Aktuelle Neurologie 2014; 41(07): 392-396
DOI: 10.1055/s-0034-1384606
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Neue Behandlungsziele bei Multipler Sklerose: Mögliche neuroprotektive Aspekte etablierter und neuer Immuntherapeutika

New Goals in Multiple Sclerosis Treatment: Possible Neuro-Protective Aspects of Established and Newer Immunotherapeutics
A. Salmen
1   Klinik für Neurologie, St. Josef-Hospital, Ruhr-Universität Bochum
,
R. Linker
2   Klinik für Neurologie, Universitätsklinikum Erlangen
,
R. Gold
1   Klinik für Neurologie, St. Josef-Hospital, Ruhr-Universität Bochum
› Author Affiliations
Further Information

Publication History

Publication Date:
12 August 2014 (online)

Zusammenfassung

Multiple Sklerose (MS) ist eine immunmediierte chronisch verlaufende und progressive Erkrankung des Zentralnervensystems (ZNS), die durch Entzündungs- und neurodegenerative Prozesse gekennzeichnet ist. Neben der Immunmodula­tion gewinnt das Therapieziel der Neuroprotektion zunehmend Bedeutung. Zielparameter zur Erfassung derselben sind auf experimenteller und klinischer Ebene mehr in den Fokus gerückt. Dies ist insbesondere im Hinblick auf langfristige und patientenbezogene Krankheitsfolgen von großer Bedeutung wie der Akkumulation von Behinderung, kognitivem Abbau und Lebensqualität. Aufgrund des breiter werdenden Spektrums zur Verfügung stehender Immuntherapeutika werden therapeutische Entscheidungen zukünftig immer komplexer.

Abstract

Multiple sclerosis (MS) is an immune-mediated chronic progressive disorder of the central nervous system (CNS) characterized by inflammatory and neurodegenerative processes. Thus, besides immunomodulation, the therapeutic goal of neuroprotection has become more important. Measurement strategies and surrogate markers to objectify neurodegeneration have been focused on both experimental and clinical level. Especially in terms of long-term patient-related outcomes such as burden of disability, cognitive decline and quality of life, these parameters are highly relevant. With the widening spectrum of immunotherapeutic drugs available for treatment of MS, therapeutic deci­sions are getting more and more complex.

