Liver Injury From Tumor Necrosis Factor-α Antagonists: Analysis of Thirty-four Cases

Abstract

BACKGROUND & AIMS Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists. METHODS We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis. RESULTS The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti–TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2–104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation. CONCLUSIONS Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. ClinicalTrials.gov: Number, NCT00345930

New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease

“…Among the subgroup of patients in our study who underwent liver biopsy, all had an autoimmune hepatitis-like pattern of liver injury (an active hepatitis with interface activity and plasma cells, often with centrilobular hepatocyte necrosis/dropout), which is the commonest form reported in the literature. 12,13,15,18,19,21,23,[29][30][31] It is important to identify, as it can be severe requiring infliximab cessation and responds to treatment with corticosteroids. We could not identify any significant predictors that could differentiate definite from probable anti-TNF-induced liver injury, and specifically risk factors for autoimmune hepatitis on anti-TNF therapy.…”

“…22 The largest published series of 34 patients with 6 unique patients and 28 from the literature included only 12 patients with IBD, 11 due to infliximab and 1 related to adalimumab. 23 Case series may have a propensity to skew the data towards more severe disease, overlooking more frequently occurring mild cases and as such can lead to erroneous estimation of the true incidence. In addition, liver enzyme abnormalities in rheumatological or other autoimmune diseases may not be pertinent to an IBD cohort due to differences in comorbidity, use of concomitant medications, as well as inherent propensity to autoimmune liver disease.…”

Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis

“…As autoimmune hepatitis is characterised by hepatic inflammation and the proliferation of liver-infiltrating cytotoxic lymphocytes that differentiate and proliferate along a type 1 cytokine pathway, 227 agents that neutralise pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-a), have a strong rationale as anti-fibrotic therapies. 228 Such agents, however, including etanercept, 229,230 infliximab, 47,230 and pentoxifylline, 231 have either not improved mortality, had serious side effects, or exhibited no anti-fibrotic activity in diverse non-autoimmune liver diseases. Infliximab did rescue 7 of 11 patients with steroid-refractory autoimmune hepatitis, 47 but concerns about infectious complications 47,228 and drug-induced autoreactivity 230,[232][233][234] have justified a cautious interest in this agent.…”

Severe hepatic toxicity after administration of infliximab in psoriasis treatment

“…In general, patients who experienced increases in ALT and AST were asymptomatic, and these abnormal values have declined or disappeared from stopping or continuing treatment with infliximab or modification of concomitant therapies. In aftermarket studies, have been rarely reported cases of jaundice and non-infectious hepatitis, some with autoimmune hepatitis [4,5]. However, there were isolated cases of liver failure which led to liver transplantation or death.…”