Der Nervenarzt

, 79:1123 | Cite as

Therapieentscheidungen bei Multipler Sklerose

Aktuelles zur Früh- und Eskalationstherapie
Leitthema

Zusammenfassung

Das immunpathogenetische Verständnis der Multiplen Sklerose (MS) und die Möglichkeiten ihrer Therapie haben sich in den zurückliegenden Jahren maßgeblich verändert. Inzwischen gibt es verschiedene zugelassene Immuntherapien zur Behandlung der schubförmigen MS. Dabei stellt sich die Frage, wann der optimale Zeitpunkt zur Einleitung einer Therapie gegeben ist. Inzwischen besteht allgemeiner Konsens, dass die meisten Patienten von einer Frühtherapie profitieren. Dennoch bleibt die Frage, wie eine „frühe MS“ zu definieren ist und ob Patienten mit einem insgesamt gutartigen Verlauf zwingend eine Therapie benötigen. Darüber hinaus ist der behandelnde Arzt mit der Frage konfrontiert, wann ein immunmodulierendes Therapieverfahren nicht mehr wirksam ist und eine Eskalation der Therapie notwendig wird.

In dieser Übersichtsarbeit werden die aktuellen Daten zur Frühtherapie der MS, allen voran dem sog. klinisch isolierten Syndrom, mit den gängigen Immunmodulatoren zusammengefasst und darüber hinaus Optionen in der Therapieeskalation, beispielsweise mit dem monoklonalen Antikörper Natalizumab, diskutiert.

Schlüsselwörter

Multiple Sklerose Klinisch isoliertes Syndrom Frühtherapie Immunmodulation Eskalationstherapie Natalizumab Mitoxantron Rituximab 

Choice of early and escalation treatment options for multiple sclerosis

 

Summary

Recent advances in understanding of the immunopathogenesis of multiple sclerosis (MS) have led to the development of new treatment options. To date several immunomodulatory agents have been licensed for the treatment of relapsing-remitting MS. However, some debate remains on the optimal time point for initiating therapy. While there is general consensus on the benefit of an early treatment start, the issues of how to define “early MS” and how to identify patients with a “benign” disease course have not yet been finally addressed. Further open questions include the situations of treatment failure and therapeutic escalation. Here we summarize available data from studies on early treatment with immunomodulatory drugs for a first demyelinating event, also referred to as clinically isolated syndrome. Furthermore, options for the escalation of immunomodulatory therapy will be discussed, e.g. with the recently licensed monoclonal antibody natalizumab.

Keywords

Multiple sclerosis Clinically isolated syndrome Early treatment Immunomodulation Escalation therapy Natalizumab Mitoxantrone Rituximab 

