03 (-1.54, 1.49) -0.04 (-1.57, 1.50)

TOC_8 (IV)+MTX -0.10 (-1.47, 1.27) -0.06 (-1.54, 1.42) -0.51 (-2.55, 1.53) -0.08 (-1.48, 1.32) -0.04 (-1.42, 1.35)

531


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

GOL_STD

(SC)+MTX 0.19 (-1.25, 1.64) - -0.10 (-1.64, 1.44) -0.11 (-1.43, 1.22) 0.02 (-1.31, 1.35)

INF_STD+MTX -0.003 (-0.93, 0.92) -0.43 (-1.48, 0.62) 0.75 (-0.45, 1.96) -0.11 (-1.02, 0.79) 0.01 (-0.95, 0.98)

INF_STD -0.30 (-3.62, 3.02) -0.14 (-3.89, 3.61) - -0.01 (-3.76, 3.75) 0.19 (-3.68, 4.06)

CERTO_STD

+MTX -0.005 (-1.25, 1.24) - -0.10 (-1.58, 1.37) 0.47 (-0.72, 1.66) 0.03 (-1.18, 1.24)

RIT_STD -0.85 (-3.49, 1.79) -0.11 (-3.22, 3.01) - -0.20 (-3.21, 2.81) 0.04 (-3.23, 3.32)

RIT_STD+MTX -0.98 (-4.25, 2.28) -0.12 (-3.74, 3.49) - -0.10 (-3.61, 3.40) 0.16 (-3.58, 3.89)

BAR_4+MTX -0.06 (-2.52, 2.41) - -0.20 (-2.69, 2.28) -1.07 (-5.28, 3.15) 0.01 (-2.28, 2.29)

HD203+MTX -0.02 (-1.40, 1.37) - - 0.01 (-1.40, 1.43) 0.42 (-1.31, 2.14)

SB4+MTX -0.01 (-1.29, 1.27) - - 0.002 (-1.29, 1.30) 0.45 (-1.20, 2.11)

CT-P13+MTX -0.01 (-1.12, 1.11) - 0.76 (-0.56, 2.09) -0.11 (-1.20, 0.99) 0.01 (-1.11, 1.13)

SB2+MTX 0.06 (-1.17, 1.30) - 0.78 (-0.74, 2.29) -0.13 (-1.45, 1.19) 0.01 (-1.31, 1.33)

SB5+MTX -0.24 (-2.56, 2.08) - -0.17 (-2.53, 2.19) 0.32 (-1.81, 2.45) -0.08 (-2.23, 2.08)

ABP501+MTX 0.10 (-1.82, 2.03) - -0.12 (-2.19, 1.95) 0.43 (-1.50, 2.36) 0.01 (-1.92, 1.93)

532


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

TOF_STD+MTX ADA_STD

+MTX -0.02 (-0.82, 0.78) - 0.003 (-0.80, 0.81) -0.01 (-0.78, 0.75) -0.02 (-0.81, 0.78)

TOC_4 (IV) -0.23 (-1.76, 1.31) - - -0.42 (-1.99, 1.15) -0.05 (-1.62, 1.51)

TOC_8 (IV) -0.13 (-1.39, 1.12) - -0.34 (-2.10, 1.41) -0.42 (-1.80, 0.95) -0.01 (-1.35, 1.33)

TOC_4 (IV)+MTX -0.10 (-1.64, 1.45) - - -0.41 (-1.94, 1.13) -0.05 (-1.60, 1.51)

TOC_8 (IV)+MTX -0.17 (-1.53, 1.19) - -0.39 (-2.30, 1.53) -0.45 (-1.86, 0.97) -0.04 (-1.43, 1.36)

GOL_STD

(SC)+MTX 0.18 (-1.19, 1.55) - 0.04 (-1.33, 1.41) -0.48 (-1.83, 0.87) 0.01 (-1.34, 1.36)

INF_STD+MTX -0.11 (-1.16, 0.93) - 0.86 (-0.52, 2.24) -0.50 (-1.62, 0.61) -0.02 (-1.11, 1.07)

INF_STD -0.28 (-3.65, 3.08) - - -0.41 (-4.19, 3.36) 0.15 (-3.79, 4.10)

CERTO_STD

+MTX -0.10 (-1.01, 0.81) - 0.01 (-0.90, 0.92) 0.09 (-0.71, 0.88) 0.01 (-0.89, 0.92)

RIT_STD -0.90 (-3.54, 1.74) - - -0.56 (-3.59, 2.47) 0.02 (-3.24, 3.29)

RIT_STD+MTX -1.00 (-4.24, 2.24) - - -0.46 (-4.01, 3.09) 0.08 (-3.64, 3.81)

BAR_4+MTX -0.01 (-2.44, 2.43) - -0.11 (-2.47, 2.25) -1.52 (-5.75, 2.72) -0.04 (-2.32, 2.24)

HD203+MTX -0.07 (-1.38, 1.23) - - -0.38 (-1.82, 1.07) 0.39 (-1.36, 2.14)

533


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

SB4+MTX -0.11 (-1.37, 1.14) - - -0.40 (-1.74, 0.94) 0.41 (-1.27, 2.10)

CT-P13+MTX -0.08 (-1.26, 1.09) - 0.88 (-0.62, 2.37) -0.49 (-1.76, 0.78) -0.02 (-1.25, 1.21)

SB2+MTX -0.05 (-1.44, 1.35) - 0.88 (-0.77, 2.54) -0.53 (-1.98, 0.93) -0.03 (-1.43, 1.38)

SB5+MTX -0.23 (-2.25, 1.79) - -0.04 (-1.92, 1.85) -0.06 (-1.90, 1.79) -0.08 (-1.92, 1.76)

ABP501+MTX 0.09 (-1.49, 1.66) - 0.01 (-1.57, 1.59) 0.05 (-1.57, 1.68) 0.002 (-1.58, 1.58)

TOC_4 (IV) TOF_STD

+MTX -0.19 (-1.63, 1.25) - - -0.41 (-1.92, 1.10) -0.05 (-1.56, 1.46)

TOC_8 (IV) -0.10 (-1.36, 1.17) - -0.38 (-2.09, 1.34) -0.42 (-1.74, 0.90) -0.01 (-1.29, 1.28)

TOC_4 (IV)+MTX -0.11 (-1.56, 1.35) - - -0.40 (-1.89, 1.10) -0.05 (-1.56, 1.46)

TOC_8 (IV)+MTX -0.11 (-1.44, 1.22) - -0.41 (-2.30, 1.47) -0.44 (-1.80, 0.92) -0.05 (-1.38, 1.29)

GOL_STD

(SC)+MTX 0.20 (-1.13, 1.52) - 0.03 (-1.30, 1.36) -0.48 (-1.79, 0.83) 0.02 (-1.30, 1.33)

INF_STD+MTX -0.08 (-1.01, 0.84) - 0.86 (-0.47, 2.18) -0.50 (-1.53, 0.53) -0.02 (-1.03, 1.00)

INF_STD -0.37 (-3.71, 2.97) - - -0.40 (-4.17, 3.36) 0.16 (-3.73, 4.05)

CERTO_STD

+MTX -0.08 (-1.21, 1.04) - -0.001 (-1.08, 1.08) 0.10 (-0.89, 1.09) 0.02 (-1.04, 1.08)

534


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

RIT_STD -0.89 (-3.58, 1.80) - - -0.58 (-3.63, 2.46) 0.01 (-3.25, 3.27)

RIT_STD+MTX -0.99 (-4.27, 2.29) - - -0.46 (-3.99, 3.07) 0.09 (-3.63, 3.81)

BAR_4+MTX -0.01 (-2.39, 2.37) - -0.12 (-2.41, 2.18) -1.46 (-5.65, 2.73) -0.04 (-2.29, 2.21)

HD203+MTX -0.08 (-1.38, 1.22) - - -0.37 (-1.79, 1.04) 0.39 (-1.31, 2.08)

SB4+MTX -0.09 (-1.32, 1.14) - - -0.39 (-1.69, 0.90) 0.40 (-1.23, 2.04)

CT-P13+MTX -0.04 (-1.16, 1.07) - 0.86 (-0.58, 2.30) -0.50 (-1.70, 0.71) -0.01 (-1.18, 1.15)

SB2+MTX -0.04 (-1.33, 1.24) - 0.87 (-0.76, 2.49) -0.53 (-1.93, 0.87) -0.03 (-1.38, 1.33)

SB5+MTX -0.17 (-2.38, 2.04) - -0.05 (-2.14, 2.05) -0.05 (-2.08, 1.97) -0.08 (-2.11, 1.96)

ABP501+MTX 0.13 (-1.64, 1.91) - 0.002 (-1.76, 1.77) 0.05 (-1.75, 1.85) 0.0002 (-1.77, 1.77)

TOC_8 (IV) TOC_4 (IV) 0.07 (-1.13, 1.27) 0.10 (-1.15, 1.36) - -0.001 (-1.24, 1.24) 0.04 (-1.17, 1.25)

TOC_4 (IV)+MTX 0.01 (-1.28, 1.30) 0.005 (-1.34, 1.35) - 0.01 (-1.35, 1.38) -0.001 (-1.34, 1.34)

TOC_8 (IV)+MTX 0.06 (-1.14, 1.27) 0.01 (-1.24, 1.27) - 0.01 (-1.24, 1.27) 0.04 (-1.18, 1.26)

GOL_STD

(SC)+MTX 0.51 (-1.41, 2.43) - - -0.06 (-1.80, 1.68) 0.06 (-1.71, 1.83)

535


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

INF_STD+MTX 0.26 (-1.26, 1.79) -0.39 (-1.99, 1.20) - -0.07 (-1.62, 1.48) 0.05 (-1.50, 1.60)

INF_STD -0.35 (-3.70, 2.99) -0.09 (-3.93, 3.75) - 0.02 (-3.90, 3.94) 0.23 (-3.80, 4.25)

CERTO_STD

+MTX 0.14 (-1.48, 1.75) - - 0.51 (-1.12, 2.15) 0.07 (-1.58, 1.72)

RIT_STD -0.59 (-3.67, 2.50) -0.10 (-3.52, 3.32) - -0.14 (-3.41, 3.13) 0.06 (-3.44, 3.56)

RIT_STD+MTX -0.90 (-4.39, 2.60) -0.05 (-3.82, 3.73) - -0.02 (-3.76, 3.71) 0.21 (-3.66, 4.09)

BAR_4+MTX 0.09 (-2.46, 2.65) - - -1.02 (-5.32, 3.29) 0.05 (-2.47, 2.57)

HD203+MTX 0.11 (-1.58, 1.81) - - 0.04 (-1.77, 1.85) 0.45 (-1.59, 2.49)

SB4+MTX 0.14 (-1.46, 1.74) - - 0.03 (-1.68, 1.73) 0.48 (-1.50, 2.47)

CT-P13+MTX 0.25 (-1.36, 1.86) - - -0.06 (-1.73, 1.60) 0.05 (-1.60, 1.71)

SB2+MTX 0.27 (-1.50, 2.05) - - -0.10 (-1.93, 1.72) 0.06 (-1.73, 1.85)

SB5+MTX 0.01 (-2.68, 2.70) - - 0.40 (-2.03, 2.84) -0.02 (-2.48, 2.43)

ABP501+MTX 0.30 (-2.01, 2.62) - - 0.46 (-1.79, 2.71) 0.06 (-2.13, 2.25)

TOC_4 (IV)+MTX TOC_8 (IV) -0.01 (-1.22, 1.20) -0.10 (-1.38, 1.18) - 0.02 (-1.23, 1.27) -0.04 (-1.27, 1.20)

536


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

TOC_8 (IV)+MTX -0.004 (-0.86, 0.85) -0.11 (-1.11, 0.89) -0.01 (-0.98, 0.95) -0.01 (-0.87, 0.85) -0.02 (-0.87, 0.83)

GOL_STD

(SC)+MTX 0.32 (-1.38, 2.03) - 0.39 (-1.54, 2.32) -0.07 (-1.69, 1.54) -0.02 (-1.60, 1.56)

INF_STD+MTX 0.10 (-1.10, 1.31) -0.50 (-1.94, 0.93) 1.24 (-0.67, 3.14) -0.09 (-1.44, 1.26) 0.02 (-1.32, 1.35)

INF_STD -0.36 (-3.64, 2.92) -0.20 (-4.01, 3.62) - 0.04 (-3.84, 3.93) 0.16 (-3.82, 4.14)

CERTO_STD

+MTX 0.03 (-1.34, 1.41) - 0.39 (-1.44, 2.21) 0.51 (-0.93, 1.96) 0.03 (-1.40, 1.45)

RIT_STD -0.65 (-3.51, 2.22) -0.19 (-3.49, 3.10) - -0.13 (-3.31, 3.06) 0.04 (-3.33, 3.40)

RIT_STD+MTX -0.92 (-4.37, 2.53) -0.17 (-3.90, 3.56) - -0.01 (-3.62, 3.60) 0.17 (-3.67, 4.01)

BAR_4+MTX 0.05 (-2.36, 2.45) - 0.30 (-2.38, 2.98) -1.03 (-5.35, 3.29) -0.01 (-2.40, 2.38)

HD203+MTX 0.08 (-1.44, 1.61) - - 0.06 (-1.61, 1.72) 0.38 (-1.54, 2.30)

SB4+MTX 0.04 (-1.34, 1.42) - - 0.05 (-1.51, 1.61) 0.43 (-1.40, 2.26)

CT-P13+MTX 0.07 (-1.29, 1.44) - 1.23 (-0.76, 3.22) -0.08 (-1.54, 1.39) 0.004 (-1.44, 1.45)

SB2+MTX 0.11 (-1.40, 1.63) - 1.24 (-0.88, 3.35) -0.13 (-1.79, 1.54) 0.002 (-1.60, 1.60)

SB5+MTX -0.08 (-2.57, 2.41) - 0.32 (-2.32, 2.96) 0.39 (-1.95, 2.74) -0.06 (-2.42, 2.30)

537


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

ABP501+MTX 0.24 (-1.85, 2.33) - 0.39 (-1.99, 2.77) 0.49 (-1.62, 2.61) 0.00 (-2.05, 2.05)


(IV)+MTX -0.01 (-1.20, 1.18) 0.004 (-1.26, 1.27) - -0.03 (-1.29, 1.23) 0.02 (-1.22, 1.25)

GOL_STD

(SC)+MTX 0.28 (-1.68, 2.24) - - -0.11 (-1.85, 1.62) 0.03 (-1.72, 1.79)

INF_STD+MTX 0.06 (-1.46, 1.59) -0.40 (-1.97, 1.18) - -0.10 (-1.64, 1.44) 0.05 (-1.49, 1.60)

INF_STD -0.39 (-3.74, 2.96) -0.09 (-3.91, 3.73) - 0.01 (-3.87, 3.90) 0.21 (-3.79, 4.21)

CERTO_STD

+MTX 0.002 (-1.65, 1.65) - - 0.51 (-1.09, 2.12) 0.07 (-1.56, 1.71)

RIT_STD -0.55 (-3.62, 2.52) -0.05 (-3.50, 3.40) - -0.16 (-3.49, 3.16) 0.10 (-3.42, 3.62)

RIT_STD+MTX -0.85 (-4.40, 2.69) -0.11 (-3.92, 3.70) - -0.06 (-3.78, 3.66) 0.21 (-3.69, 4.11)

BAR_4+MTX 0.13 (-2.39, 2.66) - - -1.01 (-5.29, 3.27) 0.08 (-2.44, 2.60)

HD203+MTX 0.10 (-1.62, 1.83) - - 0.04 (-1.76, 1.83) 0.45 (-1.61, 2.52)

SB4+MTX 0.05 (-1.56, 1.66) - - 0.002 (-1.69, 1.70) 0.47 (-1.49, 2.44)

CT-P13+MTX 0.05 (-1.58, 1.68) - - -0.09 (-1.75, 1.57) 0.05 (-1.61, 1.70)

SB2+MTX 0.12 (-1.61, 1.85) - - -0.12 (-1.91, 1.68) 0.05 (-1.73, 1.83)

538


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

SB5+MTX -0.20 (-2.87, 2.47) - - 0.37 (-2.08, 2.81) -0.04 (-2.50, 2.42)

ABP501+MTX 0.22 (-2.10, 2.53) - - 0.44 (-1.81, 2.68) 0.04 (-2.17, 2.24)

GOL_STD

(SC)+MTX

TOC_8

(IV)+MTX 0.37 (-1.35, 2.09) - 0.40 (-1.69, 2.49) -0.06 (-1.72, 1.59) 0.03 (-1.58, 1.64)

INF_STD+MTX 0.16 (-1.16, 1.48) -0.37 (-1.83, 1.08) 1.26 (-0.79, 3.32) -0.06 (-1.48, 1.35) 0.05 (-1.33, 1.43)

INF_STD -0.41 (-3.65, 2.83) -0.07 (-3.83, 3.69) - 0.03 (-3.80, 3.86) 0.20 (-3.76, 4.16)

CERTO_STD

+MTX 0.04 (-1.42, 1.50) - 0.42 (-1.58, 2.41) 0.54 (-0.96, 2.03) 0.06 (-1.44, 1.56)

RIT_STD -0.62 (-3.58, 2.33) -0.06 (-3.38, 3.26) - -0.10 (-3.31, 3.10) 0.08 (-3.31, 3.47)

RIT_STD+MTX -0.97 (-4.49, 2.56) -0.06 (-3.82, 3.69) - 0.02 (-3.62, 3.65) 0.22 (-3.63, 4.06)

BAR_4+MTX 0.10 (-2.38, 2.59) - 0.30 (-2.49, 3.10) -1.05 (-5.36, 3.27) 0.03 (-2.40, 2.46)

HD203+MTX 0.10 (-1.45, 1.64) - - 0.07 (-1.63, 1.77) 0.41 (-1.54, 2.36)

SB4+MTX 0.06 (-1.39, 1.51) - - 0.07 (-1.52, 1.67) 0.45 (-1.43, 2.33)

CT-P13+MTX 0.15 (-1.30, 1.61) - 1.26 (-0.87, 3.40) -0.07 (-1.61, 1.47) 0.03 (-1.47, 1.53)

SB2+MTX 0.17 (-1.42, 1.77) - 1.28 (-1.00, 3.55) -0.08 (-1.80, 1.64) 0.04 (-1.60, 1.69)

539


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

SB5+MTX -0.10 (-2.69, 2.49) - 0.33 (-2.41, 3.07) 0.39 (-1.98, 2.75) -0.05 (-2.43, 2.33)

ABP501+MTX 0.28 (-1.91, 2.47) - 0.43 (-2.09, 2.94) 0.52 (-1.63, 2.67) 0.03 (-2.06, 2.12)

INF_STD+MTX GOL_STD

(SC)+MTX -0.26 (-1.54, 1.02) - 0.86 (-0.69, 2.40) -0.005 (-1.34, 1.33) -0.004 (-1.34, 1.33)

INF_STD -0.61 (-3.95, 2.73) - - 0.14 (-3.73, 4.02) 0.16 (-3.86, 4.19)

CERTO_STD

+MTX -0.24 (-1.81, 1.32) - -0.02 (-1.50, 1.46) 0.58 (-0.85, 2.02) 0.02 (-1.42, 1.47)

RIT_STD -1.02 (-3.91, 1.88) - - -0.05 (-3.15, 3.05) 0.10 (-3.16, 3.37)

RIT_STD+MTX -1.05 (-4.57, 2.47) - - 0.04 (-3.54, 3.62) 0.13 (-3.61, 3.86)

BAR_4+MTX -0.26 (-2.90, 2.39) - -0.12 (-2.58, 2.35) -0.93 (-5.21, 3.35) 0.01 (-2.40, 2.42)

HD203+MTX -0.20 (-1.85, 1.45) - - 0.12 (-1.50, 1.74) 0.40 (-1.50, 2.29)

SB4+MTX -0.24 (-1.74, 1.26) - - 0.12 (-1.40, 1.65) 0.44 (-1.37, 2.25)

CT-P13+MTX -0.29 (-1.70, 1.11) - 0.84 (-0.81, 2.49) -0.01 (-1.48, 1.46) -0.02 (-1.48, 1.45)

SB2+MTX -0.19 (-1.73, 1.34) - 0.87 (-0.94, 2.67) -0.03 (-1.67, 1.62) -0.02 (-1.64, 1.60)

SB5+MTX -0.45 (-2.92, 2.02) - -0.10 (-2.50, 2.30) 0.39 (-1.93, 2.71) -0.12 (-2.45, 2.22)

540


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

ABP501+MTX -0.15 (-2.19, 1.89) - -0.02 (-2.11, 2.06) 0.54 (-1.58, 2.66) -0.01 (-2.08, 2.06)

INF_STD INF_STD

+MTX -0.81 (-4.04, 2.43) 0.30 (-3.33, 3.92) - 0.09 (-3.61, 3.80) 0.17 (-3.69, 4.02)

CERTO_STD

+MTX 0.02 (-1.19, 1.22) - -0.85 (-2.31, 0.62) 0.61 (-0.58, 1.80) 0.03 (-1.17, 1.23)

RIT_STD -0.84 (-3.62, 1.94) 0.32 (-2.80, 3.45) - -0.09 (-3.11, 2.93) 0.04 (-3.17, 3.26)

RIT_STD+MTX -1.00 (-4.29, 2.30) 0.32 (-3.28, 3.93) - 0.04 (-3.43, 3.52) 0.14 (-3.56, 3.84)

BAR_4+MTX -0.03 (-2.46, 2.39) - -0.96 (-3.45, 1.53) -0.98 (-5.19, 3.24) -0.01 (-2.28, 2.27)

HD203+MTX -0.02 (-1.31, 1.28) - - 0.14 (-1.29, 1.56) 0.41 (-1.28, 2.09)

SB4+MTX -0.03 (-1.24, 1.18) - - 0.13 (-1.17, 1.43) 0.44 (-1.17, 2.06)

CT-P13+MTX -0.01 (-0.57, 0.55) - 0.001 (-0.57, 0.57) 0.005 (-0.61, 0.61) -0.005 (-0.57, 0.56)

SB2+MTX 0.05 (-0.82, 0.91) - 0.01 (-0.90, 0.92) -0.01 (-0.95, 0.93) -0.01 (-0.90, 0.89)

SB5+MTX -0.19 (-2.48, 2.10) - -0.93 (-3.32, 1.46) 0.45 (-1.73, 2.62) -0.08 (-2.26, 2.10)

ABP501+MTX 0.10 (-1.76, 1.95) - -0.90 (-2.99, 1.20) 0.55 (-1.39, 2.48) -0.03 (-1.96, 1.91)

CERTO_STD

+MTX INF_STD 0.20 (-3.08, 3.48) - - 0.50 (-3.27, 4.27) -0.17 (-4.13, 3.79)

541


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

RIT_STD -0.27 (-4.26, 3.72) 0.03 (-4.70, 4.77) - -0.16 (-4.93, 4.61) -0.02 (-4.86, 4.82)

RIT_STD+MTX -0.73 (-5.25, 3.80) 0.04 (-5.10, 5.17) - 0.01 (-5.23, 5.24) 0.001 (-5.28, 5.28)

BAR_4+MTX 0.50 (-3.64, 4.65) - - -1.06 (-6.56, 4.45) -0.18 (-4.61, 4.25)

HD203+MTX 0.36 (-2.96, 3.69) - - -0.002 (-3.84, 3.83) 0.30 (-3.79, 4.38)

SB4+MTX 0.30 (-2.94, 3.54) - - -0.003 (-3.87, 3.86) 0.33 (-3.76, 4.42)

CT-P13+MTX 0.26 (-3.03, 3.54) - - -0.07 (-3.81, 3.67) -0.15 (-4.05, 3.74)

SB2+MTX 0.41 (-2.95, 3.78) - - -0.07 (-3.93, 3.79) -0.16 (-4.08, 3.76)

SB5+MTX 0.17 (-3.95, 4.29) - - 0.37 (-3.88, 4.62) -0.23 (-4.56, 4.10)

ABP501+MTX 0.44 (-3.21, 4.10) - - 0.47 (-3.62, 4.56) -0.15 (-4.39, 4.09)

RIT_STD CERTO_STD+

MTX -0.82 (-3.60, 1.96) - - -0.67 (-3.73, 2.39) -0.04 (-3.29, 3.22)

RIT_STD+MTX -1.01 (-4.38, 2.37) - - -0.55 (-4.11, 3.00) 0.08 (-3.67, 3.82)

BAR_4+MTX 0.08 (-2.33, 2.49) - -0.11 (-2.52, 2.31) -1.57 (-5.84, 2.70) -0.05 (-2.40, 2.30)

HD203+MTX -0.01 (-1.48, 1.47) - - -0.48 (-1.99, 1.04) 0.37 (-1.45, 2.19)

542


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

SB4+MTX -0.03 (-1.36, 1.31) - - -0.50 (-1.91, 0.92) 0.41 (-1.35, 2.16)

CT-P13+MTX -0.001 (-1.31, 1.31) - 0.86 (-0.71, 2.43) -0.60 (-1.95, 0.75) -0.03 (-1.36, 1.30)

SB2+MTX 0.03 (-1.46, 1.51) - 0.86 (-0.87, 2.60) -0.62 (-2.14, 0.90) -0.04 (-1.54, 1.47)

SB5+MTX -0.18 (-2.41, 2.05) - -0.06 (-2.18, 2.06) -0.15 (-2.18, 1.88) -0.10 (-2.16, 1.97)

ABP501+MTX 0.20 (-1.60, 1.99) - 0.00 (-1.83, 1.83) -0.03 (-1.84, 1.78) -0.003 (-1.83, 1.82)

RIT_STD+MTX RIT_STD -0.34 (-3.15, 2.46) -0.01 (-2.90, 2.88) - 0.10 (-2.98, 3.19) 0.04 (-2.87, 2.94)

BAR_4+MTX 0.71 (-2.96, 4.37) - - -0.97 (-6.23, 4.30) -0.03 (-3.85, 3.79)

HD203+MTX 0.81 (-2.00, 3.61) - - 0.18 (-2.99, 3.35) 0.32 (-3.13, 3.77)

SB4+MTX 0.74 (-2.10, 3.57) - - 0.18 (-2.98, 3.34) 0.34 (-3.12, 3.80)

CT-P13+MTX 0.84 (-1.96, 3.64) - - 0.10 (-2.98, 3.18) -0.05 (-3.27, 3.18)

SB2+MTX 0.88 (-2.03, 3.78) - - 0.07 (-3.12, 3.25) -0.03 (-3.37, 3.31)

SB5+MTX 0.69 (-2.73, 4.11) - - 0.55 (-3.03, 4.13) -0.10 (-3.78, 3.59)

ABP501+MTX 0.83 (-2.17, 3.83) - - 0.59 (-2.86, 4.03) -0.06 (-3.56, 3.44)

543


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

BAR_4+MTX RIT_STD

+MTX 1.08 (-3.19, 5.35) - - -0.92 (-6.71, 4.87) -0.12 (-4.37, 4.12)

HD203+MTX 0.84 (-2.53, 4.22) - - 0.07 (-3.63, 3.76) 0.30 (-3.56, 4.15)

SB4+MTX 0.92 (-2.43, 4.27) - - 0.10 (-3.53, 3.74) 0.33 (-3.52, 4.19)

CT-P13+MTX 0.99 (-2.32, 4.29) - - -0.01 (-3.57, 3.54) -0.14 (-3.87, 3.58)

SB2+MTX 1.03 (-2.45, 4.51) - - -0.04 (-3.66, 3.57) -0.13 (-3.92, 3.66)

SB5+MTX 0.81 (-3.20, 4.82) - - 0.42 (-3.57, 4.40) -0.14 (-4.23, 3.95)

ABP501+MTX 1.06 (-2.40, 4.51) - - 0.48 (-3.38, 4.34) -0.07 (-4.03, 3.88)

HD203+MTX BAR_4+MTX -0.05 (-2.61, 2.52) - - 1.10 (-3.16, 5.36) 0.37 (-2.26, 3.00)

SB4+MTX -0.08 (-2.58, 2.42) - - 1.10 (-3.17, 5.37) 0.41 (-2.22, 3.03)

CT-P13+MTX 0.04 (-2.50, 2.58) - 0.98 (-1.58, 3.53) 1.01 (-3.22, 5.24) 0.02 (-2.33, 2.37)

SB2+MTX -0.004 (-2.47, 2.46) - 0.97 (-1.69, 3.63) 0.95 (-3.36, 5.26) 0.01 (-2.45, 2.47)

SB5+MTX -0.24 (-3.59, 3.11) - 0.06 (-3.05, 3.17) 1.46 (-3.25, 6.17) -0.08 (-3.12, 2.96)

ABP501+MTX 0.15 (-2.83, 3.14) - 0.09 (-2.77, 2.94) 1.46 (-3.15, 6.07) 0.005 (-2.75, 2.76)

544


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

SB4+MTX HD203+MTX 0.01 (-1.24, 1.27) - - 0.01 (-1.37, 1.39) 0.03 (-1.28, 1.35)

CT-P13+MTX 0.03 (-1.36, 1.42) - - -0.12 (-1.66, 1.42) -0.40 (-2.18, 1.37)

SB2+MTX 0.08 (-1.49, 1.64) - - -0.15 (-1.86, 1.56) -0.40 (-2.30, 1.49)

SB5+MTX -0.19 (-2.69, 2.32) - - 0.33 (-2.04, 2.71) -0.50 (-3.08, 2.08)

ABP501+MTX 0.17 (-1.89, 2.22) - - 0.42 (-1.75, 2.60) -0.42 (-2.79, 1.96)

CT-P13+MTX SB4+MTX 0.07 (-1.25, 1.38) - - -0.11 (-1.55, 1.32) -0.44 (-2.15, 1.27)

SB2+MTX 0.06 (-1.47, 1.59) - - -0.15 (-1.76, 1.47) -0.45 (-2.30, 1.40)

SB5+MTX -0.20 (-2.58, 2.19) - - 0.34 (-1.95, 2.62) -0.52 (-3.06, 2.02)

ABP501+MTX 0.15 (-1.87, 2.17) - - 0.44 (-1.66, 2.54) -0.45 (-2.78, 1.89)

SB2+MTX CT-P13+MTX 0.05 (-1.02, 1.11) - 0.01 (-1.07, 1.09) -0.02 (-1.14, 1.11) -0.004 (-1.07, 1.06)

SB5+MTX -0.18 (-2.53, 2.17) - -0.93 (-3.39, 1.53) 0.44 (-1.82, 2.70) -0.07 (-2.32, 2.18)

ABP501+MTX 0.11 (-1.82, 2.04) - -0.90 (-3.08, 1.28) 0.54 (-1.49, 2.57) -0.02 (-2.04, 2.01)

SB5+MTX SB2+MTX -0.20 (-2.64, 2.24) - -0.93 (-3.48, 1.63) 0.47 (-1.89, 2.84) -0.05 (-2.39, 2.28)

545


Difference of log

OR (95% CI) - All

Drug Doses

Difference of log

OR (95% CI) -

Studies

Published Before

2007

Difference of log

OR (95% CI) -

Studies Published

in 2007 Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference log OR

(95% CI) of SA vs

REF - Studies


MTX Patients

ABP501+MTX 0.07 (-2.06, 2.20) - -0.90 (-3.20, 1.40) 0.56 (-1.60, 2.72) -0.003 (-2.15, 2.15)

ABP501+MTX SB5+MTX 0.17 (-2.41, 2.75) - 0.01 (-2.47, 2.49) 0.10 (-2.32, 2.52) 0.06 (-2.37, 2.49)



comparison was not present in the sensitivity analysis. Pink cells indicate the sensitivity analysis has a lower effect estimate than the reference case. Green cells indicate the


ABA = abatacept; ABP501 = biosimilar adalimumab; ADA = adalimumab; BAR_4 = 4mg baricitinib; CERTO = certolizumab pegol; CI = confidence interval; csDMARD =

conventional synthetic disease-modifying anti-rheumatic drug; CT-P13 = biosimilar of infliximab; ETN = etanercept; GOL= golimumab; HCQ = hydroxychloroquine;

HD203=etanercept biosimilar; INF = infliximab; IV = intravenous; MTX = methotrexate; log OR = log odds ratio; RIT = rituximab; SB2 = biosimilar infliximab 3mg/kg; SB4 =

biosimilar etanercept 50mg; SB5 = biosimilar adalimumab; SC = subcutaneous; SSZ = sulfasalazine; STD = standard dose; TOC_4 = tocilizumab 4mg/kg; TOC_8 = 8mg/kg

tocilizumab; TOF = tofacitinib

546

Table 54. WDAE Sensitivity Analysis Results Compared to the Reference Case (Post Hoc Table)




Time Point Analysis

(12 to 16 Weeks)

Difference log OR (95%

CI) of SA vs REF - Studies

With Patients Who Were

All IR MTX and Biologic

Naïve

Difference log OR (95% CI)

of SA vs REF - Exclude

Asian-Only Studies

Difference log OR


- Include Only Asian-

Only Studies

csDMARD+MTX Placebo+MTX 0.85 (-1.31, 3.01) 0.01 (-1.17, 1.18) -0.69 (-2.07, 0.69) 0.95 (-0.82, 2.73)

SSZ+HCQ

- -0.02 (-1.62, 1.58) -0.04 (-1.60, 1.53) -

MTX+SSZ+HCQ

- 0.05 (-1.55, 1.65) 0.04 (-1.56, 1.64) -

ETN_STD

0.45 (-1.49, 2.40) 0.03 (-0.61, 0.67) 0.004 (-0.62, 0.63) -

ETN_STD+MTX

0.20 (-1.66, 2.07) 0.001 (-0.59, 0.59) -0.02 (-0.60, 0.56) 0.28 (-1.12, 1.68)

ABA_STD (IV)+MTX

0.13 (-2.58, 2.84) -0.02 (-1.18, 1.15) 0.08 (-0.68, 0.85) -1.97 (-3.78, -0.15)

ADA_STD+MTX

0.14 (-0.71, 0.99) -0.03 (-1.02, 0.95) 0.01 (-0.79, 0.80) 3.19 (0.36, 6.02)

TOF_STD+MTX

0.07 (-0.64, 0.79) - -0.01 (-0.75, 0.73) 0.28 (-0.72, 1.28)

TOC_4 (IV)

- - 0.08 (-1.33, 1.50) -

TOC_8 (IV)

- - 0.17 (-1.09, 1.43) -0.38 (-1.65, 0.89)

TOC_4 (IV)+MTX

- - 0.14 (-1.28, 1.56) -

TOC_8 (IV)+MTX

- - 0.11 (-1.16, 1.38) -

547




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

GOL_STD

(SC)+MTX

0.24 (-0.96, 1.44) -0.43 (-1.68, 0.82) -0.48 (-1.72, 0.76) 1.41 (-0.07, 2.89)

INF_STD+MTX

-0.38 (-1.89, 1.12) 0.03 (-0.81, 0.87) 0.05 (-0.79, 0.89) -0.01 (-0.85, 0.84)

INF_STD

-0.02 (-3.81, 3.77) 0.21 (-3.52, 3.94) 0.05 (-3.61, 3.71) -

CERTO_STD +MTX

0.18 (-0.94, 1.30) -0.02 (-1.03, 0.99) 0.004 (-0.93, 0.94) -

RIT_STD

- - 0.11 (-3.09, 3.30) -

RIT_STD+MTX

- - 0.09 (-3.57, 3.76) -

BAR_4+MTX

-0.11 (-2.34, 2.13) -0.19 (-2.58, 2.20) -0.13 (-2.56, 2.29) -0.73 (-3.66, 2.20)

HD203+MTX

- - - 0.25 (-1.49, 1.99)

SB4+MTX

- 0.01 (-1.04, 1.07) -0.02 (-1.06, 1.02) -

CT-P13+MTX

- -0.15 (-1.20, 0.91) -0.13 (-1.17, 0.91) 0.69 (-0.42, 1.80)

