All right, so I'm going to talk about rheumatoid arthritis-associated lung disease. And as I said, I have no conflicts. I'm from the Cleveland Clinic, working with ILD and RLD and transplant patients. So the agenda for the next 10 to 15 minutes is mainly to review manifestations of RA lung disease with a focus on ILD, our approach to treatment options, and to RA-ILD. So rheumatoid arthritis can affect the lungs in many different ways. It can affect the airways, causing bronchiectasis, bronchiolitis, the pleura, leading to pleuritis, pleural effusion. All of these are relatively common complications. And the parenchyma, which is what I'm going to focus on today, leading to interstitial lung disease, and can often cause nodules as well. My focus is going to be more on ILD today, just because we have about 12 minutes. And I think that's all we could really cover. So RA, as you probably know, is the most common inflammatory arthritis, affecting about 1% of the world's population. ILD is incredibly common in RA patients. The onset is typically within the first five years, although you can see patients beyond that as well. 20% of patients do have ILD preceding or concomitant with the diagnosis of RA. Clinical ILD is common, seen in about 10% of patients, more or less, depending on the cohort you look at. And subclinical ILD, which is more like ILAs, or presence of chest x-ray or CT infiltrates in the absence of disease, can be seen in up to 50% of patients. So overall, if you crunch the numbers, if you have 1% of the population approximately having RA, and about 50% of them have some sort of clinical or subclinical disease, that's a pretty common disease, which we all will see as pulmonologists at some point of time or the other. ILD can have a significant impact on our patients who have RA. And this was a cohort from Rochester, Minnesota, where they looked at their population compared to patients who developed RA versus who did not. This was about, I believe, 600 patients or so up there. The average survival in the patients who developed ILD was 2.6 years compared to almost 10 years for RA patients without ILD. So our patients who do develop clinical ILD do significantly worse than those that do not. It is the second most common cause of death in RA. ILD has a significant impact on quality of life. And even as subclinical patients, those with ILAs can often progress in the first couple of years after diagnosis. So something to be aware of and be mindful of, since it can have a significant impact. In terms of what we see on imaging, and this has been our standard modality for screening and diagnosis, a UIP pattern, unlike a lot of the other autoimmune diseases, which my colleagues will talk about, is the most common pattern seen in RA patients in about 50%-70%, I would say, of patients with RA. The pattern can be slightly atypical. So unlike IPF, which is mostly basilar predominant, RA patients can have more upper lobe disease, can have more bronchocentric disease. And in one study, about 10% of patients who had a UIP pattern had an atypical pattern. So something to be mindful of, that in RA patients, you may not see the typical apicobasilar distribution. NSIP, about 30% or so of patients, better prognosis, which we'll talk about in a minute, and more treatment responsive than UIP patients. Bronchiolitis can be seen in about 10%-15% of patients, again, small airway involvement, more an obstructive disease, and a pattern of nodules and often ground glass opacities on imaging. And organizing pneumonia can be seen as an isolated finding, or often on top of other diseases. So it is, it's a good prognosis, it is treatment responsive more than the other patterns. The importance of knowing what the pattern is, is that it can impact your outcomes, and it can affect your treatment algorithm, or how you think about these patients. This was a study out of the UK, where they tried to look at, compare the different patterns of disease that they saw on CT scans, and how it impacted outcomes, and compared it to IPF patients. So on this Kaplan-Meier survival curve, the black line is patients with IPF. The blue line here is patients who had a UIP pattern, both the classical IPF pattern, as well as the atypical features of more upper-low predominant. As you can see, the survival in patients with UIP, RA-UIP, and that with IPF, was similar. The red line is patients with probable UIP, and the yellow was inconsistent with UIP. So what they concluded was patients with RA-UIP have similar outcomes to IPF patients. And not surprisingly, patients who have inconsistent UIP do better than probable, who do better than the definite UIP pattern. They also looked at the extent of disease severity, and limited disease patients did much better than extensive disease patients. So not all RA-ILDs the same, and the disease pattern and extent on CT scan can be significant. Moving on for the next five to seven minutes, I'm going to talk about management. And before I get into that, just a warning or some disclosures that we don't have data. We have minimal data. There are no guidelines specific for RA-ILD patients. There's one RCT, which was published last month, so this is good timing. And most of what I'm saying is based on expert opinion, me being the expert here. So when we look at our options, there are steroids, which are probably go-to for everything we can think of. There are the immunosuppression or disease-modifying agents, and there are antifibrotics, being the three different classes. And we go into different options that expands our pool even more and makes it more confusing. And we have all these different options, which we can use in patients with autoimmune diseases. I am not going to go through all of them, but I am going to talk about a few, which we commonly use in RA, which we probably don't use in some of the other autoimmune diseases, and talk a little bit about antifibrotics as well, since that's where we have some evidence. So methotrexate, it's the big boogeyman in pulmonary medicine. We're always worried about bad things it can do. As soon as a patient comes to us, very often we end up stopping it, just being worried about could this be the cause. So this was a paper out of, which was a multi-center study. They initially looked at the French registry and wanted to see how the exposure to methotrexate impacts ILD diagnosis, or is there a difference between patients who were exposed to methotrexate versus not, in terms of ILD incidence. They found that the incidence of ILD was significantly lower, with an odds ratio of 0.4, in patients who were exposed to methotrexate, compared to those RA patients who did not receive methotrexate. And in the patients who developed ILD, the onset was significantly delayed to 11 years versus four years. So I don't know if methotrexate works for treatment of RA ILD, but at least from the data we have, it does not seem to hurt, and probably helps. Stomach methotrexate pneumonitis, since that always comes up when we talk about methotrexate, it is seen early on after exposure, usually in the first year. Incidence is about 1%. I think that's overblown. In randomized controlled trials, they did not see any cases of pneumonitis. Presentation is mainly acute, subacute HP, ground glass capacities, and poorly formed granulomas. The ULAR and ACR recently updated their recommendation, and methotrexate is now recommended with very low quality evidence over other agents