Pharmacotherapeuetic options for the treatment of Multiple sclerosis

Clinical Medicine Insights: Therapeutics

Volumn 4, Issue , 2012, Pages 145-168

  Palmer, Alan M ^a  

^a MS Therapeutics Ltd   (United Kingdom)

Author keywords

Blood brain barrier; Clinical outcome measures; CNS disease; Demyelination; Immunodulation; Neurodegeneration; Neuroinflammation; Pharmacotherapy

Indexed keywords

4 AMINOPYRIDINE; ALEMTUZUMAB; BETA INTERFERON; BETA1A INTERFERON; BIIB 017; CLADRIBINE; COLECALCIFEROL; DACLIZUMAB; DRONABINOL; FINGOLIMOD; FIRATEGRAST; FUMARIC ACID; FUMARIC ACID DIMETHYL ESTER; GLATIRAMER; IMMUNOMODULATING AGENT; INTERFERON BETA SERINE; LAQUINIMOD; LEMTRADA; MITOXANTRONE; MONOCLONAL ANTIBODY; NABIXIMOLS; NATALIZUMAB; NU 100; OCRELIZUMAB; PLACEBO; RECOMBINANT BETA INTERFERON; RITUXIMAB; ROQUINIMEX; SANOFI; TERIFLUNOMIDE; TOVAXIN; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ADD ON THERAPY; ANXIETY DISORDER; B CELL LEUKEMIA; BLOOD DISEASE; BRADYCARDIA; BREATHING DISORDER; CHEST TIGHTNESS; CLINICAL ASSESSMENT; CLINICAL EFFECTIVENESS; DIARRHEA; DISEASE SEVERITY; DIZZINESS; DOSAGE SCHEDULE COMPARISON; DOSE RESPONSE; DRUG APPROVAL; DRUG DOSE COMPARISON; DRUG EFFECT; DRUG EFFICACY; DRUG FATALITY; DRUG HALF LIFE; DRUG INDICATION; DRUG MARKETING; DRUG MONITORING; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; DRUG WITHDRAWAL; FATIGUE; FLU LIKE SYNDROME; GENE EXPRESSION REGULATION; GENE LOCUS; GENETIC ASSOCIATION; GENETIC RISK; GRAFT VERSUS HOST REACTION; HEADACHE; HEART INFARCTION; HEART PALPITATION; HERPES ZOSTER; HOT FLUSH; HUMAN; INFECTION; INJECTION SITE REACTION; LIVER DISEASE; LIVER DYSFUNCTION; LYMPHOCYTOPENIA; MALIGNANT NEOPLASTIC DISEASE; MOLECULAR PATHOLOGY; MULTIPLE SCLEROSIS; NAUSEA; NEOPLASM; NEUROBIOLOGY; NEUROLOGIC DISEASE; NONHUMAN; OUTCOME ASSESSMENT; PERICARDITIS; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; PROTEIN EXPRESSION; PSORIASIS; RECOMMENDED DRUG DOSE; RETINA MACULA EDEMA; REVIEW; RHINOPHARYNGITIS; RISK ASSESSMENT; SEIZURE; SENSORY DYSFUNCTION; SIDE EFFECT; SKIN DISEASE; SKIN MANIFESTATION; SOMNOLENCE; SWEATING; SYMPTOMATOLOGY; THROMBOCYTOPENIC PURPURA; THYROID DISEASE; TREATMENT DURATION; TREATMENT PLANNING;

EID: 84864051511     PISSN: 1179559X     EISSN: 1179559X     Source Type: Journal    
DOI: 10.4137/CMT.S8661     Document Type: Review

References (170)

