Idiosyncratic DILI and RUCAM under One Hat: The Global View

Abstract

Drugs are prescribed worldwide to treat diseases but with the risk of idiosyncratic drug-induced liver injury (iDILI). The most important difficulty is how best to establish causality. Based on strong evidence and principles of artificial intelligence (AI) to solve complex processes through quantitative algorithms using scored elements, progress was achieved with the Roussel Uclaf Causality Assessment Method (RUCAM) in its original and updated versions, often viewed now as the gold standard. As a highly appreciated diagnostic algorithm, the RUCAM is in global use with around 100,000 iDILI cases published worldwide using RUCAM to assess causality, largely outperforming any other specific causality assessment tool in terms of case numbers. Consequently, the RUCAM helps to establish a list of top-ranking drugs worldwide implicated in iDILI and to describe clinical and mechanistic features of iDILI caused by various drugs. In addition, the RUCAM was recently applied in iDILI cases of patients treated for coronavirus disease 2019 (COVID-19) infections or cancer patients treated with immune checkpoint inhibitors (ICIs), as well as in the search for new treatment options with conventional drugs in iDILI. Analyses of RUCAM-based iDILI cases are helpful to support pathogenetic steps like immune reactions, genetic predisposition as evidenced by human leucocyte antigens (HLA) genotypes for selected drugs, and the role of the gut microbiome. To achieve consistency in data collection, analysis, and specific clinical and pathogenetic presentation, researchers, regulatory agencies, and pharmaceutical firms should place iDILI and the updated RUCAM as the causality tool under one and the same hat in review articles and clinical guidelines for the diagnosis and treatment of iDILI.

Human Leucocyte Antigen Genetics in Idiosyncratic Drug-Induced Liver Injury with Evidence Based on the Roussel Uclaf Causality Assessment Method

“…The global view on the causality assessment of iDILI cases shows that the RUCAM outperforms any other tool in terms of case numbers [3], with 81,856 DILI cases assessed by the RUCAM and published worldwide from 1993 to mid-2020 [4]. Summarized are the advantages of the RUCAM's specifics (Table 3) [3].…”

“…• Fully validated method based on cases with positive re-exposure test results (gold standard), thereby providing a robust CAM [5,14] • External validation by inter-rater reliability in 3 studies [71][72][73] • Worldwide use, with 81,856 DILI cases assessed by the RUCAM published up to mid-2020, thereby outperforming any other CAM in terms of the number of cases published [4] • Valid and reproducible assessment of DILI and HILI cases [15] • A typical intelligent diagnostic algorithm in line with concepts of artificial intelligence (AI) to solve complex processes by scored items [74] • A diagnostic algorithm for objective, standardized, and quantitative causality assessment [3,5,[13][14][15][16]75]. Summing up the individual scores derived from each key element provides the final causality gradings: score ≤ 0, excluded causality; 1-2, unlikely; 3-5, possible; 6-8, probable; and ≥9, highly probable [15].…”

“…Prescribed drugs are commonly well tolerated, but some medicines may cause idiosyncratic drug-induced liver injury (iDILI) in a few individuals [1][2][3][4][5]. The rarity and unpredictable occurrence of iDILI in the general population represent a clinical challenge for studying its clinical features [6,7], but options are available for this human disease to be used as an excellent human study model of iDILI, provided the clinical diagnosis is correct [8].…”

“…Often found in published reports on cases of iDILI, alternative causes as confounding variables may invalidate the iDILI diagnosis [9], and the diagnosis of iDILI cases provided by the US LiverTox database remains debated due to not being properly assessed for causality [10][11][12]. Similarly, the characteristics of iDILI are often based on cases presented as narratives or assessed by the US DILIN method [3], which lacks proper validation via cases with a positive re-exposure test and is based on arbitrary, subjective opinions and confined to the US territory. The diagnostic problems of iDILI are best circumvented by applying the original Roussel Uclaf Causality Assessment Method (RUCAM) from 1993 [13,14], or better still, the updated RUCAM version from 2016 [15] in line with recommendations by other groups [1,5,6,, including the Chinese Drug-Induced Liver Injury (DILI) Study Group of the Chinese Society of Hepatology (CSH) and Chinese Medical Association (CMA), as published in their CSH guidelines for the diagnosis and treatment of drug-induced liver injury [42].…”

“…Because this form of DILI is idiosyncratic, it is highly suggestive of the genetic susceptibility of the exposed individual [3,6]. Much of the efforts focused on the role of the human leucocyte antigen (HLA) alleles associated with iDILI are based on specific drugs or ethnicities [6].…”