title: Neutralizing antibodies to interferon beta-1b multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial.
abstract: BACKGROUND
  The frequency and impact of neutralizing antibodies (NAbs) to interferon beta-1b (IFNβ-1b) on clinical and radiographic outcomes is controversial.
  
  
  OBJECTIVE
  To assess NAb impact in the BEYOND study.
  
  
  METHODS
  2244 patients were randomized (2:2:1) to receive IFNβ-1b, either 250 or 500 µg, or glatiramer acetate, 20 mg, and observed for 2-3.5 years. NAb titers were determined every 6 months. A titer ≥20 NU/ml was considered NAb positive. Efficacy was compared between NAb-positive and NAb-negative patients, using comprehensive statistical analyses, taking into account the delayed appearance of NAbs, the time-dependent changes in the relapse rate, spontaneous reversions to NAb-negative status, NAb-titer level, and also adjusting for baseline factors.
  
  
  RESULTS
  In the IFNβ-1b 250 µg group, NAb-positive titers were detected (≥ once) in 319 patients (37.0%); of these, 112 (35.1%) reverted to NAb-negative status. In the IFNβ-1b 500 µg group, 340 patients (40.7%) became NAb-positive and 119 (35.0%) reverted to NAb-negative status. In both IFNβ groups, especially the 250 µg arm, NAb-positive status was not associated with a convincing impact on any clinical outcome measure by any statistical analysis. By contrast, in both IFNβ groups, NAbs were associated with a very consistent deleterious impact on most MRI outcomes.
  
  
  CONCLUSIONS
  There was a notable dissociation between the impact of NAbs on MRI and clinical outcomes. On MRI measures, the impact was consistent and convincing, whereas on clinical measures a negative impact of NAbs was not found. The basis for this clinico-radiographic paradox is unknown but it suggests that the relationship between NAbs and the therapeutic effects of IFNβ-1b is complex.
authors.affiliation: University of California at San Francisco, CA 94143-0114, USA. douglas.goodin@ucsf.edu
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Goodin
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Paul
authors.initials: P
authors.lastname: O'Connor
authors.forename: Massimo
authors.initials: M
authors.lastname: Filippi
authors.forename: Barry
authors.initials: B
authors.lastname: Arnason
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Stuart
authors.initials: S
authors.lastname: Cook
authors.forename: Douglas
authors.initials: D
authors.lastname: Jeffery
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.forename: Timon
authors.initials: T
authors.lastname: Bogumil
authors.forename: Volker
authors.initials: V
authors.lastname: Knappertz
authors.forename: Rupert
authors.initials: R
authors.lastname: Sandbrink
authors.forename: Karola
authors.initials: K
authors.lastname: Beckmann
authors.forename: Rick
authors.initials: R
authors.lastname: White
authors.forename: John
authors.initials: J
authors.lastname: Petkau
authors.forename: Christoph
authors.initials: C
authors.lastname: Pohl
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood*; D003430:Cross-Sectional Studies; D004185:Disability Evaluation; D004351:Drug Resistance / Q000276:immunology*; D005682:Gadolinium; D006801:Humans; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000276:immunology* / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D012008:Recurrence; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000068576:Interferon beta-1b; D016899:Interferon-beta; D005682:Gadolinium