Hello, everyone. I think we'll get started. My name is Steve Matai. I am faculty at Johns Hopkins, a part of the Pulmonary Hypertension Program there. Although enlisted as the moderator, this is really Sandeep's brainchild he put together, so full credit to Sandeep. Unfortunately, Oksana Shlobin's unable to join us today, so I'll be presenting her talk. It'll probably be better than mine anyway, so it's good that Oksana has provided her talk for us. The topic for her talk is When to Suspect Pulmonary Hypertension in ILD, and I think this is a critical talk as the landscape of our therapeutic armamentarium has changed a little bit. We now have some approved therapy for pulmonary hypertension in the setting of interstitial lung disease, so now we have to think more carefully about what patients might be eligible for such interventions. These are her disclosures. So important that we start off with an appropriate understanding of the classification, the clinical classification of pulmonary hypertension. We'll also talk about the hemodynamic classification of pulmonary hypertension, because I think those two things, where they intersect, is important when we think about patients who might have pulmonary hypertension in the setting of ILD and what therapies might be available. So to be clear, we're talking about patients with group 3 pulmonary hypertension, interstitial lung disease, restrictive lung diseases. So the hemodynamic definition of pulmonary hypertension is shown here. We're contrasting pulmonary arterial hypertension, which you have a mean PA greater than 20, plus a wedge less than or equal to 15, and a PVR greater than 3 wood units, with pulmonary hypertension in the setting of chronic lung diseases. So we have chronic lung disease with pulmonary hypertension, where you have a mean PA elevation, plus a PVR greater than 3 wood units, and a wedge less than or equal to 15, so a precapillary pulmonary hypertension. And then severe pulmonary hypertension in the setting of chronic lung disease includes those criteria, but also either a mean PA greater than or equal to 35, with a PVR greater than 3, or a mean PA greater than 25, greater than or equal to 25, with a cardiac index of less than 2. So more severe cardiovascular impairment. And these patients still must meet criteria for precapillary pulmonary hypertension with a wedge pressure less than or equal to 15. So this is an extension of what I just discussed about when we're thinking about precapillary and postcapillary pulmonary hypertension. It's important to distinguish between patients who have isolated postcapillary pulmonary hypertension and combined pre-postcapillary pulmonary hypertension. As you can see here, the numbers for PVR thresholds are a little bit lower than what I showed you in the previous slide, and that's to reflect changes that occurred within the last two weeks. So at the ERS ESC meeting, the guidelines for pulmonary hypertension diagnosis and treatment came out, and they are suggesting that PVR thresholds should be lowered to 2 for the definition of pulmonary hypertension. So not only did we lower the mean pulmonary pressure threshold from 25 to 20, greater than 20, at the last World Symposium, there's a good chance that at the upcoming World Symposium, which will be in 2024, there may be some changes in the PVR criteria as well. So this is taken from a statement on pulmonary hypertension and chronic lung diseases from the sixth World Symposium, where the idea was trying to distinguish between patients who had more significant lung disease as a driver of their pulmonary hypertension versus those who have more pulmonary vascular disease in the setting of chronic lung disease as a driver of their pulmonary hypertension. And I'll draw your attention to the box in the middle here, where we try to distinguish between patients who have limited chronic lung disease, so an FVC of greater than 70 percent with some evidence of interstitial lung disease, minimal changes, parenchymal CT changes, and contrast that with patients who have severe chronic lung diseases with FVC of less than 70. So that threshold of 70 was felt to be relevant and a cut point that you might consider for the diagnosis of pulmonary hypertension, either group one or group three. Regardless, it's important to follow a specified algorithm for identifying pulmonary hypertension and deciding which patient needs to undergo right heart catheterization. So if you have suspicion with clinical, functional, or imaging results suggestive of pulmonary hypertension in the setting of interstitial lung disease, you need to support that with echocardiographic evidence of pulmonary hypertension or suggestion of that, and then confirm it with a right heart catheterization so you get a proper hemodynamic profile so you can adequately not only hemodynamically classify your patient, but also clinically classify your patient as either group one or group three. So what about severity of disease of the underlying lung disease and the presence of pulmonary hypertension? I think this is a common misconception that pulmonary hypertension only exists in patients who have severe restrictive lung disease. We know that's not true. And the converse is also not true, that pulmonary hypertension can't exist if there's only mild disease. Fibrosis on a CT, a scale here, or if we look at pulmonary function testing, there is no significant relationship between FVC and mean pulmonary pressure, nor is there evidence, strong evidence of CT extent of fibrosis and presence or absence of pulmonary hypertension. Where might a CT be useful? This is a diagram showing the pulmonary artery size relative to the aorta, and that might be indicative of evolving pulmonary hypertension. I say might because I see a parna staring at me because I do not like to use this parameter in my criteria, but I do think that there are some instances in which it could be suggested, but definitely not diagnostic of pulmonary hypertension. So do not rely upon this as the sole indicator. In order to diagnose pulmonary hypertension in the setting of ILD, you definitely need a right heart catheterization. But in this study, 177 IPF patients, 15% with borderline pulmonary hypertension, they stratified the patients by a PA to aortic ratio greater than 0.9, predicted a mean PA of greater than 20 with relatively good accuracy. So to what I was talking about before, the relationship between FVC and mean pulmonary pressure, this is from the RISE IIP study. So these are patients who all underwent pulmonary function testing and had right heart catheterization to prove they had pulmonary hypertension. As you can see, there's no significant relationship there between FVC and mean pulmonary pressure. But on the six-minute walk test, there actually might be some useful information. In addition to markers of pulmonary vascular disease, i.e. reduced distance, perhaps desaturation with exertion, the heart rate recovery is another parameter that you might consider. I don't know if this is routinely collected in your lab when you order a six-minute walk test, but it may be useful to look at this. And this is defined