ILD Guidelines Save

Hello. My name is Doctor. Sindhu Johnson and I'm a professor of medicine at the University of Toronto. I'd like to thank RheumNow for giving me the opportunity to share with you the American College of Rheumatology, American College of Chest Physicians guidelines for the screening, monitoring, treatment of systemic sclerosis associated interstitial lung disease. I was supported by the American College of Rheumatology to develop this work.

In the past, I've been supported by EULAR to develop classification criteria for systemic sclerosis as well as systemic lupus. And I've previously served on the steering committee of the American College of Rheumatology guidelines for vaccinations for which I now receive royalties from UpToDate. With regards to potential conflicts of interest within this presentation, I have previously served as a site investigator on several clinical trials for data that informed this guideline, notably for tocilizumab and entanenib. The steps I've taken to review and mitigate these potential biases are that I have given up all pharmaceutical relationships one year prior to the development of the ILD guidelines, and I will continue to do so for at least one year after its publication. Clinical practice guidelines.

These are considered among the most important documents that the American College of Rheumatology and American College of Chest Physicians produce for its membership. It has a number of objectives, but its primary objective is to guide healthcare professionals. Its secondary objectives are to reduce geographic practice variation. A patient's treatment options should not depend on where they live. Finally, clinical practice guidelines can be used as advocacy documents and awareness documents.

If a payer does not cover a specific test or a specific treatment, groups can use clinical practice guidelines to help advocate for their coverage. The American College of Rheumatology, American, College of Chest Physicians guidelines cover several groups of recommendations. The first group of recommendations relates to who should be screened. We know that systemic sclerosis confers an increased risk of developing interstitial lung disease compared to the general population. However, the risk of developing ILD and the risk of progression can vary across subsets or groups of patients.

In the document, we outline a number of risk factors for developing interstitial lung disease and progression of interstitial lung disease. These include autoantibodies such as SCL70 and antinuclear antibodies with nucleolar pattern, the diffuse subtype, male sex, African American race. Patients with early disease, that is the first five to seven years after onset are at increased risk of developing ILD, and those with elevated acute phase reactants such as ESR and CRP also confer an increased risk of developing twenty ILD and disease progression. It comes to screening for ILD in people with systemic sclerosis, the American College of Rheumatology conditionally recommends pulmonary function testing and high resolution CT chest. Now clinical pearl number one.

A pulmonary function test should include spirometry, lung volumes, and diffusion capacity. Often pulmonologists will use office spirometry to monitor disease, however spirometry alone is insufficient. We should be ordering full pulmonary function tests. Clinical pearl number two. A scleroderma patient who has shortness of breath may present to the emergency department, and there they will receive a CT angiogram, often because the emergency doctor wants to rule out pulmonary emboli.

However, it's important to note that a CT angiogram is performed in incomplete inspiration to maximize pulmonary artery enhancement, and this may produce atelectasis that can obscure or mimic ILD. Therefore, a CTA is inadequate to screen for ILD. A patient needs a high resolution CT chest. Once a patient has been diagnosed with interstitial lung disease, the next grouping of recommendations relates to monitoring of ILD. The American College of Rheumatology and American College of Chest Physician guidelines conditionally recommend pulmonary function testing, again with spirometry, lung volumes and diffusion capacity.

It is suggested that in systemic sclerosis PFTs occur every three to six months in the first year and then less frequently once stable. The second monitoring test is ambulatory desaturation testing every three to twelve months. This may be new to many rheumatologists and certainly does not fall within our scope of practice. However, this test falls within the scope of practice of a pulmonologist and here is one of the many reasons we should be sharing care with pulmonologists. A clinical pearl is that a six minute walk test with continuous oximetry is insufficient.

Ambulatory desaturation testing includes up titration of oxygen. The third monitoring test is high resolution CT chest as needed. With regards to other screening tests, there are several that have conditional recommendations against. These are chest x-ray, six minute walk test distance, ambulatory desaturation testing, and bronchoscopy as screening tests for ILD. There is a strong recommendation against surgical lung biopsy as a screening test for ILD.

