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Hello, everyone. Today, I will be speaking to you about emerging therapies in pulmonary fibrosis care for 2025. Um, these are my disclosures available to you. And this is our assignment today, our learning objectives, and I'll leave those up for just a second. And what we're gonna do today is we're gonna talk through a case, um, and this is a fairly real-world case for, for a, for a typical patient, um, but the details have been changed. So, first of all, what's wrong with me? So our patient is Mr. Rice. He's a 70-year-old man. Um, he comes to the clinic with at least 2 years of a daily dry cough. Um, his family reports that he's probably been coughing longer than 2 years. Um, he walks daily for exercise, but has noticed that his usual walk is resulting in a bit more shortness of breath than he thinks is normal. And also he notices shortness of breath with, for example, showering in the last year. This has been getting worse. Um, his primary care provider, he brought this to his PCP's attention. He was treated for seasonal allergies, including some nasal steroids. This did not help his symptoms at all. Um, he was subsequently referred to a cardiologist, um, given he has a history of smoking and also high BP. However, workup was negative, including a stress test. Um, he has high BP, as I mentioned. He has, uh, prostate disease. He's a former smoker, 30 pack years, quitting 15 years ago. He worked as an attorney. He's now retired. Um, during the history, he reports no environmental exposure of concern. Specifically, he has no, uh, concerning pets such as birds, birds with feathers, birds in cages in the home, uh, no mold or history of water damage in his home that he's aware of. You review his medications and there's no concerning fibrogenic medications in his history. He has no family history of specifically interstitial lung disease. Um, we do a workup for possible connect. The Tissue Disease Association, um, blood tests are negative and there's nothing on his exam or history suggestive of an underlying connective tissue disorder. The only thing you find on exam is he has some fine crackles in both lung bases, but nothing else really of of note at all. We get, um, pulmonary function testing on the patient. His vital capacity is below normal, 2.73 L or 69% of predicted. He is not obstructed and his diffusion capacity is moderately impaired, 12.61 or 48% of predicted. And we have this representative example of his CT Scan, and we will talk in some detail about the features of the CT Scan shortly, but this is his scan that you see in clinic. So, Let's talk about idiopathic pulmonary fibrosis. Um, idiopathic pulmonary fibrosis is an interstitial lung disease that has, um, both a radiological and or histological pattern of usual interstitial pneumonia or UIP. I'll use the term UIP throughout this presentation. In the absence of a cause, and this means there's no environmental factors that you could ascribe to the ILD, no associated systemic diseases such as connective tissue disease or autoimmune disease that could cause ILD and really no other causes for the ILD. So if you have someone with a UIP pattern either on CT scan or pathology. No cause, you very likely have a diagnosis of idiopathic pulmonary fibrosis. There's some nuance to this that I'm, I'm not gonna get into today, but I'm happy to answer any questions later on about those nuances if anyone has them. Um, there are some risk factors for IPF. Um, older age is a risk factor. Men tend to be affected more than women, and actually a smoking history, um, is more commonly associated with, um, IPF. Cause and effect is a little bit difficult to determine, but there certainly is at least an association there. The incidence is, is rising and certainly depends on which country you're studying, anywhere from 1 to 13 cases of IPF per 100,000 persons and the highest prevalence is in Korea, the United States, and Canada. This could be ascribed to just better reporting in those countries, but at least that's where you'll see the most um prevalence. Um, on the right, you'll see a graph that describes um IPF. Most of us understand that IPF is a progressive lung disease. However, the rate of that progression is incredibly variable. No one patient behaves the same. You may have patients that progress slowly over time. You may have patients that progress more rapidly or even Uh, declining within a few years. There are some people who do well for a long time, but they may have these bouts of exacerbations that result in rapid worsening of their lung disease. And what we do know about the exacerbation phenomenon that should a patient recover, they may continue to progress either at their prior rate or a faster rate, but they typically never recover the lung function loss during the