Fortschr Neurol Psychiatr 2005; 73(3): 143-149
DOI: 10.1055/s-2004-830102
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Unterschiedliche Wirkung der Immuntherapie auf Schübe und schleichende Progression bei Multipler Sklerose: Deutung und Konsequenzen für die Therapie

Differential Influence of Immune Therapy on Relapses and Progression in Multiple Sclerosis: Interpretation and Therapeutic ConsequencesM.  E.  Kornhuber1 , P.  Presek2 , S.  Zierz1
  • 1Klinik für Neurologie der Martin-Luther-Universität Halle-Wittenberg (Direktor Prof. Dr. S. Zierz)
  • 2Institut für Pharmakologie und Toxikologie der Martin-Luther-Universität Halle-Wittenberg (komm. Direktor Prof. Dr. P. Presek)
Further Information

Publication History

Publication Date:
15 November 2004 (online)

Zusammenfassung

Die Wirksamkeit verschiedener Substanzen auf Schubparameter ist bei Patienten mit schubhaft remittierender Multipler Sklerose (MS) gut belegt. Patienten mit progredienten MS-Verläufen profitieren dagegen von Immuntherapie kaum. Gegenwärtig wird daher der Behandlungsbeginn nach dem ersten Schub propagiert, auch mit dem Ziel, Degeneration und Behinderung entgegenzuwirken. In der vorliegenden Übersicht wird diese Vorstellung einer kritischen Prüfung unterzogen. Tatsächlich gibt es keine Evidenz, dass durch frühen Beginn einer Immuntherapie die sekundäre Progression verzögert oder abgeschwächt werden kann. Ausgedehnte Degeneration lässt sich früh im Krankheitsverlauf und unabhängig von Entzündungsaktivität fassen. Autoimmunität per se stellt offensichtlich kein ausreichendes pathogenetisches Konzept für MS dar. Alternativ wird ein Virus-Superantigen-Dualismus als Ursache der unterschiedlichen Pathomechanismen der MS vorgestellt. Zusammenfassend ist eine Evidenz-basierte Immuntherapie an der tatsächlichen Entzündungsaktivität der Erkrankung auszurichten. Geeignet ist dafür insbesondere der Abstand zwischen zwei Schüben.

Abstract

It is well established that relapses can be suppressed by different substances in patients with relapsing-remitting multiple sclerosis (MS). In contrast, patients with progressive forms of MS do hardly respond to immune therapy. Therefore, start of immune therapy after the first relapse has been proposed, especially in order to prevent degeneration and disability. This view is challenged in the present review. Actually no evidence exists in support of a retardation or an attenuation of secondary progression by early immune therapy. Widespread degeneration occurs early and progresses independently from inflammatory plaques. Therefore, autoimmunity per se is no adequate paradigm to explain MS-pathogenesis entirely. A virus/superantigen-dualism is proposed to explain the different parts of MS, instead. It is concluded that evidence-based immune therapy should be adapted to the actual inflammatory activity of the disease. A suitable parameter for this purpose is the interval between 2 relapses.

