- This is Lab Medicine Rounds, a curated podcast for physicians, laboratory professionals and students. I'm your host, Justin Kreuter, a transfusion medicine pathologist and assistant professor of laboratory medicine and pathology at Mayo Clinic. Today we're rounding with Dr. Jeffrey Winters, chair of the Division of Transfusion Medicine and Professor of Laboratory Medicine and Pathology at Mayo Clinic to talk about myasthenia graves. Thanks for joining us today, Dr. Winters.
- Yeah, no problem. I will add one thing to your introduction. I am also the medical director of the therapeutic apheresis treatment unit here at Mayo. So that's why maybe I'm qualified to talk about myasthenia graves and the use of plasma exchange in that context. - Absolutely. That's why we're targeting you. You are an international expert in therapeutic apheresis. And so given that, let's kick off with, you know, so June is myasthenia graves awareness month.
And maybe let's kick off with why is it important for apheresis physicians or those who might be involved with apheresis in some way to be aware of myasthenia graves? - Well, it's a fairly common indication. So from the treatment perspective, our neurology colleagues will frequently treat these patients with intravenous immunoglobulins.
So IVIG in an attempt to improve their muscle strength, especially in those patients that are having a decline where they're showing worsening muscle strength and they may be heading towards compromise of their ability to swallow, their ability to handle their secretions and heading towards where they're at risk for aspiration.
So they might start off by giving them IVIG, but that may not be effective in all patients especially, and we can talk a little bit later, patients who have the musk antibodies and not the acetylcholine receptor antibodies. Okay. So those patients that don't respond to IVIG or those patients that present very acutely ill and they're having a difficult time, they may be aspirating, they may end up being put on a ventilator to protect their airway and to keep them from aspirating.
We are going to move relatively quickly to initiate plasma exchange to remove, in this case, I won't say the evil humors, but rather the evil antibodies in an attempt to improve their muscle strength and to try to avoid that complication.
- Awesome. So I'm getting from you right, it's a common indication and also just the clinical importance of this really strikes home as you talk about kind of that preferred maybe first-line therapy IVIG is not effective for all patients and also highlighting that there's a couple of different subsets of patients highlighting what antibody they specifically may might even predict there's a higher rate of of failure.
And so to be aware, diving into that, what do you think apheresis nurses and physicians should kind of understand about myasthenia gravis? How we approach them? - Well I think the key is understanding again, a bit of the pathophysiology, right? So we're having autoantibodies that are directed at the motor end plate that are actually causing simplification of, you know, they're fixing complement, right?
So the acetylcholine receptors, antibody binding, fixing complement leading to damage that motor nplate the ability of the nerve to communicate with the muscle, right? That's in turn leading to decreased number of those receptors that signal drops off. And then what we're seeing there is weakness right now we can, through repeated stimulation of that nerve by giving drugs that increase the amount of acetylcholine that's in that nerve receptor, we can improve that strength Okay.
And help them. But you know, what we're seeing is that in, again, some of those patients that may not respond to IVIG, such as those that have the musk antibodies, okay. Which recognize structures that are associated with that acetylcholine receptor. So they may not respond. And then again we have people with acute exacerbations where IVIG isn't necessarily gonna be particularly effective.
So what we're looking at is, the thing that's important for the nurses and the other physicians understand is that while we see a lot of patients that are chronically getting IVIG and they're being treated, there are gonna be those patients that don't respond, those patients that have an acute exacerbation and we're gonna have to move quickly to treat them.
I think it's also important to recognize that in those patients where they are experiencing significant weakness of their bulb pharyngeal muscles, and again they're having that difficulty dealing with secretions, that this is a bit of a medical emergency. We want to avoid the potential risk and harm that would come if they would aspirate the potential risk and the harm that come from intubation.
So in my practice, in my mind, I do consider patients presenting acutely like that, having difficulty pending intubation to be an apheresis medical emergency. Meaning that we would respond to those patients in the middle of the night and really try to get to the bedside as quickly as we can.
