With the introduction of interferon-β1b in 1993 as the first FDA-approved treatment for multiple sclerosis, the era of treatment of this incurable disease began, and its natural course was permanently changed. Currently, seven different treatments for patients with multiple sclerosis with different mechanisms of action and dissimilar side effect profiles exist. These medications include interferon-β1a intramuscular (Avonex), interferon-β1a subcutaneous (Rebif), interferon-β1b subcutaneous (Betaseron/Extavia), glatiramer acetate (Copaxone), natalizumab (Tysabri), fingolimod (Gilenya), teriflunomide (Aubagio), and mitoxantrone (Novantrone). In addition, a large number of clinical trials are being conducted to assess the safety and efficacy of various experimental agents in patients with multiple sclerosis, including alemtuzumab, dimethyl fumarate, laquinimod, rituximab, daclizumab, and cladribine. In this paper, the author presents a concise and comprehensive review of present and potential treatments for this incurable disease. 1. Introduction Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the human central nervous system (CNS), which causes neurological disability in young adults [1, 2]. Presently, the etiology and cure for MS remain unknown. MS develops in individuals who are genetically susceptible following exposure to an unidentified environmental agent. Extensive epidemiological studies indicate that genetic factors play a significant role in the development of MS [1, 3, 4]. In addition, certain environmental factors such as exposure to or infection with certain viruses such as Epstein-Barr virus, low serum vitamin D levels, and smoking may contribute to the development of MS. MS is commonly a disabling disease and remains the leading cause of acquired neurological disability in young adults individuals between 15 to 45 years [5]. The peak age of onset is 29 years, and similar to other immune-mediated diseases, in most forms of MS, females outnumber the males. MS affects both white and gray matters of the CNS (whole brain disease), and its underlying neuropathology leads to loss of myelin/oligodendrocyte complex as well as neuronal and axonal degeneration (demyelination versus neurodegeneration) [6]. Clinically, MS presents with four relatively distinguishable patters: relapsing remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and relapsing progressive (RPMS). The most common clinical phenotype of MS, RRMS, may initiate with a single uni- or multifocal demyelinating attack, referred to as
References
[1]
J. H. Noseworthy, C. Lucchinetti, M. Rodriguez, and B. G. Weinshenker, “Multiple sclerosis,” The New England Journal of Medicine, vol. 343, no. 13, pp. 938–952, 2000.
[2]
F. Luessi, V. Siffrin, and F. Zipp, “Neurodegeneration in multiple sclerosis: novel treatment strategies,” Expert Review of Neurotherapeutics, vol. 12, no. 9, pp. 1061–1077, 2012.
[3]
E. M. Frohman, M. K. Racke, and C. S. Raine, “Medical progress: multiple sclerosis—the plaque and its pathogenesis,” The New England Journal of Medicine, vol. 354, no. 9, pp. 942–955, 2006.
[4]
A. Nylander and D. A. Hafler, “Multiple sclerosis,” Journal of Clinical Investigation, vol. 122, no. 4, pp. 1180–1188, 2012.
[5]
G. Disanto, J. M. Morahan, and S. V. Ramagopalan, “Multiple sclerosis: risk factors and their interactions,” CNS and Neurological Disorders—Drug Targets, vol. 11, no. 5, pp. 545–555, 2012.
[6]
L. Crespy, W. Zaaraoui, M. Lemaire et al., “Prevalence of grey matter pathology in early multiple sclerosis assessed by magnetization transfer ratio imaging,” PLoS ONE, vol. 6, no. 9, Article ID e24969, 2011.
[7]
D. H. Miller, D. T. Chard, and O. Ciccarelli, “Clinically isolated syndromes,” The Lancet Neurology, vol. 11, no. 2, pp. 157–169, 2012.
[8]
E. M. Mowry, “Natural history of multiple sclerosis: early prognostic factors,” Neurologic Clinics, vol. 29, no. 2, pp. 279–292, 2011.
[9]
S. Vukusic and C. Confavreux, “Natural history of multiple sclerosis: risk factors and prognostic indicators,” Current Opinion in Neurology, vol. 20, no. 3, pp. 269–274, 2007.
[10]
F. D. Lublin, “Clinical features and diagnosis of multiple sclerosis,” Neurologic Clinics, vol. 23, no. 1, pp. 1–15, 2005.
