Immune idiosyncratic DILI by ICIs: specifics of published cases based on evidence as evaluated for causality by RUCAM

The diagnosis of immune idiosyncratic drug-induced liver injury (iDILI) by immune checkpoint inhibitors (ICIs) is blurred by the heterogeneity of causality attribution in cancer patients; this requires information gaps to be filled through the collection of cases evaluated for causality by the Roussel Uclaf Causality Assessment Method (RUCAM). RUCAM was used in 8/11 reports (73%), providing a rather homogeneous study cohort for the following manifestation specifics: (1) consensus among the eight RUCAM-based reports that iDILI by ICIs has an immune basis; (2) age of most patients > 60 years; (3) male gender dominated by a factor ranging from 1.5- to 4.0-fold; (4) clinical manifestations at admission included weakness, vomiting, epigastric pain, and itching but not necessarily jaundice; (5) serum activities of ALT up to 3,111 U/L, with ALP up to 2,459 U/L and total bilirubin up to 300 μmol/L; (6) RUCAM-based ratio (R) revealing a pattern of hepatocellular liver injury (42%), cholestatic (39%), and mixed liver injury (19%); (7) therapeutic options require a case-by-case decision, as the natural course is variable among the cancer patients; (8) although treatment with steroids and/or ursodeoxycholic acid was commonly effective, a therapy decision has to consider whether the use of the implicated ICI should be stopped or continued; (9) prognosis depends largely on disease severity; (10) among the cancer patients with DILI by ICIs, 22% died during follow-up, mostly after progress of underlying disease. In brief, RUCAM use allows for the correct description of clinical manifestations, but more diagnostic efforts are needed for iDILI by ICIs if associated with the novel autoimmune pancreatitis type AIP-3, reflecting pancreatic involvement with possible secondary sclerosing cholangitis.