Hi, I'm Kristen Highland. I'm Director of the Rheumatic Lung Disease Program at the Cleveland Clinic in Cleveland, Ohio. I'm both a pulmonologist and a rheumatologist. These are my disclosures and I'd like to also mention that all medications I discussed should be considered off label for connective tissue disease associated interstitial lung disease with the following exceptions. Tocilizumab is approved for scleroderma associated interstitial lung disease and progressive fibrosin ILD. Tocilizumab is also approved for scleroderma associated interstitial lung disease and Trapostanil is approved for ILD associated pulmonary hypertension. So, we all know that interstitial lung disease is an umbrella term for a group of over 200 diseases and of that group, 13% of patients with interstitial lung disease have an underlying interstitial lung disease. So, this is a really important category. Interstitial lung disease is most common in our patients with scleroderma with clinically significant interstitial lung disease between 45 and 70% of our population. This is followed by mixed connective tissue disease, which is often felt to be a scleroderma spectrum connective tissue disease. Patients with polymyositis, dermatomyositis, antisynthetase syndrome have interstitial lung disease somewhere between 20 and 50%. Rheumatoid arthritis is our most common connective tissue disease. Fortunately, patients with clinically significant interstitial lung disease is only 20 to 30% of that population. We can see ILD in children's and in the minority of patients with systemic lupus erythematosus. Patients with connective tissue disease in general are female with three quarters of patients with CTD being female. Autoimmunity is more common in women. They tend to be younger and if you look at this graph on the right, you can see that the prevalence of connective tissue disease associated interstitial lung disease is similar. Whether you're 35 years of age or above 70, whereas idiopathic pulmonary fibrosis is a disease of patients that are substantially older. However, there is one caveat and that's with rheumatoid arthritis. Rheumatoid arthritis can look a whole lot like idiopathic pulmonary fibrosis and they share some demographics. Patients with rheumatoid arthritis associated interstitial lung disease are more likely to be males, are more likely to be older, are more likely to have a history of smoking and are more likely to be Caucasians. And this is the exact demographic that we see in idiopathic pulmonary fibrosis. Similar to histopathology, it has a lot of similarities where there's microscopic honeycombing, temporal and spatial heterogeneity as well as fibroblastic foci. What's different is that patients with rheumatoid arthritis associated UIP, this top panel, are more likely to have lymphocytic aggregates. These are these purple round blobs as well as evidence of pleural disease and their fibrosis is a little bit more airway centric. However, the pathobiology behind this interstitial lung disease is also similar to idiopathic pulmonary fibrosis. We have short telomeres, we have mutations in MUC5B and TERT and a variety of other polymorphisms that we see both in RA and IPF. One of the challenges is that idiopathic pulmonary fibrosis may be diagnosed before it becomes obvious that the patient has a connective tissue disease. In this study of 111 patients with IPF that were followed for 10 years, 9% developed a connective tissue disease, including rheumatoid arthritis and microscopic polyangiitis, scleroderma and Sjogren's syndrome. There's another study that suggests 30% of patients with polymyositis dermatomyositis will present with their pulmonary findings prior to their extra pulmonary findings. Another challenge is that when you do CT scans on all patients with interstitial lung disease, we find these interstitial lung abnormalities in almost everybody, greater than 80%. And we don't know what to do or what to make of this subclinical interstitial lung disease. We do know when we look at these very large studies, such as the Framingham Heart Study and COPD gene, patients with interstitial lung abnormalities have worse mortality than patients that don't. Another challenge is this entity called interstitial pneumonia with autoimmune features or IPATH. This is undifferentiated connective tissue disease confined to the lung. So there's some features that suggest autoimmunity, but these patients don't meet classic criteria for a defined connective tissue disease. They do have to have a feature from at least two domains, clinical, serologic, and morphologic. So the clinical domain could include what we call mechanics hands. This is top panel where you can see fissuring along the edge of the fingers, digital tip ulceration that we can see in patients with Raynaud's phenomenon and inflammatory arthritis or polyarticular morning stiffness lasting greater than 60 minutes. Palmar tranjectations, which are red little blood vessels that you can see on the palm, Raynaud's phenomenon, unexplained digital edema or swelling, which is a clue that the patient might eventually develop scleroderma or unexplained fixed rash on the digital extensor surfaces of the hands. Here you can see a patient with these kind of red areas over their knuckles as well as particular erythema. This is someone with gotren's sign and probably at risk for polymyositis dermatomyositis. On serologic domain, these patients have to have a moderate or higher titer ANA or an ANA that is specific to