Myasthenia gravis: Was gibt es Neues?

J. P. Sieb

doi:10.1055/s-0038-1627706

Nervenheilkunde, Inhaltsverzeichnis

Nervenheilkunde 2014; 33(07/08): 519-525
DOI: 10.1055/s-0038-1627706

Fortbildung Karlsruhe

Schattauer GmbH

Myasthenia gravis: Was gibt es Neues?

What’s new in myasthenia gravis?

J. P. Sieb

¹Neurologische Klinik, HELIOS Hanseklinikum Stralsund

› Institutsangaben

Abstract

Zusammenfassung

Der Begriff Myasthenia gravis umfasst eine heterogene Gruppe von Autoimmunerkrankungen mit einem postsynaptischen Defekt der neuromuskulären Signalübertragung. Eine Unterteilung ist möglich nach Antikörperspezifität (Acetylcholinrezeptor, MuSK, LRP4, seronegativ), Thymushistologie (Thymitis, Thymom, normal / Atrophie), Erkrankungsbeginn (vor oder nach dem 50. Lebensjahr) und Verlaufstyp (okulär, oropharyngeal, generalisiert). Die etablierten Therapieoptionen stehen seit Jahrzehnten zur Verfügung. Dies sind die Acetylcholinesteraseinhibition, die Immunsuppression mit einem Glukokortikosteroid und in der Dauertherapie Azathioprin, die Thymektomie und Krisenintervention mit einem Aphereseverfahren bzw. i.v.-Immunglobulinen. Möglicherweise wird sich mit der Einführung von monoklonalen Antikörpern das therapeutische Vorgehen maßgeblich ändern. Bereits heute sollte Rituximab bei generalisierten, therapierefraktären Krankheitsverläufen erwogen werden. Aussichtsreiche Kandidaten sind Belimumab, der die Ausdifferenzierung von B-Zellen hemmt, und Eculizumab, der an das Komplementprotein C5 bindet und die Komplementaktivierung hemmt.

Summary

This is an update on the diagnosis and treatment of myasthenia gravis. Today the term myasthenia gravis comprises a heterogeneous group of autoimmune diseases with a postsynaptic defect of neuromuscular transmission. These diseases can be classified according to antibody specificity (acetylcholine receptor, MuSK, LRP4, seronegative), thymus histology (thymitis, thymoma, normal/ atrophic), onset (before or after age 50) and course type (ocular, oropharyngeal, generalized). The established treatment options were already introduced decades ago. These are the acetylcholinesterase inhibition, prednisolone and azathioprine for the long-term immunosuppression, thymectomy and crisis intervention with an apheresis procedure or intravenous immunoglobulins. However, the introduction of monoclonal antibodies could substantially change the therapeutic approach in the forthcoming decade. Rituximab should already be considered in cases refractory to conventional treatment nowadays. Promising candidates are belimumab that inhibits the differentiation of B cells, and eculizumab, which binds to the complement protein C5 and hereby inhibits complement activation.

