Melanie Cole, MS (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And today, we're offering updates on diagnosis and treatment of interstitial lung disease and PH-ILD. Joining me is Dr. Jared Freitas. He's an Assistant Professor in the Division of Pulmonary, Critical Care, and Sleep Medicine at the University of Florida College of Medicine.

Dr. Freitas, thank you so much for joining us today. So, what are some of the most significant updates or advancements in our understanding as we think of interstitial lung disease and pulmonary hypertension interstitial lung disease? Since you've begun practicing medicine, Dr. Freitas, what do we know now that we didn't know, say, 10 or even 15 years ago?

Dr. Jared Freitas: First off, thank you so much for having me on. This is a pleasure, I'm glad that I can come on and talk to everyone about things that I'm pretty passionate about. So, to begin, because you asked a very excellent question, but that takes some unpacking. I think it's always helpful whenever we're talking about what's new to talk about what the paradigm has been up to this point.

The field of, like, interstitial lung disease has progressed significantly since I've even been in medicine. For the longest time, we didn't really have any treatments for interstitial lung disease. It's specifically for IPF, which many people think of as the poster child for interstitial lung diseases.

And that changed in 2014 when the FDA approved two anti-fibrotic medicines called nintedanib, which is the brand name Ofev or pirfenidone, which is the brand name, Esbriet. There were some landmark trials at the time that showed that both of these medicines working on different molecules and kind of a general fibrotic pathway were able to slow down the creation of scar tissue or fibrosis in the lung. And that was a huge kind of paradigm shift or game-changer at that time, and that was all the way back in 2014.

Currently, over the last decade or decade and a half, there's been a large push in the field to identify new molecules to both treat IPF as well as other interstitial lung diseases. Because, believe it or not, there are more diseases under the umbrella term ILD other than IPF.

One of them, which was just approved, is called narendomilast, and the brand name for that is Jascayd. We can kind of talk about the details of that trial and what's different.

Melanie Cole, MS: Well, I would like to hear about that. And before we do, for other providers, what are some of the early warning signs of ILD and PH-ILD that patients and general practitioners should not ignore? How can they be picked up sooner in primary care? Because, Dr. Freitas, that is often who sees these patients first.

Dr. Jared Freitas: One of my colleagues is actually working on a project about trying to get better awareness in primary care. So, that we can get earlier referrals, if there's any sort of worry about interstitial lung disease. But the issue with ILD is that the symptoms can be non-specific, especially at first. But it's usually longstanding shortness of breath decreased exercise intolerance, or patients are not able to do as much as they were before.

Sometimes, a dry cough that's been ongoing or a hacking cough that just doesn't seem to go away. And a constellation of those symptoms would prompt a provider to usually get a chest X-ray first. Sometimes, interstitial abnormalities can be picked up on that, but a high-resolution CT scan is the test of choice that would show abnormalities.

Usually, we may be the ones that are ordering that test. But especially, a provider orders one and finds abnormalities, then that should certainly prompt a referral. But definitely, not just ignoring those symptoms or ascribing them to age or obesity is important. Because a lot of times, we get patients who should have been referred sooner. And unfortunately, most of the time, there's already been damage that can't be reversed. And so, we're just working very hard to stave off any further damage.

Melanie Cole, MS: Well, along those lines then, Doctor, tell us about some of the updates in diagnosis today. You mentioned testing. And compared to five or 10 years ago, is there any diagnostic equipment, radiologic intervention, things that excite you right now that have changed?

Dr. Jared Freitas: Yeah. I think the field in general is moving farther and farther away from more invasive modalities and trying to just diagnose patients with labs and radiography alone. So for instance, like in the most recent update to the IPF guidelines, in 2022, the ATS released updates that talked about both progressive pulmonary fibrosis and IPF, and the consensus was to move away from surgical lung biopsy. And if someone is going to pursue a biopsy, if the institution has providers who are proficient in crowd biopsy, that is less invasive, and it doesn't involve a surgery.

It can be done same day as an outpatient procedure in the bronchoscopy suite. It can get biopsies that can be almost equivalent to surgical lung biopsies without the need for an inpatient stay. And then, also, just greater reliance on high-resolution CT scans. And if a pattern is what's called UIP or probable UIP without any other signs or symptoms that suggest an alternative diagnosis, that person likely has IPF, and that precludes patients from getting biopsies that they don't necessarily need.

