Myasthenia Gravis: The Role of Apheresis

This month’s episode of Lab Medicine Rounds, Justin Kreuter, M.D., interviews Jeffrey Winters, M.D., the medical director of the Therapeutic Apheresis Treatment Unit at Mayo Clinic for Myasthenia Gravis awareness month.

Episode Transcript

(00:05):
- This is Lab MedicineRounds, a curated podcast
for physicians, laboratoryprofessionals and students.
I'm your host, Justin Kreuter,
a transfusion medicine pathologist
and assistant professorof laboratory medicine
and pathology at Mayo Clinic.
Today we're rounding withDr. Jeffrey Winters, chair
of the Division of Transfusion Medicine
and Professor of Laboratory Medicine

(00:26):
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 apheresistreatment unit here at Mayo.
So that's why maybe I'm qualified
to talk about myasthenia graves
and the use of plasmaexchange in that context.

(00:47):
- Absolutely. That'swhy we're targeting you.
You are an international expertin therapeutic apheresis.
And so given that,let's kick off with, you know,
so June is myastheniagraves awareness month.
And maybe let's kick offwith why is it important
for apheresis physicians
or those who might be involvedwith apheresis in some way

(01:09):
to be aware of myasthenia graves?
- Well, it's a fairly common indication.
So from the treatment perspective,
our neurology colleagueswill frequently treat these
patients with intravenous immunoglobulins.
So IVIG in an attempt toimprove their muscle strength,

(01:29):
especially in those patientsthat are having a decline
where they're showingworsening muscle strength
and they may be heading towardscompromise of their ability
to swallow, their abilityto handle their secretions
and heading towards wherethey're at risk for aspiration.
So they might start offby giving them IVIG,
but that may not be effectivein all patients especially,

(01:53):
and we can talk a littlebit later, patients
who have the musk antibodies
and not the acetylcholinereceptor antibodies.
Okay. So those patientsthat don't respond to IVIG
or those patients thatpresent very acutely ill
and they'rehaving a difficult time,
they may be aspirating, theymay end up being put on a
ventilator to protect their airway

(02:14):
and to keep them from aspirating.
We are going to move relatively quickly
to initiate plasma exchangeto remove, in this case,
I won't say the evilhumors, 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,

(02:36):
it's a common indication
and also just the clinical importance
of this really strikes homeas you talk about kind of that
preferred maybe first-linetherapy IVIG is not effective
for all patients
and also highlightingthat there's a couple
of different subsets ofpatients highlighting
what antibody they specifically may might

(03:01):
even predict there's ahigher 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 isunderstanding again, a bit
of the pathophysiology, right?
So we're having autoantibodies

(03:22):
that are directed at the motor end plate
that are actually causingsimplification of, you know,
they're fixing complement, right?
So the acetylcholinereceptors, antibody binding,
fixing complement leading to damage
that motor nplate the abilityof the nerve to communicate
with the muscle, right?
That's in turn leading to decreased number

(03:44):
of those receptors that signal drops off.
And then what we're seeingthere is weakness right
now we can, through repeatedstimulation of that nerve
by giving drugs that increasethe amount of acetylcholine
that's in that nervereceptor, we can improve
that strength Okay.
And help them. But you know,what we're seeing is that in,

(04:08):
again, some of those patientsthat may not respond to IVIG,
such as those that havethe musk antibodies, okay.
Which recognize structuresthat are associated with
that acetylcholine receptor.
So they may not respond.
And then again we have peoplewith acute exacerbations
where IVIG isn't necessarily
gonna be particularly effective.
So what we're looking at is,the thing that's important

(04:30):
for the nurses and the otherphysicians understand is
that while we see a lot of patients
that are chronically getting IVIG
and they're being treated, thereare gonna be those patients
that don't respond, those patients
that have an acute exacerbation
and we're gonna have tomove quickly to treat them.
I think it's also important to recognize
that in those patients
where they are experiencingsignificant weakness

(04:53):
of their bulb pharyngeal muscles,
and again they're havingthat difficulty dealing with
secretions, that this is abit of a medical emergency.
We want to avoid the potential risk
and harm that would comeif they would aspirate the
potential risk and the harmthat come from intubation.
So in my practice, in my mind,

(05:15):
I do consider patientspresenting acutely like that,
having difficulty pending intubation
to be an apheresis medical emergency.
Meaning that we would respond
to those patients inthe middle of the night
and really try to get to thebedside as quickly as we can.
If it is somebody whois failing to respond
to IVIG having increasing weakness,

(05:37):
but they're doing a pretty good job
of handling their secretions,then it doesn't become so much
of an emergency where we haveto 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

(05:57):
about specifically within the context
of the American Society forApheresis guidelines, right.
Well, well the guidelinesdon't tell us what is
or is not a medical emergency
where we should come in immediately.
Well that depends uponour medical judgment
and evaluating each individual patient.
So this is a goodexample, myasthenia gravis

(06:18):
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 reallyappreciate you getting back
to the path pathology, right,
because that helps us understand why we're
approaching a certain way.

