I'll try to speak up. So this is what we're going to cover today. So try and know the various types of pH encountered in CTD patients, understand the basic pathophysiology, be familiar with the prognosis of connective tissue disease associated pulmonary hypertension, know the tools for screening for CTD, and then treatment strategies. And then we'll try to focus that on interstitial lung disease in particular. So you guys have all seen this World Health Organization grouping for pulmonary hypertension. So which one of these groups does CTD fall under? Well, pulmonary arterial hypertension certainly falls under group two, but you can also see many different manifestations of pulmonary hypertension in patients with connective tissue disease. So pulmonary venal occlusive disease. Patients can have left heart disease. It's very common in scleroderma. People talk about interstitial lung disease, but many of these patients actually have group three pulmonary hypertension. CTEF can complicate connective tissue disease, particularly in patients with antiphospholipid antibody syndrome. And then even group five in the context of renal failure, et cetera. So this is a nice diagram from Steve Matai wrote a review article on CTD pH not too long ago and kind of shows which one of the CTDs falls into these various categories and sort of what common manifestations they have. So what causes pulmonary hypertension in CTD? It's a difficult question. It's not really that well understood. There seems to be some genetic predilection in patients, and they develop endothelial dysfunction. And the thought is that that's due to inflammation and autoimmunity that leads to activation of pathogenic B and T cells. There's also seems to be differences in the way that the RV deals with pulmonary hypertension. So if you have the same increase in PVR in a patient with idiopathic pulmonary arterial hypertension, patients with connective tissue disease, the RV won't fare as well and has a worse function. And you can also see cardiac dysfunction from passive pH to left heart disease causing basically back pressure. Interstitial lung disease can cause vascular obliteration and hypoxemia, release of pulmonary vasoconstrictors. The pulmonary hypertension you see in patients with interstitial lung disease isn't simply due to like parenchymal bed destruction and hypoxemia. It's an oversimplification. Like if you biopsy lung that's distant from the area where patients have the parenchymal lung disease, you can still see pathogenic changes in the pulmonary arteries, which makes the point that the disease is not just due to the underlying lung disease. CTD from systemic sclerosis in particular seems different from other CTDs. I think you can make the argument it should be its own distinct entity. Even the histopathology is different. So lupus lesions are more typical of idiopathic pulmonary hypertension, whereas you have more fibrotic lesions in systemic sclerosis and mixed connective tissue disease sort of similar to that. So how common is CTD-PAH? If you take all comers, you know, it's a little bit poorly defined, but systemic sclerosis is the most common CTD you'll find. And if you take patients with systemic sclerosis, about 8% to 14% of them will have pulmonary hypertension. Mixed connective tissue disease is probably the second most common in at least, like if you have a patient with mixed connective tissue disease, they have the second highest prevalence in terms of likelihood of developing pulmonary hypertension, although it's a less common disease. In lupus, the amount is very low, although, you know, depending on where you're studying in Asia, lupus is actually the highest or the most common form of pulmonary hypertension due to CTD. And so this is just another graph kind of showing, you know, the prevalence in different disease states. So is CTD-PAH different prognostically than idiopathic pulmonary hypertension? It is. In fact, so patients don't live as long. There's multiple studies and registries that have demonstrated this. You know, with aggressive treatment of pulmonary hypertension, the treatment, the prognosis has been improving, but it's still not as good as patients with idiopathic. And so this is, again, you can see that one, two, and three are survival in patients with CTD-PAH, and it widens out over time. And another, this slide is actually showing that not all CTD-PAH has the same prognosis either. As I mentioned, systemic sclerosis is really sort of its own entity, and they fare the worst of all the forms of CTD-PAH. And again, this is showing the same thing. The slide on the left shows lupus versus mixed connective tissue disease in the middle, and then box C is rheumatoid arthritis. And so in all cases, systemic sclerosis does the worst. This is, again, making that same point. Systemic sclerosis does worse than lupus. So should you screen for PH in your CTD patients? The answer is yes, if it's scleroderma patients, because there's such a high prevalence. There's no standardized screening that's recommended for patients with other diseases, although I think you still need to maintain a high index of suspicion. And if they have unexplained dyspnea, then certainly think about looking for it. In patients with interstitial lung disease, I do think that it's something that in our practice we get yearly echoes, and there's a lot of different things that can steer you in the direction of pulmonary hypertension. For instance, significant desaturation that seems out of proportion to what you're seeing in terms of their PFTs or their CT scan. If they have an impaired heart rate response to exercise, that can be a pointer that they may have developed pulmonary hypertension. A disproportionately reduced DLCO, so DLCO less than 40%, would increase the likelihood that the person has it. And then really decreased distance on a six-minute walk test as well. All those things should get your attention and make you think about screening for pulmonary hypertension in a patient with interstitial lung disease. So the detect tool is an algorithm you can use that involves some clinical and lab parameters for the first step. And then if you hit a certain threshold, they recommend getting an echo and use echo criteria for the second part, and that determines who needs a right heart catheterization. I find it a little bit cumbersome to be, truth be told, some things like serum urate I'm not checking typically in