Methotrexate use linked with increased risk of skin cancer

Sweden: The use of methotrexate (MTX), an immunosuppressive drug, is associated with an increased risk of cutaneous squamous cell carcinoma (cSCC), cutaneous malignant melanoma (CMM), and basal cell carcinoma (BCC); a recent study has found. 

Patients receiving the drug include those with moderate to severe psoriasis, but a risk increase was only observed for basal cell carcinoma in this particular patient group.

Based on Danish health care registers, the study resulted from a research collaboration with the University of Southern Denmark, Aarhus University and the University of Copenhagen. The scientists identified patients born in any of the Nordic countries who, between 2004 and 2018, were diagnosed with one of three types of skin cancer: basal cell carcinoma (BCC, 131,447 patients), squamous cell carcinoma (SCC, 18,661 patients), and cutaneous malignant melanoma (CMM, 26,068 patients). Every patient with skin cancer was compared with ten age and sex-matched controls.

Minor risk for individual

The results are published in the British Journal of Cancer, and the study shows that, at a group level, it was more common for patients who developed any of the three types of skin cancer to have been treated with MTX previously. This rise in risk is presented in the study as a range: 20–38% for BCC, 37–89% for SCC, and 13-61% for CMM. The researchers also demonstrated that patients with higher doses of MTX were at higher risk for SCC and BCC. In contrast, no distinct dose–response relationship was observed for CMM.

The study’s first author, Sam Polesie, is an associate professor (docent) of dermatology and venereology at Sahlgrenska Academy, University of Gothenburg, and a dermatologist at Sahlgrenska University Hospital. He points out that the study’s findings should not be used at an individual level.

”MTX is an effective and important medicine that helps lots of patients. The absolute risk for an individual patient developing any skin cancer type remains small even if they use the drug. However, since MTX is a quite frequently used drug, our results may imply a rise in the number of skin cancer cases at the population level,” Polesie says.

Psoriasis shows different picture

When the researchers confined the study to patients with psoriasis, they found no statistical correlation linking MTX to a raised SCC or CMM risk. However, a rise in BCC risk remained.

“You could interpret this as a weakness in the study. It’s possible that the statistical analyses conceal some type of bias evident among patients with psoriasis, but we can only speculate about that. These results might also be reassuring to dermatologists who mainly use MTX as the first line therapy of systemic drugs to treat patients with moderate to severe psoriasis,” Polesie says.

”Patients with psoriasis probably have divergent sun exposure habits. Moreover, historically, light therapy was a common treatment for psoriasis. Sun exposure habits and use of light therapies were examples of important factors we couldn’t include in the study.”

Individual background factors weighed in

MTX is an often used and valuable immunosuppressive drug to treat several inflammatory and autoimmune diseases. Used since the 1950s, MTX still constitutes an important drug, particularly in the dermatology and rheumatology treatment armamentarium, since it is mainly prescribed for patients with rheumatoid arthritis and psoriasis.

Before physicians prescribe MTX, routine tests are always obtained to verify that the patient has no underlying liver or kidney disease. Simultaneously, in assessing the benefit the medicine is expected to confer, the prescribing physician always weighs in the patient’s medical condition and history.

In the past few years, several epidemiology investigations have examined if MTX is associated with an elevated risk of skin cancer, but the research findings have been somewhat contradictory.

“So this study is another contribution to the ongoing discussion about MTX and its association with skin cancer. It’s important to remain vigilant and to keep studying the associations between well-established drugs, on the one hand, and their links with cancer on the other,” Polesie says.

Reference:

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