Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole. And we have a thought leader round table for you today that will focus on scleroderma diagnosis and management, insights from a multidisciplinary team.

Joining me is Dr. Anthony Esposito. He's an Assistant Professor of Medicine in the Department of Pulmonary and Critical Care, the Co-Director of the Scleroderma Program, and the Director of Scientific and Translational Research, Interstitial Lung Disease Program at Northwestern Medicine, and he'll be moderating today's discussion.

Joining Dr. Esposito is Dr. Carrie Richardson, she's an Associate Professor of Medicine in the Division of Rheumatology and the Co-Director of the Scleroderma Center at Northwestern Medicine; and Dr. Domenico Farina, he's an Assistant Professor of Medicine in the Department of Gastroenterology and Hepatology at Northwestern Medicine.

Dr. Esposito, I turn it over to you.

Anthony Esposito, MD (Moderator): Thank you very much, and welcome, everybody. It's my distinct pleasure to be sitting with these two amazing physicians right here, Dr. Richardson and Dr. Farina, who I work very closely with to care for patients with scleroderma. And I hope that this podcast today helps illuminate how we approach care for patients with systemic disease.

So to introduce myself, as Melanie had already said, my name's Dr. Esposito. I'm a pulmonologist and I care for patients with scleroderma who have complications related to their lungs. I'll turn it over to Dr. Farina to introduce himself.

Domenico Farina, MD: Hey there. I'm Dr. Farina. I'm with the Division of Gastroenterology, kind of focused more on esophageal diseases, which play a pretty significant role with our scleroderma patients, and have a kind of distinct interest in clinical kind of background in taking care of scleroderma patients. And in our division as well, I have a couple other colleagues that I collaborate with to kind of optimize care for these patients.

Anthony Esposito, MD (Moderator): Thank you. And the co-director of our Scleroderma Program over here, the leader, Dr. Richardson, would you introduce yourself please?

Carrie Richardson, MD: Thank you. I'm Dr. Carrie Richardson, Co-Director of the Scleroderma Center. I'm on the board at the National Scleroderma Foundation and the Medical Advisory Board of the World Scleroderma Foundation. I am very happy to be here with my wonderful colleagues who help us care for patients with scleroderma. My other colleague in Rheumatology is Dr. Duncan Moore. So, we have a really great team dedicated to caring for our patients.

Anthony Esposito, MD (Moderator): Great. Great. Yeah, it's always lovely to have someone to call. I think Carrie and I speak to each other probably twice a week about caring for patients. And we also do a combined clinic together that you'll hear about. And then, obviously, share patients with Dr. Farina and some of our other colleagues in GI, really kind of focusing on the fact that this disease process called scleroderma is a systemic disease that requires more than just the rheumatologist. It requires multiple specialists that we have here at Northwestern Medicine.

So, I want to start off with a question to Dr. Richardson. Could you provide us with an overview of the Scleroderma Program at Northwestern Medicine? And can you really kind of dive into how this designated program has improved patient outcomes in coordinating care between specialties?

Carrie Richardson, MD: Yeah. So, the Scleroderma Program at Northwestern, actually, John Varga, who's now at University of Michigan and Monique Hinchcliff, who's at Yale, had a big role in developing this program. So, we serve over 800 people with scleroderma on a regular basis. Our patients frequently return to us for follow up care. We are devoted to patient care, to research, and to education.

And so, patient care is a founding mission of what we do. We really have experts across the board obviously in GI, in Pulmonary and Dermatology. We have oncologists who works with us. We offer clinical trials. And we really know the ins and outs of caring for people with scleroderma. And so, I think really one of the critical pieces that our program provides is this expertise of knowing what is scleroderma-related, what is not, what medication do we have to offer, who will benefit from those medications, and then who would benefit from something more advanced, like clinical trials. So, patient care is really the center of what we do.

Research also, that is a equally integral mission of what we do. Not only clinical research offering opportunities for new therapies for patients with scleroderma, but also the clinical and translational research that you do, which I know that you will talk about as well. But we have a multidisciplinary approach to research as well across pulmonary division, we have cardiac research happening where we're researching pulmonary hypertension, interstitial lung disease. We're doing some research on skin and doing a study of a novel device to help measure skin stiffness. So, we're really lucky at Northwestern to have this amazing research enterprise with a wonderful research infrastructure with great staff that many of our patients know really, really well. Our research coordinators are a big part of what we do. And for patients who, you know, want to participate in clinical trials, that's great. But for people who don't want to participate in clinical trials or who may not be eligible, there's many other ways that they can participate in research here at Northwestern. And our goal, obviously, is to help work to find a cure for scleroderma.

And then, education is a big part of what we do as well. I think a big part of our mission is making sure the future generation of physicians, even if they're not going into Rheumatology, if they're going into GI, that they can recognize when someone comes and they're bloated and have esophageal distension, and that there's underlying scleroderma, because sometimes often patients come to us first, us in Rheumatology. But very often, we'll see patients come to the GI doctor first or come to the pulmonologist first. And having expertise of people like you who know how to recognize scleroderma, and some appropriate testing actually really helps our patients and helps care be better.

Anthony Esposito, MD (Moderator): Yeah. So, what I'm hearing from you is not just cutting-edge patient care, but also cutting-edge research, collaboration across different specialties, access to high-end care for people that know the intricacies, in and outs of this disease process of scleroderma. That's really what we're bringing here with our scleroderma program.

