Q&A: Comorbidities in Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction, characterized by fluctuating muscle weakness.

 A steady increase of both its incidence and prevalence has been observed since the 1950s,^[1] leading to increased interest in comorbidities affecting MG patients. Nicholas Silvestri, MD, professor in the Department of Neurology at the University at Buffalo Jacobs School of Medicine & Biomedical Sciences, reviews the main comorbidities seen in MG.

In your experience, what comorbidities are commonly seen in MG patients?

There are comorbidities directly related to MG, such as thymus pathology, and others not directly related to MG, such as hypertension and type 2 diabetes. About half of MG patients have thymus hyperplasia, which likely drives their MG. Conversely, around 10%-15% of patients with generalized MG have a thymoma. Looking at it another way, about 33% of people with thymomas also have MG.^[2] During the investigation for acetylcholine receptor-positive (AChR+) MG, we always check the thymus for any pathology. This is one of the most common and well-known comorbidities in MG. Autoimmune disorders also tend to cluster with MG. About 15% of MG patients have a concomitant autoimmune disorder, which is more common in females, those with early-onset MG, and those with AChR+. The most common autoimmune thyroid diseases are Graves disease and Hashimoto thyroiditis. Other frequently reported autoimmune diseases in MG patients include rheumatoid arthritis, multiple sclerosis, alopecia, and systemic lupus erythematosus.^[3]

Will MG management have a positive effect on comorbidities such as thymoma or thyroiditis?

Yes. For example, a thymectomy addresses thymus pathology. Treating the autoimmune nature of MG could also potentially treat other autoimmune diseases. Other rare comorbidities associated with MG that could be positively affected include myocarditis and Takotsubo cardiomyopathy, particularly during a myasthenic crisis.^[2] Fatigue is a common symptom in MG patients that could improve, likely due to obstructive sleep apnea caused by pharyngeal muscle weakness.^[4,5,6,7] About a third of MG patients experience depression and 50% experience anxiety,^[8] but there is a gap in the evidence about the effect of MG treatment on psychiatric comorbidities.

On the other hand, treatment of comorbidities not directly related to MG could have a negative impact on MG patients.

Hypertension, type 2 diabetes, metabolic syndrome, hyperlipidemia, vascular disease, and osteoporosis are more commonly seen in late-onset MG patients and those with treatment-refractory disease.^[2] Steroids can exacerbate mild hypertension or prediabetes, complicating MG management. Unfortunately, about 70% of MG patients have at least two comorbidities. Sometimes, managing steroid side effects becomes more challenging than treating MG. Immunosuppressants like mycophenolate and azathioprine increase long-term infection and malignancy risks.^[9] I've seen malignancies develop over time in my practice, possibly influenced by immunosuppressants. For early-onset MG, it is important to consider a discussion about childbearing and conception.^[10] A third of women experience worsening of MG during pregnancy, and some medications — methotrexate, mycophenolate, rituximab — are contraindicated.

There are many scenarios where pharmacologic interactions may be an important concern when managing MG patients. What are the recommendations?

Good communication is crucial. Patients should be educated about the importance of disclosing their MG diagnosis to other health professionals; communication among doctors of different specialties is essential to decide on the best management strategy. There are many medications that MG patients should avoid or use cautiously.^[11] I advise patients to call my office before starting new medications, especially antibiotics. There is also a push toward prioritizing targeted therapies for MG. New treatments approved in recent years, including neonatal Fc (FcRn) receptor blockers (efgartigimod^[12] and rozanolixizumab^[13]) and complement inhibitors (eculizumab,^[14] ravulizumab,^[15] and zilucoplan^[16]) result in fewer side effects. The goal is to control MG without aggravating other medical conditions, but cost and access are important barriers.

What new developments in MG management can we expect in the next few years?

In addition to FcRn receptor blockers and complement inhibitors, there are some B-cell and chimeric antigen receptor (CAR)-T therapies being explored. B cell–directed monoclonal antibody therapies^[17] can intercept autoantibodies and prevent the generation of an inflammatory response that contributes to the pathogenesis of MG. Similarly, CAR-T cells targeting B cells^[18] can lead to a decrease in autoantibodies and inflammation. Targeted treatments can help in the management of increasingly complex MG patients.