Emerging Therapeutics for Myasthenia Gravis

  • Anna Rostedt Punga
  • Henry J. Kaminski
  • Jeffrey T. Guptill
Part of the Current Clinical Neurology book series (CCNEU)


At no time in the history of myasthenia gravis has there been a time of greater therapeutic development. This situation likely stems from the well-defined pathophysiology of MG, which has made target identification relatively straightforward for drug development in the pharmaceutical industry and academic laboratories. Financial incentives to develop therapies for rare diseases have also been a positive factor. The present review assesses conventional treatments and drugs in preclinical and clinical trials.


Azathioprine Complement Eculizumab EN101 Fc receptor Mycophenolate Prednisone Rituximab Tacrolimus 


  1. 1.
    Skeie GO, Apostolski S, Evoli A, Gilhus NE, Illa I, Harms L, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol. 2010;17:893–902.PubMedCrossRefGoogle Scholar
  2. 2.
    Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016;87:419–25.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Punga AR, Sawada M, Stalberg EV. Electrophysiological signs and the prevalence of adverse effects of acetylcholinesterase inhibitors in patients with myasthenia gravis. Muscle Nerve. 2008;37:300–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Evoli A, Bianchi MR, Riso R, Minicuci GM, Batocchi AP, Servidei S, et al. Response to therapy in myasthenia gravis with anti-MuSK antibodies. Ann N Y Acad Sci. 2008;1132:76–83.PubMedCrossRefGoogle Scholar
  5. 5.
    Evoli A, Tonali PA, Padua L, Monaco ML, Scuderi F, Batocchi AP, et al. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain. 2003;126:2304–11.PubMedCrossRefGoogle Scholar
  6. 6.
    Punga AR, Flink R, Askmark H, Stalberg EV. Cholinergic neuromuscular hyperactivity in patients with myasthenia gravis seropositive for MuSK antibody. Muscle Nerve. 2006;34:111–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Liewluck T, Selcen D, Engel AG. Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and Dok-7 myasthenia. Muscle Nerve. 2011;44:789–94.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Gallenmuller C, Muller-Felber W, Dusl M, Stucka R, Guergueltcheva V, Blaschek A, et al. Salbutamol-responsive limb-girdle congenital myasthenic syndrome due to a novel missense mutation and heteroallelic deletion in MUSK. Neuromuscul Disord. 2014;24:31–5.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Hinkle RT, Hodge KM, Cody DB, Sheldon RJ, Kobilka BK, Isfort RJ. Skeletal muscle hypertrophy and anti-atrophy effects of clenbuterol are mediated by the beta2-adrenergic receptor. Muscle Nerve. 2002;25:729–34.PubMedCrossRefGoogle Scholar
  10. 10.
    Ghazanfari N, Morsch M, Tse N, Reddel SW, Phillips WD. Effects of the ss2-adrenoceptor agonist, albuterol, in a mouse model of anti-MuSK myasthenia gravis. PLoS One. 2014;9:e87840.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Barnes PJ. Molecular mechanisms of corticosteroids in allergic diseases. Allergy. 2001;56:928–36.PubMedCrossRefGoogle Scholar
  12. 12.
    Howard FM Jr, Duane DD, Lambert EH, Daube JR. Alternate-day prednisone: preliminary report of a double-blind controlled study. Ann N Y Acad Sci. 1976;274:596–607.PubMedCrossRefGoogle Scholar
  13. 13.
    Lindberg C, Andersen O, Lefvert AK. Treatment of myasthenia gravis with methylprednisolone pulse: a double blind study. Acta Neurol Scand. 1998;97:370–3.PubMedCrossRefGoogle Scholar
  14. 14.
    Pascuzzi RM, Coslett HB, Johns TR. Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol. 1984;15:291–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Wilson RW, Ward MD, Johns TR. Corticosteroids: a direct effect at the neuromuscular junction. Neurology. 1974;24:1091–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Elion GB. Significance of azathioprine metabolites. Proc R Soc Med. 1972;65:257–60.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Abramsky O, Tarrab-Hazdai R, Aharonov A, Fuchs S. Immunosuppression of experimental autoimmune myasthenia gravis by hydrocortisone and azathioprine. J Immunol. 1976;117:225–8.PubMedGoogle Scholar
  18. 18.