I've mentioned just briefly at the very beginning, you know, jokingly, that I speak to Carrie on the phone at least twice a week, but that is actually the truth. There's a lot of collaboration that goes along both direct collaboration and then behind the scenes collaboration. For example, between Dr. Farina and I and his colleagues in GI, we also think a lot about the GI tract in relation to the lung, believe it or not, because there are outcomes that are worse for patients who have bad GI disease. So, thank you for sharing that, Dr. Richardson.

I'm going to focus again on you, at the beginning, just to kind of really help us think about the disease process of scleroderma for those who aren't familiar with it. Can you just tell us a little bit about how scleroderma is diagnosed and what are some of the challenges that you face in the process of diagnosing scleroderma? And then, what are the typical symptoms that a scleroderma patient exhibits?

Carrie Richardson, MD: Yeah, absolutely. So, I think a lot of physicians will understand when scleroderma presents in the classic way, right? When there's skin thickening, it's unmistakable. You know, you can touch the skin and you feel that it's hard or it's shiny, it's woody. And I think that, often, physicians will be quick to recognize it, but there are all these other variations of how scleroderma can present if it presents primarily in the lungs, right? Sometimes the whole picture is not put together unless somebody is really an expert at recognizing it.

So ultimately, the diagnosis of scleroderma is a clinical diagnosis. It's based on the expert's opinion of what these symptoms are due to. And so, over 90% of patients with scleroderma will have some sort of skin thickening or skin tightness. And it's a distinct kind of skin tightness. It's not like rough skin. Often, it's a deeper shiny, you know, woody smooth type of skin tightness. Over 90% will have Raynaud's, which is color change in the fingers in response to cold. And that can be red, white, and or blue. And then, over 90% of people with scleroderma will have a positive ANA if you test it by the right method.

Now, there are some places that send an ANA test, which is a basic test for autoimmunity and do it by a method called ELISA, that method is not as accurate for diagnosing scleroderma, because often the scleroderma tests are not included on that ELISA panel to test the ANA. So, here at Northwestern and at many other academic institutions, they will do an ANA by something called immunofluorescence, which is much more likely to detect a positive ANA if a person has scleroderma. So, those are three main features that sometimes people will use as a basic screen for whether someone might have scleroderma.

Now, there are some people who have a negative ANA who have no skin thickening, who don't have these classic features. There's a whole panel of antibodies that's actually quite good for detecting most-- not all-- cases of scleroderma. So, that is a test that can be sent out to specialized labs where they look at a more comprehensive profile. But often, what will be sent initially is three antibodies called the centromere antibody, the Scl-70 antibody, the RNA polymerase III. And all three of those, if they're positive, the person needs a good evaluation for scleroderma because those are suggestive that there could be scleroderma, although there can be false positives.

There are criteria for deciding whether someone should go into a research study in general, that's how they're used. They're called the 2013 ACR/EULAR classification criteria for systemic sclerosis. The gold standard that these criteria are compared to is actually expert opinion. So, they're basically trying to approximate an expert's opinion of whether someone has scleroderma. They will capture basically over 90% of people with scleroderma. They're quite accurate. But again, you know, an expert may look at someone with interstitial lung disease and Raynaud's. And based on other features, like if they have what's called a patulous esophagus, based on the pattern of the interstitial lung disease, an expert may decide that someone who doesn't meet those criteria actually does have scleroderma just based on the clinical presentation.

So, I think, you know, the criteria are good. And actually, the criteria, they're very easily accessible. If you Google 2013 ACR/EULAR criteria for systemic sclerosis, you will come up with a list of symptoms or signs that a patient may have, including the antibodies is something called telangiectasia, which are red dots on the hands and face, Raynaud's. And you can look and do kind of a quick screen of whether you think someone has scleroderma or not. If they have nine points, that would meet the diagnosis, or if they have skin thickening, that's basically the hands or anything further than the hands, that would also count towards the diagnosis.

But really, in a lot of cases, we see these gray zone cases where we have to make a clinical judgment of whether someone really fits into this category of scleroderma or not. And the one key component of this is there are also autoimmune diseases like dermatomyositis that can actually present with very similar symptoms with interstitial lung disease, with Raynaud's, rashes of all sorts. And sometimes you have to distinguish between whether you think it's due to scleroderma or whether you think it's due to something else.

Anthony Esposito, MD (Moderator): Perfect. Perfect. I think I want to deconstruct a couple things that you said. You said the word interstitial lung disease. I'm going to talk about that a little bit later, because that's probably unfamiliar to some of the people that are listening to this podcast. But I want to ask you the converse of this question. You know, I asked the cutting-edge things that we have here to make a diagnosis of scleroderma and how we might approach a patient. But have you ever had a patient come to you who has been told they had scleroderma and you have been able to reassure them that this might not be correct and redirected them into a different category?

Carrie Richardson, MD: It happens all the time. So, I would say there's a couple things. So in a lot of external labs, we've seen that some labs are not as reliable for detecting the autoantibodies. And you'll see these low levels of Scl-70, especially in RNA polymerase III, come up positive. And very frequently, the physician correctly looks up the data saying, "Oh, this is very suggestive of scleroderma." But I think there's some of that knowledge of some of the labs are not as reliable as the data would suggest. And so, often, we will retest by other methods. And usually, scleroderma antibodies, if they're present, they will remain present. They don't come and go, and they usually don't change in the level. And so, if we see someone was tested for a scleroderma antibody and it was present at a low level. And the next time they were tested, it's gone. That is more suggestive that it's actually a false positive by that lab. So, that happens all the time where people get told that they have this diagnosis and maybe get told some things about the prognosis that are really off base.

