Accelerated Atherosclerosis in Autoimmune Rheumatic Diseases

Abstract

HomeCirculationVol. 112, No. 21Accelerated Atherosclerosis in Autoimmune Rheumatic Diseases Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBAccelerated Atherosclerosis in Autoimmune Rheumatic Diseases Yehuda Shoenfeld, MD, FRCP (Hon), Roberto Gerli, MD, Andrea Doria, MD, Eiji Matsuura, PhD, Marco Matucci Cerinic, MD, Nicoletta Ronda, MD, Luis J. Jara, MD, Mahmud Abu-Shakra, MD, Pier Luigi Meroni, MD and Yaniv Sherer, MD Yehuda ShoenfeldYehuda Shoenfeld From the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel (Y. Shoenfeld, Y. Sherer); the Center for Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (R.G.); the Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Italy (A.D.); the Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (E.M.); the Department of Medicine, Division of Rheumatology, University of Florence, Firenze, Italy (M.M.C.); the Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università degli Studi di Parma, Parma, Italy (N.R.); the Clinical Research Unit, Hospital de Especialidades, Centro Medico La Raza, and Universidad Nacional Autónoma de México, Mexico City, Mexico (L.J.J.); the Autoimmune Rheumatic Diseases Unit, Department of Medicine, Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel (M.A.-S.); and the Department of Internal Medicine, University of Milan, Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.L.M.). Search for more papers by this author , Roberto GerliRoberto Gerli From the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel (Y. Shoenfeld, Y. Sherer); the Center for Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (R.G.); the Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Italy (A.D.); the Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (E.M.); the Department of Medicine, Division of Rheumatology, University of Florence, Firenze, Italy (M.M.C.); the Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università degli Studi di Parma, Parma, Italy (N.R.); the Clinical Research Unit, Hospital de Especialidades, Centro Medico La Raza, and Universidad Nacional Autónoma de México, Mexico City, Mexico (L.J.J.); the Autoimmune Rheumatic Diseases Unit, Department of Medicine, Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel (M.A.-S.); and the Department of Internal Medicine, University of Milan, Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.L.M.). Search for more papers by this author , Andrea DoriaAndrea Doria From the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel (Y. Shoenfeld, Y. Sherer); the Center for Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (R.G.); the Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Italy (A.D.); the Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (E.M.); the Department of Medicine, Division of Rheumatology, University of Florence, Firenze, Italy (M.M.C.); the Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università degli Studi di Parma, Parma, Italy (N.R.); the Clinical Research Unit, Hospital de Especialidades, Centro Medico La Raza, and Universidad Nacional Autónoma de México, Mexico City, Mexico (L.J.J.); the Autoimmune Rheumatic Diseases Unit, Department of Medicine, Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel (M.A.-S.); and the Department of Internal Medicine, University of Milan, Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.L.M.). Search for more papers by this author , Eiji MatsuuraEiji Matsuura From the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel (Y. Shoenfeld, Y. Sherer); the Center for Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (R.G.); the Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Italy (A.D.); the Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (E.M.); the Department of Medicine, Division of Rheumatology, University of Florence, Firenze, Italy (M.M.C.); the Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università degli Studi di Parma, Parma, Italy (N.R.); the Clinical Research Unit, Hospital de Especialidades, Centro Medico La Raza, and Universidad Nacional Autónoma de México, Mexico City, Mexico (L.J.J.); the Autoimmune Rheumatic Diseases Unit, Department of Medicine, Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel (M.A.-S.); and the Department of Internal Medicine, University of Milan, Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.L.M.). Search for more papers by this author , Marco Matucci CerinicMarco Matucci Cerinic From the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel (Y. Shoenfeld, Y. Sherer); the Center for Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (R.G.); the Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Italy (A.D.); the Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (E.M.); the Department of Medicine, Division of Rheumatology, University of Florence, Firenze, Italy (M.M.C.); the Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università degli Studi di Parma, Parma, Italy (N.R.); the Clinical Research Unit, Hospital de Especialidades, Centro Medico La Raza, and Universidad Nacional Autónoma de México, Mexico City, Mexico (L.J.J.); the Autoimmune Rheumatic Diseases Unit, Department of Medicine, Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel (M.A.