Time to Use the Right Classification to Predict the Severity of Checkpoint Inhibitor-Induced Liver Injury, As Assessed for Causality Using the Updated RUCAM.

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 sever-ity 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 clinico-biological 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 pat-terns with a median time to onset of 20 days after checkpoint inhibitors. Severity grading varied significantly among the classifications used. A lower incidence of se-vere 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 classifi-cation 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 transam-inases, which leads to steroid overtreatment and limits the rechallenge of ICIs.