George Karpouzas, MD, on β-2 Glycoprotein 1 IgA Antibodies and Coronary Outcomes in RA
In this podcast, George Karpouzas, MD, discusses his research that evaluated whether β-2 glycoprotein 1 IgA antibodies can predict coronary plaque burden and progression, and whether the antibodies moderate the effect of inflammation on atherosclerosis among patients with rheumatoid arthritis.
- Karpouzas GA, Ormseth SR, Hernandez E, Qui V, Budoff MJ. Beta-2-glycoprotein-I IgA antibodies predict coronary plaque burden, progression and moderate the effect of inflammation on atherosclerosis in rheumatoid arthritis. Paper presented at: American College of Rheumatology 2019; Atlanta, GA; November 8-11, 2019. https://acrabstracts.org/abstract/beta-2-glycoprotein-i-iga-antibodies-predict-coronary-plaque-burden-progression-and-moderate-the-effect-of-inflammation-on-atherosclerosis-in-rheumatoid-arthritis/
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.
A new study evaluated whether β-2 glycoprotein I IgA antibodies predict coronary plaque burden and progression, and whether the antibodies moderate the effect of inflammation on atherosclerosis among patients with rheumatoid arthritis.
Today I’m speaking with the lead author of the study, Dr George A. Karpouzas, MD, who is a professor of medicine at UCLA and chief of rheumatology at Harbor-UCLA Medical Center in Los Angeles, California.
Thank you for joining us today, Dr Karpouzas. Let’s dive into your study.
To start, what is the target of these antibodies, and how did you decide to look at the role of them in RA?
George Karpouzas: The β-2 glycoprotein one is a serum apolipoprotein that normally exerts an anticoagulant effect by displacing various coagulation proteins from antiphospholipid sites. It is generally produced in the liver.
We decided to look at them because, when you look at atherosclerotic plaques, you appreciate that there's an increasing frequency and activation of immune cells within those progressive atherosclerotic lesions. That suggests that this recognition and targeting of local antigens within the plaque is central to the plaque growth and its decivilization in the future.
Among those candidate molecules, those candidate proteins, β-2 glycoprotein one is readily expressed within human atherosclerotic plaque. So, it’s abundant within the plaque. The fact that they're being bound by different types of cells within the plaque and they colocalize with immune cells within the plaque suggested that they may be a target for immune-mediated reaction that could influence atherosclerotic plaque progression.
We do know from murine studies that if you challenge mice that are destined to develop atherosclerosis with β-2 glycoprotein one, that challenge induces antibodies against that molecule and promotes significantly the plaque burden.
Now we also know that antibodies against β-2 glycoprotein one, especially of this isotype—the IgA isotype—have been described, both in general patients and also be mentioned in RA patients. And I think the most relevant publication here is the perspective Coronary Artery Risk Development in Young Adults Study, which showed—it's a 20-year study—that showed that anti-β-2 glycoprotein one IgA presence associated with future development of a called coronary plaque calcification.
Additionally, 2 studies in general patients who had symptomatic cardiac disease showed that presence of those antibodies was 33% and 40%, respectively. And not only that, the presence of those antibodies independently associated with stroke, myocardial infarction, unstable angina, and symptomatic peripheral serial disease—that's in general patients.
However, the impact of those antibodies on coronary plaque trajectory and cardiovascular risk in rheumatoid arthritis is unknown. So we decided to evaluate the role of β-2 glycoprotein one IgA antibodies on coronary plaque progression and long-term incident cardiovascular disease events in our well-characterized cohort of patients with established rheumatoid arthritis.
Amanda Balbi: Great. And does β-2 glycoprotein one IgA presence predict coronary plaque burden or progression among patients with RA?
George Karpouzas: So, the answer is yes. And what we found is that anti-β-2 GLP1 antibodies associated with future development and progression of coronary atherosclerosis in RA above and beyond traditional cardiac risk factors, cumulative inflammation, and cumulative prednisone dose.
Now, this included both new plaque formation in segments without plaque at baseline, as well as increased stenotic severity of atherosclerotic lesions that were present at baseline.
Additionally, we found that higher antibody titers had greater effect on plaque progression. Additionally, what we found was that anti-β-2 GLP1 IgA associated with advanced remodeling of atherosclerotic lesions to high-risk plaques—plaques that are associated with cardiovascular events—persistence of such plaques in an activated state, and further delayed or prevented their dense calcification, which is basically their healing process.
Amanda Balbi: So how does β-2 GLP1 IgA interact with inflammation and affect atherosclerosis load in patients with RA?
George Karpouzas: So that's a great, great question. And it's basically a mechanistic question you're posing. So, in the presence of higher inflammatory burden, you have a higher oxidative stress. That higher oxidative stress is associated with cholesterol—especially low-density cholesterol, LDL cholesterol—oxidation into this noxious oxidized LDL form.
Now, the more oxidized LDL there is, because of inflammation, the more it's being uptaken by cells in the plaque and converts them into foam cells. Now, what happens, as you know, during atherogenesis, the β-2 glycoprotein one interacts with this oxidized LDL in the arterial wall and forms these complexes of β-2 glycoprotein one and oxidized LDL, which subsequently can be released in the circulation.
Unfortunately, these complexes are very highly immunogenic, and they may be bound, both in the plaque as well as in the periphery, by antibodies against the complex (ie, antibodies against β-2 glycoprotein one). Those immune complexes were shown to bind special receptors on the surface of macrophages, which is the main cell in the plaque that are subsequently internalized and promote the generation of formy cells, which are basically macrophages filled up with cholesterol. The more of those that accumulate and the more of those that die, the more the lipid core of the plaque increases and then a crux core forms.
Amanda Balbi: That's interesting. So which patient populations in your cohort had the worst coronary outcomes?
George Karpouzas: Obviously patients who were β-2-GLP1-IgA positive were the ones that had the worst outcomes in terms of coronary plaque progression and vulnerability. And remember, this is an adjusted analysis, which means that the contributions of other factors which are significant are accounted for. Those other factors include, obviously, cumulative inflammation, statin exposure, biologic drug exposure, as well as traditional cardiac risk factors such as age, hypertension, and obesity.
Amanda Balbi: And what is the significance of your findings, and who should be tested for these antibodies?
George Karpouzas: So our study is the first study that is basically exploring the impact of these antibodies on coronary plaque trajectory and events in rheumatoid arthritis. So should future studies corroborate our findings that indeed those antibodies associated with future development or progression of coronary atherosclerosis in RA, then formal screening may be warranted in those patients.
If they're found to be positive, our data indicates that at least stringent and durable control of inflammation is paramount, as β-2 GLP1 IgA presence moderates the effects of inflammation and plaque progression.
We recently reported that duration of statin treatment condition the impacts of cumulative effect of inflammation and plaque progression, meaning statins are protective in patients who are exposed to them for longer periods of time, regardless of the effect of inflammation. There doesn't seem to be much difference here, although we don't absolutely know whether or not the statins are equally effective in β-2 GLP1 positive patients vs β-2 GLP1 negative individuals.
We also found in ancillary analysis that stringent blood pressure control is also very important. We showed that for patients who have an average systolic blood pressure, less than 130 mm Hg, inflammation is less likely to allow a significant plaque progression, especially in the context of β-2 GLP1 IgA positivity. So, in this subset of patients, strict BP control might be of particular importance.
Now, moreover, what we know based on our study is that if you have β-2 GLP1 IgA antibodies, especially in patients who have some plaque of baseline, which is nonobstructed or not extensive, this may trigger a follow-up interrogation for assessment of progression to expensive or obstructive disease, because that treatments that could be adopted offer that can certainly change outcomes.
Amanda Balbi: What is the overall key take-home message for rheumatologists about your study?
George Karpouzas: So, I think that β-2 GLP1 IgA may be a prognostic biomarker in terms of cardiovascular disease progression and a key moderator of new incident cardiovascular events in patients with rheumatoid arthritis, as it is perhaps in the general population.
Given the accelerated cardiovascular risk of our patients inherently with rheumatoid arthritis, this is a potential biomarker that is further corroborated could actually be in our prognostic biomarkers armamentarium, as we gauge better strategies to risk stratify patients with rheumatoid arthritis.
Amanda Balbi: Absolutely. Thank you again for speaking with me today about your study.
George Karpouzas: Amanda, thank you so very much for the opportunity to communicate to the greater rheumatology community, what the key messages of our findings are.