FEATURES

Exploring the underlying causes and patient experience of myasthenia gravis

28 Jun 2021
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Professor James F. Howard, Jr.

Professor of Neurology,
Medicine and Allied Health,
The University of North Carolina at Chapel Hill, United States

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Dr. Saiju Jacob

Consultant Neurologist and Neuroimmunologist,
Clinical Service Lead for Neurology,
University Hospitals Birmingham, United Kingdom

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Ms. Nancy Law

Former Chief Executive Officer and current Board Chair,
Myasthenia Gravis Foundation of America, Colorado, United States

Despite emerging insights into the pathogenesis of autoimmune diseases, systemic board-spectrum immunosuppression remains as the backbone of treatment for these diseases.1 However, as immunosuppression is associated with numerous long-term side effects, there is a high unmet need for treatments that specifically target the underlying pathogenesis pathways.1 In the recent American Academy of Neurology (AAN) Annual Meeting held in April 2021, Professor James F. Howard, Jr., Professor of Neurology in the University of North Carolina at Chapel Hill, and Dr. Saiju Jacob, Consultant Neurologist and Neuroimmunologist in the University Hospitals Birmingham, traced the pathogenesis of rare autoimmune neuromuscular diseases including myasthenia gravis (MG), and Ms. Nancy Law, former Chief Executive Officer and current Board Chair of the Myasthenia Gravis Foundation of America, shared her first-hand experience in living with the disease.

The relationship between humoral immunity and autoimmune disease

The pathogenesis of autoimmune diseases often involves humoral immunity which is mediated by the antibodies secreted by plasma cells in the blood, as well as the complement system which enhances the clearance of pathogens.1-3 When a B-cell encounters the triggering antigen, it gives rise to a pool of plasma cells which secrete antibodies specific to the antigen.4,5 In particular, immunoglobulin (Ig) G is the most prevalent antibody with a Y-shaped structure that enables itself to bind to antigens, complement components and receptors for IgG recycling.6-8 Notably, the half-life of IgG can be prolonged through recycling, and a stable level of plasma IgG can be maintained to optimize its protection against the bacterial and viral infections.9,10

On the other hand, the complement system enhances the ability of antibodies and phagocytic cells to eliminate pathogens and promote inflammation by producing membrane attack complex (MAC).11-13 MAC is formed by the polymerization of complement component 5b (C5b), C6, C7, C8, and C9 in the complement cascade.13 Each functional MAC is sufficient to lyse cells or bacteria by membrane perforation mechanism.13 Once MACs are inserted into cell or bacterial surface, calcium flux is induced in the pore from the extracellular space or is released from the intracellular stores, leading to cell apoptosis or bacterial lysis.13

Role of pathogenic autoimmunity in the pathophysiology of generalized MG

However, when the immunologic tolerance to autoreactive immune cells breaks down, the adaptive immune system may misdirect itself by producing MACs to attack the body's own cells and drive the pathogenesis of autoimmune diseases.11,14 Importantly, this breakdown of tolerance allows the maturation of autoantibody-producing B-cells and their subsequent differentiation into autoantibody-secreting plasma cells that leads to pathogenic autoimmunity.15,16

MG is one of the autoantibody-mediated autoimmune diseases that affect neuromuscular transmission.1 In MG, key proteins in signal transmission, including acetylcholine receptor (AChR), muscle-specific kinase (MuSK) and lipoprotein receptor-related protein 4 (LRP4), are targeted by pathogenic autoantibodies that interrupt the normal synaptic function and muscle contraction.17 Notably, AChR autoantibodies (IgG1 and IgG3) contribute to 80-90% of MG cases by activating the complement system and accelerating the degradation of AChRs.17 In MG associated with AChR autoantibodies, the ongoing MAC-mediated loss of junction folds and AChRs interrupts normal signalling function and disrupts neuromuscular transmission, resulting in neuromuscular junction (NMJ) degeneration and fluctuating muscle weakness.18 In contrast, MuSK autoantibodies (IgG4) do not activate the complement system and instead block the natural activation of MuSK, leading to the progressive loss of AChRs from the motor endplate that results in synaptic failure.17 LRP4 autoantibodies (IgG1), which are found in a minority of MG cases seronegative for AChR or MuSK autoantibodies, disrupt the LRP4-agrin interaction and induce muscular weakness.17

Clinically, MG can be further divided into two subtypes: ocular MG and generalized MG (gMG).19 Ocular MG affects eyelids and extraocular muscles, resulting in ptosis and diplopia.19 On the other hand, gMG, the most common form of MG, affects not only the eyelids and extraocular muscles but also the bulbar muscles, muscles of the face and neck, respiratory muscles, and proximal limb skeletal muscles.19 The fluctuating disease course of gMG contributes significantly to the burden of patients with autoimmune dieases.20 The debilitating and unpredictable exacerbations for chronically uncontrolled gMG patients can occur at any time and impact daily activities throughout the entirety of the disease experience.21 For better disease management optimization, Prof. Howard emphasized, “There is a need to recognize the uncontrolled fluctuating nature of the disease that we need to treat in order to smoothen the landscape of symptom severity.”

Optimizing the symptom management from the lived patient experience of MG

To better understand patient’s concern and improve the current disease management, the symposium invited Ms. Nancy Law, who has been affected by MG for 25 years, to share experience as a patient with MG. She described her experience of MG was “challenging”, and the symptoms were unpredictable and difficult to live with. As patient experiences are often varied, the treatment goals between healthcare professionals (HCPs) and patients are usually mismatched: where HCPs may focus on the control of symptoms, patients may focus mainly on restoring their daily life to “feel normal”.