as the change in heart rate from peak exercise, in this case at the end of the six-minute walk test, and at one minute. So if you have abnormal parasympathetic and sympathetic tone or imbalance between the two, your heart rate will not recover, meaning the heart rate will not drop as much at the end of exercise than if you have a normal balance between sympathetic and parasympathetic tone. So if your heart rate recovery is less than 13 or less than 12 beats per minute, that suggests abnormal parasympathetic-sympathetic balance. And in several studies, it has had a relatively good correlation with the presence of pulmonary hypertension, particularly in patients with ILD. So another factor you might think about, including in your assessment of a patient with interstitial lung disease. And interestingly, there's a whole literature on heart rate recovery in general populations in cardiovascular health. If your heart rate doesn't come down after you exercise, that's not a good sign. So if you're on your Peloton and you're noticing that your heart rate's not coming down, you probably should get checked out. So what about diffusing capacity? Is that a useful tool? Well, it can be useful to predict outcomes, potentially, for patients who have pulmonary hypertension. So as shown here on the left panel, this is data separating out patients by tertile of diffusing capacity. So these are patients who have group 3 pulmonary hypertension. Diffusing capacity less than 25% is in the blue line. Those patients have the worst outcome. Similarly, if we dichotomize patients at a DLCO of 32% are predicted in a setting of group 3 pulmonary hypertension. Those with lower diffusing capacity have poor outcome. So we understand that pulmonary function tests may not be useful to predict the presence of pulmonary hypertension. CTs may be useful to suggest the presence of pulmonary hypertension based upon the PA to aorta size. And 6-minute walk distance, either desaturation with exertion out of proportion to what you might expect based upon the extent of lung disease, and perhaps even heart rate recovery might be useful points to consider when you're thinking about the likelihood of pulmonary hypertension. One thing that's very difficult to rely upon is the right ventricular systolic pressure estimate by right heart catheterization. This has been shown in numerous studies that the RVSP, when compared directly to the pulmonary artery systolic pressure measured during right heart catheterization, is often erroneous. So relying solely upon an RVSP to determine whether or not someone has pulmonary hypertension can be fraught with problems. This is a study from the Inova group showing that in patients who had right heart catheterization that proved pulmonary hypertension, 48% of RVSP was overestimated, 20% were underestimated, and only 40% were actually accurate. And that's within 10 millimeters of mercury of RVSP and pulmonary systolic pressure measurements. So do not rely upon RVSP. However, there are other information that might be useful from an echocardiogram, including measures of right ventricular function. So thinking about fractional area change, TAPC, RV diastolic stiffness might be useful parameters to understand the severity of pulmonary hypertension. So in this study, looking at fractional area change, patients with worse RV function, as evidenced by a fractional area change of less than 28%, had a worse outcome than those with more preserved RV fractional area change. This is a mixed cohort of patients with both COPD and ILDs. I don't know if we can directly attribute this all to our ILD patients, but it's a useful parameter just to understand. So of the objective findings you might consider as increasing your risk for pulmonary hypertension in the setting of ILD, we look at DLCO. So this is DLCO of less than 30% or worsening DLCO. And we'll talk about what constitutes worsening in the upcoming slides. Six-minute walk distance, if you have severe desaturation with exertion, severe reduction in your walk distance, impaired heart rate recovery. CT scan, the PA to aorta ratio greater than 0.9. I didn't mention the RV to LD ratio, but that's also useful as a potential marker of pulmonary hypertension. We mentioned some echo findings that might be useful. And then in the lab, if you send a lab and the pro BMP is higher than you would expect, that might also suggest RV dysfunction and pulmonary hypertension. So recently, there was a Delphi consensus that was published for screening for pulmonary hypertension in patients with ILD. I think this is a useful reference for you to follow. This consensus statement identified risk factors that we talked about, such as symptoms of history of pulmonary embolism or heart failure, dizziness, palpitations, syncope. Typical signs one would associate with pulmonary hypertension. And then tests. We talked about the diffusing capacity. And here's where that change in diffusing capacity comes into play. So diffusing capacity declined of greater than 15%. And I would argue that's actually 15% of the absolute value, not the percent predicted due to the precision of the measurement of DLCO. It's important to recognize there's a lot of noise around DLCO measurements. So you want to be sure that you're comparing apples and apples. If your DLCO is less than 40%, that might be considered a useful cut point. FVC to DLCO has really only been validated in the scleroderma ILD population. When looked at in other forms of ILD, it doesn't seem to perform quite as well. But if you're thinking about scleroderma ILD patients, an FVC to DLCO ratio of greater than 1.6 might be suggestive of out-of-proportion pulmonary vascular involvement relative to parenchymal lung involvement. So that's something that you can ferret away. The CT findings we talked about, RV enlargement, PA enlargement, PA or GA ratio, oxygen saturation in six-minute walk tests. So we talked about the severity of desaturation, heart rate recovery, and lower distance on six-minute walk distance. And then the serologic evaluation that we just mentioned. So if there's no suspicion based upon these findings, then perhaps no further workup is required. But if there is low suspicion or high suspicion, this consensus statement would recommend that you proceed to an echocardiogram. And following the ERS, ESC guidelines of probability of pulmonary hypertension based upon echocardiogram, you would then proceed to right heart catheterization. So if you have abnormalities in the TRJ greater than 2.8 as an example, or other findings of RV dysfunction, either RV enlargement, septal flattening, right atrial enlargement, pericardial effusion, these are all things that might lead me to send a patient for right heart catheterization. So when we go to catheterization, we find a particular hemodynamic pattern. Does it matter? Are patients with different forms of pulmonary hypertension, hemodynamic profiles, pre-capillary, isolated post-capillary, or combined pre-post-capillary, do their outcomes differ? Well, they do. But just like the old Maasai saying that a zebra takes its stripes wherever it goes, if you have pulmonary hypertension