Insights Into the Current and Future Treatment of Myasthenia Gravis

James F. Howard, MD (left), and
Nicholas J. Silvestri, MD, FAAN (right)

MYASTHENIA GRAVIS, a chronic autoimmune disease characterized by weakness and rapid fatigue of any muscles under voluntary control, has no cure. Its course is variable and is often progressive. Prior to corticosteroid treatment, approximately one-third of patients would improve spontaneously, one-third had their disease worsen, and one-third died of the disease.^1-3

Despite this, there are therapies available to manage the disease, including some more recently approved agents that allow for control of the symptoms. These symptoms can include weakness of arm or leg muscles, double vision, drooping eyelids, and difficulties with speech, as well as difficulty chewing, swallowing, and breathing.²

The predominant symptoms of myasthenia gravis are caused by antibodies against the acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK), or other AChR-related proteins in the postsynaptic muscle membrane, which drive the current diagnostic testing for the disease. Although diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, detailed clinical and neurophysiological examinations are crucial for those who are antibody negative.3,4

In a recent NeurologyLive^® Peers & Perspectives series, a pair of experts in the care of myasthenia gravis discussed the goals of treatment and the needs of specific patient populations, among other topics. Those experts—JAMES F. HOWARD JR, MD, professor of neurology, medicine, and allied health at The University of North Carolina School of Medicine in Chapel Hill; and NICHOLAS J. SILVESTRI, MD, FAAN, clinical associate professor of neurology at the University at Buffalo’s Jacobs School of Medicine and Biomedical Sciences in New York—offered their insight into patients’ lingering needs.

Treatment Approaches in Special Populations

There are a variety of types of myasthenia gravis, which all have similar symptoms but may require different treatment approaches. Those types include congenital myasthenia gravis, ocular myasthenia gravis, generalized myasthenia gravis, transient neonatal myasthenia gravis, and juvenile myasthenia gravis.

For individuals with ocular myasthenia gravis, Silvestri shared that his approach often includes the use of pyridostigmine as monotherapy. However, Howard pointed out that this may not always provide complete relief. Despite this, the method of treatment in these instances may not differ much from that for generalized disease, Silvestri explained. Regardless, it can require an individualized approach, he said.

“When I talk about individualized approach to therapy with the residents, I say, ‘If it’s an older patient with mild nondisabling ptosis and it prevents them from reading late at night, but they can [live] with it, that’s probably OK—and that’s a generalization,’” Silvestri said. “But if it’s an airline pilot who has intermittent diplopia or ptosis that causes [them] to be functionally blind, that’s a big problem. We have to get more aggressive about that.”

Individuals with ocular disease can be debilitated by it, Silvestri continued, particularly if treatment with cholinesterase inhibitors falls short. In those instances, he said, he turns to steroid treatment. “[For] those patients I can’t get on a low enough dose of steroid where I feel comfortable that the risks and benefits are somewhat maximized—at least that ratio is maximized—I will move on to an early immunosuppressant. I have a couple [patients who] had quite severe ocular myasthenia who are maintained…long-term [and are] doing really well on mycophenolate,” he said.

Howard said he believes the paradigm has shifted for this population, with more recognition of ocular symptoms being progressively difficult to treat. He explained that MRI studies have suggested that the longer these symptoms occur, the less potential there is for improvement, because the motility muscles atrophy.

“It may change some of the lack of aggressiveness that we have, and [cause us] to become even more aggressive to try to get these under control,” Howard said. “We know there’s a subgroup in South Africa, for instance, [of White patients who have] become refractory to therapy and then never recover.”

When it comes to the population of patients with MuSK-mediated myasthenia gravis, Silvestri noted that treatment with rituximab (Rituxan; Genentech) is his mainstay approach, as the literature are mostly aligned on the effects of B-cell–depleting therapy in myasthenia gravis. He explained that he will often stabilize a patient on steroid treatment, after his experience garnered less than perfect results with oral immunosuppressants. Howard echoed this with his approach, noting that he generally treats with 2 cycles of rituximab, waits, then adjusts as needed.

“[Patients] would have residual symptoms that were often disabling. As you know, it tends to be a little bit more of a severe phenotype. Honestly, the [past] few patients I’ve diagnosed with MuSK, I’ve gone fairly early to rituximab and often it takes just 1 cycle to give them a pretty long-lasting response. It does seem like an aggressive approach, but it’s been quite successful in my experience,” Silvestri said.

