Scleroderma Part 1: Clinical Presentation And Workup

Hey guys, thanks for joining me today. In this episode we'll be discussing scleroderma. Now this is a very complex disease and so I'm going to be doing a high yield overview with you today on the fundamentals of the condition. I've split it into two parts. This episode, part one, will focus on the clinical presentation and workup of systemic sclerosis, while part two, which will be really shortly, will discuss management. Now as I said, scleroderma is a very complex disease and so I was clarifying and fact-checking lots with my esteemed colleagues in preparation for this episode. In particular, I want to thank Dr. Janet Pope, Dr. Christopher Denton, Dr. Maggie Larshay, and Dr. Catherine Woodben, and lastly, a public service announcement. I know that thousands of you listen to each episode, but very few of you have rated the show on Apple podcasts, and even fewer of you have responded to the survey. And I get it. We all hate surveys, and I understand that you're busy. But if you like the show, please do two things for me. Firstly, rate it on Apple podcasts, and/or drop a review because it helps me justify our educational grants, especially if we're applying for a renewal, and it helps others find the program. Secondly, please, please, please, take just a few minutes and fill out the survey. It gives me a good sense of which topics you want to hear going forward, how I can make the show better, and whether we should continue for another season. Welcome to Roomatology for the Royal College, where we aim to bring you reviews that will strengthen your knowledge going into exams and clinical encounters. We hope you'll find it useful and enjoyable, whether you're running, lifting, cooking, grocery shopping, driving, you get the idea. I'm your host, Dr. Karim Ladak, an American trained Canadian rheumatologist. Before we start, my lawyer advised that I should say the information here only reflects what I have in my personal notes and should not be used in isolation in the management of patients, nor for your boards. I'd like to thank Organon and Pfizer for supporting this podcast through their educational grants. However, it should be noted they have absolutely no editorial say in its production. So when we use the terms systemic sclerosis and scleroderma, we tend to use them interchangeably. Though that's not exactly fair because scleroderma just means hard skin. And scleroderma is an all encompassing condition that includes both localized scleroderma, which is just where you have a segment of skin that's affected by hardening. That includes things like morphia, while systemic sclerosis is a systemic condition where you have both skin involvement and internal organ involvement. And when we talk about systemic sclerosis, we divide it into two categories. Defuse cutaneous systemic sclerosis and limited cutaneous systemic sclerosis. Defuse cutaneous disease is where the skin involvement comes proximal to the elbows and proximal to the knees, whereas limited cutaneous systemic sclerosis does not pass the elbows or the knees, though it can still involve the face and the neck often. And the rationale for breaking down systemic sclerosis by the degree of skin involvement, diffuse as in proximal to the elbows and the knees or limited as not passing the elbows and the knees is because these two phenotypes are associated with their own antibodies and with their own internal organ manifestations. So that's really it. Diffuse and limited cutaneous systemic sclerosis all encompassed within the umbrella of scleroderma, which can be localized, including things like morphia or systemic, including systemic sclerosis. Now just before we wrap up definitions here, I just want to mention one term and that is systemic sclerosis, CNAe scleroderma. This condition affects less than 5% of patients with systemic sclerosis. Patients can get the classic non-cutaneous manifestations, including rain nodes, digital ulcers, pulmonary hypertension, positive antibodies, but they don't have skin involvement and hence we call them systemic sclerosis, CNAe scleroderma. But again it's rare less than 5% of all scleroderma cases. Going forward for the rest of the podcast, you'll hear me use systemic sclerosis and scleroderma interchangeably, but I'm referring specifically to systemic sclerosis, not localized scleroderma. Epidemiology. Scleroderma is a rare disease and there's geographic variability as well, such that we tend to see more cases of it in Europe and the Americas than we would in the eastern world. Here in North America, the prevalence is about 30 per 100,000 individuals and it happens to be highest in the indigenous peoples of Canada at about 47 per 100,000 people. The condition tends to affect women more than men at a 4-to-1 ratio and while scleroderma can come on at any age, we tend to see it starting between 30 and 50 years old. Pathophysiology. Let's quickly touch on pathophysiology of scleroderma. Systemic sclerosis is a connective tissue disease. The simplistic three-pronged view of this condition is that it's characterized by the following. Number one, vasculopathy. Number two, immune dysregulation, and number three, fibrosis. Now in terms of things that trigger or drive the disease, genetics probably plays a role, but it's not enough in and of itself. For example, a twin study out of Pittsburgh in 2003 found only a 5% concordance between twins and this held up whether they were dizygotic or monozygotic. So scleroderma likely happens in genetically susceptible individuals but because of environmental factors. In different triggers have been proposed. You might have heard of silicone breast implants. We've seen case report level data suggesting that after silicone breast implants, some patients have developed scleroderma, though really in terms of sizeable epidemiologic studies, we haven't been able to prove any kind of major association or causality, however. One condition that is very clearly associated with scleroderma is malignancy. Malignancy can trigger the disease and when it does, it can be particularly severe and is strongly associated with the RNA polymerase 3 antibody. Most cases of scleroderma are not perineoplastic but I'm just giving you an example of one proven association. Anyway, that's all the pathophysiology we're going to mention. But for future reference, if you have a patient with scleroderma in your office and they're worried about passing the disease onto their children, you can tell them about the Pittsburgh study and remind them that genetics just makes up a small portion of the risk for developing scleroderma. Quiz time. Ok guys, quick quiz time to make sure that you're paying attention. Now we know that in limited cutaneous systemic sclerosis, the skin involvement goes up to the elbows and the knees. And we know that in diffuse cutaneous systemic sclerosis, the skin involvement goes past the elbows and the knees more proximally. Question one for you then is as follows. What do we call systemic sclerosis when there is no skin involvement? Sclerosis seen as scleroderma. Again, that's a rare condition affecting less than 5% of patients with systemic sclerosis. Ok, question two, true or false? Limited cutaneous systemic sclerosis does not involve the face and the