And I would have to say, very commonly, people, even when they have scleroderma, they get told things that I think are, I would say, outdated about the prognosis of someone with scleroderma. Many of our patients are actually doing quite well. And so, it is something when people get diagnosed, with good treatment, a lot of our patients do very well. And I think, you know, the earlier we treat, the better. I think we try to treat and control the inflammation together in a multidisciplinary way.

But yes, there are some other mimics of scleroderma too. There's some other rare conditions that can mimic scleroderma. There's another condition called morphea, that's just limited. It's skin thickening, limited to the skin. We'll commonly see that misdiagnosed as systemic sclerosis. And sometimes, we'll see people just with arthritis that their fingers are really puffy and sometimes curled because of arthritis. And we have many treatments for that.

And so, yes, it goes both ways. We see some people who haven't had the diagnosis who come to us and they get it. And then, we see some people who were given this diagnosis and come to us, and we can actually say, "You don't have the diagnosis" or "You have something else that we can treat."

Anthony Esposito, MD (Moderator): Yeah. So, I think the point I'm hearing from you is that not only is our program really good at ruling in a diagnosis of scleroderma, but from patients who might have been given a diagnosis of scleroderma and it's not behaving clinically the way that we would've expected, they may benefit from our program to come and actually confirm the diagnosis as a second opinion potentially.

So, you mentioned a lot of different symptoms that scleroderma patients experience. We've heard things called Raynaud's disease, where their fingers turn different colors, which we know can happen way before the diagnosis of scleroderma happens. And it can be years even before develop the other symptoms of scleroderma. You mentioned a lot of the skin findings in that and whatnot. I wanted to turn the attention a little bit to Dr. Farina over here. Can you speak to how the GI tract is involved with the scleroderma patient?

Domenico Farina, MD: Yeah, absolutely. I mean, up to 90% of our patients with scleroderma have some kind of GI-related symptom. And it ranges literally the entire GI tract as you guys have definitely seen with your patients. Probably most commonly, we see more esophageal-type symptoms. You know, the scleroderma esophagus where you get this kind of attack on the smooth muscle of the lower esophagus, dilatation can occur. And then, primarily that lower esophageal sphincter is very patulous and it is just the perfect model for acid reflux. So, acid reflux is definitely a very common symptom that we see with these patients, to the point where there's no barrier. During endoscopy, we'll see free reflux, that's kind of concerning if they do have lung findings or pathology of that kind of microaspiration playing into things. And, you know, scleroderma really does affect the motility of the entire GI tract as well.

So, we talked a little about the esophagus, gastroparesis, very common. We do see small intestinal dysmotility as well. And that can run the gamut from, you know, just increased transit times, and that predisposes our patients to things like small intestinal bacterial overgrowth, but also can run to more extreme dilatation of leaving the small bowel. That's that chronic intestinal pseudoobstruction that sometimes we see. And that's one of the more difficult manifestations of scleroderma in GI that we have to kind of manifest. And it kind of continues to run through the colon.

And then, one of the most difficult symptoms that our patients experience is actually fecal incontinence that we see in probably about 20-50% depending on the study. And anecdotally, in the scleroderma patients that we care for in part of the GI, part of the scleroderma program, we definitely see probably about a third to half of our patients experience that. And that has a tremendous impact on their quality of life and kind of how, you know, they can even plan their whole day. All their GI tract is really kind of guiding their day in, day out kind of life. And so, we see almost every kind of manifestation at every point in the GI tract of scleroderma causing symptoms in these patients.

Anthony Esposito, MD (Moderator): Yeah, I think the word scleroderma makes everyone think that it's skin disease, right? So, the word scleroderma means hardening of the skin, right? But we really should think of it as hardening of any internal organ, right? The way that you were describing it, Dr. Farina, is, you know, we're having motility issues, meaning poor movement of food through the GI tract. That can lead to constipation, that can lead to bacterial overgrowth and infection, that can lead to reflux up into the chest, which I worry about as a pulmonologist.

And so, really, people that are listening to this podcast might have heard the word systemic sclerosis. Really, they're interchangeable. We're talking about the same thing here, but there actually is a subset of patients that Dr. Richardson tends to see a lot of that actually don't have skin involvement. And so, you don't have to have the skin involvement to have scleroderma. It is a systemic disease. This is why three of us are sitting here. We probably could have had four other people sitting at this exact same table talking about scleroderma, because it really does involve a lot of the organs in the body. Dr. Farina, you talked about some of the manifestations. Can you talk to me a little bit about treatment options for these patients?