my clinic patients, but it's the best validated screening tool out there. So how do you diagnose CTDPH? Again, maintain that high index of suspicion. Make sure you're screening and systemic sclerosis. Ultimately, you really need a right heart catheterization. The only way that you can determine what kind of pulmonary hypertension they have, is it pre-capillary or post-capillary, and how best to treat it is to do a right heart catheterization. And then don't forget about CTEPH. A lot of times people forget to get imaging to rule out CTEPH, and so you may miss the boat on potentially a reversible cause of pulmonary hypertension. I just threw this in, the ESC, ERS guidelines have recently updated the definition of pulmonary hypertension, and so they've now dropped the pulmonary vascular resistance cutoff to two instead of three, and so that's a relatively recent development. So how do you go about treating CTDPH? Don't forget the basics. You want to give these patients oxygen, diuretics. Make sure you're treating the underlying lung disease, smoking cessation if they're smoking. If patients have sleep disorder, breathe and go after that and treat it. Make sure they're up to date on vaccinations. No anticoagulation unless there's some compelling indication for it in patients with CTD. This is some data from the Compara registry, and they found that there was no survival advantage and there was a trend toward harm in patients with systemic sclerosis, PAH specifically, and so in general, routine anticoagulation is not recommended. And then, you know, when you're looking at a patient with interstitial lung disease, I'm going to skip ahead a bit, you really need to decide, you know, how much interstitial lung disease do they have, and so is this a group one or a group three patient? So things that can lean you toward group one are, you know, the fact that they have a connective tissue disease in the first place, you know, I think a lot of times your index of suspicion and your desire to treat with pulmonary vasodilators, I think you're probably more inclined to do so based on that risk factor, and then you also need to really look at the imaging and look at their hemodynamics, and it's a bit of a judgment call. There's no really well-established, like, cut points in terms of, you know, this, if your FPC is at this mark and your mean PA pressure is at this mark, then this is group three versus group one. You know, with the advent of being able to treat patients with inhaled prostanoids now, it's maybe less of an important distinction, whereas previously the recommendations in group three pulmonary hypertension were to not treat and enroll in clinical trials, so I think with, now that there's some data that validates the use of inhaled prostanoids, I think we can, you know, feel better about it now, going back. So this is basically the treatment algorithm that's from the new ESC guidelines, and so you treat CTDPH, even in the context of sort of mild interstitial lung disease, similarly to how you would treat idiopathic, and so these patients should be risk stratified, you should be using multi-drug therapy, et cetera, they should have serial follow-up and reassessment, and really try to drive them down to a low-risk status. And pulmonary basal dilator therapy is effective, you know, there's been a significant reduction in morbidity and mortality in CTDPH compared to PH overall, and survival after 2010 has been better at 73% versus 65% in three years. It also decreases the time to clinical worsening, improves function in terms of six-minute walk distance, three to six months after baseline. One thing that's a little bit different about some diseases, if you look at patients with, that have mixed connective tissue disease or lupus, there may be a role for treating the underlying interstitial lung disease and using immunosuppression, and there's some old case series where they've used Cytoxan and steroids and actually improved the pulmonary hypertension. I think most pulmonary hypertension doctors would still treat with pulmonary basal dilators at the same time, but you can see improvements in PA pressures with anti-inflammatory treatment. It's not randomized controlled trial data, it's really more sort of case series, so it's not the highest quality, but that does not work in systemic sclerosis. And then this is just showing that, you know, this is a trial looking at Rituxan in patients with CTDP-AH, and it didn't quite hit statistical significance, but at 48 weeks actually did reach statistical significance in terms of change in six-minute walk distance, and so this may be something that in the future, you know, with further study, that use of Rituxan may be an option in patients with systemic sclerosis. So I think there's a lot of hesitancy to use pulmonary basal dilators in patients with interstitial lung disease. There's concerns about VQ matching, PVOD, and then there's a relative paucity of RCT data, and so as I mentioned, we, you know, you do have to approach it a little bit differently. Some of the drugs that we would typically use in group one, like Rio Ciguat, I tend to avoid, and that's based on the RISE-IAP study, which showed harm in patients with idiopathic interstitial pneumonias. And then we also tend to avoid ERAs. This is the Artemis trial that was looking at ambrescent, and it was not specifically patients with pH. They thought there was perhaps an antifibrotic benefit. The use of ambrescent in patients with idiopathic pulmonary fibrosis, it didn't pan out, and it also was associated with harm. And so in general, based on the Artemis trial, and multiple negative trials that showed no benefit in interstitial lung disease, people tend to steer clear of ERAs. So what pulmonary basal dilator do we have reasonable data for? The only one so far is inhaled triprostanil, and this is the INCREASE trial that was published recently, New England Journal, 2021. And so it was 163 patients in each arm, and they compared inhaled triprostanil to placebo, and at 16 weeks, you can see there is a placebo-corrected difference in the six-minute walk distance. And the placebo group continued to decline over time, if you follow this out. And the inhaled triprostanil group, their walks distance went up, and they were able to maintain that. There was another number of secondary endpoints that improved as well. But the change in six-minute walk distance, again, was the big thing. But there