Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development

Mult Scler. 2014 Apr;20(5):577-87. doi: 10.1177/1352458513503597. Epub 2013 Sep 5.

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.

Objectives: 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.

Keywords: Binding antibody; CXCL-10; biomarker; clinically-isolated syndrome; drug resistance; interferon-beta; multicenter study; multiple sclerosis; myxovirus protein A; neutralizing antibody; sTRAIL.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Neutralizing / blood*
  • Biomarkers / blood
  • Chemokine CXCL10 / blood
  • Demyelinating Diseases / blood
  • Demyelinating Diseases / diagnosis
  • Demyelinating Diseases / drug therapy*
  • Demyelinating Diseases / immunology*
  • Early Diagnosis
  • Europe
  • Female
  • Humans
  • Immunologic Factors / immunology*
  • Immunologic Factors / therapeutic use*
  • Interferon-beta / immunology*
  • Interferon-beta / therapeutic use*
  • Male
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting / blood
  • Multiple Sclerosis, Relapsing-Remitting / diagnosis
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy*
  • Multiple Sclerosis, Relapsing-Remitting / genetics
  • Multiple Sclerosis, Relapsing-Remitting / immunology*
  • Myxovirus Resistance Proteins / genetics
  • Predictive Value of Tests
  • Prospective Studies
  • TNF-Related Apoptosis-Inducing Ligand / blood
  • Time Factors
  • Treatment Outcome

Substances

  • Antibodies, Neutralizing
  • Biomarkers
  • CXCL10 protein, human
  • Chemokine CXCL10
  • Immunologic Factors
  • MX1 protein, human
  • Myxovirus Resistance Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Interferon-beta