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Best of CHEST Journal: Diffuse Lung Disease
Best of CHEST Journal: Diffuse Lung Disease
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So, I want to talk about the gender disparities in ILD, and we're going to kind of go through diagnosis to treatment and management. But we're going to talk about more than gender, we're going to talk about sex, and we're also going to talk about race. These are my disclosures. What we're going to do in the next 15 minutes or so is to understand how sex and gender play a role in the care that we provide to our patients with interstitial lung disease. And I'm going to highlight the differences in access to care using large prospective registries and observational data. This all started because of this patient, Rose. She was a patient that was referred to me fairly early on in my clinical career. And she was only 57, and this is actually a slide of her lung. This was her actual CT scan when she was first referred to me. So, we can see she already had very, very advanced, very severe disease. And she had been diagnosed actually quite late in her disease, but also referred to me quite late. And she hadn't received any treatment. Granted, at the time, antifibrotic medications were quite early, and so not everybody was really prescribing them. But it got me to thinking, why is this patient coming to me at such a young age, and does it have anything to do with her being a woman? And so that got me interested in looking at sex and gender disparities in the care that we provide. Before I go on, I think it's really important to talk about what is sex and what is gender. They're not the same thing. We often use them interchangeably, but they're not the same thing. Sex refers to biological attributes, so they're really, you know, a set of physiological and biological attributes, genes, chromosomes, hormones, gene expression. Whereas really, gender is more beyond identity. It's really like an expression of the person, but it also reflects social and cultural norms and beliefs. And it also reflects roles and responsibilities that we attribute to certain sexes in our cultures. So we're going to go on to talk about diagnostic differences and disparities. So you may remember this study from Dr. Simon Walsh, where he asked over 400 physicians to review cases and to score them based on the diagnostic probability and the diagnostic confidence. So I used his data to try to see if the patient's sex could influence the diagnosis that's given. And what we found was that actually, the odds of receiving a diagnosis of IPF for men was threefold that of women. And that was true, especially for CT scan patterns that were anything but the usual interstitial pneumonia pattern. To me, reflecting that, if your patient has a scan that's not the definite UIP, you as a clinician will put a lot of emphasis on the patient's sex to put your diagnosis of to give the patient a diagnosis of IPF. And that's also reflected in this table where the diagnostic confidence was much higher for diagnosis of IPF in patients who were male compared to patients who were female. And that was true across all UIP patterns. There was this recent publication by Vincent Cotin in France, where he looked at a prospective multicenter cohort of patients with ILD, and he tried to characterize the differences between men and women in their cohort on the baseline characteristics of the IPF disease. So what he did is he took his entire population of his registry and he looked at those with IPF, and then he compared it. This is a very busy slide. I'm going to draw your attention to a few key things. So one, the women patients with IPF at entry into the cohort tended to have a much better lung function. The FEC was about 10% higher than compared to men. The GAP score was also lower, suggesting also that a lower disease severity at baseline entry into the cohort. And what was really interesting is that if you look at the patient's CT scan, women had a lot less honeycombing present on their CT scan at diagnosis and at entry into the cohort. To me, maybe reflecting that either they were earlier in the disease or maybe their scan appearance is different from men. So in terms of the diagnosis, some of the take-home points for me are that men are more likely to receive a diagnosis of IPF, which kind of makes sense because in the population studies we do think that men are more likely to have IPF. There's a predominance of men with the disease, but critically that the diagnosis is made with greater confidence in men compared to women. And we know also from Professor Cotin's study and others that there are baseline characteristics that differ between men and women at IPF diagnosis. I want to move on to disparities in treatment of ILD. So this was one of the first studies to actually look at that. And Tim Dempsey looked at administrative data from Medicare participants. So he took patients who are under Medicare in the United States who had a diagnosis of idiopathic pulmonary fibrosis, and then he looked at who were the patients who failed at least one prescription for an antifibrotic medication, so either Profenadone or Nintendinib, between October 2014, when antifibrotics were first approved, up until July 2019. And critically, what he did is that he then looked at the differences in prescription of antifibrotic medication between men and women. And you can appreciate on the right-hand side that there's a significant differences in the curves between male patients in the red and female patients in blue. I also want to draw your attention that at the time, uptake of antifibrotics was quite low, at most 25%. But critically, women had 10% less prescription of antifibrotic medication during the study period, so about 15% at the end of the study here. So that's actually a really, to me, dramatic difference between antifibrotic prescription between men and women using this data. Another study looking at administrative data was actually looking at patients who were veterans, so patients who used a veteran affair healthcare system, I would say. And so they looked at this population, and again, very similar study, looked at this administrative data, and they wanted to identify patients who were prescribed at least one antifibrotic prescription. And so either at the VA or at a Medicare pharmacy. And similarly, they looked at October 2014, the onset of antifibrotic, up until 2019. And in this study, they also looked at sex and, so differences between men and women, but they also looked at patient race. So what they found was, again, that in veterans population in the United States, the uptick for antifibrotic or the prescription for antifibrotic was overall very low, around 15 to 20%. But critically, there's a huge difference between here, men and women on the right-hand side where women are in red, there's about a 5% of these people with IPF who were given at least one prescription for antifibrotic, compared to 15 to 20% of men who are