Neue Therapieansätze bei Multipler Sklerose

Zusammenfassung

Die verlaufsmodifizierende Behandlung der Multiplen Sklerose (MS) hat sich durch den Einsatz der rekombinanten Beta-Interferone und Glatirameracetat (sowie Mitoxantron in der Eskalationstherapie) innerhalb der letzten fünf Jahre verbessert. Bei frühzeitigem Einsatz und individueller Therapiemodifikation entsprechend der vorliegenden klinischen Krankheitsaktivität lassen sich die entzündlichen Aspekte der Erkrankung (Schübe und aktive Läsionen im Kernspintomogramm) in vielen Fällen gut kontrollieren. Neue Ansätze der Therapie beschäftigen sich derzeit mit der spezifischen Modulation von Molekülen, die am Entzündungsgeschehen bei der Multiplen Sklerose beteiligt sind. Hier kommen insbesondere gezielte Interventionen bei Zytokinen, Chemokinen und Adhäsionsmolekülen in Betracht. Diese Gruppen von Molekülen spielen eine entscheidende Rolle bei der Regulation der Immunzellinfiltration und Ausbreitung der Entzündung im Gehirn. Erste vielversprechende Ergebnisse konnten so mit einem humanisierten Antikörper gegen das Adhäsionsmolekül VLA-4 (Natalizumab/ Tysabri^®) in zwei Phase-III Studien erreicht werden. Weitere Fortschritte werden auch durch die Entwicklung oraler Therapeutika in diesem Bereich erwartet. Nach wie vor schwierig ist die Behandlung der progredienten Verlaufsform der MS, wenn sich eine langsam schleichende Behinderung auch ohne begleitende entzündliche Veränderungen entwickelt. Hierbei scheinen degenerative Komponenten der Erkrankung (Demyelinisierung und axonaler Schaden) zu überwiegen. Rationelle Ansatzpunkte sind hier axon/ neuroprotektive und regenerationsfördernde Therapieverfahren. Diese Stufe der Therapie befindet sich aber noch weitestgehend im experimentellen Stadium.

Summary

Disease modifying therapy of multiple sclerosis (MS) has improved during the last five years due to recombinant beta-interferons and glatiramer acetate as well as mitoxantrone for treatment escalation. Early use and individual modification of treatment allows for control of inflammatory aspects of the disease (relapses and magnetic resonance lesions) in many cases. New approaches to therapy include specific modulation of molecules involved in pathophysiology of MS. Mainly, targeted interventions of cytokine, chemokine and adhesion molecule expression are considered. These molecules are important mediators of immune cell infiltration and spreading of inflammation within the brain. Initial results from two phase-III studies with a humanized antibody against the adhesion molecule VLA-4 (natalizumab/Tysabri^®) are very encouraging. Further achievements are anticipated for the development of oral therapies. The treatment of chronic progressive MS without superimposed inflammatory disease activity is still a major problem due to the fact that degenerative aspects of the disease (demyelination and axonal loss) are prominent. New therapeutic strategies, like axon/neuroprotection or induction of regeneration are still in pre-clinical development.

