CORRESPONDENCE RESEARCH LETTER Atorvastatin Does Not Alter Interferon Beta–Induced Changes of Serum Matrix Metalloproteinase 9 and Tissue Inhibitor of Metalloproteinase 1 in Patients With Multiple Sclerosis I nterferon beta, the current cornerstone of multiple sclerosis (MS) therapy, was shown to reduce the ra- tio of matrix metalloproteinase 9 (MMP-9)–tissue in- hibitor of metalloproteinase 1 (TIMP-1) in order to attenu- ate overactive proteolysis and inhibit leukocyte migration. 1-3 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, includ- ing 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 in- crease MMP-9 activity and disrupt the proteolytic bal- ance restored by interferon beta. 1,4 In this study, we aimed to evaluate the treatment ef- fects of interferon beta alone and in combination with atorvastatin on parameters of proteolysis, ie, serum lev- els 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 Dis- ability 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 combina- tion of interferon beta-1b (250 μg every other day, sub- cutaneous) and atorvastatin calcium (40 mg orally). All of the included patients were treated de novo with in- terferon 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 diag- nosed with MS according to the McDonald criteria: dis- ease duration of 3 months or longer, an Expanded Dis- ability 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 pa- tient. The control group consisted of 10 age-matched healthy control subjects (mean age, 34.7 years) after ob- taining informed consent. Serum samples were collected by standard proce- dures and stored at -80°C until use. Active MMP-9 and TIMP-1 levels were determined with sandwich-type en- zyme-linked immunosorbent assay kits (GE Health- care, Buckinghamshire, England) that had been proven reliable in MS studies. 6 Special emphasis was paid to iden- tical sample collection and processing conditions to mini- mize 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 ac- tive MMP-9–TIMP-1 ratio (P = .002) (Figure, E) were de- tected 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 inter- val with interferon beta, TIMP-1 levels were increased in comparison with TIMP-1 levels at baseline before ini- tiation of therapy (P = .003), whereas active MMP-9 lev- els and the active MMP-9–TIMP-1 ratio were not al- tered during this treatment interval. Serum levels of active MMP-9 and TIMP-1 and the active MMP-9–TIMP-1 ra- tio were not influenced by atorvastatin as an add-on treat- ment 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 ob- servations of proteolytic dysregulation in MS and stabili- zation of the MMP-9–TIMP-1 ratio by interferon beta. 6,7 Dur- ing 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 antipro- teolytic state. Hence, our results exclude both a detrimen- tal neutralization and a synergistic effect on proteolysis by adding atorvastatin to interferon beta therapy in patients with relapsing-remitting MS. Correspondence: Dr Sellner, Department of Neurol- ogy, Klinikum rechts der Isar, Technische Universita ¨t Johann Sellner, MD Isabell Greeve, MD Stephen L. Leib, MD Heinrich P. 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