in patients with RA ILD, or in patients with RA with mild ILD. So TNF-alpha inhibitors, another very commonly used medication for RA. Not a lot of data in ILD patients. This was about 42 patients who had RA ILD and were on TNF inhibitors, and they found that a year after treatment, there was no change, no worsening, no improvement in many different parameters, including CT ILD extent. So it potentially stabilizes ILD, but very, very minimal and poor quality data. However, the reason we worry about it is there have been over 100 reports of rapidly progressive ILD and potentially increasing mortality in ILD patients. This was not borne out in cohort studies, not borne out in randomized controlled trials, but it is something to be mindful of. My practice is if they're on it, they're doing okay, I keep it on. If they're doing poorly or getting worse, I would stop the medication. Moving on to Abariceb, this is a T cell inhibitor, which here they looked at, again, RA ILD patients, most of them with mild disease, about 60% with asymptomatic or mild dyspnea, and they found that most patients, over 90% had stable dyspnea, over 75% had stable CT findings. So again, commonly used with RA, potentially helps stabilize disease. In this study, which was retrospective, most patients had very mild disease. So potentially works, but we don't really know. Rituximab is another favorite of pulmonologists, I think we use it for everything. This was a study looking out of the UK, looking at rituximab for RA ILD patients, and what they found was it did help decrease the rate of progression, in the sense the DLCO rate or decline decreased one year after rituximab, and from an FEC standpoint, there was, I would say, stabilization, perhaps mild improvement in that time. In this study, 60% of patients had NSIP, so slightly atypical for what we would see with just RA ILD patients. So to put it all together, I don't think there's any evidence supporting a single agent or which agent to use in RA, and I'm sure there are other studies which I haven't quoted here which could show some different findings. So pick your poison is what I would say for RA. Main indication where I would start these medicines is if you have joint disease. It could help stabilize inflammatory ILD, and we often use it in our NSIP and OP patients, especially if you're having trouble getting them off of steroids. Moving on, the next few minutes, I'm going to talk about antifibrotics, again, something we're all used to as pulmonologists if we take care of IPF patients. So this was the in-built trial where they looked at about 663 patients for non-IPF progressive disease, patients who've progressed in the last two years. They all had a fibrotic pattern, and they were not on immune suppression. Out of this cohort, about 90 patients or 89 patients were with RA, and 75% of those had a UIP pattern. They did find that there was a significant reduction in the rate of progression in terms of FVC. In the overall population, the relative reduction was 57%. In patients with a UIP pattern, the reduction was slightly more at 61%. Based on this study, nintenamib or OFEV is approved for progressive fibrotic ILD, which includes RA-ILD. So that is something we have been using, and we have been prescribing for our progressive patients. The other study we just came out, which Dr. Danoff was one of the lead authors, was the TRAIL-1 study, which was published last month. Here they looked at specifically patients with RA-ILD, and they enrolled 123 patients, and they had to stop the study early because of COVID and poor enrollment. The inclusion criteria here was slightly different. This was fibrotic disease, but they did not have to be progressive. Unlike the in-built study, 90% of the patients were on DMARDs, and about 50% of patients had a UIP pattern, which is similar to what we would expect in RA-ILD patients. This study was a negative study in the sense there was no difference in the primary endpoint, which was a composite outcome of drop in FVC more than 10% or mortality. However, they did find a decrease in rate of decline of FVC, and if you look here, there's a difference of 80 cc's per year between the aspirate or between the profanadone and the control group. In patients who had, when they looked at the subgroups of patients with and without a UIP pattern, the UIP population did show the same kind of difference. In fact, improved, increased difference between the two groups, but in patients who did not have a UIP pattern, which was about 40 something percent of the population, there was no difference between the profanadone and the placebo group. This is not yet approved for, or FDA approved for RA-ILD, based at least on this trial yet. It may, I'm not sure, down the road. But my takeaway is yes, it does seem to work in terms of decreasing rate of progression in RA-ILD patients where fibrosis perhaps works better in patients with a UIP pattern. So in conclusion, UIP is the most common form of RA-ILD, and I think RA patients behave more like IPF than they do like other autoimmune lung diseases. While DMRDs may help stabilize disease, mainly inflammatory disease, it's not something I commonly start on RA-ILD patients unless they look very inflammatory on CT or they have organ, or we are having trouble getting them off steroids. They are low risk for pulmonary toxicity, and I do not stop them unless I have a good reason to. And antifibrotics I think are going to be the future, at least for the RA group of patients. They do help slow down the rate of progression. Thank you. I'm going to talk for the next 12 to 15 minutes about managing interstitial lung disease associated with autoimmune myositis. And I chose, rather than printing up a nice picture of Johns Hopkins, I liked your Cleveland Clinic logo, I wanted to show some of the things that, as a pulmonologist, you may be less familiar with, and that is the skin manifestations of dermatomyositis. And often when we're looking at patients who have interstitial lung disease associated with inflammatory myopathies, the key is to actually recognize the skin disease, because many of our patients are clinically amyopathic, so they don't really come in complaining of weakness necessarily, but they'll often have very subtle skin findings. The other thing I wanted to highlight in this image, and I'm not sure it's terribly well shown because it's kind of bright in the room, but most of the books that you'll see will show you the manifestations of dermatomyositis on light-colored skin, on Caucasian skin. And I think it's really important to recognize the features of disease on other skin that's melanotic. And so you can see in the top left, you'll see what we call, it is called technically periungual erythema, but it's actually darkening and ragged cuticles. The next one on the top is a classic dermatomyositis with Gautrin's findings. In the bottom left, you can see a punched-out lesion that we might see in MDA-5. And on the right is another finding that you may not have seen, which is actually calcinosis, and this can go along with patients who have dermatomyositis or scleroderma. So what I want to do in the next couple of minutes, and I'm sorry, I do have disclosures, none are specifically related to this, but I want to be absolutely clear that I do work with some of the companies. And as you heard, I was involved with that clinical trial in RA. I want to talk about the spectrum of myositis-associated