Good morning, everyone, and thanks for coming. I'm Yubin Li, I'm from Cleveland Clinic. This session, we'll have a strong nucleus faculties. I just want to introduce briefly for the sake of time, Dr. Kleder is from Cleveland Clinic. Dr. McGriddon is from Massachusetts General Hospital. Marco here is still on the boat, but he will be here. I am from University of Vermont. And Dr. Neelam Goyal is from Stanford University. There will be a change on the schedule. Dr. Marco here will speak at last, and Dr. Neelam Goyal will speak as the third speaker. Without further ado, we'll start with Dr. Benjamin Kleder. So as I'm getting this loaded up, I just wanted to start by thanking Dr. Li for really chairing this session and getting this group together and including me. I think this is a really important and timely debate that we have in the neuromuscular community. And my hope is that this session really fosters some ongoing conversations amongst us about how we can wisely and responsibly use a lot of these new tools that we have at our fingertips for the treatment of patients with myasthenia gravis. My position in this debate is going to be that we should continue the use of traditional immunotherapies for patients with MG. I have no financial disclosures. And to start, just so everyone's on the same page, I think we need to define what traditional therapy is. And that's really defined as immunotherapy that's utilized for MG patients prior to the approval of eculizumab in 2017. So that includes corticosteroids and non-steroidal immunosuppressive treatments, things like mycophenolate and azathioprine. That's really gonna be the bulk of my discussion. It also includes rescue therapies, immune globulins and plasmapheresis, thymectomy, and also rituximab, I consider in this category. Just based on the amount of time that we've been using it, almost 25 years, its cost, and also its mechanism of action of actually reducing antibody production, I think it really aligns it more with this traditional immunotherapy camp. As opposed to newer or novel therapies, really come in two groups, complement inhibitors and FCRN antagonists. So in thinking about my position, I really was kind of thinking if I had MG, what would be the ideal therapy for me? Well, I would want a therapy that was effective, tolerable, and safe. I think that goes without saying. I would also want a therapy that I maybe didn't have to be on for the rest of my life, or at least a therapy that the dose of it could be reduced over time. I would want something that's affordable and something that's convenient that didn't tie me to an infusion or an injection. And I would argue that only traditional therapies meet these criteria. We don't know if patients treated with novel therapies can have their dose reduced over time. We don't know if novel therapies can lead to sustained remission. Certainly, these treatments aren't affordable and they're not convenient. So I really think I have the easiest platform of the morning, and that's arguing for these traditional therapies. And I think there are several pillars that really support their continued use. These are effective for the majority of MG patients and can be used in populations that don't have access to novel therapies like seronegative individuals. These are affordable. They can lead to remission in a significant portion of patients. They're safe and well-tolerated. And also one thing I think that's difficult to quantify is just our experience with these drugs, how long we've been using them. They have a very well-known side effect profile, which I think can't necessarily be said for some of the novel agents. How are we doing with traditional immunotherapy? The answer is quite good. So this was from the Duke Retrospective Registry that followed almost 400 patients. And the treatment goal was minimal manifestation status or better. So minimal manifestation status is no functional limitations from MG but may have just mild weakness on exam. And you can see after a couple years, greater than 80% of patients are reaching this goal. And it was demonstrated that patients who underwent thymectomy were more likely to reach this optimal outcome. This was also borne out in a prospective trial, the MGTX trial. On the left, you can see the Kaplan-Meier curves for both prednisone and thymectomy plus prednisone groups. And again, after a couple of years, the majority of patients do reach minimal manifestation status or better. On the right, those curves demonstrate how many patients can be actually completely withdrawn from prednisone and still maintain this minimal manifestation status. And again, the red curve being the thymectomy patients were more likely to maintain this optimal outcome despite being totally withdrawn from prednisone. Now, many of the trials of these novel agents are using a slightly different outcome measure and that's minimal symptom expression. That's defined as an MGADL score of zero or one or an MGQL score of zero to three. So I think it's helpful when we're kind of comparing some of this historical data to these new trials to really understand how these two metrics really track with one another. This was a study that looked at 85 newly diagnosed generalized MG patients. They were all treated with corticosteroids and about half also received a calcineurin inhibitor. And you can see after about two years, the patients who achieve minimal symptom expression is very similar to the percentage of patients who are in minimal manifestation status and on low doses of prednisone, five milligrams a day or less. So these metrics tend to track pretty well with each other after a couple of years. So if we use that previous trial, the traditional therapy trial that demonstrated that after six months, 45% of patients are in minimal symptom expression. After two years, that percentage increases to 60% and compare that to these novel agents. I think it's pretty plain to see that not as many patients in these newer trials are reaching this metric. I think another thing that I want to point out is in some of the open label extensions, it doesn't seem like the longer patients are on these drugs. It's increasing the percent that reach this minimal symptom expression. Now, I'm comparing trials. These are different patient populations. But I think this really calls into question the thought that these novel therapies are better. And I'm gonna harp on this a lot during my portion, that we really need comparative effectiveness trials in the MG world. We really need to understand, are these newer treatments better? Because I think comparing some of these trials, I'm not so certain. For the next portion of my talk, I'm gonna actually kind of parse through some of each of the different components of traditional therapy. The first one being corticosteroids. So many historical cohorts that looked at corticosteroids demonstrated that these are very effective. 80 to 90% of patients either are in remission or experience marked improvement when treated with corticosteroids. Their onset of action is relatively quick. They can be used and maintain minimal manifestation status at relatively low doses. I think it's also important to note that the dose can be tailored to the patient's disease severity. So patients with mild to moderate disease don't necessarily require high-dose prednisone for disease control. And even in those who do initially require high-dose prednisone, the dose can be rapidly tapered. So again, thinking about some of these historical cohorts where 80 to 90% of people experience either marked improvement or remission, and comparing it to some of these novel therapies, what's reported in a lot of these novel trials is a two- or three-point improvement in an MGADL score. A two-point improvement is thought to be a clinically significant difference. And what you can see with these novel therapies is that a quarter or more of patients don't respond in these trials at all to these novel therapies. And when you compare the response of these novel therapies to placebo, the MGADL improvement is modest. So I think it would be fascinating if we had a trial that compared just prednisone monotherapy to one or more of these newer agents in newly-diagnosed generalized MG patients. My money's gonna be on steroids. Yes, corticosteroids do have toxicity. There is a risk of transient worsening when you start. That worsening is often very mild. I think it's important to recognize that steroid toxicity is dose- and duration-dependent. And many of the side effects from corticosteroids actually exhibit this threshold effect where the side effect is only seen above a certain threshold dose. And that dose for many of these threshold side effects is often five to seven and a half milligrams a day. So if we're able to get patients down to relatively low doses of corticosteroids, the likelihood of developing many of these side effects is very low. We also know that low-dose prednisone doesn't seem to affect quality of life in MG patients. And in myasthenia gravis and other autoimmune diseases like rheumatoid arthritis, which tends to afflict an older population, low-dose steroids can be used effectively and safely for