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Meta-Analysis
. 2015 Jan 20;1(1):CD007356.
doi: 10.1002/14651858.CD007356.pub2.

Rituximab for rheumatoid arthritis

Maria Angeles Lopez-Olivo  1 , Matxalen Amezaga Urruela, Lynda McGahan, Eduardo N Pollono, Maria E Suarez-Almazor
Affiliations
Meta-Analysis

Rituximab for rheumatoid arthritis

Maria Angeles Lopez-Olivo et al. Cochrane Database Syst Rev. .

Abstract

Background: Rituximab is a selective, B-cell depleting, biologic agent for treating refractory rheumatoid arthritis (RA). It is a chimeric monoclonal antibody targeted against CD 20 that is promoted as therapy for patients who fail to respond to other biologics. There is evidence to suggest that rituximab is effective and well tolerated when used in combination with methotrexate for RA.

Objectives: To evaluate the benefits and harms of rituximab for the treatment of RA.

Search methods: We conducted a search (until January 2014) in electronic databases (The Cochrane Library, MEDLINE, EMBASE, CINAHL, Web of Science), clinical trials registries, and websites of regulatory agencies. Reference lists from comprehensive reviews were also screened.

Selection criteria: All controlled trials comparing treatment with rituximab as monotherapy or in combination with any disease modifying anti-rheumatic drug (DMARD) (traditional or biologic) versus placebo or other DMARD (traditional or biologic) in adult patients with active RA.

Data collection and analysis: Two review authors independently assessed the risk of bias and abstracted data from each study.

Main results: We included eight studies with 2720 patients. For six studies selection bias could not be evaluated and two studies were considered to have low risk of bias. The level of evidence ranged from low to high, but was rated as moderate for most outcomes. We have prioritised reporting of rituximab (two 1000 mg doses) in combination with methotrexate since this is the approved dose and most commonly used combination. We also reported data on other combinations and doses as supplementary information in the results section of the review.American College of Rheumatology (ACR) 50 response rates were statistically significantly improved with rituximab (two 1000 mg doses) in combination with methotrexate compared with methotrexate alone at 24 to 104 weeks. The RR for achieving an ACR 50 at 24 weeks was 3.3 (95% CI 2.3 to 4.6); 29% of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate achieved the ACR 50 compared to 9% of controls. The absolute treatment benefit (ATB) was 21% (95% CI 16% to 25%) with a number needed to treat (NNT) of 6 (95% CI 4 to 9).At 52 weeks, the RR for achieving clinical remission (Disease Activity Score (DAS) 28 joints < 2.6) with rituximab (two 1000 mg doses) in combination with methotrexate compared with methotrexate monotherapy was 2.4 (95% CI 1.7 to 3.5); 22% of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate achieved clinical remission compared to 11% of controls. The ATB was 11% (95% CI 2% to 20%) with a NNT of 7 (95% CI 4 to 13).At 24 weeks, the RR for achieving a clinically meaningful improvement (CMI) in the Health Assessment Questionnaire (HAQ) (> 0.22) for patients receiving rituximab combined with methotrexate compared to patients on methotrexate alone was 1.6 (95% CI 1.2 to 2.1). The ATB was 24% (95% CI 12% to 36%) with an NNT of 5 (95% CI 3 to 13). At 104 weeks, the RR for achieving a CMI in HAQ (> 0.22) was 1.4 (95% CI 1.3 to 1.6). The ATB was 24% (95% CI 16% to 31%) with a NNT of 5 (95% CI 3 to 7).At 24 weeks, the RR for preventing radiographic progression in patients receiving rituximab (two 1000 mg doses) in combination with methotrexate was 1.2 (95% CI 1.0 to 1.4) compared to methotrexate alone; 70% of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate had no radiographic progression compared to 59% of controls. The ATB was 11% (95% CI 2% to 19%) and the NNT was 10 (95% CI 5 to 57). Similar benefits were observed at 52 to 56 weeks and 104 weeks.Statistically significantly more patients achieved a CMI on the physical and mental components of the quality of life, measured by the Short Form (SF)-36, in the rituximab (two 1000 mg doses) in combination with methotrexate-treated group compared with methotrexate alone at 24 to 52 weeks (RR 2.0, 95% CI 1.1 to 3.4; NNT 4, 95% CI 3 to 8 and RR 1.4, 95% CI 1.1 to 1.9; NNT 8, 95% CI 5 to 19, respectively); 34 and 13 more patients out of 100 showed an improvement in the physical component of the quality of life measure compared to methotrexate alone (95% CI 5% to 84%; 95% CI 7% to 8%, respectively).There was no evidence of a statistically significant difference in the rates of withdrawals because of adverse events or for other reasons (that is, withdrawal of consent, violation, administrative, failure to return) in either group. However, statistically significantly more people receiving the control drug withdrew from the study compared to those receiving rituximab (two 1000 mg doses) in combination with methotrexate at all times (RR 0.40, 95% CI 0.32 to 0.50; RR 0.61, 95% CI 0.40 to 0.91; RR 0.48, 95% CI 0.28 to 0.82; RR 0.58, 95% CI 0.45 to 0.75, respectively). At 104 weeks, 37% withdrew from the control group and 20% withdrew from the rituximab (two 1000 mg doses) in combination with methotrexate group. The absolute risk difference (ARD) was -20% (95% CI -34% to -5%) with a number needed to harm (NNH) of 7 (95% CI 5 to 11).A greater proportion of patients receiving rituximab (two 1000 mg doses) in combination with methotrexate developed adverse events after their first infusion compared to those receiving methotrexate monotherapy and placebo infusions (RR 1.6, 95% CI 1.3 to 1.9); 26% of those taking rituximab plus methotrexate reported more events associated with their first infusion compared to 16% of those on the control regimen with an ARD of 9% (95% CI 5% to 13%) and a NNH of 11 (95% CI 21 to 8). However, no statistically significant differences were noted in the rates of serious adverse events.