1. Koch-Henriksen N, Sorensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010;9(5):520-32.
2. Palmer AM. Immunomodulatory medicines for multiple sclerosis: Progress and prospects. Drug Development Research. 2011;72:664-72.
3. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-17.
4. Wundes A, et al. Contribution of intangible costs to the economic burden of multiple sclerosis. J Med Econ. 2010;13(4):626-32.
5. Bol Y, et al. Fatigue and heat sensitivity in patients with multiple sclerosis. Acta Neurol Scand. 2012.
6. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907-11.
7. Miller DH, Leary SM. Primary-progressive multiple sclerosis. Lancet Neurol. 2007;6(10):903-12.
8. Pandey K, Lublin FD. Clinically isolated syndrome and multiple sclerosis: rethinking the arsenal. Curr Treat Options Neurol. 2009;11(3):193-202.
9. Fisniku LK, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain. 2008;131(Pt 3): 808-17.
10. Trojano M. Multiple sclerosis: The evolving diagnostic criteria for multiple sclerosis. Nat Rev Neurol. 2011;7(5):251-2.
11. Koch M, et al. The natural history of secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2010;81(9):1039-43.
12. Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain. 2006;129(Pt 3):606-16.
13. Pearce JM. Historical descriptions of multiple sclerosis. Eur Neurol. 2005;54(1):49-53.
14. Murray TJ. The history of multiple sclerosis: the changing frame of the disease over the centuries. J Neurol Sci. 2009;277 Suppl 1:S3-8.
15. Ebers GC, et al. A population-based study of multiple sclerosis in twins. N Engl J Med. 1986;315(26):1638-42.
16. Baranzini SE, et al. Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature. 2010;464(7293): 1351-6.
17. Moller E, et al. Speculations on mechanisms of HLA associations with autoimmune diseases and the specificity of "autoreactive" T lymphocytes. Immunol Rev. 1990;118:5-19.
18. Barcellos LF, et al. Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Hum Mol Genet. 2006;15(18):2813-24.
19. Patsopoulos NA, et al. Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann Neurol. 2011;70(6):897-912.
20. Sawcer S, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359):214-9.
21. Kemppinen AK, et al. Systematic review of genome-wide expression studies in multiple sclerosis. BMJ Open. 2011;1(1):e000053.
22. Orton SM, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006;5(11):932-6.
23. WHO Atlas Multiple Sclerosis. 2008.
24. Chao MJ, et al. MHC transmission: insights into gender bias in MS susceptibility. Neurology. 2011;76(3):242-6.
25. Simpson S Jr, et al. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82(10):1132-41.
26. Niino M. Vitamin D and its immunoregulatory role in multiple sclerosis. Drugs Today (Barc). 2010;46(4):279-90.
27. Grigorian A, et al. Pathogenesis of multiple sclerosis via environmental and genetic dysregulation of N-glycosylation. Semin Immunopathol. 2012.
28. Ramagopalan SV, et al. Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol. 2011;70(6):881-6.
29. Soilu-Hanninen M, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83(5): 565-71.
30. Waksman BH. Multiple sclerosis. More genes versus environment. Nature. 1995;377(6545):105-6.
31. Cabre P, et al. Role of return migration in the emergence of multiple sclerosis in the French West Indies. Brain. 2005;128(Pt 12):2899-910.
32. Kakalacheva K, Lunemann JD. Environmental triggers of multiple sclerosis. FEBS Lett. 2011;585(23):3724-9.
33. Goverman J, et al. Transgenic mice that express a myelin basic proteinspecific T cell receptor develop spontaneous autoimmunity. Cell. 1993; 72(4):551-60.
34. Filli L, et al. Spatiotemporal distribution of white matter lesions in relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler. 2012.
35. Pender MP, Greer JM. Immunology of multiple sclerosis. Curr Allergy Asthma Rep. 2007;7(4):285-92.
36. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol. 2005;23:683-747.
37. Haegert DG. Multiple sclerosis: a disorder of altered T-cell homeostasis. Mult Scler Int. 2011;2011:461304.
38. Ousman SS, et al. Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Nature. 2007;448(7152):474-9.
