Rheumatoid Arthritis and Aortic Stenosis: A Plausible Link—Now What?

In a large cohort of mostly male subjects, people with rheumatoid arthritis (RA) had a higher risk of developing aortic stenosis, needing an aortic valve intervention, or dying of aortic stenosis, investigators report in JAMA Internal Medicine.

While an inflammatory link is plausible between the two, what’s not clear is whether RA plays a causative role, whether specific RA medications might help to blunt aortic valve damage, or indeed, how such an effect—or a remedy—could be studied.

“Our study really doesn't get at any sort of causal relationship; this a large-scale epidemiological study,” senior author Bryant England, MD, PhD (Nebraska Medical Center, Omaha), told TCTMD. “The big thing this really highlights is that valvular disease is something we also need to be thinking about in terms of increased cardiovascular risk and rheumatoid arthritis. It's not just MI, stroke, and heart failure, but more broadly, some of these other cardiovascular manifestations may be overrepresented, too.”

England, along with first author Tate Johnson, MD (VA Nebraska-Western Iowa Health Care System, Omaha), and colleagues, linked data from the Veterans Health Administration (VHA) and the Centers for Medicare & Medicaid Services between 2000 and 2019 to match patients who had RA with up to 10 patients who did not have the condition, then followed them for an aortic stenosis diagnosis, intervention, or death.

As we think about our treatment approaches that keep people functioning and [offer] a good quality of life, we also have to be considering what are the things that we're doing that also give them longevity. Bryant England

They found that out of more than 73,000 patients diagnosed with RA (of whom nearly 88% were male), the composite rate of aortic stenosis events per 1,000 person-years was 3.97 (95% CI 3.81-4.13), significantly higher than that seen among patients without RA (2.45; 95% CI 2.41-2.49). Rates of aortic stenosis intervention per 1,000 person-years also were higher among patients with versus without RA (1.02; 95% CI 0.95-1.11 vs 0.70; 95% CI 0.77-0.82), as was the rate of death (0.17; 95% CI 0.14-0.20 vs 0.11; 95% CI0.10-0.12).

“We know that people with rheumatoid arthritis have decreased longevity, but when we look at death certificates, 95% of the time it's not RA on the death certificate,” said England. Rather, “cardiovascular disease is the most common. So, as we think about our treatment approaches that keep people functioning and [offer] a good quality of life, we also have to be considering what are the things that we're doing that also give them longevity.”

A Reasonable Link . . . Now What?

Commenting on the study for TCTMD, Catherine Otto, MD (University of Washington, Seattle), observed: “It's not at all surprising that any systemic inflammatory disease like rheumatoid arthritis would be associated with calcific aortic stenosis, because the key to pathogenesis is inflammation, plus lipid infiltration and calcification, so it seems totally reasonable.”

What’s not known is what can be done about it, she continued. When it comes to altering the trajectory of a chronic disease, the focus is typically on modifiable risk factors. “If a person's a smoker, we can try to encourage them to not smoke,” said Otto. “But if people have rheumatoid arthritis, we can't encourage them to not have rheumatoid arthritis, that's not going to work.”

What’s needed is some elucidation of what effects RA medications might have in diminishing the adverse effects of the inflammatory state on other organs, she added. “As a patient, you want to know: is [one particular medication] just treating the symptoms, the arthritis and the pain? Or are you preventing damage to other organs that you can't see?”

England highlighted to TCTMD that having elevated inflammatory markers, or taking the medications reserved for the most severe rheumatoid arthritis symptoms, were factors that appeared to increase the risk of aortic stenosis. This suggests “that it's not just that rheumatoid arthritis is associated with a higher risk, but if you have more severe rheumatoid arthritis, your risk is even higher,” he explained. “We obviously need to explore that further and understand, what are the mechanisms linking rheumatoid arthritis with aortic stenosis, and then whether or not we can use that information to try and risk stratify people.”

Both England and Otto agreed that any kind of randomized trial studying the impact of specific RA medications on blunting aortic valve effects would premature. Moreover, Otto pointed out, as with other disease processes that appear to trigger or accelerate aortic valve disease, studying the phenomenon, or identifying agents against it, requires huge number of patients and a protracted follow-up, making traditional randomized trials unfeasible. Pragmatic studies or mendelian randomized trial designs might be a better way to get at these questions, she suggested.

In the meantime, observational studies can help point the way, although this one—relying as it did on the VHA data set—is somewhat “disappointing,” she noted, given the low proportion of women. “Rheumatoid arthritis is predominantly a disease in women,” she pointed out, with a female-to-male ratio of about 2:1. It’s also very common, affecting approximately 1% of the population. While the low representation of women in this study is a reflection of the data they authors chose to look at, most studies today would include a sex-specific analysis to try to tease out any insights, she said.

“They do note . . . that female sex was lower risk for having aortic valve disease, which is not surprising: it's more common in men. But that still kind of means that I think the association needs to be studied in women,” said Otto.

To TCTMD, England confirmed that, given the demographics of the VA, “we did not have enough women to do an analysis only among women.”