TORONTO, Canada; PHILADELPHIA, Penn; ANKARA, Turkey—The high rates of coronary artery disease (CAD) and renal damage in patients with systemic lupus erythematosus (SLE) have spurred a search for ways to identify patients who are at particular risk early enough to intervene. Three research groups recently reported potential markers that might help. The investigators found that:

•  Patients whose total cholesterol levels are high in the first blood test after SLE diagnosis are at increased risk for renal deterioration and renal death¹
•  High homocysteine levels might identify patients with SLE who are already developing coronary artery calcifications²
•  Elevated high-sensitivity C-reactive protein (hs-CRP) may be a warning flag for coronary artery disease, even in patients whose lupus is relatively inactive³

High Cholesterol at SLE Diagnosis Signals Kidney Risk in Lupus
Annaliese Tisseverasinghe, Paul R. Fortin, MD, and colleagues at the University of Toronto's Arthritis Centre of Excellence in Toronto, Ontario, have identified a high initial total cholesterol reading in the first available test after SLE diagnosis as a warning of impending kidney damage.¹ These investigators suggest that not only do lupus-related kidney problems disturb lipid profiles, but dyslipidemia in lupus patients accelerates the renal damage.

The increased risk was found in patients with SLE whose first-available total cholesterol levels were higher than 5.2 mmoles/L (about 200 mg/dL). Tisseverasinghe reports that such patients had higher rates of renal deterioration and death associated with renal disease. The investigators also point out that as many as 75% of patients with SLE have at least one serum total cholesterol measurement >5.2 mmoles/L within 3 years after diagnosis.

Tisseverasinghe studied the effects of total cholesterol and 15 other variables on renal deterioration, end-stage renal disease (ESRD), and death in 1060 patients with SLE who were registered in the University of Toronto Lupus Databank. The analysis showed that elevated total serum total cholesterol in the first-available sample obtained at the SLE clinic was associated with adverse renal outcomes and with renal death (but not with nonrenal mortality).

"[I]ndependent of any association with proteinuria or steroid therapy, an elevated total cholesterol level portends a worse renal outcome," Tisserverasinghe writes.

This finding supports a role for nonimmunologic mechanisms in the progression of kidney disease in SLE and may help explain why ESRD develops in a subset of lupus patients despite a decline in extrarenal SLE disease activity and a decrease in the need for lupus medications.

Tisseverasinghe says that more work is needed on hypercholesterolemia over time, time trends in treatment, renal function, and lupus activity to help determine whether the associations between cholesterol levels and renal deterioration and death are indirect or whether persistent hypercholesterolemia "is predictive of adverse renal outcomes and thus could have pathogenic and clinical implications." If so, more aggressive monitoring of total cholesterol levels and interventions to tame them might help lupus patients stave off kidney damage.

Homocysteine Tags Lupus Patients Whose Arteries Should Be Checked

Joan M. Von Feldt, MD, of the University of Pennsylvania in Philadelphia reports that elevated homocysteine levels might identify patients with SLE likely to have premature atherosclerosis and that coronary artery calcification in such patients can be detected early by electron beam computed tomography (EBCT).² She notes that folic acid supplementation might be useful in such patients.

Dr. Von Feldt compared the incidence and extent of coronary artery calcification in female patients with SLE and in age- and race-matched female controls. She found that coronary artery calcification was both more common and more extensive in the patients with SLE, and that those with damaged arteries also had higher homocysteine levels. Mean homocysteine was 14.0 μmoles/L in patients with SLE and coronary artery calcification vs 11.0 μmoles/L in patients with SLE who had healthier arteries (P = .003). Coronary artery calcification also was associated with lower kidney function and longer disease duration.

"This study is the first to identify hyperhomocysteinemia as a statistically significant risk marker for coronary artery calcification, as assessed by EBCT," Dr. von Feldt writes. "... Because folic acid can lower homocysteine concentrations, SLE patients with hyperhomocysteinemia may be able to lower their risk of atherosclerotic cardiovascular disease and consequent excess morbidity and mortality by using vitamin supplements that contain folic acid."

Cardiac Damage Develops Even When Lupus Seems Quiet

Even patients in whom SLE seems quiescent remain at increased risk for cardiovascular disease and future cardiac events, according to Omer Karadag, MD, and associates in the Department of Rheumatology at Hacettepe University Faculty of Medicine in Ankara, Turkey.³

The Turkish researchers studied novel cardiovascular risk factors and cardiac event predictors in 25 female patients with SLE whose SLE disease activity index (SLEDAI) scores were <4, and in 22 healthy control women. "SLE is associated with severe and premature cardiovascular disease, which cannot be explained by traditional risk factors alone," Dr. Karadag points out.

The two groups had no significant differences in family history of premature CAD, blood pressure, body mass index, lipoprotein-A, homocysteine, fibrinogen, serum amyloid A levels, or apoprotein A-1 and B levels. However, the patients with SLE had significantly higher levels of high-sensitivity C-reactive protein (hs-CRP) and lower flow-mediated dilatation (FMD) from the brachial artery, measured at baseline and during reactive hyperemia. Brachial artery FMD is used as a surrogate marker of endothelial function.

"We found that the endothelial function of lupus patients was negatively correlated with hs-CRP levels. Endothelial dysfunction may be due to an ongoing inflammation or subclinical atherosclerosis in those patients. Impaired endothelial function in inactive SLE patients may suggest that those patients have an increased risk of CAD and future cardiac events," Dr. Karadag says.

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References

1. Tisseverasinghe A. Lim S. Greenwood C, et al. Association between serum total cholesterol level and renal outcome in systemic lupus erythematosus. Arthritis Rheum. 2006;54:2211-2219.
2. Von Feldt JM, ScalI LV, Cucchiara AJ, et al. Homocysteine levels and disease duration independently correlate with coronary artery calcification in patients with systemic lupus erythematosus. Arthritis Rheum. 2006;54:2220-2227.
3. Karadag O, Calguneri M. Atlar E, et al. Novel cardiovascular risk factors and cardiac event predictors in female inactive systrmic lupus erythematosus patients. Clin Rheumatol. 2006; [Epub ahead of print]