The Science Behind Scleroderma

- 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. We invite you to share your thoughts and suggestions by email. Please direct any suggestions to MCL education@mayo.edu and reference this podcast. If you've enjoyed lab Medicine Rounds, please subscribe and until our next rounds together, we encourage you to continue to connect lab medicine and the clinical practice through insightful conversations.