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Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis

BMJ 2016; 353 doi: (Published 21 April 2016) Cite this as: BMJ 2016;353:i1777
  1. Glen S Hazlewood, assistant professor1 2 3 4,
  2. Cheryl Barnabe, assistant professor1 2 4,
  3. George Tomlinson, associate professor5,
  4. Deborah Marshall, associate professor2 4,
  5. Dan Devoe, research assistant4,
  6. Claire Bombardier, professor5 6 7
  1. 1Department of Medicine, University of Calgary, Calgary, AB, Canada, T2N4Z6
  2. 2McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada, T2N4Z6
  3. 3Institute of Health, Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada, M5T3M6
  4. 4Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada, T2N4Z6
  5. 5Department of Medicine and Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada, M5G2C4
  6. 6Toronto General Research Institute, University Health Network, Toronto, ON, Canada, M6J3S3
  7. 7Mount Sinai Hospital, Division of Rheumatology, Toronto, ON, Canada, M5T3L9
  1. Correspondence to: G S Hazlewood, 3330 Hospital Dr NW, Calgary, AB, Canada T2N1N1 glenhazlewood{at}
  • Accepted 22 March 2016


Objective To compare methotrexate based disease modifying antirheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naive to or with an inadequate response to methotrexate.

Design Systematic review and Bayesian random effects network meta-analysis of trials assessing methotrexate used alone or in combination with other conventional synthetic DMARDs, biologic drugs, or tofacitinib in adult patients with rheumatoid arthritis.

Data sources Trials were identified from Medline, Embase, and Central databases from inception to 19 January 2016; abstracts from two major rheumatology meetings from 2009 to 2015; two trial registers; and hand searches of Cochrane reviews.

Study selection criteria Randomized or quasi-randomized trials that compared methotrexate with any other DMARD or combination of DMARDs and contributed to the network of evidence between the treatments of interest.

Main outcomes American College of Rheumatology (ACR) 50 response (major clinical improvement), radiographic progression, and withdrawals due to adverse events. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior.

Results 158 trials were included, with between 10 and 53 trials available for each outcome. In methotrexate naive patients, several treatments were statistically superior to oral methotrexate for ACR50 response: sulfasalazine and hydroxychloroquine (“triple therapy”), several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%), compared with 41% with methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression, but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of 5 units on the Sharp-van der Heijde scale. Triple therapy had statistically fewer withdrawals due to adverse events than methotrexate plus infliximab. After an inadequate response to methotrexate, several treatments were statistically superior to oral methotrexate for ACR50 response: triple therapy, methotrexate plus hydroxychloroquine, methotrexate plus leflunomide, methotrexate plus intramuscular gold, methotrexate plus most biologics, and methotrexate plus tofacitinib. The probability of response was 61% with triple therapy and ranged widely (27-70%) with other treatments. No treatment was statistically superior to oral methotrexate for inhibiting radiographic progression. Methotrexate plus abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments.

Conclusions Triple therapy (methotrexate plus sulfasalazine plus hydroxychloroquine) and most regimens combining biologic DMARDs with methotrexate were effective in controlling disease activity, and all were generally well tolerated in both methotrexate naive and methotrexate exposed patients.


  • Contributors: GH developed the concept for the study, wrote the protocol, and participated in all stages of the study including literature search and data abstraction; he did all analyses and wrote and revised the manuscript. ChB edited and revised the protocol and manuscript and assisted with the literature search and data abstraction. GT edited and revised the protocol and manuscript and assisted with developing the concept and the analysis and interpretation of the data. DM edited and revised the protocol and manuscript and assisted with developing the concept for the study. DD edited and revised the manuscript and assisted with the data abstraction. ClB edited and revised the protocol and manuscript and assisted with developing the concept for the study. All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. GH is the guarantor.

  • Funding: Partial funding was provided by the Arthur J E Child chair in rheumatology outcomes research.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organization for the submitted work; GH has received fellowship funding supported by the Canadian Rheumatology Association, the Arthritis Society, and UCB Pharma, honorariums and travel expenses from Abbott, and honorariums from UCB Pharma and has participated in an advisory board meeting for Amgen; GH was supported by an Alberta Innovates health solutions clinical fellowship; ChB holds the Canadian Rheumatology Association/Arthritis Society clinician investigator salary award and is a Canadian Institutes of Health Research new investigator (community-based primary healthcare); in the past two years, ChB has participated in advisory boards for Roche and UCB and received honorariums from UCB and Amgen and an unrestricted travel grant from Celgene; DM is supported by a Canada Research chair in health systems and services research and an Arthur J E Child chair in rheumatology; in the past year, DM has received honorariums from Abbvie for a seminar; ClB has received grant support from Janssen, Pfizer, Amgen, Abbott/Abbvie Canada, BMS, Celgene, Eli Lilly, Fresenius Kabi, Hoffman La Roche, Sanofi, UCB, and Calea, has acted as a consultant for AstraZeneca, Abbott/Abbvie Canada, and BMS, and has participated in advisory board meetings for Janssen, Pfizer, Amgen, and AstraZeneca. ClB also holds a Pfizer chair and a Canada Research chair in knowledge transfer for musculoskeletal care; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethics approval: Not needed.

  • Transparency declaration: The lead author (the manuscript’s guarantor) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Data sharing: No additional data available.

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