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Jeffrey J. Swigris, DO: Welcome to Medscape InDiscussion. I'm Dr Jeff Swigris, and today we'll be discussing interstitial lung disease (ILD) — specifically, a form of ILD associated with connective tissue disease (CTD). This disorder is known as CTD-ILD.
ILD is an umbrella term we use. When we think of the causes or the etiologies of ILD, I like to group them into four different categories.
The first category is exposures — a category that includes mold, mildew, birds, and bacteria. These are things that patients might inhale; they're aerosolized and typically organic antigens. Other entities that fit into the exposure category are things that can be inhaled, such as dusts or medications, and other causes, such as external beam radiation therapy. So exposures are a broad category.
A small percentage of patients will have what we call familial disease — a first-degree relative with ILD. This is the second category.
The third category is idiopathic or unknown cause. The most common entity in that category is IPF, or idiopathic pulmonary fibrosis.
Finally, the fourth category is ILD associated with systemic autoimmune disease, including CTDs, which is going to be the topic of our discussion today.
To help me disentangle some of the complexities associated with CTD-ILD, I am just delighted to have my friend and colleague, Dr Sonye Danoff — an internationally recognized leader in the field of ILD. She is professor of medicine in the Division of Pulmonary and Critical Care Medicine and director of the Interstitial Lung Disease Program, as well as associate director of the Myositis Center, all at Johns Hopkins University School of Medicine in Baltimore. I really can't think of a better person to have here today to talk about this topic. Sonye, welcome.
Sonye K. Danoff, MD, PhD: Thank you so much, Jeff. I'm so excited to have an opportunity to talk with you about this.
Swigris: Great. Before we get into the discussion, we like to hear how our guests have ended up in this field. How did you develop an interest in ILD — specifically, your interest in CTD-ILD?
Danoff: Like a lot of people in pulmonary medicine, my choices were directed by the patients that I interacted with. I had a very young woman — a 30-year-old nurse whom I took care of as an early fellow. She presented having come from being the head nurse of a trauma center. She very abruptly developed shortness of breath and came in with pneumothorax. Unfortunately, at that time — which was over 20 years ago — we watched her as she progressively became increasingly short of breath, ultimately went to the ICU, and then, very sadly, died. I was struck by the fact that this young woman, who was presenting with what we would now consider a rapidly progressive ILD in the context of a previously unrecognized CTD, really spoke to the fact that this was an area of unmet need. That shaped my career afterward. I have always been very interested in understanding the ILD that occurs in groups who perhaps haven't had as much attention: minority populations and women. That's what got me into CTD-ILD.
Swigris: That case highlights one of the important epidemiologic features of CTD-ILD. When we think of IPF, most commonly we're dealing with patients in their mid- or late 60s at the time of diagnosis. Given the propensity for systemic autoimmunity to affect women and certainly patients on the younger end of the age spectrum, a lot of our patients, like the one you describe, are young, vibrant people looking forward to several decades more of life, and then this devastating condition hits them.
Let's start with rheumatoid arthritis (RA). I'm sure we're going to use that acronym a lot throughout the conversation. RA is certainly one of the most, if not the most, CTD-related type of ILD. The most common pattern that we see on a CT scan, or on a surgical lung biopsy, in a patient with RA and ILD associated with it would be usual interstitial pneumonia (UIP). We know that's not the only pattern; it's just the most common one. If you have a patient who presents with RA-ILD and the CT pattern is UIP, talk to us about how you approach drug therapy for that patient.
Danoff: RA is a complicated topic because we see patients who are diagnosed with RA on the basis of a rheumatoid factor biomarker and evidence of arthritis. One of the perspectives that I have, having worked with individuals who have myositis for a long time, is that we also can see rheumatoid factor being elevated in patients with autoimmune myositis. The first thing I like to do is make sure that we have the right disease entity. If the patient really has RA, make certain that they do have an erosive arthritis.
The second thing that makes RA complicated is that many of the therapies used for the treatment of joint disease can have an impact on the lungs. As you pointed out, one of the major categories of ILD is this external drug–associated category. So, really make sure that a patient is not on a medication that can be associated with lung disease. Although methotrexate tends to have a bad reputation, it's probably the drug that I'm least concerned about. I'm more concerned about tumor necrosis factor (TNF) inhibitors, which, although very rarely, can be associated with ILD.
Then we really get to the issue of patients having a systemic disorder, as well as ILD. Is there a single drug that can be used to treat both the systemic disorder as well as the ILD? This is a topic about which you really need to have a very thoughtful conversation with the patient, because this is where joint decision-making really comes in.
