Matthew Baker, MD, on Interstitial Lung Disease Among Patients With RA Treated with DMARDs

Dr Baker reviews the findings of his recent research into the association of interstitial lung disease among patients with rheumatoid arthritis who have been treated with both biologic and targeted disease-modifying antirheumatic drugs.

Matthew Baker, MD, is the clinical chief in the Division of Immunology and Rheumatology at Stanford University and the codirector of the Stanford Multidisciplinary Sarcoidosis Program. 

TRANSCRIPT:

Any views and opinions expressed are those of the authors and/or participants and do not necessarily reflect the views, policy, or position of the Rheumatology & Arthritis Learning Network or HMP Global, its employees, and affiliates.

Welcome to this podcast from the Rheumatology & Arthritis Learning Network. I'm your moderator, Rebecca Mashaw. Today we're talking with Dr. Matthew Baker, assistant professor of medicine at Stanford University in Palo Alto, California, about his research into the incidence of interstitial lung disease among patients with rheumatoid arthritis who have been treated with biologic and targeted synthetic DMARDs. Thanks very much for joining us and telling us about your research. This sounds very interesting.

Dr. Matthew Baker:

Yeah, thanks for having me.

Rebecca Mashaw:

So, what led you to choose this topic of whether the risk of ILD among patients with rheumatoid arthritis is modified by treatment with various types of DMARDs?

Dr. Matthew Baker:

ILD affects a small but significant proportion of patients with rheumatoid arthritis and can be really devastating for a subset of those patients, and at this point we really don't have clear guidelines on how to treat patients with RA who develop ILD. This study didn't directly address that question, which is a much harder question to answer with retrospective claims data, which is what we used for this study. So, instead, we asked a question that is more answerable using this type of data, which is looking at whether the treatment then maybe prevents the onset of ILD, and our hope was that we would see a positive signal there and that that might lead to additional studies, interventional studies, prospective studies to see if this could actually be helpful for understanding how to better treat patients.

Rebecca Mashaw:

How significant is that risk of ILD among patients with RA? You said it's a small but significant number.

Dr. Matthew Baker:

Yeah, it depends on the study that you look at. Most of this is really based on observational data, and it's been reported 10 up to as high as 30% of patients with RA, and other observational studies have shown that the risk of death in patients with RA and ILD is about 3 times higher than patients with RA without ILD. And in our own practice here, we've seen patients need to go for lung transplant, for instance, because the fibrosis in the lungs progresses to the point where they really can't function. And so right now, many groups are in the process of studying this more prospectively, which is always a more accurate way to really get a sense of how many patients are affected and what those risk factors are.

Rebecca Mashaw:

So, what did your research reveal? What did you find out?

Dr. Matthew Baker:

In our study we used a claims database, so we're limited in the sense that this is not looking at individual charts where we can really understand exactly what's happening with each individual patient. However, the benefit is that we can look at many thousands, tens of thousands of patients all at once. We used the Optum database, which is deidentified claims data, and looked over a period of about 16 years, and we included patients over the age of 18 with kind of a standard claims-based definition of rheumatoid arthritis based on the diagnosis codes in the dataset, as well as receiving a medicine that really would be pretty specific to RA, so we feel pretty confident that we're looking at real patients with RA.

And we looked at patients who had at least 1 year of enrollment in the dataset before they received one of the medicines we were interested in, and that allowed us to know that it was a new start for that medicine, and also in that year prior we could exclude patients who already had interstitial lung disease, because we're interested in seeing who develops it after the start of the treatment. And so then we basically followed those patients, and fortunately other groups have done very nice work to define how you can identify interstitial lung disease in patients with RA using datasets like this, and they've validated that and it has a very high specificity. So, we used their methods to then look for patients who developed ILD in basically all the follow-up time we had after starting the treatment.

