Thank you, everyone, for showing up in Hawaii and for this session. My name is Rachana Krishna. I'm at the Medical University of South Carolina in Charleston. I'm one of the ILD pulmonologists there. And we have a good panel here today. Thank you to the panel members for helping with this talk. We have Dr. Erin Wilfong, who is a uniquely trained rheumatologist and pulmonologist. She's at Vanderbilt. And we'll be giving the rheumatology perspective. And we have Dr. Andrew Chirg, who is a lung pathologist at the University of British Columbia in Canada. And Dr. Jonathan Chung, who is a thoracic radiologist, now going to be at UCSD, I understand. So he's going to do the radiology perspective. And then we'll come back and we'll do a case together. And then we'll hopefully have time for questions, which will be important. So we'll get started soon. So Dr. Erin Wilfong will go first. All right, thank you so much. So the goals for this, for my part of the presentation, is really going to be about appreciating the importance of recognizing CTD-ILD. So I'm not actually going to talk about therapeutics at all in this talk. I'll point out some reviews at the end that are useful. But I've seen more CTD-ILD as a pulmonologist than I ever saw as a rheumatology fellow. And so you guys, whether you want to be or not, you're on the front lines. And so that's why the approach I've taken today is really to help you recognize the things that we're taught in rheumatology fellowship that show up in your clinic. And so that's the way that I want to approach this. We'll review the key manifestations. I've got lots of pictures, both of Caucasian skin and skin of color. And then we'll understand when to refer for rheumatology avail. So why does this matter? Why is this such a big issue to properly identify CTD-ILD? And the real reason is that immunosuppression improves outcomes. Antifibrotic slow decline. If you treat somebody with CTD-ILD with immunosuppression, they can improve their lung function. And this is true for systemic sclerosis, myositis, RA. And even patients with UIP improve with treatment. This is a new paper this year. It led out of Colorado, but other centers were included that looked at patients with RA and what happened to them when they were started on lung targeted immunosuppression, being mycophenolate, Rituxoraza. And what you can see is that when they're started on therapy, their decline stopped overall. And these are UIP, right? So there's a benefit for UIP. Same for scleroderma. So this is a small study. But again, looking at mycophenolate versus placebo for six months. And again, in UIP, mycophenolate patients over six months did not have an appreciable difference in lung function. And you see that FVC decline in six months on patients who did not get anything. And in myositis, probably one of the other more common causes, when you treat with immunosuppression, these patients do markedly better than patients with IPF. So recognizing this is key because it actually helps us find these patients, treat them, and prolong their life, and improve their quality of life. And I want to start by talking about interstitial pneumonia with autoimmune features and really highlight that this is a research classification criteria. So this was never validated for diagnosis. This is for research, as are actually all of the ACR guidelines for classification of scleroderma, RA, myositis. These were designed for homogenous research populations, not for clinical use for diagnosis. And so it's a thought construct. And the thought construct saying that if we have serologic abnormalities that are concerning for autoimmunity, if we have morphologic abnormalities like NSIP or organizing pneumonia or clinical features, those patients may be more likely to have a rheumatologic disease and may be more likely to respond to immunosuppression. And when this was subsequently looked at, a positive ANA alone is not going to change your outcomes if you treat with immunosuppression or not. Those patients really had no difference. But if you focus on patients with clinical domain and with morphological domain, those patients had a survival benefit over IPF patients. And so again, IPF is really trying to say, can we find patients on the spectrum of connective tissue disease who would be more likely to benefit from treatment? And it's critical to realize that multiple rheumatic diseases can cause ILD. Rheumatoid arthritis is by far the most prevalent. This is in 1% to 2% of the general population, depending on the series, 16% to 40% of patients with RA-ILD. So really common. Myositis is under-recognized, I think. I think it's out there more than we recognize. Scleroderma, of course. Ankylvasculitis in an IPF. And so really evaluating signs and symptoms of this disease. And just once again, please don't use the classification criteria to diagnose somebody. It won't work. So what about RA-ILD? So RA-ILD has to be CCP positive. If it's a rheumatoid factor positive, it is not causing your ILD. The CCP antibodies are likely pathogenic. And so again, RA-ILD equals CCP positive. Now, if you're RF positive, you may have something else. But be very cautious calling that RA. Look for your myositis, your anka, your scleroderma, some other cause. And it's even prevalent in elderly persons, 10% to 15% at least. 10% of patients with RA-ILD will develop their lung disease prior to articular disease. And uncontrolled articular disease will drive progression. So really important to work closely with your rheumatology colleagues. These patients need to be aggressively treated from an articular standpoint. And they may need additional adjuvant therapies. For the inflammatory myositis, this is very heterogeneous. It's kind of, you know, there's all different flavors of asthma. There's all different immune endotypes. There are all different types of myositis. And the autoantibodies best correlate with disease presentations. So realize that what we're really looking at here are the ones that can cause lung disease, commonly antisynthetase syndrome, MDA-5, the overlap antibodies, Ku and PMSCL. And then Rho-52 can be seen with any of those and is a bad player. So patients who are Rho-52 positive tend to have more ILD, tend to have a more progressive course. And these can also present as ILD-limited. And that makes it really hard to diagnose when it's limited to the lung. This is most commonly seen in antisynthetase and MDA-5. And I want to really highlight that these disproportionately affect