ILD Treatment Save

Hi. I'm doctor Bryant England, rheumatologist at the University of Nebraska. Thanks for joining me today to discuss some key points in the treatment of RA interstitial lung disease. The first key point is that the right treatment for RA interstitial lung disease starts with doing the right assessment of RA interstitial lung disease. Now when we think about assessing for interstitial lung disease, there's some core things that we need to do.

Our best test is a high resolution, computed tomography imaging of the chest. This is a non contrast image that tells us information about the pattern of interstitial lung disease, the extent of interstitial lung disease, as well as other relevant findings such as airway disease or nodules. Complementing this, we want to obtain pulmonary function tests, complete pulmonary function tests that includes spirometry, lung volumes, and diffusion capacity with our forced vital capacity, our total lung capacity, our DLCO being the measures we most closely monitor. We wanna remember to talk to the patient and ask them about shortness of breath, dyspnea on exertion, cough, and assessing what their current activity level is. And then finally, we wanna follow these values over time because even more informative than a detailed assessment at one point is understanding what the trajectory of their imaging, their pulmonary physiology, and their symptoms are over time.

But assessment of RA interstitial lung disease doesn't end with assessing the ILD. We also need to assess the other systemic aspects of disease. So this includes assessing their joints and measuring disease activity and functional status. We wanna assess what therapies patients have been on in past, whether these have been efficacious or not, and whether they've had any adverse effects from these medicines. Once we've done this, we can really start to understand where on the spectrum of severity a certain patient falls.

We can have a spectrum of severity for the lung disease. We can have a spectrum of severity for their articular or other systemic manifestations. And we want to understand that first before we start talking about treatment. Once we've established where on that spectrum a patient falls, then we have a couple options. So we have an option of using immunomodulatory therapy, and we have the option of using anti fibrotic therapies.

Now with the immunomodulatory therapies, one of the first questions that comes up is what do we do with the therapies patients might already be on when we detect interstitial lung disease? This is particularly the case with methotrexate or tumor necrosis factor inhibitors, which some people have concern about the safety of their use in people who have ILD. Now some recent data suggesting maybe we were a little more concerned with that than we need to be. But each of those decisions is individualized on a patient by patient case. A question we have had is how those immunomodulatory therapies might stabilize lung function over time.

And some recent data suggest that indeed if we use immunomodulatory therapy for patients with RA ILD, we might stabilize both our FEC or DLCL values. Now recent ACR chest guidelines have highlighted some specific therapies we might prefer to use in people who have RA interstitial lung disease. These include azathioprine, rituximab, and mycophenolate and cyclophosphamide. Now I don't frequently use mycophenolate or cyclophosphamide in RA interstitial lung disease, in part because mycophenolate really doesn't have any efficacy for articular disease and because of the serious toxicity of cyclophosphamide. In place, people frequently will use aptacit or tocilizumab instead.

In addition to immunomodulatory therapy, we have anti fibrotic agents we can use to help slow progression as well. These include metendonib, profanidone, and then the newest medicine that's being evaluated right now is Nirindomolast. What we do know is that when we are choosing these therapies and working with our patients to treat RAILD, that RAILD management is a team effort and not a one time event. So for these patients, we want to engage a pulmonologist to be part of the care team. Pulmonologists are very useful in helping us monitor the disease over time.

The symptoms, the pulmonary physiology, interpreting their chest computed tomography images. When we measure those, again, wanna measure those over time to understand the patient's trajectory of disease as we're intervening. And if we see signs of progression, by symptoms, physiology, or chest imaging, we need to think about making adjustments to their therapy. Need We to think about maybe having this patient evaluated for lung transplant, whether this patient might need supplemental oxygen or benefit from pulmonary rehabilitation. So in conclusion, the treatment of RA ILD starts with thoroughly assessing the systemic nature of RA interstitial lung disease, evaluating the lungs, evaluating the joints, and other systemic manifestations.