However, there may be other reasons why one may choose to perform these tests. For example, if a patient has difficulty performing PFTs, a bronchoscopy may be required to rule out infection, sarcoidosis, lymphoma or alveolar haemorrhage. A surgical lung biopsy may be used to rule out malignancy. Similarly, there are conditional recommendations against the use of chest x-ray, six minute walk test distance and bronchoscopy for monitoring ILD. However, these tests may be used if a patient has difficulty performing PFTs, or to rule out infection or alveolar hemorrhage.

The next grouping of recommendations relates to the first line treatment of ILD in people with systemic sclerosis. The treatment options are presented as preferred, that is those that are expected to be most commonly prescribed, and additional therapies, those that may be used in certain situations. There are many situations that might lead a provider to choose a different treatment option for ILD, For example, comorbidities or extra pulmonary disease activity. And so I'd like to draw your attention to the first green box labeled systemic sclerosis. You will see there are a menu of treatment options as first line ILD therapy.

The first indicated therapy is mycophenolate. And as you can see, this is the first first line therapy across several systemic autoimmune rheumatic diseases. However, one may consider tocilizumab, rituximab, cyclophosphamide, nintedanib, or azathioprine as a first line ILD treatment in systemic sclerosis. There is a strong recommendation against the use of glucocorticoids in people with systemic sclerosis associated interstitial lung disease. And this is due to the increased risk of inducing a scleroderma renal crisis.

Now while this may be common knowledge to most rheumatologists, many of our pulmonology colleagues are not aware of this. So here is an opportunity for you to educate our colleagues in your consultation notes. The next grouping of recommendations relates to progression of ILD after first line therapy. For the purpose of the guideline, the in build criteria for progression were used. However, you do not have to use these criteria.

Again, I'll draw your attention to the first box labeled systemic sclerosis. Again, there is a menu of options that one can choose from. In this case, if mycophenolate was not the first line ILD therapy, a second line treatment would be mycophenolate. However, one could also consider rituximab, nintedinib, tocilizumab, cyclophosphamide, as well as referral for autologous hematopoietic stem cell transplant at an experienced center. There is a strong recommendation against long term glucocorticoids in people with systemic sclerosis associated ILD, again due to the increased risk of inducing a scleroderma renal crisis.

One may also consider at this point referral to a lung transplant center for evaluation due to their progressive disease. The final grouping of recommendations relates to rapidly progressive ILD, That is a subpopulation of ILD characterized by rapid regression from no oxygen or a patient's baseline oxygen requirement to a high oxygen requirement or intubation. Usually this occurs over days to weeks without a documented alternative cause such as infection or heart failure. Rapidly progressive ILD is considered a new disease of our era, and typically associated with inflammatory myositis, those who have MDA-five antibodies. However, rarely it can be seen in people with systemic sclerosis.

In this situation, the guidelines conditionally recommend combination therapy with intravenous glucocorticoids, as well as two additional therapies, rituximab, cyclophosphamide, or mycophenolate. However, I will share with you that many high volume centres in The US tend to prefer IVIG and calcineurin inhibitors such as tacrolimus. And this is largely due to their concerns about increased risk of infection in an intubated patient on rituximab or cyclophosphamide. The guideline document contains additional tables. One relates to medication dosing and monitoring.

This may be helpful for medications that you are less familiar with such as tacrolimus. In this table, we outline the starting dose, frequency and monitoring recommendations. There are additional tables that highlight other interventions that one might consider in the treatment of scleroderma associated ILD, but we're just beyond the scope of the guideline. This includes exercise, palliative care, physiotherapy, pulmonary rehabilitation and supplemental oxygen. There are also other pharmacologic therapies such as gastroesophageal reflux management, PJV prophylaxis, promotility agents and vaccinations.

I was involved with the ACR guidelines for vaccinations in people with rheumatic diseases. And I'd like to draw to your attention rituximab. It's conditionally recommended that we should continue rituximab in patients who need it. However, with regards to the influenza vaccine, we should continue to give it on schedule, but delay subsequent rituximab dosing for at least two weeks after the influenza vaccine if disease allow disease activity allows. And this is to help, the immunogenicity of the vaccine.

With regards to the COVID vaccine, it is recommended with regards to cyclophosphamide that we time cyclophosphamide administration that it occurs one week after each vaccine dose when feasible. And finally, with regards to the other conventional and targeted immunosuppressive therapies, such as JAK inhibitors and MMF, it is recommended to withhold these medications for one to two weeks as disease activity allows after each COVID nineteen vaccine dose. So in summary, the ACR CHEST guidelines provide a risk based approach to the screening and monitoring of ILD in people with systemic sclerosis associated ILD. It provides a range or a menu of treatment options for these patients. And these treatment options are based on the best published evidence, expert experience, and patient's values and preferences.