long durations. So I really think that corticosteroids can be the initial treatment for rapid disease control. Their dose can be tailored to the disease severity, and you can begin to taper these drugs with a goal of getting patients down to a safe dose. In patients who have either an intolerance to steroids or you're not able to get down to a safe low dose, that's when you may reach for a nonsteroidal immunosuppressive treatment. These have been demonstrated to increase the likelihood of patients achieving minimal manifestation status. Many patients treated with these drugs can discontinue steroids. And those who can't, the majority are on an acceptably low dose. They can be used without steroids for mild disease. They're obviously easy to administer. And I think what we learned from the PROMIS-MG trial that was published just this last year is that these can be used at lower doses and are still effective for MG patients. Yes, we know that the steroid-sparing effect of these drugs does take a long time to realize. This was kind of a seminal trial in 1998 that looked at azathioprine that demonstrated that the steroid-sparing effect of this medication wasn't seen until probably after a year. But steroid-sparing effect is not the same thing as clinical effect. So this was a retrospective study published by Dr. Heyer here who demonstrated that patients treated with mycophenolate monotherapy, those are the shaded circles here, did have improvement in their disease by six months. So the clinical onset of these nonsteroidal treatments is probably less than six months. And similar data also exists for azathioprine. Again, another thing that I commonly hear is that novel agents are more tolerable than traditional therapies. And again, I question that. I compiled discontinuation rates either due to adverse event or death from a couple open-label extensions, one for f-cortigamide and eculizumab, and then kind of lined that up to the discontinuation rates for some of these longer trials looking at nonsteroidal immunosuppressive treatments. And I would argue that rates of discontinuation are the same between novel therapies and these older treatments. So again, I'm not so sure that novel therapies are in fact better tolerated. An important point about these nonsteroidals is that they can be tapered effectively over time. So retrospective studies looking at both azathioprine and mycophenolate demonstrated that two-thirds of patients who had stable disease were able to either discontinue these drugs or at least be on lower doses. Yes, a third of patients had exacerbations when the dose was lowered. I think that's further evidence that these drugs, in fact, do work. But patients can be tapered from these over time. And I think that has important implications for safety and side effect profile. I think this is a point that kind of speaks for itself, and that's that novel therapies are affordable, or sorry, traditional therapy is affordable, novel therapies are not. This was a study from 2019 that looked at out-of-pocket costs for some of these MG meds. At the time of this study's publication, only eculizumab was available for analysis. And you can see that a quarter of patients were expected to pay more than $3,000 a month for eculizumab and compare that to some of these other traditional therapies. One thing that I have mentioned is that traditional therapies do have the potential to put patients into remission. So large retrospective studies looking at long-term outcomes in MG and patients treated with traditional therapies demonstrate that 20% of patients can reach complete stable remission, so that's no disease activity off all immunosuppressive drugs. On top of that, anywhere from 20 to 40% of patients can also achieve pharmacologic remission. So again, very, very, very good long-term outcomes. Many patients are able to come off drugs over time. Now, some may argue that the evidence base for nonsteroidals isn't as good. We've had a lot of negative trials looking at things like mycophenolate, methotrexate, even chacralimus. And I think there may be some methodological problems there. Some trials have been too short. Many of these trials had an active comparator arm and that's steroids, and so it may be difficult to show an early effect of these drugs compared to steroids. But again, I think there really is an unmet need for additional comparative-effectiveness trials. Certainly, nonsteroidals do have a very, very small risk of cancer. Importantly, though, that risk is really influenced by dose and duration. Using these drugs for less than five years has a very, very nominal increased rate of cancer. So I think arguing for the importance of tapering people and getting them on lower doses to reduce this risk. So nonsteroidals really can limit steroid use over time. They, along with steroids, do have the possibility of helping patients achieve remission. These are affordable. And again, their dose can be reduced over time in patients with well-controlled disease, and this really limits the long-term side-effect profile of these drugs. In the last minute or two, I'm just going to touch briefly on immune globulin and plasmapheresis. Obviously, we all know that these are beneficial for crisis. There's class one evidence that they can lead to improvement in moderate to severe disease or worsening disease. I think something that I often hear is that f-cortigamide is like medical plasmapheresis, and I would argue that they're not the same thing. Plasmapheresis is removing complement components. It's removing inflammatory cytokines. So I don't think, especially in the context of crisis, that f-cortigamide is ever going to replace plasmapheresis. Some may argue that the steroid-sparing effect with IVIG has not been demonstrated. In that trial, though, that was published in 2023, I think that's because 63% of patients in the steroid-only arm were able to have a 50% dose reduction in their steroids. So showing a benefit over and above that is really difficult. Most trials that have looked at steroid-sparing effect have failed. It's just a very, very difficult measure to meet. Again, if we compare the effectiveness of IVIG in moderate to severe disease to some of these newer agents, looking at a change in QMG score from placebo, I would argue that the clinical effect of IVIG for moderate to severe disease is largely similar to these novel agents. And so I've just listed a couple of potential roles for IVIG. I would even consider this in a patient who is either steroid intolerant or a non-responder, somebody with severe disease. I would maybe reach for IVIG before a novel therapy, simply because the yearly cost of maintenance IVIG is a quarter of these novel therapies. So just from a cost perspective, I think this really kind of beats out the novel therapies. This slide, I think, could be a talk in and of itself. There's been a lot of debate over the years for the role of rituximab in the treatment of MG. I think we're learning that new-onset disease and younger patients seem to respond better. Certainly, I would argue that for musk patients, a CD20 depleting agent should be something you would reach for before thinking about a novel agent. Again, thinking about the cost, especially if you're going to use maybe one or two doses, similar to what was done in the RINOMAX trial, the cost of rituximab, it's not even in the same realm as some of these newer agents. So just a couple of final thoughts. Traditional therapy is very effective for the majority of MG patients. It might be more efficacious than newer therapies. But again, we need comparative effectiveness trials to know that for sure. These drugs can produce long-lasting remission. Their doses can be reduced over time, and this improves the safety and tolerability of the therapy. We have long-term experience with these drugs. They have a very well-known side effect profile. They're much more cost effective compared to newer therapies. And so at the end of the day, I think traditional therapy should still be considered the first line for the treatment of most MG patients. Thank you. Thank you. Thanks, Ben. Nice talk. Next, we have Dr. Guidon come to tell everything Dr. Cleter said was wrong. Okay, so I just want to give a little background also on the debate. So Yubing, you know, thank you very much for the invitation. He reached out to all of us and said, do you want to do a debate? And we said, of course, we'd love to debate. And then he assigned us different perspectives. So my main disclosure is, you know, that we were asked to argue for a certain perspective and obviously, you know, personal opinions are not being represented here fully. So my task today is to really refute the excellent talk that my colleague just gave. And we're going to say traditional therapy should be minimized for patients with myasthenia gravis. These are my disclosures. So when we look at, you know, what, so we, there's been some really good registry studies, you know, that have been done looking at what patients are actually on. And the myasthenia gravis patient registry is one of them. You know, we see that most, when we look at current treatment, past treatment, most patients