I might start by treating with azathioprine, which is an immunosuppressant that is both very effective for ILD as well as effective in joint control. If the patient does not improve with that, then I might think about rituximab and focus on the inflammatory component. Perhaps the greatest change in the field has been based on a couple of recent studies, including the INBUILD study, which showed that patients who have progressive fibrotic disease may get worse even though you've done all the right things. So, if my patient gets better and stabilizes on an immunosuppressive, I'm going to stick with the immunosuppressive.
We're going to think about whether there is a lull in disease activity. Can the treatment be tapered? But if the patient's disease continues to progress, then I'm going to think about using an antifibrotic agent, on the basis of the INBUILD study.
Swigris: Very helpful; there's a lot to unpack in there. I wish we had an hour to spend just on that topic alone. Of course, we're talking to our rheumatology colleagues and trying to come up with the right regimen that's going to control joints and target the lungs as well. Even if [a patient has] UIP, if you can confirm RA, are you more likely to start with an immunosuppressant, knowing that there are probably lymphoid follicles and an inflammatory component to the UIP or in addition to UIP?
Danoff: Yes, I do tend to start with immunosuppressive therapy. I know that this is an area in which there's still a lot of debate and there perhaps aren't data to decide what the right answer is, but that would be my approach to it. Having more tools in the armamentarium makes life more complicated, but in a good way. If you find that the patient progresses despite starting an immunosuppressive agent, the fact that you can then consider adding an antifibrotic increases the options available for the patient.
Swigris: Let's shift gears for a moment. I want to mention this entity IPAF, or interstitial pneumonia with autoimmune features, but first I want to get on my soapbox for just a minute and remind the audience that patients with IPAF are folks whom we say have "the flavor" of having a systemic autoimmune disease that is driving their ILD. IPAF is not meant to be a diagnosis; it is meant to be a research classification. So, you may get patients who are referred to you in whom the diagnosis is IPAF, with the question being, "What do we do?" Let's remind ourselves that IPAF is a research classification, and it is not a clinical summary diagnosis. I may have a patient, for example, whom I say has IPF, even as their clinical summary diagnosis, but who also meets IPAF criteria.
Can you help us out with how to handle this? What's the approach you take if somebody comes in and meets IPAF criteria? How does that influence your approach to their drug therapy?
Danoff: I will join you on your soapbox. Although the IPAF designation had a purpose in terms of trying to identify a group of patients who need to be better understood, unfortunately, what's happened is that it's morphed into this clinical designation, which is really not helpful as far as I'm concerned. What it points out is that for many patients who present with ILD as an early or principal component of their systemic autoimmune disease, they may not meet criteria that have been defined by rheumatologic associations. It doesn't mean that they don't have the disease; it just means that they have a different "flavor" of the disease.
As an example, I'm sure you're very well aware that the antisynthetase antibodies are included in the list of potential defining features for IPAF, and my view is that if you have a patient who presents with anti-PL-12 and interstitial lung disease, they have an autoimmune disease: they have antisynthetase syndrome. What I think is very helpful is not to use the IPAF designation. Instead, look at what features make you think that a patient has an autoimmune component. If it's based on an autoantibody, then I tend to follow the autoantibodies.
So, for instance, if it's a defining autoantibody, such as anti-PM/Scl or anti-MDA-5, and the patient just has ILD, I will treat along the pathway for that disease. If I have a patient who has very strong features of scleroderma, such as severe Raynaud phenomenon, esophageal dysmotility, or pulmonary hypertension, then I'll treat down a scleroderma pathway. The key is to throw out the concept that in order to have a diagnosis of a systemic autoimmune disease, you have to meet all of the kinds of classification that have been defined, very appropriately, but from a different lens — from the lens of patients who present with more of their systemic disease than with their lung disease. I think you must tailor your therapy, but I would generally follow a pathway of immunosuppression in patients like that.
Swigris: So, immune suppression first, and if they progress — if there's not another immunosuppressant that you might add, either in combination or as an alternative — then you're thinking about adding nintedanib, for example.
