Editorial Calls for Monitoring of Low-Dose Methotrexate Users for Adverse Events in Light of New RCT Data


The use of low-dose methotrexate in rheumatoid arthritis dates back more than 30 years, but despite these decades of clinical use, data on adverse effects have come mostly from observational studies rather than randomized controlled trials (RCTs), the authors say.

A secondary analysis of a randomized controlled trial investigating low-dose methotrexate in patients at risk of cardiovascular events has provided estimates of risk for adverse events (AEs), some infrequent but serious, such as hepatic, pulmonary, hematologic toxicity, and skin cancer.

Low-dose methotrexate is a first-line therapy for rheumatoid arthritis (RA) and is commonly used in other rheumatic diseases. The use of low-dose methotrexate in RA dates back more than 30 years, but despite these decades of clinical use, data on adverse effects has come mostly from observational studies rather than randomized controlled trials, the authors say. AEs identified by observational studies of patients with rheumatic diseases taking low-dose methotrexate include liver toxicity, gastrointestinal upset, pulmonary AEs, increased incidence of any cancer, melanoma, lung cancer, and non-Hodgkin lymphoma. However, these observational data have been limited by lack of a placebo group.

To address this knowledge gap, AEs of interest were monitored for and blindly adjudicated in the current trial (Cardiovascular Inflammation Reduction Trial; CIRT). Participants were randomized to low-dose methotrexate (maximum 20 mg/week; median dose 15 mg/week) or placebo, and both groups received 1 mg/day folic acid, 6 days/week.

Over the median follow-up period of 23 months, 87.0% of participants in the low-dose methotrexate group experienced any AE of interest, compared to 81.5% in the placebo group; the relative risk of AEs of interest in the methotrexate group was 17% higher than the placebo group.

Although the rate of renal AEs was lower by 15% in the methotrexate group, other AEs were higher. Skin cancer doubled and gastrointestinal AEs rose 23%. Infectious AEs rose 15%, pulmonary AEs rose 42%, and hematologic AEs rose 22%.

In an accompanying editorial, Vivian P. Bykerk, MD, of the Hospital for Special Surgery and Weill Cornell Medical College, states that the authors of this safety analysis should be commended for establishing these estimates of AE risk, which can be used to improve monitoring of patients using methotrexate.

Both the author of the editorial and those of the trial acknowledge the question of whether these data are generalizable to patients with RA. However, in the editorial Bykerk notes the rates of AEs were similar to previous estimates based on observational studies.

Over the decades of low-dose methotrexate use for RA, new and advanced therapies have been developed for RA and other forms of inflammatory arthritis. Today, patients with intolerable or potentially serious side effects are able to discontinue treatment with methotrexate and switch to another therapy; in fact, as stated in the editorial, approximately 30% of these patients use biologics without methotrexate, according to registry data.

According to Bykerk, this is the first well-powered, placebo-controlled trial of low-dose methotrexate designed to provide accurate estimates of serious AEs, providing valuable information that can improve monitoring of patients on methotrexate going forward.


Solomon DH, Glynn RJ, Karlson EW, et al. Adverse effects of low-dose methotrexate: a randomized trial [published online February 18, 2020]. Ann Intern Med. doi:10.7326/M19-3369.

Bykerk VP. A call to systematically monitor for adverse events in users of low-dose methotrexate therapy [published online February 18, 2020]. Ann Intern Med. doi:10.7326/M20-0435.

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