veterans with IPF who were given at least one prescription of antifibrotic. And then when we look at patient race, again, there's significant differences across race in terms of receiving treatment with antifibrotic in the U.S. in veterans population. If you look at the red dotted line here, those are patients with black ancestry were significantly less likely to receive a prescription for an antifibrotic. So I want to spend a little bit more time on this study that we conducted. And we looked at it. It was a collaboration between myself, Deji Adegunsoye, and Rob Sheehy out of Australia. And we wanted to see in perspective longitudinal registries of patients with ILD and IPF if we could identify sex and race-based differences in the treatment of ILD. So our question was, does the patient sex assigned at birth or patient's race influence ILD treatment initiation? And so this observational study grouped three large prospective registry, three large cohorts. So the Canadian Pulmonary Fibrosis Registry, the Australasian Interstitial Lung Disease Registry, and the University of Chicago Registry. And we looked at patient sex and race as our primary exposure. And our outcome was initiation of at least one ILD-related medication for treatment. We used time-to-event analysis to look at the differences. Again a very busy slide, but I think it's important because we need to highlight that these are three different prospective cohorts, so there are automatically going to be differences in patient characteristics across cohorts. So critically, the patients in the Australasian registry were older than the patients in Canada and the patients in Chicago. In the University of Chicago, the lung function was significantly lower in the 60s at entry into the cohort. And then race was where things were actually quite different across cohort. So the University of Chicago had a much higher population of black patients, but the Canadian and Australian registries had a much higher proportion of Asian patients. And the other difference also is that in University of Chicago registry, they do a lot of surgical lung biopsy, which we don't do in Canada and Australia, it seems like. So around 40% of patients in Chicago had received lung biopsy. And the other thing that we did is we didn't just look at IPF, we looked at patients with all ILD across the board. And so we looked at the proportion of treated patients at any time during the follow-up, and we found significant difference in the Canadian cohort. So in our Canadian registry for pulmonary fibrosis, women were less likely to receive treatment. And the proportion of women who were treated was much lower than men. And that was true mostly for IPF and connective tissue disease ILD, but that was seen across the board for all diagnosis here. These differences were not seen in the Australasian registry and in the University of Chicago registry. And so this is the difference according to patient race. So again, in Canada, we're not doing very well in our prospective registry, but patients who are of non-white ancestry were much less likely to receive treatment for their ILD. And this, again, was true for all diagnosis, but also for IPF and connective tissue disease ILD. So to me, the take-home point of those treatment studies are really that women in general looking at administrative data and registry tend to be undertreated, and patients who are of black racial background also tend to be undertreated. There is substantial heterogeneity in treatment initiation across cohorts. We only looked at three cohorts, but if we were to look at many more cohorts, I'm sure we would find a lot of heterogeneity across centers, across countries, et cetera. So for me, this raises really important questions on the causes that are underlying this. Is this more a social or cultural barriers to treatment? Are there other barriers to care? And what are the roles of the physician and healthcare practitioner when they see these patients? And finally, I want to end with a study looking at inclusion of women and patients of different races in clinical research for IPF. So we performed a systematic review and meta-analysis where we wanted to assess the representation of race and gender of patients in IPF clinical trials. And we also looked at registry studies. And what we found was that this is looking at the proportion of non-white participants that were included. We separated them into the randomized control trials and observational registry study. And you can see that overall, there was only a 14% inclusion of people who were non-white across clinical trials, which is a major, major problem in terms of generalizability of our clinical trial results to the population of patients that we actually see in the clinic. And when we looked at women, we also found that in patients with IPF trial, that there were only 24% of women included in registry and trial. But that was significantly different when comparing registry and randomized trial. So in clinical trials, only 22% of women are included, whereas in registry, it's closer to 27% to 30%. And so that tells me that we are also not doing a very, very good job at being very inclusive in our clinical trials of IPF treatment. So what are the next steps? For me, it's clear now, it's well-established that there are sex-based disparities, but also race-based disparities in the management and the care of patients with ILD. And I think the next steps really are going to be to look at underlying causes of these disparities. Why are they there? Why do they exist? Are they related to gender and gender-related variables, like roles and societal expectations? We also really need to delve deeper into racial differences in ILD care, and a lot of my colleagues are doing that. We need to understand if there are social determinants to these disparities. And then finally, I think as physicians and clinicians, we need to examine our own perceptions and attitudes towards our patients. Are we treating them, even if we're not doing this consciously, are we treating our patients differently depending on what they look like? And finally, I think we need to advocate for greater inclusion in research, both in clinical trials, but also in registry studies, so that the data that we gather from our research really reflects the true population of ILD patients that we see in clinical practice. And so with that, I want to thank you. I want to thank all our collaborators and co-investigators, and all the people who've been doing this work on disparities of care in ILD. So thank you very much. Okay, so we're going to move on to our second talk of the session. Dr. Chan Newton is going to talk to us about genetics in ILD. Dr. Newton is an assistant professor at University of Texas Southwestern, and he's done extensive work and research on genetics in ILD, so he's going to give us an update on that topic. Yes, thank you for the introduction. Thanks for inviting me to speak here today. So my talk today really is going to focus on three