If it is somebody who is failing to respond to IVIG having increasing weakness, but they're doing a pretty good job of handling their secretions, then it doesn't become so much of an emergency where we have to go in and protect them. So I think that's an important concept for the apheresis physician, the apheresis nurse to understand. Okay. Frequently I asked about specifically within the context of the American Society for Apheresis guidelines, right.
Well, well the guidelines don't tell us what is or is not a medical emergency where we should come in immediately. Well that depends upon our medical judgment and evaluating each individual patient. So this is a good example, myasthenia gravis where you may have a patient population where it's not an emergency, they're not crashing and burning, we can wait or you may have a patient population that we really need to move quickly.
- You were mentioning, I really appreciate you getting back to the path pathology, right, because that helps us understand why we're approaching a certain way.
You were saying about with, you know, musk antibodies and, and having that higher failure rate to IVIG are, are there any hypotheses on why that may be or this is just kind of comes back to this is the, we're - Sure the hands, I have not heard why IVIG in particular may be less effective in those patients, but it has been reported through many clinical trials and so it's frequently that those are the patients that have the musk antibodies that are coming to the apheresis unit for
chronic more long-term therapy trying to to to, to treat that particular entity. - Thank you. It going to unpack a little bit as you talk about, you know, it's important to recognize the, the medical emergency versus, you know, when it's not an emergency, but we may still end up doing therapeutic apheresis.
And I realize now I'm asking you a question specifically about your practice, but is there a different way you approach your therapeutic apheresis, whether it's emergency or non-emergent for myasthenia gravis in terms of, you know, volume exchange or frequency? I'm just kind of curious
how you think about those things. I mean - Really it's not so my prescription that I, that I personally prescribe for the patients with myasthenia, for those that are more, that are emergent versus those that are, that are, that are not so much really doesn't change. So again here at Mayo I'm usually doing a one volume plasma exchange. I'm going to be using albumin as my replacement fluid because it is a better side effect profile.
Obviously if there is some risk of bleeding, whatever that may be risk because they've recently had a surgical procedure or something is planned, then we'll supplement at the end of the procedure with some fresh frozen plasma to replace coag factors. But again, albumin's gonna be the major thing. One plasma volume exchange, usually for most neurologic indications to allow a bit of re-equilibration between the bloodstream where I can remove the antibody, right.
And the extravascular site sometimes out in the nervous system, maybe a little less of an issue here with myasthenia as opposed to something that's in the central nervous system like multiple sclerosis or some of the demyelinating illnesses. But usually it's gonna be every other day. So if you look at the ASFA guidelines, they're talking about six to seven treatments over 10 to 14 days.
So I may change in this context, if I have somebody who's acutely decompensating, I may be a bit more aggressive in that I will take my seven treatments, which is usually what we prescribe and I might do seven daily. I might front load a bit and do three to four daily and then every other day afterwards.
Whereas again, if it's more of that chronic then I'm gonna be probably doing every other day just trying to and following their symptoms and their muscle strength to make a determination whether we need to do the full course of seven or whether we can get by with something less.
So that may be the one thing, I may be a bit more aggressive doing daily procedures in somebody who is really decompensating compared to the more yeah, they don't look so bad, so we're gonna just sort of do them a less frequently. - Yeah, that makes sense to me from this idea of the pathology, the pathophysiology of, of what's going on.
You, you mentioned about kind of, kind of thinking more long-term or chronic, in so far this conversation we've been kind of focused to, you know, emergency or non-emergency. But really kind of thinking about in the kind of acute setting is, is there any difference on how we should approach or think about maybe long-term apheresis treatment for these patients?
- Yeah, so I think one thing I wanna touch really quickly before we move on to this topic is it's in with this topic is we can talk again about the ASFA categories. I think it's always important to cycle back to that within the guidelines. Category one is a first line therapy, either standalone or conjunction with another therapy. Category two is a second line therapy. You do something else first and then you can add the apheresis treatment onto it.
