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The association between adipokines and stigmata of atherosclerosis in patients with systemic lupus erythematosus
The Egyptian Rheumatologist xxx (xxxx) xxx
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The association between adipokines and stigmata of atherosclerosis in patients with systemic lupus erythematosus Zahra Rezaieyazdi a, Zahra Mirfeizi a, Mohammad Reza Hatef a, Golnaz Gholami b, Sima Sedighy c, Habibollah Esmaily d, Mahmoud Reza Azarpazhooh e, Asieh Karimani f, Masoumeh Salari a,⇑ a
Rheumatology Department, Rheumatic Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran Internal Medicine Department, Rheumatic Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran Rheumatology Research Center, Golestan University of Medical Sciences, Gorgan, Iran d Epidemiology and Biostatistics Department, Mashhad University of Medical Sciences, Mashhad, Iran e Neurology Department, Ghaem Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran f Pharmacodynamics and Toxicology Department, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran b c
a r t i c l e
i n f o
Article history: Received 8 February 2020 Accepted 25 February 2020 Available online xxxx Keywords: SLE Leptin Adiponectin Atherosclerosis Adipokine IMT
a b s t r a c t Aim of the work: Early cardiovascular disease is an important cause of morbidity and mortality in systemic lupus erythematosus (SLE). The study was designed to assess the relationship between the serum levels of adipokines and atherosclerotic risk factors in SLE patients. Patients and methods: 56 patients and 31 control were included. Serum levels of leptin, adiponectin, traditional and new risk factors for atherosclerosis including plasma glucose levels, lipid profile, highsensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule-1 (VCAM-1) and homocysteine were measured. The intima-media thickness (IMT) of the carotid was measured by ultrasonography. The SLE disease activity index (SLEDAI-2k) was assessed. Results: The patients mean age was 30.8 ± 9.9 years, disease duration was 55.7 ± 59.3 months and were 54 (91.5%) females and 5 (8.5%) males. Serum adiponectin levels were significantly lower in patients (3. 58 ± 0.4 ng/ml) compared to control (3.9 ± 0.26 ng/ml) (p < 0.001) while leptin levels were comparable. Serum adiponectin levels correlated with triglyceride (r = 0.3, p = 0.003) and high-density lipoprotein (HDL) (r = 0.2, p = 0.04). Serum leptin significantly correlated with the BMI and total cholesterol (r = 0.43, p = 0.002 and r = 0.3, p = 0.04 respectively) as well as with the anti-double stranded deoxyribonucleic acid (anti-dsDNA) (r = 0.28, p = 0.04). There was lack of a meaningful relationship between serum adiponectin and leptin levels and disease duration or risk factors such as hsCRP, VCAM, homocysteine and IMT as well as with the SLEDAI-2k or complement. Conclusions: Serum adiponectin levels inversely correlate with HDL. A significant correlation of leptin with BMI and total cholesterol was found in SLE. None of the two adipokines were associated with atherosclerosis as assessed with the carotid IMT or with the disease activity. Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Systemic lupus erythematosus (SLE) is a disorder of immune regulation where cytokine imbalance and genetic factors are implicated in its pathogenesis [1]. It is a chronic autoimmune connective tissue disease characterized by antibody production, immune complex formation, extensive inflammation and involvement of various organs and systems [2].
Peer review under responsibility of Egyptian Society of Rheumatic Diseases. ⇑ Corresponding author at: Rheumatology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. E-mail address: [email protected] (M. Salari).
