This summary of a Cochrane review presents what we know from research about the effect of methotrexate in combination with other drugs compared to methotrexate alone for rheumatoid arthritis (RA).
What is rheumatoid arthritis and what is methotrexate?
When you have rheumatoid arthritis, your immune system, which normally fights infection, attacks the lining of your joints. This makes your joints swollen, stiff and painful. The small joints of your hands and feet are usually affected first. There is no cure for RA at present, so the treatments aim to relieve pain and stiffness and improve your ability to move. Drugs such as methotrexate also aim to help prevent permanent damage to your joints that can happen if RA is not treated.
Methotrexate is a Disease-Modifying Anti-Rheumatic Drug (DMARD). Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune system. Methotrexate is a common treatment for RA and may be prescribed in combination with other drugs, especially in people who are not improving on methotrexate alone. DMARDs like methotrexate come as tablets, capsules and, in some cases, injections.
What the research says
There is probably little or no difference in symptoms of RA when taking methotrexate in combination with other disease-modifying anti-rheumatic drugs (DMARDs) or methotrexate alone.
There may be slightly more side effects when taking methotrexate in combination with other disease-modifying anti-rheumatic drugs (DMARDs) than methotrexate alone. Side effects may include stomach problems, liver problems, anaemia or infection.
In people who never took DMARDs before,
16 out of 100 stopped taking methotrexate because of harmful effects or no benefit
19 out of 100 (12 to 32) stopped taking methotrexate in combination with another DMARD
In people who did not improve with methotrexate,
19 out of 100 stopped taking methotrexate because of harmful effects or no benefit
16 out of 100 (9 to 28) stopped taking methotrexate in combination with another DMARD
In people who did not improve with other DMARDs,
35 out of 100 stopped taking methotrexate because of harmful effects or no benefit
26 out of 100 (14 to 47) stopped taking methotrexate in combination with another DMARD
9 out of 100 people stopped taking methotrexate because of side effects
14 out of 100 (10 to 18) stopped taking methotrexate in combination with another DMARD
When the balance of efficacy and toxicity is taken into account, the moderate level of evidence from our systematic review showed no statistically significant advantage of the MTX combination versus monotherapy. Trials are needed that compare currently used MTX doses and combination therapies.
Methotrexate (MTX) is among the most effective disease modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) with less toxicity and better tolerability.
To evaluate the efficacy and toxicity of MTX monotherapy compared to MTX combination with non-biologic DMARDs in adult with RA.
Trials were identified in MEDLINE (1950 to 2009), EMBASE (1980 to 2009), the Cochrane Controlled trials Registry (CENTRAL) (up to 2009), the American and European scientific meeting abstracts 2005-9, the reference lists of all relevant studies, letters, and review articles.
Randomized controlled trials comparing MTX monotherapy versus MTX combined with other non-biologic DMARDs of at least 12 weeks of trial duration in adult RA patients.
Two reviewers independently identified eligible studies,extracted the data, and assessed the risk of bias of relevant studies.The efficacy analysis was stratified into 3 groups based on previous DMARDs use: DMARD naive, MTX inadequate response, and non-MTX DMARDs inadequate response. The toxicity analysis was stratified by DMARD combination and pooled across trials for each combination. Our prespecified primary analysis was based on total withdrawal rates for efficacy or toxicity.
A total of 19 trials (2,025 patients) from 6,938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (risk ratio (RR) 1.16, 95% CI.0.70 to 1.93, absolute risk difference(ARD) 5%, 95%CI-3% to 13%). Trials in MTX or non-MTX DMARDs inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups with RR 0.86 95% CI 0.49 to1.51, ARD -2 %, 95% CI-13 % to 8 % and RR 0.75 95% CI 0.41 to 1.35, ARD -10%, 95% CI -31% to 11%, respectively. Significant reductions of pain and improvement in physical function (measured by Health Assessment Questionnaire or HAQ) were found in the MTX combination group, but only in MTX-inadequate responders (absolute risk difference -9.72%, 95%CI -14.7% to -4.75% for pain and mean difference (MD) -0.28, 95%CI -0.36 to -0.21 (0-3) for HAQ).