Cardiovascular disease in systemic lupus erythematosus: A comprehensive update

Journal of Autoimmunity 82 (2017) 1e12

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Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm

Cardiovascular disease in systemic lupus erythematosus: A comprehensive update Mayra Giannelou a, b, Clio P. Mavragani a, c, d, * a

Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Greece Department of Rheumatology, General Hospital of Athens “G. Gennimatas”, Greece c Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Greece d Joint Academic Rheumatology Program, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 31 May 2017 Accepted 31 May 2017 Available online 9 June 2017

Heightened rates of both cardiovascular (CV) events and subclinical atherosclerosis, documented by imaging and vascular function techniques are well established in systemic lupus erythematosus (SLE). While traditional CV factors such as smoking, dyslipidemia, diabetes mellitus (DM), hypertension, central obesity and hyperhomocysteinemia have been reported to be prevalent in lupus patients, they do not fully explain the high rates of ischemic events so far reported, implying that other factors inherent to disease itself could account for the enhanced risk, including disease duration, activity and chronicity, psychosocial factors, medications, genetic variants and altered immunological mechanisms. Though the exact pathogenesis of atherosclerosis in the setting of lupus remains ill defined, an imbalance between endothelial damage and atheroprotection seems to be a central event. Insults leading to endothelial damage in the setting of lupus include oxidized low density lipoprotein (oxLDL), autoantibodies against endothelial cells and phospholipids, type I interferons (IFN) and neutrophil extracellular traps (NETs) directly or through activation of type I IFN pathway. Increased oxidative stress, reduced levels of the normally antioxidant high density lipoprotein (HDL), increased levels of proinflammatory HDL (piHDL) and reduced paraoxonase activity have been related to increased oxLDL levels. On the other hand, impaired atheroprotective mechanisms in lupus include decreased capacity of endothelial repair-partly mediated by type I IFN- and dampened production of atheroprotective autoantibodies. In the present review, traditional and disease related risk factors for CV disease (CVD) in the setting of chronic autoimmune disorders with special focus on SLE will be discussed. © 2017 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Epidemiology of CVD in SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Traditional CVD risk factors in SLE (Fig. 1, Table 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3.1. Metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3.1.1. Increased waist-to-hip ratio/obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.1.2. Insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.1.3. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.1.4. Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.2. Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.3. Hyperhomocysteinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Disease related contributors of atherosclerosis in SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 4.1. Demographics/clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

* Corresponding author. Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, M. Asias 75, 11527, Athens, Greece. E-mail address: [email protected] (C.P. Mavragani). http://dx.doi.org/10.1016/j.jaut.2017.05.008 0896-8411/© 2017 Elsevier Ltd. All rights reserved.

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4.2. 4.3. 4.4.

5. 6. 7. 8.

Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Immunological mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4.4.1. Endothelial insults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4.4.2. Impaired atheroprotective mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Psychosocial factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Association with other comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 CVD risk management in SLE patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1. Introduction For years atherogenesis was considered solely a degenerative process, resulting from passive lipid deposition on the arterial wall leading eventually to the gradual occlusion of the vessel and the subsequent ischemic events. Cumulative evidence over the last years strongly support the active involvement of the immune system in the generation of the atherosclerotic plaque as well as the interconnection between chronic autoimmune/inflammatory disorders and excessive cardiovascular burden, not easily attributed to traditional cardiovascular (CV) risk factors [1,2]. In young women with systemic lupus erythematosus (SLE) -the prototype of systemic autoimmune diseases- the risk for myocardial infarction (MI) has been found to be 50 times higher compared to healthy women of similar age distribution [3]. While traditional risk factors associated with atherosclerosis including smoking, dyslipidemia, diabetes mellitus (DM), hypertension and increased body mass index (BMI) are present in lupus patients, standard Framingham scores do not fully explain the high rates ischemic events so far reported [4]. On this basis, lupus is now regarded as an independent risk factor for the development of CV comorbidity [3,5], implying that other factors inherent to disease itself contribute to the CV burden seen in these patients. In the present review, traditional and disease related risk factors for CV disease (CVD) in the setting of chronic autoimmune disorders with special focus on SLE will be discussed. 2. Epidemiology of CVD in SLE SLE is a highly heterogeneous autoimmune disease, affecting women of childbearing age, with substantial mortality and morbidity. The effect of SLE on atherosclerotic disease has been recognized since the 70s, when Urowitz et al. displayed a bimodal mortality peak for lupus patients; the first was attributed to disease activity and infections and the second to CVD [6]. Three decades later, progress in disease treatment had resulted in decrease of mortality due to disease activity; however CV and infectious complications remain the main causes of death in these patients [7]. The prevalence of ischemic heart disease in SLE patients is estimated between 3.8 and 16% [8e12], conferring a 10-fold risk compared to the general population [4] and a 50-fold risk in young women at reproductive age [3]. In a recent Taiwanian study in 1207 SLE patients compared to 9656 age/sex-matched controls, the estimated adjusted hazard ratio for acute MI was 5.11 for SLE patients in general and 6.28 for female SLE patients [13]. The corresponding figure in the first year of diagnosis was 5.63 [14]. The risk of stroke in SLE patients was also found to be increased by 2e8-fold in different studies [4,14,15]. Of interest two independent groups highlighted the increased risk for stroke particularly during the first year of disease diagnosis, with adjusted calculated hazard ratios

