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Immunotherapy of multiple sclerosis

  • Sven G. Meuth (a1), Stefan Bittner (a1) and Heinz Wiendl (a1)

Abstract:

Multiple sclerosis (MS) is regarded as a prototypic inflammatory autoimmune central nervous system disorder causing neurological disability in young adults. Recommended basic immunomodulatory therapies of MS are currently interferon beta and glatiramer acetate. Both have proven to be clinically and paraclinically effective and clinical evidence suggests that treatment should be initiated as early as possible.

However, despite the fact that therapeutic options for MS have significantly been widened over the past decade there is still tremendous activity in the search for new treatment options for MS.

One important development in the field is reflected by the substantial number of promising results for oral therapies. Various phase III clinical trials are currently being initiated or are already underway evaluating the efficacy of a variety of orally administered agents, including cladribine, teriflunomide, laquinimod, fingolimod and fumaric acid. It is hoped that these oral therapies for MS further broaden our armament for MS therapy.

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References

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1.Compston, A & Coles, A. Multiple sclerosis. Lancet 2002;359:12211231.
2.Kieseier, BC, Hemmer, B, & Hartung, HP. Multiple sclerosis-novel insights and new therapeutic strategies. Curr Opin Neurol 2005;18:211220.
3.Brex, PA, Ciccarelli, O, O'Riordan, JI, Sailer, M, Thompson, AJ, & Miller, DH. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002;346:158164.
4.Rodriguez, M, Siva, A, Cross, SA, O'Brien, PC, & Kurland, LT. Optic neuritis: a population-based study in Olmsted County, Minnesota. Neurology 1995;45:244250.
5.McDonald, WI, Compston, A, Edan, G, Goodkin, D, Hartung, HP, Lublin, FD, McFarland, HF, Paty, DW, Polman, CH, Reingold, SC, Sandberg-Wollheim, M, Sibley, W, Thompson, A, van den Noort, S, Weinshenker, BY, & Wolinsky, JS. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121127.
6.Polman, CH, Reingold, SC, Edan, G, Filippi, M, Hartung, HP, Kappos, L, Lublin, FD, Metz, LM, McFarland, HF, O'Connor, PW, Sandberg-Wollheim, M, Thompson, AJ, Weinshenker, BG, & Wolinsky, JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;58:840846.
7.Tintore, M, Rovira, A, Rio, J, Tur, C, Pelayo, R, Nos, C, Tellez, N, Perkal, H, Comabella, M, Sastre-Garriga, J, & Montalban, X. Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis? Neurology 2008;70:10791083.
8.Weinshenker, BG, Bass, B, Rice, GP, Noseworthy, J, Carriere, W, Baskerville, J, & Ebers, GC. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain 1989;112 (Pt 6):14191428.
9.Weinshenker, BG, Bass, B, Rice, GP, Noseworthy, J, Carriere, W, Baskerville, J, & Ebers, GC. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989;112 (Pt 1):133146.
10.Kieseier, BC & Wiendl, H. Oral disease-modifying treatments for multiple sclerosis: the story so far. CNS Drugs 2007;21:483502.
11.Stuve, O, Bennett, JL, Hemmer, B, Wiendl, H, Racke, MK, Bar-Or, A, Hu, W, Zivadinov, R, Weber, MS, Zamvil, SS, Pacheco, MF, Menge, T, Hartung, HP, Kieseier, BC, & Frohman, EM. Pharmacological treatment of early multiple sclerosis. Drugs 2008;68:7383.
12.Wiendl, H & Hohlfeld, R. Therapeutic approaches in multiple sclerosis: lessons from failed and interrupted treatment trials. BioDrugs 2002;16:183200.
13.Jacobs, LD, Beck, RW, Simon, JH, Kinkel, RP, Brownscheidle, CM, Murray, TJ, Simonian, NA, Slasor, PJ, & Sandrock, AW. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000;343:898904.
14.Comi, G, Filippi, M, Barkhof, F, Durelli, L, Edan, G, Fernandez, O, Hartung, H, Seeldrayers, P, Sorensen, PS, Rovaris, M, Martinelli, V, & Hommes, OR. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001;357:15761582.
15.Beck, RW, Chandler, DL, Cole, SR, Simon, JH, Jacobs, LD, Kinkel, RP, Selhorst, JB, Rose, JW, Cooper, JA, Rice, G, Murray, TJ, & Sandrock, AW. Interferon beta-1a for early multiple sclerosis: CHAMPS trial subgroup analyses. Ann Neurol 2002;51:481490.