[11]
A. P. Borazanci, M. K. Harris, R. N. Schwendimann et al., “Multiple sclerosis: clinical features, pathophysiology, neuroimaging and future therapies,” Future Neurology, vol. 4, no. 2, pp. 229–246, 2009.
[12]
B. G. W. Arnason, “Interferon β in multiple sclerosis,” Clinical Immunology and Immunopathology, vol. 81, no. 1, pp. 1–11, 1996.
[13]
Y. M. Huang, N. Stoyanova, Y. P. Jin et al., “Altered phenotype and function of blood dendritic cells in multiple sclerosis are modulated by IFN-β and IL-10,” Clinical and Experimental Immunology, vol. 124, no. 2, pp. 306–314, 2001.
[14]
S. Shapiro, Y. Galboiz, N. Lahat, A. Kinarty, and A. Miller, “The “immunological-synapse” at its APC side in relapsing and secondary-progressive multiple sclerosis: modulation by interferon-β,” Journal of Neuroimmunology, vol. 144, no. 1-2, pp. 116–124, 2003.
[15]
Y. Zang, J. Hong, R. Robinson, S. Li, V. M. Rivera, and J. Z. Zhang, “Immune regulatory properties and interactions of Copolymer-I and β-interferon 1a in multiple sclerosis,” Journal of Neuroimmunology, vol. 137, no. 1-2, pp. 144–153, 2003.
[16]
V. Ozenci, M. Kouwenhoven, N. Teleshova, M. Pashenkov, S. Fredrikson, and H. Link, “Multiple sclerosis: pro- and anti-inflammatory cytokines and metalloproteinases are affected differentially by treatment with IFN-β,” Journal of Neuroimmunology, vol. 108, no. 1-2, pp. 236–243, 2000.
[17]
V. ？zenci, M. Kouwenhoven, Y. M. Huang, P. Kivis？kk, and H. Link, “Multiple sclerosis is associated with an imbalance between tumour necrosis factor-alpha (TNF-α)- and IL-10-secreting blood cells that is corrected by interferon-β (IFN-β) treatment,” Clinical and Experimental Immunology, vol. 120, no. 1, pp. 147–153, 2000.
[18]
A. Minagar, A. Long, T. Ma et al., “Interferon (IFN)-β1a and IFN-β1b block IFN-γ-induced disintegration of endothelial junction integrity and barrier,” Endothelium, vol. 10, no. 6, pp. 299–307, 2003.
[19]
M. Lowery-Nordberg, E. Eaton, E. Gonzalez-Toledo et al., “The effects of high dose interferon-β1a on plasma microparticles: correlation with MRI parameters,” Journal of Neuroinflammation, vol. 8, article 43, 2011.
[20]
S. Haghjooy Javanmard, M. Saadatnia, V. Homayouni et al., “Interferon-β-1b protects against multiple sclerosis-induced endothelial cells apoptosis,” Frontiers in Bioscience (Elite Edition), vol. 4, pp. 1368–1374, 2012.
[21]
A. Prat, A. Al-Asmi, P. Duquette, and J. P. Antel, “Lymphocyte migration and multiple sclerosis: relation with disease course and therapy,” Annals of Neurology, vol. 46, no. 2, pp. 253–256, 1999.
[22]
A. Minagar, J. S. Alexander, R. N. Schwendimann et al., “Combination therapy with interferon β-1a and doxycycline in multiple sclerosis: an open-label trial,” Archives of Neurology, vol. 65, no. 2, pp. 199–204, 2008.
[23]
The IFNB Multiple Sclerosis Study Group, “Interferon β-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial,” Neurology, vol. 43, no. 4, pp. 655–661, 1993.
[24]
D. W. Paty and D. K. B. Li, “Interferon β-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial,” Neurology, vol. 43, no. 4, pp. 662–667, 1993.
[25]
D. H. Miller, P. D. Molyneux, G. J. Barker, D. G. MacManus, I. F. Moseley, and K. Wagner, “Effect of interferon-β1b on magnetic resonance imaging outcomes in secondary progressive multiple sclerosis: results of a European multicenter, randomized, double-blind, placebo-controlled trial. European study group on interferon-β1b in secondary progressive multiple sclerosis,” Annals of Neurology, vol. 46, no. 6, pp. 850–859, 1999.
[26]
D. F. Mark, S. D. Lu, A. A. Creasey, R. Yamamoto, and L. S. Lin, “Site-specific mutagenesis of the human fibroblast interferon gene,” Proceedings of the National Academy of Sciences of the United States of America, vol. 81, no. 18, pp. 5662–5666, 1984.
[27]
L. Kappos, C. Polman, C. Pozzilli, A. Thompson, and F. Dahlke, “Placebo-controlled multicentrerandomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis,” The Lancet, vol. 352, no. 9139, pp. 1491–1497, 1998.
[28]
G. Ebers, A. Traboulsee, D. Langdon, D. Goodin, A. Konicezny, and The Betaseron/Betaseron LTF Study Group, “The interferon β-1b 16-year long-term follow-up study: the results,” in Proceedings of the 58th Annual Meeting of the American Academy of Neurology, pp. 01–079, San Diego, Calif, USA, 2006.
[29]
D. S. Goodin, A. T. Reder, G. C. Ebers et al., “Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial,” Neurology, vol. 78, no. 17, pp. 1315–1322, 2012.
[30]
H. Panitch, D. S. Goodin, G. Francis et al., “Randomized, comparative study of interferon β-1a treatment regimens in MS: The evidence trial,” Neurology, vol. 59, no. 10, pp. 1496–1506, 2002.
[31]
G. C. Ebers, G. Rice, J. Lesaux et al., “Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis,” The Lancet, vol. 352, no. 9139, pp. 1498–1504, 1998.
[32]
L. D. Jacobs, D. L. Cookfair, R. A. Rudick et al., “Intramuscular interferon β-1a for disease progression in relapsing multiple sclerosis,” Annals of Neurology, vol. 39, no. 3, pp. 285–294, 1996.
[33]
R. A. Rudick, D. E. Goodkin, L. D. Jacobs et al., et al., “Impact of interferon β-1a on neurologic disability in relapsing multiple sclerosis,” Neurology, vol. 49, no. 2, pp. 358–363, 1997.
[34]
J. H. Simon, L. D. Jacobs, M. Campion et al., et al., “Magnetic resonance studies of intramuscular interferon β-1a for relapsing multiple sclerosis,” Annals of Neurology, vol. 43, no. 1, pp. 79–87, 1998.
[35]
D. Teitelbaum, M. Fridkis-Hareli, R. Arnon, and M. Sela, “Copolymer 1 inhibits chronic relapsing experimental allergic encephalomyelitis induced by proteolipid protein (PLP) peptides in mice and interferes with PLP-specific T cell responses,” Journal of Neuroimmunology, vol. 64, no. 2, pp. 209–217, 1996.
[36]
D. Teitelbaum, A. Meshorer, T. Hirshfeld, R. Arnon, and M. Sela, “Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide.,” European Journal of Immunology, vol. 1, no. 4, pp. 242–248, 1971.
[37]
M. Fridkis-Hareli, D. Teitelbaum, I. Pecht, R. Arnon, and M. Sela, “Binding of copolymer 1 and myelin basic protein leads to clustering of class II MHC molecules on antigen-presenting cells,” International Immunology, vol. 9, no. 7, pp. 925–934, 1997.
[38]
M. B. Bornstein, A. Miller, S. Slagle et al., et al., “A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis,” The New England Journal of Medicine, vol. 317, no. 7, pp. 408–414, 1987.
[39]
K. P. Johnson, B. R. Brooks, J. A. Cohen et al., “Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability,” Neurology, vol. 57, no. 12, supplement, pp. S46–S53, 2001.
[40]
G. L. Mancardi, F. Sardanelli, R. C. Parodi et al., “Effect of copolymer-1 on serial gadolinium-enhanced MRI in relapsing remitting multiple sclerosis,” Neurology, vol. 50, no. 4, pp. 1127–1133, 1998.
[41]
G. Comi, M. Filippi, and J. S. Wolinsky, “European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis,” Annals of Neurology, vol. 49, no. 3, pp. 290–297, 2001.
[42]
H. Lenk, U. Müller, and S. Tanneberger, “Mitoxantrone: mechanism of action, antitumor activity, pharmacokinetics, efficacy in the treatment of solid tumors and lymphomas, and toxicity,” Anticancer Research, vol. 7, no. 6, pp. 1257–1264, 1987.