Authors' conclusions: Evidence from eight studies suggests that rituximab (two 1000 mg doses) in combination with methotrexate is significantly more efficacious than methotrexate alone for improving the symptoms of RA and preventing disease progression.

PubMed Disclaimer

Conflict of interest statement

Dr Suarez‐Almazor is the recipient of a K24 career award from the National Institute for Musculoskeletal and Skin Disorders.

Figures

1
1
Flow diagram of included studies. aStudy reported results on cycle 1 and cycle 2 (re‐treatment) bRe‐treatment was permitted at 24 weeks for patients not responding at least 20%
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Twenty‐nine out of every 100 rituximab plus methotrexate recipients experience a clinical improvement of 50% versus 9 methotrexate recipients.
5
5
Funnel plot of comparison: 1 Benefits ‐ RTX (2*1000 mg) + MTX versus MTX, outcome: 1.2 ACR 50.
1.1
1.1. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 1 ACR20.
1.2
1.2. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 2 ACR 50.
1.3
1.3. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 3 ACR 70.
1.4
1.4. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 4 ACR 90.
1.5
1.5. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 5 DAS 28.
1.6
1.6. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 6 LDA (DAS28 =or<3.2).
1.7
1.7. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 7 Clinical Remission (DAS28<2.6).
1.8
1.8. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 8 Moderate or good EULAR response.
1.9
1.9. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 9 HAQ‐DI.
1.10
1.10. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 10 HAQ‐DI MCID=‐0.22.
1.11
1.11. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 11 SF‐36 PCS.
1.12
1.12. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 12 SF‐36 PCS (=or>MCID of 5 or 5.42).
1.13
1.13. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 13 SF‐36 MCS.
1.14
1.14. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 14 SF‐36 MCS (=or>MCID of 5 or 6.33).
1.15
1.15. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 15 FACIT‐F.
1.16
1.16. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 16 FACIT‐F MCID>= 4or 3.56.
1.17
1.17. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 17 VAS‐pain.
1.18
1.18. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 18 Total radiographic score.
1.19
1.19. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 19 Joint Space Narrowing.
1.20
1.20. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 20 Radiologic erosions.
1.21
1.21. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 21 No radiographic progression.
1.22
1.22. Analysis
Comparison 1 Benefits ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 22 No worsening of erosions.
2.1
2.1. Analysis
Comparison 2 Benefits ‐ RTX monotherapy versus MTX monotherapy, Outcome 1 ACR 20.
2.2
2.2. Analysis
Comparison 2 Benefits ‐ RTX monotherapy versus MTX monotherapy, Outcome 2 ACR 50.
2.3
2.3. Analysis
Comparison 2 Benefits ‐ RTX monotherapy versus MTX monotherapy, Outcome 3 ACR 70.
2.4
2.4. Analysis
Comparison 2 Benefits ‐ RTX monotherapy versus MTX monotherapy, Outcome 4 DAS 28.
2.5
2.5. Analysis
Comparison 2 Benefits ‐ RTX monotherapy versus MTX monotherapy, Outcome 5 Moderate or good EULAR response.
2.6
2.6. Analysis
Comparison 2 Benefits ‐ RTX monotherapy versus MTX monotherapy, Outcome 6 HAQ‐DI.
2.7
2.7. Analysis
Comparison 2 Benefits ‐ RTX monotherapy versus MTX monotherapy, Outcome 7 % of patients achieving HAQ‐DI MCID=‐0.25.
3.1
3.1. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 1 ACR 20.
3.2
3.2. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 2 ACR 50.
3.3
3.3. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 3 ACR 70.
3.4
3.4. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 4 ACR 90.
3.5
3.5. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 5 DAS 28.
3.6
3.6. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 6 LDA (DAS28 =or<3.2).
3.7
3.7. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 7 Clinical Remission (DAS28<2.6).
3.8
3.8. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 8 Moderate or good EULAR response.
3.9
3.9. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 9 HAQ‐DI.
3.10
3.10. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 10 HAQ‐DI MCID=‐0.22.
3.11
3.11. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 11 SF‐36 PCS.
3.12
3.12. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 12 SF‐36 PCS (=or>MCID of 5 or 5.42).
3.13
3.13. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 13 SF‐36 MCS.
3.14
3.14. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 14 SF‐36 MCS (=or>MCID of 6.33).
3.15
3.15. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 15 FACIT‐F.
3.16
3.16. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 16 FACIT‐F (= or > MCID of 3.5 or 4).
3.17
3.17. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 17 VAS pain.
3.18
3.18. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 18 Total radiographic score.
3.19
3.19. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 19 Joint Space Narrowing.
3.20
3.20. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 20 Radiologic erosions.
3.21
3.21. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 21 No radiographic progression.
3.22
3.22. Analysis
Comparison 3 Benefits ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 22 No increase in erosion score.
4.1
4.1. Analysis
Comparison 4 Benefits ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 1 ACR 20.
4.2
4.2. Analysis
Comparison 4 Benefits ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 2 ACR 50.
4.3
4.3. Analysis
Comparison 4 Benefits ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 3 ACR 70.
4.4
4.4. Analysis
Comparison 4 Benefits ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 4 DAS 28.
4.5
4.5. Analysis
Comparison 4 Benefits ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 5 Moderate or good EULAR response.
4.6
4.6. Analysis
Comparison 4 Benefits ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 6 HAQ‐DI.
4.7
4.7. Analysis
