Controversies in ILD Save

Hello, everyone. Welcome to Tuesday Night Rheumatology. This session is going to be on ILD, just like all the Tuesday night rheumatologists in the month of September, where we have a campaign called Room to Breathe, all about ILD. In these Tuesday night rheumatology sessions, we focus on a specific issue. Last week we talked about treatment and future treatment.

Tonight, we're gonna be talking about controversies in ILD. I wanna remind you, again, Tuesday night, 7PM, all throughout September. Next week, we're gonna do journal club, two very important journal articles that have defined the treatment paradigm in ILD. And then in our last week, we're going to have a session devoted to diagnosis screening and monitoring. Tonight, our session on controversies in ILD, I'm joined by the experts, and I'm going to ask them to introduce themselves.

I'm Jack Cush in Dallas, Texas. Elena?

Hello, everyone. My name is Elena Jerns. I'm a rheumatologist at Mayo Clinic in Rochester, Minnesota.

Janet. Janet Pope, welcome to At Room Now. I'm a rheumatologist in London, Ontario,

Canada. And Doctor. Sparks.

Hey everyone, my name is Jeff Sparks. I'm a rheumatologist at Brigham Women's Hospital in Boston, Massachusetts, and very excited to be part of this campaign for the entire month of September.

I want to thank each of these three folks have been part of the advisory committee that has been working for a few months on generating content, speakers, topics and whatnot. And so I can't thank you guys enough for your expertise. I've learned tons in a very short period of time. And we have lots and lots of content. So far, what we've learned, and I'm gonna use RAILD as an example.

And these are things that we covered in part last week and has currently been covered on the website and content that we've already generated. But I like the three S rule. I learned that from Jeff about two years ago, that is seropositivity, smoking and sex being male with UIP really increases the risk of having UIP significantly. So the 3S rule is really important. These patients with ILD are at much higher risk of serious infections with at least a threefold higher risk and a three to fivefold higher risk of mortality.

So this is bad, bad news. You can know who's really at risk by looking at what happens to their FVCs in the first six months. Rapid progression of that FVC leads to significantly worse outcomes. And you can define it with a few serial tests as far as your FVCs. The question is going to be how to treat them.

And does our treatment as rheumatologists with DMARDs change what happens with ILD? There's a little bit of data on that and that kind of suggests that that might be so. But we need to know about the more specific therapies for ILD, when to add immunosuppressants, when to add anti fibrotic fibrotic. And the good news is we have twenty twenty three from the ACR and twenty twenty five from UR recommendations on the management of ILD. Any comments from our panel on just this information that's already been laid out?

Jeff?

Well, I'll just emphasize, we think RA is doing very well, and it is. We have a lot more treatment options. The joints overall are less likely to erode. This is the outlier. This is one of the few outcomes across all of rheumatoid arthritis that it's not getting better.

The prevalence seems to be increasing. We're still having excess mortality risk. These patients still get infected. So, from a rheumatoid arthritis standpoint, these are the patients that you worry about and that our current therapies have not put a big dent in. And obviously, we need a lot better data, we need more trials, and it's great that there are some recommendations from both organizations, but nearly all of them are conditional as you've highlighted.

That's really just because we don't have the trials that needed. And this is our most common rheumatic disease. So to me, it's a call to arms that we need better data.

Yeah, Janet and Elena, you've been working in this for a number of years now, noting how important this is and that research is needed. Any comment?

I'll make a brief one. I think that those listening who were on last week heard excellent description of how the recommendations got to what they're like now. And I think sometimes a conditional recommendation is because, as Jeff said, the data are missing, but that we have enough, I'll call it real world data and subsets of studies that we have enough data to say that interstitial lung disease is probably going to do a lot better when we treat the RA disease effectively, but that I think it's my opinion now that some drugs are more lung friendly than others. And that's pretty important to note. And I'm not going to go through my list, but I just think some have more data than others.

We're going to get into controversies thereafter.

Right. Elena?

Yeah, I will add that it is exciting that we're getting these guidelines for ILD. I think it is improving our understanding how common it is. It's going to improve it even more once some of these conditional recommendations come into action in the clinics, where more people with Sjogren's will get screened, more people with myositis will get screened. Hopefully most of them are getting screened already. So I think we will be, getting more data, and I'm excited to be part of it.

Last week, Janet alluded to, we talked a lot about the ACR and ULR guidelines and how they are, number one, that rheumatologists are aware of them and that they are aware of what it means to screening, how to screen, who to screen. Big thing we heard from Shane Shapiro from the University of Toronto last week, that he really liked about the guidelines, especially the EULAR guidelines is that everybody should get screened pretty much. An RA that has risk factors, but pretty much everyone should be screened and HRCT is the way to go. And I think that's significant shift in how we consider this. So to prepare and to move the discussion along for this particular session on controversies, we did a survey of rheumatologists, a one time email went out on Monday morning, when less than twenty four hours, 35 of you responded, eighty five percent being rheumatologists, five percent being advanced practice providers.

