Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome
Unmet Needs And New Developments In ILD Treatment - AJMC
The panel participants relay unmet needs they have found when treating ILD, and discuss promising therapy developments that could improve the treatment landscape.
Ryan Haumschild, PharmD, MS, MBA: I want to talk about emerging therapies and what's that unmet need that still exists? We've heard you discuss this a little bit earlier, but I want to think about, what are some of the unmet needs that we need to identify in the treatment of interstitial lung disease? Dr Highland, I'm going to look to you first to tell us, where do we need to go, what is that unmet need, and how do we get there?
Kristin Highland, MD: Thank you. There's a couple unmet needs. Number 1 is we have great studies in IPF [idiopathic pulmonary fibrosis] and we have great studies in scleroderma, but there are a whole lot of other interstitial lung diseases that we don't have great studies in. We probably will never have great studies in [them] because they're less common and they're more heterogeneous and more difficult to study. We certainly need help with knowing how to treat those patients. We have shown that we can lump patients together in studies like INBUILD and so that's encouraging. We need to have the flexibility to apply the data we've learned from one disease and apply that to the biological nature of another interstitial lung disease. We have to be able to translate therapies to those other diseases. I think a big need, though, is precision medicine. We need biomarkers. We need to know which patient is going to respond best to which therapy. I screen patients for interstitial lung disease with scleroderma and not all of those patients are going to progress. If you take the patient with rheumatoid arthritis and do a CT [computed tomography] scan on them, you'll find evidence of interstitial lung disease in more than 80% of those patients. Dr Culver talked about these interstitial lung disease abnormalities, these little bits of abnormalities that we're not sure are going to progress into full interstitial lung disease. We need to be able to figure out which patient is going to progress, and which patient is not. We have disease trajectories, not only in IPF but also in scleroderma, in rheumatoid arthritis, and myositis, where we have our slow progressors and our steep progressors. Although we know some risk factors for progression, there are a lot of patients that we don't know who's going to progress, and who's not going to progress, without time. I would say, better biomarkers and a better precision medicine approach to taking care of our patients is a true unmet need.
Ryan Haumschild, PharmD, MS, MBA: Our colleagues in lung cancer, when I think of non-small cell lung cancer, have so much precision medicine targets of small molecules and large molecules. It's totally changed the treatment landscape, as you mentioned, Dr Highland. I think, too, that's what payers are almost looking for as well. As we start to look at these combination therapies and these high-cost medications, how can we identify patients that would best respond or might be early progressors? It's even part of diversity equity inclusion. Creating better treatment pathways, more frontline treatment with patients that might be underserved or might have some genetic abnormality that leads them to progressing further and requiring a transplant. I think that's really, from a managed care perspective, just like you said, from a diagnosis, I think that plays in the economic outcome because you want to provide the best value, even if it costs a lot of dollars, to those patients that need it the most and how do we identify them? Hopefully in the future, as precision medicine grows, we can steal some of that precision medicine trending and bring it into interstitial lung disease. I think it would really change the way we're approaching treatment for so many patients and get them access to therapy sooner. With that, I do want to turn it over to Dr Noble because we brought up some of his thoughts early on about where he sees treatment in the current state, but I'm curious, what do you think are the most promising developments on the horizon with all the patients that we've spoken about, whether it's screening, diagnosis like precision medicine therapy, or just overall treatment?
Paul Noble, MD: I don't want to throw water on what's been an exciting conversation, but I have been a little bit discouraged over the last couple years. Now, granted, I'm not as involved as I was with pirfenidone and nintedanib in the early stages, but most of the conversations I've had in the clinical trials we're involved with are either trying to come up with a better-tolerated pirfenidone or inhaled pirfenidone or other drugs that will slow the loss of lung function, but not have the tolerability issues. There isn't anything that I'm aware of right now that's really looking at a promising approach to making people better. The reason I think that's the case for IPF is– and I will use the CF [cystic fibrosis] analogy because the drugs for CF target the underlying disease mechanism–one of the things we know about IPF is that the alveolar type 2 cells are just not normal. They don't regenerate properly. The antifibrotics, they make it harder for fibroblast to make collagen, which is important, but it doesn't treat the underlying cause. Until we get some therapeutic approaches that look at rejuvenating these alveolar type 2 cells, I don't think that we're going to see FVCs [forced vital capacity] go up. I don't want to diminish the importance of having better-tolerated drugs, because at least I'd be curious with Kristin and Dan, but in my practice, which is exclusively fibrotic lung diseases, IPF patients, I would say maybe two-thirds are on after a year. They really struggle with tolerating the drugs. If we did have drugs that people would stay on for 5 years I do think it would translate into improved outcomes. There's the one [INAUDIBLE] has a drug that targets one of the integrins, which is how TGF-β [transforming growth factor] gets activated. Now 2 others failed; Biogen [INC. Cambridge, MA] failed, and there was another small molecule company for toxicity. We'll see [how they do], they're in phase 2. I'm sure you guys are participating as well. I am on that scientific advisory board, with some optimism. But I'd like to see more bolder approaches to how we [treat]. If we don't see somebody get an FVC tick up in 6 months, move on to the next drug. Maybe it's because I'm getting a little bit more senior and before I hang up my cleats, I really want to see people breathe better, walk further, and live longer. Where I trained the adage was we just need to diagnose it early and prevent progression because we're never going to get people better. I don't want to believe that.
