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Is low-dose methotrexate associated with a higher risk of melanoma development?

Kathryn Schwarzenberger, MD

Clinical Applications

Dr. Schwarzenberger is the physician editor of DermWorld. She interviews the author of a recent study each month. 

By Kathryn Schwarzenberger, MD, FAAD, February 1, 2023

In this month’s Clinical Applications column, Physician Editor Kathryn Schwarzenberger, MD, FAAD, talks with Anita Wluka, PhD, FRACP, MBBS, professor in the School of Public Health and Preventive Medicine at Monash University in Melbourne, Australia, about her — and her co-authors’ Mabel K. Yan, MBBS, Charlie Wang, MBBS, Rory Wolfe, PhD, and Victoria J. Mar, MBBS — JAMA Derm paper, ‘Association between low-dose methotrexate exposure and melanoma.’

DermWorld: For the readers who may have not yet read your interesting study, can you summarize your study and results for us?

Headshot for Dr. Wluka
Anita Wluka, PhD, FRACP, MBBS
Dr. Wluka: We performed a systematic review examining whether the use of methotrexate increased the incidence of melanoma. We included randomized controlled trials, cohort studies, and case control studies that reported the odds or risk of cutaneous melanoma in those exposed to low-dose methotrexate compared to those who were unexposed. We found 17 studies (eight randomized controlled trials, five cohort studies, and four case control studies) that examined this question. Twelve studies, including 16,642 cases of melanoma were pooled in the primary analysis. Indications for methotrexate included rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel disease and were unknown in five studies.

The study showed that compared to unexposed individuals, those exposed to low-dose methotrexate had a small increase in risk of melanoma (pooled relative risk, 1.15; 95% CI, 1.08-1.22), but this did not persist in a sensitivity analysis excluding the largest study (pooled relative risk, 1.11; 95% CI, 1.00-1.24). The results were similar in subgroup analyses. Using geographical population melanoma incidence rates, a number needed to harm of 18,630 was calculated in Australia, and 41,425 in North America.

Thus, although low-dose methotrexate exposure was associated with an increased melanoma risk, the absolute risk increase could be considered negligible.

DermWorld: What prompted this study? Why was this an issue of concern?

Dr. Wluka: Dr. Yan’s recently awarded PhD comprised a broad range of work that aimed to better describe optimal surveillance strategies for people at high risk of melanoma. Methotrexate is widely used by dermatologists, rheumatologists, and other internists to manage inflammatory disease, including inflammatory arthritis, where its use is the foundation of therapy. Despite decades of clinical use, whether methotrexate use increases the rate of melanoma has not been systematically examined, although previous studies have suggested this may be the case.

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DermWorld: Did you get the results you were expecting?

Dr. Wluka: While it was not surprising that low-dose methotrexate increased the risk of melanoma, I was pleasantly reassured that the magnitude of risk was so low, even in Australia where the incident risk of melanoma is relatively high.

DermWorld: Your study was designed as a systemic review and meta-analysis, and your article mentions some of the limitations of the study. Could you design a better way to look at this question?

Dr. Wluka: We designed this review and meta-analysis to take into account the indication for therapy, as the different autoimmune diseases may affect the risk of melanoma incidence. We were unable to incorporate the cumulative dose of methotrexate, the potential latency period from initial exposure to low-dose methotrexate and follow up for melanoma, or other specific risk factors for melanoma (e.g., sun exposure, personal and family history of melanoma, and skin phenotype). Ideally, these would be incorporated, and the study may require a larger number of participants than were examined, particularly regarding each indication. This was a large review, identifying studies including 889,799 participants with 17,513 cases of melanoma.

DermWorld: Will your findings change your care? Should dermatologists feel comfortable prescribing methotrexate at this point?

Dr. Wluka: Associate Professor Victoria Mar, a dermatologist, believes that these findings are reassuring to dermatologists and physicians prescribing methotrexate. This provides more robust data with which to inform patients of the risk of therapy. The calculated numbers needed to harm were relatively high. To obtain a new case of melanoma, 18,630 individuals in Australia would need to be exposed to low-dose methotrexate, where the risk of disease is high. The number needed to harm was even higher in North America, with 41,425 needed to be exposed to induce a new melanoma. These figures provide strong data to facilitate shared decision making with patients, and may be seen to be reassuring, as this increase in risk of incident melanoma may be considered negligible.

Anita Wluka, PhD, FRACP, MBBS, is a professor in the School of Public Health and Preventive Medicine at Monash University in Melbourne, Australia. Her co-authors include Mabel K. Yan, MBBS, Charlie Wang, MBBS, Rory Wolfe, PhD, and Victoria J. Mar, MBBS. Their paper appeared in JAMA Dermatology.

Drs. Yan and Wang are supported by Australian Government Research Training Program Scholarships. Dr. Mar is supported by a National Health and Medical Research Council Early Career Fellowship. The funding bodies gave no input in the study design or execution.

Disclaimer: The views and opinions expressed in this article do not necessarily reflect those of DermWorld.