We asked a number of questions, like 12 questions altogether, where we talk about some of the acronyms and then terminology, we'll refer to that, specifically about IPAF, what it is and how autoimmunity plays in. We get into the methotrexate controversy that rheumatologists and pulmonologists love to do spar about. Then specifically management looking at UIP as an example, and we'll discuss some other smaller issues like cancer risk, whether our patients can get transplant, what's the role of AI in the future. So first question, when we ask rheumatologists, how comfortable are you at distinguishing and diagnosing the different types of ILD that are related to connective tissue disease, systemic autoimmune rheumatic disease, and these other terms, IPAF, PIFILD, It's an AEIOU kind of world in pulmonary rheumatology. And I like this answer because I think this reflects my own thinking.

Forty two percent, forty three percent not confident, forty five percent somewhat confident. This is very sobering. Only seven percent of us really have this nailed. Think the seven percent are the panelists I'm gonna have on these TNRs, right? They're the ones that we're looking to.

Only five percent of you are confused by the acronyms. Let's go over those first. Elena, can you explain those CTD we know? SARD, IPAF, can you tell us what those are?

Yeah, CTD is going out of fashion. The new preferred term is SARD, systemic autoimmune rheumatic disease. This was a term that was proposed by the ACR chest guidelines on SARD ILDs that recently came out. IPAP is interstitial pneumonia without immune features, which is, we'll, I'm sure, talk about more, but this is my clinical and research focus. That's the interstitial pneumonia where patients have some autoimmune features, but they don't meet any criteria for any SARD.

And SARD being myositis, Sjogren's, RA, scleroderma. Is progressive pulmonary fibrosis, and that's a term that was introduced by American Thoracic Society. There was a recent guideline on it. So essentially, anybody with pulmonary fibrosis who is progressing, and there are a few definitions for that, they define it by increase in respiratory symptoms, increase, in the radiographic appearance of fibrosis, decline in pulmonary function. So there are a few criteria that these patients need to satisfy.

And ILD is progressive fibrosing ILD, not necessarily used more commonly than I will say that somewhat confident is where I often am myself, because it can be hard to say. It can be hard to say. And a lot of the times, the data is very subjective. So depending on who is looking at your CT scan, hopefully with the emergence of qualitative CTs, quantitative CTs, can get this answered a little bit more objectively in terms of the progression of fibrosis. But I think sometimes it is hard to tell, so I'm with you there.

So that's surprising. Janet and Jeff, are you in that same boat? Are you sometimes only somewhat confident and maybe with time you get more confident, Janet?

So first of all, I understand where Alina's coming from because I might be a little bit more confident, but the terms are not always standardized. So some trials is defined as an X percent of pulmonary fibrosis on an HRCT and a worsening of FVC by a certain percent over, you know, months or even up to two years and or DLCO going down even further over months or a couple years not to be thought that it's from infection or other reasons. And so that's why I would almost be between I'm straddling the purple and the blue because sometimes it is difficult to note. I also think that sometimes these terms are used in order to get access to a drug with of course a person with ILD. But I'd probably sometimes bend the rules a bit if I had someone with IPAF that we'll talk about later who might need treatment.

We got to decide what really are we going to call them to get appropriate treatment.

So Jeff, I think some of the confusion can be from the acronym. Sometimes it can be from diagrams like this about what is ILD and it looks like it's an insane Christmas list. So I'll put up a slide and ask you to sort of just give us a sort of an organizational overview of ILD and any comments you like.

Sure. I'm impressed that, so many people were confident and not as many people were confused by the acronyms and you could have put more on there, honestly. So this, is one of these busy slides and this is intimidating about ILD and this is how a pulmonologist thinks of how to classify that. On the left side are the idiopathic pneumonias, the most prototypic one being IPF, which basically is fibrotic, typically is idiopathic, so doesn't have a rheumatic disease, doesn't have an exposure, and those patients do very poorly. Kind of a cousin to that are non specific interstitial pneumonias or NSIP.

Those are typically a more inflammatory phenotype, at least on the imaging. And you can see a smattering of different other subtypes that are less common. The autoimmune ILDs, and this will be a controversy we probably go into later, The pulmonologists prefer the term CTD ILDs. We are seeming to prefer the term SARD ILDs. And then, Elena Jerns, here is, really studying IPAP, which is ILD.

It's bona fide ILD, and then it has a few features of autoimmune diseases, but not enough to be either diagnosable or classifiable if you're thinking about either clinical or research. Obviously, we're very comfortable about diagnosing the underlying rheumatic disease that are listed there. Certainly, some people have overlap syndrome, which can make things difficult. Probably the most common one, at least by prevalence, would be systemic sclerosis ILD. MCTD ILD is pretty common as well, myositis.

From a number standpoint, while RA ILD is relatively less common, maybe about ten percent of patients, there are the most number of RA patients. So, an absolute standpoint, there are a lot of patients with RA ILD, and certainly a lot of people are unclassifiable. Then you start thinking about sarcoidosis, which is rheumatology adjacent but has its own natural history. Then really thinking about occupational exposures. Smoking is the one that comes out, but obviously pulmonologists are very good about figuring out who has birds in their house, who's spelunking, silica exposures from occupational exposures.

So, this is intimidating, and often people don't fit neatly into one of these boxes, which is challenging. Things that aren't on this list, of course, smoking injury, infection injury, drug injury, radiation, and people, GERD. So these are really complicated patients, obviously thinking about malignancy and atypical infections as well in our patients that are immune suppressed.

All right, I think they're off to a fabulous start with you guys really giving good perspective and organization to this. I want to encourage our audience that if you have questions, please put them in the Q and A box and I'll be addressing those as we go along. Let me see. We don't have any in there yet. Don't think, let me look, Q and As.