neck. False. While the skin involvement on the limbs only goes up to the elbows and the knees, you can also have facial and neck skin involvement in patients with limited cutaneous systemic sclerosis. Clinical presentation. So skin is the classic organ that's involved in scleroderma. And we will get into that momentarily. But I want you to remember that there are some other clinical features that are deeper than just the skin, which are common in both limited and diffuse systemic sclerosis. And these include Raynode's Phenomenon or Gastrosophagear Reflux disease. But scleroderma's clinical manifestations can vary. And I've already told you before that the skin phenotype corresponds with the internal organ involvement. And sometimes, or more specifically up to 20% of the time, patients with scleroderma can have overlap with other connective tissue diseases as well. And when they do, it's usually the limited cutaneous phenotype rather than the diffused cutaneous phenotype. But that's enough of that. Let's jump into specific system manifestations and we're going to start with the skin. Inflammatory skin disease is common and almost universal, such that more than 95% of patients with scleroderma are going to have skin disease. And remember those that don't, we refer to them as systemic sclerosis, CNA scleroderma. Now, the skin changes of scleroderma start in the distal fingers or toes and they spread approximately. Initially, you can get puffiness from inflammation and microvascular disease. But as the collagen builds up, the skin becomes tighter. And this makes it difficult to move. involved joints. So for example, if the fingers are involved, patients can have difficulty flexing or extending their fingers. Same goes for the wrist and the same even goes for the jaw. And so eventually patients can develop contractures or squareodactyl where you have such severe tightness that the fingers curl and lose mobility. And in the case of facial involvement, patients can develop small oral apertures. But it's not just hardening and tightening of the skin. There are other dermatologic abnormalities that can develop because of the inflammation and fibrosis. And probably one of the most common and bothersome ones is an itch. It's a horrible itch, though thankfully it can resolve after the early inflammatory phases of scleroderma subside within the skin. Patients can also get changes in their pigment. We call it salt and pepper skin where there's depigmentation, i.e. salt and hyperpigmentation or pepper. They can lose fat and we call that lipoatrophy. When the skin becomes disturbed, they can lose hair or they can lose their ability to sweat where the skin has hardened. And in or under the skin, we can also see calcinosis, which is where calcium salts deposit into the skin and subcutaneous tissues. And they tend to show up in the hands, but we can also see calcinosis in the elbows and the knees. And the last mucocutaneous manifestation that's worth mentioning is telangiectasia's. Now these are dilated or broken blood vessels that appear as red spots that blanche when you push on them. And they can show up in the skin or mucus membranes. They occur both in limited and diffuse cutaneous systemic sclerosis, but are more frequent in the limited cutaneous phenotype. Now something useful to know about the skin hardening is that it usually platose after about three to five years. And after that, it can even soften or atrophy to a variable degree. And as I've said to you earlier, the skin disease is very relevant because different phenotypes are associated with different degrees of skin involvement. I read something really interesting in a nature paper by Manchester's Dr. Arian Herrick, which she said simply but very truly. And I'll quote her here, quote, "Skin involvement in early diffuse systemic sclerosis is a very visible and accessible window into the disease process." The reason she and her colleagues wrote this is because a high skin score correlates with poorer survival. And the faster the skin progresses, the higher the risk of early mortality. And the faster the skin progresses, the higher the risk of sclerodermorinal crisis. And the more progressive a patient's skin fibrosis, the higher their risk for interstitial lung disease. And so the takeaway from this piece of the episode on cutaneous manifestations in scleroderma is not just that you get skin thickening and hardening from the tips of the fingers and toes moving approximately with early inflammation and puffiness associated with an itch and pigmentation changes and tightening or sclerodactyly or even small oral apertures and calcinosis and telangetages. But also that the degree of skin involvement and how aggressive it is can mirror what's going on under the skin in the internal organs or predict risk for internal organ involvement such as things like sclerodermorinal crisis or interstitial lung disease. And before we move on from skin disease, I'm going to leave you with data from one more study to chew on. A prospective observational study from Pittsburgh that looked at 287 patients found that the more the skin softened with time, the better the patients overall disease prognosis, which is a nice thing to watch. In terms of constitutional symptoms, patients with scleroderma can have fatigue, they can have anorexia, weight loss, and weakness. When it comes to musculoskeletal manifestations very quickly, patients can develop arthritis or inflammatory arthritis and they can develop myocytus or myopathy. In this section, I want us to elaborate on five more major specific organ manifestations. And these are Raynode's phenomenon, interstitial lung disease, pulmonary hypertension, gastrointestinal manifestations, and sclerodermorinal crisis. And we're going to start it up with Raynode's. So Raynode phenomenon or Raynode is prevalent in the majority of patients with scleroderma. And it results from a digital vasculopathy that almost every patient with systemic sclerosis is going to have. Raynode's is classically described as a sudden onset, triphasic color change that goes from white from the vasoconstriction and the pre-capillary arterials to blue or purple from cyanosis and then eventually to red from post-yschemic hyperemia. And these color changes are sharply demarcated from the surrounding normally perfused tissues in the fingers. Now, some patients are not going to have that classic triphasic color change. And so I asked a sclerodermor expert what she would be willing to call Raynode's phenomenon. And she said as long as she sees power, then regardless of whether they have red, blue, or both, she's willing to call it Raynodes. And by the way, clinically, Raynode's phenomenon is often accompanied by paresthesia and pain in the ischemic areas. Now, Raynode's phenomenon is not uncommon in the general healthy population. Idiopathic or primary Raynodes is a condition we see in about 10% of our population more often than women than men. But this is not the same as systemic sclerosis associated Raynodes phenomenon. And the reason I say that is because primary Raynodes is a purely vasospastic condition. Scleroderma associated Raynodes though is a more severe and more persistent ischemia that's driven by a different process than just vasospasm. You see, it's also driven by a