New and emerging disease modifying therapies for multiple sclerosis

Annals of the New York Academy of Sciences

Volumn 1247, Issue 1, 2012, Pages 117-137

  Saidha, Shiv ^a   Eckstein, Christopher ^b   Calabresi, Peter A ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF SOUTH ALABAMA COLLEGE OF MEDICINE   (United States)

Author keywords

Alemtuzumab; Anti CD20; BG12; Cladribine; Daclizum b; Fingolimod; Laquinimod; Monoclonal antibodies; Multiple sclerosis; Teriflunomide

Indexed keywords

ALEMTUZUMAB; BETA1A INTERFERON; CLADRIBINE; CYCLOPHOSPHAMIDE; DACLIZUMAB; FINGOLIMOD; FUMARIC ACID DIMETHYL ESTER; GLATIRAMER; LAQUINIMOD; LEFLUNOMIDE; METHYLPREDNISOLONE; OCRELIZUMAB; OFATUMUMAB; RECOMBINANT BETA INTERFERON; RITUXIMAB; ROQUINIMEX; TERIFLUNOMIDE;

ABDOMINAL PAIN; ADD ON THERAPY; ALOPECIA; ARTHRALGIA; ARTICLE; ATRIOVENTRICULAR BLOCK; AUTOIMMUNE DISEASE; AUTOIMMUNE HEMOLYTIC ANEMIA; BLOOD BRAIN BARRIER; BRADYCARDIA; BREAST CANCER; BUDD CHIARI SYNDROME; BURKITT LYMPHOMA; CARDIOTOXICITY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CHILL; CHORIOCARCINOMA; CHRONIC LYMPHATIC LEUKEMIA; DIARRHEA; DRUG BINDING; DRUG EFFICACY; DRUG ERUPTION; DRUG FATALITY; DRUG FEVER; DRUG INDUCED HEADACHE; DRUG MEGADOSE; DRUG MONITORING; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSPEPSIA; ENCEPHALITIS; EOSINOPHILIA; FATIGUE; GASTROINTESTINAL SYMPTOM; GOODPASTURE SYNDROME; HAIRY CELL LEUKEMIA; HEART INFARCTION; HERPES SIMPLEX ENCEPHALITIS; HERPES VIRUS INFECTION; HERPES ZOSTER; HERPETIC STOMATITIS; HOT FLUSH; HUMAN; HYPERCOAGULABILITY; HYPERTENSION; HYPERTHYROIDISM; HYPERTRANSAMINASEMIA; HYPOTHYROIDISM; IDIOPATHIC THROMBOCYTOPENIC PURPURA; IMMUNOSUPPRESSIVE TREATMENT; INFECTION; INJECTION SITE REACTION; INTERSTITIAL LUNG DISEASE; KIDNEY FAILURE; LATENT TUBERCULOSIS; LEUKEMIA; LISTERIOSIS; LIVER INJURY; LIVER TOXICITY; LOW DRUG DOSE; LOWER RESPIRATORY TRACT INFECTION; LUNG TOXICITY; LYMPHADENOPATHY; LYMPHOCYTE COUNT; LYMPHOCYTE PROLIFERATION; LYMPHOCYTOPENIA; LYMPHOCYTOTOXICITY; LYMPHOMA; MELANOMA; MENINGITIS; MICROANGIOPATHY; MULTIPLE CYCLE TREATMENT; MULTIPLE SCLEROSIS; NAUSEA; NEOPLASM; NEUTROPENIA; NONHODGKIN LYMPHOMA; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OPPORTUNISTIC INFECTION; OVARY CANCER; PANCREAS CANCER; PANCYTOPENIA; PARESTHESIA; PERICARDITIS; POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME; PROMYELOCYTIC LEUKEMIA; RESPIRATORY TRACT INFECTION; RETINA MACULA EDEMA; RHEUMATOID ARTHRITIS; RHINOPHARYNGITIS; SIDE EFFECT; SINUSITIS; SKIN CANCER; SYSTEMIC LUPUS ERYTHEMATOSUS; THROMBOCYTOPENIA; THYROID DISEASE; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; URTICARIA; UTERINE CERVIX CANCER; UTERINE CERVIX CARCINOMA; UTERUS MYOMA; VASOSPASM; VOMITING; WEIGHT REDUCTION;

EID: 84856432895     PISSN: 00778923     EISSN: 17496632     Source Type: Book Series    
DOI: 10.1111/j.1749-6632.2011.06272.x     Document Type: Article

References (161)

1. Anderson, D.W., J.H. Ellenberg, C.M. Leventhal, et al 1992. Revised estimate of the prevalence of multiple sclerosis in the United States. Ann. Neurol. 31: 333-336.
