Myasthenia Gravis: Making Progress for More Accurate Diagnoses and Targeted Treatments

Myasthenia gravis (MG) is the prototypical autoimmune disorder affecting the postsynaptic portion of the neuromuscular junction (NMJ). In roughly 85% of cases, generalized MG is caused by antibodies to the acetylcholine receptor (AChR); this is true in about half of purely ocular cases.¹ These antibodies exert their pathogenic effect in 1 of 3 ways. First, they can functionally block the AChR, not allowing for the binding of acetylcholine. Second, they can crosslink AChRs, leading to increased internalization and degradation. Third, they can bind to AChRs and activate complement, leading to destruction of the NMJ. About 7% of all cases of generalized MG are caused by antibodies to muscle-specific tyrosine kinase (MuSK), and 1% are caused by antibodies against lipoprotein-related protein 4 (LRP4), both of which play a role in clustering of AChRs on the postsynaptic membrane, interference with which also leads to impaired neuromuscular transmission.²

The prevalence of MG is approximately 10 to 20 cases per 100,000 population. The incidence of MG is estimated to be 5 to 30 cases per million person-years. The incidence of MG has increased over time because of more sensitive diagnostic testing, more effective treatments, and improved overall survival, with a consequent increase in the likelihood of developing late-onset MG.³

Classification and Clinical Presentation

There are numerous ways to categorize MG, such as ocular vs generalized disease. Ocular symptoms, leading to ptosis or diplopia, are the initial manifestation in most people with MG.¹ Most people will progress to generalized disease, involving muscles other than ocular muscles, preferentially involving bulbar, respiratory, axial, and proximal appendicular muscles. Generalization occurs in about 90% of individuals and most often occurs within 2 to 3 years of the initial onset of symptoms.⁴

Early-onset MG is defined as development of symptoms before age 50 years, and late-onset MG is development of symptoms after age 50. There is a female predominance in the early-onset group, with symptoms most often first appearing in the second or third decade of life. There is a slight male predominance in later-onset disease.⁵ Another important classification is the presence or absence of thymic disease. Abnormalities of the thymus gland, including thymoma and thymic hyperplasia, have been reported to occur in association with MG. The incidence of thymoma is roughly 15% and occurs irrespective of age.⁶ The incidence of thymic hyperplasia has been variably reported from 50% to 70% and is more often seen in individuals with early-onset disease and in the presence of AChR antibodies.⁷

The hallmark of MG is fatigable weakness in affected muscles, with individuals often experiencing worsening symptoms with prolonged activity using those muscles, and more prominent weakness toward the end of the day. Muscle fatigability must be distinguished from fatigue and tiredness, which are nonspecific and occur in any number of medical conditions. This can cause confusion, however, because individuals with MG also frequently report fatigue as a common, often debilitating, and difficult to control symptom.⁸ Given the association of MG with other comorbidities, such as dysthyroid disease and obstructive sleep apnea, these and other potential contributors to fatigue should be investigated in individuals with MG experiencing severe or persistent fatigue despite optimization of control of other MG symptoms.

Myasthenic crisis (MC), a true neurologic emergency, is defined as respiratory failure caused by MG. It is estimated to occur in 15% to 20% of individuals with generalized MG, and can be the presenting symptom in a minority of these cases.⁹ The cause of MC can be identified in roughly two-thirds of cases, and is most often attributable to an infection, trauma, stress, or surgery. Most individuals survive MC with treatment, which is reviewed in the following.

Diagnosis

A history of fatigable weakness of predominantly ocular, bulbar, axial, or proximal appendicular muscles is strongly suggestive of a diagnosis of MG. Often, fatigable weakness can be detected on a carefully performed neurologic examination. Given the fluctuating and variable nature of symptoms, however, it is possible for a person to have a normal examination in clinic, particularly if the visit is early in the day or after treatment with acetylcholinesterase inhibitors, such as pyridostigmine. It is therefore instructive to ask the individual to give examples of how their symptoms affect their day-to-day physical activities.

