Refocusing generalized myasthenia gravis: Patient burden, disease profiles, and the role of evolving therapy

Abstract

Background and purpose: Generalized myasthenia gravis (gMG) continues to present significant challenges for clinical management due to an unpredictable disease course, frequent disease fluctuations, and varying response to therapy. The recent availability of new pharmacologic therapies presents a valuable opportunity to reevaluate how this disease is classified, assessed, and managed and identify new ways to improve the clinical care of patients with gMG.

Methods: Narrative review was made of publications identified via searches of PubMed and selected congresses (January 2000-September 2022).

Results: New consensus definitions are required to ensure consistency, to better characterize patients, and to identify patients who will benefit from specific drugs and earlier use of these agents. There is a need for more frequent, standardized patient assessment to identify the cause of motor function deficits, provide a clearer picture of the disease burden and its impact on daily living and quality of life (QoL), and better support treatment decision-making. Novel approaches that target different components of the immune system will play a role in more precise treatment of patients with gMG, alongside the development of new algorithms to guide individualized patient management.

Conclusions: gMG has a physical, mental, and social impact, resulting in a considerable burden of disease and substantially decreased QoL, despite standard treatments. The availability of novel, targeted treatments that influence key pathological mediators of gMG, together with new biomarkers, offers the potential to optimize patient management and ultimately enables a greater number of patients to achieve minimal manifestation status and a reduced burden of disease.

Keywords: classification; disease burden; generalized myasthenia gravis; pathophysiology; targeted therapy.

FIGURE 1

Main immunopathogenic mechanisms of the acetylcholine receptor (AChR) and muscle‐specific kinase (MuSK) myasthenia gravis (MG) disease subgroups. Pathogenic mechanisms of MG autoantibodies at the neuromuscular junction (NMJ). (a) At the healthy NMJ, neural agrin stimulation induces interaction between lipoprotein receptor‐related protein 4 (LRP4) and MuSK, leading to MuSK autophosphorylation and activation and the phosphorylation and clustering of AChRs. A retrograde signal for presynaptic development is sent via LRP4. (b) MG antibodies of immunoglobulin (Ig) G1 and IgG3 subclass against AChR have three pathogenic mechanisms: (i) cross‐linking and increased turnover of AChR leading to reduced AChR levels at the NMJ [23]; (ii) activation of the classical complement cascade, formation of the membrane attack complex (MAC), and complement‐mediated damage of the postsynaptic membrane; and (iii) direct block of function by preventing the binding of acetylcholine [19]. (c) Bispecific IgG4 antibodies of IgG4 subclass against MuSK bind monovalently to MuSK and block LRP4–MuSK interaction, thus interrupting the agrin–LRP4–MuSK–Dok7 signaling axis and causing reduced densities of AChR at the synapse. A further effect is the disruption of a retrograde signal from LRP4 to the motor neuron. Divalent binding of MuSK IgG leads to dimerization, autophosphorylation, and activation of MuSK independent of agrin stimulation and causes the formation of ectopic AChR clusters. Created with BioRender. Reproduced from: Koneczny I, Herbst R. Myasthenia gravis: pathogenic effects of autoantibodies on neuromuscular architecture. Cells. 2019;8(7):671; doi:10.3390/cells8070671. Licensed under CC BY 4.