39. Mathey EK, et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med. 2007;204(10):2363-72.
40. Palmer AM. The role of the blood-CNS barrier in CNS disorders and their treatment. Neurobiol Dis. 2010;37(1):3-12.
41. Abbott NJ, et al. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37(1):13-25.
42. Pribyl TM, et al. The human myelin basic protein gene is included within a 179-kilobase transcription unit: expression in the immune and central nervous systems. Proc Natl Acad Sci U S A. 1993;90(22):10695-9.
43. Zelenika D, Grima B, Pessac B. A new family of transcripts of the myelin basic protein gene: expression in brain and in immune system. J Neurochem. 1993;60(4):1574-7.
44. Pender MP, et al. CD8 T cell deficiency impairs control of Epstein-Barr virus and worsens with age in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83(3):353-4.
45. Jafari N, Safari N, HThe association between cigarette smoking and multiple sclerosis. J Neurol Sci. 2011;15:311(1-2):78-85.
46. Engelhardt B, Ransohoff RM. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol. 2005;26(9):485-95.
47. Sperandio M. Selectins and glycosyltransferases in leukocyte rolling in vivo. FEBS J. 2006;273(19):4377-89.
48. Carlow DA, et al. PSGL-1 function in immunity and steady state homeostasis. Immunol Rev. 2009;230(1):75-96.
49. Engelhardt B. Immune cell entry into the central nervous system: involvement of adhesion molecules and chemokines. J Neurol Sci. 2008;274(1-2): 23-6.
50. Holmoy T, Vartdal F. The immunological basis for treatment of multiple sclerosis. Scand J Immunol. 2007;66(4):374-82.
51. Wekerle H. Immune pathogenesis of multiple sclerosis. Neurol Sci. 2005; 26 Suppl 1:S1-2.
52. Kutzelnigg A, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128(Pt 11):2705-12.
53. Kebir H, et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007;13(10): 1173-5.
54. Huppert J, et al. Cellular mechanisms of IL-17-induced blood-brain barrier disruption. FASEB J. 2010;24(4):1023-34.
55. Brownell B, Hughes JT. The distribution of plaques in the cerebrum in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1962;25:315-20.
56. Fisniku LK, et al. Magnetization transfer ratio abnormalities reflect clinically relevant grey matter damage in multiple sclerosis. Mult Scler. 2009;15(6):668-77.
57. Tallantyre EC, et al. Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease. Brain. 2009;132(Pt 5):1190-9.
58. Phillips JT, 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.
59. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444-52.
60. Goodkin DE, et al. Inter-and intrarater scoring agreement using grades 1.0 to 3.5 of the Kurtzke Expanded Disability Status Scale (EDSS). Multiple Sclerosis Collaborative Research Group. Neurology. 1992;42(4): 859-63.
61. D'Souza M, Kappos L, Czaplinski A. Reconsidering clinical outcomes in Multiple Sclerosis: relapses, impairment, disability and beyond. J Neurol Sci. 2008;274(1-2):76-9.
62. Cutter GR, et al. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain. 1999;122(Pt 5): 871-82.
63. Rudick RA, Cutter G, Reingold S. The multiple sclerosis functional composite: a new clinical outcome measure for multiple sderosis trials. Mult Scler. 2002;8(5):359-65.
64. Rudick RA, et al. Disability progression in a clinical trial of relapsingremitting multiple sclerosis: eight-year follow-up. Arch Neurol. 2010; 67(11):1329-35.
65. Ebers GC, et al. Disability as an outcome in MS clinical trials. Neurology. 2008;71(9):624-31.
66. Kragt JJ, et al. How similar are commonly combined criteria for EDSS progression in multiple sclerosis? Mult Scler. 2006;12(6):782-6.
67. Balcer LJ. Clinical outcome measures for research in multiple sclerosis. J Neuroophthalmol. 2001;21(4):296-301.
68. Amato MP, Portaccio E. Clinical outcome measures in multiple sclerosis. J Neurol Sci. 2007;259(1-2):118-22.
69. Goodman AD, et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol. 2010;68(4):494-502.
70. Blight AR. Treatment of walking impairment in multiple sclerosis with dalfampridine. Ther Adv Neurol Disord. 2011;4(2):99-109.
71. Inusah S, et al. Assessing changes in relapse rates in multiple sclerosis. Mult Scler. 2010;16(12):1414-21.