Comparison 4 Benefits ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 7 HAQ‐DI MCID=‐0.22.
5.1
5.1. Analysis
Comparison 5 Benefits ‐ RTX (2 x 500 mg) + MTX + TNFi versus MTX + TNFi, Outcome 1 ACR 20.
5.2
5.2. Analysis
Comparison 5 Benefits ‐ RTX (2 x 500 mg) + MTX + TNFi versus MTX + TNFi, Outcome 2 ACR 50.
5.3
5.3. Analysis
Comparison 5 Benefits ‐ RTX (2 x 500 mg) + MTX + TNFi versus MTX + TNFi, Outcome 3 LDA (DAS28 =or<3.2).
5.4
5.4. Analysis
Comparison 5 Benefits ‐ RTX (2 x 500 mg) + MTX + TNFi versus MTX + TNFi, Outcome 4 Clinical Remission (DAS28<2.6).
5.5
5.5. Analysis
Comparison 5 Benefits ‐ RTX (2 x 500 mg) + MTX + TNFi versus MTX + TNFi, Outcome 5 HAQ‐DI MCID=‐0.25.
6.1
6.1. Analysis
Comparison 6 Withdrawals ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 1 Total discontinuations.
6.2
6.2. Analysis
Comparison 6 Withdrawals ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 2 Lack of efficacy.
6.3
6.3. Analysis
Comparison 6 Withdrawals ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 3 Adverse Events.
6.4
6.4. Analysis
Comparison 6 Withdrawals ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 4 Other reasons.
7.1
7.1. Analysis
Comparison 7 Withdrawals ‐ RTX monotherapy versus MTX monotherapy, Outcome 1 Total discontinuations.
7.2
7.2. Analysis
Comparison 7 Withdrawals ‐ RTX monotherapy versus MTX monotherapy, Outcome 2 Lack of efficacy.
7.3
7.3. Analysis
Comparison 7 Withdrawals ‐ RTX monotherapy versus MTX monotherapy, Outcome 3 Adverse Events.
7.4
7.4. Analysis
Comparison 7 Withdrawals ‐ RTX monotherapy versus MTX monotherapy, Outcome 4 Other reasons.
8.1
8.1. Analysis
Comparison 8 Withdrawals ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 1 Total discontinuations.
8.2
8.2. Analysis
Comparison 8 Withdrawals ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 2 Lack of efficacy.
8.3
8.3. Analysis
Comparison 8 Withdrawals ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 3 Adverse Events.
8.4
8.4. Analysis
Comparison 8 Withdrawals ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 4 Other reasons.
9.1
9.1. Analysis
Comparison 9 Withdrawals ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 1 Total discontinuations.
9.2
9.2. Analysis
Comparison 9 Withdrawals ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 2 Lack of efficacy.
9.3
9.3. Analysis
Comparison 9 Withdrawals ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 3 Adverse Events.
9.4
9.4. Analysis
Comparison 9 Withdrawals ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 4 Other reasons.
10.1
10.1. Analysis
Comparison 10 Withdrawals ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 1 Total discontinuations.
10.2
10.2. Analysis
Comparison 10 Withdrawals ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 2 Adverse events.
11.1
11.1. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 1 Any Adverse Event.
11.2
11.2. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 2 Serious Adverse Events.
11.3
11.3. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 3 Infections.
11.4
11.4. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 4 Serious infections.
11.5
11.5. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 5 Death.
11.6
11.6. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 6 Arthralgia.
11.7
11.7. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 7 Cardiac event (any).
11.8
11.8. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 8 Cardiac event (serious).
11.9
11.9. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 9 Cough.
11.10
11.10. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 10 Diarrhea.
11.11
11.11. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 11 Exacerbation of RA.
11.12
11.12. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 12 Fatigue.
11.13
11.13. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 13 HACA.
11.14
11.14. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 14 Headache.
11.15
11.15. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 15 Hypertension.
11.16
11.16. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 16 Infusion‐related reactions (1st course ‐1st infusion).
11.17
11.17. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 17 Infusion‐related reaction (1st course ‐2nd infusion).
11.18
11.18. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 18 Infusion‐related reaction (2nd course).
11.19
11.19. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 19 Infusion‐related reaction (3rd course).
11.20
11.20. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 20 Infusion‐related reaction (4th course).
11.21
11.21. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 21 Infusion‐related reaction (5th course).
11.22
11.22. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 22 Lower gastrointestinal events.
11.23
11.23. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 23 Malignancy.
11.24
11.24. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 24 Nasopharyngitis.
11.25
11.25. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 25 Nausea.
11.26
11.26. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 26 Pyrexia.
11.27
11.27. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 27 Upper respiratory tract infection.
11.28
11.28. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 28 Urinary tract infection.
11.29
11.29. Analysis
Comparison 11 Harms ‐ RTX (2 x 1000 mg) + MTX versus MTX, Outcome 29 Vascular disorders.
12.1
12.1. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 1 Any Adverse Event.
12.2
12.2. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 2 Serious Adverse Events.
12.3
12.3. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 3 Serious Infections.
12.4
12.4. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 4 Death.
12.5
12.5. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 5 Any Event Associated with 1st Infusion.
12.6
12.6. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 6 Arthralgia.
12.7
12.7. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 7 Back pain.
12.8
12.8. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 8 Cough.
12.9
12.9. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 9 Dyspnea.
