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Results of the literature search and disposition of the potentially relevant studies* Number is not equal to the sum of number from each database due to duplication among databasesAbbreviations :‐ CENTRAL = Cochrane Central Register of Controlled Trials, ACR = American College of rheumatology, EULAR =European League Against Rheumatism, RA = Rheumatoid arthritis, MTX =Methotrexate, RCT = Randomised controlled trial
Figuras y tablas -
Figure 1

Results of the literature search and disposition of the potentially relevant studies

* Number is not equal to the sum of number from each database due to duplication among databases

Abbreviations :‐ CENTRAL = Cochrane Central Register of Controlled Trials, ACR = American College of rheumatology, EULAR =European League Against Rheumatism, RA = Rheumatoid arthritis, MTX =Methotrexate, RCT = Randomised controlled trial

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Figuras y tablas -
Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 1 ACR response of DMARD naive.
Figuras y tablas -
Analysis 1.1

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 1 ACR response of DMARD naive.

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 2 ACR response of MTX inadequate response.
Figuras y tablas -
Analysis 1.2

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 2 ACR response of MTX inadequate response.

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 3 ACR response of non‐MTX DMARDs inadequate response.
Figuras y tablas -
Analysis 1.3

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 3 ACR response of non‐MTX DMARDs inadequate response.

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 4 EULAR response of DMARD naive.
Figuras y tablas -
Analysis 1.4

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 4 EULAR response of DMARD naive.

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 5 EULAR response of non‐MTX DMARDs inadequate response.
Figuras y tablas -
Analysis 1.5

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 5 EULAR response of non‐MTX DMARDs inadequate response.

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 6 Withdrawal due to lack of efficacy (stratified by DMARDs use before randomisation).
Figuras y tablas -
Analysis 1.6

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 6 Withdrawal due to lack of efficacy (stratified by DMARDs use before randomisation).

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 7 Withdrawal due to lack of efficacy (by regimen).
Figuras y tablas -
Analysis 1.7

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 7 Withdrawal due to lack of efficacy (by regimen).

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 8 Combined withdrawal due to lack of efficacy or toxicity (stratified by DMARDs use before randomisation).
Figuras y tablas -
Analysis 1.8

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 8 Combined withdrawal due to lack of efficacy or toxicity (stratified by DMARDs use before randomisation).

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 9 Combined withdrawal due to lack of efficacy or toxicity (stratified by regimen).
Figuras y tablas -
Analysis 1.9

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 9 Combined withdrawal due to lack of efficacy or toxicity (stratified by regimen).

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 10 Combined withdrawal due to lack of efficacy or toxicity at 6 months.
Figuras y tablas -
Analysis 1.10

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 10 Combined withdrawal due to lack of efficacy or toxicity at 6 months.

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 11 Combined withdrawal due to lack of efficacy or toxicity at 12 months.
Figuras y tablas -
Analysis 1.11

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 11 Combined withdrawal due to lack of efficacy or toxicity at 12 months.

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 12 Combined withdrawal due to lack of efficacy or toxicity at 24 months.
Figuras y tablas -
Analysis 1.12

Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 12 Combined withdrawal due to lack of efficacy or toxicity at 24 months.

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 1 Total adverse events.
Figuras y tablas -
Analysis 2.1

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 1 Total adverse events.

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 2 GI side effects.
Figuras y tablas -
Analysis 2.2

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 2 GI side effects.

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 3 Abnormal liver function (Transaminitis).
Figuras y tablas -
Analysis 2.3

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 3 Abnormal liver function (Transaminitis).

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 4 Mucositis.
Figuras y tablas -
Analysis 2.4

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 4 Mucositis.

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 5 Haematological side effects.
Figuras y tablas -
Analysis 2.5

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 5 Haematological side effects.

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 6 Infection.
Figuras y tablas -
Analysis 2.6

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 6 Infection.

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 7 Withdrawal due to adverse reaction (by regimen).
Figuras y tablas -
Analysis 2.7

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 7 Withdrawal due to adverse reaction (by regimen).

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 8 Withdrawal due to adverse events (stratified by DMARDs use before randomisation).
Figuras y tablas -
Analysis 2.8

Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 8 Withdrawal due to adverse events (stratified by DMARDs use before randomisation).

Comparison 3 Swollen joint count, Outcome 1 Swollen joint count: MTX inadequate response.
Figuras y tablas -
Analysis 3.1

Comparison 3 Swollen joint count, Outcome 1 Swollen joint count: MTX inadequate response.

Comparison 3 Swollen joint count, Outcome 2 Swollen joint count: Non‐MTX DMARDs inadequate response.
Figuras y tablas -
Analysis 3.2

Comparison 3 Swollen joint count, Outcome 2 Swollen joint count: Non‐MTX DMARDs inadequate response.