have been on steroids, azathioprine, mycophenolate. And then, you know, a very low percentage have been on cyclosporine, tacrolimus, methotrexate, cyclophosphamide, not surprisingly, also rituximab, IVIG. Some patients have been on IVIG and plasmapheresis. And it's important to know that this was a cross-sectional analysis that was done, that was published in 2019. So it was right before some of the newer agents came commercially available. We also know that patients are on combination therapies. So this registry study also, you know, nicely illustrated the overlapping therapies that most of our patients require. With that, one could argue that they are not effective. So when we looked at past therapy, current therapy on the left, and looked at mean ADL and mean QOL on the right, these patients still had high MGADLs, still had high MGQOLs, even with traditional therapies. And so I'm going to argue today that immunosuppression of traditional therapies is too broad. The time to benefit is too long. The burden of side effects is too high. And the cancer risk is too elevated. First, immunosuppression is too broad. Our traditional therapies have a non-selective mechanism of action. The drugs were approved for other disorders. And most importantly, we cannot predict who will respond to which therapy. And this is a very bad combination with drugs that take a long time to onset of benefit. We start drugs and don't know whether we're going to have benefit for six months to up to 18 months. We also can't determine minimally effective doses a priori. Some patients require higher doses. And some, what we would typically consider to be sub-therapeutic doses, are actually therapeutic for our patients. And so I would argue, when we think about in the prior argument that side effects are dose-dependent, well, it would be very helpful to understand what dose a patient is going to need. And we just don't know that. We also see a high rate of off-target side effects due to broad immunosuppression myasthenia. There were some nice publications in the European Journal of Neurology in 2020, which looked at a high, which showed that there was a high rate of serious infections, which was defined as emergency department admission, emergency department visits or admission. In this cohort of MG patients, about a third experienced a serious infection, meeting that definition within five years of diagnosis. And it was usually a respiratory infection. Compared to age and sex match controls and adjustment for confounders, MG patients had a 39% increased risk of serious infection. We also see a high rate of infection in the placebo group of phase three trials. And I just highlighted two trials. Of course, there are others that I could highlight. But the placebo group in Regaine, who were on traditional therapies, 19% had upper respiratory infections. In ADAPT, looking at efgartigamide, 5% had upper respiratory infections and urinary tract infections. And the only reason I think that that rate was lower than the placebo group in Regaine is that it was a shorter study in the primary study. And we've all heard from our patients that the side effects can be worse than the myasthenia. And next, we're going to talk about the role of corticosteroids in myasthenia. And really, it is the best treatment and also can be the worst treatment. So we often think about bridge therapy in myasthenia. And so I live in Boston. There are lots of bridges over the Charles River. And when we're talking about bridge therapy and using prednisone for a short period of time, many patients think it's like this bridge, kind of stylized, short. It's a footbridge. You can easily walk over, no traffic. But in fact, for most patients, it's more like the Zakem Bridge, cable-stayed bridge, or the Longfellow Bridge, a steel rib arch bridge. And what happens is that there are two parallel bridges that we're traversing. One is efficacy, and one is side effects. And you don't know which is going to win out. You don't know who's going to get to your destination first. And the side effects of corticosteroids are very profound. We've all seen this in our patients. And they can be difficult to measure. We know that the side effects are wide-reaching, neuropsychiatric, mood changes, depression, anxiety, insomnia, ophthalmic complications, cataracts, glaucoma, infectious, cardiovascular, can cause fluid overload, dermatologic, which can really have a large impact on patients young and old with acne, impaired wound healing, metabolic and endocrine complications. We've all seen steroid-induced diabetes, which is profound. Some patients never recover from that. Weight gain, adrenal suppression, cushingoid features. We have gastrointestinal side effects, GERD, even gastric ulcers. And then musculoskeletal, osteoporosis increases our fracture rate. And there have been multiple efforts to quantify steroid side effects. There's the glucocorticoid toxicity index, which was published by John Stone, the adverse event unit published by Dr. Harrer. And we really have limitations in steroid use in children due to concerns about stunted growth, and the elderly due to their high risk of steroid complications. Sometimes dosing is limited, particularly in the elderly, by those complications. I would argue that steroids are really not an option anymore for our population in the U.S. Our rates of overweight and obesity in the U.S. combined are 73%, and 11% of patients in the U.S. have diabetes. So the burden is obvious for our patients, and really a main driver of reduced quality of life, particularly in our younger patients who happen to be a majority of women. Plus, steroids are a shared burden. It's a lot of work to have somebody on steroids. It requires a lot of in-between visit, monitoring, monitoring blood glucoses, bone density, electrolytes, weight, blood pressure, ocular pressures, cataracts, skin exams, fluid status, mood, sleep, infections. We have to ask about all of those things when we see our patients. Plus, we need to think ahead. We need to prevent complications with GI prophylaxis. We need to think about prevention of osteoporosis and PCP prophylaxis in some. There are also structural challenges to having patients on steroids. There's a PCP shortage that we know of. Patients travel long distances to sites with MG expertise, and we might not have a direct link to a primary care doctor to help manage and prevent complications. So in general, multiple providers may need to be involved to best keep our patients on steroids healthy. The other thing, this is the Harvard Bridge, which is a steel-hunched girder bridge, very, very long. When you're on that bridge, sometimes you feel like you're never going to get to your destination, and that's true for some patients on steroids. Approximately 20% to 30% of patients are resistant to steroids. They do not improve. Plus, now we'll shift our attention to some of the other traditional therapies. And so maintenance and rescue IVIG and plasmapheresis are really not benign. Reactions are common with IVIG. Approximately 80% of patients have a flu-like reaction. Greater than 50% have headache, and that can be mild headache all the way to aseptic meningitis. And IVIG can really be intolerable for patients with a migraine history. There are dermatologic adverse events and then infusion reactions. Some of the uncommon and rare events, which we've all seen, are thrombotic or embolic events, MI, stroke, DVT, and PE, hemolytic anemia. And then, of course, there is a risk of severe infusion reaction, renal dysfunction, hypotension, anaphylaxis. Risks of plasma exchange are related to central access. And we know that increasingly, particularly if our patients have had many IV therapies in the past, they are requiring central access when they get plasmapheresis. It also removes the neurobiologics. And there's limited availability in many regions, including a time commitment for many patients, which is a big difficulty when trying to maintain employment. And we know that plasmapheresis does not drive the disease into remission. When we think about side effects of our immunosuppressive therapies, I would argue that they're not insignificant. So we know from the PROMIS-MG trial, which looked at newly diagnosed patients and compared azathioprine to mycophenolate, we know that the rate of adverse events was high, and serious adverse events was particularly high, particularly with azathioprine. And most of those adverse events that were serious were hepatotoxicity, and they actually led to drug discontinuation. We know that about 15% in this trial, and we've all seen in our practices, mycophenolate can lead to severe diarrhea, which is really dose limiting and can lead to discontinuation for some. There is also a lot of lab monitoring that goes along with this, which is a burden for patients and a big responsibility for the physicians prescribing. Many times we'll get monitoring labs quite frequently after initiating azathioprine, and then also on mycophenolate, and that continues at a lower frequency, but indefinitely. Additionally, these drugs are, azathioprine is category D in pregnancy, and mycophenolate has a black box warning in