women and individuals of color. One of my colleagues frequently says that we are anti-racist and ageist. If you have a young woman of color, she does not have IPF. Please get her to see a rheumatologist because we can probably help you figure out what's going on if it's not clear hypersensitivity. Lab screening needs to include a CK, aldolase, LDH, and extended myositis panel. And I want to spend a moment walking through these skin findings because they look different on Caucasian skin and of skin of color. So what you can see here is that in Caucasian skin, you're going to have these red knuckles. That's just going to be hyperpigmented on skin of color. For a heliotrope rash, which is going to be more red and violaceous, can just be along the lash line. That's going to transluminate purple on your skin of color. So get your otoscope or your ophthalmoscope and shine light on that eyelid. And it'll almost look like a purple eye shadow. And then mechanic's hands, again, cracking on the sides of the hands will be seen there. MDA5 autoantibodies, again, one of the most common and most deadly forms of myositis ILD. This can be lethal 70% at one year in some series. This is very interferon-mediated. Mycophenolate may not work well for these people. So the best data is for calcineurins, JAK inhibitors, and rituximab. Practically speaking, somebody can walk out of your office with a tacrolimus prescription. It's going to be a little bit harder to get the other two in their hands quickly. Some of my colleagues at Brigham and Women's are working with dermatology, and everyone is being diagnosed with eczema. And so since JAKs are approved for eczema, that may be a way to get around some of that for your MDA5s. We all do it. All right, so other things to think about for exams. So palmar papules, so this is one of the pathognomonic findings of MDA5. If you have these two findings, you don't need the antibody, just start treating. And you're going to have almost Osler's nodes at the creases of the hands. It's going to be very tender. It can ulcerate. It's going to be a little bit reddish-purplish, because it's kind of a vasculopathic lesion. Or you can have ulcerations. Now, all of the pictures in the ACR are of these huge ulcer knuckles. It'll get there. But when it starts, it's just going to be gotchons with a very small white dot in the middle where it's starting to ulcerate. Please don't let it get all the way ulcerated before we recognize it. OK. All right. For systemic sclerosis, 50% of patients will have ILD. This tends to be an early manifestation. So if you have somebody who gives you a history that they've had signs and symptoms of scleroderma for 30 years, and they were just incidentally found to have ILD, probably not going to be a huge problem for them. It tends, if it's going to be bad, to progress early. It can occur with any of the scleroderma autoantibodies. We're taught a lot that SCL70 has ILD, and centromere has pulmonary hypertension. That doesn't really hold very well in the real world. Almost all of these patients, over 95%, should be ANA positive. And they should have Raynaud's phenomenon. Lots of folks will tell you that they have Raynaud's. If you show them pictures on Google Images, they will either, if they have it, start critiquing the pictures and telling you exactly how theirs is different from the pictures online, or they look at you with horror. So that's something I use very commonly to help tease that apart. Again, a couple few things to highlight. So telangiectasias on Caucasian skin are going to be these red papules. On skin of color, it's just going to be brown, hyperpigmented, squared-off spots. It's not going to be as red as you'd expect on Caucasian skin. Another thing to recognize is ankylovasculitis. This is an uncommon cause of interstitial lung disease. Tends to be UIP, tends to have worse patterns, and you should screen for it as well. Just keep in mind, most patients with DAH will not hemoptysis. I know we're not focusing on that today, but worth mentioning. In terms of the ATS guidelines, for patients with a new ILD diagnosis, they should be screened for CTDs. So how do I approach this screening for CTD-ILD? So history, do they have inflammatory arthritis? So arthritis that's worse in the morning when they first wake up. Do they have myalgias or weakness? Do they have Raynaud's? Do they have rash? Putting them in a hospital gown. Actually doing a really good skin exam, making sure that there aren't any rashes we're missing. And then if you're at a university, they're going to have already vetted a panel for you, but I know lots of folks in the audience are not at a university hospital. These are the codes for LabCorp that they now send to RDL that are Mayo labs that you can use. So when would I say that patients should be referred to rheumatology? Any time that you're worried, right? If there's anything on your history or physical or labs that's concerning for a possible CTD, send them. I tell my pulmonary colleagues, I'd rather see eight patients who don't have anything to find that one person who does than miss a bunch of people not seeing enough rule-outs. Anyone with an SIP pattern without a clear etiology should be seen by a rheumatologist. And anyone who is female, sex, non-Caucasian race, and individuals under 40 are the highest risk. So it's never wrong. There's no risk to a conversation when we're thinking about surgical lung biopsy potentially. And so the key takeaways, CTD-ILD is treatable, but we have to recognize it. And these patients are more likely to present to you in pulmonary clinic than they are to rheumatologists. Immunosuppression may benefit CTD-UIP especially early. And close collaboration is critical. And finding a rheumatologist who's comfortable with these folks and just having a good open relationship can be beneficial. These are some key references. Please note the ACR actually just published their CTD-ILD guideline about six weeks ago now. So that's there, along with some other references. And thank you for your attention. I'm going to go over the session notes before Dr. Chung can start his session. I forgot to do that in the beginning. But a reminder to everyone that all the sessions can be evaluated through the mobile app. And we will have an audience response question for the last session. So we can use the QR code. I'll show that at the beginning of the slides. And then CME claiming will open Wednesday, October 11 at noon. So we'll have Dr. Chung. Thank you