SB2+MTX

- 0.03 (-1.21, 1.28) 0.06 (-1.19, 1.32) -

SB5+MTX

- -0.09 (-2.25, 2.07) -0.07 (-2.14, 1.99) -

ABP501+MTX

- - 0.08 (-1.68, 1.83) -

548




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

SSZ+HCQ csDMARD +MTX - -0.05 (-2.06, 1.96) 0.67 (-1.44, 2.78) -

MTX+SSZ+HCQ

- 0.05 (-1.90, 1.99) 0.74 (-1.36, 2.83) -

ETN_STD

-0.39 (-1.75, 0.97) 0.02 (-1.13, 1.18) 0.70 (-0.67, 2.08) -

ETN_STD+MTX

-0.65 (-1.81, 0.51) -0.005 (-1.02, 1.01) 0.67 (-0.60, 1.93) -0.65 (-1.75, 0.45)

ABA_STD (IV)+MTX

-0.71 (-4.14, 2.73) -0.01 (-1.68, 1.66) 0.77 (-0.82, 2.35) -3.11 (-5.66, -0.56)

ADA_STD+MTX

-0.67 (-2.98, 1.65) 0.01 (-1.52, 1.53) 0.72 (-0.87, 2.30) 2.50 (-0.87, 5.87)

TOF_STD+MTX

-0.76 (-3.02, 1.50) - 0.70 (-0.86, 2.26) -0.67 (-2.71, 1.38)

TOC_4 (IV)

- - 0.80 (-1.17, 2.76) -

TOC_8 (IV)

- - 0.88 (-0.99, 2.74) -1.37 (-3.55, 0.82)

TOC_4 (IV)+MTX

- - 0.84 (-1.11, 2.80) -

TOC_8 (IV)+MTX

- - 0.83 (-1.04, 2.69) -

GOL_STD

(SC)+MTX

-0.64 (-3.07, 1.80) -0.41 (-2.10, 1.28) 0.23 (-1.62, 2.08) 0.53 (-1.74, 2.80)

INF_STD+MTX

-1.21 (-3.76, 1.35) 0.04 (-1.38, 1.46) 0.74 (-0.83, 2.31) -0.94 (-2.87, 1.00)

549




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

INF_STD

-0.91 (-5.26, 3.44) 0.20 (-3.68, 4.07) 0.72 (-3.12, 4.56) -

CERTO_STD +MTX

-0.65 (-3.07, 1.76) -0.0004 (-1.54, 1.54) 0.71 (-0.95, 2.37) -

RIT_STD

- - 0.82 (-2.62, 4.26) -

RIT_STD+MTX

- - 0.79 (-3.05, 4.63) -

BAR_4+MTX

-1.11 (-4.17, 1.95) -0.20 (-2.85, 2.46) 0.52 (-2.30, 3.34) -1.92 (-5.33, 1.49)

HD203+MTX

- - - -0.67 (-2.17, 0.83)

SB4+MTX

- -0.002 (-1.34, 1.34) 0.67 (-0.86, 2.19) -

CT-P13+MTX

- -0.13 (-1.70, 1.44) 0.56 (-1.13, 2.24) -0.24 (-2.31, 1.83)

SB2+MTX

- 0.04 (-1.67, 1.75) 0.74 (-1.11, 2.59) -

SB5+MTX

- -0.07 (-2.56, 2.41) 0.63 (-1.86, 3.11) -

ABP501+MTX

- - 0.77 (-1.44, 2.99) -

MTX+SSZ+HCQ SSZ+HCQ - 0.04 (-1.82, 1.90) 0.06 (-1.80, 1.92) -

ETN_STD

- 0.05 (-1.66, 1.77) 0.04 (-1.62, 1.71) -

550




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

ETN_STD+MTX

- 0.03 (-1.69, 1.75) 0.01 (-1.67, 1.69) -

ABA_STD (IV)+MTX

- 0.01 (-1.95, 1.97) 0.10 (-1.62, 1.82) -

ADA_STD+MTX

- 0.07 (-1.76, 1.90) 0.04 (-1.68, 1.77) -

TOF_STD+MTX

- - 0.01 (-1.71, 1.73) -

TOC_4 (IV)

- - 0.10 (-1.97, 2.18) -

TOC_8 (IV)

- - 0.23 (-1.74, 2.21) -

TOC_4 (IV)+MTX

- - 0.14 (-1.92, 2.20) -

TOC_8 (IV)+MTX

- - 0.15 (-1.85, 2.15) -

GOL_STD

(SC)+MTX

- -0.42 (-2.45, 1.61) -0.48 (-2.51, 1.55) -

INF_STD+MTX

- 0.07 (-1.73, 1.87) 0.08 (-1.70, 1.86) -

INF_STD

- 0.20 (-3.84, 4.24) 0.10 (-3.78, 3.98) -

CERTO_STD +MTX

- 0.01 (-1.86, 1.88) 0.05 (-1.77, 1.86) -

RIT_STD

- - 0.16 (-3.38, 3.71) -

551




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

RIT_STD+MTX

- - 0.14 (-3.82, 4.09) -

BAR_4+MTX

- -0.23 (-3.11, 2.65) -0.22 (-3.12, 2.68) -

HD203+MTX

- - - -

SB4+MTX

- 0.03 (-1.91, 1.96) -0.01 (-1.90, 1.88) -

CT-P13+MTX

- -0.11 (-2.02, 1.79) -0.11 (-1.98, 1.77) -

SB2+MTX

- 0.08 (-1.95, 2.11) 0.11 (-1.90, 2.12) -

SB5+MTX

- -0.05 (-2.76, 2.66) -0.05 (-2.64, 2.54) -

ABP501+MTX

- - 0.06 (-2.30, 2.42) -

ETN_STD MTX+SSZ +HCQ - -0.02 (-1.73, 1.69) -0.04 (-1.76, 1.69) -

ETN_STD+MTX

- -0.06 (-1.75, 1.62) -0.07 (-1.77, 1.64) -

ABA_STD (IV)+MTX

- -0.06 (-2.03, 1.90) 0.04 (-1.72, 1.81) -

ADA_STD+MTX

- -0.04 (-1.93, 1.85) -0.03 (-1.86, 1.80) -

TOF_STD+MTX

- - -0.05 (-1.83, 1.73) -

552




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

TOC_4 (IV)

- - 0.06 (-2.05, 2.16) -

TOC_8 (IV)

- - 0.14 (-1.87, 2.16) -

TOC_4 (IV)+MTX

- - 0.10 (-2.03, 2.23) -

TOC_8 (IV)+MTX

- - 0.08 (-1.94, 2.10) -

GOL_STD

(SC)+MTX

- -0.49 (-2.48, 1.50) -0.51 (-2.52, 1.49) -

INF_STD+MTX

- -0.02 (-1.82, 1.78) -0.002 (-1.83, 1.83) -

INF_STD

- 0.12 (-3.92, 4.16) -0.02 (-4.04, 4.00) -

CERTO_STD +MTX

- -0.04 (-1.90, 1.83) -0.02 (-1.87, 1.84) -

RIT_STD

- - 0.13 (-3.42, 3.68) -

RIT_STD+MTX

- - 0.13 (-3.85, 4.11) -

BAR_4+MTX

- -0.30 (-3.19, 2.60) -0.22 (-3.14, 2.70) -

HD203+MTX

- - - -

SB4+MTX

- -0.05 (-1.94, 1.85) -0.05 (-1.96, 1.85) -

553




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

CT-P13+MTX

- -0.19 (-2.11, 1.73) -0.19 (-2.11, 1.74) -

SB2+MTX

- -0.02 (-2.05, 2.01) 0.02 (-2.04, 2.09) -

SB5+MTX

- -0.10 (-2.78, 2.58) -0.10 (-2.76, 2.55) -

ABP501+MTX

- - 0.02 (-2.37, 2.41) -

ETN_STD+MTX ETN_STD -0.26 (-0.96, 0.44) -0.03 (-0.58, 0.52) -0.02 (-0.56, 0.52) -

ABA_STD (IV)+MTX

-0.28 (-3.53, 2.97) -0.05 (-1.38, 1.29) 0.08 (-0.90, 1.07) -

ADA_STD+MTX

-0.28 (-2.40, 1.85) -0.04 (-1.22, 1.13) 0.01 (-1.00, 1.02) -

TOF_STD+MTX

-0.38 (-2.45, 1.70) - -0.02 (-0.99, 0.95) -

TOC_4 (IV)

- - 0.07 (-1.47, 1.61) -

TOC_8 (IV)

- - 0.16 (-1.24, 1.55) -

TOC_4 (IV)+MTX

- - 0.14 (-1.40, 1.68) -

TOC_8 (IV)+MTX

- - 0.11 (-1.29, 1.51) -

GOL_STD

(SC)+MTX

-0.24 (-2.49, 2.01) -0.46 (-1.87, 0.95) -0.48 (-1.87, 0.90) -

554




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

INF_STD+MTX -0.80 (-3.18, 1.58) 0.01 (-1.04, 1.05) 0.04 (-0.98, 1.07) -

INF_STD -0.50 (-4.76, 3.77) 0.20 (-3.60, 4.00) 0.06 (-3.63, 3.75) -

CERTO_STD +MTX -0.26 (-2.49, 1.98) -0.05 (-1.25, 1.14) 0.004 (-1.12, 1.13) -

RIT_STD - - 0.10 (-3.13, 3.32) -

RIT_STD+MTX - - 0.12 (-3.60, 3.84) -

BAR_4+MTX -0.66 (-3.58, 2.26) -0.21 (-2.68, 2.26) -0.14 (-2.64, 2.36) -

HD203+MTX - -0.17 (-1.28, 0.94) - -

SB4+MTX - - -0.02 (-1.04, 0.99) -

CT-P13+MTX - -0.17 (-1.39, 1.05) -0.14 (-1.33, 1.05) -

SB2+MTX - 0.02 (-1.38, 1.42) 0.06 (-1.34, 1.46) -

SB5+MTX - -0.11 (-2.36, 2.15) -0.06 (-2.20, 2.08) -

ABP501+MTX - - 0.06 (-1.80, 1.92) -

ABA_STD (IV)+MTX ETN_STD +MTX -0.03 (-3.25, 3.18) -0.03 (-1.33, 1.28) 0.09 (-0.86, 1.05) -2.41 (-4.72, -0.09)

555




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

ADA_STD+MTX -0.03 (-2.07, 2.02) -0.01 (-1.15, 1.13) 0.03 (-0.95, 1.01) 3.16 (-0.04, 6.36)

TOF_STD+MTX -0.11 (-2.10, 1.87) - 0.02 (-0.92, 0.96) 0.01 (-1.71, 1.73)

TOC_4 (IV) - - 0.11 (-1.41, 1.63) -

TOC_8 (IV) - - 0.18 (-1.19, 1.55) -0.71 (-2.57, 1.16)

TOC_4 (IV)+MTX - - 0.16 (-1.35, 1.67) -

TOC_8 (IV)+MTX - - 0.13 (-1.25, 1.51) -

GOL_STD

(SC)+MTX 0.03 (-2.14, 2.19) -0.43 (-1.82, 0.95) -0.45 (-1.83, 0.92) 1.20 (-0.82, 3.23)

INF_STD+MTX -0.54 (-2.82, 1.75) 0.04 (-0.98, 1.06) 0.08 (-0.93, 1.09) -0.26 (-1.87, 1.36)

INF_STD -0.28 (-4.52, 3.97) 0.20 (-3.60, 4.00) 0.07 (-3.61, 3.74) -

CERTO_STD +MTX 0.01 (-2.13, 2.16) - 0.03 (-1.08, 1.13) -

RIT_STD - - 0.12 (-3.10, 3.34) -

RIT_STD+MTX - 0.19 (-2.75, 3.13) 0.15 (-3.52, 3.83) -

BAR_4+MTX -0.39 (-3.26, 2.48) -0.18 (-2.64, 2.28) -0.10 (-2.60, 2.40) -1.26 (-4.50, 1.99)

556




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

HD203+MTX - - - -0.01 (-1.04, 1.02)

SB4+MTX - 0.01 (-0.85, 0.88) 0.003 (-0.85, 0.85) -

CT-P13+MTX - -0.14 (-1.34, 1.06) -0.11 (-1.29, 1.08) 0.43 (-1.34, 2.21)

SB2+MTX - 0.05 (-1.33, 1.43) 0.08 (-1.30, 1.47) -

SB5+MTX - -0.09 (-2.32, 2.15) -0.04 (-2.17, 2.09) -

ABP501+MTX - - 0.10 (-1.74, 1.94) -

ADA_STD+MTX ABA_STD

(IV)+MTX -0.01 (-2.88, 2.85) 0.03 (-1.48, 1.54) -0.08 (-1.19, 1.03) 5.65 (2.29, 9.01)

TOF_STD+MTX -0.08 (-2.92, 2.77) - -0.11 (-1.19, 0.96) 2.32 (0.26, 4.37)

TOC_4 (IV) - - 0.003 (-1.59, 1.60) -

TOC_8 (IV) - - 0.07 (-1.41, 1.55) 1.64 (-0.59, 3.86)

TOC_4 (IV)+MTX - - 0.05 (-1.54, 1.64) -

TOC_8 (IV)+MTX - - 0.03 (-1.46, 1.52) -

GOL_STD

(SC)+MTX 0.17 (-2.78, 3.12) -0.42 (-2.10, 1.26) -0.55 (-2.01, 0.91) 3.60 (1.31, 5.89)

557




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

INF_STD+MTX -0.58 (-3.68, 2.51) 0.05 (-1.15, 1.26) -0.03 (-1.05, 0.99) 2.03 (0.07, 3.99)

INF_STD -0.08 (-4.75, 4.59) 0.28 (-3.56, 4.13) -0.01 (-3.74, 3.73) -

CERTO_STD +MTX 0.03 (-2.94, 3.00) 0.02 (-1.50, 1.55) -0.08 (-1.31, 1.15) -

RIT_STD - - 0.05 (-3.18, 3.27) -

RIT_STD+MTX - - 0.02 (-3.71, 3.75) -

BAR_4+MTX -0.31 (-3.87, 3.25) -0.20 (-2.86, 2.46) -0.21 (-2.76, 2.34) 1.20 (-2.40, 4.80)

HD203+MTX - - - 2.38 (-0.15, 4.92)

SB4+MTX - 0.04 (-1.53, 1.60) -0.10 (-1.39, 1.19) -

CT-P13+MTX - -0.12 (-1.48, 1.24) -0.21 (-1.40, 0.97) 2.76 (0.68, 4.84)

SB2+MTX - 0.07 (-1.44, 1.59) -0.001 (-1.38, 1.38) -

SB5+MTX - -0.07 (-2.50, 2.36) -0.15 (-2.36, 2.05) -

ABP501+MTX - - -0.005 (-1.89, 1.88) -

TOF_STD+MTX ADA_STD +MTX -0.08 (-0.91, 0.75) - -0.03 (-0.84, 0.79) -2.98 (-5.94, -0.01)

558




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

TOC_4 (IV) - - 0.09 (-1.52, 1.70) -

TOC_8 (IV) - - 0.17 (-1.30, 1.64) -3.66 (-6.84, -0.48)

TOC_4 (IV)+MTX - - 0.14 (-1.46, 1.74) -

TOC_8 (IV)+MTX - - 0.13 (-1.34, 1.60) -

GOL_STD

(SC)+MTX 0.11 (-1.35, 1.58) -0.41 (-2.00, 1.19) -0.48 (-1.97, 1.02) -1.77 (-5.00, 1.47)

INF_STD+MTX -0.54 (-2.27, 1.18) 0.05 (-1.22, 1.33) 0.04 (-1.12, 1.19) -3.24 (-6.22, -0.25)

INF_STD -0.13 (-4.03, 3.78) 0.26 (-3.62, 4.14) 0.08 (-3.68, 3.83) -

CERTO_STD +MTX 0.04 (-0.95, 1.02) -0.01 (-0.97, 0.95) -0.01 (-0.92, 0.89) -

RIT_STD - - 0.10 (-3.13, 3.32) -

RIT_STD+MTX - - 0.07 (-3.61, 3.75) -

BAR_4+MTX -0.34 (-2.72, 2.05) -0.21 (-2.83, 2.41) -0.18 (-2.72, 2.37) -4.59 (-8.85, -0.32)

HD203+MTX - - - -3.14 (-6.50, 0.21)

SB4+MTX - 0.02 (-1.42, 1.46) -0.03 (-1.35, 1.28) -

559




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

CT-P13+MTX - -0.14 (-1.56, 1.29) -0.14 (-1.44, 1.16) -2.59 (-5.66, 0.49)

SB2+MTX - 0.06 (-1.51, 1.63) 0.05 (-1.42, 1.52) -

SB5+MTX - -0.03 (-1.93, 1.87) -0.06 (-1.96, 1.83) -

ABP501+MTX - - 0.05 (-1.51, 1.61) -

TOC_4 (IV) TOF_STD +MTX - - 0.12 (-1.46, 1.71) -

TOC_8 (IV) - - 0.19 (-1.26, 1.63) -0.69 (-2.30, 0.92)

TOC_4 (IV)+MTX - - 0.16 (-1.42, 1.74) -

TOC_8 (IV)+MTX - - 0.14 (-1.30, 1.58) -

GOL_STD

(SC)+MTX 0.18 (-1.21, 1.58) - -0.45 (-1.91, 1.00) 1.20 (-0.58, 2.99)

INF_STD+MTX -0.47 (-2.13, 1.19) - 0.07 (-1.05, 1.20) -0.28 (-1.57, 1.02)

INF_STD -0.05 (-3.93, 3.84) - 0.08 (-3.68, 3.83) -

CERTO_STD +MTX 0.12 (-1.07, 1.31) - 0.02 (-1.07, 1.11) -

RIT_STD - - 0.10 (-3.15, 3.35) -

560




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

RIT_STD+MTX - - 0.10 (-3.62, 3.82) -

BAR_4+MTX -0.21 (-2.53, 2.11) - -0.15 (-2.66, 2.36) -1.12 (-4.19, 1.96)

HD203+MTX - - - -0.04 (-2.04, 1.97)

SB4+MTX - - -0.02 (-1.32, 1.27) -

CT-P13+MTX - - -0.11 (-1.40, 1.18) 0.40 (-1.09, 1.88)

SB2+MTX - - 0.08 (-1.38, 1.54) -

SB5+MTX - - -0.06 (-2.16, 2.03) -

ABP501+MTX - - 0.09 (-1.66, 1.83) -

TOC_8 (IV) TOC_4 (IV) - - 0.08 (-1.16, 1.31) -

TOC_4 (IV)+MTX - - 0.04 (-1.30, 1.37) -

TOC_8 (IV)+MTX - - 0.06 (-1.17, 1.28) -

GOL_STD

(SC)+MTX - - -0.57 (-2.45, 1.31) -

INF_STD+MTX - - -0.04 (-1.68, 1.61) -

561




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

INF_STD - - -0.02 (-3.93, 3.89) -

CERTO_STD +MTX - - -0.11 (-1.82, 1.59) -

RIT_STD - - 0.04 (-3.43, 3.52) -

RIT_STD+MTX - - 0.09 (-3.72, 3.90) -

BAR_4+MTX - - -0.23 (-2.98, 2.52) -

HD203+MTX - - - -

SB4+MTX - - -0.11 (-1.85, 1.63) -

CT-P13+MTX - - -0.22 (-1.98, 1.54) -

SB2+MTX - - -0.02 (-1.90, 1.87) -

SB5+MTX - - -0.16 (-2.67, 2.35) -

ABP501+MTX - - -0.04 (-2.27, 2.20) -

TOC_4 (IV)+MTX TOC_8 (IV) - - -0.05 (-1.32, 1.22) -

TOC_8 (IV)+MTX - - -0.04 (-0.90, 0.81) -

562




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

GOL_STD

(SC)+MTX - - -0.66 (-2.43, 1.11) 1.85 (-0.08, 3.79)

INF_STD+MTX - - -0.11 (-1.63, 1.42) 0.40 (-1.12, 1.93)

INF_STD - - -0.10 (-3.97, 3.77) -

CERTO_STD +MTX - - -0.18 (-1.73, 1.38) -

RIT_STD - - -0.08 (-3.48, 3.33) -

RIT_STD+MTX - - -0.04 (-3.87, 3.79) -

BAR_4+MTX - - -0.34 (-3.01, 2.32) -0.41 (-3.61, 2.80)

HD203+MTX - - - 0.67 (-1.49, 2.83)

SB4+MTX - - -0.20 (-1.82, 1.43) -

CT-P13+MTX - - -0.30 (-1.94, 1.35) 1.08 (-0.59, 2.76)

SB2+MTX - - -0.11 (-1.89, 1.67) -

SB5+MTX - - -0.23 (-2.70, 2.24) -

ABP501+MTX - - -0.12 (-2.26, 2.02) -

563




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

TOC_8 (IV)+MTX TOC_4 (IV)+MTX - - 0.02 (-1.22, 1.26) -

GOL_STD

(SC)+MTX - - -0.64 (-2.55, 1.27) -

INF_STD+MTX - - -0.09 (-1.74, 1.56) -

INF_STD - - -0.05 (-3.98, 3.87) -

CERTO_STD +MTX - - -0.14 (-1.82, 1.55) -

RIT_STD - - 0.03 (-3.45, 3.52) -

RIT_STD+MTX - - 0.01 (-3.84, 3.86) -

BAR_4+MTX - - -0.30 (-3.05, 2.45) -

HD203+MTX - - - -

SB4+MTX - - -0.15 (-1.88, 1.58) -

CT-P13+MTX - - -0.27 (-2.04, 1.50) -

SB2+MTX - - -0.05 (-1.94, 1.84) -

SB5+MTX - - -0.22 (-2.76, 2.33) -

564




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

ABP501+MTX - - -0.09 (-2.35, 2.16) -

GOL_STD

(SC)+MTX TOC_8 (IV)+MTX - - -0.62 (-2.40, 1.15) -

INF_STD+MTX - - -0.07 (-1.61, 1.47) -

INF_STD - - -0.06 (-3.89, 3.76) -

CERTO_STD +MTX - - -0.13 (-1.71, 1.45) -

RIT_STD - - -0.03 (-3.44, 3.38) -

RIT_STD+MTX - - 0.02 (-3.81, 3.86) -

BAR_4+MTX - - -0.30 (-2.98, 2.38) -

HD203+MTX - - - -

SB4+MTX - - -0.15 (-1.77, 1.48) -

CT-P13+MTX - - -0.26 (-1.92, 1.39) -

SB2+MTX - - -0.06 (-1.85, 1.74) -

SB5+MTX - - -0.20 (-2.66, 2.27) -

565




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

ABP501+MTX - - -0.05 (-2.19, 2.09) -

INF_STD+MTX GOL_STD

(SC)+MTX -0.61 (-2.50, 1.27) 0.47 (-1.01, 1.95) 0.52 (-0.97, 2.01) -1.41 (-3.10, 0.28)

INF_STD -0.26 (-4.29, 3.77) 0.69 (-3.24, 4.63) 0.58 (-3.28, 4.45) -

CERTO_STD +MTX -0.06 (-1.71, 1.59) 0.40 (-1.19, 2.00) 0.49 (-1.09, 2.07) -

RIT_STD - - 0.61 (-2.77, 3.99) -

RIT_STD+MTX - - 0.62 (-3.19, 4.43) -

BAR_4+MTX -0.39 (-2.91, 2.12) 0.21 (-2.47, 2.89) 0.31 (-2.41, 3.03) -2.31 (-5.57, 0.95)

HD203+MTX - - - -1.22 (-3.49, 1.04)

SB4+MTX - 0.44 (-1.18, 2.06) 0.46 (-1.17, 2.08) -

CT-P13+MTX - 0.28 (-1.35, 1.90) 0.33 (-1.29, 1.94) -0.75 (-2.59, 1.09)

SB2+MTX - 0.48 (-1.28, 2.24) 0.54 (-1.22, 2.30) -

SB5+MTX - 0.33 (-2.20, 2.85) 0.39 (-2.05, 2.84) -

ABP501+MTX - - 0.54 (-1.61, 2.68) -

566




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

INF_STD INF_STD +MTX 0.41 (-3.34, 4.16) 0.19 (-3.52, 3.90) 0.05 (-3.56, 3.67) -

CERTO_STD +MTX 0.59 (-1.28, 2.46) -0.04 (-1.34, 1.25) -0.05 (-1.31, 1.22) -

RIT_STD - - 0.08 (-3.18, 3.34) -

RIT_STD+MTX - - 0.06 (-3.69, 3.81) -

BAR_4+MTX 0.18 (-2.50, 2.86) -0.23 (-2.77, 2.31) -0.20 (-2.80, 2.39) -0.77 (-3.83, 2.29)

HD203+MTX - - - 0.24 (-1.68, 2.15)

SB4+MTX - -0.02 (-1.36, 1.31) -0.07 (-1.39, 1.25) -

CT-P13+MTX - -0.17 (-0.80, 0.46) -0.18 (-0.80, 0.44) 0.68 (-0.03, 1.39)

SB2+MTX - 0.01 (-0.91, 0.93) 0.02 (-0.90, 0.94) -

SB5+MTX - -0.12 (-2.47, 2.22) -0.09 (-2.38, 2.20) -

ABP501+MTX - - 0.01 (-1.92, 1.94) -

CERTO_STD +MTX INF_STD 0.13 (-3.77, 4.04) -0.24 (-4.06, 3.57) -0.07 (-3.82, 3.69) -

RIT_STD - - 0.03 (-4.71, 4.78) -

567




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

RIT_STD+MTX - - 0.03 (-5.09, 5.15) -

BAR_4+MTX -0.17 (-4.59, 4.24) -0.48 (-4.92, 3.96) -0.27 (-4.65, 4.11) -

HD203+MTX - - - -

SB4+MTX - -0.20 (-4.08, 3.67) -0.10 (-3.86, 3.67) -

CT-P13+MTX - -0.38 (-4.13, 3.38) -0.22 (-3.87, 3.42) -

SB2+MTX - -0.15 (-3.96, 3.66) -0.002 (-3.71, 3.70) -

SB5+MTX - -0.25 (-4.51, 4.00) -0.15 (-4.26, 3.97) -

ABP501+MTX - - -0.08 (-4.06, 3.90) -

RIT_STD CERTO_STD+MT

X - - 0.09 (-3.16, 3.33) -

RIT_STD+MTX - - 0.07 (-3.64, 3.77) -

BAR_4+MTX -0.37 (-2.85, 2.12) -0.18 (-2.80, 2.44) -0.16 (-2.75, 2.44) -

HD203+MTX - - - -

SB4+MTX - 0.02 (-1.44, 1.48) -0.03 (-1.43, 1.37) -

568




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

CT-P13+MTX - -0.13 (-1.58, 1.31) -0.14 (-1.55, 1.27) -

SB2+MTX - 0.04 (-1.55, 1.63) 0.05 (-1.51, 1.62) -

SB5+MTX - -0.04 (-2.18, 2.10) -0.06 (-2.17, 2.04) -

ABP501+MTX - - 0.06 (-1.74, 1.87) -

RIT_STD+MTX RIT_STD - - 0.02 (-2.88, 2.92) -

BAR_4+MTX - - -0.33 (-4.22, 3.56) -

HD203+MTX - - - -

SB4+MTX - - -0.14 (-3.46, 3.19) -

CT-P13+MTX - - -0.25 (-3.57, 3.06) -

SB2+MTX - - -0.03 (-3.45, 3.38) -

SB5+MTX - - -0.20 (-3.90, 3.50) -

ABP501+MTX - - -0.09 (-3.62, 3.43) -

BAR_4+MTX RIT_STD +MTX - - -0.31 (-4.68, 4.06) -

569




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

HD203+MTX - - - -

SB4+MTX - - -0.15 (-3.89, 3.59) -

CT-P13+MTX - - -0.24 (-4.04, 3.56) -

SB2+MTX - - -0.03 (-3.89, 3.82) -

SB5+MTX - - -0.19 (-4.31, 3.94) -

ABP501+MTX - - -0.10 (-4.00, 3.81) -

HD203+MTX BAR_4+MTX - - - 1.24 (-2.14, 4.63)

SB4+MTX - 0.22 (-2.41, 2.85) 0.14 (-2.50, 2.77) -

CT-P13+MTX - 0.07 (-2.56, 2.70) 0.02 (-2.65, 2.69) 1.49 (-1.66, 4.65)

SB2+MTX - 0.24 (-2.46, 2.95) 0.21 (-2.54, 2.96) -

SB5+MTX - 0.10 (-3.19, 3.40) 0.08 (-3.17, 3.34) -

ABP501+MTX - - 0.22 (-2.75, 3.19) -

SB4+MTX HD203+MTX - - - -

570




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

CT-P13+MTX - - - 0.46 (-1.59, 2.51)

SB2+MTX - - - -

SB5+MTX - - - -

ABP501+MTX - - - -

CT-P13+MTX SB4+MTX - -0.14 (-1.62, 1.34) -0.10 (-1.56, 1.36) -

SB2+MTX - 0.04 (-1.59, 1.67) 0.09 (-1.52, 1.71) -

SB5+MTX - -0.10 (-2.50, 2.30) -0.04 (-2.35, 2.26) -

ABP501+MTX - - 0.09 (-1.97, 2.14) -

SB2+MTX CT-P13+MTX - 0.19 (-0.93, 1.31) 0.20 (-0.91, 1.32) -

SB5+MTX - 0.07 (-2.37, 2.50) 0.09 (-2.28, 2.47) -

ABP501+MTX - - 0.19 (-1.84, 2.23) -

SB5+MTX SB2+MTX - -0.10 (-2.61, 2.41) -0.09 (-2.56, 2.37) -

ABP501+MTX - - 0.01 (-2.14, 2.15) -

571




Time Point Analysis

(12 to 16 Weeks)





Naïve



Asian-Only Studies

Difference log OR



Only Studies

ABP501+MTX SB5+MTX - - 0.13 (-2.31, 2.57) -


reference case. Only treatment comparisons from the sensitivity analysis that were also present in the reference case were compared; dashes indicate where the treatment comparison

was not present in the sensitivity analysis. Pink cells indicate the sensitivity analysis has a lower effect estimate than the reference case. Green cells indicate the sensitivity analysis has

a higher effect estimate than the reference case.

ABA = abatacept; ABP501 = biosimilar adalimumab; ADA = adalimumab; BAR_4 = 4mg baricitinib; CERTO = certolizumab pegol; CI = confidence interval; csDMARD = conventional

synthetic disease-modifying anti-rheumatic drug; CT-P13 = biosimilar of infliximab; ETN = etanercept; GOL= golimumab; HCQ = hydroxychloroquine; HD203=etanercept biosimilar; INF

= infliximab; IV = intravenous; MTX = methotrexate; log OR = log odds ratio; RIT = rituximab; SB2 = biosimilar infliximab 3mg/kg; SB4 = biosimilar etanercept 50mg; SB5 = biosimilar

adalimumab; SC = subcutaneous; SSZ = sulfasalazine; STD = standard dose; TOC_4 = tocilizumab 4mg/kg; TOC_8 = 8mg/kg tocilizumab; TOF = tofacitinib

572

Table 55. ACR50 Sensitivity Analysis Results Compared to the Reference Case – Conventional Synthetic DMARD as the Common Comparator


Difference of log

OR (95% CI) - All

Drug Doses


(95% CI) - Studies

Published in 2007

Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference of log

OR (95% CI) -

Restricted Time

Point Analysis (12

to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

ETN_STD PLACEBO+csDMARD -0.15 (-1.59, 1.30) 0.03 (-6.42 , 6.48) -0.06 (-1.57, 1.46) - -

ETN_STD

+csDMARD

-0.32 (-1.42, 0.79) 0.01 (-5.73 , 5.74) -0.02 (-1.17, 1.14) -0.93 (-2.19, 0.34) -

ADA_STD

+csDMARD

-0.01 (-1.43, 1.42) 0.01 (-5.91 , 5.93) -0.12 (-1.22, 0.98) -0.002 (-1.05, 1.05) 0.01 (-1.21, 1.24)

TOC_8

(IV)+csDMARD

0.004 (-1.00, 1.01) -0.003 (-4.90 , 4.89) 0.29 (-0.76, 1.34) 0.01 (-0.98, 1.00) -

CERTO_STD+

csDMARD

-0.25 (-1.68, 1.18) 0.01 (-6.40 , 6.42) 0.01 (-1.54, 1.55) 0.01 (-1.46, 1.47) -

BAR_4+

csDMARD

-0.01 (-1.42, 1.40) 0.00 (-5.66 , 5.66) -0.06 (-1.55, 1.42) -0.002 (-1.41, 1.41) 0.00 (-1.36, 1.36)

SIR_100+

csDMARD

-0.38 (-2.66, 1.91) -0.03 (-12.20 , 12.14) - 0.02 (-3.02, 3.07) -0.02 (-2.94, 2.90)

SIR_50+

csDMARD

-0.37 (-2.64, 1.89) -0.02 (-12.57 , 12.53) - 0.02 (-3.04, 3.07) -0.02 (-2.94, 2.90)

ETN_STD+

csDMARD ETN_STD -0.17 (-1.53, 1.20) -0.02 (-3.45 , 3.42) 0.04 (-1.40, 1.48) - -

ADA_STD+

csDMARD

0.15 (-1.88, 2.17) -0.02 (-4.50 , 4.47) -0.06 (-1.93, 1.81) - -

TOC_8

(IV)+csDMARD

0.15 (-1.61, 1.91) -0.03 (-3.72 , 3.66) 0.35 (-1.50, 2.19) - -

CERTO_STD+

csDMARD

-0.11 (-2.13, 1.92) -0.02 (-4.84 , 4.80) 0.06 (-2.10, 2.21) - -

573


Difference of log

OR (95% CI) - All

Drug Doses


(95% CI) - Studies

Published in 2007

Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference of log

OR (95% CI) -

Restricted Time

Point Analysis (12

to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

BAR_4+

csDMARD

0.14 (-1.88, 2.15) -0.03 (-4.11 , 4.04) 0.001 (-2.12, 2.12) - -

SIR_100+

csDMARD

-0.25 (-2.94, 2.44) -0.07 (-10.07 , 9.94) - - -

SIR_50+

csDMARD

-0.25 (-2.94, 2.43) -0.06 (-10.42 , 10.31) - - -

ADA_STD+

csDMARD ETN_STD+csDMARD 0.31 (-1.49, 2.11) 0.004 (-3.77 , 3.78) -0.10 (-1.70, 1.49) 0.93 (-0.71, 2.57) -

TOC_8

(IV)+csDMARD

0.32 (-1.17, 1.80) -0.01 (-2.93 , 2.91) 0.30 (-1.26, 1.86) 0.94 (-0.68, 2.55) -

CERTO_STD+

csDMARD

0.06 (-1.75, 1.87) -0.003 (-4.15 , 4.15) 0.02 (-1.91, 1.94) 0.94 (-1.00, 2.87) -

BAR_4+

csDMARD

0.30 (-1.50, 2.10) -0.01 (-3.42 , 3.39) -0.05 (-1.92, 1.82) 0.92 (-0.96, 2.80) -

SIR_100+

csDMARD

-0.08 (-2.61, 2.46) -0.04 (-9.54 , 9.46) - 0.96 (-2.34, 4.27) -

SIR_50+

csDMARD

-0.07 (-2.59, 2.44) -0.03 (-9.94 , 9.88) - 0.95 (-2.36, 4.27) -

TOC_8

(IV)+csDMARD ADA_STD+csDMARD 0.01 (-1.74, 1.75) -0.02 (-3.73 , 3.70) 0.41 (-1.11, 1.94) 0.01 (-1.43, 1.46) -

CERTO_STD+

csDMARD

-0.25 (-2.27, 1.78) -0.002 (-4.87 , 4.86) 0.13 (-1.77, 2.02) 0.01 (-1.79, 1.80) -

