Neue Therapieoptionen bei der Multiplen Sklerose

Zusammenfassung

Die Therapieoptionen der Multiplen Sklerose (MS) haben sich im Vergleich zu noch vor einigen Jahren insbesondere für den Bereich der schubförmig remittierenden Verläufe deutlich erweitert. Darüber hinaus hat die Aktualisierung der Diagnosealgorithmen zu einer Vereinfachung und Beschleunigung der Diagnosestellung geführt und die Definition der unterschiedlichen MS-Verlaufsformen wurde operationalisiert mit dem Fokus der Feststellung von Aktivität und Progression als wesentlichen Determinanten. Das Paradigma der Frühtherapie der MS ist etabliert, so dass in der Zusammenschau dieser Neuerungen Therapieentscheidungen immer komplexer werden. Neben der Nutzen-Risiko-Abwägung der einzelnen Substanzen sind auch individuelle patientenbezogene Faktoren relevant, zum Beispiel besondere Lebenssituationen und Familienplanung. Im vorliegenden Artikel werden neue und etablierte verlaufsmodifizierende Therapiemöglichkeiten im Kontext der verschiedenen Verlaufsformen und der Nutzen-Risiko-Bewertung diskutiert.

Abstract

Therapeutic options in the treatment of multiple sclerosis (MS) have broadened notably over the past years, especially for relapsing-remitting forms of MS. The revision of the diagnostic criteria simplified and accelerated MS diagnosis, definitions of disease courses were operationalized focussing on disease activity and progression as major determinants. The paradigm of an early treatment initiation is accepted and evidence-based. All these aspects have led to an increasing complexity of therapeutic decision making. Besides a benefit-risk-evaluation for each substance, individual patient-related factors have to be considered, e.g. life and family planning. This article reviews new and established disease-modifying drugs in the context of disease courses and stages and benefit-risk-considerations.

