{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T03:08:34Z","timestamp":1791947314650,"version":"4.3.4"},"reference-count":44,"publisher":"American Medical Association (AMA)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Dermatol"],"published-print":{"date-parts":[[2022,10,1]]},"abstract":"Importance<\/jats:title>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.<\/jats:p><\/jats:sec>Objective<\/jats:title>To determine whether methotrexate exposure is associated with an increased risk of cutaneous melanoma.<\/jats:p><\/jats:sec>Data Sources<\/jats:title>MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from inception to May 12, 2022, for eligible studies.<\/jats:p><\/jats:sec>Study Selection<\/jats:title>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.<\/jats:p><\/jats:sec>Data Extraction and Synthesis<\/jats:title>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.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>Prespecified outcome was the odds ratio, hazard ratio, or risk ratio of cutaneous melanoma comparing low-dose methotrexate exposure with nonexposure.<\/jats:p><\/jats:sec>Results<\/jats:title>Seventeen studies (8 RCTs, 5 cohort studies, 4 case-control studies) were eligible for inclusion, and of these, 12 studies with 16\u202f642 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\u202f630 was calculated in Australia, and 41\u202f425 in North America.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>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.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamadermatol.2022.3337","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T15:33:46Z","timestamp":1661960026000},"page":"1157","source":"Crossref","is-referenced-by-count":31,"title":["Association Between Low-Dose Methotrexate Exposure and Melanoma"],"prefix":"10.1001","volume":"158","author":[{"given":"Mabel K.","family":"Yan","sequence":"first","affiliation":[{"name":"Victorian Melanoma Service, The Alfred Hospital, Melbourne, Victoria, Australia"},{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlie","family":"Wang","sequence":"additional","affiliation":[{"name":"Victorian Melanoma Service, The Alfred Hospital, Melbourne, Victoria, Australia"},{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory","family":"Wolfe","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria J.","family":"Mar","sequence":"additional","affiliation":[{"name":"Victorian Melanoma Service, The Alfred Hospital, Melbourne, Victoria, Australia"},{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita E.","family":"Wluka","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"4","key":"doi220043r1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.4708","article-title":"Estimated projection of US cancer incidence and death to 2040.","volume":"4","author":"Rahib","year":"2021","journal-title":"JAMA Netw Open"},{"issue":"3","key":"doi220043r2","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.v71.3","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"issue":"6","key":"doi220043r5","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1007\/s40258-017-0341-y","article-title":"Estimated healthcare costs of melanoma in Australia over 3 years post-diagnosis.","volume":"15","author":"Elliott","year":"2017","journal-title":"Appl Health Econ Health Policy"},{"issue":"6","key":"doi220043r6","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1136\/annrheumdis-2019-216655","article-title":"EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update.","volume":"79","author":"Smolen","year":"2020","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"doi220043r7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/ajd.2012.53.issue-1","article-title":"The use of methotrexate in dermatology: a review.","volume":"53","author":"Shen","year":"2012","journal-title":"Australas J Dermatol"},{"issue":"3","key":"doi220043r8","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/s41584-020-0373-9","article-title":"Methotrexate and its mechanisms of action in inflammatory arthritis.","volume":"16","author":"Cronstein","year":"2020","journal-title":"Nat Rev Rheumatol"},{"issue":"2","key":"doi220043r9","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1001\/jamadermatol.2015.3029","article-title":"Risk of nonmelanoma skin cancer associated with the use of immunosuppressant and biologic agents in patients with a history of autoimmune disease and nonmelanoma skin cancer.","volume":"152","author":"Scott","year":"2016","journal-title":"JAMA Dermatol"},{"issue":"6","key":"doi220043r10","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1002\/(ISSN)1529-0131","article-title":"Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate.","volume":"59","author":"Buchbinder","year":"2008","journal-title":"Arthritis Rheum"},{"issue":"12","key":"doi220043r11","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1002\/acr2.v2.12","article-title":"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.","volume":"2","author":"Vanni","year":"2020","journal-title":"ACR Open Rheumatol"},{"issue":"6","key":"doi220043r12","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1111\/bjd.15170","article-title":"Methotrexate treatment and risk for cutaneous malignant melanoma: a retrospective comparative registry-based cohort