ILD and Autoimmune Disease Save

Well, thanks so much. My name is Scott Matson. I'm an assistant professor of medicine. I'm a pulmonologist, and I'm at the University of Kansas here in Kansas City. And I'm excited to talk today about one of my favorite topics, which is treatment, treatment complications and rheumatoid arthritis associated interstitial lung disease or RE ILD.

So one of the reasons I think this is a really pressing and important topic is, what we're dealing with here is a group of patients who have really poor outcomes, even with the significant advances that the rheumatology community has been able to make in the management of the underlying synovial disease. And what's true is that RAILD outcomes remain pretty devastating, and the development of pulmonary fibrosis and interstitial lung disease for these patients leads to significant loss of function, significant impacts on quality of life, and unfortunately really shortens the lifespan for these patients that otherwise have been doing really well on the therapy that rheumatologists have been prescribing in the last ten to fifteen years. And I think there's two primary limitations, two primary concerns about complications, which really just I think largely come from the fact that we lack any prospective high quality randomized studies of the primary standard of care. And this leads to these sort of two major concerns, I think, that pulmonologists and rheumatologists alike, I think, feel for these patients and really can only be overcome through, as I mentioned before, a desperate need for prospective randomized data. And the two concerns we have, I think, in immunomodulation are quite clear.

So on one hand, patients who have pulmonary fibrosis have, I think, one sort of concern for bioplausibility for responding to immune suppression or immunomodulation. And that's of course, we think of scars as sort of benign, no longer inflammatory, very likely to not reverse given the nature of scarring. And then I think the second thing is supported by evidence in similar conditions in that fifteen years ago, pulmonologists like myself were treating patients with pulmonary fibrosis who had idiopathic versions of the disease. A group of patients with IPF looked quite similar to REILD patients, and historically we would treat those IPF patients with immunomodulatory therapy. And in 2012, those patients with IPF were randomized by a group of investigators to receive that kind of strategy.

And what they found is that that kind of immunomodulatory use in those patients was associated with worse survival, and that was mediated largely by more respiratory hospitalizations for likely infection and ILD exacerbations, again, probably driven by an increased risk of viral infections leading to lung injury. And so we have this problem now in this space where guideline therapy, based on observational data, some of which our group itself has contributed to, supports the use of a whole strategy that carries this really concerning complication, which is perhaps these are patients that may not respond positively to immunomodulation anymore because of the nature of scarring in the lung from RA, and that maybe these patients are more like those idiopathic pulmonary fibrosis patients. And so how do we balance that concern over the complications of this therapy? While on the other hand, we know that from other auto inflammatory interstitial lung disease conditions like scleroderma, that the use of immunomodulation is associated with improvement in quality of life and improvement in measures of lung function over time from the scleroderma lung studies. And when seeing patients who have rheumatoid arthritis, I think all of us feel this pull of we want to use something that can make people feel better, and we want to use something that can improve their current functional status.

And immune modulation, I think, offers that enticing possibility. And then, you know, our group has looked at the role of immunomodulation on pulmonary function testing trajectory. And, we find that immunomodulation is associated with stability of lung function in a group of patients that are declining pretty rapidly. And we find that that stabilization is independent of the amount of fibrosis on a CT scan and independent of the underlying ILD pattern. And so unfortunately, I'm not sure that there's an easy way out of this because a lot of people have been presuming that rheumatoid arthritis has a couple of different flavors.

There's a more fibrotic phenotype and then a less fibrotic phenotype radiographically. And I think the observational data would at least support the hypothesis that if patients are going to respond well to immunomodulation, that seems to be totally unrelated to their underlying fibrotic extent or their underlying pattern on CT scan, which I think makes the problem complex because it remains totally true that there are patients within this population that likely do benefit from added immunomodulation. And there are certainly groups of patients here that disease activity is certainly the most important metric that I target in my population when thinking about initial treatment in this group, but it's really what do you do after that? Once the patient comes to you with adequate disease control, having developed interstitial lung disease on appropriate DMARDs, you know, what do you do and what can you offer to those patients? We have one strategy that's supported by guidelines, but really not supported by the kind of evidence we need to show its safety, which is immunomodulation.

