Immune checkpoint inhibitors (ICIs) have changed the landscape of cancer therapy. Liver toxicity occurs in up to 25% of patients treated with ICIs. The aim of our study was to describe the different clinical patterns of ICI-induced hepatitis and to assess their outcome. We conducted a retrospective observational study of patients with checkpoint inhibitor-induced liver injury (CHILI) discussed in multidisciplinary meetings between December 2018 and March 2022 in three French centres specialised in ICI toxicity management (Montpellier, Toulouse, Lyon). The hepatitis clinical pattern was analysed by the ratio of serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) (R value = (ALT/ULN)/(ALP/ULN)) for characterisation as cholestatic (R ≤2), hepatocellular (R ≥5), or mixed (2 <R <5). We included 117 patients with CHILI. The clinical pattern was hepatocellular in 38.5%, cholestatic in 36.8%, and mixed in 24.8% of patients. High-grade hepatitis severity (grade ≥3 according to the Common Terminology Criteria for Adverse Events system) was significantly associated with the hepatocellular hepatitis (p <0.05). No cases of severe acute hepatitis were reported. Liver biopsy was performed in 41.9% of patients: granulomatous lesions, endothelitis, or lymphocytic cholangitis were described. Biliary stenosis occurred in eight patients (6.8%) and was significantly more frequent in the cholestatic clinical pattern (p < 0.001). Steroids alone were mainly administered to patients with a hepatocellular clinical pattern (26.5%), and ursodeoxycholic acid was more frequently used in the cholestatic pattern (19.7%) than in the hepatocellular or mixed clinical pattern (p <0.001). Seventeen patients improved without any treatment. Among the 51 patients (43.6%) rechallenged with ICIs, 12 (23.5%) developed CHILI recurrence. This large cohort indicates the different clinical patterns of ICI-induced liver injury and highlights that the cholestatic and hepatocellular patterns are the most frequent with different outcomes. ICIs can induce hepatitis. In this retrospective series, we report 117 cases of ICI-induced hepatitis, mostly grades 3 and 4. We find a similar distribution of the different patterns of hepatitis. ICI could be resumed without systematic recurrence of hepatitis.

Summary: Background and Aims: While immune checkpoint inhibitors (ICIs) are revolutionising cancer therapy, checkpoint inhibitor‐induced liver injury is a significant immune‐related side effect of this immunotherapy. This study focuses on the severity classifications and characteristics of patients with checkpoint inhibitor‐induced hepatitis.Methods: A retrospective analysis of patients with severe Checkpoint Inhibitor‐induced hepatitis grade 3 and 4 according to the recommended Common Terminology Criteria for Adverse Events (CTCAE) classification was conducted. Data on clinicobiological characteristics, treatment and outcomes were collected from 3 university hospitals, and causality was assessed by using the updated Roussel Uclaf Causality Assessment Method. The severity of hepatitis was assessed using the Model for End‐stage Liver Disease score, the Drug‐Induced Liver Injury Network, and the Drug‐Induced Liver Injury International Expert Working Group classifications.Results: We retrospectively included 100 patients presenting various hepatitis patterns with a median time to onset of 20 days after checkpoint inhibitors. Severity grading varied significantly among the classifications used. A lower incidence of severe cases was observed when using the Drug‐Induced Liver Injury classifications instead of the recommended CCTCAE classification, and this was correlated with outcomes.Conclusions: This retrospective study challenges the efficacy of the CTCAE classification in defining the severity of Checkpoint Inhibitor‐induced hepatitis and suggests that the traditional hepatology‐focused scores may be more relevant. The CTCAE classification is inconsistent and gives equal weight to jaundice and elevated transaminases, which leads to steroid overtreatment and limits the rechallenge of ICIs.

Introduction: Checkpoint Inhibitor‐induced Liver Injury (CHILI) is a frequent complication of immune checkpoint inhibitors (ICIs). Corticosteroids are the standard treatment but have many limitations. Ursodeoxycholic acid (UDCA) offers an alternative for managing cholestatic CHILI, but its efficacy remains underexplored.Methods: A multicenter retrospective study included 27 patients treated with first‐line UDCA monotherapy. Data were collected from diagnosis to week 52, assessing liver enzyme improvement, recurrence, and outcomes.Results: UDCA alone achieved improvement in 81.5% of patients, with an average response time of 39.3 days. Among patients, 77.8% had severe CHILI (CTCAE grade ≥ 3). Macroscopic bile duct injury was observed in 37%, associated with higher recurrence rates (75%, p < 0.001). Recurrent CHILI led to chronic CHILI in all cases. ICI rechallenge was conducted in 52% of patients, with only 23% experiencing relapse.Conclusion: UDCA monotherapy appears effective for cholestatic CHILI, presenting a viable alternative to corticosteroids. Further prospective studies are warranted.