study.","volume":"176","author":"Polesie","year":"2017","journal-title":"Br J Dermatol"},{"key":"doi220043r13","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.2147\/CLEP.S269446","article-title":"Use of immunomodulating drugs and risk of cutaneous melanoma: a nationwide nested case-control study.","volume":"12","author":"Berge","year":"2020","journal-title":"Clin Epidemiol"},{"issue":"15","key":"doi220043r14","doi-asserted-by":"publisher","first-page":"2008","DOI":"10.1001\/jama.283.15.2008","article-title":"Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.","volume":"283","author":"Stroup","year":"2000","journal-title":"JAMA"},{"key":"doi220043r15","doi-asserted-by":"publisher","first-page":"b2535","DOI":"10.1136\/bmj.b2535","article-title":"Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.","volume":"339","author":"Moher","year":"2009","journal-title":"BMJ"},{"issue":"I4898","key":"doi220043r16","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials.","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"doi220043r18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/oxfordjournals.epirev.a036298","article-title":"Quantitative methods in the review of epidemiologic literature.","volume":"9","author":"Greenland","year":"1987","journal-title":"Epidemiol Rev"},{"issue":"7414","key":"doi220043r19","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses.","volume":"327","author":"Higgins","year":"2003","journal-title":"BMJ"},{"issue":"1","key":"doi220043r21","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1002\/(ISSN)1529-0131","article-title":"The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.","volume":"54","author":"Breedveld","year":"2006","journal-title":"Arthritis Rheum"},{"issue":"3","key":"doi220043r22","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1002\/art.39953","article-title":"Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment.","volume":"69","author":"Fleischmann","year":"2017","journal-title":"Arthritis Rheumatol"},{"issue":"3","key":"doi220043r23","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1002\/art.39450","article-title":"Long-term outcomes among participants in the WEGENT trial of remission-maintenance therapy for granulomatosis with polyangiitis (Wegener\u2019s) or microscopic polyangiitis.","volume":"68","author":"Pu\u00e9chal","year":"2016","journal-title":"Arthritis Rheumatol"},{"issue":"6","key":"doi220043r24","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1136\/annrheumdis-2020-219213","article-title":"Filgotinib in combination with methotrexate or as monotherapy versus methotrexate monotherapy in patients with active rheumatoid arthritis and limited or no prior exposure to methotrexate: the phase 3, randomised controlled FINCH 3 trial.","volume":"80","author":"Westhovens","year":"2021","journal-title":"Ann Rheum Dis"},{"issue":"7","key":"doi220043r25","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1002\/art.2019.71.issue-7","article-title":"Etanercept and methotrexate as monotherapy or in combination for psoriatic arthritis: primary results from a randomized, controlled phase III trial.","volume":"71","author":"Mease","year":"2019","journal-title":"Arthritis Rheumatol"},{"issue":"10","key":"doi220043r26","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1002\/art.v72.10","article-title":"Efficacy and safety of upadacitinib monotherapy in methotrexate-naive patients with moderately-to-severely active rheumatoid arthritis (SELECT-EARLY): a multicenter, multi-country, randomized, double-blind, active comparator-controlled trial.","volume":"72","author":"van Vollenhoven","year":"2020","journal-title":"Arthritis Rheumatol"},{"issue":"9410","key":"doi220043r27","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/S0140-6736(04)15640-7","article-title":"Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial.","volume":"363","author":"Klareskog","year":"2004","journal-title":"Lancet"},{"issue":"7","key":"doi220043r28","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1038\/ajg.2017.96","article-title":"Extracolonic cancer in inflammatory bowel disease: data from the GETECCU Eneida Registry.","volume":"112","author":"Chaparro","year":"2017","journal-title":"Am J Gastroenterol"},{"issue":"4","key":"doi220043r29","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1093\/rheumatology\/key352","article-title":"Abatacept initiation in rheumatoid arthritis and the risk of cancer: a population-based comparative cohort study.","volume":"58","author":"Montastruc","year":"2019","journal-title":"Rheumatology (Oxford)"},{"issue":"1","key":"doi220043r30","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.jaad.2017.02.032","article-title":"Methotrexate treatment in patients with a history of cutaneous melanoma and the risk of a consecutive primary melanoma: a national retrospective registry-based cohort study.","volume":"77","author":"Polesie","year":"2017","journal-title":"J Am Acad Dermatol"},{"issue":"1","key":"doi220043r31","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1111\/ajd.v63.1","article-title":"Effect of methotrexate on melanoma risk in older adults: secondary analysis of a randomised controlled trial.","volume":"63","author":"Yan","year":"2022","journal-title":"Australas J Dermatol"},{"issue":"4","key":"doi220043r32","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1111\/bjd.v183.4","article-title":"Methotrexate