title: Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development.
abstract: BACKGROUND
  Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis (MS) patients. NAbs evolve in up to 44% of treated patients, usually between 6-18 months on therapy.
  
  
  OBJECTIVE
  To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution.
  
  
  METHODS
  We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment in this prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2.
  
  
  RESULTS
  We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b treatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers ≥ 1:2400 predicted NAb evolution with a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the BAb/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAb-negative samples, respectively, were also diminished compared to BAb/NAb-negative samples.
  
  
  CONCLUSIONS
  BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its abrogation by anti-IFN-b antibodies.
authors.affiliation: Department of Neurology, Innsbruck Medical University, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Hegen
authors.forename: A
authors.initials: A
authors.lastname: Millonig
authors.forename: A
authors.initials: A
authors.lastname: Bertolotto
authors.forename: M
authors.initials: M
authors.lastname: Comabella
authors.forename: G
authors.initials: G
authors.lastname: Giovanonni
authors.forename: M
authors.initials: M
authors.lastname: Guger
authors.forename: M
authors.initials: M
authors.lastname: Hoelzl
authors.forename: M
authors.initials: M
authors.lastname: Khalil
authors.forename: J
authors.initials: J
authors.lastname: Killestein
authors.forename: R
authors.initials: R
authors.lastname: Lindberg
authors.forename: S
authors.initials: S
authors.lastname: Malucchi
authors.forename: M
authors.initials: M
authors.lastname: Mehling
authors.forename: X
authors.initials: X
authors.lastname: Montalban
authors.forename: C H
authors.initials: CH
authors.lastname: Polman
authors.forename: D
authors.initials: D
authors.lastname: Rudzki
authors.forename: F
authors.initials: F
authors.lastname: Schautzer
authors.forename: F
authors.initials: F
authors.lastname: Sellebjerg
authors.forename: P S
authors.initials: PS
authors.lastname: Sørensen
authors.forename: F
authors.initials: F
authors.lastname: Deisenhammer
mesh_terms: D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D054357:Chemokine CXCL10 / Q000097:blood; D003711:Demyelinating Diseases / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*; D042241:Early Diagnosis; D005060:Europe; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology* / Q000627:therapeutic use*; D016899:Interferon-beta / Q000276:immunology* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D064547:Myxovirus Resistance Proteins / Q000235:genetics; D011237:Predictive Value of Tests; D011446:Prospective Studies; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D057134:Antibodies, Neutralizing; D015415:Biomarkers; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007155:Immunologic Factors; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D016899:Interferon-beta
keywords: Binding antibody; CXCL-10; biomarker; clinically-isolated syndrome; drug resistance; interferon-beta; multicenter study; multiple sclerosis; myxovirus protein A; neutralizing antibody; sTRAIL