title: Neutralizing antibodies, MxA expression and MMP-9/TIMP-1 ratio as markers of bioavailability of interferon-beta treatment in multiple sclerosis patients: a two-year follow-up study.
abstract: BACKGROUND
  The objective of this study was to correlate the detection of neutralizing antibodies (NAbs) by the cytopathic effect (CPE) assay, with the expression of myxovirus resistance protein A (MxA), and the ratio between matrix metalloproteinase 9 (MMP-9) and its tissular inhibitor (TIMP-1), in order to evaluate their usefulness as markers of interferon beta (IFN-beta) bioavailability.
  
  
  METHODS
  Pairs of blood and serum samples were collected from 50 patients with multiple sclerosis (MS) during 2 years of IFN-beta treatment. Expression of MxA, MMP-9 and TIMP-1 were analysed by quantitative PCR, and NAbs were measured by CPE assay.
  
  
  RESULTS
  During the study, 60% of patients presented NAbs. The number of serum samples that were NAbs+ was significantly increased amongst patients with relapses (41/92 vs. 33/108, P = 0.04). With one serum sample and with a NAb titre >100 tenfold reduction unit (TRU), 66.7% of patients with MS suffered from relapses, 41.7% suffered from progression, and 75% was not an optimal clinical responder. We did not find any significant difference in MxA. We found that 62.5% of patients with MS patients whose ratio was increased twofold after 2 years suffered from relapses, 37.5% suffered from progression, and 68.7% was not an optimal clinical responder.
  
  
  CONCLUSIONS
  The early detection of NAbs by CPE assay and the finding of only one serum sample with a NAb titre >100 TRU seem to be markers of low bioavailability of IFN-beta, whilst a twofold decrease in the MMP-9/TIMP-1 ratio by quantitative PCR assay seems to be a marker of high bioavailability of IFN-beta.
authors.affiliation: Unidad de Esclerosis Múltiple, Servicio de Neurología, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Garcia-Montojo
authors.forename: M I
authors.initials: MI
authors.lastname: Dominguez-Mozo
authors.forename: V
authors.initials: V
authors.lastname: de las Heras
authors.forename: M
authors.initials: M
authors.lastname: Bartolome
authors.forename: A
authors.initials: A
authors.lastname: Garcia-Martinez
authors.forename: R
authors.initials: R
authors.lastname: Arroyo
authors.forename: R
authors.initials: R
authors.lastname: Alvarez-Lafuente
mesh_terms: D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D019204:GTP-Binding Proteins / Q000097:blood; D006801:Humans; D007155:Immunologic Factors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016899:Interferon-beta / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D064547:Myxovirus Resistance Proteins; D011446:Prospective Studies; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood
chemical_list: D057134:Antibodies, Neutralizing; D015415:Biomarkers; D007155:Immunologic Factors; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D016899:Interferon-beta; D020780:Matrix Metalloproteinase 9; D019204:GTP-Binding Proteins