We have immunomodulatory and anti fibrotic therapies that we can use to try and slow progression of this potentially devastating disease. Unfortunately, the evidence for a specific agent to prefer over another is rather weak. So all of these will be individualized decisions. And we need to engage and build that multidisciplinary team to optimally care for these patients over time and monitor them closely over time for any signs of progression of their disease. So thanks for joining me to watch and talk about treatment of RA interstitial lung disease.

Hi everyone. My name is Elizabeth Volkmann and I'm an adult rheumatologist at the University of California, Los Angeles, where I direct the scleroderma center and where I also co direct the CTB ILD program. I'd like to speak with you today about disease modifying therapies for patients who have connective tissue disease related interstitial lung disease. We also refer to this now as SARD ILD. And there actually is accumulating evidence that disease modifying therapies exist for ILD.

Much of the literature comes from studying patients who have systemic sclerosis related ILD or SSC ILD. So the first studies that were conducted in this area were called the scleroderma lung studies. These were studies that were sponsored by the NIH. In the first scleroderma lung study, it compared cyclophosphamide to placebo for SSE ILD, demonstrating that treatment with cyclophosphamide had a favorable effect on lung function, as well as radiological fibrosis and self reported dyspnea and quality of life. The second scleroderma lung study compared cyclophosphamide to mycophenolate for SSC ILD.

In this study, there were similar benefits in terms of treatment with mycophenolate and cyclophosphamide. So there were no between treatment arm differences. Both treatments led to improvements in lung function and radiological fibrosis, as well as self reported dyspnea and quality of life. But not surprisingly, patients who were treated with mycophenolate had a better safety profile than those patients who were treated with cyclophosphamide. Following the scleroderma lung studies, there was a large global trial that was conducted comparing Nintentative to placebo for SSC ILD.

This was the largest study that had ever been conducted in connective tissue disease related ILD, and it enrolled over 500 patients from around the world. In this study, treatment with nintanatib slowed the decline in lung function in patients with SSC ILD compared with placebo. It's important to note that in this study, patients were allowed to take background therapy with mycophenolate. So there was a subgroup of patients in this study who were treated with a combination of mycophenolate plus nidtetinib, and these patients actually had the best outcomes. And then following this study, there was another study called the FOCUS trial.

Now the FOCUS trial also looked at patients with systemic sclerosis related ILD, but it was a very specific type of patients with systemic sclerosis. These patients had early disease, they had diffuse cutaneous sclerosis, and they had elevated acute phase reactants, meaning that they had signs of active inflammation. Not all of the patients in this study had ILD, but in this study, which was primarily designed to look at the effects of tocilizumab on skin in patients with systemic sclerosis, they discovered that tocilizumab had a favorable effect on FVC. So those patients who were randomized to tocilizumab had stabilization in their FVC, whereas those patients who were randomized to placebo actually had a decline in their FVC. Now, it's important to note the difference between this trial and the SENSUS trial and that in the FOCUS trial, patients weren't allowed to be on background therapy with mycophenolate.

So we don't actually know how tocilizumab would compare with patients getting background therapy or getting treatment with nintanatib. Since this time, there's been a few studies looking at rituximab for patients with CTD ILD. In addition to a small trial that was done in Japan looking at patients with systemic sclerosis related ILD, there was another study that was done in The UK called the RECITAL trial. And this was a unique trial because it did not just include patients with systemic sclerosis related ILD, it also included patients with myositis related ILD, as well as mixed connective tissue disease. And in this study, they compared treatment with mycophenolate with treatment with cyclophosphamide.

And at six months, there was actually similar improvements in FVC between both treatment arms. But again, not surprisingly, the patients treated with rituximab had a better safety profile than those treated with cyclophosphamide. There's been another sort of basket trial looking at patients with CTV, ILD, and rituximab. And this is another study called the EVER ILD trial. And this was another European study where they looked at patients who had interstitial lung disease with an NSIP pattern.

