Cholestatic drug-induced liver injury in a rheumatoid arthritis patient receiving leflunomide: a clinical case report

Authors

  • M. Mihaylova Department of Nephrology, Hematology, and Gastroenterology, Faculty of Medicine, Medical University – Pleven, Bulgaria; Clinic of Gastroenterology, University Hospital „Georgi Stranski“ – Pleven, Bulgaria Author https://orcid.org/0000-0001-7960-4373
  • B. Zhelezarova Department of Cardiology, Pulmonology, Endocrinology and Rheumatology, Faculty of Medicine, Medical University – Pleven, Bulgaria; Clinic of Rheumatology, University Hospital „Georgi Stranski“ – Pleven, Bulgaria Author

DOI:

https://doi.org/10.2478/AMB-2026-0019

Keywords:

drug-induced liver injury, immunomodulatory agents, hepatotoxicity, rheumatoid arthritis, nonsteroidal anti-inflammatory drugs

Abstract

Abstract. Drug-induced liver injury (DILI) is a significant clinical challenge due to its variable presentation and lack of specific biomarkers. Leflunomide, an immunomodulatory agent commonly used in rheumatoid arthritis, carries a known risk of hepatotoxicity, typically presenting with a hepatocellular pattern. We report a clinical case of a 59-year-old male patient with seropositive rheumatoid arthritis who developed cholestatic DILI following combined therapy with leflunomide and aceclofenac. Diagnosis was established based on clinical presentation, laboratory findings, exclusion of alternative causes, and a high Roussel Uclaf Causality Assessment Method (RUCAM) score. Cholestatic DILI associated with leflunomide is relatively rare, making this case a valuable contribution to understanding atypical presentations of hepatotoxicity in rheumatoid arthritis patients. Discontinuation of the implicated agents and initiation of supportive therapy, including corticosteroids and hepatoprotective agents, resulted in gradual clinical and biochemical recovery. This case emphasises the importance of careful monitoring for liver toxicity during combined immunomodulatory and nonsteroidal anti-inflammatory therapy and illustrates the challenges in diagnosing cholestatic DILI, a less common but clinically significant pattern of liver injury.

Author Biography

  • M. Mihaylova, Department of Nephrology, Hematology, and Gastroenterology, Faculty of Medicine, Medical University – Pleven, Bulgaria; Clinic of Gastroenterology, University Hospital „Georgi Stranski“ – Pleven, Bulgaria



References

Hadzhieva B, Dimitrov M, Petkova V. Pharmaceutical regulation of herbal medicinal products in the countries of the European Union, the USA, Canada and Japan. Acta Medica Bulgarica. 2023;50(3):71-74.

CIOMS Working Group. Drug-Induced Liver Injury: Current status and future directions. [Internet]. Geneva: CIOMS; 2020. Available from: https://cioms.ch/wp-content/uploads/2020/06/CIOMS_DILI_Web_16Jun2020.pdf

European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019;70(6):1222–1264.

Stavrakeva K, Popova M, Esad M, et al. Drug-induced liver toxicity. Acta Medica Bulgarica. 2025;51(4):77-85.

Li J, Zhao W, Wang R, et al. Mapping the incidence of drug-induced liver injury: A systematic review and meta-analysis. Liver Int.2023;43(12):2826–2837.

FDA Drug Safety Communication: Risks of liver injury with leflunomide. [Internet]. U.S. Food and Drug Administration (FDA). 2021. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-risk-liver-injury-leflunomide

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–. Leflunomide. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548725/

Devarbhavi H, Ghabril M, Barnhart H, et al. Leflunomide-induced liver injury: Differences in characteristics and outcomes in Indian and U.S. registries. Liver Int. 2022;42(6):1323–1329.

Mielnik P, Sexton J, Fagerli KM, et al. Discontinuation rate of sulfasalazine, leflunomide and methotrexate due to adverse events in a real-life setting (NOR-DMARD). Rheumatol Adv Pract. 2023;7(2):rkad053.

Miladi S, Ben Yacoub S, Boussâa H, et al. Leflunomide in rheumatoid arthritis: Factors associated with therapeutic maintenance. Revmatologia. 2024;32(1):5–11.

Nikolov RP. Adverse reactions associated with the use of non-steroidal anti-inflammatory drugs and non-opioid analgesics. Revmatologia. 2010;18(1):18-27.

Meunier L, Larrey D. Recent advances in hepatotoxicity of nonsteroidal anti-inflammatory drugs. Ann Hepatol. 2018;17(2):187–191.

Kim S, Lee S, Lee J, Yu K. Modeling of aceclofenac metabolism to major metabolites in healthy volunteers. Biopharm Drug Dispos. 2016;37(9):480–491.

Drug Interaction Report: diclofenac, leflunomide. [Internet]. Drugs.com. Available from: https://www.drugs.com/interactions-check.php?drug_list=869-0%2C14400&professional=1

Ahmed T, Ahmad J. Recent advances in the diagnosis of drug-induced liver injury. World J Hepatol. 2024;16(2):186–192.

Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89(6):806–815.

Danan G, Teschke R. RUCAM in drug and herb induced liver injury: The updated version. Int J Mol Sci. 2016;17(1):14.

LiverTox: Roussel Uclaf Causality Assessment Method (RU-CAM) in Drug Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. 2012; Updated 2019 May 4. Available from:https://www.ncbi.nlm.nih.gov/books/NBK548272

Chalasani N, Younossi Z, Lavine JE, et al. AASLD Practice Guidance: Drug-Induced Liver Injury. Hepatology. 2017;65(6):2036–2094.

Bokan G. Leflunomide hepatotoxicity in rheumatoid arthritis: Case report and literature review.Slovenian J Gastroenterol. 2024;2:1–5.

Salmi AR, Islahudin F, Shamsuddin AF, Shahril NS. A study on leflunomide-induced liver injury in rheumatoid arthritis patients. Res J Pharm Technol. 2013;6(5):556–561.

Chalasani NP, Hayashi PH, Bonkovsky HL, et al. The diagnosis and management of idiosyncratic drug induced liver injury. Am J Gastroenterol. 2014;109(7):950–966.

Bessone F, Hillotte GL, Tamagnone N, et al. Ursodeoxycholic acid for the management of drug-induced liver injury: Role of hepatoprotective and anti-cholestatic mechanisms. J Clin Transl Hepatol. 2025;13(2):162–168.

Li M, Luo Q, Tao Y, et al. Pharmacotherapies for drug-induced liver injury: A current literature review. Front Pharmacol. 2022;12:806249.

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Published

06.02.2026

How to Cite

Mihaylova, M., & Zhelezarova, B. (2026). Cholestatic drug-induced liver injury in a rheumatoid arthritis patient receiving leflunomide: a clinical case report. Acta Medica Bulgarica, 53(Suppl 1), 113-117. https://doi.org/10.2478/AMB-2026-0019