being 6.5 and 3.7 respectively [14,15]. In a recent meta-analysis, the prevalence of subclinical atherosclerotic disease -assessed by carotid ultrasound for detection of arterial wall thickening or plaque formation- was also found to be higher in SLE patients compared to controls, showing higher carotid intima-medial thickness (IMT) scores and a 2.5 fold increase in the prevalence of carotid plaques, both surrogate markers of subclinical atherosclerosis [16]. Coronary artery calcification detected by electron beam computerized tomography was also higher in lupus populations compared to healthy controls, at a range from 30 to 58% [17,18]. Moreover, endothelial dysfunction estimated by flow mediated dilatation (FMD) was prevalent in SLE patients compared to controls (54.8 vs 26.3%, respectively) predicting higher IMT values [19], as previously suggested [20]. Finally, aortic stiffness -a significant indicator of early vascular aging assessed by aortic pulse wave velocity (aPWV), was found to be impaired in SLE patients at a similar degree compared to hypertensive patients, implying that SLE exerts a comparable effect on early vascular aging as hypertension [21]. Of note, increased PWV and arterial stiffness of the proximal aorta were observed in children and adolescents with active SLE, suggesting a potential role of inflammation in the increased arterial stiffness observed in young patients [22]. Concomitant investigation of the common carotid artery for stiffness and wall thickening (IMT) in patients with SLE revealed IMT as more suitable for assessment of vascular damage, while stiffness variables better reflect endothelial and vessel functional state [23,24]. It should be also mentioned that atherosclerotic plaques can occur in the absence of high IMT values in SLE [25] and have been found to be more robustly correlated with clinical coronary artery disease than IMT [26]. A recent study has suggested a positive relationship between QT interval length on the electrocardiogram and presence of arterial stiffness in SLE patients, with a possible use for CVD risk stratification [27].

3. Traditional CVD risk factors in SLE (Fig. 1, Table 1) 3.1. Metabolic syndrome Metabolic syndrome (MetS) viewed as a constellation of central obesity, insulin resistance, dyslipidemia and hypertension, was found to be prevalent in lupus patients compared to age matched controls at a rate ranging from 15.8 to 32.4 vs 4.2e10.9%, depending on the mean age of the study subjects and definitions implemented [28e30]. In lupus patients the presence of Mets has been associated with racial/ethnic origin (Hispanic or Black African), increasing age and disease related characteristics such as baseline renal disease, Systemic Lupus International Collaborative Clinics (SLICC) damage index>1 and higher disease activity, as well as coronary atherosclerosis, arterial stiffness and inflammatory biomarkers [30e33].

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Table 1 Traditional and disease related features in lupus related cardiovascular disease (CVD).

