This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.
Nicholas J. Silvestri, MD: Welcome to Medscape InDiscussion on myasthenia gravis (MG). I'm your host, Dr Nick Silvestri. This is episode two of our first season, and today we'll discuss critical pharmacotherapy strategies for MG. What are the nuances of medication management with immunotherapies and acetylcholinesterase inhibitors? What are the important characteristics to consider when prescribing pyridostigmine, steroids, steroid-sparing agents, and newer therapies, such as complement inhibitors and the only Fc receptor antagonist efgartigimod? And how is the future of MG management shaping up? For expert guidance, we've invited Dr Neelam Goyal, clinical associate professor in the Department of Neurology within the Division of Neuromuscular Medicine at Stanford University in Palo Alto, California. Welcome, Neelam.
Neelam Goyal, MD: Thank you for having me.
Silvestri: Neelam, I will ask this to all my guests throughout the course of this series. Tell us what it is that made you want to specialize in neurology and focus on MG, and what do you do to stay engaged today?
Goyal: I would say that my path has not been straightforward. I don't know what it has been for you, but I went to medical school excited about emergency medicine, then fell in love with neuroscience, but more excited about brain and brain disorders. However, in residency I was very intrigued by neuromuscular disease, so more of the peripheral nervous system away from the brain. I remember a 3 AM consult for wrist drop. For those who don't know, this is when you cannot lift the wrist up. It was 3 AM, and I was completely exhausted, but I was very intrigued and excited to localize the lesion. So, that solidified my passion for peripheral nerve diseases. And then during fellowship and as an attending, I've been really attracted to MG and immune-mediated neuromuscular diseases. And you may agree that this is such a gratifying patient population. The patients can be very sick, but most do well, and it's a chronic disease. We follow them for years as they have children, sometimes even grandchildren. It's just very exciting to be part of that. In terms of your second question regarding staying up-to-date, I attend national meetings like the American Academy of Neurology (AAN) and American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) where I give talks. I listen to talks from you and other experts in neuromuscular medicine, and review posters. I also remain up-to-date by reviewing articles in PubMed and case-based series. Podcasts such as this are also a wonderful way to stay engaged.
Silvestri: That's great, Neelam, and I always enjoy collaborating with you and giving talks with you as well. And one of those talks that we've given together in the past is focused on pharmacotherapy of MG. So, without further ado, let's get into our questions. If you wouldn't mind, let's start with how acetylcholinesterase inhibitors work to improve muscle strength and reduce symptoms of MG. Give us a rundown.
Goyal: Before we can get into the nitty gritty, we must understand both the anatomy of neuromuscular junction transmission and the pathophysiology of MG. So, taking a step back, the nerve talks to the muscle, and it does that by sending a signal down the nerve and releasing acetylcholine, which then diffuses across the synaptic cleft; this is the space between the nerve and the muscle. Then, it attaches to an acetylcholine receptor on the muscle, which then leads to muscle contraction. This is how normal nerve-muscle contraction works. In this region, in the synaptic cleft, we have this enzyme called acetylcholinesterase. The job of this enzyme is to get rid of any excess acetylcholine that's remaining in the synaptic cleft. You can imagine in a normal state, you don't want this neurotransmitter, the acetylcholine, to keep exciting the receptor. The enzyme gets rid of the receptor, gets rid of the neurotransmitter acetylcholine. Now going back to MG: MG is an autoimmune disease. Your body is attacking primarily the acetylcholine receptor, so the transmission can't get through, and you get muscle weakness. Now, most of this is due to an attack against the receptor and abnormal muscle membrane. So, the way acetylcholinesterase inhibitors work is that we block this enzyme. If you think about it, it makes sense because in the disease state, we want the acetylcholine to hang out in the cleft for longer. So whatever receptors are remaining, there's a greater chance that they get excited, and we get muscle contraction. One medication that we have available that does this is called pyridostigmine. Regarding side effects, patients can have abdominal cramping, diarrhea, muscle contractions, cramps, and muscle twitching, and this can sometimes limit its use.
Silvestri: Absolutely. And I think what tends to be one of the limiting factors in my patients using acetylcholinesterase inhibitors are the side effects rather than lack of efficacy. But if your clinic patients are anything like mine, those with generalized MG typically do not have adequate treatment control purely with acetylcholinesterase inhibitors. So, take me through your treatment paradigm when it comes time to move on past acetylcholinesterase inhibitors, using steroids and immunosuppressants or what we sometimes refer to as steroid-sparing agents.
