Hepatotoxicity Related to Antirheumatic Drugs

From Nature Reviews Rheumatology

Guruprasad P Aithal, BSc, MBBS, MD, PhD, FRCP


Abstract

Antirheumatic agents are among commonly used drugs associated with adverse hepatic reactions. Sulfasalazine and azathioprine are among the most important causes of acute hepatotoxicity. Because such a large number of people take NSAIDs, even the rare occurrence of hepatotoxicity from these agents might contribute substantially to the total burden of drug-induced liver disease. A wide spectrum of hepatotoxic effects is described with antirheumatic drugs. Studies investigating genetic susceptibility to diclofenac hepatotoxicity have expanded our understanding of the potential drug-specific, class-specific and general factors involved in its pathogenesis, and methotrexate-associated liver disease demonstrates the interaction between drug, host and environmental factors that determines the likelihood and magnitude of liver disease. Infliximab therapy is associated with typical drug-induced autoimmune hepatitis. Although validated causality assessment methods have been used to objectively assess the strength of the association between a drug and a clinical event, in practice the diagnosis of drug-induced liver injury (DILI) involves a clinical index of suspicion, pattern recognition, the establishment of a temporal relationship between drug exposure and the adverse event, and the exclusion of alternative explanations for the clinical presentation. Detailed understanding of genetic and environmental factors underlying an individual's susceptibility would enable risk reduction and potentially primary prevention of hepatotoxicity.
Introduction

Idiosyncratic hepatotoxicity is best described as an adverse hepatic reaction; that is, unexpected on the basis of the pharmacological action of a drug, hence unpredictable in its nature. During drug development, concordance between detection of hepatotoxic effects in animal studies and human trials remains poor (about 55%).[1] In addition, the frequency of clinically relevant liver injury is too low to assess accurately in clinical trials;[2] this difficulty is compounded by trial rules that mandate discontinuation of the medication at a point when 'self-resolving liver enzyme elevations' cannot be distinguished from drug-induced liver injury (DILI). Therefore, unexpected adverse hepatic reactions continue to account for the withdrawal of drugs from the market. Reports of acute liver failure associated with the NSAID bromfenac led to its withdrawal in 1998. Marketing of another NSAID, nimesulide, was suspended in Finland and Spain due to concerns regarding hepatotoxicity,[3] and the drug has never been approved in several other countries owing to similar concerns. Lumiracoxib, a selective inhibitor of cyclooxygenase-2, has been associated with serious liver injury at a rate of 6.39 incidents per 100,000 users (C. Paulding, personal communication). This association has led to the drug's widespread withdrawal or non-approval.[4] Such post-marketing withdrawals add to the overall cost of drug development.

Antirheumatic agents as a group are commonly associated with hepatotoxicity. A population-based case-control study that included 1.64 million subjects found sulfasalazine and azathioprine to be among the most hepatotoxic drugs of any class, both associated with an incidence of liver injury of about 1 per 1,000 users.[5] NSAIDs are among the most widely used medications worldwide. In the USA, 6% of the adult population reported using a prescription NSAID in a month and 24% non-prescription ibuprofen.[6] Therefore, even if rare, the occurrence of NSAID hepatotoxicity would contribute substantially to the total burden of drug-induced liver disease because of the large number of people taking these drugs.

A variety of terms has been used to define and characterize adverse hepatic reactions attributable to drugs ( Box 1 ). Despite clarification of these terms, case definitions and descriptions of hepatotoxicity are applied inconsistently in the literature. This Review includes a description of the spectrum of hepatotoxic effects related to antirheumatic agents, and the current understanding of the pathogenesis underlying these adverse reactions, which could point to opportunities for risk reduction.

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