Clinician Perspectives on Diagnosing and Managing Generalized Myasthenia Gravis

This interview has been lightly edited for clarity.

The American Journal of Managed Care (AJMC^®): How do you establish a definitive diagnosis of generalized myasthenia gravis? What role do serologic markers, electrodiagnostics, and clinical assessments play?

NOWAK: That’s an excellent question. A definitive diagnosis of myasthenia gravis, including generalized myasthenia gravis, is truly important. The background is that this is an autoimmune condition, and many times we need to utilize immune therapies or immunosuppressive therapies. The way we go about diagnosing a patient is based on their clinical symptoms as well as their exam findings. Myasthenia gravis presents with weakness, typically fluctuating weakness, where there is a fatigable component to that weakness. Based on a pattern of weakness and examination findings, we develop a suspicion for myasthenia gravis, and that typically results in us testing for some of the markers, including autoantibodies that we can detect in the blood. Those include acetylcholine receptor [AChR] autoantibodies, which can be seen in about 70% to 80% of patients with generalized myasthenia gravis, followed by MuSK [muscle-specific kinase] autoantibodies, which can be observed in somewhere between 5% and 10% of patients with generalized myasthenia gravis.

Electrodiagnostic studies also play a critical role, especially when there is a diagnostic dilemma or when patients test negative on the commonly tested antibodies, for instance, or if we want a more immediate answer to the question [of whether] they have myasthenia. So we do things like repetitive nerve stimulation testing, which can be abnormal in about 60% to 70% of patients who have myasthenia gravis, and also single-fiber EMG [electromyography], which is abnormal or positive in perhaps 95% or more of patients, although that’s less specific for myasthenia gravis. The interpretation of the electrodiagnostics is important so that we don’t misdiagnose patients with generalized myasthenia gravis as opposed to another neuromuscular condition.

Clinical assessments certainly play a role, and as I noted before, some of the examination features and symptoms, some of them not specific necessarily to myasthenia gravis, such as shortness of breath or weakness, all of those pieces together help us come to a conclusion and hopefully a definitive diagnosis.

AJMC: When distinguishing generalized myasthenia gravis from other conditions, what are the most common disorders that may have similar symptoms, and what do you look for to ensure the diagnosis is correct?

NOWAK: With muscle disorders in general, things like myositis can present with muscle weakness. Some of our patients with myasthenia gravis present with slurred speech or difficulty chewing or swallowing, which are referred to as bulbar symptoms. There is something called bulbar ALS [amyotrophic lateral sclerosis], or Lou Gehrig disease, that can present very similarly. Careful examination, looking at the findings as well as some of the electrodiagnostic features, is really important to establish a definitive diagnosis of myasthenia gravis. That is key because, once established, we typically move forward with immune therapies.

AJMC: Do you routinely distinguish among antibody subtypes, and how does this impact your treatment choices?

NOWAK: Antibody subtyping is important. For instance, AChR autoantibody–positive generalized myasthenia gravis is actually immunologically distinct from MuSK antibody–positive disease in that MuSK autoantibodies are IgG4, and so it is an IgG4-mediated disease. There’s no known role, at least as we currently understand, of complement. Based on the currently available targeted therapies, such as C5 complement inhibitors, which are currently FDA approved, that would not be something that we would give to patients with MuSK antibody–positive myasthenia gravis. It is important for us to understand which antibody subtype [we are dealing with] as we apply some of the newer medication options for our patients.

That stands to also be furthered with seronegative patients. The currently available FDA-approved therapies that we have are not for seronegative patients; there’s still a question mark as to whether there is clinical benefit in that subgroup. So, the limitation is there for the use of those treatments. That’s not to say that patients who are seronegative might not benefit. I think we still have a lot of work to do to examine that population and understand the role of certain therapies and how best to apply those therapies to patients with seronegative myasthenia gravis. It’s an ever-evolving process, but I think understanding the antibody subtype is important, as that can help us determine the most appropriate next step for our patients with myasthenia gravis.

AJMC: What are your criteria for initiating advanced therapies such as neonatal fragment crystallizable receptor (FcRn) antagonists or complement inhibitors? Do you base your decision on failure of steroids or immunosuppressive drugs, frequency of exacerbations, or steroid-related toxicity?

