Rheumatoid Arthritis and Cardiovascular Disease

Kimberly P. Liang, MD, assistant professor of medicine in the Division of Rheumatology and Clinical Immunology, has researched numerous aspects of atherosclerotic damage and cardiovascular disease in the presence of rheumatoid arthritis (RA) and vasculitis.

Dr. Liang’s primary interests are in the heterogeneity of rheumatic diseases and their pathological link to the development of atherosclerosis and vascular disease. Her current research focus is investigating the evaluation of risks, determinants, and management strategies of premature cardiovascular disease (CVD) in RA. Dr. Liang’s studies involve the use of a novel, noninvasive vascular study approach that can provide measures of subclinical atherosclerosis and surrogate markers of future CVD events. Dr. Liang also has an interest in developing expertise in novel vascular techniques and applying these technologies to the diagnosis and follow-up of rheumatic disease patients with vascular diseases. Apart from these research interests, she also is actively engaged in multiple clinical trials and observational studies of patients with systemic lupus erythematosus (SLE), vasculitis, and RA.

Dr. Liang has current NIH funding through an R21 grant that is investigating whether sildenafil (Viagra) use in RA patients can improve endothelial dysfunction (as assessed by brachial artery flow-mediated dilation and peripheral arterial tone), as well as improve serum biomarkers of atherosclerosis and inflammation.

Dr. Liang’s recently completed, NIH-funded K23 award investigated whether RA patients were more likely to develop vulnerable, atherosclerotic plaques than non-RA patients. In order to make this determination,

Dr. Liang used a novel microbubble-contrast-enhanced carotid ultrasound (CU) imaging technique. Dr. Liang is currently analyzing all of the data from the K23 studies for future publication and has presented some of the findings at the last several Annual Scientific Meetings of the American College of Rheumatology.

Cardiovascular Disease and RA: Risks and Likely Mechanisms

Regarding relative risk, patients with RA are approximately twice as likely as non-RA patients to develop cardiovascular disease during their lifetime.

“There is a general understanding that systemic inflammation is important to the rise of CVD, and the systemic inflammation seen in RA is likely contributing to or magnifying any existing inflammation in the body. The presence of antinuclear antibodies (ANA) and rheumatoid factor also are associated with CVD. Presumably, immune dysfunction — the autoimmunity itself — likely is a contributing factor. For sure, there are many factors in individuals with RA that increase their CVD risk,” says Dr. Liang.

RA and CVD: Clinical Trials to Test Primary CVD Prevention Strategies Using Novel Agents

Because the increased risk of CVD in RA patients appears not to be wholly explained by traditional CVD risk factors such as diet, obesity, exercise, and genetics, the auto-immunity and systemic inflammatory response may be causative to some degree. Specifically, inflammation mediates premature endothelial dysfunction, which is one of the early stages of atherosclerosis and is strongly associated with a risk of future CVD events.

Managing or mitigating endothelial dysfunction, then, may decrease the CVD risk in RA. Dr. Liang’s R21 grant is designed to test this exact scenario using the medication sildenafil, which functions as a PDE5 inhibitor as well as supporting endothelial function.

“This is a crossover trial that we suspect will shed light on whether sildenafil can prevent endothelial dysfunction in the presence of RA. We have designed a six-month trial in which participants are randomized into either a three-month, 50 mg per day cohort or a placebo group. This is followed by a two-week washout phase, at which point the cohorts will crossover and receive the opposite therapy for an additional three months,” says Dr. Liang.

Dr. Liang’s study has two specific aims. The first is to determine whether sildenafil has beneficial effects on endothelial function in patients with RA. The study also seeks to determine whether sildenafil use improves biomarker levels of atherosclerosis and inflammation during treatment. Further, if successful, this trial will provide the necessary evidence for expansion into larger trials exploring the use of sildenafil as a CVD preventive measure in other rheumatic diseases that also are characterized by high CVD risk, such as systemic lupus erythematosus.

K23 Award: Identifying Vulnerable Plaque in Rheumatoid Arthritis

Dr. Liang received K23 funding in 2011 to study the use of microbubble-contrast-enhanced-carotid ultrasound (CU) in rheumatoid arthritis in relation to atherosclerotic plaque vulnerability. Dr. Liang concluded these studies in 2017 and is currently in the process of data analysis and manuscript preparations to publish the findings.

Dr. Liang’s K23 grant had three specific aims:

1. Determine whether patients with RA have an increased density of carotid artery adventitial vasa vasorum compared to control patients without RA, after controlling for traditional CV risk factors. Hypothesis: The density of carotid artery adventitial vasa vasorum as assessed by CU will be higher in RA patients than controls after adjusting for traditional CV risk factors.

2. Determine whether both traditional CV risk factors and inflammatory modulators of plaque vulnerability are associated with increased density of carotid artery adventitial vasa vasorum, as assessed by CU, in RA patients. Hypothesis: Traditional CV risk factors and inflammatory modulators of plaque vulnerability are associated with increased density of carotid artery adventitial vasa vasorum in RA patients.

3. Determine whether increased disease activity measures in RA are associated with increased density of carotid artery adventitial vasa vasorum, as assessed by CU. Hypothesis: Increased density of carotid artery adventitial vasa vasorum is associated with increased RA disease activity measures, even after controlling for traditional CV risk factors.

“Our study was designed to determine whether patients with RA have an increased density of carotid artery adventitial vasa vasorum compared to non-RA controls. We also sought to determine whether both traditional CV risk factors and inflammatory or RA-related modulators of plaque vulnerability were associated with increased density of carotid artery adventitial vasa vasorum as seen using microbubble-contrast-enhanced carotid ultrasound imaging. Finally, we wanted to know whether an increase in disease activity measures in RA was associated with an increased density of the carotid artery adventitial vasa vasorum,” says Dr. Liang.

Preliminary results from the study found that the adventitial vasa vasorum density was higher in the RA group than the controls.

“These findings are in line with our hypothesis that rheumatoid arthritis patients develop these early findings of subclinical vulnerable plaque in their carotid arteries more so than non-RA patients. I am looking forward to publishing our findings in full in the coming months, and I recently presented aspects of this research during the 2018 American College of Rheumatology Annual Meeting.”

Large Vessel Vasculitis Pilot Study

Dr. Liang currently has a pilot study in progress (funded by the Vasculitis Foundation) that uses microbubble-contrast-enhanced carotid ultrasound as a way of differentiating between disease activity and damage in cases of active and inactive giant cell arteritis or Takayasu arteritis.

“This study will allow us to compare the densities of the adventitial vasa vasorum in cases of active or inactive vasculitis, using microbubble contrast-enhanced carotid ultrasound. Because it appears that in large vessel vasculitis the earliest signs of inflam-mation and disease activity present in the adventitial vasa vasorum (i.e., vasa vasoritis), you would expect to see an increased density indicative of active disease. By making comparisons between control groups, it may turn out that this type of noninvasive diagnostic test can be helpful in monitoring disease activity, thereby allowing clinicians a better opportunity to intervene and manage possible disease flares in these patients over time,” says Dr. Liang.

References

Does Sildenafil Improve Endothelial Dysfunction in Rheumatoid Arthritis? NIH Project Number: 5R21AR069174-02. ClinicalTrials.gov Identifier: NCT02908490. Principal Investigator: Kimberly Liang, MD. Status: Currently recruiting participants.