Roussel Uclaf Causality Assessment Method for Drug-Induced Liver Injury: Present and Future

Abstract

Among the causality assessment methods used for the diagnosis of drug-induced liver injury (DILI), Roussel Uclaf Causality Assessment Method (RUCAM) remains the most widely used not only for individual cases but also for prospective and retrospective studies worldwide. This first place is justified by the characteristics of the method such as precise definition and classification of the liver injury, which determines the right scale in the scoring system, precise definition of the seven criteria, and the validation approach based on cases with positive rechallenge. RUCAM is used not only for any types of drugs but also for herbal medicines causing herb-induced liver injury, (HILI) and dietary supplements. In 2016, the updated RUCAM provided further specifications of criteria and instructions to improve interobserver variability. Although this method was criticized for criteria such as the age and alcohol consumption, recent consensus meeting of experts has recognized their value and recommended their incorporation into any method. While early studies searching for DILI in large databases especially in electronic medical records were based on codes of diseases or natural language without causality assessment, the recommendation is now to include RUCAM in the search for DILI/HILI. There are still studies on DILI detection or the identification of biomarkers that take into consideration the cases assessed as “possible,” although it is well known that these cases reduce the strength of the association between the cases and the offending compound or the new biomarker to be validated. Attempts to build electronic RUCAM or automatized application of this method were successful despite some weaknesses to be corrected. In the future, more reflections are needed on an expert system to standardize the exclusion of alternative causes according to the clinical context. Education and training on RUCAM should be encouraged to improve the results of the studies and the day-to-day work in pharmacovigilance departments in companies or in regulatory agencies. It is also expected to improve RUCAM with biomarkers or other criteria provided that the validation process replaces expert opinion by robust standards such as those used for the original method.

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

“…Both, this original RUCAM [21,22] and the updated RUCAM of 2016 [8] became the most widely used algorithms for causality assessment in DILI and have been applied in more than 46,266 DILI cases published between 2014 and 2019 [17]. Currently preferred is the RUCAM version updated in 2016 [8], along with additional details [9,23]. As a liver specific, item scoring, structured and validated causality assessment method (CAM), RUCAM outperforms other CAMs on the market, which are no equally valid substitutes for RUCAM [8].…”

Worldwide Use of RUCAM for Causality Assessment in 81,856 Idiosyncratic DILI and 14,029 HILI Cases Published 1993–Mid 2020: A Comprehensive Analysis

“…In parallel, more and more publications on DILI and HILI cases refer to RUCAM (Roussel Uclaf Causality Assessment Method) for causality assessment [ 10 , 11 , 12 , 13 ]. The original RUCAM was first published in 1993 [ 14 ] and updated in 2016 [ 15 ] with additional information on its use and perspectives [ 16 , 17 ], which is now the preferred version to be used in future cases of DILI and HILI [ 15 ]. It is widely recognized that causality assessment in DILI and HILI is a multifaceted approach [ 7 , 8 , 9 , 15 ], a real medical challenge, for which a diagnostic quantitative algorithm such as RUCAM is an easy tool for case evaluation [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] to solve complex conditions [ 18 ].…”

“…The RUCAM algorithm is a structured, standardized, transparent, liver specific and quantitative diagnostic clinical scale based on key elements of liver injury, which are individually scored and provide a score for five-degree causality grading from unrelated up to highly probable causality levels [ 15 ]. Since key elements are specifically described and scored, assessments are objective with little risk of subjectivity [ 15 , 16 , 17 ] commonly observed if the approach to assess causality lacks scored key elements [ 19 ]. RUCAM can help expand our knowledge by enlarging population analysis with prospective and scored causality assessment, allowing for harmonized interpretation of data across populations [ 20 ].…”

“…RUCAM can help expand our knowledge by enlarging population analysis with prospective and scored causality assessment, allowing for harmonized interpretation of data across populations [ 20 ]. In this context, RUCAM should be viewed as a cornerstone approach assessing causality of liver injury cases [ 15 , 16 , 17 , 21 ], because robust diagnostic biomarkers are rarely available due to misconducted studies as outlined by EMA (European Medicines Agency: Formerly London, UK, now Amsterdam, Netherlands) [ 21 ].…”

Use of Evidence-Based Herbal Medicines for Patients with Functional Gastrointestinal Disorders: A Conceptional Framework for Risk-Benefit Assessment and Regulatory Approaches

“…In spite of the widespread use and safety monitoring requirements that are in many jurisdictions identical to chemically defined medications, only very few cases of adverse events have been observed and reported [75] and very recently a 2 cases of a liver failure after treatment with STW5 has been reported [68,76]. In these 2 cases, causality was supported by a positive Roussel Uclaf Causality Assessment Method score [77] that suggested a highly probable link. In addition, in 1 case [76] the authors used monocyte-derived hepatocyte-like cells to test the medications the patients had used prior to the manifestation of the liver failure and the patient's cells responded with a release of liver enzymes after exposure to STW5.…”