Ultimately, what we found, and so the treatments that we looked at were 1 major drug from each class of either biologic or targeted synthetic DMARDs. We looked at adalimumab or Humira, which is the most commonly prescribed TNF inhibitor in our group; abatacept; rituximab; tocilizumab, or Actemra, which is the most common IL-6 inhibitor; and then tofacitinib, which has the earliest approval. It's been around since 2012, so there's the most follow-up data for that JAK inhibitor. And what we found was that if we just looked at the crude incidence rates of developing ILD across those different treatment groups per 1,000 patient-years, there was a significant difference between the groups, and tofacitinib had the lowest incidence rate of developing ILD.

Those are just crude rates and so they don't take into account lots of other variables that might influence that number, and so more importantly, we used Cox proportional-hazards models, where we adjusted for things like age, sex, race, ethnicity, education, geographic region, comorbidities, outpatient visit frequency, which can affect how different claims might get listed. And then also concomitant immunosuppressive medication use, which is important because if they're on different amounts of methotrexate or steroids, that could have an effect as well. So, after we plugged all that into the model and adjusted, the same general result came out, which was that there was a reduced risk of developing interstitial lung disease in the patients who were treated with tofacitinib. And it equated to about a 69% reduced risk compared to patients being treated with adalimumab, which was the reference group for all the comparisons.

Rebecca Mashaw:

That's a substantial reduction in risk at 69%—but now we're bumping up against the ORAL Surveillance study and some of the things that came out of that, which was in part a black box warning on not just tofa but also on upadacitinib as well, and on any JAK inhibitors probably that will come along. And that was primarily because of the adverse events that were found among patients with RA. Now, that group tended to be somewhat older and they already had at least 1 pre-existing risk factor for cardiovascular disease, as I recall.

Dr. Matthew Baker:

Mm-hmm.

Rebecca Mashaw:

So, with all of that information, so you've got the additional risk that's been identified, but then you have this substantial reduction in risk of a very devastating complication of RA in terms of ILD—how do you balance that? What particular risks do you think JAK inhibitors really present for these patients, and have you seen anything in your own practice that alleviates some concern about whether JAK inhibitors are safe for this group?

Dr. Matthew Baker:

It's a great question and one that I think everybody in rheumatology continues to grapple with, and governing bodies and probably regulatory bodies too, because there's a lot to unpack in all of the studies that have been done, the ORAL Surveillance trial and then multiple post hoc analyses of that study as well as real-world data that mostly recapitulates, but some that don't because it's looking at different patients.

So, I think just to kind of reiterate your point, the ORAL Surveillance study was a phase 4 post-marketing study that was meant to be a noninferiority study to see if tofacitinib was noninferior to either adalimumab or etanercept with regard to major adverse cardiovascular events and malignancies. And as you mentioned, the patients who were enrolled had at least 1 cardiovascular risk factor—so either current cigarette smoker, hypertension, dyslipidemia, diabetes, family history of early heart disease, extra-articular RA, which puts patients at a higher risk of heart disease, or just known coronary artery disease.

So, I would say many of our patients do have one of those risk factors, but there's certainly many that don't, and so it doesn't necessarily apply to all of our patients. And the punchline, as you said, was that there was definitely a trend towards increased risk of major adverse cardiovascular events and then a significant increase in new cancers in the patients treated with tofacitinib compared to one of the TNF inhibitors. And so based on that, the American College of Rheumatology put out some basic guidance that says it should be a shared decision-making between patients and providers, and the European Medicines Agency actually issued a communication advising against first-line use of JAK inhibitors. So, I think based on that, now I think for many people in practice JAK inhibitors are probably less commonly used as first-line therapy, given these newly understood risks, and reserved for maybe second or third-line. And also, now we know from some of the post hoc analysis that it appears the largest risk is really in patients over the age of 65 or with extensive long-term smoking history, either current or past, so for that population, we tried to avoid it.

So, I think to answer your question, it's certainly complicated. I think there's still a good reason to use JAK inhibitors in a number of patients and I think it can be done appropriately with the right counseling and discussion, and then there's probably a subset of patients where it should be avoided. And in the future, as it relates directly to this study, I think if we had very strong evidence and data that said X patients have a very high risk of developing ILD, one could make the case that it would be worth the potential risk to avert that consequence.

Rebecca Mashaw:

So, it's all about risk-benefit balance?

Dr. Matthew Baker:

That's right, yeah, and shared decision-making with the patient, for sure.

Rebecca Mashaw:

And that seems to be the rule across all of these autoimmune diseases, that shared decision-making is essential when you're deciding what kind of path you're going to follow for treatment, and making sure your patient's comfortable with the risks and understands the balance. That seems to be just a given these days.

Dr. Matthew Baker:

Yeah, that's right.

Rebecca Mashaw:

If a patient's already showing signs that they're developing ILD, is it still feasible to try treatment with tofacitinib if they haven't been on it for their arthritis?

Dr. Matthew Baker:

Right. I mean, our study provided no data to support this, because again, we didn't study it in a treatment aspect, but there are very small case reports or case series that have shown benefit in a small number of patients with RA-ILD as well as a few other autoimmune rheumatic diseases like dermatomyositis, which also can develop ILD as a consequence. So, I think that's really the million-dollar question that we don't know, is if a patient, as soon as you identify ILD developing in a patient with RA, what is the best therapy to put them on? And I think based on not a lot of data, I think people have historically thought maybe rituximab or maybe abatacept, and so I think those are commonly used.

That's also why it's very hard to study it retrospectively with claims data, because these decisions often get made already and there's kind of confounding by indication. But I think based on what we know thus far, it would be very reasonable to switch that patient to a JAK inhibitor to see. We just don't know. Fortunately, there actually are 2 prospective studies going on right now, one in Mexico and one in Sweden. They're small and open label, relatively small but not too small, and so maybe that will provide some additional evidence that ILD may improve with tofacitinib treatment.

Rebecca Mashaw:

So, there's still a lot to dig out about this?

Dr. Matthew Baker:

Yeah, definitely. Yeah, much more to do. It's way too early to say this should be the treatment.

Rebecca Mashaw:

So, what steps do you think a practicing rheumatologist who has patients with RA should be taking in terms of monitoring them for cardiovascular illnesses, for early signs of ILD, but these patients being treated with tofacitinib or perhaps upadacitinib, what should they be looking for?

Dr. Matthew Baker:

I think the first part of the question in terms of screening for ILD is there's no guidelines right now on whether RA patients should be screened for ILD, and if so, how? And there are a number of studies that are working on that. There's a study out of Mass General Brigham by Jeff Sparks called SAIL-RA, where they're following patients over 5 years and getting chest X-rays and CTs and other things to maybe hopefully develop some parameters around how patients should be screened. There's another 1,200-patient study that's sponsored by Boehringer Ingelheim that's looking, again prospectively following patients to hopefully determine risk factors and things like that. So, TBD on really how best to sort of monitor for the ILD.

In terms of the risks associated with JAK inhibitors, again, there's also not guidelines, but I think given that the 2 things that we're worried about are cardiovascular and malignancy, certainly making sure your patients have age-appropriate cancer screening is critical. So, for patients who are older, getting colonoscopies, getting prostate cancer studies, getting mammograms, et cetera, and then usually in conjunction with a primary care, optimizing the risk mitigation for things that are intervenable. So, if the patient has hypertension, making sure that's treated, if they have dyslipidemia, making sure that's treated. All the modifiable risk factors should be dealt with.

Rebecca Mashaw:

So, are you going to continue research yourself into this topic? And is the efficacy of upadacitinib also being investigated in the context of some of these new studies?

Dr. Matthew Baker:

Yeah, we would love to do additional follow-up studies, particularly looking at upadacitinib, which has had a large uptake. The issue there is that it was approved in August of 2019, and so we don't have a long enough follow-up time yet to determine how many patients will potentially develop ILD. We need a little more time to elapse where there's been a large uptake of upadacitinib use, but I think we're interested in doing that study and I think these observational studies and prospective studies right now are focused on tofacitinib, but I imagine they'll also expand to other JAK inhibitors in the future.

Rebecca Mashaw:

Well, this is really interesting. It's going to be fascinating to see how these prospective studies turn out, the kind of information that you glean from that. So, we look forward to talking with you about this again in the future.

Dr. Matthew Baker:

That's great. Yeah. Thanks for having me.