Metabolic syndrome Increased waist to hip ratio (0.85) Insulin resistance Hypertension Lupus dyslipidemia piHDL Smoking Hyperhomocysteinemia a

Prevalence

OR

Association

Reference

15.8e32.4% 15.6e41%

3.1

Coronary atherosclerosis- aortic PWV Aortic PWV

[28e30,55] [34e36,119]

44.1% 33-74%

2.2 1.03e6.8

[12,29,39] [12,43,49e53,55,72]

36-60%

1.0e3.4

45% 0e71.2% 11.6e81.2%

2.5e16.1 1.37e7.7 1.08e2.06

Carotid plaque/IMT- vascular eventa Presence of carotid plaque - Progression of plaque/IMT, arterial stiffnessProgression of coronary artery calcium- Vascular eventa Presence of carotid plaque- Vascular eventa-Progression of CVD, coronary artery calcium, IMT Coronary artery disease- carotid plaque/IMT Carotid plaque, coronary calcium progression, vascular eventa Presence or progression of coronary artery calcification - Coronary artery disease- Arterial stiffness- Progression of carotid plaque/IMT

[12,17,25,53,63,66,72,96] [43,70e72] [12,16,25,43,48,52,53,76,77,133] [17,94,96e102]

Cardiovascular, cerebrovascular or peripheral vascular.

3.1.1. Increased waist-to-hip ratio/obesity Increased waist-to-hip ratio, sedentary lifestyle and obesity were found to be prevalent in SLE patients compared to controls [16,34e36]. Of interest, increased BMI levels were found to be significantly associated with subclinical atherosclerosis in both adult and pediatric lupus populations [37,38]. 3.1.2. Insulin resistance Insulin resistance as defined by the World Health Organization (WHO) criteria was also found to occur more frequently in lupus patients compared to controls (44.1 vs 24.8%) in association with high BMI, waist circumference, hypertension, corticosteroid treatment and SLICC damage index [29,39]. Given that adipokines -molecules produced by the adipose tissue- have been previously implicated in the pathogenesis of insulin sensitivity and MetS in the general population [40], a growing number of studies investigated their potential role in the context of lupus. Though the data are rather conflicting, altered adipokine profiles including adiponectin and leptin have been previously linked to insulin resistance and carotid plaque formation, but not coronary atherosclerosis in the setting of lupus [41e44]. Of interest, leptin -known for its atherogenic properties- was included in a risk profile model, aimed to serve as predictor for atherosclerosis progression in SLE patients [45]. Insulin resistance along with atherogenic dyslipidemia and carotid wall thickening has been also linked to increased levels of circulating fatty acid-binding protein 4 (FABP4). The latter belong to a family of proteins considered as a possible marker of metabolic risk since they bind long chain fatty acids and regulate fatty acid uptake, transport, and metabolism [46]. 3.1.3. Hypertension Hypertension is a well-recognized risk factor for CVD development in SLE patients [10,47] as evidenced by several studies reporting its contribution in both plaque formation and arterial stiffening [43,48e52]. A longitudinal study by Kiani et al. investigating the determinants of atherosclerosis progression in 187 SLE patients, identified age and hypertension as independently associated factors with the progression of carotid IMT and plaque [53]. Several studies so far revealed an increased prevalence of arterial hypertension in lupus patients, ranging from 33 to 74% [54e57]. In an effort to investigate potential contributors of HT in a cohort of 112 lupus patients, Sabio et al., identified renal disease, insulin levels and SLE disease activity index (SLEDAI) as independent predictors of hypertension in these individuals. Of interest, non obesity- related insulin levels was the main predictor of hypertension in the younger age subset (<40 y), while age and obesity in the older group (>40 y) [56]. In a subsequent study, examining the

