title: Risk of liver injury among methotrexate users: A meta-analysis of randomised controlled trials.
abstract: OBJECTIVE
  Methotrexate is an effective treatment for a variety of inflammatory diseases. Robust evidence on the risk of serious liver injury is lacking. The aim of this study was to evaluate the relative risk and severity of liver disease among patients treated with methotrexate.
  
  
  METHODS
  We searched PubMed and the Cochrane Central Register of Controlled Trials from 1 January 1990 to 24 April 2014 for double-blind randomised controlled trials of methotrexate versus comparator agents in adults with rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease. Studies with less than 100 subjects or of less than 24 weeks' duration were excluded. Two investigators independently searched both the databases. All authors reviewed the selected studies. We compared relative risk (RR) differences using the Mantel-Haenszel random effects method to assess total liver adverse events, minor liver enzyme abnormalities (≤ 3 ULN), major liver enzyme abnormalities (>3 ULN or treatment withdrawal) and a composite outcome of liver failure, fibrosis, cirrhosis or death.
  
  
  RESULTS
  A total of 32 studies with 13,177 participants met our inclusion criteria. Methotrexate was associated with an increased risk of total adverse liver events, RR = 2.19 (95% CI: 1.73-2.77, I(2) = 68%), as well as minor and major liver enzyme abnormalities, RR = 2.16 (95% CI: 1.67-2.79, I(2) = 68%) and RR = 2.63 (95% CI: 1.90-3.64, I(2) = 10%), respectively. Patients treated with methotrexate were not at increased risk of liver failure, cirrhosis or death, RR = 0.12 (95% CI: 0.01-1.09, I(2) = 0%).
  
  
  CONCLUSIONS
  Our study found an increased risk of elevated transaminases but not liver failure, cirrhosis or death with methotrexate compared to other agents. We were unable to assess long-term liver toxicity due to the short duration of included clinical trials.
authors.affiliation: Department of Rheumatology, Galway University Hospitals, Merlin Park, Galway, Ireland; National University of Ireland, Galway, Ireland. Electronic address: drrichardconway@gmail.com.
authors.forename: Richard
authors.initials: R
authors.lastname: Conway
authors.affiliation: Department of Rheumatology, Connolly Hospital, Blanchardstown, Dublin, Ireland.
authors.forename: Candice
authors.initials: C
authors.lastname: Low
authors.affiliation: Department of Rheumatology, Galway University Hospitals, Merlin Park, Galway, Ireland.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coughlan
authors.affiliation: National University of Ireland, Galway, Ireland.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: O'Donnell
authors.affiliation: Department of Rheumatology, Galway University Hospitals, Merlin Park, Galway, Ireland.
authors.forename: John J
authors.initials: JJ
authors.lastname: Carey
mesh_terms: D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D012306:Risk; D018570:Risk Assessment
chemical_list: D007166:Immunosuppressive Agents; D008727:Methotrexate
keywords: Drug-induced liver injury; Hepatitis; Liver; Meta-analysis; Methotrexate