Domenico Farina, MD: Yeah. Depending on the symptoms, we have a few treatment options. And actually, I'd say we've had a couple exciting kind of developments in the last couple years. So, in particular, you know, we see a lot of the esophageal manifestations, kind of going to Dr. Richardson's point sometimes of one thing that we offer here at Northwestern is we get these referrals from gastroenterologists who've been taking care of folks primarily with GI illnesses and really bad reflux, someone they're considering for even anti-reflux surgery. And one of the ways that we kind of see these patients is they come to us for their a pre-anti-reflux surgery evaluation. And you kind of look at the patient and you go, "This is a little bit atypical. This is very extreme esophagitis. I'm looking at some of the motility studies you've had and endoscopies." And then, it just kind of clicks in our head that, "Is there something else going on? And can we pull you away from potentially a surgery that might go very poorly for you because of that inability to really move the esophagus?" So in terms of that anti-reflux part that we're talking about is Voquezna, Benoprazan, that's been on the market now for about two and a half years. It is 10 to 100 times stronger depending on the pharmacologic study compared to the classic PPIs.

So, one of the things that we were often doing with our scleroderma patients up until just a few years ago is we'd have them on 150% of the max dose of a proton pump inhibitor. We had them overlapping that with an H2 blocker. We had them opening up capsules, and still we would do these endoscopies and there would be just the most awful inflammation you'd ever seen. And this is actually one of the things that we're looking at in our own group right now, is rates of healing. And for the first time ever, we're seeing folks who have had healed esophagitis with benoprazan. So, that's kind of an exciting development that's helping us kind of care for these patients who have really bad reflux.

One of the issues that we have with caring for these reflux patients, with the esophagus in particular, is that kind of remodeling that kind of happens as the disease can affect the esophagus anatomy, leading to difficulty swallowing. And unfortunately, we don't have great treatments for correcting the swallowing separate from kind of lifestyle modifications controlling that reflux.

But one thing that's kind of classically been taught within our realm with our surgeons here. And, you know, kind of going to the point of that multidisciplinary approach is bringing up these patients with our surgeons and our benign esophageal conferences. When we have that bad case, the person who is aspirating despite sleeping almost upright, they don't eat after 3:00 PM, doing everything they can and they're still waking up choking in the middle of the night. And the classic teaching had been you can never do surgery on these patients. But with careful patient selection, you know, working with kind of minimal fundoplications, those wraps, especially in those patients who have a hiatal hernia. And I saw a scleroderma esophagus. We've had some success in those individualized cases.

Another big kind of thing that we kind of focus on is the gastroparesis component. G-POEM has been something that we've used in scleroderma. That's still kind of an evolving discussion on the right patient selection, but that's basically a procedure to cut the muscle at the bottom of the esophagus. What's great about it is that it is an endoscopic, minimally invasive procedure. And for the right patient, that's a good option. But I think you guys have probably seen over the years, a lot of the medications that we have that improve the muscle function of the stomach and the gut, they have a lot of side effects. Very poor, side effect profile, poorly tolerated.

Similar to the benoprazan is prucalopride. That's been on the market now for about five years or so. That kind of works on the serotonin receptors on the GI tract and is kind of a more diffuse medication. It actually doesn't work specifically on the stomach. We actually get promotility. So, improved muscle function from prucalopride involving the whole GI tract, including potentially the esophagus, which is something that we're kind of interested in exploring a little bit more. But that can be an outstanding medication to help our patients who are feeling that bloating, the nausea, the constipation, because it can actually help all of those things.

One thing that is very helpful for GI symptoms is actually involving our kind of ancillary support services. So, we have dieticians that can be very helpful, pelvic floor therapists in particular, and then our behavioral medicine team, and our GI group as well because of the significant impact these symptoms can have on our patient's quality of life. So, we have a couple new medications, like I mentioned. But one of those things is augmenting medical therapy and lifestyle with these additional services.

One thing that you guys probably see a lot of too is that small intestinal bacterial overgrowth. You know, one thing at Northwestern that we do, I think better than a lot of other places is that kind of lack of empiric treatment. You know, a lot of GIs when they do know that the scleroderma is acting on the gut with their patients. The instinct or the knee-jerk reaction is to just throw rifaximin in particular. "Here's some rifaximin," and a lot of times our patients come to us or they come to the scleroderma program and they're like, "I've tried this medication. It doesn't work for me." And actually doing breath testing and trying to actually see which of these gases are elevated can sometimes help us guide to a different antibiotic regimen that may lead to better success. I always just still warn these folks, it's going to be a frustrating process. Very high rates of recurrence. But if we can at least target those antibiotics or come up with alternating regimens, that really can improve their quality of life in the long run.

I think another thing that we do as well, kind of to piggyback off of that, is actually doing that motility testing. So rather than the guesswork, using things as rudimentary as a small bowel follow through or anorectal manometry, esophageal manometry, specifically with our patients with fecal incontinence. The anorectal manometry can be really invaluable to kind of really understand what's happening that could be contributing to the loss of bowel function. And that can help with both pelvic floor therapy, retraining our patients and trying to find the right balance between kind of working with constipation or diarrhea. And sometimes, it's a tough kind of balance between the two and how we can kind of help them manage their symptoms.

Anthony Esposito, MD (Moderator): Yeah. And unfortunately, some of the medications we give our patients...

Domenico Farina, MD: I did want to go there.

Anthony Esposito, MD (Moderator): Do cause some of those things, right? So, complicating a lot of the problems. Thank you for that walkthrough. I was interested, you mentioned some of these really cutting-edge kind of surgical, minimally invasive surgical procedures that are these offered at other places or is this something that is, you know, unique to what we do here at Northwestern?