patterns of nighttime blood pressure in female lupus patients, an adverse nighttime blood pressure pattern (steady, non-dipping hypertension or nocturnal hypertension/reverse dipping) was more frequent in SLE; these patterns were independently associated with increased carotid-femoral PWV [58]. 3.1.4. Dyslipidemia The association of increased levels of total cholesterol (TC), low density lipoprotein (LDL) and decreased levels of high-density lipoprotein (HDL) cholesterol with increased risk for CVD in the general population is well established and acknowledged for many years [59e62]. Reported rates of dyslipidemia in SLE patients range from 36% at time of diagnosis to more than 60% within a three year follow up [63]. In a systematic literature review by Tselios et al., dyslipidemia in lupus patients has been reported to contribute to both clinical and subclinical CVD as well as to kidneys and brain end organ damage [53,64]. In lupus patients, the classical pattern of dyslipidemia is characterized by elevated levels of very-low-density lipoprotein cholesterol (VLDL), triglycerides and low levels of HDL and can be aggravated by disease activity [65,66]; Olusi et al. confirmed these alterations additionally reporting increased rates of the LDL atherogenic phenotype namely small, dense LDL molecules -identified by LDL subclass analysis- in lupus patients compared to controls [67]. Additionally, circulating lipoprotein remnant particles and the intermediate density lipoprotein (IDL) fraction have been also strongly associated with IMT values in lupus patients [68], while small HDL particles have been associated with activation of the complement system, also shown to be linked to higher IMT values [69]. A newly recognized proinflammatory HDL subtype, known as piHDLs, also occur in a larger proportion of patients with SLE compared to RA, in association with carotid artery plaque formation, documented CVD and low physical activity. piHDLs which derive from structural HDL changes as a result of chronic inflammation, lose their atheroprotective properties since they are no longer able to reverse cholesterol transport and clear oxLDL from the subendothelial space, a first step for endothelial injury [70e73]. Furthermore, levels of apoA-I -the major apolipoprotein component of HDL- are reduced in SLE patients with IgG anticardiolipin antibodies [74]. 3.2. Smoking Smoking in the setting of lupus has been associated with CVD, cerebrovascular and peripheral vascular events [75e77] as well as with markers of subclinical atherosclerosis but not arterial stiffness

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[25,43,48,52,78,79], though the data are pretty conflicting [17,80]. Smoking has also been identified as risk factor for progression of coronary artery calcification after adjusting for age, gender and ethnicity [53]. Of note, smokers were less likely to respond to belimumab treatment than non-smokers [81], for reasons not clearly understood.

plaque formation, clinical CVD and arterial stiffness [32,80,103,106]. Additionally, non-calcified coronary plaque (NCP), abnormal flow mediated dilatation (FMD) values, arterial stiffness and progression in aortic calcium were found to be more common in adult and pediatric lupus populations with active disease [22,101,107,108]. 4.2. Medications

3.3. Hyperhomocysteinemia Hyperhomocysteinemia is a recognized risk factor for premature atherosclerosis and thrombotic risk in the general population through adverse effects on the endothelium, inhibition of nitric oxide synthesis, proliferation of smooth muscle cells and platelet activation [82e87]. Hyperhomocysteinemia can either originate from dysfunction of the methylene tetrahydrofolate reductase (MTHFR) enzyme as a result of functional genetic alterations, or a variety of factors including folic acid/vitamin B12 and cystathionine beta-synthase (CBS) deficiency, or renal dysfunction [88]. Several studies so far reported increased homocysteine levels in lupus patients compared to healthy controls at a rate ranging from 11.6-81.2 vs 0.8e20% [17,34,89e92]. Of interest, homocysteine levels in SLE patients have been previously linked to macrophage activation as evidenced by increased serum neopterin concentrations already known to be associated with atherosclerosis and CV risk in the general population [93]. In the setting of lupus, elevated homocysteine levels emerged as a risk factor for subsequent development of coronary artery disease, thrombotic events [94,95] and markers of subclinical atherosclerosis including coronary artery calcification, carotid plaque/high IMT values and aortic calcium progression [96e101]. In contrast, in the study by Perna et al., raised homocysteine levels have been linked to arterial stiffness, but not to the presence or extent of carotid atherosclerosis [102]. Data from our lupus cohort also support the role of hyperomocystenemia as an independent predictor for plaque formation and increased IMT scores (unpublished observations). 4. Disease related contributors of atherosclerosis in SLE Several contributors inherent to lupus itself have been previously proposed to promote CVD and include clinical and genetic contributors, as well as immunological mechanisms involving both the innate and adaptive immunity arms (Fig. 1, Table 2).

