title: Investigation of heterogeneity in the association between interferon beta and disability progression in multiple sclerosis: an observational study.
abstract: OBJECTIVE
  It was recently reported that there was no significant overall association between interferon beta exposure and disability progression in relapsing-remitting multiple sclerosis (RRMS) patients in an observational study from Canada. In the current study, the potential for heterogeneity in the association between exposure to interferon beta and disability progression across patients' baseline characteristics was investigated.
  
  
  METHODS
  RRMS patients treated with interferon beta (n = 868) and two cohorts of untreated patients (829 contemporary and 959 historical controls) were included. The main outcome was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained Expanded Disability Status Scale (EDSS) score 6 using a multivariable Cox model, with treatment as a time-varying predictor, testing interaction effects for five pre-specified baseline characteristics: sex, age, disease duration, EDSS and annualized relapse rate (ARR) based on the previous 2 years.
  
  
  RESULTS
  Significant heterogeneity was found in the association of interferon beta exposure and disability progression only across ARR, and only when treated patients were compared with historical controls (P = 0.005 at a Bonferroni-adjusted alpha of 0.01). For patients with ARR>1, treatment-exposed time was associated with a hazard ratio of 0.38 (95%CI 0.20-0.75) for disability progression compared with the unexposed time.
  
  
  CONCLUSIONS
  RRMS patients with more frequent relapses at baseline may be more likely to benefit from interferon beta treatment with respect to long-term disability progression.
authors.affiliation: Department of Medicine, Division of Neurology and Brain Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Shirani
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: M E
authors.initials: ME
authors.lastname: Karim
authors.forename: J
authors.initials: J
authors.lastname: Petkau
authors.forename: P
authors.initials: P
authors.lastname: Gustafson
authors.forename: C
authors.initials: C
authors.lastname: Evans
authors.forename: E
authors.initials: E
authors.lastname: Kingwell
authors.forename: M L
authors.initials: ML
authors.lastname: van der Kop
authors.forename: J
authors.initials: J
authors.lastname: Oger
authors.forename: H
authors.initials: H
authors.lastname: Tremlett
mesh_terms: D000328:Adult; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology; D012189:Retrospective Studies
chemical_list: D007155:Immunologic Factors; D016899:Interferon-beta
keywords: British Columbia; disability progression; interferon beta; multiple sclerosis; observational studies