interstitial lung disease, and then I want to talk about approaches to treatment. I want to tell you about a patient who I actually saw fairly recently. This is a woman who, 63, from West Africa. She had been in the U.S. for 25 years. She was completely well until February of this year, then developed shortness of breath and got admitted to a local hospital for pneumonia. And then there was also some thought about heart failure. She gets diarrheas, treated with antibiotics and discharged. Very reasonable. If you get ill in the winter, pneumonia is a pretty reasonable thing to think that a person has. But seven days later, she comes back and she has worsening dyspnea and hypoxemia. And now the question of her having interstitial lung disease comes up. And she gets treated with steroids and she gets discharged now on three liters of oxygen. So over the course of very few weeks, she's gone from needing nothing to needing three liters. She comes back into the same hospital 14 days later, basically in hypoxemic respiratory failure on a high-flow nasal cannula. And now, because the thought is maybe she has some sort of systemic disease, she gets more labs drawn and she has a CK over 1,000 and an aldolase over 40. And so suddenly the idea that she might be a patient who has autoimmune myositis pops up. And she ends up getting transferred to us. And I'll tell you more about her story a little bit later. I do want to show you her imaging, because I think that this is something that, you know, every time I see this, I get a sort of a lump in my throat where a patient who has been completely well shows up in your emergency room, your ICU, on your floor, who has one of these very diffuse inflammatory lung diseases, where clearly, although this looks like at baseline that it was probably an NSIP pattern, that it's become so diffuse that you're really now starting to think about this as being an ARDS. Or in our prior vocabulary, we would have called it a Hammond-Rich or an AIP. And this patient really meets that definition very rapidly progressive over a short period of time, now in hypoxemic respiratory failure. OK. So my question to you is, what are you going to do? This patient shows up. You've seen these patients. This patient shows up in your emergency room. I should have warned you these are ARS questions. So what would you do? Let's see if I can get this to work. OK. So do you want to do a bronchoscopy? Do you want to get some PFTs, understand where she is? Do you want to get autoimmune serology? Do you want to order an echo? Do you want to start her on an immunosuppressant, like an oral mycophenolate? All right. OK. I love it. OK. So part of the thing is that we always describe this as being like you get one choice. But the reality is we're doing everything all at once. This woman is in your ICU. You're getting an echo. You're starting her on meds. You're maybe getting a bronch because you're not sure what you're dealing with. This could be an infection. But one of the things I think is really important is to have that very on the tip of your mind that you need to send autoimmune serologies. And part of the reason we know that this needs to be done is that we know that across all autoimmune diseases, there's actually a relatively high prevalence of interstitial lung disease. And it varies. You're hearing about a bunch of these today. But what I'll point out is that in the polymyositis, dermatomyositis, it can be as 80% of patients have interstitial lung disease. We consider myositis to be rare. But in the world of interstitial lung disease, it's the most common thing that I see, certainly in terms of newly diagnosed interstitial lung disease. And so when we have a patient who comes in with a new ILD, and really regardless of how they present, but particularly if they present acutely, these are the things that we're going to be sending off on them. And again, what we're looking for is a clue that we've got an autoimmune disease. So sometimes all we find is that we have a really high SED rate in CRP because not all of the labs, not all of the diseases that people have have an autoantibody that we can test for in a lab. However, I do want to spend a minute and just point out that there are a large number of myositis autoantibodies. The ones that are probably best known are the antisynthetase, which are directed against tRNA synthetases. There are eight of them that are recognized and tested for. There are also myositis-specific antibodies, and I'll point out MDA5, which was relatively recently recognized, causes a lot of our acute myositis rapidly progressive ILD. But also the myositis-associated antibodies, like Rho52. We increasingly see patients who are presenting with ILD with Rho52 alone. Chances are they have another antibody, we just don't know how to test for it yet. So just to kind of keep in mind that it's really important to be looking for these. These are not antibodies like ANA, where you'll see them just through the population. If you see somebody who has a PL12, that's a pretty significant antibody. And now why do I say this? And that's because I work hand-in-hand with our rheumatologists, and one of the things we've had to come to terms with over time is that when you talk to a rheumatologist, myositis is a group of disorders that are defined by muscle weakness and or pain or skin rash. And these are the sorts of things that our rheumatology colleagues are looking for. But really to a pulmonologist, this is what autoimmune myositis is. It's a group of interstitial lung disease characterized by these unique autoantibodies and variable muscle and skin involvement. So a lot of the discussions we have with our rheumatologists is where they say to me, well, you know, but the patient doesn't have this classic finding, so they don't meet current ACR criteria. I'm like, I don't care. This patient has an antibody that is a very rare autoantibody, and they have interstitial lung disease. Give them time. They'll develop the skin rash, or they'll develop the muscle abnormalities. But this is autoimmune myositis. And the word I like to use for those patients is pneumomyositis. That is, just like there's dermatomyositis, there is pneumomyositis. When you look at a study, this is a study that Josh Solomon did a while ago now, looking at how often the lung is involved versus how often the muscles are involved, what you can see is that there are certain autoantibodies like PL12 and PL7 and KS that are essentially uniquely lung disease. And so when we see people who pop up with a PL12 or a PL7, I'm not really looking for anything other than lung involvement when I'm evaluating the patient. Now when you think about what a rheumatologist sees, a rheumatologist sees patients who come in with muscle weakness and pain, and therefore they tend to see more JO1 patients where muscle involvement is a more common feature. This is just to point out that MDA5, which I think now everybody is familiar with, has an incredibly high rate of lung involvement, but also to point out the fact that the degree of lung involvement actually depends on the continent that you're on. And so in Asia, this is really very uniquely associated with rapidly progressive interstitial lung disease. In the U.S., it's not nearly as tightly linked to that rapidly progressive disease, and in fact, we see many folks who have very mild lung disease associated with MDA5 in the U.S. But having ILD is actually incredibly