Was gibt es Neues bei der Multiplen Sklerose?

Zusammenfassung

Im Jahr 2011 wurden die Ergebnisse einer Reihe interessanter klinischer Phase II und III Studien bei Patienten mit schubförmiger Multipler Sklerose (MS) vorgestellt oder publiziert. Hierbei handelt es sich zum einen um Studien mit neuen oralen Substanzen wie z. B. Laquinimod, Teriflunomid oder BG-12, zum anderen um Studien, welche die Effekte sogenannter „Biologicals“ untersuchten, also Substanzen mit hoher biologischer Wirksamkeit und gezielter hochselektiver Wirkweise. Auf Basis positiver Phase III Studienergebnisse wurden die Zulassungsverfahren bei einigen Substanzen initiiert (BG-12, Teriflunomid, Alemtuzumab, Laquinimod). Es gab jedoch auch unerwartete Ergebnisse, welche zumindest teilweise auf Besonderheiten der jeweiligen Studienpopulationen mit überraschend niedriger Schubaktivität und geringer Behinderungsprogression zurückzuführen sind, teils durch Imbalancen der jeweiligen Subgruppen in Folge der Randomisierung erklärt werden können. Darüber hinaus wurden im Jahr 2011 interessante neue Ergebnisse zu Genetik und Umweltfaktoren, Immunologie und Diagnostik vorgestellt und publiziert. In diesem Artikel möchten wir einen Überblick über die jüngsten Entwicklungen auf dem Gebiet der MS geben und die wichtigsten und interessantesten Ergebnisse aus dem Bereich der MS-Therapie zusammenfassen und vorstellen.

Abstract

In 2011, the results of a number of interesting clinical phase II and III studies on patients suffering from relapsing-remitting multiple sclerosis have been presented or published. These included studies investigating not only the anti-inflammatory potential of newly developed oral drugs such as laquinimod, teriflunomide or BG-12, but also the so-called biologicals, i. e., drugs with high biological activity and highly selective mode of action. Some of the positive clinical phase III studies resulted in initiation of the respective approval procedures for some of these substances such as, for example, BG-12, teriflunomide, and alemtuzumab. However, there were also some disappointments and unexpected results, which can at least partially be explained by imbalances in the study populations and by unexpectedly low rates of clinical signs of disease activity in the control groups. Moreover, very interesting new results in the fields of genetics and environmental factors, immunology and diagnostics were presented in 2011. This review reports on the latest findings and developments in the area of MS research and therapy from 2011.

Schlüsselwörter

Multiple Sklerose - Immunologie - klinische Studien - orale Therapieansätze - monoklonale Antikörper

Keywords

multiple sclerosis - immunology - clinical studies - oral drugs - monoclonal antibodies