so much. Great pleasure to be here. So I'll be talking about the imaging, specifically CT of connected tissues related ILD. So I'll be covering a lot of different things, a little bit kind of in a surface level standpoint. If you have a deeper question about a specific CTD, we can talk afterwards. These are my disclosures, none of which are directly pertinent to this talk. So if after this talk, you guys can recognize the common pulmonary manifestations of CTD, ILD on CT, understand the general pulmonary complications of common CTDs, and you list the most common pulmonary manifestations of specific CTDs, I feel like it would have been successful. All right, so these are all the things that we're going to cover today. So I have now 14 minutes to do this. I can do this. Believe it or not, I can actually do this. So we're going to start with myositis first. Before we do that, we're actually going to talk about just kind of overview of generally when you should start thinking about CTD. So if someone kind of came off the street and you did a CT scan, you saw some of these manifestations, when should your interest be piqued and say, oh, this might actually be a connective tissue disease related case and not just your run-of-the-mill IPF case. So obviously, we talked about demographics already. But in terms of the CT scan themselves, if you see specific interstitial pneumonia patterns, like any pneumonia pattern, even if it's UIP, you should think about CTD, at least in the back of your mind. Obviously, if it's NSIP, nonspecific interstitial pneumonitis, or organized pneumonia, or lymphocytic interstitial pneumonitis, these kind of patterns, obviously, it goes higher up on your differential diagnosis. But even a regular UIP pattern can be attributed to CTD-ILD. Obviously, pleural disease is also associated with connective tissue disease, so things like pleural effusions, pleural thickening especially. Sometimes we all see pericardial thickening. Certain patients with CTD can also develop bronchiexis, obliterated bronchiolitis, or follicular bronchiolitis, which manifests as central lobular nodules. And obviously, we know the association with pulmonary hypertension. OK, so this is a nice table. And we'll go back to this table for you guys who likes tables. My summary slide will be this table. But depending on what type of CTD you have, the different patterns of lung disease, the interstitial, idiopathic interstitial pneumonia patterns, will be more or less common. So in RA, UIP is really the most common pattern that I see in my clinical practice. I think the data supports that. But you can also see NSIP in organizing pneumonia as well. These patients will also sometimes develop obliterated bronchiolitis and bronchiectasis. In the setting of systemic sclerosis, NSIP, that's the one that I see most often. But every once in a while, you'll see UIP as well. In the setting of myositis, or polydermatomyositis, and their cousin, the antisynthetic syndrome, the NSIP-OP combined pattern is very funny. It likes to occur together. I'll show you some examples of that and how that evolves longitudinally over time. Very, very characteristic. Sometimes you'll just see the NSIP pattern. Sometimes you'll see more of an OP pattern. But these two things usually occur together, especially in initial presentation, when the patient's having sort of an acute flare. And in Sjogren's syndrome, we think about LIP. And that's usually actually, in the chronic setting, a diffuse cystic lung disease. Okay, so let's hit it. Let's talk about, I said I was gonna start with myositis, I lied. I'm gonna start with rheumatoid arthritis. Rheumatoid arthritis, I already talked about. The most common pattern we see is UIP. And we talked about the airway disease as well. In these patients, I always kind of, I keep an eye out for any pleural disease, any chronic pleural fusion, pleural thickening, also pericardial thickening as well. These patients can develop pulmonary hypertension. And then necrobiotic nodules can form in these patients as well. It's sort of the same histopathology as the skin lesions that these patients get. We're not gonna talk about that. I don't really consider that interstitial lung disease. But if you're interested, I could show you some examples on my phone later. We just don't have the time. So this is a classic UIP pattern of pulmonary fibrosis that we see in rheumatoid arthritis. Clearly peripheral, clearly basal predominant. This patient actually has something called the exuberant honeycombing sign. So if the fibrosis is comprised of greater than 70%, so not the lung, the fibrosis component is comprised of greater than 70% of honeycombing, we call it exuberant honeycombing sign. And so we have shown, we did a study here that came out of University of Chicago when I was there. That's now been validated by the Inova group. That showed that if you have that exuberant honeycombing sign and a UIP pattern, much, much more likely to be connective tissue disease related, usually RA, sometimes mixed connective tissue disease, as opposed to IPF. So that's actually very powerful. Also, we saw these other signs as well. There's something called the straight edge sign. What's a straight edge sign? It means on the coronal plane, if with like a straight line, you would demarcate normal from abnormal lung, much, much, much more likely to be CTD related UIP, as opposed to UIP from IPF. And the other sign that we saw was this thing called the anterior upper lobe sign, which means, sure, you have basal predominant pulmonary fibrosis, but you have some fibrosis in the anterior aspect of the upper lobes bilaterally as well. Some people call it the propeller sign or the four corner sign. You have four corners, anterior upper lobes over here, and then posterior lower lobes back here. So four corners, some people call it the four corner sign. But that also is more likely to be associated with CTD than IPF, but not as strong of a signal, okay? All right, here's an example of some follicular bronchiolitis in someone with rheumatoid arthritis. I'm not going to go into pathology because I'll embarrass myself in front of Dr. Chirg, but clearly we see central lobular ground glass nodularity within the lung fragment here in this typical CT presentation of this manifestation. Here's a patient with rheumatoid arthritis. And so not strictly interstitial lung disease, but I just had to show it because this is so classic. You see the mosaic attenuation here on the axial plane. You