BAR_4+

csDMARD

-0.01 (-2.02, 2.00) -0.02 (-4.15 , 4.11) 0.06 (-1.79, 1.91) -0.002 (-1.75, 1.75) -0.02 (-1.84, 1.80)

574


Difference of log

OR (95% CI) - All

Drug Doses


(95% CI) - Studies

Published in 2007

Onward

Difference log OR

(95% CI) of SA vs

REF - EOT Data for

Adaptive Studies

Difference of log

OR (95% CI) -

Restricted Time

Point Analysis (12

to 16 Weeks)

Difference log OR

(95% CI) of SA vs

REF - Studies With

Patients Who Were

All IR MTX and

Biologic Naïve

SIR_100+

csDMARD

-0.38 (-3.05, 2.29) -0.03 (-10.10 , 10.05) - 0.02 (-3.20, 3.24) -0.03 (-3.21, 3.15)

SIR_50+

csDMARD

-0.39 (-3.04, 2.27) -0.02 (-10.48 , 10.44) - 0.003 (-3.23, 3.24) -0.03 (-3.22, 3.15)

CERTO_STD+

csDMARD

TOC_8

(IV)+csDMARD -0.25 (-2.01, 1.50) 0.01 (-4.70 , 4.73) -0.29 (-2.15, 1.58) -0.005 (-1.78, 1.77) -

BAR_4+

csDMARD

-0.003 (-1.72, 1.72) 0.01 (-3.96 , 3.98) -0.35 (-2.15, 1.46) -0.01 (-1.72, 1.71) -

SIR_100+

csDMARD -0.39 (-2.88, 2.10) -0.02 (-10.12 , 10.07) - 0.01 (-3.20, 3.23) -

SIR_50+

csDMARD -0.38 (-2.86, 2.10) -0.01 (-10.48 , 10.45) - 0.01 (-3.20, 3.22) -

BAR_4+

csDMARD

CERTO_STD+

csDMARD 0.25 (-1.77, 2.26) -0.001 (-4.26 , 4.26) -0.06 (-2.20, 2.08) -0.003 (-2.04, 2.03) -

SIR_100+

csDMARD -0.15 (-2.83, 2.54) -0.03 (-10.12 , 10.05) - 0.01 (-3.37, 3.39) -

SIR_50+

csDMARD -0.14 (-2.82, 2.53) -0.03 (-10.48 , 10.42) - 0.01 (-3.39, 3.40) -

SIR_100+

csDMARD BAR_4+csDMARD -0.38 (-3.05, 2.28) -0.02 (-10.71 , 10.68) - 0.02 (-3.33, 3.38) -0.03 (-3.25, 3.19)

SIR_50+

csDMARD -0.39 (-3.05, 2.28) -0.02 (-11.10 , 11.06) - 0.01 (-3.35, 3.37) -0.03 (-3.26, 3.19)

SIR_50+

csDMARD SIR_100+csDMARD 0.01 (-1.78, 1.79) 0.01 (-4.40 , 4.43) - 0.003 (-1.77, 1.78) 0.01 (-1.73, 1.75)



575



ADA = adalimumab; BAR_4 = 4mg baricitinib; CERTO = certolizumab pegol; CI = confidence interval; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN

= etanercept; IV = intravenous; MTX = methotrexate; log OR = log odds ratio; SIR_50 = sirukumab 50mg every two weeks ; SIR_100= sirukumab 100mg

every two weeks ; STD = standard dose; TOC_8 = 8mg/kg tocilizumab

576

Table 56. DAS28 Sensitivity Analysis Results Compared to the Reference Case – Conventional Synthetic

DMARD as a Common Comparator


ETN_STD Placebo+csDMARD 0.01 (-3.86, 3.89)

ETN_STD+csDMARD

-0.01 (-2.67, 2.66)

ADA_STD+csDMARD

0.00 (-3.27, 3.27)

TOC_8 (IV)+csDMARD

-0.002 (-2.97, 2.97)

INF_STD+csDMARD

0.02 (-4.15, 4.19)

BAR_4+csDMARD

0.005 (-4.22, 4.23)

SIR_100+csDMARD

-0.01 (-4.15, 4.14)

SIR_50+csDMARD

-0.001 (-4.20, 4.20)

ETN_STD+csDMARD ETN_STD -0.01 (-3.90, 3.88)

ADA_STD+csDMARD

-0.004 (-4.68, 4.67)

TOC_8 (IV)+csDMARD

-0.01 (-4.88, 4.87)

INF_STD+csDMARD

0.01 (-5.71, 5.72)

BAR_4+csDMARD

-0.01 (-5.73, 5.72)

SIR_100+csDMARD -0.01 (-5.73, 5.70)

SIR_50+csDMARD -0.01 (-5.77, 5.76)

ADA_STD+csDMARD ETN_STD+ csDMARD 0.01 (-3.23, 3.26)

TOC_8 (IV)+csDMARD 0.01 (-3.96, 3.98)

INF_STD+csDMARD 0.03 (-4.91, 4.96)

BAR_4+csDMARD -0.004 (-4.97, 4.96)

577


SIR_100+csDMARD 0.001 (-4.93, 4.93)

SIR_50+csDMARD 0.01 (-4.94, 4.96)

TOC_8 (IV)+csDMARD ADA_STD+ csDMARD 0.01 (-4.39, 4.40)

INF_STD+csDMARD 0.02 (-5.33, 5.38)

BAR_4+csDMARD -0.01 (-5.33, 5.31)

SIR_100+csDMARD -0.02 (-5.31, 5.27)

SIR_50+csDMARD -0.002 (-5.33, 5.33)

INF_STD+csDMARD TOC_8 (IV)+csDMARD 0.01 (-5.12, 5.14)

BAR_4+csDMARD 0.01 (-5.12, 5.13)

SIR_100+csDMARD -0.004 (-5.10, 5.09)

SIR_50+csDMARD -0.001 (-5.14, 5.14)

BAR_4+csDMARD INF_STD+csDMARD -0.02 (-5.95, 5.91)

SIR_100+csDMARD -0.002 (-5.93, 5.93)

SIR_50+csDMARD -0.02 (-5.97, 5.92)


SIR_50+csDMARD 0.01 (-5.99, 6.00)

SIR_50+csDMARD SIR_100+csDMARD 0.005 (-4.20, 4.21)

Difference in standardized mean difference represents the comparison of the sensitivity analysis to the reference case. Each column

presents the comparison of one sensitivity analysis to the reference case. Only treatment comparisons from the sensitivity analysis

that were also present in the reference case were compared; dashes indicate where the treatment comparison was not present in the

sensitivity analysis. Pink cells indicate the sensitivity analysis has a lower effect estimate than the reference case. Green cells

indicate the sensitivity analysis has a higher effect estimate than the reference case.

ADA = adalimumab; BAR_4 = 4mg baricitinib; CI = confidence interval; csDMARD = conventional synthetic disease-modifying anti-

rheumatic drug; ETN = etanercept; INF = infliximab; IV = intravenous; SIR_50 = sirukumab 50mg every two weeks; SIR_100=

sirukumab 100mg every two weeks; STD = standard dose; TOC_8 = 8mg/kg tocilizumab

578

Table 57. HAQ-DI Sensitivity Analysis Results Compared to the Reference Case – Conventional Synthetic



ETN_STD+csDMARD PLACEBO+csDMARD -0.01 (-6.24, 6.23)

TOC_8 (IV)+csDMARD

0.002 (-6.23, 6.24)

BAR_4+csDMARD

0.00 (-6.24, 6.24)

SIR_100+csDMARD

0.02 (-6.26, 6.29)

SIR_50+csDMARD

0.01 (-6.25, 6.27)

TOC_8 (IV)+csDMARD ETN_STD+csDMARD -0.003 (-8.84, 8.84)

BAR_4+csDMARD

-0.001 (-8.80, 8.80)

SIR_100+csDMARD

0.02 (-8.81, 8.86)

SIR_50+csDMARD

0.02 (-8.85, 8.88)

BAR_4+csDMARD TOC_8 (IV)+csDMARD -0.01 (-8.88, 8.85)

SIR_100+csDMARD

0.01 (-8.83, 8.84)

SIR_50+csDMARD

0.01 (-8.84, 8.86)


SIR_50+csDMARD 0.01 (-8.87, 8.88)

SIR_50+csDMARD SIR_100+csDMARD 0.004 (-6.25, 6.26)

Difference in mean difference represents the comparison of the sensitivity analysis to the reference case. Each column presents the comparison of one sensitivity analysis to the reference case. Only treatment comparisons from the sensitivity analysis that were also present in the reference case were compared; dashes indicate where the treatment comparison was not present in the sensitivity analysis. Pink cells indicate the sensitivity analysis has a lower effect estimate than the reference case. Green cells indicate the sensitivity analysis has a higher effect estimate than the reference case.

579

BAR_4 = 4mg baricitinib; CI = confidence interval; csCSDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN = etanercept; IV = intravenous; ; SIR_50 = sirukumab 50mg every two weeks ; SIR_100= sirukumab 100mg every two weeks; STD = standard dose; TOC_8 = 8mg/kg tocilizumab

Table 58. WDAE Sensitivity Analysis Results Compared to the Reference Case – Conventional Synthetic



Difference of log

OR (95% CI) - All

Drug Doses

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies



Time Point Analysis

(12 to 16 Weeks)

ETN_STD PLACEBO+

csDMARD -0.02 (-1.29, 1.24) 0.01 (-1.25, 1.27) -

ETN_STD+

csDMARD

-0.01 (-1.22, 1.20) 0.003 (-1.22, 1.23) 0.86 (-1.35, 3.07)

ADA_STD+

csDMARD

-0.03 (-1.64, 1.58) -0.002 (-1.62, 1.62) -

TOC_8

(IV)+cscsDMARD

0.01 (-0.71, 0.72) 0.06 (-0.65, 0.78) 0.002 (-0.72, 0.73)

CERTO_STD+

csDMARD

0.001 (-1.11, 1.11) -0.002 (-1.12, 1.12) -0.01 (-1.13, 1.11)

BAR_4+ csDMARD

-0.001 (-1.21, 1.21) 0.01 (-1.11, 1.13) 0.02 (-1.19, 1.23)

ETN_STD+

csDMARD ETN_STD 0.002 (-0.99, 0.99) 0.01 (-0.99, 1.00) -

ADA_STD+

csDMARD

-0.003 (-1.44, 1.43) -0.003 (-1.45, 1.45) -

TOC_8

(IV)+csDMARD

0.04 (-1.42, 1.50) 0.06 (-1.39, 1.51) -

CERTO_STD+

csDMARD

0.03 (-1.65, 1.71) -0.001 (-1.69, 1.69) -

BAR_4+ csDMARD

0.03 (-1.72, 1.78) 0.001 (-1.68, 1.68) -

ADA_STD+

csDMARD

ETN_STD+

csDMARD -0.004 (-1.05, 1.04) -0.005 (-1.06, 1.05) -

TOC_8

(IV)+csDMARD 0.03 (-1.39, 1.45) 0.06 (-1.38, 1.49) -0.87 (-3.18, 1.45)

CERTO_STD+

csDMARD 0.02 (-1.62, 1.66) -0.02 (-1.68, 1.64) -0.88 (-3.36, 1.59)

BAR_4+ csDMARD 0.03 (-1.70, 1.75) 0.003 (-1.64, 1.65) -0.86 (-3.38, 1.65)

580


Difference of log

OR (95% CI) - All

Drug Doses

Difference log OR

(95% CI) of SA vs

REF - EOT Data

for Adaptive

Studies



Time Point Analysis

(12 to 16 Weeks)

TOC_8

(IV)+csDMARD

ADA_STD+

csDMARD 0.05 (-1.72, 1.81) 0.07 (-1.71, 1.84) -

CERTO_STD+

csDMARD 0.03 (-1.92, 1.97) -0.01 (-1.96, 1.95) -

BAR_4+ csDMARD 0.03 (-1.98, 2.04) 0.005 (-1.95, 1.96) -

CERTO_STD+

csDMARD

TOC_8

(IV)+csDMARD -0.004 (-1.33, 1.32) -0.07 (-1.40, 1.26) -0.01 (-1.36, 1.33)

BAR_4+ csDMARD -0.004 (-1.41, 1.41) -0.06 (-1.39, 1.28) 0.02 (-1.39, 1.43)

BAR_4+ csDMARD CERTO_STD+

csDMARD 0.004 (-1.64, 1.65) 0.01 (-1.59, 1.60) 0.04 (-1.62, 1.69)

Difference in log odds ratios represents the comparison of the sensitivity analysis to the reference case. Each column presents the





ADA = adalimumab; BAR_4 = 4mg baricitinib; CERTO = certolizumab pegol; CI = confidence interval; csDMARD = conventional

synthetic disease-modifying anti-rheumatic drug; ETN = etanercept; IV = intravenous; MTX = methotrexate; log OR = log odds ratio;

STD = standard dose; TOC_8 = 8mg/kg tocilizumab

581

APPENDIX 9: DETAILED NMA RESULTS FOR THE OUTCOMES ACR20

AND ACR70 AMONG PATIENTS WITH INADEQUATE RESPONSE TO

METHOTREXATE

Table 59. ACR20, Methotrexate as a Common Comparator: Odds Ratios, Relative Risks and Risk Difference

for All Treatment Comparisons – Random Effects Model


Placebo Placebo+MTX 0.18 (0.05, 0.71) 0.24 (0.07, 0.78) -0.23 (-0.29, -0.07)

csDMARD+MTX 1.22 (0.49, 3.27) 1.15 (0.58, 1.94) 0.04 (-0.13, 0.28)

LEF_10 0.46 (0.09, 2.66) 0.55 (0.12, 1.77) -0.14 (-0.27, 0.23)

MTX+HCQ 2.30 (0.42, 14.13) 1.64 (0.51, 2.82) 0.20 (-0.15, 0.56)

MTX+SSZ 1.03 (0.18, 6.56) 1.02 (0.25, 2.44) 0.01 (-0.23, 0.44)

MTX+SSZ+HCQ 4.68 (1.57, 15.98) 2.20 (1.34, 2.88) 0.37 (0.10, 0.57)

ETN_STD 2.12 (1.06, 4.45) 1.58 (1.04, 2.18) 0.18 (0.01, 0.36)

ETN_STD+MTX 4.60 (2.58, 8.71) 2.18 (1.73, 2.62) 0.36 (0.23, 0.49)

ABA_STD (IV)+MTX 4.00 (2.46, 6.65) 2.08 (1.69, 2.45) 0.33 (0.21, 0.44)

SAR_200 0.48 (0.07, 3.84) 0.57 (0.09, 2.05) -0.13 (-0.28, 0.32)

TOF_STD+MTX 5.44 (2.99, 10.48) 2.30 (1.84, 2.72) 0.40 (0.26, 0.52)

TOF_STD 0.94 (0.16, 5.68) 0.96 (0.22, 2.34) -0.01 (-0.24, 0.41)

ADA_STD+MTX 4.19 (2.92, 6.04) 2.11 (1.82, 2.40) 0.34 (0.26, 0.42)

TOC_4 (IV) 2.67 (1.00, 7.49) 1.77 (1.00, 2.51) 0.24 (0.0003, 0.46)

TOC_8 (IV) 4.38 (2.39, 8.35) 2.15 (1.67, 2.59) 0.35 (0.21, 0.48)

TOC_4 (IV)+MTX 2.73 (1.55, 4.92) 1.78 (1.32, 2.24) 0.24 (0.10, 0.38)

TOC_8 (IV)+MTX 3.86 (2.27, 6.84) 2.05 (1.63, 2.47) 0.32 (0.20, 0.44)

GOL_STD (SC) 0.79 (0.15, 4.61) 0.84 (0.20, 2.19) -0.05 (-0.24, 0.36)

GOL_STD

(SC)+MTX 3.66 (2.10, 6.35) 2.01 (1.57, 2.43) 0.31 (0.18, 0.43)

GOL_STD (IV)+MTX 4.34 (1.68, 11.00) 2.14 (1.39, 2.72) 0.35 (0.12, 0.52)

INF_STD+MTX 3.09 (1.93, 5.02) 1.88 (1.50, 2.26) 0.27 (0.15, 0.38)

582

CERTO_STD 1.82 (0.41, 9.67) 1.45 (0.50, 2.64) 0.14 (-0.15, 0.50)

CERTO_STD+MTX 5.62 (3.59, 9.08) 2.32 (1.99, 2.64) 0.41 (0.31, 0.49)

RIT_STD 3.15 (0.89, 10.92) 1.89 (0.92, 2.72) 0.28 (-0.02, 0.52)

RIT_STD+MTX 4.49 (1.24, 16.35) 2.16 (1.15, 2.88) 0.36 (0.05, 0.57)

ADA_STD 0.36 (0.06, 2.20) 0.45 (0.09, 1.61) -0.17 (-0.28, 0.19)

BAR_4+MTX 4.49 (2.47, 8.17) 2.16 (1.70, 2.58) 0.36 (0.22, 0.48)

HD203+MTX 6.39 (1.77, 24.61) 2.40 (1.43, 3.02) 0.43 (0.13, 0.61)

SB4+MTX 5.06 (1.74, 16.11) 2.25 (1.41, 2.89) 0.38 (0.13, 0.57)

ANBAI+MTX 6.03 (2.34, 15.97) 2.36 (1.65, 2.89) 0.42 (0.20, 0.57)

CT-P13+MTX 4.41 (1.89, 10.70) 2.15 (1.48, 2.71) 0.35 (0.15, 0.52)

SB2+MTX 2.68 (0.92, 7.66) 1.77 (0.94, 2.53) 0.24 (-0.02, 0.47)

SB5+MTX 4.24 (1.51, 11.84) 2.12 (1.31, 2.76) 0.35 (0.09, 0.53)

ZRC-3197+MTX 3.85 (1.07, 14.27) 2.05 (1.05, 2.83) 0.32 (0.01, 0.56)

ABP501+MTX 4.72 (1.74, 12.85) 2.20 (1.42, 2.80) 0.37 (0.13, 0.54)

DMARD+MTX Placebo 6.91 (1.57, 30.65) 4.75 (1.39, 16.81) 0.27 (0.07, 0.50)

LEF_10 2.60 (0.89, 7.26) 2.27 (0.90, 5.04) 0.09 (-0.01, 0.36)

MTX+HCQ 12.99 (1.68, 103.50) 6.55 (1.50, 25.89) 0.42 (0.06, 0.78)

MTX+SSZ 5.79 (0.70, 48.35) 4.10 (0.73, 19.18) 0.23 (-0.04, 0.65)

MTX+SSZ+HCQ 26.46 (5.27, 134.20) 9.00 (2.73, 31.58) 0.59 (0.31, 0.80)

ETN_STD 11.99 (3.64, 37.09) 6.55 (2.29, 19.93) 0.40 (0.24, 0.55)

ETN_STD+MTX 26.02 (7.05, 91.48) 9.15 (2.92, 30.79) 0.59 (0.42, 0.71)

ABA_STD (IV)+MTX 22.63 (5.09, 92.49) 8.72 (2.60, 31.12) 0.56 (0.36, 0.69)

SAR_200 2.69 (0.57, 12.75) 2.32 (0.59, 7.23) 0.10 (-0.03, 0.47)

TOF_STD+MTX 30.87 (6.62, 133.10) 9.64 (2.85, 34.17) 0.62 (0.42, 0.76)

TOF_STD 5.29 (1.58, 17.91) 3.79 (1.49, 9.38) 0.21 (0.03, 0.54)

ADA_STD+MTX 23.71 (5.55, 92.59) 8.90 (2.66, 31.69) 0.57 (0.39, 0.67)

TOC_4 (IV) 14.97 (2.72, 80.14) 7.29 (1.98, 27.58) 0.46 (0.19, 0.70)

TOC_8 (IV) 24.79 (5.51, 108.10) 8.97 (2.68, 32.12) 0.58 (0.37, 0.73)

583

TOC_4 (IV)+MTX 15.31 (3.42, 65.66) 7.40 (2.20, 26.86) 0.47 (0.26, 0.62)

TOC_8 (IV)+MTX 21.70 (4.93, 93.15) 8.56 (2.58, 30.73) 0.55 (0.35, 0.69)

GOL_STD (SC) 4.44 (1.52, 12.77) 3.37 (1.45, 7.59) 0.18 (0.03, 0.48)

GOL_STD

(SC)+MTX 20.89 (4.50, 85.44) 8.44 (2.47, 30.12) 0.54 (0.33, 0.68)

GOL_STD (IV)+MTX 24.61 (4.43, 115.70) 8.85 (2.52, 31.62) 0.57 (0.30, 0.76)

INF_STD+MTX 17.63 (3.94, 68.99) 7.93 (2.34, 27.91) 0.50 (0.30, 0.63)

CERTO_STD 10.39 (4.76, 23.18) 5.81 (2.96, 11.38) 0.37 (0.13, 0.61)

CERTO_STD+MTX 31.99 (7.30, 129.60) 9.75 (2.93, 34.57) 0.63 (0.45, 0.75)

RIT_STD 17.71 (2.67, 108.30) 7.69 (1.96, 29.26) 0.50 (0.16, 0.76)

RIT_STD+MTX 25.46 (3.73, 162.10) 8.87 (2.34, 32.93) 0.58 (0.24, 0.81)

ADA_STD 2.00 (0.62, 6.71) 1.84 (0.65, 4.89) 0.06 (-0.03, 0.32)

BAR_4+MTX 25.60 (5.49, 105.50) 9.09 (2.68, 32.20) 0.58 (0.37, 0.72)

HD203+MTX 35.73 (6.25, 207.20) 9.75 (2.92, 33.39) 0.65 (0.34, 0.84)

SB4+MTX 28.62 (5.60, 135.10) 9.24 (2.80, 31.75) 0.60 (0.33, 0.80)

ANBAI+MTX 34.22 (6.22, 168.40) 9.80 (2.81, 34.44) 0.64 (0.38, 0.81)

CT-P13+MTX 25.14 (4.84, 116.00) 8.99 (2.61, 31.91) 0.58 (0.33, 0.76)

SB2+MTX 15.27 (2.66, 78.73) 7.29 (1.95, 27.05) 0.46 (0.17, 0.70)

SB5+MTX 23.70 (4.12, 126.80) 8.72 (2.44, 31.75) 0.57 (0.28, 0.78)

ZRC-3197+MTX 21.86 (3.14, 140.40) 8.38 (2.14, 31.50) 0.55 (0.20, 0.80)

ABP501+MTX 26.77 (4.64, 135.90) 9.08 (2.54, 32.41) 0.59 (0.31, 0.79)

LEF_10 csDMARD+MTX 0.38 (0.06, 2.36) 0.49 (0.10, 1.70) -0.17 (-0.44, 0.19)

MTX+HCQ 1.87 (0.30, 11.51) 1.41 (0.44, 3.14) 0.15 (-0.24, 0.52)

MTX+SSZ 0.84 (0.14, 5.37) 0.90 (0.22, 2.40) -0.04 (-0.35, 0.38)

MTX+SSZ+HCQ 3.83 (1.22, 13.18) 1.88 (1.10, 3.56) 0.31 (0.05, 0.55)

ETN_STD 1.73 (0.68, 4.21) 1.37 (0.82, 2.50) 0.13 (-0.09, 0.32)

ETN_STD+MTX 3.74 (1.86, 7.66) 1.89 (1.25, 3.35) 0.31 (0.14, 0.45)

ABA_STD (IV)+MTX 3.27 (1.10, 9.34) 1.81 (1.04, 3.64) 0.29 (0.02, 0.49)

584

SAR_200 0.39 (0.05, 3.37) 0.50 (0.08, 1.94) -0.16 (-0.45, 0.28)

TOF_STD+MTX 4.45 (1.42, 13.70) 2.00 (1.14, 4.06) 0.35 (0.08, 0.57)

TOF_STD 0.78 (0.11, 5.00) 0.85 (0.19, 2.37) -0.05 (-0.38, 0.37)

ADA_STD+MTX 3.43 (1.20, 9.08) 1.85 (1.08, 3.65) 0.30 (0.04, 0.49)

TOC_4 (IV) 2.18 (0.55, 8.45) 1.52 (0.71, 3.29) 0.18 (-0.14, 0.48)

TOC_8 (IV) 3.58 (1.12, 11.01) 1.86 (1.05, 3.78) 0.30 (0.03, 0.53)

TOC_4 (IV)+MTX 2.23 (0.74, 6.48) 1.55 (0.86, 3.16) 0.19 (-0.07, 0.42)

TOC_8 (IV)+MTX 3.14 (1.05, 9.24) 1.78 (1.02, 3.57) 0.27 (0.01, 0.49)

GOL_STD (SC) 0.64 (0.11, 4.03) 0.74 (0.17, 2.16) -0.09 (-0.38, 0.32)

GOL_STD

(SC)+MTX 2.99 (0.96, 8.80) 1.75 (0.98, 3.55) 0.26 (-0.01, 0.48)

GOL_STD (IV)+MTX 3.54 (0.88, 12.79) 1.84 (0.94, 3.78) 0.30 (-0.03, 0.55)

INF_STD+MTX 2.52 (0.85, 7.21) 1.64 (0.93, 3.30) 0.22 (-0.04, 0.44)

CERTO_STD 1.50 (0.28, 8.24) 1.26 (0.42, 2.87) 0.09 (-0.26, 0.46)

CERTO_STD+MTX 4.61 (1.56, 12.84) 2.02 (1.18, 4.01) 0.36 (0.10, 0.56)

RIT_STD 2.58 (0.51, 12.23) 1.64 (0.67, 3.54) 0.22 (-0.16, 0.54)

RIT_STD+MTX 3.68 (0.72, 18.10) 1.86 (0.84, 3.95) 0.30 (-0.08, 0.60)

ADA_STD 0.29 (0.04, 2.01) 0.39 (0.08, 1.53) -0.20 (-0.47, 0.15)

BAR_4+MTX 3.66 (1.15, 10.93) 1.88 (1.06, 3.83) 0.31 (0.03, 0.52)

HD203+MTX 5.20 (1.35, 20.32) 2.04 (1.14, 3.92) 0.37 (0.07, 0.61)

SB4+MTX 4.13 (1.29, 13.79) 1.92 (1.12, 3.62) 0.33 (0.06, 0.56)

ANBAI+MTX 4.91 (1.25, 18.72) 2.04 (1.10, 4.11) 0.37 (0.05, 0.61)

CT-P13+MTX 3.61 (0.97, 12.59) 1.86 (0.99, 3.83) 0.30 (-0.01, 0.55)

SB2+MTX 2.19 (0.51, 8.95) 1.53 (0.68, 3.32) 0.19 (-0.16, 0.48)

SB5+MTX 3.46 (0.82, 13.67) 1.83 (0.91, 3.83) 0.29 (-0.05, 0.56)

ZRC-3197+MTX 3.15 (0.61, 15.31) 1.76 (0.76, 3.80) 0.27 (-0.11, 0.58)

ABP501+MTX 3.88 (0.95, 14.29) 1.89 (0.98, 3.89) 0.32 (-0.01, 0.57)

MTX+HCQ LEF_10 4.99 (0.50, 51.22) 2.80 (0.64, 14.57) 0.31 (-0.14, 0.71)

585

MTX+SSZ 2.24 (0.22, 23.41) 1.79 (0.32, 10.36) 0.13 (-0.28, 0.57)

MTX+SSZ+HCQ 10.19 (1.49, 70.94) 3.89 (1.19, 18.03) 0.48 (0.09, 0.74)

ETN_STD 4.60 (0.94, 21.86) 2.84 (0.97, 11.75) 0.30 (-0.01, 0.50)

ETN_STD+MTX 10.03 (1.86, 52.91) 3.95 (1.27, 17.39) 0.49 (0.14, 0.67)

ABA_STD (IV)+MTX 8.83 (1.40, 50.69) 3.79 (1.16, 17.49) 0.47 (0.08, 0.65)

SAR_200 1.04 (0.17, 6.87) 1.03 (0.22, 4.31) 0.004 (-0.27, 0.35)

TOF_STD+MTX 11.89 (1.84, 72.05) 4.17 (1.27, 19.37) 0.53 (0.14, 0.72)

TOF_STD 2.03 (0.42, 10.08) 1.67 (0.51, 5.71) 0.11 (-0.15, 0.44)

ADA_STD+MTX 9.18 (1.49, 50.61) 3.84 (1.18, 17.88) 0.48 (0.09, 0.64)

TOC_4 (IV) 5.83 (0.75, 41.71) 3.14 (0.86, 15.44) 0.36 (-0.07, 0.65)

TOC_8 (IV) 9.59 (1.49, 57.08) 3.89 (1.18, 17.98) 0.48 (0.10, 0.69)

TOC_4 (IV)+MTX 5.95 (0.94, 35.53) 3.22 (0.97, 15.22) 0.37 (-0.01, 0.58)

TOC_8 (IV)+MTX 8.42 (1.35, 49.89) 3.71 (1.14, 17.21) 0.45 (0.07, 0.65)

GOL_STD (SC) 1.70 (0.40, 7.57) 1.48 (0.50, 4.94) 0.07 (-0.16, 0.37)

GOL_STD

(SC)+MTX 8.02 (1.24, 46.54) 3.66 (1.10, 17.03) 0.44 (0.05, 0.64)

GOL_STD (IV)+MTX 9.45 (1.24, 61.87) 3.84 (1.10, 17.75) 0.47 (0.05, 0.72)

INF_STD+MTX 6.86 (1.09, 37.92) 3.44 (1.04, 15.91) 0.40 (0.02, 0.59)

CERTO_STD 4.00 (1.10, 14.89) 2.51 (1.06, 7.68) 0.25 (0.02, 0.52)

CERTO_STD+MTX 12.35 (1.98, 70.74) 4.23 (1.29, 19.78) 0.54 (0.16, 0.71)

RIT_STD 6.81 (0.79, 54.45) 3.32 (0.88, 16.17) 0.39 (-0.05, 0.71)

RIT_STD+MTX 9.73 (1.11, 81.95) 3.79 (1.05, 18.28) 0.47 (0.02, 0.77)

ADA_STD 0.77 (0.16, 3.95) 0.81 (0.22, 3.01) -0.03 (-0.29, 0.21)

BAR_4+MTX 9.80 (1.54, 56.99) 3.90 (1.20, 18.09) 0.49 (0.10, 0.68)

HD203+MTX 13.77 (1.72, 106.30) 4.23 (1.26, 19.36) 0.54 (0.12, 0.80)

SB4+MTX 11.00 (1.59, 72.35) 4.00 (1.23, 17.89) 0.50 (0.11, 0.75)

ANBAI+MTX 13.23 (1.76, 90.23) 4.25 (1.26, 19.74) 0.54 (0.13, 0.77)

CT-P13+MTX 9.67 (1.35, 60.88) 3.88 (1.14, 17.88) 0.48 (0.07, 0.71)

586

SB2+MTX 5.87 (0.75, 41.17) 3.14 (0.86, 15.13) 0.36 (-0.07, 0.65)

SB5+MTX 9.17 (1.23, 64.67) 3.78 (1.10, 17.76) 0.46 (0.05, 0.73)

ZRC-3197+MTX 8.43 (0.93, 71.83) 3.62 (0.97, 17.51) 0.44 (-0.02, 0.75)

ABP501+MTX 10.33 (1.33, 70.89) 3.92 (1.13, 18.06) 0.49 (0.07, 0.74)

MTX+SSZ MTX+HCQ 0.45 (0.11, 1.77) 0.65 (0.23, 1.37) -0.16 (-0.46, 0.12)

MTX+SSZ+HCQ 2.03 (0.53, 8.19) 1.31 (0.84, 3.50) 0.16 (-0.12, 0.46)

ETN_STD 0.92 (0.16, 5.17) 0.96 (0.51, 3.01) -0.02 (-0.39, 0.35)

ETN_STD+MTX 1.98 (0.38, 10.38) 1.32 (0.79, 4.07) 0.16 (-0.17, 0.50)

ABA_STD (IV)+MTX 1.75 (0.26, 10.27) 1.26 (0.71, 4.15) 0.13 (-0.24, 0.50)

SAR_200 0.21 (0.02, 3.08) 0.37 (0.05, 1.96) -0.30 (-0.72, 0.23)

TOF_STD+MTX 2.36 (0.35, 14.85) 1.39 (0.78, 4.52) 0.20 (-0.18, 0.58)

TOF_STD 0.41 (0.04, 4.67) 0.61 (0.13, 2.48) -0.19 (-0.65, 0.33)

ADA_STD+MTX 1.82 (0.29, 10.37) 1.28 (0.73, 4.13) 0.14 (-0.23, 0.50)

TOC_4 (IV) 1.16 (0.15, 8.62) 1.07 (0.49, 3.60) 0.03 (-0.39, 0.46)

TOC_8 (IV) 1.92 (0.28, 11.72) 1.30 (0.72, 4.22) 0.15 (-0.23, 0.53)

TOC_4 (IV)+MTX 1.19 (0.18, 7.14) 1.08 (0.58, 3.54) 0.04 (-0.34, 0.42)

TOC_8 (IV)+MTX 1.68 (0.26, 10.35) 1.24 (0.69, 4.07) 0.12 (-0.25, 0.50)

GOL_STD (SC) 0.34 (0.03, 3.46) 0.54 (0.12, 2.12) -0.22 (-0.65, 0.27)

GOL_STD

(SC)+MTX 1.60 (0.24, 9.41) 1.22 (0.68, 3.97) 0.11 (-0.27, 0.49)

GOL_STD (IV)+MTX 1.87 (0.24, 13.55) 1.29 (0.64, 4.33) 0.15 (-0.28, 0.56)

INF_STD+MTX 1.35 (0.20, 7.85) 1.14 (0.63, 3.74) 0.07 (-0.31, 0.44)

CERTO_STD 0.80 (0.09, 7.16) 0.90 (0.28, 3.08) -0.05 (-0.51, 0.43)

CERTO_STD+MTX 2.45 (0.38, 14.53) 1.41 (0.81, 4.55) 0.21 (-0.16, 0.57)

RIT_STD 1.36 (0.15, 11.54) 1.14 (0.46, 3.94) 0.07 (-0.40, 0.52)

RIT_STD+MTX 1.95 (0.22, 16.57) 1.30 (0.58, 4.30) 0.15 (-0.31, 0.59)

ADA_STD 0.15 (0.01, 1.78) 0.29 (0.05, 1.47) -0.34 (-0.74, 0.11)

BAR_4+MTX 1.95 (0.29, 11.91) 1.32 (0.73, 4.31) 0.16 (-0.23, 0.53)

587

HD203+MTX 2.75 (0.36, 19.90) 1.43 (0.73, 4.55) 0.22 (-0.20, 0.61)

SB4+MTX 2.20 (0.32, 14.49) 1.35 (0.71, 4.18) 0.18 (-0.22, 0.56)

ANBAI+MTX 2.62 (0.33, 18.18) 1.42 (0.75, 4.67) 0.21 (-0.20, 0.60)

CT-P13+MTX 1.93 (0.26, 12.78) 1.30 (0.67, 4.20) 0.15 (-0.26, 0.55)

SB2+MTX 1.17 (0.14, 8.57) 1.07 (0.46, 3.60) 0.04 (-0.41, 0.46)

SB5+MTX 1.85 (0.23, 13.27) 1.28 (0.62, 4.20) 0.14 (-0.30, 0.55)

ZRC-3197+MTX 1.69 (0.18, 13.88) 1.23 (0.52, 4.16) 0.12 (-0.37, 0.56)

ABP501+MTX 2.06 (0.26, 14.67) 1.32 (0.66, 4.30) 0.16 (-0.27, 0.57)