• Literatur

• 1 Weber F, Fontaine B, Cournu-Rebeix I et al. IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations. Genes Immun 2008; 9: 259-263
• 2 Hoffjan S, Akkad DA. The genetics of multiple sclerosis: an update 2010. Mol Cell Probes 2010; 24: 237-243
• 3 Sawcer S, Hellenthal G, Pirinen M et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476: 214-219
• 4 Munger KL, Levin LI, Hollis BW et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006; 296: 2832-2838
• 5 Pierrot-Deseilligny C, Souberbielle JC. Is hypovitaminosis D one of the environmental risk factors for multiple sclerosis?. Brain 2010; 133: 1869-1888
• 6 Simpson Jr S, Taylor B, Blizzard L et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol 2010; 68: 193-203
• 7 Mowry EM, Krupp LB, Milazzo M et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol 2010; 67: 618-624
• 8 von Essen MR, Kongsbak M, Schjerling P et al. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol 2010; 11: 344-349
• 9 Correale J, Ysrraelit MC, Gaitan MI. Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain 2009; 132: 1146-1160
• 10 Kimball SM, Ursell MR, O’Connor P et al. Safety of vitamin D3 in adults with multiple sclerosis. Am J Clin Nutr 2007; 86: 645-651
• 11 Stein MS, Liu Y, Gray OM et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology 2011; 77: 1611-1618
• 12 Sumaya CV, Myers LW, Ellison GW. Epstein-Barr virus antibodies in multiple sclerosis. Arch Neurol 1980; 37: 94-96
• 13 Serafini B, Rosicarelli B, Franciotta D et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med 2007; 204: 2899-2912
• 14 Lassmann H, Niedobitek G, Aloisi F et al. Epstein-Barr virus in the multiple sclerosis brain: a controversial issue – report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain 2011; 134: 2772-2786
• 15 Lucas RM, Ponsonby AL, Dear K et al. Current and past Epstein-Barr virus infection in risk of initial CNS demyelination. Neurology 2011; 77: 371-379
• 16 Tzartos JS, Khan G, Vossenkamper A et al. Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology 2012; 78: 15-23
• 17 Hauser SL, Waubant E, Arnold DL et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358: 676-688
• 18 Leandro MJ, Cambridge G, Ehrenstein MR et al. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54: 613-620
• 19 Martin Mdel P, Cravens PD, Winger R et al. Depletion of B lymphocytes from cerebral perivascular spaces by rituximab. Arch Neurol 2009; 66: 1016-1020
• 20 Bar-Or A, Fawaz L, Fan B et al. Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS?. Ann Neurol 2010; 67: 452-461
• 21 Weber MS, Prodhomme T, Patarroyo JC et al. B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell deple­tion in central nervous system autoimmunity. Ann Neurol 2010; 68: 369-383
• 22 Lyons JA, San M, Happ MP et al. B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide. Eur J Immunol 1999; 29: 3432-3439
• 23 Harp CT, Ireland S, Davis LS et al. Memory B cells from a subset of treatment-naive relapsing-remitting multiple sclerosis patients elicit CD4(+) T-cell proliferation and IFN-gamma production in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Eur J Immunol 2010; 40: 2942-2956
• 24 Fillatreau S, Sweenie CH, McGeachy MJ et al. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002; 3: 944-950
• 25 Hirotani M, Niino M, Fukazawa T et al. Decreased IL-10 production mediated by Toll-like receptor 9 in B cells in multiple sclerosis. J Neuroimmunol 2010; 221: 95-100
• 26 Knippenberg S, Peelen E, Smolders J et al. Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naive/memory Breg ratio during a relapse but not in remission. J Neuroimmunol 2011; 239: 80-86
• 27 Weiner HL. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J Neurol 2008; 255 (Suppl. 01) 3-11
• 28 Diestel A, Aktas O, Hackel D et al. Activation of microglial poly(ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage. J Exp Med 2003; 198: 1729-1740
• 29 Mildner A, Mack M, Schmidt H et al. CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 2009; 132: 2487-2500
• 30 Ajami B, Bennett JL, Krieger C et al. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 2011; 14: 1142-1149
• 31 Berer K, Mues M, Koutrolos M et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 2011; 479: 538-541
• 32 Lee YK, Menezes JS, Umesaki Y et al. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2011; 108 (Suppl. 01) 4615-4622
• 33 Esplugues E, Huber S, Gagliani N et al. Control of TH17 cells occurs in the small intestine. Nature 2011; 475: 514-518
• 34 Morris Z, Whiteley WN, Longstreth Jr WT et al. Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2009; 339: b3016
• 35 Lebrun C, Bensa C, Debouverie M et al. Association between clinical conversion to multiple sclerosis in radiologically isolated syndrome and magnetic resonance imaging, cerebrospinal fluid, and visual evoked potential: follow-up of 70 patients. Arch Neurol 2009; 66: 841-846
• 36 Okuda DT, Mowry EM, Beheshtian A et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology 2009; 72: 800-805
• 37 Okuda DT, Mowry EM, Cree BA et al. Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome. Neurology 2011; 76: 686-692
• 38 De Stefano N, Stromillo ML, Rossi F et al. Improving the characterization of radiologically isolated syndrome suggestive of multiple sclerosis. PLoS One 2011; 6: e19452
• 39 Costello F, Coupland S, Hodge W et al. Quantifying axonal loss after optic neuritis with optical coherence tomography. Ann Neurol 2006; 59: 963-969
• 40 Costello F, Hodge W, Pan YI et al. Tracking retinal nerve fiber layer loss after optic neuritis: a prospective study using optical coherence tomography. Mult Scler 2008; 14: 893-905
• 41 Fisher JB, Jacobs DA, Markowitz CE et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 2006; 113: 324-332
• 42 Syc SB, Saidha S, Newsome SD et al. Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis. Brain 2011;