Patients with SLE are prone to premature atherosclerosis [3] of which myocardial infarction is the main presentation. Vascular events are 7–10 times more common in SLE patients under 45 years of age [2,3] and early heart involvement plays a significant role in morbidity and mortality [4]. Systemic inflammation and autoimmune vascular damage are the main driving events behind cardiovascular disease (CVD) [5]. Chronic inflammation, antibody production and atherosclerotic risk factors such as hypertension, central obesity, dyslipidemia, and glucose intolerance contribute to the development of early atherosclerosis [6]. Some of these risk factors may be the result of corticosteroid use [7]. Clinical factors associated with coronary heart disease (CHD) in SLE include disease activity [8], nephritis, hypocomplementemia, anti-double
https://doi.org/10.1016/j.ejr.2020.02.010 1110-1164/Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Z. Rezaieyazdi, Z. Mirfeizi, M. Reza Hatef et al., The association between adipokines and stigmata of atherosclerosis in patients with systemic lupus erythematosus, The Egyptian Rheumatologist, https://doi.org/10.1016/j.ejr.2020.02.010
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stranded deoxyribonucleic acid (antidsDNA), antiphospholipid antibodies [9], oxidative stress, C-reactive protein (CRP)[11] and elevated homocysteine [10]. Insulin sensitivity, obesity, dyslipidemia and intima-media thickness (IMT) are altered in SLE patients, especially those with metabolic syndrome (MetS) with an associated increase in disease activity and damage as well as increased risk of atherosclerosis [11,12]. Even SLE patients without traditional major cardiovascular factors may have increased risk of future cardiac events [13]. The adipose tissue secretes a group of cytokines, including leptin and adiponectin [3,14], that have autocrine, paracrine and endocrine functions [4,15]. Leptin is related to adipose tissue mass and is higher in women [4]. It is related to vascular proliferation, plaque formation and decreased arterial dispensability which contribute to the progression of atherosclerosis [16]. Adiponectin, a protein derived from adipose tissue is reduced in obese patients [14] and plays an important role in the increased insulin sensitivity in skeletal muscles and the liver [4]. Due to anti-inflammatory and anti-thrombotic effects, it is important in protecting from atherosclerosis and MetS. Low levels of adiponectin are associated with insulin resistance, dyslipidemia, and increased coronary calcifications [17,18]. Since conventional cardiovascular risk factors and MetS partially account for the increased risk of CVDs in SLE, the role of inflammatory mediators such as adipokines in the acceleration of atherosclerosis has been suggested [19–21]. Cardiac complications of lupus are potentially serious eventhough the pathogenesis is incompletely justified [22]. The aim of the present study was to determine the serum levels of leptin and adiponectin and to assess their relation to atherosclerotic risk factors and disease activity in patients with SLE.
2. Patients and methods This cross-sectional study included 59 patients fulfilling the Systemic Lupus International Collaborating Clinics classification (SLICC) criteria for SLE [23] at the Rheumatology clinics of two University Hospitals (Ghaem and Imam Reza) in Mashhad, Iran, between 2013 and 2014. All patients were diagnosed with SLE at least 1 year prior to the study and those under the age of 16, pregnant, use estrogen or progesterone containing drugs, or have malignancy were excluded. 31 healthy age and sex matched healthy individuals were considered as controls. All subjects willingly filled out informed consent sheets and the study was approved by the Ethics Committee of the Mashhad University of Medical Sciences (Number: 88667). Parameters including age; sex; body mass index (BMI); diabetes; hypertension; hyperlipidemia; previous atherosclerotic disease such as ischemic heart disease, coronary bypass surgery or angioplasty, stroke, peripheral vascular disease, and claudication; premature ovarian failure; and history of drug consumption were recorded through careful observation, interview, and physical exam performed on every patient. The SLE disease activity index 2000 (SLEDAI-2k) was assessed [24] and patients were categorized into 3 groups with scores 4 (inactive), 5–9 (mild to moderate) and 10 (high). This stratification of SLEDAI was done arbitrarily. In patients, anti-dsDNA, C3, and C4 were measured using indirect immunofluorescence assay. The fasting blood glucose (FBG) and lipid profile were assessed. The high-sensitivity C-reactive protein (hs-CRP) ELISA kit (Parsazmoon, Iran), the human vascular cell adhesion molecule 1 (VCAM-1) ELISAkit (Cusabio, China), and the homocysteine enzyme immunoassay (EIA) (Axis-Shield, Scotland), were applied to quantify hs-CRP, VCAM1, and homocysteine levels, respectively. The sandwich enzyme-linked immunosorbent assay (ELISA) kits (Bio-Equip, China) and (Abnova, Tiawan) were used to determine serum leptin and adiponectin levels, respectively.