MTX+SSZ+HCQ MTX+SSZ 4.54 (1.12, 18.79) 2.11 (1.03, 7.24) 0.34 (0.02, 0.58)

ETN_STD 2.06 (0.34, 11.61) 1.53 (0.64, 6.17) 0.17 (-0.25, 0.46)

ETN_STD+MTX 4.46 (0.82, 23.35) 2.13 (0.94, 8.52) 0.35 (-0.04, 0.60)

ABA_STD (IV)+MTX 3.92 (0.56, 24.00) 2.04 (0.83, 8.54) 0.32 (-0.12, 0.60)

SAR_200 0.47 (0.03, 6.75) 0.58 (0.07, 3.84) -0.12 (-0.58, 0.36)

TOF_STD+MTX 5.27 (0.77, 34.22) 2.24 (0.93, 9.55) 0.39 (-0.05, 0.67)

TOF_STD 0.91 (0.08, 10.38) 0.94 (0.17, 5.07) -0.02 (-0.50, 0.45)

ADA_STD+MTX 4.08 (0.63, 23.48) 2.07 (0.87, 8.63) 0.34 (-0.10, 0.59)

TOC_4 (IV) 2.60 (0.33, 18.71) 1.71 (0.61, 7.49) 0.22 (-0.26, 0.57)

TOC_8 (IV) 4.24 (0.64, 26.81) 2.09 (0.86, 8.82) 0.34 (-0.10, 0.63)

TOC_4 (IV)+MTX 2.63 (0.39, 16.68) 1.73 (0.70, 7.43) 0.23 (-0.21, 0.52)

TOC_8 (IV)+MTX 3.75 (0.55, 23.08) 2.00 (0.82, 8.55) 0.31 (-0.13, 0.59)

GOL_STD (SC) 0.77 (0.07, 8.13) 0.84 (0.16, 4.48) -0.05 (-0.51, 0.40)

GOL_STD

(SC)+MTX 3.58 (0.51, 21.48) 1.96 (0.80, 8.26) 0.30 (-0.15, 0.58)

GOL_STD (IV)+MTX 4.15 (0.52, 29.63) 2.05 (0.79, 8.75) 0.33 (-0.14, 0.66)

INF_STD+MTX 3.02 (0.44, 18.11) 1.84 (0.74, 7.77) 0.26 (-0.19, 0.53)

CERTO_STD 1.79 (0.18, 17.24) 1.40 (0.38, 6.43) 0.12 (-0.36, 0.57)

CERTO_STD+MTX 5.49 (0.82, 32.60) 2.27 (0.95, 9.53) 0.40 (-0.04, 0.66)

RIT_STD 3.04 (0.32, 26.09) 1.80 (0.59, 8.06) 0.25 (-0.26, 0.64)

588

RIT_STD+MTX 4.38 (0.46, 36.44) 2.06 (0.73, 8.91) 0.33 (-0.17, 0.69)

ADA_STD 0.35 (0.03, 3.93) 0.46 (0.07, 2.84) -0.16 (-0.60, 0.23)

BAR_4+MTX 4.40 (0.62, 27.25) 2.11 (0.86, 8.89) 0.35 (-0.10, 0.63)

HD203+MTX 6.15 (0.79, 46.73) 2.28 (0.92, 9.41) 0.40 (-0.05, 0.72)

SB4+MTX 4.93 (0.70, 33.33) 2.15 (0.89, 8.87) 0.36 (-0.08, 0.67)

ANBAI+MTX 5.88 (0.71, 42.54) 2.30 (0.90, 9.65) 0.40 (-0.07, 0.71)

CT-P13+MTX 4.32 (0.56, 30.03) 2.09 (0.82, 8.97) 0.34 (-0.13, 0.65)

SB2+MTX 2.62 (0.31, 19.41) 1.71 (0.60, 7.34) 0.22 (-0.27, 0.57)

SB5+MTX 4.11 (0.50, 31.58) 2.04 (0.77, 8.89) 0.33 (-0.15, 0.66)

ZRC-3197+MTX 3.72 (0.39, 32.66) 1.96 (0.67, 8.55) 0.30 (-0.21, 0.67)

ABP501+MTX 4.55 (0.56, 33.04) 2.12 (0.81, 9.00) 0.35 (-0.13, 0.67)

ETN_STD MTX+SSZ+HCQ 0.45 (0.14, 1.36) 0.73 (0.48, 1.17) -0.19 (-0.41, 0.08)

ETN_STD+MTX 0.98 (0.36, 2.53) 0.99 (0.78, 1.51) -0.01 (-0.18, 0.22)

ABA_STD (IV)+MTX 0.85 (0.23, 2.83) 0.95 (0.68, 1.59) -0.04 (-0.27, 0.25)

SAR_200 0.10 (0.01, 0.97) 0.27 (0.04, 0.99) -0.47 (-0.76, -0.01)

TOF_STD+MTX 1.16 (0.30, 4.14) 1.05 (0.75, 1.75) 0.03 (-0.21, 0.32)

TOF_STD 0.20 (0.03, 1.48) 0.45 (0.10, 1.16) -0.36 (-0.69, 0.08)

ADA_STD+MTX 0.89 (0.25, 2.77) 0.96 (0.72, 1.59) -0.02 (-0.24, 0.25)

TOC_4 (IV) 0.57 (0.12, 2.42) 0.81 (0.43, 1.44) -0.13 (-0.45, 0.20)

TOC_8 (IV) 0.93 (0.24, 3.31) 0.98 (0.68, 1.65) -0.02 (-0.26, 0.28)

TOC_4 (IV)+MTX 0.58 (0.15, 2.02) 0.81 (0.54, 1.39) -0.13 (-0.37, 0.17)

TOC_8 (IV)+MTX 0.82 (0.22, 2.85) 0.93 (0.65, 1.58) -0.04 (-0.29, 0.25)

GOL_STD (SC) 0.17 (0.02, 1.12) 0.40 (0.09, 1.05) -0.39 (-0.70, 0.03)

GOL_STD

(SC)+MTX 0.78 (0.20, 2.63) 0.92 (0.63, 1.55) -0.05 (-0.30, 0.23)

GOL_STD (IV)+MTX 0.92 (0.20, 3.95) 0.97 (0.58, 1.69) -0.02 (-0.33, 0.30)

INF_STD+MTX 0.66 (0.18, 2.15) 0.86 (0.60, 1.43) -0.09 (-0.33, 0.19)

CERTO_STD 0.39 (0.07, 2.37) 0.68 (0.23, 1.35) -0.21 (-0.57, 0.18)

589

CERTO_STD+MTX 1.20 (0.34, 3.94) 1.06 (0.79, 1.75) 0.04 (-0.18, 0.32)

RIT_STD 0.67 (0.12, 3.62) 0.87 (0.40, 1.61) -0.09 (-0.46, 0.28)

RIT_STD+MTX 0.95 (0.17, 5.10) 0.98 (0.51, 1.73) -0.01 (-0.37, 0.33)

ADA_STD 0.08 (0.01, 0.56) 0.21 (0.04, 0.77) -0.51 (-0.77, -0.13)

BAR_4+MTX 0.96 (0.25, 3.30) 0.99 (0.68, 1.64) -0.01 (-0.26, 0.28)

HD203+MTX 1.34 (0.29, 6.18) 1.08 (0.66, 1.76) 0.06 (-0.25, 0.35)

SB4+MTX 1.07 (0.28, 4.08) 1.02 (0.65, 1.63) 0.01 (-0.26, 0.29)

ANBAI+MTX 1.27 (0.28, 5.62) 1.07 (0.69, 1.82) 0.05 (-0.25, 0.36)

CT-P13+MTX 0.94 (0.21, 3.68) 0.98 (0.62, 1.68) -0.01 (-0.31, 0.29)

SB2+MTX 0.57 (0.11, 2.55) 0.81 (0.41, 1.47) -0.13 (-0.46, 0.22)

SB5+MTX 0.91 (0.18, 4.02) 0.97 (0.56, 1.67) -0.02 (-0.35, 0.30)

ZRC-3197+MTX 0.83 (0.14, 4.40) 0.94 (0.45, 1.69) -0.04 (-0.42, 0.31)

ABP501+MTX 1.00 (0.21, 4.20) 1.00 (0.60, 1.69) 0.001 (-0.32, 0.31)


ABA_STD (IV)+MTX 1.89 (0.79, 4.44) 1.32 (0.91, 2.06) 0.15 (-0.06, 0.35)

SAR_200 0.23 (0.03, 1.60) 0.37 (0.06, 1.23) -0.29 (-0.51, 0.11)

TOF_STD+MTX 2.57 (0.99, 6.65) 1.45 (1.00, 2.28) 0.22 (-0.003, 0.43)

TOF_STD 0.45 (0.09, 2.35) 0.62 (0.15, 1.42) -0.18 (-0.44, 0.20)

ADA_STD+MTX 1.98 (0.86, 4.33) 1.34 (0.95, 2.07) 0.16 (-0.03, 0.35)

TOC_4 (IV) 1.26 (0.37, 4.27) 1.12 (0.58, 1.92) 0.06 (-0.24, 0.34)

TOC_8 (IV) 2.07 (0.80, 5.34) 1.36 (0.91, 2.14) 0.17 (-0.05, 0.39)

TOC_4 (IV)+MTX 1.29 (0.50, 3.20) 1.13 (0.73, 1.81) 0.06 (-0.17, 0.28)

TOC_8 (IV)+MTX 1.83 (0.74, 4.54) 1.30 (0.89, 2.05) 0.15 (-0.07, 0.36)

GOL_STD (SC) 0.37 (0.08, 1.81) 0.54 (0.14, 1.29) -0.22 (-0.45, 0.14)

GOL_STD

(SC)+MTX 1.73 (0.67, 4.17) 1.28 (0.85, 2.00) 0.13 (-0.09, 0.34)

GOL_STD (IV)+MTX 2.04 (0.61, 6.61) 1.35 (0.80, 2.19) 0.17 (-0.12, 0.42)

INF_STD+MTX 1.45 (0.60, 3.37) 1.19 (0.80, 1.87) 0.09 (-0.12, 0.29)

590

CERTO_STD 0.86 (0.22, 3.68) 0.93 (0.36, 1.63) -0.04 (-0.31, 0.28)

CERTO_STD+MTX 2.66 (1.10, 6.11) 1.47 (1.04, 2.27) 0.23 (0.02, 0.42)

RIT_STD 1.48 (0.34, 6.29) 1.20 (0.55, 2.11) 0.09 (-0.25, 0.40)

RIT_STD+MTX 2.10 (0.47, 9.35) 1.36 (0.68, 2.30) 0.17 (-0.18, 0.46)

ADA_STD 0.17 (0.03, 0.89) 0.29 (0.06, 0.94) -0.33 (-0.52, -0.03)

BAR_4+MTX 2.11 (0.80, 5.21) 1.37 (0.92, 2.13) 0.18 (-0.05, 0.38)

HD203+MTX 3.01 (0.83, 11.28) 1.49 (0.91, 2.29) 0.24 (-0.04, 0.47)

SB4+MTX 2.38 (0.82, 7.31) 1.41 (0.91, 2.12) 0.20 (-0.05, 0.41)

ANBAI+MTX 2.85 (0.84, 9.24) 1.49 (0.93, 2.35) 0.24 (-0.04, 0.46)

CT-P13+MTX 2.07 (0.68, 6.28) 1.36 (0.84, 2.19) 0.17 (-0.09, 0.41)

SB2+MTX 1.27 (0.35, 4.42) 1.12 (0.56, 1.93) 0.06 (-0.25, 0.34)

SB5+MTX 1.99 (0.57, 6.97) 1.33 (0.76, 2.19) 0.16 (-0.14, 0.42)

ZRC-3197+MTX 1.82 (0.41, 8.03) 1.29 (0.61, 2.22) 0.14 (-0.21, 0.44)

ABP501+MTX 2.21 (0.63, 7.32) 1.38 (0.81, 2.22) 0.19 (-0.11, 0.43)

ABA_STD (IV)+MTX ETN_STD+MTX 0.87 (0.39, 1.87) 0.95 (0.73, 1.25) -0.03 (-0.20, 0.14)

SAR_200 0.10 (0.01, 0.81) 0.26 (0.04, 0.93) -0.48 (-0.69, -0.05)

TOF_STD+MTX 1.19 (0.50, 2.74) 1.05 (0.80, 1.38) 0.04 (-0.15, 0.21)

TOF_STD 0.20 (0.04, 1.18) 0.44 (0.10, 1.05) -0.37 (-0.62, 0.04)

ADA_STD+MTX 0.91 (0.44, 1.78) 0.97 (0.78, 1.25) -0.02 (-0.17, 0.13)

TOC_4 (IV) 0.58 (0.18, 1.87) 0.81 (0.45, 1.22) -0.13 (-0.39, 0.13)

TOC_8 (IV) 0.95 (0.39, 2.24) 0.98 (0.72, 1.31) -0.01 (-0.20, 0.18)

TOC_4 (IV)+MTX 0.59 (0.25, 1.35) 0.82 (0.58, 1.12) -0.12 (-0.31, 0.07)

TOC_8 (IV)+MTX 0.84 (0.37, 1.86) 0.94 (0.70, 1.25) -0.04 (-0.22, 0.14)

GOL_STD (SC) 0.17 (0.03, 0.93) 0.39 (0.10, 0.98) -0.40 (-0.63, -0.02)

GOL_STD

(SC)+MTX 0.80 (0.34, 1.75) 0.92 (0.68, 1.23) -0.05 (-0.24, 0.13)

GOL_STD (IV)+MTX 0.94 (0.30, 2.79) 0.98 (0.61, 1.36) -0.01 (-0.28, 0.21)

INF_STD+MTX 0.67 (0.30, 1.43) 0.86 (0.65, 1.15) -0.09 (-0.27, 0.08)

591

CERTO_STD 0.40 (0.09, 1.89) 0.67 (0.24, 1.18) -0.22 (-0.51, 0.12)

CERTO_STD+MTX 1.22 (0.55, 2.57) 1.06 (0.85, 1.37) 0.04 (-0.12, 0.21)

RIT_STD 0.69 (0.16, 2.71) 0.87 (0.41, 1.33) -0.09 (-0.42, 0.20)

RIT_STD+MTX 0.98 (0.23, 3.99) 0.99 (0.52, 1.43) -0.004 (-0.34, 0.25)

ADA_STD 0.08 (0.01, 0.46) 0.21 (0.04, 0.72) -0.52 (-0.69, -0.18)

BAR_4+MTX 0.98 (0.40, 2.19) 0.99 (0.73, 1.30) -0.005 (-0.20, 0.17)

HD203+MTX 1.39 (0.44, 4.51) 1.10 (0.70, 1.39) 0.07 (-0.20, 0.24)

SB4+MTX 1.10 (0.43, 2.82) 1.03 (0.70, 1.29) 0.02 (-0.20, 0.18)

ANBAI+MTX 1.31 (0.41, 4.05) 1.08 (0.73, 1.46) 0.06 (-0.20, 0.26)

CT-P13+MTX 0.96 (0.33, 2.68) 0.99 (0.65, 1.35) -0.01 (-0.25, 0.20)

SB2+MTX 0.58 (0.17, 1.94) 0.81 (0.42, 1.23) -0.12 (-0.42, 0.14)

SB5+MTX 0.92 (0.27, 2.94) 0.97 (0.58, 1.37) -0.02 (-0.30, 0.21)

ZRC-3197+MTX 0.84 (0.20, 3.56) 0.94 (0.47, 1.40) -0.04 (-0.38, 0.24)

ABP501+MTX 1.02 (0.31, 3.14) 1.01 (0.63, 1.38) 0.01 (-0.27, 0.22)

SAR_200 ABA_STD (IV)+MTX 0.12 (0.02, 1.02) 0.27 (0.04, 1.01) -0.46 (-0.66, 0.004)

TOF_STD+MTX 1.36 (0.62, 3.09) 1.10 (0.85, 1.43) 0.07 (-0.11, 0.24)

TOF_STD 0.23 (0.04, 1.49) 0.46 (0.10, 1.15) -0.34 (-0.60, 0.09)

ADA_STD+MTX 1.05 (0.55, 1.93) 1.02 (0.82, 1.29) 0.01 (-0.13, 0.15)

TOC_4 (IV) 0.67 (0.22, 2.09) 0.85 (0.47, 1.27) -0.10 (-0.36, 0.16)

TOC_8 (IV) 1.09 (0.50, 2.48) 1.03 (0.77, 1.36) 0.02 (-0.16, 0.20)

TOC_4 (IV)+MTX 0.68 (0.32, 1.45) 0.86 (0.61, 1.16) -0.09 (-0.27, 0.09)

TOC_8 (IV)+MTX 0.97 (0.47, 2.03) 0.99 (0.75, 1.29) -0.01 (-0.17, 0.16)

GOL_STD (SC) 0.20 (0.03, 1.26) 0.41 (0.10, 1.08) -0.38 (-0.61, 0.05)

GOL_STD

(SC)+MTX 0.91 (0.43, 1.90) 0.97 (0.72, 1.26) -0.02 (-0.19, 0.14)

GOL_STD (IV)+MTX 1.08 (0.37, 3.05) 1.03 (0.65, 1.40) 0.02 (-0.24, 0.23)

INF_STD+MTX 0.77 (0.40, 1.46) 0.91 (0.70, 1.16) -0.06 (-0.21, 0.09)

CERTO_STD 0.46 (0.09, 2.56) 0.70 (0.24, 1.32) -0.19 (-0.51, 0.19)

592

CERTO_STD+MTX 1.40 (0.71, 2.78) 1.11 (0.90, 1.42) 0.07 (-0.07, 0.22)

RIT_STD 0.78 (0.21, 3.03) 0.91 (0.44, 1.39) -0.06 (-0.37, 0.22)

RIT_STD+MTX 1.12 (0.28, 4.49) 1.04 (0.55, 1.49) 0.03 (-0.30, 0.28)

ADA_STD 0.09 (0.01, 0.59) 0.22 (0.04, 0.79) -0.49 (-0.66, -0.13)

BAR_4+MTX 1.12 (0.50, 2.43) 1.04 (0.78, 1.36) 0.03 (-0.16, 0.19)

HD203+MTX 1.59 (0.40, 6.51) 1.15 (0.68, 1.56) 0.10 (-0.22, 0.32)

SB4+MTX 1.26 (0.39, 4.31) 1.08 (0.67, 1.48) 0.05 (-0.22, 0.27)

ANBAI+MTX 1.52 (0.50, 4.45) 1.14 (0.77, 1.51) 0.09 (-0.16, 0.28)

CT-P13+MTX 1.11 (0.42, 2.89) 1.04 (0.70, 1.39) 0.02 (-0.20, 0.22)

SB2+MTX 0.67 (0.21, 2.09) 0.85 (0.45, 1.27) -0.09 (-0.36, 0.16)

SB5+MTX 1.06 (0.33, 3.26) 1.02 (0.61, 1.42) 0.01 (-0.26, 0.24)

ZRC-3197+MTX 0.96 (0.23, 3.85) 0.99 (0.49, 1.44) -0.01 (-0.34, 0.26)

ABP501+MTX 1.18 (0.38, 3.48) 1.06 (0.66, 1.45) 0.04 (-0.23, 0.25)

TOF_STD+MTX SAR_200 11.55 (1.34, 93.11) 4.03 (1.11, 24.99) 0.52 (0.07, 0.73)

TOF_STD

1.97 (0.42, 9.15) 1.62 (0.54, 5.83) 0.10 (-0.16, 0.40)

ADA_STD+MTX 8.81 (1.06, 67.47) 3.71 (1.02, 23.07) 0.47 (0.01, 0.65)

TOC_4 (IV) 5.67 (0.56, 52.38) 3.04 (0.77, 19.96) 0.35 (-0.14, 0.65)

TOC_8 (IV) 9.20 (1.05, 74.74) 3.76 (1.02, 23.69) 0.47 (0.01, 0.69)

TOC_4 (IV)+MTX 5.70 (0.66, 46.29) 3.11 (0.84, 19.53) 0.36 (-0.10, 0.59)

TOC_8 (IV)+MTX 8.10 (0.95, 65.62) 3.59 (0.98, 22.54) 0.45 (-0.01, 0.66)

GOL_STD (SC) 1.68 (0.25, 10.60) 1.45 (0.38, 6.92) 0.07 (-0.26, 0.39)

GOL_STD

(SC)+MTX 7.72 (0.89, 60.21) 3.54 (0.96, 22.24) 0.44 (-0.03, 0.64)

GOL_STD (IV)+MTX 9.00 (0.91, 79.82) 3.70 (0.96, 23.08) 0.46 (-0.02, 0.73)

INF_STD+MTX 6.49 (0.77, 49.90) 3.29 (0.90, 20.46) 0.40 (-0.06, 0.60)

CERTO_STD 3.90 (0.66, 22.54) 2.44 (0.80, 11.14) 0.24 (-0.09, 0.56)

CERTO_STD+MTX 11.88 (1.39, 92.66) 4.09 (1.12, 25.28) 0.53 (0.07, 0.72)

RIT_STD 6.59 (0.59, 68.42) 3.23 (0.78, 21.20) 0.38 (-0.12, 0.72)

593

RIT_STD+MTX 9.48 (0.82, 99.76) 3.68 (0.92, 23.64) 0.46 (-0.05, 0.77)

ADA_STD 0.75 (0.28, 1.99) 0.80 (0.37, 1.81) -0.03 (-0.24, 0.08)

BAR_4+MTX 9.44 (1.07, 73.58) 3.79 (1.02, 23.39) 0.48 (0.01, 0.69)

HD203+MTX 13.42 (1.30, 134.10) 4.10 (1.10, 25.00) 0.53 (0.06, 0.81)

SB4+MTX 10.56 (1.06, 97.36) 3.86 (1.03, 24.05) 0.49 (0.01, 0.76)

ANBAI+MTX 12.88 (1.24, 116.60) 4.14 (1.08, 25.83) 0.53 (0.05, 0.78)

CT-P13+MTX 9.30 (0.97, 83.02) 3.75 (0.99, 23.79) 0.47 (-0.01, 0.72)

SB2+MTX 5.57 (0.55, 55.28) 3.03 (0.75, 20.29) 0.35 (-0.14, 0.65)

SB5+MTX 8.85 (0.92, 85.90) 3.65 (0.97, 23.02) 0.45 (-0.02, 0.74)

ZRC-3197+MTX 8.05 (0.70, 92.22) 3.46 (0.84, 22.84) 0.43 (-0.08, 0.75)

ABP501+MTX 9.85 (1.00, 92.15) 3.78 (1.00, 24.73) 0.48 (-0.001, 0.75)

TOF_STD TOF_STD+MTX 0.17 (0.03, 1.17) 0.42 (0.09, 1.05) -0.40 (-0.67, 0.03)

ADA_STD+MTX 0.77 (0.39, 1.47) 0.92 (0.76, 1.15) -0.06 (-0.19, 0.09)

TOC_4 (IV) 0.49 (0.15, 1.65) 0.77 (0.42, 1.17) -0.16 (-0.43, 0.10)

TOC_8 (IV) 0.80 (0.33, 1.93) 0.93 (0.70, 1.23) -0.05 (-0.23, 0.14)

TOC_4 (IV)+MTX 0.50 (0.21, 1.14) 0.78 (0.55, 1.05) -0.16 (-0.34, 0.03)

TOC_8 (IV)+MTX 0.71 (0.31, 1.59) 0.90 (0.68, 1.17) -0.07 (-0.25, 0.10)

GOL_STD (SC) 0.15 (0.02, 0.94) 0.37 (0.09, 0.98) -0.44 (-0.69, -0.01)

GOL_STD

(SC)+MTX 0.67 (0.29, 1.53) 0.88 (0.65, 1.16) -0.09 (-0.27, 0.09)

GOL_STD (IV)+MTX 0.79 (0.25, 2.38) 0.93 (0.59, 1.28) -0.05 (-0.31, 0.17)

INF_STD+MTX 0.57 (0.25, 1.23) 0.82 (0.62, 1.08) -0.13 (-0.30, 0.05)

CERTO_STD 0.33 (0.07, 1.94) 0.64 (0.22, 1.20) -0.26 (-0.58, 0.13)

CERTO_STD+MTX 1.04 (0.48, 2.17) 1.01 (0.82, 1.28) 0.01 (-0.14, 0.17)

RIT_STD 0.58 (0.13, 2.37) 0.83 (0.39, 1.26) -0.12 (-0.45, 0.16)

RIT_STD+MTX 0.83 (0.19, 3.47) 0.94 (0.50, 1.35) -0.04 (-0.38, 0.22)

ADA_STD 0.07 (0.01, 0.45) 0.20 (0.04, 0.72) -0.56 (-0.74, -0.19)

BAR_4+MTX 0.82 (0.35, 1.94) 0.94 (0.71, 1.24) -0.04 (-0.22, 0.14)

594

HD203+MTX 1.17 (0.27, 5.08) 1.04 (0.61, 1.43) 0.03 (-0.29, 0.26)

SB4+MTX 0.93 (0.27, 3.32) 0.98 (0.61, 1.35) -0.02 (-0.30, 0.22)

ANBAI+MTX 1.11 (0.34, 3.44) 1.03 (0.70, 1.37) 0.02 (-0.23, 0.23)

CT-P13+MTX 0.81 (0.28, 2.36) 0.94 (0.62, 1.28) -0.05 (-0.28, 0.17)

SB2+MTX 0.49 (0.14, 1.65) 0.77 (0.40, 1.16) -0.16 (-0.44, 0.10)

SB5+MTX 0.78 (0.23, 2.46) 0.93 (0.56, 1.28) -0.05 (-0.33, 0.17)

ZRC-3197+MTX 0.71 (0.17, 2.84) 0.90 (0.45, 1.30) -0.07 (-0.41, 0.19)

ABP501+MTX 0.86 (0.26, 2.67) 0.96 (0.61, 1.30) -0.03 (-0.30, 0.19)

ADA_STD+MTX TOF_STD 4.47 (0.71, 26.87) 2.21 (0.89, 9.78) 0.35 (-0.08, 0.60)

TOC_4 (IV) 2.83 (0.37, 21.70) 1.81 (0.63, 8.31) 0.23 (-0.23, 0.59)

TOC_8 (IV) 4.68 (0.71, 30.76) 2.23 (0.89, 9.96) 0.36 (-0.08, 0.64)

TOC_4 (IV)+MTX 2.90 (0.44, 18.71) 1.84 (0.73, 8.36) 0.25 (-0.19, 0.53)

TOC_8 (IV)+MTX 4.13 (0.64, 26.30) 2.14 (0.85, 9.63) 0.33 (-0.10, 0.60)

GOL_STD (SC) 0.84 (0.17, 4.11) 0.89 (0.28, 2.78) -0.03 (-0.35, 0.28)

GOL_STD

(SC)+MTX 3.90 (0.58, 24.37) 2.08 (0.82, 9.22) 0.32 (-0.12, 0.59)

GOL_STD (IV)+MTX 4.56 (0.59, 33.33) 2.20 (0.81, 9.91) 0.35 (-0.12, 0.66)

INF_STD+MTX 3.31 (0.51, 20.08) 1.96 (0.78, 8.76) 0.28 (-0.15, 0.54)

CERTO_STD 1.97 (0.46, 8.29) 1.48 (0.65, 4.41) 0.13 (-0.17, 0.43)

CERTO_STD+MTX 6.00 (0.93, 37.56) 2.42 (0.98, 10.74) 0.42 (-0.01, 0.67)

RIT_STD 3.31 (0.38, 29.41) 1.93 (0.63, 8.98) 0.27 (-0.22, 0.64)

RIT_STD+MTX 4.75 (0.52, 43.31) 2.19 (0.76, 10.04) 0.35 (-0.15, 0.71)

ADA_STD 0.38 (0.12, 1.25) 0.49 (0.18, 1.18) -0.14 (-0.41, 0.03)

BAR_4+MTX 4.76 (0.70, 30.07) 2.24 (0.89, 9.94) 0.36 (-0.08, 0.64)

HD203+MTX 6.77 (0.81, 55.59) 2.43 (0.93, 10.73) 0.42 (-0.04, 0.74)

SB4+MTX 5.39 (0.72, 38.66) 2.29 (0.90, 10.03) 0.38 (-0.07, 0.69)

ANBAI+MTX 6.42 (0.83, 45.99) 2.43 (0.94, 10.71) 0.42 (-0.04, 0.72)

CT-P13+MTX 4.71 (0.63, 33.28) 2.22 (0.86, 10.07) 0.35 (-0.10, 0.66)

595

SB2+MTX 2.85 (0.35, 21.99) 1.81 (0.62, 8.36) 0.24 (-0.24, 0.59)

SB5+MTX 4.49 (0.56, 35.11) 2.17 (0.80, 9.91) 0.34 (-0.13, 0.67)

ZRC-3197+MTX 4.13 (0.43, 37.14) 2.09 (0.69, 9.39) 0.32 (-0.19, 0.69)

ABP501+MTX 5.00 (0.63, 38.09) 2.27 (0.84, 10.11) 0.37 (-0.11, 0.69)

TOC_4 (IV) ADA_STD+MTX 0.63 (0.23, 1.90) 0.83 (0.47, 1.22) -0.11 (-0.35, 0.13)

TOC_8 (IV) 1.04 (0.52, 2.19) 1.02 (0.78, 1.28) 0.01 (-0.15, 0.16)

TOC_4 (IV)+MTX 0.65 (0.33, 1.29) 0.84 (0.61, 1.10) -0.10 (-0.26, 0.06)

TOC_8 (IV)+MTX 0.92 (0.48, 1.80) 0.97 (0.75, 1.22) -0.02 (-0.17, 0.13)

GOL_STD (SC) 0.19 (0.03, 1.15) 0.40 (0.09, 1.05) -0.39 (-0.61, 0.03)

GOL_STD

(SC)+MTX 0.88 (0.45, 1.68) 0.95 (0.72, 1.19) -0.03 (-0.19, 0.11)

GOL_STD (IV)+MTX 1.03 (0.37, 2.85) 1.01 (0.65, 1.34) 0.01 (-0.24, 0.21)

INF_STD+MTX 0.74 (0.40, 1.34) 0.89 (0.69, 1.12) -0.07 (-0.22, 0.07)

CERTO_STD 0.44 (0.09, 2.42) 0.69 (0.23, 1.27) -0.20 (-0.51, 0.17)

CERTO_STD+MTX 1.34 (0.80, 2.30) 1.10 (0.93, 1.29) 0.06 (-0.05, 0.17)

RIT_STD 0.75 (0.20, 2.74) 0.90 (0.43, 1.32) -0.07 (-0.38, 0.19)

RIT_STD+MTX 1.07 (0.28, 4.15) 1.02 (0.55, 1.41) 0.02 (-0.30, 0.25)

ADA_STD 0.09 (0.01, 0.56) 0.21 (0.04, 0.77) -0.51 (-0.66, -0.14)

BAR_4+MTX 1.07 (0.56, 2.05) 1.02 (0.80, 1.25) 0.02 (-0.14, 0.15)

HD203+MTX 1.52 (0.40, 6.22) 1.13 (0.67, 1.48) 0.09 (-0.22, 0.29)

SB4+MTX 1.21 (0.39, 3.97) 1.06 (0.66, 1.40) 0.04 (-0.22, 0.24)

ANBAI+MTX 1.44 (0.51, 4.01) 1.12 (0.76, 1.41) 0.08 (-0.16, 0.25)

CT-P13+MTX 1.05 (0.41, 2.74) 1.02 (0.69, 1.33) 0.01 (-0.21, 0.20)

SB2+MTX 0.64 (0.21, 1.97) 0.84 (0.44, 1.23) -0.10 (-0.37, 0.14)

SB5+MTX 1.01 (0.39, 2.64) 1.00 (0.64, 1.29) 0.002 (-0.23, 0.18)

ZRC-3197+MTX 0.92 (0.27, 3.18) 0.97 (0.51, 1.32) -0.02 (-0.32, 0.21)

ABP501+MTX 1.12 (0.44, 2.87) 1.04 (0.69, 1.31) 0.03 (-0.20, 0.19)

TOC_8 (IV) TOC_4 (IV) 1.64 (0.59, 4.57) 1.21 (0.84, 2.09) 0.12 (-0.11, 0.35)

596

TOC_4 (IV)+MTX 1.02 (0.37, 2.80) 1.01 (0.68, 1.74) 0.004 (-0.23, 0.25)

TOC_8 (IV)+MTX 1.44 (0.53, 3.86) 1.16 (0.81, 1.99) 0.09 (-0.14, 0.32)

GOL_STD (SC) 0.29 (0.04, 2.18) 0.49 (0.11, 1.45) -0.27 (-0.60, 0.18)

GOL_STD

(SC)+MTX 1.37 (0.43, 4.25) 1.14 (0.74, 2.07) 0.08 (-0.19, 0.34)

GOL_STD (IV)+MTX 1.62 (0.40, 6.28) 1.21 (0.70, 2.22) 0.11 (-0.21, 0.41)

INF_STD+MTX 1.16 (0.37, 3.45) 1.07 (0.70, 1.93) 0.04 (-0.22, 0.30)

CERTO_STD 0.69 (0.11, 4.56) 0.84 (0.26, 1.90) -0.09 (-0.48, 0.34)

CERTO_STD+MTX 2.10 (0.69, 6.29) 1.31 (0.90, 2.35) 0.17 (-0.07, 0.42)

RIT_STD 1.18 (0.23, 5.71) 1.07 (0.48, 2.11) 0.04 (-0.35, 0.39)

RIT_STD+MTX 1.68 (0.33, 8.71) 1.22 (0.60, 2.32) 0.12 (-0.26, 0.45)

ADA_STD 0.13 (0.02, 1.05) 0.26 (0.05, 1.03) -0.39 (-0.67, 0.01)

BAR_4+MTX 1.67 (0.51, 5.25) 1.22 (0.80, 2.20) 0.12 (-0.15, 0.39)

HD203+MTX 2.38 (0.47, 12.78) 1.34 (0.74, 2.50) 0.19 (-0.17, 0.50)

SB4+MTX 1.90 (0.43, 8.84) 1.26 (0.72, 2.38) 0.15 (-0.19, 0.46)

ANBAI+MTX 2.26 (0.55, 9.10) 1.33 (0.81, 2.43) 0.18 (-0.13, 0.47)

CT-P13+MTX 1.65 (0.43, 6.21) 1.22 (0.73, 2.23) 0.12 (-0.19, 0.41)

SB2+MTX 1.00 (0.23, 4.22) 1.00 (0.49, 1.95) -0.001 (-0.34, 0.33)

SB5+MTX 1.58 (0.37, 6.52) 1.19 (0.66, 2.24) 0.11 (-0.23, 0.42)

ZRC-3197+MTX 1.45 (0.28, 7.34) 1.15 (0.55, 2.23) 0.09 (-0.29, 0.42)

ABP501+MTX 1.75 (0.41, 7.08) 1.23 (0.71, 2.31) 0.13 (-0.20, 0.43)

TOC_4 (IV)+MTX TOC_8 (IV) 0.62 (0.31, 1.21) 0.83 (0.63, 1.08) -0.11 (-0.27, 0.05)

TOC_8 (IV)+MTX 0.88 (0.51, 1.51) 0.96 (0.79, 1.17) -0.03 (-0.15, 0.10)

GOL_STD (SC) 0.18 (0.03, 1.19) 0.40 (0.09, 1.06) -0.39 (-0.64, 0.04)

GOL_STD

(SC)+MTX 0.84 (0.35, 1.90) 0.94 (0.69, 1.28) -0.04 (-0.23, 0.15)

GOL_STD (IV)+MTX 0.98 (0.31, 3.04) 0.99 (0.62, 1.41) -0.004 (-0.27, 0.23)

INF_STD+MTX 0.71 (0.31, 1.53) 0.88 (0.65, 1.19) -0.08 (-0.26, 0.10)