important. If you have it, it doubles your risk of dying from your myositis, doubles your risk of death. And depending on what type you have, if you have a clinically amyopathic dermatomyositis or MDA5, it can actually even further impair your likelihood of survival. So I want to do essentially an approach to thinking about treatment. And again, I'm going to say exactly the same thing that Dr. Sehgal said, which is we do not have a lot of randomized controlled trials. And this picture is here to remind me that we do not do a randomized controlled trial to determine if a parachute helps your outcome if you jump out of a plane. And the reason is that it just doesn't make sense to do that randomized controlled trial. And so this is very similar. We need to treat these patients. These patients are often amazingly sick. And therefore, we need to treat. And we do need to understand which drugs are best for which circumstances. But you're not going to see a lot of randomized controlled trials in this area, at least until we have the networks we need in order to do them. So just to kind of go back, a lot of the therapy is based on contemporary therapy for muscle and skin. Corticosteroids were the initial therapy. I'm actually going to show you the study that shows that steroids alone are not sufficient. And then the rest of it is largely case series. So this is actually the study that indicated that you couldn't just treat with prednisone. This is something I see frequently in patients who are treated and they're given a course of prednisone. They have organizing pneumonia. They get better. The prednisone is tapered. And just as in this study, patients relapse within 6 to 12 months of stopping steroids. And that's because the trigger's not gone. It's the autoimmune disease. So then we move into, what kind of drugs can you use as steroid sparing agents? This is a study, a retrospective study we did at Hopkins where we looked at 110 patients. And basically, if I had to tell you what the take-home message is, is almost any steroid sparing agent is better than nothing at all. And they all seem to work in terms of improving FBC and decreasing steroid need. And so that's true for mycophenolate and azathioprine. That's definitely true for the calcineurin inhibitors, which are drugs that are, I think, perhaps slightly more commonly used in Asia and Europe than we do in the U.S., but are still incredibly effective drugs. And similarly for IVIG, so any of these drugs is a reasonable next step, but steroids alone is probably not reasonable. This is a study that was done looking at refractory CTDs. Most of the studies that have been done have actually had groups that include myositis but are not unique to myositis. And this one, again, included five of the eight refractory patients in this study were myositis ILDs. And basically it was if you failed steroids and cyclophosphamide, you got Rituxan. And basically what it shows is, you know, Rituxan works pretty well too. This is a study that was just presented at ATS. It's only in abstract form currently, but basically it's a study in the UK looking at cyclophosphamide versus Rituximab. Again, there were a number of myositis patients in here. It amounted to about half of the patient population. And what you can see is, in comparison to cyclophosphamide, Rituximab is essentially equal. And why does this matter? Because very frequently our colleagues from rheumatology will suggest using cyclophosphamide as the first drug if a patient presents with an interstitial lung disease that's very severe. And this shows you that Rituximab is probably an equivalent medication. Now what I'm going to do in the next slide is I'm going to actually tell you what it is that we do. And I have to say, this is completely an approach. Do not take this as endorsed by any society. But basically what we've used is the strategy of, what does the patient look like when they walk in? If they have mild disease and they really don't have symptoms, we will watch those patients. Because although I didn't point it out, there are many patients who have CT evidence of interstitial lung disease but do not have clinically apparent interstitial lung disease, which will be a theme, I think, amongst all of us. If they do, we will start a steroid sparing agent. If they do have symptoms but they have very mild disease, we may never give steroids to that patient because they don't need it. They don't need that rapid intervention. On the other side, where we have the very severe hospitalized patients, if they have not been on a drug previously, we will essentially give solumetrol and IVIG and then we'll initiate tacrolimus. And that is just a pattern that has worked for us. Every single institution has something they feel comfortable with and that they use as their common approach. But this is our common approach. The thing you'll see missing on mine is that we do not use cyclophosphamide anymore, or at least we try to avoid it. Not because it doesn't work. It works great. It's just unpredictable. You may end up with patients with no white count afterwards and then you have to worry about infection. And then what we'll do is we'll keep reassessing. If they get worse, there are other things that you can do. We give rituximab. We even consider Plex sometimes if a patient is very severely ill. But the bottom line is that patients move side to side in this. So as they get better, then they move into this stack and then they might move into this stack. The other thing is don't wait for autoantibody testing. They take so long. If you think the patient has an acute myositis consistent interstitial lung disease, go ahead and treat aggressively because these patients often don't have a long time if you wait to get a diagnosis. All right. And I cannot stop without talking about supportive care. Every one of our ILD patients should have supportive care. This is a wonderful diagram that was set up by colleagues, Manon and colleagues. And I think every one of our patients should have the benefit of this supportive care. And so just in summary regarding immunosuppressives, they're inappropriately selected and monitored. I should definitely point out everybody needs to be monitored when they're on immunosuppressants. It can improve FEC and DLCO. Not shown, they're effective in treatment of muscle and skin disease in contrast to antifibrotics which only treat the lung. And some patients progress despite immunosuppressive therapy. And then you have to decide about whether you're going to escalate therapy or whether you're going to change and potentially add in an antifibrotic. And I'll leave that to the discussion section. Oh, I should tell you about our patient. She got pulse steroids, IVIG, tacrolimus, rituximab. She was intubated for two months in our ICU. I spent a lot of time talking with her family regarding goals of care. And she was transitioned to inpatient rehab. She's fully weaned from a ventilator and she's on supplemental oxygen. So this was a win. All right. Thank you all very much. How do I get out of this? Okay. I'll just use the pad. The pad? Okay. Okay. I'm Kristen Hyland. I'm Director of the Rheumatic Lung Disease Program at the Cleveland Clinic. And I'm trained in both pulmonary, which I did first, and rheumatology. I told my rheumatologist, I'm going to do a little bit of both. I'm going to do a little bit of both. I'm a big P, little R. I try to stay in the lungs as much as