Schlüsselwörter

Multiple Sklerose - Immuntherapie - klinische Studien - humanisierte Antikörper

Keywords

Multiple sclerosis - immunotherapy - clinical studies - humanized antibodies

• Literatur

• 1 Multiple Sklerose Therapie Konsensus Gruppe (MSTCG). Escalating immunotherapy of multiple sclerosis – New aspects and practical application. J Neurol 2004; 251: 1329-39.
• 2 Kappos L. et al. Interferon beta-1b in secondary progressive MS: A combined analysis of the two trials. Neurology 2004; 63: 1779-87.
• 3 Hughes RA. Interferon beta 1a for secondary progressive multiple sclerosis. J Neurol Sci 2003; 206: 199-202.
• 4 Hartung H. et al. Mitoxantrone in progressive multiple sclerosis: A placebo-controlled, doubleblind, randomised, multicentre trial. Lancet 2002; 360: 2018-25.
• 5 Scott LJ, Figgitt DP. Mitoxantrone: A review of its use in multiple sclerosis. CNS Drugs 2004; 18: 379-96.
• 6 MSTKG. Immunmodulatorische Stufentherapie der Multiplen Sklerose – Neue Aspekte und praktische Umsetzung. Nervenarzt 2002; 73: 556-63.
• 7 Grauer O. et al. Glukokortikosteroid-Therapie bei Optikusneuritis und Multipler Sklerose. Nervenarzt 2001; 72: 577-89.
• 8 Schmidt J. et al. T-cell apoptosis in situ in experimental autoimmune encephalomyelitis following methylprednisolone pulse therapy. Brain 2000; 123: 1431-41.
• 9 Sellebjerg F. et al. Report of an EFNS Task Force on treatment of multiple sclerosis relapse. Eur J Neurol. 2005 in Druck.
• 10 Sellebjerg F. et al. A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology 1999; 52: 1479-84.
• 11 Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology 2003; 61: 1528-32.
• 12 Sorensen PS. et al. IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology 2004; 63: 2028-33.
• 13 Craig J. et al. A randomised controlled trial comparing rehabilitation against standard therapy in multiple sclerosis patients receiving intravenous steroid treatment. J Neurol Neurosurg Psychiatry 2003; 74: 1225-30.
• 14 O’Connor PW. et al. Randomized multicenter trial of natalizumab in acute MS relapses: Clinical and MRI effects. Neurology 2004; 62: 2038-43.
• 15 Keegan M. et al. Plasma exchange for severe attacks of CNS demyelination: predictors of response. Neurology 2002; 58: 143-6.
• 16 Ruprecht K. et al. Plasma exchange for severe optic neuritis: Treatment of 10 patients. Neurology 2004; 63: 1081-3.
• 17 Wiendl H. et al. Multiple sclerosis: potential therapeutic options and update of ongoing studies. Nervenarzt 2004; 75: 536-52.
• 18 Coles A. et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999; 46: 296-304.
• 19 Coles A, Deans J, Compston A. Campath-1H treatment of multiple sclerosis: Lessons from the bedside for the bench. Clin Neurol Neurosurg 2004; 106: 270-4.
• 20 Bielekova B. et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci USA 2004; 101: 8705-8.
• 21 Miller D. et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348: 15-23.
• 22 Food and Drug Administration (FDA). U.S. Tysabri ^® (natalizumab) approval letter. www.fda.gov/cder/drug/infopage/natalizumab/default.htm 2004
• 23 Rastetter W, Molina A, White CA. Rituximab: Expanding role in therapy for lymphomas and autoimmune diseases. Annu Rev Med 2004; 55: 477-503.
• 24 Rizvi SA, Bashir K. Other therapy options and future strategies for treating patients with multiple sclerosis. Neurology 2004; 63 (Suppl. 06) S47-54.
• 25 Monson NL. et al. Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol 2005; 62: 258-64.
• 26 Brinkmann V. et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002; 277: 21453-7.
• 27 Fujino M. et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 2003; 305: 70-7.
• 28 Meininger V. et al. Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials. Amyotroph Lateral Scler Other Motor Neuron Disord 2004; 5: 107-17.
• 29 Kovarik JM, Burtin P. Immunosuppressants in advanced clinical development for organ transplantation and selected autoimmune diseases. Expert Opin Emerg Drugs 2003; 8: 47-62.
• 30 Frohman EM. et al. Mycophenolate mofetil in multiple sclerosis. Clin Neuropharmacol 2004; 27: 80-3.
• 31 Mach F. Toward a role for statins in immunomodulation. Mol Interv 2002; 2: 478-80.
• 32 Youssef S. et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 2002; 420: 78-84.
• 33 Vollmer T. et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004; 363: 1607-8.
• 34 Zajicek J. et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003; 362: 1517-26.
• 35 Confavreux C. et al. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998; 339: 285-91.
• 36 Kim S. et al. Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis. Neurology 1999; 52: 1230-1238.
• 37 Kruse N. et al. Variations in cytokine mRNA expression during normal human pregnancy. Clin Exp Immunol. 1999 in Druck.
• 38 Soldan SS. et al. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol 2003; 171: 6267-74.
• 39 Kappos L. et al. Alternatives to current diseasemodifying treatment in MS: What do we need and what can we expect in the future?. J Neurol 2004; 251 (Suppl. 05) v57-v64.
• 40 Tan IL. et al. Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials. Mult Scler 2000; 6: 99-104.
• 41 Zemke D, Majid A. The potential of minocycline for neuroprotection in human neurologic disease. Clin Neuropharmacol 2004; 27: 293-8.
• 42 Nessler S. et al. Effect of minocycline in experimental autoimmune encephalomyelitis. Ann Neurol 2002; 52: 689-90.
• 43 Metz LM. et al. Minocycline reduces gadoliniumenhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol 2004; 55: 756.
• 44 Rieckmann P, Smith K. Multiple Sclerosis: More than inflammation and demyelination. Trends Neurosci 2001; 24: 435-7.
• 45 Yong VW. Prospects for neuroprotection in multiple sclerosis. Front Biosci 2004; 9: 864-72.
• 46 Linker R. et al. CNTF is a major protective factor in demyelinating CNS disease: A neurotrophic cytokine as modulator in neuroinflammation. Nature Med 2002; 8: 620-4.
• 47 Kalkers NF. et al. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: A pilot study. Mult Scler 2002; 8: 532-3.
• 48 Pluchino S, Furlan R, Martino G. Cell-based remyelinating therapies in multiple sclerosis: evidence from experimental studies. Curr Opin Neurol 2004; 17: 247-55.
• 49 Fassas A, Kimiskidis VK. Stem cell transplantation for multiple sclerosis: What is the evidence?. Blood Rev 2003; 17: 233-40.
• 50 Hohlfeld R. The prospects for neuroprotection in MS. Int MS J 2003; 10: 103-5.
• 51 Stangel M. Remyelinating and neuroprotective treatments in multiple sclerosis. Expert Opin Investig Drugs 2004; 13: 331-47.
• 52 Kesselring J. Neurorehabilitation in multiple sclerosis-what is the evidence-base?. J Neurol 2004; 251 (Suppl. 04) IV25-9.