In order to screen for carotid plaques and determine the IMT every patient and control underwent right and left common carotid Doppler ultrasound examination (Medison-man 8000EX) with linear 10 MHz probe; a plaque was defined as a specific area with hyper-echogenicity or a focal elevation in to the lumenat least 50% of the artery circumference. The mean thickness of the sum of left and right sides was recorded. 2.1. Statistical analysis Data were statistically analyzed using the Statistical Package for the Social Sciences (SPSS) version 11.5. Implementing the Kolmogorov-Smirnov test, for the parametric data (independentsamples t-test and Pearson correlation coefficient) and for nonparametric (Mann-Whitney, Kruskal-Wallis, and Spearman rank correlation coefficient) were used. The results from the Kolmogorov-Smirnov test showed that the variables of age and BMI had a normal distribution. The receiver operating characterisitic (ROC) curves were determined. A p-value < 0.05 was regarded as significant. 3. Results This study was performed on 59 SLE patients; 54 (91.5%) were females and 5 (8.5%) males (F:M 10.8:1). Similarly in the control, 27 (87.1%) were female and 4 (12.9%) male (6.75:1) (p = 0.4). The mean age in SLE and control was 30.8 ± 9.9 and 34.2 ± 6.5 years, respectively (p = 0.06). The disease duration was 55.7 ± 59.3 month. The BMI was also comparable 23.9 ± 5.2 for patients and 24.1 ± 4. 1for control (p = 0.8). All patients (100%) received prednisolone, 57 (96.6%) received antimalarials and 11 (18.6%) received cyclophosphamide (CYC). 6 (10.7%) received mycophenolate mofetil (MMF), 15 (25.4%) received azathioprine (AZA), 7 (11.9%) received methotrexate (MTX) and 10 (16.9%) received statins. The cardiovascular system was involved in 9 (15.2%) patients; 3 (5%) pectoris angina, 5 (8.4%) had pericarditis and 1 (1.6%) had a cardiovascular intervention done; renal affection was present in 18 (30.5%) and neuropsychiatric in 5 (8.4%): 2 (3.3%) psychosis, 2 (3.3%) seizure and 1 (1.6%) cerebrovascular accident (CVA). 12 patients and 2 control had hypertension and were comparable (p = 0.07). Only 2 were diabetic. 5 patients had carotid plaque and the mean carotid IMT was 0.39 ± 0.08 and 0.36 ± 0.08 for patients and control, respectively (p = 0.07). Based on SLEDAI-2k, 29 were inactive, 13 had mild-moderate activity and 17 patients were highly active. The patients had a SLEDAI-2k score of 7.9 ± 7.3. The risk factors of atherosclerosis in the patients and control are presented in Table 1.
Table 1 Risk factors of atherosclerosis in the systemic lupus erythematosus patients and control. Variable mean ± SD
SLE patients (n = 59)
Control (n = 31)
p
BMI LDL (mg/dl) HDL (mg/dl) hs-CRP (mg/dl) Homocysteine (mmol/L) VCAM1 (ng/ml) Cholesterol (mg/dl) Triglycerides (mg/dl) WBC (103/mm3) Platelets (103/mm3) Adiponectin (ng/ml) Leptin (ng/ml) IMT (mm)
23.95 ± 5.2 121.7 ± 32.8 44.7 ± 9.3 2.5 ± 3.02 24.1 ± 8.1 853.3 ± 369.3 181.9 ± 43.4 135.6 ± 45.8 5.74 ± 2.6 230.3 ± 86.3 3.6 ± 0.4 20.1 ± 55.5 0.39 ± 08
24.1 ± 4.2 98.8 ± 37.9 47.13 ± 8.2 3.1 ± 11.8 12.4 ± 1.9 364.3 ± 175.5 184.1 ± 147.9 72 ± 34.7 5.6 ± 0.9 199.9 ± 76.2 3.9 ± 0.26 8.2 ± 7 0.36 ± 0.08
0.86 0.001 0.17 0.68 <0.001 <0.001 0.92 <0.001 <0.001 <0.001 <0.001 0.28 0.08
BMI: body mass index, LDL: low density lipoprotein, HDL: high density lipoprotein, hs-CRP: high sensitivity C-reactive protein, VCAM1: vascular cell adhesion molecule-1, WBC: white blood cells, IMT: intima media thickness.