And then on the other hand, we have this other new and novel treatment strategy for these populations of patients, which is the use of anti fibrotic drugs. And anti fibrotics like nantetinib and profanidone, which are FDA approved for these kinds of conditions, What we know about those therapies is that they are safe. So there have been thousands at this point of patients in randomized controlled trials of both of those anti fibrotic drugs without any concerning safety signals. And that's on top of a decade of clinical experience using these drugs where we know that even though they're difficult to tolerate, there seems to be no concerning safety signals in the last decade of use. But what we also know about those drugs is that none of those RCTs have ever shown a meaningful benefit, a statistically significant or clinically significant benefit for survival or for quality of life for these patients.

And patients on anti fibrotic in these studies get worse, they just don't get quite as worse, quite as bad as that placebo group. And the complications from these drug classes really have to do with the difficulty of patients to tolerating these therapies. Patients have significant GI side effects from both. There's diarrhea in one and there's a photosensitive sun rash in another. And up until recently, there was also concern about financial toxicity for these therapies, although that's lessening in the era of those both coming off patent now or shortly.

But it does, I think, put us into this sort of difficulty. We have a strategy with immunomodulation that might offer a way for patients to feel better and function better, But there are potential complications of using that strategy, and it may be that they could be profound, it could be that we could be harming people with that strategy. And on the other hand, we have a strategy, anti fibrotic based treatment, which we know doesn't make people feel better, and we know doesn't make people live longer, at least in that first year, but is safe. And that puts us all in a pretty difficult position. And the final thing I'll say about managing these patients that makes this very difficult is that not only do we lack the empiric evidence to make some of these most important clinical decisions that we all face, but I find that it's a very difficult situation in an individual patient to understand, because we will often make therapeutic choices and then see the patient back and see how they're doing to make a determination of whether or not what we picked was right for them.

And in progressive pulmonary fibrosis, that's quite difficult because patients usually do get worse. And so having a patient come back feeling slightly worse or with some small decline on their pulmonary function tests puts me, and I think most people, in a difficult spot because of course, if they're getting worse and the medicine is supposed to slow that progression, what we have to sort of argue against is a counterfactual that we never know the real answer to, which is what would that patient have looked like at that same time point had we done nothing? And how much of our therapy is making or driving some of their symptoms of feeling worse? How much of our therapy is actually making them feel better than they would have had they not been on that therapy? And so it's a difficult place.

I don't have a lot of honest answers, but what I would say is I think it just calls for us in this position to do two things, which is one is I think it's important to be honest about this with ourselves, with the community. It's important to be honest about what we know and don't know when we think about these guidelines, because I think if we're truly honest, we know less than I think we hope. And I think that means that we have two important calls, which is honesty, and the second is to generate that data because we can do it. It's just a matter of getting interested parties together and asking the right questions. And so I think, and my hope and I know that in ten or fifteen years, I think a lot of these questions are going to be answered.

I look forward to working with all of you to try to figure that out. So thanks, and if you want to hear more on these topics, just check out RheumNow, and I appreciate the time.

Hi. I'm doctor Bryant England, rheumatologist at the University of Nebraska. Thanks for joining me to discuss interstitial lung disease and mortality in systemic autoimmune rheumatic diseases. In systemic autoimmune rheumatic diseases, disease complications arise from the systemic nature of the disease. That's why the s is first.

So across our systemic autoimmune rheumatic diseases, we know that these patients can experience poor quality of life, disability, and even reduced survival. And frequently, what's driving that reduced survival is the systemic nature of these diseases, their involvement of the kidneys, of the heart, or of the lungs. Now we pay particular attention to the lungs in interstitial lung disease because this is a frequent systemic feature of our systemic autoimmune rheumatic diseases. In systemic sclerosis, myositis, or mixed connective tissue disease, up to fifty percent of people will have interstitial lung disease. In rheumatoid arthritis or Sjogren's disease, that number might be about ten percent of people afflicted with interstitial lung disease.