(06:38):
You were saying about with,you know, musk antibodies and,
and having that higherfailure rate to IVIG are,
are there any hypotheses on why
that may be
or this is just kind of comesback to this is the, we're
- Sure the hands, I have not heard

(06:59):
why IVIG in particular maybe less effective in those
patients, but it has been reported
through many clinical trials
and so it's frequentlythat those are the patients
that have the muskantibodies that are coming
to the apheresis unit for
chronic more long-termtherapy trying to to to,

(07:22):
to treat that particular entity.
- Thank you. It goingto unpack a little bit
as you talk about, youknow, it's important
to recognize the, the medicalemergency versus, you know,
when it's not an emergency,
but we may still end updoing therapeutic apheresis.

(07:44):
And I realize now I'm asking you
a question specificallyabout your practice,
but is there a differentway you approach your
therapeutic apheresis,whether it's emergency
or non-emergent formyasthenia gravis in terms of,
you know, volume exchange

(08:06):
or frequency?
I'm just kind of curious
how you think about those things. I mean
- Really it's not so myprescription that I,
that I personallyprescribe for the patients
with myasthenia, for those that are more,
that are emergent versusthose that are, that are,

(08:26):
that are not so muchreally doesn't change.
So again here at Mayo I'musually doing a one volume
plasma exchange.
I'm going to be using albuminas my replacement fluid
because it is a betterside effect profile.
Obviously if there is somerisk of bleeding, whatever
that may be risk
because they've recentlyhad a surgical procedure

(08:48):
or something is planned, thenwe'll supplement at the end
of the procedure withsome fresh frozen plasma
to replace coag factors.
But again, albumin'sgonna be the major thing.
One plasma volume exchange, usually
for most neurologicindications to allow a bit
of re-equilibrationbetween the bloodstream

(09:08):
where I can remove the antibody, right.
And the extravascular sitesometimes out in the nervous
system, maybe a little less ofan issue here with myasthenia
as opposed to something
that's in the central nervoussystem 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,

(09:29):
they're talking about sixto seven treatments over 10
to 14 days.
So I may change in this context,
if I have somebody who'sacutely decompensating,
I may be a bit more aggressive in
that I will take my seventreatments, which is usually
what we prescribe andI might do seven daily.
I might front load a bitand do three to four daily

(09:52):
and then every other day afterwards.
Whereas again, if it's more of
that chronic then I'm gonnabe probably doing every other
day just trying to andfollowing their symptoms
and their muscle strength tomake a determination whether we
need to do the full course of seven
or whether we can getby with something less.
So that may be the one thing,
I may be a bit more aggressivedoing daily procedures in

(10:15):
somebody who is reallydecompensating compared
to the more yeah, they don't look so bad,
so we're gonna just sort ofdo them a less frequently.
- Yeah, that makes senseto 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

(10:36):
or chronic, in so far thisconversation we've been kind
of focused to, you know,emergency or non-emergency.
But really kind ofthinking about in the kind
of acute setting is, isthere any difference on
how we should approach
or think about maybelong-term apheresis treatment
for these patients?
- Yeah, so I think one thingI wanna touch really quickly

(11:00):
before we move on to thistopic is it's in
with this topic is we can talk again about
the ASFA categories.
I think it's alwaysimportant to cycle back
to that within the guidelines.
Category one is a first linetherapy, either standalone
or conjunction with another therapy.
Category two is a second line therapy.
You do something else first
and then you can add theapheresis treatment onto it.
So when we talk about theacute exacerbations of somebody

(11:22):
who is going downhill quickly
and potentially intubated, thatis a category one indication
for plasma exchange.
When we talk about the chronicmanagement of patients,
so people that are on sort ofa 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 firstis usually again intravenous

(11:46):
immunoglobulin as well assome immunosuppressants
and the other things thatare normally added to try
to increase the amount of
within the neuromuscular junction, right?
The change that's coming
that we see now is thereare some interesting new
medications that are on the market
and they actually, the firstof this new class of drugs

(12:09):
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 classesof drugs of which F od is,
are actually neonatal FC
receptor blockers.

(12:29):
Okay, so what, what in theworld'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 ofthe body including the liver.

(12:50):
And so they are critically important
for actually recycling IVIG
or recycling immunoglobulins,not IVIG, but immunoglobulins.
Okay. So what happens is IGis taken up appendic vesicles,
they bind the FC receptor
and that prevents them from being broken
down within the vesicle.
And then as that vesiclecomes back up to the surface

(13:11):
and opens back up, that immunoglobulin
that was bound is releasedback 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 thatthe IgG cannot bind to them.
And so when they're inthat little pento vesicle,

(13:31):
they actually getdegraded 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 havereferred to this almost
as like a plasma exchange in a bottle
where you can give this

(13:52):
and decrease immunoglobulinlevels through this medication.
Now it's not quick,
it's not like when I do my plasma exchange
and I'm dropping somebody'sIgG circulating in their
plasma by 70%, it'sobviously much longer term.
But in those people thatare requiring some sort
of maintenance therapy fortheir myasthenia gravis,

(14:16):
this is something thatcan be given to them
that actually causes shorteningof the half-life of the
antibody and can help improve their
muscle strength long term.
So you'll see I, I seefairly frequent ads on TV
when I'm exercising onmy exercise bike in the
morning for T guard.

