{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:44:01Z","timestamp":1787028241241,"version":"build-2736575974"},"reference-count":62,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>This article discusses rheumatoid arthritis (RA) as a chronic, systemic autoimmune disease leading to progressive joint damage and multi-organ complications. The complex pathogenesis of the disease is presented, involving the interaction of environmental, genetic, and immunological factors, including the role of autoantibodies and proinflammatory cytokines. Particular attention is paid to leflunomide, a disease-modifying antirheumatic drug (DMARD), which primarily works by inhibiting the DHODH enzyme, leading to reduced T and B cell proliferation. The additional anti-inflammatory properties of the drug\u2019s active metabolite, teriflunomide, and its impact on signaling pathways related to the immune response are also discussed. This article examines the variability in patient responses to leflunomide treatment in terms of both efficacy and toxicity, with particular emphasis on the potential role of pharmacogenetic factors. It was pointed out that polymorphisms in genes related to drug metabolism, transport, and mechanism of action may influence the pharmacokinetics and safety of the therapy. It was also emphasized that the available data are primarily derived from observational studies and small cohorts, and the results are often inconsistent. Although some genetic variants and plasma teriflunomide concentrations show potential as predictors of treatment response, the current level of evidence does not support the routine use of pharmacogenetic testing in clinical practice. The article emphasizes that the pharmacogenetics of leflunomide represents a promising, yet still exploratory, avenue of research in the context of personalized RA therapy. It emphasizes the need for larger, well-designed clinical trials and the development of standardized guidelines, which would be necessary before the potential implementation of such strategies in routine clinical practice.<\/jats:p>","DOI":"10.3390\/genes17050573","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T15:45:34Z","timestamp":1779291934000},"page":"573","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of Pharmacogenetics in the Effectiveness of Rheumatoid Arthritis Treatment with Leflunomide"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6821-0086","authenticated-orcid":false,"given":"Paulina","family":"Plewa","sequence":"first","affiliation":[{"name":"Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3739-2066","authenticated-orcid":false,"given":"Anna","family":"J\u0119drasiak","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5427-3069","authenticated-orcid":false,"given":"Oliwia","family":"Jerzy\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8798-5415","authenticated-orcid":false,"given":"Aleksandra","family":"Dach","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Doma\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6557-1208","authenticated-orcid":false,"given":"Andrzej","family":"Pawlik","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wu, D., Luo, Y., Li, T., Zhao, X., Lv, T., Fang, G., Ou, P., Li, H., Luo, X., and Huang, A. (2022). Systemic complications of rheumatoid arthritis: Focus on pathogenesis and treatment. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1051082"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kondo, N., Kuroda, T., and Kobayashi, D. (2021). Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222010922"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1016\/j.immuni.2022.11.009","article-title":"The pathogenesis of rheumatoid arthritis","volume":"55","author":"Alivernini","year":"2022","journal-title":"Immunity"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ki, Y., Yang, H.I., and Kim, K.S. (2023). Etiology and Pathogenesis of Rheumatoid Arthritis-Interstitial Lung Disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241914509"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00281-022-00912-0","article-title":"Genetics of rheumatoid arthritis","volume":"44","author":"Padyukov","year":"2022","journal-title":"Semin. Immunopathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"210011","DOI":"10.1183\/16000617.0011-2021","article-title":"Rheumatoid arthritis-interstitial lung disease: Manifestations and current concepts in pathogenesis and management","volume":"30","author":"Kadura","year":"2021","journal-title":"Eur. Respir. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1007\/s10067-023-06654-0","article-title":"What are the core recommendations for rheumatoid arthritis care? Systematic review of clinical practice guidelines","volume":"42","author":"Conley","year":"2023","journal-title":"Clin. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1002\/acr.24596","article-title":"2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis","volume":"73","author":"Fraenkel","year":"2021","journal-title":"Arthritis Care Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Radu, A.F., and Bungau, S.G. (2021). Management of Rheumatoid Arthritis: An Overview. Cells, 10.","DOI":"10.3390\/cells10112857"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1007\/s13555-022-00713-1","article-title":"Oral Conventional Synthetic Disease-Modifying Antirheumatic Drugs with Antineoplastic Potential: A Review","volume":"12","author":"Hsieh","year":"2022","journal-title":"Dermatol. Ther."},{"key":"ref_11","unstructured":"Shrestha, S., Engstrom, A., and Engstrom, K. (2025). Leflunomide, StatPearls Publishing."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Miao, F., Li, X., Zhao, L., Zhang, S., Geng, M., Ye, C., Shi, Y., and Lei, T. (2025). Leflunomide-Mediated Immunomodulation Inhibits Lesion Progression in a Vitiligo Mouse Model. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26146787"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3298","DOI":"10.1038\/s41598-025-33177-2","article-title":"Integrative biochemical and computational analysis of leflunomide-induced redox alterations in Nauphoeta cinerea","volume":"16","author":"Kamdem","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/bcp.12760","article-title":"Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis","volume":"81","author":"Hopkins","year":"2016","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5318","DOI":"10.1093\/rheumatology\/keab153","article-title":"Rituximab plus leflunomide in rheumatoid arthritis: A randomized, placebo-controlled, investigator-initiated clinical trial (AMARA study)","volume":"60","author":"Behrens","year":"2021","journal-title":"Rheumatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1002\/psp4.46","article-title":"Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients","volume":"4","author":"Hopkins","year":"2015","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhao, F., Chen, Y., Liu, H., Jin, L., Feng, X., Dai, B., Chen, M., Wang, Q., Yao, Y., and Liao, R. (2025). The interaction between a leflunomide-response methylation site (cg17330251) and variant (rs705379) on response to leflunomide in patients with rheumatoid arthritis. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1499723"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Dhiman, A., and Garkhal, K. (2025). Leflunomide Applicability in Rheumatoid Arthritis: Drug Delivery Challenges and Emerging Formulation Strategies. Drugs Drug Candidates, 4.","DOI":"10.3390\/ddc4030036"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"242","DOI":"10.5114\/wo.2010.14431","article-title":"Pharmacogenetics in hormonal therapy of breast cancer","volume":"14","author":"Supernat","year":"2010","journal-title":"Wsp\u00f3\u0142czesna Onkol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1136\/ard.59.11.841","article-title":"Leflunomide: Mode of action in the treatment of rheumatoid arthritis","volume":"59","author":"Breedveld","year":"2000","journal-title":"Ann. Rheum. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1006\/clim.1999.4777","article-title":"Mechanism of action for leflunomide in rheumatoid arthritis","volume":"93","author":"Fox","year":"1999","journal-title":"Clin. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"174233","DOI":"10.1016\/j.ejphar.2021.174233","article-title":"Efficacy and safety of dihydroorotate dehydrogenase (DHODH) inhibitors \u201cleflunomide\u201d and \u201cteriflunomide\u201d in COVID-19: A narrative review","volume":"906","author":"Kaur","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","first-page":"20","article-title":"Mechanism of action of leflunomide in rheumatoid arthritis","volume":"53","author":"Fox","year":"1998","journal-title":"J. Rheumatol. Suppl."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1111\/j.1365-2249.2004.02555.x","article-title":"Suppressive effect of leflunomide metabolite (A77 1726) on metalloproteinase production in IL-1beta stimulated rheumatoid synovial fibroblasts","volume":"137","author":"Migita","year":"2004","journal-title":"Clin. Exp. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.cyto.2005.06.002","article-title":"Effects of the active metabolite of leflunomide, A77 1726, on cytokine release and the MAPK signalling pathway in human rheumatoid arthritis synoviocytes","volume":"31","author":"Bertin","year":"2005","journal-title":"Cytokine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1136\/ard.2008.096743","article-title":"Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK\/STAT pathway","volume":"68","author":"Ortiz","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3725","DOI":"10.7150\/ijbs.93465","article-title":"Antirheumatic drug leflunomide attenuates atherosclerosis by regulating lipid metabolism and endothelial dysfunction via DHODH\/AMPK signaling