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Aktuelle Neurologie 2003; 30(9): 433-441
DOI: 10.1055/s-2003-43425
Übersicht
© Georg Thieme Verlag Stuttgart · New York

Immunmodulierende Therapiestrategien bei der multiplen Sklerose: Übersicht und aktueller Stand klinischer Studien

Disease Modifying Therapeutic Strategies in Multiple Sclerosis: An Update on Recent and Ongoing TrialsH.  Wiendl1 , H.  C.  Lehmann2 , R.  Hohlfeld3 , H.-P.  Hartung2 , B.  C.  Kieseier2
  • 1Neurologische Klinik, Eberhard-Karls-Universität Tübingen
  • 2Neurologische Klinik, Heinrich-Heine-Universität Düsseldorf
  • 3Institut für Klinische Neuroimmunologie, Klinikum Großhadern, Ludwig-Maximilians-Universität München
Dr. Wiendl, Prof. Hohlfeld, Prof. Hartung und Priv.-Doz. Kieseier haben an zahlreichen Studien der in der Arbeit genannten Präparate teilgenommen. Ebenso haben sie Honorare seitens der Pharmaindustrie für Beratung und/oder Referententätigkeiten erhalten
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Publikationsverlauf

Publikationsdatum:
06. November 2003 (online)

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Zusammenfassung

Die Therapie der multiplen Sklerose (MS) hat sich über die letzten Jahre dramatisch verändert. Neue Erkenntnisse über die Pathogenese und die Entwicklung neuer pathogenetischer Konzepte haben zusammen mit Verbesserungen bei der Durchführung klinischer Studien und der Magnetresonanztomographie zu einem deutlichen Fortschritt der Behandlung der MS geführt. Immunmodulierende Medikamente wie Interferon-β, Glatiramerazetat und - seit kurzem - Mitoxantron haben eine Effektivität in randomisierten, doppelgeblindeten, plazebokontrollierten Phase-III-Studien gezeigt. Dieser Artikel gibt eine Übersicht über die wichtigsten klinischen Studien der derzeit verfügbaren immunmodulierenden und immunsuppressiven Substanzen in der Behandlung der MS unter besonderer Berücksichtigung der Empfehlungen der trinationalen deutschsprachigen Multiple-Sklerose-Therapie-Konsensus-Gruppe.

Abstract

The therapeutic approach to multiple sclerosis (MS) has changed dramatically over the past decade. Novel insights in the pathogenesis and development of pathophysiological concepts together with improvements in clinical trial design and magnetic resonance imaging have led to significant advances in the management of MS through a variety of immunomodulatory therapies. Interferons, glatiramer acetate and - recently - mitoxantrone showed effectiveness in the treatment of MS in randomized, double-blind, placebo-controlled phase III trials. This review analyses the most important clinical trials with the currently available immunomodulatory and immunosuppressive treatments considering the recommendations of the German/Austrian/Swiss Multiple Sclerosis Therapy Consensus Group.