in the setting of another disease, your outcomes are worse. And that's what this study shows here, that regardless of the form of pulmonary hypertension, either pre-capillary, post-capillary, or combined pre-post-capillary, your outcomes were impaired. So it's imperative to get all of these parameters. I think we're doing a better job with education. I've been doing this now for 20 years, which is difficult for me to articulate. I can't believe it's been that long. But I would say in the first 10 years, we saw a lot of patients getting right heart catheterizations without cardiac output or cardiac index measurements. And hopefully, in the last 10 years, I have not seen that from our referring providers. Hopefully, you're not having the same type of issues ongoing. But it's imperative to have these types of information all listed here to understand what phenotype we're dealing with. So here's a summary figure from that consensus statement I was talking about. And again, I'll refer you to that paper by Frank Rahaghi, who's the lead author. It's in CHEST from this year, where there is an algorithm designed for early detection of pulmonary hypertension in the setting of ILD. And with that, I'm happy to... What time are we doing time-wise? I'm right on time. I think we'll let Aparna... You're next, right? We'll let Aparna Balasubramanian, who's an assistant professor at Johns Hopkins and has the unfortunate yoke around her of having to work with me. But she's going to talk to us about how pulmonary hypertension in the setting of ILD... I can't remember the full title of your talk. Differs from COPD. Okay. Great. Aparna? All right. Thank you. And I appreciate all of you staying for this session this afternoon. I know it's late in the day. So I'm going to be speaking about comparing pulmonary hypertension in interstitial lung disease versus COPD. The sort of subtext of this talk is, you know, not all group 3 pulmonary hypertension is the same. And so what must we consider in different forms of group 3 pulmonary hypertension? And Steve is obviously going to be kind of following that up with a talk on CTD-ILD shortly. I have nothing to disclose, sadly, but one holds out hope. So the objectives for this talk, I'm going to be speaking a little bit about the epidemiology of pulmonary hypertension and COPD in interstitial lung disease. I'll talk a little bit about the differences in histopathology between the two diseases. And then we'll discuss morbidity and mortality. I am not going to be touching on treatment. I'll allow Dr. Sahai to talk about the treatment with respect to interstitial lung disease. But I will make a couple comments about COPD treatment. First big caveat is that the prevalence numbers of both the underlying disease as well as prevalence in pulmonary hypertension is very variable. And the reason for that is that studies are inherently based off of selection biases for who is selected for prevalence studies. With that said, the following numbers seem to be roughly where we land for both disease states. So generally in COPD, the U.S. disease prevalence is thought to be around 16 million, not surprising. Prevalence does vary by COPD disease severity, although it is not necessarily linked to COPD disease severity. And I'll get into that a little bit more. What is particularly interesting is that individuals with COPD tend to have a much higher prevalence of mild to moderate disease. And with increasing studies, we're getting a sense of that number kind of creeping upwards. You can see the range here is very, very wide, going from 15 to 85 percent, again, based on the selection of the study that was done. The sort of conservative estimate that tends to be accepted is somewhere around 20 to 35 percent. By contrast, severe pulmonary hypertension has a much lower prevalence in COPD, around 1 to 5 percent. But even if we take that sort of conservative estimate of 20 to 35 percent, that's about 4.8 million people in the United States who will have COPD and pulmonary hypertension. So you should expect to see it. By contrast, if we look at interstitial lung disease, the prevalence, it's a relatively rare disease, the prevalence in the United States from a 2019 estimate was around 650,000 people living with the disease. Prevalence of pulmonary hypertension varies dramatically by etiology and also, again, by disease severity. So the numbers that I'm demonstrating here are primarily from IPF studies. Mild to moderate pulmonary hypertension tends to have a prevalence of around 30 to 50 percent in IPF. And severe pulmonary hypertension is more common than it is in IPF, sorry, more common than it is in COPD for IPF patients, with around 10 percent prevalence. And again, if we take a sort of conservative estimate of around 40 percent of individuals having pulmonary hypertension with interstitial lung disease, that puts us at around 300,000. So what about rates of change in progression of pulmonary hypertension in COPD versus interstitial lung disease? Well, what's traditionally sort of quoted is that COPD rates of progression are slow, with a change in mean pulmonary pressures of about 1.5 to 2.8 millimeters per year. If we look at where that actually comes from, it comes from two studies. You can sort of tell by the typeface that they were old studies, both from the 1980s, before the advent of long-term oxygen therapy. And it is literally those two studies that have 1.8 percent and 2.5 percent that give us this range of values. What's particularly important to note for both of these studies is that they required individuals to have survived at least two years in order to be able to calculate their rate of change in mean pulmonary pressure. And that's relevant because survival for COPD pulmonary hypertension is not good. And so there's a high selection bias in this study looking at individuals with relatively mild pulmonary hypertension and their rate of progression over time. By contrast, we also don't really have much data on progression in interstitial lung disease. This is one study done out of the Inova group looking at 44 patients with IPF who were referred for transplant. They measured their pulmonary pressures at referral and then again at the actual transplant time. And they saw that there was a rate of, on average, 3.9 millimeters per month change in those who had or developed pulmonary hypertension versus 1.2 in those who never had pulmonary hypertension at either time point. What I wanna draw your attention to, though, is that that distribution is really not normal, which is what's seen on the panel on the left. Most of those patients really had a, over 40% had very little movement in their pulmonary arterial pressures, but there was sort of 10% of individuals who had over 10 millimeters mercury change per month, which drove up that average. And on the panel on the right is the scatter plot looking at baseline mean PA pressure on the x-axis and transplant mean PA pressure on the y-axis. And you can sort of imagine two best fit lines that really kind of highlight these differences in the groups. One that sort of demonstrates a relatively modest change in their mean