CERTO_STD 0.42 (0.08, 2.33) 0.68 (0.23, 1.29) -0.21 (-0.54, 0.17)

597

CERTO_STD+MTX 1.28 (0.58, 2.79) 1.08 (0.85, 1.42) 0.05 (-0.11, 0.22)

RIT_STD 0.72 (0.17, 2.87) 0.88 (0.42, 1.36) -0.08 (-0.41, 0.21)

RIT_STD+MTX 1.03 (0.25, 4.21) 1.01 (0.53, 1.47) 0.01 (-0.33, 0.27)

ADA_STD 0.08 (0.01, 0.55) 0.21 (0.04, 0.77) -0.51 (-0.70, -0.14)

BAR_4+MTX 1.02 (0.42, 2.41) 1.01 (0.75, 1.36) 0.01 (-0.19, 0.19)

HD203+MTX 1.45 (0.34, 6.41) 1.12 (0.65, 1.56) 0.08 (-0.25, 0.31)

SB4+MTX 1.15 (0.34, 4.20) 1.05 (0.65, 1.48) 0.03 (-0.25, 0.27)

ANBAI+MTX 1.37 (0.43, 4.33) 1.10 (0.74, 1.51) 0.07 (-0.19, 0.28)

CT-P13+MTX 1.01 (0.33, 2.95) 1.00 (0.66, 1.41) 0.002 (-0.25, 0.22)

SB2+MTX 0.61 (0.18, 2.09) 0.82 (0.43, 1.27) -0.12 (-0.40, 0.16)

SB5+MTX 0.97 (0.29, 3.09) 0.99 (0.59, 1.40) -0.01 (-0.29, 0.22)

ZRC-3197+MTX 0.88 (0.20, 3.71) 0.96 (0.48, 1.43) -0.03 (-0.37, 0.25)

ABP501+MTX 1.08 (0.32, 3.38) 1.02 (0.64, 1.43) 0.02 (-0.26, 0.24)


GOL_STD (SC) 0.29 (0.05, 1.85) 0.48 (0.11, 1.29) -0.28 (-0.54, 0.14)

GOL_STD

(SC)+MTX 1.34 (0.59, 2.94) 1.13 (0.81, 1.59) 0.07 (-0.13, 0.26)

GOL_STD (IV)+MTX 1.59 (0.52, 4.71) 1.20 (0.74, 1.76) 0.11 (-0.16, 0.33)

INF_STD+MTX 1.13 (0.53, 2.39) 1.06 (0.77, 1.50) 0.03 (-0.15, 0.21)

CERTO_STD 0.67 (0.13, 3.76) 0.82 (0.27, 1.59) -0.10 (-0.43, 0.28)

CERTO_STD+MTX 2.07 (0.98, 4.30) 1.30 (0.99, 1.79) 0.17 (-0.004, 0.33)

RIT_STD 1.15 (0.28, 4.48) 1.06 (0.50, 1.71) 0.03 (-0.30, 0.32)

RIT_STD+MTX 1.66 (0.40, 6.78) 1.21 (0.63, 1.84) 0.12 (-0.22, 0.38)

ADA_STD 0.13 (0.02, 0.89) 0.25 (0.05, 0.94) -0.40 (-0.60, -0.03)

BAR_4+MTX 1.64 (0.73, 3.70) 1.21 (0.88, 1.70) 0.12 (-0.07, 0.30)

HD203+MTX 2.33 (0.57, 10.06) 1.34 (0.77, 1.97) 0.19 (-0.14, 0.42)

SB4+MTX 1.86 (0.55, 6.57) 1.26 (0.76, 1.86) 0.14 (-0.15, 0.38)

ANBAI+MTX 2.21 (0.71, 6.85) 1.32 (0.87, 1.90) 0.18 (-0.08, 0.39)

598

CT-P13+MTX 1.62 (0.57, 4.60) 1.21 (0.78, 1.77) 0.11 (-0.13, 0.33)

SB2+MTX 0.98 (0.30, 3.21) 0.99 (0.51, 1.58) -0.004 (-0.29, 0.26)

SB5+MTX 1.55 (0.47, 4.99) 1.19 (0.70, 1.77) 0.10 (-0.18, 0.34)

ZRC-3197+MTX 1.41 (0.34, 5.79) 1.15 (0.57, 1.78) 0.08 (-0.26, 0.35)

ABP501+MTX 1.72 (0.53, 5.47) 1.23 (0.75, 1.81) 0.13 (-0.16, 0.36)


GOL_STD

(SC)+MTX 0.95 (0.43, 2.03) 0.98 (0.72, 1.31) -0.01 (-0.20, 0.16)

GOL_STD (IV)+MTX 1.12 (0.37, 3.25) 1.04 (0.66, 1.44) 0.03 (-0.23, 0.24)

INF_STD+MTX 0.80 (0.38, 1.65) 0.92 (0.69, 1.23) -0.05 (-0.22, 0.12)

CERTO_STD 0.47 (0.09, 2.65) 0.71 (0.24, 1.34) -0.18 (-0.51, 0.20)

CERTO_STD+MTX 1.46 (0.71, 2.94) 1.13 (0.90, 1.46) 0.08 (-0.07, 0.24)

RIT_STD 0.81 (0.20, 3.18) 0.92 (0.44, 1.42) -0.05 (-0.37, 0.23)

RIT_STD+MTX 1.16 (0.29, 4.65) 1.05 (0.56, 1.52) 0.03 (-0.29, 0.29)

ADA_STD 0.09 (0.01, 0.62) 0.22 (0.04, 0.81) -0.48 (-0.67, -0.12)

BAR_4+MTX 1.16 (0.51, 2.55) 1.05 (0.78, 1.39) 0.03 (-0.15, 0.21)

HD203+MTX 1.65 (0.41, 6.95) 1.17 (0.68, 1.62) 0.10 (-0.21, 0.33)

SB4+MTX 1.31 (0.39, 4.59) 1.09 (0.67, 1.53) 0.06 (-0.22, 0.29)

ANBAI+MTX 1.57 (0.51, 4.73) 1.15 (0.77, 1.55) 0.10 (-0.16, 0.30)

CT-P13+MTX 1.14 (0.41, 3.20) 1.05 (0.69, 1.45) 0.03 (-0.21, 0.24)

SB2+MTX 0.69 (0.21, 2.29) 0.86 (0.45, 1.32) -0.09 (-0.37, 0.18)

SB5+MTX 1.09 (0.34, 3.44) 1.03 (0.62, 1.46) 0.02 (-0.26, 0.25)

ZRC-3197+MTX 1.01 (0.24, 4.07) 1.00 (0.49, 1.49) 0.001 (-0.34, 0.27)

ABP501+MTX 1.23 (0.38, 3.77) 1.07 (0.67, 1.49) 0.05 (-0.23, 0.26)

GOL_STD

(SC)+MTX GOL_STD (SC) 4.65 (0.72, 27.21) 2.38 (0.89, 10.14) 0.35 (-0.07, 0.60)

GOL_STD (IV)+MTX 5.47 (0.74, 35.89) 2.50 (0.89, 10.57) 0.38 (-0.07, 0.67)

INF_STD+MTX 3.93 (0.64, 22.32) 2.22 (0.84, 9.47) 0.32 (-0.11, 0.55)

CERTO_STD 2.34 (0.62, 8.92) 1.67 (0.76, 4.77) 0.17 (-0.10, 0.45)

599

CERTO_STD+MTX 7.14 (1.15, 41.86) 2.74 (1.05, 11.71) 0.45 (0.03, 0.68)

RIT_STD 4.01 (0.46, 32.93) 2.17 (0.68, 9.82) 0.30 (-0.18, 0.66)

RIT_STD+MTX 5.71 (0.66, 48.62) 2.49 (0.83, 10.85) 0.38 (-0.10, 0.72)

ADA_STD 0.45 (0.10, 2.24) 0.55 (0.15, 1.88) -0.11 (-0.41, 0.13)

BAR_4+MTX 5.67 (0.88, 32.96) 2.55 (0.95, 10.60) 0.40 (-0.03, 0.64)

HD203+MTX 8.05 (1.04, 61.01) 2.75 (1.01, 11.47) 0.45 (0.01, 0.75)

SB4+MTX 6.42 (0.93, 42.65) 2.61 (0.97, 10.88) 0.41 (-0.02, 0.70)

ANBAI+MTX 7.72 (1.04, 51.37) 2.76 (1.01, 11.65) 0.45 (0.01, 0.73)

CT-P13+MTX 5.61 (0.78, 35.92) 2.53 (0.91, 10.69) 0.39 (-0.06, 0.67)

SB2+MTX 3.41 (0.45, 24.05) 2.05 (0.68, 9.00) 0.27 (-0.19, 0.60)

SB5+MTX 5.38 (0.70, 38.74) 2.47 (0.86, 10.64) 0.38 (-0.08, 0.69)

ZRC-3197+MTX 4.89 (0.52, 40.45) 2.37 (0.75, 10.37) 0.35 (-0.15, 0.70)

ABP501+MTX 5.96 (0.77, 40.67) 2.56 (0.91, 10.96) 0.40 (-0.06, 0.69)

GOL_STD (IV)+MTX GOL_STD (SC)+MTX 1.18 (0.39, 3.53) 1.06 (0.67, 1.50) 0.04 (-0.22, 0.26)

INF_STD+MTX 0.84 (0.41, 1.75) 0.94 (0.70, 1.26) -0.04 (-0.21, 0.13)

CERTO_STD 0.50 (0.10, 2.93) 0.72 (0.25, 1.40) -0.17 (-0.49, 0.22)

CERTO_STD+MTX 1.54 (0.76, 3.16) 1.15 (0.92, 1.51) 0.09 (-0.06, 0.26)

RIT_STD 0.86 (0.22, 3.37) 0.94 (0.45, 1.46) -0.03 (-0.36, 0.25)

RIT_STD+MTX 1.23 (0.30, 4.97) 1.08 (0.56, 1.57) 0.05 (-0.29, 0.30)

ADA_STD 0.10 (0.02, 0.65) 0.22 (0.04, 0.82) -0.47 (-0.65, -0.10)

BAR_4+MTX 1.23 (0.55, 2.74) 1.07 (0.80, 1.45) 0.05 (-0.14, 0.23)

HD203+MTX 1.74 (0.43, 7.45) 1.19 (0.69, 1.67) 0.12 (-0.20, 0.35)

SB4+MTX 1.38 (0.42, 4.95) 1.11 (0.69, 1.60) 0.07 (-0.21, 0.31)

ANBAI+MTX 1.65 (0.55, 5.00) 1.17 (0.79, 1.61) 0.11 (-0.14, 0.31)

CT-P13+MTX 1.21 (0.43, 3.44) 1.07 (0.71, 1.50) 0.04 (-0.20, 0.26)

SB2+MTX 0.73 (0.22, 2.42) 0.88 (0.46, 1.36) -0.07 (-0.36, 0.19)

SB5+MTX 1.15 (0.36, 3.70) 1.05 (0.63, 1.51) 0.03 (-0.24, 0.27)

ZRC-3197+MTX 1.06 (0.26, 4.36) 1.02 (0.51, 1.54) 0.01 (-0.32, 0.29)

600

ABP501+MTX 1.28 (0.41, 4.07) 1.09 (0.68, 1.54) 0.06 (-0.21, 0.29)

INF_STD+MTX GOL_STD (IV)+MTX 0.72 (0.25, 2.06) 0.88 (0.63, 1.40) -0.08 (-0.29, 0.18)

CERTO_STD 0.43 (0.07, 2.87) 0.69 (0.23, 1.43) -0.20 (-0.56, 0.22)

CERTO_STD+MTX 1.30 (0.47, 3.77) 1.09 (0.82, 1.70) 0.06 (-0.14, 0.30)

RIT_STD 0.73 (0.16, 3.44) 0.89 (0.42, 1.54) -0.07 (-0.42, 0.26)

RIT_STD+MTX 1.05 (0.22, 5.18) 1.01 (0.53, 1.68) 0.01 (-0.35, 0.33)

ADA_STD 0.08 (0.01, 0.67) 0.21 (0.04, 0.83) -0.50 (-0.74, -0.09)

BAR_4+MTX 1.04 (0.34, 3.19) 1.01 (0.72, 1.60) 0.01 (-0.22, 0.27)

HD203+MTX 1.48 (0.31, 7.58) 1.12 (0.64, 1.83) 0.08 (-0.26, 0.38)

SB4+MTX 1.17 (0.28, 5.25) 1.05 (0.63, 1.73) 0.03 (-0.27, 0.33)

ANBAI+MTX 1.40 (0.37, 5.48) 1.10 (0.73, 1.77) 0.07 (-0.21, 0.35)

CT-P13+MTX 1.02 (0.28, 3.75) 1.01 (0.65, 1.63) 0.01 (-0.27, 0.29)

SB2+MTX 0.62 (0.15, 2.50) 0.83 (0.42, 1.44) -0.11 (-0.43, 0.21)

SB5+MTX 0.98 (0.25, 3.96) 0.99 (0.59, 1.63) -0.005 (-0.31, 0.30)

ZRC-3197+MTX 0.89 (0.18, 4.51) 0.96 (0.47, 1.64) -0.02 (-0.38, 0.31)

ABP501+MTX 1.09 (0.27, 4.43) 1.03 (0.62, 1.68) 0.02 (-0.28, 0.31)

CERTO_STD INF_STD+MTX 0.59 (0.13, 3.38) 0.77 (0.26, 1.48) -0.13 (-0.44, 0.25)

CERTO_STD+MTX 1.82 (0.94, 3.56) 1.23 (0.98, 1.59) 0.13 (-0.01, 0.28)

RIT_STD 1.03 (0.26, 3.87) 1.01 (0.48, 1.55) 0.01 (-0.32, 0.28)

RIT_STD+MTX 1.45 (0.37, 5.85) 1.15 (0.61, 1.67) 0.09 (-0.24, 0.34)

ADA_STD 0.12 (0.02, 0.77) 0.24 (0.05, 0.88) -0.43 (-0.60, -0.06)

BAR_4+MTX 1.45 (0.68, 3.11) 1.15 (0.85, 1.53) 0.09 (-0.09, 0.26)

HD203+MTX 2.07 (0.52, 8.56) 1.27 (0.74, 1.76) 0.16 (-0.16, 0.38)

SB4+MTX 1.65 (0.51, 5.68) 1.19 (0.73, 1.68) 0.11 (-0.17, 0.34)

ANBAI+MTX 1.96 (0.67, 5.76) 1.25 (0.85, 1.69) 0.15 (-0.10, 0.34)

CT-P13+MTX 1.43 (0.69, 2.98) 1.14 (0.84, 1.42) 0.08 (-0.09, 0.22)

SB2+MTX 0.87 (0.34, 2.22) 0.94 (0.54, 1.31) -0.03 (-0.25, 0.17)

SB5+MTX 1.37 (0.43, 4.28) 1.13 (0.67, 1.61) 0.07 (-0.20, 0.30)

601

ZRC-3197+MTX 1.24 (0.32, 5.08) 1.09 (0.54, 1.64) 0.05 (-0.28, 0.32)

ABP501+MTX 1.52 (0.50, 4.60) 1.17 (0.73, 1.62) 0.10 (-0.17, 0.31)

CERTO_STD+MTX CERTO_STD 3.10 (0.55, 14.97) 1.59 (0.86, 4.64) 0.27 (-0.11, 0.58)

RIT_STD 1.71 (0.21, 12.01) 1.28 (0.51, 3.99) 0.13 (-0.34, 0.54)

RIT_STD+MTX 2.46 (0.30, 18.05) 1.46 (0.63, 4.47) 0.21 (-0.26, 0.60)

ADA_STD 0.19 (0.05, 0.83) 0.32 (0.09, 0.90) -0.28 (-0.57, -0.03)

BAR_4+MTX 2.45 (0.41, 12.10) 1.48 (0.77, 4.35) 0.21 (-0.18, 0.54)

HD203+MTX 3.49 (0.49, 23.25) 1.61 (0.79, 4.68) 0.27 (-0.14, 0.63)

SB4+MTX 2.76 (0.45, 15.68) 1.52 (0.76, 4.30) 0.23 (-0.17, 0.58)

ANBAI+MTX 3.30 (0.49, 19.39) 1.60 (0.81, 4.70) 0.27 (-0.14, 0.62)

CT-P13+MTX 2.42 (0.38, 13.39) 1.46 (0.72, 4.36) 0.21 (-0.20, 0.56)

SB2+MTX 1.47 (0.20, 8.98) 1.21 (0.51, 3.73) 0.09 (-0.35, 0.48)

SB5+MTX 2.31 (0.33, 14.42) 1.43 (0.68, 4.35) 0.20 (-0.24, 0.57)

ZRC-3197+MTX 2.11 (0.25, 15.48) 1.39 (0.56, 4.28) 0.17 (-0.31, 0.58)

ABP501+MTX 2.57 (0.37, 15.34) 1.49 (0.71, 4.41) 0.22 (-0.21, 0.58)


RIT_STD+MTX 0.80 (0.21, 3.12) 0.93 (0.50, 1.28) -0.05 (-0.37, 0.19)

ADA_STD 0.06 (0.01, 0.42) 0.19 (0.04, 0.70) -0.57 (-0.73, -0.20)

BAR_4+MTX 0.79 (0.38, 1.68) 0.93 (0.72, 1.16) -0.05 (-0.21, 0.11)

HD203+MTX 1.13 (0.29, 4.67) 1.03 (0.61, 1.36) 0.02 (-0.29, 0.23)

SB4+MTX 0.90 (0.28, 3.15) 0.97 (0.60, 1.29) -0.02 (-0.30, 0.19)

ANBAI+MTX 1.08 (0.37, 3.12) 1.02 (0.70, 1.30) 0.01 (-0.23, 0.19)

CT-P13+MTX 0.78 (0.29, 2.09) 0.93 (0.63, 1.21) -0.05 (-0.28, 0.14)

SB2+MTX 0.48 (0.15, 1.49) 0.77 (0.40, 1.12) -0.17 (-0.44, 0.08)

SB5+MTX 0.75 (0.25, 2.26) 0.92 (0.56, 1.22) -0.06 (-0.32, 0.15)

ZRC-3197+MTX 0.69 (0.18, 2.66) 0.89 (0.45, 1.25) -0.08 (-0.40, 0.16)

ABP501+MTX 0.83 (0.28, 2.43) 0.95 (0.61, 1.24) -0.04 (-0.29, 0.16)


602

ADA_STD 0.11 (0.01, 1.04) 0.24 (0.04, 1.02) -0.42 (-0.73, 0.01)

BAR_4+MTX 1.42 (0.37, 5.71) 1.14 (0.74, 2.38) 0.08 (-0.20, 0.40)

HD203+MTX 2.05 (0.33, 12.79) 1.26 (0.68, 2.68) 0.15 (-0.24, 0.51)

SB4+MTX 1.59 (0.31, 9.00) 1.17 (0.66, 2.52) 0.10 (-0.25, 0.47)

ANBAI+MTX 1.93 (0.39, 9.42) 1.24 (0.75, 2.62) 0.14 (-0.19, 0.48)

CT-P13+MTX 1.39 (0.30, 6.65) 1.13 (0.67, 2.38) 0.08 (-0.25, 0.42)

SB2+MTX 0.85 (0.17, 4.54) 0.93 (0.46, 2.11) -0.04 (-0.40, 0.35)

SB5+MTX 1.34 (0.26, 7.07) 1.11 (0.62, 2.39) 0.07 (-0.29, 0.43)

ZRC-3197+MTX 1.22 (0.21, 7.66) 1.08 (0.51, 2.40) 0.04 (-0.35, 0.44)

ABP501+MTX 1.49 (0.30, 7.30) 1.15 (0.66, 2.45) 0.09 (-0.26, 0.44)

ADA_STD RIT_STD+MTX 0.08 (0.01, 0.76) 0.21 (0.04, 0.87) -0.50 (-0.78, -0.06)

BAR_4+MTX 1.00 (0.25, 4.10) 1.00 (0.69, 1.88) -0.001 (-0.26, 0.33)

HD203+MTX 1.42 (0.23, 8.82) 1.10 (0.62, 2.13) 0.07 (-0.30, 0.43)

SB4+MTX 1.12 (0.21, 6.52) 1.04 (0.61, 2.04) 0.02 (-0.31, 0.40)

ANBAI+MTX 1.35 (0.27, 6.63) 1.09 (0.69, 2.07) 0.06 (-0.25, 0.40)

CT-P13+MTX 0.98 (0.21, 4.65) 0.99 (0.62, 1.91) -0.004 (-0.31, 0.34)

SB2+MTX 0.59 (0.11, 3.16) 0.82 (0.41, 1.66) -0.12 (-0.46, 0.27)

SB5+MTX 0.94 (0.18, 4.90) 0.98 (0.56, 1.89) -0.01 (-0.35, 0.35)

ZRC-3197+MTX 0.85 (0.14, 5.38) 0.95 (0.45, 1.90) -0.03 (-0.42, 0.36)

ABP501+MTX 1.05 (0.20, 5.25) 1.01 (0.60, 1.97) 0.01 (-0.32, 0.37)

BAR_4+MTX ADA_STD 12.48 (1.83, 79.54) 4.82 (1.31, 25.02) 0.52 (0.14, 0.70)

HD203+MTX 17.85 (2.14, 143.20) 5.22 (1.41, 26.73) 0.57 (0.17, 0.82)

SB4+MTX 14.15 (1.82, 102.00) 4.92 (1.32, 25.17) 0.53 (0.14, 0.77)

ANBAI+MTX 16.90 (2.10, 125.90) 5.22 (1.38, 27.30) 0.57 (0.17, 0.79)

CT-P13+MTX 12.45 (1.68, 88.33) 4.75 (1.26, 25.14) 0.51 (0.12, 0.73)

SB2+MTX 7.55 (0.89, 57.61) 3.89 (0.93, 21.09) 0.39 (-0.03, 0.67)

SB5+MTX 11.84 (1.49, 93.36) 4.64 (1.21, 24.79) 0.49 (0.09, 0.75)

ZRC-3197+MTX 10.85 (1.13, 97.03) 4.44 (1.07, 24.09) 0.47 (0.03, 0.76)

603

ABP501+MTX 13.08 (1.61, 97.81) 4.80 (1.25, 25.11) 0.52 (0.11, 0.76)

HD203+MTX BAR_4+MTX 1.43 (0.35, 6.21) 1.11 (0.65, 1.55) 0.07 (-0.24, 0.31)

SB4+MTX 1.13 (0.34, 4.18) 1.04 (0.64, 1.47) 0.03 (-0.25, 0.27)

ANBAI+MTX 1.35 (0.42, 4.25) 1.09 (0.73, 1.49) 0.06 (-0.19, 0.27)

CT-P13+MTX 0.98 (0.35, 2.86) 0.99 (0.67, 1.38) -0.004 (-0.24, 0.21)

SB2+MTX 0.60 (0.18, 2.01) 0.82 (0.43, 1.26) -0.12 (-0.40, 0.15)

SB5+MTX 0.95 (0.30, 3.04) 0.98 (0.59, 1.38) -0.01 (-0.28, 0.22)

ZRC-3197+MTX 0.86 (0.21, 3.45) 0.95 (0.48, 1.41) -0.03 (-0.36, 0.24)

ABP501+MTX 1.05 (0.33, 3.26) 1.02 (0.64, 1.41) 0.01 (-0.25, 0.23)

SB4+MTX HD203+MTX 0.79 (0.18, 3.58) 0.94 (0.60, 1.54) -0.04 (-0.32, 0.27)

ANBAI+MTX 0.94 (0.18, 4.71) 0.99 (0.65, 1.67) -0.01 (-0.30, 0.32)

CT-P13+MTX 0.69 (0.14, 3.31) 0.90 (0.58, 1.58) -0.07 (-0.35, 0.27)

SB2+MTX 0.42 (0.08, 2.20) 0.75 (0.38, 1.37) -0.19 (-0.51, 0.18)

SB5+MTX 0.66 (0.12, 3.37) 0.89 (0.52, 1.55) -0.08 (-0.40, 0.27)

ZRC-3197+MTX 0.60 (0.09, 3.78) 0.86 (0.42, 1.56) -0.10 (-0.48, 0.27)

ABP501+MTX 0.74 (0.14, 3.57) 0.92 (0.56, 1.58) -0.06 (-0.37, 0.27)

ANBAI+MTX SB4+MTX 1.19 (0.27, 5.03) 1.05 (0.68, 1.71) 0.03 (-0.26, 0.33)

CT-P13+MTX 0.88 (0.21, 3.40) 0.96 (0.61, 1.59) -0.03 (-0.31, 0.27)

SB2+MTX 0.53 (0.11, 2.42) 0.79 (0.40, 1.41) -0.14 (-0.47, 0.20)

SB5+MTX 0.83 (0.18, 3.54) 0.94 (0.56, 1.58) -0.04 (-0.35, 0.27)

ZRC-3197+MTX 0.75 (0.13, 4.23) 0.91 (0.45, 1.61) -0.06 (-0.43, 0.29)

ABP501+MTX 0.93 (0.20, 3.79) 0.98 (0.59, 1.61) -0.02 (-0.32, 0.29)

CT-P13+MTX ANBAI+MTX 0.73 (0.20, 2.75) 0.91 (0.60, 1.39) -0.06 (-0.32, 0.21)

SB2+MTX 0.44 (0.11, 1.81) 0.75 (0.40, 1.23) -0.18 (-0.47, 0.13)

SB5+MTX 0.70 (0.17, 2.84) 0.90 (0.54, 1.40) -0.07 (-0.37, 0.22)

ZRC-3197+MTX 0.64 (0.13, 3.18) 0.87 (0.43, 1.41) -0.09 (-0.44, 0.22)

ABP501+MTX 0.78 (0.19, 3.18) 0.93 (0.58, 1.43) -0.05 (-0.33, 0.23)

SB2+MTX CT-P13+MTX 0.60 (0.18, 1.99) 0.83 (0.46, 1.28) -0.12 (-0.38, 0.15)

604

SB5+MTX 0.96 (0.25, 3.66) 0.99 (0.58, 1.54) -0.01 (-0.31, 0.27)

ZRC-3197+MTX 0.86 (0.18, 4.14) 0.95 (0.47, 1.56) -0.03 (-0.39, 0.29)

ABP501+MTX 1.07 (0.27, 3.92) 1.02 (0.62, 1.58) 0.01 (-0.29, 0.28)

SB5+MTX SB2+MTX 1.58 (0.35, 6.90) 1.19 (0.66, 2.34) 0.11 (-0.23, 0.43)

ZRC-3197+MTX 1.44 (0.27, 7.72) 1.16 (0.55, 2.34) 0.08 (-0.30, 0.44)

ABP501+MTX 1.74 (0.41, 7.56) 1.23 (0.71, 2.41) 0.13 (-0.20, 0.44)

ZRC-3197+MTX SB5+MTX 0.91 (0.20, 4.37) 0.97 (0.49, 1.67) -0.02 (-0.37, 0.31)

ABP501+MTX 1.11 (0.29, 4.23) 1.03 (0.64, 1.73) 0.02 (-0.26, 0.31)

ABP501+MTX ZRC-3197+MTX 1.22 (0.25, 5.81) 1.07 (0.64, 2.13) 0.04 (-0.28, 0.39)

Random-Effect



Criteria 963.498



Criteria 1010.91

Total Patients

20,191

Total Studies

63

2-arm 52

3-arm 9

4-arm 1

5-arm 1

ABA=abatacept, ABP501=biosimilar adalimumab, ADA=adalimumab, ANBAI=AnBaiNuo (biosimilar etanercept), BAR_4 =4mg baricitinib,

CERTO=certolizumab pegol, CT-P13=biosimilar infliximab, csDMARD=conventional synthetic disease modifying antirheumatic drug, ETN=etanercept, GOL=golimumab, HCQ=hydroxychloroquine, HD203=biosimilar etanercept, INF=infliximab, IV=intravenous, LEF_10= 10mg

leflunomide, MTX=methotrexate, OR=odds ratio, RD=risk difference, RR=relative risk, RIT=rituximab, SAR_200=200mg sarilumab, SB2=

biosimilar infliximab, SB4=biosimilar etanercept, SB5=biosimilar adalimumab, SC=subcutaneous, SSZ=sulfasalazine, STD = standard dose, TOC_4=tocilizumab 4mg/kg, TOC_8= tocilizumab 8mg/kg, TOF=tofacitinib, ZRC-3197=biosimilar adalimumab

605

Figure 49. Consistency Plot for ACR20 Inadequate Response to Methotrexate

Table 60. ACR70, Methotrexate as a Common Comparator: Odds Ratios, Relative Risks and Risk Difference

for All Treatment Comparisons – Random Effects Model


Placebo Placebo+MTX 0.15 (0.003, 2.53) 0.16 (0.003, 2.41) -0.03 (-0.04, 0.05)

csDMARD+MTX 1.74 (0.36, 9.47) 1.69 (0.37, 7.42) 0.02 (-0.02, 0.21)

MTX+HCQ 1.68 (0.09, 34.70) 1.64 (0.09, 16.38) 0.02 (-0.03, 0.50)

MTX+SSZ 0.81 (0.03, 21.20) 0.82 (0.03, 12.77) -0.01 (-0.04, 0.38)

MTX+SSZ+HCQ 1.79 (0.25, 15.02) 1.74 (0.25, 10.30) 0.02 (-0.03, 0.30)

ETN_STD 2.90 (0.89, 11.02) 2.72 (0.89, 8.29) 0.06 (-0.004, 0.23)

ETN_STD+MTX 6.54 (2.38, 21.36) 5.51 (2.27, 13.01) 0.15 (0.04, 0.38)

ABA_STD

(IV)+MTX 5.75 (2.37, 15.31) 4.95 (2.26, 10.51) 0.13 (0.04, 0.31)

TOF_STD 0.70 (0.01, 35.68) 0.70 (0.01, 16.58) -0.01 (-0.04, 0.52)

TOF_STD+MTX 4.43 (1.80, 11.49) 3.97 (1.75, 8.60) 0.10 (0.03, 0.25)

SAR_200 0.52 (0.003, 51.33) 0.53 (0.003, 19.25) -0.02 (-0.04, 0.60)

ADA_STD+MTX 4.00 (2.11, 7.74) 3.64 (2.03, 6.40) 0.09 (0.04, 0.17)

0

1

2

3

4

5

6

7

0 1 2 3 4 5 6 7

Inco

nsis

ten

cy M

od

el

Consistency Model

606


TOC_4 (IV) 0.43 (0.06, 2.70) 0.44 (0.06, 2.55) -0.02 (-0.03, 0.05)

TOC_8 (IV) 1.60 (0.57, 4.48) 1.57 (0.58, 4.02) 0.02 (-0.01, 0.10)

TOC_4 (IV)+MTX 2.31 (0.70, 7.49) 2.22 (0.70, 6.17) 0.04 (-0.01, 0.17)

TOC_8 (IV)+MTX 3.63 (1.44, 9.34) 3.33 (1.42, 7.35) 0.08 (0.01, 0.21)

GOL_STD (SC) 3.50 (0.03, 323.10) 3.23 (0.03, 27.41) 0.07 (-0.03, 0.88)

GOL_STD (SC)

+MTX 6.65 (2.08, 23.21) 5.58 (2.01, 13.63) 0.16 (0.03, 0.40)

GOL_STD (IV)

+MTX 3.17 (0.56, 18.13) 2.95 (0.56, 11.65) 0.07 (-0.01, 0.35)

INF_STD+MTX 4.28 (1.68, 11.84) 3.85 (1.64, 8.78) 0.10 (0.02, 0.25)

CERTO_STD 8.91 (0.07, 1099.00) 6.98 (0.07, 30.28) 0.20 (-0.03, 0.94)

CERTO_STD+MTX 6.28 (2.46, 16.54) 5.32 (2.34, 11.14) 0.15 (0.05, 0.32)

RIT_STD 3.90 (0.41, 56.61) 3.54 (0.41, 20.59) 0.09 (-0.02, 0.62)

RIT_STD+MTX 6.62 (0.70, 89.47) 5.55 (0.70, 23.38) 0.15 (-0.01, 0.71)

ADA_STD 0.16 (0.001, 11.18) 0.17 (0.001, 8.35) -0.03 (-0.04, 0.25)

BAR_4+MTX 9.52 (3.37, 29.14) 7.38 (3.10, 15.47) 0.22 (0.07, 0.46)

HD203+MTX 7.99 (1.14, 62.84) 6.46 (1.14, 21.16) 0.19 (0.005, 0.64)

SB4+MTX 7.95 (1.21, 61.18) 6.42 (1.20, 21.07) 0.18 (0.01, 0.64)

ANBAI+MTX 8.66 (1.08, 117.10) 6.87 (1.08, 24.59) 0.20 (0.002, 0.76)

CT-P13+MTX 8.09 (1.75, 40.94) 6.49 (1.70, 17.98) 0.19 (0.02, 0.55)

SB2+MTX 3.86 (0.58, 25.86) 3.51 (0.59, 14.41) 0.09 (-0.01, 0.43)

ZRC-3197+MTX 3.35 (0.46, 24.84) 3.10 (0.47, 14.08) 0.07 (-0.02, 0.43)

ABP501+MTX 4.77 (0.88, 28.43) 4.23 (0.88, 15.03) 0.11 (-0.004, 0.46)

csDMARD+MTX Placebo 11.41 (0.61, 737.10) 10.63 (0.63, 662.50) 0.05 (-0.02, 0.22)

MTX+HCQ 10.83 (0.26, 1524.00) 9.92 (0.27, 1059.00) 0.04 (-0.03, 0.52)

MTX+SSZ 5.27 (0.10, 1006.00) 5.04 (0.11, 670.60) 0.02 (-0.04, 0.40)

MTX+SSZ+HCQ 11.54 (0.52, 1019.00) 10.63 (0.54, 804.90) 0.05 (-0.02, 0.32)

607


ETN_STD 18.88 (1.58, 892.10) 16.90 (1.51, 792.60) 0.08 (0.02, 0.24)

ETN_STD+MTX 42.68 (3.01, 2203.00) 34.16 (2.65, 1704.00) 0.17 (0.07, 0.39)

ABA_STD (IV)

+MTX 38.41 (2.02, 2282.00) 31.68 (1.86, 1665.00) 0.16 (0.05, 0.33)

TOF_STD 4.76 (0.47, 79.33) 4.49 (0.47, 49.06) 0.02 (-0.004, 0.50)

TOF_STD+MTX 30.07 (1.56, 1610.00) 25.90 (1.50, 1319.00) 0.12 (0.03, 0.27)

SAR_200 3.73 (0.14, 129.70) 3.57 (0.14, 67.03) 0.01 (-0.01, 0.58)

ADA_STD+MTX 27.00 (1.47, 1255.00) 23.62 (1.41, 1093.00) 0.11 (0.03, 0.20)

TOC_4 (IV) 2.87 (0.09, 207.90) 2.83 (0.09, 199.60) 0.01 (-0.06, 0.08)

TOC_8 (IV) 10.57 (0.54, 598.40) 9.99 (0.56, 537.80) 0.04 (-0.03, 0.13)

TOC_4 (IV)+MTX 15.33 (0.71, 817.30) 14.08 (0.73, 718.60) 0.06 (-0.02, 0.19)

TOC_8 (IV)+MTX 24.23 (1.24, 1198.00) 21.40 (1.21, 1068.00) 0.10 (0.01, 0.23)

GOL_STD (SC) 22.35 (1.86, 922.50) 16.75 (1.84, 237.00) 0.10 (0.0003, 0.87)

GOL_STD (SC)

+MTX 44.58 (2.04, 3157.00) 35.31 (1.90, 2117.00) 0.18 (0.04, 0.42)

GOL_STD (IV)

+MTX 21.27 (0.77, 1616.00) 18.73 (0.78, 1218.00) 0.09 (-0.01, 0.37)