12.10
12.10. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 10 Exacerbation of RA.
12.11
12.11. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 11 Hypertension.
12.12
12.12. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 12 Hypotension.
12.13
12.13. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 13 Nasopharyngitis.
12.14
12.14. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 14 Nausea.
12.15
12.15. Analysis
Comparison 12 Harms ‐ RTX monotherapy versus MTX monotherapy, Outcome 15 Rash.
13.1
13.1. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 1 Any Adverse Event.
13.2
13.2. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 2 Serious Adverse Events.
13.3
13.3. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 3 Infections.
13.4
13.4. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 4 Serious Infections.
13.5
13.5. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 5 Death.
13.6
13.6. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 6 Arthralgia.
13.7
13.7. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 7 Cardiac event (any).
13.8
13.8. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 8 Cardiac event (serious).
13.9
13.9. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 9 Diarrhea.
13.10
13.10. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 10 Exacerbation of RA.
13.11
13.11. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 11 Fatigue.
13.12
13.12. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 12 HACA.
13.13
13.13. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 13 Headache.
13.14
13.14. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 14 Hypertension.
13.15
13.15. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 15 Infusion‐related reactions (1st course ‐ 1st infusion).
13.16
13.16. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 16 Infusion related reaction (1st course ‐2nd infusion).
13.17
13.17. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 17 Infusion related reaction (2nd course).
13.18
13.18. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 18 Infusion related reaction (3rd course).
13.19
13.19. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 19 Infusion related reaction (4th course).
13.20
13.20. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 20 Infusion related reaction (5th course).
13.21
13.21. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 21 Lower gastrointestinal events.
13.22
13.22. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 22 Malignancy.
13.23
13.23. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 23 Nasopharyngitis.
13.24
13.24. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 24 Nausea.
13.25
13.25. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 25 Upper respiratory tract infection.
13.26
13.26. Analysis
Comparison 13 Harms ‐ RTX (2 x 500 mg) + MTX versus MTX, Outcome 26 Vascular disorders.
14.1
14.1. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 1 Any Adverse Event.
14.2
14.2. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 2 Serious Adverse Events.
14.3
14.3. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 3 Serious Infections.
14.4
14.4. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 4 Death.
14.5
14.5. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 5 Any Event Associated with 1st Infusion.
14.6
14.6. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 6 Arthralgia.
14.7
14.7. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 7 Back pain.
14.8
14.8. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 8 Cough.
14.9
14.9. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 9 Dyspnea.
14.10
14.10. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 10 Exacerbation of RA.
14.11
14.11. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 11 Hypertension.
14.12
14.12. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 12 Hypotension.
14.13
14.13. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 13 Nasopharyngitis.
14.14
14.14. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 14 Nausea.
14.15
14.15. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 15 Pruritus.
14.16
14.16. Analysis
Comparison 14 Harms ‐ RTX (2 x 1000 mg) + CTX versus MTX, Outcome 16 Rash.
15.1
15.1. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 1 Any Adverse Event.
15.2
15.2. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 2 Serious adverse events.
15.3
15.3. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 3 Grade 3 adverse events.
15.4
15.4. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 4 All infections.
15.5
15.5. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 5 Grade 3 infections.
15.6
15.6. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 6 Serious infections.
15.7
15.7. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 7 Any Event Associated with 1st infusion.
15.8
15.8. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 8 Any Event Associated with 2nd infusion.
15.9
15.9. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 9 Arthralgia.
15.10
15.10. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 10 Coronary artery occlusion.
15.11
15.11. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 11 Diarrhea.
15.12
15.12. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 12 Exacerbation of RA.
15.13
15.13. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 13 Fatigue.
15.14
15.14. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 14 HACA.
15.15
15.15. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 15 Headache.
15.16
15.16. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 16 Influenza.
15.17
15.17. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 17 Muscle spasms.
15.18
15.18. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 18 Nasopharyngitis.
15.19
15.19. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 19 Nausea.
15.20
15.20. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 20 Peripheral edema.
15.21
15.21. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 21 Pneumonia.
15.22
15.22. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 22 Postoperative infection.
