George Karpouzas, MD, on Coronary Atherosclerosis Progression in RA


In this podcast, George Karpouzas, MD, talks about his study that evaluated the impact of inflammation, cardiac risk factors, duration of medication exposure, and their interactions on coronary plaque progression among patients with rheumatoid arthritis.

Additional Resource:

  • Karpouzas GA, Ormseth SR, Hernandez E, Budoff MJ. Impact of cumulative inflammation, cardiac risk factors, and medication exposure on coronary atherosclerosis progression in rheumatoid arthritis. Arthritis Rheumatol. 2020;72(3):400-408.


George A. Karpouzas, MD, is a professor of medicine at the University of California, Los Angeles, and chief of rheumatology at The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center in Los Angeles, California.



Amanda Balbi: Hello everyone, and welcome to another installment of Podcasts360—your go-to resource for medical news and clinical updates. I’m your moderator Amanda Balbi with Consultant360 Specialty Network.

Cardiovascular disease is markedly increased among patients with rheumatoid arthritis, partly due to accelerated atherosclerosis from chronic inflammation. In a new study, a research team explored the incidence and progression of coronary atherosclerosis and identified determinants among patients with RA. Specifically, they evaluated the impact of inflammation, cardiac risk factors, duration of medication exposure, and their interactions on coronary plaque progression.

Speaking with us today about this study is lead author Dr George A. Karpouzas, MD, who is a professor of medicine at UCLA and chief of rheumatology at Harbor-UCLA Medical Center.

Thank you for joining us today, Dr Karpouzas. Let’s dive into your study.

To start, how common is coronary atherosclerosis among patients with RA, and how commonly does the plaque progress?

George Karpouzas: We found that 71% of patients who get an evaluation of their coronary arteries, noninvasively with computed tomography angiography, demonstrate presence of coronary plaque. This is much more common compared to controls that are age, gender, and geolocation matched, who have about 45% prevalence of coronary atherosclerosis.

Now, in terms of coronary plaque progression, our study evaluated this progression over a span of 7 years. We found that 48% of patients with rheumatoid arthritis progressed their coronary plaque. That means they either developed new plaque in segments of their arteries that did not previously harbor plaque or progress made worse the stenotic severity of prevalent plaque at baseline.

Amanda Balbi: And so what factors help to identify these patients with RA who have a higher risk of coronary atherosclerosis?

George Karpouzas: Before I answer this question, I would like to make sure the audience understands that plaque composition is equally or more important than plaque progression or burden itself. Known calcified plaques (or soft plaques) and plaques with both noncalcified and calcified components are the ones that are most dangerous and the most overrepresented in patients who develop heart attacks.

Fully calcified plaques are essentially plaques that have healed that have completed their cycle and very present basically mummification of bioactive lesions. When the plaque gets into that state, that basically indicates that the plaque is healed, and the risk is going down.

In terms of identifying there for patients have higher risk of coronary atherosclerosis, a variety of factors are associated with that. And those factors specifically pertain to types of plaques that are overrepresented in patients.

For example, age—greater age is associated with greater risk of having plaque, and it's also associated mostly with greater risk of having calcified plaque, meaning plaque that has extinguished its life. It is less commonly associated with soft plaque. Disease activity is the second very important consideration for rheumatologists.

Disease activity is specifically associated with more dangerous plaque—the 2 types of plaques that I described earlier (noncalcified and mixed plaque)—compared to calcified plaque. So, if a patient has residual disease activity, it's much more likely they're going to have this dangerous type of plaque than a healed plaque.

Additionally, there are biomarkers that we have shown that can be associated with plaque presence but also can predict how severe is this plaque. That biomarker is highly sensitive cardiac troponin I. It's a structural myocardial biomarker that basically shows you how much myocardial damage you incur in a patient that does not have symptoms of overt cardiac disease.

All 3 can associate with your risk of having plaque or more plaque or a specific type of plaque, as well as burden and severity of plaque.

Amanda Balbi: So, what is the impact of inflammation, cardiac risk factors, duration of medication exposure on coronary plaque progression?

George Karpouzas: That's a very good question. It’s actually the crux of this manuscript that was recently published in A&R from our group. What we found in this manuscript is basically that cumulative inflammation—so inflammation over this period of time that we observed patients from the baseline interrogation of their coronaries to the follow up interrogation of their coronaries—is actually the most stable and reproducible predictor of coronary atherosclerosis progression.

The second one obviously is age, and there's not very much we can do about increasing age. The third that we most certainly can do something about is the cumulative dose of prednisone the patients have been exposed to throughout this period of time.

Those 3 factors in general are associated, specifically, with every metric of coronary plaque burden increase over this period of time. Now classic cardiac risk factors for example, hypertension or obesity, can be associated with specific types of plaque, if you will.

When you're looking at coronary calcification, which pertains to more calcified or mixed plaques, then hypertension and obesity most certainly are associated with the fat.

In terms of different medications, now we are talking about RA-specific medications, such as methotrexate or biologic DMARDs.

Now, we interrogated those, and what we found is basically that biologic utilization is associated with prevention of noncalcified plaque progression. Remember this is the plaque that is the most noxious, as it pertains to risk for cardiovascular events in the future.

So it appears that biologicals stem, if you will, the rates of progression of the plaque. And when we look specifically to see what they actually do in individual plaques, we're finding that they first of all stabilized plaques that are having vulnerable plaque characteristics, they help precipitate and promote transitional noncalcified blocks into fully calcified plaques.

Earlier in atherosclerosis, when you have no coronary plaque or all you have is a little bit of soft plaque, we're finding that they are actually preventing new plaque from forming in segments that didn't have plaque before.

When we interrogated methotrexate, we did not find any significant effect of methotrexate in plaque progression in any way—in our hands, at least, in our cohort.

Now when we look at medication accessory therapies that we use in those patients, let's say for hypercholesterolemia like statins, we made some interesting observations. Statins appear to—like the biologicals and independent of them—to stem or prevent progression of noncalcified plaque.

The most interesting thing that statins actually did is they moderated—they conditioned—the effect of inflammation of total plaque progression. So the longer statins were used, the more the obliterated the impact of inflammation on coronary plaque progression.

If you, let's say, are receiving statins for over 50% of the observation time, there is literally not increased risk from higher inflammation to cause plaque progression. This is not the case in patients that were treated for a shorter period of time.

Amanda Balbi: Specifically, how did statins affect patients with RA and coronary atherosclerosis?

George Karpouzas: Again, what I told you earlier is what statins do generally in the patient itself. When we looked at the individual coronary plaques and what statins do to them, similar to the biologics but also independently of the biologics, they also promote this healing of noncalcified plaques into calcified plaques.

And the other thing that they additionally do is they make those noncalcified plaques regress in size. So, they restrict their volume, which is a very important thing because that is how statins also have been shown to work in the general population. So it's very soothing to find that the work similarly in patients with rheumatoid arthritis.

Additionally, as biologics did as well, they also protect from the development of new plaque in segments that did not have plaque at baseline.

Amanda Balbi: Great. What would you say are the key take-home messages from your study for rheumatologists?

George Karpouzas: The most important key message is that inflammation always should be controlled to the best of our capability. As we showed, inflammation was the most reproducible predictor of plaque progression, whatever metric you used to measure that.

Keeping, however, in mind that sustained remission is only attainable—literally based on what we currently know about 15% of patients—not every patient will be able to be fully controlled and for extended period of time. In those patients is when you, for example, have the capability with specific medications or accessory therapies to sort of boost this protective effect against coronary atherosclerosis progression.

As I mentioned, for example, statin use and longer use of statins in appropriate patients most certainly is protected against coronary plaque progression, especially for longer periods of time when it's used. Additionally, what I didn't mention earlier is that stringent control of systolic blood pressure also can moderate the effect of residual inflammation on coronary plaque progression.

We found that patients who, over the span of 7 years, had time-averaged systolic blood pressure of less than 126 mm Hg were protected against plaque progression as rendered by higher levels of inflammation.

Higher levels of inflammation were much less likely to cause progression of coronary plaque in patients whose blood pressure was less than 126 mm Hg. So, that's not to say that the targets that we are striving for of blood pressure or of lipidemia control at this point should be different than the general patients.

It's just that we should apply similarly to the general patients published guidelines in aggressively monitoring and treating those in patients with rheumatoid arthritis.

Amanda Balbi: Absolutely. Thank you again for speaking with me today about your study.

George Karpouzas: Thank you very much for this opportunity.