Literatur

  • 1 Hohlfeld R, Wiendl H. The ups and downs of multiple sclerosis therapeutics.  Ann Neurol. 2001;  49 281-284
    CrossrefPubMedGoogle Scholar
  • 2 Filippi M, Dousset V, McFarland H F. et al . Role of magnetic resonance imaging in the diagnosis and monitoring of multiple sclerosis: consensus report of the White Matter Study Group.  J Magn Reson Imaging. 2002;  15 499-504
    CrossrefPubMedGoogle Scholar
  • 3 McFarland H F, Barkhof F, Antel J, Miller D H. The role of MRI as a surrogate outcome measure in multiple sclerosis.  Mult Scler. 2002;  8 40-51
    CrossrefPubMedGoogle Scholar
  • 4 McDonald W I, Compston A, Edan G. et al . Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.  Ann Neurol. 2001;  50 121-127
    CrossrefPubMedGoogle Scholar
  • 5 Rieckmann P, Toyka K. Multiple-Sklerose-Therapie-Konsensus-Gruppe. Immunmodulatorische Stufentherapie der multiplen Sklerose. Neue Aspekte und praktische Umsetzung, März 2002.  Nervenarzt. 2002;  73 556-563
    CrossrefPubMedGoogle Scholar
  • 6 Hohlfeld R. Biotechnological agents for the immunotherapy of multiple sclerosis: Principles, problems and perspectives.  Brain. 1997;  120 865-916
    CrossrefPubMedGoogle Scholar
  • 7 Noseworthy J H, Lucchinetti C, Rodriguez M, Weinshenker B G. Multiple sclerosis.  N Engl J Med. 2000;  343 938-952
    CrossrefPubMedGoogle Scholar
  • 8 Hemmer B, Archelos J J, Hartung H P. New concepts in the immunopathogenesis of multiple sclerosis.  Nat Rev Neurosci. 2002;  3 291-301
    PubMedGoogle Scholar
  • 9 Weinshenker B G, Bass B, Rice G P. et al . The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability.  Brain. 1989;  112 133-146
    CrossrefPubMedGoogle Scholar
  • 10 Schumacher F A, Beeve G W, Kibler R F. et al . Problems of experimental trials of therapy in multiple sclerosis.  Ann N Y Acad Sci. 1965;  122 552-568
    PubMedGoogle Scholar
  • 11 Lublin F D, Reingold S C. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis.  Neurology. 1996;  46 907-911
    CrossrefPubMedGoogle Scholar
  • 12 Luccinetti C F, Brueck W, Rodriguez M, Lassmann H. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis.  Brain Pathol. 1996;  6 259-274
    CrossrefPubMedGoogle Scholar
  • 13 Lucchinetti C, Bruck W, Parisi J. et al . Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.  Ann Neurol. 2000;  47 707-717
    CrossrefPubMedGoogle Scholar
  • 14 Lassmann H, Bruck W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy.  Trends Mol Med. 2001;  7 115-121
    CrossrefPubMedGoogle Scholar
  • 15 Lucchinetti C, Bruck W, Noseworthy J. Multiple sclerosis: recent developments in neuropathology, pathogenesis, magnetic resonance imaging studies and treatment.  Curr Opin Neurol. 2001;  14 259-269
    CrossrefPubMedGoogle Scholar
  • 16 Goodin D S, Frohman E M, Garmany G P. et al . Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines.  Neurology. 2002;  58 169-178
    CrossrefPubMedGoogle Scholar
  • 17 Jacobs L D, Beck R W, Simon J H. et al . Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.  N Engl J Med. 2000;  343 898-904
    CrossrefPubMedGoogle Scholar
  • 18 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
    CrossrefPubMedGoogle Scholar
  • 19 The IFNβ Multiple Sclerosis Study Group . Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial.  Neurology. 1993;  43 655-661
    PubMedGoogle Scholar
  • 20 The IFNβ Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group . Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial.  Neurology. 1995;  45 1277-1285
    PubMedGoogle Scholar
  • 21 Jacobs L D, Cookfair D L, Rudick R A. et al . Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).  Ann Neurol. 1996;  39 285-294
    CrossrefPubMedGoogle Scholar
  • 22 The Once Weekly Interferon for MS Study Group . Evidence of interferon beta-1a dose response in relapsing-remitting MS: the OWIMS Study.  Neurology. 1999;  53 679-686
    PubMedGoogle Scholar
  • 23 The PRISMS Study Group . PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS.  Neurology. 2001;  56 1628-1636
    PubMedGoogle Scholar
  • 24 Johnson K P, Brooks B R, Cohen J A. et al . 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 1268-1276
    CrossrefPubMedGoogle Scholar
  • 25 Johnson K P, Brooks B R, Cohen J A. et al . Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group.  Neurology. 1998;  50 701-708
    CrossrefPubMedGoogle Scholar
  • 26 Johnson K P, Brooks B R, Ford C C. et al . Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group.  Mult Scler. 2000;  6 255-266
