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Myasthenia gravis — autoantibody characteristics and their implications for therapy

Key Points

  • The characteristic muscle weakness in myasthenia gravis (MG) is caused by antibodies directed against the neuromuscular junction

  • MG is divided into subgroups on the basis of specific antibodies, other biomarkers, and clinical characteristics, such as age of onset, presence of thymoma, and involvement of ocular muscles

  • The most common antibodies detected in MG are antibodies against acetylcholine receptors (AChRs), muscle-specific kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4)

  • Additional antibodies of interest in MG are directed against agrin, titin, KV1.4, ryanodine receptors, collagen Q, and cortactin

  • Therapy should be tailored to the individual patient and guided by MG subgroup, and can include symptomatic drug therapy, immunosuppressive drug therapy, thymectomy and/or supportive therapy

  • The aim of treatment should be normal or near-normal function, which in most patients requires long-term immunosuppressive treatment with a drug combination that is individualized for the patient for optimal effectiveness

Abstract

Myasthenia gravis (MG) is an autoimmune disorder caused by autoantibodies that target the neuromuscular junction, leading to muscle weakness and fatigability. Currently available treatments for the disease include symptomatic pharmacological treatment, immunomodulatory drugs, plasma exchange, thymectomy and supportive therapies. Different autoantibody patterns and clinical manifestations characterize different subgroups of the disease: early-onset MG, late-onset MG, thymoma MG, muscle-specific kinase MG, low-density lipoprotein receptor-related protein 4 MG, seronegative MG, and ocular MG. These subtypes differ in terms of clinical characteristics, disease pathogenesis, prognosis and response to therapies. Patients would, therefore, benefit from treatment that is tailored to their disease subgroup, as well as other possible disease biomarkers, such as antibodies against cytoplasmic muscle proteins. Here, we discuss the different MG subtypes, the sensitivity and specificity of the various antibodies involved in MG for distinguishing between these subtypes, and the value of antibody assays in guiding optimal therapy. An understanding of these elements should be useful in determining how to adapt existing therapies to the requirements of each patient.

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Figure 1: Neuromuscular junction in myasthenia gravis (MG).

References

  1. 1

    Gilhus, N. E. Myasthenia and neuromuscular junction. Curr. Opin. Neurol. 25, 523–529 (2012).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Querol, L. & Illa, I. Myasthenia and the neuromuscular junction. Curr. Opin. Neurol. 26, 459–465 (2013).

    Article  PubMed  Google Scholar 

  3. 3

    Verschuuren, J. J.G. M. et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase, and low-density lipoprotein receptor-related protein 4. Autoimmune Rev. 12, 918–923 (2013).

    CAS  Article  Google Scholar 

  4. 4

    Gilhus, N. E. & Verschuuren, J. J. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 14, 1023–1036 (2015).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Heldal, A. T., Owe, J. F., Gilhus, N. E. & Romi, F. Seropositive myasthenia gravis; a nationwide epidemiologic study. Neurology 73, 150–151 (2009).

    Article  PubMed  Google Scholar 

  6. 6

    Carr, A. S. et al. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol. 10, 46 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Owe, J. F., Daltveit, A. K. & Gilhus, N. E. Causes of death among patients with myasthenia gravis in Norway between 1951 and 2001. J. Neurol. Neurosurg. Psychiatry 77, 203–207 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Skeie, G. O. et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur. J. Neurol. 17, 893–902 (2010).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Otsuka, K. et al. Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signalling. Sci. Rep. 5, 13928 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Messeant, J. et al. MuSK frizzled-like domain is critical for mammalian neuromuscular junction formation and maintenance. J. Neurosci. 35, 4926–4941 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Zisimopoulou, P., Brenner, T., Trakas, N. & Tzartos, S. J. Serological diagnostics in myasthenia gravis based on novel assays and recently identified antigens. Autoimmune Rev. 12, 924–930 (2013).

    CAS  Google Scholar 

  12. 12

    Romi, F., Skeie, G. O., Gilhus, N. E. & Aarli, J. A. Striational antibodies in myasthenia gravis; reactivity and possible clinical significance. Arch. Neurol. 62, 442–446 (2005).

    Article  PubMed  Google Scholar 

  13. 13

    Romi, F., Aarli, J. A. & Gilhus, N. E. Myasthenia gravis patients with ryanodine receptor antibodies have distinctive clinical features. Eur. J. Neurol. 14, 617–620 (2007).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Suzuki, S. et al. Autoimmune targets of heart and skeletal muscles in myasthenia gravis. Arch. Neurol. 66, 1334–1338 (2009).