Literatur

  • 1 The IFNB multiple sclerosis study group . Interferon β-1b is effective in relapsing-remitting multiple sclerosis: clinical results of a multicenter, randomized, double-blind, placebo-controlled trial.  Neurology. 1993;  43 655-661
  • 2 PRISMS study group . Randomized double-blind placebo-controlled study of interferon-1a in relapsing/remitting multiple sclerosis.  Lancet. 1998;  352 1498-1504
  • 3 Jacobs L D, Cookfair D L, Rudick R A. et al . Intramuscular interferon β-1a for disease progression in relapsing multiple sclerosis.  Ann Neurol. 1996;  39 285-294
  • 4 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.  Neurology. 1995;  45 1268-1276
  • 5 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
  • 6 Youdkin P L, Ellison G W, Ghezzi A. et al . Overview of azathioprine treatment in multiple sclerosis.  Lancet. 1991;  338 1051-1055
  • 7 Jacobs L D, Beck R W, Simon J H. et al . Intramuscular interferon β-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS study group.  N Engl J Med. 2000;  28 898-904
  • 8 Comi G, Filippi M, Barkhof F. et al . Effect of early intervention treatment on conversion to definite multiple sclerosis: a randomised study.  Lancet. 2001;  357 1576-1582
  • 9 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
  • 10 Coyle P K, Hartung H-P. Use of interferon β in multiple sclerosis: rationale for early treatment and evidence for dose- and frequency-dependent effects on clinical response.  Mult Scler. 2002;  8 2-9
  • 11 Filippini G, Munari L, Incorvaia B, Ebers G C, Polman C, D'Amico R, Rice G PA. Interferons in relapsing remitting multiple sclerosis: a systematic review.  Lancet. 2003;  361 545-552
  • 12 Confavreux C, Vukusic S, Adelaine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis.  Brain. 2003;  126 770-782
  • 13 Panitch H, Goodin D S, Francis G. et al . Randomized, comparative study of interferon β-1a treatment regimens in MS. The EVIDENCE trial.  Neurology. 2002;  59 1496-1506
  • 14 Durelli L, Verdun E, Barbero P. et al . Every other day interferon β-1b versus once-weekly interferon β-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN).  Lancet. 2002;  359 1453-1460
  • 15 Kappos L, Patzold U, Dommasch D. et al . Cyclosporine versus azathioprine in the long-term treatment of multiple sclerosis - results of the German multicenter study.  Ann Neurol. 1988;  23 56-63
  • 16 Goodkin D E. Northamerican study group on Interferon β-1b in secondary progressive MS . Interferon β-1b in secondary progressive MS: clinical and MRI results of a 3-year randomised controlled trial.  Neurology. 2000;  54 2352 (Abstract)
  • 17 Secondary progressive efficacy trial of recombinant interferon β-1a in MS study group . Randomised controlled trial of interferon β-1a in secondary progressive MS - clinical results.  Neurology. 2001;  56 1496-1504
  • 18 Cohen J A, Goodman A D, Heidenreich F R. et al . Benefit of interferon (β)-1a on MSFC progression in secondary progressive MS.  Neurology. 2002;  59 679-687
  • 19 Kappos L. and the European study group on Interferon β-1b in secondary progressive MS . Placebo-controlled multicentre randomized trial of interferon β-1b in treatment of secondary progressive multiple sclerosis.  Lancet. 1998;  352 1491-1497
  • 20 Paty D, Kappos L, Stam Moraga M. et al .Long-Term observational efficacy and safety follow-up of the PRISMS cohort. 19th Congress of the European committee for treatment and research in multiple sclerosis. Milan, Italy 17 - 20 September 2003: P555
  • 21 Hommes O R, Sorensen P S, Fazekas F. et al . Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo - controlled trial.  Lancet. 2004;  364 1149-1156
  • 22 Confavreux C, Vukusic S, Moreau T, Adelaine P. Relapses and progression of disability in multiple sclerosis.  New Engl J Med. 2000;  243 1430-1438
  • 23 Weinstein A, Schwid S R, Schiffer R B. et al . Neuropsychological status in multiple sclerosis after treatment with glatiramer acetate (Copaxone).  Arch Neurol. 1999;  56 319-324
  • 24 Fischer J S, Priore R L, Jacobs L D. et al . Neuropsychological effects of interferon β-1a in relapsing multiple sclerosis.  Ann Neurol. 2000;  48 885-892
  • 25 Achiron A, Barak Y. Cognitive impairment in probable multiple sclerosis.  J Neurol Neurosurg Psychiatr. 2003;  74 443-446
  • 26 Zivadinov R, Sepcic J, Nasuelli D. et al . A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis.  J Neurol Neurosurg Psychiatr. 2001;  70 773-780