2. Marburg, O. 1906. Die sogennate akute multiple Sklerose. Jahrb. Psychiatrie 27: 211-312.
3. Putnam, T. 1936. Studies in multiple sclerosis. Arch. Neurol. Psych. 35: 1289-1308.
4. Prineas, J. 2001. Pathology of multiple sclerosis. In Handbook of Multiple Sclerosis. In Anonymous. S. Cook, Ed.: 289-324. Marcel Dekker. New York
5. Frohman, E.M., M.K. Racke & C.S. Raine 2006. Multiple sclerosis-the plaque and its pathogenesis. N. Engl. J. Med. 354: 942-955.
6. van Waesberghe, J.H., W. Kamphorst, C.J. De Groot, et al. 1999. Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann. Neurol. 46: 747-754.
7. De Stefano N., S. Narayanan, G.S. Francis, et al 2001. Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch. Neurol. 58: 65-70.
8. Compston, A. & A. Coles 2002. Multiple sclerosis. Lancet 359: 1221-1231.
9. Miller, D.H. 2004. Biomarkers and surrogate outcomes in neurodegenerative disease: lessons from multiple sclerosis. NeuroRx 1: 284-294.
10. Minneboo A., B.M. Uitdehaag, P. Jongen, et al 2009. Association between MRI parameters and the MS severity scale: a 12 year follow-up study. Mult. Scler. 15: 632-637.
11. Calabrese M., M. Atzori, V. Bernardi, et al 2007. Cortical atrophy is relevant in multiple sclerosis at clinical onset. J. Neurol. 254: 1212-1220.
12. Calabrese M., F. Agosta, F. Rinaldi, et al 2009. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch. Neurol. 66: 1144-1150.
13. Rawes, J.A., V.P. Calabrese, O.A. Khan, et al 1997. Antibodies to the axolemma-enriched fraction in the cerebrospinal fluid and serum of patients with multiple sclerosis and other neurological diseases. Mult. Scler. 3: 363-369.
14. Madigan, M.C., N.S. Rao, W.N. Tenhula, et al 1996. Preliminary morphometric study of tumor necrosis factor-alpha (TNF alpha)-induced rabbit optic neuropathy. Neurol. Res. 18: 233-236.
15. Shindler, K.S., E. Ventura, M. Dutt, et al 2008. Inflammatory demyelination induces axonal injury and retinal ganglion cell apoptosis in experimental optic neuritis. Exp. Eye Res. 87: 208-213.
16. Frischer, J.M., S. Bramow, A. Dal-Bianco, et al 2009. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132: 1175-1189.
17. Delgado, S. & W.A. Sheremata 2006. The role of CD4+ T-cells in the development of MS. Neurol. Res. 28: 245-249.
18. Mosmann, T.R., H. Cherwinski, M.W. Bond, et al 1986. Two types of murine helper T cell clone: I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136: 2348-2357.
19. Crawford, M.P., S.X. Yan, S.B. Ortega, et al 2004. High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay. Blood 103: 4222-4231.
20. Haas J., A. Hug, A. Viehover, et al 2005. 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. 35: 3343-3352.
21. Kumar M., N. Putzki, V. Limmroth, et al 2006. CD4+CD25+FoxP3+ T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis. J. Neuroimmunol. 180: 178-184.
22. Lovato L., S.N. Willis, S.J. Rodig, et al 2011. Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis. Brain 134: 534-541.
23. Lo, A.C., J.A. Black & S.G. Waxman 2002. Neuroprotection of axons with phenytoin in experimental allergic encephalomyelitis. Neuroreport 13: 1909-1912.
24. Lo, A.C., C.Y. Saab, J.A. Black, et al 2003. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. J. Neurophysiol. 90: 3566-3571.
