{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T13:35:34Z","timestamp":1780580134441,"version":"3.54.1"},"reference-count":34,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background and Aim: Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis of unknown etiology that symmetrically involves the synovial joints and leads to erosive arthritis. However, when inflammation remains uncontrolled, it not only affects the joints but also increases the risk of various systemic complications, particularly cardiovascular diseases, osteoporosis, and malignancies such as lymphoma. Early initiation of disease-modifying antirheumatic drugs (DMARDs) has been shown to yield superior outcomes in terms of both clinical response and the prevention of joint damage. Nevertheless, the development of hepatotoxicity during treatment may necessitate dose adjustments or even modifications of the therapeutic protocol. Our aim in this study was to retrospectively evaluate the changes in liver enzyme levels in RA patients before and during treatment, especially in MTX and combination therapies using MTX, and to evaluate how these abnormalities affect treatment strategies. Materials and Methods\/Results: Among the 33 patients included in this study, 15 exhibited elevated liver enzymes prior to treatment, whereas 18 developed hepatic enzyme abnormalities during therapy. Of the 12 patients receiving methotrexate (MTX) monotherapy and the 15 patients using MTX within a combination regimen, a total of 7 patients (21%) continued to present with elevated liver enzymes during follow-up. Among these, 5 patients (19%) were managed successfully by reducing the MTX dose, while MTX therapy had to be completely discontinued in 2 patients (7%). Notably, all 7 patients who required treatment modification due to persistent enzyme elevation belonged to the group with pre-existing liver enzyme abnormalities and were receiving MTX as part of a combination therapy regimen. Conclusions: These findings indicate that hepatotoxicity risk in RA patients can be effectively managed through close laboratory monitoring and timely dose reduction, with treatment discontinuation being required only in rare cases.<\/jats:p>","DOI":"10.3390\/jcm14207213","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T11:57:42Z","timestamp":1760529462000},"page":"7213","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Liver Enzyme Elevations in Rheumatoid Arthritis: Clinical Relevance and Influence on Treatment Strategies"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2076-1934","authenticated-orcid":false,"given":"Yahya","family":"Atayan","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Medical Faculty, Inonu University, Battalgazi 44000, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8516-9769","authenticated-orcid":false,"given":"Servet","family":"Yolbas","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Medical Faculty, Inonu University, Battalgazi 44000, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emin","family":"Bodakci","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gaziantep City Hospital, Gaziantep 27470, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/S0002-9343(01)00872-5","article-title":"Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: Comparison of two cohorts who received different treatment strategies","volume":"111","author":"Lard","year":"2001","journal-title":"Am. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1136\/ard.2008.099861","article-title":"Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: A systematic review and meta-analysis","volume":"68","author":"Katchamart","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.4254\/wjh.v9.i26.1092","article-title":"Risk of liver disease in methotrexate treated patients","volume":"9","author":"Conway","year":"2017","journal-title":"World J. Hepatol."},{"key":"ref_4","unstructured":"National Institute of Diabetes and Digestive and Kidney Diseases (2012). LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, National Institute of Diabetes and Digestive and Kidney Diseases. Bookshelf ID: NBK547852."},{"key":"ref_5","first-page":"1017","article-title":"Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: A systematic review","volume":"27","author":"Visser","year":"2009","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1002\/art.37723","article-title":"Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis","volume":"65","author":"Wasko","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"i1777","DOI":"10.1136\/bmj.i1777","article-title":"Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: Abridged Cochrane systematic review and network meta-analysis","volume":"353","author":"Hazlewood","year":"2016","journal-title":"BMJ"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/rheumatology\/kem279","article-title":"Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis","volume":"47","author":"Wessels","year":"2008","journal-title":"Rheumatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1002\/1529-0131(200107)44:7<1515::AID-ART273>3.0.CO;2-7","article-title":"Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: A forty-eight week, multicenter, randomized, double-blind, placebo-controlled study","volume":"44","author":"Laan","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_10","first-page":"1727","article-title":"Risk factors for methotrexate-induced abnormal laboratory monitoring results in patients with rheumatoid arthritis","volume":"31","author":"Kent","year":"2004","journal-title":"J. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1093\/rheumatology\/keh088","article-title":"Folate supplementation and methotrexate treatment in rheumatoid arthritis: A review","volume":"43","author":"Whittle","year":"2004","journal-title":"Rheumatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s11420-005-0133-z","article-title":"Combination therapy for rheumatoid arthritis in the era of biologicals","volume":"2","author":"Gibofsky","year":"2006","journal-title":"HSS J."