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Atherosclerosis in Systemic Lupus Erythematosus

Course Authors

Ji Lee, M.D., Bernard Hojaili, M.D., Elena Peeva, M.D., and Peter Barland, M.D.

Dr. Peeva is Assistant Professor, Albert Einstein College of Medicine, and Dr. Hojaili is a member of the Department of Medicine, Jacobi Hospital in the Bronx, and the Rheumatology Division of the Albert Einstein College of Medicine. Dr. Lee is a resident at UMDJ-University Hospital, Newark, NJ.

The authors report no commercial conflicts of interest.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 
Learning Objectives

Upon completion of this Cyberounds®, you should be able to:

  • Describe the inflammatory nature of atherosclerosis and implications of chronic inflammation in the development of premature atherosclerosis in SLE

  • Describe mechanisms involved in accelerated atherogenesis in lupus, as well as therapy-related factors that may contribute to development of premature atherosclerosis in SLE

  • Discuss preventive measures that may help reduce the risks of premature atherosclerosis in patients with SLE.

 

Atherosclerosis, a process defined as a deposition of atheromatous plaques containing cholesterol and lipids on the innermost layer of the walls of large and medium-sized arteries, occurs in response to injury to the arterial wall. Atherosclerosis is characterized by a migration of smooth muscle cells into the intima of the vessels and accumulation of lipids, which are then taken up by macrophages. The lipid-laden macrophages called "foam cells" proliferate and lead to the formation of plaque. If the plaque ruptures, a cascade of events ultimately provokes intravascular thrombosis.

Although there is a strong association between atherosclerosis and blood cholesterol level, other factors, mainly pro-inflammatory, are also implicated in the initiation of the vascular lesion and the overall damage caused by atherosclerosis. Shear stress, toxins or immune complexes may lead to endothelial injury. Subsequent to the injury, adhesion molecules such as ICAM-1, VCAM-1, P-selectin and E-selectin are expressed on the surface of the endothelial cells. These molecules facilitate the binding of monocytes and T-cells to the endothelium.

Proinflammatory cytokines like IL-1 and TNF-alpha stimulate the monocytes and T-cells to enter into the intima and cause inflammation. The monocytes differentiate into macrophages with scavenger receptors that facilitate the uptake of oxidized low-density lipoprotein (oxLDL). With proliferation of macrophages and smooth muscle cells, along with the accumulation of lipids, a fibrous plaque is formed. Macrophages produce collagenases which weaken the extracellular matrix and make it prone to rupture. With rupture of the plaque, the intimal macrophages produce procoagulant tissue factor which promotes the recruitment of platelets and initiation of thrombogenesis.(1)

Atherosclerosis and SLE

Based on the knowledge accumulated over the past decade and summarized above, atherosclerosis is considered an inflammatory disease that is enhanced under certain conditions, such as hypercholesterolemia or hypertension. Therefore, it is not surprising that premature atherosclerosis is common in autoimmune diseases including SLE.

Atherosclerosis is a major cause of morbidity and mortality in SLE with cardiovascular disease being the third most important cause of death in SLE patients after infectious and renal diseases. Over the past two decades, improvements in antibiotic and immunosuppressive therapy have reduced the incidence of infections and renal disease in SLE by 25%, whereas atheroma-related manifestions have increased to 24%. Female lupus patients 35-40 year-old are 50 times more likely to have an MI than women of similar age without SLE.(2) Also, 18-44 year-old SLE patients are twice as likely to be hospitalized with an acute myocardial infarction compared to women without lupus.(3) An electron beam computed tomography (ECT) study demonstrated that the rate of coronary artery calcifications increased more than 3-fold in the SLE group compared to an age, sex and race matched control group.(4) Finally, ultrasound studies of carotid artery and femoral arteries described a 3-fold increase in the rate of atherosclerotic plaques in SLE patients, and these plaques closely correlate with the presence of coronary atheromas.(5)

Because of the significantly higher rate of atherosclerosis in premenopausal SLE patients compared to the general population, numerous studies have investigated the mechanisms of accelerated atherogenesis in lupus. Potential mechanisms include chronic inflammation and an excess of traditional risk factors such as hypertension, hyperlipidemia, smoking, obesity and sedentary lifestyle.(2) Although classic Framingham risk factors definitely promote premature atherosclerotic process in lupus patients, SLE itself was found to be the strongest independent factor for cardiovascular disease. The risk for myocardial infarction was increased 8.3 times after controlling for Framingham risk factors.(6) Also, proteinuria, impaired renal function, low complement 3 levels and cumulative steroid dose above 30 g were all associated with coronary artery calcification in lupus.(7)

Renal involvement, observed in up to 60-70% of SLE patients, seems to be an important risk factor for accelerated atherosclerosis in lupus. The reasons may be multifold. For example, immune complexes commonly seen in patients with lupus nephritis have a predilection to accumulate in perivascular sites where they elicit inflammation characterized by plasma leakage and recruitment of polymorphonuclear leukocytes. The leucocytes then release mediators, which cause the development of vessel wall lesions and subsequent activation of the coagulation system.(9) In addition, when lupus nephritis progresses to the nephrotic syndrome, it leads to hyperlipidemia, a traditional risk factor for atherosclerosis.