And this is the most common pattern we see in patients who have connective tissue disease related ILD. And so, in this study, the majority of patients had CTD ILD, some had idiopathic NSIP. And this study compared combination therapy of mycophenolate plus rituximab versus mycophenolate alone. And at six months, those patients who were treated aggressively with a combination therapy actually had a better outcome in terms of FVC than patients treated with mycophenolate alone. And then there's some hot off the press study information that I wanted to share with you.

This is looking at a new emerging medicine called narendolamast. And so, this was just published in May in the New England Journal of Medicine. And in this study, they looked at patients who had progressive pulmonary fibrosis, and it could be due to different causes. So not everyone in the study had connective tissue disease related ILD, but some of the patients had other types of ILD like hypersensitivity pneumonitis. In this study, patients were allowed to receive background therapy with either nantenativ or parfenidone.

And in this study, treatment with nirandolamaz again had a more favorable effect on FVC course than patients randomized to placebo. But it's important to note in this study that patients were not permitted to enter the study if they were on any background immunomodulatory therapy with drugs like mycophenolate or rituximab or tocilizumab to be eligible for this study. What this means is that while narendolumab looks to be a promising agent for ILD in the setting of CTD, we don't know how it would compare to our existing therapies. So, I want to leave you with some words of wisdom in that if you have a patient with CTD ILD, first of all, there are treatments that can help these patients. So at one time we didn't have great options for these patients, but now we do.

It's important, however, to monitor these patients very closely. So if you start a patient on mycophenolate or on nintenatib, you need to follow their lung function closely, look at their radiological changes on CT, and determine whether the treatment is really helping them. If it's not helping them and they're not getting better, then it's time to switch to another therapy. And I think over time we'll have more and more treatment options for our patients, including possibly CAR T therapy and other cell therapies. And I just really want to thank you for your time today.

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Hello, my name is John Giles. I'm the Director of the Inflammatory Arthritis Clinical Center here at Cedars Sinai Medical Center, and I co direct the RA translational research program in the Cal Autoimmunity Institute here. And it is a great pleasure to be able to speak with you today about the non pharmacologic management of interstitial lung disease. A few disclosures that are listed here, but none of them are relevant to this topic. I want to start out the discussion about the non pharmacologic management of ILD with just a little excerpt from the companion piece to the 2023 ACR and ATS recommendations for the management, monitoring and treatment of interstitial lung disease and connective tissue diseases.

And the first is just a little bit about the patient perspective and what the patients are expecting for the management of their disease, specifically with goals of treatment. Here that this is from the publication here, the patient states her goal was to survive and then achieve small life goals with her children, go back to work, talk without choking and smell flowers again. You notice that her goals of treatment are I wanted to be treated with a medication. She wants to be treated with something that has a result, but maybe not isn't necessarily a medication. The other side is the side effects with treatment.

One of the answers from the patient panel was it depends on how sick I am and how badly I need to manage my disease symptoms and the balance between side effects and what the anticipated effect is. And there was a concern in this piece that some patients, especially who maybe don't have a dangerous level of ILD, may not think that the side effects of many of the pharmacologic treatments are worth the risk. Which brings us to thinking about how we can help our ILD patients across the different diseases maintaining their lifestyle and happiness in a way that maybe doesn't involve immunosuppressants, immunomodulators or anti fibrotic. In addition, how we can combine other non pharmacologic modalities with these treatments actually make the patients better off. And I will say that there's not a strong evidence base for many of these, and many of them are adapted from other diseases such as idiopathic pulmonary fibrosis.

So this is based on recommendations, again, from the 2023 ACR and American College of Chest Physicians guideline. This is the treatment guideline. This was just published last year in August, so just about a year since its publication. I want to concentrate on table four from this, which is the recommendations for additional integrative and pharmacologic interventions that can be considered in patients with connective tissue disease ILDs. And from pharmacologic here, we're not meaning immunomodulators or anti fibrotic, but adjunctive therapies.