were differences in clinical worsening, and pro-BNP, as you might expect. So a lot of times, patients with PH and interstitial lung disease have a very poor prognosis. Group 3 pulmonary hypertension has a much worse prognosis than other forms of pulmonary hypertension. And so don't forget about lung transplant in these patients. It's a little more complicated because of other comorbidities in extra-pulmonary disease, but they can undergo it safely, and I think that's what we're going to talk about soon. So in conclusion, CTD-PH is different from IPH. The histopathology is different, the RV response to increases in PVR is different, the prognosis is different. There's some variability among CTDs, particularly systemic sclerosis. Not all CTD-PH is PAH, and we need better risk stratification tools for CTD-PAH, but overall can still apply the ones that we use. Treatments are largely the same, except for potentially immunosuppression in some patients, and in interstitial lung disease, avoiding ERAs, Rio Ciguat, et cetera. So that concludes my talk, and I think we're going to do questions. So my name is Anupam Kumar, and honestly, apologies that we are skipping the order of the session. Ideally, the flow would have been Sebald talking about ILD management in the context of CTD, followed by Dr. King, and then lung transplant is, of course, a last resort for these patients. I don't have any disclosures pertaining to this presentation. If at any point you can't hear me, please just raise your hands, okay? So as far as objectives are concerned, I'm hopeful that at the end of my talk and the end of the session, really, that you have a reasonable idea of the phenotyping, the basics of phenotyping patients with CTD-ILD, and some basics of the strategies of disease monitoring in this group of patients, which I'll be referring to as CTD-ILD from now on. That you will have some concepts of how to risk stratify these patients, and also look at the outcomes, and we'll, of course, try to differentiate between systemic sclerosis ILD patients and non-systemic sclerosis patients. And we'll also discuss briefly about the unique extra pulmonary considerations in CTD-ILD. Without going into the details, the whole spectrum of CTD-ILDs includes conditions such as systemic sclerosis, rheumatoid arthritis, myositis, and all the other conditions mentioned here. If you look at the prevalence of ILD, clinically significant ILDs, anywhere between 25% to even up to 80% in conditions like anti-synthetic syndrome. What's notable here is by far the most common radiologic and histologic subtype is nonspecific interstitial pneumonia, except in rheumatoid arthritis where you have usual interstitial pneumonia, and so that's why these patients behave very similar to patients with idiopathic pulmonary fibrosis. There are two other things that you have to keep in mind. One is there are non-ILD pulmonary manifestations these patients can have, which is what differentiated a little bit from the IPF, the more famous sibling, such as pulmonary hypertension, which has an impact on its natural history and prognosis, but even conditions such as aspiration pneumonia, even obstructive lung disease, such as in patients with rheumatoid arthritis who can have airway-centric fibrosis, bronchiectasis, patients with anti-synthetic syndrome and myositis may have respiratory myopathy or diaphragmatic involvement. So these are all things that actually will be taken into consideration when you're evaluating a patient for lung transplantation and also has an impact on its natural history and even prognosis. So once you have established a diagnosis of CTD-ILD, and without really emphasizing this, the value of consensus diagnosis and multidisciplinary meeting is quite important even in the context of CTD-ILD, very similar to IPF, I would say. So once you have a consensus diagnosis, then the order of business is such that you go about establishing a baseline. Now, this is done through a combination of subjective and objective variables, and then you chalk out a strategy for how to monitor these patients. And when you monitor these patients, you have to keep in mind what are the risk factors for progression. Now, it's not the same for every condition. So if you look at systemic sclerosis, for example, diffuse cutaneous disease, African American race, advanced age, shorter disease duration, the presence of anti-topoisomerase antibodies, these are all risk factors for progression. For rheumatoid arthritis, that would be an older male who has smoked in the past or is currently smoking, presence of anti-CCP antibodies, these are all factors that portend worse prognosis. And from my side, as you all have seen, patients with rapidly progressive ILD in the context of antisyndrome. So you have to keep that in mind when you decide on what are the things you'll be monitoring and how frequently you're going to be monitoring these patients. And then, let's say, over the next three to six months, or maybe even a year, you decide that, well, this patient has been phenotyped into perhaps a stable disease, slow progression, or they may have progressive disease. And a progressive disease, remember, if your patient is progressing, whether it's symptoms or based on objective data, you have to keep in mind some of the extra pulmonary factors that I mentioned already, such as it could be pulmonary hypertension making things worse. It could be respiratory myopathy making things worse. It could be drug toxicity. I mean, these patients are on immunosuppression, so they could have pulmonary toxicity from those medications. So all and any of these factors can also cause disease progression, so you have to keep that in mind when you monitor these patients. Now, you have phenotyped this patient, and let's say you think this patient is in the inflammatory phenotype, or as the CT scan here shows, presence of ground glass capacities, predominantly nonspecific indistinguishable pneumonia, organizing pneumonia, a combination of these things. And then, you're going to try and treat them with immunosuppression, or you're in the fibrotic phenotype, where they have progressive pulmonary fibrosis. Now, this kind of dichotomy, of course, is easier said than done. A lot of these patients can have overlaps. So this is a really simplistic model of how you do it. You also have to be mindful of some of the comorbidities. Like I said, pulmonary hypertension, gastroesophageal