PA pressures, while one that sort of demonstrates a much more significant change in their mean PA pressures. This study did also take a look at 14 individuals with COPD and they found eight of whom had a mean PA pressure of 25 at a transplant evaluation, and they found a relatively slow rate of change. So I think overall it's reasonable to assume that individuals with COPD have a lower rate of progression in their mean PA pressures than those with IPF, but I would argue that we probably don't know exactly what that rate is. Moving on to histopathology, if we're thinking about interstitial lung disease, major component of both interstitial lung disease pulmonary hypertension and COPD pulmonary hypertension is understanding vascular density. And so vascular density is very heterogeneous and varies by degree of fibrosis. So if we look at the two panels on the left with the bar graphs, you can see that as fibrotic score increases, vascular density tends to decrease, and this is again in patients with IPF. What's kind of interesting is the second panel here, looking at individuals who are controls with fibrotic scores of zero, and they actually had lower vascular density than individuals who had some mild degree of fibrosis, which I would argue suggests an adaptive response to the beginnings of fibrotic change that with an increase in sort of vascular density in response to that fibrosis that ultimately gets overcome by worsening progression of their fibrotic lung disease. Similar to other forms of pulmonary hypertension, there's intimal proliferation, muscularization of microvasculature all the way up to the medium to large size vessels. And similar to group one pulmonary hypertension, PAH, you can see plexiform lesions in individuals with IPF and pulmonary hypertension, as well as some venous occlusion has been observed, which is what's pictured in the panel in the middle. And finally, vascular remodeling may not necessarily correlate with PH severity, which is an interesting finding in IPF and interstitial lung disease, and that's what's pictured in the graph on the right. By contrast, in COPD pulmonary hypertension, vascular remodeling very strongly correlates with hemodynamics, but does not necessarily correlate with COPD severity. And I wanna highlight here that it's important that what Steve mentioned about pulmonary function testing and FEC and FEV1 not correlating with hemodynamics is true, but also histopathologically, there are differences when it comes to interstitial lung disease and when it comes to COPD about the correlations between vascular remodeling and hemodynamics. In COPD-PH, we also see intimal thickening and muscularized arterioles, which is what's pictured in the panel on the left, but there's very minimal muscular hypertrophy of larger vessels like we see in interstitial lung disease. And muscular, sorry, microvascular muscularization is increased, and capillary density is reduced in severe pulmonary hypertension as compared to mild to moderate pulmonary hypertension, as you can see on the graph. One thing that does get sort of described, and again is sort of dogma, is that COPD-PH patients tend to not have similar group one type vascular remodeling. We don't see plexiform lesions. We don't see venous occlusion. And it's true that venous occlusion has not yet been observed, but certainly plexiform lesions have been observed in patients with COPD and pulmonary hypertension, raising the question, of course, of is this group one pulmonary hypertension with COPD as a comorbidity, or is it COPD with a severe vascular phenotype? So moving on to patients in morbidity, and Steve is certainly going to give me a look here for equating pulmonary hypertension with a PA to aorta ratio, but as most of us know, morbidity is worse in both COPD pulmonary hypertension, in both COPD and interstitial lung disease when pulmonary hypertension is a concomitant disorder. This is a study looking specifically at exacerbation, so a unique morbidity to COPD patients based off of PA to aorta ratio that was published in the New England Journal in 2012. And you can see that once you hit a threshold of about PA to aorta ratio of one and beyond, there's a sudden and dramatic increase in the number of exacerbations. Now, whether those were true exacerbations, this was done in COPD gene, these exacerbations were not adjudicated. So whether these were true COPD exacerbations versus heart failure exacerbations is not yet clear. If we look at IPF and morbidity in patients with IPF pulmonary hypertension compared to those who did not have pulmonary hypertension, you can see that, in general, there were more individuals who walked less far on their six-minute walk distance, more individuals that needed oxygen, and more individuals that required assistance with their ADLs as pulmonary pressures increased. And if we're comparing group three pulmonary hypertension to other forms of pulmonary hypertension, we find that group three pH actually has the worst morbidity of all forms of pulmonary hypertension. So the table at the top is data from the Compara registry looking at individuals with IPAH, COPD pulmonary hypertension, and ILD pulmonary hypertension. And you can see that the group three individuals tended to have worse functional class as well as worse six-minute walk distance. And then the two panels at the bottom here are data from PBDomics that Steve and I are working on looking at patient-reported outcomes on health-related quality of life. On the left is the Emphasis 10 score, noting that, again, group three patients have the worst Emphasis 10 score of all five groups of pulmonary hypertension. And on the right is a spider plot of the Short Form 36 score, again, a health-related quality of life score. And you can see kind of beautifully that individuals with group three pulmonary hypertension, particularly with respect to physical functioning, health-related quality of life, do much worse than individuals with group one or the national US norm. Moving on to survival, this has been repeatedly shown across a variety of different studies, but group three pulmonary hypertension does much worse when it comes to mortality than other forms of pulmonary hypertension. This is across three studies here. On the left is a registry study out of Lyon, France. In the middle is the Gießen Registry, and on the right is the Aspire Registry. And it's a pretty consistent outcome across fairly different proportions of individuals with COPD versus ILD within the group three groups here. All three of these studies also went on to look at differences between COPD pulmonary hypertension and other forms of group three pulmonary hypertension, and ILD in specific. And you can see that generally the trend is pretty similar across all three studies, that ILD pulmonary hypertension has worse survival than individuals with COPD pulmonary hypertension among those with group three. But I will highlight that the survival differences are very dramatically different across these different studies. And part of the reason for that is because of the individuals that were included in each of these registries. In particular, the