ILD Assessment and Management Save

Hello, everyone. My name is Doctor. Elena Jerns. I'm talking to you from Rochester, Minnesota. Today we will talk about biomarkers in interstitial lung disease or ILD.

Before we begin, I do want to make it clear that we'll talk about blood based biomarkers. There's a lot of interest in radiomics and biomarkers based on the radiographic appearance, but we're not gonna touch on them today and we're not gonna talk about biomarkers in bronchoalveolar lavage fluid, although those are very interesting. So there has been a lot of interest in biomarkers in the last couple decades. So you're gonna see a lot of studies on those. I confess I have a couple of those out there myself.

And biomarkers in ILD have gained so much interest because people are trying to figure out how to diagnose ILD and how to determine which patients with ILD will progress and which ones won't. So there have been many ways for people to try to figure it out. So you'll see studies with proteomics, metabolomics, genomics, all sorts of omics you can imagine, and most of them are really not panning out to truly be clinically useful yet. And I think a big drawback for those studies is that a lot of those patients with ILD that they're studying, particularly for diagnosis purposes, they're not necessarily validated. So we're not ever entirely sure, are they truly autoimmune ILDs, are they truly having the diagnosis that the researchers are thinking they do.

So I want to talk to you about a few biomarkers that might actually be useful for you in your everyday practice in your rheumatology clinic. So first, some of the biomarkers that might come out of the research world that you might start seeing and that you might be seeing already in studies as sort of like an exploratory endpoint are KL6, Krebs Fonden Lungin six, and SPA and SPV, Surfactant Protein A and Z. So those biomarkers seem to be correlating with fibrosis in a variety of ILDs. They seem to be doing a little bit better in non autoimmune ILDs based on a recent meta analysis, but regardless, they might be useful and they might be coming to the lab near you. Which biomarkers do I use?

My clinical and research interests lies predominantly in interstitial pneumonia without immune features, or IPAF. Biomarkers are a huge part of my practice and a huge part of how I view those patients. A panel that I check on every patient with ILD that comes through my door is myositis antibody panel. Myositis antibodies have a great importance in patients with ILD. Particularly in patients with IPAF, myositis specific antibodies, such as antisynthetase antibodies, NDA5, SRP, TIF1 gamma, they have been shown to really give a very similar behavior to the ILD as defined myositis ILD.

There was a study that looked like IPAP with MSA versus IPAP without MSA and various types of autoimmune ILDs and also idiopathic pulmonary fibrosis, or IPF, and found that IPAT with MSAs behaved very similarly in terms of response to immunosuppression and survival as myositis ILD. Definitely, if somebody has ILD, no features of myositis, but has PL7, PL12, I will be immunosuppressing them because those seem to be quite an inflammatory type of interstitial lung disease. Another biomarker that I check routinely on all of my patients is SSA-fifty two or ROW 52. ROW 52 has been consistently shown to be associated with poor prognosis in a variety of ILDs. It has been shown to be associated with poor prognosis in scleroderma and even in IPAF and idiopathic pulmonary fibrosis and other autoimmune ILDs.

If I have somebody who has positive SSA-fifty two, I'm just a little bit more nervous about the course that their ILD is gonna take. I might be checking their pulmonary function test maybe a little bit more often and checking on them maybe a little bit more frequently. My favorite test that I wanna talk to you about are telomeres. So telomeres, if you remember, are those little things, those six nucleotide repeats on the ends of chromosomes that maintain the chromosomes and they shorten with, cellular replication and aging. Turns out that short telomeres predispose you to having pulmonary fibrosis or interstitial lung disease.

It has been seen in idiopathic pulmonary fibrosis and now we are seeing that it is true in autoimmune ILDs as well. So if somebody has short telomeres, you always wonder, is it due to some sort of effect of toxic chemicals, is it due to their age, Or is it due to a genetic variant that causes premature shortening of the telomeres? Telomere biology disorders can give you pulmonary fibrosis, but can also give you things like liver cirrhosis, early brain, blood dyscrasias, and you can see it in a variety of ILDs, again, autoimmune ILDs, in idiopathic pulmonary fibrosis, and unclassifiable ILDs. Okay, so I see a patient who has early pulmonary fibrosis or tells me they have early green or family history of pulmonary fibrosis, I'll be checking their telomeres. If they have short telomeres, I know these patients are not going to do well.

