Rheum + Pulm Collaborations in ILD Save

Hello, my name is Paul Della Ripa.

I'm Rachel Putman.

And we are here today to talk about interstitial lung disease and the title of our talk is the rheumatologist and the pulmonologist and ILD, different approaches to the same patient. As an introduction, ILD associated with connective tissue diseases can have a mortality that can rival idiopathic pulmonary fibrosis. Risk factors for ILD in different connective tissue diseases are identifiable. Inflammatory disease can be treated with anti inflammatory agents and data suggests that fibrotic disease may be amenable to treatments employed in IPF. Early identification of those at risk for ILD and frequent monitoring is important to assess for progression of disease and an opportunity for treatment, clinical trials and if needed lung transplantation.

So here are the clinical scenarios from my perspective as a rheumatologist that I would encounter in practice. I meet a patient with connective tissue disease and I'm wondering, do they have ILD or are they at a higher risk for it? The second scenario would be that we have a patient with known ILD, known connective tissue disease on immunosuppression with newly discovered and progressive interstitial lung disease. What do I do? And the third scenario is the patient presents with interstitial lung disease and are referred by a pulmonologist And the question they're asking is, does this patient have an underlying connective tissue disease?

So these are the connective tissue diseases we all know that we deal with associated with interstitial lung disease. By far the top three are rheumatoid arthritis, mostly a UIP pattern, scleroderma, which is typically an NSIP pattern, typically fibrotic, the disease is most prominent or occurs in the first four years and inflammatory myositis, which is a more inflammatory disease, typically NSIP or organizing pneumonia with special consideration for MDA-five which can present with a rapidly progressive course. But all of the diseases that we deal with by and large can result in interstitial lung disease, but we'll focus our discussion. So the rheumatologist view of the lung is I know that many of my patients will be at some sort of risk for ILD. What kind of risk assessment can I do on the first visit to determine who needs to be screened for ILD upfront?

What about patients sent to me by pulmonary with findings suggestive of inflammatory disease? How do I approach that? And I now understand that a thorough cardiopulmonary assessment is important in the care of patients with rheumatic diseases as these are the leading causes of morbidity and mortality in this group of patients. However, there are several guidelines on screening and treatment, so this makes my decision making more challenging. And this slide is just a few of the recommendations and guidelines and other, suggestions about how we deal with patients with connective tissue disease ILD.

So what I'm trying to say is that this field is in flux, recommendations are available and I think they sometimes present a challenge, when we're being asked to do something that we weren't doing before, and that's where we are right now. So the key points for the rheumatologist regarding screening is that screening will be primarily the responsibility of the rheumatologist and unless you're in a specialized ILD center or clinic, the rheumatologist is going to be the one who has to think about that and then decide about whether to order a high resolution CT scan based on risk factors and this will require starting with repeated and detailed questions on issues of cough, chest pain, dyspnea, and a careful lung examination and then these types of findings, any positive findings will trigger additional testing and or pulmonary consultation. Ambulatory oximetry, while not sensitive or specific and not recommended in ACR guidelines is however a non invasive tool in the office at point of care that is both feasible and can accelerate the diagnostic process. Other measures such as risk calculators, biomarkers and we believe soon lung ultrasound will hopefully make this process more streamlined involving less radiation and cost effective.

So key points regarding treatment considerations do not delay treatment for progressive or clearly inflammatory lung disease. Remember inflammatory lung disease left untreated can remodel and turn to fibrosis. Seek early pulmonary consultation when there's any questions and then decisions on the use of fibrotic are still in flux, but generally speaking are offered when there is predominantly or significant fibrosis where there appears to be progression based on decline in PFTs or worsening high res CT findings or clinical features otherwise, not explainable, but I'll leave this to Doctor. Putman to describe in more detail. So collaboration and consultation are the key.

Collegial colleagues in pulmonary, collegial colleagues in radiology and in pathology, and a reliable PFT lab are the things that you need, to be better at this. And with that, I will turn it over to my esteemed colleague.