see these areas that look like ground glass opacity. Believe it or not, these are not areas of ground glass opacity. Those are areas of normal lung. And the hypodense areas are the areas of abnormal lung. We see the mosaic attenuation in really nice detail on the coronal plane. So how do you differentiate mosaic attenuation and decide, well, what's the abnormal? Is it the ground glassy kind of hyperdense stuff or is it the hypodense stuff? You can look at the airways. Remember that large airway disease and small airway disease, they run together. They're like a gang, right? So you can look at the bronchi. You actually see the manifestations of bronchial wall thickening or bronchial dilation within these areas of hypodensity. Because remember, they go together, right? They're just different sort of sides of that coin. And so that's one way to differentiate what's abnormal in these patients with this kind of very interesting, very diffused mosaic attenuation within the lung parenchyma. This patient had RA obliterated bronchiolitis. Some other examples here. This patient had chronic pleural thickening bilaterally. Beautiful example of rounded atelexis in the right lower lobe. Happens non-uncommonly. We also can follow these patients with MRI. This patient was, someone was scared this was a cancer, even though I told them, no, this is classically rounded atelexis. So we followed them with MRI for two years. That was actually, this was a headache. But we did it. You do weird things for VIP patients. This was an unfortunate VIP patient. The VIP patients always get the worst care, right? This is an example of like the worst care I've provided to a patient in my time at National Jewish. Doing something that probably didn't need to be done. Anyhow, we did it. It was not cancer, it was rounded atelexis. Okay, so that's all right. Let's now talk about systemic sclerosis. So as I alluded to before, what are you looking for? NSIP pattern of pulmonary fibrosis here. Very commonly, these patients also have esophageal dysmotility, which manifests as esophageal dilation on CT, oftentimes with the internal gas to a level. Again, that associated with pulmonary hypertension. In these patients, there is an associated with lung cancer. So I always in the back of my mind, I make sure there's no nodules that are slowly growing, especially within those areas of fibrosis. Here's a beautiful example of NSIP, a little bit more fibrotic here. Exuberant traction bronchiexis, reticulation with ground glass opacity. And I think you guys can see, and let's see, let's use a laser pointer here. So is that coming through? Yes, excellent. Okay, so using a laser pointer, you can see the internal gas fluid level within the esophageal dilation. Here's the MINIP, so not MIP, MINIP, minimum intensity projection image, which is really good for bringing out bronchiectasis. We see beautiful examples of this very florid traction bronchiectasis, which is not uncommon in the setting of NSIP, sometimes out of proportion to the degree of interstitial lung disease. Another example of NSIP here, clearly here it's more parabronchovascular. There is clearly subplural sparing here. Esophagus is a little bit dilated. But this subplural sparing is very specific for NSIP pattern of pulmonary fibrosis. NSIP, as we discussed previously, almost always secondary. Almost always secondary, usually due to some sort of CTD-ILD. And this is beautiful subplural sparing. Unfortunately, I don't see many of these cases anymore. I think they're all picked up in the community. Now the NSIP case I get are all kind of ugly, weird. You can't really see the subplural sparing. You've got to get two other colleagues to come over and ask, is that subplural sparing? Is that not? We only get the hard cases now. But I'm sure most of you guys are aware of that kind of thing. Thankfully, I think the curriculum that we have in radiology is helping. But it just makes my life harder, unfortunately. All right. Now let's talk about myositis. So we're talking about polymyositis, dermamyositis, and antisynthetic syndrome. So again, it's the OP-NSIP pattern. I'm not going to talk about autoantibodies. Again, I would embarrass myself in this audience and certainly with this panel here. So I'm not going to talk about Jowon. I'm surprised I even can't on my mouth. But I'm going to talk about CT, right? OP-NSIP, that's kind of what we're looking for. Antisynthetic syndrome, it's the same CT pattern. I'm not going to talk about autoantibodies here. I just refuse to do it. So here's the classic presentation. The first CT scan that you oftentimes will see in these patients with a myositis, you see basal predominant consolidation with some areas of maybe mild ground glass opacity. And the bronchi are a little dilated. So most of this is organized pneumonia. And there's probably a little bit of NSIP underneath it. So NSIP is more ground glassy. Organized pneumonia is more consolidated. And we know that organized pneumonia in its inflammatory phase can give you some transient bronchial dilation. So you notice I didn't say bronchiectasis, because this is transient bronchial dilation. This is not chronic irreversible bronchial dilation. So bronchial dilation here, beautiful example of perilobular consolidation on the coronal plane. You guys see that? Beautiful, right? This is like to die for good. And so there's unfortunately only one paper out there from Japan that showed this perilobular consolidation of lung bases, very, very specific for organizing pneumonia. So I talk about this all the time. But no one else has validated this. Maybe someone in the audience can do this. But bottom line, very, very good for organized pneumonia. Patients, corticosteroid treatment. Six weeks later, the patient comes back for follow-up CT. And as you guys know, that OP, it just dies, right? It smells corticosteroids, and it just melts away. And so this is what happens. And we're left with a little bit of an NSIP pattern here. Ground glass opacity, a little reticulation, some bronchial dilation. I'll show you just one more example here. How long am I doing for time? Four minutes? I can do this? Another example here, we see basal predominant ground glass opacity and consolidation. But that same exact pattern, it's like so characteristic. Patient gets corticosteroids. Eight weeks later, you come back and the consolidation melts away. You're left with that underlying ground glass. This longitudinal course, oh, so classic for myositis. It really is. And