72. Confavreux C, et al. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343(20):1430-8.
73. Tremlett H, et al. Impact of multiple sclerosis relapses on progression diminishes with time. Neurology. 2009;73(20):1616-23.
74. Barkhof F, et al. MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials. Nat Rev Neurol. 2012;8(1):13-21.
75. Filippi M, Rocca MA. MR imaging of multiple sclerosis. Radiology. 2011; 259(3):659-81.
76. Filippi M, et al. Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol. 2012;11(4):349-360.
77. Sormani MP, et al. Combined MRI lesions and relapses as a surrogate for disability in multiple sclerosis. Neurology. 2011;77(18):1684-90.
78. Hobart J, et al. The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure. Brain. 2001;124(Pt 5):962-73.
79. Fisk JD, et al. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994;18 Suppl 1: S79-83.
80. Hobart JC, et al. Getting the measure of spasticity in multiple sclerosis: the Multiple Sclerosis Spasticity Scale (MSSS-88). Brain. 2006;129(Pt 1): 224-34.
81. Gold R, Linington C, Lassmann H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain. 2006; 129(Pt 8):1953-71.
82. Hohlfeld R, Wekerle H. Immunological update on multiple sclerosis. Curr Opin Neurol. 2001;14(3):299-304.
83. Baker D, et al. Critical appraisal of animal models of multiple sclerosis. Mult Scler. 2011;17(6):647-57.
84. Constantinescu CS, et al. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol. 2011;164(4):1079-106.
85. Borden EC, et al. Interferons at age 50: past. current and future impact on biomedicine. Nat Rev Drug Discov. 2007;6(12):975-90.
86. Schrempf W, Ziemssen T. Glatiramer acetate: mechanisms of action in multiple sclerosis. Autoimmun Rev. 2007;6(7):469-75.
87. Kala M, Miravalle A, Vollmer T. Recent insights into the mechanism of action of glatiramer acetate. J Neuroimmunol. 2011;235(1-2):9-17.
88. La Mantia L, Munari LM, Lovati R. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev. 2010;5:CD004678.
89. Carter NJ, Keating GM. Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis. Drugs. 2010;70(12):1545-77.
90. Clerico M, et al. Recombinant interferon beta or glatiramer acetate for delaying conversion of the first demyelinating event to multiple sclerosis. Cochrane Database Syst Rev. 2008;2:CD005278.
91. Racke MK, Lovett-Racke AE, Karandikar NJ. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology. 2010; 74 Suppl 1:S25-30.
92. Plosker GL. Interferon-beta-1b: a review of its use in multiple sclerosis. CNS Drugs. 2011;25(1):67-88.
93. Koch-Henriksen N, et al. The clinical effect of neutralizing antibodies against interferon-beta is independent of the type of interferon-beta used for patients with relapsing-remitting multiple sclerosis. Mult Scler. 2009;15(5):601-5.
94. Beer K, et al. The prevalence of injection-site reactions with diseasemodifying therapies and their effect on adherence in patients with multiple sclerosis: an observational study. BMC Neurol. 2011;11:144.
95. Balak DM, et al. Cutaneous adverse events associated with disease-modifying treatment in multiple sclerosis: a systematic review. Mult Scler. 2012.
96. Rio J, et al. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann Neurol. 2006;59(2):344-52.
97. Rice GP, et al. Interferon in relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev. 2001;4:CD002002.
98. Ebers GC, et al. Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial. J Neurol Neurosurg Psychiatry. 2010;81(8):907-12.
99. Rojas JI, et al. Interferon Beta for primary progressive multiple sclerosis. Cochrane Database Syst Rev. 2010;1:CD006643.
100. La Mantia L, et al. Interferon beta for secondary progressive multiple sclerosis. Cochrane Database Syst Rev. 2012;1:CD005181.
101. Rojas JI, et al. Interferon beta for primary progressive multiple sclerosis. Cochrane Database Syst Rev. 2009;1:CD006643.
102. Kappos L, et al. Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology. 2004;63(10):1779-87.
103. Palmer AM. Brain disorders, brain medicines and the blood-brain barrier, in Nova Science Publishers, C.A.a.V. E, Editor, Nova Science Publishers: Horizons in Neuroscience Research. 2012:97-122.