Goyal: Acetylcholinesterase inhibitors or pyridostigmine are a great way to start because they're usually well tolerated, and they work fast. They're in your system in 30 minutes, they peak in 2 hours, and they're out of your system by 4 hours. But as we think about the pathophysiology of the disease, this is a symptomatic or a Band-Aid treatment. We're not actually treating the underlying autoimmune attack. So, a reasonable way to start would be to start the patient on pyridostigmine. And because that works quickly, you can check in with them in a week to see if it's working. Most patients, like you alluded to, will continue to have symptoms or exam findings, especially if they have at least moderate-level disease and are generalized. At that point, we will move down the algorithm to the next medications — all of these will suppress the immune system. So, for me, my second medication will be steroids, and prednisone is the most often used oral formulation. Depending on the severity of the disease, I will typically add a steroid-sparing agent like mycophenolate mofetil or azathioprine. Steroids will take anywhere from 2 weeks or a month to work. But the steroid-sparing agents can take 3, 6, 9, 12 months to work. The goal of the steroid-sparing agent is to reduce the dependance on prednisone over time. But let's say the patient has a contraindication to prednisone, or some patients will say, "No, I'm not willing to do that." Then we must think about other therapies that are typically invasive therapies because we don't have a lot of options for other things that work quickly. Here we can consider intravenous immunoglobulins (IVIG). I would say efgartigimod as well. In some centers, they may go to plasma exchange, but it's a little bit harder at my center and a bit more invasive. If you're able to do steroids and a steroid-sparing agent, and the patient responds well, then our goal would be to start tapering the steroids.
Silvestri: Yeah, that makes a lot of sense, Neelam. I think the way we practice and the line of therapies that we employ are very similar. And I'm sure, in terms of putting patients on these therapies, you get good control of the MG, but sometimes it comes at a cost, right? It comes at the cost of side effects. Tell me about the types of side effects that you encounter with your patients on these various therapies and what kind of monitoring you do or risk mitigation that you perform.
Goyal: Starting from the top with pyridostigmine or our acetylcholinesterase inhibitors, I'll go through some of the side effects that they can experience, but no blood or imaging monitoring is required. Then going down the list, we have steroids — and as you know, lots of both acute and chronic side effects. This is a medication that we have a love-hate relationship. We love it because it's easy, it's cheap, and it works, but we hate it because of the multiple side effects. When I start a patient on steroids, I will check for any evidence of latent infection, so I'll check for tuberculosis, hepatitis, HIV. Again, the thought is that if I immunosuppress them, these infections may come out. We know steroids can cause issues with blood pressure and lead to diabetes as well as high cholesterol, so I will check their baseline hemoglobin A1c and their lipid profile. Steroids also can cause damage to bone health, especially at low doses. If I have a high-risk patient like an elderly postmenopausal woman, I may do a baseline DEXA scan. If it's a low-risk individual, then I may add a DEXA scan long term. But all patients will require vitamin D and calcium. Now, moving forward years into therapy, they do need to be closely monitored by their primary care doctor and sometimes endocrinologists to evaluate for some of the other long-term side effects. Regarding the steroid-sparing agents, depending on the medication that you start, you will need blood monitoring. Typically, that's monthly when you first start the medication or if you increase the dose. Then I typically switch to 3-6 months when they're on maintenance therapy. Most of these medications do have a risk of malignancy when used for multiple years. I do recommend dermatological evaluation. Then, of course, since we're immunosuppressing them, I do recommend that they're up-to-date on their vaccinations. Some of our newer therapies, like the FcRn inhibitors, do drop the IgG levels, but we do not need to monitor that. In terms of the complement inhibitors, the main thing is to vaccinate against meningococcal infection and keep up-to-date with that vaccination schedule.
Silvestri: That's a great rundown of the various side effects and monitoring, and I think it's equally important to talk to our patients with MG who are on these medications, not only about their symptoms due to MG, but really ask about the side effects and do our best to try to relieve those symptoms as well. Now, the next episode we have will be with Chip Howard from the University of North Carolina, and he's going to talk to us about the data behind the use of medications such as eculizumab, ravulizumab, and efgartigimod, but I'm curious, even before we get to Chip in the next episode, can you tell me how you've incorporated some of these agents into your practice?
