MANCHESTER, UK—Patients with rheumatoid arthritis (RA) have increased cardiovascular (CV) morbidity and mortality that cannot be explained by traditional CV risk factors alone. Chronic inflammation associated with RA might accelerate atherosclerosis, and TNF inhibitors might reduce CV risk both by cooling chronic inflammation and by direct effects on other factors associated with CV disease (CVD). Drs. William G. Dixon and Deborah P. M. Symmons review the role of TNFα in CV disease in Annals of the Rheumatic Diseases.1 They suggest that one pay careful attention to the data accumulating on CV outcomes in RA patients treated with TNF inhibitors.

"There is a strong body of evidence to support a theoretical role of anti-TNFα therapy in reducing the cardiovascular burden associated with RA. Research into this area needs to be targeted towards pathways and endpoints to which TNFα is integral." —William G. Dixon, MD.
"There is a strong body of evidence to support a theoretical role of anti-TNFα therapy in reducing the cardiovascular burden associated with RA. Research into this area needs to be targeted towards pathways and endpoints to which TNFα is integral," writes Dr. Dixon, of the epidemiology unit at the University of Manchester, in the UK.

TNF plays many roles in cardiovascular disease

The authors review many ways TNFα contributes to the pathophysiology of CVD. These include:
● Impeding insulin-mediated glucose uptake in skeletal muscle and increasing circulating free fatty acids
● Increasing endothelial cell dysfunction
● Increasing collagen breakdown in the fibrous cap of atherosclerotic plaques, and increasing the risk of plaque rupture
● Promoting a prothrombotic state by upregulating proteins involved in hemostasis
● "Priming" the cerebral vascular system to be sensitive to brain ischemia (the Schwartzman reaction)
● Both promoting and impeding repair after myocardial infarction (MI) or stroke

"Given this body of evidence linking inflammation, and specifically TNFα, to the initiation and progression of CVD, one might expect anti-TNFα therapy to reduce the burden of CVD in patients with RA. ... It may potentially improve lipid profiles, reduce insulin resistance, prevent fatty streak formation, stabilize plaques, reduce thrombus formation, and/or improve recovery. However, the complexities of cytokine pathways and interactions often mean that what initially seems biologically plausible may not ultimately occur," the authors write.

Current Evidence that TNF Inhibitors Change CVD Burden in RA

Actual evidence that TNF inhibitors relieve the burden of CVD in patients with RA is thin on the ground, however. The authors cite small studies showing that infliximab improves insulin resistance in the most resistant tertile of patients with RA or ankylosing spondylitis, and that infliximab improves endothelial function in patients with RA. They also point out that 3 years of TNF inhibitor treatment did not reduce the progression of subclinical atherosclerosis in eight RA patients, but note that to show such improvement, studies should look at RA patients with no signs of atherosclerosis at baseline (to study initiation of atherosclerosis) and at patients who already have evidence of unstable plaques (to study plaque stabilization).

Patients with congestive heart failure (CHF) typically have raised levels of TNFα, but a trial of etanercept in severe CHF was stopped early because interim analysis showed general lack of efficacy along with worse outcomes in patients with moderate-to-severe CHF treated with the TNF inhibitor. "As a consequence, severe heart failure is a contraindication to anti-TNFα therapy in patients with RA," Dr. Dixon writes.

TNF inhibitor trials in RA have not focused on CV events and/or have not been large enough to detect small changes in such events. Observation studies have suggested the TNF inhibitors might reduce the risk of a first CV event, but have not been able to segment CV events into those that might be influenced by TNFα and those not likely to involve the cytokine. Dr. Dixon notes that the studies that have looked at MI rates in patients with RA treated with biologic therapy have also not been able to adjust for some important confounders such as disease severity.

"As follow-up time accrues for patients followed by the national registries, we are likely to better understand the effect that anti-TNF therapy has on both cardiovascular morbidity and mortality," the authors conclude.

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Reference

1. Dixon WG, Symmons DPM. What effects might anti-TNFα therapy be expected to have on cardiovascular morbidity and mortality in rheumatoid arthritis? A review of the role of TNFα in cardiovascular pathophysiology. Ann Rheum Dis. 2007; doi:10.1136/ard.2006.063867. [Epub ahead of print].