Howard inquired about Silvestri’s methodology for pediatric patients, a group for which Silvestri said it is important to consider thymectomy. Both experts expressed that high-dose steroid treatment is often undesirable because of growth and behavioral issues. Howard noted that he will use lower doses of steroids and will often utilize intravenous immunoglobulin because it can be administered at home. “I think that’s going to change,” he said. “I think there’s a role for our newer therapies in these kids, and we’re having success.”

Similarly with immunosuppressant therapy, long-term treatment can have unwelcome results for younger patients, particularly for girls. “Female children become women of childbearing age. I do worry about those medications in women of childbearing age that have potential teratogenic properties. [It’s] something to keep in mind. I would say I employ thymectomy in those children fairly frequently, and I do try to minimize the doses of other medications just to try to mitigate [adverse] effects,” Silvestri said. For patients who are pregnant, the pair noted that pyridostigmine, prednisone, and intravenous immunoglobulin are all safe to consider.

“It’s our firm belief that anyone who is pregnant with [myasthenia gravis] needs to be followed in a high-risk pregnancy clinic,” Howard said. “And you, as a team, take care of the patients as you taper them off their immunosuppressants. Some feel that azathioprine is safe. I disagree with that. There’s very old literature that [says] it’s second generation that has teratogenic effects— not first generation—and that scares me to death, so we’ll pull them off. We will use prednisone [because it] does not cross the placental barrier. But it’s the adverse events to the prednisone in [the mother] that then subsequently affect the fetus—hypertension, diabetes, etc. But prednisone doesn’t cross. From that perspective, it’s fairly safe.”

Howard added, “With the neonates, we treat as if they were whatever that subtype is as a child, other than thymectomy, which I won’t do on neonates. But I’ve often done plasma exchange. Not using a big system, but rather small-volume removals and spun down and reinfusion, and that’s been effective as well.”

Unmet Needs and Future Directions

Despite the progress in treatment and the ongoing development in the pipeline, there are lingering needs for those with myasthenia gravis. Seronegative individuals face difficulties because many treatment approaches, including complement inhibitors and neonatal Fc receptor (FcRn) antagonists, are not accessible to them.

“For patients with severe ocular disease—those who maybe we don’t treat aggressively enough—there’s an unmet need. And, certainly, [there’s an unmet need] in patients who don’t respond to any of the therapies that are currently available,” Silvestri said. He also noted that although response rates with complement inhibitors and FcRn antagonists are quite good, not every patient is going to benefit. “There is going to be a minority of patients where other options are necessary,” he said.

“In addition, we need more data in our pediatric populations. We have trials going on with eculizumab [Soliris; Alexion], and trials will be starting with efgartigimod [Vyvgart; Argenx SE] in the pediatric population, [as well as] ravulizumab [Ultomiris; Alexion], [and] zilucoplan [UCB]—once it’s approved,” Howard said. He also said that the European Medicines Agency mandates for small trials in the pediatric populations have added to their knowledge in the past few decades.

For both Howard and Silvestri, one of the biggest lingering needs exists among the aforementioned pregnant and childbearing population. For Howard, the necessity is primarily for safety data during pregnancy. Good data exist for complement inhibition with eculizumab in paroxysmal nocturnal hemoglobinuria, but not in myasthenia. “[Although] it represents a very small portion of the total population, for your practice and my practice, it represents the bulk of the patients we see because no one knows what to do with them,” Howard said.

“The other area that is lacking, though that is starting to change, is information on health economics,” Howard continued. “We know the cost of medication [and] hospitalization, but we don’t have good handles on what the societal cost is. What does it cost if [you develop] diabetes because you’re on tacrolimus or prednisone, and what’s the lifetime cost now of managing your diabetes or severe osteoporosis?”

Watch the full 14-episode Peers & Perspectives^® series, “Updates in the Management of Myasthenia Gravis” here: www.neurologylive.com/mg-peers

REFERENCES
1. Myasthenia gravis fact sheet. National Institutes of Health. Updated March 2020. Accessed September 12, 2022. https://www.ninds.nih.gov/myasthenia-gravis-fact-sheet
2. Howard JF. Clinical overview of MG. Myasthenia Gravis Foundation of America. June 2015. Accessed September 12, 2022. https://myasthenia.org/Professionals/Clinical-Overview-of-MG
3.Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren JJGM. Myasthenia gravis. Nat Rev Dis Primers. 2019;5(1):30. doi:10.1038/s41572-019-0079-y
4. Dresser L, Wlodarski R, Rezania K, Soliven B. Myasthenia gravis: epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021;10(11):2235. doi:10.3390/jcm10112235