persistent and progressive narrowing of the blood vessel lumen. And so while both primary and scleroderma associated Raynodes phenomenon can be triggered by cold or emotional stress, patients with systemic sclerosis will have a lower threshold before they develop an episode of Raynodes. And so you can more commonly see their Raynodes throughout the year, even with relatively not so cold weather. You might often hear that air-conditioned buildings or putting their hands into a fridge will set off an attack. And the severity of these attacks can vary. They can range all the way from infrequent mild attacks up to severe e-reverse boschemia with gangrene. Now, as I said, primary or idiopathic Raynodes phenomenon is quite common. And so if you have it or your loved one has it, you're kind of wondering, you know, wait a second, do I have scleroderma? Well, the age of onset for primary Raynodes is usually under 30 years of age. And secondary etiologies, things like scleroderma tend to happen after the age of 40. And that 30 to 40 year mark, that's sort of a gray zone. Now, in terms of timing, remember we said that limited and diffuse cutaneous systemic sclerosis have their own phenotypes. While in the limited cutaneous systemic sclerosis cohort, Raynodes tends to be the first clinical manifestation and predates skin disease and other clinical manifestations by many years. Whereas in the diffuse cutaneous systemic cohort, Raynodes phenomenon is often much closer in terms of time to other clinical manifestations such as skin sclerosis. Two more things I want to mention before we move on from Raynodes phenomenon are number one, more severe ischemic manifestations. And this includes fingertip ulcers and critical ischemia. So fingertip ulcers will develop in about 50% of patients with systemic sclerosis. These are primarily ischemic, though you can also see ulceration on the extensor surfaces. And these tend to be more from skin tension and trauma. These fingertip ulcers can be super painful which makes sense if you think about the fact that our fingers are such sensitive areas. And when patients develop these ulcers, they can really impair function and hurt the patient's quality of life. Again, because of that pain, they can also easily become infected. And so they really are no bueno. In terms of healing up, digital ulcers can often heal on their own and can do even better with good wound care. But the median time to heal is approximately two and a half months. It can be much shorter or it can be much longer and take up to years for a digital ulcer to heal up. And another more severe manifestation of digital ischemia that results from progressive vasculopathy is critical ischemia. Now you'll see different definitions for critical ischemia. But speaking to one of our scleroderma experts, she defines it as a gangrenous black digit or even a cold finger that hasn't yet developed gangrene, but has a large digital ulcer on it. And unfortunately, about five percent of patients will develop critical ischemia. And lastly, Raynodes doesn't just affect the fingers. It can also affect the toes, the nose, the ears, the lips, even the nipples. So the next manifestation we're going to talk about now is interstitial lung disease, aka fibrosin ovulitis, aka pulmonary fibrosis. Interstitial lung disease or ILD is common in scleroderma. So common in fact that it's part of the 2013 ACR ULAR classification criteria for systemic sclerosis. Now the estimates vary based on which study you look at, but let's say something like 50 to 80% of patients with systemic sclerosis are going to have interstitial lung disease. It's more common in patients with diffuse disease rather than limited disease, but it can happen in both. And apart from the diffuse cutaneous skin subtype, there are other risk factors for the development or progression of ILD. These include the SCL-70 antibody, aka the topoisom raise antibody, recent onset of disease because ILD is an early clinical manifestation that usually presents in the first five years of the non-ray node symptoms. While on the other hand, the anti-centramir antibody is protective, as is a normal high-resolution CT at the time of presentation. Now thankfully despite the prevalence of scleroderma associated ILD, not all patients will have severe disease or even respiratory symptoms. In fact, less than half are going to develop clinically significant interstitial lung disease. For those who do develop symptoms, the most common ones are shortness of breath, typically shortness of breath and exertion to start with, and then it progresses, as well as a dry cough and fatigue. Rarely patients might complain of chest discomfort or even hemoptysis. And on exam when you listen to their lungs, the classic finding is fine crackles at the bases. It sounds kind of like Velcro being torn apart. Ultimately as you follow these patients, their clinical course will be variable. Most are going to have a slow decline in lung function, but it can be rapid as well. And you can usually tell very quickly which phenotype they're going to be based on your serial monitoring of their symptoms and objective markers such as PFTs. And I should mention here that interstitial lung disease associated with systemic sclerosis is important. It is the most frequent cause of systemic sclerosis-related death. According to a 2010 study from the ULAR scleroderma trials and research database, 35% of scleroderma-related death and 20% of overall mortality are from pulmonary fibrosis. And the severity of initial testing on PFTs and by CAT scan are independent predictors of mortality down the road for that patient. The next big non-skin organ manifestation I want us to discuss is number three of five pulmonary hypertension. Pulmonary hypertension is a big problem in patients with systemic sclerosis. When we say pulmonary hypertension, we mean a mean pulmonary artery pressure more than 20 millimeters of mercury based on the most recent definitions as of 2018. So again, mean pulmonary artery pressure more than 20 millimeters of mercury. And generally when we speak about pulmonary hypertension outside of scleroderma, there are five groups. Group one is the most common form of pulmonary hypertension in systemic sclerosis, comprising about two-thirds of cases in the disease, and it's driven by a vasculopathy. And therefore, the name we give this group one cause of pulmonary hypertension in scleroderma is pulmonary arterial hypertension. And we see pulmonary arterial hypertension in about 10% of all patients with systemic sclerosis. Patients can also get other groups of pulmonary hypertension in scleroderma. These include group two, which might be from scleroderma induced left ventricular dysfunction like myocardial fibrosis, group three from hypoxic phasoconstriction, secondary tinterstitial lung disease, group four, secondary to chronic thromboembolic pulmonary hypertension, or CTF, or even another rare cause of group one pulmonary hypertension called pulmonary venooclusive disease. But for time sake, we're just going to focus on pulmonary arterial hypertension for the rest of the talk. The symptoms of pulmonary hypertension are pretty non-specific. They can include shortness of breath, fatigue, weakness, chest pain, and even dizziness because blood can't flow