J Neurol. 2003 Sep;250(9):1037-43
Dubois MD PhD B, Leary MRCP SM, Nelissen I, Opdenakker MD PhD G, Giovannoni
PhD G, Thompson MD AJ.
Institute of Neurology, London, UK.
BACKGROUND:
Interferon- beta (IFNbeta) acts by a variety of mechanisms in relapsing-remitting multiple sclerosis (MS).
One of these is a cellular down-regulation of gelatinase B or matrix metalloproteinase-9 (MMP-9), which is known from biochemical, biological and immunohistochemical evidences to play a disease-promoting role in MS.
AIMS:
a) To investigate the influence of IFNbeta-1a (30 or 60 micro g I.M./week) on serum MMP-9 levels in patients with primary progressive MS (PPMS).
b) To correlate serum MMP-9 levels with clinical and magnetic resonance imaging (MRI) findings.
METHODS:
Serial blood samples were collected every 3 months from 49 patients participating in a phase II trial of IFNbeta-1a in PPMS.
Serum MMP-9 was quantified by ELISA and correlations with clinical (EDSS) as well as MRI findings (brain and spinal cord atrophy, ventricular volume, T1 and T2 lesion load) were calculated.
RESULTS:
No significant differences were found between serial serum MMP-9 levels in IFNbeta-treated versus placebo-treated patients.
MMP-9 levels did not differ between patients who progressed or did not progress during the study interval.
Although mean absolute serum MMP-9 levels over the study period correlated with an increase in T2 lesion load (relative T2 change: r=0.51, p<0.001; absolute T2 change: r=0.30, p=0.038), absolute increase in brain ventricular volume (r=0.29, p=0.05) and increased brain atrophy (r=0.35, p=0.02), only the correlation with T2 lesion load was sustained throughout the study period.
No correlations were found between MMP-9 levels and relative changes in ventricular volume or with relative/absolute changes in T1 lesion load and in spinal cord atrophy.
None of the MRI measures correlated with MMP-9 changes between baseline levels and those on treatment.
CONCLUSION:
Although some evidence suggests a down-regulating effect of IFNbeta on MMP-9, this was not confirmed for a once weekly intramuscular dose of IFNbeta-1a in patients with PPMS.
The sustained correlation between serum MMP-9 and changes in T2 volumes, and the lack of correlation with clinical or MRI measures of disease progression may suggest that MMP-9 is more directly related to non-specific central nervous system damage than to axonal loss.