Literatur

  1. 1.
    Rodriguez M, Siva A, Cross SA et al. (1995) Optic neuritis: a population-based study in Olmsted County, Minnesota. Neurology 45: 244–250PubMedGoogle Scholar
  2. 2.
    Tintore M, Rovira A, Rio J et al. (2006) Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology 67: 968–972PubMedCrossRefGoogle Scholar
  3. 3.
    Tintore M, Rovira A, Rio J et al. (2008) Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis? Neurology 70: 1079–1083PubMedCrossRefGoogle Scholar
  4. 4.
    McDonald WI, Compston A, Edan G et al. (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50: 121–127PubMedCrossRefGoogle Scholar
  5. 5.
    Polman CH, Reingold SC, Edan G et al. (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the „McDonald Criteria“. Ann Neurol 58: 840–846PubMedCrossRefGoogle Scholar
  6. 6.
    Frohman EM, Goodin DS, Calabresi PA et al. (2003) The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 61: 602–611PubMedGoogle Scholar
  7. 7.
    Wujek JR, Bjartmar C, Richer E et al. (2002) Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. J Neuropathol Exp Neurol 61: 23–32PubMedGoogle Scholar
  8. 8.
    Kuhlmann T, Lingfeld G, Bitsch A et al. (2002) Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125: 2202–2212PubMedCrossRefGoogle Scholar
  9. 9.
    Hirst CL, Swingler R, Compston A et al. (2008) Survival and cause of death in multiple sclerosis: a prospective population based study. J Neurol Neurosurg Psychiatry (in press)Google Scholar
  10. 10.
    Kremenchutzky M, Rice GP, Baskerville J et al. (2006) The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain 129: 584–594PubMedCrossRefGoogle Scholar
  11. 11.
    Confavreux C, Vukusic S, Moreau T et al. (2000) Relapses and progression of disability in multiple sclerosis. N Engl J Med 343: 1430–1438PubMedCrossRefGoogle Scholar
  12. 12.
    Dalton CM, Brex PA, Miszkiel KA et al. (2002) Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis. Ann Neurol 52: 47–53PubMedCrossRefGoogle Scholar
  13. 13.
    Fisniku LK, Brex PA, Altmann DR et al. (2008) Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 131: 808–817PubMedCrossRefGoogle Scholar
  14. 14.
    Filippi M, Horsfield MA, Morrissey SP et al. (1994) Quantitative brain MRI lesion load predicts the course of clinically isolated syndromes suggestive of multiple sclerosis. Neurology 44: 635–641PubMedGoogle Scholar
  15. 15.
    Jacobs LD, Beck RW, Simon JH et al. (2000) Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343: 898–904PubMedCrossRefGoogle Scholar
  16. 16.
    Comi G, Filippi M, Barkhof F et al. (2001) Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 357: 1576–1582PubMedCrossRefGoogle Scholar
  17. 17.
    Beck RW, Chandler DL, Cole SR et al. (2002) Interferon beta-1a for early multiple sclerosis: CHAMPS trial subgroup analyses. Ann Neurol 51: 448–456CrossRefGoogle Scholar
  18. 18.
    Kinkel RP, Kollman C, O’Connor P et al. (2006) IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 66: 678–684PubMedCrossRefGoogle Scholar
  19. 19.
    Kappos L, Polman CH, Freedman MS et al. (2006) Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 67: 1242–1249PubMedCrossRefGoogle Scholar
  20. 20.
    Polman C, Kappos L, Freedman MS et al. (2008) Subgroups of the BENEFIT study: risk of developing MS and treatment effect of interferon beta-1b. J Neurol 255: 480–487PubMedCrossRefGoogle Scholar
  21. 21.
    Kappos L, Freedman MS, Polman CH et al. (2007) 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 370: 389–397PubMedCrossRefGoogle Scholar
  22. 22.
    Hartung HP, Polman C, Bertolotto A et al. (2007) Neutralising antibodies to interferon beta in multiple sclerosis: expert panel report. J Neurol 254: 827–837PubMedCrossRefGoogle Scholar
  23. 23.
    Rieckmann P (2006) Escalating immunomodulatory therapy of multiple sclerosis. Update (September 2006). Nervenarzt 77: 1506–1518PubMedCrossRefGoogle Scholar
  24. 24.
    Ransohoff RM (2007) Natalizumab for multiple sclerosis. N Engl J Med 356: 2622–2629PubMedCrossRefGoogle Scholar
  25. 25.
    Baron JL, Madri JA, Ruddle NH et al. (1993) Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma. J Exp Med 177: 57–68PubMedCrossRefGoogle Scholar
  26. 26.
    Andrian UH von, Engelhardt B (2003) Alpha4 integrins as therapeutic targets in autoimmune disease. N Engl J Med 348: 68–72CrossRefGoogle Scholar
  27. 27.
    Miller DH, Khan OA, Sheremata WA et al. (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348: 15–23PubMedCrossRefGoogle Scholar
  28. 28.
    Polman CH, O’Connor PW, Havrdova E et al. (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354: 899–910PubMedCrossRefGoogle Scholar
  29. 29.
    Rudick RA, Miller D, Hass S et al. (2007) Health-related quality of life in multiple sclerosis: effects of natalizumab. Ann Neurol 62: 335–346PubMedCrossRefGoogle Scholar
  30. 30.
    Kleinschmidt-DeMasters BK, Tyler KL (2005) Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353: 369–374PubMedCrossRefGoogle Scholar
  31. 31.
    Langer-Gould A, Atlas SW, Green AJ et al. (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353: 375–381PubMedCrossRefGoogle Scholar
  32. 32.
    Van Assche G, Van RM, Sciot R et al. (2005) Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 353: 362–368CrossRefGoogle Scholar
