Standard of Care in Myasthenia Gravis


Nicholas Silvestri, MD, FAAN, reviews the standard of care and initial treatments patients with myasthenia gravis (MG) receive, as well as several new treatment options that have recently become available for MG (eculizumab, efgartigimod alfa-fcab, ravulizumab-cwvz).

Nicholas Silvestri, MD, FAAN: In terms of treating myasthenia gravis [MG], no patients are alike. There are some nuances from patient to patient. Things we take into account are age, comorbid medical conditions, and other medications. But most patients with gMG [generalized myasthenia gravis] start on a combination including pyridostigmine, which is an acetylcholinesterase inhibitor. Because pyridostigmine rarely works completely in a patient with generalized myasthenia gravis, we’re often concomitantly starting prednisone or steroids. But because prednisone isn’t a great long-term option for patients because of the numerous risks of adverse effects, we’ll put them on an oral immunosuppressant medication like mycophenolate or azathioprine. Because those medicines take about a year to become effective, we’re usually using steroids as a bridge. If patients don’t respond well to an oral immunosuppressant—it’s not controlling their symptoms, it doesn’t allow us to taper the dose of steroids, or if there are intolerability issues—the next line traditionally had been putting patients on intravenous immunoglobulin. Some people are still doing that, but most of us are moving on to efgartigimod, which is a recently approved fetal neonatal receptor antagonist. After that we’re considering complement-based therapy, such as eculizumab or ravulizumab. Because patients with myasthenia gravis may also experience exacerbations or crises of their symptoms, some of the therapies often employed in those situations are intravenous immunoglobulin as well as plasma exchange.

In terms of when to use the immunosuppressant or immunomodulatory therapies in patients with myasthenia gravis, I start them pretty much right away. Pyridostigmine, in and of itself, is rarely completely beneficial. You do need to address the autoimmune nature of myasthenia gravis. Though steroids work effectively and quickly, they’re not a great long-term option. I’m typically starting patients on immunosuppressant therapy from the get-go. Those medicines take about a year to become effective, so the sooner I start them, the sooner they become effective, and the sooner I can get patients off steroids.

In terms of treating mild or moderate patients vs severe patients, there are some differences. The treatment paradigm that I outlined a question or 2 ago is very relevant to patients with mild or moderate [disease]. When it comes to patients with severe [disease], that can be more difficult to manage. Oftentimes, you need to use a high dose of steroids. In situations when you’re using 60 or 80 mg of prednisone, that can lead to a lot of complications. You don’t necessarily want to keep patients on that high dose for that long. You might think to use something else and escalate therapy quickly because you don’t want to wait a year for an oral immunosuppressant to become effective. In patients with a little more severe course early on, in addition to transit use of high-dose corticosteroids, I may also go right to IVIG, intravenous immunoglobulin, or more recently to a medication like efgartigimod or ravulizumab a little early on in their disease course.

We’ve had a number of new agents approved for the treatment of myasthenia gravis, starting in 2017 with the approval of eculizumab and followed by the approval in 2022 of ravulizumab. Both agents are complement inhibitors—they block the conversion of C5 into C5a and C5b. When acetylcholine receptor antibodies—the pathogenic antibody in myasthenia gravis—activates complement at the neuromuscular junction, it causes complemented mediated destruction of the neuromuscular junction. Using eculizumab or ravulizumab and blocking the conversion of C5 into C5a and C5b reduces inflammation at the neuromuscular junction and prevents the formation of the membrane attack complex. It prevents this destruction of the neuromuscular junction. That’s how it works in myasthenia gravis. The other medication that was recently approved in late 2021 to treat myasthenia gravis is efgartigimod, a fetal neonatal receptor antagonist. Essentially, this medication is blocking the recirculation of pathogenic IgG—in the case of myasthenia gravis, acetylcholine receptor antibodies—as well as nonpathogenic IgG, back into the circulation. It’s effectively reducing antibody levels and preventing that antibody-mediated attack on the neuromuscular junction.

Based on the mechanism of action of the recently approved therapies, they’ve both been shown in clinical trials and real-world experience to be efficacious in the treatment of myasthenia [gravis]. They’ve both been shown to be relatively safe. I don’t think we know which is more effective. There probably isn’t an answer to that. Some patients respond better to complement inhibitors, and some respond better to FcRn. It would be spectacular if we had a biomarker that would allow us to understand who would respond better to what therapies early on, so we could get patients on those therapies feeling better sooner.

In terms of biomarkers and MG, we have a very good diagnostic biomarker in those cases: the acetylcholine receptor antibodies. We have MuSK antibodies in a subset of the population. We have electrodiagnostic testing, specifically single-fiber EMG [electromyography], but we don’t have a biomarker that predicts response to therapy well. We consider that the Holy Grail in myasthenia gravis, so hopefully we’ll have it soon.

Transcript edited for clarity.

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