Gießen Registry, notably individuals with ILD had much worse functional class and had higher pulmonary vascular resistances as compared to the COPD individuals within that cohort, which might explain why both the Aspire Registry and the Lyon Registry, median survival for COPD patients was around two years and was reasonably consistent, whereas we don't even hit the median survival within the Gießen Registry for COPD patients. So overall takeaways from this, COPD pulmonary hypertension is likely something you are going to encounter much more commonly than ILD pulmonary hypertension, but ILDPH tends to be more rapidly progressive and more commonly severe. ILDPH has vascular remodeling in regions with fibrosis and severity tends to reflect the degree of fibrosis, histopathologically at least. COPD pulmonary hypertension vascular changes don't seem to correlate quite as well with the degree of airflow obstruction or with their degree of COPD disease histopathologically. Morbidity is worse in both ILD and COPD with concurrent pulmonary hypertension and is worse than that observed in group one pulmonary hypertension. And survival in both COPD and ILD pulmonary hypertension is also worse than PAH and likely worse among those with ILD compared to those with COPD. And I'm gonna pause here and take, I guess not questions now. Sounds good. Thank you. Thanks, Marta. All right. To keep with our theme of staying on time, I will get started with the talk describing contrast between CTD-ILDPH and IIPPH. Okay, here are my disclosures. So I'll start with a case of a 72-year-old woman with progressive dyspnea who presents for evaluation. She has known pulmonary fibrosis and is currently on attentive therapy. She notes dyspnea with more than 50 feet on flat ground. Her pertinent review of systems include orthopnea, no chest pain, occasional palpitations. She has systemic hypertension. Exam findings show that systemic hypertension, borderline tachycardia, 92% on room air. She has an elevated JVP, a loud second heart sound, some vulcar-like crackles, and one plus edema. Her PFTs are shown here, showing some restriction and moderate to severe diffusing abnormality. CT has classic description of UIP. Echo report shows mild LVH with normal systolic function, enlarged left atrium. The RV is mildly dilated with an RVSP of 48 millimeters of mercury, a normal RA, and no effusion. So, does this patient have pulmonary hypertension? The answer to that is we don't know yet. And how should we diagnose and treat a patient like this? But the additional question I would ask is does your algorithm change if her fingers look like this? Or like this? Or her face looks like this? Or like this? So, in the next couple minutes, we're gonna contrast our approach to patients with CTD-ILD and possible pH versus those with other forms. So, I'll talk a little bit about the epidemiology of pH and ILD, the pathogenesis of pH and ILD, and the diagnostic criteria. I'll spend a minute talking about the differences potentially in treatment of CTD-ILD pH versus IIP pH, but I'll let the rest of the talk, Sandeep, to discuss that in more detail. So, we talked a bit about the epidemiology of pH and ILD. Here's where I try to put it all together on one table. This is for my own review of the literature, so don't take this as dogma. But to highlight a couple points that we've mentioned a couple times, the incidence and prevalence vary by the underlying lung disease. pH is not directly related to the severity of the lung disease. And as Aparna alluded to, the data are skewed by single center studies in biased populations. So, if you go into a literature and pull a study in IPF and it comes from the Inova group, they do a great job of characterizing their patients, but the prevalence of pH is gonna be very high because they're a transplant center. So, we know that in transplant population, the prevalence of pH is gonna be much higher than if we had an unselected population in an ILD clinic, as an example. But if I put together the prevalence ranges across the spectrum of diseases of IPF versus CTD-ILD, you can see that in general, the scleroderma population has the highest prevalence of CTD-ILD pH, and the prevalence of IPF pH varies based upon the population study. But it's an intriguing concept to consider the overlap between pulmonary arterial hypertension and interstitial lung disease. The prevailing theories of endothelial cell injury leading to endothelial cell dysfunction, and then some branch point where this seems to be more of a vascular phenomenon versus a parenchymal phenomenon was highlighted in several reviews a decade ago. If I throw on top here that I have autoantibodies stimulating the endothelial cell injury, you might understand why patients with CTD might be at higher risk for having pulmonary vascular involvement, and I'm gonna try to convince you that in general, we believe that to be the case. So, the Fifth World Symposium tried to address this issue of what is significant lung disease to help us distinguish between group one and group three. I talked about that in the previous talk, how this FBC threshold of 70% might be a reasonable threshold. What I didn't mention in that talk was that that threshold was made for patients who have IPF, specifically excluded patients with CTD-ILD, because of this higher risk of having pulmonary vascular involvement, and perhaps having pulmonary hypertension in the setting of those diseases. I also have to contrast that the World Symposium recommendations of what we do in clinical trials. So in clinical trials, typically the criteria are a total lung capacity of less than 70%, predicted, or a DLCO of less than 40%, and moderate to severe fibrosis on CT of the chest, and that's what's been imposed by clinical trials to exclude ILDs, so we're talking about PAH populations. So, how do you define moderate to severe fibrosis? Exactly, I don't know what that means. So you imagine, there's a lot of subjective things that go into this when we think about how to exclude significant ILD when we're thinking about ILD, excuse me, PAH studies. What about clinical trials to include ILD? So, for instance, the more recent study we're gonna talk about, the INCREASE trial, was listed here. So typically, we would think of CT evidence of having diffuse parenchymal lung disease as a criterion. CT evidence of less than 5% of honeycoma would exclude patients. And then, the FVC of less than 70%, predicted, was included in our CTD, as a CTD criterion for the study, the INCREASE study, as an additional criterion for patients with ILD in the setting of CTD. Okay, so I'm gonna show some data that presented years ago now that, unfortunately, I haven't put out there yet for public consumption other than in Munich or Vienna, I guess. But this is a study we did a while ago, just looking at how the definition of ILD would influence our clinical classification. So, it was patients with scleroderma, we had 50 patients at this time, where we clinically classified them based upon our own impression. Were they group one or group three? And then, we said, okay, let's look at, if we use a clinical trial