- 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.
Ashima Makol associate professor of Medicine, vice chair
and practice Chair in the division of Rheumatology chair
for the Connective Tissue Disease Group,
and director for the scleroderma clinic here at Mayo Clinic
in Rochester, Minnesota.
Thanks for joining us Dr. Makol.
- Thank you Dr. Kreuter for having me.
- So I'm really excited to talk about this
because this podcast episode is going live
during scleroderma awareness month.
And so I thought we could maybe kick it off
with why is it important for healthcare professionals
to be aware of scleroderma?
- Yes, that's a great question.
So we'll get started by really saying
that scleroderma is a rare systemic inflammatory
autoimmune disease, which I think is one
of the most commonly undiagnosed, misdiagnosed,
misunderstood, and mismanaged medical condition
that as rheumatologists sometimes deal with.
I think spreading the awareness about this rare condition is
critical because it comes in many shapes
and forms, it impacts kids and adults
and it has one of the highest morbidity
and mortality associated with some
of our systemic rheumatic diseases.
So early diagnosis,
recognizing the internal organ involvement in some variants
in particular Earth scleroderma, really helps get started
with a good therapeutic plan
and a prognostic understanding of what
that particular patient is dealing with
to optimize outcomes in the long run.
- Wow. So you really kind of laid it on
justifiably thick there.
It's impressive. So it's a rare disease,
but you really kind of hit on how such poor understanding
of it and yet it has such significant consequences
for the patient.
So it's important, although it's,
I suppose a rare disease, it's one
that we should be thinking of and,
and hence why this awareness month we're celebrating.
You know, a portion of our,
of our listeners are coming from a laboratory
medicine background.
I wonder if we could kind of dive into that a little bit
and could you kind of elaborate on, you know,
what are some important things for laboratory professionals
to understand about scleroderma?
- Yes, and one of the things I want to point out
before we go into lab diagnosis is, as I mentioned,
you know, scleroderma really is a broad term
that encompasses a whole slew of different diseases.
So while it can be something called localized scleroderma
that can impact the skin
and underlying tissues,
mainly the subcutaneous tissue in a very patchy distribution
that can be more systemic scleroderma,
where it can be something that we call diffuse cutaneous
or limited cutaneous and, and that limited
and diffuse is really based on the extent
of skin involvement.
There are patients, however,
who have very classic internal organ findings of
what we call systemic sclerosis
and they might have absolutely no skin involvement.
And that's kind of confusing for a lot of people
because the term scleroderma is derived from sclero
and derma that literally means thick, hard, tight skin.
And that's one of the hallmark features of the condition.
Along with other features like raynaud's
where fingers change colors in the cold become pale,
dead white, purplish blue and red.
But some of these symptoms can be present at the outset.
They may develop over time.
Sometimes the skin manifestations may never develop,
while patients could have internal organ disease like
pulmonary hypertension
or GI dysmotility, they can have interstitial lung disease
that might bring them to light.
So it's a whole gamut of different subspecialty areas
that these patients might really present in
and undergo workup at.
But lab medicine is very, very important
and critical in the big picture
because there are some classic blood markers
that are associated
with scleroderma also integrated into the classification
criteria for systemic sclerosis,
which are a positive ANA that can be seen in close
to 90% plus patients.
So that's a very good broad screening marker.
And if you especially run into a centromere pattern
or a nuclear or pattern that is highly predictive
of a possible scleroderma spectrum condition in
that patient, you can see more specific lab markers like the
centromere antibody itself that is associated
with the limited cutaneous phenotype that is the scl-70
or the topoisomerase 1 antibody that is more associated
with the diffuse cutaneous phenotype
or development of interstitial lung disease
and RNA polymerase III,
which is a marker often people forget about.
But that is also in the classification criteria
and very strongly associated with a rapid skin progression.
It is associated with scleroderma renal crisis
and also a much higher risk of malignancy in one out
of three individuals who carry that blood marker.
So these patients really should be screened
for these antibodies right at the outset,
given the prognostic capability
and a prediction of some of these internal organ
or comorbid manifestations that can come along.
But there are a whole host of rarer antibodies that
that are out there as well that like the RNP
or the fibrillin antibody
that can also be seen in scleroderma patients,
especially the systemic sclerosis.
- Wow. So I mean this really highlights, you know,
again your background as an internal medicine physician
and as a rheumatologist
because of all the different manifestations of this,
why somebody with your background really needs
to be involved with diagnosis and
and treatment of these patients,
I really appreciate you highlighting how is,
if I'm hearing you right,
like the laboratory testing can really help you, you know,
rule in or or potentially rule out this rare diagnosis
as well as it can help you understand
where does it fit in within the scleroderma
scleroderma spectrum.