104. Engelhardt B, Kappos L. Natalizumab: targeting alpha4-integrins in multiple sclerosis. Neurodegener Dis. 2008;5(1):16-22.
105. Pucci E, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev. 2011;10:CD007621.
106. Hellwig K, Gold R. Progressive multifocal leukoencephalopathy and natalizumab. J Neurol. 2011.
107. Bozic C, et al. Anti-John Cunnigham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1. Ann Neurol. 2011;70(5):742-50.
108. Yousry TA, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354(9): 924-33.
109. Lanzillo R, et al. Natalizumab vs. interferon beta 1a in relapsing-remitting multiple sclerosis: a head-to-head retrospective study. Acta Neurol Scand. 2011.
110. Kallweit U, et al. Sustained efficacy of natalizumab in the treatment of relapsing-remitting multiple sclerosis independent of disease activity and disability at baseline: real-life data from a swiss cohort. Clin Neuropharmacol. 2012;35(2):77-80.
111. Phillips JT, 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):970-9.
112. Fox RJ, et al. Multiple sclerosis: advances in understanding, diagnosing, and treating the underlying disease. Cleve Clin J Med. 2006;73(1):91-102.
113. Martinelli Boneschi F, et al. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2005;4:CD002127.
114. Fox EJ. Management of worsening multiple sclerosis with mitoxantrone: a review. Clin Ther. 2006;28(4):461-74.
115. Pelletier D, Hafler DA, Fingolimod for multiple sclerosis. N Engl J Med. 2012;366(4):339-47.
116. Cohen JA, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402-15.
117. Roskell NS, et al. Annualized relapse rate of first-line treatments for multiple sclerosis: a meta-analysis, including indirect comparisons versus fingolimod. Curr Med Res Opin. 2012.
118. Goodman AD, Hyland M. Dalfampridine in multiple sclerosis. Drugs Today (Barc). 2010;46(9):635-9.
119. Cornblath DR, Bienen EJ, Blight AR. The Safety Profile of Dalfampridine Extended Release in Multiple Sclerosis Clinical Trials. Clin Ther. 2012.
120. Sastre-Garriga J, et al. THC and CBD oromucosal spray (Sativex(R) in the management of spasticity associated with multiple sclerosis. Expert Rev Neurother. 2011;11(5):627-37.
121. Rowan WC, et al. Cross-linking of the CAMPATH-1 antigen (CD52) triggers activation of normal human T lymphocytes. Int Immunol. 1995;7(1):69-77.
122. Coles AJ, et al. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012; 78(14):1069-78.
123. Coles AJ, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359(17):1786-801.
124. Coles AJ, et al. Alemtuzumab versus interferon beta-1a in early relapsingremitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011;10(4):338-48.
125. Cossburn M, et al. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology. 2011;77(6):573-9.
126. Bielekova B, et al. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A. 2006;103(15):5941-6.
127. Bielekova B, et al. Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch Neurol. 2009;66(4):483-9.
128. Liu J, et al. Daclizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev. 2010;6:CD008127.
129. Hauser SL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-88.
130. He D, et al. Rituximab for relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev. 2011;12:CD009130.
131. Kappos L, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378(9805):1779-87.
132. Fox E, et al. A randomized clinical trial of autologous T-cell therapy in multiple sclerosis: subset analysis and implications for trial design. Mult Scler. 2011.
133. Haring N, et al. Early detection of renal damage caused by fumaric acid ester therapy by determination of urinary beta2-microglobulin. Br J Dermatol. 2011;164(3):648-51.
134. Ghoreschi K, et al. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med. 2011;208(11):2291-303.
135. Palmer AM. Teriflunomide, an inhibitor of dihydroorotate dehydrogenase for the potential oral treatment of multiple sclerosis. Curr Opin Investig Drugs. 2010;11(11):1313-23.
136. Claussen MC, Korn T. Immune mechanisms of new therapeutic strategies in MS-Teriflunomide. Clin Immunol. 2011.