There are several reports suggesting prior medication exposure as a modulator of CVD risk among SLE patients. Thus, longer duration of corticosteroid use has been associated with MI and angina [3], while higher cumulative doses of steroids with carotid plaque formation [52,109]. Prednisone use has been shown to be associated with altered lipoprotein profiles and increased Framingham scale scores providing a potential mechanism for the enhanced atherogenic risk [110e112]. On the other hand, in a pediatric lupus cohort, a protective role of moderate doses of corticosteroids for carotid IMT was revealed; this effect was not however retained in either low or high steroid doses [38]. While azathioprine use has been also associated with increased rated of clinical CVD, carotid plaque and higher carotid IMT values in adult and pediatric lupus patients [38,79,103], cyclophosphamide, cyclosporine, hydroxychloroquine and mycophenolate mofetil (MMF) have been viewed as potential atheroprotective agents in both clinical and experimental grounds. Thus, lower incidence of the use of cyclophosphamide has been identified as independent determinant of carotid plaque [80] and cyclosporine use was shown to display protective properties regarding carotid arterial thickening (IMT) [113]; these data point towards the benefits of aggressive treatment. Antimalarials are commonly used in lupus treatment and are reported to be beneficial against CVD through cholesterol lowering [112,114], reduction of thrombotic risk [115,116] and possibly through dampening of type I interferon (IFN) production [117], which is viewed as a major pathogenetic determinant in lupus related atherosclerosis [118] (see below). Additionally, antimalarial use has been inversely associated with plaque [80] and carotid/femoral arterial stiffness [119] and was shown to be protective against MetS [55]. Data derived from experimental models prone to both SLE and atherosclerosis also support a potentially beneficial role for MMF [120], though it did not seem to prevent atherosclerosis progression in a small lupus cohort after a two-year period [121]. 4.3. Genetics

4.1. Demographics/clinical features A number of studies evaluated specific disease parameters and their effect on atherosclerotic disease in SLE patients. Male sex, advanced age, antiphospholipid antibodies (APLs), impaired renal function as well as previous arterial events have been all designated as reliable predictors for atherosclerotic disease in these patients [79,98,103]. Moreover, low total white blood cell count, lymphopenia and renal disease have been associated with carotid IMT and arterial stiffness [48,104]. Notably, a recent study revealed carotid plaques to occur twice more commonly in SLE patients with nephritis compared to age-matched non-nephritis SLE patients and population controls; this excess risk among nephritis individuals was mainly attributed to concomitant hypertension [105]. Disease duration, chronic organ damage reflected by SLICC damage index and disease activity were identified by numerous studies as important factors for CVD development in the setting of lupus. Longer disease duration has been independently associated with coronary artery calcification and carotid plaque formation [80,98], as well as progression [99] while SLICC score was found to be independently associated with increased IMT scores, carotid

Though a growing body of evidence suggests implication of genetic contributors in the pathogenesis of atherosclerosis in the general population, genetic data on lupus related atherosclerosis are rather scarce. In an initial study in patients with SLE of Swedish ethnic origin, the presence of the rs10181656(G) signal transducer and activator of transcription factor 4 (STAT4) allele-previously shown to be a risk variant for lupus [122]- conferred increased susceptibility for arterial events and ischemic cerebrovascular disease in the context of SLE [123]. Additionally, a small study including a limited number of patients of Egyptian descent revealed mannose binding lectin variants, which have been implicated in coronary in-stent restenosis, as potential contributors to high carotid IMT values and CVD risk factors [124]. Recent data from our group, identified MTHFR677TT genotypean established risk factor for CVD in the general population[125e127], as independent contributor for plaque formation and arterial wall thickening, following adjustment for traditional CV risk factors and disease related features including age, sex, BMI, cholesterol and triglyceride levels, presence of arterial

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Fig. 1. Traditional and disease related features as contributors to lupus related atherosclerosis.

Table 2 Associations of disease related features with cardiovascular disease (CVD). Disease related features Demographics Age Sex (male) Disease duration Clinical manifestations Renal disease Leucopenia/Lymphopenia SLEDAI SLICC Medications Corticosteroids Hydroxychloroquine Azathioprine Cyclophosphamide MMF Genetics STAT4 Mannose Binding lectin MTHFR BAFF Immunological mechanisms Atherogenic (endothelial insults) oxLDL Autoantibodies Type I IFN NETs Atheroprotective Impaired endothelial repair Reduced production of atheroprotective IgM antibodies

hypertension, smoking (pack/years), disease duration and total steroid dose (unpublished results). In previous reports, no association of MTHFR polymorphisms with coronary artery calcification in SLE patients has been detected [98,128].