  • 27 De Sonneville L M, Boringa J B, Reuling I E. et al . Information processing characteristics in subtypes of multiple sclerosis.  Neuropsychologia. 2002;  40 1751-1765
  • 28 Foong J, Rozewicz L, Chong W K. et al . A comparison of neuropsychological deficits in primary and secondary progressive multiple sclerosis.  J Neurol. 2000;  247 97-101
  • 29 Gayou A, Brochet B, Dousset V. Transitional progressive multiple sclerosis: a clinical and imaging study.  J Neurol Neurosurg Psychiatr. 1997;  63 396-298
  • 30 De Stefano N, Narayanan S, Francis S J, Smith S, Mortilla M, Tartaglia M C, Bartolozzi M L, Guidi L, Federico A, Arnold D L. Diffuse axonal and tissue injury in patients with multiple sclerosis with low lesion load and no disability.  Arch Neurol. 2002;  59 1565-1571
  • 31 Filippi M, Bozzali M, Rovaris M, Gonen O, Kasevadas C, Ghezi A, Martinelli V, Grossman R I, Scotti G, Comi G, Falini A. Evidence for widespread axonal damage at the earliest clinic stage of multiple sclerosis.  Brain. 2003;  126 433-437
  • 32 Filippi M, Rocca M A, Martino G, Horsfield M A, Comi G. Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis.  Ann Neurol. 1998;  43 809-814
  • 33 Parry A, Corkill R, Blamire A M, Palace J, Narayanan S, Arnold D, Styles P, Mathews P M. β-Interferon treatment does not always slow the progression of axonal injury in multiple sclerosis.  J Neurol. 2003;  250 171-178
  • 34 Anlar O, Kisli M, Tombul T, Ozbek H. Visual evoked potentials in multiple sclerosis before and after two years of interferon therapy.  Int J Neurosci. 2003;  113 483-489
  • 35 Bednarik J, Kadanka Z. Multimodal sensory and motor evoked potentials in a two-year follow-up study of MS patients with relapsing course.  Acta Neurol Scand. 1992;  86 15-18
  • 36 Iragui V J, Wiederholt W C, Romine J S. Serial recordings of multimodality evoked potentials in multiple sclerosis: a four year follow-up study.  Can J Neurol Sci. 1986;  13 320-326
  • 37 Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Brück W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time.  Brain. 2002;  125 2202-2212
  • 38 Leary S M, Davie C A, Parker G J, Stevenson V L, Wang L, Barker G J, Miller D H, Thompson A J. 1H magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis.  J Neurol. 1999;  246 1023-1026
  • 39 McDonnell G V, Cabrera-Gomez J, Calne D B, Li D K, Oger J. Clinical presentation of primary progressive multiple sclerosis 10 years after the incidental finding of typical magnetic resonance imaging brain lesions: the subclinical state of primary progressive multiple sclerosis may last 10 years.  Mult Scler. 2003;  9 204-209
  • 40 Zhang J, Markovic-Plese S, Lacet B. et al . Increased frequency of interleukin2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis.  J Exp Med. 1994;  179 973-978
  • 41 Belfrage H, Dohlsten M, Hedlund G. et al . Enhanced and prolonged efficacy of superantigen-induced cytotoxic T lymphocyte activity by interleukin-2 in vivo.  Cancer Immunol Immunother. 1995;  41 87-94
  • 42 Thompson A J, Polman C, Miller D H. et al . Primary progressive multiple sclerosis.  Brain. 1997;  120 1085-1096
  • 43 Vukusic S, Confavreux C. Primary and secondary multiple sclerosis.  J Neurol Sci. 2003;  206 153-155
  • 44 Kornhuber M E, Zierz S. Möglichkeiten und Grenzen der Immuntherapie der Multiplen Sklerose. Inflammatorische und degenerative Anteile der Erkrankung erfordern ein neues pathogenetisches Konzept.  Nervenarzt. 2003;  74 537-538
  • 45 Kornhuber M E, Ganz C, Lang R. et al . Focal encephalitis in the Lewis rat induced by intracerebral enterotoxin superantigen and amplified by activated intravenous splenocytes.  Neurosci Lett. 2002;  324 93-96
  • 46 Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.  Ann Neurol. 2000;  47 707-717
  • 47 Sotgiu S, Serra C, Mameli G. et al . Multiple sclerosis-associated retrovirus and MS prognosis: an observational study.  Neurology. 2002;  59 1071-1073
  • 48 Perron H, Jouvin-Marche E, Michel M. et al . Multiple sclerosis retrovirus particles and recombinant envelope trigger abnormal immune response in vitro, by inducing polyclonal Vβ16 T-lymphocyte activation.  Virology. 2001;  287 321-332

Dr. med. M. E. Kornhuber

Neurologische Klinik der Universität Halle-Wittenberg

Ernst-Grube-Str. 40

6097 Halle (Saale), Deutschland

Email: malte.kornhuber@medizin.uni-halle.de