Comparison 4 Tender joint count, Outcome 1 Tender joint count: DMARD naive.
Figuras y tablas -
Analysis 4.1

Comparison 4 Tender joint count, Outcome 1 Tender joint count: DMARD naive.

Comparison 4 Tender joint count, Outcome 2 Tender joint count: MTX inadequate response.
Figuras y tablas -
Analysis 4.2

Comparison 4 Tender joint count, Outcome 2 Tender joint count: MTX inadequate response.

Comparison 4 Tender joint count, Outcome 3 Tender joint count: Non‐MTX DMARDs inadequate response.
Figuras y tablas -
Analysis 4.3

Comparison 4 Tender joint count, Outcome 3 Tender joint count: Non‐MTX DMARDs inadequate response.

Comparison 5 Pain, Outcome 1 Pain: DMARD naive.
Figuras y tablas -
Analysis 5.1

Comparison 5 Pain, Outcome 1 Pain: DMARD naive.

Comparison 5 Pain, Outcome 2 Pain: MTX inadequate response.
Figuras y tablas -
Analysis 5.2

Comparison 5 Pain, Outcome 2 Pain: MTX inadequate response.

Comparison 5 Pain, Outcome 3 Pain: Non‐MTX DMARDs inadequate response.
Figuras y tablas -
Analysis 5.3

Comparison 5 Pain, Outcome 3 Pain: Non‐MTX DMARDs inadequate response.

Comparison 6 Patient global assessment, Outcome 1 Patient global assessment: DMARD naive.
Figuras y tablas -
Analysis 6.1

Comparison 6 Patient global assessment, Outcome 1 Patient global assessment: DMARD naive.

Comparison 6 Patient global assessment, Outcome 2 Patient global assessment: MTX inadequate response.
Figuras y tablas -
Analysis 6.2

Comparison 6 Patient global assessment, Outcome 2 Patient global assessment: MTX inadequate response.

Comparison 6 Patient global assessment, Outcome 3 Patient global assessment: Non‐MTX DMARDs inadequate response.
Figuras y tablas -
Analysis 6.3

Comparison 6 Patient global assessment, Outcome 3 Patient global assessment: Non‐MTX DMARDs inadequate response.

Comparison 7 Physician global assessment, Outcome 1 Physician global asessment: MTX inadequate response.
Figuras y tablas -
Analysis 7.1

Comparison 7 Physician global assessment, Outcome 1 Physician global asessment: MTX inadequate response.

Comparison 7 Physician global assessment, Outcome 2 Physician global assessment: Non‐MTX inadequate response.
Figuras y tablas -
Analysis 7.2

Comparison 7 Physician global assessment, Outcome 2 Physician global assessment: Non‐MTX inadequate response.

Comparison 8 HAQ, Outcome 1 HAQ: DMARD naive.
Figuras y tablas -
Analysis 8.1

Comparison 8 HAQ, Outcome 1 HAQ: DMARD naive.

Comparison 8 HAQ, Outcome 2 HAQ: MTX inadequate response.
Figuras y tablas -
Analysis 8.2

Comparison 8 HAQ, Outcome 2 HAQ: MTX inadequate response.

Comparison 8 HAQ, Outcome 3 HAQ: Non‐MTX DMARDs inadequate response.
Figuras y tablas -
Analysis 8.3

Comparison 8 HAQ, Outcome 3 HAQ: Non‐MTX DMARDs inadequate response.

Comparison 9 ESR, Outcome 1 ESR: DMARD naive.
Figuras y tablas -
Analysis 9.1

Comparison 9 ESR, Outcome 1 ESR: DMARD naive.

Comparison 9 ESR, Outcome 2 ESR: MTX inadequate response.
Figuras y tablas -
Analysis 9.2

Comparison 9 ESR, Outcome 2 ESR: MTX inadequate response.

Comparison 9 ESR, Outcome 3 ESR: Non‐MTX DMARDs inadequate response.
Figuras y tablas -
Analysis 9.3

Comparison 9 ESR, Outcome 3 ESR: Non‐MTX DMARDs inadequate response.

Comparison 10 CRP, Outcome 1 CRP: DMARD naive.
Figuras y tablas -
Analysis 10.1

Comparison 10 CRP, Outcome 1 CRP: DMARD naive.

Comparison 10 CRP, Outcome 2 CRP: MTX inadequate response.
Figuras y tablas -
Analysis 10.2

Comparison 10 CRP, Outcome 2 CRP: MTX inadequate response.

Comparison 10 CRP, Outcome 3 CRP: Non‐MTX DMARDs inadequate response.
Figuras y tablas -
Analysis 10.3

Comparison 10 CRP, Outcome 3 CRP: Non‐MTX DMARDs inadequate response.

