High-Density Lipoprotein Prevents Oxidation and Inflammation

There are many mechanisms designed to clear OxLDL from the subendothelial space, such as macrophage engulfment using scavenger receptors, and enhanced reverse cholesterol transport mediated by high-density lipoprotein (HDL). Both HDL and its major apolipoprotein constituent, apolipoprotein A-1 (apoA-1), have also been shown to prevent and reverse LDL oxidation and ECA. Thus, HDL function could be of equal or even greater importance to HDL quantity in preventing ATH. However, during the acute phase response, such as in the postsurgical period or during influenza infection, HDL can be converted from the usual antiinflammatory state to proinflammatory HDL (piHDL). Thus, HDL can be described as a chameleonlike lipoprotein: antiinflammatory in the basal state and proinflammatory during the acute phase response. This acute phase response, however, can also become chronic and may be a mechanism for HDL dysfunction in SLE.

High-Density Lipoprotein Prevents Oxidation and Inflammation

There are many mechanisms designed to clear OxLDL from the subendothelial space, such as macrophage engulfment using scavenger receptors, and enhanced reverse cholesterol transport mediated by high-density lipoprotein (HDL). Both HDL and its major apolipoprotein constituent, apolipoprotein A-1 (apoA-1), have also been shown to prevent and reverse LDL oxidation and ECA. Thus, HDL function could be of equal or even greater importance to HDL quantity in preventing ATH. However, during the acute phase response, such as in the postsurgical period or during influenza infection, HDL can be converted from the usual antiinflammatory state to proinflammatory HDL (piHDL). Thus, HDL can be described as a chameleonlike lipoprotein: antiinflammatory in the basal state and proinflammatory during the acute phase response. This acute phase response, however, can also become chronic and may be a mechanism for HDL dysfunction in SLE.

Traditional and SLE-Specific Risk Factors for ATH in SLE

Before therapeutic strategies to prevent CV complications in patients with SLE can be implemented, it is critical to identify at-risk patients. Traditional Framingham cardiac risk factors are likely to increase risk in patients with lupus in a similar manner to the general population. Indeed, traditional risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, old age, tobacco use, and postmenopausal status have all been associated with atherosclerotic disease in SLE. Petri and colleagues found that 53% of patients with SLE from the Hopkins Lupus Cohort had at least 3 traditional cardiac risk factors. Some traditional risk factors may also interact with the management of SLE disease activity; for example, smoking decreases responsiveness to antimalarial therapy. Some risks such as diabetes and hyperlipidemia may also be increased as secondary effects of glucocorticoid therapy, whereas others may be directly influenced by SLE disease activity. For instance, high levels of very-low-density lipoprotein and triglycerides and low levels of HDL have been described as the lupus pattern and are more strikingly noted in patients with active disease.

Although traditional cardiac risk factors clearly play a role in the pathogenesis of ATH in SLE, they do not fully explain the increased risk. For example, after controlling for gender, blood pressure, diabetes, cholesterol, smoking, and left ventricular hypertrophy in a Canadian cohort, Esdaile and colleagues found that the relative risk attributed to SLE for MI and stroke were 10.1 and 7.9, respectively. In a separate cohort, Chung and colleagues found that 99% of patients with SLE were identified as low risk using the Framingham risk calculator, with a 10-year risk estimate of less than 1%; however, 19% of patients with SLE in the cohort had coronary calcium on electron beam computed tomography (EBCT). Similarly, in an SLE cohort from Toronto, the mean Framingham 10-year risk of a cardiac event did not differ between 250 patients with SLE and 250 controls. This study did reveal, however, a higher prevalence of nontraditional cardiac risk factors in patients with SLE, including premature menopause, sedentary lifestyle, and increased waist-to-hip ratio. Thus, although patients with SLE are subject to the same traditional risk factors as the general population, these factors do not adequately account for the significantly increased level of CVD.