So here are their recommendations and and and the paper, because I guess because of length, there's no actual discussion of any of this in the text. So you only get this in this particular table. But in terms of interventions, they recommend exercise, which can include things like aerobic exercise, resistance training, Tai Chi, palliative care, obviously are people for people who are expected to to not do well in the long long run. Physiotherapy that can include chest physiotherapy, incentive spirometry and others pulmonary rehabilitation, which is cardiopulmonary rehabilitation and resistance training, which is very similar to exercise. There's not a strong evidence base here in any one of our particular rheumatic disease ILDs.

Smoking cessation obviously is kind of a no brainer, and then supplemental oxygen is also often required in many of these patients. And then what I would also consider sort of non pharmacologic management are using drugs that are not directly related to the physical manifestations or the tissue manifestations of of the ILD. So particularly for patients with scleroderma ILD, you want to minimize their gastroesophageal reflux with a number of measures, because reflux of acid into the lungs can be associated with worsening, both in terms of symptoms and perhaps even with parenchymal damage for appropriate patients who are immunosuppressed prophylaxis with antibiotics against pneumocystis. Again, mostly for scleroderma patients are promotility agents, again, because of the reflux. And then a very important aspect of the non pharmacologic management of ILD is to make sure that patients are appropriately up to date with their vaccines, especially COVID-nineteen.

I think many of us who see these patients can think of at least at least several people with a fixed amount of interstitial lung disease who, after they got COVID-nineteen pneumonia, had a very, very precipitous drop in in their quality of life because of what looks like progressive disease on top of their their prior, maybe fairly stable ILD. So developing a pulmonary infection in these patients can be quite devastating and anything we can do to prevent that is better for them. I have some additional ones that were not included here in the guideline, and some of these are, I think, going to be more important to some ILD patients and less important to some others. So, for example, early transplant evaluation is applicable to ILD patients who have extensive disease or appearing like they're progressing relatively rapidly. And the reason for this is that when things start to progress rapidly even more, it's very difficult to get all of the elements of the transplant evaluation done relatively quickly.

So checking off all the boxes on what the transplant team needs at an early stage is good. This is sometimes difficult with patients because they can often think of transplant as as a defeat sometimes. But I try to reassure them that what we're doing is prior planning and not accepting that that we have been defeated in terms of treating their ILD. Another important element is optimizing treatment for other non respiratory diseases like COPD, and we often see that our patients have can have multiple forms of lung disease, especially COPD, because of the risk of smoking for both ILD and COPD. Screening and managing concomitant sleep apnea is important because the patient is experiencing dyspnea and whether that's from their ILD or something else could play a role.

They're also often very fatigued. And if the fatigue is from an alternate source, then then this is important. Emotional and mental health management is important because these patients because of their disease and especially if there's a decline in their respiratory abilities, they can become quite depressed and definitely quite anxious if they have a lot of dyspnea. And so making sure that that their mental health needs are addressed, it can be actually a very key aspect of their management because we see that when patients get depressed, they often eat less, they can't maintain their weight and they lose some of their ability to to take their medications effectively, keep up with their appointments and other things. Another is to consider interstitial lung disease associated pulmonary hypertension as a cause of dyspnea.

I think this gets overlooked sometimes. Extensive parenchymal involvement from ILD can lead to pulmonary hypertension. When the patient feels short of breath, it could be this could be a contributor in and taking care of this, either by doing a right heart cath echocardiogram, etc. We can identify this as a source and treat it separately from the way that ILD is treated otherwise. Patients on lots of steroids can get steroid induced myopathy, which can include diaphragmatic weakness.

That can also be a source of dyspnea, and that's something we should consider. Weight management is complicated in these patients because of the inflammatory nature of their disease and because of dyspnea, they can lose weight, And it's important for these patients to maintain or gain weight if they keep them from becoming frail and sarcopenic, but also to help to build back up muscle. And then in obese patients with ILD, weight loss may actually help their symptoms, may not help immunomodulate. We don't know, but may not help that, but may help their symptoms. And then, of course, something that's also often overlooked is modifying environmental and occupational inhalant exposures.