16.Kinkel, RP, Kollman, C, O'Connor, P, Murray, TJ, Simon, J, Arnold, D, Bakshi, R, Weinstock-Gutman, B, Brod, S, Cooper, J, Duquette, P, Eggenberger, E, Felton, W, Fox, R, Freedman, M, Galetta, S, Goodman, A, Guarnaccia, J, Hashimoto, S, Horowitz, S, Javerbaum, J, Kasper, L, Kaufman, M, Kerson, L, Mass, M, Rammohan, K, Reiss, M, Rolak, L, Rose, J, Scott, T, Selhorst, J, Shin, R, Smith, C, Stuart, W, Thurston, S, & Wall, M. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 2006;66:678684.
17.Kappos, L, Polman, CH, Freedman, MS, Edan, G, Hartung, HP, Miller, DH, Montalban, X, Barkhof, F, Bauer, L, Jakobs, P, Pohl, C, & Sandbrink, R. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006;67:12421249.
18.Kappos, L, Freedman, MS, Polman, CH, Edan, G, Hartung, HP, Miller, DH, Montalban, X, Barkhof, F, Radu, EW, Bauer, L, Dahms, S, Lanius, V, Pohl, C, & Sandbrink, R. Effect of early vs. 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 2007;370: 389397.
19.Barkhof, F, Filippi, M, Miller, DH, Scheltens, P, Campi, A, Polman, CH, Comi, G, Ader, HJ, Losseff, N, & Valk, J. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997;120 (Pt 11):20592069.
20.Brex, PA, O'Riordan, JI, Miszkiel, KA, Moseley, IF, Thompson, AJ, Plant, GT, & Miller, DH. Multisequence MRI in clinically isolated syndromes and the early development of MS. Neurology 1999;53:11841190.
21.Dalton, CM, Brex, PA, Miszkiel, KA, Hickman, SJ, MacManus, DG, Plant, GT, Thompson, AJ, & Miller, DH. Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis. Ann Neurol 2002;52:4753.
22.Fazekas, F, Barkhof, F, Filippi, M, Grossman, RI, Li, DK, McDonald, WI, McFarland, HF, Paty, DW, Simon, JH, Wolinsky, JS, & Miller, DH. The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 1999;53:448456.
23.McFarland, HF, Barkhof, F, Antel, J, & Miller, DH. The role of MRI as a surrogate outcome measure in multiple sclerosis. Mult Scler 2002;8:4051.
24.The 5-year risk of MS after optic neuritis. Experience of the optic neuritis treatment trial. Optic Neuritis Study Group. Neurology 1997;49:14041413.
25.Fisniku, LK, Brex, PA, Altmann, DR, Miszkiel, KA, Benton, CE, Lanyon, R, Thompson, AJ, & Miller, DH. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008;131:808817.
26.Coyle, PK & Hartung, HP. Use of interferon beta in multiple sclerosis: rationale for early treatment and evidence for doseand frequency-dependent effects on clinical response. Mult Scler 2002;8:29.
27.Corboy, JR, Goodin, DS, & Frohman, EM. Disease-modifying Therapies for Multiple Sclerosis. Curr Treat Options Neurol 2003;5:3554.
28.Kieseier, BC, Seifert, T, Giovannoni, G, & Hartung, HP. Matrix metalloproteinases in inflammatory demyelination: targets for treatment. Neurology 1999;53:2025.
29.Yong, VW. Differential mechanisms of action of interferonbeta and glatiramer acetate in MS. Neurology 2002;59:802808.
30.Yong, VW, Chabot, S, Stuve, O, & Williams, G. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology 1998;51:682689.
31.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;43:662667.
32.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;43:655661.
33.Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology 1995;45:12771285.
34.Jacobs, LD, Cookfair, DL, Rudick, RA, Herndon, RM, Richert, JR, Salazar, AM, Fischer, JS, Goodkin, DE, Granger, CV, Simon, JH, Alam, JJ, Bartoszak, DM, Bourdette, DN, Braiman, J, Brownscheidle, CM, Coats, ME, Cohan, SL, Dougherty, DS, Kinkel, RP, Mass, MK, Munschauer, FE, 3rd, Priore, RL, Pullicino, PM, Scherokman, BJ, Whitham, RH, & et al.Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996;39:285294.
35.Rudick, RA, Goodkin, DE, Jacobs, LD, Cookfair, DL, Herndon, RM, Richert, JR, Salazar, AM, Fischer, JS, Granger, CV, Simon, JH, Alam, JJ, Simonian, NA, Campion, MK, Bartoszak, DM, Bourdette, DN, Braiman, J, Brownscheidle, CM, Coats, ME, Cohan, SL, Dougherty, DS, Kinkel, RP, Mass, MK, Munschauer, FE, Priore, RL, Whitham, RH, & et al.Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology 1997;49:358363.