-S.); and the Department of Internal Medicine, University of Milan, Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.L.M.). Search for more papers by this author , Nicoletta RondaNicoletta Ronda From the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel (Y. Shoenfeld, Y. Sherer); the Center for Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (R.G.); the Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Italy (A.D.); the Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (E.M.); the Department of Medicine, Division of Rheumatology, University of Florence, Firenze, Italy (M.M.C.); the Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università degli Studi di Parma, Parma, Italy (N.R.); the Clinical Research Unit, Hospital de Especialidades, Centro Medico La Raza, and Universidad Nacional Autónoma de México, Mexico City, Mexico (L.J.J.); the Autoimmune Rheumatic Diseases Unit, Department of Medicine, Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel (M.A.-S.); and the Department of Internal Medicine, University of Milan, Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.L.M.). Search for more papers by this author , Luis J. JaraLuis J. Jara From the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel (Y. Shoenfeld, Y. Sherer); the Center for Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (R.G.); the Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Italy (A.D.); the Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (E.M.); the Department of Medicine, Division of Rheumatology, University of Florence, Firenze, Italy (M.M.C.); the Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università degli Studi di Parma, Parma, Italy (N.R.); the Clinical Research Unit, Hospital de Especialidades, Centro Medico La Raza, and Universidad Nacional Autónoma de México, Mexico City, Mexico (L.J.J.); the Autoimmune Rheumatic Diseases Unit, Department of Medicine, Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel (M.A.-S.); and the Department of Internal Medicine, University of Milan, Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.L.M.). Search for more papers by this author , Mahmud Abu-ShakraMahmud Abu-Shakra From the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel (Y. Shoenfeld, Y. Sherer); the Center for Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (R.G.); the Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Italy (A.D.); the Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (E.M.); the Department of Medicine, Division of Rheumatology, University of Florence, Firenze, Italy (M.M.C.); the Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università degli Studi di Parma, Parma, Italy (N.R.); the Clinical Research Unit, Hospital de Especialidades, Centro Medico La Raza, and Universidad Nacional Autónoma de México, Mexico City, Mexico (L.J.J.); the Autoimmune Rheumatic Diseases Unit, Department of Medicine, Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel (M.A.-S.); and the Department of Internal Medicine, University of Milan, Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.L.M.). Search for more papers by this author , Pier Luigi MeroniPier Luigi Meroni From the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel (Y. Shoenfeld, Y. Sherer); the Center for Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (R.G.); the Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Italy (A.D.); the Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (E.M.); the Department of Medicine, Division of Rheumatology, University of Florence, Firenze, Italy (M.M.C.); the Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università degli Studi di Parma, Parma, Italy (N.R.); the Clinical Research Unit, Hospital de Especialidades, Centro Medico La Raza, and Universidad Nacional Autónoma de México, Mexico City, Mexico (L.J.J.); the Autoimmune Rheumatic Diseases Unit, Department of Medicine, Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel (M.A.-S.); and the Department of Internal Medicine, University of Milan, Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.L.M.). Search for more papers by this author and Yaniv ShererYaniv Sherer From the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Israel (Y. Shoenfeld, Y. Sherer); the Center for Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (R.G.); the Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Italy (A.D.); the Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (E.M.); the Department of Medicine, Division of Rheumatology, University of Florence, Firenze, Italy (M.M.C.); the Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università degli Studi di Parma, Parma, Italy (N.R.); the Clinical Research Unit, Hospital de Especialidades, Centro Medico La Raza, and Universidad Nacional Autónoma de México, Mexico City, Mexico (L.J.J.); the Autoimmune Rheumatic Diseases Unit, Department of Medicine, Soroka Medical Center and Ben-Gurion University, Beer-Sheva, Israel (M.A.-S.); and the Department of Internal Medicine, University of Milan, Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.L.M.). Search for more papers by this author Originally published22 Nov 2005https://doi.org/10.1161/CIRCULATIONAHA.104.507996Circulation. 