 
  • Literatur

  • 1 Lublin FD, Reingold SC. 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
  • 2 Hafler DA, Slavik JM, Anderson DE et al. Multiple sclerosis. Immunol Rev 2005; 204: 208-231
  • 3 Hohlfeld R, Wekerle H. Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: from pipe dreams to (therapeutic) pipelines. Proc Natl Acad Sci USA 2004; 101 (Suppl. 02) 14599-14606
  • 4 Kalinowska-Lyszczarz A, Losy J. The role of neurotrophins in multiple sclerosis-pathological and clinical implications. Int J Mol Sci 2012; 13: 13713-13725
  • 5 Barres BA. Ciliary neurotrophic factor enhances the rate of oligodendrocyte generation. Mol Cell Neurosci 1996; 8: 146-156
  • 6 Louis JC, Magal E, Takayama S et al. CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science 1993; 259: 689-692
  • 7 Linker RA, Maurer M, Gaupp S et al. CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nat Med 2002; 8: 620-624
  • 8 Kerschensteiner M, Gallmeier E, Behrens L et al. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation?. J Exp Med 1999; 189: 865-870
  • 9 Stadelmann C, Kerschensteiner M, Misgeld T et al. BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells?. Brain 2002; 125: 75-85
  • 10 Linker RA, Lee DH, Demir S et al. Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis. Brain 2010; 133: 2248-2263
  • 11 Amato MP, Langdon D, Montalban X et al. Treatment of cognitive impairment in multiple sclerosis: position paper. J Neurol 2013; 260: 1452-1468
  • 12 Bosma L, Kragt J, Polman C et al. Walking speed, rather than Expanded Disability Status Scale, relates to long-term patient-reported impact in progressive MS. Mult Scler 2013; 19: 326-333
  • 13 Hulst HE, Steenwijk MD, Versteeg A et al. Cognitive impairment in MS: Impact of white matter integrity, gray matter volume, and lesions. Neurology 2013; 80: 1025-1032
  • 14 Papadopoulou A, Müller-Lenke N, Naegelin Y et al. Contribution of cortical and white matter lesions to cognitive impairment in multiple sclerosis. Mult Scler 2013; 19: 1290-1296
  • 15 Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33: 1444-1452
  • 16 Fischer JS, Rudick RA, Cutter GR et al. The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force. Mult Scler 1999; 5: 244-250
  • 17 Cutter GR, Baier ML, Rudick RA et al. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 1999; 122 (Pt 5) 871-882
  • 18 Kuhner C, Burger C, Keller F et al. Reliability and validity of the Revised Beck Depression Inventory (BDI-II). Results from German samples. Nervenarzt 2007; 78: 651-656
  • 19 Kalbe E, Calabrese P, Fengler S et al. DemTect, PANDA, EASY, and MUSIC: cognitive screening tools with age correction and weighting of subtests according to their sensitivity and specificity. J Alzheimers Dis 2013; 34: 813-834
  • 20 Penner IK, Raselli C, Stocklin M et al. The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue. Mult Scler 2009; 15: 1509-1517
  • 21 Fisk JD, Pontefract A, Ritvo PG et al. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci 1994; 21: 9-14
  • 22 Fisk JD, Ritvo PG, Ross L et al. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis 1994; 18 (Suppl. 01) S79-S83
  • 23 Marrie RA, Miller DM, Chelune GJ et al. Validity and reliability of the MSQLI in cognitively impaired patients with multiple sclerosis. Mult Scler 2003; 9: 621-626
  • 24 Learmonth YC, Dlugonski D, Pilutti LA et al. Psychometric properties of the Fatigue Severity Scale and the Modified Fatigue Impact Scale. J Neurol Sci 2013; 331: 102-107
  • 25 Krupp LB, LaRocca NG, Muir-Nash J et al. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989; 46: 1121-1123
  • 26 Cella DF, Dineen K, Arnason B et al. Validation of the functional assessment of multiple sclerosis quality of life instrument. Neurology 1996; 47: 129-139
  • 27 Acaster S, Swinburn P, Wang C et al. Can the functional assessment of multiple sclerosis adapt to changing needs? A psychometric validation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis. Mult Scler 2011; 17: 1504-1513
  • 28 Davie CA, Barker GJ, Webb S et al. Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 1995; 118 (Pt 6) 1583-1592
  • 29 De Stefano N, Matthews PM, Fu L et al. Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 1998; 121 (Pt 8) 1469-1477
  • 30 Lukas C, Minneboo A, de Groot V et al. Early central atrophy rate predicts 5 year clinical outcome in multiple sclerosis. J Neurol Neurosurg Psychiatry 2010; 81: 1351-1356
  • 31 Rovaris M, Filippi M, Minicucci L et al. Cortical/subcortical disease burden and cognitive impairment in patients with multiple sclerosis. AJNR 2000; 21: 402-408
  • 32 Popescu V, Ran NC, Barkhof F et al. Accurate GM atrophy quantification in MS using lesion-filling with co-registered 2D lesion masks. Neuroimage Clin 2014; 4: 366-373
  • 33 Jacobsen C, Hagemeier J, Myhr KM et al. Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study. J Neurol Neurosurg Psychiatry 2014; Epub ahead of print
  • 34 Hofstetter L, Naegelin Y, Filli L et al. Progression in disability and regional grey matter atrophy in relapsing-remitting multiple sclerosis. Mult Scler 2014; 20: 202-213