All right, so we're transition a little bit. We're going to change to talking about my pulmonologist view of the lung and ILD. So when I see patients in clinic, my mindset is often to try and sort of understand the etiology of it and understanding when I'm looking at the CAT scan sort of whether the lung disease is primarily inflammatory or That helps me not only with determining diagnosis, but really trying to think about how I'm putting the which sort of treatment pathway I'm moving them down. When I think about sort of general diagnostic categories, the sort of a lot of the big three would be idiopathic pulmonary fibrosis, connective tissue disease associated ILD, and then hypersensitivity pneumonitis. We also see a good amount of drug induced or other very specific exposure induced ILD, and then sarcoidosis as well, which again, as doctor Del Repa said, has its own set of very specific presentations.

And then my assessment of whether connective tissue disease exists or if it exists isn't the culprit involves a series of questions examining the patient and this is something where partnering with a rheumatologist has been incredibly helpful for me. I've been able to really improve my examination skills and feel a lot more confident in my ability to pick up these patients even when I'm seeing them without a rheumatologist. And then ordering the appropriate serology is to help try and uncover whether there's an underlying connective tissue disease. We talk about using the high resolution CAT scan as a guide to prognosis and really what I'm thinking about sort of inflammatory versus fibrotic, we have three examples here that are sort of across the spectrum of disease. So looking here at the panel all the way to the left, we have a predominant a UIP pattern, so a usual interstitial pneumonia pattern, which is primarily seen in patients with idiopathic pulmonary fibrosis.

But of those that fall have a connective tissue disease, about sixty percent of people with RA associated ILD will have a UIP pattern. It's also sometimes seen in ANCA vasculitis and it's classically seen I've sort of defined as having honeycombing, so these rows of stacking cysts at the bases of the lungs. And this is a primarily fibrotic disease that would be treated with anti fibrotics. We can get into a little bit of some of the controversies around treatments with anti inflammatories in some of those patients. And here in the middle, have an example of what would be a primarily inflammatory CT scan.

So here we have areas of consolidation around the bronchovascular your bundles here around the airways and the sub and the subpleural areas. And then there's areas of ground glass surrounding, and this would be sort of most consistent with an organizing pneumonia type of pattern, a very inflammatory disease. We see this most commonly in antisynthetase syndrome. And then all the way here on the right, here is primarily reticular changes, a little bit of surrounding ground glass, mostly consistent with the on the fibrotic spectrum of NSIP. And this I would say we most classically see in scleroderma patients parsysmosis sclerosis associated ILD.

And when we think about these things, think about whether how we can impact the inflammation that exists to help prevent remodeling and the development of ultimate fibrosis over time. So when I think about my skills at screening for a rheumatic disease, they have definitely varied and I hope improved over time, but I would say are definitely varied amongst many of my colleagues. They're based on your own skill set, people's experience, and also interest. It has to be something that as a pulmonologist you are interested in and wanna gain that skill set. There are some colleagues will rely exclusively on labs to rule out a connective tissue disease, but that can be really problematic because if you're testing for diseases that there's no clinical phenotype for you can get false positives and it can be difficult to know what to do with those tests.

Also as everyone in the audience here knows there's also patients that have zero negative diseases and so then you can sort of write something off that is present if you're only relying on serologies to make this test, make these diagnoses. But you should have a really low threshold than I do in patients with a possible connective tissue disease and ILD to consult with a dedicated and interested rheumatologist. And as Doctor. Della says, let's get Rheum on board here for this. And I would also say the interested rheumatologist is a really important part of this because I do think this is a sort of special subset of people in rheumatology.

And people are really interested and we can work well together, we are able to provide such better care for these really complex patients. And then we often end up with these ambiguous cases where they have ILD, maybe some serologies or maybe some symptoms but not enough to clearly make a diagnosis. We often will sort of lump people into the idiopathic pneumonias with autoimmune features which is sort of a research diagnosis but puts us into a little bit more of a probably inflammatory category but bears sort of further monitoring I think more than anything else. And then I think as we both think about this, questions that I ask before I'm considering treatment. So if I have someone who has known connective tissue disease, for example RA, is it clear their connective tissue disease is being adequately treated?

So are their joints really well controlled on their current medication or are they having sort of active joint flares on top of it? And then if they are, then that may lead me to have a different conversation with rheumatologists about should we change medications altogether and think about something that might treat lungs and joints. Or in patients that are incredibly stable and very happy who've gone through multiple medications and now are doing really well on something is it an add that I want to do for their lungs and that really requires me and a conversation with a rheumatologist to really be able to make that assessment and that's where working together is invaluable in taking care of these patients. I do think it's important as pulmonologists to get a bit comfortable with assessing disease activity in these patients and not just referring them back to the rheumatologist to help us figure this out because sometimes depending on availability, travel for patients, that can take some time and you could be missing treating patients with active disease. So they have obvious involved joints, do they have labs relevant inflammatory markers, active skin or muscle disease, and this is where working closely with your rheumatologist can be helpful.

And then as I'm sure you guys are all aware, the being wary of esophageal dysfunction and aspiration, particularly in our systemic sclerosis patients can really complicate ILD. And sometimes what we're it's gonna be difficult to determine early on whether what we're seeing is all sort of the consequence of recurrent aspiration or whether it's truly an ILD or whether it's an ILD that's being worsened by this. So making sure we're staying on top of those things, looking at the medical management, sometimes surgical management, those things can be really important. And then finally, think one of my biggest roles when I'm seeing these patients in clinic is what are the triggers to refer these patients for a lung transplant evaluation? Often they're younger patients that have complicated medical histories and are on multiple medications and sometimes it requires earlier referral because they can be difficult to transplant given sort of lots of other comorbidities and there can be certain only certain centers that are comfortable.

And so this is the type of thing that a specialized pulmonologist can really help figure out what the right timing for those referrals are. And then Paul, I don't know if you wanna talk a little bit about this or I

You can go ahead.

Yeah. So I think this is one that is, and I think in our group, we go back and forth about this quite a bit, but there's a little bit of a controversy about thinking about how immune suppression can impact pulmonary function trajectory in patients, particularly thinking about those with RAILD. So there are some data looking at a couple 100 patients that were included in this analysis looking at patients with RAILD. There were about ninety patients on azathioprine, forty three percent on azathioprine, thirty six percent on mycophenolate, and twenty percent on rituximab. And they looked at the analysis of how patients did who were on immunosuppressive therapy versus not.

What they found was that there was an improvement in the forced vital capacity percent predicted after twelve months of treatment with one of these agents, and that was about a four percent predicted improvement. Now statistically significant, think we can go back and forth about the clinical significance of this, but we don't have a lot of things in interstitial lung disease necessarily that results in an improved trajectory in lung function. So the question is in these patients with RA ILD should they all be on background immune suppressive therapy even if they have sort of primarily fibrotic interstitial lung disease? Now the patients that were included in this and some of them did have that usual interstitial pneumonia the same one that looks like IPF. And we know from prior trials in IPF from many years ago that immune suppression in patients who have idiopathic pulmonary fibrosis actually leads to an increased rate of death.

So the question is here, although the radiology pattern may be the same, is it the way you get there, does that matter in terms of how you're responding to treatment? So having sort of an idiopathic component which is probably genetic plus some sort of environmental exposure different than having underlying connective tissue disease leading to the same radiologic outcome and is that why we're seeing a difference or is this the type of thing that if we did a large scale prospective trial we might find similar outcomes to Panther. I think right now it remains something that we don't know the answer to yet and something we debate back and forth about I think has given us all some comfort in saying that having patients like this who have primarily fibrosis on an anti inflammatory therapy may be helpful for them or at least not harmful. And then these are the sort of change over time in these patients that had RAILD and whether they were treated or not and panel A is just the FVC percent predicted over time. What you can see is that prior to starting treatment with therapy, there was a decline, and then there was a stabilization to a slight improvement similar from the non UIP pattern to the UIP pattern, and you got similar changes in the DLCO.