Short telomere lengths, and when I say short telomere lengths, it's peripheral leukocyte or granulocyte telomere lengths. Those patients have poor survival, increased need for lung transplant, and worse response to immunosuppression. More on that later. Those patients, I might be referring to lung transplant earlier and I might be watching them very, very closely. Also, telomere lengths matters for the choice of therapy.

There has been a study of non IPF ILDs where the authors looked at leukocyte telomere links and looked at the effect of immunosuppression, and they found that those with short telomeres actually did worse when they were exposed to mycophenolate and or avathioprine. And they were looking at SARD ILDs, Systemic Atomy Rheumatic Disease ILDs, they were looking at hypersensitivity pneumonitis, and they were looking at unclassifiable ILD, IPAF probably, they really found a significant association in hypersensitivity pneumonitis and unclassifiable ILDs, probably because they didn't have enough patients with short telomeres in the Sard ILD group. So I wonder if they had more patients. There might have been a significant correlation there as well. Still, if I am worried about a patient, I will be checking their telomere links before I ever start mycophenolate or abathioprine.

Here, in Rochester, Minnesota, we check telomere links by using cloak fish. I know it is not available everywhere, but I think with increased awareness, increased ordering, increased interest, it is going to be more available in the future. Thank you so much for listening. It's been a pleasure talking to you today. Until next time.

Hi, I'm Doctor. Janet Pope. I'm reporting for RheumNow, and my Twitter handle is janitburdeaux. And this is an exciting month of September with respect to learning a lot about ILD in our patients. So what about assessing and staging patients with ILD in your practice?

So let's start a bit with a case. I have a 52 year old man. He's had diffuse cutaneous systemic sclerosis. So the diffuse subset of scleroderma for about three years. He has ILD and he asked me how severe is it.

He also asked is this going to kill him because he's now work disabled and he really needs to know with respect to will and trying to have funds for his families. So there is a side note that's of interest. He did work for about thirty years in window manufacturing in a factory, And any production of silica dust is an increased risk for both ILD, not just silicosis, but ILD also for scleroderma. So I did suggest he see occupational health and he went forward with a workman's compensation claim. However, back to the story.

So he's been on mycophenolate mofetil and repeat dosing of rituximab and his PFTs have improved by approximately seven percent. When we look at his HRCT, he has an NSIP pattern, so the non specific interstitial pneumonia. So how am I going to stage him and what should we do and how should we be systematic? And then how do I answer his questions about how long has he got, doc? So how do we help answer this prognosis?

Well, idiopathic pulmonary fibrosis, there isn't really universally accepted staging for connective tissue disease associated interstitial lung disease or what we say is CTD ILD. So I think it's important to be systematic. So I look in several areas, symptoms, imaging, pulmonary function testing, and maybe biomarkers. But if you're not doing research, even following a C reactive protein that you'd follow anyway at times is important. So what about symptoms, the clinical assessment?

It's important to ask about dyspnea and you can't just say you're short of breath or people take it literally right here sitting in front of them. You have to say things like compared to last year, is it more difficult to do? And then you say activities. So you want to know if things have changed and you wanna know, is it exertional with mild or moderate exertion, or even just doing activities of daily living or having a shower and getting dressed, or even at rest. It's also important to ask about cough.

Cough is a poor prognosis if it's chronic in our patients with ILD, with their connective tissue disease, and ask about fatigue. Then we do think about functional status. So just like we would do a hack for someone with rheumatoid arthritis, we're going to look at function. You can do oxygen sat. I'm not going to do it on the hands of scleroderma patients because they have thick skin and Raynaud's.

So you can do the sat on their earlobe or you can do a sat after they walk around. And then I'm going to look at disease activity. For instance, this patient has scleroderma but other CTD or rheumatoid arthritis, is there active arthritis, is it active myositis, is there active lupus, etcetera. And basically if it's someone with rheumatoid you want their disease in remission wherever possible so that that will prevent or slow progression of the lung disease. Okay, what's next?