She commented that the potential of new therapy provides a shift in treatment goals and enables MG patients to live with a more stable and predictable disease with a safer treatment approach, without concerns of “trade-offs” in symptom management. With the improved treatment options, patients are no longer worried about long-term risks of immunosuppressive therapies, such as opportunistic infections, osteoporosis, diabetes, and cancers. She felt hopeful that patients diagnosed today can have a better balance in the treatment efficacy and side-effects, have the chance to return to normal life activities.

She further shared the results of an international patient-led qualitative analysis conducted across Europe and the United States.22 To help HCPs improve the management of their patients, the analysis gathered 114 patient insights from various sources.22 After an in-depth discussion with the international patient global council, consensus statements describing the lived experience of MG patients were consolidated into the following: MG patients have to constantly adapt to activities and life due to the fluctuating and unpredictable nature of MG; MG patients make sacrifices and trade-offs between treatment and quality-of-life; and lastly, there are perceived differences between MG patients and their HCPs regarding the optimal symptom control and quality-of-life.22 Based on her opinion and the study results, Prof. Howard concluded that in order to minimize the sense of disconnect between HCPs and patients to optimize the management of MG, “We need to listen to the patients and need better tools to assess the patients’ overall functional aspects. I think it is important that we and the healthcare community hear the voices from these patients.”

Conclusion

MG is a rare autoimmune neuromuscular disorder characterized by a defective transmission of nerve impulses to muscles caused by an autoimmune attack against the NMJ. The characteristic feature of MG is a fluctuating fatigable muscle weakness which can range from mild forms affecting eye muscles only to a severe generalized form. Chronically uncontrolled gMG patients face different difficulties and burdens in their daily lives and require long-term immunosuppressive therapies, but the serious risks associated with these treatments have created concerns among the patient community. To optimize the current MG management and help patients resume their normal life, it is therefore important for HCPs to listen to their patients’ opinions on treatment goals and utilize safer treatment options.
 

Approved on 2/7/2021
Approval code: TWHK-N-DA--2100001

This is an advertorial article, published and distributed through unrestricted support from UCB Pharma (Hong Kong Limited), for the purpose of continuing medical education only. The views expressed in this publication reflect the experience and/or opinion of the author(s) and are not necessarily those of editors and publisher. Because of rapid advances in medicine, independent verification of clinical diagnoses, medical suitability and dosage should be made before treatment prescription.


References
  1. Ludwig RJ et al. Mechanisms of autoantibody-induced pathology. Front Immunol. 2017;8:603.
  2. Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24-S32.
  3. Janeway CA Jr et al. The humoral immune response. In: Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, US: Garland Science; 2001:Chapter 9.
  4. Alberts B et al. B cells and antibodies. In: Alberts B et al. Molecular Biology of the Cell. 4th ed. New York, US: Garland Science; 2002.
  5. Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S41-52.
  6. Molnar C, Gair J. Antibodies. In: Molnar C, Gair J. Concepts of Biology-1st Canadian Edition. 1st ed. Victoria, Canada: BCcampus; 2015:23.3.
  7. Janeway CA Jr et al. The structure of a typical antibody molecule. In: Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, US: Garland Science; 2001:Chapter 3.
  8. Kang TH, Jung ST. Boosting therapeutic potency of antibodies by taming Fc domain functions. Exp Mol Med. 2019;51(11):1-9.
  9. Patel DD, Bussel JB. Neonatal Fc receptor in human immunity: Function and role in therapeutic intervention. J Allergy Clin Immunol. 2020;146(3):467-478.
  10. Gable KL, Guptill JT. Antagonism of the neonatal Fc receptor as an emerging treatment for myasthenia gravis. Front Immunol. 2020;10:3052.
  11. Howard JF Jr. Myasthenia gravis: the role of complement at the neuromuscular junction. Ann N Y Acad Sci. 2018;1412(1):113-128.
  12. Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013;33(6):479-92.
  13. Merle NS et al. Complement system part I - Molecular mechanisms of activation and regulation. Front Immunol. 2015;6:262.
  14. Smith DA, Germolec DR. Introduction to immunology and autoimmunity. Environ Health Perspect. 1999;107(Suppl 5):661-665.
  15. Janeway CA Jr et al. Self-tolerance and its loss. In: Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, US: Garland Science; 2001:Chapter 13.
  16. Theofilopoulos AN et al. The multiple pathways to autoimmunity. Nat Immunol. 2017;18(7):716-724.
  17. Phillips WD, Vincent A. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Res. 2016;5:F1000 Faculty Rev-1513.
  18. Engel AG, Fumagalli G. Mechanisms of acetylcholine receptor loss from the neuromuscular junction. Ciba Found Symp. 1982;(90):197-224.
  19. Engel AG, Arahata K. The membrane attack complex of complement at the endplate in myasthenia gravis. Ann N Y Acad Sci. 1987;505:326-32.
  20. Behin A, Le Panse R. New Pathways and Therapeutic Targets in Autoimmune Myasthenia Gravis. J Neuromuscul Dis. 2018;5(3):265-277.
  21. Khadilkar SV et al. Once myasthenic, always myasthenic? observations on the behavior and prognosis of myasthenia gravis in a cohort of 100 patients. Neurol India. 2014;62(5):492-497.
  22. Law N et al. The lived experience of myasthenia gravis (MG): A patient-led analysis. Presented at: American Academy of Neurology Virtual Annual Meeting 2021; 17-22 April 2021. Abstract P2.064.
MYASTHENIA GRAVIS
AUTOIMMUNE NEUROMUSCULAR DISORDER