scleroderma, nucleolar, or centromere pattern or rheumatoid factor greater than two times the upper limit of normal or a variety of other autoantibodies that are associated with specific connective tissue diseases. We know that a portion of healthy volunteers have these low titer ANAs and these low titer rheumatoid factors, so they are not included in the serologic domain. We don't know quite what to make out of those patients with low titer autoantibodies, but moderate to high titer meets the serologic domain. In regards to morphologic domain, pretty much any of the histopathologies other than usual interstitial pneumonia, that's the one that goes with IPF, suggests, you know, could this be an underlying connective tissue disease? Some people say in the setting of NSIP, this is a connective tissue disease until proven otherwise. If the patient has a biopsy and there's these lymphoid aggregates or a lot of lymphoplasmic infiltration, that's highly suggestive of a connective tissue disease. Or we see multi-compartment involvement. They have interstitial lung disease plus pleural or pericardial disease or airway disease. And of course, you all care about pulmonary vasculopathy. Here's one of those lymphoid aggregates again. Here's a biopsy that just shows diffuse lymphocytic infiltration. These are these blue little dots. So we see the whole alphabet soup in connective tissue disease associated interstitial lung disease. We see all of these major interstitial pneumonias that can be idiopathic, but often suggest an underlying connective tissue disease, as well as some of the rare interstitial pneumonias. And here you can see that in all of our connective tissue diseases, besides rheumatoid arthritis, NSIP is the most common histopathology seen. In rheumatoid arthritis, it's UIP, the same histopathology that we see with IPF. Here is a patient with NSIP. NSIP has some similarities to UIP in that it is peripheral. It tends to be lower lobe predominant, but clues that this is NSIP is that there is some subpleural sparing. We can see ground glass, opacities, that some of this hazy stuff. You can have fibrotic NSIP where you have reticulation, as well as some traction, bronchiectasis and bronchiolectasis, but you don't see honeycombing. Honeycombing is something that we associate with UIP or IPF. And here you can see histopathology in scleroderma is that NSIP histopathology, and that's this diffuse lymphocytic infiltration, this diffuse thickening of the interstitial with collagen. That's this pink stuff where usual interstitial pneumonia has a more of a patchwork pattern, which we'll see in a minute. Here you can see a copy of a CT scan in a patient with UIP. Again, this is IPF, but we can also see it in rheumatoid arthritis. It is also peripheral. It's also worse in the lower lobes, but now we don't see that ground glass opacity. We see evidence of honeycombing. We still see some evidence of traction, bronchiectasis, and a lot of reticulation. So it is a little bit challenging to tell the difference between UIP and fibrotic NSIP without a well-trained chest radiologist. But when you're seeing ground glass opacity and subplural sparing, NSIP, honeycombing, UIP. And UIP can be seen in rheumatoid arthritis and interstitial lung disease. And here you see a fibroblastic foci, and they will talk about temporal and spatial heterogeneity. Organizing pneumonia looks just like it sounds. It looks like pneumonia where there is consolidation. In fact, these patients are often misdiagnosed as having an infectious pneumonia and given a variety of rounds of antibiotics. They don't get better. They eventually get steroids. These are patients to have a high clinical suspicion for an underlying connective tissue disease. Lymphocytic interstitial pneumonia. This is one that I associate often with Sjogren's syndrome. You can see these thin wall cysts. Some patients have some reticulation. Here's a little line here. There's a little septal thickening right here. Sometimes there's lung nodules and consolidation. And then diffuse alveolar damage. Think of this like ARDS. These patients are acutely ill. They're presenting to the ICU. Sometimes they present this way and have nothing outside the lung. We commonly see this in patients with polymyositis or dermatomyositis, where these patients are acutely ill and often on a ventilator. When I think of these pathologies, when I see NSIP or organized pneumonia, or I see an overlap between the two of those, I think this is potentially reversible. When I see LIP or these cysts with LIP or this honeycombing associated with UIP, that is typically not reversible. My next step is to try to make the connective tissue disease diagnosis. I do a really detailed review of systems. Starting from, is your hair falling out all the way to do your feet hurt? Skin exam, joint exam. I look at their nail-filled capillaries with a little handheld microscope device that I have. When you see abnormalities there, because connective tissue disease is really a vascular process that suggests that the patient may have an underlying connective tissue disease. I do screening serologies. Everybody gets an ANA to screen for scleroderma and a rheumatoid factor, but I get the rest of the autoantibodies to look for less common rheumatologic abnormalities. These patients need to be re-evaluated time and time again, and they need to be referred to rheumatology. We know that approximately 15% of patients who previously were diagnosed as having idiopathic