exacerbation. Um, we'll talk a lot today about the different mechanisms of the fibrosis process, but in simplest terms, it's the result of an alveolar epithelial cell injury of unknown cause in IPF that results in aberrant healing of the injury. This aberrant healing results in progressive fibrosis that often is irreversible, especially in the case of idiopathic pulmonary fibrosis. So, the concept is injury. Healing is done poorly, leading to fibrosis. Um, this is just an example of, of the, um, the myriad mechanisms of fibrosing ILDs, and I think, as I said before, the commonality is there's some inciting damage. In IPF, that damage is, um, of unknown cause. However, the damage could be from other factors if you have an ILD of known cause. For example, chronic. Inflammation from an exposure in your environment, the autoimmunity that we see in connective tissue diseases resulting in epithelial cell activation damage, and this process may result in normal healing, as you'll see there. In fact, that probably happens most of the time. Most of us don't, aren't aware that we are undergoing alveolar epithelial cell damage because the lungs heal normally, but For reasons unknown, there certainly is some susceptibility, as you can see they're on the right hand of the slide. Some patients heal aberrantly. There's multiple cytokines and fibrotic signaling mechanisms that lead to this process. IL4, IL-13 are some of the implications. Um, in the, uh, implicated cell signaling mechanisms that lead to activation of TGF beta1, PDGF, and we end up getting migration and proliferation of fibroblasts into, um, this extracellular matrix that can, uh, that has a differentiation of the fibroblasts into myofibroblasts laying down a fibrosis that again progresses over time. Um, the, the way I like to explain this to Uh, both, um, providers that I'm, uh, educating or even patients is that Um, it's like the process is like, um, hitting a row of dominoes that progress once you Um, hit the first domino down, things start to fall in a lot of different pathways and you have them lined up a certain way, and you may stop the falling of dominoes in one row, but it tends to progress down the other rows. So once this process starts, it's very difficult to reverse it. And the reason for that is that there's so many different pathways that the fibrosis can occur down. It's hard to stop it with just one intervention along one of those pathways. Some of the risk factors for patients to heal apparently cigarette smoking, as I mentioned before, we know that some patients have mutations in the telomere genes that predispose them to early fibrosis and progressive fibrosis, and there is at least one promoter variant in the MUC5B gene that we can see here that we know that that also predisposes patients to having more fibrosis than someone without that mutation. Um, it's really incumbent upon us as providers to determine what type of ILD the patient has. Um, it's very common in our practice for us to think of all fibrosing interstitial lung diseases as being IPF. And as you can see from this slide, this simply is not true. There are innumerable types of interstitial lung disease and one of the first duties we have as providers is determining where they fall along this pathway. I think that a very simple way to think about this is that you ILDs of known cause and ILDs of unknown cause or idiopathic interstitial lung disease. There are some rare lung disease diseases you can see they're on the rise, granulomatous ILDs, and then this other category that includes some rare lung diseases that I won't talk about today. But if you look down the pathway of idiopathic interstitial lung diseases, you'll see there's really 6 major phenotypes there. There's smoking-related ILD, there's acute ILD, and then there's the fibrosing ILDs which include IPF. Um, when we see a patient for the first time, the most important thing that we do is take a detailed history. We can very often determine the type of ILD the patient has just from taking the story. So these are the things that we have to ask our patients, uh, at that first visit. Describe their symptoms. Um, do they have shortness of breath or cough? Dry cough is typical but not universal. We have plenty of patients that have productive cough and that's just the flavor of their disease. Uh, the timing of the symptoms, is their symptoms. Um, of onset over a few days or is it weeks to months. An IPF history typically is more insidious in terms of these symptoms occurring over weeks to months. We want to take a detailed occupational and environmental history. This gets at exposures, the things that we're exposed to that typically lead to a fibrosing ILD are occur in places where we spend most of our time, and that's work and home. So you want to really get a good idea of what the job environment is like.