‘Negligible’ melanoma risk observed in patients treated with methotrexate

Findings from a comprehensive systematic review and meta-analysis showed a “negligible” risk for melanoma among individuals treated with methotrexate.

Mabel K. Yan, MBBS, of the Victorian Melanoma Service at The Alfred Hospital, Anita E. Wluka, MBBS, PhD, of the School of Public Health and Preventive Medicine at Monash University, and colleagues noted that findings from previous studies have demonstrated a possible association between methotrexate and melanoma.

“Because previous studies have suggested an association, patients ask about this risk,” Yan told Healio. “Melanoma awareness is perhaps higher in Australia than elsewhere, as melanoma is relatively more common here.”

Wluka added that despite the increased incidence of melanoma in the country, previous research has not shown the benefit of population-based screening.

“However, certain subgroups of the population may be at increased risk,” Wluka told Healio. “Thus, Dr. Yan's PhD aimed to explore strategies to improve accurate risk stratification. Quantifying the risk associated with methotrexate may target preventive strategies appropriately.”

The researchers reviewed Embase, Cochrane and ClinicalTrials.gov databases from inception through May 12, 2022, for case-control studies, cohort studies or randomized, controlled trials investigating associations between methotrexate exposure and melanoma risk.

Results were calculated in terms of odds ratios, hazard ratios or risk ratios of melanoma risk in patients who had been exposed to methotrexate compared with those who had not.

Initially, 17 studies were included. There were eight randomized, controlled trials, five cohort studies and four case-control studies. The final analysis included data for 16,642 melanoma cases from 12 studies.

In these studies, methotrexate was used to treat rheumatoid arthritis, psoriasis, psoriatic arthritis and inflammatory bowel disease. The indication was unknown in five of the data sets.

Results showed a pooled relative risk for melanoma in the methotrexate-exposed group compared with non-exposure (pooled RR = 1.15; 95% CI, 1.08-1.22). However, in a sensitivity analysis excluding the largest study, this association failed to persist (pooled RR = 1.11; 95% CI, 1-1.24).

“We were surprised by the low absolute risk of melanoma associated with methotrexate,” Wluka said. “However, we did not have full information regarding the duration of therapy and other factors that may increase the risk.”

Similar findings were reported in subgroup analyses looking at either an immunomodulator alone or with methotrexate.

The researchers added that the number needed to harm for melanoma incidence rates was 18,630 in Australia and 41,425 in North America.

“While this study showed an increase in risk of melanoma, this was similar to the lifetime cancer risk associated with an X-ray of the hip in a young adult,” Yan said. “Thus, the risk of melanoma related to methotrexate could be considered negligible.”