    Article  PubMed  Google Scholar 

  15. 15

    Leite, M. I. et al. IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis. Brain 131, 1940–1952 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Tsonis, A. I. et al. MuSK autoantibodies in myasthenia gravis detected by cell-based assay: a multinational study. J. Neuroimmunol. 284, 10–17 (2015).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Unwin, N. Refined structure of the nicotinic acetylcholine receptor at 4 Å resolution. J. Mol. Biol. 346, 967–989 (2005).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Kordas, G. et al. Direct proof of the in vivo pathogenic role of the AChR autoantibodies from myasthenia gravis patients. PLoS ONE 9, e108327 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Heldal, A. T., Eide, G. E., Romi, F., Owe, J. F. & Gilhus, N. E. Repeated acetylcholine receptor antibody-concentrations and association to clinical myasthenia gravis development. PLoS ONE 9, e114060 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Yang, L. et al. Non-radioactive serological diagnosis of myasthenia gravis and clinical features of patients from Tianjin, China. J. Neurol. Sci. 301, 71–76 (2011).

    Article  PubMed  Google Scholar 

  21. 21

    Jacob, S., Viega, S. & Leite, M. I. Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis. Arch. Neurol. 69, 994–1001 (2012).

    Article  PubMed  Google Scholar 

  22. 22

    Cruz, P. M. R. et al. Clinical features and diagnostic usefulness of antibodies to clustered acetylcholine receptors in the diagnosis of seronegative myasthenia gravis. JAMA Neurol. 72, 642–649 (2015).

    Article  Google Scholar 

  23. 23

    Plomp, J. J., Huijbers, M. G., van der Maarel, S. M. & Verschuuren, J. J. Pathogenic IgG4 subclass autoantibodies in MuSK myasthenia gravis. Ann. NY Acad. Sci. 1275, 114–122 (2012).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Kawakami, Y. et al. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology 77, 1819–1828 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Chang, T. et al. Clinical and serological study of myasthenia gravis using both radioimmunoprecipitation and cell-based assays in a South Asian population. J. Neurol. Sci. 343, 82–87 (2014).

    Article  PubMed  Google Scholar 

  26. 26

    Higuchi, O. et al. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann. Neurol. 69, 418–422 (2011).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Zisimopoulou, P. et al. A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J. Autoimmun. 52, 139–145 (2014).

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Pevzner, A. et al. Anti-LRP4 autoantibodies in AChR- and MuSK-antibodynegative myasthenia gravis. J. Neurol. 259, 427–435 (2012).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Lu, Y. et al. A role for LRP4 in neuronal cell viability is related to apoE-binding. Brain Res. 1177, 19–28 (2007).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Shen, C. et al. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J. Clin. Invest. 123, 5190–5202 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Tzartos, J. S. et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann. Clin. Trans. Neurol. 2, 80–87 (2014).

    Article  Google Scholar 

  32. 32

    Gasperi, C. et al. Anti-agrin autoantibodies in myasthenia gravis. Neurology 82, 1976–1983 (2014).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Zhang, B. et al. Autoantibodies to agrin in myasthenia gravis. PloS ONE 9, e91816 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Witzemann, V., Chevessier, F., Pacifici, P. G. & Yampolsky, P. The neuromuscular junction: selective remodeling of synaptic regulators at the nerve/muscle interface. Mech. Dev. 130, 402–411 (2013).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Szczudlik, P. et al. Anti-titin antibody in early and late onset myasthenia gravis. Acta Neurol. Scand. 130, 229–233 (2014).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Powers, K. et al. Titin force is enhanced in actively stretched skeletal muscle. J. Exp. Biol. 217, 3629–3636 (2014).

    Article  PubMed  Google Scholar 

  37. 37

    Gautel, M. et al. Titin antibodies in myasthenia gravis: identification of a major antigenic region of titin. Neurol. 43, 1381–1385 (1993).