15.23
15.23. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 23 Pruritus.
15.24
15.24. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 24 Sinusitits.
15.25
15.25. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 25 Upper respiratory tract infections.
15.26
15.26. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 26 Urinary tract infections.
15.27
15.27. Analysis
Comparison 15 Harms ‐ RTX + MTX + TNFi versus MTX + TNFi, Outcome 27 Vaginal Mycosis.
16.1
16.1. Analysis
Comparison 16 Disease duration (subgroup analysis), Outcome 1 ACR 50.
17.1
17.1. Analysis
Comparison 17 Previous treatment (subgroup analysis), Outcome 1 ACR 50.
18.1
18.1. Analysis
Comparison 18 Study quality (subgroup analysis), Outcome 1 ACR 50.
19.1
19.1. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 1 ACR 20.
19.2
19.2. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 2 ACR 50.
19.3
19.3. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 3 ACR 70.
19.4
19.4. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 4 ACR 90.
19.5
19.5. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 5 DAS 28‐ESR.
19.6
19.6. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 6 LDA (DAS28 =or<3.2).
19.7
19.7. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 7 Clinical Remission (DAS28<2.6).
19.8
19.8. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 8 Moderate or good EULAR response.
19.9
19.9. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 9 HAQ‐DI.
19.10
19.10. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 10 HAQ‐DI MCID=‐0.22.
19.11
19.11. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 11 SF‐36 PCS.
19.12
19.12. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 12 SF‐36 PCS (=or>MCID of 5 or 5.42).
19.13
19.13. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 13 SF‐36 MCS.
19.14
19.14. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 14 SF‐36 MCS (=or>MCID of 6.33).
19.15
19.15. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 15 FACIT‐F.
19.16
19.16. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 16 FACIT‐F (=or>MCID of 3.5).
19.17
19.17. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 17 VAS Pain.
19.18
19.18. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 18 Total radiographic score.
19.19
19.19. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 19 Joint space narrowing.
19.20
19.20. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 20 Radiographic erosions.
19.21
19.21. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 21 No radiographic progression.
19.22
19.22. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 22 No worsening of erosions.
19.23
19.23. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 23 Total discontinuations.
19.24
19.24. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 24 Discontinuation due to lack of efficacy.
19.25
19.25. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 25 Discontinuations due to adverse Events.
19.26
19.26. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 26 Discontinuations due to other reasons.
19.27
19.27. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 27 Any Adverse Event.
19.28
19.28. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 28 Serious Adverse Events.
19.29
19.29. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 29 Infections.
19.30
19.30. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 30 Serious Infections.
19.31
19.31. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 31 Death.
19.32
19.32. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 32 Arthralgia.
19.33
19.33. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 33 Cardiac event (any).
19.34
19.34. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 34 Cardiac event (Serious).
19.35
19.35. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 35 Diarrhea.
19.36
19.36. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 36 Exacerbation of RA.
19.37
19.37. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 37 Fatigue.
19.38
19.38. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 38 HACA.
19.39
19.39. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 39 Hypertension.
19.40
19.40. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 40 Infusion‐related reactions (1st course ‐1st infusion).
19.41
19.41. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 41 Infusion‐related reaction (1st course ‐2nd infusion).
19.42
19.42. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 42 Infusion‐related reaction (2nd course).
19.43
19.43. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 43 Infusion‐related reaction (3rd course).
19.44
19.44. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 44 Infusion‐related reaction (4th course).
19.45
19.45. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 45 Infusion‐related reaction (5th course).
19.46
19.46. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 46 Lower gastrointestinal events.
19.47
19.47. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 47 Malignancy.
19.48
19.48. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 48 Pneumonia.
19.49
19.49. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 49 Urinary tract infection.
19.50
19.50. Analysis
Comparison 19 Dosage 2 x 1000 mg versus 2 x 500 mg (sensitivity analysis), Outcome 50 Vascular disorders.
20.1
20.1. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 1 ACR 20.
20.2
20.2. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 2 ACR 50.
20.3
20.3. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 3 ACR 70.
20.4
20.4. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 4 DAS 28.
20.5
20.5. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 5 Moderate or good EULAR response.
20.6
20.6. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 6 HAQ‐DI.
20.7
20.7. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 7 HAQ‐DI MCID=‐0.22.
20.8
20.8. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 8 Total discontinuations.
20.9
20.9. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 9 Withdrawals due to lack of efficacy.
20.10
20.10. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 10 Withdrawals due to adverse events.