treatment for patients with psoriasis and risk of cutaneous melanoma: a nested case-control study.","volume":"183","author":"Polesie","year":"2020","journal-title":"Br J Dermatol"},{"issue":"3","key":"doi220043r33","doi-asserted-by":"publisher","first-page":"131","DOI":"10.5414\/CP203604","article-title":"Association between malignancy and methotrexate and biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.","volume":"58","author":"Inose","year":"2020","journal-title":"Int J Clin Pharmacol Ther"},{"issue":"11","key":"doi220043r34","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1097\/MIB.0000000000001191","article-title":"Risk factors and clinical outcomes in patients with IBD with melanoma.","volume":"23","author":"Nissen","year":"2017","journal-title":"Inflamm Bowel Dis"},{"issue":"1","key":"doi220043r35","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.jaad.2021.01.084","article-title":"Psoriasis and risk of cutaneous melanoma: a retrospective, comparative, registry-based cohort study.","volume":"86","author":"Polesie","year":"2022","journal-title":"J Am Acad Dermatol"},{"issue":"2","key":"doi220043r36","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.cgh.2013.03.034","article-title":"Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation.","volume":"12","author":"Kappelman","year":"2014","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"3","key":"doi220043r37","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1111\/php.1983.38.issue-3","article-title":"Photosensitization by methotrexate photoproducts.","volume":"38","author":"Chahidi","year":"1983","journal-title":"Photochem Photobiol"},{"issue":"62","key":"doi220043r38","doi-asserted-by":"publisher","first-page":"106132","DOI":"10.18632\/oncotarget.v8i62","article-title":"Immune system and melanoma biology: a balance between immunosurveillance and immune escape.","volume":"8","author":"Passarelli","year":"2017","journal-title":"Oncotarget"},{"issue":"7","key":"doi220043r39","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1111\/exd.2004.13.issue-7","article-title":"Methotrexate markedly reduces the expression of vascular E-selectin, cutaneous lymphocyte-associated antigen and the numbers of mononuclear leucocytes in psoriatic skin.","volume":"13","author":"Sigmundsdottir","year":"2004","journal-title":"Exp Dermatol"},{"issue":"2","key":"doi220043r40","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1111\/phpp.1995.11.issue-2","article-title":"Recurrent recall of sunburn by methotrexate.","volume":"11","author":"Guzzo","year":"1995","journal-title":"Photodermatol Photoimmunol Photomed"},{"issue":"5","key":"doi220043r43","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1111\/ijcp.12142","article-title":"When does a difference make a difference? interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed.","volume":"67","author":"Citrome","year":"2013","journal-title":"Int J Clin Pract"},{"issue":"1","key":"doi220043r44","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.arthro.2017.08.235","article-title":"Computed tomography scans in patients with young adult hip pain carry a lifetime risk of malignancy.","volume":"34","author":"Wylie","year":"2018","journal-title":"Arthroscopy"},{"key":"doi220043r3","volume-title":"Cutaneous Melanoma: Etiology and Therapy","author":"Matthews","year":"2017"},{"key":"doi220043r4","volume-title":"Skin Cancer in Australia","author":"Australian Institute of Health Welfare","year":"2016"},{"key":"doi220043r41","volume-title":"Risk Matters in Healthcare: Communicating, Explaining and Managing Risk","author":"Mohanna","year":"2001"},{"key":"doi220043r17","doi-asserted-by":"crossref","unstructured":"Moola? S, Munn? Z, Tufanaru? C, . Chapter 7: systematic reviews of etiology and risk. In: Aromataris E, Munn Z, eds. JBI Manual for Evidence Synthesis. JBI; 2020. Accessed March 24, 2022. https:\/\/jbi-global-wiki.refined.site\/space\/MANUAL\/4687372\/Chapter+7%3A+Systematic+reviews+of+etiology+and+risk","DOI":"10.46658\/JBIMES-20-08"},{"key":"doi220043r20","unstructured":"Globocan. Estimated number of new cases in 2020, worldwide, both sexes, all ages. International Agency for Research on Cancer. Published 2020 Accessed July 22, 2022. https:\/\/gco.iarc.fr\/"},{"key":"doi220043r42","unstructured":"Australian Institute of Health and Welfare. Cancer Data in Australia. Australian Institute of Health and Welfare; 2021. Accessed July 22, 2022. https:\/\/www.aihw.gov.au\/reports\/cancer\/cancer-data-in-australia\/contents\/summary"}],"container-title":["JAMA Dermatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamadermatology\/articlepdf\/2795482\/jamadermatology_yan_2022_oi_220043_1666117420.35364.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T15:09:18Z","timestamp":1666192158000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamadermatology\/fullarticle\/2795482"}},"subtitle":["A Systematic Review and Meta-analysis"],"short-title":[],"issued":{"date-parts":[[2022,10,1]]},"references-count":44,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2022,10,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamadermatol.2022.3337","relation":{},"ISSN":["2168-6068"],"issn-type":[{"value":"2168-6068","type":"print"}],"subject":[],"published":{"date-parts":[[2022,10,1]]}}}