    Lewis RA, Selwa JF, Lisak RP. Myasthenia gravis: immunological mechanisms and immunotherapy. Ann Neurol. 1995;37(Suppl 1):S51–62.PubMedCrossRefGoogle Scholar
  19. 19.
    Kronke M, Leonard WJ, Depper JM, Arya SK, Wong-Staal F, Gallo RC, et al. Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci U S A. 1984;81:5214–8.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Matsuda S, Moriguchi T, Koyasu S, Nishida E. T lymphocyte activation signals for interleukin-2 production involve activation of MKK6-p38 and MKK7-SAPK/JNK signaling pathways sensitive to cyclosporin A. J Biol Chem. 1998;273:12378–82.PubMedCrossRefGoogle Scholar
  21. 21.
    Tindall RS, Phillips JT, Rollins JA, Wells L, Hall K. A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann N Y Acad Sci. 1993;681:539–51.PubMedCrossRefGoogle Scholar
  22. 22.
    Sanders DB, Evoli A. Immunosuppressive therapies in myasthenia gravis. Autoimmunity. 2010;43:428–35.PubMedCrossRefGoogle Scholar
  23. 23.
    Nagaishi A, Yukitake M, Kuroda Y. Long-term treatment of steroid-dependent myasthenia gravis patients with low-dose tacrolimus. Intern Med. 2008;47:731–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Shimojima Y, Matsuda M, Gono T, Ishii W, Tokuda T, Ikeda S. Tacrolimus in refractory patients with myasthenia gravis: coadministration and tapering of oral prednisolone. J Clin Neurosci. 2006;13:39–44.PubMedCrossRefGoogle Scholar
  25. 25.
    Allison AC, Kowalski WJ, Muller CD, Eugui EM. Mechanisms of action of mycophenolic acid. Ann N Y Acad Sci. 1993;696:63–87.PubMedCrossRefGoogle Scholar
  26. 26.
    Meriggioli MN, Rowin J. Single fiber EMG as an outcome measure in myasthenia gravis: results from a double-blind, placebo-controlled trial. J Clin Neurophysiol. 2003;20:382–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Haberal M, Karakayali H, Emiroglu R, Basaran O, Moray G, Bilgin N. Malignant tumors after renal transplantation. Artif Organs. 2002;26:778–81.PubMedCrossRefGoogle Scholar
  28. 28.
    Perez MC, Buot WL, Mercado-Danguilan C, Bagabaldo ZG, Renales LD. Stable remissions in myasthenia gravis. Neurology. 1981;31:32–7.PubMedCrossRefGoogle Scholar
  29. 29.
    NINDS. Common data elements: Myasthenia Gravis [online]. Accessed 10 Apr 2017.
  30. 30.
    Fulvio B, Mantegazza R. European database for myasthenia gravis: a model for an international disease registry. Neurology. 2014;83:189–91.PubMedCrossRefGoogle Scholar
  31. 31.
    Myasthenia Gravis Foundation of America. MG Patient Registry [online]. Accessed 10 Apr 2017.
  32. 32.
    Hiepe F, Radbruch A. Plasma cells as an innovative target in autoimmune disease with renal manifestations. Nat Rev Nephrol. 2016;12:232–40.PubMedCrossRefGoogle Scholar
  33. 33.
    Willcox HN, Newsom-Davis J, Calder LR. Cell types required for anti-acetylcholine receptor antibody synthesis by cultured thymocytes and blood lymphocytes in myasthenia gravis. Clin Exp Immunol. 1984;58:97–106.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Vincent A. Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol. 2002;2:797–804.PubMedCrossRefGoogle Scholar
  35. 35.
    Liu Y, Wang W, Li J. Evaluation of serum IgG subclass concentrations in myasthenia gravis patients. Int J Neurosci. 2011;121:570–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Niks EH, van Leeuwen Y, Leite MI, Dekker FW, Wintzen AR, Wirtz PW, et al. Clinical fluctuations in MuSK myasthenia gravis are related to antigen-specific IgG4 instead of IgG1. J Neuroimmunol. 2008;195:151–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Guptill JT, Oakley D, Kuchibhatla M, Guidon AC, Hobson-Webb LD, Massey JM, et al. A retrospective study of complications of therapeutic plasma exchange in myasthenia. Muscle Nerve. 2013;47:170–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Kane RC, Farrell AT, Sridhara R, Pazdur R. United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res. 2006;12:2955–60.PubMedCrossRefGoogle Scholar
  39. 39.