If you would like to review the document for yourself, it is freely available to all ACR members. You just go to their website, rheumatology.org. There you'll click clinical tools and guidelines, and you will find the ILD guidelines. The guidelines are also freely available on the ACR clinical practice guideline and criteria app. This can be downloaded from the Apple Store or from, Google Play.

I'd like to thank everyone who was involved in the development of these guidelines. And finally, I'd like to thank you for your attention.

I'm Anna Hoffmann Wold, a rheumatologist from the Oslo and Zurich University Hospital. Today, I will talk about the management of interstitial lung disease in rheumatic diseases, which we will refer to as connective tissue disease, which also includes RA. And I will present you some of the data from our guideline, was very recently published in the Annals of Rheumatic Diseases and the European Respiratory Journal. And our task force was based on the two societies, as I said, the European Respiratory Society and EULAR. And we included a large panel of both pulmonologists, rheumatologists, we also had a radiologist, a pathologist involved and patient research partners.

We also used methodologies both from EULA and ERS. But as it was an ERS initiative, we followed the ERS GRADE methodology. And our entire guideline is based on strong and conditional recommendations, either for or against. And we phrase in our guideline our answers as we recommend when it's a strong recommendation or we suggest if it's a conditional recommendation. I will try to keep on this wording also while I'm talking to you about the results.

But just if you also read the paper, these are already pointing you into the direction whether we have a strong or conditional recommendation. And we were initially asking ourselves about how should we screen patients, how should we diagnose them, monitor and treatment. And we divided these four main categories into five PICO questions and 10 narrative questions who are supportive for our PICO questions. And then we answered them per disease. And we looked at our diseases as groups into systemic sclerosis, rheumatoid arthritis, idiopathic inflammatory myopathies, or other connective tissue diseases, which included Sjogren disease, mixed connective tissue disease, and SLE.

At the end, of this, we ended up with 25 PICO questions and 28 narrative questions, and we could make 18 conditional recommendations, six strong recommendations for the PICO questions, one we couldn't answer. And we had at the end for the narrative questions, 23 conditional recommendations, no recommendations, and three strong recommendations. And to really understand our guideline, it is also important to understand the questions we were asking each other because this is a little bit the basis for the answers. And I will talk about today, just briefly show you the questions and then go straight to the algorithms which we built, which are very practical for clinical practice to use for you. But if you want to see all the details, please look at our publications and you will also find an overview of every single recommendation and suggestions.

So for the screening, we were asking ourselves, can we replace lung function tests or can we use lung function tests instead of HRCT for the screening? And can we use lung ultrasound instead of HRCT for the screening of ILD? Then we were also asking ourselves which patients should be screened and how often should patients be rescreened? So if the initial HRCT was negative. That was one of the questions we couldn't answer.

So there was no recommendation we built this very nice screening algorithm. And here you can see that it's really based on the underlying rheumatic disease. So for systemic strokes, so for all diseases we said that lung function tests cannot replace HRCT. So HRCT is the screening approach for our patients. Also, lung ultrasound is at that time point not able to replace HRCT.

And then to see at which patient we should screen for systemic sclerosis and mixed connective tissue disease, we strongly recommend that you screen all patients. For myositis, we say that if a patient has risk factors, then also a strong recommendation to screen this patient using HRCT. If you have a myositis patient who does not have risk factors for ILD, we have a conditional recommendation for screening these patients. So what it means for myositis is also that you should screen all of your myositis patients at time point of diagnosis with an HRCT except for inclusion body myositis. When it comes to RA and Schrogerland, it's really about to identify the at risk patient.

The at risk patient is defined as having two or more risk factors for the development of ILD, And these patients should also be screened with an HRCT. While RA patients and Sjogren patients with no risk factors do not need to be screened. All of these risk factors are also identified by the literature review and available in the document. And of course, at the time point once you do screen, you do identify pathologies, also always consider doing a lung function test in these patients. When we talk about diagnosis, here we looked at no PICO questions, but for the narrative questions we were asking, how should we evaluate patients at baseline once we diagnose ILD?