Schlüsselwörter

Acetylcholinrezeptor - Immunsuppression - Muskelschwäche - Thymektomie

Keywords

Acetylcholine receptor - immunosuppression - muscular weakness - thymectomy

Volltext

Referenzen

Literatur
1 Aarli JA. Herzmyasthenie: myasthenia of the heart. Arch Neurol 2009; 66: 1322-3.
2 Alkhawajah NM, Oger J. Late-onset myasthenia gravis: A review when incidence in older adults keeps increasing. Muscle Nerve 2013; 48: 705-10.
3 Baggi F. et al. Complete stable remission and autoantibody specificity in myasthenia gravis. Neurology 2013; 80: 188-95.
4 Behin A. et al. Severe neonatal myasthenia due to maternal anti-MuSK antibodies. Neuromuscul Disord 2008; 18: 443-6.
5 Bharat A. et al. Incidence and risk factors for progressive multifocal leukoencephalopathy among patients with selected rheumatic diseases. Arthrit Care Res (Hoboken) 2012; 64: 612-5.
6 Collongues C. et al. Rituximab in refractory and non-refractory myasthenia: A retrospective multicenter study. Muscle Nerve 2012; 46: 687-91.
7 Cortese I. et al. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2011; 76: 294-300.
8 De Lapiscina EH. et al. Myasthenia gravis: Sleep quality, quality of life, and disease severity. Muscle Nerve 2012; 46: 174-80.
9 Diaz-Manera J. et al. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology 2012; 78: 189-93.
10 Evoli A. et al. Response to therapy in myasthenia gravis with anti-MuSK antibodies. Ann N Y Acad Sci 2008; 1132: 76-83.
11 Farrugia ME. et al. MRI and clinical studies of facial and bulbar muscle involvement in MuSK antibody-associated myasthenia gravis. Brain 2006; 129: 1481-92.
12 Fee DB, Kasarskis EJ. Myasthenia gravis associated with etanercept therapy. Muscle Nerve 2009; 39: 866-70.
13 Gomez AM. et al. Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis. J Immunol 2011; 186: 2503-13.
14 Heckmann JM. et al. A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis. BMC Neurology 2011; 11: 97.
15 Hehir MK, Burns TM, Alpers J. et al. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis: outcomes in 102 patients. Muscle Nerve 2010; 41: 593-8.
16 Howard Jr JF, Barohn RJ, Cutter GR. et al. A randomized, double-blind, placebo-controlled Phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve 2013; 48: 76-84.
17 Jarius S, Paul F, Franciotta D. et al. Neuromyelitis optica spectrum disorders in patients with myasthenia gravis: ten new aquaporin-4 antibody positive cases and a review of the literature. Multiple Sclerosis 2012; 18: 1135-43.
18 Kassardjian CD, Murray BJ, Kokokyi S. et al. Effects of napping on neuromuscular fatigue in myasthenia gravis. Muscle Nerve 2013; 48: 816-8.
19 Katzberg HD, Barnett C, Bril V. Predictors of response to immunomodulation in patients with myasthenia gravis. Muscle Nerve 2012; 45: 648-52.
20 Kerkeni S, Marotte H, Miossec P. Improvement with rituximab in a patient with both rheumatoid arthritis and myasthenia gravis. Muscle Nerve 2008; 38: 1343-5.
21 Köhler W, Sieb JP. Myasthenia gravis, 4. Aufl. Bremen: UNI-MED; 2012
22 Koneczny I, Cossins J, Waters P. et al. MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters. PLoS One 2013; 08: e80695.
23 Leite MI. et al. Myasthenia gravis and neuromyelitis optica spectrum disorder: a multicenter study of 16 patients. Neurology 2012; 78: 1601-7.
24 Leite MI, Jacob S, Viegas S. et al. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 2008; 131: 1940-52.
25 Lindberg C, Bokarewa M. Rituximab for severe myasthenia gravis – experience from five patients. Acta Neurol Scand 2010; 122: 225-8.
26 Maddison P, McConville J, Farrugia ME. et al. The use of rituximab in myasthenia gravis and Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 2011; 82: 671-3.
27 Maggi L, Mantegazza R. Treatment of myasthenia gravis: focus on pyridostigmine. Clin Drug Investig 2011; 31: 691-701.
28 Matsuda M, Dohi-Iijima N, Nakamura A. et al. Increase in incidence of elderly-onset patients with myasthenia gravis in Nagano Prefecture, Japan. Intern Med 2005; 44: 572-7.