And then, I think, ongoing research is happening in terms of incorporating xenon MRIs into diagnosing patients with interstitial lung disease. That is an area of ongoing research, and it hasn't been adopted or approved of by the kind of governing societies as a whole. But I think in the next five to 10 years, that's something that's an active area of research that could become a more widely adopted diagnostic modality, when either diagnosing patients with interstitial lung disease or looking for progression, because that's a big thing that we take care of.

Once we diagnose someone, we're constantly seeing them in close follow-up and patients may be having worsening symptoms, but their CT scans or pulmonary function tests may not be sensitive enough to pick that up. So, that could be something in the future that is more widely used to help us actually pick up disease progression so we can make changes in their management before we start seeing some of that evidence of new scar on CT scan, for instance.

Melanie Cole, MS: That's so interesting, and what an exciting time in your field. And Dr. Freitas, as we think of all of the exciting technologies and interventions, for example, when we think of digital monitoring, home spirometry, or even telemedicine, which has come onto the scene, what of these have been shown to improve outcomes or quality of life in ILD and PH-ILD patients? Are there any non-drug interventions that really excite you right now?

Dr. Jared Freitas: For me, what comes to mind is trying to get better access to people for pulmonary rehab. I think that in and of itself is it can really improve someone's quality of life. I think that's a big area that, as a community, we need to work on because a lot of improving quality of life, I'm trying to say.

A lot of our patients, despite the medications that we have that can help alter the course of the disease, a lot of times they don't necessarily improve symptoms. And I find that's one of the biggest ways people actually can feel better is through exercise therapy or pulmonary rehab. And a lot of the research and a lot of excitement is around new medication and drug therapy. But something as simple as trying to get people better access to pulmonary rehab programs, I think, is key because it keeps people engaged and keeps people functional.

A good way of doing that is a lot of telemedicine-based rehab programs. I think that is definitely a modality, especially as our population is aging not a lot of these programs that you can go to in person, and it can be difficult for people to travel. So definitely, leveraging people's access to their smartphone or laptop and helping them try to exercise at home is pretty important.

Melanie Cole, MS: Well, as an exercise physiologist myself, I couldn't agree more with you there.

Dr. Jared Freitas: There you go. That's good.

Melanie Cole, MS: But when we think of the challenges of adherence, right? And getting people to actually engage in these modalities from your clinical experience, when we think of those challenging aspects of managing care, what strategy or models besides things like telemedicine and pulmonary rehab, such as multidisciplinary clinics, have you found most effective?

Dr. Jared Freitas: Therein lies the benefit a larger tertiary or quaternary center specifically like an ILD clinic, that you can get coordination of care with other specialties more easily and we can help treat patients who have systemic diseases of which interstitial lung disease is only a part of.

Here at UF, we have very good collaboration between us in the ILD clinic, our rheumatology colleagues, radiology, pathology, and gastroenterology and dermatology. Because a lot of our patients, for instance, with regards to sarcoid, we have a neurosarcoid specialist and cardiac sarcoid. Sarcoid sometimes can be treated as it's like its own special disease. But my point is that a lot of patients are not affected just in the lungs. For instance, patients with systemic sclerosis, they can have terrible esophageal dysmotility, pulmonary hypertension, interstitial lung disease, terrible skin lesions, Raynaud's.

So, they may need a whole host of doctors and what's nice about being a center that takes care of those patients is that we have personal relationships with those doctors who also manage them. And so, we can reach out to them on behalf of that patient, discuss their case, try to make management decisions, that are going to affect multiple systems.

And so, I think that can help with comprehensive care. That's why sometimes can be helpful for patients to seek out specialty care at a larger center that has all these specialties, because that can kind of group their care so that they don't have to keep seeing subspecialists who are at different institutions, which can create a lot of issues for those people with different people seeing different things.

So, I think in ILD especially, it's definitely a team sport. It's very difficult to just be a solo practitioner. Because a lot of times, the diagnosis is not clear nor the management. And so, we need everyone's help to patients get their best outcome.

Melanie Cole, MS: So along those lines, and it is a comprehensive approach with that multidisciplinary care that you were discussing, speak a little bit about current guidelines and how balancing the use of steroids, immunosuppressive drugs versus the anti-fibrotic therapies that you mentioned in different ILD subtypes. And as you say, it's not a solo practice. And so, there's going to be theories opinions on these. But when we think of connective tissue-related ILD or hypersensitivity pneumonitis, what do you think about the guidelines? How do they suggest balancing the use of these meds?

Dr. Jared Freitas: That's a big part of why our clinic exists and why ILD specialists are there because it's not necessarily straightforward. And so when we talk about ILD, there's roughly, if you think of it as a pie chart, there's five or six main categories.