Then what is the role of BAL and what is the role of lung biopsy in diagnosing ILD in rheumatic diseases? And I can already say that lung biopsy does not play

of IRD in rheumatic diseases. BAL is only considered as important if you have any suspicion for coexisting conditions. So it also doesn't

play play a a role in the diagnosis, but we still conditionally recommend it if you have a doubt whether there's an infection or any other underlying cause. Then very importantly, what we do recommend for diagnosis is once you diagnose a patient with IRD on HRCT, you should at that time point already assess the prognosis, risk of progression and risk of development of severe disease. And here we identified several categories how you should do this. We said you should use clinical risk factors and again, we do have identified risk factors for RA, systemic sclerosis and myositis who are at clinical higher risk of worse ILD or ILD progression. So these you should use.

You should look at the lung function test, how impaired is FVC, how impaired is DLCO, in some patients also FEV1 for airway disease. Then you should look at the HRCT pattern and extend. You should conduct a six minute walking test and look does the patient desaturate, and you should use patient reported outcome measures especially to map respiratory symptoms. All of these tools will give you an idea how this patient is at risk of progression and more severe disease. This already should make up your mind and you should write it down in the charts.

Is this a patient at higher risk or not? And I will come back to this when we talk about monitoring because this is exactly the same approach you should also do it every visit over time to monitor. So then let's talk about monitoring. So first our questions again were no PICO questions, but we were asking ourselves what is the role of the six minute walking test? What is the role of PROs or patient reported outcome measures?

And in which patients there should be a follow-up with PFTs and how often, so how often should they come back for lung function tests, and we ask ourselves when should we repeat an HRCT. And all these questions again led up to building these algorithms for every patient group. So here you have first this systemic sclerosis IRD monitoring approach. And to monitor systemic cirrhosis interstitial lung disease patients, you should exactly as I just told you for the diagnosis, make up your mind, is this a patient at higher risk of severe disease and progressive disease? Or is this a patient at lower risk?

Once you have made up your mind, you should in the next step take into account, is this a patient with shorter disease duration or longer disease duration? And what this gives you, this risk score of risk profile and disease duration is to identify the patients who need a closer monitoring and a less closer monitoring. So a high risk patient with a short disease duration has a closer follow-up than a patient at low risk with longer disease duration. But every patient should get a lung function test considered for the follow-up and HRCT again with a pattern and extend, the six minute walking test with desaturation and the measurement of patient reported outcome measures. So when we look at patients with systemic sclerosis ILD at high risk with short disease duration, that patient should come back after three to six months for a lung function test and at twelve months for an HRCT.

And at six to twelve months, the patient should conduct a six minute walking test and the patient reported outcome measure. However, for these two compared to the PFTs and HFCT, we did not identify any literature. So this is really based on expert opinion and suggestions from the experts, not based on the evidence we identify. And this is also how you should read the entire algorithms. If we provide you with colored boxes stating something like the frequency of monitoring, then this is based on data.

If we, in the algorithm, give you white boxes with a blue frame, this is a suggestion from the task force when to repeat the different tools in the monitoring of our patients. And actually the risk assessment should be done at every visit the patient comes back because risk factors can change. A patient can be more at risk even after a longer disease duration or have less risk factors and get into the category of being less prone of developing more severe disease. The risk factors we identified, the clinical risk factors in Seussenisosis ILD for a more severe disease which you should look out for in clinical practice, where male gender, older age, inflammations or with increased CRP ESR, the presence of anti Tauqua isomerase one antibodies, lung function tests and the extent of iodine hrct and especially the combination of recent onset of systemic sclerosis with rapid skin progression and more extensive skin fibrosis. The other algorithms for RA, myositis and other CTD ILDs are exactly the same as for sausagesidrosis IRD.

Always make up your mind whether this is at a higher risk of progression and severe disease patient, look at the disease duration, and then look at is this a high risk patient, a low risk patient with short and long disease duration, and tailor your management approach individually. And again, we suggest lung function test, ATACT, six minute walking test with desaturation and patient reported outcome measures. And based on the algorithms, you can really look at how often you should monitor your patient. For myositis, you should especially look out for patients who are male, older age. Now for rheumatoid arthritis, I'm sorry, you should really look out for patients who are male, older age, who have anti CCP and RF factors, who have low baseline lung function, who have the UIP pattern on HRCT or histological patterns of UIP, and in patients who have a higher articular disease activity.