    Bontscho J, Schreiber A, Manz RA, Schneider W, Luft FC, Kettritz R. Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis. JASN. 2011;22:336–48.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med. 2008;14:748–55.PubMedCrossRefGoogle Scholar
  41. 41.
    Gomez AM, Willcox N, Vrolix K, Hummel J, Nogales-Gadea G, Saxena A, et al. Proteasome inhibition with bortezomib depletes plasma cells and specific autoantibody production in primary thymic cell cultures from early-onset myasthenia gravis patients. J Immunol. 2014;193:1055–63.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Gomez AM, Vrolix K, Martinez-Martinez P, Molenaar PC, Phernambucq M, van der Esch E, et al. Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis. J Immunol. 2011;186:2503–13.PubMedCrossRefGoogle Scholar
  43. 43.
    Hiepe F. Therapy of antibody-mediated autoimmune diseases by bortezomib (TAVAB) [online]. Accessed 18 Apr 2017.
  44. 44.
    Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754–66.PubMedCrossRefGoogle Scholar
  45. 45.
    Moreau P, van de Donk NW, San Miguel J, Lokhorst H, Nahi H, Ben-Yehuda D, et al. Practical considerations for the use of daratumumab, a novel CD38 monoclonal antibody, in myeloma. Drugs. 2016;76:853–67.PubMedCrossRefGoogle Scholar
  46. 46.
    Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ, et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res. 2011;17:2734–43.PubMedCrossRefGoogle Scholar
  47. 47.
    Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431–40.PubMedCrossRefGoogle Scholar
  48. 48.
    Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384–94.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Thiruppathi M, Rowin J, Ganesh B, Sheng JR, Prabhakar BS, Meriggioli MN. Impaired regulatory function in circulating CD4(+)CD25(high)CD127(low/-) T cells in patients with myasthenia gravis. Clin Immunol. 2012;145:209–23.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Cao Y, Amezquita RA, Kleinstein SH, Stathopoulos P, Nowak RJ, O’Connor KC. Autoreactive T cells from patients with myasthenia gravis are characterized by elevated IL-17, IFN-gamma, and GM-CSF and diminished IL-10 production. J Immunol. 2016;196:2075–84.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Gomez AM, Willcox N, Molenaar PC, Buurman W, Martinez-Martinez P, De Baets MH, et al. Targeting plasma cells with proteasome inhibitors: possible roles in treating myasthenia gravis? Ann N Y Acad Sci. 2012;1274:48–59.PubMedCrossRefGoogle Scholar
  52. 52.
    Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–32.PubMedCrossRefGoogle Scholar
  53. 53.
    Waite JC, Skokos D. Th17 response and inflammatory autoimmune diseases. Int J Inflamm. 2012;2012:819467.CrossRefGoogle Scholar
  54. 54.
    Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Aguilo-Seara G, Xie Y, Sheehan J, Kusner LL, Kaminski HJ. Ablation of IL-17 expression moderates experimental autoimmune myasthenia gravis disease severity. Cytokine. 2017;96:279–85.PubMedCrossRefGoogle Scholar
  56. 56.
    Schaffert H, Pelz A, Saxena A, Losen M, Meisel A, Thiel A, et al. IL-17-producing CD4(+) T cells contribute to the loss of B-cell tolerance in experimental autoimmune myasthenia gravis. Eur J Immunol. 2015;45:1339–47.PubMedCrossRefGoogle Scholar
  57. 57.
    Mu LL, Sun B, Kong QF, Wang J, Wang G, Zhang S, et al. Disequilibrium of T helper type 1, 2 and 17 cells and regulatory T cells during the development of experimental autoimmune myasthenia gravis. Immunology. 2009;128:e826–36.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Roche JC, Capablo JL, Larrad L, Gervas-Arruga J, Ara JR, Sánchez A, et al. Increased serum interleukin-17 levels in patients with myasthenia gravis. Muscle Nerve. 2011;44:278–80.PubMedCrossRefGoogle Scholar
  59. 59.