Please cite this article as: Z. Rezaieyazdi, Z. Mirfeizi, M. Reza Hatef et al., The association between adipokines and stigmata of atherosclerosis in patients with systemic lupus erythematosus, The Egyptian Rheumatologist, https://doi.org/10.1016/j.ejr.2020.02.010
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The mean adiponectin level was significantly lower in patients (3.6 ± 0.4 ng/ml) compared to control (3.9 ± 0.3 ng/ml) (p < 0.001). The serum leptin in patients was 20.1 ± 55.5 ng/ml and 8.2 ± 7 ng/ml in control (p = 0.28) (Fig. 1). Serum adiponectin in females (3.6 ± 0.4 ng/ml) was significantly higher than in males (3.1 ± 0.5 ng/ml) (p = 0.02); for leptin, levels were 10.84 ± 11 ng/ml and 4.08 ± 2.3 ng/ml, respectively (p = 0.01). There was no significant difference in the serum levels of adiponectin (p = 0.4) and leptin (p = 0.5) between those with and without renal involvement. Serum adiponectin levels correlated with triglyceride (r = 0.3, p = 0.003) and high-density lipoprotein (HDL) (r = 0.27, p = 0.04). Serum leptin significantly correlated with the BMI and total cholesterol (r = 0.43, p = 0.002) and r = 0.3, p = 0.04 respectively) as well as with the anti-dsDNA (r = 0.2, p = 0.04). There was lack of a meaningful relationship between serum adiponectin and leptin levels and disease duration or risk factors such as hsCRP, VCAM, homocysteine and IMT as well as with the SLEDAI-2k, C3 or C4 (Table 2). In patients, leptin and adiponectin were not significantly correlated (r = 0.07, p = 0.6). The sensitivity and specificity of leptin and adiponectin in discriminating patients from control are presented (Table 3, Fig. 2).
Table 2 Correlation of serum adiponectin and leptin levels with traditional and new cardiovascular risk factors, disease activity and intima media thickness in systemic lupus erythematosus patients. Risk factors Rs (p)
Age Dis. Dur. BMI FBG TG LDL HDL Total Cho hs-CRP VCAM-1 Homocysteine C3 C4 Anti-dsDNA SLEDAI-2k IMT
SLE patients (n = 59) Adiponectin
Leptin
0.01 (0.92) 0.2 (0.15) 0.01 (0.94) 0.01 (0.94) 0.3 (0.003) 0.17 (0.2) 0.27 (0.04) 0.02 (0.86) 0.21 (0.13) 0.05 (0.74) 0.13 (0.36) 0.03 (0.80) 0.09 (0.52) 0.05 (0.74) 0.09 (0.51) 0.14 (0.32)
0.01 (0.93) 0.08 (0.57) 0.43 (0.002) 0.04 (0.76) 0.06 (0.67) 0.03 (0.84) 0.06 (0.69) 0.3 (0.04) 0.26 (0.07) 0.22 (0.13) 0.07 (0.62) 0.08 (0.61) 0.13 (0.39) 0.28 (0.04) 0.03 (0.84) 0.05 (0.73)
LDL = low-density lipoprotein, TG = triglyceride, HDL = high-density lipoprotein, FPG = fasting blood glucose. hsCRP = high-sensitivity C-reactive protein, VCAM1 = vascular cell adhesion molecule. Bold values are significant at p < 0.05
4. Discussion Adipokines alter metabolism via the production of cytokines that lead to the malfunctioning of the vascular endothelium, alteration of the lipid profile, hypertension and may rupture atherosclerotic plaques. They are potential risk factors for early atherosclerosis in SLE [5]. In this study, adiponectin and leptin levels showed no correlation with atherosclerosis as assessed by the carotid IMT in patients with SLE. The role of adipokines in MetS and disease activity in SLE has been investigated. An increase in the level of leptin in SLE patients has been reported [25,26]. Chung et al. demonstrated increased BMI with higher leptin levels in SLE patients and found a significant correlation with triglycerides and cholesterol levels [26]. The association between higher leptin levels and increased BMI has also been recognized by Xu et al. [27]. Scotece et al. have also investigated this relationship as a risk factor for CVD in patients with SLE [28]. Higher levels of leptin have been shown by Vadacca and coworkers to be significantly related to vascular compromise [19]. In the investigation by Viswanath et al., leptin was considered an important factor in the context of inflammation. The levels of leptin are higher in females in
Fig. 1. Serum adipokine and leptin levels in systemic lupus erythematosus patients and control.
