title: Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNβ-1b study.
abstract: Compared with controls, multiple sclerosis (MS) patients die, on average, 7-14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon β-1b, mortality was reduced by 46-47% in the two groups who received active therapy during the RCT. To determine whether the excessive deaths observed in placebo-treated patients was due to MS-related causes, we analysed the causes-of-death (CODs) in these three, randomised, patient cohorts.
  
  
  
  Long-term follow-up (LTF) of the pivotal RCT of interferon β-1b.
  
  
  
  Eleven North American MS-centres participated.
  
  
  
  In the original RCT, 372 patients participated, of whom 366 (98.4%) were identified after a median of 21.1 years from RCT enrolment.
  
  
  
  Using multiple information sources, we attempted to establish COD and its relationship to MS in deceased patients.
  
  
  
  An independent adjudication committee, masked to treatment assignment and using prespecified criteria, determined the likely CODs and their MS relationships.
  
  
  
  Among the 366 MS patients included in this LTF study, 81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years. COD, MS relationship, or both were determined for 88% of deaths (71/81). Patients were assigned to one of nine COD categories: cardiovascular disease/stroke; cancer; pulmonary infections; sepsis; accidents; suicide; death due to MS; other known CODs; and unknown COD. Of the 69 patients for whom information on the relationship of death to MS was available, 78.3% (54/69) were adjudicated to be MS related. Patients randomised to receive placebo during the RCT (compared with patients receiving active treatment) experienced an excessive number of MS-related deaths.
  
  
  
  In this long-term, randomised, cohort study, MS patients receiving placebo during the RCT experienced greater all-cause mortality compared to those on active treatment. The excessive mortality in the original placebo group was largely from MS-related causes, especially, MS-related pulmonary infections.
authors.affiliation: Department of Neurology,  University of California, San Francisco, California,  USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Goodin
authors.forename: George C
authors.initials: GC
authors.lastname: Ebers
authors.forename: Gary
authors.initials: G
authors.lastname: Cutter
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Cook
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Donnell
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Reder
authors.forename: Marcelo
authors.initials: M
authors.lastname: Kremenchutzky
authors.forename: Joel
authors.initials: J
authors.lastname: Oger
authors.forename: Mark
authors.initials: M
authors.lastname: Rametta
authors.forename: Karola
authors.initials: K
authors.lastname: Beckmann
authors.forename: Volker
authors.initials: V
authors.lastname: Knappertz