So it's open and you can drop in your questions and we'll ask real time and we'll say your name and where you're from and send you a check maybe, probably not. So here's the first set of questions that deal with IPAF interstitial pneumonia with autoimmune features. I like that you distinguished it from SARS, which has more certain autoimmune base. So the question is, should IPAF be regarded as an autoimmune ILD? A third of you said that it depends on the autoantibody profile.

A third said, I don't know. Fifteen percent, sixteen percent said it depends on the chest CT, and twelve percent, she asked, sure, why not? Elena, what do you think of these results?

Seems like a real world example. And I think everybody is right. Everybody is right here because, in some cases, IFAF can be autoimmune and sometimes it really depends on what their autoantibodies are, and I'll go into it a little bit more. IPAF really is probably a mix of things. So IPAF is, it's actually a research designation, even though we all love to use it as a diagnostic designation.

And we love to say, Okay, this is IPAP, autoimmune, let's give them immunosuppression. It is technically not entirely correct. What we saw with IPAP classification criteria that came out in 2015, it actually alerted people that there is this disease entity that we don't understand enough about, and really, those classification criteria were designed to really encourage trials of these patients. We didn't see it as much, but we are seeing it some. There are definitely a lot more studies on IPAF now that came out since the introduction of those criteria, and we can understand a little bit more what patients have been studied.

And we're seeing that, for example, IPAP with myositis specific antibodies, so like antisynthetase antibodies, my tool antibody, SRP, those tend to behave the same as myositis ILD, so ILD with a SARD myositis. So those patients have a very similar response to immunosuppression and a very similar survival prognosis as well. And what's really interesting, it actually doesn't seem to matter whether they have this UIP, the usual interstitial pneumonia pattern of damage, which is thought to be really kind of fibrotic and not autoimmune pattern, or if they have an SIP. So they seem to respond to immunosuppression regardless of the underlying lesion. And I'm sure Jeff will talk about it a little bit more, but in RA UIP, we often attempt immunosuppression as well, because we know that they have an autoimmune disease.

So depending on the autoantibodies, some IPAF really should be regarded as an autoimmune disease, and there is a movement now in the myositis world to really call IPAF with myositis specific antibodies, just myositis ILD. So if you all are familiar with the criteria within IPAF, so in order to meet classification criteria in IPAF, the patient needs to meet two out of three domains, and that's serologic domain, clinical domain, and morphologic domain. And within the serologic domain, there's a list of all of those autoantibodies, and there's been a call to remove the myositis specific antibodies from there, and I think it is an appropriate call, and I think we need to revise the IPAC criteria based on that. And I think the more we study, the more we revise the IPAC criteria, I think we're going to become more confident about what we're dealing with.

I like that those are in flux, but how does a rheumatologist handle this fact? A patient who has IPF, idiopathic pulmonary fibrosis. There's going to be a lot of action in the lungs and a lot of stimulation of immune cells in the lungs and alveolar macrophages. And I'm not surprised that they make autoantibodies that may not be pathogenic. So how do you make that distinguish?

Someone just has an epiphenomenal ANA. Mean, I tweeted the results of your iPass study and comorbidities, which I thought was great. Two zero one patients and eighty percent had an ANA, I think fifty percent had a rheumatoid factor, fourteen percent had CCP. And you showed that these people with iPath met the criteria, as you mentioned, that they had a much higher incidence of comorbidity and death as you would expect if it was a real disease and not just epiphenomenal antibodies. But there must be this subset of people who have antibodies that aren't pathogenic.

So how do we distinguish?

Yeah, and that's a really good question. We actually did a study, I'm hoping to publish it soon. It was presented at EULAR a couple of years ago, where we looked at lung transplant recipients. So we looked at patients who received lung transplants, and of course, then we have access to their biopsies and we're able to review those biopsies. So a lot of those patients that were regarded as IPF prior to transplant actually had positive serologies, and then on explant, they had inflammation, more than just mild inflammation.

They had some sort of NSIP patterns. So these autoantibodies probably do reflect something that's going on within the lungs. Now, are not doing a lot of biopsies on these people because a lot of times it doesn't necessarily change management. A lot of times they have other comorbidities and we want to try other things. Perhaps we should be thinking about doing more biopsies on them.

But even if you do a biopsy, you might not get the best sample and it might still not be diagnostic. A lot of those people who had transplants, they had biopsies before that showed UIP, but then you examine their explanted lung and it's actually more like NSIP and they actually technically meet IPAC criteria.

Okay. So before I go on the next question, I'll ask for a few comments, short comments from Janet and Jeff. Janet?

Right. So a quick one. Think, Alina, think your way of thinking about this is quite interesting. However, it's the difference as you're seeing in a way, I'm going to sort of summarize it between lumping and splitting. If I have a patient with NSIP and they're short of breath and they have Raynaud's, a strongly positive whatever antibody.

I don't see much much else going on. I can't make a diagnosis even though it's a centromere or a nucleol or a kind of interesting antibody or a Smith or something if if we're looking at the ENA. I think really in the end you're going to say well let's just treat. Let's just say I can't really say your eye path for getting a treatment pathway but you most align with a lupus patient or which isn't in the guidelines on the ACR? Are you most aligned with kind of your scleroderma like?

And I think interesting Jack there is a question in the audience that is exactly this kind of thing. Was the person I passed because they were an IPF pattern established pulmonary fibrosis had CCP positive and then eventually got their RA. So if these folks live long enough is it just their first manifestation of what they were going to get and some of them will never get there the same way we'll see VDOS that isn't yet scleroderma kind of thing. So that for those reasons, I really think that people are, you know, there should be controversies in how we vote the one third, one third and one third voting other.

Jeff.

You know, this, I think, is a really important area because these patients exist and they're really tough. And, you know, this is, I think, an illustration about when a research definition is applied to the clinic and it's just frustrating. These people have a real disease. They have ILD. Typically, ILD is quite severe, honestly.

And the pulmonologists see them and they find antibodies or some Raynaud's, etcetera, and they send them to the rheumatologist and we say they don't have a rheumatic disease. And it does tend towards frustration for both providers. They kind of fall through the cracks. The pulmonologists don't want to treat. The rheumatologists don't want to treat.

Next thing you know, months has gone by. So it's a, you know, really, we really need to make progress on these patients and honing the research definition and knowing how to apply it to the clinic because at the moment, like I said, they're falling through the cracks.

While it sounds like it's a nicely defined entity that needs a lot of research, I'm going to draw the analogy and say that IPAF is to a more certain SARD, just like undifferentiated connective tissue disease is to what will evolve into scleroderma myositis, or a lupus, etc. And I think that that makes sense because it's really a parallel, it's just a different organ system. But it should nonetheless lead to a heightened concern. I like Elena's point that maybe you can't just blow off the ANA or the rheumatoid factor in these people like you would in an ANA positive consult. It may mean more in the setting of lung fibrosis.

So let's go to the next question. When would you use immunosuppressive in someone with IPAF? Janet, I want you to tackle this. The audience answered a third saying, well, I would use it to control what I think is autoimmune disease. A third said they would ask pulmonary what to do.

Fifteen percent would say with specific auto antibodies and fifteen percent, I think because it was a leftover answer with a non UIP pattern, I guess there's this thing may I only gave him a few choices here. So Janet what do you think of these answers?

Well first of all I'd be very interested if it's the same people voting those same colors each time just because there might be really different schools of thought here. So first of all I'll agree with Jeff that if we say this isn't I cannot diagnose RA. If somebody's CCP is 200 and they have a UIP pattern and they have to have something else. They might just have arthralgia. As we say, they don't have inflammatory arthritis.

They have to have something from a category of symptoms and antibodies and then the morphology, which to us will just say is the CT pattern. So you can understand that if if we say, you like you hit the nail on the head as well, Jack, that if you have an autoimmune ish disease and it looks like you're heading towards a scleroderma pattern or a scleroderma phenotype even though so they have dysphagia, we'll say a centromere ANA and Raynaud's late onset, couple dilated capillaries, but not enough to make no sclerodactyly, not enough to make an actual diagnosis. And they have IPF kind of pattern like a UIP or even an NSIP, I might say, you know what, they're worsening, let's treat them. You don't have scleroderma but I'm to go down the pathway. So that is what I think a third are kind of saying.

Another third you go back and forth with rest, but the pulmonologists lean on us for this. They want us to kind of, we might be the prescribers, they might be the prescribers, they're very confident and comfortable if it's progressing pulmonary fibrosis. But I think with the NSIP IPAF kind of individual, they're leaning on us to say like, is this a rituximab patient or is this like, are you going to give methotrexate or MMF? So I think that the people that are working with their pulmonologist, we just answer the question they ask. Do they have a CTD or do they have a SARD?

And we go, Nope. They need more than that from us just to know. Specific autoantibodies, I think it's not just what the antibodies are but the titer. We're all going to pay a lot more attention to an ANA of onetwelve 100 as opposed to onetwenty. We're going to pay more attention if you have some very specific autoantibodies.

And as Alina said, they're going to probably get rid of those myositis that were in PAB, well, myositis like patients and just say, you know what, these people have an entity that is apt to progress. Just treat them. So that's, you know, removing those people too. So various antibody guidance. And then with a non UIP, because they might be answering that, some of the people listening that answered this, and thank you for doing the survey, they might be thinking, well, in other words, no matter what the diagnosis, if it's UIP, maybe my pulmonology colleague takes the lead.

And if it's not UIP, maybe the rheumatologist takes the lead. So that answer there, the fifteen percent, is really tough to know the thinking behind the answer. Again, it does show that we have a lot of ways to go that this is controversial, what to do.

Okay, so I wanna underscore the point that Janet made, which is the pulmonologists are looking for us to help them. And this is where co management and discussion really is gigantically important. Our next questions in this area is, how would you treat a SARD with UIP? And how would you treat an RA ILD with a UIP? So on the left, thirty percent want to refer.

Twenty five percent will use immunosuppression. Twenty two will say it depends on the SARD, which are a scleroderma, whatever, and twenty one percent are saying fibrotic. And then when we ask on the right, RAILD, thirty two percent will use immunosuppressors, sorry, anti fibrotic in eighteen percent, and both immunosuppressants and anti fibrotic in forty seven percent. Jeff, this is something that you're really involved do you think of these answers? What's the guidance here?

What should we be doing when we see UIP?

You didn't have an all of the above option I see, because I think you can make a case for many of these for sure. I'll take the one on the left first. I mean, granted, RALD is just a subset of that one. You know, I think, you know, just low hanging fruit, you know, even in patients that clearly have UIP and ILD, and you know, there's always some diagnostic challenge related to infection and GERD and cancer, etcetera. But, you know, even in patients who are very confident with the diagnosis, I do think co management with pulmonary is, you know, almost always paramount because there's going to be questions about prognosis monitoring.

You know, how often do you get PFTs? How often do you get HRCT? So, I think the refer to pulmonary is certainly part of the backbone here related to the multidisciplinary discussion. And I actually do like how the recent ULARS guidelines outlined this and that if there is undertreated rheumatic activity, that you really should try to get the underlying disease under control. And obviously, it'd be great if that was the same med that is pulmonary friendly and that we know has good data.

Certainly, best data is systemic sclerosis. Know, oddly, the UIP pattern is not the predominant pattern in those patients. You know, considering let's just take RALD now. Certainly if their joints are flaring, you want to try to get them on a DMARD that gets them into remission or at least low disease activity. You know, and maybe this is a case where some at least moderate dose prednisone might be warranted, particularly if they're symptomatic or you think they're rapidly progressing.

And, you know, there luckily are at least some options that have some data. Tocilizumab has an FDA indication for systemic sclerosis ILD, so you could make a case of using that for RA. Abatacept has some nice observational data, and rituximab probably has some of the strongest data related to treating both the joints and the lungs. The question is whether you throw everything at them at once related to anti fibroidics and inflammatories, whether you do this sequentially, and I think typically I do try to go down the immunosuppression route first in RAILD, and if needed, on antifibrotics later if they're progressing through that. But there might be some cases where you kind of go all in at the outset in someone that's rapidly progressive, and luckily that's not the commonality in RAILD.

D. And also just knowing, just keeping in mind that at least the currently approved anti fibrotic are poorly tolerated. So that's another reason to think about doing this sequentially because if they have a side effect, if they're on MMF and nantinenib, for example, and they have diarrhea, you're not exactly sure which med to blame. To extricate both of those medications right off the bat may not be the best for them.

So where

is it? Can do the whole hour on this question.

I know, I know. So where does nuntedinib fit in? If you're going to use immunosuppressants first, fine. But is there a subset of these patients? Must they be UIP?

Must they have a lot of fibrosis to be a good candidate for entendenib?

At least in RA ILD, the UIP pattern seems to be more responsive to both antifibrotics, nantinenib and prevenidone. Systemic sclerosis is a little bit more of a wild card given that NSIP is the predominant pattern, and these drugs do seem to work for them, at least nantinenib. But in RAILD, for non UIP pattern, I'm not sure that I would be reaching for nantinenib or profanidone, at least without exhausting the other options first.

Okay. And I think you want to see that it's progressing because somebody again, if like last week when there was a mentioning of screening all these people with HRCTs at the beginning, we're going to have smokers, older onset RA patients that will have some scarring bilateral from they have emphysema and a little bit of scarring or they have old pneumonia. So it's atypical scarring in that it's only mostly on one side or not at the basis. We're going to find a lot of things that even with honeycombing scarring or traction bronchiectasis kind of words that they might not be progressing. So I think for us as rheumatologists to really seek help in this area is if they don't have a hugely fibrotic CT.

So if it's under twenty percent, which is still a lot or even under ten percent, under twenty percent, but over ten, I'm going get help from a pulmonologist anyway. But I think really you progressing or is it stable? Because all you're going to do right now with the anti fibrotic on the market is you will not stabilize necessarily, you certainly won't improve on average you slow worsening. So that's where I think Jeff, I fully agree that even if it looks pretty fibrotic with the RA, we know that controlling the extrapyramidal disease activity is a good thing for ILD and having it out of control is a bad thing. That's I think also why we would reach for our immune suppressants in an RA patient, even if they're fairly fibrotic in their lungs.

Okay, let's get on to the next issue, which I want everyone to refrain from going a little too berserk over and that being methotrexate and what we in rheumatology think about methotrexate. So here are the ground rules on this. I'm gonna read you the three questions. You're gonna memorize the answers. I'm gonna go to a summary slide, and we can discuss that for about six minutes.

Okay? Otherwise, can do as Jeff said, an hour on this. And so first question, how confident are you distinguishing between ILD due to the disease or idiopathic from methotrexate pneumonitis? And forty nine percent say they're somewhat confident. Twenty five percent say they're confident.

22, twenty three percent saying, No, not confident at all, and some want to wait for the pulmonologist. Next question. In an RA patient on methotrexate, they develop and then are also treated for their ILD and you're going to make the decision about what to do. Will you continue the methotrexate? Yes, fifty two percent.

You're going to ask for pulmonary input twenty six percent. You're going to stop methotrexate nineteen percent. And no one's getting a lung biopsy. I kind of agree with that. And then I asked the same question in a different way.

I think you kind of showed the same true colors. What's your position about treating patients with pre existing lung disease? Again, fifty eight percent say it's okay to use methotrexate if it's needed. Twenty seven percent are exercising caution about using methotrexate in this setting. Eight percent are avoiding methotrexate, and seven percent are consulting.

This is a very controversial area where rheumatology and pulmonary don't often agree on what should happen. I have this summary slide, which is meant to be instructive, that shows that this should be a non issue because hypersensitivity pneumonitis happens early after methotrexate is initiated. It's an acute onset, it's hypersensitivity pneumonitis. On bronchoalveolar lavage, they have lots of polys and they're steroid responsive. On the other hand, RA lung, RAILD, is very slow, takes years to develop.

They often have extra articular manifestations and RA damage and deformity, they're often seropositive, and BAL shows mononuclear cells and they're not steroid responsive. And methotrexate related stuff goes away with steroids and rheumatoid lung does it, has very poor ten year survival. Yet I put in a number of citations which say it's a mixed bag. If you look at the meta analyses on this, it basically says there's very little evidence to suggest methotrexate makes ILD worse. But there is evidence that says that it may be true, which is why some pulmonologists still hold true to this.

So I'm gonna ask my panel to each give you their opinion. I'm gonna start with Elena because she's gotta deal with this over the kitchen table every night because she's married to a pulmonologist. How does that go over dinner?

Well, my husband is very much, pro rheumatology thinking. So he was an early adopter that methotrexate is totally fine.

Okay.

So it goes very well. So, yeah, methotrexate hypersensitivity, I agree with you. It's very hard to distinguish in literature because there is such a mixed bag where they really just had a new diagnosis of ILD. I have had patients that I had to begrudgingly diagnose with methotrexate hypersensitivity. It was very temporally related to me starting methotrexate, and then they were saying, oh, I'm feeling short of breath and kind of coughing a little bit more.

So then I stopped and they, Oh my gosh, improved. So it does happen, but it does not happen in such a profound manner as what ILD is going to look like. I really like that the Spanish Society for Rheumatology actually gives guidelines on the methotrexate already in the RA ILD. So they really don't encourage discontinuation and really just a conversation whether they still need the methotrexate upon diagnosis. Thankfully, I don't have to deal with methotrexate too, too much.

I don't have to argue about it too much just because I'm seeing so much more eye path, and most of the time I will be really targeting their lungs mostly. There is data that methotrexate helps with ILD in RA, but that's not an average patient that I'm seeing.

All right, Janet. So just I think a quick clinical pearl here. To me hypersensitivity pneumonitis with methotrexate, the differential diagnosis is an atypical infection, viral, as for instance COVID or PJP or Legionella or some atypical thing because they often have some eosinophilia because it's kind of an allergic thing and it can fully resolve. It usually responds to stopping the drug and steroids, but most people are bronched and then covered if they suspect any infection. So I think for the listeners, it should not at all be confused, as Jack said.

It should not be confused with a chronic interstitial smoldering and then worsening lung disease. And in fact, maybe our biggest mimicker of an ILD would be those MDA-five that they come in to hospital and are presenting with severe lung disease, rapidly progressive and could be lethal and that's not all the MDA-5s. That might sort of in your mind say oh they had inflammatory, myositis and I started them on methotrexate now this is happening. We blame it more on the MDA-five than the methotrexate but otherwise shouldn't even be in the differential.

Jeff any comment?

All right. I know I don't have the whole hour, so I'm gonna give you some actual data. This is a study that Dan Solomon and I hope to run as a secondary analysis of the cardiovascular inflammation reduction trial, which the largest methotrexate placebo controlled trial ever done. 2,400 participants were randomized to methotrexate, 2,400 randomized to placebo, followed for over two years, and we adjudicated every case. There were seven cases of pneumonitis out of two thousand four hundred patients, zero point three percent.

This is really, really, really rare. And I'll say having tracked down their charts, this was not ILD. This is what you're talking on the left, acute onset, fluffy, fevers, inflammatory, steroid responsive. The other bit of data is that our group did a meta analysis where we looked at every DMARD to see whether there's a future risk of ILD, and we found, seven observational studies that we felt were of high quality that looked at methotrexate versus an alternative comparator. These patients had RA, and the odds of having future incident ILD was zero point four nine.

So less than one meaning perhaps protective. Being cautious, we didn't say it was lowering risk, but it certainly was not increasing risk. So, this is really reassuring about this is an infrequent complication. It's a very different phenotype than ILD, and it doesn't seem to put people down the road to developing ILD in the future.

That's really encouraging. All right. I really appreciate the perspectives on this because there is still a lot of talk, Mainly because we see a lot of ILD and we worry about methotrexate like everyone else. What is the greatest challenge for rheumatologists in dealing with ILD, start ILD or iPath? Delays in diagnosis forty percent, applying guideline recommendations twenty eight percent.

Non specific symptoms, I think that's a real big problem because when you start worrying about this? The earliest symptoms are quite non specific. Then referral and care issues. Anybody want to tackle any of that?

Yeah, I'll take the non specific symptoms part related to screening because what I get talked to a lot is who should we screen and when is it diagnosis versus screening? And the simple answer is, you know, if they're symptomatic, you're going down a diagnostic pathway. And if they're not symptomatic, you're screening. And honestly, the line is so gray, it's incredible because how you ask someone, are you short of breath? They'll say, no.

Can you walk up the stairs? No, I can't. Can you walk three blocks? No, I can't. The amount of sedentary activity, deconditioning, particularly in patients with rheumatic diseases.

So, I think just assessing the symptoms is really hard, not even talking about cough and sputum and chest pain. Sometimes we'll find patients who clearly have ILD, a great extent of UIP, and we look at their questionnaire and they say not symptomatic. When I call them up, tell them about the results, talk about a treatment plan, they suddenly become symptomatic. So I do think that it's really tough to really tease out what's really going on with patients.

Janet, anyone take another part of that pie. What do you think?

Right, so delay in diagnosis. So, okay, I think in scleroderma, it's super important to screen and we do because it's anywhere from as low as twenty five percent to as high as over fifty percent of our patients with systemic sclerosis will have ILD. About half of those, it'll be relevant that it'll probably kill them. So it's not everybody with ILD is going to progress enough to do them in, but many will. When it comes to RA, there will be a delay in diagnosis, and often what happens is when you're going to start an advanced therapy, you do a chest x-ray because for all advanced therapies other than rituximab, we're screening for tuberculosis.

So often the delay is nobody's listened to the bases of their lungs. Again, if you could spend literally thirty seconds per patient with RA in the room, and I do it with all the SARDs, listen to the bases of the lungs bilaterally every visit. You are going to pick up crackles and you're going to get really good at picking up the fine as well. The course are really obvious, but if you don't listen, it's harder to know. And if I go and do an HRCT on every single patient, I'll get a diagnosis group, I'll get an overdiagnosis of false positives, I'm going to get pesky nodules that you have to follow like with 15 other low res regular CTs, etc.

So I'm not sure that in rheumatoid arthritis if I am going to try to treat to a target to remission and if they don't have high and rich risk factors, older age, men, strongly positive RF, smokers, poor disease control and damage, all those things, if they don't have that, I might delay in the diagnosis if there's a 32 year old woman because I am going listen to her bases, but I'm not doing an HRCT on her. I'm just not. Now someone can someday show me the data that I'm wrong, but an RA, it's truly eight percent in the Rochester incident group. It's eight percent in many groups of clinically relevant ILD. There's more ILD than that, and Jeff's group is actually screening a bunch of RA patients to help teach us something about this.

But I don't want to make a diagnosis of something they read about that could be a lethal complication if it's a misdiagnosis. But delay in diagnosis, you don't want to pick them up either when they're so short of breath that they now have hypoxia, they're aspirating that we haven't addressed any of it, and they have pulmonary hypertension.

Elena Kant.

Yes. So I really wanted to emphasize, about applying, guideline recommendations to patients. I think it is a great challenge for rheumatology. And in the ACR chest guidelines, I mean, we just, as Jeff mentioned, we just didn't have the data to really give strong recommendations. And we had the most data on some of the oldest drugs, right, azathioprine and mycophenolate, and they're not really the medications that we as often reach for anymore, especially azathioprine.

So I completely empathize that it is very confusing. We did not have a lot of data to provide really clear recommendations. The EULAR recommendations have the benefit of having some more studies that came out after those ACR chest guidelines came out, but even they are not very strong in many cases, but they do include more drugs. So really, I don't have a great piece of advice for this. I would say keeping up with the literature, remembering that rituximab really has probably some of the strongest data in the most of our SARDs, and waiting, I guess, for the updated recommendations.

And another mention of IPAF, IPAF was not mentioned in the guidelines. So I understand where it is very confusing and very difficult to apply the guideline recommendation to them because they're not even mentioned. So we don't know how to treat them. So that's all to say, there's a lot of work to be done. I hope to contribute to clearing this up in the future years.

So Jeff, I want to ask you a question about rituximab because you kind of alluded to the same point that Elena just did that there seems to be some stronger data maybe. But we've looked at studies, you and I at ACR and EULAR, where they looked at cohorts treated with biologic DMARDs who had ILD. Are very general here. And it showed no difference between the many different biologic classes, MOAs, TNF inhibitors, abatacep, B cell depletion. IL-six might have been in there or not.

So it doesn't stand out that way, but in some studies it does stand out. So should rheumatologists be thinking rituximab first or should they just be thinking be aggressive with the underlying disease as the paramount starting point?

Well, I'll plug that next week, Is it next week there'll be the journal club that will talk about RECITAL, which is a trial of rituximab versus cyclophosphamide, which I think is pretty strong data. Cut to the chase, it showed no difference in efficacy but much better tolerability for rituximab, and we think cyclophosphamide works. So, to me, that's actually really helpful data that rituximab, is helpful in its trial data. The, studies you're alluding to, and we actually have one in the works as well that will be presented at ACR, is using a target trial emulation of observational data, really, really, really large data sets, finding every RA patient, finding those who have ILD, and then finding their first biologic and seeing how the prognosis is. You know, the kind of sticking point that I'll self reflect on given that we're doing some of these as well is that you have two organs that are perhaps both active, perhaps only one of them active.

And, you know, I think in those kind of data sets, you might choose, you know, a TNF inhibitor for someone with a little bit ILD, but a lot of RA articular activity, and vice versa, you might choose rituximab with a lot of ILD and just a little or no arthritis. And those kind of data sets really can't distinguish between those scenarios and basically just kind of treats them as equal. So, suspicion is that there's a channeling towards more severe patients being treated with rituximab. Perhaps that tempers the Those are tough patients and they do okay, you're happy. Vice versa, if you have very mild ILD and a lot of arthritis and you use abatacept, those patients are not going to do very poorly from their lungs.

We know the drug works for their joints. And at the end, that's a wash and those kind of really big data sets that the drugs look equal. But I think if we really had a trial, a dream trial would be to do rituximab versus abatacept or tocids, etcetera, to really know exactly what they're doing at baseline and what the extent of ILD is, what their pattern is, and really understanding what the outcomes are going to be. We are working towards that as well, as you can imagine.

So this question I wanna spend no more than sixty seconds on, who should be treated with combination therapies? I asked this because these patients are really bad, the outcomes are really bad. We wait until they're really bad, and then we start treating them with one drug or whatever. And all of you answered about half that patients with severe progressive disease should get combination. And combination means either combination immunosuppressive or an immunosuppressive with an anti fibrotic is kind of what I'm going for here.

Twenty percent want pulmonary guidance, twenty percent want say those who fail monotherapy. I need a forward answer from each of you as to whether this is right or whether we should just stick to the guidelines. Jeff, you go ahead.

I have a four letter answer, MDA-five. Those patients I would treat as combination immune suppressant. They're rapidly progressive. It's a very lethal in a short amount of time. So those I really give them the full court press.

Think all the rest of them are conditional. There might be a few cases here and there. I might try a combination, but the ones that aren't quite as rapid, I might do sequential therapy instead of comment.

Janet, what would the guidelines say about this answer?

The guidelines would give that very low level evidence, but that's because there is evidence. So the intended trial, both SENSUS and scleroderma in BUILD, which was non IPF patients including our SARD patients in it. And in the latter trial the SARD ones they weren't allowed their background immune suppressants but short answer long answer in a lot of studies, it's Nintendonib plus and Nirandelomast, there was one that will come out soon that seems well tolerated. They could be on Nintendonib and so two fibrotic together, anti fibrotic, but they weren't allowed on immune suppressants that could affect lung. So the short answer is I think no matter what we do, it might not be with guidelines.

There might be some evidence you look to. I think anybody worsening on current therapy, my question is always do I add or switch? And I think the first drug gave some benefit like the and then I'm gonna add basically the anti fibrotic or the next in an active RA patient or an active scleroderma skin as well as lungs. I'm gonna add two immune suppressants, but it's a data free zone, some of what I'm telling you. Elena?

Yeah, I tend to be fairly aggressive, especially with anybody with myositis antibodies. Most of these patients are coming to me on high doses of prednisone, so whatever combination I choose will usually be less, will have less side effects and less immunosuppression than those sixty milligrams of prednisone they've been on. Not to say that everybody's kept on those for weeks. There is an ever ILD trial that compared rituximab plus mmap versus mmap alone in a variety of ILDs with NSIP pattern, and IPAP was represented there. And patients who got combination therapy actually did better with no increase in severe infections.

So this is a very important trial for me. And again, one that emphasizes the use of rituximab and also one that emphasizes combination therapy and ILD.

All right, our last slide, we have two minutes left. These are questions that may exist in the minds of many. First is an ILD patient that we see in our clinics, presumably either an IPAF or a SARD, and they have an associated ILD, should we be evaluating them for lung cancer because of that? Because there are some reports suggesting there may be a link. Anyone want to answer that?

I might answer really fast. So scar carcinoma is very rare. I've seen it in systemic sclerosis under a few times.

Did you say

Yeah, so on and the scar this long standing the idea is the long standing whether it's fibrotic nsip kind of pattern or or whatever you can actually get because it's abnormal cells they can I guess mutate more and you get carcinoma? It doesn't happen very often at all. I think it's a real thing and super What

about regular, you know, small cell, non cell?

I'm gonna say, so these people are sometimes their risk is uncontrolled inflammation, but smoking is a huge risk of all things bad in lungs. However, am I gonna do PET scans on all these people? Not right now. But they're getting CT scans. HRCT is a bit different than a regular CT looking for a little nodule.

Jeff?

Yeah, I think these people, I mean, you worry about them for many reasons, but they are getting serial lung imaging for the most part. I will say, in patient that has bonafide ILD, I'm not too worried about radiation risk, I'm not just monitoring with PFTs. I do think getting an HRCT, you know, about annually makes sense. And, you know, if they have speculated features and, you know, mass like, you know, lymph node that's borderline, definitely low threshold for a repeat CT scan. These patients might need to be biopsied for lung cancer evaluation just to really make sure.

Think these people are monitored pretty close. Think that's already on the radar.

The last question is going to be for Elena. Is any of our patients who have ILD that's severe enough, could they be transplant candidates or is the autoimmune disease make them a non candidate?

They should absolutely be referred for lung transplant. Actually, the other Doctor. Jerns will be talking about it, at some point during this month, but there are actual guidelines from ICEHLT,

which

is the, Heart and Lung Transplant, Association that clearly indicates, that, people with autoimmune ILDs should be transplanted when needed, And it does not necessarily lead to worse outcomes.

I want to thank our panel for a fabulous discussion. I want to thank our sponsor, Boehringer Ingelheim, who has sponsored this month, Room to Breathe, focus on ILD and specifically this webinar. Next week, as Jeff alluded to, we'll be doing Journal Club and talking about pivotal trials. Our two discussants are gonna be pulmonologist Toby Maher and rheumatologist Sherben Assassi. And we're gonna have two pivotal trials.

Think you're gonna like that just as well. That's next week and our final week's gonna be on screening and monitoring. Folks, thank you very much for the time. Great discussion. Good night.