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  • Print publication year: 2011
  • Online publication date: December 2011

40 - Statins in multiple sclerosis

from Section III - Clinical trials of multiple sclerosis therapies


Dimethyl fumarate (DMF) is an oral therapy in development for multiple sclerosis (MS). Fumaric acids were first studied in MS in a Phase 1, open-label, baseline-controlled trial using the combination fumaric acid ester preparation Fumaderm. Based upon the encouraging Phase 1 results, Fumapharm partnered with Biogen Idec to conduct a Phase 2 trial of DMF in relapsing-remitting multiple sclerosis (RRMS). The use of DMF in autoimmune diseases arose from a personal view of the immune system, whereby autoimmunity is caused by disruption in the Krebs's cycle. The Phase 2 trial found that 720 mg/d of BG00012 reduced active inflammation. The Phase 3 trials provide pivotal and definitive evidence regarding the safety and efficacy of BG00012 in MS. Ongoing laboratory studies and advanced imaging studies in the Phase 3 trials are evaluating the neuroprotective effects of BG00012. Fumaric acids such as BG00012 are an exciting new class of potential MS treatment.


1. Ginsberg HN. Effects of statins on triglyceride metabolism. Am J Cardiol 1998; 81(4A):32B–5B.
2. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995; 333:621–7.
3. Steinman L. Immune therapy for autoimmune diseases. Science 2004; 305:212–16.
4. Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 2001; 7:687–92.
5. Dunn SE, Youssef S, Goldstein MJ, et al. Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. J Exp Med 2006; 203:401–12.
6. Weber MS, Youssef S, Dunn SE, et al. Statins in the treatment of central nervous system autoimmune disease. J Neuroimmunol 2006; 178:140–8.
7. Youssef S, Stuve O, Patarroyo JC, 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.
8. Aktas O, Waiczies S, Smorodchenko A, et al. Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med 2003; 197:725–33.
9. Stanislaus R, Gilg AG, Singh AK, Singh I. Immunomodulation of experimental autoimmune encephalomyelitis in the Lewis rats by Lovastatin. Neurosci Lett 2002; 333:167–70.
10. Nath N, Giri S, Prasad R, Singh AK, Singh I. Potential targets of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor for multiple sclerosis therapy. J Immunol 2004; 172:1273–86.
11. Hakamada-Taguchi R, Uehara Y, Kuribayashi K, et al. Inhibition of hydroxymethylglutaryl-coenzyme a reductase reduces Th1 development and promotes Th2 development. Circ Res 2003; 93:948–56.
12. Pahan K, Sheikh FG, Namboodiri AM, Singh I. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest 1997; 100:2671–9.
13. Greenwood J, Walters CE, Pryce G, et al. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J 2003; 17:905–7.
14. Neuhaus O, Strasser-Fuchs S, Fazekas F, et al. Statins as immunomodulators: comparison with interferon-beta 1b in MS. Neurology 2002; 59:990–7.
15. Waiczies S, Prozorovski T, Infante-Duarte C, et al. Atorvastatin induces T cell anergy via phosphorylation of ERK1. J Immunol 2005; 174:5630–5.
16. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6:1399–402.
17. Ganne F, Vasse M, Beaudeux JL, et al. Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits urokinase/urokinase-receptor expression and MMP-9 secretion by peripheral blood monocytes–a possible protective mechanism against atherothrombosis. Thromb Haemost 2000; 84:680–8.
18. Bellosta S, Via D, Canavesi M, et al. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol 1998; 18:1671–8.
19. Chang CH, Flavell RA. Class II transactivator regulates the expression of multiple genes involved in antigen presentation. J Exp Med 1995; 181:765–7.
20. Dustin ML, Shaw AS. Costimulation: building an immunological synapse. Science 1999; 283:649–50.
21. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996; 383:787–93.
22. Panitch HS, Hirsch RL, Haley AS, Johnson KP. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1987; 1:893–5.
23. Khoury SJ, Hancock WW, Weiner HL. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. J Exp Med 1992; 176:1355–64.
24. Begolka WS, Vanderlugt CL, Rahbe SM, Miller SD. Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiple sclerosis. J Immunol 1998; 161:4437–46.
25. Zhang X, Jin J, Peng X, Ramgolam VS, Markovic-Plese S. Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol 2008; 180:6988–96.
26. Jorritsma PJ, Brogdon JL, Bottomly K. Role of TCR-induced extracellular signal-regulated kinase activation in the regulation of early IL-4 expression in naive CD4+ T cells. J Immunol 2003; 170:2427–34.