SLE-Specific Risk Factors

Antiphospholipid Antibodies

Although antiphospholipid antibodies (aPL) cause venous and arterial clotting and have been associated with MIs in the general population, the association with ATH in patients with SLE has been inconsistent. In the LUMINA (Lupus in Minorities: Nature vs Nurture) cohort study, aPL were an independent risk factor for CV or cerebrovascular events. In the Hopkins Lupus cohort, lupus anticoagulant was the only antiphospholipid associated with MI. More recently, however, there was no association of aPL with events in an inception cohort of 1249 patients with SLE. Several studies using measures of subclinical ATH have not found any significant associations with aPL after adjustment for confounding factors.

C-Reactive Protein

C-reactive protein (CRP) is a well-established predictor of CV events in the general population, especially in combination with hypercholesterolemia. It is thought that CRP is not solely a marker of systemic inflammation, but rather may play a direct role in the pathogenesis of ATH. For example, CRP has been shown in vitro to activate complement and stimulate endothelial cells to express adhesion molecules and MCP-1. In subjects with SLE, however, the role of CRP as a predictor of ATH is less clear. Elevated CRP levels have been associated with CV events in the LUMINA cohort, and high-sensitivity CRP (hs-CRP) levels were associated with CV mortality in a prospective Swedish lupus cohort. hs-CRP has also been associated with both cross-sectional and longitudinal progression of carotid IMT. Several other studies, however, did not find an association between ATH and CRP in SLE.

Proinflammatory HDL

As noted above, antiinflammatory HDL function is as important as quantity in the prevention of ATH. During states of chronic inflammation, such as in patients with SLE, HDL can be converted from the usual antiinflammatory state to the proinflammatory form and can actually increase oxidation of LDL and inflammation. The author’s group has found that HDL function is abnormal in many women with SLE; 45% of women with SLE, compared with 20% of patients with rheumatoid arthritis and 4% of controls, had piHDL that was unable to prevent oxidation of LDL. HDL dysfunction has also been described in primary antiphospholipid syndrome, because HDL isolated from patients with antiphospholipid syndrome had blunted beneficial effects on VCAM-1 expression, superoxide production, and monocyte adhesion after activation of human aortic endothelial cells. Subsequent studies in the authors’ longitudinal cohort of 300 patients with SLE and 168 controls have demonstrated that piHDL is strongly associated both with cross-sectional and longitudinal progression of carotid plaque and IMT.

Paraoxonase

Serum paraoxonase 1 (PON1) is a serum esterase that is secreted primarily by the liver and is associated with HDL in plasma. PON1 has been identified as one of the important components of HDL that prevents lipid peroxidation and blocks the proinflammatory effects of mildly OxLDL. Decreased levels of PON activity have also been associated with ATH in the general population. Altered levels of PON activity have also been seen in patients with SLE. In one study, PON activity was reduced in patients with SLE and antiphospholipid syndrome compared with controls, although there was no reduction in the total antioxidant capacity of the plasma. In another study of 55 patients with SLE, titers of anti-apoA-1 antibodies were inversely correlated to PON1 activity, and in vitro studies confirmed that apoA-1 antibodies have a direct inhibitory effect on PON activity. Decreased PON activity has been associated with increased carotid artery IMT and abnormal-flow-mediated dilation in patients with primary antiphospholipid antibody syndrome and was also associated with atherosclerotic events in a small cross-sectional study of 37 patients with SLE.

Adipocytokines

The adipokine leptin is an anorectic peptide that acts on the hypothalamus to modulate food intake, body weight, and fat stores. Obese people have high circulating leptin levels, but they develop leptin resistance similar to insulin resistance in type II diabetes. Hyperleptinemia in the general population associates with hypertension, metabolic syndrome, oxidative stress, and ATH. Conversely, adiponectin levels are inversely correlated with adipose tissue mass and are reduced in type II diabetes and CVD.