pregnancy. So really limited in use for our women of childbearing potential. We also know that from Dr. Herr's work, which was recently published, that combination therapy leads to more higher burden of adverse events. And we saw from our registry study just how many patients are on combination therapy. In the adverse event unit study, being on three MG meds was associated with a higher burden of adverse events. And so these adverse events exist in isolation, but then also are compounded by being on multiple therapies. Our calcineurin inhibitors are not used very often in the US, but tacrolimus is used quite a bit in Asia. The side effects are hypertension, nephrotoxicity, and many drug-drug interactions, which really limit their use, particularly in our older population. We'll touch on rituximab. So rituximab also is not benign. There can be infusion reactions, sometimes require desensitization. Infection has a rate of approximately 15% to 20% of severe infections. Again, mostly pneumonia, but also CMV, PML, and PML. We think it's possible from the reported literature, though hasn't been studied systematically, that thymoma may increase this risk of infection. We can see on the right a patient who developed PML who had thymoma, was on rituximab. Additionally, hypogammaglobulinemia is common and can be very prolonged, even after discontinuation of rituximab, up to two years, and may be associated with this increased infection risk. And in some patients, it is so profound that it requires replacement IVIG. We also know that there can be viral reactivation, including hepatitis B, and we have to screen for this. And sometimes we are required to use antivirals. And lastly, we know that immunosuppression, particularly broad immunosuppression, causes reduction of host defense mechanisms, which detect and eliminate abnormal cells. Our traditional immunosuppressive agents may accelerate progression of actinic keratosis to squamous cell carcinoma. There's an increased risk of non-melanoma skin cancer, which has been studied in MG patients in Denmark. These patients were three to four times more likely to have been exposed to azathioprine for more than five years in patients who developed skin cancer compared to patients who did not. And compared to non-MG patients, MG patients without thymoma have a similar risk overall of cancer, but they have two times the risk of lymphoma. We also have to keep in mind that patients have comorbid cancer. So in a recent study by Dr. Dodd et al., almost 30% of our patients have a history of cancer, any thymoma, but also other cancers. And we don't know exactly what the immunosuppressive agents does to increase risk of recurrence or accelerate those cancers that exist. And lastly, maintenance therapies have a long time to onset of benefit and to maximal benefit. And so we know that particularly azathioprine, we can see in the light color here the beginning of benefit and then maximum benefit. We know that it can take up to six to 12 months to really start to have benefit and then maximum benefit is typically not reached until a year or more. Thymectomy also has, in most patients, delayed onset of benefit as it has been studied. Some of the other agents like rituximab and prednisone, IVIG, and Plex have rapid onset of benefit, but then obviously wearing off. So if you don't re-dose, then you have return of symptoms. So in summary, traditional therapies are non-selective, they're too broadly immunosuppressive, steroid side effects are intolerable for our patients, they're off-target side effects, we have an increased risk of cancer, and a slow onset. And so we're going to hear some arguments that are the counterpoints. We're going to hear about all of the new FDA-approved drugs for myasthenia and how they should be used and the rich pipeline. And I would argue that we're just not there yet. We need to minimize traditional therapies, but our existing drugs don't provide the solutions we need. We need better and additional symptomatic therapies and then increased ability to predict severe disease in response to therapy. We need targeted therapies that drive disease into remission, that can be tapered, are delivered orally or with infrequent self-injections, don't require frequent lab monitoring, have a good safety data in pregnancy and for breastfeeding, and have a favorable side effect profile with no significant long-term cancer risks. Thank you. Dr. Guidon, thank you very much. Now we will switch gears to the neurosurgery, and we'll have Dr. Goyal come up first. I just want to make sure, don't misguide Dr. Goyal's intensity. She can be very threatening. All right, thank you for that introduction. All right, for the next 16 minutes or so, my job is going to be to convince you that novel immunotherapies should be expanded in MG management. Here are my disclosures. So when I think about expanded use of novel therapies, I think about them in non-classical MG and ACHR-positive GMG in expanded scenarios. So for my talk, I'm going to review the rationale why the novel therapies should be used in these situations, and also a review of data. So before I start, I just want to mention two things. My slides are very data-heavy, and so to stay within a lot of time, I'm going to just really give you the punchline, but they are available to download and for you to review the data more closely. And like what was said earlier, these topics were assigned to us, so really I'm going to go with it, really try to push and make my case, but remember, this is really an exploration of data and not a recommendation or a treatment guidance. So with that, let's jump in. So seronegative generalized myasthenia is MG with no detectable antibodies in the serum. It represents about 10% of all-comer GMG, and these patients present the same as antibody-positive GMG. So what's the rationale? Well, seronegative GMG is felt to be antibody-mediated. Either these antibodies are not detectable by our current assays, or they're to antibodies to different targets that have yet not been discovered. We know from data that seronegative MG responds to immunosuppression similar to antibody-positive MG, and we have muscle biopsy evidence that seronegative MG, there is complement-mediated damage. So in summary, novel therapies should work in seronegative GMG. So what about clinical trial data? Well, no data for complement inhibition, but for FCRN inhibition, the ADAPT study allowed for a small portion of seronegative patients. There were about 18 patients in each arm, and as you can see, the seronegative patients had a robust response to F-gartigamide. Unfortunately, a similar response was also seen in placebo. But in ADAPT+, you could see that that response was even more robust, and it was maintained during the open extension. What about real-world data? So we have about eight cases in the literature with good response to ecolizumab in seronegative refractory GMG. And for FCRN inhibition, we have one case report and two relatively large care series. And if you look at the figures on the left, you can, on the right, you can see that after that first cycle, many of these patients are responding to FCRN inhibition. And currently, there is an ongoing trial of F-gartigamide in seronegative GMG, which is currently recruiting. Moving on to pediatric MG. So this is patients that have onset of MG before age 18. We typically think of these patients as having milder disease with more ocular MG. However, 10% of these patients will go into crisis. So here, we do have one phase three open-label study in adolescent patients of ecolizumab, which was weight-based. And as you can see on the figure on the right, with QMG and MG ADL data, you can see that rapid response of after just one infusion that's maintained up to 26 weeks. No case reports or case series that I was able to find, but there are multiple current ongoing clinical trials, so more data to come in pediatric MG. In regards to ocular MG, so this is MG that's restricted to the ocular muscles and represents about 15% of all-comer MG. So what would be the rationale for this expanded use and in what situations? So I would say that we can consider this in our resistant ocular MG patients. So we know OMG is not life-threatening, but can have a high impact on quality of life. Resistant ocular MG can require chronic and high-dose steroids, which we just heard are associated with many long-term toxicities. Also about 20% of ocular MG can lead to fixed weakness. So resistant OMG could be a subgroup where we can consider these novel therapies. Another case could be a prevention of generalization. So most patients that present with ocular MG are going to generalize, and currently there's mixed data on how to predict generalization or if immunomodulation can prevent this. However, if we had strong data that aggressive early therapy could prevent generalization, then this could be a subgroup where we could consider novel therapies. In regards to data, we don't have any clinical trial or case reports that I was able to find. However, for ecolizumab, efgart-tigimod, and rosanolixizumab, ocular subdomains of other MG outcome measures were reviewed in the Phase 3 trial, and it was