pathway","volume":"20","author":"Jiang","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_28","first-page":"1877","article-title":"Therapeutic response to leflunomide in combo therapy and monotherapy is associated to serum teriflunomide (A77 1726) levels","volume":"2","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1124\/dmd.109.027482","article-title":"Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide-treated patients with rheumatoid arthritis","volume":"37","author":"Grabar","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jpba.2011.01.034","article-title":"Quantitation of total and free teriflunomide (A77 1726) in human plasma by LC-MS\/MS","volume":"55","author":"Rakhila","year":"2011","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"291","DOI":"10.5414\/CPP48291","article-title":"Pharmacokinetic comparison and bioequivalence of two leflunomide formulations in humans: A single dose, randomized, open-label, two-way crossover study","volume":"48","author":"Park","year":"2010","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"421","DOI":"10.2165\/00003088-200241060-00003","article-title":"Clinical pharmacokinetics of leflunomide","volume":"41","author":"Rozman","year":"2002","journal-title":"Clin. Pharmacokinet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/j.1365-2125.2005.02415.x","article-title":"Population pharmacokinetics and association between A77 1726 plasma concentrations and disease activity measures following administration of leflunomide to people with rheumatoid arthritis","volume":"60","author":"Chan","year":"2005","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_34","unstructured":"U.S. Food and Drug Administration (2012). Leflunomide (Arava) NDA 202992\u2014Clinical Pharmacology Review."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s10067-012-2122-1","article-title":"Leflunomide in dialysis patients with rheumatoid arthritis\u2014A pharmacokinetic study","volume":"32","author":"Bergner","year":"2013","journal-title":"Clin. Rheumatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1517\/17425255.2016.1121233","article-title":"The effect of gene polymorphisms on patient responses to rheumatoid arthritis therapy","volume":"12","author":"Tarnowski","year":"2016","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"R163","DOI":"10.1186\/ar3911","article-title":"Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis","volume":"14","author":"Wiese","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s00228-008-0498-2","article-title":"Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients","volume":"64","author":"Rozman","year":"2008","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_39","first-page":"426","article-title":"Genetic polymorphisms in metabolic pathways of leflunomide in the treatment of rheumatoid arthritis","volume":"33","author":"Soukup","year":"2015","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.2217\/14622416.9.8.1005","article-title":"Pharmacogenomic Importance of ABCG2","volume":"9","author":"Cusatis","year":"2008","journal-title":"Pharmacogenomics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00228-010-0916-0","article-title":"Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level","volume":"67","author":"Kim","year":"2011","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.coph.2020.08.002","article-title":"Drug-resistance in rheumatoid arthritis: The role of p53 gene mutations, ABC family transporters and personal factors","volume":"54","author":"Zhang","year":"2020","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.2217\/pgs-2020-0146","article-title":"Frequency and Impact of DHODH, ABCG2 and CYP2C19 SNPs on the Therapeutic Efficacy, Tolerability and Toxicity of Leflunomide","volume":"22","author":"Makarem","year":"2021","journal-title":"Pharmacogenomics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"331","DOI":"10.2174\/157016006778992778","article-title":"Pharmacogenomics of the human ATP-binding cassette transporter ABCG2","volume":"4","author":"Gardner","year":"2006","journal-title":"Curr. Pharmacogenom."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1097\/01.fpc.0000230422.50962.91","article-title":"Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics","volume":"16","author":"Niemi","year":"2006","journal-title":"Pharmacogenet. Genom."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Liu, Y., Yin, Y., Sheng, Q., Lu, X., Wang, F., Lin, Z., Tian, H., Xu, A., and Zhang, J. (2014). Association of ABCC2 -24C>T polymorphism with high-dose methotrexate plasma concentrations and toxicities in childhood acute lymphoblastic leukemia. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0082681"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"303","DOI":"10.2217\/14622416.10.2.303","article-title":"The Effect of Exon (19C>A) Dihydroorotate Dehydrogenase Gene Polymorphism on Rheumatoid Arthritis Treatment with Leflunomide","volume":"10","author":"Pawlik","year":"2009","journal-title":"Pharmacogenomics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1002\/acr.24236","article-title":"Precision Medicine with Leflunomide: Consideration of the DHODH Haplotype and Plasma Teriflunomide Concentration and Modification of Outcomes in Patients with Rheumatoid Arthritis","volume":"73","author":"Wiese","year":"2021","journal-title":"Arthritis Care Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1146\/annurev.immunol.14.1.397","article-title":"Role of cytokines in rheumatoid arthritis","volume":"14","author":"Feldmann","year":"1996","journal-title":"Annu. Rev. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S1734-1140(09)70033-7","article-title":"IL-1\u03b2, IL-6, and TNF gene polymorphisms do not affect the treatment outcome of rheumatoid arthritis patients with leflunomide","volume":"61","author":"Pawlik","year":"2009","journal-title":"Pharmacol. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Chen, Y., Wang, Q., Liu, H., Jin, L., Feng, X., Dai, B., Chen, M., Xin, F., Wei, T., and Bai, B. (2023). The prognostic value of whole-genome DNA methylation in response to Leflunomide in patients with Rheumatoid Arthritis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1173187"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/acr2.11171","article-title":"DAS28-CRP Cutoffs for High Disease Activity and Remission Are Lower Than DAS28-ESR in Rheumatoid Arthritis","volume":"2","author":"Greenmyer","year":"2020","journal-title":"ACR Open Rheumatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1002\/acr.23825","article-title":"Translating Treatment Effects Between Rheumatoid Arthritis Activity Measures and American College of Rheumatology Responses in Direct Comparison Trials","volume":"71","author":"Dasgupta","year":"2019","journal-title":"Arthritis Care Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1136\/ard.2004.025205","article-title":"Therapeutic drug monitoring of A77 1726, the active metabolite of leflunomide: Serum concentrations predict response to treatment in patients with rheumatoid arthritis","volume":"64","author":"Jansen","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/978-1-4939-3252-8_21","article-title":"Quantitation of Teriflunomide in Human Serum\/Plasma Across a 40,000-Fold Concentration Range by LC\/MS\/MS","volume":"1383","author":"Rule","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1515\/dmpt-2021-0236","article-title":"Therapeutic drug monitoring of teriflunomide: Do plasma concentrations predict response to leflunomide in patients with rheumatoid arthritis?","volume":"38","author":"Rawdha","year":"2023","journal-title":"Drug Metab. Pers. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Nieh, H.V., and Roman, Y.M. (2025). Major Allele Frequencies in. J. Pers. Med., 15.","DOI":"10.3390\/jpm15070274"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1111\/cts.12771","article-title":"Pharmacogenomics in Asian Subpopulations and Impacts on Commonly Prescribed Medications","volume":"13","author":"Lo","year":"2020","journal-title":"Clin. Transl. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/978-1-59745-205-2_5","article-title":"Pharmacogenomics of drug-metabolizing enzymes and drug transporters in chemotherapy","volume":"448","author":"Bosch","year":"2008","journal-title":"Methods Mol. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e4044","DOI":"10.1097\/MD.0000000000004044","article-title":"Diffuse alveolar damage in a patient with rheumatoid arthritis under prolonged leflunomide treatment: A Case Report and Literature Review","volume":"95","author":"Keng","year":"2016","journal-title":"Medicine"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1093\/rheumatology\/keab790","article-title":"Development and validation of a prognostic model for leflunomide discontinuation with abnormal blood tests during long-term treatment: Cohort study using data from the Clinical Practice Research Datalink Gold and Aurum","volume":"61","author":"Nakafero","year":"2022","journal-title":"Rheumatology"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Conti, V., Corbi, G., Costantino, M., De Bellis, E., Manzo, V., Sellitto, C., Stefanelli, B., Colucci, F., and Filippelli, A. (2020). Biomarkers to Personalize the Treatment of Rheumatoid Arthritis: Focus on Autoantibodies and Pharmacogenetics. Biomolecules, 10.","DOI":"10.3390\/biom10121672"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/5\/573\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T15:53:57Z","timestamp":1779292437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/5\/573"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":62,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["genes17050573"],"URL":"https:\/\/doi.org\/10.3390\/genes17050573","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,18]]}}}