title: Hepatic reactions during treatment of multiple sclerosis with interferon-beta-1a: incidence and clinical significance.
abstract: BACKGROUND
  Hepatic dysfunction, manifested as liver enzyme elevations, occurs frequently in patients who are treated with interferon, however, data for patients with multiple sclerosis are limited.
  
  
  OBJECTIVE
  To retrospectively assess the safety profile of interferon-beta-1a therapy with respect to liver function during clinical trials and postmarketing surveillance in the treatment of multiple sclerosis.
  
  
  METHODS
  Adverse effects and laboratory abnormalities were analysed from six randomised, controlled clinical trials (five of which were placebo-controlled) that assessed the use of interferon-beta-1a in patients with multiple sclerosis. Treatment data were collected for 2819 patients for up to 12 months, of whom 1995 received interferon-beta-1a (337 [12%] received Avonex intramuscular therapy, and 1658 [59%] received Rebif subcutaneous therapy), and 824 (29%) received placebo. Data for 2 years were collated for 1178 patients (from two studies). Total weekly interferon doses were 22-132 microg. Postmarketing surveillance data were also analysed.
  
  
  RESULTS
  In patients receiving interferon-beta-1a, there were significant elevations of alanine aminotransferase (ALT) levels, of all grades of severity, in up to 59% of patients at 6 months, up to 64% of patients at 12 months and up to 67% of patients at 24 months; ALT elevations were asymptomatic and dose related. More than 50% of elevations in liver enzymes occurred during the first 3 months of treatment, and more than 75% occurred during the first 6 months. Elevated enzyme levels resolved spontaneously or with dosage adjustment. Although the overall incidence of liver enzyme elevation was high during the early months of therapy, after 2 years, the proportion of patients with abnormal liver enzyme levels was 11% of those receiving Rebif 44 microg three times weekly compared with 6% of placebo-treated patients. Only 0.4% of patients discontinued interferon-beta-1a treatment because of hepatic adverse effects. Serious symptomatic interferon-related hepatic toxicity occurs, but is uncommon. Concomitant medication use was not associated with increased risk.
  
  
  CONCLUSIONS
  Asymptomatic hepatic dysfunction is common in patients with multiple sclerosis who are treated with interferon-beta-1a, and is dose related. Adverse effects are mainly mild and transient, with little impact on adherence to therapy, although rare serious events can occur. Regular liver function monitoring during the first 6 months is recommended.
authors.affiliation: Serono Inc, Rockland, Massachusetts, USA. gordon.francis@serono.com
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Francis
authors.forename: Yves
authors.initials: Y
authors.lastname: Grumser
authors.forename: Enrica
authors.initials: E
authors.lastname: Alteri
authors.forename: Alain
authors.initials: A
authors.lastname: Micaleff
authors.forename: Fanny
authors.initials: F
authors.lastname: O'Brien
authors.forename: Jonathan
authors.initials: J
authors.lastname: Alsop
authors.forename: Margaretha
authors.initials: M
authors.lastname: Stam Moraga
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects*; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D002986:Clinical Trials as Topic; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008107:Liver Diseases / Q000201:enzymology; D008111:Liver Function Tests; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000628:therapy*; D010349:Patient Compliance; D011358:Product Surveillance, Postmarketing; D012189:Retrospective Studies
chemical_list: D000276:Adjuvants, Immunologic; D016899:Interferon-beta; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin; D000068556:Interferon beta-1a