showed that there was improvement. And currently there is a planned trial for efgart-tigimod in ocular MG that's planned but not yet recruiting. Moving on to MG with thymoma. So 10% of MG will have thymoma. We believe that patients with thymoma have a worse prognosis and may need novel therapies. Also, novel therapies can be used to stabilize MG prior to thymoma surgery. No clinical trial data, but in real-world data, we do have a case series from Japan where 5 out of 11 patients with thymoma responded well to ecolizumab. There's also a large case series of efgart-tigimod from the U.S. where 4 patients had thymoma at the time of treatment, and 3 out of 4 responded to efgart-tigimod. And there's also a single case report from the thoracic surgery literature of a 47-year-old that responded to efgart-tigimod and then had thymectomy with good surgical outcome. What about pregnancy? So we know that there is an increased risk of MG relapse in the third trimester of pregnancy and the postpartum period. So what's the rationale of using novel therapies in our pregnant patients? Well, really, the main concern is safety. We think that they should be efficacious. And what about considerations? Well, one is that if you have a young woman who's on a novel therapy and she's doing well and stable, because we're not sure if we should use these novel therapies in pregnant patients, you may have to taper the patient off this medication prior to pregnancy, and that could lead to a relapse. The other is physician behavior. We may be using novel therapies less in our women of childbearing age because we're concerned about toxicity if they were to get pregnant or the need to wean, and pregnancy may not be even in their goals. So we may be using them less. And third, we know that MG can get worse during that third trimester. These patients may not respond to traditional therapies. So here we have an unmet need. So currently, no clinical trial data. Regarding real world, there are two case reports of ecolizumab in pregnancy with good outcome. We have over 10 years of safety data of ecolizumab in other disease states with over 200 pregnancies, over 180 live births with no safety concerns. Regarding FCRN inhibition, there are pregnancy registries for efgartigamot and rosanolixizumab, but the data is not currently available. Yesterday at the MGFA, there was an abstract of a young woman who had efgartigamot in first and second trimester with good outcome. Moving on to checkpoint inhibitor-induced MG, or ICIMG. So what is the rationale here? So ICIMG can be new onset or relapse of premorbid MG. ICIMG has a more severe phenotype. In one case series, it had about a 30% mortality rate. These patients can be resistant to plasma exchange or IVIG and so may warrant novel therapy. And these patients tend to be largely antibody positive and generalized. So no clinical trial data, but regards to real world data, we have about four case reports of ecolizumab use in ICIMG with good outcome. And there's a case series of two patients with ICIMG that had good response to efgartigamot. Moving on now to ACHR positive MG, but in expanded scenarios, starting with MG crisis. So MG crisis is defined as worsening of myasthenic weakness requiring intubation or non-invasive ventilation to avoid intubation. So this occurs in about 12% to 16% of our MG patients. And about 20% of these patients are actually refractory to IVIG and plasma exchange. MG crisis is associated with a high burden of cost and high burden of disease with an estimated in-hospital mortality of 4.5%. And so we know novel therapies work quickly and with high efficacy, making a case for their use in this situation. So currently there's no clinical trial data, but how about real world data? So for complement inhibition, we have that same case series from Japan where seven out of the 11 patients were in crisis and responded well to ecolizumab. There is a case series of three ventilator-dependent MG patients, which you can see on the graph on the right. Each of them represents one patient and their MG outcome measures after initiation of ecolizumab, and you can see how robust and quick that response was. And there's one case report of Revilizumab in a 34-year-old patient in MG crisis, very refractory, plasma exchange, IVIG, rituximab, responded very well to Revilizumab and was able to be discharged after two weeks of the first dose. This is a really busy slide, but there has been recent explosion in the literature for data for using FCRN inhibition in MG crisis. So five different case reports and one large case series of 10 patients. And so if you look at the graph on the right top, you can see that with the initiation of Efgart-Tigimod, there's a nice response to the MG ADL. And as a reminder, the higher the number, the more sick the patients are, and the maximum score is 24. So you can see that these patients were very symptomatic and really did quite well with treatment. And on the bottom is a case report of a 47-year-old, very sick, refractory to many medications, responded very well to Efgart-Tigimod and was able to be discharged. What about varying dosing regimens? So this is really more for FCRN inhibitors that are currently given in a cyclical fashion. So as you can see with the results for the ADAPT study and myCaringi study, there's great robust response to the treatment, but once it's taken away, there can be return of symptoms. And this non-continuous dosing can really be problematic for our patients because we don't want the symptoms to come back. So there was a clinical trial, the ADAPT Next study, that looked at fixed cycles of Efgart-Tigimod versus giving Efgart-Tigimod every two weeks. And as you can see on the graph on the bottom right, both groups responded very well to Efgart-Tigimod and the response was similar. For rosanolixizumab, after completion of the Phase 3 study, they were enrolled into the open-label extension where there was one-to-one continuous dosing with the 7mg and the 10mg per kilogram. This was planned for 52 weeks but terminated early due to COVID. But as you can see on the graph, the response was maintained and there were no side effect concerns. And then lastly, what about early use? So as these novel therapies have come to the market, we have initially considered them for our refractory population. However, there is data that early use of fast-acting therapies can lead to better outcomes. So there is data for complement inhibition. So the ELEVATE study was a retrospective observational study that compared early ecolizumab initiators, which was defined at patients that started the medication within two years of diagnosis versus late, so after two years. And what the study showed was that early ecolizumab initiators had a 100% likelihood of having a greater than two-point decline of MGADL versus 61% of the late initiators. Also, the depth of response was greater in the early initiators, which had a median MGADL decline of 6.5 versus 3 in the late. So in summary, I hope that I've convinced you that novel therapies should be expanded in non-classical and ACHR-positive GMG in expanded scenarios. Here I have the color coding of the different levels of data that we have for each situation. But if we think about rationale, I hope I've convinced you that it exists robustly for all of these situations. Thank you. Dr. Goyal talked to me at least 10 times before today, and her only worry is about the time for her presentation, and I can tell you from that perspective, she did wonderfully. Thank you. We have the last speaker, my good friend, Dr. Heer, and he's going to tell you something negative about all these new therapies. So, first of all, thank you to the AANEM for allowing us to do this fun session today and to my colleagues for their awesome presentations. And I also wanted to thank them for making funny name tags. I picked Troublemaker because of this session. Anybody who hasn't seen them, go get one, they're pretty funny. So I'm going to talk a little bit about novel therapies and whether or not they should be restricted to specific MG populations. And rather than present this in a way that I feel like I know the answers or any of us know the answers, I really want to see if I can encourage people to think a little bit outside the box or how we might move forward as a community. So this editorial ran in the New York Times a couple of weeks ago from a former professor of mine who I don't agree with on very much, but I do agree with him on this, that thinking and learning cannot be outsourced and we need to encourage more sort of thinking among our students and among ourselves. And we need to sort of fight against what I call groupthink or what some people call groupthink. And in Myasthenia, I think the groupthink in Myasthenia is a few key points. So first, new treatments are safer and more effective than traditional ones. Second, people are healthier with MG in 2024 and have a better quality of life. Third, prednisone is the only medication that causes side effects. And fourth, new treatments will be cost effective. And I also just want to emphasize as I'm starting this talk that a lot of the developments that we've had over the last