25. Kapoor, R. 2010. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 9: 681-688.
26. Mi S., B. Hu, K. Hahm, et al 2007. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat. Med. 13: 1228-1233.
27. Calza L., M. Fernandez & L. Giardino 2010. Cellular approaches to central nervous system remyelination stimulation: thyroid hormone to promote myelin repair via endogenous stem and precursor cells. J. Mol. Endocrinol. 44: 13-23.
28. Frohman, E.M., J.G. Fujimoto, T.C. Frohman, et al 2008. Optical coherence tomography: a window into the mechanisms of multiple sclerosis. Nat. Clin. Pract. Neurol. 4: 664-675.
29. Saidha S., C. Eckstein & J.N. Ratchford 2010. Optical coherence tomography as a marker of axonal damage in multiple sclerosis. CML-Multiple Sclerosis 2: 33-43.
30. Paty, D.W. & D.K. Li UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. 1993. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43: 662-667.
31. The IFNB Multiple Sclerosis Study Group. 1993. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43: 655-661.
32. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. 1998. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 352: 1498-1504.
33. Jacobs, L.D., D.L. Cookfair, R.A. Rudick, et al. The Multiple Sclerosis Collaborative Research Group (MSCRG). 1996. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann. Neurol. 39: 285-294.
34. Johnson, K.P., B.R. Brooks, J.A. Cohen, et al. The Copolymer 1 Multiple Sclerosis Study Group. 1995. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 45: 1268-1276.
35. Racke, M.K. & A.E. Lovett-Racke 2011. Glatiramer acetate treatment of multiple sclerosis: an immunological perspective. J. Immunol. 186: 1887-1890.
36. Reder, A.T., G.C. Ebers, A. Traboulsee, et al 2010. Cross-sectional study assessing long-term safety of interferon-beta-1b for relapsing-remitting MS. Neurology 74: 1877-1885.
37. Ford C., A.D. Goodman, K. Johnson, et al 2010. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult. Scler. 16: 342-350.
38. Sandberg-Wollheim M., D. Frank, T.M. Goodwin, et al 2005. Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis. Neurology 65: 802-806.
39. Weber-Schoendorfer, C. & C. Schaefer 2009. Multiple sclerosis, immunomodulators, and pregnancy outcome: a prospective observational study. Mult. Scler. 15: 1037-1042.
40. Salminen, H.J., H. Leggett & M. Boggild 2010. Glatiramer acetate exposure in pregnancy: preliminary safety and birth outcomes. J. Neurol. 257: 2020-2023.
41. Kuhlmann T., G. Lingfeld, A. Bitsch, et al 2002. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125: 2202-2212.
42. Kappos L., M.S. Freedman, C.H. Polman, et al 2007. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 370: 389-397.
43. Jacobs, L.D., R.W. Beck, J.H. Simon, et al. CHAMPS Study Group. 2000. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N. Engl. J. Med. 343: 898-904.
44. Comi, G. 2009. Shifting the paradigm toward earlier treatment of multiple sclerosis with interferon beta. Clin. Ther. 31: 1142-1157.
45. Mikol, D.D., F. Barkhof, P. Chang, et al 2008. 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. 7: 903-914.
46. O'Connor P., M. Filippi, B. Arnason, et al 2009. 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. 8: 889-897.
47. Yednock, T.A., C. Cannon, L.C. Fritz, et al 1992. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 356: 63-66.
48. Osborn L., C. Hession, R. Tizard, et al 1989. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 59: 1203-1211.
49. Elices, M.J., L. Osborn, Y. Takada, et al 1990. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell 60: 577-584.
50. Polman, C.H., P.W. O'Connor, E. Havrdova, et al 2006. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354: 899-910.
51. Naismith, R.T. & D. Bourdette 2011. Interruption of natalizumab therapy for multiple sclerosis: What are the risks? Neurology 76: 1854-1855.
52. Rudick, R.A., W.H. Stuart, P.A. Calabresi, et al 2006. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N. Engl. J. Med. 354: 911-923.