},{"key":"ref_13","first-page":"104","article-title":"Methotrexate hepatotoxicity in patients with rheumatoid arthritis","volume":"2","author":"Sotoudehmanesh","year":"2010","journal-title":"Middle East. J. Dig. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3949\/ccjm.52.2.129","article-title":"Hepatotoxicity of prolonged methotrexate therapy for rheumatoid arthritis","volume":"52","author":"Mackenzie","year":"1985","journal-title":"Cleve Clin. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1136\/ard.2008.101378","article-title":"Elevated liver enzyme tests among patients with RA or PsA treated with methotrexate and\/or leflunomide","volume":"69","author":"Curtis","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1007\/s10067-012-2136-8","article-title":"Risk of ALT elevation in rheumatoid arthritis patients treated with methotrexate","volume":"32","author":"Dirven","year":"2013","journal-title":"Clin. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1002\/acr.22294","article-title":"Identification of risk factors for elevated transaminases in methotrexate users through an electronic health record","volume":"66","author":"Schmajuk","year":"2014","journal-title":"Arthritis Care Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/art.39480","article-title":"2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis","volume":"68","author":"Singh","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1002\/art.1780370304","article-title":"Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity","volume":"37","author":"Kremer","year":"1994","journal-title":"Am. Coll. Rheumatol. Arthritis Rheum."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00393-003-0458-2","article-title":"Termination of disease-modifying antirheumatic drugs in rheumatoid arthritis and in psoriatic arthritis. A comparative study of 270 cases","volume":"62","author":"Ujfalussy","year":"2003","journal-title":"Z. Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1002\/art.1780371013","article-title":"Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study","volume":"37","author":"Kaplan","year":"1994","journal-title":"Arthritis Rheum."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1111\/1756-185X.13576","article-title":"Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up","volume":"22","author":"Eriksson","year":"2019","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"67","DOI":"10.2174\/1573397115666190618124407","article-title":"Methotrexate Hepatotoxicity in Rheumatoid Arthritis: An Analysis of the Physicians\u2019 Policy","volume":"16","author":"Anvari","year":"2020","journal-title":"Curr. Rheumatol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1136\/ard.2008.094474","article-title":"Multinational evidencebased recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: Integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative","volume":"68","author":"Visser","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1002\/art.1780350203","article-title":"Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months","volume":"35","author":"Kremer","year":"1992","journal-title":"Arthritis Rheum."},{"key":"ref_26","first-page":"489","article-title":"Liver biopsy findings in patients with rheumatoid arthritis undergoing longterm treatment with methotrexate","volume":"16","author":"Rau","year":"1989","journal-title":"J. Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R143","DOI":"10.1186\/ar3085","article-title":"Rare incidence of methotrexate-specific lesions in liver biopsy of patients with arthritis and elevated liver enzymes","volume":"12","author":"Quintin","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/anr.1780320202","article-title":"Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A prospective study with baseline and sequential biopsy samples","volume":"32","author":"Kremer","year":"1989","journal-title":"Arthritis Rheum."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1002\/art.1780360307","article-title":"Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis","volume":"36","author":"Walker","year":"1993","journal-title":"Arthritis Rheum."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1136\/ard.2008.093690","article-title":"Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: A systematic literature research","volume":"68","author":"Salliot","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.amjmed.2004.02.032","article-title":"DMARDs and risk of serious hepatic adverse events in RA patients","volume":"117","author":"Suissa","year":"2004","journal-title":"Am. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9614241","DOI":"10.1155\/2017\/9614241","article-title":"Review of routine laboratory monitoring for RA patients on biologics\/DMARDs","volume":"2017","author":"Rigby","year":"2017","journal-title":"Int. J. Rheumatol."},{"key":"ref_33","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":"ref_34","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.rdc.2022.03.005","article-title":"Treatment Guidelines in Rheumatoid Arthritis","volume":"48","author":"Singh","year":"2022","journal-title":"Rheum. Dis. Clin. N. Am."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/20\/7213\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T12:18:13Z","timestamp":1760530693000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/20\/7213"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,13]]},"references-count":34,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["jcm14207213"],"URL":"https:\/\/doi.org\/10.3390\/jcm14207213","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,13]]}}}