couple of years have been truly remarkable with the development of newer therapies in Myasthenia. It's been incredible to watch it happen. But I want to talk a little bit about the evidence. So when I think about choosing a treatment for a patient with Myasthenia, I often feel like I'm looking at the beer case at City Market in Burlington, Vermont. And I think of the concept of treatment value. So when we think about a treatment, we think about clinical benefit and quality of life over all the negative things that could be associated with a treatment. And the goals of therapy that we still hold true to in Myasthenia talk about achieving minimal or no symptoms for our patients with minimal to no side effects as the goals of therapy. So with an eye towards that, I'm going to emphasize some of the points that were made earlier by my colleagues. Dr. Claytor was talking about the number of patients who can achieve minimal manifestations or minimal symptom of expression in patients with Acetylcholine Receptor Disease. Because that's really what our patients want. They want to be asymptomatic. And I just want to highlight that a lot of the more traditional therapies are usually pretty good at doing this. Mycophenolate, Azathioprine, Rituximab all achieve a 60% to 80% or 90% minimal manifestations or better category status. Although it may take a little bit of time to get there, a year or longer. How does that compare to some of the newer therapies? Again, just to emphasize, this was already shown, but I think it's important to emphasize it. Eculizumab, Zylucaplan, Efgardagamod, Rosanolixuzumab, somewhere between 20% to 40% of patients are achieving minimal symptom expression, which is how it's described in these newer trials. However, one of the differences is that it seems to happen faster. So the trophy goes to the more traditional medicines for the depth of improvement for our patients. But as far as getting there quicker, the newer therapies may be a bit faster. So thinking about special populations, so new onset myasthenia may be a good time to think about a newer medicine or a more aggressive therapy to start. So there's some great data from Dr. Utsujizawa's lab in Japan looking at early induction therapy. And patients who were given very high doses of solumedrol and plasma exchange can achieve a very quick onset of minimal manifestations with 5 milligrams of prednisone or less, 40% within the first year. And it's a durable response that goes on, which is the green line there. And the response happens quickly. So minimal manifestations occurred in the first three to six months after getting this induction therapy. And it lasts for years going forward. And this is not typically how we practice in the United States, but we may need to move in this direction. And then the Rhinomax data looking at rituximab, again, this was given to patients early in the course of their illness with acetylcholine receptor patients. And 60% to 80% of patients achieved minimal manifestation status. And they did it quickly after the onset of these therapies, and it was durable. How do the newer medicines do? So we just saw the data from raviolizumab. And patients who are given raviolizumab in the first two years of their condition tend to have a bit more robust response. But again, emphasizing we're not talking about minimal manifestations on this slide. We're looking at a mean improvement in the ADL score, which was four points, which is not exactly minimal manifestations. And then another population that we might want to think about for newer generation therapies are the patients with refractory myasthenia. And we heard yesterday at the MGFA meeting about some of the different immunologic profiles of patients who've had disease that's been going on for a long time in the keynote address. And that may be why some of these newer medicines are effective for this category of patients that fall into the refractory category, where they've failed therapy with a number of different therapies. And the REGAIN trial of eculizumab studied just these patients in particular. And there was an excellent response with improvements in ADL for patients who weren't getting better on other therapies, suggesting an important role of complement for this particular cohort. More recently, there's some data on fgartugamod in the autoimmune refractory population as well, showing an improvement in the MG composite score as well. So I think, thinking about efficacy in special populations, I think traditional medicines do have a role in achieving minimal manifestations. Dr. Gudon was talking about being too broad with action in the immune system. And that may actually be a good thing. Maybe we need to target more of the pathways in myasthenia to get to that good clinical status. Next generation therapies probably have a big role in refractory patients. We need to understand better if therapies are more effective in earlier onset in MG. And I think a huge need for our community is that we need a biomarker to understand who's going to respond to which of the therapies we have. Because there are large groups of non-responders with traditional medicines and next generation therapies. And we need to understand these patients better. So now I'm going to move on to some of the reasons why we might want to restrict some of the newer therapies, or at least think about how we're going to use them. So again, thinking about treatment value, one of the negative things is side effects or adverse events. And we did a study a number of years ago that showed that adverse events are the biggest concerns of MG physicians and MG patients. So we really need to understand that for the therapies that we're going to expose them to. And in MG, I think one of the group thinks is that we think only about the side effects of prednisone. But I like to think of it more of an iceberg. And there are all these other therapies that also cause potential side effects. Or to be a bit more provocative, the iceberg of ignorance. It's easy to compare your drug to high dose prednisone. But what we need to do is compare our drugs to all those other medicines on the bottom of the iceberg. Dr. Katie Dodd's group in England published this paper this past year, which we saw some of the data for. And it was looking at long term side effects of mycophenolate, methotrexate, and azathioprine. And what she showed was that azathioprine was not a very well tolerated medicine. Many of their patients discontinued therapy. She also showed that 60 to 80% of patients with these therapies have side effects. And you can see in the dark bars there some of the ones that were more common. But I think it's good to understand that traditional therapies have side effects. In addition, next generation therapies also have side effects. And complement drugs, we have to consider the possibility of Neisseria meningitis. We have to vaccinate our patients. Now we have to give our patients prophylactic antibiotics for the first two months while they're waiting for vaccination status to come on board. For the FCRN inhibitors, we are seeing higher rates of infections in our patients. And we also have to consider the possibility of rebound symptoms in MG when we're driving antibody levels down. But I like to think of it as the table three and four problem. So every study's got one of these tables of side effects, but they're not comparable. We can't compare any of our medicines looking at one trial versus the next one with percentages of different types of side effects. So our group's been working on comparative side effect burden. Similar to Dr. Dodd's group, our group in Vermont saw 75% of our patients with side effects when we were asking them about them. And the adverse event iceberg in our small subset in Vermont, we actually saw two drugs with the highest level of side effect burden in our cohort. It was Eculizumab and Azathioprine. But most of these patients were on combination therapy, especially patients with Eculizumab. So I think what we're seeing is that the more therapies we give, as I've discussed earlier, the more likely we might be to have side effects. But I think we have a lot to learn. So in conclusion, on side effects, we need comparative adverse event studies looking at the negative side of the equation. Steroids are not the only source of side effects. We need to think about the long-term implications of our medicines, and we need to understand if the newer generation of therapies does indeed have a lower side effect burden. Now I'd like to move to the controversial topic of cost. When Dr. Gwathmey's group asked a number of physicians about what they considered to be the most important things to consider with newer generation therapies, affordability was second to side effect burden. So for all of you former or current bioethicists in the audience, I think we're all very good as physicians at the first three. So beneficence, doing good for our patients, autonomy, helping our patients make good decisions, and doing no harm to our patients. But it's really the fourth principle of bioethics that's relevant here, which is distributive justice. So while we treat patients, we also treat populations