Reference [12,17,25,31,43,48e50,52e54,72,94,97e100,103,108] [17,25,31,49,94,103] [31,51,53,80,97e99,102,108] [48,49,94,98,104,105] [48,53,104] [22] [32,80,101,103,106] [3,52,72,96,101,103,109e112] [55,80,111,112,119] [12,38,79,103] [80] [113,120] [123] [124]

[132,133] [12,76,77,79,139,141,142] [151e156] [157,158] [161,165,166] [167e169]

Given that B-cell activating factor (BAFF) has been proposed as a significant contributor in the pathogenesis of SLE and potentially of atherosclerosis [129,130], we also explored whether BAFF genetic variants could confer increased susceptibility in both lupus and

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lupus related atherosclerotic risk in a lupus cohort of 250 patients. The prevalence of the minor A allele and the AA genotype of the rs12583006 BAFF variant was significantly higher in SLE patients compared to healthy controls and was significantly associated with plaque formation after adjustment for age and sex (unpublished results). 4.4. Immunological mechanisms Though the exact mechanisms of atherosclerosis in the setting of lupus remain ill defined, an imbalance between endothelial damage, as a result of several insults and atheroprotective mechanisms seems to be a central event (Fig. 2). The insults which ultimately lead to endothelial apoptosis and activation include a. deposition of oxLDL b. autoantibodies against phospholipids and endothelial cells c. type I IFNs, and d. neutrophil extracellular traps (NETs). As a result, chemokines and proinflammatory cytokines, including monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-8, tumor necrosis factor alpha (TNFa) and IL-6 are secreted and several adhesion molecules such as vascular cell (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and E-selectin are overexpressed on the endothelium promoting T cells, monocytes and dendritic cells attraction. Once they reached the subendothelial space monocytes further differentiate into macrophages and through phagocytosis of abundant oxLDL become foam cells, which consist the basis for plaque formation. 4.4.1. Endothelial insults 4.4.1.1. oxLDL. Lipoprotein oxidation, an early event in atherogenesis, results in the formation of a multitude of oxidation products which in turn trigger a local immune response [131]. Higher levels of oxidized epitopes on LDL are found in lupus patients, in association with coronary or peripheral arterial disease, carotid plaque and high IMT values and renal involvement [132,133]. Several mechanisms have been shown to account for the increased oxidized (ox)LDL levels in the setting of lupus. These

include reduced levels of the normally antioxidant HDL and increased piHDL levels [72], as a result of oxidant-generating enzymes of neutrophil extracellular traps (NETs), previously shown to be elevated in lupus patients [134]. Additionally, circulating antibodies to apoA-I -detected in 32.5% of SLE patients and 22.9% of primary antiphospholipid syndrome patients- [135], together with antiphospholipid antibodies (APLs) have been associated with reduced paraoxonase activity [136]- a component of HDL particles implicated in the metabolism of lipid peroxides resulting in increased oxidation of LDL [136,137]. Finally, heightened exposure to oxidative stress seen in lupus patients could be an additional explanation [138]. 4.4.1.2. Autoantibodies. Several autoantibodies have been identified and are considered to be involved in endothelial injury in the context of lupus. Among these, anti-endothelial cell (AEC) antibodies, and APLs seem to play a significant role, though the underlying mechanisms are not fully elucidated. Autoantibodies to endothelial cells (AEC) can directly activate endothelial cells ([139] and are detected in 73% of SLE patients [140,141]); while they have been associated with lupus disease activity and vasculitic manifestations [141], endothelial dysfunction in clinical grounds has not been documented [142]. APLs have been shown to activate the endothelium in both in vitro and in vivo experimental models [143] and inhibit the binding of annexin A5 -a protein shown to prevent plaque ruptureto the endothelium [144]. APLs have been identified as independent predictors of cerebrovascular or peripheral vascular events [76,77] and MI, but not atherosclerosis [145,146]. While they have been proposed as predictors for carotid plaque formation in lupus patients [79], this observation was not confirmed by others [3,72,80]. On the other hand, presence of anti-OxLDLantibodies has been identified in up to 80% of SLE patients with antiphospholipid syndrome and are more commonly found in SLE patients with a history of CVD [96,147], but seem to be markers of atherogenesis rather

Fig. 2. An imbalance between atherogenic insults and atheroprotective mechanisms in lupus related atherosclerosis. IFN: interferon, oxLDL: oxidized LDL, NETs: Neutrophil extracellular traps.