Not only SLE itself, but also some of the medications used to treat lupus, contribute to the development of premature atherosclerosis. Prolonged steroid treatment, for example, induces an atherogenic lipid profile characterized by increased VLDL, triglycerides and LDL, and decreased HDL. These lipid disturbances, along with steroid-induced hypertension and hyperglycemia, are all factors for early atherosclerosis. Chronic corticosteroid use has been associated with increased risk of both myocardial infarction and carotid atherosclerosis - 1.7 relative risk for symptomatic coronary artery disease and 1.2 for stroke.(8)

On the molecular level, several specific mechanisms involved in accelerated atherosclerosis in SLE have been described. Immune complexes that bind C1q endothelial receptors, thereby up-regulating the adhesion molecules on the surface of endothelial cells, are one of the proposed factors. The CD40-CD40 Ligand costimulatory pathway for T lymphocyte activation also appears to be up-regulated in SLE. This pathway seems to promote atherogenesis by enhancing expression of endothelial adhesion molecules and the intercellular adhesion molecule-1. The enhanced expression of adhesion molecules results in the accumulation of inflammatory cells in blood vessel walls. The CD-40-CD-40 Ligand pathway also promotes macrophage production of IL-1, thereby amplifying inflammation.(10)

In SLE patients, antibodies to lipoproteins ApoA, ApoB and ApoH have been described. Such antibodies interfere with lipid metabolism and thereby promote atherogenesis.(11) Recent studies have also shown that anti-endothelial cell antibodies are present in SLE. These antibodies provoke endothelial cell activation and over-expression of adhesion molecules such as ICAM, and to antibody-induced apoptosis.(12),(13)

As discussed in a previous Cyberounds® anti-phospholipid antibodies are frequently present in patients with SLE and appear to be procoagulants. A link between these antibodies and the occurrence of myocardial infarctions has been described. There is still controversy as to whether antiphospholipid antibodies such as anticardiolipin or lupus anticoagulant are associated with accelerated atherosclerosis.(14),(15)

Clinical Implications

Screening for Atherosclerosis

Atherosclerosis can be screened in various ways. In the general population, lab tests such as the fasting lipid profile and homocysteine are used. CRP, a measure of general inflammation, has recently been shown to be an independent risk factor for both cardiovascular disease and stroke.(16),(17) Carotid intima media thickness (IMT), known to be closely related to the presence of coronary atheroma, can be measured by B-mode ultrasonography, whereas coronary artery calcification can be detected by electron beam computed tomography (EBT).

The National Cholesterol Education Program (NCEP) and the United States Preventive Services Task Force (USPSTF) have developed specific guidelines for atherosclerosis screening in the general population but these guidelines can not readily be applied to SLE patients since they tend to develop atherosclerosis at much earlier ages than the general population. Although there are, at present, no specific guidelines with respect to when, who and how to screen SLE patients for atherosclerosis, there are features of the disease which can help clinicians decide if screening would be helpful. These include the severity of disease (especially nephritis) and/or prolonged use (probably more than five years) and cumulative dose (probably more than 10 grams) of corticosteroid therapy. Lupus patients with these characteristics should be screened carefully. CRP and homocysteine should be considered for early screening since both have been demonstrated to be independent determinants for subclinical atherosclerosis.(18),(19),(20)

Prevention of Atherosclerosis

Primary prevention is key and the first step in management should be aggressive risk factor reduction. Global measures such as tight blood pressure control with a goal of less than 130/85 mm Hg using beta blockers, nitrates and ACE inhibitors can also be applied to SLE patients. In addition, lipid reduction to LDL<130 mg/dL, or even <100 mg/dL with HMG-CoA reductase inhibitors (statins), maintaining a normal fasting plasma glucose of <126, smoking cessation, weight control with BMI<25, anti-platelet therapy with aspirin and an increase in physical activity should all be encouraged. As far as SLE-specific therapy, steroids should be used judiciously since it has been demonstrated that these medications increase the risk for traditional risk factors. Therefore, the steroid dose should be decreased as soon as the disease is under control and steroid-sparing agents should be considered early.