NOWAK: Any patient with inadequate disease control should be considered for some of the newer targeted therapies or advanced therapies. We do find from clinical trial evidence that an FcRn antagonist, for instance, or a C5 complement inhibitor has a time to clinical benefit that is rather quick; within a few weeks, by a month or so, patients who will respond start to have a response. Most of the time, the challenge with initiating some of the advanced or targeted therapies is insurance approval. And so, we do have to follow a step approach. For a lot of our patients, even in 2025, the initial treatment is corticosteroids or prednisone; then we consider some of the other oral immunosuppressive therapies that we’ve had available to us for the past 2 or 3 decades. One is called azathioprine, and the other is mycophenolate. Those are the 2 most commonly used, at least in the United States. However, that said, sometimes those oral medications are contraindicated in the setting of a patient having perhaps an underlying malignancy or a patient being of childbearing potential; in those cases, we wouldn’t utilize some of those oral immunosuppressive therapies.

Corticosteroids also have a limit from a toxicity perspective, as you mentioned. So, although a low dose might be reasonable in the short term, a moderate to high dose of prednisone in the long term is not reasonable or appropriate, and it is a significant burden for our patients. It is a bit nuanced, and the approach that I take is very personalized to the patient based on their age, perhaps their [sex], and their other comorbidities. For example, if someone has uncontrolled diabetes, even a small amount of steroid [such as] prednisone might not be best, so using an advanced therapy to stabilize that patient would likely be [not only] reasonable but also probably most appropriate. Similarly, if someone has difficulties with their weight and is morbidly obese, initiating a steroid therapy might not be best in the short term, but moving forward with some of the advanced therapies that can work in the majority of patients rather quickly would be important. Even a medication such as azathioprine or mycophenolate, the 2 oral medications commonly used in the US, can take several months to achieve clinical benefit. That’s a long time for patients to wait if they [want] something that works quickly to help control their disease. And also it is a potential risk if you don’t control disease quickly because the patient may have a further worsening and even a myasthenic crisis or an exacerbation. That’s a very complex answer, but I do think taking into consideration the many factors of one’s patient before making a decision is important.

AJMC: When choosing among targeted agents, such as efgartigimod, rozanolixizumab, zilucoplan, or ravulizumab, do you consider route of administration, antibody status, comorbidities, and patient preference?

NOWAK: Absolutely. Let me start with antibody status, which is important. For instance, MuSK antibody–positive patients would not be eligible for complement inhibitors. The 3 currently available complement inhibitors are eculizumab, ravulizumab, and zilucoplan, as that’s an IgG4-mediated disease with no known role of the complement system. And [they’re] not approved for MuSK antibody–positive patients as opposed to, for instance, the FcRn antagonists. Those were initially approved for AChR antibody–positive myasthenia gravis, but some recent approvals of the FcRn antagonists also include AChR antibody–positive and MuSK antibody–positive patients. It’s important for us to know what the antibody subtype is, but probably less important for the FcRn antagonists in terms of selecting a choice. But you would probably, based on insurance authorization, go with one that has a dual indication for both autoantibodies.

Route of administration is something that we consider all the time. Some patients have poor venous access or veins, and so intravenous or chronically infused medication can be challenging. Utilizing a subcutaneous option for that patient is important to consider. Also, some of the medications that are administered subcutaneously can be self-administered. So, the route of administration matters based on the patient’s lifestyle and their ability to go to an infusion center or have home infusions or home injections, depending on their schedule, and then also the frequency of administration.

These are all very personal to the patient, and we consider them. My approach is to review the options available with the patient. The way that I go about framing it is based on the mechanism of action and the choices under those umbrellas. So, the 2 FDA-approved mechanism-of-action umbrellas, at least for generalized myasthenia gravis, would be the FcRn antagonists and the C5 complement inhibitors, and then we should review those with our patients. We certainly have other options that are not FDA approved, and perhaps other options coming in the near future will [necessitate] an expanded discussion with our patients as to the pros and cons and the differences in frequency, route of administration, and things of that sort.

AJMC: How do current treatment guidelines, such as those from the Myasthenia Gravis Foundation of America (MGFA), American Academy of Neurology (AAN), or international consensus guidance, inform your clinical decisions?

NOWAK: The guidelines or guidance publications provide a framework by which we approach treatment for our patients. None of the guidelines or guidance statements necessarily tell you that this is what you do for every patient in a very systematized manner. Often, we’ll start patients on pyridostigmine, then move forward to corticosteroids, and then consider a nonsteroidal oral immunosuppressive therapy. Then, depending on how a patient does, we move forward with some of the advanced therapies—complement inhibitors, B-cell depleting therapy, FcRn antagonists—so it’s pretty nuanced. I think they provide a framework by which physicians, specifically neurologists in this case, can approach a patient and their treatment journey.

