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.
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.
Garcia-Montojo
M
M
Unidad de Esclerosis Múltiple, Servicio de Neurología, Hospital Clínico San Carlos, Madrid, Spain.
Dominguez-Mozo
M I
MI
de las Heras
V
V
Bartolome
M
M
Garcia-Martinez
A
A
Arroyo
R
R
Alvarez-Lafuente
R
R
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
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