So this is a frequent systemic manifestation we're seeing in our patients. Unfortunately, when we find interstitial lung disease in these patients, it just exacerbates the already bad outcomes that patients are predisposed to getting. So we know that interstitial lung disease can cause reduced quality of life, reduced function, reduced survival, and this is on top of what the disease was already doing to begin with. Illustrating this point, we look at cohort studies of rheumatoid arthritis or systemic sclerosis. People who have the complication of interstitial lung disease have their lifespan shortened by about five years compared with people with RA or systemic sclerosis who do not have the manifestation of interstitial lung disease.

Now just having interstitial lung disease doesn't tell us everything we need to know. There's a lot of heterogeneity of the disease that's reflected in survival. So one of those aspects is in the interstitial lung disease pattern. So studies have generally shown that the pattern of usual interstitial pneumonia or UIP does have a worse prognosis and poor survival compared with other patterns. Another feature is the extent of the disease.

So whether that's based on pulmonary physiology or the PFTs or if that's based on extent of disease and a high res CT of the chest, how severe the disease is by that assessment does give us valuable prognostic information in terms of survival. So if ILD is frequent in patients with systemic autoimmune rheumatic diseases and it's bad, what can we do to combat this and try and preserve longevity for our patients? Well, one of the things that we're trying to do is we're trying to identify interstitial lung disease earlier. In some cases, that might mean that we screen for it in a patient who doesn't have any symptoms. And certainly in cases like system systemic sclerosis or myositis or mixed connective tissue disease where that prevalence is approaching fifty percent, it seems very reasonable to preemptively screen people with a high res CT and pulmonary function tests.

In some diseases like rheumatoid arthritis or Sjogren's where that prevalence is much lower, we may want other risk factors or at least regularly assess for symptoms. And at the earliest sign of those, then go ahead and get a CT or pulmonary function test. Once we've identified interstitial lung disease early, then we try to optimize our therapy to slow the progression of disease. Now that starts with assessing what therapies a patient might be on right now and whether those therapies need to be adjusted or added to. We have immunomodulatory therapies that can help us slow the progression of lung disease.

We also have antifibrotic therapies that can help us slow the progression of lung disease. And on a case by case basis, we'll choose which of those and potentially the combination of those to help preserve the pulmonary physiology. We also have nonpharmacologic interventions that we want to include in these situations. That includes counseling on smoking cessation or if they're exposed to other inhaled exposures, protective measures. Things like supplemental oxygen use assessments and getting patients referrals to pulmonary rehab, or potentially lung transplant evaluations are other options for how we can try and preserve longevity for our patients.

So in summary, we know that interstitial lung disease increases the risk of death in patients with systemic autoimmune rheumatic diseases, and that's in addition to their already reduced survival from the disease itself. Now interstitial lung disease is a heterogeneous disorder with distinct patterns and distinct expression in terms of how severe the extent of involvement. That's very valuable for us as we're talking with the patient about the prognosis, and following patients over time is even more helpful to understand their disease trajectory. Now through early identification, optimizing their pharmacologic and nonpharmacologic therapies, as well as risk factor modification, we're doing everything we can to try and preserve longevity for our patients. Now thanks for joining me to talk about interstitial lung disease and mortality and systemic autoimmune rheumatic diseases.

Hello. I'm Nancy Carderen. I'm a rheumatologist based in Northern California and I'd like to talk a little bit with you today about Sjogren's interstitial lung disease. So was very happy to see that in the recent 2023 ACR chest guidelines that Sjogren's was also included in the guideline development. But I'm going to target a little bit on guidelines that Sjogren's pulmonologists and rheumatologists published in CHEST in 2021.

I think Sjogren's is probably not on the radar for rheumatologists, lung involvement as much as many of the other diseases are diseases like scleroderma or rheumatoid. But it's important to know that if you do screening in studies where they have done screening high resolution CT scans, that up to sixty percent of people with definite Sjogren's have lung abnormalities that are visible on the scan. So I think it's under recognized. So I think my main message today is for all those listening is really just to think about it. And even if you have Sjogren's alone or Sjogren's associated with another autoimmune disease, don't forget about the lungs.