27. Cannella B, Raine CS. The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol 1995; 37:424–35.
28. Etienne S, Adamson P, Greenwood J, Strosberg AD, Cazaubon S, Couraud PO. ICAM-1 signaling pathways associated with Rho activation in microvascular brain endothelial cells. J Immunol 1998; 161:5755–61.
29. Adamson P, Etienne S, Couraud PO, Calder V, Greenwood J. Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway. J Immunol 1999; 162:2964–73.
30. Etienne-Manneville S, Manneville JB, Adamson P, Wilbourn B, Greenwood J, Couraud PO. ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J Immunol 2000; 165:3375–83.
31. Adamson P, Wilbourn B, Etienne-Manneville S, et al. Lymphocyte trafficking through the blood-brain barrier is dependent on endothelial cell heterotrimeric G-protein signaling. FASEB J 2002; 16:1185–94.
32. Walters CE, Pryce G, Hankey DJ, et al. Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis. J Immunol 2002; 168:4087–94.
33. Yong VW, Chabot S, Stuve O, Williams G. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology 1998; 51:682–9.
34. Weber MS, Prod'homme T, Steinman L, Zamvil SS. Drug Insight: using statins to treat neuroinflammatory disease. Nat Clin Pract Neurol 2005; 1:106–12.
35. Bonet S, Garcia Villena I, Tomas Santos P, Tapia Mayor I, Gussinye Canabal P, Mundet Tuduri X. [When and how do we treat our hypercholesterolemic patients?]. Aten Primaria 1999; 24:397–403.
36. Vollmer T, Durkalsi V, Tyor W, et al. An open-label, single arm study of simvastatin as a therapy for multiple sclerosis (MS). Neurology 2003; 60:A84 (abstract).
37. Waubant P, Mass JA, Cohen, et al. ITN020AI Study Management Team, Spencer and Zamvil. A randomized double-blind controlled study of atorvastatin in patients with clinically isolated syndrome: the STAyCIS study. submitted.
38. Costello F, Stuve O, Weber MS, Zamvil SS, Frohman E. Combination therapies for multiple sclerosis: scientific rationale, clinical trials, and clinical practice. Curr Opin Neurol 2007; 20:281–5.
39. Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology 2008; 71:1390–5.
40. Lee SJ, Qin H, Benveniste EN. Simvastatin inhibits IFN-gamma-induced CD40 gene expression by suppressing STAT-1alpha. J Leukoc Biol 2007; 82:436–47.
41. Darnell JE, Jr., Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994; 264:1415–21.
42. Rudick RA, Pace A, Rani MR, et al. Effect of statins on clinical and molecular responses to intramuscular interferon beta-1a. Neurology 2009; 72:1989–93.
43. Paul F, Waiczies S, Wuerfel J, et al. Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis. PLoS ONE 2008; 3:e1928.
44. Lanzillo R, Orefice G, Quarantelli M, et al. Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing-remitting active multiple sclerosis patients: a longitudinal controlled trial of combination therapy. Mult Scler 2010; 16:450–4.
45. Togha M, Karvigh SA, Nabavi M, et al. Simvastatin treatment in patients with relapsing-remitting multiple sclerosis receiving interferon beta 1a: a double-blind randomized controlled trial. Mult Scler 2010; 16:848–54.
46. Sellner J, Weber MS, Vollmar P, Mattle HP, Hemmer B, Stuve O. The combination of interferon-beta and HMG-CoA reductase inhibition in multiple sclerosis: enthusiasm lost too soon? CNS Neurosci Ther 2010; 16:362–73.
47. Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology 2001; 56:702–8.
48. Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest 2000; 105:967–76.
49. Weber MS, Starck M, Wagenpfeil S, Meinl E, Hohlfeld R, Farina C. Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain 2004; 127:1370–8.
50. Kim HJ, Ifergan I, Antel JP, et al. Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J Immunol 2004; 172:7144–53.
51. Weber MS, Prod'homme T, Youssef S, et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med 2007; 13:935–43.
52. Stuve O, Youssef S, Weber MS, et al. Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. J Clin Invest 2006; 116:1037–44.
53. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383–9.
54. Jukema JW, Bruschke AV, van Boven AJ, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995; 91:2528–40.
55. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998; 339:1349–57.
56. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. J Am Med Assoc 2004; 292:2585–90.
57. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 2002; 346:539–40.
58. Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case-control study. Neurology 2002; 58:1333–7.
59. Gaist D, Garcia Rodriguez LA, Huerta C, Hallas J, Sindrup SH. Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? Eur J Clin Pharmacol 2001; 56:931–3.