    Gradolatto A, Nazzal D, Truffault F, Bismuth J, Fadel E, Foti M, et al. Both Treg cells and Tconv cells are defective in the myasthenia gravis thymus: roles of IL-17 and TNF-alpha. J Autoimmun. 2014;52:53–63. Epub 2014 Jan 7.PubMedCrossRefGoogle Scholar
  60. 60.
    Xie Y, Li HF, Jiang B, Li Y, Kaminski HJ, Kusner LL. Elevated plasma interleukin-17A in a subgroup of myasthenia gravis patients. Cytokine. 2016;78:44–6.PubMedCrossRefGoogle Scholar
  61. 61.
    Yi JS, Guidon A, Sparks S, Osborne R, Juel VC, Massey JM, et al. Characterization of CD4 and CD8 T cell responses in MuSK myasthenia gravis. J Autoimmun. 2014;52:130–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Pinelli DF, Ford ML. Novel insights into anti-CD40/CD154 immunotherapy in transplant tolerance. Immunotherapy. 2015;7:399–410.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Chen J, Yin H, Xu J, Wang Q, Edelblum KL, Sciammas R, et al. Reversing endogenous alloreactive B cell GC responses with anti-CD154 or CTLA-4Ig. Am J Transplant. 2013;13:2280–92.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Im SH, Barchan D, Maiti PK, Fuchs S, Souroujon MC. Blockade of CD40 ligand suppresses chronic experimental myasthenia gravis by down-regulation of Th1 differentiation and up-regulation of CTLA-4. J Immunol. 2001;166:6893–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S. Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood. 2005;105:735–41.PubMedCrossRefGoogle Scholar
  66. 66.
    Sheng JR, Li L, Ganesh BB, Vasu C, Prabhakar BS, Meriggioli MN. Suppression of experimental autoimmune myasthenia gravis by granulocyte-macrophage colony-stimulating factor is associated with an expansion of FoxP3+ regulatory T cells. J Immunol. 2006;177:5296–306.PubMedCrossRefGoogle Scholar
  67. 67.
    Sheng JR, Li LC, Ganesh BB, Prabhakar BS, Meriggioli MN. Regulatory T cells induced by GM-CSF suppress ongoing experimental myasthenia gravis. Clin Immunol. 2008;128:172–80.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Sheng JR, Muthusamy T, Prabhakar BS, Meriggioli MN. GM-CSF-induced regulatory T cells selectively inhibit anti-acetylcholine receptor-specific immune responses in experimental myasthenia gravis. J Neuroimmunol. 2011;240-241:65–73.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Rowin J, Thiruppathi M, Arhebamen E, Sheng J, Prabhakar BS, Meriggioli MN. Granulocyte macrophage colony-stimulating factor treatment of a patient in myasthenic crisis: effects on regulatory T cells. Muscle Nerve. 2012;46:449–53.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Monson NL, Cravens PD, Frohman EM, Hawker K, Racke MK. Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol. 2005;62:258–64.PubMedCrossRefGoogle Scholar
  71. 71.
    Robeson KR, Kumar A, Keung B, DiCapua DB, Grodinsky E, Patwa HS, et al. Durability of the rituximab response in acetylcholine receptor autoantibody-positive myasthenia gravis. JAMA Neurol. 2017;74:60–6.PubMedCrossRefGoogle Scholar
  72. 72.
    Diaz-Manera J, Martinez-Hernandez E, Querol L, Klooster R, Rojas-García R, Suárez-Calvet X, et al. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology. 2012;78:189–93.PubMedCrossRefGoogle Scholar
  73. 73.
    Baek WS, Bashey A, Sheean GL. Complete remission induced by rituximab in refractory, seronegative, muscle-specific, kinase-positive myasthenia gravis. J Neurol Neurosurg Psychiatry. 2007;78:771.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Hain B, Jordan K, Deschauer M, Zierz S. Successful treatment of MuSK antibody-positive myasthenia gravis with rituximab. Muscle Nerve. 2006;33:575–80.PubMedCrossRefGoogle Scholar
  75. 75.
    Lisak RP, Ragheb S. The role of B cell-activating factor in autoimmune myasthenia gravis. Ann N Y Acad Sci. 2012;1274:60–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Kim JY, Yang Y, Moon JS, Lee EY, So SH, Lee HS, et al. Serum BAFF expression in patients with myasthenia gravis. J Neuroimmunol. 2008;199:151–4.PubMedCrossRefGoogle Scholar
  77. 77.
