Association Between Low-Dose Methotrexate Exposure and Melanoma

Importance Methotrexate is widely used for the treatment of inflammatory disorders, including rheumatoid arthritis. Studies suggest that methotrexate may be associated with an increased risk of melanoma. Objective To determine whether methotrexate exposure is associated with an increased risk of cutaneous melanoma. Data Sources MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from inception to May 12, 2022, for eligible studies. Study Selection Case-control studies, cohort studies, or randomized clinical trials (RCTs) were included if they examined the odds or risk of cutaneous melanoma in individuals exposed to low-dose methotrexate in comparison with individuals unexposed. No language limitations were applied. Data Extraction and Synthesis Two independent reviewers extracted data on study characteristics and outcome data. The Meta-analysis of Observational Studies in Epidemiology guidelines were followed. To assess study quality, the Cochrane risk of bias tool was used for RCTs, and the Joanna Briggs Institute Checklist was used for cohort and case-control studies. Odds ratio from case-control studies and relative risk or hazard ratio from cohort studies or RCTs were pooled, and a random-effects model meta-analysis was conducted. Main Outcomes and Measures Prespecified outcome was the odds ratio, hazard ratio, or risk ratio of cutaneous melanoma comparing low-dose methotrexate exposure with nonexposure. Results Seventeen studies (8 RCTs, 5 cohort studies, 4 case-control studies) were eligible for inclusion, and of these, 12 studies with 16 642 cases of melanoma were pooled in the primary analysis. Indications for methotrexate included rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel disease and were unknown in 5 studies. Compared with unexposed individuals, study participants with methotrexate exposure had a small increased risk of melanoma (pooled relative risk, 1.15; 95% CI, 1.08-1.22), but this did not persist in a sensitivity analysis excluding the largest study (pooled relative risk, 1.11; 95% CI, 1.00-1.24). Subgroup analyses according to comparator group (comparing methotrexate exposure with either immunomodulator alone vs immunomodulator and methotrexate) or the indication for methotrexate being rheumatoid arthritis provided similar risk estimates. Using geographical population melanoma incidence rates, a number needed to harm of 18 630 was calculated in Australia, and 41 425 in North America. Conclusions and Relevance In this systematic review and meta-analysis, low-dose methotrexate exposure was associated with an increased melanoma risk, but the absolute risk increase could be considered negligible.