reflux disease, sleep disorders, and things like that. But when your patients are progressing, whether they belong to the inflammatory phenotype or the progressive fibrotic phenotype, that's when you start thinking about lung transplant. And over the next few slides, I'm going to argue why these patients are good candidates for lung transplantation with some caveats. And as you all know, there is a recent concept that has emerged of the progressive pulmonary fibrotic phenotype of indistinguishable lung disease, essentially a cohort of disorders other than IPF that may all progress. They're all characterized by what we call a self-sustaining fibrosis. They all lead to eventual accelerated decline in lung function and even mortality. And definitely, a lot of autoimmune ILD patients can belong to the progressive fibrotic phenotype, somewhere in the line of about 40% of these patients, actually. So those are the kind of patients that you would be thinking about lung transplant ahead of time. When you talk about lung transplants, especially since 2005, since the advent of the lung allocation score, when we moved from patients being transplanted based on when they were put in the waiting list, we moved to a system where we transplant patients based on how sick they are or what are their chances of dying if they don't get a lung transplant. And as you can see here, since then, the blue panel and the yellow panel is a combination of idiopathic indistinguishable pneumonia and ILD that is not idiopathic indistinguishable pneumonia. So that blue plus yellow panel constitutes the dominant category of patients getting transplantation. This is more so recently, since the cystic fibrosis patients have other medications. So really, we are seeing more than 50% to 60% of patients at any individual transplant centers are getting transplanted for indistinguishable lung disease. But when it comes to CTD-ILD, that's a significant minority of these patients. A majority of patients are being transplanted for idiopathic pulmonary fibrosis. Now the number that's coded out there is less than 1%, which might be a case when patients really show up to transplant centers for transplant, sometimes we don't really make a good effort to find out do they really have CTD-ILD or they just get labeled as pulmonary fibrosis. But rheumatoid arthritis, and remember what I said, UIP seems to be the dominant category in rheumatoid arthritis. Rheumatoid arthritis is the most common CTD-ILD that requires lung transplant, about close to 30%. And the transplant community recognizes that transplanting these patients, there are a few nuances to that. So for example, it clearly states that these are patients who are candidates for transplant if there are no extra pulmonary contraindications for transplant, and there is substantial variability. And I'm going to show you certain data for these two things, both extra pulmonary considerations and substantial variability. Let's talk a little bit about systemic sclerosis, and then we'll go back to non-systemic sclerosis. So for lung transplant and systemic sclerosis, for example, your 54-year-old male, African-American who was a previous smoker, with what you can see has some fibrotic lung disease and emphysema. You have an echo and a right heart cath clearly showing pulmonary hypertension, but there is a pulmonary venous component as well, and has positive Raynaud's, is going to behave differently from your 63-year-old female with pulmonary arterial hypertension. You can see the dilated PA on the CT with no real evidence of ILD or minimal ILD, if anything. And then right heart cath and echo showing evidence of significant pulmonary arterial hypertension without evidence of cardiac involvement. So these two patients are going to behave completely differently when you think about transplant for them is also going to be different. And the transplant community, again, recognizes that in the most recent guidelines published by the International Society of Heart Lung Transplant, there was a proposal made to really divide these patients into three cohorts. So patients with predominantly ILD, predominantly pulmonary hypertension, but pay attention to that middle category. Patients with more than 20% ILD, or what's called as extensive systemic sclerosis disease, with pulmonary hypertension, a group three disease, these patients have by far the worst prognosis. And I'm not going to go into details of PH, because Dr. King already talked about it. But you know that pulmonary hypertension systemic sclerosis can be of different types, predominantly in group one. And differentiating group one versus some of these other groups are, of course, your patients can have overlap, matters. Because a three-year survival for if you have a completely isolated PAH is about 65% at three years. Whereas if you have ILD or group three secondary to ILD, that second category of patients I showed you, that's about 35%. So really making that distinction and a very astute and meticulous workup of these patients matters. When it comes to pulmonary hypertension, other types of CTD, we already talked about how it's most prevalent in systemic sclerosis. But it's not the only CTD ILD with pulmonary hypertension. And CTD ILD patients can have pulmonary hypertension from a multitude of factors. It could be from vasoconstriction, remodeling, vasculopathy, incident thrombosis, hypoxic vasoconstriction. In a patient with systemic sclerosis can have PVOD. You can basically have group one, two, and three. And if you have antiphospholipid antibody type of phenotype, then you certainly can have venous thromboembolic disease and group four disease as well. The reason why I'm really harping on this point is because if you are an ILD doctor or a pulmonologist out there who is seeing these patients, then you have to really look for pulmonary hypertension. So I have a very low threshold for getting echocardiogram early for these patients. And so I repeat and echo if pulmonary hypertension or some sort of cardiac dysfunction is suspected. And certainly, I have a very low threshold for right heart catheterization. And why does it matter as a transplant pulmonologist if the patient has pulmonary hypertension? It really does matter because we know that pulmonary hypertension, just the mere presence of pulmonary hypertension and right ventricular dysfunction actually increases mortality in the disease category itself. But not just