Optimizing therapeutics in the management of patients with multiple sclerosis: A review of drug efficacy, dosing, and mechanisms of action

Biologics: Targets and Therapy

Volumn 7, Issue 1, 2013, Pages 247-258

  Damal, Kavitha ^a   Stoker, Emily ^a   Foley, John F ^a  

^a Rocky Mountain Multiple Sclerosis Clinic   (United States)

Author keywords

Dimethyl fumarate; Glatiramer acetate; Immunomodulation; Interferons; Monoclonal antibodies; Multiple sclerosis

Indexed keywords

BETA1A INTERFERON; CORTICOTROPIN; FINGOLIMOD; FUMARIC ACID DIMETHYL ESTER; GLATIRAMER; INTERFERON BETA SERINE; METHYLPREDNISOLONE; NATALIZUMAB; TERIFLUNOMIDE;

ABDOMINAL PAIN; ALOPECIA; AMINOTRANSFERASE BLOOD LEVEL; ANEMIA; ANGINA PECTORIS; APOPTOSIS; ARTHRALGIA; ASTHENIA; BACKACHE; CELL ADHESION; CYTOKINE PRODUCTION; DEGRADATION; DEMYELINATION; DEPRESSION; DIARRHEA; DISEASE ACTIVITY; DISEASE COURSE; DOSE RESPONSE; DRUG BINDING; DRUG EFFICACY; DRUG INHIBITION; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; DYSPNEA; ERYTHEMA; FATIGUE; FEVER; FLU LIKE SYNDROME; FLUSHING; GASTROENTERITIS; GASTROINTESTINAL DISEASE; GASTROINTESTINAL SYMPTOM; HEADACHE; HEART PALPITATION; HUMAN; HYPERTENSION; IMMUNE RESPONSE; INFLUENZA; INJECTION SITE REACTION; LEUKOPENIA; LIVER FUNCTION TEST; LUNG INFECTION; LYMPHOCYTE COUNT; LYMPHOCYTE PROLIFERATION; MULTIPLE SCLEROSIS; MYALGIA; MYELIN SHEATH; PARESTHESIA; PRURITUS; QUALITY OF LIFE; RASH; REVIEW; SIDE EFFECT; THORAX PAIN; TREATMENT OUTCOME; URINARY TRACT INFECTION; URTICARIA; VASODILATATION; VIRUS INFECTION;

EID: 84888400062     PISSN: 11775475     EISSN: 11775491     Source Type: Journal    
DOI: 10.2147/BTT.S53007     Document Type: Review

References (135)

1. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006; 354(9): 899-910.
2. Williams R, Rigby AS, Airey M, Robinson M, Ford H. Multiple sclerosis: its epidemiological, genetic, and health care impact. J Epidemiol Community Health. 1995; 49(6): 563-569.
3. Compston A, Coles A. Multiple sclerosis. Lancet. 2002; 359(9313): 1221-1231.
4. Compston A, Coles A. Multiple sclerosis. Lancet. 2008; 372(9648): 1502-1517.
5. Keegan BM, Noseworthy JH. Multiple sclerosis. Ann Rev Medic. 2002; 53: 285-302.
6. Koch-Henriksen N. The Danish Multiple Sclerosis Registry: a 50-year follow-up. Mult Scler. 1999; 5(4): 293-296.
7. Mayr WT, Pittock SJ, McClelland RL, Jorgensen NW, Noseworthy JH, Rodriguez M. Incidence and prevalence of multiple sclerosis in Olmsted County, Minnesota, 1985-2000. Neurology. 2003; 61(10): 1373-1377.
8. Hawkins SA, McDonnell GV. Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatry. 1999; 67(2): 148-152.
9. Whitacre CC, Reingold SC, O'Looney PA, et al. A gender gap in autoimmunity: Task Force on Gender, Multiple Sclerosis and Autoimmunity. Science. 1999; 283(5406): 1277-1278.
10. Orton SM, Herrera BM, Yee IM, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006; 5(11): 932-936.
11. Kister I, Chamot E, Salter AR, Cutter GR, Bacon TE, Herbert J. Disability in multiple sclerosis: a reference for patients and clinicians. Neurology. 2013; 80(11): 1018-1024.
12. Sadovnick AD, Ebers GC, Wilson RW, Paty DW. Life expectancy in patients attending multiple sclerosis clinics. Neurology. 1992; 42(5): 991-994.
13. Charcot JM. Histologie de la sclerose en plaques. Gaz Hop Civ Mil Empire Ottoman. 1868; 41: 554-555.
14. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69(2): 292-302.
15. Stangel M, Fredrikson S, Meinl E, Petzold A, Stuve O, Tumani H. The utility of cerebrospinal fluid analysis in patients with multiple sclerosis. Nat Rev Neurol. 2013; 9(5): 267-276.
16. Kuenz B, Deisenhammer F, Berger T, Reindl M. Diagnostic biomarkers in multiple sclerosis. Expert Opinion Medical Diagn. 2007; 1(2): 225-233.
17. Katsavos S, Anagnostouli M. Biomarkers in multiple sclerosis: an up-to-date overview. Mult Scler Int. 2013; 2013: 340508.
18. Leone MA, Barizzone N, Esposito F, et al. Association of genetic markers with CSF oligoclonal bands in multiple sclerosis patients. PloS One. 2013; 8(6): e64408.
19. Rudick RA. The elusive biomarker for personalized medicine in multiple sclerosis: the search continues. Neurology. 2012; 79(6): 498-499.
20. Oberwahrenbrock T, Schippling S, Ringelstein M, et al. Retinal damage in multiple sclerosis disease subtypes measured by high-resolution optical coherence tomography. Mult Scler Int. 2012; 2012: 530305.
21. Vukusic S, Confavreux C. Primary and secondary progressive multiple sclerosis. J Neurol Sci. 2003; 206(2): 153-155.
22. Hagman S, Raunio M, Rossi M, Dastidar P, Elovaara I. Disease-associated inflammatory biomarker profiles in blood in different subtypes of multiple sclerosis: prospective clinical and MRI follow-up study. J Neuroimmunol. 2011; 234(1-2): 141-147.
23. Freedman MS, Selchen D, Arnold DL, et al. Treatment optimization in MS: Canadian MS Working Group updated recommendations. Can J Neurol Sci. 2013; 40(3): 307-323.
24. Kieseier BC, Wiendl H, Hemmer B, Hartung HP. Treatment and treatment trials in multiple sclerosis. Curr Opin Neurol. 2007; 20(3): 286-293.
25. Spain RI, Cameron MH, Bourdette D. Recent developments in multiple sclerosis therapeutics. BMC Med. 2009; 7: 74.
26. Filippini G, Brusaferri F, Sibley WA, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev. 2000; (4): CD001331.
27. Rudick RA, Cohen JA, Weinstock-Guttman B, Kinkel RP, Ransohoff RM. Management of multiple sclerosis. N Engl J Med. 1997; 337(22): 1604-1611.
28. Berkovich R. Treatment of acute relapses in multiple sclerosis. Neurotherapeutics. 2013; 10(1): 97-105.
29. Burton JM, O'Connor PW, Hohol M, Beyene J. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev. 2012; 12: CD006921.
30. Myhr KM, Mellgren SI. Corticosteroids in the treatment of multiple sclerosis. Acta Neurologica Scand Suppl. 2009; (189): 73-80.
31. Lassmann H. Pathology and disease mechanisms in different stages of multiple sclerosis. J Neurol Sci. Epub June 2, 2013.
32. Bø L, Esiri M, Evangelou N, Kuhlmann T. Demyelination and remyelination in multiple sclerosis. In: Duncan ID, Franklin RJM, editors. Myelin Repair and Neuroprotection in Multiple Sclerosis. New York: Springer; 2013: 23-45.
33. Crayton H, Heyman RA, Rossman HS. A multimodal approach to managing the symptoms of multiple sclerosis. Neurology. 2004; 63(11 Suppl 5): S12-S18.
34. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33(11): 1444-1452.