Pulmonary function tests. Now I don't think you need to master pulmonary function tests, but there's some things you want. I want both flows, which are done routinely, but I also want volumes. So you wanna look at FVC percent predicted or the forced vital capacity. And by the way, it's very similar to the, usually in our patients to the TOC, the total lung capacity.

And I'm looking at percent predicted because I wanna know change over time. I pay a lot of attention to the diffusing capacity and there are staging cutoffs that are sometimes used, mild restrictive where DLCO is still greater than 60%, FVC percent predicted is greater than 70%. And if you remember, 80% predicted to 120% predicted might be normal in an individual if you don't know where they started before they got their ILD. And then you would stage moderate or severe. And severe is pretty poor prognosis in general, FEC percent predicted less than 50% DLCO percent predicted less than 40%.

However, what's even more important are the changes over time, which is why I'm asking about functional dyspnea over time, but also PFTs over time. So we have a few rules in scleroderma and they've been used in these ILD trials including RA patients or other patients with UIP or R types of patients. So decline of FEC percent predicted of greater than ten percent in a short period of time, like six or twelve months or even twenty four months, that is maintained as opposed to reversible if they had a cold or something and then it improves, that is significant progression. Or a decline in the diffusing capacity greater than 15% predicted in the same timeframe. One or either or both is a bad sign.

Okay, then I'm going to also stage by high res CT scan. Now, again, you might look at the scan, but you certainly will read the report if you're ordering it. And you wanna co manage for the PFTs and for the HRCT with your local smart pulmonologist, and you better find one you can work with, it's a good idea. So patterns matter and the extent matters. So an NSIP pattern is better than a UIP pattern.

So NSIP is the non specific interstitial pneumonia and that's the most common pattern for many of our patients with connective tissue diseases. RA patients still have almost equal usual interstitial pneumonia, UIP, that's the more progressive fibrotic pattern. And scleroderma patients have a little bit more NSIP, but any of our patients could have either pattern or a mixed pattern. So that's important, the pattern. Then the extent is important.

So how much of the lung is involved? So usually it's the basis we're looking for honeycombing. That's a bad sign if you see that word or that phrase and traction bronchiectasis is also in general a bad sign. Our scleroderma patients already have a dilated esophagus. So that would probably be mentioned as well.

And we're looking to see if there's also superimposed aspiration, which is more in the mid zones, whereas the NSIP or the UIP start at the basis. So what do radiologists tell us if we ask? Is this, again thinking mild, moderate, or severe? Less than twenty percent involvement versus twenty to forty percent or greater than forty percent. Each of those patterns and some patterns being worse than others and the extent is really important.

And where their PFTs are at is important, but how fast they've gotten there so the change over time is important. Okay, what else should we do? I think doing periodic echocardiograms, I would do in this patient anyway because he has systemic sclerosis and we monitor for pulmonary hypertension. But two bad problems in your lungs are far worse than one. So pulmonary arterial hypertension is often group three in our patients with ILD and scleroderma because of hypoxia.

But some patients have a vasculopathy kind of pattern and then they might have hypoxia out of keeping with their ILD. So that's really difficult and we need expert people to help us with that. And obviously if you suspect pulmonary arterial hypertension by the echo and dyspnea, maybe hopefully not, but maybe JVP's up or pitting edema, so signs of right heart failure, we would like to diagnose it before then. Then you get an expert in pulmonary arterial hypertension to help you and they have to do a right heart cath. The other thing, and again when I say to do it, this doesn't mean you need to do it, you need to work with your pulmonologist, but checking for hypoxia regularly.

And what do we think about checking at rest? And again, avoiding their fingers with the sat monitor if they have scleroderma, try their ear lobes, or you can do an arterial gas, more invasive of course though. But I look at rest, I look walking them around a bit and then checking with a sat on while they walk, they just carry it around with them. And a lot of the automated blood pressure cuffs that you might have in your office will have a sat monitor on it as well. And also lying down, some people are quite hypoxic at night, so you might want to check lying down.

What's really important though is a multidisciplinary approach. So we need the pulmonologist, the rheumatologist, and we often involve the radiologist. And really we have to also say who's responsible for what? Am I going to treat the scleroderma and you're treating the lungs? Am I going to do both?

