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Low-Dose Methotrexate Exposure Minimally Increases Risk of Melanoma

"Comprehensively defining the risk of melanoma associated with low-dose methotrexate is important for clinicians across several medical disciplines."

A systematic review and meta-analysis indicated that low-dose methotrexate, a commonly used treatment for a variety of inflammatory disorders, exposure was associated with a small increased risk of developing melanoma. However, after sensitivity analysis, the absolute risk was considered negligible, according to a study published in JAMA Dermatology.1

“Globally, the incidence of melanoma is increasing, and it is projected to become the second most common cancer in the US by 2040,” investigators explained. “Despite decades of clinical use, some studies suggest that low-dose methotrexate may be associated with an increased risk of skin cancer.”

Case-control studies, cohort studies, and randomized clinical trials (RCTs) were included from MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov if they analyzed the odds or risk of cutaneous melanoma in individuals who were exposed to low-dose methotrexate and compared with individuals who were unexposed. Searches were performed from inception through May 2022. Two independent reviewers isolated data on study characteristics and outcome data, following the Meta-analysis of Observational Studies in Epidemiology guidelines. Study quality was determined using the Joanna Briggs Institute Checklist for cohort and case-control studies, while the Cochrane risk of bias tool was used for RCTs. A random-effects model meta-analysis was also conducted.

Of the 17 studies eligible for inclusion (8 RCTs, 5 cohort studies, and 4 case-control studies), 12 studies with 16,642 cases of melanoma were ultimately included in the primary analysis. Rheumatic diseases featured in the studies included rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (PsO), and inflammatory bowel disease.

Initially, patients with methotrexate exposure had a small increased risk of melanoma when compared with those who were unexposed (pooled relative risk, 1.15; 95% CI, 1.08-1.22). However, this increased risk was not significant in a sensitivity analysis that excluded the largest study, which included the general population as a comparison group (pooled relative risk, 1.11; 95% CI, 1.00-1.24).

While methotrexate was associated with a 15% increased risk of melanoma, the absolute risk increase was low to minimal. The subgroup analyses comparing methotrexate exposure with either an immunomodulator alone or immunomodulator and methotrexate combination therapy, as well as patients with rheumatoid arthritis receiving methotrexate, resulted in similar risk estimates. In terms of melanoma incidence rates, the number needed to harm was relatively high, with 18,630 in Australia (a region in which the estimated lifetime risk of melanoma is 1 in 15 people) and 41,425 in North America.

The studies did not adjust for melanoma risk factors, such as family history, history of sunburn, total nevus count, and cumulative UV radiation exposure. Further, investigators were only able to evaluate confounding by indication in the few studies that included only patients with RA or PsO, with reduced power. Patients receiving methotrexate treatment may be more likely to be diagnosed with melanoma as they are more engaged with the healthcare system, thus creating the possibility of detection bias in the observational studies. However, the study utilized a comprehensive search strategy including multiple databases and applied strict eligibility criteria during the identification process.

“The absolute increase in risk is small, even in populations at relatively high risk of melanoma,” investigators concluded. “This finding provides information to better inform patients when initiating methotrexate therapy. To distinguish the degree of risk associated with methotrexate in populations with inflammatory disease, large prospective studies with longer follow-up are required. Future studies examining the effect of methotrexate continuation after the diagnosis of melanoma are required to inform practice.”


Mabel K. Yan, Charlie Wang, Rory Wolfe, Victoria J. Mar, Anita E. Wluka. Association Between Low-Dose Methotrexate Exposure and Melanoma A Systematic Review and Meta-analysis. Jama. Published online August 31, 2022.