so I'll cut to the chase here. SLE usually will not cause interstitial lung disease, OK? You don't have to take a picture of this. If all you care about is ILD, it usually doesn't cause it. So what's more common? It's going to be like pneumonia. It's going to be pulmonary hemorrhage, things like that. And for the sake of time, I'm just going to go through this quickly. It can give you psoriasis, obviously. So you can get pleural disease. You can get pericardial disease. It's the same here. Patient has clearly bilateral pleural and pericardial thickening. Also, this phenomenon does occur. I used to think it didn't occur, but this is such a real thing. This patient, we tried to get them to take a good breath three times. We said, I kept not yelling. I don't yell. But I instructed my technologist that they need to get this patient to get better breath because the lung barns were way too low. Three times I did this, right? I was like, gosh, I will go myself. So I trudged in there in my white coat. And I explained to the patient, I'm like, you need to take a good breath in. And I coached him. This is how you do it. Let me show you how you do it. Breath in, out, and then deep breath in. Double breathe on, and then in deep inspiration, you hold it. And so the patient was breathing, and I was like, are you breathing? Are you taking any breaths? And like, I'm doing my best, doctor. I'm doing my best. I just can't do it. And then I was like, do you happen to have SLE, lupus? And the patient's like, yes, doctor, I have lupus. And so this is an example of the shrinking lung syndrome. I'm sure you guys have heard of it. So the diaphragm, this patient inherently was so weak, she couldn't take, or he couldn't take a good breath. And then I felt like a total jerk, right? Appropriately so, OK? Example of pulmonary hemorrhage here, basically about pulmonary hemorrhage, very nonspecific. And then Sjogren's syndrome, these patients, so in terms of the interstitial pneumonias, they're going to develop LIP most commonly. But sometimes they get NSIP. Sometimes they get UIP as well. But LIP is what I see most commonly. And in the chronic setting, it's going to be a cystic lung disease, the LIP. They can also get large and small airway disease. And every once in a while, they will develop that malt lymphoma, that really chronic lymphomas that usually are not that scary. And so when you start thinking about malt lymphomas, it's when you see chronic consolidation or chronic nodules slowly, slowly, slowly going over time. But again, I think at that point, you were probably actually worried more about an adenocarcinoma or squamous cell carcinoma. When you find out that's only lymphoma, you actually are probably pretty relieved. Thank goodness. So anyhow, here's an example of LIP and Sjogren's syndrome. So it's a cystic lung disease, which tends to be basilar predominant. And it's bronchovascular and subplural. But you don't need to remember all that. All you need to know is it's a cystic lung disease. And then you would just ask your radiologist, well, this is a cystic lung disease. Take me down the cystic lung disease diagnostic pathway and help me figure out what the heck this is. And there is an algorithm out there, which I wish I had time to share with you, but I don't. That is like 85%, 90% accurate, just based purely on imaging. So that's all you got to do. Just remember, LIP is a basilar predominant cystic lung disease. Sometimes you'll see concomitant nodules and patchy ground glass opacity in the inflammatory phase. I mentioned that it tends to be parabronchovascular. That's why very often, next to the cyst here, you'll see a little dot. And the mixed connective tissues, we'll just briefly talk about this. Remember, this is not related to, so when I was a medical student, boy, I should have studied harder. I thought mixed connective tissue disease and undifferentiated connective tissue disease was the same thing. So the rheumatologist in the audience and on the panel probably is embarrassed of me, right? And I will not tell you I went to medical school, because I don't want to embarrass my medical school. But it's not. Mixed connective tissue disease is different. It's a real, defined diagnosis, as opposed to undifferentiated connective tissue disease, which now we call IPAP, is something separate. In terms of imaging, what are we looking for? We're really looking for an NSIP pattern of pulmonary fibrosis. This is what we most commonly see, though UIP can also occur. And at least in my clinic, I see a good amount of UIP in the setting of mixed connective tissue disease. This case was shared with me by Dr. Lynch from National Jewish. And just very, very briefly, I'm going to talk about interstitial pneumonia with autoimmune features. This, again, is a research category. I don't even want to call it a diagnosis at this point, because sometimes people hear diagnosis, and they try to diagnose people with IPAP. Remember, this is sort of a research designation. And this was formerly known as undifferentiated connective tissue disease. And as alluded to previously, this is sort of these cases where it kind of feels like a connective tissue disease, but you can't define it per the guidelines. And so if you look at how you establish a designation of IPAP, imaging actually does come into play. So if you have NSIP, OP, or LIP, it supports this designation of IPAP. But if you actually look at the data, more cases are related to UIP than NSIP, which is very interesting. So it's not using that imaging side to achieve diagnosis. But really, this is a research designation, and we need to figure out what the heck is going on there. And so in summary, remember, this is probably a takeaway for you guys who like to take pictures. This is the picture to take. Remember, RA, UIP, systemic sclerosis, NSIP, myositis, OP, NSIP, Sjogren's syndrome, LIP. And this is just to prove that in Chicago, we do get good weather. It just lasts three weeks, and usually is not actually when the kids are out of school. So anyhow, this is in Chicago. So anyhow, thank you very much for your attention. Now Dr. Church will present the pathology perspective. OK, so I'm very briefly going to talk about the pathology that you see in connective tissue disease. And you've seen all of that, and I don't think we have to spend too much time on objectives. The point to remember, two points to remember. First of all, although you can clinically and radiologically make some distinctions about the