Danoff: Yes. My general expectation is that a patient who has an inflammatory lung disease will get better. It's not that they will get worse less quickly; they will get better when I treat them. What I'm really looking for in treating these patients is improvement in lung function or at least stabilization of lung function, and that often will take multiple types of immunosuppression. I wish it were easy to say, you go on this drug and you take this dose, and that's how it's going to fix you. But especially with patients with CTDs, you have to be very willing to think about whether you need to add another immunosuppressant, or change immunosuppressants, or rethink it — if the reason the patient's not getting better is not because their ILD is getting worse, but because they have pulmonary hypertension now. It really does require that kind of constant reevaluation to try to assess that.
Then, certainly, there are patients who, despite all appropriate immunosuppression, will have progression of fibrosis. My goal is that they're going to get better and that they will never have to use an antifibrotic.
Swigris: Let's talk about systemic sclerosis–related ILD (SSc-ILD). We know that ILD is common in patients with systemic sclerosis. You mentioned treatment options, and now the systemic sclerosis treatment options are growing, which might be creating more confusion for us about where these different therapeutic options fit in the treatment paradigm. Recently, tocilizumab became available and was approved by the US Food and Drug Administration (FDA) because of its effect on preserving decline in forced vital capacity (FVC). Mycophenolate, at least in large trials, has been shown also to be effective. We have cyclophosphamide.
Talk to us about where tocilizumab fits into this treatment paradigm. If you want, why don't you talk a little bit about how we think about it and why? Why does it seem to be for this specific subgroup?
Danoff: This is a good example. I often tell the people whom I work with that you never do a randomized controlled trial of wearing a parachute when you jump out of an airplane, because sometimes what you need to do is use all of the data that exist and you don't have to actually test everything.
I think that one of the reasons tocilizumab has had a lot of focus on it is because it's [been studied in] a randomized controlled trial. Interestingly, it was done in a very early patient population. The primary endpoint was not lung disease, it was skin disease, and it failed to achieve its primary endpoint, which was to reduce the evidence of sclerosis in the skin. The other important thing is that tocilizumab didn't alter quality-of-life endpoints, so it was typically used in a group of patients who were otherwise untreated.
What it tells you is that when you're dealing with a systemic inflammatory disease, being on an immunosuppressant is better than not. My approach is that you look at the patient as a whole and think of tocilizumab as another option, but I'm not sure that I would be more likely to reach for tocilizumab than mycophenolate in a patient who was previously untreated. I think that it is going to probably take another 10 or 15 years before we can really recognize those patients who are most likely to respond to tocilizumab.
My presupposition when I treat a patient is that their lung function is going to get better. Again, what I'm looking for is improvement in lung function, as opposed to slowing the rate of decline. I think that the jury is still out on exactly where tocilizumab is going to be used, but for me it's still probably a second-line agent, rather than my first-line agent. I would still reach for mycophenolate first.
Swigris: You brought up the really good point that in the trial in which tocilizumab was studied, the primary endpoint was skin; FVC was a secondary endpoint. These were patients who were recently diagnosed, patients who had robust inflammatory markers. So, we're talking about early active disease.
I think if skin is a major manifestation, I'm certainly not reaching for tocilizumab. We know that both mycophenolate and cyclophosphamide have some beneficial effects on skin. There's still a lot to learn about that entity — about combination drug therapy and systemic sclerosis.
Final question, which really gets into your wheelhouse on antisynthetase in the myositis spectrum. You touched a little bit on your approach, but let's get a little bit more specific: You have a patient with antisynthetase — somebody with characteristic antisynthetase syndrome who has ILD. Let's say they have an anti-Jo-1 or anti-PL-7 antibody. How do we think about therapy for them, as a starter?
Danoff: The way I usually divide this is based on the acuity at presentation. Often, we can see the patients who have come in because they have muscle disease and then they're found to have some lung disease. Maybe they're already on some immunosuppression, maybe they're not. But for a mild patient who has ILD, I'll certainly be watching them using pulmonary function testing. But if their symptoms are really very mild or they don't really have symptoms, and they just have a radiographic finding, I may just watch them or I might start them on a steroid-sparing agent without using a steroid.
Swigris: Are you likely to reach for one over another for your steroid-sparing drug?
Danoff: The biggest issues are, one, do they have joint involvement? In this case, I prefer azathioprine. And two, are they planning to become pregnant? You can't use mycophenolate in a patient who has any intention or potential for pregnancy. So, those scenarios would push me toward azathioprine.
Swigris: How about cyclosporine? Do you guys use calcineurin antagonists first-line?
Danoff: We do, but we mainly use tacrolimus and mostly use it in patients who have MDA-5 antibodies.
Swigris: Got it.
Danoff: That's where I found the sweet spot is — that tacrolimus is incredibly effective in [patients who have] MDA-5 [antibodies], even at very low doses.