Several small cohort studies have shown elevated leptin levels in adult and pediatric patients with SLE. In the authors’ cohort, leptin levels were significantly higher in patients with SLE with carotid plaque than in those without plaque and also weakly correlated with carotid IMT in both a cross-sectional and a prospective longitudinal study even after accounting for confounding factors such as age, hypertension, and diabetes. In another cohort, adiponectin levels were significantly and independently associated with carotid plaque in SLE. However, Chung and colleagues found no significant relationship between leptin or adiponectin levels and coronary calcification in SLE.

Homocysteine

Homocysteine is another predictor of ATH in the general population. Homocysteine may play a direct role in the pathogenesis of SLE through its toxic effects on the endothelium. Homocysteine also increases free oxygen radicals, stimulates monocytes to secrete MCP-1 and IL-8, enhances foam cell formation in vessel walls, and is prothrombotic. Hyperhomocysteinemia can result from increased age, renal insufficiency, medications such as methotrexate, as well as genetic and/or dietary factors.

In one cohort study of 337 patients with SLE, hyperhomocysteinemia was an independent predictor of stroke and CV events. In several other studies, elevated levels of homocysteine in SLE correlated with cross-sectional and longitudinal progression of subclinical ATH in SLE. In other recent studies of SLE, however, homocysteine levels did not correlate with ATH.

Biomarker Panels

Through the longitudinal cohort study of CVD in SLE at University of California Los Angeles, the authors have identified several potential biomarkers for the progression of subclinical ATH. These biomarkers include piHDL, leptin levels greater than or equal to 34 ng/mL, soluble TNF-like weak inducer of apoptosis levels greater than 373 pg/mL, homocysteine levels greater than or equal to 12 mmol/L, age greater than or equal to 48 years, and history of diabetes. Although each identified variable was predictive for the longitudinal development of carotid plaque in multivariate analysis, no individual variable reflected a balanced risk profile with strong positive predictive value (PPV) and negative predictive value (NPV), specificity (Sp), and sensitivity (Sn). For example, presence of diabetes had 98% Sp for the presence of plaque in the authors’ cohort; however, Sn was only 13%.

The authors next hypothesized that a panel of predictors may give a more complete assessment of atherosclerotic risk than any one individual predictor. Using this theory, they created a risk variable, PREDICTS (Predictors of Risk for Elevated Flares, Damage Progression and Increased Cardiovascular Disease in SLE), with low risk defined as the baseline presence of 0 to 2 predictors and high risk as 3 or more predictors or diabetes plus more than 1 predictor. In multivariate analysis controlling for other CV risk factors and disease factors, patients with high baseline PREDICTS risk had a 27.7-fold increased odds ratio (OR) for any carotid plaque at baseline or follow-up ( P <.001), a 15.5-fold increased OR for new plaque progression, and 8.0-fold increased OR for IMT progression ( P <.001). The high PREDICTS variable had an NPV for plaque presence of 94%, a PPV of 64%, Sp of 79%, and Sn of 89%, giving this combination variable better overall predictive value compared with any individual marker. This panel needs to be refined and validated in other SLE cohorts, but it does highlight the concept that a combination of risk factors may more accurately capture the processes that lead to the development of ATH than any individual marker.

Minimizing Framingham Risk Factors

In the future, it is likely that novel SLE-specific risk prediction panels will be developed and validated for identification of high-risk patients who should be targeted with therapeutic interventions to prevent CV complications. At present, expert panels in both the United States and Europe recommend that patients with SLE should be annually screened for traditional modifiable risk factors for CVD, including smoking status, blood pressure, body mass index, diabetes, and serum lipids ; however, no randomized clinical trials for the prevention of ATH in SLE exist to guide clinicians once high-risk patients are identified. Our current screening and treatment strategies are extrapolated from the best available evidence for the general population, with some modifications for consideration of lupus-specific issues.

