S1202 Drug-Induced Liver Injury (DILI) Ascribed to Non-Steroidal Anti-inflammatory Drugs (NSAIDs) in the USA: An Update With Genetic Correlations From the U.S. Drug-Induced Liver Injury Network (DILIN)

Abstract

Introduction: NSAIDs are widely used throughout the world, mainly for management of chronic inflammatory and painful conditions. NSAIDs rarely cause idiosyncratic, non-dose dependent liver injury. Recent evidence from the US DILIN, as well as elsewhere, implicates host immune responses as central to pathogenesis of such idiosyncratic DILI. Previously, we reported the US DILIN experience with NSAID DILI for 2004-2013.1 Aim: To update our clinical experience and report on HLA and other genetic factors recently described as important in idiosyncratic DILI. Methods: The US DILIN, begun in 2004; is comprised of clinical sites [currently 7 in number], a data coordinating center, and the NIDDK. We enroll subjects with suspected DILI and follow them for at least 6 months.2 We adjudicate causality both with RUCAM, and RECAM3 and by a Delphic approach4 and grade severity from mild to fatal or requiring liver transplant.5 Between Sep 2004 and Mar 2022, we enrolled 2,626 subjects and adjudicated causality at 6 months in 2,498. Following adjudication, we identified 55 [41 (75%) women] as definitely [ >95%], highly likely [75-95%], or probably [51-74% likely] due to NSAIDs. Results: Diclofenac was the causative drug in 29/55 [53%] of cases, followed by celecoxib [7], ibuprofen [5], etodolac and meloxicam [4 each]. Median latency was 51 d. With the notable exceptions of meloxicam and oxaprozin [n=2], the type of liver injury was hepatocellular with median R 15-25. 4 subjects died within 6 mo of onset, and 2 others [1 each due to diclofenac and celecoxib] required liver transplants. 7 had chronic DILI at 6+ mo. HLA DRB1*03:01 was more frequent in those with NSAID DILI than in matched controls, and 6/10 had the ancestral AI extended haplotype. The likelihood of carrying the DRB1*04:03 allele increased with causality score confidence and with more severe DILI [p =0.006]. Conclusion: NSAID DILI is relatively rare in the US. The most common cause is diclofenac, which, if prescribed, should carry with it special warnings of risk and close observation, as in the package insert. The increased frequencies of HLA DRB1*03:01, an HLA type known to be associated with SLE and other auto-immune disorders, and the extended ancestral AI haplotype, suggests that immune-mediated responses are of central importance in pathogenesis.