AJMC: Are there any recent updates from the MGFA or AAN regarding the use of FcRn inhibitors, complement inhibitors, or thymectomy?

NOWAK: The most recent update to the international guidance was in 2020, and it was published in 2021 in Neurology.¹ There is currently an update to that guidance underway, but it’s not yet available or published.

AJMC: What clinical markers or end points guide your decisions to continue, switch, or discontinue advanced therapies?

NOWAK: The best clinical marker that we have is how a patient is doing: their examination and their symptoms, and how their symptoms might fluctuate and impact their everyday activities. That’s primarily what we use to help guide our decision-making in terms of the advanced therapies—and all therapies, but certainly the advanced therapies. For instance, once a complement inhibitor or an FcRn antagonist is initiated, based on the clinical trial data, patients should start to see benefits within several weeks. We do monitor for clinical benefits and whether that benefit is complete or incomplete. Not all patients will respond to all therapies. There’s no way for us to necessarily predict ahead of time. If there is a lack of response or an inadequate response to treatment with some of the advanced therapies or targeted therapies, we look to further optimize that, whether that be further optimizing the schedule or looking to make a switch or even looking to add on an additional therapy with the understanding that whatever therapy we initiated was beneficial but inadequate at completely controlling the patient’s myasthenia gravis.

In terms of thymectomy, it is done for patients with thymoma. Thymectomy is also done for patients with generalized AChR antibody–positive myasthenia gravis. We typically recommend it for younger patients. The thymus does shrink over time, so as we get older, it turns to fat, and the likely benefit of thymectomy is probably less. The best data we have for the role of thymectomy are from the international thymectomy study in myasthenia gravis [phase 3 MGTX; NCT00294658].² For the patient population enrolled in that study, the average age was in the 30s. In an evidence-based manner, we do apply thymectomy and we do advise thymectomy in younger patients, for sure. That doesn’t mean that it won’t be beneficial in patients who are older, but certainly for those younger than 50 years, thymectomy should be very strongly considered, in my view. The thing with thymectomy that we need to keep in mind is that clinical benefits are not immediate. It can take several months and sometimes even a year or longer to appreciate clinical benefits in those who have undergone thymectomy.

AJMC: How often do you reassess patients for therapy optimization? Do you have a plan for eventual de-escalation or reinduction if stable?

NOWAK: Most of our patients are seen in clinic every 2 to 3 months after their initial diagnosis to optimize their treatment plan. Again, it depends on the severity of their generalized myasthenia gravis, which can range from relatively mild to quite severe. We see the sicker patients more often, certainly every 2 to 3 months. But as the patient stabilizes, the visits become less frequent, and so we’ll see patients every 4 to 6 months. Most of our patients are seen about twice a year in the office. Usually, the frequency is much more intensive during the first 1 to 2 years until we get a good handle on what medications they need for disease stabilization and maintenance and/or good control of their condition, depending on how stable a patient is.

For instance, if we utilize steroids for our patients, if the patient has good response and good benefit, and we’ve replaced it with some other alternative medication, we will taper the prednisone slowly down to hopefully off to zero. In terms of some of the other medications that we have, it’s very much dependent on how a patient is doing. This is a chronic condition, so most patients need to be on some form of chronic maintenance therapy for their myasthenia gravis.

In terms of eventual de-escalation or reinduction, some of our patients, as we optimize their plan of care or try to decrease their amount of immunotherapy, do have a worsening of their myasthenia gravis during that period. Sometimes, the worsening is triggered by infection, for instance, or other types of stressors such as surgery, so in those cases, there’s a reason for that. But if the myasthenia gravis starts to worsen again, we do need to intensify their immunotherapy regimens.

AJMC: What do you find exciting about the ongoing research into new therapies for generalized myasthenia gravis?

NOWAK: There are some new emerging targeted therapy strategies that focus on upstream mechanism of action, including targeting B-cell medications that look at either CD20-directed B-cell depletion or CD19-directed depletion, as well as some of the chimeric antigen receptor T-cell or cell-based therapies that focus on targeting B cells. Many of these are under investigation or their trials were recently completed, but it’s really exciting that we might in the future have another mechanism of action beyond complement inhibition and FcRn inhibitors to add to our toolbox for the treatment of generalized myasthenia gravis.

References

1. Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-122. doi:10.1212/WNL.0000000000011124
2. Wolfe GI, Kaminski HJ, Aban IB, et al; MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-522. doi:10.1056/NEJMoa1602489