Did I understand that right?
- Yeah. So lab testing I think is extremely helpful,
but it is not everything.
I think the clinical picture
of a patient really trumps a lot of things.
So there are patients who can have ANA negative scleroderma
as I mentioned earlier.
There are over 90% patients who are going to be
having a positive ANA, but that is not universally true.
There are patients with classic skin findings,
interstitial lung disease raynaud's with digital ulcers, to
langatasias, GI dysmotility.
So the whole spectrum that diagnoses a patient
with this particular disease entity, yet many
of these may lack a autoimmune marker on their blood work.
So seeing a rheumatologist is critical in the right setting.
The faster we initiate that process,
if we have suspicious symptoms, especially early on
where there is tightening of skin involving the fingers
or puffy fingers in particular, puffy more in comparison
to their baseline
and something that is more pervasive,
not the fluctuate puffiness that we see,
but that in combination with raynaud's in particular
or joint pain in the hands should prompt people
to think about scleroderma.
- I think you just prompted all of our listeners
to look down at their hands right now and check that out.
I appreciate you kind of for the hypochondriacs among us,
kind of allay our fears a little bit to kind
of say you're talking about something
that is pervasive if I'm understanding
- That that is true.
That is true, absolutely. So,
- So as you talk through
and talk about, you know, these lab tests are having value,
but as you're pointing out it,
it's really a full picture they contribute
but it really also takes the astute physician
that's als another group of our audience.
If you were to, you know, highlight something
for our clinician listeners
or maybe something for our student listeners
who are in training still in the health care professions,
is there something you'd like to just kind of highlight
or underline about scleroderma?
- Yes. So scleroderma, as I mentioned, you know, many,
many different ways it can present.
But these are, you know, I would say
one of the key things to keep in mind is
what is highlighted in the ACR 2013 criteria
and that is puffy fingers.
You know, these puffy fingers are not your benign jargon.
This is a medical jargon
and that that's important to keep in mind.
A pervasive puffiness of the fingers in combination
with new onset raynaud's especially late in life
after the age of 40,
should definitely be taken very seriously.
It might be the first sign towards a pointer
that this might be a brewing autoimmune disease
in that individual.
Now you could also have other things like lupus
or potentially mixed connective tissue disease in
that spectrum of conditions as well.
But I think it should put a plug in your mind about
potentially looking for an ANA
to start the screening process.
And if you're highly suspicious about inflammatory arthritis
or if the patient has GI symptoms of
uncontrolled GERD that has been fairly longstanding
and poorly managed, if there is difficulty breathing
or concern about cardiopulmonary symptoms as well,
getting them to the right subspecialty areas
and starting off with a comprehensive rheumatology
evaluation may be high yield.
There is also certain basic physical examination maneuvers
that I would like to highlight as a rheumatologist
because this is not something
that we were trained on very early in our med school
or even internal medicine training.
But we, we look at the skin and we look at the joints
and sometimes we just ignore what
our nail beds can demonstrate
and give us a hyperview of in terms of the microcirculation.
So there are some structural abnormalities
of the microcirculation that we can look at
in the nail nail folds
of scleroderma patients in particular,
or patients who have raynauds that starts late in life.
And these may be another pointer towards the
potential development of scleroderma
where there are dilations
or what we call giant capillary loops, micro hemorrhages.
There is features of neovascularization
and this can be seen simply within ophthalmoscope
or a dermatoscope at the bedside at
by looking at the nail beds.
But we have more sophisticated ways of doing it
with a nail fold video oscopy
that is an advanced imaging procedure
that magnifies the nail fold 200 times to get a better sense
of what those structural changes look like
and that are very classic findings of scleroderma
that can be high yield in that situation.
- Wow, that's fantastic. Thanks for highlighting that.
I'm curious as you talk through, if I go to one
of your earlier answers,
you were talking about the different findings
that we might find out, you know, with the ANA
different patterns with antibodies.
You said there was a whole host of, of other
things in development as laboratory markers.
Is, are the testing that might be done in support
of a patient with scleroderma, is that strictly diagnostic
or is there like a therapeutic
or prognostic role as well?
- So most of those lab markers are diagnostic
and prognostic.
They have certain key phenotypes associated with them.
So one out of 10 people
with a centromere antibody will develop pulmonary
hypertension, which can be complicated
by right heart failure and so forth in the long term.