possible. And I'm going to talk about scleroderma. There are multiple things that can happen in scleroderma, including pulmonary hypertension. But I'm going to focus on scleroderma-associated interstitial lung disease. I have several disclosures. I am working with a number of pharmaceutical companies on various clinical trials in scleroderma. I also would like to point out that we only have a few drugs that are FDA-approved for scleroderma. Luckily, I can say that. A few years ago, we had zero. Nintendidib is approved for scleroderma-interstitial lung disease, and progressive fibrosin ILD and tocilizumab is approved for scleroderma-associated interstitial lung disease. So I'd like to kind of echo what Dr. Danoff said, is that these connective tissue diseases can be very subtle sometimes. And in 2013, the criteria for scleroderma was revised to include not only the fibrotic changes, the skin changes, which is the hallmark of scleroderma, but to incorporate some of the vascular changes and immunologic changes. So for those of you that are evaluating an interstitial lung disease patient, scleroderma can be quite subtle in some patients. You could have a digital ulcer and a telangiectasia and a scleroderma-associated autoantibody and a history of renal phenomenon, and you have a diagnosis of scleroderma without the typical skin involvement that you might be accustomed to. When I think of the trajectory of scleroderma, I think of interstitial lung disease as something that happens very early, when there's a lot of inflammation happening. And the vasculopathy happens a little bit more down the road. But you can have ILD at any time, and you can have pulmonary hypertension at any time, even as a presenting manifestation. But as a rule of thumb, think about interstitial lung disease as something that's happening very early in the disease process. And to make things even more challenging, there are patients that have both pulmonary hypertension and interstitial lung disease. So the prevalence of interstitial lung disease depends on how you look for it. If you're looking on autopsy or HRCT, you can see evidence of interstitial lung disease in a majority of patients. Fortunately, chronic respiratory failure or clinically significant ILD is in the range of 10% to 15%. It's more likely to occur in patients with diffuse skin involvement, which means they have skin involvement on their trunk and their proximal limbs. But you can also see this in limited cutaneous scleroderma. This is the old CREST variant, where the skin involvement is limited to below the knee, below the elbow, and the face and neck. So all patients with scleroderma need to be evaluated for the presence of interstitial lung disease. And that's because it's a leading cause of morbidity and mortality, with an 80% survival at five years and less than a 50% survival at 15 years. Scleroderma ILD is generally something we see in the fifth decade. It's female predominant. And it has worse prognosis in African-Americans, and particularly African-American men. And so there was a Delphi consensus regarding screening and monitoring recommendations. And so upon the diagnosis of scleroderma, all patients need to be screened for interstitial lung disease. And this includes pulmonary function testing, but also a baseline HRCT. And just like Dr. Danoff said, in myositis, these patients need to be followed for progression. And we know that pulmonary function testing can miss interstitial lung disease. We have between 120% predicted and 80% predicted for normal, for force vital capacity. And so in this study, there were over 60% of patients that had significant interstitial lung disease on HRCT, with an FEC greater than 80% predicted. And so without that baseline HRCT, there's a high false negative rate, high risk of misdiagnosis in clinical practice. Unlike rheumatoid arthritis, the histopathology of scleroderma interstitial lung disease and our other connective tissue diseases is that of NSIP. And it is a fibrotic NSIP. And so sometimes it can be a little bit tricky to distinguish this from patients with more of a UIP pattern. But typically you see some degree of ground glass opacities. And the pathogenesis of scleroderma interstitial lung disease is similar to the pathogenesis of our other connective tissue disease associated interstitial lung diseases, where there is a tissue injury in a genetically susceptible individual. That injury may be gastroesophageal reflux, which is super important. It may be something that is in the environment, like organic solvents, silica. Could be a virus. Could be related to oxidative stress. And that causes an epithelial injury, but there's also a vascular injury. We know that if we do bronchoscopy on these patients, there's elevated levels of thrombin in the BAL. And this results in tissue hypoxia and ineffective angiogenesis. We also have disordered autoimmunity that leads to inflammation. We used to think that scleroderma was just a T cell disease, but we are increasingly recognizing the role of B cells. And ultimately this leads to fibrosis. So it's a combination of disordered fibrotic, vascular, and immunologic pathways that drive this disease. And because it's NSIP, if you look at the entire cohort, there's a slower rate of decline in forced vital capacity compared with IPF, for instance. But we still have those patients that are slow progressors, intermediate, and rapid progressors. And it's those rapid progressors that we really want to be able to identify and intervene early in. So one simple way of staging patients with scleroderma interstitial lung disease is the GO staging method out of the Brompton, where you just look at the CT scan. And you have five minutes to decide, is there less than 10% fibrosis, greater than 30%? And that's limited versus extensive. If you're like, well, I'm not sure. Somewhere in that 10% to 30% range, maybe it's 20%. Then you look at the FEC. If the FEC is greater than 70%, that's limited. Extent of ILD, if it's less than 70%, the patient has extensive disease. And so these are the patients we probably should be treating, those with extensive disease. But we probably should be treating those with less extensive disease that show evidence of progression, that their forced vital capacity has dropped by 10%. Or their diffusion has dropped by greater than 15% with a more moderate decline in forced vital capacity. Or they have worsening HRCT. Or symptoms that you can attribute to ILD. Or these are patients that you know are set up to do poorly. And so what are those risk factors? African-Americans, the male gender, genetic polymorphisms, diffuse patients, diffuse cutaneous infections, particularly with the anti-SCL70 antibody are more likely to do poorly. Those with a lot of vascular manifestations, like nail fold capillary abnormalities or digital ulcers, or if they already have pulmonary hypertension and primary cardiac dysfunction and ILD, that's a bad combination. And again, patients with early disease you have to be the most worried about. So the father of modern rheumatology used to say no drug has truly failed until it's been tried in scleroderma. But we have had some successes. And the first early success was the assembly of the scleroderma mafia to actually study scleroderma interstitial lung disease. And we're looking forward to the rheumatoid arthritis mafia and the myositis mafia doing the same things. But the scleroderma mafia really set the way on