Comparison 11 DAS, Outcome 1 DAS: DMARD naive.
Figuras y tablas -
Analysis 11.1

Comparison 11 DAS, Outcome 1 DAS: DMARD naive.

Comparison 11 DAS, Outcome 2 DAS: Non‐MTX DMARDs inadequate response.
Figuras y tablas -
Analysis 11.2

Comparison 11 DAS, Outcome 2 DAS: Non‐MTX DMARDs inadequate response.

Comparison 12 Modified Sharp's score, Outcome 1 Modified Sharp's score: DMARD naive.
Figuras y tablas -
Analysis 12.1

Comparison 12 Modified Sharp's score, Outcome 1 Modified Sharp's score: DMARD naive.

Comparison 12 Modified Sharp's score, Outcome 2 Modified Sharp's score: MTX inadequate response.
Figuras y tablas -
Analysis 12.2

Comparison 12 Modified Sharp's score, Outcome 2 Modified Sharp's score: MTX inadequate response.

Summary of findings for the main comparison. MTX combination compared to MTX monotherapy for Rheumatoid arthritis

MTX combination compared to MTX monotherapy for Rheumatoid arthritis

Patient or population: patients with Rheumatoid arthritis
Settings: Efficacy and toxicity
Intervention: MTX combination
Comparison: MTX monotherapy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

MTX monotherapy

MTX combination

ACR 50 response of DMARDs naive patients
Number of responders
Follow‐up: 12‐24 months

291 per 1000

512 per 1000
(186 to 1000)

RR 1.76
(0.64 to 4.85)

127
(2 studies3)

⊕⊕⊝⊝
low1,2

Absolute Risk Difference=19% (0%, 40%), Relative Percent Change=76% (‐36%, 385%), NNT=not statistically significant.

ACR 50 response of MTX inadequate responders
number of responders
Follow‐up: 6‐12 months

61 per 1000

277 per 1000
(153 to 500)

RR 4.54
(2.51 to 8.2)

404
(3 studies7)

⊕⊕⊕⊝
moderate4,5,6

Absolute Risk Difference=22% (15%, 28%), Relative Percent Change=354% (151%, 720%), NNT=5 (3,10).

ACR 50 response of non‐MTX DMARDs inadequate responders
number of responders
Follow‐up: 12‐24 months

154 per 1000

259 per 1000
(145 to 460)

RR 1.68
(0.94 to 2.99)

158
(2 studies10)

⊕⊕⊕⊝
moderate8,9

Absolute Risk Difference=11% (‐12%, 34%), Relative Percent Change=68% (‐6%, 199%), NNT=not statistically significant.

Withdrawal due to lack of efficacy or toxicity of DMARDs naive patients
number of withdrawals
Follow‐up: 12‐24 months

165 per 1000

191 per 1000
(115 to 318)

RR 1.16
(0.7 to 1.93)

405
(5 studies12)

⊕⊕⊕⊝
moderate1,11

Absolute Risk Difference=5% (‐3%, 13%), Relative Percent Change=16% (‐30%, 93%), NNT= not statistically significant.

Withdrawal due to lack of efficacy or toxicity of MTX inadequate responders
number of withdrawals
Follow‐up: 6‐12 months

185 per 1000

159 per 1000
(91 to 279)

RR 0.86
(0.49 to 1.51)

476
(3 studies14)

⊕⊕⊕⊝
moderate5,6,13

Absolute Risk Difference=‐2% (‐13%, 8%), Relative Percent Change=‐14% (‐51%, 51%), NNT= Not statistically significant.

Withdrawal due to lack of efficacy or toxicity of non‐MTX DMARDs inadequate responders
number of withdrawals
Follow‐up: 6‐24 months

345 per 1000

259 per 1000
(141 to 466)

RR 0.75
(0.41 to 1.35)

329
(5 studies18)

⊕⊝⊝⊝
very low8,9,15,16,17

Absolute Risk Difference=‐10% (‐31%, 11%), Relative Percent Change=‐25% (‐59%, 35%), NNT=Not statistically significant.

Withdrawal due to adverse reactions (Pooled across regimens)
number of withdrawals
Follow‐up: 6‐60 months

86 per 1000

137 per 1000
(103 to 182)

RR 1.59
(1.2 to 2.12)

1624
(17 studies19)

⊕⊝⊝⊝
very low1,4,5,6,8,11,13,15,17

Absolute Risk Difference=6% (3%, 9%), Relative Percent Change=59% (20%, 112%), NNT= 18 (10, 47).