• Literatur

• 1 Hafler DA, Slavik JM, Anderson DE et al. Multiple sclerosis. Immunol Rev 2005; 204: 208-231
• 2 Gold R, Hanschke S, Hemmer B et al. DGN/KKNMS Leitlinie zur Diagnose und Therapie der MS – Online-Version. , Stand: 13.08.2014. 2014 (Stand: 14.9.2014) http://www.kompetenznetz-multiplesklerose.de/images/stories/PDF_Dateien/Leitlinie/dgn-kknms_ms-ll_20140813.pdf
• 3 Lublin FD, Reingold SC, Cohen JA et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83: 278-286
• 4 Polman CH, Reingold SC, Banwell B et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292-302
• 5 Bar-Or A, Gold R, Kappos L et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the DEFINE study. J Neurol 2013; 260: 2297-2305
• 6 Freedman MS, De Stefano N, Barkhof F et al. Patient subgroup analyses of the treatment effect of subcutaneous interferon beta-1a on development of multiple sclerosis in the randomized controlled REFLEX study. J Neurol 2014; 261: 490-499
• 7 Hutchinson M, Fox RJ, Miller DH et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study. J Neurol 2013; 260: 2286-2296
• 8 Wolinsky JS, Truffinet P, Bauer D et al. Efficacy of teriflunomide in patients with early stage MS: analysis of the TOPIC study using 2010 McDonald diagnostic criteria. Mult Sclero 2014; 20 (S1): 67-284 P095
• 9 Jacobs LD, Beck RW, Simon JH et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000; 343: 898-904
• 10 Barkhof F, Polman CH, Radue EW et al. Magnetic resonance imaging effects of interferon beta-1b in the BENEFIT study: integrated 2-year results. Arch Neurol 2007; 64: 1292-1298
• 11 Kappos L, Freedman MS, Polman CH et al. 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 2007; 370: 389-397
• 12 Comi G, Martinelli V, Rodegher M et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 2009; 374: 1503-1511
• 13 Comi G, Filippi M, Barkhof F et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357: 1576-1582
• 14 Miller AE, Wolinsky JS, Kappos L et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014; 13: 977-986
• 15 Fachinformation Natalizumab. (last accessed Sep 14 2014). http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/000603/WC500044686.pdf 2013
• 16 Anonymous. Fachinformation Gilenya. (last accessed Sep 14 2014). http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/002202/WC500104528.pdf 2014
• 17 Fachinformation Lemtrada. (last accessed Sep 14 2014). http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf 2013
• 18 Calabresi PA, Kieseier BC, Arnold DL et al. Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol 2014; 13: 657-665
• 19 Khan O, Rieckmann P, Boyko A et al. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol 2013; 73: 705-713
• 20 Freedman MS, Wolinsky JS, Wamil B et al. Teriflunomide added to interferon-beta in relapsing multiple sclerosis: a randomized phase II trial. Neurology 2012; 78: 1877-1885
• 21 Lublin FD, Cofield SS, Cutter GR et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol 2013; 73: 327-340
• 22 Hawker K, O'Connor P, Freedman MS et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009; 66: 460-471
• 23 Novartis International AG. Novartis provides update on fingolimod Phase III trial in primary progressive MS (PPMS). (last accessed Dec 15 2014). http://hugin.info/134323/R/1875463/660871.pdf 2014
• 24 Kappos L, Weinshenker B, Pozzilli C et al. Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology 2004; 63: 1779-1787
• 25 Bramanti P, Sessa E, Rifici C et al. Enhanced spasticity in primary progressive MS patients treated with interferon beta-1b. Neurology 1998; 51: 1720-1723
• 26 Salmen A, Gold R, Chan A. Management of disease-modifying treatments in neurological autoimmune diseases of the central nervous system. Clin Exp Immunol 2014; 176: 135-148
• 27 Gergely P, Nuesslein-Hildesheim B, Guerini D et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Dermatol 2012; 167: 1035-1047
• 28 Goodin DS, Reder AT, Ebers GC et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNbeta-1b trial. Neurology 2012; 78: 1315-1322
• 29 Hunt D, Kavanagh D, Drummond I et al. Thrombotic microangiopathy associated with interferon beta. N Engl J Med 2014; 370: 1270-1271
• 30 Rote-Hand-Brief: Hämophagozytisches Syndrom (HPS) bei Patienten unter Fingolimod-Therapie (Gilenya). (last accessed Sep 14 2014). http://www.akdae.de/Arzneimittelsicherheit/RHB/Archiv/2013/20131115.pdf 2013
• 31 Bloomgren G, Richman S, Hotermans C et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366: 1870-1880
• 32 Dahlhaus S, Hoepner R, Chan A et al. Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients. J Neurol Neurosurg Psychiatry 2013; 84: 1068-1074
• 33 Hoepner R, Ahlbrecht J, Faissner S et al. Clinical and paraclinical findings in natalizumab-associated infratentorial progressive multifocal leukoencephalopathy patients. J Neurol Neurosurg Psychiatry 2014; 85: 1177-1178
• 34 Biogen Idec International. Tysabri fact sheet. (last accessed Oct 13 2014). 2014 http://www.biogenidec-international.com/tysabri_fact_sheetaspx?ID=4698
• 35 Yousry TA, Pelletier D, Cadavid D et al. Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2012; 72: 779-787
• 36 Plavina T, Subramanyam M, Bloomgren G et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2014; 76: 802-812
• 37 Cohen JA, Coles AJ, Arnold DL et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012; 380: 1819-1828
• 38 Coles AJ, Compston DA, Selmaj KW et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008; 359: 1786-1801
• 39 Coles AJ, Fox E, Vladic A et al. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol 2011; 10: 338-348
• 40 Coles AJ, Twyman CL, Arnold DL et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012; 380: 1829-1839
• 41 Coles AJ, Fox E, Vladic A et al. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 2012; 78: 1069-1078
• 42 Papadopoulou A, D'Souza M, Kappos L et al. Dimethyl fumarate for multiple sclerosis. Expert opinion on investigational drugs 2010; 19: 1603-1612
• 43 Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367: 1098-1107
• 44 Fox RJ, Miller DH, Phillips JT et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367: 1087-1097
• 45 Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid. N Engl J Med 2013; 368: 1657-1658
• 46 van Oosten BW, Killestein J, Barkhof F et al. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med 2013; 368: 1658-1659
• 47 Sweetser MT, Dawson KT, Bozic C. Manufacturer's response to case reports of PML. N Engl J Med 2013; 368: 1659-1661
• 48 Rote-Hand-Brief: Tecfidera (Dimethylfumarat): Bei einer Patientin mit schwerer und lang anhaltender Lymphopenie trat eine progressive multifokale Leukenzephalopathie (PML) auf. (last accessed Dec 15 2014). http://akdae.de/Arzneimittelsicherheit/RHB/20141204.pdf 2014
• 49 Fachinformation Plegridy. (last accessed Sep 14 2014). http://ec.europa.eu/health/documents/community-register/2014/20140718129034/anx_129034_de.pdf 2014
• 50 Balague C, Pont M, Prats N et al. Profiling of dihydroorotate dehydrogenase, p38 and JAK inhibitors in the rat adjuvant-induced arthritis model: a translational study. Br J of Pharmacol 2012; 166: 1320-1332
• 51 Fachinformation Aubagio. (last accessed Sep 14 2014). http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/002514/WC500148682.pdf 2013
• 52 O'Connor P, Wolinsky JS, Confavreux C et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365: 1293-1303
• 53 Confavreux C, O'Connor P, Comi G et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014; 13: 247-256