Welcome to UAB MedCast, a continuing education podcast for medical professionals, providing knowledge that is moving medicine forward. Here's Melanie Cole.

Melanie Cole, MS (Host): Welcome to UAB MedCast. I'm Melanie Cole. And today, we're offering an update on the diagnosis and management of progressive pulmonary fibrosis. Joining me is Dr. Teja Kulkarni. She's a specialist in Pulmonology and Critical Care Medicine, an Associate Professor, and the Director of the Interstitial Lung Disease Program at UAB Medicine.

Dr. Kulkarni, thank you so much for joining us today. So, what had been the thought previously regarding progressive pulmonary fibrosis, PPF? We did a previous podcast on this topic. Tell us a little bit about what's different. Any exciting updates to share?

Teja Kulkarni, MD: thank you, Melanie, for having me today. It is an exciting time in the field for pulmonary fibrosis, and there are some exciting updates to discuss. On our previous podcast, MedCast, we discussed a lot about what is progressive pulmonary fibrosis and how we diagnose PPF. That is the terminology we have been using.

And then, since then, well, we've learned a lot more about PPF and how patients who have PPF behave in terms of their disease progression, how are they similar to or different to idiopathic pulmonary fibrosis, which is the more common type of pulmonary fibrosis that we hear a lot about.

Additionally, there's also excitement about a new therapeutic option to treat patients with progressive pulmonary fibrosis, and that's something we can talk about as well.

Melanie Cole, MS: Well, thank you. It certainly is exciting, as you say. So, why don't we start with some of the gaps or challenges that you still see? As we think of the updates, Dr. Kulkarni, since you've begun practicing medicine and as you were just saying, the understanding of PPF, when we think about that, what are some of the challenges that you still see in management and diagnosis, access to care? What are some of those challenges?

Teja Kulkarni, MD: So, PPF is not a single disease, but it is a behavioral phenotype of fibrotic interstitial lung disease. And so, we have idiopathic pulmonary fibrosis, and then we have the non-IPF interstitial lung diseases. And that can comprise of autoimmune interstitial lung diseases or, SARD ILD as we now call it, those that are related to exposures like hypersensitivity pneumonitis, some smoking-related conditions, and several others that fall into this category, right?

So, the way we think about it is that there is that initial phase where the pathogenesis of each of these types of ILD may vary from exposures to, like, an autoimmune process that triggers this with contribution from aging and genetic predisposition. But as the disease progresses, there is a shared downstream pathway that is very similar to idiopathic pulmonary fibrosis that can activate and sustain this complex interplay that leads to differentiation of what we call myofibroblasts. Now, these are cells that orchestrate the fibrogenesis and change this tissue structure in the lungs. And from this, there's this pro-fibrotic milieu of a feed-forward loop and self-perpetuating fibrosis. And so, understanding that this is not, like, one single disease, but how patients behave and what is the prognosis has been very exciting. And we've learned over time what this means and how, can this be different from idiopathic pulmonary fibrosis.

Melanie Cole, MS: Well, thank you for that. So how has the definition or diagnostic criteria for PPF evolved in recent years. As far as what that means for frontline clinicians? I'd like you to speak about the most important clinical indicators that should prompt providers to suspect PPF rather than stable interstitial lung disease.

Teja Kulkarni, MD: So, progressive pulmonary fibrosis is defined by a combination of lung function symptoms and what we see on a CT scan. So for a formal definition, based on the 2022 guidelines, so clinically, we ask patients if they have worsening symptoms of either dyspnea or cough.

Physiologically, we're looking at their lung function test. So, is there an absolute decline in FVC greater than or equal to 5%? FVC is forced vital capacity or the DLCO, which is diffusion capacity by greater than 10%. And then, we look at their CT scans. Is there increase in fibrotic features such as reticulations, which are now more coarse, traction bronchiectasis, development of honeycomb changes? And if a patient meets two out of the three criteria over a 12-month period, they meet the definition for progressive pulmonary fibrosis.

Melanie Cole, MS: So, what role then for these frontline practitioners does imaging, pulmonary function tests, multidisciplinary discussion, what role does that all play in confirming this progression?

Teja Kulkarni, MD: That's a very important question, and oftentimes we think this is, "Oh, just the pulmonologist's job." But no, it does require a multidisciplinary approach for early diagnosis of PPF in this patient population. Because we know that there are therapeutic options for these patients, it's important to diagnose them early, so that we can halt disease progression.

Once the patient progresses further and further from this point of diagnosis, there's very little we can then do to reverse the fibrotic extent. And so it becomes very important for the pulmonologist to not only look at the pulmonary function tests we're getting in clinic and talking to the patient, but also discussing with the radiologist and talking about their concerns about any potential signs for disease progression and trying to look for these signs of progression on the CT scan.

Now well, visually, it may not always be easy, and that has been one of our biggest challenges perhaps. Especially in a setting where there is not a trained thoracic radiologist, it becomes imperative for the pulmonologist to look through the CT report and the images and actually talk to the radiologist about their concerns.

