Exposure to low-dose methotrexate is associated with an increased risk of melanoma, although the absolute increase in risk is small, according to a meta-analysis published in JAMA Dermatology.

To assess the risk of melanoma associated with methotrexate, researchers evaluated data from 17 studies — 8 randomized controlled trials, 5 cohort studies, and 4 case-control studies. 

The analysis encompassed 889,799 patients who were receiving methotrexate as treatment for rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory bowel disease, or unknown indications. 

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A total of 17,513 patients developed melanoma. Exposure to low-dose methotrexate was associated with a 15% increase in the risk of melanoma (relative risk [RR], 1.15; 95% CI, 1.08-1.22), when compared with no methotrexate exposure. 

The association was similar when the analysis included only the 10 studies that had at least 2 years of follow-up (RR, 1.14; 95% CI, 1.04-1.25). However, the risk became more modest after a sensitivity analysis (RR, 1.11; 95% CI, 1.00-1.24). 

Based on the estimated 15% increased risk of melanoma, the researchers calculated the number needed to harm (NNH). The NNH was 196,078 globally, 18,630 for Australia, and 41,425 for North America. This translated to an absolute risk increase of 0.0005% globally, 0.005% in Australia, and 0.002% in North America.

“In this systematic review and meta-analysis, results show an association of methotrexate with a higher risk of incident malignant melanoma,” the researchers wrote. “Methotrexate may contribute to melanoma development via its immunosuppressive effects and photosensitizing properties.”

Disclosures: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Yan MK, Wang C, Wolfe R, Mar VJ, Wluka AE. Association between low-dose methotrexate exposure and melanoma. A systematic review and meta-analysis. JAMA Dermatol. Published online August 31, 2022. doi:10.1001/jamadermatol.2022.3337