So when we talk about the acute exacerbations of somebody who is going downhill quickly and potentially intubated, that is a category one indication for plasma exchange. When we talk about the chronic management of patients, so people that are on sort of a maintenance therapy that is, they're not acutely deteriorating, that is a category two.
So again, we do something else first and that something else first is usually again intravenous immunoglobulin as well as some immunosuppressants and the other things that are normally added to try to increase the amount of within the neuromuscular junction, right?
The change that's coming that we see now is there are some interesting new medications that are on the market and they actually, the first of this new class of drugs that's on the market is called T guard or now we're going to try not to massacre this name right od okay. And what these new classes of drugs of which F od is, are actually neonatal FC receptor blockers. Okay, so what, what in the world's a neonatal FC receptor?
Well those are the receptors that are located on the placenta that actually help transport IgG from mom into baby. Okay? Now it turns out that those are not just on the placenta, but they're in other sites of the body including the liver. And so they are critically important for actually recycling IVIG or recycling immunoglobulins, not IVIG, but immunoglobulins.
Okay. So what happens is IG is taken up appendic vesicles, they bind the FC receptor and that prevents them from being broken down within the vesicle. And then as that vesicle comes back up to the surface and opens back up, that immunoglobulin that was bound is released back into the circulation. So what these drugs, this new category of drugs does is it actually blocks those neonatal FC receptors. And so the result is that the IgG cannot bind to them.
And so when they're in that little pento vesicle, they actually get degraded and broken down. So what these new classes of drugs are actually doing is actually decreasing the half-life of IgG in the human body. So some people have referred to this almost as like a plasma exchange in a bottle where you can give this and decrease immunoglobulin levels through this medication.
Now it's not quick, it's not like when I do my plasma exchange and I'm dropping somebody's IgG circulating in their plasma by 70%, it's obviously much longer term. But in those people that are requiring some sort of maintenance therapy for their myasthenia gravis, this is something that can be given to them that actually causes shortening of the half-life of the antibody and can help improve their muscle strength long term.
So you'll see I, I see fairly frequent ads on TV when I'm exercising on my exercise bike in the morning for T guard. So it's, it's interesting, we may be seeing these class of medications being rolled out for other indications where traditionally we've done plasma exchange, at least not probably for the acute illnesses that we treat with plasma exchange, but maybe for some of the chronic maintenance ones.
And then since I'm a blood banker, I'm gonna throw this in, there are clinical trials out there utilizing these drugs in the context of hemolytic disease of the fetus. And newborn again makes sense. It's binding that FC receptor in the placenta and preventing IgG from crossing over into baby. We can hopefully avoid whatever mom's antibody is that recognizes baby's red cells from making into the circulation and causing that.
So there are clinical trials of other agents in that same category of drugs that are, that are out there. - That's really exciting. And, and I guess, I guess I kind of as listened to you, I kind of paraphrase that medication, at least when I'm thinking about using it for myasthenia gras gravis is it kind of shuts off the body's recycling program for immune globulin. And usually I'm thinking about, you know, IgG as having kind of that, I think it might be like 21 day, one month half-life.
Is it kind of known what it kind of would shorten it to or is it really quite individual specific because of, I - Wanna say it's cutting it down to about a week or less. So it's, it's actually making a significant drop in the half life of the drug. So again, somebody is like coming in and I can't, I'm so weak I can't handle my secretions, I'm going to aspirate, I'm going to end up with a pneumonia, I need to be put on a ventilator. This ain't gonna work for them. Right? Okay.
But that person who's got weakness, it's difficult to control. You could start administering that before they get into an instance where they're sort of extremists and then hopefully avoid getting there. - Wow. I imagine the quality of life is a lot better too if they're not routinely have to interrupt their lives to, to come in to get a, a chronic plasma exchange.