So that is definitely a reason
to follow serial echocardiograms in these individuals
or the individuals
that have an RNA polymerase three antibody,
we definitely re recommend
that they buy a blood pressure meter
and check their blood pressure periodically at home
because a 20 point rise in their systolic
or of sustained more than 10 point diastolic blood pressure
elevation can be the first sign
of potentially a scleroderma renal crisis where they can get
renal dysfunction to the point of needing dialysis.
And the sooner we can pick that up,
the sooner we can start them on ACE inhibitors
and get them into the hospital
to control their blood pressure urgently,
the better the long-term outcomes are in that individual.
But we don't follow these titers sequentially like we do in
lupus, for example,
where we assess double stranded DNL complement levels
that are more indicative
of an improvement in disease activity or remission.
So majority of the benefit
of lab testing in scleroderma is largely
diagnostic and prognostic.
- Wow. So I
I think one thing I'm curious about in this, you know,
as you talk about these changes that can happen,
and I think you're getting a little bit
of adrenal discharge from me as you're talking about this
'cause I have an appreciation for
how the immune system sometimes can seem
to turn on a dime, right?
As as it's designed to do to to fight infection.
The, like, can you give our audience listeners kind
of a sense for, you know,
how dynamic can this disease be when you talk about,
you know, somebody can develop these changes with, you know,
hypertension and, and have like medical consequences.
'cause when I hear you say that
and talk about pulmonary hypertension, right?
Heart failure, that definitely gets my attention
and something definitely we wanna mitigate.
What, what are we talking about for how,
how rapid does this come about?
- Yes, yes. And that's a very important question.
I think no two scleroderma patients are the same
and no two scleroderma journeys are going
to be the same long-term.
And that, and that's a key point
because there, there can be
patients with very higher immune suppression
through their entire disease course.
Whereas the other patients
with more diffused cutaneous phenotype in particular have a
very rapid onset of lots
of different internal organ manifestations within their
first five years of disease.
That is the timeframe during which we see the most rapid
trajectory for internal organ disease,
whether it be skin progression, joint inflammation,
whether it be interstitial lung disease progression,
and you know,
other manifestations like myocarditis for example.
But pulmonary hypertension on the other hand is a late
manifestation and can often develop post five years
to 10 years of disease.
So some of those monitoring strategies need to continue
beyond the five year mark, even though you might have dealt
with a big storm initially.
So first five years are very key
to keep these patients under really close follow up.
But subsequent to that as well,
periodic monitoring under the care of a rheumatologist is
very helpful in my opinion.
- Well, I really appreciate like you sharing your expertise
and helping all of our listeners really kind of follow on,
get an appreciation for how dynamic
this rare disease can be
and how important it is that we are thinking about this
and aware of this diagnosis.
A couple of times through our conversation here,
you've mentioned, you know,
how this is evolving and, and changing.
I'm kind of curious for your thoughts on
what's on the horizon for folks
that are diagnosed with scleroderma.
I'm, I'm kind of keeping an eye
for our student listeners right, who might be, you know,
interested in research
or may wanna be following in, in your footsteps to become a,
a rheumatologist with this particular interest.
How is the field evolving?
- Yeah, the field is evolving really rapidly
and I'm really excited about that
because we have so much more
to offer our patients than has existed ever before.
Just in the last couple
of years we've had two FDA approved medications,
very different from immune suppressants.
So one is an antifibrotic medication, which is called
nintedanib, and
that is a whole different pathway of intervention
to preserve lung function.
In particular in these patients term, there are number
of new immune suppressants in the pipeline.
We're able to offer long transplants,
hematopoietic stem cell transplant.
It's actually an approved indication
for stem cell transplant now as well as CAR T cell therapy.
That is one of the exciting areas
of investigation currently, we've had some patients go into
remission with deep B-cell depletion
that is sustained
and it is impressive the trajectory of these patients
because we don't, we've never seen that sort of response
with scleroderma patients, even though it's a handful.
It might be single center studies at this point,
but we're very excited to see how this pans out
and extend the benefits of therapies like this
to maybe a larger spectrum of the population.
This is really a very horrible
and challenging disease to manage when it's severe,
and I think there's a lot of room for advancement there.
- Wow. I I wanna say thank you for the shout out
for those students who might be interested in pathology.
As Dr. Makol said that we, you know, cellular therapy,
regenerative medicine is,
is playing a role in assisting in helping these patients.
So if you're interested in pathology lab medicine,
we have a home for you if you're interested in
scleroderma as well.
- There you go. - So thank you so much.
We've been rounding with Dr. Makol.
Thank you so much for, for talking about scleroderma
and helping us celebrate this scleroderma awareness month.
- Thank you for the kind invitation.
- My pleasure. And to all of our listeners, thank you
for joining us today.
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