What are we going to do? And then never forget about general care, and this is true for any of our CTD or RA patients with ILD. Vaccinations, so flu shot regularly, an age appropriate flu shot. Over 65 gets a stronger flu shot. COVID vaccines regularly.

The pneumonia shot, so that's now Prevnar twenty is the one, it's one and done even if they've had the Pneumovax before in our immune suppressed patients with ILD. Exercising regularly, you can get them off to a program even though they don't have obstructive lung disease and might not have coronary artery disease, just get them in a heart failure program, a coronary artery disease program, or a COPD program if there is no ILD program. Avoiding others who have infections, breathing exercises, so deep breaths are important, warning the patients of worsening signs like pitting edema, chronic cough or signs of infection, so new sputum, change in sputum color, fever, and identifying and treating hypoxia. So I think this will help where you're going to frame how a patient is doing. So let's go back to my patient, 52.

Fortunately on MMF, imrituximab, he has actually improved and he feels better. He has an NSIP pattern and it's less than 20% on his HRCT. So he's got a good prognosis because PFTs have improved and so have symptoms. He doesn't have a chronic cough, he's not hypoxic, he is a non smoker, he has an NSAP pattern which is better than a UIP pattern, and he doesn't have much extent on HRCT. What if he worsens?

Well in addition to rituximab and MMF, then I would think is this progressive pulmonary fibrosis? Does he need something else like Nintendonib? Is he worsened because there's a superimposed infection? Is he worsened because something else is going on? So you look at other chronic low grade infections, meds, etcetera.

So I think this gives you a framework in which to be an excellent co manager on your patients with CTD ILD. For this, I thank you.

Hi, my name is Alicia Hintz and I am an assistant professor at Mayo Clinic and co director of the scleroderma clinic in Rochester, Minnesota. It is my pleasure to discuss with you today in this video the management of Split Stemic Sclerosis associated ILD, which I will probably shorten to SSC ILD. ILD occurs in about forty-sixty percent of patients with scleroderma and about half of those patients may experience progressive ILD and may benefit from immunomodulatory therapy. As highlighted in the 2023 ACR Chest Guidelines for the Management of SAARD ILD, we now thankfully have several evidence based therapies that we can utilize to treat ILD and scleroderma. The guideline also highlighted that there are still many unanswered questions and I hope to provide some considerations on how we might approach the clinical situations when answers might not be immediately clear.

So in this video, I will focus on how clinical phenotypes help inform the selection of treatments, review monitoring strategies to assess for ILD progression, discuss situations in which PFTs may not be the most accurate for ILD monitoring, as well as offer some practical solutions or practical considerations for repeat CT imaging and treatment monitoring. So first, differentiating patients who are at high or low risk for ILD progression is really the first step in managing SSE ILD. One key clinical risk factor for progression is early disease. So, in determining disease duration, we typically use the first non Raynaud's symptom onset. Patients, you know, ILD is one of the early manifestations of scleroderma, so patients often do have ILD on their baseline CT or will develop it usually within the first one to three years of disease onset.

The highest risk period for progression is about five to seven years, so that is a period where we might employ a little bit more frequent PFT monitoring. As such, disease duration is incredibly important when you are deciding to initiate treatment because you are probably going to consider treatment decisions in a person with six months with 15% ILD on their CT rather than a person that is ten to fifteen years ago with the same amount of ILD on their CT scan. Other established risk factors include a positive anti SCL70, a nucleolar pattern on ANA, diffuse cutaneous subtype, African heritage, elevated acute phase reactants, and a baseline CT with greater than 20% ILD. However, it is really important to note that patients without these risk factors may still experience progression, and it is also important to note that patients may have different rates of progression, and it is really important that we are looking at those trends over time. The decision to initiate treatment, particularly in those patients with early disease, really should be based on shared decision making.