(14:37):
So it's, it's interesting,we may be seeing these class
of medications being rolledout for other indications
where traditionally we'vedone plasma exchange, at least
not probably for the acuteillnesses that we treat
with plasma exchange, but maybe for some
of the chronic maintenance ones.
And then since I'm a bloodbanker, I'm gonna throw this in,

(14:59):
there are clinical trials outthere utilizing these drugs in
the context of hemolyticdisease of the fetus.
And newborn again makes sense.
It's binding that FCreceptor in the placenta
and preventing IgG fromcrossing over into baby.
We can hopefully avoidwhatever mom's antibody is
that recognizes baby's redcells from making into the

(15:19):
circulation and causing that.
So there are clinical trialsof other agents in that same
category of drugs thatare, that are out there.
- That's really exciting.
And, and I guess, I guess Ikind 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

(15:42):
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 itkind of would shorten it to
or is it really quite individualspecific because of, I

(16:02):
- Wanna say it's cutting itdown to about a week or less.
So it's, it's actuallymaking 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 Ican't handle my secretions,
I'm going to aspirate, I'm goingto end up with a pneumonia,

(16:24):
I need to be put on a ventilator.
This ain't gonna workfor them. Right? Okay.
But that person who's got weakness,
it's difficult to control.
You could start administering that
before they get into aninstance where they're sort
of extremists and thenhopefully avoid getting there.

(16:46):
- Wow. I imagine the quality
of life is a lot better tooif they're not routinely have
to interrupt their livesto, 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 machinefor 45 minutes to an hour

(17:10):
and a half as well as, youknow, potentially issues
with regard to vascular accessand things of that nature.
- Well I'm really glad youtake, took us into kind
of what's the future ofchronic exchange look like
for these patients and the promise
of this new medication will beexciting to follow that data
and understand who this is is working for.
Maybe one way we cankind of close out this,

(17:32):
this episode you broughtup the ASFA guidelines, so
to highlight for our listeners,that's the American Society
for Apheresis guidelines thatcome out every three years.
And if Dr. Winters, if youwanna kind of close this out
with know for listeners who may not
yet be involved in therapeutic apheresis

(17:55):
and maybe this podcast kindof reawakens an interest,
where do you think, are there journals
or websites that yourecommend that people go to
that are interested in thefield 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 journalapheresis focused journal

(18:19):
that has the highest impact factor.
So I will put a plugin for that.
I would encourage people toconsider if you have access
to the journal to take a a apeak at the American Society
for Apheresis guidelines.
They were published involume 38, issue two of 2023.
They are published every three years.

(18:41):
So the committee that publishesthem is working on that now.
And it represents basically these one
to two page fact sheetsin alphabetical order
that are put together witha very standardized format
to provide the very basicinformation on the disease,
the treatments other than apheresis,

(19:03):
the pathophysiologic rationalefor 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 ornot you're having efficacy
and what's the plasma volume

(19:23):
or what's the volume that's exchanged.
And this covers not only plasma exchange
but also Photopheresis RedCell Exchange LDL apheresis,
as well as some treatments
that are not availablein the United States such
as immuno absorption, which is available
outside the United States.
So I always can sayyou're not gonna go wrong.

(19:44):
Taking a look at the guidelines in the
Journal of Clinical Apheresis.
Other resources that I wouldsuggest, there are a couple
of other journals that frequentlyfocus on at therapeutic
apheresis and dialysis is another journal
that has a very apheresis focus.
And so that would be another one

(20:04):
that I would throw out there.
Many of the hematology based journals and
or transfusion medicinebased 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 fromthe standpoint of books.
There is a handbook thathas been published by the

(20:27):
Association for the Anthe 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 Managementby Laboratory Methods.
There is a chapter onhemapheresis in there,
again, conflict of Interest.

(20:48):
I was a co-author on thatchapter of some other people.
So you're stuck with myperspective on things.
But it is, the goal is to givea very basic broad coverage
for people that are wanting a textbook
that is a bit more in depth.
Apheresis principles inPractice is published by,
again, A A BB.

(21:09):
There are actually threevolumes 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, buthopefully it'll be out

(21:31):
by the A A BB meeting in October.
So again, apheresis Principlesand Practice fourth edition.
And once again, I guess I shouldpay 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 theconflicts of interest. Dr.

(21:53):
Whitters. I think, youknow, 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 myastheniagravis Awareness month
and have this conversation.
Thanks for joining us today.
- Okay. Thank you for having me
and I hope everybody has alistening, has a a good day

(22:15):
and a good rest of the week.
- And thanks all our listenersfor joining us today.
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