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Fortschreitender Krankheitsverlauf

Aktuelle Therapien und Zukunftsoptionen für die progrediente Multiple Sklerose

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InFo Neurologie & Psychiatrie Aims and scope

Zusammenfassung

Die Therapie der Multiplen Sklerose hat sich in den letzten Jahren durch die Entwicklung neuer Medikamente für die schubförmige Phase der Erkrankung umfangreich gewandelt. Die Entwicklung von Medikamenten bei Progression hingegen war bisher — abgesehen von einem gerade in Europa zugelassenen B-Zell-depletierenden Antikörper — weniger erfolgreich. Im Folgenden werden das Verständnis von pathogenetischen Veränderungen bei Progression, etablierte und aktuell zugelassene Therapieverfahren sowie zukünftig interessante Ziele für neue Behandlungsansätze dargestellt.

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Literatur

  1. Kantarci OH, Lebrun C, Siva A et al. Primary Progressive Multiple Sclerosis Evolving From Radiologically Isolated Syndrome. Ann Neurol 2016; 79:288–94

    Article  Google Scholar 

  2. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 2012; 8:647–56

    Article  CAS  Google Scholar 

  3. Kutzelnigg A, Lucchinetti CF, Stadelmann C et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005; 128: 2705–12

    Article  Google Scholar 

  4. Nikic I, Merkler D, Sorbara C et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nature medicine 2011; 17:495–9

    Article  CAS  Google Scholar 

  5. Heppner FL, Greter M, Marino D et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nature medicine 2005; 11:146–52

    Article  CAS  Google Scholar 

  6. Giuliani F, Hader W, Yong VW. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction. Journal of leukocyte biology 2005; 78:135–43

    Article  CAS  Google Scholar 

  7. Brundula V, Rewcastle NB, Metz LM et al. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002; 125:1297–1308

    Article  Google Scholar 

  8. Miron VE, Boyd A, Zhao JW et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nature neuroscience 2013; 16:1211–8

    Article  CAS  Google Scholar 

  9. Koch MW, Zabad R, Giuliani F et al. Hydroxychloroquine reduces microglial activity and attenuates experimental autoimmune encephalomyelitis. Journal of the neurological sciences 2015; 358:131–7

    Article  CAS  Google Scholar 

  10. Bigaud M, Guerini D, Billich A et al. Second generation S1P pathway modulators: research strategies and clinical developments. Biochimica et biophysica acta 2014; 1841:745–58

    Article  CAS  Google Scholar 

  11. Choi JW, Gardell SE, Herr DR et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. PNAS 2011; 108:751–6

    Article  CAS  Google Scholar 

  12. Lublin F, Miller DH, Freedman MS et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2016, DOI: 10.1016/s0140-6736(15)01314-8

  13. Kappos L, Bar-Or A, Cree BAC et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 2018; 391:1263–73

    Article  CAS  Google Scholar 

  14. Peferoen LA, Breur M, van de Berg S et al. Ageing and recurrent episodes of neuroinflammation promote progressive experimental autoimmune encephalomyelitis in Biozzi ABH mice. Immunology 2016; 149:146–56

    Article  CAS  Google Scholar 

  15. Wong WT. Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Frontiers in cellular neuroscience 2013; 7:22

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Hametner S, Wimmer I, Haider L et al. Iron and neurodegeneration in the multiple sclerosis brain. Ann Neurol 2013; 74:848–61

    Article  CAS  Google Scholar 

  17. Stephenson E, Nathoo N, Mahjoub Y et al. Iron in multiple sclerosis: roles in neurodegeneration and repair. Nat Rev Neurol 2014; 10:459–68

    Article  CAS  Google Scholar 

  18. Haider L, Fischer MT, Frischer JM et al. Oxidative damage in multiple sclerosis lesions. Brain 2011; 134:1914–24

    Article  Google Scholar 

  19. Weigel KJ, Lynch SG, LeVine SM. Iron chelation and multiple sclerosis. ASN neuro 2014; 6:e00136

    PubMed  PubMed Central  Google Scholar 

  20. Lynch SG, Peters K, LeVine SM. Desferrioxamine in chronic progressive multiple sclerosis: a pilot study. Multiple sclerosis (Houndmills, Basingstoke, England) 1996; 2:157–60

    Article  CAS  Google Scholar 

  21. Lynch SG, Fonseca T, LeVine SM. A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cellular and molecular biology (Noisy-le-Grand, France) 2000; 46:865–9

    CAS  Google Scholar 

  22. Faissner S, Mahjoub Y, Mishra M et al. Unexpected additive effects of minocycline and hydroxychloroquine in models of multiple sclerosis: Prospective combination treatment for progressive disease? Multiple sclerosis (Houndmills, Basingstoke, England) 2017; DOI: 10.1177/1352458517728811

  23. Linker RA, Lee DH, Ryan S et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011; 134:678–92

    Article  Google Scholar 

  24. Strassburger-Krogias K, Ellrichmann G, Krogias C et al. Fumarate treatment in progressive forms of multiple sclerosis: first results of a single-center observational study. Ther Adv Neurol Disord 2014; 7:232–8

    Article  CAS  Google Scholar 

  25. Trapp BD, Peterson J, Ransohoff RM et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338:278–85

    Article  CAS  Google Scholar 

  26. Sorbara CD, Wagner NE, Ladwig A et al. Pervasive axonal transport deficits in multiple sclerosis models. Neuron 2014; 84:1183–90