[43]
L. S. Rosenberg, M. J. Carvlin, and T. R. Krugh, “The antitumor agent mitoxantrone binds cooperatively to DNA: evidence for heterogeneity in DNA conformation,” Biochemistry, vol. 25, no. 5, pp. 1002–1008, 1986.
[44]
J. M. Fidler, S. Q. DeJoy, and J. J. Gibbons Jr., “Selective immunomodulation by the antineoplastic agent mitoxantrone. I. Suppression of B lymphocyte function,” Journal of Immunology, vol. 137, no. 2, pp. 727–732, 1986.
[45]
B. Bellosillo, D. Colomer, G. Pons, and J. Gil, “Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells,” British Journal of Haematology, vol. 100, no. 1, pp. 142–146, 1998.
[46]
H. P. Hartung, R. Gonsette, N. K？nig et al., “Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial,” The Lancet, vol. 360, no. 9350, pp. 2018–2025, 2002.
[47]
R. J. Crossley, “Clinical safety and tolerance of mitoxantrone,” Seminars in Oncology, vol. 11, no. 3, supplement 1, pp. 54–58, 1984.
[48]
V. Martinelli, M. Radaelli, L. Straffi, M. Rodegher, and G. Comi, “Mitoxantrone: benefits and risks in multiple sclerosis patients,” Neurological Sciences, vol. 30, supplement 2, pp. S167–S170, 2009.
[49]
R. G. Ghalie, G. Edan, M. Laurent et al., “Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS,” Neurology, vol. 59, no. 6, pp. 909–913, 2002.
[50]
C. Cattaneo, C. Almici, E. Borlenghi, M. Motta, and G. Rossi, “A case of acute promyelocytic leukaemia following mitoxantrone treatment of multiple sclerosis,” Leukemia, vol. 17, no. 5, pp. 985–986, 2003.
[51]
C. Heesen, M. Bruegmann, J. Gbdamosi, E. Koch, A. M？nch, and C. Buhmann, “Therapy-related acute myelogenous leukaemia (t-AML) in a patient with multiple sclerosis treated with mitoxantrone,” Multiple Sclerosis, vol. 9, no. 2, pp. 213–214, 2003.
[52]
J. Bines, D. M. Oleske, and M. A. Cobleigh, “Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer,” Journal of Clinical Oncology, vol. 14, no. 5, pp. 1718–1729, 1996.
[53]
D. H. Miller, O. A. Khan, W. A. Sheremata et al., “A controlled trial of natalizumab for relapsing multiple sclerosis,” The New England Journal of Medicine, vol. 348, no. 1, pp. 15–23, 2003.
[54]
W. A. Sheremata, A. Minagar, J. S. Alexander, and T. Vollmer, “The role of α-4 integrin in the aetiology of multiple sclerosis: current knowledge and therapeutic implications,” CNS Drugs, vol. 19, no. 11, pp. 909–922, 2005.
[55]
S. Ghosh, E. Goldin, F. H. Gordon et al., “Natalizumab for active Crohn's disease,” The New England Journal of Medicine, vol. 348, no. 1, pp. 24–32, 2003.
[56]
B. Engelhardt and L. Kappos, “Natalizumab: targeting α4-integrins in multiple sclerosis,” Neurodegenerative Diseases, vol. 5, no. 1, pp. 16–22, 2007.
[57]
T. A. Yednock, C. Cannon, L. C. Fritz, F. Sanchez-Madrid, L. Steinmann, and N. Karin, “Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin,” Nature, vol. 356, no. 6364, pp. 63–66, 1992.
[58]
N. Tubridy, P. O. Behan, R. Capildeo et al., “The effect of anti-α4 integrin antibody on brain lesion activity in MS,” Neurology, vol. 53, no. 3, pp. 466–472, 1999.
[59]
C. H. Polman, P. W. O'Connor, E. Havrdova et al., “A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis,” The New England Journal of Medicine, vol. 354, no. 9, pp. 899–910, 2006.
[60]
R. A. Rudick, W. H. Stuart, P. A. Calabresi et al., “Natalizumab plus interferon β-1a for relapsing multiple sclerosis,” The New England Journal of Medicine, vol. 354, no. 9, pp. 911–923, 2006.
[61]
R. A. Rudick and A. Sandrock, “Natalizumab: α4-integrin antagonist selective adhesion molecule inhibitors for MS,” Expert Review of Neurotherapeutics, vol. 4, no. 4, pp. 571–580, 2004.