I think historically people thought that IPF caused the majority of interstitial lung disease. But IPF is represents maybe fifth to a quarter of patients who have ILD. And the other pieces of the pie are made up of sarcoidosis, connective tissue disease, ILD, hypersensitivity pneumonitis, and sort of a grab bag of smoking-related interstitial lung diseases, what we call pneumoconioses, drug-related ILDs, and some of the more rare diagnoses.

And so, our job is twofold. When someone comes to us, they may already come to us with a diagnosis. And it's our job to confirm that was the correct one, and then see if they have had disease progression, how best we can modify or improve that treatment. Or they may come to us as an undifferentiated patient, and we need to make that diagnosis and then initiate treatment. And so, what the guidelines suggest is we need a very comprehensive evaluation, which includes taking a good history and physical. If they've had previous biopsies, obtaining them. So, we can review the slides and have our pathologists review that with us.

Making sure we have a high-resolution CT scan and acquiring previous CT scans to look at disease progression. Looking at their pulmonary function tests. If we feel that their presentation could be related to a connective tissue disease. We get a wide variety of autoimmune serologies, that could help point us in one direction or another for a connective tissue disease ILD.

And then, once we have all this data, we meet together as a multidisciplinary group and present the patients. And we have input from our pulmonologists, radiologists, pathologists, and needed a rheumatologist, and we make a decision as to what we think the diagnosis is and then what our treatment plan is.

It doesn't have a special name. It's just a multidisciplinary discussion, but that's recommended on the guidelines, and there's data out there that suggests we make more accurate diagnoses and patient outcomes are better when that happens. Once that takes place, if we determine the patient has a connective tissue disease-related ILD, that would benefit from immunosuppression, we will go ahead and start patients on that.

However, if we think it's related to smoking-related interstitial lung disease or IPF, immunosuppression wouldn't necessarily help those patients. And specifically in IPF, it could hurt those patients. And then, I know on this podcast before, we've talked about patients with short telomere syndrome.

There's lots of data coming out recently that suggests if your patient does have telomere biology disease, immunosuppression could actually worsen that patient. So, that question of whether or not to start someone on an immunosuppression versus just removing like an antigen that's in their environment or starting them on an anti-fibrotic. It's a question that we face every day, and it is helpful to be seeing a pulmonologist that specializes in interstitial lung diseases because they can have the expertise to help make that nuanced decision.

That's kind of a brief overview of the whole process of what we do. But we don't make those decisions lightly because the medicines aren't easy and can have significant amount of side effects and we need to monitor their labs quite frequently. And so, we need to be careful in which patients we actually start them on.

Melanie Cole, MS: You've given us a lot to think about, and it's really important information. And so, when should lung transplant be considered for ILD or PH-ILD patients? What are realistic expectations, Dr. Freitas? And how early should general practitioners start that conversation or referrals? You've mentioned early referral for better outcome. How early should these conversations take place for referrals to transplant centers?

Dr. Jared Freitas: We have some data to inform us or at least guidelines to inform us on that, both from the transplant societies and from ATS that, you know, any patient that has been diagnosed with IPF should be referred given the nature of the disease that most of the time and progressive and patients will get worse.

And so, it's important to establish care with that patient, while they're still very sick, so that the transplant team can do a comprehensive evaluation evaluating all of their organ systems and then also their social background to make sure that they can appropriately manage a transplanted organ. So, IPF is one of those things.

And then, the other thing is it's someone, who with chronic respiratory failure, like interstitial lung disease that is starting on oxygen or is already, is on oxygen at rest, that's definitely a time to refer. So if you see someone with interstitial lung disease, who is getting worse, that's also a good time to refer.

Because at the end of the day, it's better for your patient to be seeing a transplant pulmonologist and them telling your patient that, "Thanks for coming to see us. You're a little too early. I'm going to send you back to your pulmonologist whoever is managing your care." And then, the opposite of that where it's like, "Well, I wish you would've sent this patient sooner."

So, I think, there are specific diagnoses like IPF. And then, if you have someone who's starting on oxygen or is just rapidly getting worse, those are all good times to send your patient to transplant. But hopefully, if you're seeing an ILD specialist, we're working with that patient to prevent that progression so they don't have to get there. And that's where this new drug, nirendomilast, is entering the fray, which I'd love to talk about.