papers that have been published in CHEST in the last year. So we're going to use those three papers really to highlight a few concepts on how we can use genetic information in our care of patients with interstitial lung disease. So here are my disclosures. So the first concept we're going to talk about today is how we could potentially use genetics to inform what our expectations would be for a patient's ILD natural history. We're going to then discuss how we can use genetics, and in particular family history, to enrich for clinical screening for early interstitial lung disease. And then we're going to review an expert opinion on the recommendations for how we should be using genetic testing in clinical practice. So the first paper here, we're going to discuss natural history of ILD mutation carriers, specifically those with surfactant gene mutation carriers. So this was a study published by Clay and colleagues out of the Netherlands entitled Progressive Disease with Low Survival in Adults with Pulmonary Fibrosis Carrying Surfactant Related Gene Mutations. So if you remember, we can break up interstitial lung diseases into lots of different categories, but one stratification that we can do is by familial versus sporadic interstitial lung disease. This is typically what we do in genetic studies. We want to enrich our cohorts with familial patients so we can identify rare genes that are causative of pulmonary fibrosis. So if we break this down from familial to sporadic, we see that two primary pathways are implicated by the genetics of interstitial lung disease. And so these are the telomere-related genes and the surfactant metabolism genes. If you look on this here under the familial ILD, you can see that there's a much larger proportion of patients who have a telomere gene mutation. But around 3% to 8% of familial pulmonary fibrosis cohorts will have individuals with surfactant-related gene mutations. These are surfactant protein C, surfactant protein A1, A2, and then ABCA3. And these are typically adult-onset interstitial lung disease. But we see a similar trend in patients with sporadic interstitial lung disease. These are groups of patients who don't have another family member that they know of that has pulmonary fibrosis, so we label them as sporadic. But we see that these two primary pathways can still be present even in a patient who doesn't have a family history of pulmonary fibrosis. Importantly, though, is that we've published several papers now that have shown that telomere gene mutations are associated with rapid progression and poor survival across a variety of clinical scenarios in patients with interstitial lung disease. But we really don't know all that much about the phenotypes of the surfactant gene mutation carriers or their natural history. Primarily because they're much less prevalent. So the investigators here gathered individuals from their genetics clinic and from their ILD clinic over a span of 20 years. Okay, so this is 1997 to 2017. And they broke these patients down into three groups. The ones that had surfactant-related gene mutations. They found 48 subjects over 20 years. So it tells you how rare these mutations are. And they compared them to patients with familial pulmonary fibrosis and those with sporadic pulmonary fibrosis. Of the patients with surfactant-related gene mutation carriers, of the 48 patients, only 23 actually made it through their inclusion-exclusion criteria. And of those individuals, they had 12 with a surfactant protein C mutation and less with surfactant protein A2 or ABCA3. All the patients with familial pulmonary fibrosis, they did screen for these surfactant-related gene mutations. So they know that this cohort does not have a surfactant-related gene mutation. And their sporadic IPF patients, they screened if they had disease onset less than 55 years old. So this is their table one. So the important points here is that patients with surfactant-related gene mutations in this left column had disease onset at the age of, on average, 45 years old, compared to two decades later of those with other familial pulmonary fibrosis or sporadic IPF. So these patients developed disease much earlier in life. There's almost a 50-50 male-to-female ratio, as opposed to familial pulmonary fibrosis, sporadic pulmonary fibrosis, which is primarily male. Looking at their phenotypes, they did HRCTs on all the surfactant-related gene mutation carriers. And the majority of them actually had an inconsistent-with-UIP pattern. And primarily that was because of the presence of ground glass opacities. But despite that, of the patients who underwent surgical lung biopsy, which was only 11, the vast majority had a usual interstitial pneumonia pattern on biopsy. And that includes five patients who had an inconsistent-with-UIP scan, still had a pathologic usual interstitial pneumonia pattern on biopsy. They did evaluate the kind of natural history, so the trajectory of forced phytocapacity over time. And what they found is that patients with surfactant-related gene mutations had a similar trajectory to the patients with familial pulmonary fibrosis and sporadic IPF. So there was no significant difference, at least stratified by these genetic groups. They also tried to look at the influence of treatments. They looked at no treatment versus immunomodulatory treatments versus antifibrotics. Their sample size is quite small here, especially for the surfactant-related gene mutation carriers. But in general, they found that patients who were initiated on treatment had a faster decline in FEC, but did not quite reach statistical significance. And importantly, they didn't really account for indication for treatment here. In looking at the survival, they found that patients across these three groups had a very similar survival, with a median survival of around three years, between three and four years. So patients with surfactant-related gene mutations tend to progress just as quickly as patients with familial pulmonary fibrosis of other types and sporadic idiopathic pulmonary fibrosis. So what this study tells us is that, as we kind of already knew, these surfactant-related gene mutations are rare, even among familial pulmonary fibrosis and sporadic IPF cohorts. So it really reinforces the fact that we're not seeing a lot of these patients, but the ones that we are seeing tend to be much, much younger. So disease onset less than 50 years old. They often will have atypical radiographic findings, despite having a pathologic UIP. And despite their younger age, their median survival is the same. So a 45-year-old that develops disease, their prognosis is somewhere in the three- to four- to five-year range, just like an older patient with sporadic IPF. The FEC trajectory in response to treatment appears to be very similar to sporadic IPF and familial pulmonary fibrosis. There were limitations to the study, so they did not actually screen all their familial pulmonary fibrosis for telomere-related gene mutations, so we don't know how to compare