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17-02-2020 | Rheumatology | News | Article

Editor's pick

Low-dose methotrexate use ‘has inherent risks’

Author:
Claire Barnard

medwireNews: Treatment with low-dose methotrexate is associated with a “small to moderate” increase in the risk for pulmonary, gastrointestinal, hematologic, and infectious adverse events (AEs), as well as skin cancer, researchers report.

“We believe that the current data provide what are perhaps the first objective measurements of true toxicity associated with use of [low-dose methotrexate] – risks that need to be balanced with the clear clinical benefits of this drug’s use in the setting of rheumatoid arthritis [RA] or psoriasis,” write the researchers in the Annals of Internal Medicine.

These risk estimates are based on a prespecified secondary analysis of the CIRT study, a randomized controlled trial of low-dose methotrexate (≤20 mg/week) versus placebo, given alongside folic acid (1 mg/day on 6 days/week), for the prevention of major adverse cardiac events in high-risk individuals.

Daniel Solomon (Brigham and Women’s Hospital, Boston, Massachusetts, USA) and study co-authors point out that the CIRT trial did not include patients with rheumatic diseases, but represented “a contemporary clinical trial that included recommended use of folic acid to reduce drug-associated toxicities.”

Overall, 87.0% of 2391 participants treated with low-dose methotrexate experienced an adjudicated AE of interest over a median follow-up of 23 months, compared with 81.5% of 2395 individuals given placebo, translating into a significant hazard ratio (HR) of 1.17.

When AEs of interest were analyzed separately, individuals in the methotrexate arm had a significantly higher risk for pulmonary, gastrointestinal, hematologic, and infectious AEs than those in the placebo group, with HRs of 1.42, 1.23, 1.22, and 1.15, respectively.

The overall risk for cancer was not significantly different among patients treated with methotrexate versus placebo, but the risk for skin cancer was doubled in the methotrexate group (HR=2.04).

Conversely, Solomon and team found an “unanticipated and small” reduction in the risk for renal AEs among methotrexate-treated patients (HR=0.85), which was driven primarily by improvements in estimated glomerular filtration rates (eGFR). They suggest this could be explained by low-dose methotrexate improving eGFR “through its effect on inflammation,” but stress that “[m]ethotrexate is renally cleared, and thus kidney function needs to be monitored during treatment, even with [low-dose methotrexate].”

Writing in an accompanying editorial, Vivian Bykerk (Hospital for Special Surgery, New York, USA) says that the study results “[remind] us that [methotrexate] use has inherent risks and warrants vigilance for symptomatic, laboratory, and infrequent but clinically serious AEs.”

She says: “The question arises whether these data are generalizable to patients with RA or [inflammatory arthritis] treated with [methotrexate], who often receive doses higher than those used in CIRT” and have sociodemographic and clinical differences.

Nonetheless, she believes that the risk estimates “are largely congruent with those expected in [methotrexate]-treated patients with rheumatic diseases,” noting that “no large-scale, randomized, placebo-controlled trial of [methotrexate] has ever been performed in any rheumatic disease.”

The researchers “should be commended for providing estimates of AEs that can inform improved systematic monitoring of patients using [methotrexate],” concludes Bykerk.

medwireNews is an independent medical news service provided by Springer Healthcare. © 2020 Springer Healthcare part of the Springer Nature group

Ann Intern Med 2020; doi:10.7326/M19-3369
Ann Intern Med 2020; doi:10.7326/M20-0435

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