systemically as well as it wants to when it gets caught up in the lungs. And this is a serious condition pulmonary arterial hypertension is associated with a three-year mortality somewhere between 20 and 48%. Now all your patients with systemic sclerosis are going to be at risk of pulmonary arterial hypertension, including both the diffuse and limited cutaneous subtypes. But the greatest risk is in those patients who are anti-centramar positive, those with extensive telangictatias, and those with longer disease duration. Because unlike interstitial lung disease, pulmonary hypertension is not an early manifestation, but a later manifestation. So again, higher risk of pulmonary arterial hypertension if you're anti-centramar positive. In those patients who have extensive telangictatias, and the way I think about this is that they're both blood vessel problems. So more telangictatias, more blood vessel problems, more pulmonary hypertension, more blood vessel problems. And lastly, those with a longer disease duration because pulmonary hypertension is a late clinical manifestation. The last point I want to make about prognosis is that the traditional belief was that patients with scleroderma associated pulmonary arterial hypertension had a worse prognosis than patients with idiopathic pulmonary arterial hypertension, even when you adjusted for the hemodynamic measurements. However, nowadays, newer data would suggest that if you use aggressive therapy up front, the treatment outcomes become much more similar, which is great news for our patients. Internal organ manifestation number four or five I want to discuss is the gastrointestinal manifestations. The GI system is the most commonly involved internal organ system in scleroderma, and disease involvement can be anywhere from the mouth to the anus. But the esophagus is the most commonly affected gastrointestinal organ. We see involvement in up to 90% of patients with systemic sclerosis. Esophageal symptoms will include things like heartburn, regurgitation, vomiting, dysphasia, atypical chest discomfort, changes in voice, chronic cough, and asthma. And the reason for these laryngeal or respiratory symptoms is because of acid reflux. Now 30% of patients with esophageal disease can even be asymptomatic, especially early on in their disease course. And so it can be challenging to diagnose esophageal disease in early systemic sclerosis. To explain it a little bit better, let's discuss the mechanism. Now you can get smooth muscle atrophy and neuropathy in the esophagus that lead to decreased peristasis in the lower two thirds of the esophagus, as well as a reduced tone in the lower esophageal sphincter, i.e. kind of a floppy open regurgitant sphincter. And the technical term for this on imaging because you can see it on imaging is a patchless lower esophageal sphincter. And so what happens when you have neuropathy and muscle atrophy with impaired peristasis in the lower two thirds of the esophagus, or basically a big ole floppy lower esophageal sphincter that refluxes contents back into the esophagus, while you get ineffective esophageal transit, and the longer the disease duration, the more severe the esophageal manifestations tend to be. Now unfortunately because of the esophageal dysmortality and a lot of the resulting reflux, patients will frequently develop baritisophagus, as well as chronic micro aspirations that can worsen their ILD. Now before we finish up with the gastrointestinal symptom, I'm just going to quickly remind you once again that scleroderma can affect anything from the mouth to the anus, and so commonly patients can also experience stomach, intestinal, and anal disease. And this happens because of fibrosis, myopathy, neuropathy, which translate to poor gastric emptying, bad constipation, small intestinal bacterial overgrowth or SIBO, and very commonly something that we tend to neglect to ask patients or educate them about, and that is fecal and contents. And the last internal organ involvement that I want us to chat about is scleroderma renal crisis. This is a life threatening complication, and with scleroderma renal crisis, 15% of patients will be dead at the one year mark, so it really is not a joke, and it's something you should be well informed about. Now the truth is, it used to be the leading cause of death in scleroderma until ACE inhibitors were introduced in the 80s, and I'm by no means saying that 15% mortality at one year is a good number, but it's certainly a lot better than it used to be. Let's talk about risk factors. Scleroderma renal crisis is more frequently seen in diffuse cutaneous, rather than limited cutaneous systemic sclerosis. It can happen in both, but it's just much more common in the diffuse patients. Other risk factors include rapidly progressive skin thickening, remember what Dr. Herrick said, that skin involvement in early diffuse disease is a very accessible and visible window into the internal disease process. And you'll also see that there are other clinical manifestations, including things like a paracardial effusion or tendon friction rubs. But the two clinical risk factors, apart from skin and paracardial effusion and tendon friction rubs that I want you to remember, are the RNA polymerase 3 antibody, so again RNA polymerase 3, and so systemic glucocorticoids, particularly when we get to prednisone 15 milligrams po daily or higher. And for that reason, I would caution you, be very, very, very careful. If you are planning on starting steroids in a patient with systemic sclerosis, particularly if your patient has diffuse cutaneous systemic sclerosis, particularly if they have RNA polymerase three, and particularly if they are within the first five years of their non-ranodes manifestations, because just like IOD and unlike pulmonary hypertension, sclerodermal renal crisis is an early complication of the disease process. Now, I think that's enough of a warning. Let's talk about the microscopic level of sclerodermal renal crisis very quickly. What you get is an accelerated hypertension and thrombotic microangeopathy. Something likely triggers endothelial activation and smooth muscle proliferation, leading to proliferative vasculopathy, thrombosis, fibrenoid necrosis, and ultimately, it leads to glomerular ischemia. When the glomeruli suffer ischemia, this causes the renin levels to skyrocket and in response blood pressure jumps and worsens the whole process and therefore it's a terrible spiral. And clinically what this will look like is a sudden and marked increase in blood pressure and a rapidly progressive oligiric or anuric renal failure. So the blood pressure climbs and urine outputs drops along with the rest of the patient's renal function. You may also hear of sclerodermal renal crisis described as a malignant hypertension syndrome, which just means that it's the most severe form of hypertension one that comes on quickly and is associated with multiple end organ complications. And your patient can have a variety of symptoms resulting from this. These include symptoms of renal failure other than just low urine output and symptoms of hypertension, including hypertensive encephalopathy, characterized by headache, confusion, altered mental status, blurry vision. And they might also be short of breath from developing