these two groups. And like I said, they're limited by sample size, and the treatment stuff is limited by confounding and indication bias. But based on these data, we really should consider genetic sequencing if someone has a family history of pulmonary fibrosis or has a young age of onset. We should consider genetic screening for asymptomatic relatives of patients who are found to have a surfactant-related gene mutation, and then we could even consider clinical screening for asymptomatic surfactant-related gene mutation carriers. I'll expand on this a little bit more in the other papers. So the next paper we're going to talk about is out of the Columbia group, led by Claire McGruder, looking at radiographic lung abnormalities in first-degree relatives of patients with different subtypes of pulmonary fibrosis. So as you all know, in someone that has established ILD, at some point they were normal, right? They weren't born with ILD. They developed it at some point in their lifespan. We know that once someone starts developing ILD, they have a decline in their lung function and they have an increase in their symptom burden, right? This just makes sense. As they're developing disease, things are progressing. So what many groups have tried to do is identify early disease called ILA, if you see it on HRCT or CT, so interstitial lung abnormalities, or preclinical ILD. There's lots of different names for this, but the concept is similar, identifying disease at its very earliest stages. And the point of this is if we can identify it early, then we can monitor frequently, we can potentially initiate some sort of treatment, depending on what we think is going on with them. We know that ILAs or preclinical ILD are relatively common. So in community-dwelling adults, these have been identified in 2 to 9% of the population. But if you look at family members, so relatives of people with interstitial lung disease, specifically with IPF, they tend to have a much higher prevalence of 14 to 36% in different studies. So this tends to be an enriched group, just a relative of someone with pulmonary fibrosis. But the question is here is what's the prevalence of ILA or preclinical ILD in family members that don't have IPF? They have some other form of interstitial lung disease. So the investigators here identified families with familial pulmonary fibrosis and families of patients with sporadic pulmonary fibrosis of all different types, including connective tissue disease, unclassifiable ILD, IPF, and HP. In total, they identified 98 at-risk participants. So again, these are asymptomatic individuals, but they're relatives of someone with pulmonary fibrosis. They did HRCTs on all of them, and they found that around 20% of relatives of familial pulmonary fibrosis kindred had early evidence of interstitial lung disease or interstitial lung abnormalities. And they found that around 8% of sporadic pulmonary fibrosis relatives had early evidence of disease. They found lots of different subtypes of interstitial lung abnormalities or patterns of ILAs. So they found people with a probable UIP pattern. They found people with an HP pattern, even someone with a PPFE pattern. And interestingly, there was one patient who had a left upper lobe spiculated nodule that they sent for surgical resection, concerned for malignancy. But the PATH specimen that I'm showing here on the right, this nodule was actually elastin fibers. This PATH specimen also had subplural fibrosis. And in the bottom right panel, they're highlighting fibroblastic foci. So this actually represents an early-stage interstitial lung disease. They looked for risk factors. So what increased someone's risk of developing ILAs? And they found two primary risk factors. The first is age. For every year increasing age, there was around a 9% increased risk of developing early interstitial lung disease. And people who had the risk allele for the MUC5B SNP also had a 300% higher risk of developing ILA over time. So this tells us that relatives of pulmonary fibrosis patients, regardless of the subtype of the proband, are enriched for ILAs or preclinical ILD. About 20% of asymptomatic relatives of familial pulmonary fibrosis, kindred, can have interstitial lung abnormalities. But they found here that about 8% of asymptomatic relatives of sporadic pulmonary fibrosis, which is actually near population level of what we've seen in other studies of population level. This is lower than other groups have found in their screening studies, and it may be due to the way that we ascertain family history or even ascertainment bias, selection bias from these studies. This confirmed that genetic information, specifically the MUC5B SNP, might help us to enrich a screening population of at-risk individuals. Again, this is limited by small sample size and likely at least some element of non-random recruitment. So again, common theme here, things that we should consider as clinicians is that clinical screening, including HRCTs and PFTs, in asymptomatic relatives of FPF kindred, regardless of the diagnosis we give the proband. And again, if ILA or preclinical disease is present, then we should follow those individuals closely, right, because they're at risk of developing established interstitial lung disease over time. The last paper I'm going to talk about is one that I was actually involved in. So this is a statement that the Pulmonary Fibrosis Foundation sponsored us to put out regarding the role of genetic testing in familial pulmonary fibrosis. So the Pulmonary Fibrosis Foundation put together a group of pulmonologists, geneticists, and genetic counselors with the goal of putting out a statement to actually at least put out recommendations on when we should be considering genetic testing in our patients. So the reason that this was put forth is that there's been an explosion of genetic information over the last decade or so. And what we have found is that genetic information actually offers actionable information for when we're caring for our patients. As I've shown in the previous two studies, genetic information can highlight family members that are at risk of developing pulmonary fibrosis. In certain circumstances, it can even give information on extra pulmonary manifestations that can develop in individuals, and in some cases can even give us some sort of estimation or expectation on what their disease course is going to look like if they develop disease. So we put the paper together with the goal of summarizing the genetic variation, which I'm not going to talk a lot about here, but also to describe the clinically available genetic testing methods, and then review indications for genetic testing. So we all agree that if we're going to use genetic information, then we have to get really good at taking a family history. And so we put in a couple of recommendations on how to take that family history. So you want to ask about generations, three or four generations above, and a couple of generations below if they're available. And you want