53. Major, E.O. 2010. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu. Rev. Med. 61: 35-47.
54. Ransohoff, R.M. 2010. PML risk and natalizumab: more questions than answers. Lancet Neurol. 9: 231-233.
55. Koralnik, I.J. 2006. Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name? Ann. Neurol. 60: 162-173.
56. Hutchinson, M. 2007. Natalizumab: a new treatment for relapsing remitting multiple sclerosis. Ther. Clin. Risk Manag. 3: 259-268.
57. Sandrock A., C. Hotermans, S. Richman, et al 2011. Risk stratification for progressive mulitfocal leukoencephalopathy (PML) in MS patients: role of prior immunosuppressant use, natalizumab treatment duration, and anti-JCV antibody status [abstract]. Neurology 76(Suppl. 4): A248.
58. Clifford, D.B., A. De Luca, D.M. Simpson, et al 2010. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 9: 438-446.
59. Gorelik L., M. Lerner, S. Bixler, et al 2010. Anti-JC virus antibodies: implications for PML risk stratification. Ann. Neurol. 68: 295-303.
60. Khatri, B.O., S. Man, G. Giovannoni, et al 2009. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 72: 402-409.
61. Vermersch P., L. Kappos, R. Gold, et al 2011. Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology 76: 1697-1704.
62. Tan K., R. Roda, L. Ostrow, et al 2009. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 72: 1458-1464.
63. Hellwig K., A. Haghikia & R. Gold 2011. Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult. Scler.
64. Gold, R. 2011. Oral therapies for multiple sclerosis: a review of agents in phase III development or recently approved. CNS Drugs 25: 37-52.
65. Brinkmann, V. 2004. FTY720: mechanism of action and potential benefit in organ transplantation. Yonsei Med. J. 45: 991-997.
66. Brinkmann V., A. Billich, T. Baumruker, et al 2010. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 9: 883-897.
67. Matloubian M., C.G. Lo, G. Cinamon, et al 2004. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427: 355-360.
68. Kowarik, M.C., H.L. Pellkofer, S. Cepok, et al 2011. Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS. Neurology 76: 1214-1221.
69. Miron, V.E., A. Schubart & J.P. Antel 2008. Central nervous system-directed effects of FTY720 (fingolimod). J. Neurol. Sci. 274: 13-17.
70. Kappos L., J. Antel, G. Comi, et al 2006. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N. Engl. J. Med. 355: 1124-1140.
71. O'Connor P., G. Comi, X. Montalban, et al 2009. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 72: 73-79.
72. Comi G., P. O'Connor, X. Montalban, et al 2010. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results. Mult. Scler. 16: 197-207.
73. Kappos L., E.W. Radue, P. O'Connor, et al 2010. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362: 387-401.
74. Cohen, J.A., F. Barkhof, G. Comi, et al 2010. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 362: 402-415.
75. Schmouder R., S. Aradhye, P. O'Connor, et al 2006. Pharmacodynamic effects of oral fingolimod (FTY720) [abstract]. Mult. Scler. 12: S101-S102.
76. Schwarz A., M. Korporal, W. Hosch, et al 2010. Critical vasospasm during fingolimod (FTY720) treatment in a patient with multiple sclerosis. Neurology 74: 2022-2024.
77. Leypoldt F., A. Munchau, F. Moeller, et al 2009. Hemorrhaging focal encephalitis under fingolimod (FTY720) treatment: a case report. Neurology 72: 1022-1024.
78. Beutler, E. 1992. Cladribine (2-chlorodeoxyadenosine). Lancet 340: 952-956.
79. Sipe, J.C. 2005. Cladribine for multiple sclerosis: review and current status. Expert Rev. Neurother. 5: 721-727.
80. Beutler, E. 1994. New chemotherapeutic agent: 2-chlorodeoxyadenosine. Semin. Hematol. 31: 40-45.
81. Giovannoni G., G. Comi, S. Cook, et al 2010. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N. Engl. J. Med. 362: 416-426.
82. Montillo M., A. Tedeschi, S. O'Brien, et al 2003. Phase II study of cladribine and cyclophosphamide in patients with chronic lymphocytic leukemia and prolymphocytic leukemia. Cancer 97: 114-120.
83. Bruneau, J.M., C.M. Yea, S. Spinella-Jaegle, et al 1998. Purification of human dihydro-orotate dehydrogenase and its inhibition by A77 1726, the active metabolite of leflunomide. Biochem. J. 336(Pt 2): 299-303.
