Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis

Friedemann Paul, Sonia Waiczies, Jens Wuerfel, Judith Bellmann-Strobl, Jan Dörr, Helmar Waiczies, Mareile Haertle, Klaus D Wernecke, Hans-Dieter Volk, Orhan Aktas, Frauke Zipp, Friedemann Paul, Sonia Waiczies, Jens Wuerfel, Judith Bellmann-Strobl, Jan Dörr, Helmar Waiczies, Mareile Haertle, Klaus D Wernecke, Hans-Dieter Volk, Orhan Aktas, Frauke Zipp

Abstract

Background: Recent data from animal models of multiple sclerosis (MS) and from a pilot study indicated a possible beneficial impact of statins on MS.

Methodology/principal findings: Safety, tolerability and effects on disease activity of atorvastatin given alone or in combination with interferon-beta (IFN-beta) were assessed in a phase II open-label baseline-to-treatment trial in relapsing-remitting MS (RRMS). Patients with at least one gadolinium-enhancing lesion (CEL) at screening by magnetic resonance imaging (MRI) were eligible for the study. After a baseline period of 3 monthly MRI scans (months -2 to 0), patients followed a 9-month treatment period on 80 mg atorvastatin daily. The number of CEL in treatment months 6 to 9 compared to baseline served as the primary endpoint. Other MRI-based parameters as well as changes in clinical scores and immune responses served as secondary endpoints. Of 80 RRMS patients screened, 41 were included, among them 16 with IFN-beta comedication. The high dose of 80 mg atorvastatin was well tolerated in the majority of patients, regardless of IFN-beta comedication. Atorvastatin treatment led to a substantial reduction in the number and volume of CEL in two-sided multivariate analysis (p = 0.003 and p = 0.008). A trend towards a significant decrease in number and volume of CEL was also detected in patients with IFN-beta comedication (p = 0.060 and p = 0.062), in contrast to patients without IFN-beta comedication (p = 0.170 and p = 0.140). Immunological investigations showed no suppression in T cell response but a significant increase in IL-10 production.

Conclusions/significance: Our data suggest that high-dose atorvastatin treatment in RRMS is safe and well tolerated. Moreover, MRI analysis indicates a possible beneficial effect of atorvastatin, alone or in combination with IFN-beta, on the development of new CEL. Thus, our findings provide a rationale for phase II/III trials, including combination of atorvastatin with already approved immunomodulatory therapy regimens.

Trial registration: ClinicalTrials.gov NCT00616187.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Flow chart of study patients.
Figure 1. Flow chart of study patients.

References

    1. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation. 2000;101:207–213.
    1. Zipp F, Waiczies S, Aktas O, Neuhaus O, Hemmer B, et al. Impact of HMG-CoA reductase inhibition on brain pathology. Trends Pharmacol Sci. 2007;28:342–349.
    1. Stanislaus R, Singh AK, Singh I. Lovastatin treatment decreases mononuclear cell infiltration into the CNS of Lewis rats with experimental allergic encephalomyelitis. J Neurosci Res. 2001;66:155–162.
    1. Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002;420:78–84.
    1. Aktas O, Waiczies S, Smorodchenko A, Dorr J, Seeger B, et al. Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med. 2003;197:725–733.
    1. Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363:1607–1608.
    1. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6:1399–1402.
    1. McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004;363:2015–2021.
    1. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50:121–127.
    1. Troiano R, Hafstein M, Ruderman M, Dowling P, Cook S. Effect of high-dose intravenous steroid administration on contrast-enhancing computed tomographic scan lesions in multiple sclerosis. Ann Neurol. 1984;15:257–263.
    1. Wuerfel J, Bellmann-Strobl J, Brunecker P, Aktas O, McFarland H, et al. Changes in cerebral perfusion precede plaque formation in multiple sclerosis: a longitudinal perfusion MRI study. Brain. 2004;127:111–119.
    1. Richert ND, Ostuni JL, Bash CN, Duyn JH, McFarland HF, et al. Serial whole-brain magnetization transfer imaging in patients with relapsing-remitting multiple sclerosis at baseline and during treatment with interferon beta-1b. AJNR Am J Neuroradiol. 1998;19:1705–1713.
    1. Neuhaus O, Strasser-Fuchs S, Fazekas F, Kieseier BC, Niederwieser G, et al. Statins as immunomodulators: comparison with interferon-beta 1b in MS. Neurology. 2002;59:990–997.
    1. Wandinger KP, Lunemann JD, Wengert O, Bellmann-Strobl J, Aktas O, et al. TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Lancet. 2003;361:2036–2043.
    1. Kano Y, Ohnuma T, Okano T, Holland JF. Effects of vincristine in combination with methotrexate and other antitumor agents in human acute lymphoblastic leukemia cells in culture. Cancer Res. 1988;48:351–356.
    1. Brunner E, Domhof S, Langer F. Nonparametric analysis of longitudinal data in factorial experiments. New York, NY: J Wiley; 2002.
    1. Bielekova B, Richert N, Howard T, Blevins G, Markovic-Plese S, et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci U S A. 2004;101:8705–8708.
    1. Massacesi L, Parigi A, Barilaro A, Repice AM, Pellicano G, et al. Efficacy of azathioprine on multiple sclerosis new brain lesions evaluated using magnetic resonance imaging. Arch Neurol. 2005;62:1843–1847.
    1. Then BF, Kumpfel T, Schumann E, Held U, Schwan M, et al. Monthly intravenous methylprednisolone in relapsing-remitting multiple sclerosis - reduction of enhancing lesions, T2 lesion volume and plasma prolactin concentrations. BMC Neurol. 2006;6:19.
    1. Birnbaum G, Altafullah I, Reder AT. A double blind placebo controlled trial of atorvastatin in combination with subcutaneous interferon beta 1a in persons with multiple sclerosis. Neurology. 2007;68:A206–A207.
    1. Waiczies S, Prozorovski T, Infante-Duarte C, Hahner A, Aktas O, et al. Atorvastatin Induces T Cell Anergy via Phosphorylation of ERK1. J Immunol. 2005;174:5630–5635.
    1. Dunn SE, Youssef S, Goldstein MJ, Prod'homme T, Weber MS, et al. Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. J Exp Med. 2006;203:401–412.

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