to specifically target manifestations that fall within genetic syndromes. So in the telomere pathway, you want to ask about personal or family history of not just pulmonary fibrosis, but bone marrow disease, liver disease, squamous cell cancers of the head and neck, and premature grain. In patients or in families with a surfactant pathway mutation, you want to know about, again, pulmonary fibrosis. But you want to know if this is adult onset or pediatric onset. You want to know about brain and thyroid lesions, and then concomitant or coexistent lung adenocarcinoma with pulmonary fibrosis. And then the Hermansky-Pudlock syndrome, you want to ask about not just pulmonary fibrosis, but platelet dysfunction, neutropenia, and albinism. So in the genetic testing methods, we have two primary tests. The first is genetic sequencing. These come as gene panels, which is where we're just sequencing the genes that have been previously implicated in familial pulmonary fibrosis. But you can also do whole exome or whole genome. We typically don't recommend doing that from a clinical standpoint, just from cost and interpretation. So we recommend gene panel testing. The results of these panels come back according to the American College of Medical Genetic Standards as pathogenic, likely pathogenic, VUS, likely benign or benign. In familial pulmonary fibrosis cohorts, we expect around 30 percent to come back as a positive, meaning pathogenic or likely pathogenic mutation. The second test we can do is called telomere length measurement, where we actually collect blood samples, send it to a lab, and do flow fish measurement of the telomere length. This often will come back as a number, so it's an objective measure, and they're usually stratified according to the age-adjusted percentile, where we consider less than 10th percentile probably abnormally short. So who should we be doing genetic testing on? So we agree that we should be doing genetic testing on individuals who have a family history of pulmonary fibrosis, specifically in those patients who have pulmonary fibrosis in the family, but also have other manifestations that suggest one of these genetic syndromes of a telomere pathway mutation, surfactant mutation, or Hermansky-Pudlock syndrome. We should also consider doing genetic testing in someone with early-onset pulmonary fibrosis, so we define that here as less than 50. The Europeans just put out a statement that also follows very closely with this and also recommended doing genetic testing in individuals diagnosed with an idiopathic interstitial lung disease at less than 50 years old. We also said that we should probably not do genetic testing on people who don't have a family history or a personal or family history suggestive of a genetic syndrome, not just yet. We also recommend to do telomere-length measurement on people that had a clinical scenario that was consistent with the short telomere syndrome, regardless of their family history, and then even to assess the pathogenicity of a telomere-related variant of undetermined significance. So, in summary, the results of genetic testing can actually inform an individual's ILD natural history, at least give a baseline expectation that this patient may progress quickly or not. Relatives of pulmonary fibrosis patients are enriched for early disease, so interstitial lung abnormalities, preclinical ILD, whatever you want to call it, that is an enriched population. And so family history and genetic information can actually refine that risk and help to identify individuals that maybe we should be screening clinically. And that clinical genetic testing should be considered in specific clinical situations. So with that, I'd like to thank you. Take any questions. So we're going to move on to our third and final talk from this session. Dr. Oldham from the University of Michigan is going to give us an overview of what's coming for ILD in the next year or so. All right. Thank you, Julie. Thank you to the CHESS organizers for the invite. So I'm Justin Oldham, University of Michigan. Not going to be talking specifically about the CHESS journal and papers coming out of that today, but rather trying to pull in a lot of what's been published over the last year and looking forward to the next year. These are my disclosures. So the objectives are I'm going to talk about over the last year and a half or so some of the advances we've had in the field of ILD, but also diffuse lung disease, not just ILD, and highlight how some of these advances are likely to inform our field moving forward. So I'm going to specifically be talking about three things, one being this progressive pulmonary fibrosis paradigm that has emerged, new therapies that are under investigation for IPF, PPF, and then other diffuse lung diseases, and then talk about some of the, I think, more interesting biomarker work that's been done recently and where we're going with that. So starting off with progressive pulmonary fibrosis, or PPF. As most of you are probably aware, the inbuilt trial was published a few years ago, showing that nintendonibs slowed regression of disease relative to placebo. This was the protocol paper published in 2017, which essentially put out this new term of progressive fibrosing ILD, the rationale being, you know, while patients with IPF have this classic fibrosing ILD, there's data that suggests that patients with non-IPF ILD develop this IPF-like progressive phenotype, and so they proposed this term, PFILD, as part of this inbuilt trial. And of course, these are the results, compared to placebo, nintendonib resulted in less loss of vital capacity over time, and for this reason was approved for those who met this criteria for progressive pulmonary fibrosis phenotype. The results were strikingly similar to what we had seen in the Impulsus trial in 2014, which was done in IPF, suggesting that, you know, those with IPF and PPF have a pretty similar trajectory, and this drug does pretty similar things. This was a bit complicated by the fact that this trial set forth a set of criteria, the PFILD criteria, now called PPF, concurrently there were a handful of other trials being performed or being designed that define things a little bit differently, so there was the relief trial, which just used a 5% FVC decline over 6 to 24 months, there was this Profenodone trial for unclassifiable ILD, which just allowed a 5% FVC decline or worsening symptoms, there was a Ureachia kind of opinion piece put out, which said, actually, we should be using inbuilt criteria, plus a 5% FVC decline, and 15% relative DLCO decline, which was the first time we were bringing DLCO into the mix, there was some other opinion pieces saying, actually, we should be using inbuilt, plus just 15% DLCO decline. So in an attempt to bring all this together, an international consensus statement was put forth that updated how we diagnosed and treated IPF, but also proposed this progressive pulmonary fibrosis phenotype, PPF, which is supposed to replace PFILD and all these other