2005;112:3337–3347Atherosclerosis is a multifactorial process that commences in childhood but manifests clinically later in life. Atherosclerosis is increasingly considered an immune system–mediated process of the vascular system. The presence of macrophages and activated lymphocytes within atherosclerotic plaques supports the concept of atherosclerosis as an immune system–mediated inflammatory disorder.1,2 Inflammation can aggravate atherosclerosis via different mechanisms secondary to autoimmunity, infectious diseases, and other proatherogenic changes that occur during the inflammatory state.Autoimmune rheumatic diseases (AIRDs) are associated with higher rates of cardiovascular morbidity and mortality, primarily secondary to accelerated atherosclerosis. This phenomenon can be attributed to traditional risk factors for atherosclerosis and use of specific drugs, such as corticosteroids, but also might be the result of other autoimmune and inflammatory mechanisms that are aggravated in AIRDs. Several AIRDs exhibit increased overt cardiovascular disease (CVD) prevalence as well as findings of advanced subclinical atherosclerosis, which may precede the appearance of a clinical disease and thus be a target of early identification and preventive therapy.Cells of the immune system can be found within atherosclerotic plaques, which suggests that they have a role in the atherogenic process. Their migration and activation within the plaques can be secondary to various stimuli, including infectious agents.3 These cells probably aggravate atherosclerosis, because CD4+ and CD8+ T-cell depletion reduced fatty streak formation in C57BL/6 mice. In addition, after crossing of apolipoprotein E (ApoE)-knockout mice with immunodeficient scid/scid mice, the offspring had a 73% reduction in aortic fatty streak lesions compared with the immunocompetent apoE mice. Moreover, when CD4+ T cells were transferred from the immunocompetent to the immunodeficient mice, they increased lesion area in the latter by 164%.4 It is therefore not surprising that as in autoimmune diseases, the cellular components within atherosclerotic plaques secrete various cytokines, including many interleukins as well as tumor necrosis factor-α and platelet-derived growth factor.A cellular immune response specifically directed against heat-shock proteins (HSPs), oxidized low-density lipoprotein (oxLDL), and β2-glycoprotein-I (β2GPI) has been reported, suggesting a direct involvement of these molecules in atherosclerosis.1 β2GPI can be found in human atherosclerotic lesions obtained from carotid endarterectomies, it is abundantly expressed within the subendothelial regions and the intimal-medial border of human atherosclerotic plaques, and it colocalizes with CD4+ lymphocytes.5 On transfer of lymphocytes obtained from β2GPI-immunized LDL-receptor–deficient mice into syngeneic mice, the recipients exhibited larger fatty streaks compared with mice that received lymphocytes from control mice. However, T-cell depletion of lymphocytes failed to induce this effect.6 Therefore, T cells specific for β2GPI are capable of increasing atherosclerosis, suggesting that β2GPI is a target autoantigen in atherosclerosis. There are probably many more such specific cell lines reacting with specific antigens that can modulate atherosclerosis by either aggravating or decreasing its extent (proatherogenic or antiatherogenic).Several autoantibodies are associated with atherosclerosis and its manifestations in humans. Animals provide good models for studying the effect of these autoantibodies on atherosclerosis. Active immunization of LDL-receptor–deficient mice with anti-cardiolipin (aCL) antibodies resulted in development of high titers of mouse aCL and increased atherosclerosis compared with control subjects.7 Immunization of mice with β2GPI resulted in pronounced cellular and humoral responses to β2GPI, with high titers of anti-β2GPI antibodies concomitant with larger atherosclerotic lesions that contained abundant CD4+ cells.OxLDL is the type of LDL that is more likely to undergo uptake by macrophages, which turn into the foam cells characterizing atherosclerotic lesions. Anti-oxLDL antibodies are present in patients with atherosclerosis, those with AIRDs, and healthy individuals.8 In multivariate analyses, anti-oxLDL autoantibodies discriminated better between patients with peripheral vascular disease and control subjects than did any of the different lipoprotein analyses. There was also a tendency for higher autoantibody levels in patients with more extensive atherosclerosis.9 The autoantibodies to oxLDL were investigated in several AIRD groups, including patients with systemic sclerosis (SSc),10 systemic vasculitides,8 and systemic lupus erythematosus (SLE).10 The antibody levels were higher in those patient groups than in control subjects. There was a correlation between the total level of immunoglobulins and the level of antibodies against oxLDL, whereas no correlation was demonstrated between the levels of the total immunoglobulin and the levels of antibodies to unrelated antigens (Epstein-Barr virus and purified protein derivative of Myocobacterium tuberculosis). This finding suggests that elevated total immunoglobulin levels in SLE patients are selective for some specific antibodies, including autoantibodies against oxLDL.10Accelerated Atherosclerosis in