35. Weinstock-Guttman B, Ransohoff RM, Kinkel RP, Rudick RA. The interferons: biological effects, mechanisms of action, and use in multiple sclerosis. Ann Neurol. 1995; 37(1): 7-15.
36. Lin L. Betaseron. Dev Biol Stand. 1998; 96: 97-104.
37. Weber F, Janovskaja J, Polak T, Poser S, Rieckmann P. Effect of interferon beta on human myelin basic protein-specific T-cell lines: comparison of IFNbeta-1a and IFNbeta-1b. Neurology. 1999; 52(5): 1069-1071.
38. Rudick RA, Ransohoff RM, Lee JC, et al. In vivo effects of interferon beta-1a on immunosuppressive cytokines in multiple sclerosis. Neurology. 1998; 50(5): 1294-1300.
39. Yong VW, Chabot S, Stuve O, Williams G. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology. 1998; 51(3): 682-689.
40. Kieseier BC. The mechanism of action of interferon-beta in relapsing multiple sclerosis. CNS Drugs. 2011; 25(6): 491-502.
41. Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology. 1993; 43(4): 662-667.
42. [No authors listed]. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 1993; 43(4): 655-661.
43. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996; 39(3): 285-294.
44. Fernandez O, Antiquedad A, Arbizu T, et al. Treatment of relapsing-remitting multiple sclerosis with natural interferon beta: a multicenter, randomized clinical trial. Mult Scler. 1995; 1 Suppl 1: S67-S69.
45. Ponomarenko NA, Durova OM, Vorobiev II, et al. Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen. Proc Natl Acad Sci U S A. 2006; 103(2): 281-286.
46. Ponomarenko NA, Durova OM, Vorobiev II, et al. Catalytic activity of autoantibodies toward myelin basic protein correlates with the scores on the multiple sclerosis expanded disability status scale. Immunol Lett. 2006; 103(1): 45-50.
47. Valli A, Sette A, Kappos L, et al. Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients. J Clin Invest. 1993; 91(2): 616-628.
48. Ota K, Matsui M, Milford EL, Mackin GA, Weiner HL, Hafler DA. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature. 1990; 346(6280): 183-187.
49. Wolinsky JS. Copolymer 1: a most reasonable alternative therapy for early relapsing-remitting multiple sclerosis with mild disability. Neurology. 1995; 45(7): 1245-1247.
50. Fridkis-Hareli M, Teitelbaum D, Gurevich E, et al. Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells-specificity and promiscuity. Proc Natl Acad Sci U S A. 1994; 91(11): 4872-4876.
51. Gran B, Tranquill LR, Chen M, et al. Mechanisms of immunomodulation by glatiramer acetate. Neurology. 2000; 55(11): 1704-1714.
52. Berger A. Th1 and Th2 responses: what are they? BMJ. 2000; 321(7258): 424.
53. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995; 45(7): 1268-1276.
54. Korczyn AD, Nisipeanu P. Safety profile of copolymer 1: analysis of cumulative experience in the United States and Israel. J Neurol. 1996; 243(4 Suppl 1): S23-S26.
55. Munari L, Lovati R, Boiko A. Therapy with glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev. 2004; (1): CD004678.
56. La Mantia L, Munari LM, Lovati R. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev. 2010; (5): CD004678.
57. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992; 356(6364): 63-66.
58. Leger OJ, Yednock TA, Tanner L, et al. Humanization of a mouse antibody against human alpha-4 integrin: a potential therapeutic for the treatment of multiple sclerosis. Hum Antibodies. 1997; 8(1): 3-16.
59. Kent SJ, Karlik SJ, Rice GP, Horner HC. A monoclonal antibody to alpha 4-integrin reverses the MR-detectable signs of experimental allergic encephalomyelitis in the guinea pig. J Magn Reson Imaging. 1995; 5(5): 535-540.
60. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2003; 348(1): 15-23.
61. Kent SJ, Karlik SJ, Cannon C, et al. A monoclonal antibody to alpha 4 integrin suppresses and reverses active experimental allergic encephalomyelitis. J Neuroimmunol. 1995; 58(1): 1-10.
62. Elices MJ. Natalizumab. Elan/Biogen. Curr Opin Investig Drugs. 2003; 4(11): 1354-1362.
63. Bauer M, Brakebusch C, Coisne C, et al. Beta1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity. Proc Natl Acad Sci U S A. 2009; 106(6): 1920-1925.
64. Coisne C, Mao W, Engelhardt B. Cutting edge: natalizumab blocks adhesion but not initial contact of human T cells to the blood-brain barrier in vivo in an animal model of multiple sclerosis. J Immunol. 2009; 182(10): 5909-5913.
65. Sheremata WA, Vollmer TL, Stone LA, Willmer-Hulme AJ, Koller M. A safety and pharmacokinetic study of intravenous natalizumab in patients with MS. Neurology. 1999; 52(5): 1072-1074.
66. O'Connor P, Miller D, Riester K, et al. Relapse rates and enhancing lesions in a phase II trial of natalizumab in multiple sclerosis. Mult Scler. 2005; 11(5): 568-572.