- Well, I don't know. All the patients love chatting with my nurses - Instead - Of vacation for them in some ways, but no really they, yeah, they don't like coming in and being tied to a machine for 45 minutes to an hour and a half as well as, you know, potentially issues with regard to vascular access and things of that nature.
- Well I'm really glad you take, took us into kind of what's the future of chronic exchange look like for these patients and the promise of this new medication will be exciting to follow that data and understand who this is is working for. Maybe one way we can kind of close out this, this episode you brought up the ASFA guidelines, so to highlight for our listeners, that's the American Society for Apheresis guidelines that come out every three years.
And if Dr. Winters, if you wanna kind of close this out with know for listeners who may not yet be involved in therapeutic apheresis and maybe this podcast kind of reawakens an interest, where do you think, are there journals or websites that you recommend that people go to that are interested in the field in learning more? - Well, okay, so conflict of interest, I'm the editor in chief of the Journal of Clinical Apheresis.
Okay. So this is the journal apheresis focused journal that has the highest impact factor. So I will put a plugin for that. I would encourage people to consider if you have access to the journal to take a a a peak at the American Society for Apheresis guidelines. They were published in volume 38, issue two of 2023. They are published every three years. So the committee that publishes them is working on that now.
And it represents basically these one to two page fact sheets in alphabetical order that are put together with a very standardized format to provide the very basic information on the disease, the treatments other than apheresis, the pathophysiologic rationale for why apheresis would work. And then guidance on important things for doing your prescription.
Like what's your replacement fluid, how frequently you do it, what are you monitoring to determine whether or not you're having efficacy and what's the plasma volume or what's the volume that's exchanged. And this covers not only plasma exchange but also Photopheresis Red Cell Exchange LDL apheresis, as well as some treatments that are not available in the United States such as immuno absorption, which is available outside the United States. So I always can say you're not gonna go wrong.
Taking a look at the guidelines in the Journal of Clinical Apheresis. Other resources that I would suggest, there are a couple of other journals that frequently focus on at therapeutic apheresis and dialysis is another journal that has a very apheresis focus. And so that would be another one that I would throw out there. Many of the hematology based journals and or transfusion medicine based journals will also have articles dealing with apheresis, therapeutic apheresis.
But these journals tend to be very focused solely on apheresis. And I have other stuff from the standpoint of books. There is a handbook that has been published by the Association for the An the Incident of Blood and Biotherapies, A A BB. So it's a very nice handbook. I know many of the authors. Another common resource I think is Henry's Diagnosis Management by Laboratory Methods. There is a chapter on hemapheresis in there, again, conflict of Interest.
I was a co-author on that chapter of some other people. So you're stuck with my perspective on things. But it is, the goal is to give a very basic broad coverage for people that are wanting a textbook that is a bit more in depth. Apheresis principles in Practice is published by, again, A A BB. There are actually three volumes for that work.
One volume one is therapeutic apheresis, volume two is donor apheresis, and volume three is actually going, is stem cell collections, collection of mononuclear cells for CAR T and Photopheresis. That is still in, in, in, we're, we're working to get that out there. It's being prepared, but hopefully it'll be out by the A A BB meeting in October. So again, apheresis Principles and Practice fourth edition. And once again, I guess I should pay a conflict of interest.
I'm the editor in chief of that work as well. So I, yeah, I have some thought, but what's in that, what's in that book as - Well? Well, thank you for all the conflicts of interest. Dr. Whitters. I think, you know, you're a friend and and colleague, but you've highlighted that this wasn't just favoritism. I, I'm asking really the right expert to help us celebrate myasthenia gravis Awareness month and have this conversation. Thanks for joining us today.
- Okay. Thank you for having me and I hope everybody has a listening, has a a good day and a good rest of the week. - And thanks all our listeners for joining us today. We invite you to share your thoughts and suggestions via email to MCL [email protected]. If you've enjoyed this podcast, please subscribe until our next rounds together. We encourage you to continue to connect lab medicine and the clinical practice through educational conversations.