cardiac strain or pulmonary edema. So again, sclerodermal renal crisis, sudden and marked increase in blood pressure, rapidly progressive oligiric or anuric renal failure. The tricky part about this condition is that 10% of patients with sclerodermal renal crisis are going to be not hypertensive, but normal intensive, where the blood pressure is in the normal range. Though often these patients have blood pressure that's higher than their baseline. And so while it's not "hypertension" in that it's not over 140 over 90 millimeters of mercury, it's still a relative hypertension for what they're used to. And unfortunately, those normal intensive patients tend to have worse outcomes in the long term compared to truly hypertensive patients. And that could just be reflective of the fact that sclerodermal renal crisis is picked up later because they're not technically hypertensive per definition. And therefore treatment has started later and therefore we don't get on top of the disease process before it spirals out of control. Quick time. All right guys, question one. Please name four manifestations of systemic sclerosis in the skin. Now I'm gonna give you eight. So if you can come up with some bonus ones that's even better, but try for at least four. And I'll give you a couple of seconds. All right, here we go. Number one, thickening and tightening of the skin that starts in the fingers and toes and extends approximately. Number two, itch. Number three, salt and pepper skin. Number four, lipoatrophy or loss of fat. Number five, loss of hair. Number six, loss of the ability to sweat. Number seven, calcinosis, and number eight, telangictatias. All right, question two. Please tell me if the three following conditions are early or late manifestations of systemic sclerosis. The first one is interstitial lung disease. Is that early or late? Early. It usually happens in the first five years. How about pulmonary hypertension? That tends to be a later complication. And scleroder merino crisis. Like ILD, scleroder merino crisis is an early manifestation. Question three, please list some risk factors for scleroder merino crisis. I'm gonna list six, but if you can get even four, I'd be very impressed. Diffuse skin disease. Rapidly progressive skin thickening. Paracardial effusion. Tendon friction rubs. RNA polymerase three. And corticosteroid use. Particularly when we're exceeding 15 milligrams of prednisone daily. Oh, and we should probably also include early disease because typically, scleroder merino crisis occurs within the first five years of non-ranos manifestations. And lastly, question four. Pulmonary hypertension is a common problem in scleroderma. And it's defined as a mean pulmonary artery pressure over 20 millimeters of mercury. There are different groups of pulmonary hypertension. Can you tell me which groups of pulmonary hypertension you can see in scleroderma? I'll give you a couple of seconds. All right, they are group one pulmonary arterial hypertension. This is the most common. However, you can also get group two if there's left ventricular disease. Group three, if there's hypoxic lung disease, like from interstitial lung disease or chronic aspirations. And you can get group four or CTF. Workup. All right, guys, let's talk about the workup of systemic sclerosis. Now, much of the workup, and as you'll eventually see in scleroderma part two, the management of systemic sclerosis revolve around specific organ manifestations. So in this workup section, we're going to start with the antibodies, and then we're going to jump into specific organ system manifestations and how to investigate them. Auto antibodies. All right, let's start with ANAs or the anti-nuclear antibodies. Now, ANAs are positive in over 90% of patients with systemic sclerosis, and typically we like to detect these by indirect immunofluorescence. The classic ANAs subtypes in systemic sclerosis are as follows. Anti-centramar, anti-topoisomerase one, or the anti-SCL 70, anti-RNA polymerase three, and then there are some other less common ones, including anti-THTO, anti-PM SCL, or anti-RNP. But I think for now, we'll just focus on the three classic antibodies in systemic sclerosis, which comprise 80% of sclerodermy patients' serologies. And these are the anti-centramar, the anti-topoisomerase one, or SCL 70, and the anti-RNA polymerase three. Let's start with anti-centramar. This antibody corresponds with limited cutaneous systemic sclerosis, and its presence increases the risk of pulmonary arteriohypertension, though it's protective against interstitial lung disease. And that is in sharp contrast to the anti-topoisomerase one, or anti-SCL 70 antibody. The anti-topoisomerase one is associated with diffuse cutaneous systemic sclerosis, and it increases the risk of ILD, but it's protective against pulmonary arteriohypertension. And lastly, RNA polymerase three. This auto-antibody is associated with diffuse cutaneous systemic sclerosis. It is associated with a lower risk of interstitial lung disease, but significantly increased risk of sclerodermal renal crisis, and carries an associated risk of malignancy. Now, I do suggest you order the auto-antibodies, because first of all, it can help you establish the diagnosis, and be because these antibodies are associated with distinct clinical phenotypes and outcomes. And therefore, they'll influence how you're monitoring or managing patients, so for example, if your patient is RNA polymerase three positive, you might be more vigilant about possible underlying malignancy, and you'll probably be much more intense about blood pressure monitoring, and creatinine checks, then say, for example, if they were anti-topoisomerase one, or anti-centramere positive. Let's now focus on the workup of rain loads. And the first test here you should be doing is a simple bedside investigation called nail folds capillaroscopy. And this is a non-invasive way for you to look at the small blood vessels in the fingers. It's an excellent test, and can help differentiate between cases of primary rain loads from those related to connective tissue diseases like scleroderma. And I'm gonna back this up with some data. According to a cohort study from the UK's Leeds Hospital, if you take a patient with rain loads in whom the differential includes early systemic sclerosis, then the absence of nail folds capillary changes is very valuable. [BLANK_AUDIO] excluding systemic sclerosis. And in fact, they found that negative, nail-fold capillaroscopy has a 90% negative predictive value for ruling out systemic sclerosis. And I'm going to suggest here that you Google some images or watch a YouTube video because a picture says 1,000 words, but I'm going to try to describe what you will see and give the abnormalities some names. The technique is that you use a low magnification device, something like a dermatoscope or even an ophthalmoscope. And you're going to look at the capillaries at the nail-fold. Normally, the capillaries will run parallel to the surface of the skin toward the nail, their homogeneous and nice and regularly distributed, and they have a hairpin-like turn at the end. Again, I suggest you Google this. In systemic sclerosis, you can get enlargement of the capillary loops. We call those giant capillaries. You can get micro-hemorrhages. And