Drug-Induced Liver Injury [DILI] ascribed to Non-steroidal Anti-inflammatory Drugs [NSAIDs] in the USA— Update with Genetic Correlations

Abstract

Objective: To describe patients with NSAID-DILI, including genetic factors associated with idiosyncratic DILI. Methods: In DILIN, subjects with presumed DILI are enrolled and followed for at least 6 months. Causality is adjudicated by a Delphic approach. HLA sequencing of multiethnic NSAID-DILI patients and HLA allele imputation of matching population controls were performed following overall, class and drug-based association analysis. Significant results were tested in a non-Hispanic White (NHW) case-control replication cohort. Results: Between September 2004 and March 2022, causality was adjudicated in 2498, and 55 (41 [75%] women) were assessed as likely due to NSAIDs. Median age at onset was 55 y (range 22-83 y). Diclofenac was the causative drug in 29, celecoxib in 7, ibuprofen in 5, etodolac and meloxicam each in 4. Except for meloxicam and oxaprozin (n = 2), the liver injury was hepatocellular with median R 15-25. HLA-DRB104:03 and HLA-B35:03 were significantly more frequent in NSAID-DILI patients than in non-NSAID DILI controls. Interestingly, 85% of the HLA-DRB104:03 carriers developed DILI due to the use of acetic acid derivative NSAIDs, supporting the hypothesis that HLA-DRB104:03 could be a drug and/or class risk factor. HLA-B35:03 but not HLA-DRB104:03 association was confirmed in the independent NHW replication cohort, which was largely driven by diclofenac. Conclusions: Despite prevalent use, NSAID-DILI is infrequent in the United States. Diclofenac is the most commonly implicated, and adherence to warnings of risk and close observation are recommended. The increased frequency of HLA-B35:03 and DRB104:03, driven by diclofenac, suggests the importance of immune-mediated responses.