67. Sheremata WA, Minagar A, Alexander JS, Vollmer T. The role of alpha-4 integrin in the aetiology of multiple sclerosis: current knowledge and therapeutic implications. CNS Drugs. 2005; 19(11): 909-922.
68. O'Connor P. Natalizumab and the role of alpha 4-integrin antagonism in the treatment of multiple sclerosis. Expert Opin Biol Ther. 2007; 7(1): 123-136.
69. Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007; 68(17): 1390-1401.
70. Rudick RA, Miller D, Hass S, et al. Health-related quality of life in multiple sclerosis: effects of natalizumab. Ann Neurol. 2007; 62(4): 335-346.
71. Balcer LJ, Galetta SL, Calabresi PA, et al. Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Neurology. 2007; 68(16): 1299-1304.
72. Phillips JT, Giovannoni G, Lublin FD, et al. Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis. Mult Scler. 2011; 17(8): 970-979.
73. Weinstock-Guttman B, Galetta SL, Giovannoni G, et al. Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS. J Neurol. 2012; 259(5): 898-905.
74. Cadavid D, Jurgensen S, Lee S. Impact of natalizumab on ambulatory improvement in secondary progressive and disabled relapsing-remitting multiple sclerosis. PloS One. 2013; 8(1): e53297.
75. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. March 2, 2006; 354(9): 911-923.
76. Biogen Idec. Tysabri (natalizumab): benefit/risk update and PML risk stratification. 2013. Available from: http: //www. slideshare. net/gavingiovannoni/natalizuman. Accessed September 17, 2013.
77. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012; 366(20): 1870-1880.
78. Plavina T, Subramanyam M, Bloomgren G, et al. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis. Poster presented at: 27th Annual Meeting of the CMSC and the Fifth Cooperative Meeting of the CMSC-ACTRIMS; May 29-June 1, 2013; Orlando, FL.
79. Schwab N, Schneider-Hohendorf T, Posevitz V, et al. L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. Neurology. 2013; 81(10): 865-871.
80. Foley JF. Natalizumab related PML: an evolving risk stratification paradigm. Poster presented at: American Academy of Neurology 2013 Annual Meeting; March 16-23, 2013; San Diego, CA.
81. Gonsette RE. Neurodegeneration in multiple sclerosis: the role of oxidative stress and excitotoxicity. J Neurol Sci. 2008; 274(1-2): 48-53.
82. Brosnan CF, Cannella B, Battistini L, Raine CS. Cytokine localization in multiple sclerosis lesions: correlation with adhesion molecule expression and reactive nitrogen species. Neurology. 1995; 45(6 Suppl 6): S16-S21.
83. Wierinckx A, Brevé J, Mercier D, Schultzberg M, Drukarch B, Van Dam AM. Detoxication enzyme inducers modify cytokine production in rat mixed glial cells. J Neuroimmunol. 2005; 166(1-2): 132-143.
84. Miller E, Wachowicz B, Majsterek I. Advances in antioxidative therapy of multiple sclerosis. Current medicinal chemistry. Epub June 25, 2013.
85. Bogdan C. Nitric oxide and the immune response. Nat Immunol. 2001; 2(10): 907-916.
86. Nathan C, Shiloh MU. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc Natl Acad Sci U S A. 2000; 97(16): 8841-8848.
87. Hibbs JB Jr, Taintor RR, Vavrin Z, Rachlin EM. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1988; 157(1): 87-94.
88. Smith KJ, Kapoor R, Felts PA. Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathol. 1999; 9(1): 69-92.
89. Su KG, Banker G, Bourdette D, Forte M. Axonal degeneration in multiple sclerosis: the mitochondrial hypothesis. Curr Neurol Neurosci Rep. 2009; 9(5): 411-417.
90. Albrecht P, Bouchachia I, Goebels N, et al. Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation. 2012; 9: 163.
91. Schilling S, Goelz S, Linker R, Luehder F, Gold R. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol. 2006; 145(1): 101-107.
92. Vandermeeren M, Janssens S, Borgers M, Geysen J. Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells. Biochem Biophys Res Commun. 1997; 234(1): 19-23.
93. Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011; 134(3): 678-692.
94. Kohen R, Nyska A. Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol. 2002; 30(6): 620-650.
95. Scannevin RH, Chollate S, Jung MY, et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther. 2012; 341(1): 274-284.
96. Schimrigk S, Brune N, Hellwig K, et al. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol. 2006; 13(6): 604-610.
97. Wakkee M, Thio HB. Drug evaluation: BG-12, an immunomodulatory dimethylfumarate. Curr Opinion Investig Drugs. 2007; 8(11): 955-962.
98. Kappos L, Gold R, Miller DH, et al. 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(9648): 1463-1472.
99. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012; 367(12): 1098-1107.
100. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012; 367(12): 1087-1097.
101. Hutchinson M, Fox RJ, Miller DH, et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study. Journal of Neurology. 2013; 260(9): 2286-2296.
102. Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid. N Engl J Med. 2013; 368(17): 1657-1658.
103. van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013; 368(17): 1658-1659.
104. Sweetser MT, Dawson KT, Bozic C. Manufacturer's response to case reports of PML. N Engl J Med. 2013; 368(17): 1659-1661.
105. Zeyda M, Poglitsch M, Geyeregger R, et al. Disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: involvement of impaired integrin activation and immunologic synapse formation. Arthritis Rheum. 2005; 52(9): 2730-2739.
106. O'Connor PW, Li D, Freedman MS, et al. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006; 66(6): 894-900.
107. Warnke C, Meyer zu Hörste G, Hartung HP, Stüve O, Kieseier BC. Review of teriflunomide and its potential in the treatment of multiple sclerosis. Neuropsychiatr Dis Treat. 2009; 5: 333-340.
108. Fox RI, Herrmann ML, Frangou CG, et al. Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol. 1999; 93(3): 198-208.
109. Herrmann ML, Schleyerbach R, Kirschbaum BJ. Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology. 2000; 47(2-3): 273-289.
110. Oh J, O'Connor PW. Teriflunomide for the treatment of multiple sclerosis. Semin Neurol. 2013; 33(1): 45-55.
111. Iglesias-Bregna D, Hanak S, Ji Z, et al. Effects of prophylactic and therapeutic teriflunomide in transcranial magnetic stimulation-induced motor-evoked potentials in the Dark Agouti rat model of experimental autoimmune encephalomyelitis. J Pharmacol Exp Ther. Epub Jul 26.
112. Merrill JE, Hanak S, Pu SF, et al. Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis. J Neurol. 2009; 256(1): 89-103.
113. Sanofi. Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis (TOPIC). Available from: http: //clinicaltrials. gov/show/NCT00622700. Identifier: NCT00622700. Accessed September 27, 2013.
114. Olsson T, Zhi WW, Höjeberg B, et al. Autoreactive T lymphocytes in multiple sclerosis determined by antigen-induced secretion of interferon-gamma. J Clin Invest. 1990; 86(3): 981-985.
115. Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002; 296(5566): 346-349.
116. Yopp AC, Randolph GJ, Bromberg JS. Leukotrienes, sphingolipids, and leukocyte trafficking. J Immunol. 2003; 171(1): 5-10.
117. O'Sullivan C, Dev KK. The structure and function of the S1P1 receptor. Trends Pharmacol Sci. 2013; 34(7): 401-412.
118. Xie JH, Nomura N, Koprak SL, Quackenbush EJ, Forrest MJ, Rosen H. Sphingosine-1-phosphate receptor agonism impairs the efficiency of the local immune response by altering trafficking of naive and antigen-activated CD4ooT cells. J Immunol. 2003; 170(7): 3662-3670.
119. Yanagawa Y, Masubuchi Y, Chiba K. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats, III. Increase in frequency of CD62L-positive T cells in Peyer's patches by FTY720-induced lymphocyte homing. Immunology. 1998; 95(4): 591-594.
120. Yanagawa Y, Sugahara K, Kataoka H, Kawaguchi T, Masubuchi Y, Chiba K. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. J Immunol. 1998; 160(11): 5493-5499.
121. Chiba K, Yanagawa Y, Masubuchi Y, et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol. 1998; 160(10): 5037-5044.
122. Fujino M, Funeshima N, Kitazawa Y, et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther. 2003; 305(1): 70-77.
123. Miron VE, Ludwin SK, Darlington PJ, et al. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am J Pathol. 2010; 176(6): 2682-2694.
124. Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010; 362(5): 387-401.
125. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010; 362(5): 402-415.
126. Lindsey JW, Haden-Pinneri K, Memon NB, Buja LM. Sudden unexpected death on fingolimod. Mult Scler. 2012; 18(10): 1507-1508.
127. Ratchford JN, Costello K, Reich DS, Calabresi PA. Varicella-zoster virus encephalitis and vasculopathy in a patient treated with fingolimod. Neurology. 2012; 79(19): 2002-2004.
128. Rukovets O. FDA investigates PML in patient taking Gilenya. 2013. Available from: http: //journals. lww. com/neurotodayonline/blog/breakingnews/pages/post. aspx?PostID1240. Accessed September 17, 2013.
129. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996; 39(3): 285-294.
130. [No authors listed]. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet. 1998; 352(9139): 1498-1504.
131. O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011; 365(14): 1293-1303.
132. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012; 380(9856): 1819-1828.
133. Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012; 366(11): 1000-1009.
134. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013; 381(9884): 2167-2175.
135. Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011; 378(9805): 1779-1787.