Rheumatoid ArthritisPatients with rheumatoid arthritis (RA) have a reduced life expectancy, with standardized mortality ratios ranging from 0.87 to 3.0.11 CVDs represent the main cause of death in both clinical and community-based cohorts of RA populations.11,12 In addition, there is evidence that mechanisms determining enhanced CVD mortality in RA are present very early during the natural history of the disease.12 Several types of cardiac involvement can occur in RA. However, ischemic heart disease secondary to atherosclerosis seems to represent the main cause of CVD deaths in RA populations.11,13 Cigarette smoking is a risk factor for development of RA and has a dose-dependent relationship with both disease severity and rheumatoid factor production.14 However, different studies failed to identify smoking as a predictor of CVD mortality in seropositive RA and inflammatory polyarthritis.15 RA treatment and lifestyle of RA patients may favor physical inactivity, hypertension, diabetes mellitus, and obesity, but there is no clear evidence that these factors are implicated in accelerated atherosclerosis in RA.11,13 Methotrexate, widely used to treat RA, increases plasma levels of homocysteine, which is a novel, and potentially modifiable, risk factor for CVD in the general population.16 Concomitant folate supplementation during methotrexate treatment prevented that increase of homocysteine and, more importantly, reduced CVD mortality in RA patients.16 Data on dyslipidemia in RA are conflicting, and the more convincing findings, a decrease of high-density lipoprotein (HDL) cholesterol and an increase in small LDL levels, appear to be secondary to chronic inflammation rather than to primary metabolic alteration in RA.11RA by itself seems to represent a significant risk factor for early atherosclerosis and CVD development.15 In this setting, a number of epidemiological, clinical, and laboratory investigations suggested that chronic inflammation and immune dysregulation characterizing RA have a key role in accelerating atherosclerosis.11–13 Like the RA joint, atherosclerotic plaques are characterized by enhanced expression of adhesion molecules and by abundance of proinflammatory cytokine-secreting cells attracted by locally activated endothelium and chemokines. The release of a number of collagen-breaking mediators is likely to exert a fundamental role in destabilization of atherosclerotic plaques as well as erosion of cartilage and bone into the RA joint. According to these observations, it is conceivable that the chronic systemic inflammation characterizing RA may trigger early events, accelerating diffuse atherosclerosis development. It has been shown that excess cardiovascular mortality occurs prevalently in RA patients with more widely diffuse disease, with lung involvement and vasculitis, who have markers of systemic inflammation.17Although this may support a role for rheumatoid vasculitis in promoting atherosclerosis, there are several lines of evidence suggesting that a dysfunction, rather than a full-blown “vasculitic phenotype,” is the leading event to early endothelial damage in RA. Functional abnormalities of the endothelium have been found in distinct cohorts of RA patients, independently of patients’ age, duration of the disease, degree of disease activity, or seropositivity.18,19 Despite the fact that different factors could alter endothelium homeostasis, prevalent data support the view that abnormal endothelial function in RA is essentially linked to inflammation. In a recent evaluation of young RA patients with low disease activity, endothelial dysfunction, assessed by brachial flow–mediated vasodilatation, was predicted independently by LDL cholesterol and by the mean levels of C-reactive protein (CRP), as evaluated at different time points (Figure 1). Persistent endothelial dysfunction predisposes to organic damage of the vascular wall that, in a preclinical stage, before overt disease, can be detectable by ultrasound measurement of carotid intimal-medial thickness (IMT). Many investigations provided evidence of increased carotid IMT in RA.20–22 This finding could not be explained by corticosteroid treatment but appeared to be essentially associated with markers of systemic inflammation and disease duration, thereby emphasizing the importance of RA as a risk factor for atherosclerosis. Download figureDownload PowerPointFigure 1. Brachial flow–mediated vasodilatation (FMV) assessed on the brachial artery by ultrasonography in a normal control subject (A) and in a patient with RA (B). FMV, expressed as the relative increase in brachial artery diameter during hyperemia and defined as 100×(posthyperemia diameter−basal diameter)/basal diameter], was 12% in the normal subject and 3% in the RA patient.Among the immunological factors shared by the pathogenic processes of atherosclerosis and RA, a particular subset of CD4+ T cells that lacks surface CD28 molecule (CD4+CD28−) has given rise to a great concern in recent years. These cells are expanded, probably stimulated by endothelial autoantigens,22 in the peripheral blood of unstable angina pectoris patients and a subgroup of RA patients.22 Furthermore, they infiltrate the atherosclerotic plaques and display a high proinflammatory and tissue-damaging