of patients, and we have limited resources. So my current and former mentor, the late, great Ted Burns, put up this slide, How Bad Can the Environment Can Throw Away One Plastic Bottle Bee? Ask 30 million people. So we have the Orphan Drug Act in the United States, which has really been a boon for development of drugs, as evidenced by yesterday's MGFA session, where we talked about countless new therapies on the horizon. And what does this drug act do? So it gives seven years of market exclusivity to a company who develops a drug for an orphan disease. There are 500 orphan drugs approved as of 2020, and the average orphan drug price increased 27-fold between 1998 and 2017. Back when Ted put these slides together a number of years ago, if 30% of patients with a rare disease were treated with an orphan drug at $100,000 per year, that would be $1 trillion. But as we all know, medicines for myasthenia cost more than $100,000 per year. So how does this compare, conventional versus next-generation therapy? So first I'm putting up a chart of conventional therapies, and I'll just say that it is very hard to find the cost of different treatments. I'm presenting what's in the literature. So prednisone, mycophenolate, azathioprine, rituximab range in cost from $180 per year to $20,000 per year, versus some of the newer generation therapies that range from $300,000 a year to $700,000 to $800,000 per year. And a study was done with the ICER group in Boston looking at cost-benefit analysis, and to achieve one quality-adjustive light fear with a year of eculizumab therapy, it would cost $3.3 million for one quality. Dr. Guptill did a study a number of years ago estimating the cost of treating myasthenia population in insured patients, and this is before next-generation therapies, and the average annual pharmacy cost was about $9,000. Compared to today, so just to do a thought experiment, if 10% of our patients were taking a newer generation therapy that's about 10,000 people, at an average annual cost of $500,000 per year, which is just the wholesale cost, that would be $5 billion per year to treat 10,000 patients, which is an astronomical number. So one might say, well, what is the cost to society of these patients, and how does that compare? This interesting study was done and published two years ago looking at some of the cost burden of the overall cost of care for myasthenia, which includes societal costs for patients and pharmaceutical costs, and you can see here patients treated with chronic IVIG or multiple immunosuppressants, the mean total cost for those patients was $118,000 to $70,000 per year. If you look just at the pharmacy cost for those patients, the mean was $3,000 to $6,000 per year, which is a bit different than $500,000 per year. So I think these medicines are very expensive, and whether or not the cost of these medicines justifies their widespread application from a societal standpoint remains to be discussed. So I think when thinking about cost of care, the current model is likely unsustainable with the current cost of treatments. Individual physicians, medical societies really have a role in thinking through distributive justice. We may want to think about restricting the use of our newer, more expensive therapies for certain populations of patients, and we need some comparative cost-effectiveness data for our patients. So just to conclude, traditional and next-generation therapies probably both have roles in 2024. We need better biomarkers to predict roles of response. We need comparative effectiveness data, and we need a better approach to cost. Thank you for your attention. Thank you. Dr. Herr, thank you so much. So in the sake of time, I'm going to just discuss maybe a couple of cases. So we'll leave time for questions. This is me, and this is my disclosure. All right, 86-year-old female presented with ptosis, dysarthria, head drop for about two weeks. Past my history, I had a remote history of uterine cancer, otherwise typical common medical illness. The ACHR antibodies, all three are positive. So when all three are positive, there's virtually no chance for a non-myothenic condition. CT chest with no thymelma. She was actually put on periodostegamine, which actually improved symptoms significantly, but returned very quickly. When she came to see us, it's week four, the ADL score was none. So what would you do? Time options? Start prenisone, start AD sour cream or microfinilate, start one of the company inhibitors, and plan for the next year. The reason for the next year is the insurance company you approve for one year. Start FCRN therapy, or start combination therapy. If you want to come up with which one, Dr. Kalitter, which one do you want to do? So I think that there are multiple reasonable things to do in this scenario. Certainly this is an elderly person that has more medical comorbidities, so I would be a little bit more concerned about starting a high dose of prednisone in this individual. They have a relatively high MGADL score, that's moderate MG, so they're very clearly impaired by their disease. So in this case, I may think about combination therapy, potentially with something like an induction to lead to rapid improvement in symptoms, something like IVIG, and potentially also adding on maybe a lower dose of prednisone to maintain improvement once you decide to stop that induction therapy. Certainly you could use an FCRN antagonist as sort of induction in this case, and also use prednisone. I mean, we know sometimes with FCRN antagonists that there can be some degree of antibody rebound once you stop the drug. So I think I would probably opt for combination therapy here. Thank you. Dr. Goyal, do you have any different opinion? It sounds like a dog clitoris surrendered to you. I also like the idea of starting a non-steroidal, so I'd probably think about a non-steroidal, so option B, and then discuss, do some shared decision making with options of what was previously mentioned, low dose prednisone, just easy to order, but I understand there's a lot of comorbidities or consideration of IV therapy in addition. Thank you. I just want to tell you what happened to this patient. Again, this may not be the, as I declared earlier, there may not be the only appropriate approach, and he was started on prednisone 20 mg a day and initiated on one FCRN therapy. Six weeks later, and the MGEDL reduced to one. In the next six months, he actually only received two cycles of FCRN therapy. The prednisone was gradually reduced to five mg a day at about four months. At six months, the prednisone monotherapy of five mg MGEDL was zero. There had been no significant side effects so far. So I just want to make two comments that have been talked about earlier. One is early aggressive treatment, whether it's IVAG, IV mesoprednisone, it's probably used less, and PLEX, complement inhibitor, FCRN therapies. They typically result in rapid improvement, while typically could spare the usage of high dose prednisone for longer duration. And a low dose prednisone here is used to maintain improvement or remission, and you can argue that you can use non-steroidal anti-inflammatory medications to do the same thing. Case number two. 35 years old female, presented with double vision, ptosis, dysarthria, arm and leg weakness for about a month. Antibodies very high, titer 42.3, nanomolar CT chest, no thymoma, generalized myasthenia gravis, and plasma hysterectomy, pre-clinic, septic, rare migraines. Symptoms actually controlled well on prednisone 20, and periodoxymin 60 mg three times a day. This lady is a little bit stubborn, and has very strong opinion, and she's only interested in treatment that could elude remission. What would you do? Continue prednisone and periodoxymin. Option B, start one of the following steroid sparing agent. Number three, start a company inhibitor. Number four, start epithelial therapy. Number five, consider somatectomy. Doctor here. This is fun. I never have confidence you will agree with me anyway. I think for this woman, I think it is important to consider thymectomy for a 35-year-old person, especially early in the onset of their illness. I think it's likely to have a disease-modifying effect in this case, and it could be done not minimally invasively with either robotic or thoroscopic guided surgery. In addition to that, this is a person of child-bearing age, so you have to be very careful with option B. All four of those medicines could have problems with a pregnancy, so we'd have to have a discussion with the patient, and if this is a woman who wants to be pregnant sometime in the near future, prednisone may actually be the best option for her, with tapering following a thymectomy might be the best strategy to start. Doctor Guidon. Can I ask more questions? Yes, please. Is she having prednisone side effects? I don't remember. Probably not. Let's assume not. Pregnant. Pregnant. All right. What are her pregnancy plans? She already has two children. Is she planning more, or is she on birth control? Probably not. Planning more or on birth control? She is probably not on birth control, and she probably does not want more pregnancy. Okay. And does she work? Yes. Okay. And