disparate measures or proposed measures of progressive disease. And so this is what they said in this opinion piece. And I call it opinion piece for a reason. There is worsening symptoms, plus a physiologic decline of either 5% FVC or DLCO of 10%, or a radiologic progression based on a radiologist saying, yeah, it looks kind of worse. And so these three things, if you have two of them, you meet criteria for progressive pulmonary fibrosis. The Canadian group, well, I guess, Canadian and Australian groups were pursuing this asking whether this PPF guideline resulted in some sort of different phenotype than all these other proposed definitions that we'd seen. And as they found, with the exception of the UILD trial, all these phenotypes mostly overlapped. There were some patients that didn't quite fit any but one of them. There are some that fit numerous. A handful of patients met all four or five they looked at. But outcomes did look relatively similar. Other side of the world, my group was doing something similar where we were assessing whether these previously proposed criteria along with the PPF criteria resulted in some different phenotype. And what we did was we took a little bit of a different approach. We didn't say, you know, let's look at these kind of globally. We said, you know, there needs to be an anchor, there needs to be some ground truth in the way we approach this. And so we thought that a 10% FVC decline was probably the best ground truth out there because this has been associated with subsequent mortality across just about every ILD and done just about every different way, whether it be a prospective or retrospective post-hoc trial analysis. 10% FVC decline is almost invariably associated with worse outcomes. So we took this 10% FVC decline, called it ground truth, and then said, let's look at how all these other proposed criteria perform in the absence of a 10% FVC decline. And so this is just a figure showing how many patients have 10% FVC relative decline over on the left there. And mind you, this is all a non-IPF ILD, right, so PPF is not IPF. And so, you know, almost 60% of patients, or I'm sorry, a little over 40% of patients had a 10% FVC decline. And then all the red boxes are those who met criteria in the absence of 10% FVC decline. So these are kind of small groups. You know, a good chunk of patients had a 10% FVC decline. A good chunk had 5% FVC decline. But as you got to these combinations of needing, you know, radiographic progression plus FVC decline, the groups got smaller and smaller. And you know, the take-home of this was, you know, this Kaplan-Meier on the left was all-comers at the time of diagnosis. This Kaplan-Meier looks like every other one that's been published. And those with IPF in red do a lot worse than those with every other condition. Those who have connective tissue disease who are in green do better than the others. So this is nothing new. But if you look at those who have PPF, as we're calling it, in this case defined by 10% FVC decline, these groups look pretty similar. You know, they're overlying one another. There's very little difference. And so from this, we were able to, you know, say with a high degree of confidence that having a 10% FVC decline, irrespective of the ILD subtype, results in pretty uniformly poor outcomes. That wasn't true of all the other criteria that we validated. And so, you know, while 10% FVC decline is probably a good anchor for PPF, the rest of these are all over the map. And you know, if you have 5% to 9% FVC decline and you have HP, then yeah, you look a lot like IPF. But if you have CTD, you don't. You still have better outcomes. And that was true of just about every criteria we looked at. And so, you know, these studies along with the consensus statement led to multiple letters to the editor basically decrying the fact that there was pretty poor evidence used to come up with these PPF criteria. Some of them I would say are completely evidence-free. And so, you know, there needs to be some work done to this. There were alongside these letters urgent calls to revise these criteria because, you know, if we start trying to implement them and design trials based on them, you know, we might be doing a disservice to our patients. And then there's been numerous grant proposals, which is really what's needed to effectively study this in a prospective fashion and establish which of these criteria actually matter. So we've got one here in the U.S. through the NIH, led by myself, Fernando Martinez and Andrew Noth. There's a group in the U.K. being led by Manuela Funke-Chamberlain and Michael Kreuter. And then the Injustice Study in the U.K. is actually already funded, is almost completed, and that's being led by Gizli Jenkins. So my hope is we'll soon start having some answers to this. Moving on to new therapies for IPF, PPF, and other diffuse lung diseases. So we greet 2024 with a bit more pessimism than we greeted 2023. Of course, this year we've had three major Phase III failures, one being from the Fibrogen Company with the Zephyrus trial, another being the Starscape trial from Roche and Genentech, and the final being the Isabella trial from Galapagos. We all had a lot of optimism that one of these were going to come through, and unfortunately none did. Not all is lost, though. We do have new trials coming, notably the Fibronear IPF and ILD trials, which these are the designs of but is based on this New England Journal paper, with pretty impressive Phase II results showing that compared to placebo, this novel agent essentially blunted FVC decline. It was a short trial, you know, obviously needs to be confirmed in Phase IIIs, but this Phase III trial is quite far along. IPF is no longer recruiting. We should have a readout in the next year. Teton trial is a Phase III of inhaled troprostenil for IPF, and it's based on this prior data published in the New England Journal, not in IPF, but actually in Group III pulmonary hypertension, so pH due to ILD. And what they found was, you know, in walk distance, which is kind of the primary outcome of most pH trials, those who got inhaled troprostenil did better or had an increase in their walk distance compared to those who received placebo. Interestingly, in a post hoc analysis of this group, they collected lung function in these patients, and what they found was that those who got inhaled troprostenil actually had stabilization of their FVC over time, whereas those who did not actually had ongoing FVC decline. And so based on this very interesting secondary analysis designed this Phase III Teton trial, which will now be testing inhaled troprostenil in IPF, specifically not for pH but for the disease and using FVC as the primary outcome. Then there is the PRECISIONS trial, which I am a co-investigator on. So this study is the first PRECISION medicine trial being done in ILD, being led by Fernando Martinez and Emery Noth, and it's based on this paper that I published when I was still in Emery's lab back in 2015 or so. Man, I'm