Goyal: Yeah, absolutely. And I'm sure, Nick, you can echo this. Participating in a clinical trial really gives us a preview into how to use these medications and gives us some confidence to start using them early. And I think going in knowing the mechanism of action, the efficacy, and the duration of benefit, there is a sense of where they will fit in the algorithm. But I have to say, I'm still learning from my patients using these medications. I would say that for efgartigimod, I'm thinking about it at that second round when either I can't use steroids or perhaps they did not respond well to IVIG. It is IV, so we must think about how to get the drug to the patient. For some patients who have had plasma exchange due to crisis, about 10% will present in crisis — 5%-10% for those patients transitioning to efgartigimod as an outpatient, because we do think patients who respond to PLEX will respond to efgartigimod. I also think about it as a bridge therapy while we're waiting for my steroid-sparing agent, which can take 6-12 months to work. Regarding the complement inhibitors, I think it's a great option, especially with the longer-acting ravulizumab with every 8-week infusions. Here, I am thinking about them as long-term therapy because I don't think we have good understanding on how to taper patients off these medications. So, an ideal candidate for complement inhibition for me is maybe someone whom I can't get off steroids, someone who is not tolerating oral steroid-sparing agents. And I think it is reasonable that these medications may work fast. I have experience with one patient who was in crisis in the hospital. The patient had IVIG plasma exchange; we could not extubate the patient, and they responded beautifully to a complement inhibitor within days. So, each patient is unique, but I think about complement inhibitors more in that long-term-steroid-sparing-agent type of box or bucket.
Silvestri: That makes a lot of sense, and I agree with you. I think we're all still learning about these therapies, as they are relatively new with more on the horizon. As we look forward in the treatment paradigm of MG, what therapies in development are you most looking forward to seeing coming to market?
Goyal: Yeah, just like you alluded, Nick, it's such an exciting time to be treating MG. Like we said, most patients do well, but there is a lot of toxicity with our standard therapies. These therapies that are currently coming out — the FcRn, the complement inhibitors — it's very exciting because it's very targeted. They work with less of that systemic toxicity. However, they are targeting more downstream effects. If you think about the disease, you have some B-cell that's making this pathogenic antibody, and we're targeting its downstream effect. We're targeting the amount of these pathogenic antibodies or their ability to activate complement. I think what might be more exciting in the future — and patients always say that the Holy Grail is they want a cure — is if we could selectively attack that B-cell that's making the antibody. And here, I'm getting to CAR-T therapy as that upstream benefit. I am excited to see these therapies, of course, with the thought about side effects and that balance as well.
Silvestri: Excellent. Thanks so much, Neelam. After having said all this, what would you like listeners to do differently after hearing this podcast?
Goyal: Being at a tertiary center and seeing patient referrals for MG, there are two things that I see that I would love our listeners to practice differently. One is suboptimal treatment. MG is a rare disease. But in my clinic, we see a lot of MG. We feel very confident with it, and we feel confident with these medications — both the standard and the new therapies. If you treat patients with MG, please let your goal be normal or full remission. We want the patients to go back to normal, and we feel that we can do so in most of these cases. So, please don't stop at pyridostigmine. If you do feel uncomfortable with the newer therapies, with immunosuppressives, we are here to help you. So, number one, the aim is we don't stop at suboptimal treatment. The second thing that breaks my heart is seeing a patient on high doses of prednisone for prolonged periods. Recently, I saw a 25-year-old woman who has been on 40 mg of prednisone for a year. And that's just not okay. I think our community doctors are doing a great job, but these medications have a lot of toxicity, and [we have many alternatives to steroids]. I would say you want to taper to 10 mg or lower. If you cannot get there, please try other medications. Think about the newer medications. And, of course, we're here for you if you need to send your patient to an academic center. We're happy to help.
Silvestri: I can certainly echo those sentiments. I think that we really need to shoot for normalcy or quite near normalcy in our patients with MG, because with all these therapies that are at our disposal, that is a reality. That is something we can make happen. Neelam, thank you. You've done an excellent job of outlining the pharmacological treatment of MG, and I've really enjoyed this discussion with you here today.
Goyal: Absolutely. Thank you for having me.
Silvestri: Of course. To our listeners, thanks for joining our discussion on MG with our guest, Dr Neelam Goyal. There's much more ahead in the coming episodes, so be sure to check out the Medscape app and share, save, and subscribe if you enjoyed this episode. I'm Dr Nick Silvestri for Medscape InDiscussion.
Safety and Efficacy of Eculizumab in Anti-acetylcholine Receptor Antibody-positive Refractory Generalised Myasthenia Gravis (REGAIN): A Phase 3, Randomised, Double-blind, Placebo-controlled, Multicentre Study
Medscape © 2023 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Treating Myasthenia Gravis? Don't Stop at Pyridostigmine - Medscape - Jun 22, 2023.