You know, usually the standard of care has typically been to evaluate whether patients do experience progression, especially in those early patients. It is challenging because sometimes, especially in patients with significant clinical risk factors, that decision, you know, we start to consider, do we go ahead and start treatment at baseline? And I think it is important to kind of really have that talk with the patient because some patients may be more hesitant to start immunosuppression. For example, maybe they have a lot of comorbid disease that places them higher risk for infections versus maybe your 45 year old patient who loves to run marathons and having any sort of progression that might affect their respiratory system, breathlessness, is a really important consideration for them. In terms of what treatment to start on, based on both hierarchical ranking of head to head votes in the twenty twenty three ACR, SARD, ILD guidelines, as well as the American Thoracic Society's SSE guidelines that were published in 2024, the first line treatment for systemic sclerosis associated ILD is typically mycophenolate.

However, other organ manifestations really may influence the choice of therapies. In terms of mycophenolate, the treatment dose is considered to be fifteen hundred mg twice daily and that is consistent with the SLS-two study. In patients that may not tolerate mycophenolate or CellCept, it is very reasonable and I do recommend trialing MyForteq, especially in patients who have demonstrated stability. So when do we reach for Tocilizumab and Entenativ, the two medications that have received approval by the FDA for systemic sclerosis ILD? In making those decisions, I think it is really important that we evaluate the patients that were actually enrolled in that trial.

Additionally, I think it is, you know, we also have this situation in which we do not necessarily have a lot of evidence to guide us whether monotherapy or combination therapy is the best approach. But at least sort of when I discuss these I may highlight at least an approach to considering these therapies. So starting with the FOCUS trial, which was a multicenter, randomized, double blind, placebo controlled Phase III trial, which compared subcutaneous tocilizumab to placebo for forty eight weeks. This enrolled a very specific population of scleroderma that had disease, a disease duration of sixty months or less, and they also had elevated acute phase reactants. The primary outcome was actually to look at change from baseline in skin scores between the two groups, which did not reach its primary endpoint but several secondary endpoints did look at lung function decline over time between those two groups.

It showed in the Tocilizumab arm that there was a lot of stability that was seen actually in the FVC, whereas in the placebo group there was a significant decline. Also, on Tocilizumab, fewer patients reached the endpoint of a 10% decline in FVC as well. So, kinds of data did help lead to the FDA approval. But how do we actually apply this in clinical practice? The challenge in using Tocilizumab is that it was studied in a very specific subset of patients with active diffuse systemic sclerosis.

This is a population that we are typically utilizing mycophenolate to treat that cutaneous disease and that also can stabilize lung function. Particular situations that I might consider the use of Tocilizumab would be those patients with progressive ILD. And I also think it is quite beneficial, especially if patients do have inflammatory arthritis and progressive ILD, as it really is a nice drug to treat those manifestations. The question always becomes, you know, do we add on therapy or do we switch therapy? Because this subset of patients is usually being treated for active cutaneous disease with mycophenolate, I would typically add on tocilizumab to mycophenolate.

As time progresses, I think, you know, and we have greater evidence from kind of real world use, we will start to understand whether the tocilizumab may be applied to other patient populations with systemic sclerosis. But at this time, I really tend to use clinical phenotypes to guide when to reach for tocilizumab. Moving on to the SENSUS trial, which was a multi center international randomized placebo controlled trial that evaluated Nantenatib one hundred and fifty mg twice daily versus placebo. All cutaneous subsets of scleroderma were included as long as they met specific ILD progression criteria within twenty four months and also had at least ten percent ILD. The population that was ultimately enrolled in the study actually had more severe ILD, around thirty five percent in both groups.

Also in this study, stable background mycophenolate was allowed. Natinib did decrease very modestly the rate of decline in FVC compared to placebo. It did also show that combination Natentative and mycophenolate did provide a greater numerical preservation of lung function than the mycophenolate and placebo arm. So I think this does provide us, at least with some indirect evidence, that combination therapy with mycophenolate and nantenativ may be a helpful strategy. Clinical scenarios that I think about adding Nantenative include patients with progressive lung disease with more of those fibrotic features.

I do tend to add Nantenadib onto the mycophenolate as well. It also can be useful in patients with other contraindications to immunosuppression such as recurrent severe infections, but a side effect of diarrhea, which is quite common, can limit its use. The last agent I'll mention, which is also listed as a preferred option for first line treatment of SSE ILD and the SAARD guidelines, is the use of rituximab. Rituximab is supported by the use of a couple clinical trials, which included patients actually with SARD ILD rather than specifically focusing on systemic sclerosis ILD. One study compared rituximab to cyclophosphamide and showed actually that both arms even experienced an increase in FVC after only about six months.

