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Figure.
Mean (SEM) serum levels of active matrix metalloproteinase 9 (MMP-9) (A), tissue inhibitor of metalloproteinase 1 (TIMP-1) (C), and active MMP-9–TIMP-1 ratio (E) in control subjects (n = 10) and in patients with relapsing-remitting multiple sclerosis (MS) at baseline (n = 28). Mean (SEM) serum levels of active MMP-9 (B), TIMP-1 (D), and active MMP-9–TIMP-1 ratio (F) in patients with relapsing-remitting MS following either a monotherapy of interferon beta for 9 months (n = 12) or a monotherapy of interferon beta for 3 months followed by a combination therapy of interferon beta and atorvastatin for 6 months (n = 16).

Mean (SEM) serum levels of active matrix metalloproteinase 9 (MMP-9) (A), tissue inhibitor of metalloproteinase 1 (TIMP-1) (C), and active MMP-9–TIMP-1 ratio (E) in control subjects (n = 10) and in patients with relapsing-remitting multiple sclerosis (MS) at baseline (n = 28). Mean (SEM) serum levels of active MMP-9 (B), TIMP-1 (D), and active MMP-9–TIMP-1 ratio (F) in patients with relapsing-remitting MS following either a monotherapy of interferon beta for 9 months (n = 12) or a monotherapy of interferon beta for 3 months followed by a combination therapy of interferon beta and atorvastatin for 6 months (n = 16).

1.
Yong  VWZabad  RKAgrawal  SGoncalves Dasilva  AMetz  LM Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. J Neurol Sci 2007;259 (1-2) 79- 84
PubMed
2.
Leppert  DWaubant  EBurk  MROksenberg  JRHauser  SL Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis. Ann Neurol 1996;40 (6) 846- 852
PubMed
3.
Stüve  ODooley  NPUhm  JH  et al.  Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. Ann Neurol 1996;40 (6) 853- 863
PubMed
4.
Kieseier  BCArchelos  JJHartung  HP Different effects of simvastatin and interferon beta on the proteolytic activity of matrix metalloproteinases. Arch Neurol 2004;61 (6) 929- 932
PubMed
5.
Polman  CHReingold  SCEdan  G  et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005;58 (6) 840- 846
PubMed
6.
Fainardi  ECastellazzi  MBellini  T  et al.  Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis. Mult Scler 2006;12 (3) 294- 301
PubMed
7.
Waubant  EGoodkin  DEGee  L  et al.  Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis. Neurology 1999;53 (7) 1397- 1401
PubMed
Research Letters
May 2008

Atorvastatin Does Not Alter Interferon Beta–Induced Changes of Serum Matrix Metalloproteinase 9 and Tissue Inhibitor of Metalloproteinase 1 in Patients With Multiple Sclerosis

Arch Neurol. 2008;65(5):672-677. doi:10.1001/archneur.65.5.672

Interferon beta, the current cornerstone of multiple sclerosis (MS) therapy, was shown to reduce the ratio of matrix metalloproteinase 9 (MMP-9)–tissue inhibitor of metalloproteinase 1 (TIMP-1) in order to attenuate overactive proteolysis and inhibit leukocyte migration.13 Matrix metalloproteinases, a family of extracellular matrix-degrading enzymes, are involved in the pathogenesis of MS by facilitating leukocyte migration, disruption of the blood-brain barrier, processing of cytokines and their receptors, and demyelination.1

Immunomodulatory properties of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, including atorvastatin, may be beneficial for the treatment of MS. Among the immunomodulatory effects proposed for statins, increased attention is drawn to the modulation of MMPs. In vitro results suggest that statins may increase MMP-9 activity and disrupt the proteolytic balance restored by interferon beta.1,4

In this study, we aimed to evaluate the treatment effects of interferon beta alone and in combination with atorvastatin on parameters of proteolysis, ie, serum levels of active MMP-9 and TIMP-1 and the active MMP-9–TIMP-1 ratio in patients with relapsing-remitting MS.

Methods

Sequential serum samples were obtained from 28 patients (mean age, 33.4 years; mean Expanded Disability Status Scale score, 2.0) participating in the Swiss Atorvastatin and Betaferon in Multiple Sclerosis Trial with approval of the Cantonal Ethical Review Board (permit 17/05). In this study, patients with relapsing-remitting MS are treated with interferon beta-1b monotherapy (250 μg every other day, subcutaneous) or with a combination of interferon beta-1b (250 μg every other day, subcutaneous) and atorvastatin calcium (40 mg orally). All of the included patients were treated de novo with interferon beta for 3 months, prior to randomization to a monotreatment or combination treatment (n = 12 and n = 16, respectively). Patients in the Swiss Atorvastatin and Betaferon in Multiple Sclerosis Trial were diagnosed with MS according to the McDonald criteria: disease duration of 3 months or longer, an Expanded Disability Status Scale score of 0 to 3.5 at baseline, and at least 1 relapse in the past 2 years.5 A 1-month interval between the last relapse and/or prednisone treatment was mandatory for baseline enrollment of the respective patient. The control group consisted of 10 age-matched healthy control subjects (mean age, 34.7 years) after obtaining informed consent.