Ryan Haumschild, PharmD, MS, MBA: It's a bold comment, but I like it because you're challenging us to get better. You like bold, I know Dr Culver likes boring, visits that is, and as he talks about seeing better performance where he gets to talk about life with his patients, I think that is exciting.Dr Culver, from your perspective, what do you think is promising, on the horizon here for the treatment of interstitial lung disease?
Daniel Culver, DO: Thank you. I think that I agree with everything that's been said. There are really 3 buckets in my mind. One of them is doing what we're doing but doing it better. That's less toxic versions of the medicines that we have, targeting similar mechanisms perhaps. The second thing I think is more analogous to how we manage heart failure, which is probably another disease that we really don't get to the underlying pathophysiologic issue. When you look at the mechanisms of IPF, it's complex, it's multifactorial, there's issues with alveolar epithelial cell senescence, there's issues with myofibroblast activation and proliferation and there's issues with the lung mechanics as well. So, it's a feed-forward mechanism that has multiple exit and entry ramps, and that feeds back on itself. It may be that interdicting 1 particular spot in this is not enough and that we have to really take this as a multifaceted approach and tamp it down in several different areas to really have effect. I think cancer is a good analogy. I suppose heart failure is another analogy. Paul is right, that doesn't fix the underlying problem. I think we should aspire to the third bucket, which is, let's get those cells back to how they should be. Let's get that basement membrane restored and do lung regeneration. That should be the ultimate goal, but until we get to there, I think we need to think about being very open to multimodal therapy and not thinking that in a complex pathophysiologic network that targeting 1 particular molecule or 1 particular mechanism is going to be enough for our patients. I don't think it is. I'll make 1 more comment of something that was said earlier, which is related to the payers and how we access these approaches. And I'll point out that there are other places that do it differently than the United States. There are some data suggesting some outcome differences between Canada and the United States. One of the things that I think is important that happens in some of these other places is that patients with these diseases are channeled into expert centers, into reference centers, into centers of excellence. I do think that it would be attractive and appropriate to have some places where there's a little easier access to therapies and diagnostics. That's based on experience; there's evidence for that. I think that would get patient care better, would drive down costs, and it would really allow patients to have the best possible outcomes.
Ryan Haumschild, PharmD, MS, MBA: Payers have to work towards having good tolerability and adherence, because if something performs great in a clinical trial but it doesn't translate to real-world evidence then we're back at ground zero.
This transcript has been edited for clarity.
New Guidelines For Managing Interstitial Lung Disease Associated With Connective Tissue Diseases
EULAR - The European Alliance of Associations for Rheumatology - has worked with the European Respiratory Society (ERS) to develop new clinical practice guidelines for interstitial lung disease (ILD) associated with connective tissue diseases (CTD). Such collaboration between pulmonology and rheumatology societies is key to optimise patient management and improve outcomes across Europe.
CTD is a diverse group of disorders that includes systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), Sjögren disease (SjD), systemic lupus erythematosus (SLE) and mixed CTD (MCTD). Rheumatoid arthritis (RA) was also included in this new work. But despite differences in the underlying diseases, ILD is a frequent manifestation across them - and is associated with high morbidity and mortality.
Clinical practice guidelines would help to standardize screening, diagnosis, treatment, and follow-up for patients with CTD-ILD. To address this gap, EULAR and the ERS formed a task force - including pulmonologists and rheumatologists, plus colleagues from radiology and histopathology and patient representatives. A literature review was performed, and the collected evidence used to formulate recommendations.
The group answered 5 PICO (Patients, Intervention, Comparison, Outcomes) and 10 narrative questions (NQ), resulting in 50 disease-specific recommendations across screening, diagnosis, monitoring, and treatment for patients with CTD-ILD or RA-ILD.
Two simultaneous publications - in the September 2025 issue of the European Respiratory Journal and Annals of Rheumatic Diseases - also include a series of specific ILD management algorithms for each of the underlying rheumatic diseases, which have been developed based on the recommendations and usual clinical practice.
