Myasthenia gravis in 2025: five new things and four hopes for the future

Abstract

The last 10 years has brought transformative developments in the effective treatment of myasthenia gravis (MG). Beginning with the randomized trial of thymectomy in myasthenia gravis that demonstrated efficacy of thymectomy in nonthymomatous MG, several new treatment approaches have completed successful clinical trials and regulatory launch. These modalities, including B cell depletion, complement inhibition, and blockade of the neonatal Fc receptor, are now in use, offering prospects of sustained remission and neuromuscular protection in what is a long-term disease. In this review, we update our clinico-immunological review of 2016 with these important advances, examine their role in treatment algorithms, and focus attention on key issues of biomarkers for prognostication and the growing cohort of older patients, both those with long-term disease, and late-onset MG ('LOMG'). We close by expressing our four hopes for the next 5-10 years: improvements in laboratory medicine to facilitate rapid diagnosis, effective strategies for neuromuscular protection, more research into and better understanding of pathophysiology and treatment response in older individuals, and the potentially transformative role of therapies aimed at delivering a durable response such as chimeric antigen receptor (CAR) T cells. Our postscript summarizes some emerging themes in the field of serological and online biomarkers, which may develop greater stature in the next epoch.

Keywords: Clinical guidelines; Myasthenia gravis; Neuromuscular junction; Older adults; Rituximab; Thymectomy.

Fig. 1

Summary of the B cell lineage differentiation and associated cell-surface phenotypes. Bone marrow emigrant naïve antigen-inexperienced B cells encounter antigen and T cells in a germinal center. Germinal centers are most commonly located in lymph nodes and spleen. The T cells express CD40L and secrete IL-2, IL-21 and TNFa, among other factors which help naïve B cells differentiate into CD27+ unswitched (IgD+) and switched (IgG+) memory B cells. Unswitched memory B cells may also express IgM. These then differentiate into antibody-secreting cells (below the dashed line: plasmablasts, short- and long-lived plasma cells) whose survival is supported by IL-6, BAFF and APRIL. Short-lived plasma cells may reside in tissues including bone marrow. Long-lived plasma cells typically niche in the bone marrow, but can reside in the central nervous system in states of inflammation. Antibodies in blue = IgG, red = IgD; yellow = IgM. Figure and caption reproduced with minor alteration from: Condition-dependent generation of aquaporin-4 antibodies from circulating B cells in neuromyelitis optica, Wilson et al. [22] This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Fig. 2

Advances in treatment in acetylcholine-receptor antibody (AChR-Ab)-positive myasthenia gravis (MG). Panel A depicts a timeline of new treatments available since 2016. Panel B shows the role of these new therapeutic approaches in the pathophysiological cascade of AChR-Ab MG, with the three main mechanisms (complement activation, cross-linking and internalization, and reduced receptor clustering) delineated in (ii) and (iv). (i) Thymectomy acts at the level of the thymus to halt autoimmunization and pathogenic antibody production. Anti-CD20 therapy acts later in this pathway to remove antibody-secreting B cells from circulation; (ii) Trials of anti-complement agents work by disrupting the complement cascade activated by IgG1 antibodies, which, left unchecked, leads to tissue damage at the neuromuscular junction; (iii) the mechanism of FcRN inhibition is by blocking IgG recycling; pathogenic antibodies cannot bind to occupied FcRN receptors and are degraded instead of being returned to the circulation; (iv) at the NMJ, pathogenic antibodies can act by direct receptor blockade as well as by receptor cross-linking and internalization. Ab antibody, AChR acetylcholine receptor(s), APC antigen-presenting cell, FcRN neonatal Fc receptor, MG Myasthenia Gravis. Image created with Biorender