    Article  Google Scholar 

  38. 38

    Romi, F. et al. Anti-voltage-gated potassium channel Kv1.4 antibodies in myasthenia gravis. J. Neurol. 259, 1312–1316 (2012).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Suzuki, S. et al. Cardiac involvements in myasthenia gravis associated with anti-Kv1.4 antibodies. Eur. J. Neurol. 21, 223–230 (2014).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Skeie, G. O. et al. Ryanodine receptor antibodies in myasthenia gravis: epitope mapping and effect on calcium release in vitro. Muscle Nerve 27, 81–89 (2003).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Zoltowska, K. M. et al. Collagen Q: a potential target for autoantibodies in myasthenia gravis. J. Neurol. Sci. 348, 241–244 (2015).

    Article  Google Scholar 

  42. 42

    Gallardo, E. et al. Cortactin autoantibodies in myasthenia gravis. Autoimmun. Rev. 13, 1003–1007 (2014).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Gronseth, G. H. & Barohn, R. J. Thymectomy for autoimmune myasthenia gravis (an evidence-based review). Neurology 55, 7–15 (2000).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    VanderPluym, J. et al. Clinical characteristics of pediatric myasthenia: a surveillance study. Pediatrics 132, e939–944 (2013).

    Article  PubMed  Google Scholar 

  45. 45

    Guptill, J. T., Sanders, D. B. & Evoli, A. Anti-MuSK antibody myasthenia gravis; clinical findings and response to treatment in two large cohorts. Muscle Nerve 44, 36–40 (2011).

    Article  PubMed  Google Scholar 

  46. 46

    Kerty, E., Elsais, A., Argov, Z., Evoli, A. & Gilhus, N. E. EFNS/ENS guidelines for the treatment of ocular myasthenia gravis. Eur. J. Neurol. 21, 687–693 (2014).

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Palace, J., Newsom-Davis, J. & Lecky, B. A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Neurology 50, 1778–1783 (1998).

    CAS  Article  PubMed  Google Scholar 

  48. 48

    Benatar, M., Sanders, D. B., Wolfe, G. I., McDermott, M. P. & Tawil, R. Design of the efficacy of prednisone in the treatment of ocular myasthenia (EPITOME) trial. Ann. NY Acad. Sci. 1275, 17–22 (2012).

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Benatar, M. & Kaminski, H. Medical and surgical treatment for ocular myasthenia (review). Cochrane Database Syst. Rev. 12, CD005081 (2012).

    PubMed  Google Scholar 

  50. 50

    Norwood, F. et al. Myasthenia in pregnancy; best practice guidelines from a UK multispeciality working group. J. Neurol. Neurosurg. Psychiatry 85, 538–543 (2014).

    Article  PubMed  Google Scholar 

  51. 51

    Hehir, M. K. et al. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis; outcomes in 102 patients. Muscle Nerve 41, 593–598 (2010).

    CAS  Article  PubMed  Google Scholar 

  52. 52

    The Muscle Study Group. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 71, 394–399 (2008).

  53. 53

    Sanders, D. B. et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 71, 400–406 (2008).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Diaz-Manera, J. et al. Long-lasting treatment of rituximab in MuSK myasthenia. Neurology 78, 189–193 (2012).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Keung, B. et al. Long-term benefit of rituximab in MuSK autoantibody myasthenia gravis patients. J. Neurol. Neurosurg. Psychiatry 84, 1407–1409 (2013).

    Article  PubMed  Google Scholar 

  56. 56

    Iorio, R. et al. Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. J. Neurol. 262, 1115–1119 (2015).

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Mandawat, A. et al. Comparative analysis of therapeutic options used for myasthenia gravis. Ann. Neurol. 68, 797–805 (2010).

    Article  PubMed  Google Scholar 

  58. 58

    Barth, D. et al. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology 76, 2017–2023 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Gilhus, N. E. Acute treatment for myasthenia gravis. Nat. Rev. Neurol. 7, 132–134 (2011).

    Article  PubMed  Google Scholar 

  60. 60

    Gajdos, P., Chevret, S. & Toyka, K. V. Intravenous immunoglobulin for myasthenia gravis (review). Cochrane Database Syst. Rev. 12, CD002277 (2012).

    PubMed  Google Scholar 

  61. 61

    Lazaridis, K. et al. Specific adsorbents for myasthenia gravis autoantibodies using mutants of the muscle nicotinic acetylcholine receptor extracellular domains. J. Neuroimmunol. 278, 19–25 (2015).

    CAS  Article  PubMed  Google Scholar 

  62. 62

    Steinman, L. The road not taken: antigen-specific therapy and neuroinflammatory disease. JAMA Neurol. 70, 1100–1101 (2013).

