{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T08:52:47Z","timestamp":1777711967724,"version":"3.51.4"},"reference-count":17,"publisher":"The Journal of Rheumatology","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Rheumatol"],"accepted":{"date-parts":[[2012,11,6]]},"published-print":{"date-parts":[[2013,3]]},"abstract":"<jats:sec><jats:title>Objective.<\/jats:title><jats:p>To assess the safety of treating patients with rheumatoid arthritis with a combination of methotrexate (MTX) and leflunomide (LEF) in comparison to MTX monotherapy, in clinical practice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods.<\/jats:title><jats:p>The Safety of Methotrexate in Combination with Leflunomide in Rheumatoid Arthritis (SMILE) study was a multicenter, observational, cross-sectional, retrospective safety study. The study was conducted by the Optimising Patient Outcomes in Australian Rheumatology-Quality Use of Medicines Initiative (OPAL QUMI). Data were deidentified for patient, clinic, and clinician prior to collection from 13 participating rheumatology practices (25 rheumatologists). Comparative analysis of safety for the different treatments, primarily with regard to neutropenia and liver abnormalities, was performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results.<\/jats:title><jats:p>In total, 2975 patients were included in the study: 74% female, 26% male, mean age 62 years (SD 13.6). Distribution of therapy: MTX monotherapy 52.2%, LEF monotherapy 7.3%, MTX plus LEF 13.9%, and neither MTX nor LEF 26.6%. Comorbid liver disease was reported in 8.1% of patients. Liver function abnormalities were reported in 12% of the MTX monotherapy group, 16% of the LEF monotherapy group, 19% of the MTX-LEF combination group, and 14% of the group not taking either drug. Neutropenia was reported in 2.3% of the MTX monotherapy group, 5.5% of the LEF monotherapy group, 3.9% of the MTX-LEF combination group, and 4.2% of the group not taking either drug.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion.<\/jats:title><jats:p>The combination of MTX and LEF was well tolerated, with adverse events comparable to those of monotherapy and the other nonbiologic disease-modifying antirheumatic drug treatment group.<\/jats:p><\/jats:sec>","DOI":"10.3899\/jrheum.120922","type":"journal-article","created":{"date-parts":[[2013,1,16]],"date-time":"2013-01-16T04:25:40Z","timestamp":1358310340000},"page":"228-235","source":"Crossref","is-referenced-by-count":38,"title":["The SMILE Study \u2014 Safety of Methotrexate in Combination with Leflunomide in Rheumatoid Arthritis"],"prefix":"10.3899","volume":"40","author":[{"given":"PAUL","family":"BIRD","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"HEDLEY","family":"GRIFFITHS","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"KATHLEEN","family":"TYMMS","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"DAVE","family":"NICHOLLS","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"LYNDEN","family":"ROBERTS","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MARK","family":"ARNOLD","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SIMON","family":"BURNET","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JULIEN","family":"de JAGER","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JAMES","family":"SCOTT","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JANE","family":"ZOCHLING","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"GEOFF","family":"LITTLEJOHN","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2262","published-online":{"date-parts":[[2013,1,15]]},"reference":[{"key":"2025021211251274000_40.3.228.1","doi-asserted-by":"publisher","DOI":"10.1080\/03009740802360632"},{"key":"2025021211251274000_40.3.228.2","doi-asserted-by":"crossref","first-page":"726","DOI":"10.7326\/0003-4819-137-9-200211050-00007","article-title":"Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial","volume":"137","author":"Kremer","year":"2002","journal-title":"Ann Intern Med"},{"key":"2025021211251274000_40.3.228.3","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780381111"},{"key":"2025021211251274000_40.3.228.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)09403-3"},{"key":"2025021211251274000_40.3.228.5","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.159.21.2542"},{"key":"2025021211251274000_40.3.228.6","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(199907)42:7<1322::AID-ANR4>3.0.CO;2-P"},{"key":"2025021211251274000_40.3.228.7","unstructured":"National Institutes of Health-National Cancer Institute . Common terminology criteria for adverse events (CTCAE). Version 4.03,14 June 2010. Washington, DC: U.S. Department of Health and Human Services; 2010. [Internet. Accessed Nov 8, 2012.] Available from: http:\/\/evs.nci.nih.gov\/ftp1\/CTCAE\/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf"},{"key":"2025021211251274000_40.3.228.8","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.126532"},{"key":"2025021211251274000_40.3.228.9","doi-asserted-by":"publisher","DOI":"10.2165\/11316650-000000000-00000"},{"key":"2025021211251274000_40.3.228.10","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.101378"},{"key":"2025021211251274000_40.3.228.11","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0b013e328344fddb"},{"key":"2025021211251274000_40.3.228.12","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0b013e328344f2e4"},{"key":"2025021211251274000_40.3.228.13","doi-asserted-by":"crossref","first-page":"480","DOI":"10.5694\/j.1326-5377.1991.tb93847.x","article-title":"Neutropenia due to low-dose methotrexate therapy for psoriasis and rheumatoid arthritis may be fatal","volume":"155","author":"Mayall","year":"1991","journal-title":"Med J Aust"},{"key":"2025021211251274000_40.3.228.14","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.090153"},{"key":"2025021211251274000_40.3.228.15","doi-asserted-by":"publisher","DOI":"10.1002\/art.20253"},{"key":"2025021211251274000_40.3.228.16","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/S0140-6736(04)15969-2","article-title":"Interstitial lung disease and disease modifying anti-rheumatic drugs","volume":"363","author":"Scott","year":"2004","journal-title":"Lancet"},{"key":"2025021211251274000_40.3.228.17","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kep052"}],"container-title":["The Journal of Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.3899\/jrheum.120922","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T19:25:44Z","timestamp":1739388344000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.jrheum.org\/lookup\/doi\/10.3899\/jrheum.120922"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,1,15]]},"references-count":17,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2013,3,1]]},"published-print":{"date-parts":[[2013,3]]}},"alternative-id":["10.3899\/jrheum.120922"],"URL":"https:\/\/doi.org\/10.3899\/jrheum.120922","relation":{},"ISSN":["0315-162X","1499-2752"],"issn-type":[{"value":"0315-162X","type":"print"},{"value":"1499-2752","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,1,15]]}}}