Domenico Farina, MD: I would say the most, specifically the G-POEM that peroral endoscopic myotomy, looking at that pyloric muscles, it's like kind of like a pyloroplasty, so cutting the muscle. But rather than doing it laparoscopically, doing it internally, is typically still kind of in the bastion of most academic medical centers. It's more of the art of the patient selection, and that's kind of where our experience really plays into it, that kind of finding out who might be the best person for it.

And then, I'd say too, in terms of if you ever were to consider anti-reflux surgery and scleroderma, I have patients who come to me with articles, case reports, like, "Hey, you know, this is killing me. You know, you guys told me, or another center told me that I can't get surgery," and kind of delving down and go to the right surgeon. And not as the surgeon, I really rely on my surgical colleagues to tell me what they need to think about when they're fixing the diaphragm as part of that surgery, how they're going to tailor that fundoplication. I think experience goes into it. And that kind of helps things that maybe aren't necessarily unique to Northwestern, but trying to achieve the best outcome with them.

Anthony Esposito, MD (Moderator): Yeah. I think I'm hearing a lot of multidisciplinary talk here. So, you know, we've been saying this a lot about multidisciplinary. Again, we have three different specialties sitting at this table right here. We've heard, other specialties that are involved, like surgeons that are involved. Sometimes, we heard about dieticians being involved.

I want to stress something that I've heard from both of you that multidisciplinary doesn't just mean multidisciplinary within like Pulmonary versus GI versus Rheumatology. Multidisciplinary also means kind of within our own specialties, right? We've heard a little bit about Dr. Farina's experience with the different parts of the GI tract. Certainly, within Rheumatology, there's experts in scleroderma, but there's also experts in other autoimmune diseases as well. And I want to talk a little bit about our program here, focusing a little bit on the pulmonology side of it.

Unfortunately, about 40-60%, depending on which cohort, which group of patients that you're studying with scleroderma will end up with a disease process known as interstitial lung disease. Interstitial lung disease is a little bit hard for people to understand. But the way that I like to explain to my patients is that it exists on kind of a spectrum of inflammation and fibrosis. And when we say the word fibrosis, we're really meaning scarring, and we're getting back to that scleroderma, right? I said that word, systemic sclerosis, scleroderma hardening. So, think of it as hardening of the GI tract.

Now, we have hardening of the lung. This happens very early in the course of a scleroderma patient's presentation. Dr. Richardson mentioned the criteria that we use from like a research end to define what scleroderma actually is. One of the criteria is actually having interstitial lung disease. That gives you points towards a diagnosis of a scleroderma, it makes it more likely that that patient who's presenting has scleroderma.

I have colleagues within my own division of Pulmonology who also practice in a realm known as pulmonary hypertension. This is also very common in patients with scleroderma. This is hardening of the arteries within the lung of the individual. And that can lead to really high pressures, hence the word hypertension. And that could put a lot of pressure on the heart, and could put a patient into heart failure. And we have that specialty here at Northwestern where we have a lot of experience treating patients with medications, sometimes with advanced therapies through IV, to try to really take the stress off of that heart, and really optimize their function.

Kind of backing up into the interstitial lung disease realm, which is where I live, Dr. Richardson had mentioned that she gets patients that come in and, you know, they didn't know they had scleroderma. And then, she a lot of times will find that they have interstitial lung disease. And that's by recognizing as a program that interstitial lung disease is a very key feature of this disease process, and it's very common. And we do a very good job, I think, screening our patients for this lung disease. I know that my colleagues in Rheumatology, Dr. Richardson being one of them, frequently get pulmonary function tests in our patients, right? Not just to diagnose interstitial lung disease, but also to follow the course of that. It's also a standard practice in our group to actually get a CT scan, which is the gold standard of diagnosis for interstitial lung disease to really see at diagnosis when it's most commonly diagnosed, does someone have under underlying interstitial lung disease? And the reason we're doing this is actually because the number one reason why patients with scleroderma die is from their lung disease. And a lot of that is interstitial lung disease, and then also the pulmonary hypertension that I mentioned.

And when we're thinking about that, the main symptom of patients with interstitial lung disease is shortness of breath. But when we're thinking about a scleroderma patient, there's actually a lot of reasons why they can be short of breath. And so, you really have to think really hard about why that patient is short of breath, and not just anchor on the fact that they have interstitial lung disease.

You know, in Dr. Farina's realm, maybe the patient's very bloated and we need to really work on their GI tract. And it's because their belly is up in their stomach because their GI tract is just not moving. And I'm relying on my GI colleagues to really help relieve that shortness of breath. Or maybe it's because their skin is really tight, and their chest can't, can't expand against that really tight skin, because it's almost like you have a rubber band around your chest and you're trying to take a breath. And I'm really relying on my Rheumatology colleagues. And so, you know, it's not just the disease process within the lung itself. It involves the GI tract, it involves the skin, it involves a lot of other things: the medications the patient's taking, whether or not they're actually in heart failure from their pulmonary hypertension and they're short of breath from that, and we're relying on our Cardiology colleagues. And so, multidisciplinary within a specialty and multidisciplinary between specialties, I think, is something that is really important and really shines through here in our scleroderma program.