how to study these patients with connective tissue disease and ILD. And so their first study randomized patients to oral cyclophosphamide for one year versus placebo for one year. And then they were followed for an additional year on nothing. And what this study showed was that there was a very modest improvement in forced vital capacity, 2.6 milliliters, or 2.6%, which is not a whole lot of milliliters, versus a decline in patients on placebo. But when they followed these patients for two years, that treatment effect was gone. And certainly cyclophosphamide has a lot of toxicity, as we've already heard, and we cannot leave people on cyclophosphamide forever. And so that prompted scleroderma lung study number two, where this was originally designed to be a superiority study, because the investigators thought you'll be on oral cyclophosphamide for a year, and then you'll be on placebo for a year, so you will have lost your treatment effect, versus mycophenolate for the full two years. Well interestingly, in this study, the cyclophosphamide arm did not lose their treatment effect. This was a negative study. But it showed that mycophenolate worked pretty much just as well as cyclophosphamide, and it certainly had less toxicity. And so at this point, mycophenolate more or less became the standard of care in the United States. And then along comes the FOCUS study. Now this was a skin study, where the lung was a secondary endpoint. And it was a negative skin study. It did not show any effect in the skin, which there's a lot of endpoint issues when you're trying to do a skin study. But in this study, patients were recruited that were highly inflammatory, had very early disease. They had diffuse skin disease with a pretty significant skin involvement by modified rodent skin score. They had elevated inflammatory markers, a CRP, sed rate, platelets, and they were on nothing else. And they were randomized to tocilizumab versus placebo as a sub-Q injection every week. And the primary endpoint was at 48 weeks. And so some of the lessons learned from this study is this was the patients they were recruiting were early skin disease, not lung patients. They had an average FVC of 80% predicted, yet there were over 60%, 65% of patients had underlying interstitial lung disease. And these were very, very early patients with scleroderma less than two years. So interstitial lung disease happens early. If you don't get that HRCT, you miss it. And then when they looked at the population, all patients versus if you look at the graph on the right, those are the patients with interstitial lung disease, the 65%. Almost 25% of the placebo had a drop in their FVC by 10% at 48 weeks. So progression in scleroderma happens early. And this is data from a long time ago from Dr. Steen at Georgetown that shows the greatest risk of forced vital capacity decline happens early, which is why when you look at scleroderma trials, the population that gets enrolled is usually within five to seven years of having the disease. And so the lungs was a key secondary endpoint. And you can see again on the right-hand panel, those are the patients with interstitial lung disease. There was a significant difference in forced vital capacity at 48 weeks of 238 milliliters, which is pretty significant compared to some of our other interstitial lung disease trials. In addition, they did quantitative HRCT on these patients and showed that there was less evidence of interstitial lung disease and fibrosis. So taken together, the FDA actually approached the company and said, even though your primary endpoint is negative, this lung data is significant enough. Go ahead and apply to have FDA approval. And it was approved for scleroderma-associated interstitial lung disease with the caveat that this was a very select patient population that was studied. Well, like we've heard, we tend to put rituximab in our orange juice. I have some every morning. And so does rituximab work for scleroderma interstitial lung disease? We don't really know. But in this study, the USTAR is a huge European registry of scleroderma patients. They looked at 254 scleroderma patients that were getting rituximab for all sorts of reasons. Could be their skin, could be joints, could be muscle. About 181 of them had scleroderma-associated interstitial lung disease. And there seemed to be, this is registry data, a decrease in the modified RONIN skin score. But it's hard to say what was happening with the lungs. And so we certainly await that rituximab versus cyclophosphamide study that Dr. Danoff presented for all sorts of patients with connective tissue disease to kind of inform the role for rituximab in scleroderma. So the census study, which I was fortunate to have a major role in, led to actually our very first FDA-approved therapy for scleroderma-associated interstitial lung disease, which was Nintenidib. Patients were randomized to Nintenidib versus placebo. They were allowed to be on background mycophenolate. They had to be on stable dose for six months. Or methotrexate, which is commonly used for skin disease. Mostly everybody in the United States was on background mycophenolate. Also in England, and then the rest of the world was on, or did not have background mycophenolate. And what the study showed was that there was a difference in the rate of forced vital capacity decline in patients randomized to Nintenidib, a 44% relative reduction, which is similar to the relative reduction that was seen in the IPF studies, although the actual milliliters was much more modest. And keeping in mind these patients have a slower rate of decline in their forced vital capacity due to the fact that they have NSIP. And when you look at the mycophenolate subgroups, there was no statistical difference between the four groups of mycophenolate plus Nintenidib versus mycophenolate versus Nintenidib versus neither. But there is some numerical differences. The study was not designed to show these differences. But it appears that mycophenolate plus Nintenidib does a little bit better numerically than Nintenidib alone, which is better than mycophenolate alone, which is better than neither. So this at least gives us more data that mycophenolate is helpful in addition to maybe some rationale for combination therapy. So scleroderma lung study number three, which is wrapping up, is looking at profenadone. And they're also trying to answer, should we do upfront combination therapy? So these are new patients with scleroderma interstitial lung disease that get randomized to mycophenolate plus profenadone versus mycophenolate plus placebo. And I suspect that the data from this study will be out within hopefully sometime this year. Autologous stem cell transplantation, we don't do this at the Cleveland Clinic. I did a few of these when I was at my last institution. This is something that has some recommendations in the guidelines for treating scleroderma interstitial lung disease in that there is improved event-free survival downstream. But if you look early up, there's increased morbidity and mortality. And the patients enrolled in these stem cell transplant studies, although the majority they have of these patients had interstitial lung disease, it was pretty modest with baseline force vital capacities in the high 70%, 80% range. They were getting these stem cell transplants for other threatened organ indications. And there was some modest change in force vital capacity down the road. This