connective tissue disease you're dealing with, pathologically, you can say, well, this looks like connective tissue disease, but you really cannot, as a rule, pick out one or the other from a lung biopsy. We've heard about IPATH, and I, like many people, abuse IPATH and use it as a diagnostic term. As far as anybody knows, IPATH microscopically looks like established connective tissue disease. There's not a lot of information out there, but that seems to be the situation. Apart from the ILDs, which I'll show you, there are a whole set of manifestations of connective tissue disease in the lung, and I don't have time to go through that. We've just seen some of them radiologically. An important point is CTDs, microscopically, can be classic or they can be completely weird. And there's just no way around that. And as was said in the session this morning, all of us cheat. I don't really look at ILD biopsies without doing what the imaging and the clinical story is, because otherwise you get misled, and that's one of the things that CTD can really mislead you microscopically. Hints that something is connective tissue disease are IPATH. I'll show you these. Lots of lymphoid aggregates, lymphoid aggregates with germinal centers. Lots of plasma cells, and if the plasma cell to lymphocyte ratio is greater than one, that's probably connective tissue disease. Now, you all know what NSIP is, right? See? Something new you learned today. Causes of an NSIP picture microscopically. Typically and most of the time, connective tissue disease or an IPATH. Other autoimmune diseases occasionally can do this. PBC can do this. Hashimoto thyroiditis can do this. They're pretty uncommon in the lung. HP occasionally looks exactly like NSIP, either cellular or fibrotic. And drugs. Drugs can look like anything, and they can certainly look like NSIP. Whether idiopathic NSIP exists is a bit of a controversial thing. I put it in the list. I'm not convinced that there is such an entity. If you look at all patients with connective tissue disease and you get biopsies, NSIP is the most common pattern. And the important thing to remember if you're dealing with biopsies is NSIP can be cellular or fibrotic or mixed. And as I'll show you in a second, this makes a difference. So you want your pathologist to tell you, is this purely cellular? Is it purely fibrotic? Is there an inflammatory component? Because an inflammatory component is what you can suppress. The fibrosis you have to take in a completely different approach. Here's a gross of an NSIP from an explanted lung. And notice that all of this is fibrosis, but there's no honeycombing. And I'll show you the contrast with UIP in a minute. Here is a fibrotic NSIP in a patient with rheumatoid arthritis. Notice it follows the original lung contours. In theory, NSIP exactly mimics the original underlying lung. You don't get architectural distortion. And there are a couple of lymphoid aggregates at the arrows, which again make you say, okay, this is some connective tissue disease. Here at low power, it's a little hard to see, is a cellular NSIP with lots and lots of lymphoid aggregates. When you see lymphoid aggregates like this, you know you're dealing with connective tissue disease. And here's a mixed cellular and fibrotic NSIP. Come back. And all of these are plasma cells. And these sort of infiltrates that are plasma cell rich or mostly plasma cells or all plasma cells, again, that's a hint you're dealing with connective tissue disease. This is an old paper from Andrew Nicholson, who's a pathologist at the Brompton in London. And his point is very simple. At the top, the survival in cellular NSIP basically is a treatable disease. Whereas as soon as it's fibrotic, it behaves much worse. Better than UIP-IPF, but it's not wonderful. So that's the reason to get information from your pathologist if you get a biopsy, is it cellular, is it fibrotic, is it mixed? Because that tells you what treatment to use. The combination of organizing pneumonia here on the right and a NSIP pattern, which is cellular in this case, is also very, very typical of a connective tissue disease. You can obviously see organizing pneumonia superimposed on lots of things, but this combination should make you think about connective tissue disease. UIP in connective tissue disease looks very much like IPF. And here is a gross, come back, showing you honeycombing, which you don't usually see in NSIP. This patient also has a carcinoma, and there's an increased risk of carcinoma in UIP. This has a mind of its own up here. On the right is the NSIP, and all of that smooth tan is fibrosis, but notice it does not have honeycombing. So there's a distinction between NSIP and UIP. Here's early UIP and rheumatoid arthritis. The fibrosis goes around the periphery of the lobule when it's early. And again, we've got lymphoid aggregates, a hint that this is connective tissue disease. Here's advanced UIP. So there's a lot of fibrosis, all in pink, overrunning the lung. But look at the number of lymphoid aggregates. Again, that says this is underlying connective tissue disease. And of course, in UIP of any cause, you get fibroblast foci, which are these little bits of granulation tissue that organize to produce the fibrosis. You see this in connective tissue disease UIP. You see this in IPF. You see this, by the way, in fibrotic hypersensitivity pneumonitis as well. That's not a specific finding. Another pattern that you can see in connective tissue disease is isolated centrilobular fibrosis, as here. Here's a pulmonary artery. Here's a pulmonary artery. There's fibrosis. And it's around the pulmonary artery rather than being subplural, as in UIP. Notice again, lots of lymphoid aggregates. That says this is connective tissue disease. You can see the same pattern minus the lymphoid aggregates in fibrotic HP. So centrilobular fibrosis isolated if you've got diffuse disease, either connective tissue disease or fibrotic HP. And let me just finish with lymphoid proliferation, which have become, for the pathologists, a messy business. There are all sorts of lymphoid proliferations that you can see with connective tissue disease. I've listed them here, but I'll show you them. Here's follicular bronchiolitis, which we've just heard about, where the lymphoid infiltrates are just around the bronchioles. Here is a radiologic LIP, and it's a patient with Sjogren's. Now, what does that correspond to? And this is where things get very messy. Well, it might correspond to this, which is