So these patients should be then monitored more tightly. For myositis, again, the same approach of monitoring and I hope you have understood this from my first explanations. The patients you should be very careful about are patients with myositis with increased ferritin, so again, kind of an inflammatory marker. The presence of anti MDA5 or anti synthetase antibodies and a higher extent of iodine hRCT. So these are factors you should look out for your patient and put into the higher risk of progression category.

Then we also identified some poor risk factors for especially MDA5 positive myositis patients. These were extent of iodine HSCT, higher ferritin levels, KL6, older age and low saturation. For the other diseases including Schroger and MCTD, had much less evidence but we build up the same algorithm. So use please the same algorithm. Unfortunately, we did not identify any risk factors for poor outcome.

So then the last question of our guideline was how we should treat. And here it is very important again to understand that we had three major questions. We were asking should immunosuppressive treatment versus control be used? Should antifibrotic therapy be used? Or should a combination therapy be used?

And then we wanted to identify key factors to identify the right treatment for the right patient. Again, can tell you for this, we're not able to form a recommendation because we did not identify key factors for choosing drug A for patient A and so on. So this is why we considered using the inclusion criteria of trials as the best way currently to identify the right treatment. So this means if a patient fulfils the inclusion criteria of a certain trial, where a drug was tested, this drug is more likely to be working in this patient compared to a patient not fulfilling the inclusion criteria. This does not mean that the drug does not work in these patients but it has not been tested.

So this is how we then build up the entire algorithm. So for systemic risks, say that you should look out for patients, specific patient phenotypes to identify the right drug. So if you have a patient with interstitial lung disease who has either extra pulmonary involvement such as the skin, drugs which are recommended in our guideline are mycophenolate or tocilizumab. And if you have an SSE IRD patient with no extra pulmonary organ manifestations, still that would also be a patient which you could give mycophenolate which is conditionally recommended. Then we have this very specific phenotype of early diffuse systemic sclerosis, signs of inflammation, where the patients who were included in the trial testing tocilizumab.

In this specific patient group, we strongly recommend to use tocilizumab. Then we have the patients with systemic cirrhosis who have more than ten percent IRD on HRCT, no extra pulmonary organ manifestations. In these patients, you should also consider nintedanib as a good choice for treatment. And then we have this group of high risk of progression patients where we recommend combination therapy. In these, we conditionally recommend either the combination of nintedanib and mycophenolate or a combination of immunosuppressants.

Other drugs we recommend especially for this group is cyclophosphamide or rituximab. And then we have the last group phenotype of patient with severe multi organ involvement where we really want to treat more than the lung and we are very concerned about these patients. Here again, we suggest cyclophosphamide and rituximab or the combination of immunosuppressants. So once you have chosen your phenotype, you have started the treatment, you of course need to monitor the patient. If the treatment goals are met, you can continue treatment.

If these treatment goals are not met, we could not make a recommendation because there was no evidence to tell us what to do with the patient next. So the experts then again have a couple of suggestions such as switching or adding on therapy based on again what we recommend in the first place. For RA IRD, again the treatment algorithm is very much based on identifying the phenotype. And for RA, it is really based on identifying patients who have active arthritis because these patients need to be treated to target in their joints. And here, of course, immunosuppressive therapy comes up because these are the drugs which are also recommended in the EULA recommendation for treating RA.

What we did find is some very poor evidence for abatacept rituximab and JAK inhibitors. These were small studies, retrospective, only small numbers, single center. So not very strong, but we did identify. So this is why we also have them especially mentioned under the immunosuppressive therapy for patients with RA ILD where you want to treat the joints and the lung. And then of course, we also have included tocilizumab in steroids, but this is based on expert recommendations rather than evidence.

And then on the other side, we have the RA ILD patients who have well controlled arthritis, so we don't need to treat their joints. If you only want to additional treat with another immunosuppressive, we did not identify any evidence for mycophenolate and azathioprine, but we still include them. But if you have a patient then who has in addition to well controlled arthritis severe and progressive ILD, here in these patients you should consider combination of immunosuppressants. If you have a patient with progressive pulmonary fibrosis, here there is evidence for Nintedanib either on its own or in combination with immunosuppressants. And then we also have patients with a UIP pattern where we also in addition Nintedanib also suggest to choose Pafinidone if this is available for your country.