what is her timing for, if we were going to do thymectomy, what would be a timing that would fit in with her work and two children and those things? And she works for the I.T., so it shouldn't be a problem. They don't do much for the hospital, so. See? Important questions, right? Important questions. Well, so really kind of clarifying those questions is going to be, I think, important to try to develop a plan. Certainly thymectomy is where we would want to end up. The question is timing. If she were interested in kind of early thymectomy, then we might not need to add an additional agent. You know, beforehand, we would just need to prepare her for surgery, and that could be done with IVIG, for example. And then, you know, she might not need anything else besides a tapering dose of prednisone and maybe a couple other, you know, rounds of IVIG. If she, you know, if it wasn't a good time and she was going to wait for a year, you know, we don't want to keep her on prednisone, 20 milligrams for a year, so we would probably need a bridge therapy. We talked about different types of bridges. And then, you know, we might, depending on how she was tolerating prednisone, we might add something like azathioprine with shared decision-making, you know, in the meantime. You can see that Dr. Amanda Guidon is much more considerate than I am, and I understand why my prescanning score is so low. All right. She went to an underwent a robotic thymectomy while on prednisone 20 milligram a day. Again, our CT surgeon, our obstetrician, told us that they feel comfortable operating on this prednisone dosage at actually even higher, at 30 milligram a day. The pathology basically showed a diffused follicle hyperplasia, typically early onset of myasthenia gravis. The subsequent course, you can see the five months, the prednisone discontinued, prednisone reduced, and further reduced, six months, 16 months, antibodies also reduced. And we saw her last time was six years, and she was on three milligram prednisone. She refused to come down further. She said that she can live with it. She had been in pharmacological remission for many years. Again, it's the tickle method here, thymectomy, it's very effective for young females with H.R. antibody positive general myasthenia gravis and lead to remission. I think I will stop here. If there are further cases, if you request slides, I can send to you, and I will be happy to answer questions from the audience. Thank you. Thank you. Dr. Kincaid. Excellent session, very appropriate. So the comment about biomarkers, the need for biomarkers. So we have in ACHR positive patients, we have antibody levels. And they don't correlate with disease, I think. So why don't they correlate with disease? Anybody want to take the question while you let me do it? I mean, I don't think we really know the answer to that question, but yesterday, Dr. O'Connor from Yale presented a really interesting talk, talking about antibody titers, but also antibody subtypes. And there's a change to the confirmation of the FCA arm, FAB arm, sorry, FAB arm over time where it may recognize different parts of the acetylcholine receptor and may be more or less pathological. And he actually had a slide showing a patient whose status improved steadily over time, and the antibody level went up or even stayed up. So there must be some immunologic change, but I don't think we know the answer. We need to learn. Sorry. There are, to see that there's no correlation between antibody level and disease severity is probably too strong a statement. There has been repeated studies suggest that there are some correlation. It's not perfect. It's some correlations between antibody level, especially referring to particular patients. Yes. Like Dr. Hare said, that antibodies may affect a different part of, may have different mechanism, may have different parts of the acetylcholine receptor. And we all see that a patient with very low antibodies titer have very severe disease. We also see people with very high titer with very minimal symptoms. These do occur. But for particular person, patient, there are some values to follow antibody level from time to time. Yes. Hi. Thank you for a wonderful discussion. My question is, I think many of us fall in between these two extremes, right? We use both the platform therapies and the newer treatments often in concert. What is the approach for patients who need to come off of the newer therapeutics and who maybe aren't tolerating that in concert with the more traditional therapies? Dr. Hare, you want to take that question? So, your question was, you have a patient who you're trying to taper off one of the newer therapies and they're not tolerating it well, and how to use the traditional therapies? The newer therapies are a difficult treatment burden, and so that's why you're trying to taper, but they're not tolerating. Yeah, I think that's a really good question. When we think about early use of the novel therapies, the question is, how long should we treat and when can we taper? I think with the FCRNs, because they're cyclical, it's a little bit easier to think about tapering or increasing duration between treatments. But I think with the complement inhibitors, once you start, it's really hard to know how to wean. So, I think answering your question, if you have moved to the newer therapies or the novel therapies because you've gone through all the traditional and you really haven't found a good fit that allows for the improvement of disease, then I think it is really challenging because once you're tapering and they're not tolerating, the disease is coming back. One potential option is to keep them and then retry in six months, because we do think the disease is changing over time, and then using other things like thymectomy, more of an expanded use could help as well. I don't know if my colleagues have anything to add. Yeah, just to reiterate, we all share kind of a combined approach, and we presented a specific view. I agree with everything that was said. I guess thinking about, with tapering the complement inhibitors, we've all had patients who had treatment interruption for some reason, so we've learned a little bit about tapering through trial by fire. And some patients, when they're stable, they can come off. I'm always surprised by who can come off and who can't. It's kind of interesting. With eculizumab, it can be a little bit more obvious, potentially, how to taper. So if you go to every month and then try to space it out, we've certainly tried that, but there's no data, unfortunately. We actually, for the second time, did not talk about one of the cases. The case we were able to successfully taper eculizumab, I'm sorry, one of the complement inhibitors, and stop it. And the patient has no consequences. So in some patients, I'm pretty sure you can gradually taper the medication, just like you taper prednisone. Sumit. I'm sure others are thinking, so I'll say it out loud. If only our leaders can debate as well as you all debated. So great job doing that, first of all. The second question, the actual question is, what does the society need to change, MG field researchers, pharma, so that this debate doesn't happen in two years? And the debate is settled, as it were. You have unlimited resources to settle the debate. I'm glad Dr. Harvard is sitting in the audience. I think he should lead a comparison trial between the newer and older therapists. And I'll pay him personally for doing that. Only part of it. Any other comments? Please. Thank you so much for your wonderful discussion. And I know Dr. Hare's answer to this, so he doesn't get to answer, my esteemed program director. But how do you choose between an FCRN versus a complement inhibitor for your patients? Any specific populations you like to start in one category versus the other, and why? Good question. Dr. Goyal? Sorry. So I think this reflects back a little bit to the taper question. So I like FCRN because I have this long-term plan for the patient, and I can have a good sense on how to taper. Especially for using right now with cyclical dosing, if their symptoms don't return by the time of their next cycle, I know I have this opportunity to increase the duration between. And so early in therapy, I might go for FCRN. The complement inhibitors in the patients that are, I'm thinking of the patients that I go for them a little bit earlier, are those where the oral medications, they just don't tolerate. So the nonsteroidals or perhaps thymectomies been done and it's years in, and I don't think there's much more coming from that. And so then I think years into the future, I don't have that nonsteroidal that's going to keep them in remission, so I may go for the complement inhibitor early. But again, this is just a couple of years in where this algorithm or this thinking is continuing to evolve. I think we are over time, but every speaker will stay here, answer further questions. Thank you so much for attending.

myasthenia gravis

novel therapies

immunotherapies

corticosteroids

mycophenolate

azathioprine

side effects

complement inhibitors

FCRN antagonists

ocular MG

thymoma-associated MG

MG crisis

cost-effectiveness