20.11
20.11. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 11 Withdrawals due to other reasons.
20.12
20.12. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 12 Any Adverse Event.
20.13
20.13. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 13 Serious Adverse Events.
20.14
20.14. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 14 Serious Infections.
20.15
20.15. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 15 Exacerbation of RA.
20.16
20.16. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 16 Death.
20.17
20.17. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 17 Any Event Associated with 1st Infusion.
20.18
20.18. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 18 Arthralgia.
20.19
20.19. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 19 Back pain.
20.20
20.20. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 20 Cough.
20.21
20.21. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 21 Dyspnea.
20.22
20.22. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 22 Hypertension.
20.23
20.23. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 23 Hypotension.
20.24
20.24. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 24 Nasopharyngitis.
20.25
20.25. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 25 Nausea.
20.26
20.26. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 26 Pruritus.
20.27
20.27. Analysis
Comparison 20 Concomitant treatment CTX versus MTX (sensitivity analysis), Outcome 27 Rash.
21.1
21.1. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 1 ACR 20.
21.2
21.2. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 2 ACR 50.
21.3
21.3. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 3 ACR 70.
21.4
21.4. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 4 DAS 28.
21.5
21.5. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 5 Moderate or good EULAR response.
21.6
21.6. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 6 HAQ‐DI.
21.7
21.7. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 7 HAQ‐DI MCID=‐0.22.
21.8
21.8. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 8 Total discontinuations.
21.9
21.9. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 9 Withdrawals due to lack of efficacy.
21.10
21.10. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 10 Withdrawals due to adverse Events.
21.11
21.11. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 11 Withdrawals due to other reasons.
21.12
21.12. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 12 Any Adverse Event.
21.13
21.13. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 13 Serious Adverse Events.
21.14
21.14. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 14 Serious Infections.
21.15
21.15. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 15 Death.
21.16
21.16. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 16 Any Event Associated with 1st Infusion.
21.17
21.17. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 17 Arthralgia.
21.18
21.18. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 18 Back pain.
21.19
21.19. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 19 Cough.
21.20
21.20. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 20 Dyspnea.
21.21
21.21. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 21 Exacerbation of RA.
21.22
21.22. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 22 Hypertension.
21.23
21.23. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 23 Hypotension.
21.24
21.24. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 24 Nasopharyngitis.
21.25
21.25. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 25 Nausea.
21.26
21.26. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 26 Pruritus.
21.27
21.27. Analysis
Comparison 21 Concomitant treatment MTX versus none (sensitivity analysis), Outcome 27 Rash.
22.1
22.1. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 1 ACR 20.
22.2
22.2. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 2 ACR 50.
22.3
22.3. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 3 ACR 70.
22.4
22.4. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 4 DAS 28.
22.5
22.5. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 5 Moderate or good EULAR response.
22.6
22.6. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 6 HAQ‐DI.
22.7
22.7. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 7 HAQ‐DI MCID=‐0.22.
22.8
22.8. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 8 Total discontinuations.
22.9
22.9. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 9 Withdrawals due to lack of efficacy.
22.10
22.10. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 10 Withdrawals due to adverse Events.
22.11
22.11. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 11 Withdrawals due to other reasons.
22.12
22.12. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 12 Any Adverse Event.
22.13
22.13. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 13 Serious Adverse Events.
22.14
22.14. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 14 Serious Infections.
22.15
22.15. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 15 Death.
22.16
22.16. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 16 Any Event Associated with 1st Infusion.
22.17
22.17. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 17 Arthralgia.
22.18
22.18. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 18 Back pain.
22.19
22.19. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 19 Cough.
22.20
22.20. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 20 Dyspnea.
22.21
22.21. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 21 Exacerbation of RA.
22.22
22.22. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 22 Hypertension.
22.23
22.23. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 23 Hypotension.
22.24
22.24. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 24 Nasopharyngitis.
22.25
22.25. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 25 Nausea.
22.26
22.26. Analysis
Comparison 22 Concomitant treatment CTX versus none (sensitivity analysis), Outcome 26 Rash.
See this image and copyright information in PMC