Our Interstitial Lung Disease Program is a rather large program. We see not just patients with scleroderma, we see over 1400 patients a year. And I think a majority of them are scleroderma patients. Last time I was looking at our panel, I think we have at least 400 active patients in our panel that are scleroderma and interstitial lung disease-related. And we share a lot of those patients between Dr. Richardson, Dr. Moore, who she mentioned, and myself, as well as some other colleagues in the Rheumatology realm. And we actually have again that word multidisciplinary on the interstitial lung disease level where we have cases that we present that either we don't know the diagnosis and we need help from our colleagues or it's not really behaving like we think it should on the medications that we have the patient on.

And so, once a week, we have our Interstitial Lung Disease conference, which Dr. Richardson frequently attends. Dr. Moore is sometimes there, is who's one of our colleagues in the Rheumatology Program. But we also have thoracic radiologists here who are specialized in reading these CT scans and telling us, "This actually looks like it could be scleroderma-related lung disease." We have a pathologist who's dedicated to thoracic pathology, who's also very well versed in looking at the pathology under the microscope and saying, "Yeah, this looks like inflammation or scarring that could be related to scleroderma." And we come together as a group and make a plan for the patient in my realm, in the Pulmonology realm. But we also think about things like, "Hey, you know, this might not just be injury from the lung and scleroderma in the lung. It might be injury from the GI tract." And we need to refer to our GI colleagues. So, there's a lot of back and forth that goes between all of us. And it's really great. I think that we're providing holistic and patient-centered care. I think you hit on that a lot about just, in general, thinking about the patient and exactly like, you know, not every patient is the same and really tailoring the care. And I think that's something that our colleagues here in Northwestern do very well.

I want to take the focus for a second away from the clinical aspect of our programs. And I want to talk a little bit about the research programs that we have here. We're at an academic center affiliated with Northwestern University, obviously. And so, there's a lot of opportunities for patients to participate in clinical trials, whether that be development of new drugs and also, you know, discovery research, meaning things that we don't know about the disease yet, that we're trying to figure out to really advance patient care.

Maybe I'll switch back over to you, Dr. Richardson. Do you want to speak a little bit about some of the research opportunities that we have at Northwestern in our program?

Carrie Richardson, MD: I do, but I also want you to tell us a little bit. Because I think we have quite a few clinical trials here. We have translational studies. But you are actually involved in a lot of this research, especially our registry is very large. You've been really integral with making sure that our registry has really fine data where we're getting a lot of detail about patient's lung disease and you're actually doing some pretty novel things to look at kind of machine learning methods to try to see if we can better hone in on better treatment pathways or kind of risk factors for progression for people with lung disease. So, yeah, I always love the updates too, because I think you do a lot behind the scenes and sometimes if I haven't been to a research meeting.

Anthony Esposito, MD (Moderator): So, this is our update right now, what's going on. Okay. All right. This is our lab meeting going on. But all jokes aside. So, thank you for passing it back to me. So, I'm going to pass back to you when we talk about clinical trials. And I also would love to hear on the GI side if there's any of that going on as well, as well as some discovery research. But you mentioned the word registry. So, we do have what we call our scleroderma registry. That is an opportunity for patients who come to our center and receive care as a scleroderma patient to participate in research with very minimal risk. You're not taking a drug that we don't know if is going to cost side effects or harm. You're not coming for multiple visits that are not your clinical visits.

This is literally just you allowing us to access your chart in a de-identified manner to provide us with data from the clinical record to actually do some research and try to figure out what this disease is like and what treatments actually work and what the patients look like. And so, you mentioned the word machine learning, so let me deconstruct that a little bit for people that might not know what that is. So basically, the bigger word and the word that people hear more often is, you know, artificial intelligence. And you hear these things, everybody's familiar with ChatGPT, and that's a form of like a large language model, which is a machine learning algorithm where a computer is just in the background just running a bunch of algorithms and trying to figure out the answer to a question.

We, as you've mentioned, have this registry. We now have over 1100 patients in this registry that we've curated very well at this point. It's taken a couple years to really clean out this registry and make sure that the data is very robust. But we've been able to take the information in this registry, and basically ask a computer to answer some questions for us. For example, we've asked a computer, just looking at the electronic health record, can you tell me whether or not this patient has interstitial lung disease without telling the computer that they do? Now, that might seem silly because you would look right at the CT scan and say, "Okay, clearly, they have interstitial lung disease," but take it a step back and you can ask the questions of, "What are the characteristics of the patients that have interstitial lung disease? What are those biomarkers, like those things that you can find in their blood that might actually help us detect an interstitial lung disease early? Who are the patients that are at highest risk?" We know that from a lot of other clinical trials. But, you know, sometimes things surprise us. For example, there's like a measure on a blood test that many of our patients get called the red cell distribution width, that popped out as one of the key features that predicted a lot of the outcomes, just from a machine looking at the data that we have in this registry.

We've also asked the computer to help us figure out some very robust clinical outcomes. So, for example, we want to know who's at risk for the worst outcomes. And obviously, the worst outcome would be death. And so, when we're making treatment decisions, we really need to risk stratify patients, and think about what is the risk in the short term, what is the risk in the medium term, in the long term? And we've asked the computer to really look at these features in our registry and say, "What is the likelihood at this moment that this patient would die in one year, three years and five years?" We can do this with actually very fine precision with high what we call sensitivity, meaning that there's a true positive rate that's really high and a low false negative rate. And we can do this and actually predict mortality just by taking information from the electronic health record and allowing the computer to kind of run algorithms through it and give us that data back. And that's something a patient can contribute to our program just by signing a paper and saying that it's okay to access their record. The risk is minimal, just related to, you know, privacy breach. But everything that we do is de-identified. And so, the risk is minimal, but the payoff actually could be quite good and could really advance the field.