Hypertension: Antihypertensives

Because of the high relative risk for CV morbidity and mortality in SLE, it has been suggested that SLE should be considered a cardiac risk equivalent similar to diabetes. Therefore, patients with SLE should be treated to the target blood pressure levels of 130/80, as recommended by the Joint National Committee (JNC 7) for those with other high-risk comorbid conditions. No optimum SLE-specific antihypertensive medication regimen has been established ; however, angiotensin-converting enzyme (ACE) inhibitors are generally the drugs of choice in patients with renal disease and are recommended as first-line therapy in patients with rheumatic disease by the European League Against Rheumatism (EULAR) guidelines because of their potential favorable effects on inflammatory markers and endothelial function. In addition, in one cross-sectional study, carotid ATH was associated with ACE inhibitor nonuse. Angiotensin receptor blockers can also be considered in patients who cannot tolerate ACE inhibitor therapy. Thiazide diuretics are recommended as first-line therapy for hypertension in the general population by JNC 7 and would generally also be a safe choice in subjects with SLE. Calcium channel blockers may be useful in patients with coexisting Raynaud phenomenon or pulmonary hypertension but have been associated in several cases with the development of subacute cutaneous lupus. β-Blockers have been shown to precipitate Raynaud phenomenon and thus should be used with caution in subjects with SLE.

Dyslipidemia: Statin Use

Statins are widely used in the general population to reduce CV morbidity. In addition to their lipid lowering properties, statins have a variety of direct antiinflammatory and immunomodulatory effects, including the diminished secretion of proinflammatory cytokines and chemokines. Statins also inhibit adhesion molecules, reactive oxygen species formation, T-cell activation, and the upregulation of nitric oxide synthesis. In an in vivo study of statins in a mouse model of SLE and ATH, the gld .apoE ^−/− mouse, simvastatin therapy decreased atherosclerotic lesion area and reduced lymphadenopathy, renal disease, and proinflammatory cytokine production, even though it did not alter cholesterol levels.

Although there is an abundance of data to support the use of statins in primary and secondary prevention of ATH in the general population, the data in patients with lupus have been much less consistent. In a recent small study of 21 patients with SLE, statin use improved disease activity measured by SLAM-R scores at 6 months but did not result in any changes in levels of potential cardiac biomarkers such as TNF-α, vascular endothelial growth factor, IL-6, or soluble CD40 ligand (sCD40L). In another small study of 60 patients with SLE, atorvastatin, 40 mg daily, resulted in decreased lipid and CRP levels and slowed progression of coronary calcium but demonstrated no change in myocardial perfusion defects compared with placebo. In a trial of 33 patients with lupus postrenal transplant, those randomized to fluvastatin therapy had a 73% reduction in cardiac events, although this difference did not quite reach statistical significance ( P = .06). Atorvastatin, 20 mg daily for 8 weeks, improved endothelium-dependent vasodilation in 64 women with SLE, even after accounting for the presence of traditional cardiac risk factors. In the largest trials conducted, however, the results were less promising. For example, in a 2-year randomized controlled trial of atorvastatin, 40 mg daily, in 200 women with SLE, statins did not significantly prevent progression of coronary calcium, IMT or disease activity. Similarly, a randomized controlled trial of atorvastatin conducted in 221 pediatric patients with SLE, the APPLE (Atherosclerosis Prevention in Pediatric Lupus Erythematosus) trial, also demonstrated improvements in lipid levels and hs-CRP levels but showed no significant impact on IMT progression. Many trials that have demonstrated a preventive effect of statins in the general population have larger sample sizes and a longer follow-up duration, so it is possible that increased sample sizes and study lengths might have resulted in positive studies. A secondary analysis of the APPLE trial did indicate that in pubertal patients with SLE with high baseline hs-CRP levels, atorvastatin did decrease IMT progression. This fact suggests that identification of high-risk patients for inclusion in clinical trials may increase the likelihood that beneficial therapeutics will have positive trial results. Further investigations are needed to clarify the role that statins could play in the prevention of ATH in rheumatic disease populations. Until further studies are conducted to determine the safety and efficacy of statin therapy in a broader population of patients with SLE, statin therapy should be limited to published guidelines such as the National Cholesterol Education Panel.