later on, you can also see capillary loss, which we refer to as loop dropout. And by the way, other connective tissue diseases, including dermatomyocytus, can have their own nail-fold capillary changes. So don't equate nail-fold changes automatically with systemic sclerosis, but do strongly suspect a secondary process when you see them and feel reassured when you don't. In a similar way, ANAs and scleroderma antibodies like nail-fold capillary changes are strong predictors of progression from just primary rain notes phenomenon to a secondary process like systemic sclerosis. So one study quoted a hazard ratio of about five, if you see an ANA by indirect immunofluorescence. And just the last test I would tell you about is macravascular imaging. So in case you're worried about macravascular disease, you can consider a Doppler ultrasound or angiography in patients with rain notes. But realistically, most of your patients with scleroderma are not going to get macravascular imaging because you have a pretty low pre-test probability that there's going to be something there. All right, guys, let's move on to the workup of interstitial lung disease. And we'll start with the antibodies just by saying that once again, it's helpful to get the auto-antibody profile. And in this case, an anti-SCL70 or topoisomerase one can first considerable risk for ILD, whereas the anti-centramarine antibody is relatively protective against ILD. In terms of lung-specific testing, though, really your two big ticket items are number one PFTs and number two high-resolution CT. And we'll start with the pulmonary function tests. Classically, your PFTs are going to show a reduced forced vital capacity or FVC. You can see a reduced FVC from other rare things in scleroderma, including severe involvement of the thoracic cage, like from a high bound chest or even myopathy, but the vast majority of the time. If you're seeing a reduced FVC in a patient with scleroderma, it's representative of ILD. Now, along with pulmonary volumes, you should also be including the DLCO as part of your pulmonary function testing. And the reason I say that is because it's a sensitive marker of early interstitial lung disease. It's not specific. It can also go down in pulmonary hypertension, but it certainly is sensitive. And generally, the FVC and the DLCO should drop proportionally to each other. If you find that your DLCO is dropping disproportionately to the FVC, you need to consider pulmonary hypertension. So one more time, when you're getting PFTs for interstitial lung disease in scleroderma, you should be doing both the pulmonary volumes, including FVC, but also the DLCO because it's a sensitive marker of early ILD. And you need both because early ILD doesn't necessarily mean abnormal lung volumes. Over half of patients, in fact, who have early ILD on their high-resolution CT, are going to have normal lung volumes. And that's a nice segue into the second pulmonary test, which is high-resolution CT chest. Now, this is an important initial screening tool and will be helpful to establish a baseline. Classically, the CT pattern is usually NSIP or non-specific interstitial pneumonia. And it represents over 80% of cases of scleroderma associated interstitial lung disease. And the classic finding of NSIP on high-resolution CT is a greater proportion of ground-glass opacities and less coarse reticulations. These ground-glass opacities are generally peripheral, worse at the basis, and there's often subplural sparing. Occasionally, patients can have other patterns on their CT, including UIP, which is characterized by patchy distributions of honeycombing and less ground-glass. Though it's a good thing that NSIP is more common than UIP and systemic sclerosis because NSIP probably confers a better prognosis. Oh, and I should also mention that patients with systemic sclerosis will have esophageal dysmortility. And you may remember I said earlier in the episode that patients can develop micro aspirations on a chronic basis. Well, you can see sequelae of that on the CT chest. And if you look at the images, you can also oftentimes see a dilated esophagus with a patchless lower esophageal sphincter. And now you may be wondering, where would bronchoscopy or lung biopsy fit in the workup of scleroderma associated interstitial lung disease? And the answer is that we don't usually do them unless there's diagnostic uncertainty. So if you're querying malignancy or you're querying infection in those cases, bronchoscopy and or biopsy might be warranted, but they are seldom done in the workup of scleroderma associated interstitial lung disease. Now, before we wrap up with ILD workup, I want to talk to you about recommendations for the frequency of PFTs and high resolution CT chest. The ULAR recommendations are about six years old now, and so instead I'm gonna borrow from the French position statement that came out earlier in 2023. And according to the French, you should be screening all patients initially with high resolution CT and with pulmonary function testing. The CT scan is an important initial tool and will establish a baseline. And if you have no evidence of ILD on your initial CT, it bodes very well prognostically from an ILD perspective. In terms of the PFTs, just like CT, you're gonna do them at baseline, and then you're gonna repeat them every six months for the first three to five years. And this is per the French position statement and was also endorsed by Dr. Christopher Denton and Dr. Dinesh Kanna in their Lancet review from 2017. Because remember that ILD is an early manifestation that typically starts within the first five years of the non-ranones manifestations. Unlike PFTs, you're not gonna be doing repeat serial CAT scans of the chest, but the CAT scan can be repeated if there's a deterioration in PFTs or if the patient develops symptoms or if you hear new crackles on osculation. And again, you should be examining them in every followup and you should be asking them about pulmonary symptoms at every followup. Let's now talk about the workup of pulmonary hypertension. Early screening and diagnosis of this condition has dramatically improved outcomes and therefore pretty much everybody recommends that you should be doing annual screening with trans thoracic echocardiogram. An estimate can be made of the RVSP or pulmonary arterial systolic pressure with echo. And an RVSP of 40 corresponds with the mean pulmonary artery pressure of 25. But remember though that the newest 2018 definition of pulmonary hypertension is a mean pulmonary artery pressure of more than 20, not 25. And so while an RVSP of 40 should definitely make you suspicious pulmonary hypertension, an RVSP of 35 to 40 is less clear. And at that point you should be taking into account other features including the patient's symptoms and other testing that we're gonna go over in a second. There are also certain echocardiogram features that make you more suspicious for pulmonary hypertension, including flattening of the intraventricular septum and a dilated IVC. Now the other tests that some experts recommend you do on an annual basis include the anti-proBNP, an EKG, and a DLCO, which realistically you're doing anyway every six months in the first three to five years because you're looking for ILD. These three