IFNbeta lowers MMP-9/TIMP-1 ratio, which predicts new enhancing lesions in patients with SPMS.
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 IFNbeta-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 IFNbeta 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). IFNbeta did not influence levels of MMP-2 and TIMP-2.


CONCLUSIONS
The ratio of MMP-9/TIMP-1 may predict MRI activity in SPMS. The effect of IFNbeta-1b in MS, as measured by reduction in new Gd+ lesions, may be partly explained by altering MMP-9/TIMP-1 ratio.
Waubant
E
E
UCSF Multiple Sclerosis Center, University of California, San Francisco 94117, USA. waubant@itsa.ucsf.edu
Goodkin
D
D
Bostrom
A
A
Bacchetti
P
P
Hietpas
J
J
Lindberg
R
R
Leppert
D
D
D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005682:Gadolinium; D006801:Humans; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D011237:Predictive Value of Tests; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood
D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D000068576:Interferon beta-1b; D016899:Interferon-beta; D005682:Gadolinium; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000068556:Interferon beta-1a