Table 3 The receiver operating characteristic (ROC) for serum leptin and adiponectin in discriminating systemic lupus erythematosus patients. Characteristic
Sensitivity (%) Specificity (%) PPV (%) NPV (%) Cut-point (ng/ml) AUC p-value
SLE patients (n = 5) Adiponectin
Leptin
58.9 (45–71.9) 74.2 (55.4–88.1) 80.5 (65.1–91.2) 50 (34.9–65.1) 3.7 0.76 (0.65–0.85) <0.0001
26 (14.6–40.3) 93.1 (77.2–99.2) 86.7 (59.5–98.3) 42.2 (29.9–55.2) >19.3 0.57 (0.46–0.68) 0.27
SLE: systemic lupus erythematosus, PPV: positive predictive power, NPP: negative predictive power, AUC: area under the curve
Fig. 2. The receiver operating characteristic (ROC) for serum leptin and adiponectin in discriminating systemic lupus erythematosus patients.
Please cite this article as: Z. Rezaieyazdi, Z. Mirfeizi, M. Reza Hatef et al., The association between adipokines and stigmata of atherosclerosis in patients with systemic lupus erythematosus, The Egyptian Rheumatologist, https://doi.org/10.1016/j.ejr.2020.02.010
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comparison with males even after adjusting for BMI that has to be discussed in view of increased prevalence of autoimmune diseases in females. The leptin/adiponectin ratio was introduced as an independent risk factor for insulin resistance and CVD [29]. In the present study, leptin levels were not higher in patients than the control. BMI, however, significantly correlated with serum leptin levels. This is indicative of higher leptin levels in SLE patients with increased BMI during chronic inflammation and may be considered as an independent risk factor for premature atherosclerosis. The association between elevated leptin levels and increased BMI suggests the need for changes in lifestyle to decrease the morbidity and mortality resulting from cardiovascular events [30]. In the study of Diaz Rizo et al., comparing between SLE with and without nephritis, there were no significant differences in age, BMI and serum adipokines. It was remarked to inconsistency between inflammation and adipokines [31]. In this work, there was an association between leptin and total cholesterol levels. Elevated serum leptin levels during hyperlipidemia and insulin resistance were reported as independent risk factors for CVD [26,32]. Selzer et al. noted the causative effect of inflammatory cytokines on the development of atherosclerotic plaques [33]. It has been established that adiponectin decreases in SLE [28]. Serum adiponectin levels are inversely related to BMI and insulin resistance [26]. In line with the above, our findings demonstrated significantly lower serum adiponectin levels in patients with SLE than in control; this may be due to the effect of chronic inflammation. However, no meaningful relationship was observed between the serum levels of adiponectin and age, hypertension, cholesterol, LDL, FBG and BMI in SLE patients. Triglyceride and adiponectin levels negatively correlated, which is suggestive of the effect of MetS on the lowering of adiponectin and the secondary effect on atherosclerosis. Measuring hs-CRP is a useful marker of disease activity, increased IMT and subclinical atherosclerosis in SLE especially those with positive ds-DNA [13]. Adipokines correlated with CRP levels in the study of Chung et al., in disagreement to the findings in the present work. Low adiponectin levels have been introduced as a possible risk factor for CHD but not essentially with the degree of coronary calcification [26]. Shields et al. have demonstrated similar findings in the descending aorta [34]. Xu et al. demonstrated a lack of correlation between leptin levels and coronary calcification [27]. Yet, no correlation was found between adipokines and vascular IMT in another study [35]. The present study indicated a lack of association between serum leptin and adiponectin levels with the IMT in any of the carotid artery branches. In the present study, the relationship between leptin and adiponectin levels and SLEDAI was unremarkable. In agreement, serum leptin and adiponectin levels did not correlate with disease activity [4,26]. Shang et al. found high activity disease in SLE patients with a carotid atheroma plaque compared to those without [21]. In contrast, leptin but not adiponectin correlated with disease activity in SLE patients and SLEDAI showed no relation to vascular stiffness parameters [19]. A significant correlation was found between leptin and anti-dsDNA. In another study, SLE patients had elevated serum leptin levels that correlated significantly with BMI and total cholesterol but not with the SLEDAI [36]. On the contrary, SLE disease activity was found to affect the lipid level and its control would be helpful in treatment strategies. Likewise, control of hyerlipidemia can favourably affect SLE renal disease [37]. Although lower adiponectin levels and increased leptin were found in the SLE patients, no significant relation was found to exist with carotid atherosclerosis. Unknown risk factors may contribute to premature atherosclerosis in SLE and may confound the effect of adipokines. Other factors such as race and genetics may influence the inflammatory response and must be taken into account. Hereby, among the limitations to the present study is the cross-