interstitial lung disease end up having an underlying connective tissue disease. In here, we talk about these multidisciplinary discussions. When these discussions include a rheumatologist, that can change the initial diagnosis in nearly a quarter of patients, which has treatment implications. This matters because survival is different, not only based on whether you have NSIP or UIP, but the different types of interstitial lung disease, whether you have scleroderma or undifferentiated connective tissue disease or rheumatoid arthritis. This is important prognostic information to tell your patient, as well as connective tissue diseases are systemic diseases. You need to worry about other organs and other body parts besides the lungs. Interstitial lung disease remains a leading cause of morbidity in scleroderma along with pulmonary hypertension. We see that patients with interstitial lung disease and rheumatoid arthritis also have substantially worse survival. It's the second leading cause of death in rheumatoid arthritis, following premature coronary artery disease. We need to have a low index of suspicion. In fact, patients with connective tissue disease might not even know that they're short of breath because they become more sedentary because their joints hurt, or their muscles are weak, or they just don't feel good all over. We know that pulmonary function testing may miss interstitial lung disease. In this study, 62.5% of patients with significant interstitial lung disease on chest CT scan had a normal forced vital capacity. We saw this clinically in the FOCUS study. This was the study that got Tocilizumab FDA approved. These are patients that had very, very early scleroderma. Their scleroderma was less than two years of duration. Forced vital capacity was in the 80% range. Yet, over 65% of patients had evidence of interstitial lung disease on their CT scan. If you looked at those patients, the patients with the interstitial lung disease, the patients on placebo, which is the blue line, nearly 25% of those patients had a drop in their forced vital capacity by 10% at 48 weeks. This is a very clinically significant drop in forced vital capacity. These patients would have gotten missed if they hadn't gotten that baseline HRCT. With this Delphi consensus, they recommend screening for scleroderma interstitial lung disease. I know you all know that we screen all our scleroderma patients for pulmonary hypertension as well, but they need to be screened for scleroderma-associated interstitial lung disease with an exam, pulmonary function test, and an HRCT scan upon diagnosis. Then these patients need to be followed carefully. If they have normal pulmonary function tests and HRCT, they at least need yearly pulmonary function tests. If either of these are abnormal, then you decide, do they have a lot of interstitial lung disease? Is this extensive? Treat them. Is that limited? Then repeat pulmonary function tests. Decide if they're stable or progressive. If they're progressive, they get treated. Just like an IPF, there's different types of disease progression. Overall, patients with connective tissue disease have a better trajectory than patients with idiopathic pulmonary fibrosis. But like idiopathic pulmonary fibrosis, you have your slow progressors and your steep progressors. The goal is to identify these patients so that you can intervene. What patients should be treated for interstitial lung disease? Certainly patients with extensive disease. That's greater than 20% involvement on HRCT. Or they have evidence of progression with a drop in their four-spinal capacity by 10%. Or 5% to 9% with a drop in their diffusion by 15%. Or we know that they have risk factors for progression. It depends on what type of connective tissue disease. For instance, in scleroderma patients, we know patients with an African-American race or male sex have worse outcomes. Those with diffuse skin disease, early disease, those that have pulmonary hypertension, we know there's that link between the vasculature and fibrosis. Those who already have fibrosis, these are risk factors for scleroderma ILD as well as this antitopoisomerase 1 antibody SCL70. Remember, the centromere antibody is associated with pulmonary arterial hypertension. In regards to rheumatoid arthritis, tobacco smoking, male, gender, high titer antibodies, older onset. And then risk factors for mortality are more extensive disease in that UIP pattern and progressive lung function. In our idiopathic inflammatory myopathies, these are patients with polymyositis and dermatomyositis and antisynthetase syndrome. Women, those with a lot of arthritis, fevers, these antisynthetase antibodies, possibly Japanese. One of the challenges with all our connective tissue diseases is there's not a lot of correlation between the extra pulmonary component and the pulmonary component. So how do we treat patients? Well, we can think, usually they're started on monotherapy. If they have a lot of ground glass suggesting inflammation, then these are suitable patients for an immunomodulator, something that suppresses their immune system. If they don't have much ground glass, this looks more UIP-ish, antifibrotic, they need to be followed carefully. You can consider combination therapy. And if that doesn't work, palliative care versus lung transplant, maybe even stem cell transplant, rescue therapy with a different modulator. And of course, clinical trials. We're so grateful to our patients that participate in clinical trials. And