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 In Marchesoni et al 's study, patients were not blinded.
2 In O'Dell 2006' study, blinding of outcome assessors was unclear
3 The studies which provided data are Marchesoni 2003 and O'Dell 1996.
4 In Ogrendik's study, the adequacy of randomisation, allocation concealment, and blinding of outcome assessors were unclear
5 In Kremer's study, blinding of outcome assessors was unclear
6 In Lehman's study, concomitant systemic steroid was higher in MTX group (52% in MTX vs. 18% in MTX+im gold)
7 The studies which provided data are Kremer 2002, Lehman 2005 and Ogrendik 2007.
8 In Ichikawa's study, the adequacy of randomisation, allocation concealment and blinding of the outcome assessors were unclear. Co‐interventions were not similar between the two arms of the trial.
9 In Capell's study, there is no report on concomitant NSAIDS, intra‐articular or intramuscular steroid comparing between both arms.
10 The studies which provided data are Capell 2007 and Ichikawa 2005.
11 In Taschioglu' study, the adequacy of randomisation, blinding patients and physician, and the similarity of co‐interventions were not clear.
12 The studies which provided data are Dougados 1999, Haagsma 1997, Marchesoni 2003, O'Dell 2006 and Taschioglu 2003.
13 In Tugwell's study, oral prednisolone at dose of equal or less than 10 mg/d was permitted; however, there is no report on the number of patients who took prednisolone throughout the trial.
14 The studies which provided data are Kremer 2002, Lehman 2005 and Tugwell 1995.
15 In Hanyu's study, method of randomisation was unclear. It is an open‐labelled study.
16 O'Dell 1996 ' s, Lehman et al' s, Ichikawa's, and Capell's studies favoured MTX combination therapy, while others favoured MTX monotherapy
17 O'Dell 1996 is an outlier, favouring MTX combination, while others favoured MTX monotherapy
18 The studies which provided data are Capell 2007, Ferraz 1994, Hanyu 1999, Ichikawa 2005 and O'Dell 1996.
19 The studies which provided data are Capell 2007, Dougados 1999, Haagsma 1997, Islam 2000, Taschioglu 2003, Ferraz, 1994, O'Dell 1996, Wilkins 1992, Hetland 2006, Marchesoni 2003, Tugwell 1995, Kremer 2002, Lehman 2005, O'Dell 2006, Ogrendik 2007, Ichikawa, 2005 and Hanyu 1999.

Figuras y tablas -
Summary of findings for the main comparison. MTX combination compared to MTX monotherapy for Rheumatoid arthritis
Comparison 1. MTX combo vs mono therapy (Efficacy)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 ACR response of DMARD naive Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 ACR 20

3

287

Risk Ratio (M‐H, Random, 95% CI)

1.22 [0.88, 1.68]

1.2 ACR 50

2

127

Risk Ratio (M‐H, Random, 95% CI)

1.76 [0.64, 4.85]

1.3 ACR 70

1

61

Risk Ratio (M‐H, Random, 95% CI)

2.41 [1.07, 5.44]

1.4 ACR remission

1

160

Risk Ratio (M‐H, Random, 95% CI)

1.27 [0.80, 2.03]

2 ACR response of MTX inadequate response Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 ACR 20

4

552

Risk Ratio (M‐H, Random, 95% CI)

2.51 [1.92, 3.28]

2.2 ACR 50

3

404

Risk Ratio (M‐H, Random, 95% CI)

4.54 [2.51, 8.20]

2.3 ACR 70

3

404

Risk Ratio (M‐H, Random, 95% CI)

5.59 [2.08, 15.01]

3 ACR response of non‐MTX DMARDs inadequate response Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 ACR 20

2

157

Risk Ratio (M‐H, Random, 95% CI)

1.85 [1.21, 2.83]

3.2 ACR 50

2

158

Risk Ratio (M‐H, Random, 95% CI)

1.68 [0.94, 2.99]

3.3 ACR 70

1

110

Risk Ratio (M‐H, Random, 95% CI)

1.93 [0.18, 20.65]

4 EULAR response of DMARD naive Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Good response

2

208

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.69, 1.37]

4.2 Moderate response

1

137

Risk Ratio (M‐H, Random, 95% CI)

1.37 [0.81, 2.33]

4.3 Remission

1

160

Risk Ratio (M‐H, Random, 95% CI)

1.26 [0.84, 1.88]

5 EULAR response of non‐MTX DMARDs inadequate response Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Good response

1

110

Risk Ratio (M‐H, Random, 95% CI)

3.38 [0.73, 15.53]

5.2 Moderate response

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

5.3 Remission

1

110

Risk Ratio (M‐H, Random, 95% CI)

3.86 [0.45, 33.42]

6 Withdrawal due to lack of efficacy (stratified by DMARDs use before randomisation) Show forest plot

13

1210

Risk Ratio (M‐H, Random, 95% CI)