Fig. 3

Advances in treatment in muscle-specific kinase antibody (MuSK-Ab) positive myasthenia gravis (MG). Panel A depicts a timeline of new treatments available since 2016. Panel B, A–E shows example of thymic pathology in control (A and E), AChR-Ab (B and F), seronegative, probably low-affinity AChR by modern testing methods (C and G), and MuSK-Ab (D and H). Immunofluorescence staining for CD20-expressing (green) and CD35-expressing follicular dendritic cells (red) revealed a lack of CD35 cells in control thymus (E), whereas germinal centers were more extensive in AChR-Ab (F) than negative H patients. Also, germinal centers were only found in 4/14 MuSK thymi examined [24]. Therefore, due to lack of thymic pathology, thymectomy is not indicated in MuSK MG. Panel C shows the role of new therapeutic approaches in the pathophysiological cascade of Musk MG. (i) Anti-CD20 therapy removes some antibody-secreting B cells and their precursors from circulation; (ii) the mechanism of FcRN inhibition is by blocking IgG recycling; pathogenic antibodies cannot bind to occupied FcRN receptors and are degraded instead of being returned to the circulation; (iii) most MuSK antibodies are of the IgG4 sub-class and do not activate complement. Their mechanism of action is via receptor blockade, impeding receptor clustering, and alteration of onward phosphorylation mechanisms. Ab antibody, AChR acetylcholine receptor(s), APC antigen-presenting cell, FcRN neonatal Fc receptor, MG Myasthenia Gravis, MuSK muscle-specific kinase. Image created with Biorender. Panel B reproduced from: Leite MI, Scröbel P, Jones M, et al. (2005). Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol 57:444–448. License number 5760141271853. Copyright © 2005 American Neurological Association)

Fig. 4

Treatment algorithm for gMG with AChR or MuSK antibodies. After clinical, laboratory (and radiological) diagnosis of gMG, start symptomatic therapy (pyridostigmine). In AChR-antibody positive cases under the age of 65, and all MG patients with thymoma, thymectomy should be considered. Oral steroids (aim for no more than 20 mg prednisolone/day induction dose), other oral agents (e.g. azathioprine/mycophenolate mofetil/ciclosporin/methotrexate), or anti-CD20 can be started if insufficient response to symptomatic medications or while waiting for a thymectomy procedure and subsequent response, which may take up to two years for full therapeutic effect. If severe side effects or an inadequate response to this stepped approach at 10–12 months, consideration should be given to adding in a new targeted therapy such as a complement inhibitor (AChR-Ab patients) or FcRN-inhibition (AChR and MuSK-Ab patients). IVIG and PLEX are not chronic therapies and their use is advised for rescue therapy at disease onset or in MG crisis, and, for some patients pre-surgically. The updated German guidelines propose a comparable approach [73]. Ab antibody, AChR acetylcholine receptor(s), FcRN neonatal Fc receptor, gMG (generalized) Myasthenia Gravis, IVIG intravenous immunoglobulin, MuSK muscle-specific kinase, NHSE National Health Service England, PLEX plasma exchange, thx thymectomy

Fig. 5

Changing onset of Late-Onset Myasthenia Gravis (LOMG) and Early-Onset Myasthenia Gravis (EOMG) in Northern Ireland from 1990 to 2008. IR is shown in cases per million person-years, error bars represent 95% CI. There is an almost sevenfold increase in IR of LOMG, and although there is a two-fold increase in absolute EOMG IR, the CIs overlap. Reproduced with permission from: AS Carr. Actual world epidemiology of Myasthenia Gravis (Chapter 2). In Mineo TC, editor. Novel Challenges in Myasthenia Gravis. Nova Science Publishers, Inc.: 2015. CI confidence interval, IR incidence rate

Fig. 6

Cell-based assays in myasthenia gravis. Live cell-based assays are the most sensitive method to detect antibodies in people with autoimmune myasthenia gravis. A HEK cells transfected with α-, β- and δ-AChR subunits with either the ε or γ subunit for adult or fetal AChR subunits and eGFP-tagged rapsyn is the substrate for the clustered AChR antibody assay. The AChR are shown in blue, the patient antibody in pale blue, the secondary antibody is black with a fluorochrome depicted in red and Rapsyn-eGFP in green. B HEK cells transfected with MuSK c-terminally tagged with eGFP forms the substrate for the MuSK live cell-based assay. C Examples of an AChR antibody-positive test result in the first row, a MuSK-positive test result in the second row and a negative control for the AChR antibody assay in the bottom row. AChR acetylcholine receptor(s), EGFP enhanced green fluorescent protein, HEK human embryonic kidney, IgG immunoglobulin G, MuSK muscle-specific kinase. Figure components A and B created with Biorender