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From UCSF Multiple Sclerosis Center (Drs. Waubant and Goodkin, and J. Hietpas) and Department of Epidemiology and Biostatistics (Drs. Bostrom and Bacchetti), University of California, San Francisco; and Department of Neurology (Drs. Lindberg and Leppert), University Hospital, Basel, Switzerland.
Address correspondence and reprint requests to Dr. Emmanuelle Waubant, UCSF Multiple Sclerosis Center, 350 Parnassus Avenue, Suite 908, San Francisco, CA 94117; e-mail: waubant{at}itsa.ucsf.edu
Objective: To 1)determine serum levels of matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 in patients with secondary progressive (SP) MS; 2)determine the relationship between these serum levels and MRI activity; and 3) evaluate the effect of interferon (IFN) therapy on these measures.
Background: High serum levels of MMP-9 and low levels of TIMP-1 predict the appearance of new gadolinium-enhancing (Gd+) lesions in relapsing-remitting (RR) MS.
Methods: Monthly Gd+ brain MRI and measures of serum MMP-2, MMP-9, TIMP-1, and TIMP-2 at 3-month intervals were performed for up to 3 years in 33 patients with SPMS participating in a phase III study of IFNß-1b.
Results: Patients who developed new Gd+ lesions had higher levels of MMP-9 than patients who did not develop Gd+ lesions (median 351 vs 226 ng/mL, p = 0.049). The ratio of MMP-9/TIMP-1 predicted new Gd+ lesion on the concurrent scan (OR = 2.23, 95% CI 0.99 to 4.99, p = 0.052) and on the following scan (OR = 2.16, 95% CI 1.01 to 4.63, p = 0.048), whereas levels of MMP-2/TIMP-2 did not. Median levels of TIMP-1 were higher and MMP-9 trended lower for IFNß compared to placebo recipients (TIMP-1: 1,450 vs 1,185 ng/mL, p = 0.024; MMP-9: 225 vs 339 ng/mL, p = 0.081). IFNß did not influence levels of MMP-2 and TIMP-2.
Conclusion: The ratio of MMP-9/TIMP-1 may predict MRI activity in SPMS. The effect of IFNß-1b in MS, as measured by reduction in new Gd+ lesions, may be partly explained by altering MMP-9/TIMP-1 ratio.
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