36.Simon, JH, Jacobs, LD, Campion, M, Wende, K, Simonian, N, Cookfair, DL, Rudick, RA, Herndon, RM, Richert, JR, Salazar, AM, Alam, JJ, Fischer, JS, Goodkin, DE, Granger, CV, Lajaunie, M, Martens-Davidson, AL, Meyer, M, Sheeder, J, Choi, K, Scherzinger, AL, Bartoszak, DM, Bourdette, DN, Braiman, J, Brownscheidle, CM, Whitham, RH, & et al.Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. Ann Neurol 1998;43:7987.
37.Li, DK & Paty, DW. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-beta1a in relapsing-remitting multiple sclerosis. Prevention of Relapses and Disability by Inter-feron-beta1a Subcutaneously in Multiple Sclerosis. Ann Neurol 1999;46:197206.
38.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;352:14981504.
39.PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. Neurology 2001;56:16281636.
40.Evidence of interferon beta-1a dose response in relapsing-remitting MS: the OWIMS Study. The Once Weekly Interferon for MS Study Group. Neurology 1999;53:679686.
41.Farina, C, Weber, MS, Meinl, E, Wekerle, H, & Hohlfeld, R. Glatiramer acetate in multiple sclerosis: update on potential mechanisms of action. Lancet Neurol 2005;4:567575.
42.Johnson, KP, Brooks, BR, Cohen, JA, Ford, CC, Goldstein, J, Lisak, RP, Myers, LW, Panitch, HS, Rose, JW, & Schiffer, RB. 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;45:12681276.
43.Wolinsky, JS, Comi, G, Filippi, M, Ladkani, D, Kadosh, S, & Shifroni, G. Copaxone's effect on MRI-monitored disease in relapsing MS is reproducible and sustained. Neurology 2002;59:12841286.
44.Miller, A, Spada, V, Beerkircher, D, & Kreitman, RR. Long-term (up to 22 years), open-label, compassionate-use study of glatiramer acetate in relapsing-remitting multiple sclerosis. Mult Scler 2008;14:494499.
45.Ziemssen, T, Neuhaus, O, & Hohlfeld, R. Risk-benefit assessment of glatiramer acetate in multiple sclerosis. Drug Saf 2001;24:979990.
46.Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS. Lancet 1998;352:14911497.
47.Panitch, H, Miller, A, Paty, D, & Weinshenker, B. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004;63:17881795.
48.Kappos, L, Weinshenker, B, Pozzilli, C, Thompson, AJ, Dahlke, F, Beckmann, K, Polman, C, & McFarland, H. Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology 2004;63:17791787.
49.Randomized controlled trial of interferon- beta-1a in secondary progressive MS: Clinical results. Neurology 2001;56:14961504.
50.Cohen, JA, Cutter, GR, Fischer, JS, Goodman, AD, Heidenreich, FR, Kooijmans, MF, Sandrock, AW, Rudick, RA, Simon, JH, Simonian, NA, Tsao, EC, & Whitaker, JN. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002;59:679687.
51.Miller, DH & Leary, SM. Primary-progressive multiple sclerosis. Lancet Neurol 2007;6:903912.
52.Wolinsky, JS, Narayana, PA, O'Connor, P, Coyle, PK, Ford, C, Johnson, K, Miller, A, Pardo, L, Kadosh, S, & Ladkani, D. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007;61:1424.
53.Beutler, E. Cladribine (2-chlorodeoxyadenosine). Lancet 1992;340:952956.
54.Sipe, JC. Cladribine for multiple sclerosis: review and current status. Expert Rev Neurother 2005;5:721727.
55.Beutler, E, Sipe, JC, Romine, JS, Koziol, JA, McMillan, R, & Zyroff, J. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci U S A 1996;93:17161720.
56.Sipe, JC, Romine, JS, Koziol, JA, McMillan, R, Zyroff, J, & Beutler, E. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994;344:913.
57.Romine, JS, Sipe, JC, Koziol, JA, Zyroff, J, & Beutler, E. A double-blind, placebo-controlled, randomized trial of cladri-bine in relapsing-remitting multiple sclerosis. Proc Assoc Am Physicians 1999;111:3544.
58.Filippi, M, Rovaris, M, Iannucci, G, Mennea, S, Sormani, MP, & Comi, G. Whole brain volume changes in patients with progressive MS treated with cladribine. Neurology 2000;55:17141718.
59.Filippi, M, Rovaris, M, Rice, GP, Sormani, MP, Iannucci, G, Giacomotti, L, & Comi, G. The effect of cladribine on T(1) ‘black hole’ changes in progressive MS. J Neurol Sci 2000;176:4244.
60.Rice, GP, Filippi, M, & Comi, G. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 2000;54:11451155.
61.Korn, T, Magnus, T, Toyka, K, & Jung, S. Modulation of effector cell functions in experimental autoimmune encephalo-myelitis by leflunomide-mechanisms independent of pyrimi-dine depletion. J Leukoc Biol 2004;76:950960.
62.Kaplan, MJ. Leflunomide Aventis Pharma. Curr Opin Investig Drugs 2001;2:222230.
63.Korn, T, Toyka, K, Hartung, HP, & Jung, S. Suppression of experimental autoimmune neuritis by leflunomide. Brain 2001;124:17911802.
64.Smolen, JS, Emery, P, Kalden, JR, Van Riel, PL, Dougados, M, Strand, CV, & Breedveld, FC. The efficacy of leflunomide monotherapy in rheumatoid arthritis: towards the goals of disease modifying antirheumatic drug therapy. J Rheumatol Suppl 2004;71:1320.
65.O'Connor, PW, Li, D, Freedman, MS, Bar-Or, A, Rice, GP, Confavreux, C, Paty, DW, Stewart, JA, & Scheyer, R. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 2006;66:894900.
66.Brunmark, C, Runstrom, A, Ohlsson, L, Sparre, B, Brodin, T, Astrom, M, & Hedlund, G. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J Neuroimmunol 2002;130:163172.
67.Jonsson, S, Andersson, G, Fex, T, Fristedt, T, Hedlund, G, Jansson, K, Abramo, L, Fritzson, I, Pekarski, O, Runstrom, A, Sandin, H, Thuvesson, I, & Bjork, A. Synthesis and biological evaluation of new 1,2-dihydro-4-hydroxy-2-oxo-3-quinoline-carboxamides for treatment of autoimmune disorders: structure-activity relationship. J Med Chem 2004;47:20752088.
68.Runstrom, A, Leanderson, T, Ohlsson, L, & Axelsson, B. Inhibition of the development of chronic experimental autoimmune encephalomyelitis by laquinimod (ABR-215062) in IFN-beta k.o. and wild type mice. J Neuroimmunol 2006;173:6978.
69.Yang, JS, Xu, LY, Xiao, BG, Hedlund, G, & Link, H. 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 2004;156:39.
70.Andersen, O, Lycke, J, Tollesson, PO, Svenningsson, A, Runmarker, B, Linde, AS, Astrom, M, Gjorstrup, P, & Ekholm, S. Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis. Neurology 1996;47:895900.
71.Karussis, DM, Meiner, Z, Lehmann, D, Gomori, JM, Schwarz, A, Linde, A, & Abramsky, O. Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide: a double-blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation. Neurology 1996;47:341346.
72.Polman, C, Barkhof, F, Sandberg-Wollheim, M, Linde, A, Nordle, O, & Nederman, T. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology 2005;64:987991.
73.Hiestand, PC, Rausch, M, Meier, DP, & Foster, CA. Ascomycete derivative to MS therapeutic: S1P receptor modulator FTY720. Prog Drug Res 2008;66:361, 363381.
74.Linker, RA, Kieseier, BC, & Gold, R. Identification and development of new therapeutics for multiple sclerosis. Trends Pharmacol Sci 2008;29:558565.
75.Coelho, RP, Payne, SG, Bittman, R, Spiegel, S, & Sato-Bigbee, C. The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J Pharmacol Exp Ther 2007;323:626635.
76.Miron, VE, Jung, CG, Kim, HJ, Kennedy, TE, Soliven, B, & Antel, JP. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol 2008;63:6171.
77.Mullershausen, F, Craveiro, LM, Shin, Y, Cortes-Cros, M, Bassilana, F, Osinde, M, Wishart, WL, Guerini, D, Thallmair, M, Schwab, ME, Sivasankaran, R, Seuwen, K, & Dev, KK. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem 2007;102:11511161.
78.Balatoni, B, Storch, MK, Swoboda, EM, Schonborn, V, Koziel, A, Lambrou, GN, Hiestand, PC, Weissert, R, & Foster, CA. FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encepha-lomyelitis. Brain Res Bull 2007;74:307316.
79.Fujino, M, Funeshima, N, Kitazawa, Y, Kimura, H, Amemiya, H, Suzuki, S, & Li, XK. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 2003;305:7077.
80.Kappos, L, Antel, J, Comi, G, Montalban, X, O'Connor, P, Polman, CH, Haas, T, Korn, AA, Karlsson, G, & Radue, EW. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006;355:11241140.
81.Lee, DH, Linker, RA, & Gold, R. Spotlight on fumarates. Int MS J 2008;15:1218.
82.Schimrigk, S, Brune, N, Hellwig, K, Lukas, C, Bellenberg, B, Rieks, M, Hoffmann, V, Pohlau, D, & Przuntek, H. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 2006;13:604610.

Immunotherapy of multiple sclerosis

  • Sven G. Meuth (a1), Stefan Bittner (a1) and Heinz Wiendl (a1)

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