Now, there have been several advances recently in terms of newer technology and AI tools that can help identify or capture these early signs of progression on CT scans. But we're not quite to the place where we can apply it practically in every practice setting. And so, as of today, it is still very important to have this multidisciplinary approach to the diagnosis.

Now, in addition to like all of this in terms of all the ILDs, for patients who have SARD ILD or autoimmune ILD, bringing in the rheumatologist's opinion, becomes really important as well, because they're the physicians managing that underlying autoimmune condition. And oftentimes, the PPF, while it can be the this fibrotic milieu, it can be also the autoimmune condition that is not well controlled on current therapies, and the approach to management needs to be in combination.

The diagnosis is done in combination with rheumatologist because clues that the rheumatologist can give you, "Well, their joint pain is not well controlled," or " I do see increased swelling in their joints, or the skin rash is getting worse," can give you a clue that it's actually the underlying disease that is also getting worse And we have to target that in addition to thinking about what we do to with the fibrosis.

Melanie Cole, MS: Along those lines then, Dr. Kulkarni, let's talk about treatment guidelines and approaches for managing PPF. Are there any updates that you can provide? Are there any new medications or therapeutic strategies that have emerged recently?

Teja Kulkarni, MD: Absolutely, yes. Now, the latest guidelines were published in 2022. And at that time, there was only one medication that was approved for the treatment of progressive pulmonary fibrosis. Only one antifibrotic therapy, which was nintedanib, which is either used as 150 milligrams twice daily oral, or you could reduce the dose to 100 milligrams twice daily.

The other antifibrotic therapy, pirfenidone, was evaluated. But unfortunately, due to challenges with the clinical trial design, it wasn't approved by the FDA for use in progressive pulmonary fibrosis. But there was some recommendation that if if the patient did not tolerate nintedanib, and was continuing to rapidly progress, we could consider pirfenidone as a therapeutic option.

From the antifibrotic perspective, earlier this year, niraparib was approved by the FDA for treatment of patients who have progressive pulmonary fibrosis. Now, the way the trial was designed was for us to see if patients could use this as either monotherapy by itself or in combination with nintedanib or pirfenidone. And the medication performed fairly well in all these categories, although the study wasn't powered to show definitive benefit in each of these categories separately.

Now, in the overall study population, if you consider patients who were either on antifibrotic therapy or not, this study was positive. It did show that niraparib slows down the disease progression in this patient population

Melanie Cole, MS: So with all these updates you're discussing here today as we think of those anti-fibrotic therapies and treatment strategies and even the changes to the diagnostic criteria, what have you seen, Dr. Kulkarni, as far as outcomes?

Teja Kulkarni, MD: In terms of outcomes, you know, what we do know is that idiopathic pulmonary fibrosis confers the worst prognosis. And when patients who have other types of ILD and start to meet the criteria for progressive pulmonary fibrosis, now their outcomes sort of start to parallel that what we see with idiopathic pulmonary fibrosis.

But the advantage of what we have now that we did not have 10 years ago was that we know a lot more about this disease, and we do have treatment options. So, if identified early and treated with anti-fibrotic therapies, there is a potential to slow down that disease progression. And although the data weren't statistically significant, there was a trend towards potentially reducing time to acute exacerbations as well as death

Melanie Cole, MS: And in what ways do you anticipate the landscape and disease management evolving in the coming years? Give us a little blueprint for research, what you see happening, what you hope will happen.

Teja Kulkarni, MD: Well, I'll start with what I hope will happen, is that we can actually tell our patients that we're not just slowing down your disease progression, we can maybe even stabilize a disease completely, or even maybe get to the point where we may be able to say that we can reverse some of that fibrosis. We're not quite there yet, but that would be my hope.

In terms of what else is happening, there are other clinical trials that are ongoing currently as well, which are looking at other therapeutic modalities. And targets for patients with progressive pulmonary fibrosis. There are two medications in phase III. One is inhaled treprostinil, which has been approved for treatment of patients who have ILD and concurrent pulmonary hypertension, as well as recent data that supported that inhaled treprostinil can slow down disease progression in patients with idiopathic pulmonary fibrosis, although it's not FDA-approved yet, and we're hoping it will be next year.

And then, there is another phase III trial looking at admilparant, which is an LPA1 antagonist, which is also involved in one of the pathways that worsen disease progression. And we'll have that data sometime early next year as well.

Melanie Cole, MS: So, do you have any final thoughts for other providers and what you would like them to know about the exciting work that you're doing as far as diagnosis and management of progressive pulmonary fibrosis and, you know, any final thoughts for them?

Teja Kulkarni, MD: If there's one key takeaway from this podcast, I'd say don't wait on all the diagnostic certainty to act on progression. If the patient is meeting any of these criteria, act early. Because once the disease progresses, we have lost that time. So, time lost is lung lost. And so, the focus should be yes on diagnosing early and then discussing potential therapeutic options with your patient and starting therapy early.

Melanie Cole, MS: That's great information, great advice. Thank you so much, Doctor, for joining us today. And for more information, you can always visit our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. I'm Melanie Cole.