that, they are at increased risk of primary graft dysfunction, which is a hypoxic event that a lot of these patients have after transplant almost immediately in the first 72 hours. And that can actually lead to graft loss and poor outcomes as well. So when we look at pulmonary hypertension in these patients, it also affects the selection of procedures. If a patient has severe pulmonary hypertension, often they are candidates only for bilateral lung transplantation. They cannot tolerate single lung transplant. Some of these patients may even go on to require heart lung transplant. You also have to think about supportive strategies. These patients, if they show up in the ICU before transplant, some of these patients will require the systemic vasodilator therapy, inhaled vasodilator therapy, and even require circulatory support in the form of ECMO. It also matters how we plan surgically at the time of surgery. For example, you have to pay attention to how you induce these patients, because they do not tolerate vasodilatation very well, and is often guided by PA catheters. And it even determines if you're going to do the transplant surgery under cardiopulmonary bypass or ECMO support. Now, that same 54-year-old African-American male with systemic sclerosis, this is the CT scan I already showed you. But when we paid close attention to CT, we also see, if you are seeing that marked as white arrow, a really large, pathless esophagus with a lot of debris in it. And so these patients with systemic sclerosis, as you know, have a high propensity for GI problems. Up to 80% of these patients can have esophageal dysmotility, which can be very severe. Even acts as bad as a complete peristalsis. 70% can have gastroparesis. Gastro is a fragile reflux disease. It's by far very, very common in these patients, much more common than all other type of ILDs put together. They can also have small intestinal bacterial overgrowth syndrome. So when we evaluate these patients, they're pretty comprehensive evaluations. They go through 24-hour pH prominometry, esophagram, gastric emptying study, EGD, if they can tolerate that. It involves multidisciplinary care with involvement of GI, speech-language pathology, thoracic surgery. We also prepare our patients that after surgery, depending on how bad their disease is, sometimes they have to remain nothing by mouth for a month, three months, sometimes up to six months, depending on how severe their disease is. And sometimes the presence of severe GI disease can actually exclude them from being candidates. But it's not just GI disease and lung disease that these patients have. They can have vascular disease in the form of Raynaud's phenomenon, digital ischemia, which they can actually be at risk of limb loss when they are under vasopressors and under periods of a long duration of shock. They can have digital ulcers. These patients are at risk of scleroderma renal crisis. As you'll know, the incidence is very low now. But you have to be careful using corticosteroids for a longer duration for these patients. Also remember that systemic sclerosis patients, up to 30%, can actually have active myocardial disease, myocarditis, myocardial fibrosis. And sometimes these patients will not tolerate just an isolated lung transplant. And very rarely, you may even have to think about hot lung transplant, which makes it even more complicated, often leading to excluding them from being candidates. This is a very loaded statement. When I say that gastroesophageal reflux disease and moderate to severe dysmortality increases risk of acute and chronic allograft dysfunction because really, data falls on both sides. The real premise for this statement, of course, is that there is data in our world, in the transplant world, that if your patients have GERD, as you can see on the panel or the cartoons on the left, the percent peak predicted FEV1 on the left and the mean FEV1 they achieve at the end of one year, which is a cartoon on the right. They're both lesser, statistically significantly lesser, if you have severe gastroesophageal reflux disease, to the extent that if these patients undergo fundoplication, which is that green block there, their FEV1 actually improves. Having said that, that data has not really panned out in all the studies. The Kaplan-Meier curves on the right side are showing that for patients with DFLD, which is diffuse fibrotic lung disease, if you compare them to non-systemic sclerosis and systemic sclerosis, really there were no differences in both short-term and long-term outcomes. So there are a lot of caveats to this data. But in our world, we really take GERD and severe dysmortality of esophagus into serious consideration, particularly for systemic sclerosis patients. Bottom line is, the current existing guidelines suggest that for systemic sclerosis patients, if they have severe swallowing dysfunction with recurrent aspiration, if they have severe esophageal dysfunction and complete peristalsis, and if they cannot go through surgery, if they're unwilling to be nothing by mouth, or have long periods of jejunal feeds, or if they have acute myocarditis or systolic heart failure, chronic myocardial dysfunction, then they would not be, or they should not be considered candidates for lung transplantation. And there are relative guidelines such as severe gastroparesis, history of GI bleeding, Barrett's esophagus. Now, some of these things you take, it's not like one thing you take into consideration. A lot of these patients are one, two, and three. All of these factors, it makes it even more complicated. When it comes to the lung transplant centers in the country, there is substantial variability of how we approach this. So this was actually a survey-based study. That was sent out to all the medical and surgical program directors. And you can see here that almost all of them agreed that if they have severe dysmotility, if they have BMI less than 18, and if they have severe vascular disease or digital ulcers, then they are extremely unlikely to provide transplant for these patients. What are the extra pulmonary features of other CTD ILDs? And this is not a full list, but of course, for patients with rheumatoid arthritis, you have to be mindful of upper airway involvement. A lot of these patients may have crico-retinoid arthritis, which can cause inspiratory striata, which is something anesthesia has to take into consideration. You have to really look at