[62]
M. A. Sahraian, E. W. Radue, A. Eshaghi, S. Besliu, and A. Minagar, “Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis,” European Journal of Neurology, vol. 19, no. 8, pp. 1060–1069, 2012.
[63]
P. S. S？rensen, A. Bertolotto, G. Edan et al., “Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab,” Multiple Sclerosis, vol. 18, no. 2, pp. 143–152, 2012.
[64]
M. Matloubian, C. G. Lo, G. Cinamon et al., “Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1,” Nature, vol. 427, no. 6972, pp. 355–360, 2004.
[65]
K. Chiba, “FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors,” Pharmacology and Therapeutics, vol. 108, no. 3, pp. 308–319, 2005.
[66]
L. Kappos, J. Antel, G. Comi et al., “Oral fingolimod (FTY720) for relapsing multiple sclerosis,” The New England Journal of Medicine, vol. 355, no. 11, pp. 1124–1140, 2006.
[67]
P. O'Connor, G. Comi, X. Montalban et al., “Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study,” Neurology, vol. 72, no. 1, pp. 73–79, 2009.
[68]
J. A. Cohen, F. Barkhof, G. Comi et al., “Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis,” The New England Journal of Medicine, vol. 362, no. 5, pp. 402–415, 2010.
[69]
A. Minagar, J. S. Alexander, M. A. Sahraian, and R. Zivadinov, “Alemtuzumab and multiple sclerosis: therapeutic application,” Expert Opinion on Biological Therapy, vol. 10, no. 3, pp. 421–429, 2010.
[70]
J. L. Jones, J. M. Anderson, C. L. Phuah et al., “Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity,” Brain, vol. 133, no. 8, pp. 2232–2247, 2010.
[71]
T. Moreau, J. Thorpe, D. Miller et al., “Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis,” The Lancet, vol. 344, no. 8918, pp. 298–301, 1994.
[72]
A. J. Coles, D. A. S. Compston, K. W. Selmaj et al., “Alemtuzumab vs. interferon β-1a in early multiple sclerosis,” The New England Journal of Medicine, vol. 359, no. 17, pp. 1786–1801, 2008.
[73]
A. J. Coles, E. Fox, A. Vladic et al., “Alemtuzumab versus interferon β-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes,” The Lancet Neurology, vol. 10, no. 4, pp. 338–348, 2011.
[74]
J. A. Cohen, A. J. Coles, D. L. Arnold et al., “Alemtuzumab versus interferon β 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial,” The Lancet, vol. 380, no. 9856, pp. 1819–1828, 2012.
[75]
D. H. Lee, R. A. Linker, and R. Gold, “Spotlight on fumarates,” International MS Journal, vol. 15, no. 1, pp. 12–18, 2008.
[76]
D. Moharregh-Khiabani, R. A. Linker, R. Gold, and M. Stangel, “Fumaric acid and its esters: an emerging treatment for multiple sclerosis,” Current Neuropharmacology, vol. 7, no. 1, pp. 60–64, 2009.
[77]
R. Gold, L. Kappos, A. Bar-Or, et al., “Clinical efficacy of BG-12, an oral therapy, in relapsing-remitting multiple sclerosis: data from the phase 3 DEFINE trial,” in Proceedings of the 5th Joint Teriannial Congress of European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS), Amsterdam, The Netherlands, October 2011.
[78]
L. Kappos, R. Gold, D. H. Miller 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,” The Lancet, vol. 372, no. 9648, pp. 1463–1472, 2008.
[79]
R. J. Fox, D. H. Miller, J. T. Phillips et al., “Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis,” The New England Journal of Medicine, vol. 367, no. 12, pp. 1087–1097, 2012.
[80]
R. Gold, L. Kappos, D. L. Arnold et al., “Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis,” The New England Journal of Medicine, vol. 367, no. 12, pp. 1098–1107, 2012.
[81]
A. M. Palmer, “Teriflunomide, an inhibitor of dihydroorotate dehydrogenase for the potential oral treatment of multiple sclerosis,” Current Opinion in Investigational Drugs, vol. 11, no. 11, pp. 1313–1323, 2010.
[82]
J. Killestein, R. A. Rudick, and C. H. Polman, “Oral treatment for multiple sclerosis,” The Lancet Neurology, vol. 10, no. 11, pp. 1026–1034, 2011.
