Adverse Effects of Low‐Dose Methotrexate in a Randomized Double‐Blind Placebo‐Controlled Trial: Adjudicated Hematologic and Skin Cancer Outcomes in the Cardiovascular Inflammation Reduction Trial

OBJECTIVE: Low‐dose methotrexate (LD‐MTX), a cornerstone in the treatment of rheumatoid arthritis, is associated with a moderately increased risk of anemia, leukopenia, and skin cancers, but the risks of myelosuppression and malignancy during LD‐MTX use remain incompletely described. We examined the risks of cytopenias and skin cancers among patients taking LD‐MTX versus placebo in a large randomized controlled trial (RCT). METHODS: We prespecified secondary analyses of a double‐blind, placebo‐controlled RCT that included adults with known cardiovascular disease and diabetes or metabolic syndrome in the United States and Canada. Subjects were randomly allocated to LD‐MTX (20 mg/week maximum) or placebo. All subjects received folic acid (1 mg daily for 6days/week). We assessed the frequency of blindly adjudicated hematologic and malignant adverse events (AEs). RESULTS: A total of 2391 subjects were randomized to LD‐MTX (mean dosage 14.9 mg/week), and 2395 were randomized to placebo. During follow‐up, in the LD‐MTX arm, simultaneous two‐line cytopenias (n = 92 [3.9%]) or pancytopenia (n = 13 [0.54%]) were infrequent. Pancytopenia developed as soon as 4 months and as late as 3.5 years after beginning LD‐MTX, though the latter subject had been recently diagnosed with multiple myeloma. Overall skin cancer risk was increased in users of LD‐MTX compared with users of placebo, which driven largely by a statistically significant increased risk of squamous cell skin cancer (hazard ratio [HR] 3.31; 95% confidence interval [CI] 1.63‐6.71). Melanoma was increased in LD‐MTX, but this was not statistically significant (HR 2.33; 95% CI 0.60‐9.01). CONCLUSIONS: Among subjects using LD‐MTX, simultaneous two‐line cytopenias and pancytopenia were uncommon. We found more cases of skin cancer, particularly squamous cell carcinomas, in the LD‐MTX arm than the placebo arm.