0.47 [0.32, 0.69]

6.1 DMARDs naive

5

405

Risk Ratio (M‐H, Random, 95% CI)

0.63 [0.34, 1.17]

6.2 MTX inadequate response

3

476

Risk Ratio (M‐H, Random, 95% CI)

0.42 [0.21, 0.84]

6.3 Non‐MTX DMARDS inadequate response

5

329

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.16, 0.87]

7 Withdrawal due to lack of efficacy (by regimen) Show forest plot

13

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1 MTX +SSZ

4

388

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.32, 1.94]

7.2 MTX +SSZ +HCQ

1

67

Risk Ratio (M‐H, Random, 95% CI)

0.22 [0.07, 0.68]

7.3 MTX +CQ

1

68

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.13, 71.15]

7.4 MTX +CSA

2

209

Risk Ratio (M‐H, Random, 95% CI)

0.32 [0.03, 3.05]

7.5 MTX + AZA

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

7.6 MTX + LEF

1

263

Risk Ratio (M‐H, Random, 95% CI)

0.61 [0.28, 1.35]

7.7 MTX + im Gold

1

65

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.06, 0.70]

7.8 MTX + Antibiotics

1

66

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.26, 1.24]

7.9 MTX + Bucillamine

1

47

Risk Ratio (M‐H, Random, 95% CI)

0.19 [0.05, 0.78]

7.10 MTX + Miscellaneous

1

37

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.06, 14.04]

8 Combined withdrawal due to lack of efficacy or toxicity (stratified by DMARDs use before randomisation) Show forest plot

13

1210

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.66, 1.21]

8.1 DMARD naive

5

405

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.70, 1.93]

8.2 MTX inadequate response

3

476

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.49, 1.51]

8.3 Non‐MTX DMARDS inadequate response

5

329

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.41, 1.35]

9 Combined withdrawal due to lack of efficacy or toxicity (stratified by regimen) Show forest plot

13

1210

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.66, 1.21]

9.1 MTX + SSZ

4

388

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.66, 1.53]

9.2 MTX +SSZ + HCQ

1

67

Risk Ratio (M‐H, Random, 95% CI)

0.30 [0.14, 0.65]

9.3 MTX + CQ

1

68

Risk Ratio (M‐H, Random, 95% CI)

4.0 [0.47, 33.97]

9.4 MTX + CSA

2

209

Risk Ratio (M‐H, Random, 95% CI)

1.77 [0.64, 4.89]

9.5 MTX + LEF

1

263

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.64, 1.77]

9.6 MTX + intramuscular Gold

1

65

Risk Ratio (M‐H, Random, 95% CI)

0.45 [0.20, 1.02]

9.7 MTX + Antibiotics

1

66

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.43, 1.41]

9.8 MTX + Bucillamine

1

47

Risk Ratio (M‐H, Random, 95% CI)

0.64 [0.32, 1.27]

9.9 MTX + miscellaneous DMARDs

1

37

Risk Ratio (M‐H, Random, 95% CI)

1.33 [0.51, 3.43]

10 Combined withdrawal due to lack of efficacy or toxicity at 6 months Show forest plot

3

479

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.76, 1.78]

10.1 MTX inadequate response

2

411

Risk Ratio (M‐H, Random, 95% CI)

1.10 [0.71, 1.71]

10.2 Non‐MTX DMARDS inadequate response

1

68

Risk Ratio (M‐H, Random, 95% CI)

4.0 [0.47, 33.97]

11 Combined withdrawal due to lack of efficacy or toxicity at 12 months Show forest plot

7

581

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.49, 1.49]

11.1 DMARD naive

4

339

Risk Ratio (M‐H, Random, 95% CI)

1.42 [0.77, 2.61]

11.2 MTX inadequate response

1

65

Risk Ratio (M‐H, Random, 95% CI)

0.45 [0.20, 1.02]

11.3 Non‐MTX DMARDS inadequate response

2

177

Risk Ratio (M‐H, Random, 95% CI)

0.52 [0.19, 1.42]

12 Combined withdrawal due to lack of efficacy or toxicity at 24 months Show forest plot

3

150

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.53, 1.20]

12.1 DMARD naive

1

66

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.43, 1.41]

12.2 Non‐MTX DMARDS inadequate response

2

84

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.42, 1.72]

Figuras y tablas -
Comparison 1. MTX combo vs mono therapy (Efficacy)
Comparison 2. MTX combo vs MTX monotherapy (Toxicity)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total adverse events Show forest plot

8

797

Risk Ratio (M‐H, Random, 95% CI)

1.22 [0.99, 1.50]

1.1 MTX+SSZ

4

303

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.94, 1.35]

1.2 MTX+LEF

1

263

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.92, 1.08]