definition, which was a TLC of less than 60%, or between 60 and 70%, with more than minimal ILD. The GO criteria, which is a validated algorithm in scleroderma ILD, to distinguish between limited and extensive involvement of the lungs from their interstitial lung disease, and that's defined as greater than 20% of the lung field on a CAT scan being evolved, or with less than 20%, with an FVC of less than 70%. And then, an FVC criterion, the criterion I described earlier for IPF, as proposed by the World Symposium. So, you can see here, the proportion of patients in each of these groups. When we looked at the switch between groups, based upon the definition, you can see that if we use the trials versus limited or extensive lung disease, the GO criterion, 19 patients in group one went to group three, and two patients in group three went to group one. If we looked at the trials versus FVC criteria, 17 patients went from group one to group three, and zero went from three to one. And if we looked at limited versus extensive disease versus FVC, seven switched in each group. So, the way we define extensive lung disease really impacts how we classify a patient. That's something we have not done significantly work to clarify in our CTD-ILD population. So, we talked about the diagnosis of significant pH, which is also a challenge, right? So, we have significant ILD, but what constitutes significant pH? Someone you might consider intervening upon. This is guidance from the Fifth World Symposium, which I showed earlier, regarding severe pH contrasting to mild pH. This figure is quite useful, as well, to kind of put this all together. If you're thinking about, you have a patient in front of you, you're trying to understand better how the disease might progress. What are the factors that might contribute to the determinants of outcome? So, on the top of this graphic here, we have ILD is the primary determinant of outcomes, and that occurs up until this dotted line here. And then we have pH is the predominant determinant of outcomes. And as time increases, you can see that there's increased vascular ablation and vasculopathy with progression of the interstitial process, and there's an inflection point where now pH becomes the dominant driver of outcomes compared to the pulmonary vascular, excuse me, the pulmonary parenchymal disease. Well, I would argue that our CTD patients are on a different little course, and it might be that their progression of interstitial lung disease will be the significant driver. We know in patients with scleroderma and ILD, their risk of advancing lung disease occurs most in the first three years after diagnosis, and then they tend to stabilize. So if they have significant loss of lung parenchyma, well, that will drive their course. What's happened to their pulmonary vasculature during that time? That's something we don't really know either. But I would argue that this curve is shifted over to the left in our scleroderma ILD patients or CTD ILD patients. And as I said before, no matter what we're talking about in terms of impact on outcome, if you have pulmonary hypertension in the setting of IPF, your outcomes are worse as shown here in the paper by the ANOVA group. And then if we think about scleroderma patients, so even patients who have PAH in the setting of scleroderma have a better outcome than patients who have pulmonary hypertension in the setting of ILD and scleroderma, with the five-fold increased risk of death. All right, so I'll move on to spend a minute to talk about advances in our therapeutics, and I'll leave the rest of the time to Sandeep to talk about this. But this was an important development, I think, for our care of our patients with interstitial lung disease. So as many of you know, this was a randomized control trial of 16-week duration, looking at the impact of inhaled triprostanol on six-minute walk distance. And the primary outcome was met. They had a change in six-minute walk distance, placebo-corrected, of more than 30 meters. There was a reduction in NT-proBNP, reduction in clinical worsening. And there was no difference in end-walk SpO2. So this is one of the concerns. We give the patient a pulmonary vasodilator. It leads to worsening VQ mismatch in the lungs, and that's gonna worsen oxygenation. That did not appear to be the case in this study, so that was useful information. Obviously, more common to have side effects in that arm. But here's what I want to highlight here. When you look at subgroups, the patients that tended to do well were patients with connective tissue disease. I don't know if numerically 43.5 is different from 39.5, but the magnitude of response in our CTD ILD-PH patients seemed to be good. And if you compare this to something we published a decade ago now looking at the minimal important difference for PAH patients, we think that the connective tissue disease patients actually recognize smaller changes than our IPAH patients. So a difference of about 24 meters in CTD-PAH was considered clinically relevant. We're exceeding that by nearly twofold in this population, if that is a relevant estimate of the MCID for patients with CTD ILD-PH. One last thing. Another common misconception is that these patients who have CTD ILD and PH are not candidates for lung transplantation. And I would argue that that is not the case. And in fact, even five, six years ago now, compiling the experience of expert centers, looking at outcomes in patients who had CTD ILD-PH versus IPF, and with or without PH, outcomes are very similar. So if you have a patient who has CTD ILD or CTD ILD and PH, and you believe that they are a candidate for lung transplant, they should most definitely be referred to centers with expertise in managing patients with CTD. That's the key. But don't let that preclude you from getting them evaluated. So with that, I'll summarize. The lack of routine screening and early detection protocols for PH in the setting of ILD makes it difficult to compare CTD versus ILD-PH related disease. And definitions of significant ILD and significant PH also present some challenges, as we highlighted. The impact on outcomes, however, is same in either setting. And treatment with pulmonary vasodilators may be efficacious in select patients. And importantly, lung transplantation is still an option in those patients. Thank you for your attention. And with that, I'll hand it off to Sandeep for the last talk. Thank you, Steve. And I know it's one of the last sessions of the conference, and everyone wants to rush to go home. And I'll try to rush, too. No, I'm just kidding. OK. So we'll talk about the treatment of pulmonary hypertension in the setting of interstitial lung disease, and why is that important to talk, at least in 2022 now. Because now we have some therapeutic options available for these patient population. I think Steve and Aparna already highlighted the magnitude of the problem and the issues with these patients. And I'll discuss a little bit about them, and then we'll jump into the treatment. These are my disclosures. And this session will cover treatment options for pulmonary hypertension associated with interstitial