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.
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.


METHODS
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.


METHODS
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.


METHODS
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.


RESULTS
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.
Department of Medicine, University of Calgary, Calgary, AB, Canada, T2N4Z6 McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada, T2N4Z6 Institute of Health, Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada, M5T3M6 Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada, T2N4Z6.
Glen S
GS
Hazlewood
Department of Medicine, University of Calgary, Calgary, AB, Canada, T2N4Z6 McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada, T2N4Z6 Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada, T2N4Z6.
Cheryl
C
Barnabe
Department of Medicine and Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada, M5G2C4.
George
G
Tomlinson
McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada, T2N4Z6 Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada, T2N4Z6.
Deborah
D
Marshall
Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada, T2N4Z6.
Dan
D
Devoe
Department of Medicine and Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada, M5G2C4 Toronto General Research Institute, University Health Network, Toronto, ON, Canada, M6J3S3 Mount Sinai Hospital, Division of Rheumatology, Toronto, ON, Canada, M5T3L9.
Claire
C
Bombardier
D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001685:Biological Factors / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001685:Biological Factors; D008727:Methotrexate