And so, this suggests that rituximab is a reasonable option. About thirty seven percent of patients in that trial did have SSC ILD. Another trial called Ever ILD compared rituximab and mycophenolate to mycophenolate and placebo. About fifty percent of patients in this trial, which was twenty three patients in total, were included and the combination therapy did show superiority to MMF alone. It is important to note that mycophenolate was only used at a dose of two grams per day.

So, it is unclear if sort of the changes that we are seeing is because mycophenolate was not used at its maximum dose. One thing to note was that this trial included patients only with NSIP and excluded those with more of a UIP pattern. So this might also provide some insights into sort of the imaging phenotypes that you might utilize rituximab in. Considerations for the use of rituximab is, again, other features of systemic sclerosis, particularly the extrapulmonary features such as myositis, inflammatory arthritis, or progressive lung disease in those patients on mycophenolate. So, as you know, a lot of our trials really are looking at changes in FVC from baseline.

That is what we use in clinical practice, so these outcomes, or these surrogate acts, are really quite beneficial to us as we are analyzing the data. I'd mention that there are a few caveats that are really important for us to consider in clinical practice. And that things that can affect actually FVC. So, myositis is a big one. So, in patients with myositis with active muscle disease, we can see a reduction in that FVC and total lung capacity on PFDs.

So it s important in patients with ILD and myositis that as the muscle disease improves, we really generally see that FBC and total lung capacity increase. So,

it

is helpful to monitor those trends, see where patients do peak in their FVC, and understand that that is probably their actual baseline. Once I see some stability in the peak lung functions, I will usually do another CT scan. If that CT scan does show progression of lung disease, even though technically the total lung volume is increased, well that is a pretty good indicator that there is progression of ILD. And considerations for treatment changes are reasonable. Other patient subsets that may experience a slower decline in FVC would be smokers.

Also, time of day may affect FVC, which is lowest at night and early morning and tends to be higher in the afternoons. Studies have also shown that variability in test to test PFTs may be as great as about 4%. So really, I think what this highlights is we need to consider patients comorbid conditions as well as kind of looking at those trends over time, especially early in disease, more frequent PFTs may be very helpful to establish that. So, practical considerations, when do we repeat that CT scan? The guidelines aren't clear because this really is variable from patient to patient and is based on the clinical scenario.

So, some practical quick considerations for repeating would be repeating about six to twelve months after treatment initiation or a change in therapy if a patient has shown progression. Really trending those FBCs and DLCOs and if you are seeing a decline in those to rescan. And if patient is having increased respiratory symptoms that we just can't attribute to other etiologies, a repeat scan at that point is also very reasonable. Of course, we want to keep in mind the radiation exposure for our patients, but we also want to ensure that we are treating lung disease as it tends to be, you know, mostly irreversible in patients with systemic sclerosis. Also, of course, to mention that generally we do look at echos at least once a year in patients with systemic sclerosis for development of pulmonary hypertension, which may be pulmonary arterial hypertension versus pulmonary hypertension secondary to ILD.

So, just to briefly summarize what we have talked about, mycophenolate is the preferred agent to use first line in SSC ILD, though other manifestations may impact that choice. Often in other conditions, excuse me, in other situations where patients are experiencing progression, we can consider the use of some of those other medications. Of course, those are sometimes considered as first line, but you really have to take into account the patient phenotypes. For example, the Tocilizumab used in the early active diffuse cutaneous patients, Nantenatib, very modest slowing of rates of progression, may be more useful in patients with a more fibrotic pattern and has been used in patients with more advanced disease. Rituximab has also been shown to actually improve absolute FVC from baseline.

And patients with a little bit more advanced ILD were included, but it also included patients with other SARD ILDs. So, application rituximab to the specific population of scleroderma still remains to be fully seen and evaluated. Important again to consider other risk factors that may impact FVC and if in doubt, grab that CT scan. I hope this video may aid in making decisions on choices of therapies for your patients with SSE ILD. Thanks for watching.