Wise Young
04-16-2002, 08:39 PM
[P03.070] Serum Levels of MMP-9 and TIMP-1 Predict MRI Activity in Patients with Secondary Progressive MS and Interferon Therapy Shifts MMP-9/TIMP-1 towards Normal
Emmanuelle L. Waubant, Donald E. Goodkin, Alan Bostrom, Peter Bacchetti, Jean Hietpas, Francine Hoffman, Raija Lindberg, David LeppertĀ*San Francisco, CA; Seattle, WA; Basel, Switzerland
OBJECTIVE: To (1) determine the relationship between serum levels of matrix metalloproteinase-2 (MMP-2) and -9, and tissue inhibitor of MMP-type 1 (TIMP-1) and -2 (TIMP-2) and MRI activity in patients with secondary progressive (SP) multiple sclerosis (MS), and (2) evaluate the effect of interferon beta (IFNB) therapy on these markers.
BACKGROUND: High serum levels of MMP-9, an enzyme facilitating migration of T-cells and macrophages across vascular subendothelial basement membranes, and low levels of TIMP-1, its natural inhibitor, predict the appearance of new gadolinium-enhancing (Gd+) lesions in relapsing-remitting (RR) MS. It is not known whether this imbalance persists at later stages of the disease, nor what is the effect of IFNB therapy on this imbalance.
DESIGN/METHODS: Monthly gadolinium-enhanced brain MRIs and three-monthly measures of serum MMP-2 and -9, TIMP-1 and -2 were performed for up to 3 years in 33 patients (21 females) with SPMS participating to the North American multicenter phase III study of IFNB-1b (10 on placebo, 23 on IFNB-1b eod). Within-patient median concentrations were tested for a difference between the two groups using an exact Mann-Whitney test. The relationship between serum levels of MMP-2 and 9, and TIMP 1 and -2, and presence of new Gd+ lesions was evaluated using univariate repeated measures logistic regression models. All time points within 4 weeks of steroid administration were removed from the analysis.
RESULTS: At baseline, mean age was 47.8 years +/-6.4, mean disease duration 12.8 years +/- 6.9, and median EDSS 6.0 (range 2.5-6.5). During study participation (141.8 weeks +/- 21), mean number of exacerbations was 0.33 +/- 0.6 and mean number of monthly new Gd+ lesions/patient was 1.49 +/- 0.14. 35 treatments with intravenous methylprednisolone 500 mg qd for 3 days were administered. 11 patients failed to show any new Gd+ lesions during the study. Patients who developed new Gd+ lesions during follow-up had higher levels of MMP-9 than patients who did not (respective within-patients medians 356 versus 219 ng/ml, p=0.01). In a univariate analysis, levels of MMP-9/TIMP-1 above within-patient medians predicted new Gd+ lesion on the concurrent scans (OR = 6.49, 95%CI 1.89 to 22.30, p=0.004) and to a lesser extent on the following scan (OR = 3.54, 95%CI 1.36 to 9.16, p=0.011) in the IFNB group. In contrast, levels of MMP-2 and TIMP-2 did not predict occurrence of new Gd+ lesions. Serum levels of TIMP-1 were significantly higher and MMP-9 lower on IFNB compared to placebo (respectively, within-patient median TIMP-1 : 1489 versus1178 ng/ml, p=0.01; within-patient median MMP-9 : 222 versus 361 ng/ml, p=0.03). IFNB did not influence levels of MMP-2 and TIMP-2.
CONCLUSIONS: Serum levels of MMP-9 and TIMP-1, but not MMP-2 and TIMP-2, predict MRI activity in SPMS. IFNB therapy may shift the balance between MMP-9 and TIMP-1 towards normal, thereby decreasing proteolytic activity and at least in part reducing the number of new Gd+ lesions.
Supported By: This study was supported by the National Multiple Sclerosis Society (USA) (PP0733) and the Swiss Multiple Sclerosis Society
Category - MS and Related Diseases
SubCategory - Imaging
Emmanuelle L. Waubant, Donald E. Goodkin, Alan Bostrom, Peter Bacchetti, Jean Hietpas, Francine Hoffman, Raija Lindberg, David LeppertĀ*San Francisco, CA; Seattle, WA; Basel, Switzerland
OBJECTIVE: To (1) determine the relationship between serum levels of matrix metalloproteinase-2 (MMP-2) and -9, and tissue inhibitor of MMP-type 1 (TIMP-1) and -2 (TIMP-2) and MRI activity in patients with secondary progressive (SP) multiple sclerosis (MS), and (2) evaluate the effect of interferon beta (IFNB) therapy on these markers.
BACKGROUND: High serum levels of MMP-9, an enzyme facilitating migration of T-cells and macrophages across vascular subendothelial basement membranes, and low levels of TIMP-1, its natural inhibitor, predict the appearance of new gadolinium-enhancing (Gd+) lesions in relapsing-remitting (RR) MS. It is not known whether this imbalance persists at later stages of the disease, nor what is the effect of IFNB therapy on this imbalance.
DESIGN/METHODS: Monthly gadolinium-enhanced brain MRIs and three-monthly measures of serum MMP-2 and -9, TIMP-1 and -2 were performed for up to 3 years in 33 patients (21 females) with SPMS participating to the North American multicenter phase III study of IFNB-1b (10 on placebo, 23 on IFNB-1b eod). Within-patient median concentrations were tested for a difference between the two groups using an exact Mann-Whitney test. The relationship between serum levels of MMP-2 and 9, and TIMP 1 and -2, and presence of new Gd+ lesions was evaluated using univariate repeated measures logistic regression models. All time points within 4 weeks of steroid administration were removed from the analysis.
RESULTS: At baseline, mean age was 47.8 years +/-6.4, mean disease duration 12.8 years +/- 6.9, and median EDSS 6.0 (range 2.5-6.5). During study participation (141.8 weeks +/- 21), mean number of exacerbations was 0.33 +/- 0.6 and mean number of monthly new Gd+ lesions/patient was 1.49 +/- 0.14. 35 treatments with intravenous methylprednisolone 500 mg qd for 3 days were administered. 11 patients failed to show any new Gd+ lesions during the study. Patients who developed new Gd+ lesions during follow-up had higher levels of MMP-9 than patients who did not (respective within-patients medians 356 versus 219 ng/ml, p=0.01). In a univariate analysis, levels of MMP-9/TIMP-1 above within-patient medians predicted new Gd+ lesion on the concurrent scans (OR = 6.49, 95%CI 1.89 to 22.30, p=0.004) and to a lesser extent on the following scan (OR = 3.54, 95%CI 1.36 to 9.16, p=0.011) in the IFNB group. In contrast, levels of MMP-2 and TIMP-2 did not predict occurrence of new Gd+ lesions. Serum levels of TIMP-1 were significantly higher and MMP-9 lower on IFNB compared to placebo (respectively, within-patient median TIMP-1 : 1489 versus1178 ng/ml, p=0.01; within-patient median MMP-9 : 222 versus 361 ng/ml, p=0.03). IFNB did not influence levels of MMP-2 and TIMP-2.
CONCLUSIONS: Serum levels of MMP-9 and TIMP-1, but not MMP-2 and TIMP-2, predict MRI activity in SPMS. IFNB therapy may shift the balance between MMP-9 and TIMP-1 towards normal, thereby decreasing proteolytic activity and at least in part reducing the number of new Gd+ lesions.
Supported By: This study was supported by the National Multiple Sclerosis Society (USA) (PP0733) and the Swiss Multiple Sclerosis Society
Category - MS and Related Diseases
SubCategory - Imaging