Generalized Myasthenia Gravis: AANEM 2026 Highlights

Is There Evidence Around Corticosteroid Use in Myasthenic Crisis?

The treatment of MG crisis and exacerbations continues to be a significant unmet need. According to one study, the number of hospitalizations due to MG exacerbations is increasing, especially in older patients. Although new medications are being introduced to reduce the number of these acute events and perhaps even prevent them, patients with myasthenia gravis crisis are often sent to the emergency department and admitted for treatment. At AANEM, a session was devoted to the evidence around rescue approaches to myasthenia crisis in the inpatient setting.

One of the mainstays of MG crisis treatment—corticosteroids—has surprisingly little evidence behind it. Qihua Fan, MD, a neuromuscular biologist and Assistant Professor, Virginia Commonwealth University, said, “Direct interventional trials of corticosteroids in MG exacerbation or crisis are strikingly few.” 

Dr. Fan presented a literature review on the effectiveness of corticosteroids in acute worsening of MG or myasthenic crisis, reaching back to 1985. 

Most prospective studies used intravenous methylprednisone as the active treatment, and patients most commonly had gMG or ocular MG. The highlighted studies showed a trend towards improvement (based on MG-ADL scores), with some patients experiencing a period of deterioration after administration. This worsening usually occurred at day 4 to 6 and lasted 3 to 6 days.  However, these investigations were limited by small sample sizes, and none were randomized, controlled trials with patients in manifest myasthenic crisis. 

Dr. Fan concluded, “Its use rests on expert consensus, which recommend initiating corticosteroids only after IVIG/plasma exchange has begun to take effect due to the risk of steroid-induced worsening. This is why gradual corticosteroid escalation has been preferred outside the hospital setting.”

What is the Role of Complement Inhibitors and B-Cell Therapies in Inpatient MG Management?

The pivotal studies on the efficacy and safety of complement inhibition in patients with MG are based in the outpatient environment, explained Arjun Seth, MD, Assistant Professor, Neuromuscular Disease, Feinberg School of Medicine, Northwestern Medicine. Can complement inhibitors be used in the inpatient setting? 

The evidence to support their use in the hospital is also limited, he said, generally to case study reports involving the use of eculizumab. In published articles, researchers did see positive results in those individual patients; the median time to wean these individuals off mechanical ventilation was 7 days. New studies are underway, noted Dr. Seth.

“There is more data on the use of complement inhibitors preventing relapse and hospitalization,” he concluded, “but little in their use during hospitalization in patients with MG exacerbation and crisis.” He speculated that “complement inhibition may play a role in refractory MG not responding to typical rescue therapies and may help with ventilator weaning as add-on therapy.” 

Acknowledging the lack of hard evidence, Meghana Shownkeen, MD, Neurohospitalist Fellow at Feinberg School of Medicine, Northwestern University, said, “The challenge is that inpatient practice is evolving faster than the outcomes evidence.” The result is that a new paradigm is developing, in which “inpatient teams may use targeted agents as rescue, bridge, or continuation therapies.” However, these new interventions “do not replace intensive respiratory and bulbar management in patients with MG crisis.”

The Role of C5-Targeted Therapies in gMG

On average, patients with gMG spend nearly 3 days per month on outpatient care alone, began James F. Howard, MD, Professor of Medicine at the University of North Carolina School of Medicine. When myasthenic exacerbation and crisis are factored in, their healthcare resource utilization rises dramatically, and the emotional, social, economic and work ramifications are considerable. 

Conventional gMG treatments—AChE inhibitors, immunosuppressants, thymectomy, IVIG infusions, plasma exchange—can have several drawbacks, he said, including increased risk of infections and certain malignancies because of their broad immunosuppression; persistent symptoms; delayed onset of effect (which may take many months); treatment-related adverse events; and significant QoL impacts (e.g., fatigue, prevalent and debility). 

Tuan H. Vu, MD, Professor, Department of Neurology, University of South Florida Morsani College of Medicine, explained that when anti-AChR binds to receptors, it releases a complement cascade (initially with C5, which then releases C5a, C5b, C6, C7, C8, and C9), resulting in the deposit of membrane attack complex (MAC) in the postsynaptic membrane of the muscle cell. The overall result is reduced muscle contraction. Inhibiting C5 prevents MAC formation and deposition, which can reduce the damage. 

The first C5 inhibitor, eculizumab, was tested in gMG in the REGAIN phase 3 study and open-label extension trial. It is an intravenous infusion, and like ravulizumab, it requires a loading dose before proceeding to maintenance therapy. Of 98 patients receiving eculizumab in these studies, 15% did not respond to eculizumab and in 17%, response was seen only after many months (some after a year or more), according to Dr. Vu. For the 67% who responded quickly (often within 10 weeks), least-mean square MG-ADL scores fell by approximately 60%. 

Newer C5 inhibitors offer faster responses and longer durations between maintenance doses, or the subcutaneous administration route. Using these agents, minimal symptom expression was attained by up to 69% of patients taking eculizumab, 42% for ravulizumab, and 39% for zilucoplan. Maintaining minimal symptom expression is still a problem, however. 

One of the greatest advantages of the targeted C5 therapies is their more favorable safety profile compared with conventional treatments. In the pivotal studies for eculizumab, ravulizumab, and zilucoplan, headache (15%–19%), diarrhea (≤ 15%), and injection-site reactions (only zilucoplan, 16%) were most commonly noted. Meningococcal infections were not seen in any study participant in the C5-inhibitor trials.

