OR WAIT null SECS
George Karpouzas, MD, discusses the results of a study he presented at EULAR 2023 examining associations between bDMARD use and cardiovascular risk later in life.
An analysis of data from an international consortium of people with rheumatoid arthritis suggests use of biologic disease-modifying antirheumatic drugs (bDMARDs) could help cardiovascular risk in people with rheumatoid arthritis through their effects on inflammation.
Presented at the European Congress of Rheumatology (EULAR) 2023 annual meeting by George Karpouzas, MD, professor of Medicine at the David Geffen School of Medicine at UCLA and chief of the Division of Rheumatology at Harbor-UCLA Medical Center, results of the study indicate increased disease activity and systemic inflammation at baseline associated with greater risk of major adverse cardiovascular events (MACE) in bDMARD nonusers but not in patients receiving bDMARDs.
With an interest in further understanding the role of chronic inflammation on cardiovascular risk in patients with rheumatoid arthritis, Karpouzas and a team of investigators designed the current study as an analysis of patient data from within the An International Cardiovascular Consortium for people with RA (ATACC-RA). Limiting their study to those with rheumatoid arthritis free from cardiovascular disease upon registration, investigators identified a cohort of 4370 patients for inclusion in their analysis.
The primary outcomes of interest for the analysis were MACE and any ischemic events. For the purpose4 of analysis, MACE was defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death while any ischemic events included MACE, coronary revascularization, stable angina pectoris, transient ischemic attack, and peripheral arterial disease with or without revascularization.
From the 4370-patient cohort, investigators obtained 26,534 patient-years of follow-up data. During this time period, 239 first MACE and 362 total ischemic events were recorded. Upon analysis, results indicated the incidence rates for MACE and any ischemic events were 9.3 (95% Confidence interval [CI], 8.2-10.6) and 14.2 (95% CI, 12.8-15.8) events per 1000 person-years, respectively, for those not using bDMARDs. Among bDMARD users, the corresponding rates were 5.4 (95% CI, 2.9-10.1) and 8.2 (95% CI, 5.0-13.6) events per 1000 person-years, respectively.
Further analysis suggested DAS-28 CRP (adjusted hazards ratio [aHR] 1.19 [95%CI 1.06-1.34]; P = .004) and CRP(ln) (aHR, 1.15 [1.02-1.28]; P = .017)associated with greater risk of MACE among the entire study cohort. When examining associations between inflammation measures and total ischemic events, results pointed to a significant association between DAS-28 CRP and ischemic events [aHR 1.1 (95%CI 1.07 to 1.30)], but not CRP(ln) (aHR 1.06 [95% CI, 0.97-1.16]). Investigators pointed out increased DAS28-CRP and CRP(ln) at baseline were associated with greater risk of MACE among nonusers of bDMARDs, but this association was not observed in bDMARD users.
With an interest in learning more about how the results of this study might help guide care, we sat down with Karpouzas during our on-site coverage of EULAR 2023. That conversation is the subject of the following Q&A.
HCPLive: What was the onus behind this study and was there anything about the results that was unexpected?
Karpouzas: To address your first question, we do know that biologics not only control disease activity but also influence outcomes and comorbidities in patients who are unresponsive to conventional synthetic DMARDs. Additionally, biologics have specific effects on atherosclerotic plaques that may be independent of systemic inflammation. For instance, studies have shown that biologicals are taken up by plaque cells and possess the ability to limit inflammation within the plaque itself. TNF inhibitors, which have been extensively studied, are the predominant type of biologics used. These inhibitors bind to the plaque, preventing the recruitment of inflammatory cells, which is crucial in promoting plaque growth and instability. Moreover, biologics facilitate the migration of harmful cells, such as macrophages, out of the plaque. When these cells are no longer present in the plaque, they cannot cause inflammation or plaque instability as they migrate to the nearby lymph nodes where they pose no harm. By understanding these specific mechanisms of action, and building on the findings of a previous study conducted on a smaller patient group, it was important for us to validate these effects in a larger cohort. It was our aim to demonstrate that even in patients with residual inflammation, biologic treatment effectively mitigates the impact of inflammation. It is worth noting that systemic inflammation, as we measure it, may not accurately reflect the conditions within the plaque environment. Thus, local effects on the plaque take precedence over peripheral measures. This formed the basis for our research. Now, turning to your second question, I wasn't particularly surprised by the results. As I mentioned earlier, we had already observed similar outcomes in a smaller-scale study. Our hope was to confirm these findings in a much larger cohort, which included 4370 patients.
HCPLive: Are there any limitations within this study you would want a clinician to be cognizant of when interpreting the results?
Karpouzas: Firstly, it is important to note a key limitation of this study, which is that we only assessed baseline biologic use. We are examining how baseline biologic use can potentially mitigate events that may occur seven, ten, or even more years later. It is fascinating to see that a predictor at baseline can have such a potent and long-lasting effect. However, in reality, the situation is much more nuanced. The dynamics of inflammation and biologic use over time play a critical role. In our smaller study, for instance, we analyzed time-varying biologic use, which means we assessed the risk of cardiovascular event mitigation at any given time point during biologic use. The findings were interesting but limited, as discontinuing biologics for six months resulted in a loss of the significant protective effect. This essentially aligns with your observation. It suggests that the robustness of biologic use in this study still has an impact over the long term, but what happens in between treatment periods does matter. Unfortunately, we do not have data on the events that occurred during these intervals, and this represents a major limitation of the study.
HCPLive: How important is it to make sure you are having conversations with patients who have rheumatoid arthritis regarding their increased risk of cardiovascular disease?
Karpouzas: It is of utmost importance, and quite disheartening, that studies as recent as 2018 or 2019 have shown that patients at the highest risk level are often completely unaware of their cardiovascular risk. This places a burden on both rheumatologists and primary care clinicians who provide care for these patients. Fortunately, recent studies examining the diagnosis of rheumatoid arthritis over time and specifically assessing cardiovascular risk indicate that this gap is being addressed. These studies demonstrate that there is no significant difference in the incidence of cardiovascular disease between patients with rheumatoid arthritis and those without it. However, as you mentioned, it is crucial to emphasize this point with every patient. In my practice, cardiovascular risk is certainly discussed during the initial visit and reiterated in subsequent visits. According to EU law recommendations, we are supposed to perform cardiovascular risk stratification at least once a year. Depending on whether we change medications or not, we are also encouraged, based on guidelines, to repeat cardiovascular disease assessment. This is because controlling inflammation can have unexpected effects on various parameters. For instance, lipid levels may increase despite inflammation being controlled. If we fail to assess and address these factors, there may be residual risk for these patients.