In short, the clinical practice guidelines recommend screening all patients with SSc, MCTD, and IIM (but not people with inclusion body myositis); and patients with RA and SjD who have risk factors for ILD at the time of their CTD diagnosis. The recommended tool is high-resolution computed tomography or HRCT. Lung biopsy does not play a role in identifying CTD-ILD but might be considered in a multi-disciplinary team discussion if alternative diagnoses are possible. Furthermore, at the time of ILD diagnosis, all patients should be assessed for disease severity, risk of progression, and functional ability. Clinical risk factors can be used to identify people at high or low risk of progression, as well as lung function tests, HRCT scans, 6-minute walking test, and patient-reported outcome measures - which can capture insights about a person's respiratory symptoms and their impact on daily life. A comprehensive evaluation for all CTD-ILD patients at each visit is suggested to assess their risk for poor prognosis and disease progression, with high-risk patients monitored more frequently with lung function tests, HRCT, and patient-reported outcome measures. People at lower risk should undergo the same assessments but at extended intervals.
With regards treatment, choice of therapy should consider patient-specific risk factors, as well as each person's extrapulmonary organ manifestations, potential side effects, and the risk of progressive or severe ILD. Early and/or aggressive treatment is recommended for those at risk of progressive or severe ILD, especially people with multiple risk factors or specific indicators.
Professor Anna-Maria Hoffmann-Vold - corresponding author on the paper, Head of the Inflammatory and Fibrotic Rheumatic Disease Research Area at Oslo University Hospital, and lead of translational research at University Hospital Zurich/Zurich University, said: "The new ERS/EULAR guidelines for CTD-ILD are important because they offer standardised, evidence-based recommendations for patient management, supporting the identification of high-risk individuals and enhancing outcomes. The strong collaboration between EULAR and the ERS has played a crucial role in this development, addressing both the rheumatological and pulmonary aspects of these complex conditions, which ultimately benefits our patients."
The task force recognises that the new guideline has some limitations. The work builds mostly on evidence of low certainty. This is a common challenge for rare diseases and means that most recommendations in the new work are conditional; this gap also reinforces the importance of the ongoing research agenda. However, the guideline still provides comprehensive support for clinicians and patients with CTD-ILD - and crucially many pre-defined management areas are addressed specifically for the underlying rheumatic disease, which is important due to some of the inherent differences between diseases.
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Utilizing Pirfenidone In ILD Treatment Strategy
Dr Noble discusses recent ATS guidelines regarding the use of pirfenidone in ILD.
Paul Noble, MD: Nintedanib was able to achieve FDA approval doing the same conceptual study for every patient group, by measuring the rate of decline in forced vital capacity [FVC] over 1 year. If you look at the totality of the data for pirfenidone for the approval of IPF [idiopathic pulmonary fibrosis], it's very similar if not stronger than the nintedanib data in some ways. The working hypothesis was that these drugs would probably have a similar impact on other diseases where there's progressive fibrosis. But the pirfenidone trials didn't work out as cleanly as the nintedanib trials, so it isn't a proved scientific benefit that there's a clear-cut impact on FVC in these other categories in addition to idiopathic pulmonary fibrosis. That's why the ATS [American Thoracic Society] recommended additional studies.
There are some variations of pirfenidone being developed: an inhaled form as well as a modified form that might have a longer half-life. Because pirfenidone is generic now, there aren't going to be any industry-sponsored trials looking to see whether pirfenidone is beneficial in other fibrotic lung diseases. From a functional standpoint, most clinicians see these medications as having a similar overall impact.
One interesting aspect of pirfenidone is the additional research opportunities. As I mentioned, pirfenidone is generic, so there isn't going to be a pharmaceutical company championing that. However, there are some newer approaches with pirfenidone that could be interesting. One of the holy grails and unanswered questions in fibrotic lung disease is whether an inhaled approach can be developed. Could you breathe in through an inhaler once or twice a day? Because the hallmark of idiopathic pulmonary fibrosis and the other fibrotic lung diseases is they affect only the lungs. In other autoimmune diseases, rheumatoid arthritis affects the joint, and scleroderma [affects] the skin and other organs. But could the lung be targeted directly? This is an unknown question. But there's a company that has an inhaled form of pirfenidone.
One other issue with both pirfenidone and nintedanib is that both medications have significant tolerability issues. A number of patients are unable to tolerate this medication for prolonged periods of time. Because these medications don't treat the underlying disease, the concept is that you need to take them for life. If there's a better-tolerated medication that has similar efficacy, that could be of value to patients.
In addition to the inhaled form of pirfenidone, there's also a chemically modified form that has a longer half-life. Some of the thinking on pirfenidone is that it isn't a very strong molecule. If a pirfenidone was developed with greater strength, would it potentially give equal or more efficacy? Could these chemically modified forms potentially have a better safety and tolerability profile? It will be interesting over the next few years to see whether these studies are able to be completed and what we can learn about the next generation of pirfenidone therapies.
Transcript edited for clarity.
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