The mainstay of diagnosis in MG is detection of pathogenic antibodies in serum. Traditional assays for AChR antibodies have relied on radioimmunoprecipitation assay, a method that can lead to false-negative results, particularly when antibodies are low in titer. More recently, cell-based assays have been employed, which have a higher diagnostic yield than radioimmunoprecipitation assays.¹⁰ Therefore, cell-based assays can often detect the presence of antibodies in individuals who would otherwise be classified as seronegative. Detection of antibodies has assumed greater importance as of late with the approval of newer therapeutics, indicated only for individuals with the presence of detectable antibodies in serum. In those cases of suspected MG where antibodies remain undetectable, electrodiagnosis, specifically slow repetitive nerve stimulation and single-fiber EMG, play an important role. The presence of decrement on repetitive nerve stimulation or abnormal increase in jitter on single-fiber EMG are consistent with a diagnosis of MG in the appropriate clinical context.

Once a diagnosis of MG has been made, it is imperative in cases of AChR antibody–mediated disease to assess the status of the thymus with CT or MRI of the chest to evaluate for thymoma. Thymectomy is mandatory in cases of thymoma and can also be considered as a therapeutic option in individuals with early-onset disease in nonthymomatous MG.¹¹ In these cases, thymectomy can lead to better control of symptoms and reduction in the doses of other therapies, such as corticosteroids. However, the benefits take 1 to 2 years to become clinically apparent.

Treatment

The treatment of MG has evolved considerably over time, especially over the past 6 years. Most individuals are initially treated with acetylcholinesterase inhibitors, such as pyridostigmine. These agents are modestly effective in treating individuals with ocular MG; however, they are rarely effective alone in treating individuals with generalized disease.¹² Corticosteroids, therefore, are almost always started at the time of diagnosis of generalized MG to control symptoms quickly and effectively, with most individuals experiencing initial benefit within 2 weeks. Given the multitude of adverse effects of both short- and long-term use of corticosteroids, however, oral immunosuppressants, most commonly mycophenolate mofetil and azathioprine, are also typically started early in the disease course to allow for tapering and eventual discontinuation of corticosteroids. Because these medications take up to 12 to 18 months to become fully effective, corticosteroids are most often slowly tapered over this time to bridge treatment. Oral immunosuppressants are effective in many individuals with MG, but can lead to adverse reactions. Mycophenolate can cause nausea, diarrhea, and leukopenia.¹³ Azathioprine can cause a flu-like illness at initiation in roughly 15% of individuals, along with transaminitis and leukopenia. Both agents also increase the risk of infection and minimally increase the risk of malignancy in the long term.¹³ Therefore, more targeted medications with fewer off-target side effects are perhaps a more optimal choice in the treatment of MG.

Over the past 6 years, 5 new agents have been approved for the treatment of generalized MG in the United States (Table 1). These include complement inhibitors (eculizumab [Soliris; Alexion, Boston, MA], ravulizumab [Ultomiris; AstraZeneca, Boston, MA], and zilucoplan [Zilbrysq; UCB, Atlanta, GA]) and neonatal fragment crystallizable receptor (FcRn) antagonists (efgartigimod alfa and hyaluronidase-qvfc [Vyvgart Hytrulo; Argenx SE, Amsterdam, Netherlands] and rozanolixizumab-noli [Rystiggo; UCB, Atlanta, GA]).^14-18 The introduction of these treatments into the armamentarium has altered the traditional paradigm outlined previously.

Although initially studied in a more treatment-refractory population, complement inhibitors are approved for the treatment of all individuals with AChR antibody–positive generalized myasthenia.^14-16 By inhibiting complement, these agents prevent 1 of the key pathophysiologic mechanisms of AChR antibody–mediated disease. Complement inhibitors work relatively quickly, generally within 2 to 4 weeks after initiation, and robustly, leading to a substantial reduction in symptoms in this population. Individuals must be vaccinated against Neisseria meningitidis before treatment with complement inhibitors because of an increased risk for infection with encapsulated bacteria.