    Berrih-Aknin S, Ragheb S, Le Panse R, Lisak RP. Ectopic germinal centers, BAFF and anti-B-cell therapy in myasthenia gravis. Autoimmun Rev. 2013;12:885–93.PubMedCrossRefGoogle Scholar
  78. 78.
    Avidan N, Le Panse R, Harbo HF, Bernasconi P, Poulas K, Ginzburg E, et al. VAV1 and BAFF, via NFkappaB pathway, are genetic risk factors for myasthenia gravis. Ann Clin Transl Neurol. 2014;1:329–39.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Ibtehaj N, Huda R. High-dose BAFF receptor specific mAb-siRNA conjugate generates Fas-expressing B cells in lymph nodes and high-affinity serum autoantibody in a myasthenia mouse model. Clin Immunol. 2017;176:122–30.PubMedCrossRefGoogle Scholar
  80. 80.
    Bongioanni P, Ricciardi R, Pellegrino D, Romano MR. T-cell tumor necrosis factor-alpha receptor binding in myasthenic patients. J Neuroimmunol. 1999;93:203–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Li H, Shi FD, Bai X, Huang Y, Diab A, He B, et al. Cytokine and chemokine mRNA expressing cells in muscle tissues of experimental autoimmune myasthenia gravis. J Neurol Sci. 1998;161:40–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Rowin J, Meriggioli MN, Tuzun E, Leurgans S, Christadoss P. Etanercept treatment in corticosteroid-dependent myasthenia gravis. Neurology. 2004;63:2390–2.PubMedCrossRefGoogle Scholar
  83. 83.
    Tuzun E, Meriggioli MN, Rowin J, Yang H, Christadoss P. Myasthenia gravis patients with low plasma IL-6 and IFN-gamma benefit from etanercept treatment. J Autoimmun. 2005;24:261–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Christadoss P, Goluszko E. Treatment of experimental autoimmune myasthenia gravis with recombinant human tumor necrosis factor receptor Fc protein. J Neuroimmunol. 2002;122:186–90.PubMedCrossRefGoogle Scholar
  85. 85.
    Fee DB, Kasarskis EJ. Myasthenia gravis associated with etanercept therapy. Muscle Nerve. 2009;39:866–70.PubMedCrossRefGoogle Scholar
  86. 86.
    Strober J, Cowan MJ, Horn BN. Allogeneic hematopoietic cell transplantation for refractory myasthenia gravis. Arch Neurol. 2009;66:659–61.PubMedCrossRefGoogle Scholar
  87. 87.
    Bryant A, Atkins H, Pringle CE, Allan D, Anstee G, Bence-Bruckler I, et al. Myasthenia gravis treated with autologous hematopoietic stem cell transplantation. JAMA Neurol. 2016;73:652–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Hakansson I, Sandstedt A, Lundin F, Askmark H, Pirskanen R, Carlson K, et al. Successful autologous haematopoietic stem cell transplantation for refractory myasthenia gravis—a case report. Neuromuscul Disord. 2017;27:90–3.PubMedCrossRefGoogle Scholar
  89. 89.
    Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest. 2006;116:2843–54.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Christadoss P. C5 gene influences the development of murine myasthenia gravis. J Immunol. 1988;140:2589–92.PubMedGoogle Scholar
  91. 91.
    Kusner LL, Satija N, Cheng G, Kaminski HJ. Targeting therapy to the neuromuscular junction: proof of concept. Muscle Nerve. 2014;49:749–56.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Tuzun E, Scott BG, Goluszko E, Higgs S, Christadoss P. Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis. J Immunol. 2003;171:3847–54.PubMedCrossRefGoogle Scholar
  93. 93.
    Biesecker G, Gomez CM. Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6. J Immunol. 1989;142:2654–9.PubMedGoogle Scholar
  94. 94.
    Piddlesden SJ, Jiang S, Levin JL, Vincent A, Morgan BP. Soluble complement receptor 1 (sCR1) protects against experimental autoimmune myasthenia gravis. J Neuroimmunol. 1996;71:173–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Morgan BP, Harris CL. Complement, a target for therapy in inflammatory and degenerative diseases. Nat Rev Drug Discov. 2015;14:857–77.PubMedCrossRefGoogle Scholar
  96. 96.