    Article  PubMed  Google Scholar 

  63. 63

    Marx, A. et al. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun. Rev. 12, 875–884 (2013).

    CAS  Article  PubMed  Google Scholar 

  64. 64

    Cea, G., Benatar, M., Verdugo, R. J. & Salinas, R. A. Thymectomy for non-thymomatous myasthenia gravis (review). Cochrane Database Syst. Rev. 10, CD008111 (2013).

    Google Scholar 

  65. 65

    Ye, B. et al. Video-assisted thoracoscopic surgery versus robotic-assisted thoracoscopic surgery in the surgical treatment of Masaoka stage I thymoma. World J. Surg. Oncol. 11, 157–162 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Gilhus, N. E., Nacu, A., Andersen, J. B. & Owe, J. F. Myasthenia gravis and risks for comorbidity. Eur. J. Neurol. 22, 17–23 (2015).

    CAS  Article  PubMed  Google Scholar 

  67. 67

    Chiou-Tan, F. Y. & Gilchrist, J. M. Repetitive nerve stimulation and single-fiber electromyography in the evaluation of patients with suspected myasthenia gravis or Lambert–Eaton myasthenic syndrome: review of recent literature. Muscle Nerve 52, 455–462 (2015).

    Article  PubMed  Google Scholar 

  68. 68

    Huijbers, M. G. et al. Pathogenic immune mechanisms at the neuromuscular synapse: the role of specific antibody-binding epitopes in myasthenia gravis. J. Intern. Med. 275, 12–26 (2013).

    Article  PubMed  Google Scholar 

  69. 69

    Stiegler, A. L., Burden, S. J. & Hubbard, S. R. Crystal structure of the agrin-responsive immunoglobulin-like domains 1 and 2 of the receptor tyrosine kinase MuSK. J. Mol. Biol. 364, 424–433 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Till, J. H. et al. Crystal structure of the MuSK tyrosine kinase: insights into receptor autoregulation. Structure 10, 1187–1196 (2002).

    CAS  Article  PubMed  Google Scholar 

  71. 71

    Koneczny, I., Cossins, J., Waters, P., Beeson, D. & Vincent, A. 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 8, e80695 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Stiegler, A. L., Burden, S. J. & Hubbard, S. R. Crystal structure of the frizzled-like cysteine-rich domain of the receptor tyrosine kinase MuSK. J. Mol. Biol. 393, 1–9 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Choi, H. Y. et al. Lrp4, a novel receptor for dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo. PLoS ONE 4, e7930 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Zong, Y. et al. Structural basis of agrin–LRP4–MuSK signaling. Genes Dev. 26, 247–258 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Zhang, B. et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch. Neurol. 69, 445–451 (2012).

    Article  PubMed  Google Scholar 

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Acknowledgements

N.E.G., G.O.S. and F.R. have received funding from Torbjørg Hauge's Legacy for Neurological Research and from the Norwegian Muscle Disease Association. S.J.T., K.L. and P.Z. have received grants from the Muscular Dystrophy Association of the USA and from the Greek National Strategic Reference Framework (NeuroID ISR-3257).

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All authors researched data for the Review, made substantial contributions to the discussion of the content of the article and reviewed and edited the manuscript before submission. N.E.G and S.T. wrote the article.

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Correspondence to Nils Erik Gilhus.

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Competing interests

N.E.G. has received speaker's honoraria from Octapharma, Baxter and Merck Serono. P.Z. is co-inventor in a patent related to myasthenia gravis therapy and diagnosis. S.T. is co-inventor in two patnets related to myasthenia gravis therapy and diagnosis, and is shareholder and scientific advisor of Tzartos Neurodiagnostics. Other authors declare no competing interests.

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Glossary

Antigenic modulation

Bivalent antibodies can cause crosslinking of receptors and subsequent receptor internalization.

Epitope pattern

An epitope is a localized region on an antigen capable of eliciting an immune response, and the epitope pattern refers to all epitopes involved in an immune response.

MG crisis

Severe worsening of myasthenic weakness that requires intubation or noninvasive ventilation to avoid intubation.

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Gilhus, N., Skeie, G., Romi, F. et al. Myasthenia gravis — autoantibody characteristics and their implications for therapy. Nat Rev Neurol 12, 259–268 (2016). https://doi.org/10.1038/nrneurol.2016.44

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