title: Is the treatment effect of IFN-beta restored after the disappearance of neutralizing antibodies?
abstract: OBJECTIVE
  To establish whether multiple sclerosis (MS) patients, who have lost the therapeutic effect of interferon-beta (IFN-beta) owing to neutralizing antibodies (NAbs) and subsequently revert from a NAb-positive to a NAb-negative state under continued IFN-beta-1b therapy, regain clinical effect after reversion.
  
  
  BACKGROUND
  Several studies have shown that a significant proportion of patients treated with IFN-beta develop NAbs that hamper or abolish the therapeutic effect of IFN-beta. However, some patients, who become NAb-positive under treatment with IFN-beta-1b, may revert to a NAb-negative state under continuous treatment.
  
  
  METHODS
  We identified 40 patients from the Danish IFN protocol, who fulfilled the criteria: NAb-positive status for at least 12 months followed by reversion to NAb-negative state for at least 12 months. For comparison, we included 64 matching cases that had remained NAb-negative during an observation time of at least 36 months. The two groups were clinically and demographically alike. We measured NAb-neutralizing capacity using a clinically validated cytopathic effect assay. A blood sample with a neutralizing capacity of 20% or more was considered as NAb-positive. A patient was defined as NAb-positive after two consecutive blood tests separated by at least 6 months. Reversion to a NAb-negative state required at least two consecutive negative tests. To allow for the confounding effect of time we employed a mixed Poisson model.
  
  
  RESULTS
  Patients who had been NAb-positive and reverted to a NAb-negative state regained treatment effect with the relapse rate as before the NAb-positive period adjusting for the effect of time, and the relapse rate was the same as in the permanently NAb-negative patients in corresponding time periods. The relapse rate ratio comparing the NAb-positive with the NAb-negative periods was 1.98 (95% confidence interval: 1.32-2.97).
  
  
  CONCLUSIONS
  Under NAb-positive periods, the clinical effect of IFN-beta was abolished. When NAbs disappeared spontaneously under continued treatment, patients regained the full effect of INF-beta-1b therapy with no negative carry-over effect from the previous NAb-positive period.
authors.affiliation: Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. pss@rh.regionh.dk
authors.forename: P S
authors.initials: PS
authors.lastname: Sorensen
authors.forename: N
authors.initials: N
authors.lastname: Koch-Henriksen
authors.forename: E M
authors.initials: EM
authors.lastname: Flachs
authors.forename: K
authors.initials: K
authors.lastname: Bendtzen
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000097:blood*; D005260:Female; D006801:Humans; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000008:administration & dosage* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology*; D009500:Neutralization Tests; D016012:Poisson Distribution; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D000276:Adjuvants, Immunologic; D000906:Antibodies; D000068576:Interferon beta-1b; D016899:Interferon-beta