their rehab potential. If you have severe joint-deforming arthritis, then what is the rehab potential before and after transplants? Or sometimes that can be prohibitive. For patients with myositis, you can, of course, have cancer-related myositis as a secondary phenomenon. So if you're having acute onset of myositis in a relatively older patient, or even younger patients for that matter, you have to really think about, is this a perineoplastic manifestation of an underlying cancer, particularly in adenocarcinoma? But these patients can also have significant GI disease, myopathy. So you have to take those things into consideration when you think about transplanting them. For patients with Joe Grant syndrome, there is a higher incidence of hypogammaglobulinemia. But these patients are also at higher risk of lymphoma, especially when they are under immunosuppression. So you have to be aware of that. And systemic lupus patients can be very challenging because of the inherent multi-system nature of the disease, because these patients may have lupus nephritis. And after transplant, these patients are on agents like tacrolimus, which actually increases the risk of kidney problems. And they can also have severe cardiac disease, which also need to be factored. So basically, the extra pulmonary conditions for systemic sclerosis and non-systemic sclerosis can have an impact on the candidacy and can prove to be challenging before, during, and after lung transplantation. What do you tell the patient? When it comes to outcomes for all interstitial lung diseases, this is data from 2019, of course. Their median survival, which means proportion of patients alive at five years, their median survival is about 5.2 years. And if it's not idiopathic interstitial pneumonia, that's about 6.7 years. That's slightly less than some of the other disease categories. But when it comes to CTD-ILD patients specifically, so the blue panel here is just looking at all types of CTD-ILD. That is not systemic sclerosis. And if you compare them to idiopathic pulmonary fibrosis, it seems like there is really no difference in both short-term outcomes and long-term outcomes. Similarly, for systemic sclerosis ILD patients, if you compare them to pulmonary fibrosis, again, really not much difference in terms of one-year and five-year survival, which holds good even for patients with significant GI dysfunction. And then there was a multi-center study in Europe that looked at 90 patients with systemic sclerosis that had ILD pulmonary hypertension. And it seems, collectively, for systemic sclerosis, the outcomes were similar to all the other patients, except that female gender and pulmonary arterial hypertension was supposed to be identified as risk factors with lower survival. So collectively, I think the way we see it is CTD-ILD patients compared to IPF, they have a similar risk for primary graft dysfunction, slightly longer length of stay, perhaps because of GI issues and all that. Their long-term outcomes are similar to other types of ILD. And the systemic sclerosis ILD outcomes are similar to non-systemic sclerosis CTD-ILD as well. Remember that when you refer a patient for transplant, that's not the same as being listed for transplants. Now, this is data from the pulmonary fibro, the IPF referral, but basically, if you're seeing a patient who has a UIP type of radiologic histologic subtype, if they already have compromised lung function, and especially if they're demonstrating relative decline over two years, then that's when you think about referring them for transplant. It does make it clear that if you have an inflammatory ILD and you are having disease progression despite immunosuppression, you should already think about referring them and consider referring these patients early. But of course, we don't list them early enough. That gives us time to work on all of these extra pulmonary issues they have. And they usually get listed if they have an absolute decline over six months or if they have any of the other factors that I mentioned here, such as hospitalization or significant desaturation and presence of pulmonary hypertension, which really, presence of pulmonary hypertension alone, we don't necessarily put them on transplant right away because these patients have such a high prevalence of pH. But if it is really severe and is affecting their overall oxygenation and functional capacity, then we think about listing them for transplantation. So in summary, these are your key takeaways from my session here. So CTD ILD patients, I would argue that they benefit from transplant. But you really got to be thinking about referring them early because that gives us time to work on some of these modifiable risk factors and sometimes even identifying some of the non-modifiable risk factors, which we can then be upfront with the patient about not being candidates for transplant. I would say that post-transplant outcomes are very comparable to other types of ILDs. It is very important that you establish a phenotype and you chart out a strategy as far as disease monitoring. And you have to be mindful of extra pulmonary complications when you take care of these patients pre, intra, and post-transplant. Thank you so much for listening. Thank you. Finally, I can present my part. Sorry for the confusion. I will talk about medications or other treatments that we have available to prevent the need for lung transplant, if possible, in these patients. I want to, as objectives, to learn about the immunosuppressive therapy that is available based on the trials I'm going to discuss for treatment of interstitial lung disease in the strain of connected tissue disorders, to learn about the antifibrotic therapy that we have available now, and recognize when to start the treatment and when it's necessary to adjust the treatment. So we know that there is this initial inflammatory phase in the patients with interstitial lung disease. And we know that it's clearly present in patients with autoimmune disorder as an etiology for the interstitial lung damage. So we have the participation of different cells, like lymphocytes, inflammatory cytokines and chemokines, macrophages. And then we have medications that target those cells in order to prevent progressive inflammation. In the pathologic lymphocyte signals, we have medications like cyclophosphamide, azathioprine, mycophenolate, tofacitinib, abatacept. And I will talk about them. In the