What’s already known about this topic?
• Low-dose methotrexate (MTX) is used to treat several autoimmune and immune-mediated inflammatory diseases, including psoriasis, psoriasis arthritis and rheumatoid arthritis.
• Use of MTX has previously been linked to an increased risk of skin cancer. Since MTX is an important and frequently used drug worldwide, such an association would have important implications for healthcare.
What does this study add?
• In this Danish investigation, use of a cumulative MTX dose ≥ 2.5 g was associated with an increased risk of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and cutaneous malignant melanoma (CMM) compared with no use of MTX. The association was consistent in several sensitivity analyses.
• For BCC and cSCC, a dose-response association was observed. However, the association with CMM and cSCC was not apparent when restricting the study population to patients with psoriasis which may indicate that surveillance bias influenced our results.
Plain language summary
Does methotrexate increase the risk of skin cancer?
MTX is an old immunosuppressive drug, that is often considered the first-line systemic treatment for several autoimmune and immune-mediated inflammatory diseases, including psoriasis, psoriasis arthritis and rheumatoid arthritis. In a large-scale randomised trial of whether MTX reduces the risk for cardiovascular disease, users of MTX were found more likely to develop skin cancer [1, 2, 3].
In this Danish study, we used several nationwide registers to investigate if patients using MTX had an increased risk of the three most common skin cancers: BCC, cSCC and CMM. Overall, 131,447 patients with BCC, 18,661 patients with cSCC, and 26,068 patients with CMM were identified. We compared their previous use of MTX with that of randomly selected individuals from the general population who had the same age and sex but no skin cancer diagnosis. People who had used a total of 2.5 g MTX or more had an increased risk of BCC, cSCC and CMM compared with people with no use. The risk of BCC and cSCC increased with increasing total doses of MTX (a so-called dose-response pattern). However, the link between skin cancer and use of MTX was not consistent when restricting the study population to patients with psoriasis.
In summary, we demonstrated an association between use of MTX and increased risk of skin cancer. However, the increase in risk was limited, and further studies are needed to clarify the association further.
 Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019;380:752–62.
 Solomon DH, Glynn RJ, Karlson EW, Lu F, Corrigan C, Colls J, et al. Adverse effects of low-dose methotrexate: a randomized trial. Ann Intern Med. 2020;172:369–80.
 Vanni KMM, Berliner N, Paynter NP, Glynn RJ, MacFadyen J, Colls J, et al. Adverse effects of low-dose methotrexate in a randomized double-blind placebo-controlled trial: adjudicated hematologic and skin cancer outcomes in the cardiovascular inflammation reduction trial. ACR Open Rheumatol. 2020;2:697–704.
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