tests, the anti-proBNP, an EKG and DLCO are recommended by some earlier French recommendations on the treatment of systemic sclerosis. Let's see why. So the anti-proBNP is a valid biomarker of early pulmonary arterial hypertension. And it's significantly in higher in pulmonary arterial hypertension, secondary to systemic sclerosis, then we see an adiapathic pulmonary arterial hypertension. And it's a strong predictor of survival. Such that for every 10 fold increase in the anti-proBNP, there's just over a three fold increase in the risk of death. And so it's reasonable to do that on an annual basis. EKG is used to assess for right ventricular hypertrophy, Right, Axis deviation, right? on a branch block, and other signs of right heart strain. And lastly, the DLCO is helpful because when there is an isolated decline in the DLCO, or the fall in the DLCO is disproportionate to the fall in the FVC, you should be thinking about pulmonary hypertension. Now, those are all screening tests, but really you need the gold standard or the mandatory tests for diagnosing, scleroderma associated pulmonary hypertension. And that is a right heart cath. And the reason you need the right heart cath is because it provides the pulmonary arterial wedge pressure and other important measurements to number one, confirm pulmonary hypertension. And number two, these measurements will give you the mechanism. I.e., they'll tell you if you're just dealing with pulmonary arterial hypertension in group one or groups two, three or four pulmonary hypertension. And that has implications on management. So in conclusion, you should be doing an echo annually in your patients with scleroderma. An RVSP on echo of 40 corresponds with a mean pulmonary artery pressure of 25, and therefore you should go to right heart cath. If you're between 35 and 40, you're kind of in the gray zone and you should be looking for other things that would suggest that the mean pulmonary artery pressure is over 20, because remember that's the newest definition of pulmonary hypertension. Other annual screening tests you can do include the anti-proBNP, which is a valid biomarker of early pulmonary arterial hypertension, an EKG to look for right heart strain, and look for a disproportionate decline or an isolated decline in the DLCO. At the end of the day, though, right heart cath is how you diagnose pulmonary hypertension in your patients with systemic sclerosis. Now, if you're ever unsure about whether or not you should refer a patient for right heart cath, there are algorithms out there. Probably the least complicated one is the Australian scleroderma interest group algorithm, but realistically, if you're ever unsure, just ask a colleague in cardiology or respirology to see your patient, because you don't win any awards for treating this complicated disease on your own. For time's sake, instead of going over the workup of all GI manifestations, we're just going to focus on the basics of working up a soft-gill disease. Again, if at any point in this episode or the next episode you want more depth, please answer the survey and tell me which topics you want to hear. The link is in the show notes. Anyway, jumping back into the workup of a soft-gill disease and keeping it very high yield. We have different investigations that we can do, but generally, these are only done if the PPI and non-pharmacologic measures are ineffective for controlling a patient's symptoms. In that case, the EGD is the first line test. It will help you evaluate for a soft-gitis, not just reflexive soft-gitis, but also bearance of soft-gitis, strictures, and even candida. In the case of dysphagia, EGD is still your first line. If you suspect a structural issue, like a stricture, then a barium swallow can be helpful. Versus if you are more suspicious of a motility issue, like poor contractions in the lower 2/3 of the esophagus and poor resting tone of the lower soft-gill sphincter, then Monometry is more helpful, and it's actually worth googling barium swallow scleroderma, because classically, a barium swallow will show an A parasitic esophagus with dilatation below the aortic arch, and you'll see that the lower esophageal sphincter is patchless, i.e. spread wide open. You can see contrast medium quickly empty into the stomach, and then regurgitate right back out into the esophagus, and then you'd see why patients with scleroderma have such difficulty with the soft-gill symptoms. But again, to reiterate, these tests are largely only done if proton-promp inhibitor therapy and non-pharmacologic measures fail to control the patient's symptoms. And lastly, when it comes to working up specific organ manifestations in systemic sclerosis, let's talk about the important investigations in scleroderma renal crisis. Now again, I encourage you to get the auto-antibody panel in all your patients with scleroderma, specifically here having an RNA polymerase-3 positive antibody warns you that your patient is at significantly higher risk for scleroderma renal crisis, and it happens to be more prevalent here in North America corresponding with our higher rate of renal crisis. Now in terms of laboratory testing, the creatinine can be markedly elevated. And even after blood pressure is controlled with an ACE inhibitor, which is the treatment for scleroderma renal crisis as you're going to learn in the next episode, the creatinine can still continue to climb for a few days. Now you may ask how much does the creatinine have to be elevated for you to think about scleroderma renal crisis or diagnose scleroderma renal crisis? Unfortunately there's no widely accepted definition, but according to the 2016 UK scleroderma study group or UK SSG guidelines on the diagnosis and management of scleroderma renal crisis, an over 50% increase in the serum creatinine or an absolute increase of 26.5 micromose per liter. And I think that in the United States that means about 0.3 milligrams per deciliter is what you would expect to see in true scleroderma renal crisis. Now while we're on the topic of the UK SSG guidelines, I'll also tell you that they had blood pressure criteria in their definition. And one of those was a sustained 20 point jump in the patient's baseline blood pressure. So they went from, for example, 120 to 140 or 130 to 150 millimeters of mercury systolic. Again, though, there's no widely accepted definition. So you're looking for what scleroderma renal crisis is an elevation in the creatinine that can be marked and an elevation from the patient's baseline blood pressure. Other laboratory abnormalities include hematologic features of microanthiopathic hemolytic anemia or MAHA. You can see this in about 50% of patients with scleroderma renal crisis. Now I used to think slash I was told by one of my attendings when I was a fellow that if there are no schistocytes, it's not scleroderma renal crisis. But according to a few papers, including a multi-center retrospective French study in the annals of rheumatic disease in 2008, only about half of patients are going to show laboratory criteria for MAHA. And these include things like thrombocytopenia, schistocytes, and other features of hemolysis including an elevated LDH, low haptoglobin, or an unconjugated hyperbilly rubinemia. And the last laboratory test worth talking about is the