    Zhou Y, Gong B, Lin F, Rother RP, Medof ME, Kaminski HJ. Anti-C5 antibody treatment ameliorates weakness in experimentally acquired myasthenia gravis. J Immunol. 2007;179:8562–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Howard JF Jr, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017;16(12):976–86.PubMedCrossRefGoogle Scholar
  98. 98.
    Fredslund F, Laursen NS, Roversi P, Jenner L, Oliveira CL, Pedersen JS, et al. Structure of and influence of a tick complement inhibitor on human complement component 5. Nat Immunol. 2008;9:753–60.PubMedCrossRefGoogle Scholar
  99. 99.
    Soltys J, Kusner LL, Young A, Richmonds C, Hatala D, Gong B, et al. Novel complement inhibitor limits severity of experimentally myasthenia gravis. Ann Neurol. 2009;65:67–75.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Subias M, Tortajada A, Gastoldi S, Galbusera M, López-Perrote A, Lopez Lde J, et al. A novel antibody against human factor B that blocks formation of the C3bB proconvertase and inhibits complement activation in disease models. J Immunol. 2014;193:5567–75.PubMedCrossRefGoogle Scholar
  101. 101.
    Huda R, Tuzun E, Christadoss P. Complement C2 siRNA mediated therapy of myasthenia gravis in mice. J Autoimmun. 2013;42:94–104.PubMedCrossRefGoogle Scholar
  102. 102.
    Song C, Xu Z, Miao J, Xu J, Wu X, Zhang F, et al. Protective effect of scFv-DAF fusion protein on the complement attack to acetylcholine receptor: a possible option for treatment of myasthenia gravis. Muscle Nerve. 2012;45:668–75.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Brenner T, Hamra-Amitay Y, Evron T, Boneva N, Seidman S, Soreq H. The role of readthrough acetylcholinesterase in the pathophysiology of myasthenia gravis. FASEB J. 2003;17:214–22.PubMedCrossRefGoogle Scholar
  104. 104.
    Argov Z, McKee D, Agus S, Brawer S, Shlomowitz N, Yoseph OB, et al. Treatment of human myasthenia gravis with oral antisense suppression of acetylcholinesterase. Neurology. 2007;69:699–700.PubMedCrossRefGoogle Scholar
  105. 105.
    Luo J, Lindstrom J. AChR-specific immunosuppressive therapy of myasthenia gravis. Biochem Pharmacol. 2015;97:609–19.PubMedCrossRefGoogle Scholar
  106. 106.
    Bartfeld D, Fuchs S. Specific immunosuppression of experimental autoimmune myasthenia gravis by denatured acetylcholine receptor. Proc Natl Acad Sci U S A. 1978;75:4006–10.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Ma CG, Zhang GX, Xiao BG, Link J, Olsson T, Link H. Suppression of experimental autoimmune myasthenia gravis by nasal administration of acetylcholine receptor. J Neuroimmunol. 1995;58:51–60.PubMedCrossRefGoogle Scholar
  108. 108.
    Okumura S, McIntosh K, Drachman DB. Oral administration of acetylcholine receptor: effects on experimental myasthenia gravis. Ann Neurol. 1994;36:704–13.PubMedCrossRefGoogle Scholar
  109. 109.
    Wang ZY, Qiao J, Link H. Suppression of experimental autoimmune myasthenia gravis by oral administration of acetylcholine receptor. J Neuroimmunol. 1993;44:209–14.PubMedCrossRefGoogle Scholar
  110. 110.
    Luo J, Kuryatov A, Lindstrom JM. Specific immunotherapy of experimental myasthenia gravis by a novel mechanism. Ann Neurol. 2010;67:441–51.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Luo J, Lindstrom J. Antigen-specific immunotherapeutic vaccine for experimental autoimmune myasthenia gravis. J Immunol. 2014;193:5044–55.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Araga S, Blalock JE. Use of complementary peptides and their antibodies in B-cell-mediated autoimmune disease: prevention of experimental autoimmune myasthenia gravis with a peptide vaccine. ImmunoMethods. 1994;5:130–5.PubMedCrossRefGoogle Scholar
  113. 113.
