Tate Johnson, MD, on Aortic Stenosis and Rheumatoid Arthritis

The risk of cardiovascular diseases among patients with rheumatoid arthritis goes beyond just heart attacks and strokes. Findings of a large cohort study revealed that patients with RA were at a higher risk of developing aortic stenosis—which could lead to the need for aortic valve surgery or aortic stenosis-related death.

Tate Johnson, MD, is an assistant professor in the department of internal medicine, rheumatology, and immunology with the University of Nebraska College of Medicine.

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Transcript:

Disclaimer:

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 and Arthritis Learning Network or HMP Global, its employees and affiliates.

Priyam Vora:

Welcome to this podcast from the Rheumatology and Arthritis Learning Network. I'm your host, Priyam Vora, and today we are talking with Dr. Tate Johnson. Dr. Johnson is an assistant professor in the Department of Internal Medicine, rheumatology and immunology with the University of Nebraska College of Medicine. Today we are going to discuss his research on the development of aortic stenosis among patients with rheumatoid arthritis. Thank you for joining us today.

Dr Johnson:

Yeah, appreciate you having me, excited to be here.

Priyam Vora:

I understand that there is already an established association between rheumatoid arthritis and ischemic cardiovascular disease, but not much is known about the link between RA and aortic stenosis. Is this what prompted your research?

Dr Johnson:

Yeah, you're right. Historically, I think it's been well recognized that patients with RA, cardiovascular disease is the most frequent cause of death in RA. And I think one of the most sort of studied manifestations of cardiovascular disease in RA really has been ischemic cardiovascular disease or coronary artery disease, which is probably the most frequent cause of cardiovascular disease. So rightfully so.

We recently actually conducted an analysis in a similar cohort of patients with RA, looking at specific causes of cardiovascular mortality to look at in addition to ischemic heart disease, what other things are causing this mortality gap that we're seeing in patients with RA. And we were actually surprised to find in that analysis that valvular heart disease was perhaps one of the more overrepresented, so not the most frequent, but more overrepresented causes of cardiovascular disease related death in patients with RA.

And so valvular heart disease has been described as an extra articular manifestation in RA. There's been some cross-sectional imaging studies. Small case series in the past have suggested this, but really no large epidemiologic studies to look at the risk of valvular heart disease or valvular heart disease related outcomes. And increasingly there's been an understanding that what we used to maybe think of in the case of aortic stenosis as more of a degenerative process, there's been sort of this increased understanding that there may be an inflammatory component to that, both in some non RA human studies as well as some interesting mouse models of autoimmune arthritis where these mice with autoimmune antibody mediated arthritis actually develop sort of an inflammatory valvular carditis. So kind of putting all that together is kind of what prompted our motivation to want to look at the risk of aortic stenosis, which is one of the more common causes of valvular heart disease surgery and valvular heart disease related death in the US or very burdensome condition. So that's what prompted us to want to look at this on a larger scale.

Priyam Vora:

Right. Would you describe your study?

Dr Johnson:

Yeah, so this study was using national VA data, so really large dataset. We created a cohort of about 70,000 patients with RA and matched them to non RA controls and are about 700,000 controls in our study. This was an administrative data set, and so we use diagnostic and procedure codes to identify aortic stenosis outcomes. So we identified aero stenosis diagnoses and the inpatient and then outpatient setting. We also examined for identified aortic valve related interventions. So this would be like surgical aortic valve replacement and then transcatheter aortic valve replacement. And many of those we actually linked with Medicare data outside of the VA because many of those procedures occur outside of the VA. So we spent some time linking with these other data sources to ensure that we are capturing all of these events. And then we also identified aortic stenosis related death with linkage to the National death index.

So once we kind of identified those events, we basically excluded any patients who had valvular heart disease before the start date of our study. And then we examined the risk of aortic stenosis related to RA status, and we accounted for many of our traditional cardiovascular disease risk factors, including things like body mass index, smoking status, comorbidity burden, and then we also adjusted our analysis for the frequency of healthcare utilization. So we know patients with RA are going to be seen by healthcare providers more often, just sort of with the nature of RA treatment, and oftentimes in studies that can lead to what we call detection bias, where they just may be more likely to get an echocardiogram for other reasons and then detect their aorta. So we kind of accounted for that by adjusting for the frequency of healthcare utilization.

And so then after this analysis where we looked at RA related to non RA patients and the risk of AS in RA patients, we then restricted two patients with RA to sort of explore RA related risk factors and how those might predict onset amongst patients with RA.

Priyam Vora:

Right, right. And what did you find?

Dr Johnson:

Yeah, so in our initial analysis where we're looking at patients with RA and their risk of AS compared to non RA patients, we did find that AS occurred more frequently than in patients without RA, and that was statistically significant. And so in our adjusted models, we found that patients with RA were at a 48 or nearly 50% increased risk of our composite AS outcomes. So that's any inpatient outpatient diagnosis procedure or AS related death. We found that patients were also at a higher risk of perhaps more severe aortic valve disease in the sense that they were at a over 30% increased risk of undergoing an aortic valve intervention, and then 25% increased risk of AS related death. And then we performed several sensitivity analyses where we found that these findings were robust to since [inaudible 00:06:51] where we stratified by healthcare utilization restricted based on age and such.

Priyam Vora:

So you mentioned age, gender, race. So did you find that these demographic factors also were associated with the risk of developing aortic stenosis? Any specific trends that you noticed?

Dr Johnson:

Yeah, yeah. And so in our analysis when we restricted the patients with RA to sort of look at specific risk factors of for aortic stenosis, we did see some signals as far as some of the risk factors you're mentioning.

So age obviously is one of the biggest risk factors for aortic stenosis. And so we did find that that older age was definitely associated with AS. We also found that, so obesity was associated with an increased risk and we saw a bit of a dose dependent response where higher BMI category to baseline were associated with a higher risk of aortic stenosis.

And then in our analysis, looking at RA related risk factors, the things we were looking at, so we were looking at whether sero positivity, so positive rheumatoid factor, anti CCP, we looked at whether an elevated ESR or CRP measurement a baseline as well as specific glucocorticoid or conventional BMR or biologic DMR use, whether there was any association between those at baseline and as risk. And we didn't find any association between sero positivity status and aortic stenosis.

What we did find was that patients with a higher ESR, CRP at baseline were at a modestly increased risk of AS, and then we also found that patients who had received either glucocorticoids or a biologic DMARD at baseline were at higher risk or had an association seen between that and aortic stenosis. And really what we think that that suggests rather than any specific sort of treatment effect necessarily, but we think that suggests that these are likely patients with more severe rheumatoid arthritis, and so those patients with more severe rheumatoid arthritis are also more likely to be on steroids, more likely to be on biologics. And so we think that that likely sort of explains this association and sort of suggests that perhaps more severe rheumatoid arthritis presents a higher risk of AS.

Priyam Vora:

So should the risk of developing aortic stenosis be kept in mind before the doctor prescribes certain medications or drugs?

Dr Johnson:

Yeah, that's a good question. Our paper couldn't really get at that. If you're going to sort of try and invoke any really treatment related side effects, you kind of need a specifically designed pharmaco epidemiologic study where you're following medication use over time. And we really didn't do that in our study. Really what we're able to find, we're just looking at these things at baseline.

So we think much more that in the association seen between medication use and AS in our study is probably more so explained by what we would say is sort of a confounding by indication, again meaning that patients with severe RA are more likely to be receiving these drugs. Thus, that sort of explains that association.

From our study I wouldn't make any conclusions that a rheumatologist should worry about specific medication use DMARDS and AS risk, of course we know I think it's well established as far as the adverse effects of glucocorticoids and cardiovascular risk and plausibly, could that increase cardiovascular risk over time, which might include valvular heart disease? Maybe. I don't think our study necessarily gets at that, but I think all of us understand that our goal is to minimize glucocorticoids when able.

Priyam Vora:

Is it common for patients with an autoimmune disease to be genetically predisposed to developing cardiovascular complications?

Dr Johnson:

So the genetic part is interesting as far as looking at some of the genome-wide association studies that are becoming increasingly more interesting. I don't know if anyone's necessarily gotten to the point where we have delved into that in the RA world and identified these specific genetic predisposition amongst patients with RA, but we do know more broadly speaking in autoimmune conditions is that it's just a state of chronic inflammation. And over time I think we've understood that there is this sort of systemic inflammatory burden in these diseases and an inflammatory mechanism for ischemic heart disease, heart failure. And so that sort of chronic systemic inflammation I think is kind of where we really sort of understand is predisposing these patients to cardiovascular disease complications.

Priyam Vora:

So patients with mild RA versus severe RA, are they all at the same level of risk of developing aortic stenosis?

Dr Johnson:

Yeah, again, we think our data suggests that. So this is a large epidemiologic sort of administrative database study, and so the things we were able to look at is a measure of systemic inflammation, so a SED rate or CRP as well as sort of making some of these conclusions based on the type of treatment patients were receiving. So those were kind of the surrogates for severity of RA disease activity, which in our analysis we think suggests that more severe RA might be associated with a higher risk of aortic stenosis.

In this study, we weren't able to follow the specific RA disease activity measures, so our clinical RA disease activity assessment like the DOSS 28, we don't have any longitudinal assessment of that in this study. So we can't specifically get at these different RA disease activity severity categories and how they influence AS risk. But I think that would be our hypothesis, but certainly needs further study.

Priyam Vora:

So just out of curiosity, is checking for aortic complications currently a standard practice when diagnosing or treating patients with rheumatoid arthritis?

Dr Johnson:

Yeah, no, there's not really any widely adopted screening strategies in general for any cardiovascular disease complication when patients are diagnosed with RA. I think it's something we educate our patients on. We of course focus on the evidence-based practices that we would in many other patients as far as cardiovascular risk factor management, but no accepted practices as far as screening aortic stenosis at this time.

Priyam Vora:

Would you be able to recommend any specific cardiovascular disease markers that should be routinely monitored to uncover underlying cardiovascular complications?

Dr Johnson:

Yeah, that's an interesting question and I think especially amongst folks that are interested in cardiovascular disease research and RA, I think that's almost sort of the holy grail of figuring out what's the best risk stratification strategy in patients with RA. We know that the risk calculators that are most commonly used in the general population tend to underestimate cardiovascular risk in patients with RA, but really, there hasn't been any sort of development of a widely accepted risk calculator that is more accurate. And so I think that's continually an area of research need is to identify either what's the risk stratification strategy or biomarker.

I think at this juncture, really it sort of boils down to ensuring that we're educating patients on their risk of cardiovascular disease and being very cognizant of more aggressively speaking to them about lifestyle modifiable risk factor modification, whether that's lifestyle, like smoking, routine exercise, and then just ensuring that primary care providers and rheumatologists are working together to make sure things like those modifiable risk factors like high blood pressure, lipid screening, diabetes are all managed aggressively. I think oftentimes in patients with RA, at least in my experience when we're seeing them so frequently, oftentimes sort of identify their rheumatologist as their primary care provider. And so I think that the rheumatologist has to some extent take ownership of that and at least communicate with a primary care provider and making sure that these things are being done.

Priyam Vora:

Do you have any plans to expand this to a broader study?

Dr Johnson:

Yeah, so I think to your question before as to how does the severity of rheumatoid arthritis disease activity influence aortic stenosis? I think that's an area of interest for us. We have a prospective cohort that in the VA where we do have a large population of patients with longitudinal disease activity measures. And so those are some findings that we'll be presenting actually at the ACR convergence this year, looking at how disease activity and sort of predict aortic stenosis risk.

And then I think one of the other areas of interest is sort of as we think that valvular heart disease, perhaps a bit of an under-recognized cardiovascular disease complication in RA, what we found in our prior work is that while cardiovascular risk is improving over time, there is sort of still a persistently increased risk. And some of that is explained by things like heart failure and other cardiovascular disease manifestations, and so one of my interests would be is how does valvular disease contribute or potentially explain some of this persistent cardiovascular disease risks that we're seeing in patients with RA?

Priyam Vora:

That's all for my questions. Anything you would like to add? Something I forgot maybe?

Dr Johnson:

No, I think that's great. I think we covered a lot of great information here. I think our take home from this study is really that for the rheumatologist, I guess seeing a patient in clinic, it's kind of just being aware that valvular heart disease is amongst these cardiovascular disease complications. There's been interesting studies in the past that have shown that patients with RA are maybe less likely to present with what we would say are classic symptoms of heart disease, whether it's ischemic heart disease or heart failure.

I would say it's easy to sort of mistake some of the symptoms of aortic stenosis like exercise intolerance or shortness of breath, lightheadedness for perhaps deconditioning related to a person's articular disease. So when you're hearing that not just attributing all of those symptoms to articular disease, but having sort of a high index of suspicion to think about cardiovascular disease complications, including AS, perform a careful exam, think about echocardiographic screening when you feel it's indicated.

Priyam Vora:

Thank you so much for taking the time to talk to us, Dr. Johnson. Once again for our listeners, that was Dr. Tate Johnson explaining how patients with rheumatoid arthritis are at a higher risk of developing aortic stenosis and the subsequent risks of aortic valve interventions and aortic stenosis related death. Thank you, Dr. Johnson.

Dr Johnson:

Thanks for having me. Appreciate it

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