In terms of the newest, investigational agents, cemdisiran was studied in the phase 3 NIMBLE trial (referred to elsewhere in this report to study its effect in preventing hospitalization). At 24 weeks, the least-square mean reduction in the MG-ADL score was 4.5 points for study participants taking cemdisiran alone compared with a 2.2 reduction in those taking placebo. A nearly 4-point reduction was seen also after only 8 weeks of treatment. A similar efficacy profile was noted for gefurulimab, with a 4.2-point reduction after 26 weeks compared with a 2.6-point reduction in the placebo group. 

Dr. Howard pointed out that patient selection is important: If the patient is not positive for AChR-binding antibody, the C5-inhibitors will not be effective. He thinks they would be best used in patients with high relapse rates with standard immunosuppressants or in patients who cannot taper down from high-dose corticosteroids without relapsing. All patients for whom C5 inhibitors are considered must be vaccinated against meningococcus infection.

Measuring the Impact of Ocular MG Symptoms With a Patient-Reported Score

Ocular MG is described by weakness and fatigue in the muscles controlling eyelid and eye movement. Common symptoms are drooping eyelids (ptosis) and double vision (diplopia), both of which greatly impact social engagement, work productivity, and general quality of life (including the ability to drive vehicles). 

A multinational research team evaluated the Myasthenia Gravis Impairment Index (MGII) using data generated by a phase 3 clinical study of an Fc inhibitor (ADAPT OCULUS). The MGII had already been validated in patients with gMG to characterize patient-reported symptoms and improvement; this subgroup study sought to validate its use in a blinded sample of 30 patients with ocular MG.

All patients were interviewed to explore how their symptomatology was affected during the clinical study and the impact of those symptom changes compared against the MGII scoring. The patients regarded diplopia (83%) and ptosis (73%) as the most important symptoms to them. Treatment resulted in meaningful improvements or at least symptom stability for 59% of the study participants, with benefits to functions of daily living, including driving, use of a computer screen, and social engagement. A one-category improvement on the MGII was described as the minimal change that would be characterized as meaningful. 

The researchers concluded that the “findings support the clinical relevance, interpretability, and meaningful within-patient change of the MGII (PRO) ocular score as an endpoint in ocular MG trials.”

Cases of New-Onset MG After Use of GLP-1 or PD-1 Therapy

The use of glucagon-like peptide-1 agonists (GLP-1s) is burgeoning in the treatment of weight loss, and immune checkpoint inhibitors like pembrolizumab are commonly prescribed for the treatment of many types of neoplasms. Two posters at AANEM described singular patients taking these agents who experienced MG as a potentially treatment-emergent adverse event. 

Despite the benefits of the GLP-1s in type 2 diabetes and weight loss, there is limited evidence that patients may experience autoimmune side effects of the drug class. Mao Liu, MD, Department of Neurology, Duke University Medical Center, presented the case of a 55-year-old woman with type 2 diabetes and obesity, who started semaglutide therapy. Soon afterwards, she developed ptosis, blurred vision, and vertical diplopia—all ocular symptoms of MG. She tested positive for AChR antibodies. Subsequently, she developed dysphagia, was started on a regimen of prednisone and pyridostigmine, and was referred to Dr. Liu’s center. The patient was admitted, received IVIG, and began to recover. 

“While existing research into [GLP-1s] and MG shows inconsistent results regarding direct causality, real-world data indicate an increased risk for several other autoimmune conditions,” according to Dr. Liu. “With the increasing utilization of [GLP-1s], clinicians should maintain a high degree of suspicion for new-onset autoimmune disorders such as MG.” 

In the second case study, Naeemuddin Shaikh, MD, a neurologist from Reading Hospital, West Reading, Pennsylvania, presented a poster on a 77-year-old woman with stage IV endometrial cancer, who had undergone a hysterectomy and began a cycle of pembrolizumab therapy. Three weeks after starting therapy, she manifested generalized weakness, right-sided ptosis, binocular diplopia, and dysphagia, and she was admitted to the hospital. An echocardiograph indicated an abnormally low left-ventricular ejection fraction. Lab results highlighted abnormal creatine kinase and troponin levels. 

High-dose corticosteroids were prescribed, and she was transferred to intensive care, where she underwent plasmapheresis. Dr. Shaikh concluded, “This case emphasizes early recognition of immune-mediated neuromuscular complications after pembrolizumab therapy. Prompt diagnosis and timely immunosuppressant therapy are crucial to reduce morbidity and prevent potentially fatal outcomes.”

What is Behind the Placebo-Arm Response in gMG Clinical Trials?

With a very active clinical trial environment in gMG, it would be important to understand what is driving positive responses in the placebo arms of drug intervention trials. 

Hazem Iaali, MD, a research fellow at the Mayo Clinic, conducted a literature review, yielding 429 studies, with 1,114 individuals with gMG assigned to a placebo treatment arm. Ninety-two percent were AChR-positive. “Positive results in the placebo arm was seen on the MG-ADL scale (–1.58), the QMG scale (–1.81), and the MGC scale (–3.51),” said Dr. Iaali, who stated that it was not necessarily related to the placebo effect. Other potential factors could be regression to the mean, variability in measurements, expectation effects, practice effects, and potential inflation of the baseline scores. 

Dr. Iaali emphasized that the study should be powered to account for plausible control arm responses; these are important to “reduce the possibility of false-negative results in trials of active therapies.”