Both efgartigimod and rozanolixizumab bind with high affinity to the FcRns located in endosomes within endothelial cells. The FcRns themselves serve to spare immunoglobulin G (IgG) antibodies, including pathogenic AChR IgG antibodies, from lysosomal degradation, and allow them to be recycled back into circulation. By blocking these receptors, both efgartigimod and rozanolixizumab lead to a reduction in circulating AChR antibodies, and less interference with, or damage to, the NMJ. Both agents have also been demonstrated to lead to rapid and effective reduction in symptoms attributable to MG in randomized controlled trials.^17,18 Efgartigimod is approved to treat AChR antibody–positive individuals with MG, and rozanolixizumab is approved for both AChR and MuSK antibody–positive individuals.

MuSK MG has a unique immunopathogenesis and treatment paradigm.¹⁹ This form of MG has been demonstrated to respond robustly to treatment with anti–B-cell therapies, such as rituximab. However, because MuSK MG is an IgG4-mediated disorder and this subclass of IgG does not fix complement, complement inhibitors do not have a role in the treatment of MuSK MG. Individuals with MuSK MG experience substantial cholinergic side effects from acetylcholinesterase inhibitors.

The treatment of MC largely relies on identification and treatment of the underlying cause (eg, infection), supportive care including mechanical ventilation, and treatment with either plasmapheresis or intravenous immunoglobulins.⁹ Whether any of the more recently approved therapies has a role in the treatment of MC is unclear. Furthermore, the cost of these treatments remains a barrier to individual use.

With the advent of new and more targeted treatments, the goals of care are shifting. Previously, long-term and often relatively high doses of corticosteroids were used to control symptoms of MG, but led to myriad side effects, which were accepted as the cost for adequate disease control. More widespread use of oral immunosuppressants were prescribed in an effort to spare individuals from complications associated with corticosteroid use. However, immunosuppresants are also associated with both short-term and long-term risks, the most concerning being mild increased risk of infection and malignancy. International consensus treatment guidelines²⁰ highlight that the goal of care in MG is to achieve both symptom control—minimal manifestations status or better—with few or no side effects of medications. More recently, minimal symptom expression, defined as a Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) score of 0 or 1, has been espoused as the treatment target.²¹ Although initially developed for use in clinical trials, individual-reported outcome measures, such as the MG-ADL, can be easily reported by individuals and used in clinic to monitor response to therapy.

A holistic approach to individual care must be used when making treatment decisions, including evaluation of patient history; neurologic examination; assessment of symptoms, side effects, and quality of life; and consideration of psychosocial and socioeconomic factors. Furthermore, shared decision-making with individuals and their caregivers is vital. An individualized approach to treatment in MG is important, given the heterogeneity of the disease, individual comorbidities, and the numerous and diverse treatment options available.

Future Directions

Despite recent innovations in diagnostic methods and treatment options for MG, a number of unmet needs remain. Better biomarkers for the diagnosis and assessment of disease activity are needed, and circulating microRNAs have demonstrated potential in this regard.²² Earlier diagnosis will ideally lead to quicker initiation of treatment, thus leading to better short- and long-term outcomes. It is also hoped that biomarkers can allow for better assessment of disease activity once diagnosis has been made to help predict crisis and exacerbation and optimize therapy. Additionally, there are several emerging treatment options for MG (Table 2).²³

Conclusion

Although the underlying immunopathogenesis of MG has been known since the 1970s,²⁴ recent work has led to improved testing methods, leading to quicker and more accurate diagnoses. More targeted therapies offer individuals the efficacy and safety required for optimal disease control with fewer side effects. As this work evolves, the goal of attaining minimal symptom expression with few or no side effects of treatment should be realized in more individuals with MG.