lung disease. And we will discuss about the rationale and the trial in a little bit more detail, which Steve briefly alluded to. So this is the prevalence of pulmonary hypertension in idiopathic pulmonary fibrosis. And as Steve mentioned earlier, that it varies. And if you look at different studies, it's variably reported. So you can see at the time of diagnosis, it's around 8% to 15%. Then at the time of transplant evaluation, 29% to 46%. And at the time of listing or at lung transplant, it's as high as 86%. So going back to what Steve mentioned earlier in his presentation, that if you are looking at a transplant center publication, you may find much higher as opposed to an ILD center. So pretty much as the underlying disease progresses, the prevalence of pulmonary hypertension also changes. This is in different subgroups of pulmonary fibrosis. So the top part of the slide actually shows about CPFE. And as you may know, it's combined pulmonary fibrosis and emphysema. So if you look at on the left side of the slide, initial diagnosis of CPFE with obviously a CT scan. And then in 16-month period, on an average, around 30% to 50% of patients are diagnosed with pulmonary hypertension in the setting of CPFE. And in another year, 60% of those patients, only 60% of those patients survived. As you know, this is one of the distinct phenotype of the disease which has a pretty high pulmonary vascular involvement. And I think in the slide which Steve showed earlier, if you look at this particular phenotype, it generally doesn't respond very well to the treatment also. So this is sort of very aggressive phenotype of pulmonary fibrosis. In the bottom slide, which I think Steve discussed pretty much in detail, but generally once the symptoms of systemic sclerosis start, on an average, between three to seven years patient take to develop ILDPH. And as you can see, roughly around a third of patients will end up developing interstitial lung disease and pulmonary hypertension. And then at one year, roughly 72% to 86% of systemic sclerosis ILDPH patient survival is around one year. Then it continuously with each passing year goes down. At three year survival, it goes down to almost 20 to 40%. So it clearly highlights the impact of development of pulmonary hypertension in the setting of underlying autoimmune disease. I think we have pretty much beaten this topic to death. We've discussed multiple times. I think all three of us have presented this. So I'm not going to go much into it now, how to distinguish between group one and group three. But this slide is very important, which basically highlights the multiple pathways involved. And you can see that this is so complex slide in itself what all can contribute to pulmonary hypertension in these patient population. As simple as comorbidities, like these patients can have sleep apnea, their LV diastolic dysfunction, especially in patients who have sarcoidosis or cystic fibrosis, they can have liver cirrhosis also. Then the lung parenchymal issues, fibrosis and air trapping, which leads to the pulmonary vascular bed ablation, conditions like LAM and PLCH can contribute. VQ mismatch can lead to hypoxic vasoconstriction. Inflammation, which is a hallmark in cystic fibrosis patient. And then there is another important pathway, which is vascular centric, where the endothelial dysfunction, occlusive vasculopathy, which is seen in conditions like sarcoidosis or PLCH, leads to in situ thrombosis leading to pulmonary hypertension Some patients, especially connective tissue disease patients may have concomitant conditions like PVOD, especially in scleroderma patients. So those conditions can also lead to development of pulmonary hypertension in this setting of diffused parenchymal lung disease. These are the treatment pathways in PH, and I'm sure those who manage PH patients, they're very familiar with these three classical pathways, endothelial receptor, nitric oxide, and the prostacycline pathways. And these are very well established, studied, and majority of currently approved therapies target these three pathways. I'm not going to go into very much detail about them. But then the question comes that how do we need to treat PH patients in the setting of diffused parenchymal lung disease? Again, this is the same slide which Steve showed earlier, talking about the inflection point. And then beyond that, the survival and the outcome in the ILD depends on the pulmonary hypertension or severity, and pretty much pulmonary hypertension controls the outcome of the patient. So why do we consider pulmonary hypertension or PH, group 1 PH therapies to treat group 3 PH patients? Again, as we know with the data we discussed today, that the pulmonary hypertension is a cause of significant morbidity and mortality. PH therapy has been very successful in group 1 PH, so it definitely makes them an attractive option to be tried in group 3 PH also, and see if they can be successful to treat these patient population also. However, as Steve mentioned earlier, there is always a concern about VQ mismatch, that PH medications as they vasodilate the pulmonary vasculature better can lead to a significant amount of VQ mismatch in patients with pulmonary parenchymal disease. And also they can lead to, if there is an underlying or concomitant diseases like PVOD or left heart disease, can lead to pulmonary edema. So these were the concern over the years about using the PH specific therapy to be used in these patient. Now, there are different, I wanted to highlight this statement here, which I have mentioned, that we need to understand that what leads to the development of pulmonary hypertension in the setting of interstitial lung disease. If we believe that pulmonary hypertension is simply a surrogate marker of disease progression in advanced fibrotic lung disease, then treatment with pulmonary vasodilator is unlikely to improve the outcomes. However, if we believe pulmonary hypertension in ILD is a maladaptive phenomena in which PH has developed from the discrete path of physiological derangements, then use of pulmonary vasodilators make more sense. However, we don't know what happens in the disease pathology. We believe probably both play some role. So it makes reasonable sense to consider PH specific therapy in patients with pulmonary hypertension in the setting of diffuse lung disease. Now, keeping that in mind, I think this in itself could be a separate talk. There are like a bunch of different trials and studies over the years have been done, which unfortunately have been unsuccessful. In this table, you could see different studies done in IPF patients where basentin was used, and on the right side of the slide, you could see no difference in the primary endpoint time. In the second one, again, another study with basentin, you can see here that no difference in the endpoint of IPF worsening or death. Then embryosentin, this trial pretty much gave the black box warning for embryosentin to be used in IPF patient because it had a higher hospitalization mortality and trial was terminated early. Mesitentin trial pretty much failed to show any benefit in these patient