Leflunomide for the treatment of rheumatoid arthritis in clinical practice: incidence and severity of hepatotoxicity

Drug Saf. 2004;27(5):345-52. doi: 10.2165/00002018-200427050-00006.


Objective: Leflunomide is a novel disease modifying antirheumatic drug (DMARD). Because of reports on possible hepatotoxicity and adaptations in the recommendations for monitoring liver function during leflunomide treatment, we conducted a study to evaluate the incidence and severity of hepatotoxicity.

Methods: We included consecutive rheumatoid arthritis patients starting treatment with leflunomide in the region of Friesland (The Netherlands) between January 2000 and January 2002. During follow-up patient characteristics, disease characteristics, and clinical and laboratory data on liver functions were registered. Severity of hepatotoxicity was categorised using the National Cancer Institute Common Toxicity Criteria, as moderate (grade 2), severe (grade 3) or life threatening (grade 4).

Results: One hundred and one patients were followed for a median period of 10 months (range 0.5-12). Grade 2 or 3 elevations in any liver function blood test were recorded in a total of nine patients (8.9%). No grade 4 elevations were recorded. Four patients (4%) showed grade 2-3 aminotransferase elevations. Due to grade 2 hepatotoxicity one patient (1%) was withdrawn from leflunomide treatment, and one patient continued leflunomide at a reduced dose. In eight of nine patients with grade 2-3 liver function blood tests, these elevated liver function tests occurred within 6 months after starting leflunomide. None of the patients with grade 2 or 3 toxicity had a history of hepatic disease, eight patients concomitantly used potential hepatotoxic co-medication. Eight (8%) patients used leflunomide in combination with methotrexate, and one of these patients developed hepatotoxicity. No clinical signs of serious hepatotoxicity were recorded during follow-up.

Discussion: In 8.9% of the patients, grade 2 or 3 hepatotoxicity was recorded within the first year after the start of leflunomide therapy based on liver enzyme determinations. In the majority of the patients liver enzyme elevations occurred within the first 6 months of therapy and resolved during continued follow-up. None of the patients showed clinical signs of hepatotoxicity.

Conclusion: Under continued monitoring of liver functions hepatotoxicity during leflunomide use does not seem to be a major problem in our population.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antirheumatic Agents / adverse effects*
  • Antirheumatic Agents / therapeutic use
  • Chemical and Drug Induced Liver Injury* / etiology
  • Female
  • Humans
  • Isoxazoles / adverse effects*
  • Isoxazoles / therapeutic use
  • Jaundice / chemically induced
  • Leflunomide
  • Male
  • Middle Aged


  • Antirheumatic Agents
  • Isoxazoles
  • Leflunomide