Low-dose methotrexate ups risk for skin cancer, several adverse events

Treatment with low-dose methotrexate (LD-MTX) leads to small-to-moderate increases in risks for skin cancer and gastrointestinal, infectious, pulmonary and haematologic adverse events (AEs), as well as a decrease in renal AEs, a study has shown.

In this prespecified secondary analysis of a double-blind, placebo-controlled, randomized trial in North America, 6,158 patients with known cardiovascular disease (CVD) and diabetes or metabolic syndrome were enrolled. Of these, 4,786 (median age, 65.7 years; 81.2 percent male; median body mass index, 31.5 kg/m²) were randomly assigned to either LD-MTX (≤20 mg/wk; n=2,391) or placebo (n=2,395). All participants received folic acid 1 mg/d for 6 days each week.

Median follow-up was 23 months, and median dosage was 15 mg/wk. The investigators compared risks for specific AEs of interest, as well as for all AEs, across treatment groups after blinded adjudication. Of the LD-MTX participants, 2,080 (87.0 percent) had an AE of interest compared with 1,951 (81.5 percent) in the placebo group (hazard ratio [HR], 1.17, 95 percent confidence interval [CI], 1.10–1.25).

LD-MTX was associated with increased risks of gastrointestinal (HR, 1.91, 95 percent CI, 1.75–2.10), pulmonary (HR, 1.52, 95 percent CI, 1.16–1.98), infectious (HR, 1.15, 95 percent CI, 1.01–1.30) and haematologic AEs (HR, 1.15, 95 percent CI, 1.07–1.23) compared with placebo. The two treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs, except for an increased risk for skin cancer (HR, 2.05, 95 percent CI, 1.28–3.28).

Of note, renal AEs decreased in those who received LD-MTX (HR, 0.85, 95 percent CI, 0.78–0.93).

The study was limited by the fact that the trial was carried out on patients without rheumatic disease who tolerated LD-MTX during an active run-in period, according to the investigators.

“LD-MTX is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis,” they noted.