sectional design and not taking into consideration the medications received. In conclusion, there was a lack of association between adipokines and the risk factors of age, FPG, LDL, hs-CRP, VCAM-1 and homocysteine in patients with lupus. However, serum adiponectin levels inversely correlated with HDL. A significant correlation of leptin with BMI and total cholesterol was found in SLE. None of the two adipokines were associated with atherosclerosis as assessed with the carotid IMT. There was no signficant correlation between adipokines and disease activity. Conflict of interest The authors have declared no conflict of interest. Funding This work, originating from a medical thesis (N:T 2557), was supported by a grant from the Vice Chancellor of Research at Mashhad University of Medical Sciences. References [1] Azkalany GS, Gheita TA, Gaber W, Mohey A. Clinical significance of serum TNFa and -308 G/A promoter polymorphism and serum Il-6 and -174 G/C promoter polymorphism in systemic lupus erythematosus patients. Egyptian Rheumatologist 2012;34(3):119–25. [2] Hahn BH. Systemic Lupus Erythematosus. 18th ed. New York: McGrawHill; 2012. p. 2724–35. [3] Hahn BH, Tsao BP. Pathogenesis of systemic lupus erythematosus. 8th ed. Canada: Saunders Elsevier; 2012. p. 1233–310. [4] Al M, Ng L, Tyrrell P, Bargman J, Bradley T, Silverman E. Adipokines as novel biomarkers in paediatric systemic lupus erythematosus. Rheumatology 2009;48:497–501. [5] Lee AB, Godfrey T, Rowley KG, Karschimkus CS, Dragicevic G, Romas E, et al. Traditional risk factor assessment does not capture the extent of cardiovascular risk in systemic lupus erythematosus. Intern Med J 2006;36:237–43. [6] Hak AE, Karlson EW, Feskanich D, Stampfer MJ, Costenbader KH. Systemic lupus erythematosus and the risk of cardiovascular disease: results from the nurses’ health study. Arthritis Care Res (Hoboken) 2009;61:1396–402. [7] Gustafsson J, Gunnarsson I, Börjesson O, Pettersson S, Möller S, Fei GZ, et al. Predictors of the first cardiovascular event in patients with systemic lupus erythematosus—a prospective cohort study. Arthritis Res Ther 2009;11(6): R186. [8] Pons-Estel GJ, González LA, Zhang J, Burgos PI, Reveille JD, Vilá LM, et al. Predictors of cardiovascular damage in patients with systemic lupus erythematosus: data from LUMINA (LXVIII), a multiethnic US cohort. Rheumatology 2009;48:817–22. [9] Nojima J, Masuda Y, Iwatani Y, Kuratsune H, Watanabe Y, Suehisa E, et al. Arteriosclerosis obliterans associated with anti-cardiolipin antibody/beta2glycoprotein I antibodies as a strong risk factor for ischaemic heart disease in patients with systemic lupus erythematosus. Rheumatology 2008;47:684–9. [10] Manzi S, Selzer F, Sutton-Tyrrell K, Fitzgerald SG, Rairie JE, Tracy RP, et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum 1999;42:51–60. [11] Gheita TA, Raafat HA, Sayed S, El-Fishawy H, Nasrallah MM, Abdel-Rasheed E. Metabolic syndrome and insulin resistance comorbidity in systemic lupus erythematosus: effect on carotid intima-media thickness. Z Rheumatol. 2013;72(2):172–7. [12] Rizk A, Gheita TA, Nassef S, Abdallah A. The impact of obesity in systemic lupus erythematosus on disease parameters, quality of life, functional capacity and the risk of atherosclerosis. Int J Rheum Dis. 2012;15(3):261–7. [13] Gheita TA, El-Gazzar II, Azkalany G, El-Fishawy HS, El-Faramawy A. Highsensitivity C-reactive protein (hs-CRP) in systemic lupus erythematosus patients without cardiac involvement; relation to disease activity, damage and intima-media thickness. Egyptian Rheumatologist 2012;34(4):147–52. [14] Flier JS, Maratos-Flier E. Biology of Obesity. 18th ed. New York: McGrawHill; 2012. p. 622–9. [15] De Sanctis JB, Zabaleta M, Bianco NE, Garmendia JV, Rivas L. Serum adipokine levels in patients with systemic lupus erythematosus: brief definite report. Autoimmunity 2009;42:272–4. [16] Dubey L, Hesong Z. Role of leptin in atherogenesis. Exp Clin Cardiol 2006;11 (4):269–75. [17] Maahs DM, Ogden LG, Kinney GL, Wadwa P, Snell-Bergeon JK, Dabelea D, et al. Low plasma adiponectin levels predict progression of coronary artery calcification. Circulation 2005;111:747–53.