is not something that I strongly advocate for. And certainly if you're going down that direction, go to centers of excellence that actually do this routinely. So our approach is, you know, should the patient get combination therapy? Should they get monotherapy? I usually start on the monotherapy arm. I look, how much ground glass is there? If it seems really just fibrotic, I go towards nintendonib. If there's significant ground glass, then I'm going to start an immunomodulator therapy and I'm going to think about mycophenolate, I'm going to think about tocilizumab. I may think about cyclophosphamide, however, I hardly ever do that in scleroderma due to the toxicities. These patients are going to be monitored. Evidence of progression, they're going to end up with combination therapy still monitored. I may change immunomodulator therapy. I encourage my patients to do clinical trials. I might rescue them with rituximab. I refer them for lung transplant. And you know, Dr. Sehgal here is focusing on transplant and connective tissue disease. And there are a lot of considerations to transplanting a patient with CTD. And there are some guidelines from the International Society of Heart Lung Transplant on this population. And certainly as Dr. Danoff said, we should be thinking about treating the comorbidities. We should be treating their symptoms. We should be referring them for palliative care. Now I'd like to finish just pulmonary hypertension is such an important comorbidity. And the combination of pulmonary hypertension and interstitial lung disease is particularly bad. And we do have some options. So the increased study, studied inhaled troposinol for group three, pulmonary hypertension related to interstitial lung disease. This showed at week 16 an improvement in six-minute walk distance. There was also a reduction in antiprobian P and a reduction in time to clinical worsening. But bringing it back to the vascular pathways as part of the etiology, they saw a signal. So they got force vital capacity as a safety endpoint. And they showed that there seemed to be a difference in force vital capacity in patients randomized to troposinol versus those on placebo. And so this is now being studied. Inhaled troposinol is being studied as a treatment for interstitial lung disease. So this story is yet to unfold, but I think it's pretty interesting. And so with that, I'll finish up by saying interstitial lung disease and scleroderma is a leading cause of morbidity and mortality. The pathology involves the interplay of disordered fibrotic, immunologic, and vascular pathways. There's increasing evidence for the role of immunomodulator therapy. There's added benefit of the addition of antifibrotic therapy as seen in the census study and hopefully in scleroderma lung study number three. And inhaled troposinol appears to improve outcomes in patients with connective tissue disease associated interstitial lung disease, because 26% of those patients had a connective tissue disease, primarily scleroderma, and who group three. And that is all I have. Thank you. Okay. Good morning. I hope that all of you have enough caffeine in your systems to keep going. I'll make this relatively brief, because the themes are very similar to those raised by my colleagues. So of course, we all know that ankylovasculitis is not the only kind of vasculitis, but it is very common that we make the cognitive error to rule it out without tests. So hence my little cartoon on the first slide. I'm Erin Kamak. I'm here from the University of Kentucky in beautiful Lexington, Kentucky today. I'm their new program director for Pulmonary and Critical Care Fellowship. I don't have anything to disclose. And we'll skip past the objectives. So pull out your device of choice, and we're going to do an audience response slide. So vasculitis that affects the lung predominantly affects which of the following types of vessels? Large vessels, medium vessels, small vessels, or all vessels? All right, it's hard to trick all of you. It is predominantly a small vessel vasculitis. So when we're talking about pulmonary vasculitis, we're really talking only about small vessel vasculitis. To break down a slide that's less complex than this, small vessel vasculitis includes those with a paucity of immune complexes, which are the ANCA-associated, mostly, vasculitises, and those that are immune-complex-mediated, which could be related to cryoglobulinemia, Goodpasture syndrome, henoctionline purpura, and lupus. We try not to use the former names that are listed on the slide, specifically Wegener's and Churg-Strauss. Unfortunately, Drs. Wegener, Churg, and Strauss all have mixed histories that are no longer something we want to include in medicine. So we're going to call this eGPA, GPA, and MPA. Our pulmonary manifestations come in a variety of flavors, and ILD can interact with all of them. You can have a large airway stenosis, pulmonary nodules, which may cavitate, and diffuse alveolar hemorrhage, which we all see in the ICU on a regular basis. We'll go through each of the types of pauci-immune disease first, starting with eGPA. Your patients may present with variable symptoms that could be part of any of the underlying causes like nasal polyposis, rhinosinusitis, and asthma, and they may present also variably with DAH, eosinophilic pneumonia, or migratory infiltrates. These things can be present in a milieu, they can be present in acute and subacute forms, and there are pulmonary manifestations in 70 to 90% of patients, so it's very common. It can be very difficult with eGPA patients to identify exactly which of these pieces are causing their symptoms when they first present. GPA patients are more commonly associated with nodules and cavities. They more likely have large airway stenosis, and DAH is a predominant feature of this disease as well. More than 80% of GPA patients will have pulmonary manifestations. You all have seen patients like this patient before. She has a very prominent saddle nose deformity, but I wanted to bring to your attention that this can start quite early in life and quite early in the course of disease and can be quite subtle. Patients like this may have more active disease than they seem to have at time of presentation. MPA is associated with lung predominant findings, DAH and DAD. There also may be constitutional symptoms and nephritis may be a feature. Pulmonary findings are less common than in the other post-immune diseases in 30 to 60% of patients. Anka in anka-positive vasculitis is not always present. Anka neither rules in nor rules out the diagnosis. The prevalence varies between the diseases and the type of anka may vary in the diseases. Prior to the more recent era, we predominantly did anka by direct immunofluorescence. More modern anka testing is done by ELISA. I would ask you to keep an eye on your epic when you type in your anka and ensure that you are getting the ELISA test. The pathophysiology is quite complex, but suffice to say that genetic predisposition plus a variety of possible environmental exposures is thought to result in loss of tolerance to the MPO and PR3 proteins, which are leading downstream to expression of IL-17 and other immunomodulators, which result in increased fibroblast proliferation and myofibroblast differentiation. All of the above can lead to pulmonary capillaritis, hemorrhage, and ILD. So pull your phone back out. Which of the following can cause a false positive anka? Is