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More Study Needed on Melanoma Risk From Methotrexate


Quantifying the risk of malignant melanoma from methotrexate use proved difficult in this new study, with the authors calling for larger studies with longer follow-up to guide future practice in the space.

Although investigators found a higher risk of incident cutaneous malignant melanoma among patients who took low-dose methotrexate compared with those who did not, they said this absolute risk is too small to draw definitive conclusions on a potential link and further study is need to distinguish the true degree of risk.

These results published recently in JAMA Dermatology, and they followed searches of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to May 12, 2022, for case-control studies (n = 2), nested case-control studies (n = 2), cohort studies (n = 5), and randomized clinical trials (RCTs; n = 8) that compared patient outcomes from patients who were and were not exposed to methotrexate. Twelve studies were included in the primary analysis of 16,642 melanoma cases, with methotrexate indications for rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel disease; of the original 17, “2 studies were excluded due to high risk of bias and 3 because the exposed arm included exposure to another immunomodulator,” the authors wrote.

For this study, low-dose methotrexate was defined as a dosage of 5 to 30 mg weekly.

“Methotrexate is widely used for the treatment of inflammatory disorders, including rheumatoid arthritis,” the study authors wrote. “Studies suggest that methotrexate may be associated with an increased risk of melanoma.”

Risk associated with melanoma use was 15% among exposed vs unexposed patients (pooled relative risk [RR], 1.15; 95% CI, 1.08-1.22). However, this dropped to 11% in a sensitivity analysis in which the largest study was excluded (pooled RR, 1.11; 95% CI, 1.00-1.24). For all studies included, the highest risk was 220%, while 3 showed reduced risks of 67% (n = 2) and 33% (n = 1).

The investigators highlighted that this small risk likely can’t be extrapolated to a larger patient group, particularly at the population level, because the number needed to harm (NNH) was so high. In North America, the NNH was 41,425; in Australia, 18,630; and globally, 196,078, when considering geographical population melanoma incidence rates. The corresponding absolute risk increases were 0.0005%, 0.002%, and 0.005%.

All patients included in the RCTs had active immune-mediated inflammatory disease and their outcomes were investigated in intervention arms that included methotrexate vs other immunomodulator (6 studies), methotrexate vs unspecified immunomodulator (thiopurine, JAK inhibitor, tumor necrosis factor-α inhibitors; 6 studies), and methotrexate plus immunomodulator (etanercept, abatacept, baricitinib) vs other immunomodulator (3 studies). However, most follow-ups were 1 to 2 years, which the present study authors classified as “relatively short,” and few melanoma adverse events occurred.

Among the studies with at least 10 years of follow-up, there was a 14% greater risk seen (RR, 1.14; 95% CI, 1.04-1.25), but the authors determined that 2 of these studies had a high risk of bias and moderate heterogeneity (RR, 1.24; 95% CI, 1.03-1.49; I2 = 48.4%). Minimal heterogeneity was defined as I2 of 0%.

Additional subgroup analyses produced the following:

  • Studies comparing methotrexate plus immunomodulator vs other immunomodulator: 23% greater melanoma risk (RR, 1.23; 95% CI, 0.56-2.68) but with a low degree of precision
  • Studies comparing methotrexate vs unspecified immunomodulator: 38% greater melanoma risk (RR, 1.38; 95% CI, 0.48-3.97) but with a low degree of precision
  • Studies only of participants with rheumatoid arthritis: 13% greater melanoma risk (RR, 1.13; 95% CI, 0.55-2.33) but with a wide CI
  • Studies of participants psoriasis or psoriatic arthritis: 1% greater melanoma risk (RR, 1.01; 95% CI, 0.79-1.28), or no association between melanoma risk and methotrexate exposure

“This systematic review and meta-analysis is, to our knowledge, the first to specifically examine the association between methotrexate and melanoma risk,” the authors determined, adding that their findings need to be interpreted with caution because the NNH was so high in the 3 regions evaluated and their sensitivity analysis classified the melanoma risk as not statistically significant.

However, they did note that potential reasons for the higher risk seen with methotrexate use include its immunosuppressive effects and photosensitizing properties.

“Defining the carcinogenic potential of low-dose methotrexate is crucial in the long-term care of patients with immune-mediated disease,” the investigators concluded. “There remains a need for large, prospective studies in disease populations with longer periods of follow-up.”


Yan MK, Wang C, Wolfe R, Mar VJ, Wluka AE. Association between low-dose methotrexate exposure and melanoma: a systematic review and meta-analysis. JAMA Dermatol. Published online August 31, 2022. doi:10.1001/jamadermatol.2022.3337

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