Again, monitor your patient treatment goals met, yes or no. If no, you need to of course change treatment strategies. For myositis, we have again two more or less groups. So one is the any myositis group. Here we strongly recommend immunosuppressive therapy.

There's very little evidence but we still based on clinical experience have a strong recommendation for using immunosuppressive therapy. The drugs we did identify for immunosuppressive drugs, we did identify poor low level evidence was steroids and CNI and Rituximab. So these are good treatment choices for myositis. In addition, we also add mycophenolate and azathiopen but we did not identify any evidence but we also included this as expert recommendation for immunosuppressive therapy. If you have a high risk of progression or severe multi organ involvement myositis patient, please consider upfront combination therapy which we conditionally recommend in these patients.

And here we mentioned of course high dose steroids, cyclophosphamide, rituximab, CNI and IVIG. Once a patient has progressive pulmonary fibrosis, there again we have evidence for nantitamab either in mono or in combination with immunosuppressants. And then we have this group of rapidly progressive ILD over weeks to few months that we did not identify any evidence, but we still recommend in these patients a combination therapy with hydrosteroids, cyclophosphamide or rituximab with CNI, IVIG JAK inhibitors, plasmapheresis may be considered. All these are just suggestions from the experts, no clear recommendation based on evidence. The last group is other CTD IRDs which includes sugar and MCTD.

Here we did not identify any direct evidence. So all the evidence which are formed to tell us the treatment is transferred from other diseases or studies including few of these patients. So here our main thing is again that we conditionally recommend immunosuppressive. Immunosuppressive. We did not identify any studies as I said, so we could not identify specific drugs.

But we do as the expert panel add mycophenolates, azathioprine, steroids, rituximab and cyclophosphamide in that group. If you have a high risk of progressive other CTD ILD patient with severe or severe multi organ involvement, again, also for these patients, we as experts suggest to use rituximab and cyclophosphamide or we conditionally recommend a combination of immunosuppressants based from a transferred evidence from other diseases. For again, here we do have evidence for nantidanib either in monotherapy or with immunosuppressants. So that is really the only study where we could also give evidence based on the underlying studies. Again, monitor your patient if progressive, if more severe, please add or switch therapy.

So in conclusion, be aware of all of your rheumatic disease patients to screen them for ILD. The screening approaches differ based on the underlying disease. Screen all mysitis, scleroderma and MCTD patients with HRCT RA children identify risk factors and screen the patients with risk factors with HRCT. A diagnosis, a thorough assessment of every CTD IRD patient should be conducted with a clinical risk factor approach to identify the high risk patients. Monitor your patients tailored individually based on the risk factors, including a large panel of different tools.

And then for the treatment guidelines, there are guidelines now available or guidance available based on the underlying disease. We do include different immunosuppressive therapies. We do include nintedanib and for RALD paraffinidone and a combination therapy in some of these patients. So I hope this was helpful and I really hope that our guidelines will make your clinical management of patients with rheumatic disease and interstitial lung disease easier in the future. Thank you very much for listening.

Hey everyone, this is Jeff Sparks, a rheumatologist at Brigham Women's Hospital and Harvard Medical School. I'm very excited to be contributing to the ILD campaign for RheumNow for the month of September 2025, and I'm going to talk about some caveats to the recently published 2023 ACR chest SARD ILD treatment guidelines. So this was, I'll mention at the beginning that I was part of this process and it's I think one of the biggest projects that the ACR has ever done because typically these guidelines are focusing on a single disease and a single complication. This is focused on five diseases and many different medications and it was split out into both treatment as well as screening and monitoring. And so it was really a herculean effort to get this to the finish line and there wasn't an ACR guideline prior to this effect.

You know really having this I think is really helping clinicians, helping patients, and certainly putting shining a light on a lot of the treatment gaps that we need filled with rigorous research. So with that prelude, did want to talk about some interesting caveats that came from this. And I'm really going to focus just on the treatment guideline. I think the overarching principle here is that we don't have enough trials. Obviously there's a lot of nuance between all of our rheumatic diseases.