getting old. When you stratify Panther participants, and if you remember, Panther showed that prednisone azathioprine in NAC actually resulted in worse outcomes than placebo. If you stratified those patients out by this genotype in TALUP, those with the CC genotype receiving placebo did better than those receiving NAC. It wasn't statistically significant after you do the relevant adjustments. But suggested to this group, you know, maybe NAC's not a good idea for. Those with the CT genotype, essentially no differences. Those with this TT genotype, interestingly, even after adjustment for the relevant confounders, did have a statistically better outcome when receiving NAC than those who received placebo. And so from these findings, the NH threw a whole lot of money at this trial, which allowed us to not only prospectively test this association, we're nearing full recruitment for this study here soon, but also put a lot of money towards multi-omic endotyping of the pulmonary fibrosis foundation cohort. And I'm going to talk about that in a little bit, too. So there's the PLIANT study. We don't have a primary publication here, but these are the phase 2 data, which have led now to a phase 3 being developed, similar to what we've seen with a few of the other phase 2 trials in that there is nice separation in a very small cohort, which, you know, if it persists in a phase 3, a much larger cohort suggests efficacy. So that's an exciting trial to keep an eye out for. The BMS LPA antagonist is another one. Basically compared to placebo, those who received either this 30 milligram dose or 60 milligram dose had less loss of lung function. I'm sorry, not the 30, but the 60 had less loss of lung function over time compared to placebo. So another exciting trial that's moving towards phase 3. This has all been ILD. There's, of course, other conditions besides ILD, so I'm doing on time here. We have sarcoid-associated pH. The RIO-SIGUAT was recently studied in this pretty small trial, published in CHESS, just essentially showing that in those who received the drug compared to placebo had an improvement in their walk distance, which, again, is the primary endpoint often used in these pH trials. We have a drug whose name I can't even pronounce and won't try that was also tested in sarcoid. Again, small study, but if you squint, you can see there might be some differences in FVC over time here. Phase 2 trials are not meant to show efficacy. They're meant to show safety. And when you see some suggestion of separation in the vital capacity, it certainly justifies moving to phase 3, and so that's the case here. Finally, there is not a trial, but an open-label sort of observational study that was published in NatComms here using tofacitinib in patients with sarcoid, which I thought was really interesting. This was longstanding cases of sarcoid, and so these were patients who had failed numerous regimens, and so they put them on tofacitinib and see how they did, and they did actually notice a reduction after time in some of the PET findings, along with some of the clinical features, including skin involvement, so that was interesting, too. Moving on to the biomarker stuff, so I'm going to talk first about diagnostic biomarkers. This is one where if somebody has a risk factor for a disease, you don't want to biopsy the organ in question, like the pancreas, to know if they have diabetes or something. You do a biomarker to tell you that, like an A1C. So these are how diagnostic biomarkers work. There's a handful out there. I'm just going to identify, I think, the ones that are most interesting right now. So Lita Hariri is doing some awesome work, bronchoscopic-based work called optical coherence tomography, where you put a bronchoscope in, you send this little probe out, and it actually can give you this readout of the architecture of the distal lung, where you can actually see microscopic honeycombing, and it correlates very well with what you see on biopsy, such that you don't actually have to be all that good of a pathologist to see the, or rather a reader of this technology, to see that it correlates quite well with what you see on biopsy. Marlies Wiesenbeck in Rotterdam is doing some pretty cool work as well, using exhaled breath called the ENOS, and using principal component analysis can identify these metabolomic-type profiles that separate IPF from non-IPF, but also can potentially stratify somebody with IPF, somebody with CTD, and then maybe start to parse these patients with IPATH, interstitial pneumonia with autoimmune features who aren't quite IPF, aren't quite CTD. And again, pretty impressive test performance characteristics here, albeit in a small group of patients, but if this and the prior study are validated in larger cohorts, I think it's really exciting for the field. Others are doing this with proteomic work. Chad told us about ILAs. This group out of Reykjavik showed that an eight-protein signature got up to a pretty decent AUC of 0.88 when discriminating a patient with and without ILAs. So as Chad mentioned, perhaps genetic screening in the future, protein-based screening is also something that might be a possibility. When you're pushing an AUC up over 0.9, even if it's a rare condition, it could end up being a pretty decent screening tool. Next, predictive biomarkers. So this is one where you have a disease, you test a biomarker to tell you whether a patient is going to respond to a certain treatment or not. You can think of this as like a non-small cell lung cancer, you get your PD inhibitor or your PD-1 inhibitor, tells you whether to give them a PD-1 antagonist or not. There's not a whole lot of predictive biomarker work being done in ILD, and all the good stuff is actually being done by Dr. Newton here. And so he's looked at a few different studies measuring telomere length and response to therapy. First one published here in the Blue Journal, I talked to you a little bit earlier about the Panther study, where we found some differential survival and outcomes based on this tall-up genotype. Well, he did the same thing with telomere length, finding that those who got this combination therapy didn't really do any worse than those who got placebo. You know, that's pretty much an overlying Kaplan-Meier there. However, if you had a short telomere length, your telomere length was less than 10%, and you got azathioprine and prednisone, you did quite poorly. And so it might not have been a failure of a trial because this drug is harmful to patients with IPF. It might have been a failure of a trial because we were harming patients with short telomeres. And so I think this is a really exciting field. We're obviously not going to go immunosuppressing IPF anytime soon, and so Chad very smartly moved on to non-IPF ILD because we do use a lot of immunosuppressant therapy in this group. This paper was published in the RJ where we pooled patients from a handful of different cohorts around the country, essentially asked the question of immunosuppressant