Generalized myasthenia gravis (gMG) affects most patients through a handful of well-characterized neuromuscular junction autoantibodies, but a wide range of differences among patients affect the clinical management of the disease burden, which manifests as gMG exacerbations.
Recent FDA approval of new gMG treatments have spurred research into exacerbation patterns, with the goal of reducing their severity and, ideally, preventing them.
"Several novel therapies are being studied to reduce gMG exacerbations by targeting key mechanisms of disease pathogenesis," said John Morren, MD, of the Cleveland Clinic in Ohio.
"The traditional approach to managing gMG involves broad immunosuppressive therapies, but emerging treatments focus on more precise immune modulation to improve symptom control and prevent exacerbations," he told MedPage Today.
Exacerbation Risks
Exacerbations in gMG refer to an acute worsening of muscle weakness beyond a patient's baseline. Clinically, exacerbation manifestations may include worsening ptosis, ophthalmoparesis, bulbar dysfunction, proximal limb weakness, and in severe cases, respiratory distress, which can lead to myasthenic crisis.
Several factors can trigger gMG exacerbations. "Infections, particularly respiratory and urinary tract infections, are among the most common causes," Morren said. "Certain medications, including beta-blockers, calcium channel blockers, aminoglycoside and fluoroquinolone antibiotics, and neuromuscular blocking agents, can impair neuromuscular transmission and worsen gMG symptoms."
Emotional and physical stress, surgical procedures, pregnancy, or other hormonal changes also may contribute. "Inadequate medication management, such as missed doses or rapid tapering of corticosteroids or other immunosuppressants, increases the risk of symptom deterioration," Morren noted. "Additionally, thyroid dysfunction and environmental factors like extreme temperatures or humidity can further exacerbate symptoms."
Patients who are more likely to experience exacerbations based on myasthenia gravis features include those with greater baseline impairment, thymoma, or anti-muscle specific tyrosine kinase (MuSK) antibodies. Higher Quantitative Myasthenia Gravis-Revised (QMG) scores, indicating more severe disease based on clinician ratings, have been associated with frequent exacerbations.
New data from the Myasthenia Gravis Foundation of America (MGFA) Global MG Patient Registry indicated that exacerbation risk was increased for patients with higher scores on the 24-point MG Activities of Daily Living (MG-ADL) scale. For each additional point on the MG-ADL scale, the rate of exacerbations increased by 13%.
In the MGFA patient registry study, MG-ADL scores were higher among patients who were female, younger, Black, unemployed, and uninsured, and those with greater comorbidities and shorter disease duration. Healthcare services were needed in about 50% of exacerbation cases.
Research also has shown that exacerbations persistently worsen the myasthenia gravis disease course, even after appropriate therapy.
In the U.S., MG exacerbations have been associated with a high clinical and economic burden in both commercial insurance and Medicare patients, despite treatment with conventional therapies. Mean total MG-related healthcare costs per exacerbation ranged from $26,078 to $51,120 for commercial insurance patients, and $19,903 to $49,967 for Medicare patients.
Treating Exacerbations
"The landscape of gMG treatment is rapidly evolving, with several promising therapies being evaluated to prevent exacerbations and improve long-term disease control," Morren said.
Recently approved C5 complement inhibitors like eculizumab (Soliris), ravulizumab (Ultomiris), and zilucoplan (Zilbrysq) have demonstrated efficacy in reducing gMG exacerbations by preventing membrane attack complex formation at the neuromuscular junction, Morren pointed out. Ongoing trials are evaluating next-generation complement inhibitors which may offer better efficacy and convenience, he said.
Neonatal Fc receptor (FcRn) inhibitors like efgartigimod (Vyvgart) and rozanolixizumab (Rystiggo), which reduce the levels of circulating pathogenic immunoglobulin G autoantibodies by accelerating their degradation, have been shown to rapidly improve muscle strength while lowering the risk of exacerbations, Morren noted. "Additional FcRn inhibitors, such as nipocalimab and batoclimab, have produced promising results in clinical trials and may soon achieve FDA approval," he said.
Given the role of B cells in autoantibody production, therapies targeting B-cell depletion or modulation are also being explored. Several targeted immunomodulators are being investigated for their potential to reduce exacerbations by modulating pro-inflammatory signaling. Therapies targeting Bruton's tyrosine kinase, which regulates B-cell activation and autoantibody production, also are being studied.
Chimeric antigen receptor T-cell (CAR-T) therapy and chimeric auto-antibody receptor T-cell (CAAR-T) therapy are in early-stage trials, Morren observed. "These treatments aim to selectively eliminate autoreactive B cells responsible for auto-antibody production, potentially providing a long-term reduction in exacerbations. Autologous hematopoietic stem cell transplantation is also being evaluated in refractory gMG cases to reset the immune system," he noted.
Other novel approaches include antisense oligonucleotides, which modulate acetylcholinesterase activity, and subcutaneous immunoglobulin, which may provide a more stable immunomodulatory effect compared with intravenous immunoglobulin in preventing exacerbations.
"The shift toward precision immunotherapy -- targeting specific pathways while minimizing systemic immunosuppression -- may offer better efficacy and safety profiles compared to traditional treatments," Morren said. "Future studies will help refine the use of these novel agents and their most appropriate place in treatment approaches."
Disclosures
Morren reported no conflicts of interest.