group of pathologic B signals, we have the rituximab. And in the pathologic macrophage signals, we have the tocilizumab. Cyclophosphamide was the first medication that was approved for treatment of interstitial lung disease in the setting of connective tissue disorders, basically in scleroderma, based on this double blind placebo controlled trial. Here, 158 patients were divided in two cohorts. One received the treatment with oral cyclophosphamide. One to two milligrams per kilo per day. And the other placebo for one year. And the whole cohort was follow up for one more year. This trial demonstrated significant, although modest, improvement in FVC by 2.5% after one year of treatment. However, when the cohort was re-evaluated after 24 months, was seen that the peak of the effect is achieved at 18 months. But after 24 months of discontinuation of cyclophosphamide, the effect is lost. Mycophenolate was evaluated in multiple small trials, no randomized, no control. And you can see a small number of patients. And it was showing a promising effect in patients with this pathology. The largest cohort was this one that included 125 patients with different connected tissue disease ILDs, not only scleroderma. And in a longitudinal retrospective analysis, they found that mycophenolate at the dose of three grams per day for average time of 2.5 years was associated with a stable or improved functional viral capacity. While this trial was published, the Scleroderma 2 trial was recruiting patients. This one was the second randomized controlled trial. And in here, we evaluated, again, cyclophosphamide. And this was compared with mycophenolate. So it was the first randomized trial for mycophenolate and the second trial for cyclophosphamide. The hypothesis was that perhaps mycophenolate would be better than cyclophosphamide after two years of treatment. Here we have about 70 patients in each group. One group received mycophenolate at the dose of three grams per day for two years, and the second group, cyclophosphamide, one to two milligrams per day for one year, followed by placebo during the second year. The results, although, was, I mean, the endpoint was not met. So because the results showed that both medications provide the same effect, that improved or stabilized functional viral capacity, but there was not difference. So the trial was considered with a negative result or negative endpoint, but was pretty helpful for us to know that we have the same effect with two medications, but obviously much less toxicity associated with the use of mycophenolate. So that is the base why we use mycophenolate, that we have mycophenolate so far as a first choice for treatment of these patients. Now, other medications have been evaluated, rituximab particularly. This is a meta-analysis that evaluate the effect of this medication in scleroderma ILD patients. This included 575 patients from 20 different trials, including two randomized trials, and you see the improvement in the functional viral capacity seems to be better than the one demonstrated by mycophenolate and cyclophosphamide, but when it's compared with others, really, we don't have a clear, clear evidence that this is a better choice. We are now waiting for the results of the residual trial. This one is evaluated the effect of rituximab and cyclophosphamide in patients with ILD associated with connected tissue disorders. The connected tissue disorders included here are idiopathic inflammatory myopathies, scleroderma, and misconnected tissue disorder, no rheumatoid arthritis, and this is important to keep in mind. The recruitment has been completed. The patient will be evaluated 48 weeks after the first dose of medication, and we will see what the results show. The rituximab was evaluated in this randomized double-blind placebo-controlled trial. This was for scleroderma patients, and the goal was to evaluate the effect of the medication over the skin involvement in patients with scleroderma. That point was not met, but we found that patients presented with a stable lung function through the time receiving the rituximab. These patients were patients with early stage of the interstitial lung disease and with elevated acute phase reactants. So based on this, we have another possible tool if the other medications don't work. Let me just mention some words about stem cell transplant in scleroderma. Randomized trials have shown that it had good effect over the skin involvement and had demonstrated a stability in the lung function. However, this is a procedure that is left only for patients with severely aggressive scleroderma with risk for organ failure due to the extensive side effects and toxicity associated with it. Other results are coming, particularly for treatment of ILD associated with rheumatoid arthritis. As you know, rheumatoid arthritis implies a significant challenge because most of these patients develop usual interstitial pneumonia that we know has a more aggressive behavior and refractory response to immunosuppressive therapy. So these two trials are evaluating Abatasef and Tofacitinib and we see maybe we have better tools for immunomodulation in patients with this particular diagnosis. Now, we now have the option to use anti-fibrotic therapy and this is based on the recognition of the fibrosis process that we know is present in idiopathic pulmonary fibrosis to be present in patients with other kinds of interstitial lung disease, including connected tissue disease, ILD. So here we can see a normal pathologic matrix deposition, activation of fibroblast to myofibroblast, effect of pro-fibrotic cytokines, effect of pro-fibrotic macrophages. Then different pathologic signals have been evaluated and many medications had under evaluation. I will just mention the ones that so far have been approved for IPF and what is the implication of these medications in patients with connected tissue disease, ILD. The census trial that was the safety and efficacy of nintenamib in scleroderma patients was designed with the goal to evaluate the effect of nintenamib at the same dose that we use for IPF patients, 150 milligrams BID, in patients with scleroderma and evaluate the effect at week 52 over the functional viral capacity. Here there were 280 patients in each group, placebo versus treatment. Here the patients, 50% of them actually were receiving mycophenolate and the medication was not discontinued. As you can see in the results, in the whole