84. Bartlett, R.R., M. Dimitrijevic, T. Mattar, et al 1991. Leflunomide (HWA 486), a novel immunomodulating compound for the treatment of autoimmune disorders and reactions leading to transplantation rejection. Agents Actions. 32: 10-21.
85. Alcorn N., S. Saunders & R. Madhok 2009. Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing. Drug Saf. 32: 1123-1134.
86. Williamson, R.A., C.M. Yea, P.A. Robson, et al 1995. Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound. J. Biol. Chem. 270: 22467-22472.
87. Cherwinski, H.M., R.G. Cohn, P. Cheung, et al 1995. The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis. J. Pharmacol. Exp. Ther. 275: 1043-1049.
88. Zeyda M., M. Poglitsch, R. Geyeregger, et al 2005. 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. 52: 2730-2739.
89. Elder, R.T., X. Xu, J.W. Williams, et al 1997. The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms. J. Immunol. 159: 22-27.
90. Hamilton, L.C., I. Vojnovic & T.D. Warner 1999. A771726, the active metabolite of leflunomide, directly inhibits the activity of cyclo-oxygenase-2 in vitro and in vivo in a substrate-sensitive manner. Br. J. Pharmacol. 127: 1589-1596.
91. O'Connor, P.W., D. Li, M.S. Freedman, et al 2006. A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 66: 894-900.
92. O'Connor P., J. Wolinsky, C. Confavreux, et al 2010. A placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis: clinical efficacy and safety outcomes [abstract]. Mult. Scler. 16(Suppl. 10): S23.
93. Wolinsky J., P. O'Connor, C. Confavreux, et al 2010. A placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis: magnetic resonance imaging (MRI) outcomes [abstract]. Mult. Scler. 16: S347-S348.
94. Polman, C.H., S.C. Reingold, G. Edan, et al 2005. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann. Neurol. 58: 840-846.
95. Polman, C.H., S.C. Reingold, B. Banwell, et al 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 69: 292-302.
96. Claussen, M.C. & T. Korn 2011. Immune mechanisms of new therapeutic strategies in MS-Teriflunomide. Clin. Immunol. Epub ahead of print. doi:.
97. Suissa S., M. Hudson & P. Ernst 2006. Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis. Arthritis Rheum. 54: 1435-1439.
98. Warnatz K., H.H. Peter, M. Schumacher, et al 2003. Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature. Ann. Rheum. Dis. 62: 50-57.
99. Reich K., D. Thaci, U. Mrowietz, et al 2009. Efficacy and safety of fumaric acid esters in the long-term treatment of psoriasis-a retrospective study (FUTURE). J. Dtsch. Dermatol. Ges. 7: 603-611.
100. Moharregh-Khiabani D., R.A. Linker, R. Gold, et al 2009. Fumaric acid and its esters: an emerging treatment for multiple sclerosis. Curr. Neuropharmacol. 7: 60-64.
101. Osburn, W.O. & T.W. Kensler 2008. Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat. Res. 659: 31-39.
102. Harvey, C.J., R.K. Thimmulappa, A. Singh, et al 2009. Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress. Free Radic. Biol. Med. 46: 443-453.
103. Stoof, T.J., J. Flier, S. Sampat, et al 2001. The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells. Br. J. Dermatol. 144: 1114-1120.
104. Loewe R., W. Holnthoner, M. Groger, et al 2002. Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells. J. Immunol. 168: 4781-4787.
105. Seidel P., I. Merfort, J.M. Hughes, et al 2009. Dimethylfumarate inhibits NF-{kappa}B function at multiple levels to limit airway smooth muscle cell cytokine secretion. Am. J. Physiol. Lung Cell. Mol. Physiol. 297: L326-39.
106. Gerdes S., K. Shakery & U. Mrowietz 2007. Dimethylfumarate inhibits nuclear binding of nuclear factor kappaB but not of nuclear factor of activated T cells and CCAAT/enhancer binding protein beta in activated human T cells. Br. J. Dermatol. 156: 838-842.
107. Shih, A.Y., S. Imbeault, V. Barakauskas, et al 2005. Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J. Biol. Chem. 280: 22925-22936.