    Araga S, LeBoeuf RD, Blalock JE. Prevention of experimental autoimmune myasthenia gravis by manipulation of the immune network with a complementary peptide for the acetylcholine receptor. Proc Natl Acad Sci U S A. 1993;90:8747–51.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Araga S, Xu L, Nakashima K, Villain M, Blalock JE. A peptide vaccine that prevents experimental autoimmune myasthenia gravis by specifically blocking T cell help. FASEB J. 2000;14:185–96.PubMedCrossRefGoogle Scholar
  115. 115.
    Galin FS, Chrisman CL, Cook JR Jr, Xu L, Jackson PL, Noerager BD, et al. Possible therapeutic vaccines for canine myasthenia gravis: implications for the human disease and associated fatigue. Brain Behav Immun. 2007;21:323–31.PubMedCrossRefGoogle Scholar
  116. 116.
    Shelton GD, Lindstrom JM. Spontaneous remission in canine myasthenia gravis: implications for assessing human MG therapies. Neurology. 2001;57:2139–41.PubMedCrossRefGoogle Scholar
  117. 117.
    Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715–25.PubMedCrossRefGoogle Scholar
  118. 118.
    Liu L, Garcia AM, Santoro H, Zhang Y, McDonnell K, Dumont J, et al. Amelioration of experimental autoimmune myasthenia gravis in rats by neonatal FcR blockade. J Immunol. 2007;178:5390–8.PubMedCrossRefGoogle Scholar
  119. 119.
    UCB. UCB First Three Months Interim Report 2017: UCB with a good start into 2017; 2017.Google Scholar
  120. 120.
    Argenx. ARGX-113 [online]. Accessed 8 May 2017.
  121. 121.
    Thiruppathi M, Sheng JR, Li L, Prabhakar BS, Meriggioli MN. Recombinant IgG2a Fc (M045) multimers effectively suppress experimental autoimmune myasthenia gravis. J Autoimmun. 2014;52:64–73.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Somnier FE, Langvad E. Plasma exchange with selective immunoadsorption of anti-acetylcholine receptor antibodies. J Neuroimmunol. 1989;22:123–7.PubMedCrossRefGoogle Scholar
  123. 123.
    Ptak J. Changes of plasma proteins after immunoadsorption using Ig-Adsopak columns in patients with myasthenia gravis. Transfus Apher Sci. 2004;30:125–9.PubMedCrossRefGoogle Scholar
  124. 124.
    Antozzi C, Berta E, Confalonieri P, Zuffi M, Cornelio F, Mantegazza R. Protein-A immunoadsorption in immunosuppression-resistant myasthenia gravis. Lancet. 1994;343:124.PubMedCrossRefGoogle Scholar
  125. 125.
    Grob D, Simpson D, Mitsumoto H, Hoch B, Mokhtarian F, Bender A, et al. Treatment of myasthenia gravis by immunoadsorption of plasma. Neurology. 1995;45:338–44.PubMedCrossRefGoogle Scholar
  126. 126.
    Lagoumintzis G, Zisimopoulou P, Kordas G, Lazaridis K, Poulas K, Tzartos SJ. Recent approaches to the development of antigen-specific immunotherapies for myasthenia gravis. Autoimmunity. 2010;43:436–45.PubMedCrossRefGoogle Scholar
  127. 127.
    Lagoumintzis G, Zisimopoulou P, Trakas N, Grapsa E, Poulas K, Tzartos SJ. Scale up and safety parameters of antigen specific immunoadsorption of human anti-acetylcholine receptor antibodies. J Neuroimmunol. 2014;267:1–6.PubMedCrossRefGoogle Scholar
  128. 128.
    Lazaridis K, Evaggelakou P, Bentenidi E, Sideri A, Grapsa E, Tzartos SJ. Specific adsorbents for myasthenia gravis autoantibodies using mutants of the muscle nicotinic acetylcholine receptor extracellular domains. J Neuroimmunol. 2015;278:19–25.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Anna Rostedt Punga
    • 1
  • Henry J. Kaminski
    • 2
  • Jeffrey T. Guptill
    • 3
  1. 1.Clinical NeurophysiologyUppsala University HospitalUppsalaSweden
  2. 2.Department of NeurologyThe George Washington UniversityWashington, DCUSA
  3. 3.Department of NeurologyDuke University Medical CenterDurhamUSA

Personalised recommendations