137. O'Connor PW, et al. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006;66(6):894-900.
138. Confavreux C, et al. Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years. Mult Scler. 2012.
139. Conway D, Cohen JA. Emerging oral therapies in multiple sclerosis. Curr Neurol Neurosci Rep. 2010;10(5):381-8.
140. Rammohan KW, Shoemaker J. Emerging multiple sclerosis oral therapies. Neurology. 2010;74 Suppl 1:S47-53.
141. Comi G, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;371(9630):2085-92.
142. Comi G, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366(11):1000-9.
143. Miller DH, et al. Firategrast for relapsing remitting multiple sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2012;11(2):131-9.
144. Giovannoni G, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416-26.
145. Cook S, et al. Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study. Mult Scler. 2011;17(5):578-93.
146. Zajicek JP, Apostu VI. Role of cannabinoids in multiple sclerosis. CNS Drugs. 2011;25(3):187-201.
147. Mehnert U, et al. The effect of botulinum toxin type a on overactive bladder symptoms in patients with multiple sclerosis: a pilot study. J Urol. 2010;184(3):1011-6.
148. Frohman EM, et al. Immunologic mechanisms of multiple sclerosis. Neuroimaging Clin N Am. 2008;18(4):577-88, ix.
149. Evans C, et al. Long-term persistence with the immunomodulatory drugs for multiple sclerosis: a retrospective database study. Clin Ther. 2012;34(2):341-50.
150. Noyes K, et al. Cost-effectiveness of disease-modifying therapy for multiple sclerosis: a population-based study. Neurology. 2011;77(4):355-63.
151. Nafissi S, et al. Comparing efficacy and side effects of a weekly intramuscular biogeneric/biosimilar interferon beta-1a with Avonex in relapsing remitting multiple sclerosis: A double blind randomized clinical trial. Clin Neurol Neurosurg. 2012.
152. Reingold SC, et al. The challenge of follow-on biologics for treatment of multiple sclerosis. Neurology. 2009;73(7):552-9.
153. Goodin DS, et al. Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon beta-1b trial in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83(3):282-7.
154. Leray E, et al. Evidence for a two-stage disability progression in multiple sclerosis. Brain. 2010;133(Pt 7):1900-13.
155. Palmer AM. Neuroprotective therapeutics for Alzheimer's disease: progress and prospects. Trends Pharmacol Sci. 2011.
156. Durelli L, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359(9316): 1453-60.
157. Koch-Henriksen N, et al. A randomized study of two interferonbeta treatments in relapsing-remitting multiple sclerosis. Neurology. 2006;66(7):1056-60.
158. Dhib-Jalbut S, et al. Effect of combined IFNbeta-1a and glatiramer acetate therapy on GA-specific T-cell responses in multiple sclerosis. Mult Scler. 2002;8(6):485-91.
159. Etemadifar M, Janghorbani M, Shaygannejad V. Comparison of Betaferon, Avonex, and Rebif in treatment of relapsing-remitting multiple sclerosis. Acta Neurol Scand. 2006;113(5):283-7.
160. O'Connor P, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009;8(10):889-97.
161. Mikol DD, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs. Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7(10):903-14.
162. Cohen JA, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology. 2002;59(5):679-87.
163. Li DK, Zhao GJ, Paty DW. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: MRI results. Neurology. 2001;56(11):1505-13.
164. Andersen O, et al. Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2004;75(5):706-10.
165. Panitch H, et al. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology. 2004;63(10):1788-95.
166. Kappos L, et al. Final analysis of the European multicenter trial on IFNbeta-1b in secondary-progressive MS. Neurology. 2001;57(11): 1969-75.
167. Polman CH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910.
168. Rudick RA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911-23.
169. Kappos L, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401.
170. Palmer AM and Alavijeh MS. Translational CNS medicines research. Drug Discov. Today, in press (2012).