urinalysis, which is so important whenever you have AKI. The urinalysis in scleroderma renal crisis can show mild non-nefrotic range protein urea, though generally it's a bland urinalysis. You should not see casts and you should not see true evidence of chlamarylonephritis. Oh, and very quickly before we wrap it up, we don't usually perform renal biopsies in scleroderma renal crisis, but you may consider it in cases of uncertainty. So for example, if there are features of other connective tissue diseases, or the patient has an active urine sediment, i.e. urine casts, or if you have a normal intensive patient and you're just unsure, then you could do a biopsy. And if you did, you'd likely see small vessel changes predominating overglomerular changes, and you'd see features consistent with thrombotic micrangelopathy and the classic onion skin lesion. So just to wrap it up, in conclusion, when it comes to working up scleroderma, you want your auto antibody profile, it's very helpful to see whether the patient's positive for RNA and race 3, or SCL 70, or a centromere. The rest of your workup and screening/monitoring is directed largely at the organ systems. For Raynod's phenomenon, you're going to do nailful capillaryoscopy, you're going to get antibodies, and you might consider macrovascular workup, including Doppler ultrasound and angiography, though this is seldom done. For interstitial lung disease, again, you want your auto antibody profile, you're going to be getting PFTs, including the DLCO, every six months, at least for the first three to five years, and you want to get a baseline high-res CT that can be repeated if there's a deterioration in the PFTs or new respiratory symptoms. For pulmonary arteriohypertension, patients should be getting annual echocardiograms. If you see an RVSP of 40 millimeters of mercury or higher, you send them for right heart cath, but if the patient has an RVSP between 35 and 40, it's less clear, and you should be looking for other features that would direct you one way or another. Don't forget to consider annual NT-ProBNPs, EKGs, and then DLCOs. From a GI perspective, you really only do a workup starting with the EGD. If the patients' symptoms are not controlled on a PPI and with non-pharmacologic measures. And lastly, for sclerodermarinal crisis, there's no widely accepted definition, but generally you're looking for a marked elevation in the creatinine, as well as a ligand. as a jump in the patient's blood pressure from their baseline. If you do laboratory testing in sclerodomarinal crisis, you're going to see a bland your analysis and you'll commonly see features of MAHA on their blood work. Again, sclerodomarinal crisis is strongly associated with the RNA polymerase-3 antibody. All right, guys. Question 1. Please list the three most common auto-antibodies in systemic sclerosis and their associated clinical features. OK. Number 1. Anti-centramar. Number 2. Antitopoisomerase-1, aka anti-SL-70. And number 3. RNA polymerase-3. So, in terms of associations, the centramar antibody is associated with the limited-cutaneous phenotype of systemic sclerosis. It significantly increases your risk of pulmonary arterial hypertension, though it's relatively protective against ILD. Anti-topoisomerase, aka anti-SL-70, on the other hand, is associated with diffuse-cutaneous systemic sclerosis. It increases your risk of ILD, but it's associated with the lower risk of pulmonary arterial hypertension. And lastly, RNA polymerase-3 is associated with the diffuse-cutaneous subtype. It substantially increases your risk of two things. Sclerodomarinal crisis and malignancy. Question 2. Bedside nail folds capillaryoscopy is very helpful in differentiating primary raynotes from patients with systemic sclerosis. Can you name three nail fold changes we see in scleroderma? Okay, giant capillaries, meaning enlargement of the capillary loops, micro hemorrhages, and loop dropout, which is a late finding, meaning loss of capillaries. Question 3. What's the classic imaging description of the lower esophageal sphincter in systemic sclerosis? Patulus, a patulus lower esophageal sphincter, meaning that it's wide open. Question 4. Let's see how much you remember about scleroderma renal crisis. Can you tell me which blood tests you're going to order and what you're expecting to find? Right, so creatinine is your first blood test and it may be markedly elevated. Unfortunately, there's no widely accepted definition for scleroderma renal crisis, but according to the 2016 UK scleroderma study group guidelines, the creatinine will jump 50% from baseline or at least 26.5 micromole per liter, aka about 0.3 mg/dL if you're in the United States. Other blood tests can show maha, including low platelets, schistocytes, elevated LDH, low haptoglobin, and an unconjugated hyperbilly rubinemia. Good, now what will the urinalysis show in scleroderma renal crisis? Not very much actually. The urinalysis should be bland. You may see some non-nefrotic branch protein area, but not much else. In which antibody would you expect to be positive in these patients? RNA polymerase 3. Okay, great. And for the last bit of renal crisis, can you tell me whether or not we usually perform a biopsy in these patients? We usually don't, except in cases of uncertainty. And lastly, from a practical perspective, can you tell me which tests you're routinely doing in your practice to monitor your scleroderma patients? And I'll give you a hint. The testing we do in scleroderma revolves around specific organ complications. Okay, so let's take it disease by disease. You want to monitor routinely for ILD. That's an early complication, so in the first five years you're going to be particularly vigilant. And so everybody should be getting a baseline high-res CT of their chest as well as PFTs. And the PFTs should be repeated every six months for the first three to five years. In terms of scleroderma renal crisis monitoring, everyone should be doing home blood pressure checks. That's especially true for high-risk individuals like those who are early, diffuse cutaneous disease, or RNA polymerase 3 positive. And by home blood pressure checks, I mean doing blood pressures at least twice a week. And if there's a sustained bump in blood pressure, for example, a 20 millimeter of mercury bump above baseline confirmed twice within 24 hours, then they should promptly present for medical attention. You should also routinely be doing creatinines. And the third disease we're monitoring for is pulmonary hypertension. And so every patient should get an annual echocardiogram, and you can also consider getting an annual anti-pro BNP, EKG, and DLCO. Though realistically you're doing DLCOs anyway as part of your PFTs in ILD screening. Bonus question. If you haven't done so yet, which two things are you going to do for me? Ideally now, please. And thank you. And that's it for today, guys. Great job on making it through this topic. You deserve a well-earned break. If you enjoyed today's session, please subscribe. I would also tremendously appreciate your feedback in the form of an Apple Podcast review, or feel free to email me with suggestions for future episodes, content, accuracy, or sound issues. My email is room for the RC. That's r-h-e-u-m-f-o-r-t-h-e-r-c at gmail.com. Have a great one.