PHILADELPHIA—Risk of cardiovascular disease is about 50% higher for people with rheumatoid arthritis (RA) than the general population, and is also increased as for those with other autoimmune diseases, such as systemic lupus erythematosus.
Naveed Sattar, MD, professor of metabolic medicine at the University of Glasgow, Scotland, said that the risk for vascular disease in patients with rheumatic disease accrues early. In his presentation at the ACR Clinical Research Conference here at the 2009 ACR/ARHP Annual Scientific Meeting, Dr. Sattar said there are compelling reasons to screen for cardiovascular risk in patients older than age 40 who have rheumatic disease.
“These patients are more likely to die before they get to the hospital if they have a myocardial infarction,” he said. “They are less likely to be symptomatic and are more likely to have ischemic heart disease, receive less treatment for hypertension, and develop more congestive heart failure.” If these patients survive the myocardial infarction and make it to the hospital, they have a 30-day mortality rate of about 50% to 90%, he said.
In an overview of how inflammation leads to cardiovascular disease, Muredach Reilly, MBBCh, assistant professor of medicine and pharmacology in the cardiovascular medicine division at the Hospital of the University of Pennsylvania in Philadelphia, said that changes in signaling via mechanical transduction and hypercholesterolemia induce endothelial cell dysfunction that then promotes inflammation and fatty streak formation.
When there is progression from fatty streaks to late lesions, cells in the lesions produce chemokines, cytokines, and growth factors, eventually resulting in vulnerable plaques that are prone to rupture and thrombotic events.
Assess Cardiovascular Risk
Dr. Sattar said that cardiovascular risk should be regularly assessed in patients with RA and that treatment should be given for existing risk factors, such as increased cholesterol or hypertension. Several factors are believed to be responsible for the increased risk of cardiovascular disease among patients with rheumatoid disease.
Most importantly, systemic inflammation, which can be high in RA, is an independent risk factor for cardiovascular disease that interacts with the more traditional risk factors. Patients with RA and ischemic heart disease share several risk factors, including smoking, obesity, and low physical activity, he said.
Vascular disease also tends to be undertreated in patients with RA because patient inactivity may lead to few symptoms. Several current drug therapies, such as glucocorticoids and nonsteroidal antiinflammatory drugs/coxibs, may contribute to increased risk.
High-grade inflammation affects multiple tissues and leads to endothelial dysfunction, dyslipidemia, more oxidative stress, increased levels of homocysteine, and insulin resistance. These effects accelerate atherogenesis and myocardial microvascular abnormalities, Dr. Sattar said.1
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.
The NCEP (National Cholesterol Education Program) Adult Treatment Panel III criteria for metabolic syndrome include the following, and three of the five must be present for a diagnosis of metabolic syndrome:
- Waist circumference: >40.2 inches in men; >34.6 inches in women
- Triglycerides: >150 mg/dL
- HDL cholesterol: <40 mg/dL in men; <50 mg/dL in women
- Blood pressure: >130/85 mm Hg
- Fasting plasma glucose: >110 mg/dL
Several factors are associated with insulin resistance in patients with RA, according to Dr. Giles, who is assistant professor of medicine in the division of rheumatology at Johns Hopkins University in Baltimore. These factors include macronutrient excess, often accompanied by less physical activity; obesity, whether overt or preferential partitioning; inflammation, with more RA-derived cytokines; and glucocorticoid use.
Other metabolic syndrome criteria also tend to be over-represented in RA: waist girth, hypertension, hypertriglyceridemia, low HDL cholesterol, and hyperglycemia.6
Predictors of insulin resistance in RA include increasing current prednisone use, decreasing HDL cholesterol, and increasing truncal fat mass as measured by a dual-energy X-ray absorptiometry scan. Rheumatoid factor seropositivity and cumulative prednisone dose have been linked with higher visceral fat in patients with RA, he said.
There is “no current evidence that any particular pharmacologic agent decreases cardiovascular risk by reversing insulin resistance in any rheumatic disease,” Dr. Giles said. Instead, primary efforts to reduce insulin resistance should focus on fat reduction, given the central role of visceral fat in insulin resistance.
“Maintaining a healthy body composition should be emphasized even early in disease, along with constant reappraisal of the need to continue glucocorticoids,” he said.
Kathy Holliman is a medical journalist based in New Jersey.
References
- Sattar N, McInnes IB. Vascular comorbidity in rheumatoid arthritis: Potential mechanisms and solution. Curr Opin Rheumatol. 2005;17:286-292.
- Choi HK, Heman M, Seeger J, Robins J, Wolfe F. Methotrexate therapy and mortality in patients with rheumatoid arthritis. Lancet. 2002;359:1173-1177.
- Reiss AB, Carsons SE, Anwar K, et al. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum. 2008;58:3675-3683.
- McCarey DW, McInnes IB, Madhok R, et al. Trial of atorvastatin in rheumatoid arthritis (TARA): Double-blind, randomised placebo-controlled trial. Lancet. 2004;363: 2015-2021.
- McMahon M, Grossman J, FitzGerald J, et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 2006; 54:2541-2549.
- Chung CP, Oeser A, Solus JF, et al. Prevalence of the metabolic syndrome is increased in rheumatoid arthritis and is associated with coronary atherosclerosis. Atherosclerosis. 2008;196:756-763.