population. Continuing with that, most recently, the Yosigua trial, RISE-IIP, which Steve showed a slide earlier, did not show, and actually, the trial was terminated early because of higher incidence of hospitalization and death. Then Seldenafil or PDE5 inhibitor trials, they showed some signal, but pretty much all the trials failed to meet the primary endpoint. In one of the early trials, STEP-IPF, which where it showed, I think it met the secondary endpoint of quality of life and oxygenation improvement and there was trend towards the mortality benefit, but it did not meet the primary endpoint. So you could see that all these studies have pretty much failed to show benefit in this patient population. Here, I'm talking about these two studies. One, Steve showed you earlier, and which is highlighted at the bottom in red box, and this is one of the only studies which was successfully published last year and got the FDA approval for treatment of pulmonary hypertension in the setting of interstitial lung disease. The top one is currently showing some good early signal in phase two study, I mean showed early success in the phase two, and now the phase three trial is underway currently. So we'll talk about the increased trial. This is the, I can say pivotal trial which showed improvement, I mean met the primary endpoint and showed six minute walk distance improvement, which was the primary endpoint in patients with pulmonary hypertension in the setting of ILD. So it was a double-blind placebo-controlled randomized control trial. The patients were randomized to inhale triprostanil and placebo. Patients with pulmonary hypertension associated with the ILD were included. Pulmonary hypertension was hemodynamically defined. All patients underwent right heart cath with mean pulmonary artery pressure of 25 and above with PVR of more than three would unit and VEGF less than 15, 15 or less. The primary endpoint, as mentioned earlier, was six minute walk distance at 16 weeks, and pH must be in the background of ILD evidence on the CT scan. Keep that in mind, the CT scans were not centrally adjudicated. It was the PI discretion of the interstitial lung disease. Minimum walk patient at baseline should be, minimum distance a patient should be walking was around 100 meters, and the background of anti-fibrotic therapy was allowed. So patients were allowed to continue their nintendineb or perphenidone therapy if they are on. This is the randomization tree. Total of 462 patients were assessed. 136 screen failed, 326 underwent randomization, and then 163 were randomized into either inhaled reprostanil or placebo. Eventually, 130 patients in the drug arm and 128 in the placebo arm completed the study. Around 35 patients in the placebo and 33 in the drug arm, for a variety of reasons, discontinued the study. At baseline, the six minute walk distance was 259 meters and PVR of around six would unit, which is a pretty significant pulmonary hypertension. And the mean anti-proBNP was 1,832, which is pretty significantly high as well. So this is the primary endpoint flow chart showing you the six minute walk distance. As you can see, the top part, the orange line, clearly showing improvement in the six minute walk distance in patients who received inhaled reprostanil. The placebo arm kind of went down. That means as the time went on, their walk distance went down and this led to the result of significantly, placebo corrected improvement of six minute walk distance of 31 meters, which was statistically significant. These are another parameters, and as you want to see, it shows improvement in anti-proBNP also. In inhaled reprostanil group, it went down by 396 as compared to placebo group where it went up by 1,453. And if you look at the clinical worsening events, they were also less, any event was only in 37 patients as opposed to 54 in placebo, and this was also statistically significant. And if you further go down, hospitalization was less in inhaled reprostanil group, decrease in walk distance or death was pretty much same in both the groups by the end of the study. So with these findings, inhaled reprostanil was approved by the FDA to be treated for treatment option in patients with pulmonary hypertension in the setting of ILD. Now in this slide, we're gonna discuss about another treatment option, which is inhaled nitric oxide. This is about a phase two study, double-blinded placebo-controlled dose escalation study to assess the safety and efficacy of pulsed inhaled nitric oxide versus placebo in patients at risk of pulmonary hypertension associated with pulmonary fibrosis who were already receiving long-term oxygen therapy. So the inhaled nitric oxide is delivered through a small device, which is connected with their supplemental oxygen and with that, this was delivered to the patient. And there were three different cohorts, one was at 30 parts per million, the second was on 45, and the third one where it was a dose escalation allowed from 30 to 45 for 16 weeks. Interestingly, this study used actigraphy and what we call as their primary endpoint was moderate vigorous physical activity, means that they wanted to assess if addition of inhaled nitric oxide leads to improvement in the physical activity for these patients. And as you can see, the green bar on the top here shows improvement in patients who received inhaled nitric oxide at 30 parts per million dose. In the other groups, you would see that the placebo had much fall, but relative to that, the patients who were receiving inhaled nitric oxide, they had less fall. With this, definitely these results, these are early results, they looked promising. Currently, this is in phase three, and we don't know as yet, but hopefully soon we will have that. But with all the data we discussed today, we have been successful to have at least one treatment option available for our patients in the form of inhaled triprosomal. I think with that, I would like to conclude my talk that inhaled treatment approaches have shown some promises in the treatment of PHILD. And as you can see, inhaled triprosomal and also inhaled nitric oxide appears to be helpful to these patients. Initial trials with PH-specific therapy have failed, and these drugs should be avoided. Especially, we talked about drugs like Riosiguat and Embrycentin, they should not be used in these patients. I repeatedly mentioned about the inhaled triprosomal, and hopefully inhaled nitric oxide should be available for these patients soon. And supportive treatment with the oxygen and diuretic should be continued, because as we know, oxygen is very helpful in these patients, and it mitigates the pulmonary vasoconstriction. And consider sending these patients to the specialized center as early as possible, where they can have proper evaluation, get the treatment availability, and also consideration for the transplant. Thank you so much for your time and attention. Thank you.

Inflammatory lung diseases

Interstitial lung disease

Pulmonary hypertension

Idiopathic pulmonary fibrosis

Connective tissue disease-associated ILD

Morbidity

Mortality

Inhaled treprostinil

Inhaled nitric oxide

Lung transplantation

PH