[83]
M. C. Claussen and T. Korn, “Immune mechanisms of new therapeutic strategies in MS—teriflunomide,” Clinical Immunology, vol. 142, no. 1, pp. 49–56, 2012.
[84]
P. W. O'Connor, D. Li, M. S. Freedman et al., “A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses,” Neurology, vol. 66, no. 6, pp. 894–900, 2006.
[85]
P. O'Connor, J. S. Wolinsky, C. Confavreux et al., “Randomized trial of oral teriflunomide for relapsing multiple sclerosis,” The New England Journal of Medicine, vol. 365, no. 14, pp. 1293–1303, 2011.
[86]
P. S. Giacomini and A. Bar-Or, “Laquinimod in multiple sclerosis,” Clinical Immunology, vol. 142, no. 1, pp. 38–43, 2012.
[87]
W. Brück and S. S. Zamvil, “Laquinimod, a once-daily oral drug in development for the treatment of relapsing-remitting multiple sclerosis,” Expert Review of Clinical Pharmacology, vol. 5, no. 3, pp. 245–256, 2012.
[88]
W. Brück and C. Wegner, “Insight into the mechanism of laquinimod action,” Journal of the Neurological Sciences, vol. 306, no. 1-2, pp. 173–179, 2011.
[89]
C. Wegner, C. Stadelmann, R. Pf？rtner et al., “Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis,” Journal of Neuroimmunology, vol. 227, no. 1-2, pp. 133–143, 2010.
[90]
G. Comi, O. Abramsky, T. Arbizu et al., “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,” Multiple Sclerosis, vol. 16, no. 11, pp. 1360–1366, 2010.
[91]
D. G. Maloney, “Anti-CD20 antibody therapy for B-cell lymphomas,” The New England Journal of Medicine, vol. 366, no. 21, pp. 2008–2016, 2012.
[92]
D. K. Kitsos, S. Tsiodras, E. Stamboulis, and K. I. Voumvourakis, “Rituximab and multiple sclerosis,” Clinical Neuropharmacology, vol. 35, no. 2, pp. 90–96, 2012.
[93]
M. S. Weber, T. Menge, K. Lehmann-Horn et al., “Current treatment strategies for multiple sclerosis—efficacy versus neurological adverse effects,” Current Pharmaceutical Design, vol. 18, no. 2, pp. 209–219, 2012.
[94]
S. L. Hauser, E. Waubant, D. L. Arnold et al., “B-cell depletion with rituximab in relapsing-remitting multiple sclerosis,” The New England Journal of Medicine, vol. 358, no. 7, pp. 676–688, 2008.
[95]
T. R. Malek, “The biology of interleukin-2,” Annual Review of Immunology, vol. 26, pp. 453–479, 2008.
[96]
H. Gensicke, D. Leppert, O. Yaldizli et al., “Monoclonal antibodies and recombinant immunoglobulins for the treatment of multiple sclerosis,” CNS Drugs, vol. 26, no. 1, pp. 11–37, 2012.
[97]
R. Martin, “Humanized anti-CD25 antibody treatment with daclizumab in multiple sclerosis,” Neurodegenerative Diseases, vol. 5, no. 1, pp. 23–26, 2007.
[98]
A. Cuppoletti, F. Perez-Villa, I. Vallejos, and E. Roig, “Experience with single-dose daclizumab in the prevention of acute rejection in heart transplantation,” Transplantation Proceedings, vol. 37, no. 9, pp. 4036–4038, 2005.
[99]
B. Bielekova, M. Catalfamo, S. Reichert-Scrivner et al., “Regulatory CD56bright natural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 15, pp. 5941–5946, 2006.
[100]
G. Giovannoni, R. Gold, K. Selmaj, et al., “A randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of daclizumab HYP monotherapy in relapsing-remitting multiple sclerosis: primary results of the SELECT trial,” Multiple Sclerosis, vol. 17, no. 10, pp. S507–S524, 2011.
[101]
D. Wynn, M. Kaufman, X. Montalban et al., “Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon β,” The Lancet Neurology, vol. 9, no. 4, pp. 381–390, 2010.
[102]
C. Gasperini and S. Ruggieri, “Emerging oral drugs for relapsing-remitting multiple sclerosis,” Expert Opinion on Emerging Drugs, vol. 16, no. 4, pp. 697–712, 2011.
