Multiple sclerosis: pathogenesis and treatment

Ingrid Loma, Rock Heyman, Ingrid Loma, Rock Heyman

Abstract

Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. It affects approximately 400,000 people in the United States and onset is usually during young adulthood. There are four clinical forms of MS, of which relapsing remitting type is the most common. As the etiology of MS is unknown, finding a cure will remain challenging. The main mechanism of injury appears to be inflammation and 8 agents are now FDA approved to help control MS. These agents for relapsing forms of MS target different parts of the immune system, with the end goal of decreasing and avoiding further inflammation. No agents are FDA approved for the primary progressive version of MS. FDA approved agents include four preparations of interferon β (Avonex, Rebif, Betaseron and Extavia), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri) and fingolimod (Gilenya). There are several drug undergoing phase II and III trials. The heterogeneity of the MS disease process, individual patient response, and medication toxicities continue to challenge the treating physician.

Keywords: Multiple sclerosis; glatiramer acetate.; immune response; interferon-beta; pathogenesis.

References

    1. Goldberg L, Edwards N, Fincher C, Doan Q, Al-Sabbagh A, Meletiche D. Comparing the cost effectiveness of disease modifying drugs for the first-line treatment of relapsing-remitting multiple sclerosis. J. Manag. Care Pharm. 2009;15:543–555.
    1. Weiner HL. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J. Neurol. 2008;255:3–11.
    1. Codarri L, Fontana A, Becher B. Cytokine networks in multiple sclerosis: lost in translation. Curr. Opin. Neurol. 2010;23:205–211.
    1. Gandhi R, Laroni A, Weiner HL. Role of the innate immune system in the pathogenesis of multiple sclerosis. J. Neuroimmunol. 2009;221:7–14.
    1. Kasper L, Shoemaker J. Multiple sclerosis immunology: The healthy immune system vs. the MS immune system. Neurology. 2010;74:S2–S8.
    1. Weber MS, Prod'homme T, Youssef S, Dunn SE, Rundle C, Lee L, Patarroyo JC, Stuve O, Sobel RA, Steinman L, Zam-vil SS. Type II monocytes modulate T cell mediated central nervous system autoimmune disease. Nat. Med. 2007;13:935–943.
    1. Komiyama KJ, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 2006;177:566–573.
    1. Haas J, Hug A, Veihover A, Fritzching B, Falk CS, Filser A, Vetter T, Milkova L, Korporal M, Fritz B, Storch-Hagenlocher B, Krammer PH, Suri-Payer E, Wildeman B. Reduced suppressive effect of CD4+CD25 high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur. J. Immunol. 2005;35:3343–3352.
    1. de Andres C, Aristimuno C, de las Heras V, Martinez-Gines ML, Arroyo R, Navarro J, Gimenez-Roldan S, Fernandez-Cruz E, Sanchez-Ramon S. Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis. J. Neuroimmunol. 2007;182:204–211.
    1. Haas J, Korporal M, Baling B, Fritzsching B, Schwarz A, Wildemann B. Glatiramer acetate improves regulatory T-cell function by expansion of naïve CD4+CD25+FOXP3+CD31+ T cells in patients with multiple sclerosis. J. Neuroimmunol. 2009;216:113–117.
    1. Duddy M, Niino M, Adatia F, Hebert S, Freedman M, Atkins H, Kim H, Bar-Or A. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J. Immunol. 2007;178:6092–6099.
    1. Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, Reynolds R, Aloisi F. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130:1089–1104.
    1. Hawker K. B Cells as a target of immune modulation. Ann. Indian Acad. Neurol. 2009;12:221–225.
    1. Barcellos LF, Oksenberg JR, Begovich AB, Martin ER, Schmidt S, Vittinghoff E, Goodin DS, Pelletier D, Lincoln RR, Bucher P, Swerdlin A, Pericak-Vance MA, Haines JL, Hauser SL. HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am. J. Hum. Genet. 2003;72:710–716.
    1. Milo R, Kahana E. Multiple sclerosis: geoepidemiology, gentics and the environment. Autoimmun. Rev. 2010;9:A387–A394.
    1. Fujinami RS, von Herath MG, Christen U, Whitton JL. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin. Microbiol. Rev. 2006;19:80–94.
    1. Pierrot-Deseilligny C. Clinical implications of a possible role of vitamin D in multiple sclerosis. J. Neurol. 2009;256:1468–1479.
    1. Pappas D, Oksenberg J. Multiple sclerosis pharmacogenomics: maximizing efficacy of therapy. Neurology. 2010;74:S62–S69.
    1. Borden EC, Sen GC, Uze GI, Silverman RH, Ransohoff RM, Foster GR, Stark GR. Interferons at age 50: past, current and future impact on biomedicine. Nat. Rev. Drug Discov. 2007;6:975–990.
    1. Dhib-Jalbut S, Marks S. Interferon-beta mechanisms of action in multiple sclerosis. Neurology. 2010;74:S17–S24.
    1. Rudick RA, Simonian NA, Alam JA, Campion M, Scara-mucci JO, Jones W, Coats ME, Goodkin DE, Weinstock-Guttman B, Herndon RM, Mass MK, Richert JR, Salazar AM, Munschauer FE 3rd, Cookfair DL, Simon JH, Jacobs LD. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Neurology. 1998;50:1266–1272.
