Methotrexate May Be Associated With an Increased Risk for Some Skin Cancers

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Methotrexate may be linked to an elevated risk of three types of skin cancer, according to a new study published by Polesie et al in the British Journal of Cancer. Additionally, among patients taking the drug to treat moderate to severe psoriasis, an increased risk was observed only for basal cell carcinoma.


Methotrexate—an immunosuppressive agent commonly prescribed to patients with rheumatoid arthritis and psoriasis—has been in use since the 1950s and still constitutes an important drug in the dermatology and rheumatology treatment armamentarium. Before prescribing methotrexate, physicians routinely test whether the patient has any underlying liver or kidney diseases and evaluate the patient’s medical condition and history. In the past few years, several epidemiology investigations have examined the association between methotrexate and an elevated risk of skin cancer, but research findings to date have been somewhat contradictory.

Study Methods and Results

In the new study, the researchers analyzed patient health records from the Nordic countries between 2004 and 2018, and identified 131,447 patients with basal cell carcinoma, 18,661 patients with squamous cell carcinoma, and 26,068 patients with cutaneous malignant melanoma. Each patient with skin cancer was compared with 10 control patients who were age- and sex-matched. 

The findings showed that at a group level, it was more common for patients who developed any of the three skin cancers to have been previously treated with methotrexate. Further, researchers discovered that the increased risk of developing any of the three skin cancers after taking methotrexate was 20% to 38% for basal cell carcinoma, 37% to 89% for squamous cell carcinoma, and 13% to 61% for melanoma—and that patients who had taken higher doses of methotrexate were at higher risk for squamous cell carcinoma and basal cell carcinoma, but not for melanoma. 

“[Methotrexate] is an effective and important medicine that helps lots of patients. The absolute risk for an individual patient of developing any of these skin cancer types remains small even if they use the drug. However, since [methotrexate] is a … frequently used drug, our results may imply a rise in the number of skin cancer cases at the population level,” explained first study author Sam Polesie, PhD, Associate Professor of Dermatology and Venereology at Sahlgrenska University Hospital at the University of Gothenburg

Psoriasis Subgroup Analysis

When the researchers confined the study to patients with psoriasis, they found no statistical correlation linking methotrexate to an increased risk of squamous cell carcinoma or melanoma, but they did identify an increase in the risk of developing basal cell carcinoma. 

“You could interpret this as a weakness in the study. It’s possible that the statistical analyses conceal some type of bias that was evident among patients with psoriasis, but we can only speculate about that. These results might also be interpreted as reassuring to dermatologists who mainly use [methotrexate] as the first line therapy of systemic drugs to treat patients with moderate to severe psoriasis,” Dr. Polesie highlighted. “Patients with psoriasis probably have divergent sun exposure habits. Moreover, historically, light therapy used to be a common treatment [for] psoriasis. Sun exposure habits and [the] use of light therapies were examples of important factors we weren’t able to include in the study,” he added. 


“[Our] study is another contribution to the ongoing discussion about [methotrexate] 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,” Dr. Polesie stressed. 

The researchers concluded that the use of methotrexate in patients with inflammatory and autoimmune diseases may be associated with an increased risk of developing basal cell carcinoma and squamous cell carcinoma with evidence of a dose-response pattern—though when restricting the study population to those with psoriasis, the association was not consistent with the previous results and demonstrated a heightened risk for only basal cell carcinoma.

Editor's note: For readers of The ASCO Post, it should be noted that although this study refers to methotrexate in the treatment of psoriasis and rheumatoid arthritis, methotrexate—and particularly at high dosages—is an important chemotherapeutic agent also used in the treatment of many cancers, including cancers diagnosed in children such as acute lymphoblastic leukemia (ALL) and osteosarcoma. The study reported here does not address this patient population, however.

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