INF_STD+MTX 28.99 (1.41, 1586.00) 24.89 (1.35, 1317.00) 0.12 (0.02, 0.28)

CERTO_STD 51.79 (5.91, 3344.00) 31.46 (5.01, 372.90) 0.23 (0.002, 0.94)

CERTO_STD+MTX 40.94 (2.22, 2391.00) 33.40 (2.02, 1824.00) 0.17 (0.05, 0.34)

RIT_STD 26.80 (0.69, 3834.00) 22.41 (0.71, 2000.00) 0.11 (-0.01, 0.64)

RIT_STD+MTX 45.99 (1.17, 6822.00) 34.48 (1.16, 2866.00) 0.18 (0.005, 0.74)

ADA_STD 1.16 (0.07, 24.39) 1.16 (0.07, 19.68) 0.0003 (-0.03, 0.24)

BAR_4+MTX 63.90 (3.29, 3852.00) 47.02 (2.82, 2477.00) 0.24 (0.08, 0.48)

HD203+MTX 52.59 (2.30, 3956.00) 38.39 (2.14, 2411.00) 0.21 (0.02, 0.65)

SB4+MTX 52.82 (2.36, 3966.00) 38.36 (2.18, 2312.00) 0.21 (0.03, 0.65)

ANBAI+MTX 60.41 (1.85, 6339.00) 42.34 (1.76, 2513.00) 0.22 (0.02, 0.78)

CT-P13+MTX 53.92 (2.16, 4071.00) 40.22 (1.99, 2449.00) 0.21 (0.04, 0.57)

608


SB2+MTX 25.98 (0.84, 2368.00) 22.20 (0.85, 1499.00) 0.11 (-0.01, 0.46)

ZRC-3197+MTX 22.63 (0.67, 1951.00) 19.53 (0.69, 1312.00) 0.09 (-0.01, 0.45)

ABP501+MTX 32.72 (1.20, 2318.00) 27.06 (1.18, 1529.00) 0.13 (0.01, 0.48)

MTX+HCQ csDMARD+MTX 0.94 (0.05, 20.94) 0.94 (0.05, 11.73) -0.002 (-0.16, 0.45)

MTX+SSZ 0.46 (0.02, 12.12) 0.48 (0.02, 8.17) -0.02 (-0.18, 0.33)

MTX+SSZ+HCQ 1.03 (0.12, 8.78) 1.02 (0.14, 6.91) 0.001 (-0.15, 0.24)

ETN_STD 1.65 (0.36, 7.87) 1.58 (0.40, 6.78) 0.03 (-0.10, 0.17)

ETN_STD+MTX 3.77 (1.14, 12.60) 3.20 (1.11, 10.35) 0.12 (0.02, 0.28)

ABA_STD (IV)

+MTX 3.29 (0.53, 21.05) 2.88 (0.59, 16.01) 0.10 (-0.09, 0.29)

TOF_STD 0.40 (0.003, 22.98) 0.42 (0.004, 12.00) -0.02 (-0.19, 0.47)

TOF_STD+MTX 2.54 (0.38, 15.91) 2.33 (0.44, 12.81) 0.07 (-0.12, 0.23)

SAR_200 0.30 (0.002, 32.66) 0.32 (0.002, 14.06) -0.03 (-0.20, 0.56)

ADA_STD+MTX 2.31 (0.37, 12.47) 2.14 (0.44, 10.69) 0.06 (-0.13, 0.16)

TOC_4 (IV) 0.25 (0.02, 2.63) 0.26 (0.02, 2.51) -0.04 (-0.22, 0.04)

TOC_8 (IV) 0.91 (0.12, 6.05) 0.92 (0.15, 5.58) -0.005 (-0.19, 0.09)

TOC_4 (IV)+MTX 1.32 (0.16, 9.28) 1.29 (0.19, 8.12) 0.02 (-0.17, 0.15)

TOC_8 (IV)+MTX 2.08 (0.30, 13.27) 1.95 (0.36, 11.01) 0.05 (-0.14, 0.19)

GOL_STD (SC) 1.97 (0.02, 181.60) 1.83 (0.02, 26.38) 0.04 (-0.15, 0.83)

GOL_STD

(SC)+MTX 3.86 (0.48, 27.91) 3.26 (0.54, 19.05) 0.12 (-0.09, 0.38)

GOL_STD (IV)

+MTX 1.82 (0.16, 17.81) 1.72 (0.19, 12.77) 0.04 (-0.15, 0.32)

INF_STD+MTX 2.47 (0.36, 15.92) 2.26 (0.42, 12.91) 0.07 (-0.12, 0.24)

CERTO_STD 4.83 (0.04, 644.10) 3.68 (0.04, 35.50) 0.16 (-0.12, 0.91)

CERTO_STD+MTX 3.60 (0.53, 22.08) 3.11 (0.60, 16.36) 0.12 (-0.08, 0.30)

RIT_STD 2.23 (0.13, 48.56) 2.05 (0.15, 21.26) 0.06 (-0.16, 0.59)

RIT_STD+MTX 3.78 (0.21, 73.40) 3.16 (0.24, 27.07) 0.12 (-0.12, 0.68)

609


ADA_STD 0.09 (0.001, 7.56) 0.10 (0.001, 5.72) -0.04 (-0.22, 0.20)

BAR_4+MTX 5.49 (0.75, 37.77) 4.28 (0.80, 23.05) 0.18 (-0.04, 0.44)

HD203+MTX 4.55 (0.58, 36.43) 3.61 (0.61, 18.50) 0.15 (-0.04, 0.57)

SB4+MTX 4.55 (0.63, 35.31) 3.61 (0.66, 18.36) 0.15 (-0.04, 0.57)

ANBAI+MTX 5.09 (0.32, 96.87) 3.96 (0.36, 28.51) 0.17 (-0.10, 0.73)

CT-P13+MTX 4.60 (0.47, 43.09) 3.72 (0.53, 23.88) 0.15 (-0.08, 0.52)

SB2+MTX 2.19 (0.18, 26.05) 2.03 (0.21, 16.38) 0.06 (-0.14, 0.40)

ZRC-3197+MTX 1.93 (0.15, 23.92) 1.81 (0.17, 15.31) 0.04 (-0.15, 0.40)

ABP501+MTX 2.79 (0.25, 27.88) 2.50 (0.28, 17.29) 0.08 (-0.13, 0.43)

MTX+SSZ MTX+HCQ 0.50 (0.04, 5.40) 0.53 (0.04, 4.61) -0.02 (-0.35, 0.16)

MTX+SSZ+HCQ 1.08 (0.12, 9.33) 1.07 (0.18, 8.57) 0.002 (-0.34, 0.14)

ETN_STD 1.77 (0.09, 32.61) 1.69 (0.16, 28.53) 0.03 (-0.42, 0.19)

ETN_STD+MTX 3.96 (0.23, 62.98) 3.33 (0.39, 50.50) 0.11 (-0.30, 0.32)

ABA_STD (IV)

+MTX 3.43 (0.15, 76.51) 2.99 (0.27, 60.64) 0.10 (-0.38, 0.29)

TOF_STD 0.43 (0.002, 43.65) 0.47 (0.003, 25.17) -0.02 (-0.47, 0.45)

TOF_STD+MTX 2.69 (0.12, 61.33) 2.44 (0.21, 50.06) 0.07 (-0.40, 0.23)

SAR_200 0.33 (0.001, 53.70) 0.36 (0.001, 26.40) -0.02 (-0.47, 0.53)

ADA_STD+MTX 2.41 (0.11, 50.23) 2.23 (0.21, 42.96) 0.06 (-0.41, 0.17)

TOC_4 (IV) 0.25 (0.01, 8.31) 0.27 (0.01, 8.02) -0.04 (-0.51, 0.05)

TOC_8 (IV) 0.95 (0.04, 20.86) 0.95 (0.08, 19.37) -0.003 (-0.48, 0.10)

TOC_4 (IV)+MTX 1.37 (0.05, 33.20) 1.34 (0.10, 29.48) 0.02 (-0.46, 0.16)

TOC_8 (IV)+MTX 2.14 (0.09, 49.24) 2.01 (0.18, 41.25) 0.05 (-0.43, 0.20)

GOL_STD (SC) 2.06 (0.01, 368.50) 1.85 (0.01, 75.68) 0.03 (-0.40, 0.84)

GOL_STD (SC)

+MTX 4.00 (0.16, 96.73) 3.38 (0.27, 70.14) 0.12 (-0.35, 0.37)

GOL_STD

(IV)+MTX 1.88 (0.06, 59.41) 1.78 (0.10, 44.58) 0.03 (-0.43, 0.32)

610


INF_STD+MTX 2.58 (0.11, 60.91) 2.36 (0.21, 49.66) 0.07 (-0.40, 0.24)

CERTO_STD 5.24 (0.02, 1182.00) 3.55 (0.03, 111.10) 0.14 (-0.34, 0.91)

CERTO_STD+MTX 3.77 (0.16, 83.66) 3.23 (0.28, 64.91) 0.11 (-0.37, 0.31)

RIT_STD 2.38 (0.05, 131.70) 2.15 (0.08, 67.72) 0.05 (-0.41, 0.58)

RIT_STD+MTX 4.00 (0.09, 193.40) 3.26 (0.15, 89.47) 0.11 (-0.37, 0.68)

ADA_STD 0.10 (0.0003, 12.56) 0.11 (0.001, 9.70) -0.04 (-0.51, 0.19)

BAR_4+MTX 5.70 (0.25, 139.00) 4.41 (0.39, 90.67) 0.17 (-0.30, 0.44)

HD203+MTX 4.80 (0.18, 123.30) 3.70 (0.29, 73.59) 0.13 (-0.28, 0.57)

SB4+MTX 4.82 (0.20, 124.90) 3.77 (0.30, 72.83) 0.13 (-0.28, 0.58)

ANBAI+MTX 5.47 (0.13, 258.10) 4.07 (0.21, 98.22) 0.15 (-0.33, 0.73)

CT-P13+MTX 4.87 (0.17, 145.30) 3.86 (0.28, 89.34) 0.14 (-0.32, 0.51)

SB2+MTX 2.31 (0.07, 79.25) 2.11 (0.12, 55.84) 0.05 (-0.41, 0.39)

ZRC-3197+MTX 2.04 (0.06, 70.99) 1.90 (0.10, 50.44) 0.04 (-0.41, 0.39)

ABP501+MTX 2.92 (0.09, 89.75) 2.57 (0.15, 64.21) 0.07 (-0.40, 0.43)

MTX+SSZ+HCQ MTX+SSZ 2.16 (0.19, 30.48) 2.05 (0.26, 27.81) 0.02 (-0.22, 0.20)

ETN_STD 3.62 (0.15, 92.35) 3.34 (0.23, 79.99) 0.05 (-0.30, 0.22)

ETN_STD+MTX 8.13 (0.40, 189.00) 6.65 (0.53, 148.40) 0.14 (-0.18, 0.35)

ABA_STD

(IV)+MTX 7.14 (0.25, 216.20) 6.05 (0.36, 168.00) 0.12 (-0.25, 0.31)

TOF_STD 0.89 (0.003, 121.60) 0.90 (0.005, 68.63) -0.001 (-0.36, 0.49)

TOF_STD+MTX 5.51 (0.19, 170.30) 4.83 (0.29, 139.30) 0.09 (-0.28, 0.25)

SAR_200 0.68 (0.002, 143.90) 0.69 (0.002, 70.98) -0.004 (-0.36, 0.57)

ADA_STD+MTX 4.97 (0.18, 141.70) 4.46 (0.27, 119.70) 0.09 (-0.29, 0.18)

TOC_4 (IV) 0.52 (0.01, 21.52) 0.53 (0.02, 20.79) -0.01 (-0.39, 0.06)

TOC_8 (IV) 1.96 (0.06, 58.77) 1.89 (0.10, 54.17) 0.02 (-0.36, 0.11)

TOC_4 (IV)+MTX 2.84 (0.09, 90.46) 2.68 (0.14, 80.34) 0.04 (-0.34, 0.17)

TOC_8 (IV)+MTX 4.47 (0.16, 131.70) 4.04 (0.24, 113.00) 0.07 (-0.30, 0.21)

611


GOL_STD (SC) 4.35 (0.01, 886.30) 3.63 (0.02, 209.70) 0.06 (-0.29, 0.86)

GOL_STD (SC)

+MTX 8.31 (0.27, 263.00) 6.78 (0.38, 193.40) 0.14 (-0.23, 0.40)

GOL_STD (IV)

+MTX 3.93 (0.10, 166.90) 3.57 (0.15, 130.10) 0.06 (-0.31, 0.34)

INF_STD+MTX 5.36 (0.18, 166.90) 4.71 (0.27, 134.50) 0.09 (-0.29, 0.26)

CERTO_STD 11.51 (0.03, 2672.00) 6.99 (0.04, 290.00) 0.17 (-0.23, 0.93)

CERTO_STD+MTX 7.80 (0.26, 241.30) 6.49 (0.38, 185.60) 0.14 (-0.24, 0.32)

RIT_STD 5.07 (0.08, 314.00) 4.31 (0.12, 179.70) 0.07 (-0.30, 0.60)

RIT_STD+MTX 8.40 (0.15, 539.60) 6.45 (0.21, 247.50) 0.13 (-0.25, 0.70)

ADA_STD 0.21 (0.001, 33.25) 0.22 (0.001, 27.47) -0.01 (-0.39, 0.22)

BAR_4+MTX 11.84 (0.41, 389.70) 8.92 (0.54, 257.30) 0.20 (-0.17, 0.46)

HD203+MTX 10.00 (0.32, 343.00) 7.47 (0.43, 207.00) 0.16 (-0.17, 0.60)

SB4+MTX 9.88 (0.33, 339.70) 7.37 (0.43, 198.20) 0.16 (-0.16, 0.61)

ANBAI+MTX 11.40 (0.22, 641.70) 8.18 (0.30, 256.90) 0.18 (-0.21, 0.76)

CT-P13+MTX 9.99 (0.27, 385.60) 7.71 (0.38, 232.00) 0.17 (-0.21, 0.54)

SB2+MTX 4.79 (0.11, 209.40) 4.18 (0.17, 147.50) 0.07 (-0.29, 0.42)

ZRC-3197+MTX 4.06 (0.10, 193.80) 3.63 (0.15, 138.20) 0.06 (-0.30, 0.42)

ABP501+MTX 6.03 (0.14, 256.20) 5.07 (0.21, 180.00) 0.10 (-0.28, 0.45)

ETN_STD MTX+SSZ+HCQ 1.65 (0.22, 11.62) 1.58 (0.28, 10.21) 0.03 (-0.20, 0.18)

ETN_STD+MTX

3.71 (0.61, 21.41) 3.13 (0.70, 17.17) 0.11 (-0.08, 0.30)

ABA_STD (IV)

+MTX 3.24 (0.34, 31.35) 2.84 (0.42, 23.85) 0.10 (-0.17, 0.29)

TOF_STD 0.41 (0.003, 28.51) 0.43 (0.004, 14.31) -0.02 (-0.28, 0.46)

TOF_STD+MTX 2.48 (0.24, 23.61) 2.27 (0.32, 19.02) 0.07 (-0.21, 0.23)

SAR_200 0.31 (0.001, 33.73) 0.33 (0.002, 15.05) -0.03 (-0.28, 0.54)

ADA_STD+MTX 2.26 (0.24, 19.14) 2.10 (0.32, 16.13) 0.06 (-0.22, 0.17)

TOC_4 (IV) 0.24 (0.01, 3.43) 0.26 (0.02, 3.28) -0.04 (-0.32, 0.04)

612


TOC_8 (IV) 0.90 (0.08, 8.43) 0.91 (0.11, 7.78) -0.01 (-0.28, 0.09)

TOC_4 (IV)+MTX 1.29 (0.11, 12.86) 1.26 (0.15, 11.25) 0.01 (-0.26, 0.16)

TOC_8 (IV)+MTX 2.02 (0.20, 18.46) 1.90 (0.27, 15.45) 0.05 (-0.23, 0.19)

GOL_STD (SC) 1.93 (0.01, 222.90) 1.78 (0.01, 36.70) 0.04 (-0.23, 0.83)

GOL_STD (SC)

+MTX 3.82 (0.33, 38.53) 3.22 (0.41, 27.40) 0.12 (-0.17, 0.37)

GOL_STD

(IV)+MTX 1.76 (0.12, 24.97) 1.66 (0.15, 18.19) 0.03 (-0.23, 0.32)

INF_STD+MTX 2.43 (0.24, 24.04) 2.23 (0.32, 19.32) 0.07 (-0.21, 0.23)

CERTO_STD 4.79 (0.03, 754.50) 3.50 (0.03, 48.27) 0.16 (-0.19, 0.91)

CERTO_STD+MTX 3.47 (0.36, 31.95) 3.01 (0.44, 24.54) 0.11 (-0.17, 0.30)

RIT_STD 2.18 (0.09, 61.83) 2.00 (0.12, 29.37) 0.05 (-0.24, 0.59)

RIT_STD+MTX 3.69 (0.16, 103.00) 3.06 (0.20, 39.67) 0.11 (-0.20, 0.68)

ADA_STD 0.10 (0.001, 7.53) 0.10 (0.001, 5.92) -0.04 (-0.31, 0.20)

BAR_4+MTX 5.38 (0.49, 53.60) 4.22 (0.59, 34.81) 0.18 (-0.12, 0.44)

HD203+MTX 4.43 (0.41, 48.98) 3.46 (0.47, 27.17) 0.14 (-0.11, 0.57)

SB4+MTX 4.47 (0.41, 50.39) 3.53 (0.47, 27.39) 0.14 (-0.11, 0.57)

ANBAI+MTX 5.10 (0.23, 123.00) 3.93 (0.29, 42.00) 0.16 (-0.17, 0.73)

CT-P13+MTX 4.50 (0.33, 60.42) 3.64 (0.41, 34.30) 0.15 (-0.15, 0.51)

SB2+MTX 2.16 (0.13, 34.45) 1.99 (0.16, 22.69) 0.05 (-0.22, 0.40)

ZRC-3197+MTX 1.87 (0.11, 31.35) 1.76 (0.14, 21.45) 0.04 (-0.23, 0.39)

ABP501+MTX 2.69 (0.17, 40.53) 2.40 (0.22, 25.91) 0.07 (-0.21, 0.43)

ETN_STD+MTX ETN_STD 2.26 (0.88, 5.92) 2.00 (0.90, 4.72) 0.09 (-0.02, 0.25)

ABA_STD

(IV)+MTX 1.99 (0.40, 9.18) 1.81 (0.47, 6.88) 0.07 (-0.12, 0.26)

TOF_STD 0.24 (0.003, 10.62) 0.27 (0.003, 5.70) -0.05 (-0.21, 0.42)

TOF_STD+MTX 1.52 (0.30, 7.16) 1.45 (0.36, 5.74) 0.04 (-0.15, 0.20)

SAR_200 0.18 (0.001, 14.92) 0.20 (0.001, 6.47) -0.06 (-0.22, 0.51)

613


ADA_STD+MTX 1.38 (0.31, 5.24) 1.34 (0.38, 4.58) 0.03 (-0.16, 0.14)

TOC_4 (IV) 0.15 (0.01, 1.30) 0.16 (0.02, 1.28) -0.07 (-0.25, 0.01)

TOC_8 (IV) 0.55 (0.10, 2.58) 0.57 (0.13, 2.43) -0.04 (-0.22, 0.06)

TOC_4 (IV)+MTX 0.79 (0.13, 4.09) 0.81 (0.16, 3.63) -0.02 (-0.20, 0.13)

TOC_8 (IV)+MTX 1.25 (0.25, 5.52) 1.22 (0.30, 4.67) 0.02 (-0.17, 0.16)

GOL_STD (SC) 1.15 (0.01, 90.89) 1.14 (0.01, 11.57) 0.01 (-0.17, 0.79)

GOL_STD (SC)

+MTX 2.30 (0.38, 12.87) 2.04 (0.44, 8.67) 0.09 (-0.12, 0.35)

GOL_STD (IV)

+MTX 1.07 (0.13, 8.88) 1.06 (0.15, 6.20) 0.01 (-0.19, 0.29)

INF_STD+MTX 1.49 (0.29, 7.11) 1.42 (0.34, 5.74) 0.04 (-0.15, 0.21)

CERTO_STD 2.90 (0.03, 315.00) 2.37 (0.03, 15.65) 0.13 (-0.14, 0.87)

CERTO_STD+MTX 2.16 (0.44, 9.77) 1.95 (0.51, 7.28) 0.08 (-0.11, 0.27)

RIT_STD 1.32 (0.10, 23.65) 1.27 (0.12, 10.49) 0.02 (-0.19, 0.55)

RIT_STD+MTX 2.26 (0.16, 37.93) 1.99 (0.19, 13.22) 0.09 (-0.15, 0.65)

ADA_STD 0.06 (0.001, 3.46) 0.06 (0.001, 2.75) -0.07 (-0.24, 0.16)

BAR_4+MTX 3.30 (0.62, 16.98) 2.69 (0.67, 10.42) 0.15 (-0.07, 0.41)

HD203+MTX 2.70 (0.39, 18.49) 2.27 (0.43, 8.99) 0.12 (-0.08, 0.54)

SB4+MTX 2.73 (0.43, 19.13) 2.28 (0.47, 9.12) 0.12 (-0.07, 0.54)

ANBAI+MTX 3.04 (0.26, 48.36) 2.49 (0.30, 14.06) 0.13 (-0.13, 0.70)

CT-P13+MTX 2.73 (0.36, 20.79) 2.33 (0.42, 11.07) 0.12 (-0.11, 0.49)

SB2+MTX 1.30 (0.13, 12.36) 1.26 (0.15, 7.83) 0.02 (-0.18, 0.38)

ZRC-3197+MTX 1.14 (0.10, 11.75) 1.13 (0.12, 7.57) 0.01 (-0.18, 0.37)

ABP501+MTX 1.65 (0.18, 14.12) 1.54 (0.22, 8.50) 0.05 (-0.17, 0.40)

ABA_STD (IV)

+MTX ETN_STD+MTX 0.88 (0.21, 3.49) 0.90 (0.29, 2.78) -0.02 (-0.26, 0.19)

TOF_STD

0.11 (0.001, 5.21) 0.13 (0.001, 2.92) -0.14 (-0.36, 0.33)

TOF_STD+MTX 0.67 (0.15, 2.73) 0.72 (0.22, 2.33) -0.05 (-0.29, 0.13)

614


SAR_200 0.08 (0.001, 7.23) 0.10 (0.001, 3.30) -0.14 (-0.37, 0.42)

ADA_STD+MTX 0.61 (0.16, 2.01) 0.66 (0.23, 1.84) -0.06 (-0.30, 0.08)

TOC_4 (IV) 0.07 (0.01, 0.52) 0.08 (0.01, 0.56) -0.17 (-0.40, -0.04)

TOC_8 (IV) 0.24 (0.05, 1.00) 0.29 (0.07, 1.00) -0.13 (-0.36, -0.0002)

TOC_4 (IV)+MTX 0.35 (0.06, 1.67) 0.40 (0.09, 1.56) -0.11 (-0.35, 0.06)

TOC_8 (IV)+MTX 0.55 (0.12, 2.19) 0.60 (0.18, 1.94) -0.07 (-0.31, 0.10)

GOL_STD (SC) 0.52 (0.005, 43.02) 0.58 (0.01, 5.81) -0.07 (-0.32, 0.70)

GOL_STD (SC)

+MTX 1.02 (0.19, 5.01) 1.02 (0.26, 3.48) 0.003 (-0.27, 0.27)

GOL_STD

(IV)+MTX 0.48 (0.06, 3.44) 0.54 (0.08, 2.58) -0.08 (-0.33, 0.21)

INF_STD+MTX 0.66 (0.14, 2.72) 0.71 (0.21, 2.32) -0.05 (-0.30, 0.14)

CERTO_STD 1.29 (0.01, 153.00) 1.21 (0.01, 7.25) 0.04 (-0.28, 0.79)

CERTO_STD+MTX 0.95 (0.22, 3.83) 0.96 (0.30, 3.01) -0.01 (-0.25, 0.20)

RIT_STD 0.59 (0.04, 10.54) 0.64 (0.06, 4.61) -0.06 (-0.33, 0.47)

RIT_STD+MTX 0.99 (0.07, 16.23) 0.99 (0.10, 5.56) -0.002 (-0.29, 0.57)

ADA_STD 0.03 (0.0002, 1.65) 0.03 (0.0003, 1.46) -0.17 (-0.39, 0.08)

BAR_4+MTX 1.45 (0.30, 6.66) 1.33 (0.40, 4.13) 0.06 (-0.21, 0.34)

HD203+MTX 1.21 (0.22, 6.37) 1.16 (0.27, 3.23) 0.03 (-0.17, 0.40)

SB4+MTX 1.21 (0.24, 6.43) 1.16 (0.28, 3.30) 0.03 (-0.17, 0.40)

ANBAI+MTX 1.33 (0.11, 21.11) 1.25 (0.16, 5.89) 0.04 (-0.27, 0.62)

CT-P13+MTX 1.22 (0.17, 8.11) 1.17 (0.24, 4.47) 0.03 (-0.25, 0.41)

SB2+MTX 0.59 (0.06, 4.95) 0.64 (0.09, 3.31) -0.06 (-0.32, 0.29)

ZRC-3197+MTX 0.51 (0.05, 4.69) 0.57 (0.07, 3.15) -0.07 (-0.33, 0.29)

ABP501+MTX 0.73 (0.09, 5.45) 0.77 (0.13, 3.48) -0.04 (-0.30, 0.32)

TOF_STD ABA_STD

(IV)+MTX 0.12 (0.001, 6.98) 0.14 (0.001, 3.72) -0.13 (-0.31, 0.39)

TOF_STD+MTX 0.77 (0.21, 2.77) 0.80 (0.27, 2.35) -0.03 (-0.22, 0.14)

615


SAR_200 0.09 (0.0005, 9.78) 0.11 (0.001, 4.20) -0.13 (-0.31, 0.47)

ADA_STD+MTX 0.70 (0.21, 2.07) 0.74 (0.28, 1.88) -0.04 (-0.23, 0.08)

TOC_4 (IV) 0.07 (0.01, 0.57) 0.09 (0.01, 0.60) -0.15 (-0.32, -0.04)

TOC_8 (IV) 0.28 (0.07, 1.10) 0.32 (0.09, 1.09) -0.11 (-0.29, 0.01)

TOC_4 (IV)+MTX 0.40 (0.08, 1.76) 0.45 (0.11, 1.63) -0.09 (-0.27, 0.06)

TOC_8 (IV)+MTX 0.62 (0.16, 2.30) 0.67 (0.21, 2.03) -0.05 (-0.24, 0.10)

GOL_STD (SC) 0.59 (0.01, 58.47) 0.64 (0.01, 6.81) -0.06 (-0.28, 0.74)

GOL_STD (SC)

+MTX 1.16 (0.24, 5.27) 1.13 (0.31, 3.69) 0.02 (-0.20, 0.28)

GOL_STD (IV)

+MTX 0.55 (0.08, 3.81) 0.60 (0.10, 2.75) -0.06 (-0.26, 0.22)

INF_STD+MTX 0.74 (0.24, 2.43) 0.78 (0.29, 2.09) -0.04 (-0.20, 0.12)

CERTO_STD 1.55 (0.01, 188.00) 1.40 (0.01, 7.95) 0.06 (-0.26, 0.80)

CERTO_STD+MTX 1.09 (0.28, 3.93) 1.07 (0.35, 3.07) 0.01 (-0.19, 0.21)

RIT_STD 0.67 (0.06, 10.98) 0.72 (0.07, 4.81) -0.04 (-0.26, 0.48)

RIT_STD+MTX 1.14 (0.10, 16.72) 1.11 (0.12, 5.64) 0.02 (-0.24, 0.58)

ADA_STD 0.03 (0.0002, 2.18) 0.03 (0.0003, 1.86) -0.15 (-0.33, 0.12)

BAR_4+MTX 1.65 (0.39, 6.88) 1.48 (0.47, 4.33) 0.08 (-0.15, 0.35)

HD203+MTX 1.39 (0.16, 12.18) 1.30 (0.20, 5.28) 0.05 (-0.21, 0.51)

SB4+MTX 1.39 (0.17, 12.30) 1.30 (0.21, 5.19) 0.05 (-0.21, 0.51)

ANBAI+MTX 1.51 (0.15, 23.27) 1.38 (0.18, 6.42) 0.06 (-0.21, 0.63)

CT-P13+MTX 1.39 (0.26, 7.77) 1.30 (0.32, 4.25) 0.05 (-0.17, 0.40)

SB2+MTX 0.66 (0.09, 4.85) 0.71 (0.11, 3.24) -0.05 (-0.24, 0.29)

ZRC-3197+MTX 0.58 (0.06, 5.08) 0.63 (0.08, 3.36) -0.06 (-0.26, 0.29)

ABP501+MTX 0.82 (0.11, 5.87) 0.85 (0.14, 3.71) -0.02 (-0.24, 0.33)

TOF_STD+MTX TOF_STD 6.32 (0.12, 633.20) 5.55 (0.23, 544.20) 0.09 (-0.41, 0.25)

SAR_200 0.79 (0.04, 13.10) 0.81 (0.04, 10.07) -0.001 (-0.26, 0.32)

ADA_STD+MTX 5.72 (0.11, 575.70) 5.11 (0.21, 490.70) 0.09 (-0.43, 0.19)

616


TOC_4 (IV) 0.60 (0.01, 78.81) 0.60 (0.01, 75.56) -0.01 (-0.53, 0.06)

TOC_8 (IV) 2.27 (0.04, 221.70) 2.20 (0.08, 206.50) 0.02 (-0.50, 0.11)

TOC_4 (IV)+MTX 3.30 (0.05, 362.50) 3.10 (0.11, 319.90) 0.04 (-0.46, 0.18)

TOC_8 (IV)+MTX 5.19 (0.09, 522.40) 4.69 (0.18, 440.70) 0.07 (-0.43, 0.22)

GOL_STD (SC) 4.70 (0.12, 373.20) 3.66 (0.17, 124.60) 0.05 (-0.22, 0.80)

GOL_STD (SC)

+MTX 9.64 (0.16, 1334.00) 7.87 (0.28, 953.20) 0.14 (-0.36, 0.40)

GOL_STD

(IV)+MTX 4.50 (0.06, 637.40) 4.06 (0.11, 503.00) 0.06 (-0.44, 0.34)

INF_STD+MTX 6.35 (0.10, 690.10) 5.56 (0.20, 556.50) 0.09 (-0.43, 0.26)

CERTO_STD 11.58 (0.34, 984.20) 7.07 (0.43, 192.80) 0.16 (-0.11, 0.89)

CERTO_STD+MTX 8.96 (0.16, 981.50) 7.39 (0.29, 786.60) 0.14 (-0.37, 0.32)

RIT_STD 5.58 (0.05, 1414.00) 4.77 (0.10, 818.20) 0.07 (-0.42, 0.61)

RIT_STD+MTX 9.62 (0.09, 2420.00) 7.44 (0.17, 1069.00) 0.13 (-0.38, 0.70)

ADA_STD 0.24 (0.02, 2.41) 0.27 (0.02, 2.27) -0.01 (-0.37, 0.03)

BAR_4+MTX 13.55 (0.23, 1500.00) 10.21 (0.39, 1030.00) 0.20 (-0.31, 0.46)

HD203+MTX 11.32 (0.15, 1618.00) 8.45 (0.27, 915.90) 0.16 (-0.31, 0.61)

SB4+MTX 11.51 (0.15, 1563.00) 8.60 (0.28, 951.30) 0.16 (-0.33, 0.62)

ANBAI+MTX 12.92 (0.14, 2330.00) 9.18 (0.25, 1016.00) 0.18 (-0.33, 0.75)

CT-P13+MTX 11.74 (0.16, 1624.00) 8.94 (0.29, 1022.00) 0.17 (-0.34, 0.54)

SB2+MTX 5.56 (0.06, 927.40) 4.86 (0.12, 629.50) 0.07 (-0.43, 0.43)

ZRC-3197+MTX 4.80 (0.06, 779.40) 4.26 (0.11, 558.10) 0.06 (-0.43, 0.41)

ABP501+MTX 6.89 (0.09, 920.60) 5.83 (0.17, 680.50) 0.10 (-0.39, 0.44)

SAR_200 TOF_STD+MTX 0.12 (0.001, 11.82) 0.14 (0.001, 4.98) -0.10 (-0.25, 0.49)

ADA_STD+MTX 0.91 (0.31, 2.52) 0.92 (0.38, 2.26) -0.01 (-0.16, 0.09)

TOC_4 (IV) 0.10 (0.01, 0.76) 0.11 (0.01, 0.78) -0.12 (-0.26, -0.02)

TOC_8 (IV) 0.36 (0.09, 1.39) 0.40 (0.11, 1.35) -0.08 (-0.23, 0.03)

TOC_4 (IV)+MTX 0.52 (0.11, 2.29) 0.56 (0.14, 2.07) -0.06 (-0.21, 0.09)

617


TOC_8 (IV)+MTX 0.82 (0.22, 3.01) 0.84 (0.27, 2.62) -0.02 (-0.18, 0.13)

GOL_STD (SC) 0.77 (0.01, 73.65) 0.80 (0.01, 8.65) -0.02 (-0.22, 0.77)

GOL_STD (SC)

+MTX 1.51 (0.33, 7.11) 1.41 (0.39, 4.71) 0.05 (-0.14, 0.32)

GOL_STD (IV)

+MTX 0.71 (0.10, 5.00) 0.74 (0.12, 3.61) -0.03 (-0.20, 0.26)

INF_STD+MTX 0.97 (0.26, 3.78) 0.97 (0.32, 3.12) -0.003 (-0.17, 0.17)

CERTO_STD 1.95 (0.02, 265.80) 1.71 (0.02, 10.40) 0.10 (-0.20, 0.84)

CERTO_STD+MTX 1.42 (0.37, 5.15) 1.34 (0.44, 3.89) 0.05 (-0.13, 0.24)

RIT_STD 0.88 (0.07, 14.53) 0.89 (0.09, 6.19) -0.01 (-0.21, 0.52)

RIT_STD+MTX 1.48 (0.13, 22.59) 1.38 (0.16, 7.34) 0.05 (-0.18, 0.62)

ADA_STD 0.04 (0.0003, 2.64) 0.04 (0.0003, 2.19) -0.12 (-0.27, 0.14)

BAR_4+MTX 2.15 (0.55, 8.98) 1.85 (0.61, 5.53) 0.11 (-0.09, 0.37)

HD203+MTX 1.79 (0.20, 17.23) 1.60 (0.24, 7.10) 0.08 (-0.16, 0.54)

SB4+MTX 1.80 (0.21, 16.37) 1.62 (0.26, 6.84) 0.08 (-0.15, 0.54)

ANBAI+MTX 1.99 (0.20, 31.22) 1.74 (0.23, 8.10) 0.10 (-0.16, 0.66)

CT-P13+MTX 1.81 (0.31, 11.28) 1.62 (0.36, 6.07) 0.08 (-0.13, 0.45)

SB2+MTX 0.87 (0.10, 7.08) 0.89 (0.13, 4.41) -0.01 (-0.19, 0.34)

ZRC-3197+MTX 0.76 (0.09, 6.37) 0.79 (0.11, 4.12) -0.03 (-0.20, 0.33)

ABP501+MTX 1.08 (0.16, 7.23) 1.06 (0.19, 4.51) 0.01 (-0.18, 0.35)

ADA_STD+MTX SAR_200 7.64 (0.07, 1352.00) 6.83 (0.18, 1146.00) 0.09 (-0.51, 0.19)

