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Am Fam Physician. 2015;91(1):26-27

Author disclosure: No relevant financial affiliations.

Clinical Question

Is methotrexate monotherapy appropriate for patients with rheumatoid arthritis, and do adverse effects of this treatment lead to discontinuation of therapy?

Evidence-Based Answer

Methotrexate monotherapy demonstrated statistically significant and clinically relevant improvement of symptoms and physical function compared with placebo at 12 to 52 weeks. Multiple adverse effects were reported with methotrexate use, and patients were twice as likely to discontinue methotrexate therapy when compared with placebo. (Strength of Recommendation: A, based on consistent, good-quality patient-oriented evidence.)

Practice Pointers

Rheumatoid arthritis is a chronic, inflammatory condition that can affect multiple joints, cause systemic manifestations, and lead to progressive disability as well as a decrease in life expectancy.1 The American College of Rheumatology (ACR) recommends initiating treatment with disease-modifying antirheumatic drugs (DMARDs) as mono-therapy or in combination with other nonbiologic (e.g., hydroxychloroquine [Plaquenil], leflunomide [Arava], methotrexate, minocycline [Minocin], sulfasalazine [Azulfidine]) or biologic (e.g., abatacept [Orencia], adalimumab [Humira], etanercept [Enbrel], infliximab [Remicade], rituximab [Rituxan]) DMARDs soon after diagnosis.2 This is an update of a 1997 Cochrane review of the DMARD methotrexate.

The updated review includes 732 patients from seven trials comparing methotrexate monotherapy with placebo. The mean age of participants ranged from 46 to 60 years, and 74% were women. Weekly dosages of oral or parenteral methotrexate ranged from 5 to 25 mg, and follow-up ranged from 12 to 52 weeks. Patients in the methotrexate group were more likely to have 50% improvement in their symptoms at 52 weeks compared with the placebo group based on the ACR 50, which measures the number of tender or swollen joints and other outcomes such as pain and disability (relative risk [RR] = 3.0; 95% confidence interval [CI], 1.5 to 6.0; number needed to treat [NNT] = 7; 95% CI, 4 to 22). Statistically significant improvement in physical function was noted in patients receiving methotrexate (NNT = 4; 95% CI, 3 to 7). Radiographic scores did not improve, but the rate of radiographic progression was lower for patients in the methotrexate group (RR = 0.31; 95% CI, 0.11 to 0.86; NNT = 13; 95% CI, 10 to 60). The one study that measured remission did not find participants in either group who met the criteria for remission.

Adverse effects led to discontinuation in twice as many patients in the methotrexate group as the placebo group at 12 to 52 weeks (16% vs. 8%; RR = 2.1; 95% CI, 1.3 to 3.3; number needed to harm = 13; 95% CI, 6 to 44). The most common adverse effects were infections such as upper respiratory tract infection, bronchitis, and pneumonia. Rates of liver enzyme abnormalities, stomatitis and oral ulcers, alopecia, and gastrointestinal distress were also higher in the methotrexate group. Nine more persons out of 100 who took methotrexate vs. placebo withdrew from treatment because of adverse effects. On the other hand, there was no significant difference in total number of serious adverse effects between the methotrexate and placebo groups at 27 to 52 weeks.

The 2012 ACR guidelines recommend starting DMARDs such as methotrexate monotherapy for treatment of early (i.e., less than six months) and established (i.e., six months or more) rheumatoid arthritis in patients without poor prognostic features, and in combination therapy for early and established rheumatoid arthritis in patients with poor prognostic features.2 Initial treatment with methotrexate is also endorsed by the European League Against Rheumatism.3 The American Board of Internal Medicine's Choosing Wisely initiative, in collaboration with the ACR, recommends a three-month trial of methotrexate or other conventional nonbiologic DMARDs before prescribing biologic DMARDs.4

These are summaries of reviews from the Cochrane Library.

This series is coordinated by Corey D. Fogleman, MD, assistant medical editor.

A collection of Cochrane for Clinicians published in AFP is available at

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