title: Risk of drug-induced liver injury from tumor necrosis factor antagonists.
abstract: OBJECTIVE
  Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk.
  
  
  METHODS
  We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n = 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n = 22).
  
  
  RESULTS
  Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n = 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 μmol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P = .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI.
  
  
  CONCLUSIONS
  Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Division of Gastroenterology and Hepatology, The National University Hospital of Iceland, Reykjavik, Iceland. Electronic address: einarsb@landspitali.is.
authors.forename: Einar S
authors.initials: ES
authors.lastname: Björnsson
authors.affiliation: Division of Gastroenterology and Hepatology, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Baldvin I
authors.initials: BI
authors.lastname: Gunnarsson
authors.affiliation: Division of Rheumatology, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Gerdur
authors.initials: G
authors.lastname: Gröndal
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Department of Pathology, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Jon G
authors.initials: JG
authors.lastname: Jonasson
authors.affiliation: Division of Rheumatology, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Rannveig
authors.initials: R
authors.lastname: Einarsdottir
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Department of Immunology, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Björn R
authors.initials: BR
authors.lastname: Ludviksson
authors.affiliation: Centre for Rheumatology Research, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Björn
authors.initials: B
authors.lastname: Gudbjörnsson
authors.affiliation: Division of Gastroenterology and Hepatology, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Sigurdur
authors.initials: S
authors.lastname: Olafsson
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology*; D005260:Female; D006785:Hospitals, University; D006801:Humans; D007055:Iceland / Q000453:epidemiology; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects*; D000069285:Infliximab; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D015995:Prevalence; D011446:Prospective Studies; D018570:Risk Assessment; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D008727:Methotrexate
keywords: ANA; Autoimmune Hepatitis; Liver Disease; TNF-α; Toxicity