Comment in

References

References to studies included in this review

Cohen 2006 (REFLEX) {published data only}
    1. Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al. REFLEX Trial Group. 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(9):2793‐806. [16947627] - PubMed
    1. Keystone E, Burmester GR, Furie R, Loveless JE, Emery P, Kremer J, et al. 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(6):785‐93. [PUBMED: 18512710] - PubMed
    1. 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. Annals of the Rheumatic Diseases 2009;68(2):216‐21. [PUBMED: 18388156] - PubMed
Edwards 2004 (WA16291) {published data only}
    1. Breedveld F, Agarwal S, Yin M, Ren S, Li NF, Shaw TM, Davies BE. Rituximab pharmacokinetics in patients with rheumatoid arthritis: B‐cell levels do not correlate with clinical response. The Journal of Clinical Pharmacology 2007;47(9):1119‐28. [PUBMED: 17068064] - PubMed
    1. Edwards JC, Szczepanski L, Szechinski J, Filipowicz‐Sosnowska A, Emery P, Close DR, et al. Efficacy of B‐cell‐targeted therapy with rituximab in patients with rheumatoid arthritis. The New England Journal of Medicine 2004;350(25):2572‐81. [PUBMED: 15201414] - PubMed
    1. Strand V, Balbir‐Gurman A, Pavelka K, Emery P, Li N, Yin M, et al. Sustained benefit in rheumatoid arthritis following one course of rituximab: improvements in physical function over 2 years. Rheumatology (Oxford) 2006;45(12):1505‐13. [PUBMED: 17062648] - PubMed
Emery 2006 (DANCER) {published data only}
    1. Emery P, Fleischmann R, Filipowicz‐Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, et al. DANCER Study Group. 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(5):1390‐400. [PUBMED: 16649186] - PubMed
    1. Mease PJ, Revicki DA, Szechinski J, Greenwald M, Kivitz A, Barile‐Fabris L, et al. Improved health‐related quality of life for patients with active rheumatoid arthritis receiving rituximab: Results of the Dose‐Ranging Assessment: International Clinical Evaluation of Rituximab in Rheumatoid Arthritis (DANCER) Trial. The Journal of Rheumatology 2008;35(1):20‐30. [PUBMED: 18050385] - PubMed
Emery 2010 (SERENE) {published data only}
    1. Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo‐controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)). Annals of the Rheumatic Diseases 2010;69(9):1629‐35. [PUBMED: 20488885] - PMC - PubMed
Greenwald 2011 (TAME) {published data only}
    1. Greenwald MW, Shergy WJ, Kaine JL, Sweetser MT, Gilder K, Linnik MD. Evaluation 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(3):622‐32. [PUBMED: 21360491] - PubMed
Owczarczyk 2008 {published data only}
    1. Owczarczyk K, Hellmann M, Fliedner G, Röhrs T, Maizus K, Passon D, et al. Clinical outcome and B cell depletion in patients with rheumatoid arthritis receiving rituximab monotherapy in comparison with patients receiving concomitant methotrexate. Annals of the Rheumatic Diseases 2008;67(11):1648‐9. [PUBMED: 18854518] - PubMed
Rubbert‐Roth2010 (MIRROR) {published data only}
    1. Rubbert‐Roth A, Tak PP, Zerbini C, Tremblay JL, Carreño L, Armstrong G, et al. MIRROR Trial Investigators. 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 (Oxford) 2010;49(9):1683‐93. [PUBMED: 20463186] - PMC - PubMed
Tak 2010 (IMAGE) {published data only}
    1. Tak PP, Rigby W, Rubbert‐Roth A, Peterfy C, Vollenhoven RF, Stohl W, et al. Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2‐year results from the randomised controlled trial IMAGE. Annals of the Rheumatic Diseases 2012;71(3):351‐7. - PMC - PubMed
    1. Tak PP, Rigby WF, Rubbert‐Roth A, Peterfy CG, Vollenhoven RF, Stohl W, et al. IMAGE Investigators. Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial. Annals of the Rheumatic Diseases 2011;70(1):39‐46. [PUBMED: 20937671] - PubMed

References to studies excluded from this review

Assous 2008 {published data only}
    1. Assous N, Gossec L, Dieudé P, Meyer O, Dougados M, Kahan A, Allanore Y. Rituximab therapy in rheumatoid arthritis in daily practice. The Joural of Rheumatology 2008;35(1):31‐4. - PubMed
Bingham 2010 (SIERRA) {published data only}
    1. Bingham CO 3rd, Looney RJ, Deodhar A, Halsey N, Greenwald M, Codding C, et al. Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial. Arthritis and Rheumatism 2010;62(1):64‐74. [PUBMED: 20039397] - PubMed
Bokarewa 2007 {published data only}
    1. Bokarewa M, Lindholm C, Zendjanchi K, Nadali M, Tarkowski A. Efficacy of anti‐CD20 treatment in patients with rheumatoid arthritis resistant to a combination of methotrexate/anti‐TNF therapy. Scandinavian Journal of Immunology 2007;66(4):476‐83. - PubMed
Galarza 2008 {published data only}
    1. Galarza C, Valencia D, Tobón GJ, Zurita L, Mantilla RD, Pineda‐Tamayo R, et al. Should rituximab be considered as the first‐choice treatment for severe autoimmune rheumatic diseases?. Clinical Reviews in Allergy & Immunology 2008;34(1):124‐8. - PubMed
Haraoui 2011 (RESET) {published data only}
    1. Haraoui B, Bokarewa M, Kallmeyer I, Bykerk VP, RESET Investigators. Safety and effectiveness of rituximab in patients with rheumatoid arthritis following an inadequate response to 1 prior tumor necrosis factor inhibitor: the RESET Trial. The Journal of Rheumatology 2011;38(12):2548‐56. [PUBMED: 21965646] - PubMed
Kavanaugh 2008 (ARISE) {published data only}
    1. Kavanaugh A, Rosengren S, Lee SJ, Hammaker D, Firestein GS, Kalunian K, et al. Assessment of rituximab's immunomodulatory synovial effects (ARISE trial). 1: clinical and synovial biomarker results. Annals of the Rheumatic Diseases 2008;67(3):402‐8. - PMC - PubMed
Keystone 2007 {published data only}
    1. Keystone E, Fleischmann R, Emery P, Furst DE, Vollenhoven R, 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(12):3896‐908. - PubMed
Mease 2010 (SUNRISE) {published data only}
    1. Mease PJ, Cohen S, Gaylis NB, Chubick A, Kaell AT, Greenwald M, et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. The Journal of Rheumatology 2010;37(5):917‐27. [PUBMED: 20194448] - PubMed
Ng 2005 {published data only}
    1. Ng CM, Bruno R, Combs D, Davies. Population pharmacokinetics of rituximab (anti‐CD20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial. The Journal of Clinical Pharmacology 2005;45(7):792‐801. - PubMed
Teng 2007 {published data only}
    1. Teng YK, Levarht EW, Hashemi M, Bajema IM, Toes RE, Huizinga TW, Laar JM. Immunohistochemical analysis as a means to predict responsiveness to rituximab treatment. Arthritis and Rheumatism 2007;56(12):3909. - PubMed
Teng 2009 {published data only}
    1. Teng YK, Tekstra J, Breedveld FC, Lafeber F, Bijlsma JW, Laar JM. Rituximab fixed retreatment versus on‐demand retreatment in refractory rheumatoid arthritis: comparison of two B cell depleting treatment strategies. Annals of the Rheumatic Diseases 2009;68(6):1075‐7. [PUBMED: 19435725] - PubMed
van den Bemt 2009 {published data only}
    1. Bemt BJF, Vos K, Broeder AA, Blom M, Thurlings RM, Bartelds GM, et al. A single course of rituximab does not abrogate anti‐infliximab antibodies in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 2009;68(8):1368‐9. - PubMed

References to ongoing studies

August III 2008 {published data only}
    1. A Randomized, Double‐Blind, Placebo Controlled, Multi‐Centre, Exploratory, Pilot, Phase II Trial of 150mg Atacicept Given Subcutaneously in Combination With Rituximab in Subjects With Rheumatoid Arthritis. Ongoing study March 2008.
NCT00298272 {published data only}
    1. A Randomized, Double‐Blinded, Placebo Controlled Study to Evaluate the Tolerability and Safety of Rituximab When Given in Combination With Methotrexate and Etanercept (Enbrel) or Methotrexate and Adalimumab (Humira) in Subjects With Active Rheumatoid Arthritis. Ongoing study March 2006.
NCT00422383 {published data only}
    1. A Randomized, Double‐blind Study to Evaluate the Effect of Various Re‐treatment Regimens of MabThera in Combination With Methotrexate on Treatment Response in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate. Ongoing study February 2006.
NCT00845832 {published data only}
    1. A Randomized, Active Controlled, Double‐blind, Study to Compare the Safety and Reduction in Disease Activity With the Combination of Rituximab (MabThera®)and Tocilizumab (RoActemra®) Versus Tocilizumab in Patients With Active Rheumatoid Arthritis With an Incomplete Response to Methotrexate. Ongoing study March 2009.
RUMBA {published data only}
    1. A Double‐Blind, Randomized, Multicenter, Phase II Study of the Safety and Efficacy of Two Rituximab Regimens in Subjects With Moderate to Severe Active Rheumatoid Arthritis Receiving Stable Doses of Methotrexate. Ongoing study April 2006.
SCORE 2007 {published data only}
    1. A Randomized, Placebo Controlled, Multicenter Clinical Study Investigating Efficacy of Rituximab (Mabthera/Rituxan) in the Inhibition of Joint Structural Damage Assessed by Magnetic Resonance Imaging in Patients With Rheumatoid Arthritis and Inadequate Response to Methotrexate ‐ the RA SCORE Study. Ongoing study November 2007.

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