a cyst with a little bit of fibrosis and inflammation around this cystic space. Okay, that kind of makes sense if you go back to the imaging. But then we have Sjogren's patients who have rather diffuse infiltrates. All of this blue is lymphoid infiltrate, but it's not just around the cyst, and it's not just around the bronchiole. It's rather diffuse. Or you can have lymphoid infiltrate like this, which is all the way through everything and expands the alveolar walls. This is classic original LIP. It turns out we've all of us been talking about this as if we know something, and the truth of the matter is we probably don't. This is a paper we just published. And what it says here is, and I'll quote it, what radiologists and pathologists encounter is LIP differs remarkably, but neither radiologic LIP nor pathologic LIP present with sufficiently distinct findings to delineate such cases from other patterns of diffuse benign lymphoid proliferations. Suggestion in this paper is let's get rid of LIP. And I'll show you how bad it is. This is complicated, but just look at this gray circle. These are patients with biopsies that are classic LIP. The green is radiologic cases called LIP, and you see there's almost no overlap. Almost all of these cases are something other than classic LIP. So we need to revisit this a little bit. Cyst in the lung in a patient with Sjogren's, well, they're something, but they're not, as a rule, going to be classic LIP. And in the interest of time, I think I will skip that polling question. So take-home messages. There's a very broad spectrum of ILD in patients with CTDs and IPAF. As I said, as far as I can tell, you can't separate the IPAFs from the CTDs on a biopsy. If you see numerous lymphoid aggregates, germinal centers, lots of plasma cells, that suggests CTD, IPAF, whatever the pathologic pattern may be. The important point is that purely cellular ILDs have a much better prognosis than fibrotic ones for obvious reasons. So get your pathologist to tell you, is this cellular, is it fibrotic? Because it's a guideline to what is treatable and how to treat it. And as I mentioned, pathologic and radiologic LIP are a mess. They don't really correspond at all. Thank you. All right, so again, I'm Rachana Krishna. I'm an ILD pulmonologist at MUSC and I don't have any disclosures. So we had an excellent review by our previous speakers about connective tissue disease ILD and the entity of IPAF, whether it's meaningful to use in clinical practice or not. Let's try to put it all together. I'll go over a case, but also some recent data on management of connective tissue disease and these folks, patients we see with some autoimmune features that we have hard time managing. So there'll be a ARS question for the case and we have the objectives. So since Dr. Wilfong already went over the IPAF criteria, I'm not gonna go spend too much time on it, but just something to remember, again, this is not a distinct clinical entity, but the purpose of having had this distinction is to follow these patients who have some features that they don't entirely fit with a defined connective tissue disease diagnosis that when you send to a rheumatologist, they say, okay, this doesn't fit with what we know as a clear connective tissue disease. And then as a pulmonologist, what do you do with these patients? But again, as our rheumatology colleague reminded us that these are constructs. And so we have to use them in the context of clinical scenario. And we'll go over some clues that can help with that. And yeah, so the case that I have here, this is from my clinical practice. So it's a 62-year-old white man, two months of exertional dyspnea and cough. He had a CT scan and came to the pulmonary clinic. He did have a history of Raynaud's for several years, but otherwise didn't have any other features of connective tissue disease. He worked as an engineer, had some mold exposure related to his work site several years ago, but nothing other than minor exposure, non-smoker, no significant family history for pulmonary fibrosis or connective tissue disease. And exam, looking at full skin exam and joint exam, there was not really anything specific there. Did have crackles as expected on lung exam. Lung function, mildly impaired. His barometry FEC is slightly reduced. DLCO significantly reduced and did have some desaturation on a walk test. And as part of his routine ILD workup, he got ANA, which was a high titer. ANA SSA antibody was positive and rheumatoid factor was positive, but the anti-CCP was negative. And he did have a myomarker myositis panel sent, which also showed only a positive SSA or a Rho 52 antibody. And this is the CT. I'll go over that. I'm not seeing these images, so I'm going to let it run again one more time here. So initially what I'm seeing is clearly a basal or peripheral process. There's reticulation. There's some ground glass opacity in there as well. Let it run one more time. And there's these subplural cysts, and you wonder if that's actually early subplural honeycombing or not. Probably is, but then there's a good amount of ground glass opacity and pretty exuberant traction bronchia at the lung bases. There's some areas where you can almost hallucinate a subplural sprain, but I don't think that's definitive. But this is one of these cases where I think there's enough ground glass opacity and the pattern of bronchia exists enough where I think there's probably a fibrotic NSIP pattern. But in the back of my mind, I'm like, well, it could have progressed to a UIP, and that's been described as well. Thank you. All right, I guess we have a poll. So if you want to answer the question, so what do you guys think is the diagnosis, and what would you do next? A couple more seconds. All right. So this is a 62-year-old white man with some features. He had some pain odds, but didn't really have an NSIP-looking CT, and kind of don't know if this could be connective tissue disease or not. So I'll tell you what we did. And there can be differences in practice and between centers, but before I go to what we did, I wanted to say that we sent to the rheumatologist, and our rheumatologist just wanted to remind that these are criteria, but we have to take it in the context of the clinical situation. So lung involvement is not there in the diagnosis of Sjogren's, and the rheumatologist, so with the SSA positive itself, doesn't really give the diagnosis of Sjogren's. And many times, they suggest getting a lip biopsy, because that actually increases