Refractory gMG

Patients with refractory generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive represent an ultra-rare segment of MG patients1-4 who continue to suffer from severe disease symptoms and complications despite therapies currently used for MG.1-2,11

MG is a debilitating, chronic and progressive autoimmune neuromuscular disease that typically begins with weakness in the muscles that control the movements of the eyeballs and eyelids, and often progresses to the more severe and generalized form, known as gMG, with weakness of the head, neck, trunk, limb and respiratory muscles. MG can occur at any age but most commonly begins for women before the age of 40 and men after the age of 60.2,6,9,12,13

While most gMG symptoms can be managed with existing MG therapies, 10-15% of patients are considered refractory—meaning they do not respond to multiple therapies for MG and continue to suffer profound muscle weakness and severe disease symptoms.1-2,11 Patients with refractory gMG can have difficulties walking, talking, swallowing and breathing normally. Exacerbations and complications of their disease may require hospitalization and can be life-threatening.5-7

In patients with anti-AChR antibody-positive gMG, the body’s immune system turns on itself to produce antibodies against AChR, a receptor that plays an important role in the communication between nerves and muscles.5-6 The binding of these antibodies to AChR activates the complement cascade, a part of the immune system, which leads to localized destruction of the neuromuscular junction. This impairs communication between nerve and muscle, leading to a loss of normal muscle function.8-10,14

References
1. Silvestri N, Wolfe G. Treatment-refractory myasthenia gravis. J. Clin Neuromuscul Dis. 2014;15(4):167-178.
2. Howard J. Targeting the Complement System in Refractory Myasthenia Gravis. Supplement to Neurology Reviews. February 2016.
3. Suh J., Goldstein JM, Nowak RJ. Clinical Characteristics of Refractory Myasthenia Gravis Patients. Yale J Biol Med. 2013;86(2):255-260.
4. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32000R0141&qid=1421232987002&from=EN. Accessed on June 26, 2017.
5. Howard 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(1):76-84.
6. National Institute of Neurological Disorders and Stroke. Myasthenia Gravis Fact Sheet. Publication date May 2017. http://www.ninds.nih.gov/disorders/myasthenia_gravis/detail_myasthenia_gravis.htm.
7. Sathasivam S. Diagnosis and management of myasthenia gravis. Progress in Neurology and Psychiatry. January/February 2014.
8. Tüzün E, Huda R, Christadoss P. Complement and cytokine based therapeutic strategies in myasthenia gravis. JAutoimmun. 2011;37(2):136-143.
9. Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev. Clin.Immunol. 2012;8(5), 427-428.
10. Conti-Fine, et al. Myasthenia gravis: past, present, and future. J Clin Invest. 2006; 116:2843-2354.
11. Sanders DB, Wolfe, GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87(4):419-25.
12. Huda R, Tüzün E, Christadoss P. Targeting complement system to treat myasthenia gravis. Rev. Neurosci. 2014; 25(4): 575–583.
13. Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009-8(5): 475-490.
14. Buzzard, K. A., N. J. Meyer, T. A. Hardy, D. S. Riminton and S. W. Reddel. Induction intravenous cyclophosphamide followed by maintenance oral immunosuppression in refractory myasthenia gravis. Muscle Nerve. 2015;52(2): 204-210.