Swigris: In combination with mycophenolate or as monotherapy?
Danoff: Monotherapy. We actually use intravenous immunoglobulin (IVIG) in our patients with MDA-5 [antibodies]. MDA-5 is often associated with the rapidly progressive ILDs — what we used to call the acute interstitial pneumonias. For those patients, we'll often use IVIG and steroids up front, and then if they have very severe disease, we'll certainly add a steroid-sparing agent.
The choice of the steroid-sparing agent is going to depend on the severity of disease. If the person is on azathioprine or mycophenolate, we might continue that. If they're not, we might start with tacrolimus as their first drug. Then we taper therapy as tolerated, on the basis of how patients are doing.
Swigris: Is there a role for nintedanib in this population?
Danoff: There probably will be some patients who have progressive fibrosis despite appropriate therapy, but my general experience is that — particularly with myositis, which is a very highly inflammatory disease — we can often stabilize and/or improve lung function. There probably is a subset of patients who will have progression, and that would be the patient population you would be considering for an antifibrotic. The new MINT trial is going to look at that directly. That'll give us a little bit better understanding about which patients may benefit from an antifibrotic and how that may be integrated with their immunosuppressive therapy.
Swigris: Fantastic. Let me just summarize a few key points that Dr Danoff discussed.
One is certainly talking with your patient and using shared decision-making. Probably nowhere else in the ILD world is it more important to take a multidisciplinary approach. We really need to lean on our rheumatologists and work with our rheumatologists to find the best therapeutic regimen for our patients.
You heard Dr Danoff remind us about IPAF being a research classification. You heard her remind us to tailor our therapy based on pace of presentation. So, in those patients with a more severe and/or rapid decline inflammatory presentation, we're going to be much more aggressive.
The other highlight that I'll take away is that we have a lot to learn about all these entities — about what drugs work best for which patients for which phenotype within each CTD. Sonye, are there things that you'd like our audience members to either think about differently or do differently, or just a couple of general reminders when they are taking care of their patients with CTD-ILD?
Danoff: Sure, and you know this well, because you've already been the recipient of this: It's never the wrong idea to ask a friend. When you encounter a patient with whom you're really struggling or about whom you're uncertain, refer to an ILD specialty center. I certainly reach out to my colleagues at many different centers to ask for their input and have gained incredible wisdom from many of my colleagues elsewhere.
The second thing is to be very conscious of the side effects of medications. Certainly, immunosuppressives must be monitored very carefully. First, do no harm.
Then, shared decision-making with the patient. None of these therapies will be easy, and so we really need to inform our patients about what the risks and benefits are, and work with them to find the therapies that are best suited to them.
Swigris: That's great. Sonye, thank you so much for joining me today. We really appreciate your expertise and your insight.
Danoff: Thank you for inviting me. It was great getting a chance to chat about this.
Swigris: To the audience, thank you for listening to this conversation on CTD-related ILD within the Idiopathic Pulmonary Fibrosis Podcast. Our guest has been Dr Sonye Danoff. There's much more ahead in the coming episodes, so please be sure to check out the Medscape Mobile App, and share, save, and subscribe if you enjoyed this episode. I'm Dr Jeff Swigris for Medscape InDiscussion.
Resources
Nintedanib in Progressive Fibrosing Interstitial Lung Diseases
Interstitial Pneumonia With Autoimmune Features (IPAF)
Clinical Profile of Anti-PL-12 Autoantibody
Anti-synthetase Syndrome-Related Interstitial Lung Disease With Anti-PL-12 Antibodies
Anti-PL-12 Associated Antisynthetase Syndrome – A Less Recognized Clinical Entity
Nintedanib: A Review in Fibrotic Interstitial Lung Diseases
Tocilizumab Prevents Progression of Early Systemic Sclerosis Associated Interstitial Lung Disease
Mycophenolate Mofetil as a Therapeutic Agent for Interstitial Lung Diseases in Systemic Sclerosis
Is There Still a Role for Cyclophosphamide in the Treatment of Systemic Sclerosis?
Tocilizumab in Systemic Sclerosis: A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial
Antisynthetase Syndrome: A Distinct Disease Spectrum
Syndrome in Question: Antisynthetase Syndrome (Anti-PL-7)
Pregnancy and Autoimmune Connective Tissue Diseases
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Cite this: Connective Tissue Disease-Interstitial Lung Disease - Medscape - Apr 04, 2023.
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