108. Johnson, J.A., D.A. Johnson, A.D. Kraft, et al 2008. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann. N. Y. Acad. Sci. 1147: 61-69.
109. Kappos L., R. Gold, D.H. Miller, et al 2008. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 372: 1463-1472.
110. MacManus, D.G., D. Miller, L. Kappos, et al 2008. The effect of BG00012 on conversion of gadolinium-enhancing lesions to T1-hypointense lesions [abstract]. Mult.Scler. 14: S163.
111. Hoefnagel, J.J., H.B. Thio, R. Willemze, et al 2003. Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br. J. Dermatol. 149: 363-369.
112. Nast A., I. Kopp, M. Augustin, et al 2007. German evidence-based guidelines for the treatment of Psoriasis vulgaris (short version). Arch. Dermatol. Res. 299: 111-138.
113. Andersen O., J. Lycke, P.O. Tollesson, et al 1996. Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis. Neurology 47: 895-900.
114. Karussis, D.M., Z. Meiner, D. Lehmann, et al 1996. Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide: a double-blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation. Neurology 47: 341-346.
115. Noseworthy, J.H., J.S. Wolinsky, F.D. Lublin, et al., North American Linomide Investigators. 2000. Linomide in relapsing and secondary progressive MS: part I. Trial design and clinical results. Neurology 54: 1726-1733.
116. Polman C., F. Barkhof, M. Sandberg-Wollheim, et al 2005. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology 64: 987-991.
117. Brunmark C., A. Runstrom, L. Ohlsson, et al 2002. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 130: 163-172.
118. Yang, J.S., L.Y. Xu, B.G. Xiao, et al 2004. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. J. Neuroimmunol. 156: 3-9.
119. Tselis, A. 2010. Laquinimod, a new oral autoimmune modulator for the treatment of relapsing-remitting multiple sclerosis. Curr. Opin. Investig Drugs 11: 577-585.
120. Comi G., A. Pulizzi, M. Rovaris, et al 2008. 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 371: 2085-2092.
121. Comi G., O. Abramsky, T. Arbizu, et al 2010. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study. Mult. Scler. 16: 1360-1366.
122. Gilleece, M.H. & T.M. Dexter 1993. Effect of Campath-1H antibody on human hematopoietic progenitors in vitro. Blood 82: 807-812.
123. Jones, J.L. & A.J. Coles 2008. Campath-1H treatment of multiple sclerosis. Neurodegener Dis. 5: 27-31.
124. Coles, A.J., A. Cox, E. Le Page, et al 2006. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J. Neurol. 253: 98-108.
125. Jones, J.L., C.L. Phuah, A.L. Cox, et al 2009. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J. Clin. Invest. 119: 2052-2061.
126. Thompson, S.A., J.L. Jones, A.L. Cox, et al 2010. B cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J. Clin. Immunol. 30: 99-105.
127. Coles, A.J., M. Wing, S. Smith, et al 1999. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354: 1691-1695.
128. Otton, S.H., D.L. Turner, R. Frewin, et al 1999. Autoimmune thrombocytopenia after treatment with Campath 1H in a patient with chronic lymphocytic leukaemia. Br. J. Haematol. 106: 261-262.
129. Haider, I. & M. Cahill 2004. Fatal thrombocytopaenia temporally related to the administration of alemtuzumab (MabCampath) for refractory CLL despite early discontinuation of therapy. Hematology 9: 409-411.
130. Loh Y., Y. Oyama, L. Statkute, et al 2007. Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used. Blood 109: 2643-2548.
131. CAMMS223 Trial Investigators, A.J. Coles, D.A. Compston, et al 2008. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N. Engl. J. Med. 359: 1786-1801.
132. Clatworthy, M.R., E.F. Wallin & D.R. Jayne 2008. Anti-glomerular basement membrane disease after alemtuzumab. N. Engl. J. Med. 359: 768-769.
133. Schippling, D.S. & R. Martin 2008. Spotlight on anti-CD25: daclizumab in MS. Int. MS J. 15: 94-98.
134. Waldmann, T.A. 2007. Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune diseases, and in the prevention of allograft rejection: a 25-year personal odyssey. J. Clin. Immunol. 27: 1-18.