Some have active joints, some have active skin, some have active lungs, and really it's going to take an individualized approach and to really tailor the treatment plan for individual patients. So you can imagine that guidelines are not going to cover a lot of this nuance. The other caveat is fortunately we do have some nice trials in systemic sclerosis, so the data there are relatively compelling and for better or worse that great data has to be extrapolated to other diseases where, that same rigor may not apply, to that. And I'll contrast many of the findings with rheumatoid arthritis. Certainly that's one of my research interests.

Just for sake of time, we won't have time to talk about all five diseases, the others being myositis, MCTD, and Sjogren's. So to remind you, systemic sclerosis has several trials and these culminated in the first line treatment guidelines of three agents that were preferred: mycophenolate, tocilizumab, and rituximab for systemic sclerosis. And for simplicity's sake, this again was extrapolated to many of the other diseases despite there not being many trials in the other diseases. So a very similar list showed up with rheumatoid arthritis with mycophenolate, azathioprine, and rituximab. So this is not necessarily that satisfying for clinicians treating rheumatoid arthritis because we have as first line ILD therapy mycophenolate, a therapy that we know does not work well for the joints.

Certainly there might be some patients that would benefit from mycophenolate with RA ILD, however that may mean that they would need combination therapy and mycophenolate being immune suppressing ILD patients having a lot of comorbidities already having lung damage and very susceptible to poor outcomes from infection, that's not particularly satisfying. The second is azathioprine and this one is particularly concerning for patients with rheumatoid arthritis and the usual interstitial pneumonia subtype characterized by fibrosis. The reason is that a trial in a very similar condition idiopathic pulmonary fibrosis showed that patients randomized to prednisone, azathioprine, and endacetylcysteine actually had worse outcomes including higher risk of death compared to placebo. So in patients with RA and UIP, azathioprine is also not particularly satisfying because it might portend worse outcomes. Rituximab I think is relatively more satisfying.

It might be that silver bullet that treats both the joints and the lungs. However, as we know this is typically reserved as later line therapy. It's also relatively more immunosuppressing, certainly has a very long half life, and there again there might be patients where you would jump to that right away if their ILD is very severe, but for many RA patients you'd want to try other biologics prior to that. And again a lot of this is just related to conditional recommendations and the fact that we don't have good trials. And I do understand that having a simple category and making it conditional so that many exceptions could abound is certainly the right thing to do, but it's just something to talk through when you're seeing patients.

Second I'll talk about is progression after first line, and certainly the number of options increases here. For systemic sclerosis we're talking about Nantendenib as well, which is an anti fibrotic, For rheumatoid arthritis this also expands to Nantinenib as well as another anti fibrotic Perfanidone. These actually have probably the best trial evidence across all rheumatic diseases since, Intentative had a basket trial that really did show benefit. The downside being that this only benefited slowing decline of FVC, didn't necessarily portend either mortality benefit or quality of life difference. And where you put this in the line of therapy related to someone with RA is a bit unclear.

Do you treat the whole disease with anti inflammatories or do you try to do combination with an anti inflammatory and an anti fibrotic? Do you do them simultaneously? Do you do them sequentially? And certainly all of these are conditional recommendations. There's a little more nuance for the progression after first line.

For example, patients with myositis might need calcineurin inhibitors. Patients who are really fulminant and have severe ILD might need cyclophosphamide. A few of the conditions might benefit from IVIG and JAK inhibitors also might benefit some patients with myositis. But from an RA perspective, interestingly the ACR and CHEST guidelines recommended tocilizumab as a progression after first line, but abatacept was actually not mentioned and not recommended. And that's a bit of a difference between other guideline agencies, in particular ERS who presented those guidelines at EULAR and should be published soon, as well as other countries that have guidelines, in particular the Spanish Rheumatology Society that recommends abatacept even as first line.

So you can see here that there's a lot of nuance and a lot of caveats to think about, and again the bottom line is that there's many diseases, there's many different organ systems, and many of your patients are going to need tailored therapies and we need better trials. And again we are really happy that there are good trials within systemic sclerosis, but that did mean that we had some interesting extrapolations to other diseases that may not have been a perfect fit. So anyway I think it was a great effort to start the guidelines here, and now you understand some of the caveats and hopefully can apply this to your patients. Again, thanks for your attention and hope you're enjoying the ILD campaign. Thank you.