the chance if you find lymphocytic xylitidinitis there, that increases the chance of you classifying it as Sjogren's. But again, this is not necessary and may not always change practice in some of these folks. But specifically looking at the lung, we want to know what we need to do next for the lung disease. And so we discussed a case in MBD, and after shared decision making, especially because he was very hesitant to go on immune suppression, and it's understandable that's an older white man and not the typical person you would expect to see connective tissue disease. So he underwent a surgical lung biopsy, and we'll look at that. So this is the surgical lung biopsy, which you can see at low power. It's not inflated very well, but it's not the sort of picture of fibrosis. In fact, at higher power, it looks like an NSIP picture. I think we only have those two, right? Yeah. So this looks like NSIP. You can't quite tell how much fibrosis there is in here, but it's not a lot. And we do have some lymphoid aggregates here. So he was treated for NSIP with prednisone initially, and then mycophenolate. And we followed him for about three to four years now. He's not developed any further sicker symptoms or anything to suggest Sjogren's, apart from the antibody that he had. He did have an ophthalmology evaluation, which was negative for a Shermer's test, but his lung function has been overall stable in the last three years. So as Dr. Wilfong earlier pointed out, this is a spectrum that I path to connective tissue disease. So I just wanted to look at the literature when cohorts have looked at these patients who have some features of clinical features and morphologic features of connective tissue disease. And what happens to these folks? Do they all develop into connective tissue disease? And it's actually only a minority of patients who go on to develop connective tissue disease. The longer you follow up, the percentage of patients going on to meet the classic defined criteria of connective tissue disease increases. So in longer follow-up of more than three years, only up to a quarter of them eventually meet the diagnostic criteria for CTD. And many of these cohorts, the concern is that the myositis-specific antibodies, which are your JOWAN antibodies and PL7, PL12, MDA5, JOWAN, so those are the folks that actually go on to develop all features of connective tissue disease or more classic criteria for connective tissue disease sooner. And they tend to do better with immune suppression and have better outcomes with therapy for CTD. And depending on how much of these folks are in the cohort that you're studying, the outcomes vary based on that. And again, UIP was not included in the criteria. But we do have some recent evidence to say that even in UIP, especially if they have connective tissue disease diagnosis, then immunosuppression should be considered. So again, what do we do with these folks? Management, whether to consider immunosuppression or antifibrotics or both. And again, it's based on the patient in front of you and the clinical characteristics. So if it's an older white man, it's a little bit different. Something to consider if someone is having probable UIP in an older white man, it's probably more likely to be IPF rather than if it's a younger woman, especially younger African-American women would be more likely to have connective tissue disease. You have to always look for that. And depending on extrapulmonary involvement, many of these cohorts, Raynaud's and arthralgia are one of the common findings, extrapulmonary involvement. And then if they have pulmonary vascular disease, bronchiolitis, features of pleural effusion, that would be also helpful. And also, if the pattern underlying is NSIP or organizing pneumonia, you want to treat that. And that would also favor evaluating further for connective tissue disease and considering management with immunosuppression. We had a session yesterday. If you folks attended that, there is some more evidence to say that all the patients with IPF are not really, they may have different outcomes based on leukocyte telomere length. So if they have short telomere lengths, they have worse outcomes and more in line with IPF than without. But this difference is actually not as pronounced if there is connective tissue disease-related ILD. And recent, I wanted to point out a couple of trials that have shown some randomized, this is one, these are some of the few randomized clinical trials that we have in management of connective tissue disease. And this is a French multicenter study. This was done before the COVID pandemic. And the data was just released. So these patients included had a clear connective tissue disease diagnosis, but also had idiopathic and the ones which met only the criteria for the IPF were included. So here, they randomized to both rituximab and mycophenolate versus mycophenolate only. And over six months, they saw better outcomes with only rituximab, with combination therapy with rituximab and mycophenolate. But again, it's a very short study for six months. And the infection risk was higher in the rituximab group. So something to keep in mind, especially in the setting of viral infections and COVID pandemic. This is the same data from the same study. And this is a UK-based multicenter randomized control trial, which also looked at rituximab and cyclophosphamide outcomes at 24 weeks for connective tissue disease had both scleroderma, myositis, and almost 80% of them were myositis and scleroderma in this study. And outcomes were pretty similar for both. One was not better than the other, but less corticosteroid use in the rituximab group So overall, we want to say that there's a minority of patients who have some of these autoimmune features that go on to develop connective tissue disease. But it's important to consider that in the whole context using the patient characteristics, age, gender, the antibody profile, especially looking at the myositis features, doing a very full, thorough clinical exam. And we need more randomized trials. But the guidelines that are out there from the recent ACR publication for connective tissue disease management might help guide our management. So with that, I'll stop, and we can take questions. We have a few minutes for questions. Thank you.

CTD-ILD

treatable

improving outcomes

early recognition

usual interstitial pneumonia

non-specific interstitial pneumonia

surgical lung biopsy

multidisciplinary approach

improve quality of life