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Serum gelatinase B/MMP-9 in primary progressive multiple sclerosis patients treated with interferon-beta-1a
Bénédicte Dubois1, Siobhan M Leary, Inge Nelissen
1Institute 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.
Insights
Interferon beta-1a did not alter serum MMP-9 levels in primary progressive multiple sclerosis (PPMS) patients. While MMP-9 correlated with T2 lesion load, it did not reflect overall disease progression or axonal loss.
Area of Science:
- Neuroimmunology
- Biochemistry
Background:
- Interferon-beta (IFNbeta) modulates relapsing-remitting multiple sclerosis (MS) through various mechanisms.
- Matrix metalloproteinase-9 (MMP-9) is implicated in MS pathogenesis and is a potential target for IFNbeta therapy.
Purpose of the Study:
- To evaluate the effect of intramuscular IFNbeta-1a on serum MMP-9 levels in primary progressive MS (PPMS).
- To correlate serum MMP-9 levels with clinical and MRI-defined disease parameters in PPMS patients.
Main Methods:
- A phase II trial involving 49 PPMS patients treated with IFNbeta-1a or placebo.
- Serum MMP-9 levels were measured via ELISA at 3-month intervals.
- Correlations were assessed between MMP-9 and clinical (EDSS) and MRI (lesion load, atrophy) metrics.
Main Results:
- No significant differences in serum MMP-9 levels were observed between IFNbeta-1a treated and placebo groups.
- Serum MMP-9 levels did not correlate with clinical progression or most MRI measures of disease activity.
- A sustained correlation was found between MMP-9 levels and T2 lesion load changes.
Conclusions:
- Intramuscular IFNbeta-1a at a weekly dose did not down-regulate serum MMP-9 in PPMS patients.
- MMP-9's correlation with T2 lesions suggests a role in non-specific CNS damage rather than axonal loss.
- Further research is needed to clarify MMP-9's role in MS progression.