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than active participants [131,148e150]. 4.4.1.3. Type I IFNs. Enhanced serum type I IFN activity-a key contributor in lupus pathogenesis- has been associated with decreased endothelial function (measured by FMD of the brachial artery), increased carotid IMT values and greater extent of coronary calcification in lupus patients, after controlling for traditional CVD risk factors [151]. Beyond its role in promoting endothelial cell apoptosis, type I IFN inhibits transcriptional repression of proangiogenic IL-1 pathways, stimulates recruitment of macrophages to atherosclerotic lesions and enhances foam cell formation. Additionally it has been shown to promote T cell mediated smooth muscle cell death and plaque instability and enhancement of platelet activation [152e156]. 4.4.1.4. Neutrophil extracellular traps (NETs). Neutrophil extracellular traps (NETs) are net-like chromatin fibers that are released from dying neutrophils with an ultimate goal to kill extracellular pathogens. Over the last years, a subset of neutrophils called low density granulocytes (LDGs), which are characterized by increased ability to form NETs have been implicated in the pathogenesis of lupus related atherosclerosis either directly through induction of endothelial damage or indirectly through activation of type I IFN pathway [157e159]. 4.4.2. Impaired atheroprotective mechanisms 4.4.2.1. Impaired endothelial repair. Normally, vascular damage is expected to be coupled by acceleration in repair of the endothelium. In SLE patients, decreased numbers of circulating endothelial progenitor cells (EPCs) and aberrant function of cells involved in the vascular repair have been postulated as potential contributors to the heightened atherosclerotic burden. Thus, lupus EPCs/CACs (myeloid circulating angiogenic cells) have decreased capacity to differentiate into mature endothelial cells (ECs) and synthesize decreased amounts of the molecules vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF) [118,160e163]. Increased IFN-I levels in SLE patients have been associated with distinctly reduced levels of EPCs and impaired endothelial function, while low vitamin D levels have been associated with reduced EPCs/CACs migratory and angiogenic capacity [161,164]. Reduced circulating EPCs in patients with coronary artery disease can independently predict subsequent CV events [165] and have been associated with abnormal PWV but not carotid plaque/IMT in SLE patients [166]. 4.4.2.2. Dampened production of atheroprotective autoantibodies. In a Swedish lupus cohort, it was shown that lupus patients and particularly those with CVD had decreased serum levels of autoantibodies against the apo B-100 antigens p45 and p210, implying that defective antibody-mediated clearance of LDL particles may have a role in the development of vascular damage in patients with lupus [167]. Moreover, natural IgM-antibodies to phosphorylcholine (PC) are involved in apoptotic cells clearance promoting antiinflammatory pathways; decreased levels have been found in SLE patients, in association with carotid plaque formation and increased vulnerability [168,169]. 5. Psychosocial factors While an association of depression with coronary heart disease has been long recognized in the general population, data on lupus are relatively scarce. Changes in the cardiac autonomic functions due to imbalance between the sympathetic and the parasympathetic systems and pro-inflammatory processes have been implicated [170,171]. Fatigue, anxiety, depression and perception of