So making sure that the environment in which they're living in, whether it's their home or work, is not one in which there is a lot of excessive dust, chemical exposures and even things like mold in the home. So I think there's a lot of things to consider here and patients can and the combination of all these non immunomodulator related conditions can actually have a lot of bearing on how the patient feels and their quality of life. And if we can consider these when when we treat our patients along with the immunomodulators and the anti fibrotic, then we can potentially have them lead happier and healthier lives, even with interstitial lung disease. That concludes this, and thank you for watching this section on RheumNow.

Hello, I'm John Jerns, I'm a transplant pulmonologist and intensivist at Mayo Clinic in Rochester. I'm gonna speak for a few minutes today about, transplantation for rheumatic lung disease, a real option. So lung translation in lung transplantation rheumatic disease is a real option. First, a little bit about lung transplant. Lung transplant would, modern lung transplantation started in the nineteen eighties.

And right now, we have an average survival after transplantation of about six to six and a half years. The most common indications are interstitial lung disease. Most lung transplant patients are maintained on three drug immunosuppression, usually prednisone, a calcineurin inhibitor, and a antimetabolite, either azathioprine or typically mycophenolate. The most common rheumatic diseases that go into lung transplant are scleroderma, rheumatoid arthritis, undifferentiated connective tissue disease, and Sjogren's. And there's data coming out to suggest that, many patients with Ipath also go on to lung transplantation.

There's a lot of challenges here with nomenclature, and records are not very accurate in capturing all of these. Please remember that there are rheumatic manifestations other than interstitial lung disease including pulmonary hypertension and obliterate bronchiolitis that go on to lung transplantation. Lung transplant pulmonologists are often hoping that they'll be able to find patients that have isolated lung disease. Complex multisystem diseases are worrisome for a transplant pulmonologist, but they are common in our rheumatic disease patients. Just to give you some idea, if we think about rheumatic manifestations and what the transplant pulmonologist may be concerned about, if we hear pleuritis or pericarditis as a transplant pulmonologist, I'm worried that there's gonna be surgical adhesions that may make the surgery more difficult.

If I hear about renal involvement in lupus or scleroderma, I'm gonna be worried that tacrolimus may not be tolerated well. If the patient is a woman, especially that has had children, I worry that there may be autoantibodies or HLA antibodies that may make it difficult to find donors. If there's esophageal dysmotility, sickest symptoms, GERD, I worry about kind of multi compartment gastrointestinal challenges that may increase the risk of aspiration, pneumonitis, or chronic rejection. Pulmonary hypertension, I worry that that could be a more challenging perioperative course. If there's antiphospholipid antibodies, whether or not there really is an antiphospholipid syndrome or not, we worry about increased risk of thrombotic complications, Raynaud's, skin changes, neuropathies, other MSK complaints, we might worry that these are either portals of infection or that a patient may be unable to, rehab and have threatened functionality.

And if there's neuropathies or other things that would threaten the diaphragm, we worry that we may get fresh lungs in, but that the benefit would be truncated by diaphragm disorders. And so historically, there's been a lot of concerns that rheumatic disease patients are difficult to transplant, that they may get suboptimal outcomes, and that they may have suboptimal survival. And this data, I think, has kind of best been put together so far in an ISHLT consensus document, made with pulmonologists, rheumatologists, pharmacists, surgeons in 2021 They came out in three parts, and they they addressed this head on. The historical perception that rheumatic interstitial lung disease patients and scleroderma in particular do not do as well is, not really consistent with the available literature. Just to quote from the guideline, they say the transplant centers in both US and Europe have consistently reported that outcomes in patients undergoing lung transplant for scleroderma are comparable to those that are transplanted for other interstitial lung disease.