    1. Polman CH, Bertolotto A, Deisenhammer F, Giovanni G, Hartung HP, Hemmer B, Killestein J, McFarland HF, Oger J, Pachner AR, Petkau J, Reder AT, Reingold SC, Schellekens H, Sørensen PS. Recommendations for clinical use of data on neutralizing antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol. 2010;9:740–750.
    1. Tremlet H, Yoshida E, Oger J. Liver injury associated with the B-interferons for MS: A comparison between the three products. Neurology. 2004;62:628–631.
    1. Racke M, Lovett-Racke A, Krandikar N. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology. 2010;74:S25–S30.
    1. Tennakoon DK, Mehta RS, Ortega SB, Bhoj V, Racke MK, Krandikar NJ. Therapeutic induction of regulatory cytotoxic, CD8 T cells in multiple sclerosis. J. Immunol. 2006;176:7119–7129.
    1. Bielekova B, Becker B. Monoclonal antibodies in MS: mechanisms of action. Neurology. 2010;74:S31–S40.
    1. Brown B. Natalizumab in the treatment of multiple sclerosis. Ther. Clin. Risk Manag. 2009;5:585–594.
    1. Minagar A, Alexander S, Sharain M, Zivadinov R. Alemtuzumab and multiple sclerosis: therapeutic application. Expert Opin. Biol. Ther. 2010;10:421–429.
    1. Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N. Engl. J. Med. 2008;359:1786–1801.
    1. Hauser S, Waubant E, Arnold D, Vollmer T, Antel J, Fox R, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould M, Smith C and Hermes Trial Group. B-cell depletion with rituximab in relapsing remitting multiple sclerosis. N. Engl. J. Med. 2008;358:676–688.
    1. Gea-Banacloche JC. Rituximab-associated infections. Semin Hematol. 2010;47:187–198.
    1. Liu J, Wang L, Zhan S, Tan J, Xia Y. Daclizumab for relapse remitting multiple sclerosis. Cochrane Database Syst. Rev. 2007;6:CD008127.
    1. Vollmer T, Stewart T, Baxter N. Mitoxantrone and cytotoxic drugs' mechanisms of action. Neurology. 2010;74:S41–S46.
    1. Martinelli BF, Rovaris M, Capra R, Comi G. Mitoxantrone for multiple sclerosis. Cochrane Database Syst. Rev. 2005;4:CD002127.
    1. La Mantia L, Milanese C, Mascoli N, D'Amico R, Weinstock-Guttman B. Cyclophosphamide for multiple sclerosis. Cochrane Database Syst. Rev. 2007;1:CD002819.
    1. Gray O, McDonnell GV, Forbes RB. Methotrexate for multiple sclerosis. Cochrane Database Syst. Rev. 2004;2:CD003208.
    1. Soelberg SP, Fazekas F, Lee M. Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta analysis. Eur. J. Neurol. 2002;9:557–563.
    1. Fazekas F, Lublin FD, Li D, Freedman MS, Hartung HP, Rieckmann P, Soelberg SP, Maas-Enriquez M, Sommerauer B, Hanna K. Intravenous immunoglobulin in relapsing remitting multiple sclerosis. Neurology. 2008;71:265–271.
    1. Achiron A, Kishner I, Dolev M, Stern Y, Dulitzky M, Schiff E, Achiron R. Effect of intravenous immuno-globulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis. J. Neurol. 2004;251:1133–1137.
    1. Ciccone A, Beretta S, Brusaferri F, Galea I, Protti A, Spreafico C. Corticosteroids for the long- term treatment in multiple sclerosis. Cochrane Database Syst. Rev. 2008;1:CD006264.
    1. Zivadinov R, Rudick R, De Masi R, Nasuelli D, Ukmar M, Pozzi–Mucelli R, Grop A, Cazzato G, Zorzon M. Effects of IV methylprednisolone on brain atrophy in relapsing- remitting multiple sclerosis. Neurology. 2001;57:1239–1247.
    1. Cohen J, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L and TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 2010;362:402–415.
    1. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg SP, Vermesch P, Greenberg S and CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N. Engl. J. Med. 2010;362:416–426.
    1. Rammohan K, Shoemaker J. Emerging multiple sclerosis oral therapies. Neurology. 2010;74:S47–S53.
    1. Preiningerova J. Oral laquinomod therapy in relapse remitting multiple sclerosis. Expert Opin. Investig. Drugs. 2009;18:985–989.
    1. Beutler E. Cladribine (2-chorlodeoxyadenosine) Lancet. 1992;340:952–956.
    1. Kimura A, Ohmori T, Ohkawa R, Madoiwa S, Mimuro J, Murakami T, Kobayashi E, Hoshino Y, Yatomi Y, Sakata Y. Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem Cells. 2007;25:115–124.
    1. Kappos L, Gold E, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O'Neill GN BG-12 Phase IIB Study Investigators. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372:1463–1472.
    1. Tallantyre E, Evangelou N, Constantinescu CS. Spotlight on teriflunomide. Int. MS. J. 2008;15:62–68.
    1. O'Connor PW, Li D, Freedman MS, Bar-Or A, Rice A, Confavreux C, Paty W, Stewart JA, Scheyer RA. Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006;66:894–900.
    1. Yeh EA, Chitnis T, Krupp L, Ness J, Chabas D, Kuntz N, Waubant E. Pediatric multiple sclerosis. Nat. Rev. Neurol. 2009;5:621–631.

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