- 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.
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