George Karpouzas, MD, on How bDMARDS Prevent CV Events in Patients With RA

In this podcast, George Karpouzas, MD, talks about his study that evaluated whether biologic disease-modifying antirheumatic drugs (bDMARDs) reduce long-term risk of cardiovascular events in patients with rheumatoid arthritis, as well as their mechanism of action.

Additional Resource:

• Karpouzas GA, Ormseth SR, Hernandez E, Budoff MJ. Biologics may prevent cardiovascular events in rheumatoid arthritis by inhibiting coronary plaque formation and stabilizing high‐risk lesions [published online April 21, 2020]. Arthritis Rheumatol. https://doi.org/10.1002/art.41293

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.

TRANSCRIPT:

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.

Biologic disease-modifying antirheumatic drugs (or bDMARDs) may decrease cardiovascular events among patients with rheumatoid arthritis. A recent study evaluated whether bDMARDs reduce long-term risk of cardiovascular events in patients with RA.

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, why did you choose bDMARDs over other RA medications? What are their importance?

George Karpouzas: So, as a general statement, Amanda, in the United States about 50% to 65% of patients are exposed to biologic medications. The reason they're exposed to those medications is because they had suboptimal responses with conventional synthetic DMARDs, like methotrexate or others in that realm.

Additionally, biologic DMARDs are drugs that target specific immunologic mechanisms, either cytokines that are directly linked to the progression of rheumatoid arthritis or cells that are also intricately linked with the clinical effects as well as radiographic progression in rheumatoid arthritis. The same cytokines that are significant for rendering the clinical effects of rheumatoid arthritis are also significant in rendering plaque progression in atherosclerosis.

For example, tumor necrosis-α and interleukin-6 are two well-characterized cytokines that are important, both in the pathophysiology of rheumatoid arthritis and the clinical manifestations of it, but also are intricately linked to atherosclerosis progression and plaque destabilization.

Our assumption was that perhaps the use of these medications will have more-specific effects in protecting rheumatoid arthritis patients from cardiovascular disease and atherosclerosis progression.

We also have background information from registry studies, as well as meta-analyses, that show biologic DMARDs are actually able to more efficiently protect against cardiovascular disease events in rheumatoid arthritis patients compared to methotrexate or other conventional synthetic DMARDs.

This is the reason we mainly focused on biologicals. We did examine other medications, such as methotrexate. In our hands, methotrexate did not have a protective effect against cardiovascular events in patients with rheumatoid arthritis.

Of course, the limitation of our study is that we're talking about a cohort of 160 patients, albeit very well characterized and long-term follow-up available for this cohort, it still is a small cohort.

Amanda Balbi: So how do bDMARDs affect the short- and long-term risks of cardiovascular events in patients with RA?

George Karpouzas: What we found in our study is that for as long as biologics are currently used, they are able to significantly protect against cardiovascular event risk, and that figure is an 85% protection. If you are on a biological at any given time, you have an 85% lower risk of incurring a cardiovascular event compared to a patient that is not on a biological—having adjusted for clinical cardiovascular risk scores, having adjusted for how much plaque you already had at baseline, having adjusted for other treatments and other differences that you may have from the patient that is not taking the biologic DMARD.

What is crucial to also understand—and we showed—that this effect is significant, indeed, for as long as the patient is on biological continuously. When we looked at 3 months after a biologic was discontinued, although a trend was maintained for protective effect against cardiovascular disease, it was no longer statistically significant.

The messaging is biologics can be very protective, and they can be very protective, however, for as long as they're taken and either they're stopped for over 3 months, then this effect wanes.

Amanda Balbi: So were the benefits rendered by altering the trajectory of coronary artery plaque progression or stability?

George Karpouzas: The short answer is yes. And this is the actual beauty of this study, because we are in the unique position to correlate presence of incident cardiovascular events with changes in plaque morphology, as well in plaque change, given the fact that we evaluated those patients over a 7-year period of time, and we had a baseline coronary atherosclerosis interrogation and a follow-up interrogation.

What we found, first of all, is that from the patient perspective, when you look at the patients have large, biologicals are actually having this effect on noncalcified plaque. What they do is they prevent noncalcified plaque progression—that is the earliest and most-active plaque, which also is associated with a higher risk of cardiovascular events. We actually found that the effect of biologicals is very significant and really important only for patients who have known calcified plaque or plaques who have other vulnerable characteristics, like a necrotic course.

When you use biologics in those patients, those are the patients who are the most likely to benefit. So when we looked at cardiovascular-event protection, we found that the patients who benefited the most were the ones that had these types of plaque in the beginning. Now, when you ask specifically, “What is it is that the biologics do to the individual atherosclerotic lesions—to the individual plaques?”

What we found is that they, first of all ,act throughout the entire process of atherosclerosis. It doesn't matter how early or late it is, how many years it's been going on; they act on all stages of atherosclerosis.

However, their specific effects they have may be different up on the stage of atherosclerosis. For very early disease—so, when patients have either no coronary plaque or had only very early noncalcified plaque—then the presence of biologicals prevents formation of new atherosclerotic lesions. So, prevents new plaques from forming period.

Now, for patients who have established disease, what biologics do is they actually promote protected calcification of noncalcified plaques, number one. Secondly, they are changing the composition of the plaque. They help absorb the lipid core of the plaque, and they stabilize the plaque this way.

The lowest innovation plaques, which are lipid-rich, the plaques that are most likely to cause cardiovascular events are actually disappearing under the biologic use. So this is what they actually do on a per plaque level.

Amanda Balbi: So what else do rheumatologists need to know about your study?

George Karpouzas: First off, is that they are protected throughout their use, provided they are continuing to be used. Second, their protective effect is regardless of having achieved perfect disease control.

As I mentioned earlier, we always strive to treat rheumatoid arthritis into remission, but sustained remission is an elusive goal. The point being that biologicals have the capacity to be protective against cardiovascular disease events and render those effects on plaque, regardless of perfect control attainment of inflammation.

The other thing that deserves to be mentioned is that there is still a role for appropriate use of accessory medications, which interact with inflammation in rendering this plaque progressive.

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

George Karpouzas: Thank you so very much for this opportunity. I think this is a learning a high learning curve for us. And we've had a very good fortune to be able to have our patients cooperate for so many years with us in order to complete this study. This is a study that's actually still ongoing and continually monitoring the incidence of cardiovascular events in those patients. So my most sincere thanks to our patients into our study stuff as well.