cohort, the decline of the FBC in milliliters over one year in patients on nintenamib was 52 milliliters per year. In the group with placebo was 93. For a difference of 41, that was statistically significant. In the group of patients receiving the mycophenolate or when the results were adjusted for the mycophenolate intake showed that the patients taking mycophenolate at baseline had declined in the FBC while taking nintenamib of 40 milliliters per year and the ones that received placebo declined by 66 and the ones not taking mycophenolate was 63 decline in the group receiving placebo versus, in the group receiving nintenamib, sorry, and 119 for the group receiving placebo. So these results show that basically the mycophenolate definitely does its job. So patients have some protected lung function while on mycophenolate. This trial led to the approval of nintenamib for patients with scleroderma and associated ILD. Then the same medication was evaluated in the in-built trial, but here the patients had interstitial lung disease associated with different disease than scleroderma and in fact 25% of the cohort was formed by patients with other connective tissue disorders. The patients that were included needed to have the criteria for progressive fibrotic interstitial lung disease and that was defined for this trial by decreasing the functional viral capacity by 10% or decreasing the functional viral capacity between five to 10% with associated significant respiratory symptoms and or changes, significant changes in the chest CT. Or the patient presented with significant symptoms and significant changes in the chest CT. So they had those criteria that were included and here, different from the census trial, the patients were not allowed to be on any immunosuppressive treatment. So if they were taking mycophenolate or tacrolimus or cyclophosphamide or azathioprine or prednisone, about 20 milligrams per day, they were not included. Now this group of patients were divided into groups based on the presence of UIP pattern or no UIP pattern and you can see here the group of nintenamiv and the group that didn't receive the nintenamiv but were on placebo. The dashed line represents the patients with the UIP-like pattern. So the group receiving nintenamiv, the one with UIP-like pattern decreased the FBC over one year of treatment by 87 milliliters per year and the group on nintenamiv about 80 milliliters per year. Now the difference was present in the group of patients that received only placebo. For the patients with the UIP-like pattern, the decline in the FBC was 211 milliliters and in the group of patients that didn't have UIP-like pattern the decline was about 90. So clearly the nintenamiv demonstrated that not only in scleroderma ILD patients but other connected tissue disease ILD or others connected fibrotic interstitial lung diseases, the effect is the same as was seen in the impulses trial that was the one that evaluated patients with idiopathic pulmonary fibrosis. So finally I want to talk about the relief trial. Different trials have been evaluated at Perfenidone that as well was approved for IPF. I will mention this one and basically it was a multicenter randomized trial that included patients with different case of progressive fibrotic ILD that unfortunately was prematurely terminated due to a lack of recruitment. But at week 48 they evaluated the effect of the Perfenidone in 127 patients and they found significant effect over the FBC with less decline. So it's definitely an option based on the results that we know about. So we have then coming other trials, in particular this one that will evaluate the effect of Perfenidone combined with other immunosuppressive therapies in patients with connected tissue disease associated ILD. Conclusion, so if you have patient with connected tissue disease ILD, evaluate for the compromise of the disease. Extensive disease, we define extensive disease as the presence of compromise in the chest CT above 20% or functional viral capacity less than 70% or in general patient with significant symptoms you need to evaluate if definitely you need to start treatment. Medications, based on what I just explained, we have as a first choice mycophenolate. Cyclophosphamide is the other that is approved. But we have other options as well based on what we know, rituximab, tocilizumab, and for rheumatoid arthritis, Abatacept is something that we need to consider. Now, if the patient doesn't have extensive disease, can you only observe? So definitely that's something that we need to discuss. If the patient doesn't have those criteria, less than, I mean the high resolution CT doesn't look like a more than 20% involvement on the FBCs over 70%, no significant symptoms, you can consider only follow other patients with pulmonary function tests at least every six months. But this is as well really important to recognize risk factors. And one of the important risk factors is, as Dr. Kumar said, is what is the connected tissue disease? Because the patients behave different. Rheumatoid arthritis patients, scleroderma patients, mixed connected tissue disorder, or patients with idiopathic inflammatory myopathies, particularly antisynthetase syndrome, are the ones with higher risk for progressive disease. You have sugar in patients, lupus patients, maybe you can be more, weigh more, because the possibility for fibrosis is much less. So you can consider follow up or definitive treat based on this. Now, if there is evidence of progressive fibrotic ILD as defined in the census trial, or in the last review by the ATS that was published in May, we have definition for progressive pulmonary fibrosis equivalent to this PF ILD, consider if there is decline in the ABC by 5%, increasing the chest CT involvement or significant symptoms. So if the patient has those criteria, you need to consider the addition of antifibrotic therapy, and the best evidence we have is for nintenamib. I think the big question that we have, and probably I hope we can discuss, is if upfront the patient that we are seeing has signs of fibrosis, if we should start immunosuppressive and antifibrotic therapy at the same time. Really, I don't know. Thank you so much. Now I hope we have time for some questions. Thank you.

CTD-ILD

phenotyping

immunosuppressive therapies

antifibrotic therapy

lung function

interstitial lung disease

stem cell transplant

extra-pulmonary complications

lung transplantation