title: Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases.
abstract: OBJECTIVE
  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.
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors: Marwan
authors: M
authors: Ghabril
authors: Herbert L
authors: HL
authors: Bonkovsky
authors: Clarissa
authors: C
authors: Kum
authors: Tim
authors: T
authors: Davern
authors: Paul H
authors: PH
authors: Hayashi
authors: David E
authors: DE
authors: Kleiner
authors: Jose
authors: J
authors: Serrano
authors: Jim
authors: J
authors: Rochon
authors: Robert J
authors: RJ
authors: Fontana
authors: Maurizio
authors: M
authors: Bonacini
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects*; D001327:Autoimmune Diseases / Q000139:chemically induced; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis / Q000139:chemically induced; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000009:adverse effects*; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects*; D000069285:Infliximab; D008099:Liver / Q000473:pathology; D008297:Male; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D014481:United States
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007155:Immunologic Factors; D018124:Receptors, Tumor Necrosis Factor; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept