Study Finds Methotrexate Use May Increase the Risk of Skin Cancer

Methotrexate (MTX) may increase a person’s risk of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), or cutaneous malignant melanoma (CMM), according to a study published in the journal Nature. The current findings do not suggest that there is a dose-dependent increased risk of CMM with MTX. Conversely, when the cumulative dose increased, MTX appeared to worsen the risks of developing BCC and cSCC, according to the investigators.

“Use of a cumulative MTX dose ≥2.5 g was associated with an increased risk of BCC, cSCC and CMM compared with no use of MTX…The specific indications for MTX treatment warrants discussion as the indications themselves might be associated with increased skin cancer risk,” the study authors wrote.

MTX is an essential medicine, as determined by the World Health Organization (WHO). The immunosuppressive medication is used for dermatological and rheumatological conditions, but the treatment is associated with photosensitizing properties. Both its immunosuppression and photosensitization are associated with an increased risk of skin cancer.

The Cardiovascular Inflammation Reduction Trial (CIRT) reported that MTX doubled the risk of skin cancer compared to placebo, but the study had a short follow-up and no eligible clinical prescribing practices. The current study was conducted to determine the risk of developing BCC, cSCC, and CMM from MTX, evaluating nationwide health and demographics registries of patients from Denmark who developed any of the 3 cancers between 2004 and 2018.

The data showed that 233 (1.2%) patients with cSCC cases were exposed to MTX at a cumulative dose of 2.5 g or more—patients were numbered at 1214 (0.9%) for BCC, and 183 (.07%) for CMM. MTX is often used to treat patients with severe psoriasis, but the current study found no link between the risks of CMM and cSCC among patients with psoriasis, despite the results of previous studies.

One such study came out of Sweden, which showed that the ever-use of MTX was associated with cSCC in psoriasis patients. A different meta-analysis of 16,642 melanoma cases linked MTX to an overall small increased risk and the CIRT study observed that MTX had the highest hazard ratio (HR) for cSCC. Although multiple studies have evaluated MTX with skin cancer risk, there is not a unanimous conclusion, according to the authors of the current study.

The study was limited because no data were available on sun exposure, thus the authors cannot exclude UV exposure as a confounding variable. Additionally, the study was conducted on people born in Nordic countries, who are mainly limited to skin types 1 and 3. Further, people who use MTX are more likely to have a skin examination, which can lead to surveillance bias.

“Our findings…cannot support that skin cancer risk should be an important consideration when prescribing MTX,” the study authors wrote in the article. “However, our findings do deserve further attention for future investigations that would ideally include data on UV exposure.”

Reference

Polesie S, Gillstedt M, Schmidt S, Egeberg A, Pottegård A, Kristensen K. Use of methotrexate and risk of skin cancer: a nationwide case–control study. Br J Cancer (2023). doi.org/10.1038/s41416-023-02172-7