potential that promotes vascular injury.23 The role of these cells in contributing to early development of atherosclerosis in RA has been confirmed in a recent study showing that RA patients with CD4+CD28− cell expansion have a higher degree of endothelial dysfunction and a higher carotid IMT than patients without expansion of these cells.21Accelerated Atherosclerosis in SLESLE is an autoimmune disease that may involve any organ of the body and displays a broad spectrum of clinical manifestations. It affects predominantly young women, a group of subjects generally free from atherosclerosis. However, CVDs have recently become a leading cause of morbidity and mortality among SLE patients.24 Coronary artery disease is described in SLE patients with a prevalence ranging from 6% to 10%, and the risk of developing this manifestation is 4 to 8 times higher than normal.25,26 Moreover, acute myocardial infarction was the cause of death in 3% to 25% of SLE patients in different surveys.24,27 Urowitz et al28 described a bimodal distribution of the causes of death in SLE: An “early” peak caused by SLE severity/activity or infections, and a “late” peak caused by CVD. Such a trend has been confirmed in more recent studies as well. Moreover, in postmortem studies, a significant extent of atherosclerosis was observed in more than 50% of deceased patients independently of the cause of death.29 Not only does atherosclerosis occur more frequently in SLE patients than in the general population, but there is also epidemiological and clinical evidence that it is accelerated in these patients in diabetes mellitus as well.25,26Although atherosclerosis develops early in the course of the disease, older age at diagnosis seems to be the major determinant of atherosclerosis in SLE.25,26 Moreover, in SLE patients, the mean number of modifiable traditional risk factors for atherosclerosis (ie, hypercholesterolemia, arterial hypertension, diabetes mellitus, obesity, smoking, and sedentary lifestyle) is higher than that expected in an age-, sex-, and race-matched normal population.30 In the major clinical studies on atherosclerosis, performed in Toronto,31 Baltimore,25 and Pittsburgh,26 the traditional risk factors that were the most common predictors of clinical events were older age at disease diagnosis, hypercholesterolemia, and hypertension. However, atherosclerosis cannot be explained by Framingham risk factors alone, and it has been attributed to complex interactions between traditional risk factors and factors associated with the disease per se or its treatment. Among the nontraditional risk factors, cumulative dosage and/or longer duration of corticosteroid therapy and longer duration of disease seem to be the major predictors of atherosclerosis in SLE studies.25,26 Some novel risk factors that could contribute to atherosclerosis development have been reported recently. These include inflammatory markers: CRP, fibrinogen, interleukin-6, CD40/CD40L, adhesion molecules; immunological factors: aCL, anti-β2GPI, anti-oxLDL, and anti-HSP antibodies; abnormal coagulation factors: Fibrinogen, plasminogen activator inhibitor-1, and homocysteine; and lipoprotein and modified lipids: Lipoprotein(a) and HDL.Diagnostic investigations can reveal a higher prevalence of cardiovascular lesions, because they allow the detection of subclinical atherosclerosis. Abnormalities of the coronary circulation have been reported in 40% of SLE patients by use of single photon emission computed tomography (SPECT) and dual isotope myocardial perfusion imaging (DIMPI)32 and an even higher percentage (27 of 33 patients) by use of 99mTc-SPECT.33 Coronary artery calcifications were detected by electron beam CT in 31% of SLE patients, and the extent of calcification was particularly high in SLE patients compared with control subjects.34 The most commonly used method for the detection of subclinical atherosclerosis is carotid B-mode ultrasound. By use of ultrasound, carotid plaques were found with a frequency ranging between 17% and 65% of SLE patients.35–39 Although carotid ultrasound directly investigates only the carotid artery, this technique provides an accurate measurement of subclinical atherosclerosis (Figure 2). Download figureDownload PowerPointFigure 2. IMT measurement of the common carotid arteries demonstrating normal IMT in a control subject (left) compared with an increased IMT forming an atherosclerotic plaque in an SLE patient (right).The evaluation of risk factors for clinical atherosclerosis is difficult in SLE because there is a low number of observed cardiovascular events because of low prevalence of the disease. The study of subclinical atherosclerosis has the advantage of providing a higher number of lesions leading to a more suitable evaluation of risk factors. The following studies, summarized in Table 1, evaluated the extent and clinical associations of subclinical atherosclerosis in SLE. Using the B-mode ultrasound, Manzi et al35 observed focal atherosclerotic plaques in 40% of 175 SLE women. They found an inverse relationship between disease activity measured by SLAM score and the plaque. Svenungsson et al36 performed ultrasound measurements of common carotid artery in 26 SLE patients with previous CVDs (SLE cases), 26 SLE patients with