And so, I'm going to stop there. And I want to hear a little bit about both sides, what's going on with like the clinical trial and maybe even some discovery on the Rheumatology and the GI side.

Carrie Richardson, MD: Yeah. I would say a lot of what we do is collaborations, right? Like, my job is mainly clinical care, educating fellows, medical students, and then I help other people do their awesome research, right? You know, we're doing a pulmonary hypertension study with Sanjiv Shah and Yaku looking at echocardiograms. That is done recruiting, and we're going to have hopefully some pretty exciting data published on that soon.

We have the CONQUER Registry, which is a registry of early scleroderma patients. That's a multicenter registry where I'm a PI on that study. And those are, again, contributing data to kind of learn more about early scleroderma. It's slightly different than our registry, because the data is more structured, and that there's a kind of a set of questions and questionnaires that patients go through, and there's certain blood draws that are part of it. So, it's a little bit more involved. It's every six-month visits.

We have a study that we're doing on blood markers of cancer, and that's funded by the NIH and that's with Ami Shah and then University of Pittsburgh as well. So, we're really excited about that. We're going to be recruiting patients for that very soon of looking to see if there's free tumor DNA in patients who don't have cancer with scleroderma, but may ultimately go on to maybe be diagnosed with it or not.

And then, we have a collaboration with the undergrad on looking at a wearable skin sensor that can vibrate and basically detect skin thickness. And we're pretty excited about that one as well to see if that kind of provides us a little bit more granular data about skin thickness rather than just doing the modified Rodnan skin score. And then, there's obviously, your research that you do, your collaboration with AbbVie and doing bronchoscopy data and looking at translational work there. It's very exciting.

So, there's a lot of stuff happening here that there's a huge focus here on GI. I know we do translational work on GI and that is something that we're really hoping, I think, to bring more GI research or to kind of develop that program because that it really is an unmet need for our patients. We have a lot of therapies that can really-- I mean, really, from a lung disease perspective with the multidisciplinary care, the lung disease, you know, even though traditionally it's been a greater source of risk for these patients, we actually see, in our group of scleroderma patients, GI disease is really up there with lung disease as one of the major risks to our patients' lives. And so, that's really devastating I think when patients have this chronic intestinal pseudoobstruction end up on TPN. And really, just the quality of life. And, you know, we do see patients pass away because their GI disease is just so severe. And, yeah, I guess, talking about updates, I know what's happening on the rheum side, but is there anything new happening in GI?

Domenico Farina, MD: On the GI side, I mean, you know, I mentioned a little bit about some of the medications have come about. A lot of the low-hanging fruit for us has been kind of describing our experience and trying to-- you know, so, we're not basically spinning our wheels for long periods of time where patients are miserable before we make a jump to something that is newer, but may have a benefit and kind of save them this kind of step up approach.

Specifically, on the esophageal side, scleroderma is actually a great model from a motility perspective and kind of showing us an esophagus that doesn't do any of the roles that it was designed to do at birth: propel food down and prevent things from coming back up. And actually, using that model has actually potentially helped us understand the esophagus function better in other people. So, that's a kind of a unique way of not necessarily a research study looking at scleroderma itself, but using scleroderma to help us understand esophageal physiology.

Going to your point a little bit about kind of machine learning, kind of a plug for my division chief, Dr. Pandolfino, who does a lot of the artificial intelligence machine learning. We have been collecting a lot of information from our endoscopies. And probably the future for us is using that machine learning artificial intelligence to help us using endoscopy make those diagnoses early. You know, getting that clue early on is like, "Hey, maybe there are features here, scleroderma, esophagus or dysmotility," putting together, "Hey, there's evidence of food retention on this endoscopy, erosive esophagitis. What's your pretest probability?" or I guess post-test probability after the EGD of scleroderma, or think about that and then knowing that, "Okay, based on that, what else should we do to evaluate this patient to make sure they're plugged in with the right people?" But definitely, yes, that disease burden pretty severe on our patients, some of those symptoms. And definitely, there's a lot of room for us, I think, to kind of focus on trying to improve those outcomes and clinical trials from that perspective.

Anthony Esposito, MD (Moderator): I mean, there's a lot of collaboration that we've all been talking about on patient level, but also research level. One thing that wasn't mentioned is that actually you mentioned Dr. Pandolfino. He does endoscopies and is doing biopsies in patients from a research perspective. But actually, they collaborate. And at the same time, we're doing what's called a bronchoscopy right after they did the--

Domenico Farina, MD: I was the esophageal fellow, we did a couple of those cases together. It was under him. The endoscopy-bronchoscopy tandem, one after the other, yeah.

Anthony Esposito, MD (Moderator): Yeah. And it's just really trying to figure out the interplay between the gut and the lung. And so, everything's kind of playing together in this disease process to really manifest into a disease that needs more than just one doctor caring for that patient. And that's what we have here at Northwestern Medicine.