We know that with regards to the interstitial lung types of diseases, phenotypes in Sjogren's, that NSIP accounts for about forty five percent and UIP sixteen percent. Fairly unique or at least a hallmark of Sjogren's being the lymphocyte. LIP we see about fifteen percent of the time, and organizing pneumonia about eleven percent of the time. But with the lymphocyte, we certainly can also see bronchiolar involvement in follicular bronchiolitis. So there could be a spectrum.

There's certainly a strong association connection between Sjogren's and lymphoma, which occurs in the lung about six percent of the time and amyloid as well about six percent of the time. So there's a reason to consider a baseline pulmonary function test and maybe high resolution CT scan in appropriate patients with Sjogren's. And depending on findings, certainly with nodules and monitoring patients with Sjogren's lung disease, there may be a role for PET scanning as well. One of the hallmark symptoms which can be underappreciated as something more serious in Sjogren's may be a chronic cough, which can be reflective interstitial findings or certainly in Sjogren's related to dry airways. So the spectrum of the underlying disease in Sjogren's we think about in the lung as really going from inflammation to the fibrotic state.

In the inflammatory state, the organizing pneumonia or the NSIP predominant, there's a sub phenotype that our pulmonary colleagues talk about being fibrotic phenotype of NSIP, and then to the full blown, fibrotic UIP findings. But fairly unique to Sjogren's is the presence of more nodules and particularly with cystic changes that we can see. And so the cystic formation, especially if there's a nodule that's very near the cyst, can be a clue on raising the index of suspicion for lymphoma in that area or amyloid. So important to know if those are there. The cysts can certainly become infected, which can be obviously problematic.

And if they're large, they can be prone to rupture. So certainly for people who may have certain hobbies or even a vocation of scuba diving, you want to know about those cysts ahead. And so another important reason to know what the pulmonary status in your Sjogren's patients is earlier rather than later. So just think about it. I think about kind of understanding the activity, disease activity in the setting of Sjogren's, as well as then being able to pick appropriate treatments or the feeling comfortable and just monitoring patients with the basic immunology of them.

Am I dealing with innate immunity or has it progressed down to the adaptive, to adaptive, or is it cycling in that area? In Sjogren's, because the hallmark feature is really lymphocytic infiltration of target tissue, The B cell plays a very prominent role progressing on to germinal centers and then obviously increasing the risk of lymphoma. But in thinking of where your individual patient may fall along that spectrum. With regards to treatments, from the guidelines in CHESS from 2021, And not surprising, the first line treatment is glucocorticoids. But there are certainly a reason to very quickly add on steroid sparing agent and hierarchy really is considering mycophenolate and azathioprine not surprising, but very early addition of them and titrating down the steroids as quickly as possible.

For patients that have more severe disease or if there's a really exacerbation and rapidly progressive or if it looks like you may be dealing with progression onto a fibrotic phenotype, one needs to think about adding an anti fibrotic, particularly natinitamab, and considering higher doses of steroids pulsing with methylprednisolone and adding rituximab probably over cytotoxin early on. And in the chest recommendations from 2021, that was actually a strong recommendation. Don't forget about transplant evaluation. It may not be on top of mind for Sjogren's patients, but assessing their disease severity and candidacy for transplant early is important and there's no contraindication for them to be able to be transplant candidates. There are also, depending on individual situations in patients, think about calcineurin inhibitors, particularly tacrolimus as well.

Since those guidelines were published in 2021, it's been heartening to see a number of Sjogren's centers globally have gone back and looked at their cohorts, and it's been borne out with regards what the consensus statements were and what the rationale and supporting evidence was in that guideline. So I think that so far has stood the test of experience. I think we're in an exciting time right now because with Sjogren's particular, we do not have any regulatory approved therapies. But we now have a number of late stage development programs and two very recently have announced that they've met their endpoint and are going for regulatory approval. One in particular that I'd like to mention in The US is enalumab, which has a dual activity.