  • 35 Batista S, Zivadinov R, Hoogs M et al. Basal ganglia, thalamus and neocortical atrophy predicting slowed cognitive processing in multiple sclerosis. J Neurol 2012; 259: 139-146
  • 36 Benedict RH, Hulst HE, Bergsland N et al. Clinical significance of atrophy and white matter mean diffusivity within the thalamus of multiple sclerosis patients. Mult Scler 2013; 19: 1478-1484
  • 37 Schoonheim MM, Popescu V, Rueda Lopes FC et al. Subcortical atrophy and cognition: sex effects in multiple sclerosis. Neurology 2012; 79: 1754-1761
  • 38 Calabrese M, Rinaldi F, Grossi P et al. Basal ganglia and frontal/parietal cortical atrophy is associated with fatigue in relapsing-remitting multiple sclerosis. Mult Scler 2010; 16: 1220-1228
  • 39 Yaldizli O, Penner IK, Frontzek K et al. The relationship between total and regional corpus callosum atrophy, cognitive impairment and fatigue in multiple sclerosis patients. Mult Scler 2014; 20: 356-364
  • 40 Frohman EM, Fujimoto JG, Frohman TC et al. Optical coherence tomography: a window into the mechanisms of multiple sclerosis. Nature clinical practice Neurology 2008; 4: 664-675
  • 41 Petzold A, de Boer JF, Schippling S et al. Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol 2010; 9: 921-932
  • 42 Young KL, Brandt AU, Petzold A et al. Loss of retinal nerve fibre layer axons indicates white but not grey matter damage in early multiple sclerosis. Eur J Neurol 2013; 20: 803-811
  • 43 Zimmermann H, Freing A, Kaufhold F et al. Optic neuritis interferes with optical coherence tomography and magnetic resonance imaging correlations. Mult Scler 2013; 19: 443-450
  • 44 Galetta KM, Calabresi PA, Frohman EM et al. Optical coherence tomography (OCT): imaging the visual pathway as a model for neurodegeneration. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics 2011; 8: 117-132
  • 45 Albrecht P, Ringelstein M, Muller AK et al. Degeneration of retinal layers in multiple sclerosis subtypes quantified by optical coherence tomography. Mult Scler 2012; 18: 1422-1429
  • 46 Ratchford JN, Quigg ME, Conger A et al. Optical coherence tomography helps differentiate neuromyelitis optica and MS optic neuropathies. Neurology 2009; 73: 302-308
  • 47 Naismith RT, Tutlam NT, Xu J et al. Optical coherence tomography differs in neuromyelitis optica compared with multiple sclerosis. Neurology 2009; 72: 1077-1082
  • 48 Penner IK, Stemper B, Calabrese P et al. Effects of interferon beta-1b on cognitive performance in patients with a first event suggestive of multiple sclerosis. Mult Scler 2012; 18: 1466-1471
  • 49 Zivadinov R, Munschauer FE, Ramanathan M et al. Clinical efficacy, effects on MRI and tolerability of weekly intramuscular interferon-beta-1a in patients with MS and CIS. Drugs Today (Barc) 2008; 44: 601-613
  • 50 Barkhof F, van Waesberghe JH, Filippi M et al. T(1) hypointense lesions in secondary progressive multiple sclerosis: effect of interferon beta-1b treatment. Brain 2001; 124: 1396-1402
  • 51 Azoulay D, Mausner-Fainberg K, Urshansky N et al. Interferon-beta therapy up-regulates BDNF secretion from PBMCs of MS patients through a CD40-dependent mechanism. J Neuroimmunol 2009; 211: 114-119
  • 52 Biernacki K, Antel JP, Blain M et al. Interferon beta promotes nerve growth factor secretion early in the course of multiple sclerosis. Arch Neurol 2005; 62: 563-568
  • 53 Comi G, Filippi M, Wolinsky JS. 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
  • 54 Comi G, Martinelli V, Rodegher M et al. Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome. Mult Scler 2013; 19: 1074-1083
  • 55 Ziemssen T, Kumpfel T, Klinkert WE et al. Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain 2002; 125: 2381-2391
  • 56 Aharoni R, Kayhan B, Eilam R et al. Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc Natl Acad Sci USA 2003; 100: 14157-14162
  • 57 Aharoni R, Saada R, Eilam R et al. Oral treatment with laquinimod augments regulatory T-cells and brain-derived neurotrophic factor expression and reduces injury in the CNS of mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 2012; 251: 14-24
  • 58 Thone J, Ellrichmann G, Seubert S et al. Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. Am J Pathol 2012; 180: 267-274
  • 59 Comi G, Jeffery D, Kappos L et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. New Engl J Med 2012; 366: 1000-1009
  • 60 Filippi M, Rocca MA, Pagani E et al. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry 2014; 85: 851-858
  • 61 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: 678-692
  • 62 Papadopoulou A, D’Souza M, Kappos L et al. Dimethyl fumarate for multiple sclerosis. Expert Opin Investig Drugs 2010; 19: 1603-1612
  • 63 Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. The New England journal of medicine 2012; 367: 1098-1107
  • 64 Fox RJ, Miller DH, Phillips JT et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. New Engl J Med 2012; 367: 1087-1097
  • 65 Kappos L, Gold R, Miller DH et al. Effect of BG-12 on contrast-enhanced lesions in patients with relapsing–remitting multiple sclerosis: subgroup analyses from the phase 2b study. Mult Scler 2012; 18: 314-321