TOC_4 (IV) 0.78 (0.01, 188.50) 0.78 (0.01, 182.90) -0.003 (-0.62, 0.06)

TOC_8 (IV) 2.99 (0.03, 558.10) 2.86 (0.07, 511.70) 0.03 (-0.59, 0.12)

TOC_4 (IV)+MTX 4.36 (0.04, 811.30) 4.05 (0.10, 713.90) 0.04 (-0.56, 0.18)

TOC_8 (IV)+MTX 6.87 (0.06, 1256.00) 6.18 (0.16, 1043.00) 0.08 (-0.53, 0.22)

GOL_STD (SC) 6.26 (0.09, 700.30) 4.75 (0.13, 299.30) 0.05 (-0.30, 0.81)

GOL_STD (SC)

+MTX 12.54 (0.11, 2690.00) 10.16 (0.27, 1939.00) 0.14 (-0.45, 0.40)

618


GOL_STD (IV)

+MTX 5.94 (0.05, 1518.00) 5.31 (0.10, 1140.00) 0.06 (-0.52, 0.34)

INF_STD+MTX 8.25 (0.07, 1539.00) 7.21 (0.18, 1272.00) 0.10 (-0.50, 0.26)

CERTO_STD 15.45 (0.23, 2178.00) 9.20 (0.36, 495.80) 0.16 (-0.19, 0.90)

CERTO_STD+MTX 11.80 (0.11, 2111.00) 9.69 (0.26, 1596.00) 0.14 (-0.46, 0.33)

RIT_STD 7.44 (0.04, 2532.00) 6.24 (0.09, 1579.00) 0.07 (-0.50, 0.61)

RIT_STD+MTX 12.80 (0.07, 4254.00) 9.81 (0.16, 2029.00) 0.13 (-0.45, 0.71)

ADA_STD 0.31 (0.06, 1.74) 0.33 (0.07, 1.71) -0.01 (-0.39, 0.01)

BAR_4+MTX 18.00 (0.17, 3518.00) 13.33 (0.36, 2413.00) 0.20 (-0.39, 0.46)

HD203+MTX 14.54 (0.12, 3175.00) 10.82 (0.26, 2001.00) 0.16 (-0.39, 0.61)

SB4+MTX 14.91 (0.13, 3230.00) 11.03 (0.26, 1992.00) 0.16 (-0.39, 0.62)

ANBAI+MTX 16.74 (0.12, 4580.00) 11.79 (0.24, 1980.00) 0.18 (-0.40, 0.75)

CT-P13+MTX 15.73 (0.12, 3299.00) 11.70 (0.25, 2292.00) 0.17 (-0.42, 0.54)

SB2+MTX 7.45 (0.05, 1895.00) 6.43 (0.12, 1410.00) 0.08 (-0.50, 0.43)

ZRC-3197+MTX 6.29 (0.04, 1683.00) 5.53 (0.10, 1330.00) 0.06 (-0.51, 0.42)

ABP501+MTX 9.18 (0.07, 2238.00) 7.72 (0.16, 1572.00) 0.10 (-0.47, 0.45)

TOC_4 (IV) ADA_STD+MTX 0.11 (0.01, 0.74) 0.12 (0.01, 0.76) -0.10 (-0.19, -0.02)

TOC_8 (IV) 0.40 (0.12, 1.34) 0.43 (0.13, 1.30) -0.07 (-0.16, 0.03)

TOC_4 (IV)+MTX 0.58 (0.14, 2.18) 0.61 (0.17, 1.96) -0.05 (-0.15, 0.09)

TOC_8 (IV)+MTX 0.91 (0.29, 2.83) 0.92 (0.32, 2.44) -0.01 (-0.12, 0.13)

GOL_STD (SC) 0.86 (0.01, 82.10) 0.88 (0.01, 8.34) -0.01 (-0.17, 0.79)

GOL_STD (SC)

+MTX 1.68 (0.43, 6.54) 1.54 (0.47, 4.32) 0.07 (-0.09, 0.32)

GOL_STD (IV)

+MTX 0.79 (0.12, 4.90) 0.81 (0.14, 3.51) -0.02 (-0.14, 0.26)

INF_STD+MTX 1.07 (0.35, 3.47) 1.06 (0.39, 2.84) 0.01 (-0.11, 0.17)

CERTO_STD 2.21 (0.02, 264.60) 1.91 (0.02, 9.80) 0.11 (-0.15, 0.85)

619


CERTO_STD+MTX 1.57 (0.56, 4.38) 1.47 (0.60, 3.33) 0.06 (-0.06, 0.23)

RIT_STD 0.98 (0.09, 14.54) 0.98 (0.10, 5.94) -0.003 (-0.15, 0.53)

RIT_STD+MTX 1.64 (0.16, 23.27) 1.52 (0.18, 7.03) 0.06 (-0.13, 0.63)

ADA_STD 0.04 (0.0003, 2.98) 0.05 (0.0004, 2.39) -0.11 (-0.19, 0.16)

BAR_4+MTX 2.38 (0.77, 7.94) 2.02 (0.80, 4.75) 0.12 (-0.03, 0.37)

HD203+MTX 2.02 (0.25, 17.04) 1.79 (0.28, 6.55) 0.09 (-0.11, 0.56)

SB4+MTX 1.99 (0.27, 16.35) 1.76 (0.31, 6.62) 0.09 (-0.11, 0.55)

ANBAI+MTX 2.17 (0.25, 31.37) 1.89 (0.28, 7.67) 0.11 (-0.11, 0.68)

CT-P13+MTX 2.01 (0.39, 11.12) 1.78 (0.43, 5.66) 0.10 (-0.09, 0.46)

SB2+MTX 0.96 (0.13, 6.95) 0.96 (0.15, 4.27) -0.004 (-0.14, 0.34)

ZRC-3197+MTX 0.84 (0.13, 5.46) 0.86 (0.14, 3.56) -0.02 (-0.12, 0.32)

ABP501+MTX 1.19 (0.24, 6.21) 1.17 (0.26, 3.82) 0.02 (-0.10, 0.35)

TOC_8 (IV) TOC_4 (IV) 3.67 (0.62, 28.36) 3.51 (0.63, 26.55) 0.03 (-0.02, 0.11)

TOC_4 (IV)+MTX 5.28 (0.80, 41.84) 4.92 (0.81, 37.63) 0.06 (-0.01, 0.18)

TOC_8 (IV)+MTX 8.37 (1.45, 63.45) 7.43 (1.40, 54.50) 0.09 (0.02, 0.22)

GOL_STD (SC) 8.15 (0.05, 1051.00) 7.07 (0.06, 164.70) 0.09 (-0.04, 0.89)

GOL_STD (SC)

+MTX 15.60 (1.69, 163.00) 12.55 (1.61, 116.10) 0.17 (0.03, 0.42)

GOL_STD (IV)

+MTX 7.51 (0.59, 106.80) 6.72 (0.60, 77.53) 0.08 (-0.02, 0.36)

INF_STD+MTX 10.01 (1.30, 96.82) 8.78 (1.27, 76.69) 0.11 (0.02, 0.27)

CERTO_STD 20.63 (0.13, 3203.00) 14.19 (0.13, 219.10) 0.22 (-0.03, 0.95)

CERTO_STD+MTX 14.51 (1.94, 139.10) 11.93 (1.80, 103.70) 0.16 (0.04, 0.34)

RIT_STD 9.28 (0.48, 250.80) 7.98 (0.49, 120.20) 0.10 (-0.02, 0.63)

RIT_STD+MTX 15.78 (0.83, 408.10) 12.21 (0.84, 154.20) 0.17 (-0.01, 0.73)

ADA_STD 0.39 (0.002, 38.79) 0.39 (0.002, 30.47) -0.01 (-0.07, 0.26)

BAR_4+MTX 22.26 (2.72, 222.90) 16.61 (2.41, 144.30) 0.23 (0.07, 0.48)

620


HD203+MTX 18.69 (1.31, 329.10) 14.07 (1.29, 157.60) 0.20 (0.01, 0.65)

SB4+MTX 18.50 (1.41, 321.10) 13.92 (1.38, 154.80) 0.20 (0.01, 0.65)

ANBAI+MTX 20.73 (1.24, 483.80) 15.01 (1.22, 171.00) 0.21 (0.01, 0.77)

CT-P13+MTX 18.78 (1.74, 244.70) 14.39 (1.64, 142.20) 0.20 (0.03, 0.56)

SB2+MTX 8.87 (0.64, 148.40) 7.73 (0.65, 95.99) 0.10 (-0.01, 0.45)

ZRC-3197+MTX 7.95 (0.52, 130.90) 7.05 (0.53, 88.98) 0.09 (-0.02, 0.44)

ABP501+MTX 11.08 (0.92, 161.30) 9.39 (0.92, 102.60) 0.12 (-0.004, 0.47)

TOC_4 (IV)+MTX TOC_8 (IV) 1.44 (0.40, 4.98) 1.40 (0.43, 4.36) 0.02 (-0.05, 0.13)

TOC_8 (IV)+MTX

2.28 (0.96, 5.58) 2.13 (0.96, 4.90) 0.06 (-0.003, 0.16)

GOL_STD (SC) 2.18 (0.02, 220.20) 2.05 (0.02, 23.48) 0.05 (-0.09, 0.86)

GOL_STD (SC)

+MTX 4.18 (0.88, 20.96) 3.54 (0.89, 13.92) 0.13 (-0.01, 0.38)

GOL_STD (IV)

+MTX 1.99 (0.26, 15.08) 1.88 (0.28, 10.54) 0.04 (-0.07, 0.33)

INF_STD+MTX 2.70 (0.67, 11.64) 2.47 (0.69, 9.17) 0.07 (-0.03, 0.24)

CERTO_STD 5.43 (0.04, 722.20) 4.28 (0.04, 30.32) 0.18 (-0.08, 0.92)

CERTO_STD+MTX 3.93 (1.00, 16.28) 3.38 (1.00, 11.84) 0.12 (0.0001, 0.31)

RIT_STD 2.46 (0.21, 42.90) 2.27 (0.23, 17.21) 0.06 (-0.07, 0.60)

RIT_STD+MTX 4.15 (0.35, 64.57) 3.50 (0.37, 20.60) 0.13 (-0.05, 0.69)

ADA_STD 0.10 (0.001, 7.78) 0.11 (0.001, 5.87) -0.04 (-0.13, 0.22)

BAR_4+MTX 6.01 (1.40, 27.71) 4.69 (1.35, 16.42) 0.19 (0.03, 0.44)

HD203+MTX 4.95 (0.55, 51.03) 4.01 (0.58, 20.49) 0.16 (-0.03, 0.62)

SB4+MTX 4.95 (0.58, 48.27) 4.03 (0.60, 19.74) 0.16 (-0.03, 0.62)

ANBAI+MTX 5.51 (0.51, 84.46) 4.37 (0.54, 22.94) 0.18 (-0.04, 0.74)

CT-P13+MTX 5.05 (0.80, 35.16) 4.09 (0.82, 17.87) 0.16 (-0.02, 0.52)

SB2+MTX 2.40 (0.28, 21.72) 2.22 (0.31, 13.06) 0.06 (-0.06, 0.41)

ZRC-3197+MTX 2.13 (0.23, 19.66) 2.00 (0.24, 12.27) 0.05 (-0.07, 0.40)

621


ABP501+MTX 3.00 (0.40, 24.30) 2.69 (0.43, 13.76) 0.09 (-0.05, 0.44)


GOL_STD (SC) 1.52 (0.01, 150.50) 1.45 (0.01, 18.86) 0.03 (-0.15, 0.83)

GOL_STD (SC)

+MTX 2.92 (0.54, 16.10) 2.53 (0.58, 10.73) 0.11 (-0.07, 0.37)

GOL_STD (IV)

+MTX 1.38 (0.17, 12.07) 1.34 (0.19, 8.34) 0.02 (-0.13, 0.31)

INF_STD+MTX 1.88 (0.42, 9.45) 1.75 (0.46, 7.51) 0.05 (-0.09, 0.22)

CERTO_STD 3.77 (0.03, 516.50) 3.02 (0.03, 24.41) 0.16 (-0.13, 0.90)

CERTO_STD+MTX 2.73 (0.61, 12.72) 2.40 (0.65, 9.53) 0.10 (-0.06, 0.29)

RIT_STD 1.70 (0.13, 32.18) 1.60 (0.15, 13.47) 0.04 (-0.13, 0.58)

RIT_STD+MTX 2.89 (0.22, 47.82) 2.50 (0.25, 16.40) 0.11 (-0.10, 0.67)

ADA_STD 0.07 (0.001, 5.89) 0.08 (0.001, 4.60) -0.06 (-0.19, 0.20)

BAR_4+MTX 4.13 (0.86, 21.80) 3.31 (0.88, 13.28) 0.17 (-0.02, 0.42)

HD203+MTX 3.46 (0.35, 39.92) 2.86 (0.39, 16.31) 0.14 (-0.08, 0.60)

SB4+MTX 3.45 (0.39, 37.01) 2.86 (0.43, 15.92) 0.14 (-0.08, 0.60)

ANBAI+MTX 3.86 (0.34, 66.66) 3.10 (0.38, 18.12) 0.15 (-0.09, 0.72)

CT-P13+MTX 3.49 (0.51, 26.99) 2.89 (0.55, 14.26) 0.14 (-0.06, 0.50)

SB2+MTX 1.68 (0.18, 16.43) 1.59 (0.20, 10.16) 0.04 (-0.12, 0.39)

ZRC-3197+MTX 1.46 (0.15, 15.67) 1.41 (0.17, 9.73) 0.03 (-0.13, 0.38)

ABP501+MTX 2.08 (0.25, 17.85) 1.90 (0.29, 10.69) 0.06 (-0.11, 0.42)


GOL_STD (SC)

+MTX 1.86 (0.40, 8.37) 1.68 (0.45, 5.64) 0.07 (-0.11, 0.33)

GOL_STD (IV)

+MTX 0.87 (0.12, 6.26) 0.88 (0.14, 4.51) -0.01 (-0.17, 0.27)

INF_STD+MTX 1.19 (0.31, 4.64) 1.16 (0.36, 3.79) 0.02 (-0.13, 0.19)

CERTO_STD 2.43 (0.02, 317.30) 2.06 (0.02, 12.90) 0.12 (-0.17, 0.86)

622


CERTO_STD+MTX 1.73 (0.45, 6.53) 1.59 (0.51, 4.89) 0.07 (-0.10, 0.26)

RIT_STD 1.07 (0.09, 18.14) 1.06 (0.11, 7.52) 0.01 (-0.17, 0.54)

RIT_STD+MTX 1.83 (0.16, 27.89) 1.66 (0.18, 9.14) 0.07 (-0.15, 0.64)

ADA_STD 0.04 (0.0003, 3.28) 0.05 (0.0004, 2.61) -0.10 (-0.23, 0.16)

BAR_4+MTX 2.63 (0.65, 11.05) 2.21 (0.70, 6.74) 0.13 (-0.06, 0.39)

HD203+MTX 2.17 (0.26, 20.68) 1.89 (0.29, 8.51) 0.10 (-0.12, 0.56)

SB4+MTX 2.17 (0.27, 20.54) 1.90 (0.31, 8.40) 0.10 (-0.12, 0.56)

ANBAI+MTX 2.44 (0.24, 37.88) 2.07 (0.27, 9.69) 0.12 (-0.13, 0.69)

CT-P13+MTX 2.22 (0.37, 13.64) 1.94 (0.42, 7.27) 0.10 (-0.11, 0.46)

SB2+MTX 1.07 (0.13, 8.87) 1.06 (0.15, 5.50) 0.01 (-0.16, 0.36)

ZRC-3197+MTX 0.93 (0.10, 8.13) 0.94 (0.12, 5.18) -0.01 (-0.17, 0.34)

ABP501+MTX 1.33 (0.18, 9.95) 1.28 (0.21, 5.81) 0.03 (-0.15, 0.38)

GOL_STD (SC)

+MTX GOL_STD (SC) 1.93 (0.02, 278.80) 1.74 (0.14, 192.40) 0.07 (-0.73, 0.36)

GOL_STD (IV)

+MTX 0.92 (0.01, 159.20) 0.93 (0.05, 127.30) -0.01 (-0.81, 0.29)

INF_STD+MTX 1.25 (0.01, 163.50) 1.22 (0.11, 134.20) 0.02 (-0.78, 0.23)

CERTO_STD 2.48 (0.03, 292.10) 1.78 (0.09, 51.19) 0.05 (-0.59, 0.82)

CERTO_STD+MTX 1.83 (0.02, 212.80) 1.67 (0.16, 166.80) 0.06 (-0.73, 0.29)

RIT_STD 1.17 (0.01, 311.60) 1.14 (0.04, 166.10) 0.01 (-0.79, 0.54)

RIT_STD+MTX 1.92 (0.01, 527.20) 1.68 (0.07, 242.50) 0.05 (-0.75, 0.65)

ADA_STD 0.05 (0.001, 2.40) 0.07 (0.001, 2.11) -0.08 (-0.86, 0.04)

BAR_4+MTX 2.81 (0.03, 334.60) 2.31 (0.21, 224.70) 0.12 (-0.67, 0.42)

HD203+MTX 2.31 (0.02, 335.70) 1.95 (0.13, 196.60) 0.08 (-0.68, 0.55)

SB4+MTX 2.36 (0.02, 355.00) 1.96 (0.13, 211.50) 0.08 (-0.69, 0.55)

ANBAI+MTX 2.63 (0.02, 492.20) 2.12 (0.11, 205.20) 0.09 (-0.70, 0.70)

CT-P13+MTX 2.40 (0.02, 366.10) 2.04 (0.14, 217.30) 0.09 (-0.70, 0.49)

SB2+MTX 1.10 (0.01, 184.80) 1.08 (0.06, 131.00) 0.01 (-0.80, 0.37)

623


ZRC-3197+MTX 0.96 (0.01, 173.60) 0.96 (0.05, 126.80) -0.003 (-0.80, 0.36)

ABP501+MTX 1.37 (0.01, 216.70) 1.30 (0.08, 154.70) 0.03 (-0.77, 0.40)

GOL_STD (IV)

+MTX

GOL_STD (SC)

+MTX 0.47 (0.06, 3.80) 0.52 (0.08, 2.90) -0.08 (-0.35, 0.22)

INF_STD+MTX 0.65 (0.13, 3.14) 0.69 (0.20, 2.66) -0.06 (-0.32, 0.15)

CERTO_STD 1.31 (0.01, 179.40) 1.23 (0.01, 8.46) 0.04 (-0.34, 0.80)

CERTO_STD+MTX 0.94 (0.21, 4.23) 0.95 (0.29, 3.29) -0.01 (-0.27, 0.21)

RIT_STD 0.59 (0.04, 10.37) 0.64 (0.06, 4.69) -0.06 (-0.34, 0.47)

RIT_STD+MTX 1.00 (0.07, 16.69) 1.00 (0.10, 5.75) 0.0001 (-0.31, 0.57)

ADA_STD 0.02 (0.0002, 1.98) 0.03 (0.0002, 1.71) -0.17 (-0.42, 0.10)

BAR_4+MTX 1.44 (0.29, 7.25) 1.32 (0.40, 4.62) 0.06 (-0.23, 0.34)

HD203+MTX 1.17 (0.12, 12.63) 1.13 (0.16, 5.52) 0.02 (-0.28, 0.50)

SB4+MTX 1.19 (0.13, 12.57) 1.14 (0.18, 5.64) 0.03 (-0.28, 0.50)

ANBAI+MTX 1.30 (0.11, 22.08) 1.22 (0.16, 6.39) 0.04 (-0.28, 0.62)

CT-P13+MTX 1.22 (0.17, 9.06) 1.16 (0.23, 5.04) 0.03 (-0.27, 0.41)

SB2+MTX 0.58 (0.06, 5.47) 0.64 (0.09, 3.60) -0.06 (-0.34, 0.30)

ZRC-3197+MTX 0.50 (0.05, 5.14) 0.56 (0.07, 3.52) -0.08 (-0.35, 0.29)

ABP501+MTX 0.71 (0.09, 5.98) 0.76 (0.12, 3.84) -0.04 (-0.32, 0.32)

INF_STD+MTX

GOL_STD (IV)

+MTX 1.38 (0.19, 9.90) 1.33 (0.27, 8.06) 0.03 (-0.26, 0.21)

CERTO_STD 2.70 (0.02, 430.80) 2.17 (0.02, 25.76) 0.12 (-0.25, 0.88)

CERTO_STD+MTX 1.98 (0.28, 14.60) 1.79 (0.38, 11.12) 0.08 (-0.22, 0.27)

RIT_STD 1.23 (0.07, 30.95) 1.20 (0.09, 13.89) 0.02 (-0.29, 0.55)

RIT_STD+MTX 2.11 (0.12, 50.06) 1.86 (0.15, 17.85) 0.08 (-0.26, 0.65)

ADA_STD 0.05 (0.0003, 5.14) 0.06 (0.0003, 3.96) -0.08 (-0.36, 0.18)

BAR_4+MTX 3.02 (0.40, 24.10) 2.48 (0.50, 15.33) 0.14 (-0.16, 0.41)

HD203+MTX 2.53 (0.20, 38.12) 2.13 (0.25, 17.18) 0.11 (-0.21, 0.57)

SB4+MTX 2.52 (0.20, 36.08) 2.14 (0.26, 16.97) 0.11 (-0.22, 0.57)

624


ANBAI+MTX 2.84 (0.18, 59.27) 2.32 (0.24, 19.06) 0.12 (-0.22, 0.69)

CT-P13+MTX 2.58 (0.26, 25.85) 2.18 (0.34, 15.10) 0.11 (-0.20, 0.47)

SB2+MTX 1.21 (0.09, 15.92) 1.18 (0.13, 10.36) 0.02 (-0.28, 0.37)

ZRC-3197+MTX 1.06 (0.07, 15.36) 1.06 (0.10, 9.85) 0.005 (-0.28, 0.37)

ABP501+MTX 1.52 (0.13, 17.85) 1.43 (0.18, 11.43) 0.04 (-0.26, 0.40)

CERTO_STD INF_STD+MTX 2.01 (0.01, 265.10) 1.75 (0.02, 10.75) 0.10 (-0.20, 0.85)

CERTO_STD+MTX 1.48 (0.36, 5.59) 1.39 (0.43, 4.21) 0.05 (-0.14, 0.24)

RIT_STD 0.89 (0.08, 14.99) 0.91 (0.09, 6.38) -0.01 (-0.21, 0.52)

RIT_STD+MTX 1.52 (0.13, 23.07) 1.41 (0.16, 7.63) 0.05 (-0.19, 0.62)

ADA_STD 0.04 (0.0003, 3.05) 0.04 (0.0003, 2.44) -0.11 (-0.27, 0.16)

BAR_4+MTX 2.21 (0.52, 9.59) 1.89 (0.59, 5.82) 0.12 (-0.10, 0.38)

HD203+MTX 1.86 (0.20, 17.98) 1.65 (0.24, 7.27) 0.08 (-0.16, 0.55)

SB4+MTX 1.85 (0.22, 17.08) 1.65 (0.26, 7.19) 0.08 (-0.16, 0.54)

ANBAI+MTX 2.04 (0.19, 32.51) 1.78 (0.22, 8.47) 0.10 (-0.16, 0.67)

CT-P13+MTX 1.87 (0.56, 6.57) 1.65 (0.59, 3.86) 0.08 (-0.06, 0.37)

SB2+MTX 0.89 (0.17, 4.57) 0.90 (0.19, 3.11) -0.01 (-0.14, 0.28)

ZRC-3197+MTX 0.78 (0.08, 7.16) 0.80 (0.10, 4.55) -0.02 (-0.21, 0.33)

ABP501+MTX 1.11 (0.15, 8.03) 1.09 (0.18, 4.92) 0.01 (-0.18, 0.37)

CERTO_STD+MTX CERTO_STD 0.73 (0.01, 96.36) 0.79 (0.13, 76.56) -0.05 (-0.80, 0.27)

RIT_STD 0.44 (0.002, 127.90) 0.55 (0.03, 71.96) -0.09 (-0.88, 0.51)

RIT_STD+MTX 0.76 (0.004, 215.80) 0.83 (0.05, 101.50) -0.03 (-0.84, 0.62)

ADA_STD 0.02 (0.0002, 0.90) 0.04 (0.001, 0.92) -0.21 (-0.94, -0.0001)

BAR_4+MTX 1.08 (0.01, 151.80) 1.06 (0.18, 105.00) 0.01 (-0.75, 0.39)

HD203+MTX 0.93 (0.01, 153.40) 0.95 (0.09, 96.00) -0.01 (-0.79, 0.50)

SB4+MTX 0.93 (0.01, 152.00) 0.95 (0.09, 90.47) -0.01 (-0.79, 0.51)

ANBAI+MTX 1.04 (0.01, 226.30) 1.03 (0.08, 110.60) 0.01 (-0.80, 0.62)

CT-P13+MTX 0.94 (0.01, 162.30) 0.95 (0.11, 100.90) -0.01 (-0.79, 0.44)

625


SB2+MTX 0.45 (0.003, 89.77) 0.55 (0.04, 64.44) -0.10 (-0.87, 0.32)

ZRC-3197+MTX 0.38 (0.002, 70.85) 0.48 (0.04, 52.54) -0.11 (-0.88, 0.32)

ABP501+MTX 0.56 (0.004, 89.44) 0.64 (0.06, 65.74) -0.08 (-0.85, 0.35)


RIT_STD+MTX 1.05 (0.09, 16.18) 1.04 (0.11, 5.38) 0.01 (-0.25, 0.57)

ADA_STD 0.03 (0.0002, 1.87) 0.03 (0.0003, 1.64) -0.16 (-0.34, 0.10)

BAR_4+MTX 1.52 (0.38, 6.41) 1.38 (0.47, 4.05) 0.07 (-0.16, 0.34)

HD203+MTX 1.27 (0.15, 11.98) 1.21 (0.19, 5.11) 0.04 (-0.22, 0.50)

SB4+MTX 1.27 (0.16, 11.77) 1.20 (0.20, 5.04) 0.04 (-0.22, 0.50)

ANBAI+MTX 1.41 (0.13, 21.48) 1.31 (0.17, 5.92) 0.05 (-0.23, 0.62)

CT-P13+MTX 1.27 (0.22, 8.19) 1.21 (0.28, 4.41) 0.04 (-0.20, 0.41)

SB2+MTX 0.61 (0.07, 5.22) 0.66 (0.10, 3.42) -0.06 (-0.26, 0.30)

ZRC-3197+MTX 0.54 (0.06, 4.69) 0.59 (0.08, 3.17) -0.07 (-0.27, 0.28)

ABP501+MTX 0.77 (0.11, 5.13) 0.80 (0.15, 3.33) -0.03 (-0.25, 0.31)


ADA_STD 0.04 (0.0002, 5.45) 0.05 (0.0003, 4.11) -0.10 (-0.63, 0.17)

BAR_4+MTX 2.45 (0.14, 31.02) 2.05 (0.31, 20.26) 0.12 (-0.42, 0.40)

HD203+MTX 1.99 (0.08, 46.93) 1.74 (0.15, 22.19) 0.08 (-0.46, 0.56)

SB4+MTX 2.04 (0.08, 45.14) 1.77 (0.16, 21.65) 0.08 (-0.46, 0.56)

ANBAI+MTX 2.23 (0.08, 63.47) 1.86 (0.16, 23.59) 0.09 (-0.43, 0.66)

CT-P13+MTX 2.05 (0.10, 33.25) 1.78 (0.20, 19.90) 0.08 (-0.45, 0.48)

SB2+MTX 0.96 (0.04, 19.31) 0.97 (0.08, 13.28) -0.003 (-0.53, 0.36)

ZRC-3197+MTX 0.85 (0.03, 17.56) 0.87 (0.07, 12.11) -0.01 (-0.55, 0.35)

ABP501+MTX 1.22 (0.05, 21.93) 1.18 (0.11, 14.87) 0.02 (-0.51, 0.38)

ADA_STD RIT_STD+MTX 0.02 (0.0001, 3.13) 0.03 (0.0002, 2.46) -0.16 (-0.73, 0.13)

BAR_4+MTX 1.44 (0.09, 18.06) 1.32 (0.25, 11.58) 0.06 (-0.51, 0.37)

HD203+MTX 1.18 (0.05, 26.91) 1.14 (0.12, 12.88) 0.02 (-0.56, 0.53)

626


SB4+MTX 1.20 (0.05, 25.35) 1.15 (0.12, 12.75) 0.02 (-0.56, 0.52)

ANBAI+MTX 1.31 (0.05, 37.37) 1.21 (0.13, 13.84) 0.04 (-0.54, 0.62)

CT-P13+MTX 1.20 (0.06, 18.42) 1.15 (0.16, 11.04) 0.03 (-0.54, 0.43)

SB2+MTX 0.57 (0.03, 11.19) 0.64 (0.06, 7.84) -0.06 (-0.62, 0.32)

ZRC-3197+MTX 0.49 (0.02, 10.56) 0.56 (0.05, 7.30) -0.07 (-0.63, 0.31)

ABP501+MTX 0.72 (0.03, 12.49) 0.77 (0.09, 8.64) -0.04 (-0.60, 0.34)

BAR_4+MTX ADA_STD 57.64 (0.78, 8309.00) 42.72 (0.83, 5463.00) 0.23 (-0.04, 0.48)

HD203+MTX 47.23 (0.54, 7553.00) 34.37 (0.63, 4667.00) 0.19 (-0.07, 0.64)

SB4+MTX 48.60 (0.52, 7333.00) 35.11 (0.60, 4525.00) 0.19 (-0.08, 0.64)

ANBAI+MTX

53.87 (0.49,

10860.00) 37.71 (0.57, 5150.00) 0.21 (-0.09, 0.78)

CT-P13+MTX 49.83 (0.51, 7763.00) 37.51 (0.60, 5181.00) 0.20 (-0.09, 0.56)

SB2+MTX 23.58 (0.22, 4685.00) 20.06 (0.28, 3295.00) 0.10 (-0.17, 0.45)

ZRC-3197+MTX 20.42 (0.19, 3917.00) 17.64 (0.24, 2916.00) 0.09 (-0.17, 0.44)

ABP501+MTX 29.49 (0.31, 5313.00) 24.56 (0.39, 3529.00) 0.12 (-0.14, 0.47)

HD203+MTX BAR_4+MTX 0.84 (0.09, 8.05) 0.88 (0.13, 3.72) -0.03 (-0.35, 0.44)

SB4+MTX 0.84 (0.09, 7.92) 0.88 (0.14, 3.72) -0.03 (-0.35, 0.44)

ANBAI+MTX 0.92 (0.09, 14.27) 0.94 (0.13, 4.23) -0.01 (-0.35, 0.56)

CT-P13+MTX 0.85 (0.12, 5.49) 0.89 (0.19, 3.20) -0.03 (-0.33, 0.35)

SB2+MTX 0.40 (0.05, 3.45) 0.48 (0.07, 2.39) -0.12 (-0.40, 0.24)

ZRC-3197+MTX 0.35 (0.04, 3.13) 0.43 (0.06, 2.27) -0.13 (-0.40, 0.22)

ABP501+MTX 0.50 (0.07, 3.59) 0.58 (0.10, 2.48) -0.10 (-0.38, 0.25)

SB4+MTX HD203+MTX 1.01 (0.10, 10.65) 1.01 (0.17, 6.21) 0.002 (-0.42, 0.42)

ANBAI+MTX 1.13 (0.06, 26.39) 1.09 (0.11, 9.41) 0.02 (-0.49, 0.61)

CT-P13+MTX 1.01 (0.08, 12.75) 1.01 (0.17, 7.63) 0.001 (-0.48, 0.41)

SB2+MTX 0.48 (0.03, 7.19) 0.56 (0.06, 5.00) -0.09 (-0.56, 0.29)

ZRC-3197+MTX 0.42 (0.02, 7.20) 0.49 (0.05, 5.02) -0.10 (-0.57, 0.29)

627


ABP501+MTX 0.60 (0.04, 8.70) 0.67 (0.09, 5.72) -0.07 (-0.54, 0.31)

ANBAI+MTX SB4+MTX 1.13 (0.06, 24.32) 1.09 (0.12, 8.81) 0.02 (-0.49, 0.60)

CT-P13+MTX 1.01 (0.08, 11.85) 1.00 (0.17, 7.17) 0.001 (-0.48, 0.41)

SB2+MTX 0.49 (0.03, 7.14) 0.56 (0.06, 4.95) -0.08 (-0.56, 0.29)

ZRC-3197+MTX 0.42 (0.02, 6.54) 0.49 (0.05, 4.59) -0.10 (-0.57, 0.28)

ABP501+MTX 0.59 (0.04, 7.71) 0.66 (0.09, 5.22) -0.07 (-0.55, 0.31)

CT-P13+MTX ANBAI+MTX 0.91 (0.05, 14.44) 0.93 (0.15, 8.32) -0.01 (-0.60, 0.41)

SB2+MTX 0.44 (0.02, 7.70) 0.52 (0.05, 5.30) -0.10 (-0.69, 0.29)

ZRC-3197+MTX 0.37 (0.02, 6.73) 0.46 (0.05, 4.75) -0.12 (-0.68, 0.27)

ABP501+MTX 0.54 (0.03, 8.46) 0.62 (0.08, 5.76) -0.08 (-0.65, 0.31)

SB2+MTX CT-P13+MTX 0.47 (0.06, 3.64) 0.55 (0.10, 2.70) -0.09 (-0.42, 0.22)

ZRC-3197+MTX 0.41 (0.03, 5.10) 0.49 (0.06, 3.63) -0.10 (-0.48, 0.26)

ABP501+MTX 0.59 (0.06, 5.97) 0.66 (0.10, 4.06) -0.07 (-0.46, 0.30)

ZRC-3197+MTX SB2+MTX 0.87 (0.06, 13.39) 0.89 (0.09, 8.88) -0.01 (-0.36, 0.35)

ABP501+MTX 1.25 (0.10, 16.49) 1.21 (0.14, 10.70) 0.02 (-0.34, 0.38)

ABP501+MTX ZRC-3197+MTX 1.42 (0.13, 17.42) 1.34 (0.18, 11.53) 0.03 (-0.31, 0.37)

Random-Effect


Deviance



Deviance


Total Patients

19,240

Total Studies

61

2-arm 52

3-arm 8

628


4-arm 0

5-arm 1

ABA=abatacept, ABP501=biosimilar adalimumab, ADA=adalimumab, ANBAI=AnBaiNuo (biosimilar etanercept), BAR_4= 4mg baricitinib,

CERTO=certolizumab pegol, CT-P13=biosimilar infliximab, csDMARD=conventional synthetic disease modifying antirheumatic drug,

ETN=etanercept, GOL=golimumab, HCQ=hydroxychloroquine, HD203=etanercept biosimilar, INF=infliximab, IV=intravenous, MTX=methotrexate, OR=odds ratio, RD=risk difference, RIT=rituximab, RR=relative risk, SAR_200= 200mg sarilumab, SB2= biosimilar

infliximab, SB4=biosimilar etanercept, SC=subcutaneous, SSZ=sulfasalazine, STD = standard dose, TOC_4= 4mg/kg tocilizumab, TOC_8=

8mg/kg tocilizumab, TOF=tofacitinib, ZRC-3197=biosimilar adalimumab

Figure 50. Consistency Plot for ACR70 Inadequate Response to Methotrexate

Table 61. ACR20, Conventional Synthetic DMARD as a Common Comparator: Odds Ratios, Relative Risks

and Risk Difference for All Treatment Comparisons – Random Effects Model


ETN_STD Placebo+csDMARD 2.59 (0.86, 8.43) 1.73 (0.90, 2.59) 0.23 (-0.03, 0.48)

ETN_STD+csDMARD 3.12 (1.38, 7.69) 1.88 (1.23, 2.55) 0.27 (0.07, 0.47)