  33. 33.
    Yousry TA, Major EO, Ryschkewitsch C et al. (2006) Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 354: 924–933PubMedCrossRefGoogle Scholar
  34. 34.
    Stuve O, Marra CM, Bar-Or A et al. (2006) Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol 63: 1383–1387PubMedCrossRefGoogle Scholar
  35. 35.
    Zohren F, Toutzaris D, Klarner V et al. (2008) The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans. Blood 111: 3893–3895PubMedCrossRefGoogle Scholar
  36. 36.
    Gold R, Jawad A, Miller DH et al. (2007) Expert opinion: guidelines for the use of natalizumab in multiple sclerosis patients previously treated with immunomodulating therapies. J Neuroimmunol 187: 156–158PubMedCrossRefGoogle Scholar
  37. 37.
    Kappos L, Bates D, Hartung HP et al. (2007) Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol 6: 431–441PubMedCrossRefGoogle Scholar
  38. 38.
    Mullen JT, Vartanian TK, Atkins MB (2008) Melanoma complicating treatment with natalizumab for multiple sclerosis. N Engl J Med 358: 647–648PubMedCrossRefGoogle Scholar
  39. 39.
    Yao K, Gagnon S, Akhyani N et al. (2008) Reactivation of human herpesvirus-6 in natalizumab treated multiple sclerosis patients. PLoS ONE 3: e2028PubMedCrossRefGoogle Scholar
  40. 40.
    Phillips JT, O’Connor PW, Havrdova E et al. (2006) Infusion-related hypersensitivity reactions during natalizumab treatment. Neurology 67: 1717–1718PubMedCrossRefGoogle Scholar
  41. 41.
    Hellwig K, Schimrigk S, Fischer M et al. (2008) Allergic and nonallergic delayed infusion reactions during natalizumab therapy. Arch Neurol 65: 656–658PubMedCrossRefGoogle Scholar
  42. 42.
    Krumbholz M, Pellkofer H, Gold R et al. (2007) Delayed allergic reaction to natalizumab associated with early formation of neutralizing antibodies. Arch Neurol 64: 1331–1333PubMedCrossRefGoogle Scholar
  43. 43.
    Leussink VI, Lehmann HC, Hartung HP et al. (2008) Type III systemic allergic reaction to natalizumab. Arch Neurol 65: 851–852PubMedCrossRefGoogle Scholar
  44. 44.
    Haghikia A, Fischer M, Hellwig K et al. (2008) Natalizumab im klinischen Alltag. Neutralisierende Antikörper und klinische Daten. Nervenarzt 79: 716–719PubMedCrossRefGoogle Scholar
  45. 45.
    Neuhaus O, Kieseier BC, Hartung HP (2004) Mitoxantrone (Novantrone) in multiple sclerosis: new insights. Expert Rev Neurother 4: 17–26PubMedCrossRefGoogle Scholar
  46. 46.
    Chan A, Weilbach FX, Toyka KV et al. (2005) Mitoxantrone induces cell death in peripheral blood leucocytes of multiple sclerosis patients. Clin Exp Immunol 139: 152–158PubMedCrossRefGoogle Scholar
  47. 47.
    Hartung HP, Gonsette R, Konig N et al. (2002) Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 360: 2018–2025PubMedCrossRefGoogle Scholar
  48. 48.
    Strotmann JM, Spindler M, Weilbach FX et al. (2002) Myocardial function in patients with multiple sclerosis treated with low-dose mitoxantrone. Am J Cardiol 89: 1222–1225PubMedCrossRefGoogle Scholar
  49. 49.
    Cotte S, Kruse N, Ahsen N von et al. (2008) ABC-Tranporter gene polymorphisms: potential predictors of therapeutic efficacy of mitoxantrone in mutiple sclerosis. Neurology [Suppl 11] 70: A395Google Scholar
  50. 50.
    Vollmer T, Panitch H, Bar-Or A et al. (2008) Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis. Mult Scler 14: 663–670PubMedCrossRefGoogle Scholar
  51. 51.
    Edan G, Miller D, Clanet M et al. (1997) Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry 62: 112–118PubMedCrossRefGoogle Scholar
  52. 52.
    Gladstone DE, Zamkoff KW, Krupp L et al. (2006) High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis. Arch Neurol 63: 1388–1393PubMedCrossRefGoogle Scholar
  53. 53.
    La Mantia L, Milanese C, Mascoli N et al. (2007) Cyclophosphamide for multiple sclerosis. Cochrane Database Syst Rev 1: CD002819Google Scholar
  54. 54.
    Linker RA, Weller C, Luhder F et al. (2008) Liposomal glucocorticosteroids in treatment of chronic autoimmune demyelination: long-term protective effects and enhanced efficacy of methylprednisolone formulations. Exp Neurol 211: 397–406PubMedCrossRefGoogle Scholar
  55. 55.
    Cross AH, Stark JL, Lauber J et al. (2006) Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 180: 63–70PubMedCrossRefGoogle Scholar
  56. 56.
    Petereit HF, Rubbert A (2005) Effective suppression of cerebrospinal fluid B cells by rituximab and cyclophosphamide in progressive multiple sclerosis. Arch Neurol 62: 1641–1642PubMedCrossRefGoogle Scholar
  57. 57.
    Stuve O, Cepok S, Elias B et al. (2005) Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis. Arch Neurol 62: 1620–1623PubMedCrossRefGoogle Scholar
  58. 58.
    Bar-Or A, Calabresi PA, Arnlod D et al. (2008) Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol 63: 395–400PubMedCrossRefGoogle Scholar
  59. 59.
    Hauser SL, Waubant E, Arnold DL et al. (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358: 676–688PubMedCrossRefGoogle Scholar

Copyright information

© Springer Medizin Verlag 2008

Authors and Affiliations

  1. 1.Abteilung Neurologie, St.-Josef-HospitalRuhr-UniversitätBochumDeutschland
  2. 2.Neurologische KlinikHeinrich-Heine-UniversitätDüsseldorfDeutschland

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