exposed versus non-exposed, and then measured their telomere length to determine whether outcomes were different. This is a forest plot, essentially just giving you a measurement of what their risk of outcome is for immunosuppression versus no immunosuppression stratified by your telomere length. The green there are those who received immunosuppression with a telomere length greater than 10%. So that's what we consider a relatively normal telomere length. And so in that case, there wasn't really a whole lot of harm. However, if you had short telomeres like we were seeing in IPF, Chad showed that those patients did quite poorly. It has a ratio of five if you received immunosuppression and your telomere length was low. So getting to Chad's comment about actionable genetics work earlier, I think this area is approaching prime time. Same sort of findings were in the replication cohort and then when moving on to meta-analysis. I think I'm running out of time, so I'm going to wrap up with prognostic biomarkers. So in this case, you have a disease. You measure your biomarker in hopes of reliably predicting who's going to have a bad outcome versus a favorable outcome. My group has done a fair amount of work in this area. My former fellow, Willis Bowman, published this paper in Lancet Respiratory Medicine where we did a medium throughput proteomic analysis trying to identify biomarkers that predict near-term progression, either death, 10% FEC decline, or transplant. We identified a handful that did so with statistical significance, those on the right being harmful, those on the left being protective. I'm not going to bore you with the individual biomarkers, but acknowledging that individual biomarkers are probably not going to get the job done. We've been studying individual biomarkers for 20 years, and how many are you ordering in clinic? Me neither. So what we did was we then applied machine learning to try to come up with a composite signature that's going to give enough test performance to actually justify its use, came up with 12 proteins that worked somewhat well, good sensitivity, not so good specificity, but we got to a point where we drove the negative predictive value up to over 90%. So if you had a low-risk signature, the idea is you have a less than 10% risk of progressing over the next year. Now, in IPF, that's not going to make me withhold therapy from a patient. But in someone with connective tissue disease, if I know they have less than 10% chance of progressing, I might feel comfortable holding off on the MMF or whatever immunosuppressant I was going to give. The high-risk signature is basically a wash. You don't know. It's not going to help you. As I said earlier, Precisions has a lot of money put towards multi-omic profiling. And so we've taken this initial medium-throughput signature. We've run thousands of proteins now. We have a 3,000-analyte panel. And we've started pushing these numbers much higher. So we went from 12 proteins up to about 40 proteins now. And as you can see here, all of our measures are in a range that probably, at least for me, but I think for a lot of others too, will actually help you in the clinic. If I know a patient has a less than 10% chance of progression, I'm probably comfortable with holding treatment. If I know they have a greater than 90% chance of progression, I'm sure as hell going to do something about it. So we have this NHLBI proposal, like I said, called PRIME, that's going to hopefully prospectively validate that. We've got other work going on in IPF through this Precisions study that is effectively discriminating over one year how much change in biocapacity we can expect to see in a patient with IPF. Again, it's not going to change what I do for the patient. I'm still going to give them antifibrotic therapy. But you can imagine if you're planning a clinical trial, you'd want to know if a patient was going to have a mean change of 300 mils over one year, a mean change of 100 mils over one year, or a mean change of nothing over one year. You exclude these patients right here, you need half the patients for a clinical trial. So this is, I think, a way forward in clinical trial enrichment. So to summarize, 2023 brought us this idea of PPF and a whole lot of controversy around it. I think 2024 is going to start to begin revising this phenotype, making it more precise and probably a little more useful. 2023 saw a lot of disappointing phase three trials. I'm hoping that 2024 and into 2025 will start to reverse that trend. And then 2023 marked, I think, what is the turning point for biomarker investigation. I think over the next year or two, we're going to start moving towards some clinically implementable biomarkers. So with that, I will thank you and happy to take any questions. Thank you.
Video Summary
In this session, three key topics were discussed in the field of interstitial lung disease (ILD). The first topic focused on the concept of progressive pulmonary fibrosis (PPF). PPF refers to a progressive phenotype of ILD that is similar to idiopathic pulmonary fibrosis (IPF) but can occur in non-IPF ILDs. Different proposed criteria for identifying PPF were discussed, including a consensus statement that defined PPF as worsening symptoms, a decline in lung function (either FVC or DLCO), or radiographic progression. However, there were concerns raised about the lack of strong evidence supporting these criteria, and there have been calls for additional research to validate and refine these criteria.<br /><br />The second topic discussed new therapies under investigation for IPF, PPF, and other diffuse lung diseases. Several phase III trials have failed to demonstrate efficacy, but there are ongoing trials for new agents such as F-Bernat-NIP, inhaled treprostinil, and the PRECISIONS trial for personalized medicine in ILD.<br /><br />The third topic focused on biomarkers in ILD. Diagnostic biomarkers, such as optical coherence tomography, exhaled breath analysis, and proteomic profiling, were discussed as potential tools for diagnosing ILD. Predictive biomarkers, such as telomere length and immunosuppression response, were also discussed as potential indicators of treatment response. Finally, prognostic biomarkers, including proteomic signatures, were discussed as tools for predicting disease progression and guiding treatment decisions.<br /><br />Overall, these discussions highlighted the ongoing research and advancements in the field of ILD, and emphasized the need for further research to validate and refine diagnostic, predictive, and prognostic biomarkers, as well as treatment strategies for ILD patients.
Meta Tag
Category
Diffuse Lung Disease
Session ID
2252
Speaker
Deborah Assayag
Speaker
Chad Newton
Speaker
Justin Oldham
Track
Diffuse Lung Disease
Keywords
interstitial lung disease
progressive pulmonary fibrosis
idiopathic pulmonary fibrosis
non-IPF ILDs
consensus statement
new therapies
phase III trials
biomarkers in ILD
proteomic profiling
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