Methotrexate has substantial clinical benefit in the short term treatment of people with rheumatoid arthritis

Suarez-Almazor ME, Belseck E, Shea B, Tugwell P, Wells GA

Published Online:

July 7, 2010

Methotrexate (MTX) is a dihydrofolate reductase inhibitor used in the treatment of rheumatoid arthritis (RA). Five trials and 300 participants were included in this review. Participants had severe RA of long duration and had previously failed other therapy. They received MTX treatment, or placebo, over 12 to 18 weeks. Statistically significant benefits were observed with MTX on joint counts, pain, and global and functional assessments. People on MTX were three times more likely to discontinue treatment because of adverse reactions.

Abstract (click to read)

Background:

Methotrexate (MTX) is a folic acid antagonist widely used for the treatment of neoplastic disorders. MTX inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and proteins by binding to dihydrofolate reductase. Currently, MTX is among the most commonly used drugs for the treatment of rheumatoid arthritis (RA).

Objectives:

To evaluate the short term efficacy and toxicity of methotrexate (MTX) for the treatment of rheumatoid arthritis (RA).

Search strategy:

We searched the Cochrane Musculoskeletal Group register, Cochrane Controlled Trials Register (CCTR), MEDLINE (1966 to July 1997) and EMBASE (1988 to July 1997) using the strategy developed by Dickersin 1994. The search was complemented with a bibliography search of the reference lists of the trials retrieved from the electronic search. Key experts in the area were contacted for further published and unpublished articles.

Selection criteria:

Randomized controlled trials and controlled clinical trials comparing MTX against placebo in people with RA.

Data collection and analysis:

Two reviewers determined the studies to be included based on inclusion and exclusion criteria. Data were independently extracted by two reviewers, and checked by a third reviewer, using a pre-developed form for the rheumatoid arthritis sub-group of the Cochrane Musculoskeletal Group.

The same two reviewers independently assessed the methodological quality of the trials using a validated scale (Jadad 1996). Rheumatoid arthritis outcome measures were extracted from the publications. The pooled analysis was performed using standardized mean differences (SMDs) for joint counts, pain, and global and functional assessments. Weighted mean differences (WMDs) were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios (OR) for withdrawals. A chi-square test was used to assess heterogeneity among trials. Fixed effects models were used throughout, although random effects models were used for outcomes showing heterogeneity.

Main results:

Five trials and 300 participants were included. A statistically significant benefit was observed for MTX when compared to placebo. Statistically significant differences were observed for all measures except ESR. The standardized weighted difference (effect size) between MTX and placebo for the various outcome measures varied between -0.43 and -1.5. No differences were observed in the total number of withdrawals and dropouts (OR 0.95) although participants on MTX were three times more likely to discontinue treatment because of adverse reactions (OR 3.47) and four times less likely to withdraw due to lack of response (OR 0.22). Twenty-two percent of people on MTX withdrew due to adverse effects compared to seven percent of the placebo group.

Authors' conclusions:

MTX has a substantial clinical and statistically significant benefit compared to placebo in the short term treatment of people with RA although its use is associated with a high withdrawal rate due to adverse events.

This record should be cited as:

Suarez-Almazor ME, Belseck E, Shea B, Tugwell P, Wells GA. Methotrexate for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews 1998, Issue 2. Art. No.: CD000957. DOI: 10.1002/14651858.CD000957

Assessed as up to date:

November 30, 1997

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Primary Review Group:

Musculoskeletal Group

Arthritis topics:

Rheumatoid Arthritis > Disease Modifying Anti-Rheumatic Drugs DMARDs and Slow-Acting Anti-Rheumatic Drugs SAARDs

Health topics:

Rheumatology > Rheumatoid arthritis > DMARDS & SAARDS

Cochrane Summaries^beta

Independent high-quality evidence for health care decision making

Methotrexate has substantial clinical benefit in the short term treatment of people with rheumatoid arthritis

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