Brief Report: Proatherogenic Cytokine Microenvironment in the Aortic Adventitia of Patients With Rheumatoid Arthritis

Abstract

ObjectivePatients with rheumatoid arthritis (RA) are at increased risk of developing cardiovascular disease (CVD) via mechanisms that have not yet been defined. Inflammatory pathways, in particular within the vascular adventitia, are implicated in the pathogenesis of primary CVD but could be amplified in RA at the local tissue level. The aim of this study was to examine the aortic adventitia of coronary artery disease (CAD) patients with or without RA to determine the cytokine profile contained therein.MethodsAortic adventitia and internal thoracic artery biopsy specimens obtained from 19 RA patients and 20 non‐RA patients undergoing coronary artery bypass graft surgery were examined by immunohistochemistry.ResultsInterleukin‐18 (IL‐18), IL‐33, and tumor necrosis factor (TNF) were expressed in aortic adventitia biopsy specimens from both groups, and expression of these cytokines was significantly higher in RA patients. In RA patients, IL‐33 expression in endothelial cells correlated positively with the number of swollen joints, suggesting a link between the systemic disease state and the local vascular tissue microlesion.ConclusionThe presence of the proinflammatory cytokines IL‐18, IL‐33, and TNF may play a role in the inflammatory process within the adventitia that contributes to plaque formation and destabilization. In theory, the amplified expression of these cytokines may contribute to the known increased occurrence and severity of CAD in patients with RA.

Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications

“…Aortic adventitia from rheumatoid arthritis patients undergoing coronary artery bypass grafting showed increased TNF-α and IL-18 expression compared with controls, as well as increased IL-33 and IL-33 ligand expression in endothelial cells of the aortic adventitia vasa vasora 31. These findings suggest the existence of a unique pro-inflammatory adventitial microenvironment in rheumatoid arthritis that fosters atherogenesis through linkage of innate and adaptive immune responses, key roles of IL-18 and IL-33.…”

Cardiac Impairment in Rheumatoid Arthritis and Influence of Anti-TNFα Treatment

“…In RA, inflammation and atherosclerosis are closely linked. Inflammation mediates its effects on atherosclerosis both through modulation of traditional risk factors and through direct affecting the vessel wall and contributing to plaque formation [39,40]. This systemic inflammation may result in impaired insulin sensitivity and subsequently enhance the impact of MetS.…”

“…Endothelial and myocardial dysfunction resulting from different effects of proven or potential mediators and effects on cells and tissues in chronic inflammatory disease as RA (direction of small arrows by mediator and effect mean up or downregulation; adapted from Schuett et al[3], Ahmed et al[40], Maijer et al[43]; TNFα tumor necrosis factor alpha, IL-1 interleukin 1, IL-6 interleukin 6, IL-10 interleukin 10, TGFβ transforming growth factor beta, PAI-1 plasminogen activator inhibitor 1)…”

“…Cytokines and biomarkers of endothelial dysfunction and heart failure in rheumatoid arthritis (adapted from Schuett et al[3], Yang et al[29], Ahmed et al[40], Maijer et al[43])…”

Immunopathogenesis of Rheumatoid Arthritis

“…TNF inhibition in patients leads to reduced vascular dysfunction and to improve vascular mortality commensurate with this notion (McKellar et al 2009). Moreover RA atherosclerotic plaques exhibit exaggerated cytokine expression compared to non-RA controls (Ahmed et al 2016). Similarly circulating TNF, RANKL and IL-1 are implicated in systemic osteoporosis (McInnes & Schett 2011), and TNF has been implicated in the hippocampal dysfunction that likely underlies depression in RA (Krishnadas et al 2016).…”