Leflunomide-induced liver injury: Differences in characteristics and outcomes in Indian and US registries

Abstract

Background: Leflunomide, a disease-modifying anti-rheumatic drug, has been associated with elevations of serum aminotransferases. Herein, we describe the clinical, laboratory features, and outcomes of 17 patients with leflunomide/teriflunomide hepatotoxicity from two large drug-induced liver injury (DILI) registries. Methods: Consecutive, adjudicated cases of leflunomide (n=16)-or teriflunomide (n=1)-related DILI from a single center in Bangalore, India and the multicenter US Drug-Induced Liver Injury Network (DILIN) were reviewed. Results: Nine (0.8%) of the 1070 Indian patients and 8 (0.5%) of the 1400 DILIN patients fulfilled criteria for DILI due to leflunomide- or teriflunomide. 89% of the Indian cases were women and all were associated with severe cutaneous adverse reaction (SCAR) and a median drug latency of 49 days, whereas 37.5% of the DILIN cases were female, none exhibited SCAR, and the median drug latency was 166 days. Hepatocellular injury (70%) was more common in women than men (92% vs. 20%) and was associated with younger mean age (41 vs. 59 years), higher peak INR (2.3 vs. 1.2), and higher mortality (58% vs. 0%). Mortality was observed in 6 patients from India (2 of the three with myocarditis) and 1 received liver transplantation from the USA Conclusion: Leflunomide-induced liver injury is predominantly hepatocellular. Leflunomide hepatotoxicity is more likely accompanied by SCAR, a short latency, and a higher mortality in the Indian cohort, with a predominance of females, compared to US DILIN patients. The differences in skin involvement, immunoallergic features, and outcomes among subjects from India vs. the US suggest that genetic or environmental factors are important in the pathogenesis of liver injury.