Rheumatoid Arthritis ILD Complications Save

[TRANSCRIPT]

Thanks so much. My name's Scott Matson. I'm an assistant professor of medicine, I'm a pulmonologist and I'm at the University of Kansas here in Kansas City. And I'm excited to talk today about one of my favorite topics, which is treatment complications in rheumatoid arthritis- associated interstitial lung disease or RA-ILD.

So, one of the reasons I think this is a really pressing and important topic is what we're dealing with here is a group of patients who have really poor outcomes, even with the significant advances that the rheumatology community's been able to make in the management of the underlying synovial disease.

And what's true is that RA-ILD outcomes remain pretty devastating. And the development of pulmonary fibrosis and interstitial lung disease for these patients leads to significant loss of function, significant impacts on quality of life, and unfortunately really shortens the lifespan for these patients that otherwise have been doing really well on the therapy that rheumatologists have been prescribing in the last 10 to 15 years.

I think there's two primary limitations, two primary concerns about complications, which really just largely come from the fact that we lack any prospective high-quality randomized studies of the primary standard of care. And this leads to these sort of two major concerns, I think, that pulmonologists and rheumatologists alike, feel for these patients and really can only be overcome through, as I mentioned before, a desperate need for prospective randomized data. And the two concerns we have, I think in immunomodulation are quite clear. So on one hand, patients who have pulmonary fibrosis have one sort of concern for bioplausibility for responding to immune suppression or immunomodulation. And that's of course that we think of scars as sort of benign, no longer inflammatory, very likely to not reverse given the nature of scarring.

And then I think the second thing is supported by evidence in similar conditions, in that 15 years ago, pulmonologists like myself were treating patients with pulmonary fibrosis who had idiopathic versions of the disease. A group of patients with IPF looked quite similar to RA-ILD patients and historically we would treat those IPF patients with immunomodulatory therapy. And in 2012, those patients with IPF were randomized by a group of investigators to receive that kind of strategy. And what they found is that that kind of immunomodulatory use in those patients was associated with worse survival and that was mediated largely by more respiratory hospitalizations for likely infection and ILD exacerbations, again probably driven by an increased risk of viral infections leading to lung injury.

So we have this problem now in this space where guideline therapy, all based on observational data, some of which our group itself has contributed to, supports the use of a whole strategy that carries this really concerning complication, which is - perhaps - these are patients that may not respond positively to immunomodulation anymore because of the nature of scarring in the lung from an RA and that maybe these patients are more like those idiopathic pulmonary fibrosis patients. And so how do we balance that concern over the complications of this therapy?

While on the other hand, we know that from other autoinflammatory interstitial lung disease conditions like scleroderma, that the use of immunomodulation is associated with improvement in quality of life and improvement in measures of lung function over time from the scleroderma lung studies.

And when seeing patients who have rheumatoid arthritis, I think all of us feel this pull of, we want to use something that can make people feel better and we want to use something that can improve their current functional status. And immune modulation, I think, offers that enticing possibility. And then our group has looked at the role of immunomodulation on pulmonary function testing trajectory and we find that immunomodulation is associated with stability of lung function in a group of patients that are declining pretty rapidly. And we find that that stabilization is independent of the amount of fibrosis on a CT scan and independent of the underlying ILD pattern.

And so unfortunately, I'm not sure that there's an easy way out of this because a lot of people have been presuming that rheumatoid arthritis has a couple of different flavors: there's a more fibrotic phenotype and then a less fibrotic phenotype radiographically. And I think the observational data would at least support the hypothesis that if patients are going to respond well to immunomodulation, that seems to be totally unrelated to their underlying fibrotic extent or their underlying pattern on CT scan. Which I think makes the problem complex because it remains totally true that there are patients within this population that likely do benefit from added immunomodulation. And there are certainly groups of patients here that disease activity is certainly the most important metric that I target in my population when thinking about initial treatment in this group.

But it's really, what do you do after that, once the patient comes to you with adequate disease control, having developed interstitial lung disease on appropriate DMARDs, what do you do and what can you offer to those patients?

We have one strategy that's supported by guidelines, but really not supported by the kind of evidence we need to show its safety, which is immunomodulation. And then on the other hand, we have this other new and novel treatment strategy for these populations of patients, which is the use of antifibrotic drugs. And antifibrotics like nintedanib and pirfenidone, which are FDA approved for these kinds of conditions - what we know about those therapies is that they are safe. So there have been thousands - at this point - of patients in randomized controlled trials of both of those antifibrotic drugs without any concerning safety signals. And that's on top of a decade of clinical experience using these drugs where we know that even though they're difficult to tolerate, there seems to be no concerning safety signals in the last decade of use.

But what we also know about those drugs is that none of those RCTs have ever shown a meaningful benefit, a statistically significant or clinically significant benefit for survival or for quality of life for these patients. And patients on antifibrotics in these studies get worse. They just don't get quite as worse, quite as bad as that placebo group. And the complications from these drug classes really have to do with the difficulty of patients tolerating these therapies. Patients have significant GI side effects from both. There's diarrhea in one, and there's a photo sensitive sun rash in another. And up until recently, there was also a concern about financial toxicity for these therapies, although that's lessening in the era of those both coming off patent now or shortly.

But it does, I think, put us into this sort of difficulty. We have a strategy with immunomodulation that might offer a way for patients to feel better and function better, but there are potential complications of using that strategy. And it may be that they could be profound, it could be that we could be harming people with that strategy. And on the other hand, we have a strategy of antifibrotic based treatment, which we know doesn't make people feel better. And we know it doesn't make people live longer, at least in that first year, but is safe. And that puts us all in a pretty difficult position.

The final thing I'll say about managing these patients that makes this very difficult is that not only do we lack the empiric evidence to make some of these most important clinical decisions that we all face, but I find that it's a very difficult situation in an individual patient to understand. Because we will often make therapeutic choices and then see the patient back and see how they're doing to make a determination of whether or not what we picked was right for them. And in progressive pulmonary fibrosis, that's quite difficult because patients usually do get worse. And so having a patient come back feeling slightly worse or with some small decline on their pulmonary function tests puts me and I think most people in a difficult spot because of course if they're getting worse and the medicine is supposed to slow that progression, what we have to sort of argue against is a counterfactual that we never know the real answer to, which is what would that patient have looked like at that same time point had we done nothing? And how much of our therapy is making or driving some of their symptoms of feeling worse? How much of our therapy is actually making them feel better than they would have had they not been on that therapy?

It's a difficult place. I don't have a lot of honest answers, but what I would say is I think it just calls for us in this position to do two things, which is, one is I think it's important to be honest about this with ourselves, with the community. It's important to be honest about what we know and don't know when we think about these guidelines because I think if we're truly honest, we know less than I think we hope. And I think that means that we have two important calls, which is honesty, and the second is to generate that data because we can do it. It's just a matter of getting interested parties together and asking the right questions.

And my hope, and I know that in 10 or 15 years, I think a lot of these questions are going to be answered and I look forward to working with all of you to try to figure that out.

So thanks, and if you want to hear more on these topics, just check out RheumNow, and I appreciate the time.

Editor’s note: This transcript was generated to aid readability; please refer to the video for the most accurate content.