The dotted blue line is the presumption sort of if there'd been a continued linear decline, which is a little bit difficult to completely extrapolate, but it's the pretreatment trend. And so what we're seeing here is some improvement, but really a stabilization of lung function with the starting of immune suppressant therapy here. And then I think the other big controversy that is maybe a little less controversial these days, but is the decision to add anti fibrotic therapy or not in these patients. So we're just going to review two of the major trials that have come out to look at, anti fibrotic therapy in patients that with connective tissue disease associated ILD. So the first is the INBUILD trial looking at an ententanib for progressive pulmonary fibrosis.

And now just importantly to review the diagnosis of progressive pulmonary fibrosis, that meant that within the twenty four months prior to enrolling in the trial, patients either had to have a relative decline in their forced vital capacity of 10%. They could have had a five to 10% decline plus worsening symptoms or progression on high resolution CT scan, or they could had worsening symptoms and HRCT scan progression. And notably this trial excluded patients with idiopathic pulmonary fibrosis because they had already been included in prior trials which showed a benefit of this medication. When When you look at the subgroup of people who were included in this, there were about twenty five percent of the patients included in the trial and both arms from the treatment arm and placebo arm had connective tissue disease associated ILD. They primarily included rheumatoid arthritis, systemic sclerosis and mixed connective tissue disease patients but there were ten patients with other connective tissue diseases that sort of ran across the gamut.

What you can see here is that overall, this is looking at the mean change in forced vital capacity over time, that the intendant group had a slower rate of decline in their forced vital capacity compared to the placebo group overall. And there's maybe a slight worsening in people who had a UIP like fibrotic pattern, but in the intended group they sort of did the same way they had a UIP like pattern or not. So this is a statistically significant slower rate of decline but you still know that there is a rate of decline over time and so important when you're talking with patients that this is something that can help provide maybe more stability over time but does not stop progression. And then specifically to look at nantenib for systemic sclerosis associated interstitial lung disease, there was a specific trial that came out in 2019 for this that included about five seventy six patients that received at least one dose of either nantenib or placebo. The primary endpoint was annual rate of FVC decline.

And what you can see here is that in the nantenib group over a year, there was a slower rate of decline. Again, we're still seeing decline in both groups, but about a between 40 to 60 cc difference in FVC decline in the group that got natinative compared to placebo, suggesting that there's a slower rate of decline with adding natinative in. Now there's additional data that did not lead to FDA approval yet looking at profanidone and rheumatoid arthritis associated ILD, but did show a slower rate of forced vital capacity decline. And then the newer medications that have come out from Boring or Ingelheim looking at neuroendomast neuro showed efficacy and progressive pulmonary fibrosis as well. We're focusing on the medications that are actually available for patients in the market today as that those are the ones that actually impact your treatment options.

When I'm thinking about this, it's not quite as straightforward as the trial say yes and so we should do that for these patients. First is my patient fall into one of the groups from these trials and if yes then I move to tolerability of medications. Now these medications, particularly in intend to have some substantial side effects and predominantly diarrhea being the big one. And so in my patients that have systemic sclerosis related ILD, this is already a problem, especially my interactions with other medications. My patients that are on mycophenolate need to be for other reasons.

Sometimes the addition of the two can be difficult for them to tolerate. It's also unfortunately here in The US at least a costly medication, and so I think it's really important to turn this a little bit into a shared decision making conversation with patients and making sure we're setting reasonable expectations for the role of these medications. They're not medications that are going to reverse the fibrosis that they have or make them feel better, but in other diseases they do appear to have a mortality benefit and they do slow the rate of lung function decline. I So think in the right setting and in the right patient, they can be useful, but I think it is still something that's worth having a conversation and discussion about.

So the key points of treatment considerations in dealing with connective tissue ILD. Again, this is a repetitive slide, but it's really important and a summary. Do not delay treatment for progressive or clearly inflammatory disease given the risk for remodeling. Consider early consultation whether you're a pulmonologist or a rheumatologist sooner rather than later. Decisions on the use of anti fibrotic are still in flux, but generally speaking are offered when there is a predominantly or significant fibrotic process or when there is progression.

Prospective trials on the benefit of concomitant anti inflammatory and anti fibrotic therapy are lacking at this time and newer anti fibrotic therapies down the line, will offer additional options, as we move forward.