1.3 MTX+CSA

1

61

Risk Ratio (M‐H, Random, 95% CI)

3.62 [0.82, 16.03]

1.4 MTX+AZA

1

105

Risk Ratio (M‐H, Random, 95% CI)

1.67 [1.21, 2.30]

1.5 MTX+intramuscular gold

1

65

Risk Ratio (M‐H, Random, 95% CI)

2.61 [1.22, 5.55]

2 GI side effects Show forest plot

7

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 MTX+SSZ

4

303

Risk Ratio (M‐H, Random, 95% CI)

1.75 [1.14, 2.67]

2.2 MTX+LEF

1

263

Risk Ratio (M‐H, Random, 95% CI)

1.67 [1.17, 2.40]

2.3 MTX+CSA

1

61

Risk Ratio (M‐H, Random, 95% CI)

4.13 [0.49, 34.89]

2.4 MTX+intramuscular gold

1

65

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.05, 10.87]

3 Abnormal liver function (Transaminitis) Show forest plot

7

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 MTX+SSZ

4

303

Risk Ratio (M‐H, Random, 95% CI)

1.77 [0.29, 10.78]

3.2 MTX+LEF

1

263

Risk Ratio (M‐H, Random, 95% CI)

4.30 [2.58, 7.15]

3.3 MTX+CSA

1

61

Risk Ratio (M‐H, Random, 95% CI)

3.10 [0.13, 73.16]

3.4 MTX+Bucillamine

1

46

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.13, 70.02]

4 Mucositis Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 MTX+SSZ

3

164

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.16, 2.34]

4.2 MTX+ intramuscular gold

1

65

Risk Ratio (M‐H, Random, 95% CI)

9.33 [0.55, 158.98]

5 Haematological side effects Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 MTX+SSZ

4

303

Risk Ratio (M‐H, Random, 95% CI)

2.36 [0.66, 8.48]

5.2 MTX+ intramuscular gold

1

65

Risk Ratio (M‐H, Random, 95% CI)

1.42 [0.14, 14.89]

5.3 MTX+Bucillamine

1

47

Risk Ratio (M‐H, Random, 95% CI)

0.32 [0.01, 7.48]

6 Infection Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 MTX+SSZ

2

126

Risk Ratio (M‐H, Random, 95% CI)

1.35 [0.60, 3.04]

6.2 MTX+LEF

1

263

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.60, 1.02]

6.3 MTX+ intramuscular gold

1

65

Risk Ratio (M‐H, Random, 95% CI)

1.60 [0.82, 3.13]

7 Withdrawal due to adverse reaction (by regimen) Show forest plot

17

1624

Risk Ratio (M‐H, Random, 95% CI)

1.59 [1.20, 2.12]

7.1 MTX+SSZ

5

430

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.73, 1.92]

7.2 MTX+CQ

1

68

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.33, 27.42]

7.3 MTX+SSZ+HCQ

1

67

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.14, 1.76]

7.4 MTX+AZA

1

136

Risk Ratio (M‐H, Random, 95% CI)

5.18 [1.58, 16.96]

7.5 MTX+CSA

3

369

Risk Ratio (M‐H, Random, 95% CI)

1.88 [1.02, 3.50]

7.6 MTX+LEF

1

263

Risk Ratio (M‐H, Random, 95% CI)

1.82 [0.83, 3.97]

7.7 MTX+intramuscular gold

1

65

Risk Ratio (M‐H, Random, 95% CI)

2.84 [0.34, 24.04]

7.8 MTX+ antibiotics

2

142

Risk Ratio (M‐H, Random, 95% CI)

1.90 [0.48, 7.49]

7.9 MTX+Bucillamine

1

47

Risk Ratio (M‐H, Random, 95% CI)

2.88 [0.64, 12.82]

7.10 MTX+ miscellaneous DMARDS

1

37

Risk Ratio (M‐H, Random, 95% CI)

1.42 [0.48, 4.22]

8 Withdrawal due to adverse events (stratified by DMARDs use before randomisation) Show forest plot

16

1582

Risk Ratio (M‐H, Random, 95% CI)

1.56 [1.17, 2.09]

8.1 DMARD naive

6

565

Risk Ratio (M‐H, Random, 95% CI)

1.72 [1.04, 2.83]

8.2 MTX inadequate response

4

552

Risk Ratio (M‐H, Random, 95% CI)

1.89 [1.05, 3.41]

8.3 Non‐MTX inadequate response

6

465

Risk Ratio (M‐H, Random, 95% CI)

1.53 [0.74, 3.18]

Figuras y tablas -
Comparison 2. MTX combo vs MTX monotherapy (Toxicity)
Comparison 3. Swollen joint count

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Swollen joint count: MTX inadequate response Show forest plot

3

476

Std. Mean Difference (IV, Random, 95% CI)

‐0.45 [‐0.63, ‐0.27]

1.1 Final value

0

0

Std. Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Change from baseline

3

476

Std. Mean Difference (IV, Random, 95% CI)

‐0.45 [‐0.63, ‐0.27]

2 Swollen joint count: Non‐MTX DMARDs inadequate response Show forest plot

2

135

Std. Mean Difference (IV, Random, 95% CI)

‐0.66 [‐1.15, ‐0.17]

2.1 Final value

2

135

Std. Mean Difference (IV, Random, 95% CI)

‐0.66 [‐1.15, ‐0.17]

2.2 Change from baseline

0

0

Std. Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 3. Swollen joint count
Comparison 4. Tender joint count

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tender joint count: DMARD naive Show forest plot

1

71

Mean Difference (IV, Random, 95% CI)

‐1.70 [‐6.11, 2.71]

1.1 Final value

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Change from baseline

1

71

Mean Difference (IV, Random, 95% CI)

‐1.70 [‐6.11, 2.71]

2 Tender joint count: MTX inadequate response Show forest plot

3

476

Std. Mean Difference (IV, Random, 95% CI)

‐0.51 [‐0.69, ‐0.33]

2.1 Final value

0

0

Std. Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Change from baseline

3

476

Std. Mean Difference (IV, Random, 95% CI)

‐0.51 [‐0.69, ‐0.33]

3 Tender joint count: Non‐MTX DMARDs inadequate response Show forest plot

1

67

Mean Difference (IV, Random, 95% CI)

‐4.0 [‐6.82, ‐1.18]

3.1 Final value

1

67

Mean Difference (IV, Random, 95% CI)

‐4.0 [‐6.82, ‐1.18]

3.2 Change from baseline

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 4. Tender joint count
Comparison 5. Pain

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Pain: DMARD naive Show forest plot

2

140

Mean Difference (IV, Random, 95% CI)

‐1.36 [‐5.12, 2.40]

1.1 Final value

1

70

Mean Difference (IV, Random, 95% CI)

‐1.53 [‐5.52, 2.46]

1.2 Change from baseline

1

70

Mean Difference (IV, Random, 95% CI)

0.0 [‐11.24, 11.24]

2 Pain: MTX inadequate response Show forest plot

4

515

Mean Difference (IV, Random, 95% CI)

‐9.72 [‐14.70, ‐4.75]

2.1 Final value

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Change from baseline

4

515

Mean Difference (IV, Random, 95% CI)

‐9.72 [‐14.70, ‐4.75]

3 Pain: Non‐MTX DMARDs inadequate response Show forest plot

2

108

Mean Difference (IV, Random, 95% CI)

‐5.99 [‐24.99, 13.02]

3.1 Final value

1

68

Mean Difference (IV, Random, 95% CI)

3.40 [‐9.12, 15.92]

3.2 Change from baseline

1

40

Mean Difference (IV, Random, 95% CI)

‐16.0 [‐30.26, ‐1.74]

Figuras y tablas -
Comparison 5. Pain
Comparison 6. Patient global assessment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Patient global assessment: DMARD naive Show forest plot

1

71

Mean Difference (IV, Random, 95% CI)

0.70 [‐10.24, 11.64]

1.1 Final value

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Change from baseline

1

71

Mean Difference (IV, Random, 95% CI)

0.70 [‐10.24, 11.64]

2 Patient global assessment: MTX inadequate response Show forest plot

4

520

Mean Difference (IV, Random, 95% CI)

‐8.15 [‐14.52, ‐1.79]

2.1 Final value

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Change from baseline

4

520

Mean Difference (IV, Random, 95% CI)

‐8.15 [‐14.52, ‐1.79]

3 Patient global assessment: Non‐MTX DMARDs inadequate response Show forest plot

1

67

Mean Difference (IV, Random, 95% CI)

‐10.0 [‐19.60, ‐0.40]

3.1 Final value

1

67

Mean Difference (IV, Random, 95% CI)

‐10.0 [‐19.60, ‐0.40]

3.2 Change from baseline

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 6. Patient global assessment
Comparison 7. Physician global assessment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Physician global asessment: MTX inadequate response Show forest plot

4

520

Mean Difference (IV, Random, 95% CI)

‐10.91 [‐18.98, ‐2.84]

2 Physician global assessment: Non‐MTX inadequate response Show forest plot

1

67

Mean Difference (IV, Random, 95% CI)

‐10.0 [‐14.80, ‐5.20]

Figuras y tablas -
Comparison 7. Physician global assessment
Comparison 8. HAQ

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 HAQ: DMARD naive Show forest plot

2

141

Mean Difference (IV, Random, 95% CI)