135. Wynn D., M. Kaufman, X. Montalban, et al 2010. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 9: 381-390.
136. Wuest, S.C., J.H. Edwan, J.F. Martin, et al 2011. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat. Med. 17: 604-609.
137. Bielekova B., N. Richert, T. Howard, et al 2004. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc. Natl. Acad. Sci. U.S.A. 101: 8705-8708.
138. Rojas, M.A., N.G. Carlson, T.L. Miller, et al 2009. Long-term daclizumab therapy in relapsing-remitting multiple sclerosis. Ther. Adv. Neurol. Disord. 2: 291-297.
139. Stashenko P., L.M. Nadler, R. Hardy, et al 1980. Characterization of a human B lymphocyte-specific antigen. J. Immunol. 125: 1678-1685.
140. Reff, M.E., K. Carner, K.S. Chambers, et al 1994. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83: 435-445.
141. Deans, J.P., H. Li & M.J. Polyak 2002. CD20-mediated apoptosis: signalling through lipid rafts. Immunology 107: 176-182.
142. Maloney, D.G., T.M. Liles, D.K. Czerwinski, et al 1994. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B cell lymphoma. Blood 84: 2457-2466.
143. Bar-Or A., P.A. Calabresi, D. Arnold, et al 2008. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann. Neurol. 63: 395-400.
144. Bar-Or A., L. Fawaz, B. Fan, et al 2010. Abnormal B cell cytokine responses a trigger of T cell-mediated disease in MS? Ann. Neurol. 67: 452-461.
145. Monson, N.L., P.D. Cravens, E.M. Frohman, et al 2005. Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch. Neurol. 62: 258-264.
146. Cross, A.H., J.L. Stark, J. Lauber, et al 2006. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J. Neuroimmunol. 180: 63-70.
147. Barun, B. & A. Bar-Or 2011. Treatment of multiple sclerosis with anti-CD20 antibodies. Clin. Immunol.
148. Hauser, S.L., E. Waubant, D.L. Arnold, et al 2008. B cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358: 676-688.
149. Hawker K., P. O'Connor, M.S. Freedman, et al 2009. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol. 66: 460-471.
150. Waubant, E. 2008. Spotlight on anti-CD20. Int. MS J. 15: 19-25.
151. Carson, K.R., A.M. Evens, E.A. Richey, et al 2009. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 113: 4834-4840.
152. Allison, M. 2010. PML problems loom for Rituxan. Nat. Biotechnol. 28: 105-106.
153. Kausar F., K. Mustafa, G. Sweis, et al 2009. Ocrelizumab: a step forward in the evolution of B cell therapy. Expert Opin. Biol. Ther. 9: 889-895.
154. Genovese, M.C., J.L. Kaine, M.B. Lowenstein, et al 2008. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I/II randomized, blinded, placebo-controlled, dose-ranging study. Arthritis Rheum. 58: 2652-2661.
155. Kappos L., P. Calabresi, P. O'Connor, et al 2010. Efficacy and safety of ocrelizumab in patients with relapsing-remitting multiple sclerosis: results of a phase II randomised placebo-controlled multicentre trial. Mult. Scler. 16(Suppl. 10): S33-S34.
156. Zhang, B. 2009. Ofatumumab. MAbs 1: 326-331.
157. Teeling, J.L., R.R. French, M.S. Cragg, et al 2004. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood 104: 1793-1800.
158. Teeling, J.L., W.J. Mackus, L.J. Wiegman, et al 2006. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J. Immunol. 177: 362-371.
159. Pawluczkowycz, A.W., F.J. Beurskens, P.V. Beum, et al 2009. Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of CDC are induced by OFA than by RTX. J. Immunol. 183: 749-758.
160. Ostergaard M., B. Baslund, W. Rigby, et al 2010. Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study. Arthritis Rheum. 62: 2227-2238.
161. Sorensen, P.S., J. Drulovic, E. Havrdova, et al 2010. Magnetic resonance imaging (MRI) efficacy of ofatumumab in relapsing-remitting multiple sclerosis (RRMS)-24-week results of a phase II study [abstract]. Mult. Scler. 16(Suppl 10): S37-S38.