Role of Inflammation in Atherosclerosis Associated with Rheumatoid Arthritis

https://doi.org/10.1016/j.amjmed.2008.06.014Get rights and content

Abstract

Rheumatoid arthritis (RA) is associated with excess morbidity and mortality from myocardial infarction and allied disorders. A large body of evidence supports the involvement of common proinflammatory cytokines in the development and progression of both RA and atherosclerosis. The destructive proinflammatory cascade and effector mechanisms implicated in RA resemble the chronic inflammatory processes that drive the development of atherosclerosis in general. Proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor-α produced within locally affected joints in RA may promote both traditional (e.g., dyslipidemia, insulin resistance) and nontraditional (e.g., oxidative stress) systemic cardiovascular risk factors. Expression of proinflammatory cytokines and inflammatory mediators influences all stages of atherosclerosis development, from early atheroma formation to thrombus development responsible for events such as myocardial infarction. Appreciation of the inflammatory process shared by RA and atherosclerosis should heighten the recognition of this morbid association and lead to better recognition and management of cardiovascular risk in patients with rheumatologic diseases.

Section snippets

Inflammatory mediators in rheumatoid arthritis and atherosclerosis

Although several factors contribute independently to the heightened cardiovascular risk observed in patients with RA, systemic inflammation likely contributes importantly. The cascade of events leading to atherosclerosis also participates in the pathogenesis of RA. Indeed, atherosclerosis and RA share a number of similarities, including T-cell and mast cell activation, production of proinflammatory cytokines such as tumor necrosis factor (TNF)–α and interleukin (IL)-6, and heightened expression

Endothelial dysfunction

Atherosclerotic plaques contain a variety of inflammatory and immune cells (mostly T cells and macrophages), smooth muscle cells, neovascular channels, an extracellular matrix rich in collagen and elastin, and a lipid-rich core underlying a usually intact but functionally abnormal endothelial lining in contact with the blood compartment.27, 32 Endothelial cell activation contributes early on to atherosclerosis development. Endothelial cells form the innermost surface of the artery wall and,

Plaque progression

Following the vascular wall infiltration of monocytes in early atherogenesis, monocytes develop into macrophages, and then into lipid-laden foam cells. Local expression of proinflammatory mediators such as M-CSF can amplify lesion formation and progression by promoting maturation, activation, and proliferation of mononuclear phagocytes in the intima.15, 47, 48ApoE-null mice deficient in M-CSF have considerably smaller atherosclerotic lesions and fewer advanced lesions than apoE−/− mice wild

Formation of an advanced lesion (fibrous plaque)

The evolution from fatty streak into a more complex lesion usually occurs over many years, a factor that underlies the potency of age as a risk factor for atherosclerotic events. The traditional view of this process involved evolution of fatty streaks into complicated lesions through multiplication and accumulation of smooth muscle cells in the plaque, producing an extensive extracellular matrix (Figure 2, Figure 3).27 According to current thinking, many coronary arterial lesions develop

Thrombotic complications of atheroma

Inflammation promotes not only the initiation and progression of the atherosclerotic lesion, but also the development of the complicated or disrupted lesion. As previously discussed, the concept of continuous growth of the atheroma has evolved into one of apparent bursts in atheroma growth, followed by physical disruption of the plaque (weakening of the fibrous cap that renders the plaque prone to rupture), which triggers thrombosis. Healing of disrupted plaques may lead to episodes of rapid

Summary

A large body of evidence supports the involvement of proinflammatory cytokines in the development and progression of atherosclerosis, processes that overlap considerably with the pathogenic processes seen in RA. Now considered an inflammatory disease, atherosclerosis involves the production of proinflammatory cytokines by immune cells, such as monocytes, macrophages, and T cells, at sites of atherosclerotic lesions as well as by intrinsic vascular, endothelial, and smooth muscle cells.15, 82

Author disclosures

The author of this article has disclosed the following industry relationships:

Peter Libby, MD, served on the Scientific Advisory Board of Interleukin Genetics.

Acknowledgment

I thank Rick Davis, MS, RPh, and Ms. Joan Perry for editorial assistance.

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  • Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

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