Serum samples were collected by standard procedures and stored at −80°C until use. Active MMP-9 and TIMP-1 levels were determined with sandwich-type enzyme-linked immunosorbent assay kits (GE Healthcare, Buckinghamshire, England) that had been proven reliable in MS studies.6 Special emphasis was paid to identical sample collection and processing conditions to minimize possible interference by preanalytical variations. Samples were diluted 1:40, and the detection limits were 0.5 ng/mL (active MMP-9) and 1.25 ng/mL (TIMP-1). The comparisons between control subjects and patients with MS (baseline) and intergroup treatment effects at 3, 6, and 9 months were performed with a Mann-Whitney U test. Changes over time were evaluated with a Wilcoxon signed rank test. P < .05 was considered to be statistically significant.

Results

In patients with MS, significantly higher levels of active MMP-9 (P < .001) (Figure, A) and a higher active MMP-9–TIMP-1 ratio (P = .002) (Figure, E) were detected at baseline as compared with the values found in serum samples from control subjects. Serum levels of TIMP-1 were significantly decreased in patients with MS (P = .049) (Figure, C). After a 3-month treatment interval with interferon beta, TIMP-1 levels were increased in comparison with TIMP-1 levels at baseline before initiation of therapy (P = .003), whereas active MMP-9 levels and the active MMP-9–TIMP-1 ratio were not altered during this treatment interval. Serum levels of active MMP-9 and TIMP-1 and the active MMP-9–TIMP-1 ratio were not influenced by atorvastatin as an add-on treatment during the study period (Figure, B, D, and F).

Comment

Here, we demonstrated a raised serum ratio of active MMP-9–TIMP-1 (Figure, E) and an interferon beta–induced increase of TIMP-1 levels (Figure, C) in patients with MS. These findings are consistent with previous observations of proteolytic dysregulation in MS and stabilization of the MMP-9–TIMP-1 ratio by interferon beta.6,7 During a study period of 9 months, no further alterations of the proteolytic balance were observed with interferon beta treatment. Ancillary atorvastatin treatment did not have any additional effect on the interferon beta–induced antiproteolytic state. Hence, our results exclude both a detrimental neutralization and a synergistic effect on proteolysis by adding atorvastatin to interferon beta therapy in patients with relapsing-remitting MS.

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Article Information

Correspondence: Dr Sellner, Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, D-81675 München, Germany (sellner@lrz.tum.de).

Author Contributions:Study concept and design: Sellner, Greeve, Leib, and Mattle. Acquisition of data: Sellner and Greeve. Analysis and interpretation of data: Sellner, Greeve, Leib, and Mattle. Drafting of the manuscript: Sellner and Greeve. Critical revision of the manuscript for important intellectual content: Sellner, Greeve, Leib, and Mattle. Statistical analysis: Sellner. Obtained funding: Sellner and Greeve. Administrative, technical, and material support: Sellner, Greeve, Leib, and Mattle. Study supervision: Leib and Mattle.

Financial Disclosure: Dr Mattle received honoraria and support from Bayer-Schering, Merck-Serono/Biogen-Idec, and Sanofi-Aventis.

Funding/Support: This work was supported by a grant from the Swiss MS Society (Drs Sellner and Greeve).

Additional Information: This work was performed at the Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.

Additional Contributions: Matthias Wittwer, PhD, Institute for Infectious Diseases, University of Bern, provided statistical mentoring, and Barbara Rieder, Ursula Walker, and Theres Lauterburg provided technical assistance.

References
1.
Yong  VWZabad  RKAgrawal  SGoncalves Dasilva  AMetz  LM Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. J Neurol Sci 2007;259 (1-2) 79- 84
PubMed
2.
Leppert  DWaubant  EBurk  MROksenberg  JRHauser  SL Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis. Ann Neurol 1996;40 (6) 846- 852
PubMed
3.
Stüve  ODooley  NPUhm  JH  et al.  Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. Ann Neurol 1996;40 (6) 853- 863
PubMed
4.
Kieseier  BCArchelos  JJHartung  HP Different effects of simvastatin and interferon beta on the proteolytic activity of matrix metalloproteinases. Arch Neurol 2004;61 (6) 929- 932
PubMed
5.
Polman  CHReingold  SCEdan  G  et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005;58 (6) 840- 846
PubMed
6.
Fainardi  ECastellazzi  MBellini  T  et al.  Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis. Mult Scler 2006;12 (3) 294- 301
PubMed
7.
Waubant  EGoodkin  DEGee  L  et al.  Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis. Neurology 1999;53 (7) 1397- 1401
PubMed
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