    CrossrefPubMedGoogle Scholar
  • 27 Comi G, Filippi M, Wolinsky J S. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group.  Ann Neurol. 2001;  49 290-297
    CrossrefPubMedGoogle Scholar
  • 28 European Study Group on interferon beta-1b in secondary progressive MS . Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis.  Lancet. 1998;  352 1491-1497
    CrossrefPubMedGoogle Scholar
  • 29 Kappos L, Polman C, Pozzilli C. et al . Final analysis of the European multicenter trial on IFN beta-1b in secondary-progressive MS.  Neurology. 2001;  57 1969-1975
    PubMedGoogle Scholar
  • 30 Goodkin D E,. Group NASS .The North American Study of interferon beta-1b in secondary progressive multiple sclerosis. 52nd Annual Meeting of the American Academy of Neurology. San Diego, CA; 2000
    Google Scholar
  • 31 Patten S B, Metz L M,. SPECTRIMS Study Group . Randomized controlled trial of interferon-beta-1a in secondary progressive MS: Clinical results.  Neurology. 2001;  56 1496-1504
    PubMedGoogle Scholar
  • 32 Li D K, Zhao G J, Paty D W,. University of British Columbia Analysis Research Group. The SPECTRIMS Study Group . Randomized controlled trial of interferon-beta-1a in secondary progressive MS: MRI results.  Neurology. 2001;  56 1505-1513
    CrossrefPubMedGoogle Scholar
  • 33 Cohen J A, Goodman A D, Heidenreich F R. Results of IMPACT, a phase 3 trial of interferon beta-1a in secondary progressive MS.  Neurology. 2001;  56 148-149
    PubMedGoogle Scholar
  • 34 CHAMPS . MRI predictors of early conversion to clinically definite MS in the CHAMPS placebo group.  Neurology. 2002;  59 998-1005
    PubMedGoogle Scholar
  • 35 Berger T, Rubner P, Schautzer F. et al . Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event.  N Engl J Med. 2003;  349 139-145
    CrossrefPubMedGoogle Scholar
  • 36 Beck R W, Chandler D L, Cole S R. et al . Interferon beta-1a for early multiple sclerosis: CHAMPS trial subgroup analyses.  Ann Neurol. 2002;  51 481-490
    CrossrefPubMedGoogle Scholar
  • 37 Poser C M, Paty D W, Scheinberg L. et al . New diagnostic criteria for multiple sclerosis: guidelines for research protocols.  Ann Neurol. 1983;  13 227-231
    CrossrefPubMedGoogle Scholar
  • 38 Filippini G, Munari L, Incorvaia B. et al . Interferons in relapsing remitting multiple sclerosis: a systematic review.  Lancet. 2003;  361 545-552
    CrossrefPubMedGoogle Scholar
  • 39 Cohen J A, Cutter G R, Fischer J S. et al . Benefit of interferon beta-1a on MSFC progression in secondary progressive MS.  Neurology. 2002;  59 679-687
    CrossrefPubMedGoogle Scholar
  • 40 Kurtzke J F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).  Neurology. 1983;  33 1444-1452
    CrossrefPubMedGoogle Scholar
  • 41 Fisher E, Rudick R A, Simon J H. et al . Eight-year follow-up study of brain atrophy in patients with MS.  Neurology. 2002;  59 1412-1420
    CrossrefPubMedGoogle Scholar
  • 42 MSTKG (Multiple-Sklerose-Therapie-Konsensus-Gruppe) . Immunmodulierende Stufentherapie der Multiplen Sklerose. 1. Ergänzung Dezember 2000.  Nervenarzt. 2001;  72 150-157
    CrossrefPubMedGoogle Scholar
  • 43 Leary S M, Miller D H, Stevenson V L. et al . Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial.  Neurology. 2003;  60 44-51
    CrossrefPubMedGoogle Scholar
  • 44 Montalban X. American and European Committee for Treatment and Research in Multiple Sclerosis. Baltimore; 2002
    Google Scholar
  • 45 Thompson A J, Montalban X, Barkhof F. et al . Diagnostic criteria for primary progressive multiple sclerosis: a position paper.  Ann Neurol. 2000;  47 831-835
    CrossrefPubMedGoogle Scholar
  • 46 McDonnell G V, Hawkins S A. Primary progressive multiple sclerosis: increasing clarity but many unanswered questions.  J Neurol Sci. 2002;  199 1-15
    CrossrefPubMedGoogle Scholar
  • 47 Bitsch A, Brück W. Differentiation of multiple sclerosis subtypes: implications for treatment.  CNS Drugs. 2002;  16 405-418
    PubMedGoogle Scholar
  • 48 Wolinsky J S, Comi G, Filippi M. et al . Copaxone's effect on MRI-monitored disease in relapsing MS is reproducible and sustained.  Neurology. 2002;  59 1284-1286
    PubMedGoogle Scholar
  • 49 Durelli L, Verdun E, Barbero P. et al . Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN).  Lancet. 2002;  359 1453-1460
    CrossrefPubMedGoogle Scholar
  • 50 Panitch H, Goodin D S, Francis G. et al . Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial.  Neurology. 2002;  59 1496-1506
