Leflunomide-induced Recurrent Acute Pancreatitis: A Case Confirmed by Two Sequential Positive Re-challenges

Abstract

Drug-induced pancreatitis is a rare adverse event, and establishing definitive causality requires systematic exclusion of common etiologies and, ideally, a positive re-challenge. Leflunomide, a widely used disease-modifying antirheumatic drug, has been implicated as a rare cause of acute pancreatitis, but no prior published case has achieved re-challenge confirmation. A 60-year-old woman with rheumatoid arthritis on long-term leflunomide presented with a large lesser-sac pseudocyst requiring laparoscopic cystogastrostomy. Leflunomide was restarted postoperatively, precipitating moderately severe acute pancreatitis within 5 days (serum lipase 1422 IU/mL; CT Severity Index 6/10), which resolved with conservative management. Comprehensive aetiological workup was unremarkable. On second reintroduction 1 month later, acute pancreatitis recurred within 3 days (serum lipase 1211 IU/mL). Leflunomide was permanently discontinued, and the patient has remained asymptomatic for 9 months on alternative disease-modifying therapy. Two sequential positive re-challenges, with complete resolution on each cessation and exclusion of all alternative aetiologies, confirm leflunomide as a definitive cause of acute pancreatitis – reclassifying it as a Badalov Class Ia agent (Naranjo score 9; definite) for the first time in the literature. Clinicians should consider leflunomide in the differential diagnosis of unexplained pancreatitis, to avoid re-exposure following a confirmed episode.