Some of the steroid sparing agents, however, also have atherosclerosis-promoting effects. Methotrexate is a folate antagonist which increases levels of homocysteine when used without folic acid supplements. Therefore, methotrexate should be always used in combination with folate.(21),(22) Cyclosporine, commonly used in SLE patients who have undergone renal transplantation, causes hypercholesteremia, hypertriglyceridemia, as well as elevations of LDL and VLDL levels.(23) We believe that cyclosporine should be used with caution in SLE patients and lipid levels monitored carefully. Azathioprine does not interfere significantly with the lipid metabolism.(24) In contrast, the antimalarial drug, hydroxychloroquine, widely used for articular and cutaneous manifestations of SLE, has been shown to lower cholesterol levels.(25) Hydroxychloroquine's cholesterol-lowering effect becomes even more pronounced when it is taken in combination with steroids.(26)

Conclusions

Since premature atherosclerosis and CAD are major causes of death in SLE patients, the development of specific guidelines for artherosclerosis screening in lupus is of crucial significance for the early prevention of morbidity and mortality in these patients. Further investigation of the mechanisms involved in accelerated atherosclerosis in lupus is expected to identify specific targets for the development of novel treatments for atherosclerosis. In the meantime, it is of critical importance for clinicians to diligently detect risk factors for premature atherosclerosis in SLE patients and manage them appropriately.


Footnotes

1Kao A et al. Update on vascular disease in systemic lupus erythematosus. Curr Opin Rheumatol 2003;15:519-27.
2Manzi S et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997;145:408-15.
3Ward M. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum 1999;42:338-46.
4Asanuma Y et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003 2003;349:2407-15.
5Wolak T. Duplex study of the carotid and femoral arteries of patients with systemic lupus erythematosus: a controlled study. J Rheumatol 2004;31:909-14.
6Sarzi-Puttini P, Atzeni F, Carrabba M. Cardiovascular risk factors in systemic lupus erythematosus and in antiphospholipid syndrome. Minerva Med 2003;94:63-70.
7Manger K et al. Factors associated with coronary artery calcification in young female patients with SLE. Ann Rheum Dis 2003;62:846-50.
8Zonana-Nacach A et al. Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum 2000;43:1801-8.
9Hollenbaugh D et al. Expression of functional CD40 by vascular endothelial cells. J Exp Med 1995;182:33-40.
10Schonbeck U et al. Ligation of CD40 activates interleukin 1beta-converting enzyme (caspase-1) activity in vascular smooth muscle and endothelial cells and promotes elaboration of active interleukin 1beta. J Biol Chem 1997;272:19569-74.
11Wierzbicki, AS. Lipids, cardiovascular disease and atherosclerosis in systemic lupus erythematosus. J Autoimmun. 2004; 23:353-60.
12Papa ND et al. Anti-endothelial cell IgG fractions from systemic lupus erythematosus patients bind to human endothelial cells and induce a pro-adhesive and a pro-inflammatory phenotype in vitro. Lupus1999; 8:423-9.
13
14Alves JD et al. Oxidative stress in systemic lupus erythematosus and antiphospholipid syndrome: a gateway to atherosclerosis. Curr Rheumatol Rep 2003;5:383-90.
15Sherer Y, Shoenfeld Y. Antiphospholipid antibodies: are they pro-atherogenic or an epiphenomenon of atherosclerosis? Immunobiology 2003(207):13-6.
16Ridker P et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. 2000 Mar 23;342(12):836-43. N Engl J Med 2000;342:836-43.
17Ridker P et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-9.
18Selzer F et al. Comparison of risk factors for vascular disease in the carotid artery and aorta in women with systemic lupus erythematosus. Arthritis Rheum 2004;50:151-9.
19Ridker P et al. Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) Investigators. Plasma homocysteine concentration, statin therapy, and the risk of first acute coronary events. Circulation 2002;105:1776-9.
20Petri M et al. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348:1120-4.
21Valik D, Radina M, Sterba J, Vojtesek B. Homocysteine: exploring its potential as a pharmacodynamic biomarker of antifolate chemotherapy. Pharmacogenomics. 2004; 5:1151-62.
22Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology (Oxford). 2004; 43:267-71.
23Vaziri ND, Liang K, Azad H . Effect of cyclosporine on HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expressions. J Pharmacol Exp Ther. 2000;294:778-83.
24van den Dorpel MA et al. Conversion from cyclosporine A to azathioprine treatment improves LDL oxidation in kidney transplant recipients. J Pharmacol Exp Ther. 2000 Aug;294(2):778-83.
25Munro R et al. Effect of disease modifying agents on the lipid profiles of patients with rheumatoid arthritis. Ann Rheum Dis. 1997 56:374-7.
26Wallace DJ et al. Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids. Am J Med. 1990 Sep;89(3):322-6.