DRESSed for Relapse: A Rare Case of Leflunomide‐Induced DRESS With Hepatic Complications

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a rare, potentially life-threatening hypersensitivity reaction characterized by fever, rash, eosinophilia, lymphadenopathy, and multi-organ involvement most commonly affecting the liver. Mortality ranges from 5% to 10%, primarily due to hepatic necrosis 1, 2. While anticonvulsants, allopurinol, antiretrovirals, and antibiotics are common triggers 3, 4, leflunomide is a rare but emerging culprit 5-7. Its unique pharmacokinetics, including a prolonged half-life and significant enterohepatic recirculation, pose management challenges 8. We report a rare case of leflunomide-induced DRESS, one of a limited number of published cases to date. This case also highlights the use of cholestyramine washout, a known but underutilized strategy to enhance leflunomide elimination and facilitate clinical recovery. Diagnosing DRESS can be challenging as its clinical presentation is variable and can mimic infections, autoimmune diseases, or other drug reactions. The RegiSCAR (Registry of Severe Cutaneous Adverse Reactions) scoring system is the most widely used diagnostic tool. It evaluates clinical features such as fever, hematologic abnormalities, skin rash characteristics, internal organ involvement, and exclusion of alternative causes to categorize cases as “no,” “possible,” “probable,” or “definite” DRESS 2. Management begins with immediate cessation of the offending drug. For non-severe cases, clinical and laboratory monitoring may suffice. Systemic corticosteroids are the mainstay for moderate-to-severe disease. Steroid-refractory or relapsing cases may require escalation to immunosuppressive agents such as cyclosporine, IVIG, or plasmapheresis 2, 9. These interventions increase the risk of opportunistic infections including CMV reactivation 3. We present the case of a 65-year-old woman recently diagnosed with rheumatoid arthritis who was started on leflunomide and hydroxychloroquine. Three weeks later, she developed a diffuse maculopapular rash on her extremities, which progressed to involve her trunk. She was hospitalized for a presumed drug-induced rash and showed moderate improvement with high-dose corticosteroids. However, upon tapering, her symptoms worsened, with the emergence of fever, dysphagia, and new mucosal ulcers, prompting readmission. On examination, she had hemorrhagic crusting of the lips, tongue erosions, and a confluent morbilliform rash. Laboratory workup revealed eosinophilia (16%), atypical lymphocytosis (4%), elevated AST (75 U/L), ALT (125 U/L), ALP (173 U/L), and a CRP of 6.11 mg/dL. Infectious workup was negative. Anti-nuclear antibody (ANA) was positive at a titer of 1:320 (homogeneous pattern), with negative anti-SSA, SSB, dsDNA, chromatin, and Sm/RNP antibodies. Skin biopsy showed interface dermatitis with eosinophilic infiltration, consistent with DRESS. The RegiSCAR score was 9, confirming a definite diagnosis of DRESS (Figure 1). Leflunomide and hydroxychloroquine were discontinued. Despite intravenous methylprednisolone and cyclosporine, her symptoms persisted. A cholestyramine washout was initiated to accelerate leflunomide elimination, resulting in marked clinical improvement within 48 h (Figure 2). She was discharged on cyclosporine, cholestyramine, and a corticosteroid taper. Two weeks after hospital discharge, following cyclosporine reduction to 150 mg/day, the patient re-presented with jaundice, diarrhea, pale stools, and recurrence of the rash. Laboratory studies revealed hepatic cholestasis with coagulopathy: AST 301 U/L, ALT 269 U/L, ALP 454 U/L, total bilirubin 8.0 mg/dL, direct bilirubin 6.3 mg/dL, and INR 2.17. Abdominal imaging was unremarkable. Liver biopsy showed chronic, severely active hepatitis with confluent necrosis, and a plasma cell-rich infiltrate. ANA remained positive and a low-titer anti-smooth muscle antibody was detected. Cytomegalovirus (CMV) viremia was also detected. The patient ultimately responded to high-dose intravenous steroids and was discharged on a prolonged prednisone taper with close outpatient follow-up. Approximately 12 weeks after discharge, her liver function tests normalized following completion of the prednisone taper. Leflunomide-induced DRESS is rare and presents unique management challenges due to its prolonged half-life and extensive enterohepatic recirculation. Leflunomide is metabolized in the liver to its active metabolite, teriflunomide, which has a prolonged half-life of approximately 2 weeks due to enterohepatic recirculation 8. In our case, despite initiating high-dose corticosteroids and cyclosporine, clinical improvement was only achieved after a cholestyramine washout 5, 10. This underscores the importance of considering accelerated drug elimination early in steroid-refractory cases. Cholestyramine is a non-absorbable bile acid sequestrant that binds teriflunomide in the gastrointestinal tract, preventing its reabsorption and enhancing fecal excretion. The standard washout protocol is 8 g three times daily for 11 days, which significantly accelerates teriflunomide clearance 8, 10. Although well established in overdose protocols, cholestyramine remains underutilized in DRESS management. Our case reinforces its value in persistent or relapsing presentations 10. Liver involvement occurs in up to 80% of DRESS cases, ranging from mild transaminitis to fulminant hepatic failure 3. In our patient, worsening liver function and biopsy findings revealed features of immune-mediated hepatitis and possible autoimmune sequelae. Determining the precise etiology of liver injury was challenging, with contributing factors including cyclosporine toxicity, CMV reactivation, and DRESS relapse. The timing of symptom recurrence following cyclosporine dose reduction supports DRESS relapse. This underscores the importance of gradual immunosuppressant tapering, close follow-up, and early recognition of evolving complications. Multidisciplinary management, involving dermatology, hepatology, and infectious disease specialists, was critical for guiding treatment and monitoring complications. In conclusion, leflunomide-induced DRESS is rare but clinically significant, and this case adds to the limited body of literature. Given leflunomide's prolonged half-life and enterohepatic recirculation, cholestyramine washout should be strongly considered in steroid-refractory or relapsing cases. Liver involvement can be severe and may trigger or unmask underlying autoimmune features. Immunosuppressive therapy increases the risk of opportunistic infections such as CMV reactivation. This case underscores the importance of long-term monitoring and multidisciplinary care to optimize outcomes in severe DRESS presentations. Kajal Patel drafted the manuscript and was involved in patient care. Pooja Jotwani contributed to literature review and was involved in patient care. Marie-Claire Maroun supervised the project and critically revised the manuscript. The authors thank colleagues in the Rheumatology and Dermatology Departments for their clinical support and multidisciplinary discussions involved in the care of the patient. Consent was obtained from the patient for this case report. The patient has been de-identified in the case report. The authors declare no conflicts of interest. The authors have nothing to report.