• 43 Dorr J, Wernecke KD, Bock M et al. Association of retinal and macular damage with brain atrophy in multiple sclerosis. PLoS One 2011; 6: e18132
• 44 Talman LS, Bisker ER, Sackel DJ et al. Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis. Ann Neurol 2010; 67: 749-760
• 45 Galetta KM, Calabresi PA, Frohman EM et al. Optical coherence tomography (OCT): imaging the visual pathway as a model for neurodegeneration. Neurotherapeutics 2011; 8: 117-132
• 46 Warnke C, Adams O, Gold R et al. Progressive multifocal leukoencephalopathy under natalizumab: Initial possibilities for risk stratification?. Nervenarzt 2011; 82: 475-480
• 47 Killestein J, Vennegoor A, Strijbis EM et al. Natalizumab drug holiday in multiple sclerosis: poorly tolerated. Ann Neurol 2010; 68: 392-395
• 48 Borriello G, Prosperini L, Marinelli F et al. Observations during an elective interruption of natalizumab treatment: a post-marketing study. Mult Scler 2011; 17: 372-375
• 49 West TW, Cree BA. Natalizumab dosage suspension: are we helping or hurting?. Ann Neurol 2010; 68: 395-399
• 50 Sangalli F, Moiola L, Radaelli M et al. What to expect after natalizumab in every-day clinical practice. Multiple Sclerosis 2011; 17: S405
• 51 Fox R, Kappos L, Cree B et al. Effects of a 24-week natalizumab treatment interruption on clinical and radiologic parameters of multiple sclerosis disease activity: the RESTORE study. Multiple Sclerosis 2011; 17: S509
• 52 Preiningerova J. Oral laquinimod therapy in relapsing multiple sclerosis. Expert Opin Investig Drugs 2009; 18: 985-989
• 53 Polman C, Barkhof F, Sandberg-Wollheim M et al. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology 2005; 64: 987-991
• 54 Vollmer TL, Soelberg Sorensen P, Arnold DL et al. A Placebo-controlled and active comparator phase III trial (BRAVO) for relapsing-remitting multiple sclerosis. Multiple Sclerosis 2011; 17: S507
• 55 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
• 56 Korn T, Magnus T, Toyka K et al. Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide – mechanisms independent of pyrimidine depletion. J Leukoc Biol 2004; 76: 950-960
• 57 O’Connor P, Wolinsky JS, Confavreux C et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365: 1293-1303
• 58 O’Connor P, Wolinsky JS, Confavreux C et al. Extension of a phase III trial (TEMSO) of oral teriflunomide in multiple sclerosis with relapses: clinical and MRI data 5 years after initial randomisation. Multiple Sclerosis 2011; 17: S414
• 59 Comi G, O’Connor P, Wolinsky JS et al. Extension of a phase III trial (TEMSO) of oral teriflunomide in multiple sclerosis with relapses: safety outcomes with up to 4 years of follow-up. Multiple Sclerosis 2011; 17: S182
• 60 Gold R, Kappos L, Bar-Or A et al. Clinical efficacy of BG-12, an oral therapy, in relapsing-remitting multiple sclerosis: results from the phase III DEFINE trial. Multiple Sclerosis 2011; 17: S34
• 61 Menter A, Korman NJ, Elmets CA et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol 2011; 65: 137-174
• 62 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
• 63 Linker RA, Lee DH, Stangel M et al. Fumarates for the treatment of multiple sclerosis: potential mechanisms of action and clinical studies. Expert Rev Neurother 2008; 8: 1683-1690
• 64 Kappos L, Gold R, Miller DH et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008; 372: 1463-1472
• 65 Selmaj K, Gold R, Kappos L et al. Safety and tolerability of BG-12 in the phase III DEFINE trial in patients with relapsing-remitting multiple sclerosis. Multiple Sclerosis 2011; 17: S451
• 66 Bielekova B, Richert N, Herman ML et al. Intrathecal effects of daclizumab treatment of multiple sclerosis. Neurology 2011; 77: 1877-1886
• 67 Martin JF, Perry JS, Jakhete NR et al. An IL-2 paradox: blocking CD25 on T cells induces IL-2-driven activation of CD56(bright) NK cells. J Immunol 2010; 185: 1311-1320
• 68 Sheridan JP, Zhang Y, Riester K et al. Intermediate-affinity interleukin-2 receptor expression predicts CD56(bright) natural killer cell expansion after daclizumab treatment in the CHOICE study of patients with multiple sclerosis. Mult Scler 2011; 17: 1441-1448
• 69 Giovannoni G, Gold R, Selmaj K et al. A randomized, double-blind, Plazebo-controlled study to evaluate the safety and efficacy of daclizumab HYP monotherapy in relapsing-remitting multiple sclerosis: primary results of the SELECT trial. Multiple Sclerosis 2011; 17: S508
• 70 Klotz L, Meuth SG, Wiendl H. Immune mechanisms of new therapeutic strategies in multiple sclerosis – A focus on alemtuzumab. Clin Immunol 2011;
• 71 Coles AJ, Compston DA, Selmaj KW et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008; 359: 1786-1801
• 72 Jones JL, Anderson JM, Phuah CL et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 2010; 133: 2232-2247
• 73 Jones JL, Phuah CL, Cox AL et al. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest 2009; 119: 2052-2061
• 74 Coles A, Brinar V, Arnold DL et al. Efficacy and safety results from CARE-MS I, a phase III study comparing alemtuzumab and interferonβ-1a. Multiple Sclerosis 2011; 17: S510
• 75 Hirotani M, Niino M, Sasaki H. The role of B cells in multiple sclerosis: implications for B-cell-targeted therapy. Curr Med Chem 2010; 17: 3215-3222
• 76 Kappos L, Li D, Calabresi PA et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011; 378: 1779-1787
• 77 Kappos L, Li D, Calabresi P et al. Efficacy and safety of ocrelizumab in patients with relapsing-remitting multiple sclerosis: week 96 results of a phase II, randomised, multicentre trial. Multiple Sclerosis 2011; 17: S194
• 78 Kappos L, Hartung HP, Freedman MS et al. ATAMS: a randomised trial of the B-cell-targeting agent atacicept in patients with relapsing multiple sclerosis. Multiple Sclerosis 2011; 17: S40
• 79 Hartung HP, Kieseier BC. Atacicept: targeting B cells in multiple sclerosis. Ther Adv Neurol Disord 2010; 3: 205-216