29 Molloy ES. PML and rheumatology: the contribution of disease and drugs. Clev Clin J Med 2011; 78 Suppl 2 S28-S32.
30 Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthritis Rheum 2012; 64: 3043-51.
31 Nelson Jr RP, Pascuzzi RM, Kessler K. et al. Rituximab for the treatment of thymoma-associated and de novo myasthenia gravis: 3 cases and review. J Clin Neuromuscul Dis 2009; 10: 170-7.
32 Niks EH, van Leeuwen Y, Leite MI. et al. Clinical fluctuations in MuSK myasthenia gravis are related to antigen-specific IgG4 instead of IgG1. J Neuroimmunol 2008; 195: 151-6.
33 Pakzad Z, Aziz T, Oger J. Increasing incidence of myasthenia gravis among elderly in British Columbia, Canada. Neurology 2011; 76: 1526-8.
34 Palazzo E, Yahia SA. Progressive multifocal leukoencephalopathy in autoimmune diseases. Joint Bone Spine 2012; 79: 351-5.
35 Pallaver F, Riviera AP, Piffer S. et al. Change in myasthenia gravis epidemiology in Trento, Italy, after twenty years. Neuroepidemiology 2011; 36: 282-7.
36 Pasnoor M, Wolfe GI, Nations S. et al. Clinical findings in MuSK-antibody positive myasthenia gravis: a U.S. experience. Muscle Nerve 2010; 41: 370-4.
37 Patwa HS, Chaudhry V, Katzberg H. et al. Evidence-based guideline: Intravenous immunoglobulin in the treatment of neuromuscular disorders: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2012; 78: 1009-15.
38 Pevzner A, Schoser B, Peters K. et al. Anti-LRP4 autoantibodies in AChRand MuSK-antibodynegative myasthenia gravis. J Neurol 2012; 259: 427-35.
39 Poulas K, Koutsouraki E, Kordas G. et al. AntiMuSKand anti-AChR-positive myasthenia gravis induced by d-penicillamine. J Neuroimmunol 2012; 250: 94-8.
40 Rowin J. Etanercept treatment in myasthenia gravis. Ann N Y Acad Sci 2008; 1132: 300-4.
41 Rowin J, Thiruppathi M, Arhebamen E. et al. Granulocyte macrophage colony-stimulating factor treatment of a patient in myasthenic crisis: effects on regulatory T cells. Muscle Nerve 2012; 46: 449-53.
42 Sanders DB, Hart IK, Mantegazza R. et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 2008; 71: 400-6.
43 Sieb JP. Myasthenia gravis: an update for the clinician. Clin Exp Immunol 2014; 175: 408-18.
44 Sieb JP, Köhler W. Benefits from sustained-release pyridostigmine bromide in myasthenia gravis: results of a prospective multicenter open-label trial. Clin Neurol Neurosurg 2010; 112: 781-4.
45 Spaggiari L, Casiraghi M, Guarize J. Multidisciplinary treatment of malignant thymoma. Curr Opin Oncol 2012; 24: 117-22.
46 Stein B, Bird SJ. Rituximab in the treatment of MuSK antibody-positive myasthenia gravis. J Clin Neuromuscul Dis 2011; 12: 163-4.
47 Stieglbauer K, Topakian R, Schäffer V. et al. Rituximab for myasthenia gravis: three case reports and review of the literature. J Neurol Sci 2009; 280: 120-2.
48 Sussman JD, Argov Z, McKee D. et al. Antisense treatment for myasthenia gravis: experience with monarsen. Ann N Y Acad Sci 2008; 1132: 283-90.
49 The Muscle Study Group. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 2008; 71: 394-9.
50 Tüzün E, Meriggioli MN, Rowin J. et al. Myasthenia gravis patients with low plasma IL-6 and IFNgamma benefit from etanercept treatment. J Autoimmun 2005; 24: 261-8.
51 Venuta F, Rendina EA, Anile M. et al. Thymoma and thymic carcinoma. Gen Thorac Cardiovasc Surg 2012; 60: 1-12.
52 Wu H, Xiong WC, Mei L. To build a synapse: signaling pathways in neuromuscular junction assembly. Development 2010; 137: 1017-33.
53 Yoshikawa H, Kiuchi T, Saida T. et al. Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry 2011; 82: 970-7.
54 Zebardast N, Patwa HS, Novella SP. et al. Rituximab in the management of refractory myasthenia gravis. Muscle Nerve 2010; 41: 375-8.
55 Zhang B, Tzartos JS, Belimezi M. et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol 2012; 69: 445-51.
56 Zivkovic SA, Clemens PR, Lacomis D. Characteristics of late-onset myasthenia gravis. J Neurol 2012; 259: 2167-71.