Drug Therapy

Methotrexate in rheumatoid arthritis: when NSAIDs fail

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Methotrexate has become the agent of choice for rheumatoid arthritis that does not respond to nonsteroidal anti-inflammatory drugs. In appropriately selected patients and with diligent monitoring, methotrexate in low weekly doses is effective and has a much better safety profile than was originally perceived.


In theory, methotrexate can interact with many other medications, but with low, weekly doses (7.5 to 15 mg), very few of these interactions are of clinical importance.

More than half of patients experience side effects, but only about 15% need to stop taking methotrexate within 5 years because of severe toxicity. Many side effects are manageable with dosage adjustment and exclusion of factors that may increase toxicity.

The most common side effects are gastrointestinal (nausea, dyspepsia, diarrhea, anorexia, and oral ulcers).

About one in five patients who take a cumulative dose of 3 grams of methotrexate progress at least one grade on liver biopsy, and about one in 35 develop advanced pathologic changes. The risk of advanced fibrosis is 2.5 to 5 times higher in patients who use alcohol heavily.

Methotrexate is teratogenic and must be avoided by women unwilling to use effective birth control.

Fewer than 5% of patients taking methotrexate develop bone marrow suppression.

We advise our patients to take folic acid supplements (1 mg daily), to reduce methotrexate-related side effects.



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