it rheumatoid arthritis? Is it HIV, monoclonal gammopathy, too early in the morning, tuberculosis, or all of the above? For the purposes of this question, we're going to say false positive, meaning that the primary disease here is not a vasculitis. All of the above. You are hard to trick with an all of the above question. That is absolutely correct. Rheumatoid arthritis, HIV, monoclonal gammopathy, and tuberculosis can all cause a false positive ANCA. This is why the American College of Rheumatology recommends that we not send ANCA testing unless we have symptoms of vasculitis. This is important because a false positive ANCA can really lead the team down an incorrect diagnostic track and can lead to patient harm. Since treatment for these diseases is so important, it must be so early, and it must be aggressive, it could expose the patient to quite a lot of unnecessary risk. Tools that we have to clarify the diagnosis other than ANCA testing. We can look at labs for other autoimmune and connective tissue diseases. We of course can do our high-res CT, which of course every patient should have when ILD is suspected. CT of the sinuses can help to clarify the presence of polyposis or early saddle nose deformity. Echocardiogram is mandatory because unfortunately, like my colleagues have mentioned for other diseases, pulmonary hypertension can be co-occurring. Bronchoscopy can be very useful, especially when you have a suspicion for GPA because you can have stenosis of large airways, which can be the result of quite a lot of symptoms. And tissue biopsy is also something that can be helpful. Bronchoscopy of course for diffuse alveolar hemorrhage is the confirmatory test. Interstitial lung disease in those with vasculitis is of course, just like other connective tissue diseases, associated with a worsening likelihood of survival. UIP, like in many other diseases, is the most frequent pattern that we see, although you may have some degree of ground glass capacities, reticulations, and honeycombs. Be aware also that the presence of DAH, the presence of large airways stenosis, can really impact your imaging findings as well. And it's important to really have that 360 degree view of your patient. The first presentation, like many other connective tissue diseases, may be ILD. The patient may have ILD before they have other findings of their connective tissue disease. The form first presentation. It is interesting to me that you can develop an ENCA positivity later in the course of your illness, and that it can take up to five years for a patient who really does present with obvious vasculitis to become ENCA positive. So again, ENCA neither rules in nor rules out the presence of disease. As in other lung diseases, UIP portends a worse prognosis. The relative risk of death is 4.36 for UIP. The multidisciplinary committee at your institution can be a very helpful tool to help clarify the underlying diagnosis. It's always very heartening for me when I bring a difficult case to the MDC and everyone else shrugs their shoulders and goes, oh my, I don't know. Surely it does make me feel better. I think they feel me over here. Patients with progressive disease may consider antifibrotic therapies. Testing should never be one size fits all for patients. ENCA should not be sent just for any person presenting with ILD. And ILD may be the form first, the first presentation of systemic disease. The serologic findings may lag. Radiographic and histologic findings are diverse and can affect one another. As far as management, unlike some of the other CTDs, induction therapy is a big feature of vasculitis. We hope to achieve remission in patients quickly and then maintain that remission over time. The treatment paradigm changes as we go through these phases. All of the above should require multidisciplinary care and follow up. But if, like me, you're practicing somewhere where not all patients have easy access to a rheumatologist right away, you as the pulmonary and critical care person may need to be the person who begins treatment for the patient. Waiting five or six months for a rheumatologic appointment could be deadly for the patients in this population. We of course have access to glucocorticoids, immunosuppressive agents, interventional pulmonary techniques to deal with the airway stenosis that we may experience, and of course antifibrotic therapies. The paradigm for treatment of patients that has been proposed in the pulmonary literature will often depend upon the high-res CT pattern. This is interesting because it really contradicts the paradigm for treatment that is supported by the American College of Rheumatology. As with other ILDs, UIP patients are thought to have a higher likelihood of benefiting from antifibrotic treatment. And then those who have ground glass capacities or other evidence of acute inflammation may more benefit from immunomodulatory agents, which can then be escalated in the evidence of progressive disease. The American College of Rheumatology, this is the evidence-based recommendations for the management of anka-associated vasculitis generally. They suggest that in any person who has an anka-associated vasculitis who has organ or life-threatening disease, which here I would suggest that ILD certainly qualifies for that category, induction therapy should be aggressive and should start with cyclophosphamide or rituximab with a glucocorticoid. After remission is introduced, the patient could then be converted to azathioprine, methotrexate, or rituximab with a taper of glucocorticoids. Maintenance of remission could then hopefully be maintained by a less expensive oral therapy. In patients like this, azathioprine has some randomized controlled trial data that suggests that it may be superior to methotrexate or mycophenolate. And rituximab, since it's in our orange juice, is of course here for everything. So I would argue that although the pulmonary paradigm here suggests that UIP patients may not be treated in the same way as other patients are treated, I would consider any ILD to be an organ or life-threatening disease. And if we have clear evidence that this patient has ankylovasculitis, we should be proceeding with aggressive therapy along the lines of inducing and maintaining remission. This is the way that the guidelines suggest that prednisone could be tapered for these patients over a period of 26 weeks. This allows the patient to declare themselves if their disease is going to re-flare and come out of control. So a few take-home points. Active vasculitis requires an individualized, detailed approach with a lot of different diagnostic modalities. Patient symptoms can come from any part of the pulmonary complications from vasculitis, and not all ankylovasculitis is ANCA positive. Not all ankylovasculitis is ANCA positive. We should send ANCA ELISA testing whenever vasculitis is suspected and alternative etiologies have been ruled out. Pulmonary manifestations are extremely common and are diverse. And active vasculitis requires very quick movement towards induction therapy to induce remission followed by maintenance therapy. We are very grateful that you came early this morning to spend your time with us on these difficult cases, and we hope that you will evaluate our session in the app.

interstitial lung diseases

autoimmune conditions

rheumatoid arthritis

scleroderma

vasculitis

pulmonary and critical care medicine

airways

pleura

parenchyma

quality of life