So it's a monoclonal antibody directed against the BAF receptor, but it ends up resulting in B cell death by ADCC, and it inhibits the BAF cytokine production. And so along with dovetailing on what we have had to use up to date, being rituximab, this is an exciting thing to stay tuned. And we'll be gaining a lot more information with regards to the specific treatments and how they work as we get newer treatments that come out. So thanks for listening. As you see Sjogren's, whether it's occurring by itself or with one of our other autoimmune diseases, think about whether the person has lung involvement and consider whether it's appropriate to establish their baseline pulmonary activity with PFTs, you know, plus or minus high resolution earlier rather than later.

So thanks for joining.

Hi, I'm Doctor. Janet Pope and my Twitter is janitburdope and I hope you'll be following us at RheumNow as we report on all sorts of interesting things with respect to CTD ILD. So I wanna talk about IPAF. So true or fake, idiopathic interstitial pneumonia with autoimmune features or IPAF, is it a real thing or not? So there is a definition from various societies.

The first definition was a task force in Europe and the ATS together in 2015. And what they said was it was interstitial pneumonia in patients who have features suggestive of an autoimmune disease, but they don't meet established criteria for defined connective tissue disease. So they're kind of like patients who maybe have lung as part of the CTD, but they don't have the whole other features. So what do you need to have it? And then is it really real or fake?

So you need to have interstitial pneumonia or interstitial pneumonitis. And that for our patients is usually easy to tell. It's usually in the bases, usually bilateral, usually the common patterns for our patients, NSIP or UIP. You wanna exclude other etiologies. Is it a drug effect, environmental, etcetera?

And the patients need about two or more of three domains, clinical, serological and morphological. So clinical would be Raynaud's, arthritis, mechanics hands, Goytron's sign, serologic could be a moderate or strongly positive ANA, presence of anti CCP, anti Rho, RF, JO1, etcetera. Morphologic would be basically having the right pattern. You don't have to do a lung biopsy and these patients might get a lung biopsy if they're uncertain of the diagnosis, but they usually have the patterns we're familiar with, NSIP, they could have also organizing pneumonia or even LIP. And we do know of LIP as a for instance, lymphocytic interstitial pneumonia or interstitial pneumonitis in Sjogren's.

So it's not a disease, it's a framework. You can have a UIP pattern and just like in other patients with CTD ILD, usual interstitial pneumonia is the worst prognosis. They can have the organizing pneumonia pattern, which some of you remember as being BOOP, bronchiablitis obliterans or COP, cryptogenic organizing pneumonia. So organizing pneumonia pattern often has a better prognosis and is usually steroid responsive or NSIP. And then some of these patients might over time evolve into getting a full connective tissue disease.

So there's also uncertainty. How do we see these patients? We see them two different ways. Your local or friendly pulmonologist refers them along saying, does this patient have a CTD because they have say Raynaud's antibody and they have ILD. So that's one way.

The other way is say you get a referral with a positive antibody or other features of a connective tissue disease and you realize they have ILD, but you can't make a firm diagnosis of RA or scleroderma or myositis, etcetera. Then we don't know what to do because we have trials in idiopathic pulmonary fibrosis that the pulmonologists know how to treat and that we really don't see, but we have their trials as well in the patients who are having fibrosis or having interstitial lung disease related to CTD or other reasons, but the IPAF patients aren't included in these trials. Then the final thing is it's a debate on is this legitimate or not? So people say, you know, you're gonna dilute clinical trial populations if you let them in, it doesn't predict a response to therapy, The patterns and the extent of change and the change in their PFTs of worsening or improving are more important than calling them IPAF or not. So you're gonna have to decide where do you stand?

And I kind of think it is a real thing. That's my personal opinion. And I do because it's like many things in rheumatology, we see people who don't meet classification criteria, but they're on a spectrum. We see people with features of SLE who don't have SLE. We see people with Raynaud's and a centromere antibody, but they don't have other features yet of systemic sclerosis and might never get them.

So I think IPAF is sort of on a spectrum as well that someday these people might have a CTD that is more diagnosable and many of them over their lifetime won't. So maybe like an organ specific CTD affecting the lungs, but I just made that part out. Not really a classification of anything either. Anyway, it's a framework for you to think about. Please continue to follow us during our month of September with a lot happening at RheumNow.

Thank you.