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

• Published in: European journal of neurology Vol. 17; no. 3; pp. 470 - 478
• Main Authors: Garcia-Montojo, M., Dominguez-Mozo, M. I., De Las Heras, V., Bartolome, M., Garcia-Martinez, A., Arroyo, R., Alvarez-Lafuente, R.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-03-2010; John Wiley & Sons, Inc
• Subjects: Adult; Antibodies, Neutralizing - blood; Bioavailability; Biological Availability; Biomarkers - blood; CPE; Female; Follow-Up Studies; GTP-Binding Proteins - blood; Humans; Immunologic Factors - pharmacokinetics; Immunologic Factors - therapeutic use; Interferon; interferon-beta; Interferon-beta - pharmacokinetics; Interferon-beta - therapeutic use; Male; Matrix Metalloproteinase 9 - blood; MMP-9; Multiple sclerosis; Multiple Sclerosis, Relapsing-Remitting - blood; Multiple Sclerosis, Relapsing-Remitting - drug therapy; Multiple Sclerosis, Relapsing-Remitting - immunology; MxA; Myxovirus Resistance Proteins; neutralizing antibodies; Prospective Studies; Time Factors; TIMP-1; Tissue Inhibitor of Metalloproteinase-1 - blood
• ISSN: 1351-5101; 1468-1331
• DOI: 10.1111/j.1468-1331.2009.02890.x

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.
Conclusion:  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.