Melanie Cole, MS: Well, so then why don't you? Because we're going to get ready to wrap up here, and so I'd like you to speak about the most promising areas of current research. And really, how those new drug classes, as you're about to tell us, biomarkers, genetics, regenerative therapies, how close are these to everyday clinical use? And take us from bench to bedside.

Dr. Jared Freitas: The newest drug that we have, so it's been over 10 years since there's been a new therapy for IPF, and that's nirandromolast. It's a PDE4B inhibitor, and it works on both anti-fibrotic and inflammatory pathways. And it was thought initially to be able to kind of in preclinical data that was able to halt lung scarring.

The trial itself did not show that. However, it did show that over 52 weeks. So, a whole year that they studied it, it slowed down progression of fibrotic lung disease by a significant amount similar to the previous drugs that have been improved, Ofev and Esbriet. It offers a new therapy that works in a different way that we can offer patients.

And the cool thing about the way they did this trial was they allowed enrollment of patients already on background therapy. And it showed regardless of whether you were on background therapy, which would be either Ofev or you weren't, the result was significant across the board. So, it slowed down lung scarring. That's important because it offers another therapy for patients who are already on a medication but are continuing to progress. And upfront, it may offer just a third option that we can place patients on. Or if they don't tolerate one of the medicines, we have this third medicine. So, I think it's a huge win for the community. But it's also a reminder that we can't stop here because we still have yet to find a medication that can halt fibrosis.

Another thing I'll say is that the great thing was that they did kind of parallel trials. So, they enrolled and studied the medication both in patients with just IPF as well as patients with progressive pulmonary fibrosis from a whole host of interstitial lung diseases. They found a similar effect in both groups. So, the medication is also approved for progressive pulmonary fibrosis. That's a huge deal. So, we can use it because previously the only drug we could use for patients with progressive pulmonary fibrosis was Ofev. And so, that gives us another option.

And then, with regards to pulmonary hypertension in the setting of interstitial lung disease, we had FDA approval for inhaled treprostinil, which is the brand name Tyvaso a couple years ago. That was also a huge improvement for the community. Because prior to that, there had been a lot of negative trials for oral PH medicines that were either minimally effective or not effective or actually made patients worse.

And so, this was the first medication that we could actually offer and prescribe to patients that could help improve their exercise capacity and six-minute walk distance. And so, the interesting thing about that, which was in the increased trial, was that one of the secondary outcomes that they looked at was their progression on their PFTs of their pulmonary fibrosis.

And for a portion of those patients, they saw that their PFTs either stabilized or slightly got better. And so, that was very hypothesis generating. So, it spurred a whole new group of clinical trials called the TETON trials and that looked at—so they proved that inhaled treprostinil can help patients with PH-ILD, but can it help their ILD in general? Because there's some lab work and preclinical data that shows that treprostinil can work in fibrotic pathways, and could actually help in that scenario. And so, they did three different trial groups. They looked at IPF, PPF and in different parts of the world.

And so, they recently published results from one of those groups looking at IPF and showed that it achieved its primary endpoint, that there is in fact a significant difference for patients using inhaled therapy, that they had almost 100 milliliter reduction in FVC progression on their PFTs over the course of the year. That's exciting. So, that's almost a year's time, we have two new therapies. When the previous 10, we hadn't.

Building on that, I think moving forward, we're going to be using a combination of both, inhaled and oral anti-fibrotic medications, as well as if the disease process warrants it, immunosuppression. And it's going to be a multidisciplinary care with multiple doctors if you have a systemic illness.

And then, a third big thing that's happened is the emergence of awareness of telomere biology disorders and testing for telomere length to help inform our practice. And so, I think that also is going to be you mentioned looking at genetics and whatnot, a thing that may start becoming more commonplace in the next five to 10 years as laboratories keep testing for it.

And we have more data that tells us that's something that we need to do. And so for the future, I think, what's going to be interesting is how we use more of this preclinical data or lab data. And then, seeing if we can use AI or even like machine learning to help us interpret that data to comment both on new drug therapies and then also helping us interpret radiology and picking up changes in CT scans that a human eye can't detect or something like that.

So, I think I'm very hopeful and excited for the field, because there's been a lot of rapid progression in new testing modalities and treatments in the last 10 to 15 years. And I think that there's going to be more good things to come.

Melanie Cole, MS: Thank you so much, Dr. Freitas, for joining us today and sharing your incredible expertise, and I hope you'll join us again as we learn more. So, come on and give us more updates. And thank you so much again for joining us. To learn more about this and other healthcare topics at UF Health Shands Hospital, please visit innovation.ufhealth.org. And to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole.