Suppression of inflammation has been shown to raise high-density lipoprotein (HDL) cholesterol levels, lower levels of lipoprotein(a), and dampen homocysteine, resulting in improved endothelial function. Although more data and clinical trials are needed to understand these mechanisms, there is some evidence suggesting that a tumor necrosis factor blockade can lower cardiovascular risk, even though increased lipid levels can result, Dr. Sattar said.
Methotrexate has been shown to lower the cardiovascular mortality risk by 70%.2 Reiss and colleagues reported that this agent has an atheroprotective effect through its ability to reverse cholesterol transport through activation of adenosine A2a.3
In their report, Reiss and colleagues said that the medication “can increase expression of antiatherogenic reverse cholesterol transport proteins and can counteract the effects of COX-2 inhibition.” This research suggests that the mechanism “by which [methotrexate] protects against cardiovascular disease in rheumatoid arthritis patients is through facilitation of cholesterol outflow from cells of the artery wall,” they note.
Other research has reported on the efficacy of statins in reducing cardiovascular risk in patients with RA. Research by McCarey and colleagues found that statins seem to mediate an antiinflammatory effect, although the effect was modest.4 The randomized, placebo-controlled trial with 116 patients indicated that statin use modified vascular risk factors.
Markers of Inflammation
Another speaker at the conference, Carl Grunfeld, MD, PhD, professor of medicine at the University of California, San Francisco, said that the duration of RA and markers of inflammation are the “best predictors of atherosclerosis and cardiovascular disease.” In RA, the preclinical atherosclerosis measured by carotid intima-medial thickness is increased, he said.
Some of the pro-atherogenic changes in lipoproteins identified in models of inflammation and in infection also occur in RA, Dr. Grunfeld said. These changes include decreased cholesteryl ester transfer protein, small HDL cholesterol, and paraoxonase (PON). Specifically, low PON is predictive of cardiovascular events; RA is known to decrease PON, he said.
Research by McMahon and colleagues showed that proatherogenic HDL cholesterol is increased in patients with systemic lupus erythematosus (SLE) and RA.5 This inflammatory HDL is associated with elevated levels of oxidized low-density lipoprotein (LDL). Their research found that abnormal HDLs “impair the ability to prevent LDL oxidation and may predispose to atherosclerosis.”
“There is no slam-dunk marker,” Dr. Grunfeld said. “There are many steps in atherosclerosis that can be modified, and a wide variety of changes that can promote atherosclerosis.”
Metabolic Risk in RA
The metabolic syndrome and insulin resistance have been linked cross-sectionally to subclinical atherosclerosis in RA and SLE, according to Jon Giles, MD, MPH, another speaker at the conference.