0.10 [0.09, 0.11]

1.1 Final value

1

70

Mean Difference (IV, Random, 95% CI)

0.10 [0.09, 0.11]

1.2 Change from baseline

1

71

Mean Difference (IV, Random, 95% CI)

‐0.05 [‐0.37, 0.27]

2 HAQ: MTX inadequate response Show forest plot

3

476

Mean Difference (IV, Random, 95% CI)

‐0.28 [‐0.36, ‐0.21]

2.1 Final value

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Change from baseline

3

476

Mean Difference (IV, Random, 95% CI)

‐0.28 [‐0.36, ‐0.21]

3 HAQ: Non‐MTX DMARDs inadequate response Show forest plot

1

68

Mean Difference (IV, Random, 95% CI)

‐0.17 [‐0.48, 0.14]

3.1 Final value

1

68

Mean Difference (IV, Random, 95% CI)

‐0.17 [‐0.48, 0.14]

3.2 Change from baseline

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 8. HAQ
Comparison 9. ESR

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 ESR: DMARD naive Show forest plot

2

141

Mean Difference (IV, Random, 95% CI)

‐1.62 [‐6.98, 3.74]

1.1 Final value

1

70

Mean Difference (IV, Random, 95% CI)

‐0.23 [‐3.58, 3.12]

1.2 Change from baseline

1

71

Mean Difference (IV, Random, 95% CI)

‐7.0 [‐17.72, 3.72]

2 ESR: MTX inadequate response Show forest plot

3

476

Mean Difference (IV, Random, 95% CI)

‐0.53 [‐11.47, 10.41]

2.1 Final value

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Change from baseline

3

476

Mean Difference (IV, Random, 95% CI)

‐0.53 [‐11.47, 10.41]

3 ESR: Non‐MTX DMARDs inadequate response Show forest plot

4

212

Mean Difference (IV, Random, 95% CI)

‐4.29 [‐10.72, 2.13]

3.1 Final value

3

172

Mean Difference (IV, Random, 95% CI)

‐2.94 [‐11.11, 5.24]

3.2 Change from baseline

1

40

Mean Difference (IV, Random, 95% CI)

‐9.10 [‐19.13, 0.93]

Figuras y tablas -
Comparison 9. ESR
Comparison 10. CRP

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 CRP: DMARD naive Show forest plot

1

70

Mean Difference (IV, Random, 95% CI)

0.66 [‐2.78, 4.10]

1.1 Final value

1

70

Mean Difference (IV, Random, 95% CI)

0.66 [‐2.78, 4.10]

1.2 Change from baseline

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2 CRP: MTX inadequate response Show forest plot

1

263

Mean Difference (IV, Random, 95% CI)

‐12.1 [‐19.84, ‐4.36]

2.1 Final value

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Change from baseline

1

263

Mean Difference (IV, Random, 95% CI)

‐12.1 [‐19.84, ‐4.36]

3 CRP: Non‐MTX DMARDs inadequate response Show forest plot

1

37

Mean Difference (IV, Random, 95% CI)

‐1.20 [‐2.95, 0.55]

3.1 Final value

1

37

Mean Difference (IV, Random, 95% CI)

‐1.20 [‐2.95, 0.55]

3.2 Change from baseline

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 10. CRP
Comparison 11. DAS

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 DAS: DMARD naive Show forest plot

2

208

Mean Difference (IV, Random, 95% CI)

‐0.32 [‐0.77, 0.12]

1.1 Final value

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Change from baseline

2

208

Mean Difference (IV, Random, 95% CI)

‐0.32 [‐0.77, 0.12]

2 DAS: Non‐MTX DMARDs inadequate response Show forest plot

1

40

Mean Difference (IV, Random, 95% CI)

‐1.3 [‐1.74, ‐0.86]

2.1 Final value

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Change from baseline

1

40

Mean Difference (IV, Random, 95% CI)

‐1.3 [‐1.74, ‐0.86]

Figuras y tablas -
Comparison 11. DAS
Comparison 12. Modified Sharp's score

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Modified Sharp's score: DMARD naive Show forest plot

1

58

Mean Difference (IV, Random, 95% CI)

‐3.15 [‐5.85, ‐0.45]

1.1 Final value

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Change from baseline

1

58

Mean Difference (IV, Random, 95% CI)

‐3.15 [‐5.85, ‐0.45]

2 Modified Sharp's score: MTX inadequate response Show forest plot

1

44

Mean Difference (IV, Random, 95% CI)

‐1.4 [‐2.81, 0.01]

2.1 Final value

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Change from baseline

1

44

Mean Difference (IV, Random, 95% CI)

‐1.4 [‐2.81, 0.01]

Figuras y tablas -
Comparison 12. Modified Sharp's score