Advancing the Treatment Paradigm for Myasthenia Gravis and Looking Toward the Future

Nicholas Silvestri, MD, FAAN

The origins of treating myasthenia gravis (MG), a rare neuromuscular disorder, began in the early 1930s, with the first therapies—physostigmine and neostigmine—followed by the first thymectomy in 1936. Since then, the toolbox to treat the disease has grown exponentially, with 5 major approvals in the past 15 years. Among them include mycophenolate mofetil in 2008, rituximab (Rituxan; Genentech) in 2012, eculizumab (Soliris; Alexion) in 2017, efgartigimod (Vyvgart; Argenx) in 2021, and ravulizumab (Ultomiris; AstraZeneca) in 2022.

In addition to newer therapies, options such as azathioprine, cyclophosphamide, intravenous (IV) immunoglobulin (IG), corticosteroids, and plasma exchange have all been available to patients with MG for nearly 3 decades. As the treatment paradigm continues to expand, the need to keep clinicians educated and informed remains paramount, according to Nicholas Silvestri, MD, FAAN. At the 2022 American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) annual meeting, Silvestri delivered a talk about the evolution in the treatment of MG, including the common immunosuppressive agents used, and the safety and efficacy profiles of each treatment.

Silvestri, a clinical professor at the University at Buffalo, sat down with NeurologyLive^® to discuss the reasons for choosing this topic, the advancement in MG therapeutics, and treatment approaches to key in on in the near future. He also provided context on the complexities of using multiple therapies, the importance of adverse effect profiles, and the need for a comprehensive understanding of other conditions or medications being used.

NeurologyLive^®: As the treatment landscape has grown over the past decades, what are the most noticeable differences in the care paradigm?

Nicholas Silvestri, MD: Initially, the treatment of myasthenia gravis was aimed at symptom control. Are the patient's symptoms controlled? End of story. What was really missed over time was the burden of the treatments that we use. What are the adverse effects of the treatments that we use to treat myasthenia? You had these situations where patients were doing better from a myasthenia standpoint but having other symptoms which aren't acceptable to them. As the treatment landscape has evolved, and will continue to evolve, we're not only paying attention to how well our patients doing, but also if they are tolerating their medications. Are they having any adverse effects in the short- and the long-term?

On top of that, I think that the idea behind how well people are treated in terms of efficacy is changing, too, because in the past, it was thought that if you're doing better than you were when you came to me with myasthenia, that's good enough. But now, we're really trying to push the envelope a little bit more. We're trying to make sure that we can do the best and, if we can, get patients with myasthenia to be asymptomatic or minimally symptomatic. There's a change in tolerance of how well we accept adverse effects, but also, will we be able to make people with myasthenia live happy, healthy, normal lives?

What questions are being asked when trying to figure out the optimal treatment for these patients?

It's really talking to people and taking into account what symptoms they're affected by and their other medical problems. What other medications are they on because the treatment decisions have to be done on a patient-by-patient basis. What might be a good choice for one patient might not be a good choice for another patient, either because of potential adverse effects, other medications they’re on. Other considerations include oral versus subcutaneous versus IV. It's truly a patient-by-patient decision, and we have these discussions with the patients. Patients come to me sometimes very educated—they want to be on medication, X, Y or Z. And sometimes that's a completely appropriate request, but other times, I have to provide a little education, a little discussion, on why that particular therapy may not be the best for them and why another one another one might be at that point in time.

Are there adverse effects that can exasperate the condition even further?

At every patient encounter, I try to not only ask about the disease or the symptoms, but also ask about potential adverse effects of the medications they're on. If patients have adverse effects that are significant, that are impairing their quality of life, or making them modify their life in some way or another, then it tells me that treatment is not working for them, or I must adjust the dose or think of a new medicine. In terms of tests, there aren’t any in particular I use. Most patients with myasthenia have acetylcholine receptor positive disease and a small number have muscle-specific kinase myasthenia gravis (MuSK MG). In that case, it does matter a little bit in terms of one treatment or another. Acetylcholine receptor positive responds to some treatments, whereas MuSK does not, and vice versa. So that plays a role, but other than that, we don't really use tests other than if a patient has a low white blood cell count, or has a liver problem at baseline, we might choose a different agent based on that.

Are there combination therapy approaches?

There's a lot of complexity in that. Sometimes people are on multiple therapies. A lot of times what happens is we're using steroids early on to get control of the disease but recognize it's not really a viable long-term option. In most patients, we're using another medicine that might take a little bit longer to work, like mycophenolate mofetil or azathioprine, and then on top of that, people can be on acetylcholine esterase inhibitors, like physostigmine. Many patients, at least at the beginning, are on multiple forms of therapy. We try to simplify the regimen as much as we can. There can be [complexities with switching] because basically, you want patients to be stable. You don't want patients to experience any worsening in the context of a medication change. So sometimes, tapering one medicine while titrating the other can be complex, but the bottom line is what we're aiming for is maintenance of symptom control and fewer adverse effects.

What does the future of treating myasthenia gravis look like?

In the past couple of years, we've been lucky in myasthenia. We've had 2 major classes of medications approved, we've had some complement inhibitors, and we've had an Fr receptor (FCRN) antagonist. There continue to be more of those agents in development that will likely be approved in the near future. And then there are other therapies like B-cell therapies and other forms of immunological therapies that are in the pipeline, too. The treatment paradigm, from what we've been doing over the past few years in terms of steroids, oral immunosuppressants, maybe IVIG, plasma exchange in severe cases, is going to change a little bit. With these safer or [more] effective agents that worked fairly rapidly, like complement inhibitors and FCRN antagonists, what we're doing now in myasthenia in 2022 will be a lot different in 2027.

Are there any nonpharmacological approaches that are being used to treat symptoms of MG?

The main nonmedical approach that we employ is a surgical approach—it's the removal of the thymus in people that either have a tumor in their thymus, the thymoma, or in younger patients, in order to try to spare them from some of the medications or lower doses of medications. People have been doing thymectomy in myasthenia since the 1930s. Most recently, my boss, Gil. I. Wolfe, MD, published a paper several years ago that shows that it is in fact, a safe, effective treatment. That's one of the methods we employ. But I think, to speak to your point about holistically treating the patient, what it boils down to is listening to the patient, finding out what's important to them in terms of symptoms in terms of adverse effects, and really individualizing that therapy per patient so that we can get their disease under control with a minimum of adverse effects.

Transcript edited for clarity. Click here for more coverage of AANEM 2022.