Victorian Melanoma Service, The Alfred Hospital, Melbourne, Victoria, Australia.
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
JAMA Dermatol. 2022 Oct 1;158(10):1157-1166. doi: 10.1001/jamadermatol.2022.3337.
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.
To determine whether methotrexate exposure is associated with an increased risk of cutaneous melanoma.
MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from inception to May 12, 2022, for eligible studies.
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.
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.
Prespecified outcome was the odds ratio, hazard ratio, or risk ratio of cutaneous melanoma comparing low-dose methotrexate exposure with nonexposure.
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.
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.
甲氨蝶呤被广泛用于治疗炎症性疾病，包括类风湿关节炎。研究表明，甲氨蝶呤可能与黑色素瘤风险增加有关。
确定甲氨蝶呤暴露是否与皮肤黑色素瘤风险增加相关。
从建库至 2022 年 5 月 12 日，在 MEDLINE、Embase、Cochrane 对照试验中心注册库和 ClinicalTrials.gov 上检索了合格的研究。
如果研究比较了低剂量甲氨蝶呤暴露个体与未暴露个体的皮肤黑色素瘤发病几率或风险，纳入病例对照研究、队列研究或随机临床试验（RCT）。未应用语言限制。
两名独立审查员提取了研究特征和结局数据。遵循观察性研究的荟萃分析中的偏倚风险评估工具。对于 RCT，使用 Cochrane 偏倚风险工具评估研究质量，对于队列和病例对照研究，使用 Joanna Briggs 研究所清单。合并病例对照研究的比值比，以及队列研究或 RCT 的相对风险或风险比，并进行随机效应模型荟萃分析。
主要结局为比较低剂量甲氨蝶呤暴露与未暴露时皮肤黑色素瘤的比值比、风险比或风险比。
17 项研究（8 项 RCT、5 项队列研究、4 项病例对照研究）符合纳入标准，其中 12 项研究（共纳入 16642 例黑色素瘤病例）纳入主要分析。甲氨蝶呤的适应证包括类风湿关节炎、银屑病、银屑病关节炎和炎症性肠病，5 项研究中适应证未知。与未暴露个体相比，有甲氨蝶呤暴露的研究参与者黑色素瘤风险略有增加（合并相对风险，1.15；95%CI，1.08-1.22），但在排除最大研究后敏感性分析中风险比无显著差异（合并相对风险，1.11；95%CI，1.00-1.24）。根据对照组（比较甲氨蝶呤暴露与单独免疫调节剂 vs 免疫调节剂和甲氨蝶呤）或甲氨蝶呤适应证（类风湿关节炎）进行亚组分析，提供了相似的风险估计。根据澳大利亚和北美的人群黑色素瘤发病率计算，使用甲氨蝶呤的危害比为 18630，在美国为 41425。
在这项系统评价和荟萃分析中，低剂量甲氨蝶呤暴露与黑色素瘤风险增加相关，但绝对风险增加可被认为是微不足道的。