so when we think about how we're going to treat our patients, we know that we get there through some kind of tissue injury, as well as vascular injury, coupled with autoimmunity. And this results in inflammation, release of cytokines, and the laying down of collagen and fibrosis. So the first little bit of evidence that we have came from the scleroderma lung study number one, which looked at cyclophosphamide, and scleroderma lung study number two, which compared mycophenolate to cyclophosphamide. And in these studies, we saw that both cyclophosphamide and mycophenolate resulted in modest improvements in forced vital capacity. And modest improvement in the modified broadening skin score. Then the fibrotic pathway was targeted with nintendinib. And that resulted in a relative reduction of 44% in forced vital capacity decline in scleroderma patients. And so nintendinib became the first drug FDA approved for scleroderma-associated interstitial lung disease. And then the focus study was a study of tocilizumab, where skin was the primary endpoint, and that was actually a negative study. But the lungs were a key secondary endpoint, and patients randomized to tocilizumab, the red line, whether it was all patients, or the 65% that had evidence of interstitial lung disease, had a significant difference in change in forced vital capacity of 238 milliliters, which is really quite dramatic at 48 weeks. And so with this and some other supporting CT fibrotic score data, this drug also got FDA approved for scleroderma-associated interstitial lung disease. Unfortunately, we don't have a lot of data for other connective tissue diseases. Well-powered clinical trials are lacking. And we believe the results are somewhat etiology-specific and not translatable across connective tissue diseases. So we have to be quite careful extrapolating results from IPF or scleroderma to the other CTD-ILDs. And a variety of clinical trials in rheumatoid arthritis and myositis are ongoing. Nevertheless, there are some suggestions of a variety of immunomodulator treatments in CTD-ILD, including prednisone and azathioprine and cyclophosphamide, mycophenolate, tacrolimus, and all these drugs need to be carefully monitored. We do have some data with Nintendida through the InBuild study that was a grab-bag study looking at progressive fibrotic interstitial lung disease, where about a quarter of that cohort had an underlying autoimmune interstitial lung disease. So these are patients that had a progressive phenotype. And in these patients, you could see that there was a significant relative reduction in decline in four-spinal capacity. In the overall population, patients that had a UIP-like pattern on their HRCT. Well, of course, we know that patients with connective tissue disease get pulmonary hypertension. They get pulmonary arterial hypertension, but they get pulmonary venous hypertension group two. They also get group three pulmonary hypertension, which has the worst survival curves. And one of the predictors that these patients might have underlying pulmonary hypertension with their interstitial lung disease is a drop in diffusion capacity or an elevation in the four-spinal capacity to diffusion ratio, where the diffusion is down out of proportion to the four-spinal capacity. And fortunately, you all have the increased study to talk about. And we know that about a quarter of the patients enrolled in the study had an underlying connective tissue disease. As you know, the six-minute walk was the primary endpoint with a variety of other secondary endpoints. And this showed at week 16 that patients on inhaled troposinol had a placebo-corrected difference from baseline in peak six-minute walk of 31 meters and a 42% reduction in antiprop BNP and a 39% reduction in time to clinical worsening. But more interestingly is that there was a signal that there was potentially a benefit on four-spinal capacity. And so clinical trials are ongoing looking at inhaled troposinol in regards to treatment of interstitial lung disease. So that will be a really interesting story to see unfold. And I think it's particularly relevant in connective tissue disease where we see such an overlap between, you know, these pathways of fibrosis and the vasculature as well as autoimmunity. And so I will finish by saying that the workout for connective tissue disease is an essential component of evaluation of patients with suspected interstitial lung disease. It's a leading cause of morbidity and mortality. And so patients caring for, clinicians caring for patients with connective tissue disease should be alert for the development of interstitial lung disease. The pathobiology involves the interplay of disordered fibrotic, immunologic, and vascular pathways. Treatment approaches vary by specific type of connective tissue disease and not all patients require treatment. And fibrosis does not exclude development of pulmonary vasculopathy. We certainly have a variety of unanswered questions including the ideal treatment strategy for connective tissue disease, ILD, that are not scleroderma. You know, which patients should be on antifibrotics? What about our newer DMARDs, the, you know, JAK inhibitors? What about biomarkers? You know, other things that we can use to monitor. And I am more than happy to take a look and take any questions. You can all reach out to me. My email is highlak at ccf.org. Thank you very much.

CTD-ILD

lung inflammation

fibrosis

Scleroderma

treatment options

multidisciplinary approach