I think we jumped ahead and talked about like, in the future, what the treatment processes are. But I know this podcast is a little bit about treatment for scleroderma itself. And so, I just want to take a couple minutes and talk about standard of care therapy for patients with scleroderma. I think I'll pass the baton to Dr. Richardson for that. You know, how do you treat a patient with scleroderma generally? Like, how do you approach treatment for a patient?

Carrie Richardson, MD: Yeah. So, there's no one-size-fits-all treatment for people with scleroderma. There are people who require immunosuppresive therapy, and then there's people who don't, right? People with primarily GI disease are often on promotility, you know, reflux medications, things like that. So, it really is tailored to the person. What are the manifestations you have to think about? Do they have significant skin thickening? Do they have significant lung disease? And not only that, do they have these things at present, but also are they likely to progress in the future? And are they likely to respond to therapy?

And so, when we're thinking about things like immunosuppresive treatment, there are a lot of variations in the way people practice here in the United States. The most common immunosuppressive medication when we've looked at the data is actually mycophenolate. So, that is the one that's generally the go-to. It often treats skin and lung, but you look and you'll see differently and there's different practice patterns if you look in the European quotes. They use some medications more like cyclophosphamide, which is not as commonly used in the United States.

So, we have two FDA approved treatments for scleroderma. Both of them are specifically for lung disease, so they're not scleroderma treatments. They're lung disease treatments, and that's nintedanib or Ofev, which you and your colleagues in pulmonary tend to prescribe more. And then, there's tocilizumab, which is Actemra, which is again scleroderma lung disease. It also is an arthritis treatment as well. So, mycophenolate is still viewed as essentially the standard of care therapy, and that's based on a trial SLS II, Scleroderma Lung Study II, where mycophenolate was compared to cyclophosphamide for lung disease. And there's been many years of use. You know, often, it's effective for many people. Actemra is becoming more commonly used as well since the FDA approval.

Rituximab is another treatment that sometimes people will use. Now for lung disease, as you know, there are the ACR chest guidelines for how you treat interstitial lung disease, which you are very familiar with and have written a quite a bit and spoken quite a bit on how you use and apply those guidelines. There's an art to applying the guidelines, right? And it is when you use which therapy. These therapies have not been studied head to head. And so, when you're looking at it, you're trying to compare essentially apples and oranges, right? Like you're comparing one trial to another trial where the people in this trial were completely different than the people in that trial. And this trial was designed to look at skin, but it got a lung drug approved. And this trial was designed to look at lung, but we're using it for skin.

And then, there's some differences too, right? Like in those guidelines too, people with scleroderma sometimes will have overlap conditions, right? We'll commonly see they have myositis, right? And, you know, then how you mix the myositis treatments with the scleroderma treatments, they'll commonly have inflammatory arthritis, so how you manage that. Again, this is where it becomes really important to see a lot of patients, because I think about things, right? If someone, you know, their gut, they just cannot tolerate things. Is a pill going to be the best option for them? Maybe we're going to choose an injection instead. So, you think about things like absorption, you think about things that would be comorbidities or other conditions that may be present that could influence that would tell you maybe, "I don't want to use this drug that has a cardiovascular risk because there's a high cardiovascular risk," right? Maybe there's a high infection risk, I want to be mindful of that in my use of medications that lower the immune system.

So, I think it has to be tailored to the individual patient, and you don't want to introduce a medication that will then just not help and will confuse the picture like a medication that will cause anemia. And then, we're wondering if the anemia came from the GAVE or came from the medication. And I think our multidisciplinary conversations too, like when we discuss these patients, I think, you know, often we will come to a better and more finely tuned plan than if either of us did that separately. And again, our multidisciplinary clinic where patients, essentially most of our patients are newly diagnosed or who have lung disease, and we think that's autoimmune in nature, they can see us both on the same day and actually we can discuss that plan right at the point of care instead of doing it by phone later or at separate visits and having, you know, somebody who may be limited in their mobility walk around this giant campus.

So yeah, I think, medicine is not like flying a plane. It's not as amenable to a checklist, right? Because everybody is slightly different, and there are certain things that can factor into that decision-making that take some expertise and take some experience to be able to know what should I think about when treating somebody with a medication.

Anthony Esposito, MD (Moderator): I think one of the bigger questions too is when do we stop medications?

Carrie Richardson, MD: That's a question you can answer with the registry.

Anthony Esposito, MD (Moderator): But that's a question we're not going to answer right now, because that is a harder one. And I think, again, we're highlighting the fact here that we don't live in silos here when we're treating these patients. When I see someone that's progressing with their lung disease, but I think that their inflammation is really well-controlled, I might reach out to Dr. Farina and his colleagues and say, "Hey, I really think that the GI tract is actually causing the problem in the lung." And that sounds really weird to think about. But as humans, our GI tract is actually right next to where our respiratory tract is. And so, when you have really bad reflux, that can get down in the lung and cause --- I tell my patients it's almost like throwing a match on gasoline. Like, you're just lighting everything on fire. And so, we're really relying on each other to help care for these patients. And things that might not seem related, like the GI tract and the lung actually really, really are.

Carrie Richardson, MD: I think you should collaborate.

Anthony Esposito, MD (Moderator): Well, this has been a great conversation. I've had a lot of fun with both of you. Obviously, we see each other a lot. So, it'll be great to continue our conversations, but thank you all for joining us.

Melanie Cole, MS (Host): Thank you all so very much for participating in such an enlightening round table. To refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/rheumatology to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole.