Future Treatment of ILD Save

Hello, everyone. Welcome to Tuesday Night Rheumatology. This is a webinar and this month is devoted to interstitial lung disease. And tonight we're going to be talking about the treatment of ILD and future treatment of ILD. I want to thank this campaign on ILD and the sponsor of it, is Boehringer Ingelheim.

There's a number of things that they've been most helpful with it in doing this. I want you to know that we're going to have Tuesday night rheumatology every Tuesday in the month of September going forward. Tonight is future treatment and treatment of ILD. Next week controversies in ILD. We have Elena Jorns and Jeff Sparks and Janet Pope and someone else is going to be joining us.

The third week, we're going to have a journal club on two important seminal papers on ILD. And our last week, we're going to talk about diagnosis screening and monitoring. So that's every week going forward. I wanna point you to the website which has a ton of content and specifically top right on the email, top right on the website is a therapeutic update where we have a series of videos. And the title of these videos is ILD treatment and guidelines.

And you're gonna find these really, really good. You can watch the videos as I was doing all day today, or you can listen to the podcast of those that's coming up in the next few days and it'll be on the website. So I'd like to begin by having our panelists introduce themselves. I'm the moderator, Cush from Dallas, Texas, Doctor. Johnson.

Hello everyone. My name is Doctor. Cindy Johnson. I'm a rheumatologist at the University of Toronto, director of the Toronto Scleroderma Program and director of the Clinical Epidemiology Program at the Dalla Lana School of Public Health.

Doctor. Shapira.

Hi, everybody. My name is Doctor. Shane Shapira, and I run the interstitial lung disease program as a pulmonologist at the University of Toronto, and I work closely with Doctor. Johnson. I also work with our very large lung transplant program, providing assessments and guidance for patients with ILD who are headed towards lung transplant.

And Doctor. Mattson.

Thanks. I'm happy to be here. My name is Scott Mattson. I'm a pulmonologist at the University of Kansas. I'm the director of our autoimmune interstitial lung disease clinic.

We have a translational research lab that's focused on the use of immunomodulation across forms of pulmonary fibrosis.

Okay, Doctor. Matson's got a great video that's currently on room now that you want to look at. So we're going to actually go over the survey that we sent out this week. It was a one day survey. We warned you about it on Sunday night.

We sent it to you Monday morning. With one email, we got 191 responses from mostly rheumatologists, ninety percent were rheumatologists, six percent were advanced practice providers, and a smattering of pulmonologists, which I was delighted to see. I think it was like two or 3% in there. But this is mostly a rheumatologist response to these 10 questions about treatment. These rheumatologists were mostly in private practice, about 60%, less than a third are coming from academic medicine, and 7% are trainees and fellows.

So let's get into what the questions were and where they are. I want to remind the audience that please ask questions. We want to hear your questions. We want to know what you think. If you ask questions while we're doing this program, we'll ask our panelists live at the same time that we're discussing any point that's in place, so to speak.

So our first question is in your rheumatic patients who have ILD, and again, this is often called CT ILD, term, S A R D, systemic autoimmune rheumatic disease associated ILD. In your patient, who usually treats the ILD? I must say I found this surprising, that two thirds of us are having co management by rheumatology and pulmonary. Twenty two percent of you said I'm managing it. Eleven percent said the pulmonologist is largely doing this.

So we have rheumatologists and we have pulmonologists. What's your perspective on how these people are getting managed? Scott?

Yeah, I mean, I think this is a really interesting response. And I think it probably does speak a little bit to the audience that's responding here. I what we know about the way ILD care is practiced across the world is that even if it's co management, there's various different levels of co management. You know, at some of these academic centers, for instance, where we practice, you know, we have an autoimmune lung disease clinic where rheumatologists and I sit, you know, elbow to elbow, see the same patient make decisions in real time about what we're doing initially and how we're going to change those therapies. But that's a pretty small fraction of the patients that come to our center.

Many of them are managed in a way that I think is probably more common, which is non contiguous, non simultaneous care where, you know, we may see someone write a note, maybe if we're lucky, we can send a text message to the, you know, sharing rheumatologist and talk about changes we're interested in making. But I do think it's one of the really interesting sort of aspects of caring for these people is it's a multidisciplinary care that should be driving most of these decisions. How do you build that kind of shared practice when you're seeing patients and co managing not even across the same center, but often state to state or referrals that come in from community rheumatologists to an academic center or vice versa. So I think it's, it's still probably even more diverse than what co management looks like because I think co management can look like so many different models.

Shane, is it any different in Toronto?

Yeah, I think Scott's point about what part is shared is really interesting. I mean, to me, in my experience, the shared component is for a lot of my colleagues in the pulmonary community, their job is to interpret and make sense of the PFTs and the CT scan. But then what to do with that? A lot of my colleagues really struggle, right? I think when I finished my training in around 2010, mycophenolate was like the new kid on the block and a lot of my colleagues weren't comfortable using mycophenolate.

I think a lot of the pulmonologists now are pretty comfortable using mycophenolate and scleroderma, but they're scared to do it because they don't know things like that the mycophenolate isn't gonna help with the joint disease in rheumatoid arthritis. That's the kind of thing we need our rheumatology colleagues. So I think a lot of my colleagues, they'll say their job is to interpret the PFT and the CT, and then they send a letter to say, Hey, things are getting worse. You decide what we do next.

So Cindy, what happens when you get that letter or that Cottonmouth referral?

Well, very rarely do I ever get a letter from Shane Shapiro asking me what to do next. But I will say, I'm thrilled to see the survey response that the vast majority of people are co managing in some style because that is what the ACR CHEST guidelines are calling for. Sure, you know, rheumatologists are very comfortable with immunosuppressive drugs, especially the toxic ones like cyclophosphamide, And we're comfortable with managing the multisystem disease, but there are many other aspects of ILD care like ambulatory desaturation testing, monitoring, referral for lung transplant. These things are not within the scope of a rheumatologist practice, but a pulmonologist would feel very comfortable.

Okay, that seems reasonable. I think this certainly, if it isn't what people really do, it certainly should be what I think we should be doing because we need certainly the patient is going to benefit from the crosstalk, is it not? So when I asked the rheumatologist, what determines which patient will be treated for ILD? You could see that they're given choices of ILD severity that could be by PFTs or imaging, the presence of extra pulmonary manifestations, patient age. The vast majority of chose all of these.

And so I guess I want to know is it different between pulmonary and rheumatology as to when you pull the trigger and say, I'm going to do more than, I'm going to treat the ILD specifically, whether that's with an immunosuppressant or an anti fibrotic. Cindy, what do you think?

Think who pulls the trigger depends on who the patient saw first. And so, you know, if they get to rheumatology, we're often starting, immunosuppressive therapy or moving to a biologic for the whole disease. Whereas if they see a pulmonologist first, then the pulmonologist will say this ILD needs to be treated or not treated.

Shane, is that worth it?

I'll tell

you in Canada, we're generally opposed to the concept of pulling the trigger in any circumstance. So I don't know if our patients love it if we talk about who's pulling the trigger, but I mean, I agree very much. I think all of these elements really come together and I think it really depends on the path, right? We have a whole bunch of patients who I think have IPF and then three years later, they start to get some joint disease and I've already got them on anti fibroidics. They go to the rheumatologist who says, oh, well now you've got cyanobitis and they'll start them on something for their joints.

But then the flip will be, we get a lot of patients that get referred to us from places like the scleroderma clinic because the truth is we have, particularly they'll send to us when they're looking for us to access antifibroducts, because it's not easy to get these drugs and there's different side effects monitoring. And so we might have different processes in place that make it more easier for us to access those drugs.

So let me show the next slide and then ask Shane this question. I think I'm missing something, anyway, what's the value of immunosuppressants in ILD? I'm worried that rheumatologists, we often use immunosuppressants, that's our preferred drug, because that's what we know. I worry that we may think we're controlling ILD, it's either it's onset, or it's progression by our action, and maybe not considering that we should be doing more or thinking more about ILD. So what's your impression based on the last question and some of this answer right here?

So, I mean, I think that the value of immunosuppression in general in ILD kind of depends on the patient and the clinical phenotype, right? Like I think I really want to look at every patient scan. I sort of consider looking at the CT scan with my own eyes as part of my physical exam in the clinic. So every time you come in, even if the scan was done a year ago, I'm still gonna look at that scan again because I wanna get a sense of if this is an NSIP inflammatory pattern or really fibrotic pattern. In my fibrotic patients, I might say, the real role of mycophenolate is to stabilize or to slow down loss of lung function.

But if I've got a really inflammatory patient with myositis, who's got organizing pneumonia on their CT scan, I'll actually tell them, think drugs like mycophenolate and other immunosuppressants may actually make you better, but it's gonna be slow unless we're gonna use really toxic drugs like prednisone. So we gotta be patient when we start these drugs.

Scott, I don't think I made my point last time. Maybe you can help me with, I think we think that if we're using immunosuppressants, we're treating the disease and that's good enough in treating and forestalling the ILD. Is that true or not true?

Yeah, I mean, honestly, I think this is one of the most important questions we all face from a clinical and a research perspective in this field, especially in the fibrotic autoimmune interstitial lung disease population. You know, I think immune suppression pretty clearly helps appropriate disease control, especially in like the RA population that I think about a lot. Appropriate DMARD use and appropriate disease severity scores on therapy certainly protects against the development of ILD. So that seems to be pretty clear. Targeting disease activity most of all is the sort of most appropriate, you know, guidepost in treating these systemic disease.

And then obviously, even in early onset interstitial lung disease, it appears that that's probably one of the most reasonable targets. If the joints are out of control, the extra pulmonary manifestations are out of control, treat that with immunomodulation. In terms of is immunomodulation the most appropriate treatment for those patients that have autoimmune lung disease that's fibrotic? I think like Shane said, I think there's a lot of concern and a lot of interest in the especially the pulmonary community about do you do about those patients that have a more fibrotic predominant pattern. And certainly the anti fibrotic drugs are aptly named for the use in that population.

But one of the things that we're interested in in our group is, are there patients with autoimmune interstitial lung disease that have fibrotic disease that responds well to immunomodulation? And are there radiographic patterns that predict better response? Because I think a lot of people are operating under that sort of idea that some of these patterns are more inflammatory than others. And it's difficult to say, I mean, when we've looked at some post hoc data, all the pretreatment scans across the scleroderma lung studies one and two, and we looked at quantitative measures of fibrosis in that population. And we assumed that the more fibrosis those patients had, the less FVC response they would have to immunosuppression.

And interestingly, we actually see the opposite, the greater fibrosis score in those patient populations was associated with a better FVC response to cyclophosphamide when we pooled all those patients from the scleroderma lung study. And we saw the same thing in our RE ILD cohorts. And so I think it does beg this question, which is I think we don't know the answer. I think until we get a randomized study that really looks at the role of these kinds of patterns in immunosuppression response, I think it very much remains to be seen whether or not there are some of these patients that still benefit who have fibrotic interstitial lung disease that have a greater benefit from this kind of strategy. I think there's a whole other discussion we'll probably have during the rest of this course about the role of anti fibrotic in this population.

But honestly, I think to me, this is one of the most interesting and important questions. And, that's just that's a lot about the efficacy. I think there's also a lot of very real and important concerns about the safety of adding these to those populations too, which which those data just aren't positioned to help us answer.

Right. Cindy, what do you think?

So I think there there is a role. I mean, this is this is ILD in the setting of systemic autoimmune rheumatic disease is complex. This is not a single mechanism problem. And so we've had great advances in the last fifteen or twenty years with our randomized trials of both Nintanenib and other immunosuppressives. But, you know, if we take lessons from rheumatoid arthritis, congestive heart failure, etcetera, we've learned that it's combination therapy or combination targets that will really see leaps forward.

So I think right now we're in the mindset of immunosuppressive plus so called anti fibrotic, so combination dual therapy in people that are progressing. I think this is just the tip of the iceberg. When we move to talking about the future, I think the real future will be multimodal therapy.

I have a question from the audience from Marilyn Solski, and I'm going to direct this at Shane. Shane, the question has to do with who should prescribe Nintedin, OVEF, a rheumatologist or pulmonologist? The two sides to the coin is that the doctor obviously who is treating the patient, but rheumatologists are reluctant to do so because they have no experience with it. Then the pulmonologist, I think certainly have experience with it. But does that not end up with a lot of people being undertreated if one group is unwilling to do it?

I mean, rheumatologists like Sindhu and others who are in the field who are rheumatologists that are specializing or really interested in their writing for Nintedinib. So what's the advice from pulmonary to rheumatology on starting that drug? Shane, what do you think?

Yeah, I think it really just depends on the comfort of the prescriber. So, I have no problems with the rheumatologists starting anti fibrotic on a shared patient. If they've got fibrotic lung disease, they're getting worse and they say, yeah, they're more breathless. I see that their PFTs were getting worse, but their joints are inactive and I'm gonna go for it and start anti fibrotic therapy. I'm on board.

I think that is gonna continue to be the minority of cases for the same reason why pulmonologists are a little hesitant to start rituximab. Like I start rituximab, but very few of my colleagues feel like they do it enough that they can counsel the patients appropriately, that they can deal with side effects appropriately. So I think the key is, is that if you're gonna be a rheumatologist who starts anti fibroidics, that's totally fine, but you gotta do it enough that you really feel comfortable managing side effects, knowing what to monitor for, knowing when you give up, when do you lower the dose, you got to get critical mass.

Yeah, that's really helpful. I think honestly, I think most would rather refer, but I think this speaks to the importance of co managing. So, another question from Michael, do you think that true co management side by side could lead, both rooms and poems to get more comfortable with each other's therapies. So yeah, I think it would because we have the example of room derm clinics, where they're getting really comfortable managing each side of the fence and room cardiology clinics, the same thing. I mean, the next step would be to have a combined pulmonary rheumatology clinic.

Scott, you have a autoimmune interested in Kansas. Do you have a combined clinic or should you?

Yeah we do have a combined clinic. You know it's myself and a rheumatologist and we're we see new consults as well as patients that we have shared or that people refer from from within our setting. I And think you're right I mean I think it makes these decisions pretty easy in the sense that we can co counsel the patient on you know each other's sort of expected side effects and it makes the discussion especially for you know as as Doctor. Johnson mentioned already, this multimodal therapy is likely the way many of these patients are managed now and will be managed in the future. Because it takes a while to develop that critical mass of experience with both of the medicines and monitoring the side effects simultaneously, I mean, I think it's great.

I mean, it's also true that the patients really enjoy the one clinic visit as opposed to two for the management of their ILD. So that's, you know, one of the major, I think, upsides but, but certainly it's been, you know, I've learned a lot having sat next to the rheumatologist and making these decisions.

Let me go on to the next question. And I got more questions from the audience. I did ask this question. I treat autoimmune disease and ILD because of high mortality, worse quality of life, in thirty percent, better outcomes and newer agents. Cindy, you want to address this or is it pretty accurate, in your opinion as to what's the good reason to treat, SARD ILD?

I mean, think these are all great reasons to treat it. I think the one difficult conversation to have with the patients is that patients, they want to feel better, right? They want to stop coughing, they want to be able to laugh without coughing, they want to be able to work without coughing, or, you know, they want to be able to work without their reduced exercise tolerance. But we, the treating physicians are often focused on improving survival or preventing mortality. And so our objectives and the patient's objectives may not be the same.

And so it sounds like Doctor. Shapiro already level sets in his clinic about being patient, but I think that being clear to the patient about what are our objectives, in contrast to what are their objectives is an important conversation to have.

All right. So let me go on this next issue deals with what drugs do you most rely upon? I alluded to this earlier, rheumatologists are heavily into immunosuppressants. Then if you look on the right, which one do you prefer to use? It's mostly mycophenolate in more than three quarters.

Again, around fifteen percent are using a biologic either rituximab or IL-six. Very little use of azathioprine and cyclophosphamide and antipsychotics and rheumatologists are using very little antifibrotic, that's like 5% or less in this top left graph, that green slice right there. This is saying what we've already said, but I think the question that I have is, should we be using more azathioprine and cyclophosphamide given where it stands on the current guidelines, both from ERS, UR and ACR in chest? Cindy, what do you think?

So the whole azathioprine landing on our menu of options was one of the controversies that happened after the guidelines. And you know, azathioprine is one of our traditional drugs for, you know, physicians that were treating patients in the 80s and the 90s. It's inexpensive. The evidence for it is modest at best. And there is some observational data to suggest that it may do more harm than good.

So lots of reasons for it to be controversial. The reality and so so point number two is guidelines are region specific. So the ETS, CHEST, ACR guidelines are really meant for North America, whereas the ERS guidelines are meant for Europe. And so cultures are different. Some sectors more emphasis on efficacy, less emphasis on toxicity, whereas in North America, we tend to be risk averse.

And so we don't like the toxicity of cyclophosphamide or the toxicity of steroids. So that brings me to the third and final point, is that we also have an increasing middle class, which we call the working poor. So people that are not rich enough to pay for their biologic, like tocilizumab or rituximab, but they don't have private health insurance either to pay for these drugs. So then what happens? And so it was for all of these reasons that azathioprine remained on the menu.

And if you look at, when we get to the slide later about the menu of options, you'll see that azathioprine is quite low. You know, we have better drugs that we all prefer, but what do you do if a patient is not tolerant to mycophenolate, can't take cyclophosphamide for fertility reasons and can't afford a biologic? And so azathioprine is an option in those situations.

I'm gonna put the three of you on the spot on about one drug in particular, that's mycophenolate. The guidelines say that the starting dose of mycophenolate, I believe, is fifteen hundred BID. And can each of you give me a caveat or a pearl about the one thing that most people don't know about using mycophenolate in patients with ILD? Scott, do you have a pearl?

Yeah, it's a good question. We use a lot of mycophenolate in our clinic and you know it is one of those drugs that I feel like you know there's a lot of anecdote but I feel like a lot of patients tolerate it very well without any major issues but there are a few that we see pretty rarely, the ones that we probably see most commonly and this is probably old news for most of the rheumatologists, we see hair loss in some patients, we see a colitis in a small number of patients and then almost probably the most common thing we see is herpes zoster reaction, but this is probably fairly common across many of these drugs.

So if you have to, I'm going ask Shane the same question, also ask you if you have to lower the dose, how low do you go before you switch to another drug? Shane.

To answer the first question, I think those are some good prose. I think the two prose that I would have added is just that out of all of our drugs in my older patients, I have to say, I actually like mycophenolate. Like, give someone who's 82 years old, mycophenolate or an attentive and I tell you which one they're gonna tolerate better. So I think that when we talk about quality of life, that's an important thing to think about as well. One of the ways I've been burned earlier in my career, but still every once in a while is this colitis that Scott mentioned, these patients who come, they just don't feel well, they're losing weight, they're anemic and you can't figure out what it is, they get scoped up and down and then you stop mycophenolate for a month and they're like magically cured.

So those are sort of my two pros and sorry, Jack, what was the main question you asked me that I politician didn't really answer?

You should be running for office. No, if you have to lower the dose, is two thousand good enough or will you put bail below 2,000?

Yeah, in fact, I'm actually pretty comfortable with mycophenolate mofetil using one gram twice a day. I think that's probably a pretty established and reasonable dose. We also use a lot of mycophenolate sodium and I'll use seven twenty BID in that cohort. I think that's a reasonable dose. Once I start getting down to people who can only tolerate five hundred twice a day or seven fifty twice a day.

You know, if they have mild disease, it isn't progressing much. I'll I'll take it. But if that's as high as I can go, that's when we start saying, hey, well, if you're getting worse, maybe we should be thinking about either switching to acythioprine for all the reasons Cindy mentioned, or potentially switching or adding rituximab. In fact, the lower dose, adding rituximab might be a pretty reasonable thing if they're getting worse. I don't know, Cindy, what about you?

What's your lowest dose that you'll take?

How low? One tab So either five hundred BID or three sixty BID.

I'll remind everyone the greatest teratogen that we use in rheumatology is not cyclophosphamide, it's mycophenolate. Luckily, this population isn't enriched for women of childbearing potential, but it's a significant worry nonetheless. So our next question has to do with anti fibrotic. So I want to ask our panel, are the drugs specifically nintedinib, perfenidone and others in development, are they really anti fibrotic given their mechanism of action? Tocilizumab is an IL-six inhibitor.

It's going to treat inflammation, which will help blood flow, which will maybe be anti fibrotic by helping blood flow. Nintedinib is a tyrosine kinase and don't ask me what profanidone is. Pharmacology My professor invented prophenidone and was after me for years trying to tell me it did all kinds of things. But knowing what you know about these drugs, are they really anti fibrotic? Who wants to take a stab at that?

I can jump in. I I I think we should think of these more as fibrostatic rather than anti fibrotic. I I mean, I think really and and that's helpful when we're educating our patients about them too, right? Like, I I I'll be honest, I'm not entirely sure about the anti fibrotic properties of hydroxychloroquine, so I won't comment. But like when we're talking about nantenanib specifically, you know, when when patients hear anti fibrotic, like you think antibiotics that kills all the bacteria and it cures the problem.

And I think it's important that we kind of use the term anti fibrotic and then immediately say, it's not actually anti fibrotic, it's more fibrostatic. We're hoping that it'll slow down progression, interfere with how your body makes new scar tissue so it does it more slowly. That's where I land. And I'm interested to see that provenidone only got eight point one percent because I have to say, there's no doubt Nataneta has better data, but if you really delve down deep into the relief trial and into some of the other studies in non IPF fibrotic ILD. Prophenidone almost certainly also has a pretty established role of being anti fibrotic if you can get it.

Problem is you can't get it because no one will pay for it.

Right. And then we asked, what's their value of the anti fibrotic? But I also threw in the IL-six and rheumatologists said sixty percent is stabilized and flattens FVC, which I believe to be the right answer. But eighteen percent were unsure and fifteen percent said it improves FTC. So what's the truth on these drugs?

Scott?

Yeah, I mean, really think Shane really did a great job of the way that I try to also counsel my patients. You know, if you look at every study of any of the anti fibrotic drugs, and I'll just limit this to propranolone and then tetanib for now. What we know is that they get worse patients on those therapies have a decline in their forced vital capacity over the period of the trial. That's not as significant of a decline as seen in the placebo group, but they start at a level like 72. And at the end of the trial, invariably, it will be below that both groups get worse, it's just that the treatment group doesn't get as bad as the placebo groups.

So even though you know, 59% here say stabilize and flatten, I mean, that's kind of the way I try to counsel it to patients. Really, I think that's the best case scenario. In most cases, what's actually happening is that they're getting worse, but they're not getting as bad as that counterfactual version of themselves that's not on the therapy. And that I think is really difficult from a clinical clinical standpoint, because you start somebody on the therapy and they come back and they come back invariably worse. And what you have to sort of say is, this is what we expect.

And honestly, this is the nature of this drug itself. And unfortunately, the era of these anti fibrotic drugs, there's never been a single randomized study that's shown that they improve survival over the fifty two week period. And with the exception of one post hoc analysis of the in build data, which we could talk about in-depth, but there's also never been a study of an anti fibrotic drug in the apparent RCT that showed a clinically meaningful benefit in health related to quality of life. So these are drugs that have a role, and they certainly slow down progression, But unfortunately for most people, they will never feel as good as the day you start it. And often because of the side effect burden, this is the thing that's really difficult to balance is that they will typically feel worse on those drugs in addition to the financial toxicity that was already mentioned.

So, Cinder, what's the upside?

Well, what's the upside is we're slowing down progression. So but I think we have to be really realistic. Like, you know, that that I'm glad we had the census trial. I was an investigator on the census trial. And so I'm you know, that was a step forward, but, know, I remain optimistic that the next five years we're gonna have bigger steps forward.

And I I feel like I came out pessimistic, but I use the drugs all the time and largely because I think most people have survival expected to be longer than fifty two weeks. And I think it's reasonable to say that if you have a reservation of FVC at a year, and that you multiply that by two years and three years, there probably are very meaningfully clinic, there probably are clinical survival quality of life benefits to be had in that population longer than a year. I just think it's important also to be honest about the nature of the actual data for what we know over that short time period of a year in this population.

So how do you translate the expectation of flattening the FVC to the patient and their expectations when they're having dyspnea on exertion, real limitation to how far they can walk and what they can do? How do you set that up for an expectation with the patient? I don't think we rheumatologists really know how to address that.

Oh, that's too bad because I usually mostly just tell them to go and talk to their rheumatologist about it. Oops. I thought you guys had all the answers.

Well, I can talk a lot about their underlying disease, whether it's myositis or Sjogren's or RA or scleroderma. But again, how it translates to their day to day life, know they're going to want to do whatever they can to retain their function. So that's a big motivator right there.

Yeah, and Jack, I joke, but like the truth is like, I agree with Scott and I know Sendhoo was sort of saying the same, these drugs clearly do work. And I think it's, I am very comfortable saying to my patients that delaying progression is a really meaningful thing. Like in our IPLF court, we've been using this in IPLF for a lot longer. And when I started and we first got these drugs in 2014, 2015, it's true that patients were gone. They didn't come back to my clinic after three, four, five years.

And now I've still got some folks who've been on drug for eight, nine years and who are getting worse, but pretty slow. So, I mean, I try and convey that, that it does work, but this is part of the counseling is that particularly with antifibrotics, we need to think about starting these drugs sooner rather than later. And I'm not suggesting that like everyone who comes into my door on day one gets started on an antifibrotic, but the worst thing we can do is wait until your quality of life is really impaired and then start you on a drug that's gonna slow it down from there, right? That's not the right answer. We need to kind of get in there at that sweet spot where you're clearly getting a little worse, but it's before this is really having a major impact on your quality of life so that we can slow it down from that point as much as possible.

So I wanna get into the guidelines. Today on RheumNow, we published that just came out the European guidelines, two different publications from the ERS and UR that was led by Anna Maria Volkopen, who was supposed to be here but couldn't be here this evening. Anyway, I asked the question of the audience, what guidelines are you familiar with or do you refer to in treating SARDs, that's Systemic Autoimmune Rheumatic Disease Associated ILD. Majority were familiar with the ACR chest guidelines from 2023. Doctor.

Johnson was the lead author on that. Twenty two percent were familiar with the recent ERS UR guidelines just presented at Barcelona in June and published, just last Friday, it was published. A few people are familiar with versions of the ATS guidelines from 2024, not 2025. But nonetheless, that's what we say we're familiar with. But are you really?

So let's go into these guidelines and see what they say. Here, by Doctor. Johnson and published in ANR and ACNR, the 2023 ACR and College of the Chest guideline for treatment of SARs associated ILD. I'll make two statements and then let Doctor. Johnson, the author talk about it.

I like that they divided it up by the most common diseases, scleroderma myositis, MCTD, RA, and Sjogren's. And they give you first line therapy and whether or not you should be using steroids. All of these are conditional, meaning we don't have at the time that we did is we didn't have great evidence for anything. I put in bold the drugs that stand out in certain situations because otherwise, mycophenolate, azathioprine, cyclophosphamide seems to appear on all the lists, either as first line or third line. And then steroids are okay in all of them except for systemic sclerosis.

So those are the things that stand out for me, a prescriber, rheumatologist who sees these patients. Sindhu, what more would you like to impart on the audience about these guidelines?

Well, thank you for the opportunity to explain this a little bit and I'll try to address some of your comments. So yes, so first and foremost, this was a collaboration with the ACR and CHEST. There was a large number of rheumatologists and pulmonologists involved, including Doctor. Matson. He's an author on this guideline as well.

So things to be proud of. Right, we've covered the five biggest diseases in rheumatology that have ILD as a major cause of morbidity and mortality. It did include a review of the literature, so all the major observational studies and clinical trials available at that time, But we also had the largest patient panel of any guideline in the world in rheumatology. And so why is that important? So, okay, I'm gonna take a second just to step back.

If you were practicing medicine in the 1980s and 90s, first of all, ILD was diagnosed on chest x-ray. And we often had to wait for patients to have symptoms or you had to hear crepitations. So these patients were already far advanced by the time they got diagnosed. And in the last ten or fifteen years, we've had clinical trials that you've highlighted the drugs of in this picture. So that is a big leap forward.

But Jack, you mentioned they're all conditional recommendations. Why conditional? Well, that has to do with the certainty of evidence. So clinical trials have better certainty evidence than observational studies. But the major problem we suffer from in the whole of rheumatology is small sample sizes.

Almost all of our clinical trials have hundreds of patients. You know, Janet Polk's methotrexate trial had 35 patients per arm, whereas if you look at cardiology in the statin trials or congestive heart failure trials, they have tens of thousands of patients per arm. So just by virtue of our sample sizes, that reduces the certainty of our evidence. And then the second piece is our primary outcome. You know, doctors love FVC as our primary outcome.

But if you ask patients or the FDA what outcomes do they care about, it's survival, feeling better, or functioning better. And so again, because we doctors do not include a primary outcome that matters to patients or the FDA that reduces the certainty of evidence. So right off the bat, all our recommendations at best will be conditional because there are other factors we need to take into consideration. If we had a clinical question that had five amazing clinical trials, who needs a guideline? Anybody who reads the five clinical trials will know what the answer is.

But in a setting of some evidence that's uncertain and two major organizations that have the resources to bring experts from all over North America together, we now have everybody's opinion on the evidence. But the final point that I'll make about this is that in a situation where you have low certainty evidence informing guidelines, these guidelines in particular are sensitive to patients' preferences and values. And so the therapeutic relationship is important. You really need to know the patient in front of you because whether you'll counsel them on cyclophosphamide may be very different than whether you'll counsel them on rituximab or tocilizumab. And so that's why I said it was so great that we had so many patients informing the guidelines and why things like cyclophosphamide that most doctors are afraid of because of fertility, the patient said, we want that on the menu.

Even if I'm 22 years old and may never have a child again, I wanna know what my options are. So that addresses some of your points. But just to explain this graphic, for every disease, there's a menu of options. You do not have to prescribe in this order. It is just a menu.

And so your choice of option may be, influenced by comorbidities or extrapulmonary manifestations.

I think that the plus for the prescriber was that it was good to have options other than cyclophosphamide to go to first and second. And I think that's a real plus. And it's good to see that the clinical trials in tocilizumab show up on the list for systemic sclerosis and as an option for MCTD. Then we saw the beginning of Nintedim showing up also here that goes further when we look at more recent guidelines that were just published today. Anybody want to make a comment about this before we move on to the recent EULAR guidelines?

Scott?

Yeah, I mean, I think just to further sort of bolster what Simdu has mentioned before about the azobiofarin in this guideline. I mean, I think one of the things I really appreciate about it is just the pragmatic nature of many of the recommendations on this green box. I mean, azathioprine, I think a lot of people in the rheumatology community are reasonably concerned about its use, especially in conditions like rheumatoid arthritis, where we have some obviously RCT level data for similar conditions like IPF of its arm. But I think it's reasonable to say that the evidence we have in RA ILD is pretty minimal. And there's observational data that we've looked across ILD centers for what's most commonly used and azathioprine is still the most commonly used drug prior to 2021.

So even though there are many newer options that have other other observational data, I think it's still true that in the community drugs like that are being used a lot in these populations. And for that reason, I think it was totally reasonable and pragmatic to include them in this guideline.

Cinder, did you at all address in your guideline the use of combined therapy? It seems to me that as bad as the prognosis is for these patients, and as conditional as the data is, why isn't there a much more liberal use of combination or push towards combination?

So there was extensive discussion at the voting panel around combination therapy, and the feeling was for first ILD therapy, monotherapy was the strategy. Because many patients will stabilize or not progress with monotherapy alone. However, we I don't know if you have a slide for what do you do if a patient progresses, and that's where combination therapy, has a role. Before you leave this slide though, the two classes of drugs that we've not really spoken about this evening, but I'd like to draw your attention is in the panel for myositis associated ILD, you've highlighted JAK inhibitors and there's also calcineurin inhibitors. So tacrolimus, right?

So tacrolimus and tofacitinib. For many pulmonologists and rheumatologists, the idea of using these two classes of medications for the treatment of ILD may be new.

Importantly, please correct me if I'm wrong because I'm just a country rheumatologist, but the data in myositis is way better than in all the other conditions where you can actually have a turnaround. You can actually have improvement. Is that right or have I been misled?

I think we would still call it low certainty evidence. We don't have large randomized trials. I think myositis ILD is a different beast than ILD in systemic sclerosis or even rheumatoid arthritis.

Yeah, I like that. I like that a lot.

Even I might just add that even within the myositis cohort there, they are like different animals within the genus, you like you take an MDA five patient and you compare that to a Joe one and they're just like, there is unrelated to how they're gonna behave clinically, how they're gonna respond to immunosuppressive therapy as a scleroderma is to a rheumatoid patient. They are completely different entities, all kind of lumped together. And so I think that's really, the myositis cohort here is the really complicated one. And I think it's a great one to kind of delve into if anyone wants to really sink their teeth into one of these diseases, it's the myositis and thinking of the different subtypes and the different combinations and how you treat. And there's a really lovely table that is at everyone, as a reader of these guidelines, the rapidly progressive ILD, which is a completely different entity, but tends to be that myositis cohort where you really wanna think about these drugs, the calcineurin inhibitors and other potential combination therapies.

So now we're gonna get to the ERS UR guidelines published in Alzheimer's rheumatic disease. And I'm just gonna throw out a bunch of things to start with, that there are general recommendations and there were treatment recommendations. I think on the general side, the issue had to do with screening. And the main issue was everybody should be screened is what they said, except for RA and Sjogren's patients that you should screen if they have risk factors. The risk factors are age, male, smoking, seropositivity, inflammatory markers and disease activity as risk factors.

Maybe you could say the same thing for myositis, that if they have risk factors, anti synthetase syndrome, etc, that they also need to be screened. That the screening tool is high res CT, nobody should do bronchial alveolar lavage unless you're concerned about infection. Here are the general evaluations that you should do at the start and repeatedly. And then there's this laundry list of treatment things that stood out to me is that there are specific rules for profanidone use. There are specific rules for nintedin abuse.

A lot of it has to do with fibrosis, and a lot of it has to do with going more aggressive. Who wants to give us their takeaways? The audience can read these bullets on treatment, cause it tries to address them by RA, by scleroderma associated and then other CTD ILDs. But do each of you have a favorite point that you wanna stress with the audience? Shane, do you wanna take a stab at this?

Oh, yeah, I got a favorite. So my definite favorite from the EULAR versus the really amazing publication by my colleagues on the panel from ACR. But the thing that I was really happy to see in Uilar is the idea of using CT scan for screening. The ATS, sorry, the ACR chest guidelines talk about screening with CT scan and pulmonary function testing. And I always really struggled with that for a couple reasons.

The first is that when we're doing screening, we have to remember the goal of a screening test is to rule out disease. And essentially, I would argue that a high quality, high resolution CT scan with prone images, it's done with a good protocol that doesn't show any ILD has essentially near a 99% ability to rule out disease. And so the idea that you're then gonna do PFTs on top of the CT scan to screen for or rule out disease didn't entirely make sense to me. So that's something I think makes a lot more sense and it's probably quite practical that we don't We use PFTs, don't get me wrong, I love PFTs, I do them all the time, in people who I now know have ILD, but for screening and I just wanna rule out disease, I would use HRCT and I'd pass it on to Scott. What do you think about that difference?

And do you think, are you in agreement with me or do you still think there's a role for PFTs in screening for ILD?

I think that's a really good point. I guess I don't want to get on my own, I don't want get on my particular soapbox, but I'm always a little bit worried about recommendations to screen for a condition that lacks a lot of high quality randomized prospective data in the actual clinical disease state. And so there are some of these conditions I worry a little bit about screening in general, regardless of the etiology that we screen for, just because I think we still are, as a pulmonologist and as somebody who thinks a lot about like fibrotic RA, for instance, I worry still about the lack of any prospective randomized data to support the safety of even the first line conditionally recommended therapies. I think it's the appropriate first line recommended therapy, but it's true still that there's potentially harm from some of those strategies, right? And we know that from similar fibrotic ILDs.

And so one of my global concerns in general is I share I think everybody's hope and desire and belief truly that the only way to bend the natural history of ILD is to identify it earlier and treat it earlier. But I do worry about screening for a condition and then having downstream treatments change as a result of that screening in the absence of some of the clinical data that we still desperately need in the actual clinical disease state. But to speak to Shane's point, I think that's a really great point. I think probably a CT that excludes ILD, there's probably very little added benefit to a PFT at that point.

So these guidelines were very liberal about the use of immunosuppressants to control the underlying disease as is necessary. But then they like to say that when the disease was severe or progressive, they like combinations of drugs, either combining immunosuppressants or combining Nintedinib with immunosuppressive. It seemed like Nintedinib shows up as a recommendation when there's more and more fibrosis or is you guys are great for acronyms that drive us crazy, progressive pulmonary fibrosis. So what's the rule on Nintetinib? When should we be itchy to start that?

I think it's hard for us to answer the question because none of us were on that guideline.

And again, the author of that was going to be here, but that didn't happen. You know

Do you think, I wonder, like Shane, do you think that, and Cindy, do you guys think maybe then, I mean, this is I think one of the difficulties of guidelines is you have to use, you know, the evidence, right, which is appropriate. But I think like to Shane's point earlier, profanidone has been studied in RA and in every other case where it's been studied, it has almost an identical effect and slightly different adverse effect profile, but generally in a similar impact on disease trajectory. And they lack randomized controlled trials as large as an entetinib, it does feel a little bit strange clinically when I use them 100% interchangeably and use patient factors about finances and adverse effects to choose. And then the guideline says use nantetinib and nantetinib when really probably they think that they are fundamentally interchangeable. That's the way I think about it, but I don't know what you guys think.

Well, grading guidelines, win with a clinical trial.

Yeah, totally. 100%. And you're you should, I'm just saying it's

like, immediately on top of the list, but yeah, it's a problem.

Yeah, I think it's important. The only thing I'll disagree with Scott there is that I don't think that they're exactly the same. I suspect that their targets might be a little bit different and we just don't know because no one knows how propranolone actually works, but I totally agree. I mean, every once in a while, a patient will come to me who has ILD that's in a UIP pattern, was previously thought to be IPF, they were tried on intended, they couldn't tolerate it at all, They come to me and they have progressive pulmonary fibrosis or It's really quite fibrotic, but they kind of have to make some pains and their CCP is a little bit positive. And to be honest, what I'll often do is I'll put them on profenadone because at that point they have a diagnosis of IPF.

At the same time as I refer them to rheumatology and let them sort of figure out what's going on with the joints because I mean, we were part of the trail study at our center and I totally agree with Scott, if they didn't meet their primary endpoint, there's a lot of challenges there but to be honest, there is a very consistent signal that's probably just as good as the mycophenolate signal in scleroderma that it never worked. It wasn't a positive trial and yet it's a consistent signal across multiple studies that prevented own also slows progression of fibrotic non IPF ILD.

So we also said that we were going to talk about future treatment in going forward, but we really haven't done much on that. Yet there have been some recent reports and very encouraging things. Shane, do you want to start and say are you most excited about for the future here?

Yeah, I think in my world for sure, the most exciting thing that's coming in the not too distant future actually is gonna be Nerindomilast, which is another drug made by Boringer, the same company that makes Nintendev. And Narendomolast was looked at in a phase two trial that showed some promise and then more recently at the ATS this year in San Francisco, they announced that Narendomolast hit all its primary endpoints in both IPF and non IPF ILD or what we're now calling And Nerindomolast not only did it seem to work as monotherapy but could also be combined with Nintanative as combination therapy on the fibrostatic or anti fibrotic side of things. So I think this is gonna be a really exciting new option for treatments and for me, the thing that is probably most exciting about it is not its efficacy, its efficacy was fine, but what seems really exciting is its safety profile and its toxicity. I mean, we'll see what happens in the real world, but in a clinical trial population, the side effect profile of Narendoma last, which still causes diarrhea like Nintendata, but the side effect profile was profoundly better with a much, much lower rate of discontinuation of the drug because of diarrhea, which is generally the main reason we stopped the drug.

So that's gonna be coming to both Canada and The US presumably in 2026, that's what we're hoping for. So it's not too far away before we might have a new drug available in our arsenal.

Cinder, do you have any other suggestions for the future?

Sure. Well, I mean, can't stop suggestions, but I can tell you what the future will be in the next five years. So first of all, I think we're done with carpet bombing the immune system. No more cyclophosphamide, mycophenolate, azathioprine, things that just suppress everything. I think we're gonna move more and more to targeted immunosuppressive therapy.

So drug to watch for number one is enifrelimab. So immunosuppressives that are already in the market for other diseases. It's in a clinical trial right now for scleroderma associated ILD so keep your eye out for cefnello. The other group of medications to watch out for are the small molecules. There are a number of small molecules under study in phase two and three clinical trials right now.

For example, one is an agonist of melanocortin-one receptor. Would So that be great if we now have an oral immunosuppressive therapy that's not injectable? The third is other monoclonal antibodies. The TNF like cytokine 1A is in the pipeline. That clinical trial is closed.

So the next year or two, we should expect to see results. And then finally, what I actually believe is our future is gonna be immunosuppressive therapies like monoclonal antibodies, but then hit two targets instead of one target. We already see that in oncology and that's what's improved survival dramatically in areas like breast cancer. And there is a phase two clinical trial in first scleroderma ILD that'll be a monoclonal antibody with two targets. And as I said earlier, I think combination therapy is really where we're gonna see the next major leap forward for the management of ILD.

So I only have two minutes left. I wanna ask this one question if someone can answer it. How does a rheumatologist identify the trajectory that we're worried about, the rapidly progressive patient? Can you do that based on two FVCs done three months apart? Or do you need more than that?

And what are we looking at? Because those are obviously thirty percent of patients who have ILD may not ever progress. It's the ones that are going to progress rapidly are the ones who end up in transplant or death or hospitalization. So how we identify them?

Yeah, I mean, I think for those patients who are truly that very worrisome RP ILD phenotype, three months is plenty of time and that much FVC change. I mean, generally this is a very non subtle condition. I mean, many of these are slowly progressive. And I think the ones we're worried about are those that survival is measured in the count on the on the matter of months. And so, in general, most of those patients that come in in this kind of phenotype, I think three months is honestly probably a little too long for some of the follow-up that's required to manage some of these patients.

So I think, yes, certainly, that the symptoms are usually the most important and most guiding principle for those patients. Are not subtle. They're needing a lot of oxygen rapidly is generally the what I've seen. So I think definitely two FEC should be plenty to identify that phenotype.

And lastly, rheumatologists are very concerned about the negative opinion that you cannot use methotrexate in patients who have UIP ILD or NSIP ILD, you're not supposed to use it. We can't use it with hypersensitivity pneumonitis, that makes sense. But can you provide any clarity on what we should be doing there? It's a very controversial issue.

Yeah, it's a tough one. And I'll be willing to stick my neck out and then Sindhu can cut it off if she wants. No one knows the answer. And I think that's why it's like the perennial question. But I will say, now that I've been doing this for a bit, more and more, I feel like it seems to me like methotrexate causes an acute granulomatous pneumonitis rarely it happens, it's been well documented, it's gonna happen early on after you start the drug and that's not really the stuff we're talking about here.

What we're talking about is, is a patient with rheumatoid arthritis, is the methotrexate what's causing the ILD? And I have to say the more and more I do this, the more patients I see, the more papers I read, I'm not convinced that methotrexate causes ILD. In fact, there are lots of studies that show that being on methotrexate is protective in RA because it controls the underlying inflammation and the underlying disease. But what I do think is that there's a reason why I didn't make it into those fantastic ACR chest guidelines that my panelists wrote. We really just don't have any good data that it treats the ILD.

So in my mind, if you're on methotrexate and we find that you have a little bit of interstitial changes, I don't think we need to like stop that drug and make you suffer with joint pains terribly. I think we should be monitoring you over time. And if we see that your ILD is progressing, then we say, okay, well, this drug just isn't working for all the aspects of your disease. And so now it's time to stop this one and find another drug that'll work both for your joints and your lungs. And that's sort of how my paradigm has evolved over the last fifteen years.

Would say, Cindy, I gave you the option now to completely disagree with me. Go for it.

Oh gosh, no. I never want to follow after the eloquent Doctor. Shapira. He's right 100% of the time.

Well, I think it's a good point to end. I want to thank our panel for a really great discussion, really informative. I want to encourage the audience to return here next Tuesday night where we're going to discuss controversies in ILD. I want to thank again the sponsor Boehringer Ingelheim for helping out in this effort. Have a good night everyone.

Good night.