    CrossrefPubMedGoogle Scholar
  • 51 Lublin F D. When marketing and science intersect: do patients with MS benefit?.  Neurology. 2002;  59 1480-1481
    PubMedGoogle Scholar
  • 52 Kieburtz K, McDermott M. Needed in MS: evidence, not EVIDENCE.  Neurology. 2002;  59 1482-1483
    PubMedGoogle Scholar
  • 53 Rio J, Nos C, Tintore M. et al . Assessment of different treatment failure criteria in a cohort of relapsing-remitting multiple sclerosis patients treated with interferon beta: implications for clinical trials.  Ann Neurol. 2002;  52 400-406
    CrossrefPubMedGoogle Scholar
  • 54 Noseworthy J H, O'Brien P, Erickson B J. et al . The Mayo Clinic-Canadian Cooperative trial of sulfasalazine in active multiple sclerosis.  Neurology. 1998;  51 1342-1352
    PubMedGoogle Scholar
  • 55 Clanet M, Radue E W, Kappos L. et al . A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS.  Neurology. 2002;  59 1507-1517
    CrossrefPubMedGoogle Scholar
  • 56 Flechter S, Vardi J, Pollak L, Rabey J M. Comparison of glatiramer acetate (Copaxone) and interferon beta-1b (Betaferon) in multiple sclerosis patients: an open-label 2-year follow-up.  J Neurol Sci. 2002;  197 51-55
    CrossrefPubMedGoogle Scholar
  • 57 Hartung H-P, Gonsette P, König N. et al . Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial.  Lancet. 2002;  360 2018-2025
    CrossrefPubMedGoogle Scholar
  • 58 Wyngaert F A van den, Beguin C, D'Hooghe M B. et al . A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis.  Acta Neurol Belg. 2001;  101 210-216
    PubMedGoogle Scholar
  • 59 Bastianello S, Pozzilli C, D'Andrea F. et al . A controlled trial of mitoxantrone in multiple sclerosis: serial MRI evaluation at one year.  Can J Neurol Sci. 1994;  21 266-270
    PubMedGoogle Scholar
  • 60 Millefiorini E, Gasperini C, Pozzilli C. et al . Randomized placebo-controlled trial of mitoxantrone in relapsing- remitting multiple sclerosis: 24-month clinical and MRI outcome.  J Neurol. 1997;  244 153-159
    PubMedGoogle Scholar
  • 61 Edan G, Miller D, Clanet M. et al . 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. 1997;  62 112-118
    CrossrefPubMedGoogle Scholar
  • 62 Ghalie R G, Edan G, Laurent M. et al . Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS.  Neurology. 2002;  59 909-913
    PubMedGoogle Scholar
  • 63 Spindler M, Weilbach F X, Beer M. et al . Non-invasive functional and biochemical assessment of mitroxantrone cardiotoxicity in patients with multiple sclerosis.  J Cardiovasc Pharmacol. 2003, in press; 
    PubMedGoogle Scholar
  • 64 Pette M, Hartung H P. Mitoxantrontherapie bei multipler Sklerose - Stand 2002.  Akt Neurol. 2003;  30 71-75
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 65 Ghalie R G, Mauch E, Edan G. et al . A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis.  Mult Scler. 2002;  8 441-445
    CrossrefPubMedGoogle Scholar
  • 66 Fazekas F, Deisenhammer F, Strasser-Fuchs S. et al . Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis.  Lancet. 1997;  349 589-593
    CrossrefPubMedGoogle Scholar
  • 67 Achiron A, Gabbay U, Gilad R. et al . Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses.  Neurology. 1998;  50 398-402
    PubMedGoogle Scholar
  • 68 Sorensen P S, Wanscher B, Jensen C V. et al . Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis.  Neurology. 1998;  50 1273-1281
    PubMedGoogle Scholar
  • 69 Lewanska M, Siger-Zajdel M, Selmaj K. No difference in efficacy of two different doses of intravenous immunoglobulins in MS: clinical and MRI assessment.  Eur J Neurol. 2002;  9 565-572
    CrossrefPubMedGoogle Scholar
  • 70 Sorensen P S, Fazekas F, Lee M. Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis.  Eur J Neurol. 2002;  9 557-563
    CrossrefPubMedGoogle Scholar
  • 71 Wiendl H, Hohlfeld R. Therapeutic approaches in multiple sclerosis: lessons from failed and interrupted treatment trials.  BioDrugs. 2002;  16 183-200
    PubMedGoogle Scholar
  • 72 Soelberg-Soerensen P. ESIMS. European Charcot Foundation. Venice; 2001
    Google Scholar
  • 73 Wiendl H, Kieseier B C. Disease-modifying therapies in multiple sclerosis: an update on recent and ongoing trials and future therapies.  Expert Opin Investig Drugs. 2003;  12 689-712
    CrossrefPubMedGoogle Scholar

PD Dr. Bernd C. Kieseier

Neurologische Klinik der Heinrich-Heine-Universität

Moorenstraße 5

40225 Düsseldorf

eMail: bernd.kieseier@uni-duesseldorf.de

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