7

poor sleep quality have been prevalent in SLE patients compared to healthy controls [172] with estimated rates of depression at 30% [173]. In a recent report, SLE female patients with concomitant depression were shown to have increased carotid IMT- but not plaque- progression [174]. In our lupus group, higher IMT values were found to be independently associated with State-Trait Anxiety Inventory (STAI) - a psychometric questionnaire used to assess anxiety either as a personality feature or as a current state- and in particular with trait anxiety, following adjustment for age, BMI, cholesterol and triglyceride levels, hypertension and current steroid dose; other psychometric parameters evaluated (depression, insomnia and fatigue) were not associated with IMT scores. Presence of plaque was not associated with any of the psychological features evaluated (unpublished results). 6. Association with other comorbidities Atherosclerosis and osteoporosis have been linked in the general population and this association is not fully explained by age or the presence of other shared risk factors such as smoking, physical activity, alcohol intake, menopause and hypertension [175,176]. An inverse association between bone mineral density (BMD) and carotid measurements (plaque and IMT) has been reported in SLE patients [177], while other cohorts did not confirm the association [178,179]. In our lupus cohort, an association of impaired bone health with subclinical atherosclerosis was detected; the presence of plaque was independently associated with impaired bone health (osteoporosis or osteopenia) following adjustment for disease duration, total steroid dose and premature menopause, while IMT values were inversely associated with femoral neck BMD (unpublished observations). 7. CVD risk management in SLE patients Standard guidelines for monitoring SLE patients for increased CV risk are not available [75] and rheumatologists have to rely on rheumatoid arthritis (RA) guidelines and general population data to minimize exposure to CVD risk factors in lupus patients [180e182]. Therefore, adequate control of standard Framingham risk factors (age, total cholesterol, HDL, smoking, systolic blood pressure) could be the initial goal, with methodology borrowed from the general population. Smoking cessation, maintenance of ideal weight and avoidance of sedentary lifestyle should be part of the initial approach; both physical function and strenuous exercise have been negatively associated with IMT and number of plaques [73]. Diabetes mellitus is regarded to be an equivalent of CVD and maintenance of normal fasting plasma glucose levels should be sought. Thiazolidinediones (TZDs) are peroxisome proliferatoractivated receptor gamma (PPARg) agonists, involved in adipocyte differentiation. Data derived from lupus murine models and lupus patients demonstrated a favorable effect on atherosclerosis [183,184]. In lupus patients pioglitazone use has resulted in lipid profile and insulin resistance amelioration [185]. Hypertension should be treated with a blood pressure goal of 130/80 mm Hg, according to the European guidelines on CVD prevention [186,187]. ACE inhibitors are preferably used as first line regiments in patients with renal involvement and have also been found to delay renal disease and decrease the risk of disease activity [188]; angiotensin receptor blockers can also be used when ACE inhibitors are not effective or are not well tolerated [189]. bblockers should be avoided in patients with Raynaud's phenomenon [190] and thiazide diuretics should be used with caution in SLE patients [186].

8

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Regarding dyslipidemia, statins are used for lowering LDL in the general population; in addition they are reported to have antiinflammatory properties [191]. However, data are conflicting regarding their effect in atherosclerosis prevention in the setting of lupus. A decrease in carotid IMT values has been reported after a 2year treatment with rosuvastatin [192], but this effect was not confirmed after 3 years of atorvastatin use in a pediatric lupus cohort despite their favorable effect on TC, LDL and C-reactive protein (CRP) levels [193]. Similarly, in a two year randomized placebo controlled study by Petri et al. neither progression of subclinical atherosclerosis (carotid plaque/IMT, coronary artery calcium) was delayed, nor biochemical measures of inflammation were improved [194] following treatment with atorvastatin 40 mg daily. In contrast, short-term atorvastatin treatment seem to benefit pubertal lupus patients with high CRP levels and middleaged female lupus patients with pathological arterial stiffness [195,196]. Additionally, peptides mimicking apoA-I -the major apolipoprotein component of HDL- could be of use to lower CVD risk in lupus patients; Woo et al. evaluated the effects of L-4F, (apolipoprotein A-1 mimetic peptide), alone or with pravastatin, in apoE / Fas / C57BL/6 female mice that develop osteopenia, immunoglobulin G (IgG) autoantibodies, glomerulonephritis, and atherosclerotic lesions. L-4F treatment significantly reduced all the above manifestations in this murine lupus model of accelerated atherosclerosis [197]. As already mentioned, homocysteine has a toxic effect on the endothelium and high homocysteine levels have been linked to atherosclerosis in general and lupus populations. Folic acid supplementation could lower homocysteine serum concentration and although the efficacy of this approach is not well-established, it could be an inexpensive and safe way to suppress CV risk. Furthermore, a beneficial role of folate supplementation in primary stroke prevention has been recently revealed [198]. Regarding disease related CVD risk factors as they have emerged from the literature data, older male patients with longer disease duration, renal involvement and higher SLICC values seem to constitute a high CVD risk group. As already mentioned, adequate disease control with aggressive immunomodulation could have favorable effects on atherosclerosis in the setting of lupus; antimalarials have also been shown to be protective.

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8. Conclusion The increased prevalence of CV disease is well established in SLE even after correction of the traditional risk factors. Several associations with disease related clinical, genetic and immunological features have been implicated. Further investigation is needed to determine a yet unidentified, possibly disease specific mechanism in autoimmune patients.

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