    Article  CAS  Google Scholar 

  27. Craner MJ, Newcombe J, Black JA et al. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. PNAS 2004; 101:8168–73

    Article  CAS  Google Scholar 

  28. Waxman SG. Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-current status. Nature clinical practice Neurology 2008; 4:159–69

    Article  CAS  Google Scholar 

  29. Plemel JR, Liu WQ, Yong VW. Remyelination therapies: a new direction and challenge in multiple sclerosis. Nature reviews Drug discovery 2017; DOI: 10.1038/nrd.2017.115

    Article  CAS  PubMed  Google Scholar 

  30. Mei F, Fancy SPJ, Shen YA et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nature medicine 2014; 20:954–60

    Article  CAS  Google Scholar 

  31. Green AJ, Gelfand JM, Cree BA et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet 2017; 390:2481–9

    Article  CAS  Google Scholar 

  32. Tourbah A, Lebrun-Frenay C, Edan G et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Multiple sclerosis (Houndmills, Basingstoke, England) 2016; DOI: 10.1177/1352458516667568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mi S, Hu B, Hahm K et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nature medicine 2007; 13:1228–33

    Article  CAS  Google Scholar 

  34. Howell OW, Reeves CA, Nicholas R et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011; 134:2755–71

    Article  Google Scholar 

  35. Choi SR, Howell OW, Carassiti D et al. Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. Brain 2012; 135:2925–37

    Article  Google Scholar 

  36. Magliozzi R, Howell OW, Reeves C et al. A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 2010; 68:477–93

    Article  CAS  Google Scholar 

  37. 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; 66:460–71

    Article  CAS  Google Scholar 

  38. Montalban X, Hauser SL, Kappos L et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med 2017; 376:209–20

    Article  CAS  Google Scholar 

  39. Kappos L, Weinshenker B, Pozzilli C et al. Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology 2004; 63:1779–87

    Article  CAS  Google Scholar 

  40. Patti F, Messina S, Solaro C et al. Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity. J Neurol Neurosurg Psychiatry 2016; 87:944–51

    Article  CAS  Google Scholar 

  41. Hoffmann V, Kuhn W, Schimrigk S et al. Repeat intrathecal triamcinolone acetonide application is beneficial in progressive MS patients. European Journal of Neurology 2006; 13:72–6

    Article  CAS  Google Scholar 

  42. Neill J, Belan I, Ried K. Effectiveness of non-pharmacological interventions for fatigue in adults with multiple sclerosis, rheumatoid arthritis, or systemic lupus erythematosus: a systematic review. Journal of Advanced Nursing 2006; 56:617–35

    Article  Google Scholar 

  43. Gross CC, Schulte-Mecklenbeck A, Klinsing S et al. Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2016; 3:e183

    Article  Google Scholar 

  44. Parodi B, Rossi S, Morando S et al. Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS. Acta neuropathologica 2015; 130:279–95

    Article  CAS  Google Scholar 

  45. Metz LM, Li DKB, Traboulsee AL et al. Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. N Engl J Med 2017; 376:2122–33

    Article  CAS  Google Scholar 

  46. Gentile A, Musella A, Bullitta S et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. Journal of Neuroinflammation 2016; 13:207

    Article  Google Scholar 

  47. Allaman I, Fiumelli H, Magistretti PJ et al. Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes. Psychopharmacology 2011; 216:75–84

    Article  CAS  Google Scholar 

  48. Gilgun-Sherki Y, Panet H, Melamed E et al. Riluzole suppresses experimental autoimmune encephalomyelitis: implications for the treatment of multiple sclerosis. Brain research 2003; 989:196–204

    Article  CAS  Google Scholar 

  49. Kalkers NF, Barkhof F, Bergers E et al. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Multiple sclerosis (Houndmills, Basingstoke, England) 2002; 8:532–33

    Article  CAS  Google Scholar 

  50. Tran JQ, Rana J, Barkhof F et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol Neuroimmunol Neuroinflamm 2014; 1:e18

    Article  Google Scholar 

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Authors and Affiliations

  1. St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum, Gudrunstr. 56, 44791, Bochum, Deutschland

    Simon Faissner &  Ralf Gold

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  1. Simon Faissner
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  2. Ralf Gold
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Correspondence to Simon Faissner.

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Interessenkonflikt

Die Autoren erklären, dass sie sich bei der Erstellung des Beitragsvon keinen wirtschaftlichen Interessen haben leiten lassen. S. Faissner erklärt den Erhalt von Reisekostenerstattung von Biogen Idec und Genzyme. R. Gold erklärt den Erhalt von Vortragsund Beratungshonoraren von Baxter, Bayer Schering, Biogen Idec, CLB Behring, Genzyme, Merck Serono, Novartis, Stendhal, Talecris und TEVA. Seine Klinik erhielt Drittmittelunterstützung von Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis und TEVA.

Der Verlag erklärt, dass die inhaltliche Qualität des Beitrags von zwei unabhängigen Gutachtern geprüft wurde. Werbung in dieser Zeitschriftenausgabe hat keinen Bezug zur CME-Fortbildung. Der Verlag garantiert, dass die CME-Fortbildung sowie die CME-Fragen frei sind von werblichen Aussagen und keinerlei Produktempfehlungen enthalten. Dies gilt insbesondere für Präparate, die zur Therapie des dargestellten Krankheitsbildes geeignet sind.

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Faissner, S., Gold, R. Aktuelle Therapien und Zukunftsoptionen für die progrediente Multiple Sklerose. InFo Neurologie 20, 28–36 (2018). https://doi.org/10.1007/s15005-018-2369-4

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  • DOI: https://doi.org/10.1007/s15005-018-2369-4

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