Low-dose methotrexate-related melanoma risk considered negligible

Individuals exposed to low-dose methotrexate risk developing melanoma, although the absolute risk increase remains very low, as shown in a recent meta-analysis.

Pooled data from 12 studies with 16,642 cases of melanoma showed that compared with nonexposure, exposure to methotrexate at 5–30 mg weekly doses conferred a small increase in the risk of melanoma (relative risk [RR], 1.15, 95 percent confidence interval [CI], 1.08–1.22) with minimal heterogeneity (I²=0%), but this association disappeared in a sensitivity analysis excluding the largest study (RR, 1.11, 95 percent CI, 1.00–1.24). [JAMA Dermatol 2022;doi:10.1001/jamadermatol.2022.3337]

Similar results were obtained in subgroups defined by comparator group (methotrexate vs either immunomodulator alone or immunomodulator plus methotrexate) and the indication for methotrexate.

Based on an estimated 15-percent increased melanoma risk and using geographical population melanoma incidence rates, a number needed to harm of 196,078 was calculated globally, 41,425 in North America, and 18,630 in Australia. [https://gco.iarc.fr/]

“This study provides valuable, and we believe reassuring, information to clinicians to guide prescribing and surveillance practices… We have found that although methotrexate was associated with a statistically significant 15-percent increased melanoma risk, the absolute risk increase, which takes into account population melanoma incidence rates, was very low to minimal,” according to the investigators.

“[I]n a country such as Australia, which has one of the world’s highest melanoma incidence rates, 18,000 individuals would need to be treated with methotrexate for one additional melanoma to occur. In North America, where the incidence of melanoma is relatively lower, 41,425 individuals would need to be treated for one additional melanoma to occur,” they explained.

Therefore, even though the melanoma risk estimate associated with low-dose methotrexate exposure is statistically significant, the present data must still be viewed with caution, they said.

How methotrexate contributes to melanoma development may have to do with its immunosuppressive effects and photosensitizing properties. The drug has been shown to exert additional immunosuppressive effects, such as the inhibition of tissue-specific lymphocytes. It has also been associated with photosensitivity reactions, such as the well-described photo recall of a recent sunburn in case series. [Photochem Photobiol 1983;38:317-322; Exp Dermatol 2004;13:426-434; Photodermatol Photoimmunol Photomed 1995;11:55-56]

“Defining the carcinogenic potential of low-dose methotrexate is crucial in the long-term care of patients with immune-mediated disease,” according to the investigators, who pointed to a need for large, prospective studies in disease populations with longer periods of follow-up.

“Studies assessing the effect of low-dose methotrexate therapy following a melanoma diagnosis, examining the risk of disease recurrence or subsequent primary melanoma, would also be prudent. The decision to continue or cease methotrexate therapy after a melanoma diagnosis is a common clinical question that has not been adequately addressed in the literature,” they added.