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Adverse Events Linked With Low-Dose Methotrexate

February 19, 2020

Compared with placebo, a team of researchers found that patients taking low-dose methotrexate (LD-MTX) experienced a variety of adverse events (AEs). They identified elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs. However, the authors noted in their findings, which were published online in Annals of Internal Medicine, renal AEs were decreased among patients taking LD-MTX.

“LD-MTX is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis,” the study authors explained. “Despite extensive clinical use for more than 30 years, few data on AE rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred.”

In order to investigate and better understand AE rates, risks, and risk differences comparing LD-MTX versus placebo, the research team conducted a prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. They included adult participants with cardiovascular disease and diabetes or metabolic syndrome.

According to the researchers, study participants were randomly given LD-MTX (≤20 mg/week) or placebo. Notably, all participants received folic acid, 1 mg/day, 6 days per week.

“Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication,” they noted.

Based on the study design, the authors identified 6158 participants and 4786 (81% male; median age 65.7 years; median body mass index 31.5 kg/m2) were randomly assigned to a group. More specifically, the median follow-up was 23 months and median dosage 15 mg/week.

According to the study findings, of 2391 participants assigned to receive LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The hazards for the following AEs were elevated for LD-MTX versus placebo:

  • gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]);
  • pulmonary (HR, 1.52 [CI, 1.16 to 1.98]);
  • infectious (HR, 1.15 [CI, 1.01 to 1.30]); and
  • hematologic (HR, 1.15 [CI, 1.07 to 1.23]).

“With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs.”

Finally, the study findings showed that renal AEs were actually reduced among participants in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]).

“Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased,” the research team concluded.

Julie Gould


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

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