Now it's important to note that many of those patients with other interstitial lung diseases like IPF are often older but still. When we're trying to think about rheumatic disease patients that go on to lung transplant it's helpful if their disease is controlled just like any other interstitial lung disease. There is some evidence mostly taken from other interstitial lung diseases that anybody who's transplanted from a flare may have suboptimal outcomes. And when we're trying to think about rheumatic manifestations that may need additional immunosuppression beyond those three drug immunosuppressants, you can see here, I've just taken, if you consider the options for rheumatic interstitial lung diseases, you'll see that a common theme, whether it be systemic sclerosis, myositis, mixed connective tissue disease, rheumatoid arthritis, Sjogren's, or potentially even I path, while they all have slightly different toolkit, rituximab is considered first line therapy in all of those. And so it's a broadly applicable tool that can be used to help control rheumatic diseases going into transplant, can be used peri transplant, and can be used after transplant.

And it's a medication that both rheumatologists and pulmonologists are going to have substantial familiarity with, and transplant pulmonologists are going to have substantial familiarity with. ICLGLT consensus statement does address a variety of different rheumatic agents and whether or not they can be continued off, after transplant. And while I don't want to go through all of those agents here, rituximab has reasonable evidence. It has been investigated as induction therapy in organ transplants, including thoracic organ transplants. And while, of course, we have to be aware using rituximab, especially on top of people that may be getting induction immunotherapy and three drug immunosuppression, the iCitlT consensus statements do recommend rituximab, as being a medication that can be continued before transplant, peri transplant, and at post transplant if needed to control an underlying rheumatic or connective tissue disease.

So there are a few kind of absolute contraindications that are specific to rheumatic disease patients. If a patient has active myocarditis with refractory heart failure, if there's active and uncontrolled extrapulmonary manifestations, for example, skin necrosis and non healing ulcers, if there's upper airway lesions that would not be removed with the transplant like subglottic stenosis or cricoarytenoid arthritis, If there's severe swallowing dysfunction with recurrent aspiration, that is not thought to be minimal to the therapy, oftentimes this is dealt with with a period of NPO where a patient is tube fed for a while. If a patient's unwilling to to go down that path, that can be an absolute contraindication. Severe unstable atlantoaxial joints at high risk for subluxation, symptomatic arthropathy despite optimal control of disease, diffuse or focal proliferative lupus nephritis, evidence of active muscle disease that cannot be controlled with standard post transplant immunosuppression. These might be a few of the absolute contraindications that are specific to rheumatic disease patients.

While there's much to say on this subject, in short, many of the historical beliefs about suboptimal outcomes in rheumatic disease patients with interstitial lung disease or pulmonary hypertension that go on to lung transplant have not been borne out. I want to highlight two in particular, ANCA vasculitis and MDA five myositis as being particularly scary from the transplant pulmonologist point of view. We worry that the ANCA vasculitis could return, and there are a few case reports of that. We also worry that, you might get more extra pulmonary manifestations in the vasculitides. And MDA five myositis is, notorious for very advanced lung disease requiring lots of immunosuppression, being very fast progressive with many of these patients having to be supported or bridged, with ECMO.

Most extrapulmonary manifestations are controllable with standard three drug immunosuppression post transplant. Some things that I have seen include joint disease and rheumatoid arthritis and Raynaud's and scleroderma with the usual toolkit that you would already be using for scleroderma Raynaud's being available after transplant as well. Rituximab is broadly applicable in rheumatic pulmonary diseases. It probably has the most safety data in solid organ transplant and is the most guideline supported anti rheumatic, drug to use peri and post transplant if you need something beyond the three drug immunosuppression. Of course, other things like Plaquenil can be used.

But if we're trying to look at TNF inhibitors and, JAK inhibitors and a variety of the other antirheumatic drugs, rituximab probably has the most accumulated safety and familiarity data. And the more you refer to your local or regional transplant program, the more likely they are to partner with you and hopefully together you can offer transplant to many more rheumatic disease patients than has occurred in the past. Thank you very much for your time.