RUCAM-ascertained immunology and autoimmunity specifics of six idiosyncratic drug-induced liver injury types with refined classification: their individual complex molecular interplay.

Idiosyncratic drug-induced liver injury (iDILI) is not a uniform disease but rather includes a variety of types based on immune, autoimmune, and clinical considerations. This review attempts to close information gaps regarding the role of immunity and autoimmunity involved in the different iDILI disease types. The analysis of the current literature focusing on iDILI reveals compelling evidence of a pivotal role of immunity or autoimmunity in various types of iDILI. Among the autoimmune-triggered ones are the drug-induced autoimmune hepatitis (DIAIH) and the idiosyncratic drug-induced anti-CYP autoimmune hepatitis. In contrast, clearly immune-triggered are the human leukocyte antigen (HLA)-based immune iDILI, the immune iDILI with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and the immune iDILI induced by immune checkpoint inhibitors (ICIs), but immune-triggered mechanisms account for only a part of the classic iDILI cases. For all these iDILI types, the use of the original or updated Roussel Uclaf Causality Assessment Method (RUCAM) allowed for confirming causality of the implicated drug, assisted by the simplified autoimmune hepatitis (AIH) score in the DIAIH cases and the Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) score in the cases of immune-based iDILI with SJS/TEN. All these diagnostic causality assessment algorithms are validated methods and have helped define clinical features of the different iDILI types. The first treatment goal is the cessation of the suspected drug, which alone may lead to clinical and laboratory improvement and restoration of health. However, therapy with immunosuppressive agents is often needed to treat the injury caused by immune and autoimmune processes and can lead to complete remission in all iDILI types with the exception of the classic iDILI, where only a subset of the patients achieve remission. At the molecular pathomechanistic level, there is a complex interplay mostly related to the adaptive immune system activated by the innate system. In sum, immunology and autoimmunity specifics in cases of RUCAM-ascertained iDILI types, as part of a refined classification, remain a challenging topic that can be deepened by future cases if validated diagnostic algorithms are applied.