Boston—Methotrexate, the most commonly used drug for systemic rheumatic diseases worldwide and usually the first-line medication prescribed for rheumatoid arthritis, has been around for 40 years.

Despite its use by millions of patients, however, little data is available on methotrexate’s side effects, according to a report in Annals of Internal Medicine. Brigham and Women’s Hospital researchers note that observational studies have suggested that the drug has the potential to increase risk for liver toxicity, anemia, and difficulty in breathing, but the magnitude of risk has been unknown.

To add to the information, the study team used data from the Cardiovascular Inflammation Reduction Trial (CIRT), a randomized double-blind, placebo-controlled study, to more accurately determine rates of adverse events for people taking methotrexate, including small-to-moderate elevations in risks for skin cancer, gastrointestinal, infectious, lung, and blood adverse events.

“Methotrexate is a cornerstone drug for a variety of inflammatory diseases, especially for rheumatoid arthritis,” explained Daniel Solomon, MD, MPH, a rheumatologist in the Division of Rheumatology, Inflammation and Immunology at Brigham & Women’s. “Over the decades, we've learned about the side effects but only from small studies. Questions for both physicians and patients have lingered about the drug's safety. Our study offers a detailed side-effect profile that I think will help us prescribe methotrexate in an informed way.”

To reach those conclusions, researchers examined data on 4,786 participants from CIRT who were randomized to receive low-dose methotrexate with folate or a placebo. They determined that, of 2,391 subjects who received methotrexate, 87% experienced an adverse event of interest compared with 81.5% of those who were randomized to placebo.

Dr. Solomon said the most surprising finding was a doubling of risk of skin cancer for participants taking methotrexate—53 incidents of skin cancer versus 26 for placebo. Making that finding especially concerning is patients with psoriatic arthritis, who might be treated with methotrexate, are already at increased risk of skin cancer.

Increases in gastrointestinal, infectious, pulmonary, and hematologic adverse events were also noted, although the elevations were deemed mild to moderate. As they expected, researchers documented an increase in liver-test abnormalities and five cases of cirrhosis in the methotrexate arm versus zero in the placebo arm. They point out that CIRT participants did not have rheumatoid arthritis or other rheumatic diseases and raise the possibility that adverse event rates could vary outside of the CIRT population.

“We now have real numbers we can share with patients when talking about side effects,” Dr. Solomon said. “We definitely wouldn’t suggest this drug is too dangerous to give. But having a clear side-effect profile allows us to give it with eyes wide open and better balances the risks and benefits of an age-old drug.”

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