ADA_STD+csDMARD 2.86 (1.29, 6.73) 1.81 (1.18, 2.46) 0.25 (0.06, 0.44)

TOC_8 (IV)

+csDMARD 3.12 (1.42, 6.62) 1.87 (1.25, 2.44) 0.27 (0.08, 0.44)

INF_STD 2.80 (0.66, 12.37) 1.79 (0.74, 2.81) 0.25 (-0.08, 0.54)

629


+csDMARD

CERTO_STD

+csDMARD 3.48 (1.14, 10.68) 1.96 (1.09, 2.71) 0.30 (0.03, 0.52)

BAR_4+csDMARD 2.45 (0.81, 7.44) 1.69 (0.86, 2.50) 0.21 (-0.04, 0.46)

SIR_100+csDMARD 3.62 (0.84, 16.73) 1.99 (0.89, 2.94) 0.31 (-0.04, 0.58)

SIR_50+csDMARD 3.17 (0.74, 14.26) 1.89 (0.81, 2.88) 0.28 (-0.06, 0.56)


ADA_STD+csDMARD 1.11 (0.26, 4.38) 1.05 (0.59, 2.11) 0.02 (-0.30, 0.34)

TOC_8 (IV)

+csDMARD 1.20 (0.29, 4.51) 1.08 (0.62, 2.14) 0.04 (-0.27, 0.35)

INF_STD+csDMARD 1.09 (0.17, 6.78) 1.04 (0.40, 2.26) 0.02 (-0.40, 0.41)

CERTO_STD

+csDMARD 1.35 (0.26, 6.41) 1.13 (0.56, 2.29) 0.07 (-0.30, 0.41)

BAR_4+csDMARD 0.95 (0.19, 4.43) 0.97 (0.45, 2.03) -0.01 (-0.38, 0.34)

SIR_100+csDMARD 1.40 (0.21, 9.07) 1.14 (0.47, 2.41) 0.08 (-0.35, 0.46)

SIR_50+csDMARD 1.23 (0.19, 7.84) 1.09 (0.43, 2.33) 0.05 (-0.38, 0.44)

ADA_STD+csDMARD ETN_STD+csDMARD 0.92 (0.27, 2.96) 0.96 (0.58, 1.60) -0.02 (-0.30, 0.25)

TOC_8 (IV)

+csDMARD 1.00 (0.30, 2.98) 1.00 (0.61, 1.61) -0.001 (-0.28, 0.25)

INF_STD+csDMARD 0.90 (0.16, 4.77) 0.96 (0.38, 1.73) -0.03 (-0.41, 0.33)

CERTO_STD

+csDMARD 1.12 (0.26, 4.36) 1.05 (0.54, 1.74) 0.03 (-0.31, 0.32)

BAR_4+csDMARD 0.79 (0.19, 3.02) 0.90 (0.43, 1.57) -0.06 (-0.38, 0.25)

SIR_100+csDMARD 1.16 (0.21, 6.49) 1.06 (0.45, 1.85) 0.03 (-0.36, 0.37)

SIR_50+csDMARD 1.02 (0.18, 5.56) 1.01 (0.41, 1.79) 0.004 (-0.39, 0.35)

TOC_8 (IV)

+csDMARD ADA_STD+csDMARD 1.09 (0.34, 3.22) 1.04 (0.63, 1.68) 0.02 (-0.25, 0.27)

630


INF_STD+csDMARD 0.98 (0.18, 5.27) 0.99 (0.40, 1.82) -0.01 (-0.38, 0.35)

CERTO_STD

+csDMARD 1.22 (0.30, 4.77) 1.08 (0.57, 1.82) 0.05 (-0.28, 0.34)

BAR_4+csDMARD 0.86 (0.21, 3.33) 0.93 (0.45, 1.64) -0.04 (-0.36, 0.27)

SIR_100+csDMARD 1.27 (0.24, 7.03) 1.10 (0.47, 1.93) 0.06 (-0.34, 0.39)

SIR_50+csDMARD 1.11 (0.20, 6.00) 1.04 (0.43, 1.87) 0.02 (-0.36, 0.37)

INF_STD+csDMARD

TOC_8 (IV)

+csDMARD 0.90 (0.18, 4.84) 0.96 (0.39, 1.72) -0.02 (-0.39, 0.33)

CERTO_STD+csDMA

RD 1.12 (0.29, 4.39) 1.05 (0.56, 1.73) 0.03 (-0.29, 0.32)

BAR_4+csDMARD 0.79 (0.21, 3.04) 0.90 (0.45, 1.56) -0.06 (-0.36, 0.25)

SIR_100+csDMARD 1.16 (0.23, 6.46) 1.06 (0.47, 1.84) 0.04 (-0.34, 0.37)

SIR_50+csDMARD 1.02 (0.20, 5.60) 1.01 (0.43, 1.79) 0.01 (-0.37, 0.35)

CERTO_STD

+csDMARD INF_STD+csDMARD 1.24 (0.20, 7.61) 1.09 (0.53, 2.71) 0.05 (-0.35, 0.45)

BAR_4+csDMARD 0.88 (0.14, 5.28) 0.94 (0.43, 2.39) -0.03 (-0.42, 0.37)

SIR_100+csDMARD 1.30 (0.16, 10.49) 1.11 (0.45, 2.82) 0.06 (-0.40, 0.49)

SIR_50+csDMARD 1.13 (0.14, 9.05) 1.05 (0.41, 2.72) 0.03 (-0.42, 0.47)

BAR_4+csDMARD

CERTO_STD

+csDMARD 0.70 (0.14, 3.38) 0.86 (0.42, 1.71) -0.08 (-0.42, 0.28)

SIR_100+csDMARD 1.04 (0.17, 6.88) 1.02 (0.44, 2.03) 0.01 (-0.40, 0.39)

SIR_50+csDMARD 0.91 (0.15, 5.83) 0.97 (0.40, 1.95) -0.02 (-0.42, 0.37)

SIR_100+csDMARD BAR_4+csDMARD 1.48 (0.24, 9.68) 1.17 (0.50, 2.51) 0.09 (-0.32, 0.47)

SIR_50+csDMARD 1.30 (0.21, 8.16) 1.12 (0.45, 2.41) 0.06 (-0.35, 0.44)

SIR_50+csDMARD SIR_100+csDMARD 0.87 (0.21, 3.70) 0.95 (0.49, 1.77) -0.03 (-0.34, 0.28)


631



Criteria 158.208



Criteria 166.38

Total Patients

4326

Total Studies

10

2-arm 8

3-arm 2

ADA=adalimumab, BAR_4 = 4mg baricitinib, CERTO=certolizumab pegol, csDMARD=conventional synthetic disease-modifying

anti-rheumatic drug, ETN=etanercept, GOL=golimumab, INF=infliximab, IV=intravenous, OR=odds ratio, RD=risk difference,

RIT=rituximab, RR=relative risk, SIR_100= 100mg sirukumab, SIR_50= 50mg sirukumab, STD = standard dose, TOC_8= 8mg/kg

tocilizumab

Figure 51. Consistency Plot for ACR20 Concomitant Conventional synthetic DMARD

Table 62. ACR70, Conventional Synthetic DMARD as a Common Comparator: Odds Ratios, Relative Risks

and Risk Difference for All Treatment Comparisons – Random Effects Model


0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 0.5 1 1.5 2

inco

nsi

ste

ncy

Mo

de

l

Consistency Model

632


ETN_STD Placebo+csDMARD 12.67 (2.91, 100.70) 9.65 (2.74, 37.33) 0.23 (0.06, 0.62)

ETN_STD

+csDMARD 14.45 (3.65, 107.40) 10.62 (3.34, 38.90) 0.26 (0.08, 0.64)

ADA_STD

+csDMARD 5.26 (2.46, 12.43) 4.73 (2.36, 9.85) 0.10 (0.03, 0.22)

TOC_8 (IV)

+csDMARD 5.73 (2.86, 12.10) 5.09 (2.72, 9.63) 0.11 (0.04, 0.22)

CERTO_STD

+csDMARD 8.37 (2.51, 41.97) 7.00 (2.40, 22.31) 0.16 (0.04, 0.48)

BAR_4+csDMARD 2.81 (1.22, 6.66) 2.68 (1.21, 5.84) 0.04 (0.01, 0.13)

ETN_STD

+csDMARD ETN_STD 1.15 (0.46, 2.77) 1.10 (0.59, 2.16) 0.03 (-0.16, 0.20)

ADA_STD

+csDMARD 0.41 (0.05, 2.29) 0.49 (0.11, 2.02) -0.13 (-0.56, 0.10)

TOC_8 (IV)

+csDMARD 0.45 (0.05, 2.37) 0.53 (0.12, 2.09) -0.12 (-0.55, 0.11)

CERTO_STD

+csDMARD 0.65 (0.06, 5.91) 0.72 (0.14, 3.73) -0.07 (-0.51, 0.32)

BAR_4+csDMARD 0.22 (0.02, 1.24) 0.28 (0.06, 1.21) -0.18 (-0.59, 0.02)

ADA_STD

+csDMARD ETN_STD+csDMARD 0.36 (0.04, 1.86) 0.44 (0.11, 1.67) -0.15 (-0.57, 0.08)

TOC_8 (IV)

+csDMARD 0.39 (0.05, 1.94) 0.48 (0.12, 1.74) -0.15 (-0.56, 0.09)

CERTO_STD

+csDMARD 0.57 (0.06, 4.79) 0.65 (0.14, 3.06) -0.10 (-0.52, 0.30)

BAR_4+csDMARD 0.19 (0.02, 1.00) 0.25 (0.06, 1.00) -0.21 (-0.60, 0.0003)

TOC_8 (IV) ADA_STD+csDMARD 1.09 (0.36, 3.16) 1.08 (0.42, 2.71) 0.01 (-0.13, 0.14)

633


+csDMARD

CERTO_STD

+csDMARD 1.60 (0.36, 9.17) 1.48 (0.41, 5.45) 0.06 (-0.12, 0.38)

BAR_4+csDMARD 0.54 (0.16, 1.69) 0.57 (0.19, 1.60) -0.05 (-0.18, 0.05)

CERTO_STD

+csDMARD

TOC_8 (IV)

+csDMARD 1.46 (0.35, 8.42) 1.37 (0.40, 4.96) 0.05 (-0.12, 0.38)

BAR_4+csDMARD 0.49 (0.16, 1.49) 0.53 (0.19, 1.42) -0.06 (-0.18, 0.04)

BAR_4+csDMARD

CERTO_STD

+csDMARD 0.34 (0.06, 1.47) 0.38 (0.10, 1.41) -0.11 (-0.43, 0.03)

Random-Effect



Criteria 104.238



Criteria 103.874

Total Patients

4175

Total Studies

8

2-arm 7

3-arm 1

ADA=adalimumab, BAR_4 = 4mg baricitinib, CERTO=certolizumab pegol, csDMARD=conventional synthetic disease-modifying

anti-rheumatic drug, ETN=etanercept, GOL=golimumab, IV=intravenous, OR=odds ratio, RD=risk difference, RR=relative risk, STD

= standard dose, TOC_8= 8mg/kg tocilizumab

634

Figure 52. Consistency Plot for ACR70 Concomitant Conventional synthetic DMARD

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6

Inco

nsi

ste

ncy

Mo

de

l

Consistency Model

635

APPENDIX 10: RESULTS PRESENTED IN THE FORM OF STAIRCASE TABLES

Table 63. Staircase Table, ACR20 (Placebo+csDMARD) – Random Effects Model

Placebo

+csDMARD

ETN_STD

ETN_STD

+csDMARD

ADA_STD

+csDMARD

TOC_8 (IV)

+csDMARD

INF_STD

+csDMARD

CERTO_STD

+csDMARD

BAR_4

+csDMARD

SIR_100

+csDMARD

SIR_50

+csDMARD Placebo

+csDMARD

ETN_STD

2.59

(0.86, 8.43)

ETN_STD

+csDMARD

3.12

(1.38, 7.69)

1.21

(0.40, 3.66)

ADA_STD

+csDMARD

2.86

(1.29, 6.73)

1.11

(0.26, 4.38)

0.92

(0.27, 2.96)

TOC_8 (IV)

+csDMARD

3.12

(1.42, 6.62)

1.20

(0.29, 4.51)

1.00

(0.30, 2.98)

1.09

(0.34, 3.22)

INF_STD

+csDMARD

2.80

(0.66, 12.37)

1.09

(0.17, 6.78)

0.90

(0.16, 4.77)

0.98

(0.18, 5.27)

0.90

(0.18, 4.84)

CERTO_STD

+csDMARD

3.48

(1.14, 10.68)

1.35

(0.26, 6.41)

1.12

(0.26, 4.36)

1.22

(0.30, 4.77)

1.12

(0.29, 4.39)

1.24

(0.20, 7.61)

BAR_4

+csDMARD

2.45

(0.81, 7.44)

0.95

(0.19, 4.43)

0.79

(0.19, 3.02)

0.86

(0.21, 3.33)

0.79

(0.21, 3.04)

0.88

(0.14, 5.28)

0.70

(0.14, 3.38)

SIR_100

+csDMARD

3.62

(0.84, 16.73)

1.40

(0.21, 9.07)

1.16

(0.21, 6.49)

1.27

(0.24, 7.03)

1.16

(0.23, 6.46)

1.30

(0.16, 10.49)

1.04

(0.17, 6.88)

1.48

(0.24, 9.68)

SIR_50

+csDMARD

3.17

(0.74, 14.26)

1.23

(0.19, 7.84)

1.02

(0.18, 5.56)

1.11

(0.20, 6.00)

1.02

(0.20, 5.60)

1.13

(0.14, 9.05)

0.91

(0.15, 5.83)

1.30

(0.21, 8.16)

0.87

(0.21, 3.70)

Results are reported as the odds ratio (95% credible interval). Results are interpreted by reading across the rows with the comparator in the column. Statistically significant results in

favour of the treatment are highlighted in green. Statistically significant results in favour of the comparator are highlighted in red.

ADA=adalimumab, BAR_4 = 4mg baricitinib, CERTO=certolizumab pegol, csDMARD=disease-modifying anti-rheumatic drug, ETN=etanercept, GOL=golimumab, INF=infliximab,

IV=intravenous, OR=odds ratio, RD=risk difference, RIT=rituximab, RR=relative risk, SIR_100= 100mg sirukumab, SIR_50= 50mg sirukumab, STD = standard dose, TOC_8= 8mg/kg

tocilizumab

636


PLACEBO +csDMARD

ETN_STD ETN_STD

+csDMARD ADA_STD

+csDMARD TOC_8 (IV) +csDMARD

CERTO_STD +csDMARD

BAR_4 +csDMARD

SIR_100 +csDMARD

SIR_50 +csDMARD

PLACEBO +csDMARD

ETN_STD 4.10

(0.89, 23.63)

ETN_STD +csDMARD

4.72 (1.40, 16.87)

1.15 (0.23, 5.12)

ADA_STD +csDMARD

4.05 (1.24, 13.53)

0.99 (0.12, 6.76)

0.86 (0.15, 4.64)

TOC_8 (IV) +csDMARD

3.59 (1.13, 10.97)

0.88 (0.11, 5.67)

0.76 (0.13, 3.93)

0.88 (0.16, 4.54)

CERTO_STD +csDMARD

4.32 (0.82, 23.02)

1.06 (0.09, 9.83)

0.92 (0.11, 7.14)

1.07 (0.14, 8.28)

1.21 (0.16250, 9.39)

BAR_4+csDMARD 3.09

(0.61, 15.65) 0.76

(0.07, 6.71) 0.66

(0.08, 4.86) 0.76

(0.10, 5.70) 0.86

(0.122, 6.35) 0.71

(0.07, 7.36)

SIR_100 +csDMARD

13.12 (1.10, 465.50)

3.26 (0.15, 145.90)

2.82 (0.17, 114.70)

3.28 (0.21, 137.00)

3.72 (0.23, 159.40)

3.10 (0.16, 151.60)

4.32 (0.21, 211.90)

SIR_50+csDMARD 15.90

(1.28, 571.60) 3.95

(0.17, 179.00) 3.42

(0.20, 143.00) 4.00

(0.24, 168.10) 4.47

(0.28, 190.60) 3.75

(0.18, 186.00) 5.26

(0.26, 260.60) 1.20

(0.17, 8.47) Results are reported as the odds ratio (95% credible interval). Results are interpreted by reading across the rows with the comparator in the column. Statistically significant results in


ADA = adalimumab; BAR_4 =baricitinib 4mg; CERTO = certolizumab pegol; CrI = credible interval; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN =

etanercept; IV = intravenous; OR=odds ratio; RD = risk difference; RR = relative risk; SIR_100 = 100mg sirukumab; SIR_50 = 50mg sirukumab; STD = standard dose; TOC_8 =

tocilizumab 8mg/kg

637


Placebo+csDMARD ETN_STD ETN_STD

+csDMARD

ADA_STD

+csDMARD

TOC_8 (IV)

+csDMARD

CERTO_STD

+csDMARD

BAR_4+csDMARD

Placebo+csDMARD

ETN_STD 12.67

(2.91, 100.70)

ETN_STD+csDMARD 14.45

(3.65, 107.40)

1.15

(0.46, 2.77)

ADA_STD+csDMARD 5.26

(2.46, 12.43)

0.41

(0.05, 2.29)

0.36

(0.04, 1.86)

TOC_8 (IV)

+csDMARD

5.73

(2.86, 12.10)

0.45

(0.05, 2.37)

0.39

(0.05, 1.94)

1.09

(0.36, 3.16)

CERTO_STD

+csDMARD

8.37

(2.51, 41.97)

0.65

(0.06, 5.91)

0.57

(0.06, 4.79)

1.60

(0.36, 9.17)

1.46

(0.35, 8.42)

BAR_4+csDMARD 2.81

(1.22, 6.66)

0.22

(0.02, 1.24)

0.19

(0.02, 1.00)

0.54

(0.16, 1.69)

0.49

(0.16, 1.49)

0.34

(0.06, 1.47)



ADA=adalimumab, BAR_4 = 4mg baricitinib, CERTO=certolizumab pegol, csDMARD=conventional synthetic disease-modifying anti-rheumatic drug, ETN=etanercept,

GOL=golimumab, IV=intravenous, OR=odds ratio, RD=risk difference, RR=relative risk, STD = standard dose, TOC_8= 8mg/kg tocilizumab

638

Table 66. Staircase Table, DAS28 (Placebo+csDMARD) – Random Effects Model

Placebo

+csDMARD

ETN_STD

ETN_STD

+csDMARD

ADA_STD

+csDMARD

TOC_8

(IV)+csDMARD

INF_STD

+csDMARD

BAR_4

+csDMARD

SIR_100

+csDMARD

SIR_50

+csDMARD Placebo

+csDMARD

ETN_STD -1.88

(-5.79, 1.98)

ETN_STD

+csDMARD

-1.53

(-4.20, 1.14)

0.34

(-3.54, 4.21)

ADA_STD

+csDMARD

-1.05

(-4.34, 2.20)

0.82

(-3.88, 5.52)

0.47

(-2.78, 3.70)

TOC_8 (IV)

+csDMARD

-1.50

(-4.47, 1.46)

0.38

(-4.49, 5.25)

0.03

(-3.94, 4.02)

-0.45

(-4.86, 4.01)

INF_STD

+csDMARD

-0.95

(-5.16, 3.27)

0.93

(-4.82, 6.71)

0.58

(-4.41, 5.57)

0.10

(-5.25, 5.45)

0.55

(-4.64, 5.73)

BAR_4

+csDMARD

-1.49

(-5.68, 2.73)

0.39

(-5.34, 6.09)

0.04

(-4.94, 5.00)

-0.44

(-5.75, 4.89)

-0.0011

(-5.11, 5.16)

-0.54

(-6.48, 5.42)

SIR_100

+csDMARD

-0.93

(-5.15, 3.25)

0.94

(-4.83, 6.63)

0.60

(-4.37, 5.59)

0.12

(-5.12, 5.43)

0.57

(-4.61, 5.74)

0.011

(-5.93, 5.91)

0.57

(-5.40, 6.48)

SIR_50

+csDMARD

-1.14

(-5.40, 3.04)

0.73

(-5.01, 6.46)

0.40

(-4.59, 5.36)

-0.09

(-5.42, 5.23)

0.36

(-4.84, 5.47)

-0.19

(-6.14, 5.76)

0.35

(-5.58, 6.29)

-0.20

(-4.47, 3.95)

Results are reported as the standardized mean difference (95% credible interval). Results are interpreted by reading across the rows with the comparator in the column. Statistically

significant results in favour of the treatment are highlighted in green. Statistically significant results in favour of the comparator are highlighted in red.

ADA = adalimumab; BAR_4 = 4 mg baricitinib; CrI = credible interval; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN = etanercept; GOL=golimumab;

INF = infliximab; SIR_100 = 100 mg sirukumab; SMD = standardized mean difference; STD = standard dose; TOC_4 = 4 mg/kg tocilizumab; TOC_8 = 8 mg/kg tocilizumab; TOF =

tofacitinib

639

Table 67. Staircase Table, HAQ-DI (Placebo+csDMARD) – Random Effects Model

Placebo+csDMARD

ETN_STD+csDMARD

TOC_8 (IV)+csDMARD

BAR_4+csDMARD

SIR_100+csDMARD

SIR_50+csDMARD

Placebo+csDMARD

ETN_STD+csDMARD -0.19

(-6.44, 6.13)

TOC_8 (IV)+csDMARD -0.63

(-6.91, 5.62)

-0.44

(-9.34, 8.44)

BAR_4+csDMARD -0.24

(-6.53, 6.05)

-0.05

(-8.91, 8.72)

0.40

(-8.55, 9.30)

SIR_100+csDMARD -0.14

(-6.35, 6.12)

0.05

(-8.84, 8.85)

0.49

(-8.29, 9.47)

0.10

(-8.76, 9.02)

SIR_50+csDMARD -0.37

(-6.67, 5.85)

-0.19

(-9.02, 8.69)

0.26

(-8.61, 9.07)

-0.13

(-9.10, 8.79)

-0.24

(-6.51, 6.07)

Results are reported as the mean difference (95% credible interval). Results are interpreted by reading across the rows with the comparator in the column. Statistically significant

results in favour of the treatment are highlighted in green. Statistically significant results in favour of the comparator are highlighted in red.

BAR_4 = 4 mg baricitinib; CrI = credible interval; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; MD = mean difference; SIR_100 = 100 mg sirukumab;

SIR_50 = 50 mg sirukumab; STD = standard dose; TOC_4 = 4 mg/kg tocilizumab; TOC_8 = 8 mg/kg tocilizumab

640

Table 68. Staircase Table, SF-36, Physical Component Score (Placebo+MTX) – Random Effects Model

Placebo

+MTX

ABA_STD (IV)

+MTX

TOF_STD

+MTX

ADA_STD

+MTX

GOL_STD (SC)

+MTX

GOL_STD (IV)

+MTX

INF_STD

+MTX

CERTO_STD

+MTX

CT-P13

+MTX Placebo

+MTX

ABA_STD (IV)

+MTX

4.15

(2.64, 5.75)

TOF_STD

+MTX

3.78

(1.22, 6.20)

-0.36

(-3.38, 2.48)

ADA_STD

+MTX

3.12

(0.60, 5.49)

-1.02

(-4.03, 1.79)

-0.68

(-3.01, 1.64)

GOL_STD (SC)

+MTX

4.84

(3.09, 6.69)

0.67

(-1.64, 3.10)

1.05

(-1.93, 4.27)

1.73

(-1.18, 4.89)

GOL_STD (IV)

+MTX

3.62

(1.42, 5.93)

-0.50

(-3.27, 2.26)

-0.13

(-3.41, 3.29)

0.54

(-2.72, 3.96)

-1.19

(-4.05, 1.57)

INF_STD

+MTX

4.59

(2.83, 5.95)

0.43

(-1.78, 2.18)

0.80

(-2.24, 3.62)

1.48

(-1.59, 4.26)

-0.26

(-2.89, 1.90)

0.93

(-1.99, 3.49)

CERTO_STD

+MTX

5.06

(3.72, 6.42)

0.91

(-1.20, 2.93)

1.27

(-1.49, 4.12)

1.92

(-0.76, 4.81)

0.21

(-2.06, 2.36)

1.42

(-1.23, 4.02)

0.45

(-1.39, 2.76)

CT-P13

+MTX

5.37

(2.39, 7.99)

1.22

(-2.06, 4.05)

1.58

(-2.29, 5.18)

2.27

(-1.66, 5.85)

0.51

(-3.07, 3.64)

1.73

(-2.07, 5.16)

0.78

(-1.60, 3.15)

0.32

(-3.02, 3.23)



ABA = abatacept; ADA = adalimumab; CERTO = certolizumab pegol; CrI = credible interval; CT-P13 = biosimilar infliximab; GOL = golimumab; INF = infliximab; MD = mean

difference; STD = standard dose; TOF = tofacitinib

641

Table 69. Staircase Table, SF-36, Mental Component Score (Placebo+MTX) – Random Effects Model

Placebo

+MTX

ABA_STD (IV)

+MTX

TOF_STD

+MTX

ADA_STD

+MTX

GOL_STD (SC)

+MTX

GOL_STD (IV)

+MTX

INF_STD

+MTX

CERTO_STD

+MTX

CT-P13

+MTX Placebo

+MTX

ABA_STD (IV)

+MTX

2.77

(0.04, 6.26)

TOF_STD

+MTX

1.38

(-3.09, 5.77)

-1.42

(-7.26, 3.61)

ADA_STD

+MTX

1.61

(-2.93, 6.02)

-1.18

(-7.02, 3.93)

0.23

(-4.09, 4.49)

GOL_STD (SC)

+MTX

1.87

(-1.48, 5.16)

-0.95

(-5.89, 3.27)

0.47

(-5.14, 6.03)

0.27

(-5.35, 5.81)

GOL_STD (IV)

+MTX

5.91

(1.52, 10.23)

3.12

(-2.67, 8.11)

4.56

(-1.67, 10.76)

4.29

(-1.94, 10.52)

4.02

(-1.45, 9.61)

INF_STD

+MTX

2.15

(-1.91, 6.77)

-0.67

(-4.95, 3.53)

0.78

(-5.21, 7.16)

0.54

(-5.45, 7.10)

0.31

(-4.87, 6.01)

-3.78

(-9.53, 2.73)

CERTO_STD

+MTX

3.60

(1.11, 6.13)

0.85

(-3.63, 4.49)

2.21

(-2.86, 7.38)

1.97

(-3.05, 7.20)

1.73

(-2.40, 5.99)

-2.32

(-7.20, 2.79)

1.46

(-3.82, 6.21)

CT-P13

+MTX

2.00

(-3.88, 8.56)

-0.79

(-7.01, 5.31)

0.66

(-6.63, 8.57)

0.40

(-6.93, 8.48)

0.15

(-6.55, 7.49)

-3.92

(-11.20, 4.03)

-0.14

(-4.43, 4.35)

-1.61

(-8.01, 5.45)



ABA = abatacept; ADA = adalimumab; CERTO = certolizumab pegol; CrI = credible interval; CT-P13 = biosimilar infliximab; GOL = golimumab; INF = infliximab; MD = mean

difference; STD = standard dose; TOF = tofacitinib

642

Table 70. Staircase Table, Fatigue (Placebo+MTX) – Random Effects Model

Placebo

+MTX

ETN_STD

+MTX

ABA_STD

(IV)+MTX

TOF_STD

+MTX

ADA_STD+

MTX

TOC_4 (IV)

+MTX

TOC_8 (IV)

+MTX

GOL_STD

(SC)+MTX

GOL_STD

(IV)+MTX

CERTO_STD

+MTX

SAR_200

+MTX

HD203

+MTX

Placebo

+MTX

ETN_STD

+MTX

0.47

(-0.48, 1.42)

ABA_STD

(IV) +MTX

0.43

(-0.54, 1.40)

-0.04

(-1.41, 1.32)

TOF_STD

+MTX

0.48

(-0.35, 1.41)

0.01

(-1.24, 1.38)

0.05

(-1.22, 1.43)

ADA_STD

+MTX

0.35

(-0.18, 0.96)

-0.13

(-1.17, 1.05)

-0.09

(-1.15, 1.11)

-0.14

(-1.00, 0.76)

TOC_4 (IV)

+MTX

0.28

(-0.73, 1.28)

-0.19

(-1.57, 1.23)

-0.15

(-1.54, 1.23)

-0.20

(-1.57, 1.08)

-0.06

(-1.26, 1.02)

TOC_8 (IV)

+MTX

0.37

(-0.61, 1.34)

-0.11

(-1.47, 1.28)

-0.07

(-1.44, 1.31)

-0.11

(-1.49, 1.16)

0.02

(-1.18, 1.10)

0.08

(-0.90, 1.06)

GOL_STD

(SC) +MTX

0.54

(-0.15, 1.23)

0.07

(-1.10, 1.27)

0.11

(-1.06, 1.31)

0.06

(-1.10, 1.13)

0.19

(-0.75, 1.04)

0.26

(-0.94, 1.45)

0.17

(-0.99, 1.36)

GOL_STD (IV)

+MTX

0.52

(-0.46, 1.49)

0.04

(-1.30, 1.44)

0.08

(-1.28, 1.45)

0.03

(-1.34, 1.33)

0.18

(-1.00, 1.23)

0.24

(-1.12, 1.60)

0.15

(-1.23, 1.52)

-0.02

(-1.20, 1.17)

CERTO_STD 1.25 0.78 0.81 0.77 0.91 0.97 0.88 0.71 0.73

643

+MTX (0.30, 2.22) (-0.56, 2.13) (-0.55, 2.22) (-0.58, 2.06) (-0.26, 1.96) (-0.37, 2.39) (-0.46, 2.26) (-0.46, 1.90) (-0.60, 2.08)

SAR_200

+MTX

0.54

(-0.44, 1.51)

0.07

(-1.28, 1.44)

0.11

(-1.25, 1.50)

0.06

(-1.28, 1.29)

0.20

(-0.98, 1.27)

0.26

(-1.09, 1.64)

0.18

(-1.17, 1.55)

0.0042

(-1.16, 1.19)

0.03

(-1.35,1.40)

-0.71

(-2.08, 0.67)

HD203

+MTX

0.55

(-0.82, 1.86)

0.08

(-0.89, 1.07)

0.12

(-1.57, 1.76)

0.07

(-1.60, 1.64)

0.20

(-1.30, 1.60)

0.27

(-1.42, 1.95)

0.19

(-1.52, 1.85)

0.0088

(-1.51, 1.51)

0.03

(-1.65,1.69)

-0.69

(-2.42, 0.93)

0.0063

(-1.67, 1.63)

Results are reported as the standardized mean difference (95% credible interval). Results are interpreted by reading across the rows with the comparator in the column. Statistically

significant results in favour of the treatment are highlighted in green. Statistically significant results in favour of the comparator are highlighted in red.

ADA = adalimumab; CERTO = certolizumab pegol; CrI = credible interval; ETN = etanercept; GOL = golimumab; HD203 = biosimilar etanercept; IV = intravenous; MTX =

methotrexate; SAR_200 = 200 mg sarilumab; SC = subcutaneous; SMD = standardized mean difference; STD = standard dose; TOF = tofacitinib; TOC_4 = 4 mg/kg tocilizumab;

TOC_8 = 8 mg/kg tocilizumab

644

Table 71. Staircase Table, Radiographic Progression (Placebo+MTX) – Random Effects Model

Placebo+MTX csDMARD+MTX MTX+SSZ+HCQ ETN_STD ETN_STD+MTX INF_STD+MTX CT-P13+MTX

Placebo+MTX

csDMARD+MTX -0.25 (-6.03, 5.52)

MTX+SSZ+HCQ -0.27 (-6.02, 5.48) -0.01 (-5.85, 5.90)

ETN_STD -0.23 (-4.15, 3.67) 0.03 (-5.15, 5.18) 0.04 (-5.11, 5.22)

ETN_STD+MTX -0.41 (-4.33, 3.53) -0.16 (-4.36, 4.09) -0.14 (-4.32, 4.00) -0.18 (-3.15, 2.81)

INF_STD+MTX -0.68 (-4.85, 3.46) -0.43 (-7.56, 6.71) -0.41 (-7.48, 6.62) -0.45 (-6.13, 5.23) -0.27 (-5.99, 5.46)

CT-P13+MTX -0.61 (-6.56, 5.26) -0.36 (-8.54, 7.88) -0.35 (-8.57, 7.88) -0.39 (-7.42, 6.64) -0.20 (-7.25, 6.85) 0.07 (-4.14, 4.26)



CrI = credible interval; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; CT-P13 = biosimilar infliximab; ETN = etanercept; HCQ = hydroxychloroquine; INF =

infliximab; MTX = methotrexate; SMD = standardized mean difference; SSZ = sulfasalazine; STD = standard dose

645

Table 72. Staircase Table, Serious Adverse Events (Placebo+csDMARD) – Random Effects Model

Placebo+csDMARD ADA_STD+csDMARD ETN_STD ETN_STD+csDMARD TOC_8 (IV)+csDMARD BAR_4+csDMARD

Placebo+csDMARD

ADA_STD +csDMARD

2.17 (0.55, 11.04)

ETN_STD 1.26 (0.19, 8.74) 0.58 (0.07, 3.89)

ETN_STD +csDMARD

2.35 (0.67, 9.82) 1.07 (0.32, 3.61) 1.84 (0.39, 10.80)

TOC_8 (IV) +csDMARD

1.44 (0.53, 4.06) 0.67 (0.10, 3.79) 1.15 (0.13, 10.24) 0.62 (0.11, 3.09)

BAR_4+csDMARD 0.22 (0.02, 1.13) 0.10 (0.01, 0.87) 0.16 (0.01, 2.26) 0.09 (0.01, 0.75) 0.15 (0.01, 1.02)



ADA = adalimumab; BAR_4 = 4 mg baricitinib; CrI = credible interval; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN = etanercept; IV = intravenous;

OR = odds ratio; RD = risk difference; RR = relative risk; STD = standard dose; TOC_8 = 8mg/kg tocilizumab

646

Table 73. Staircase Table, Withdrawals due to Adverse Events (Placebo+csDMARD) – Random Effects Model

PLACEBO +csDMARD

ETN_STD ETN_STD

+csDMARD ADA_STD

+csDMARD TOC_8 (IV) +csDMARD

CERTO_STD +csDMARD

BAR_4 +csDMARD

PLACEBO +csDMARD

ETN_STD 3.46 (1.07, 13.18)

ETN_STD +csDMARD

1.65 (0.53, 6.03) 0.48 (0.18, 1.29)

ADA_STD +csDMARD

1.16 (0.24, 6.08) 0.33 (0.08, 1.39) 0.70 (0.24, 1.95)

TOC_8 (IV) +csDMARD

1.95 (0.98, 4.05) 0.56 (0.12, 2.25) 1.18 (0.27, 4.64) 1.68 (0.28, 9.60)

CERTO_STD +csDMARD

1.47 (0.52, 4.78) 0.43 (0.08, 2.21) 0.90 (0.17, 4.37) 1.29 (0.18, 8.45) 0.75 (0.21, 2.96)

BAR_4+csDMARD 1.00 (0.30, 3.28) 0.28 (0.05, 1.53) 0.59 (0.10, 3.04) 0.86 (0.11, 5.98) 0.51 (0.12, 2.00) 0.67 (0.13, 3.34)



ADA = adalimumab; BAR_4 = 4mg baricitinib; CrI = credible interval; CERTO = certolizumab pegol; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ETN =

etanercept; IV = intravenous; OR = odds ratio; RD = risk difference; RR = relative risk; STD = standard dose; TOC_8 = 8mg/kg tocilizumab

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Drugs for the Management of Rheumatoid Arthritis: - CADTH

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