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Please cite this article as: Z. Rezaieyazdi, Z. Mirfeizi, M. Reza Hatef et al., The association between adipokines and stigmata of atherosclerosis in patients with systemic lupus erythematosus, The Egyptian Rheumatologist, https://doi.org/10.1016/j.ejr.2020.02.010
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The association between adipokines and stigmata of atherosclerosis in patients with systemic lupus erythematosus Zahra Rezaieyazdi a, Zahra Mirfeizi a, Mohammad Reza Hatef a, Golnaz Gholami b, Sima Sedighy c, Habibollah Esmaily d, Mahmoud Reza Azarpazhooh e, Asieh Karimani f, Masoumeh Salari a,⇑ a
Rheumatology Department, Rheumatic Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran Internal Medicine Department, Rheumatic Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran Rheumatology Research Center, Golestan University of Medical Sciences, Gorgan, Iran d Epidemiology and Biostatistics Department, Mashhad University of Medical Sciences, Mashhad, Iran e Neurology Department, Ghaem Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran f Pharmacodynamics and Toxicology Department, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran b c
a r t i c l e
i n f o
Article history: Received 8 February 2020 Accepted 25 February 2020 Available online xxxx Keywords: SLE Leptin Adiponectin Atherosclerosis Adipokine IMT
a b s t r a c t Aim of the work: Early cardiovascular disease is an important cause of morbidity and mortality in systemic lupus erythematosus (SLE). The study was designed to assess the relationship between the serum levels of adipokines and atherosclerotic risk factors in SLE patients. Patients and methods: 56 patients and 31 control were included. Serum levels of leptin, adiponectin, traditional and new risk factors for atherosclerosis including plasma glucose levels, lipid profile, highsensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule-1 (VCAM-1) and homocysteine were measured. The intima-media thickness (IMT) of the carotid was measured by ultrasonography. The SLE disease activity index (SLEDAI-2k) was assessed. Results: The patients mean age was 30.8 ± 9.9 years, disease duration was 55.7 ± 59.3 months and were 54 (91.5%) females and 5 (8.5%) males. Serum adiponectin levels were significantly lower in patients (3. 58 ± 0.4 ng/ml) compared to control (3.9 ± 0.26 ng/ml) (p < 0.001) while leptin levels were comparable. Serum adiponectin levels correlated with triglyceride (r = 0.3, p = 0.003) and high-density lipoprotein (HDL) (r = 0.2, p = 0.04). Serum leptin significantly correlated with the BMI and total cholesterol (r = 0.43, p = 0.002 and r = 0.3, p = 0.04 respectively) as well as with the anti-double stranded deoxyribonucleic acid (anti-dsDNA) (r = 0.28, p = 0.04). There was lack of a meaningful relationship between serum adiponectin and leptin levels and disease duration or risk factors such as hsCRP, VCAM, homocysteine and IMT as well as with the SLEDAI-2k or complement. Conclusions: Serum adiponectin levels inversely correlate with HDL. A significant correlation of leptin with BMI and total cholesterol was found in SLE. None of the two adipokines were associated with atherosclerosis as assessed with the carotid IMT or with the disease activity. Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Systemic lupus erythematosus (SLE) is a disorder of immune regulation where cytokine imbalance and genetic factors are implicated in its pathogenesis [1]. It is a chronic autoimmune connective tissue disease characterized by antibody production, immune complex formation, extensive inflammation and involvement of various organs and systems [2].
Peer review under responsibility of Egyptian Society of Rheumatic Diseases. ⇑ Corresponding author at: Rheumatology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. E-mail address: [email protected] (M. Salari).
Patients with SLE are prone to premature atherosclerosis [3] of which myocardial infarction is the main presentation. Vascular events are 7–10 times more common in SLE patients under 45 years of age [2,3] and early heart involvement plays a significant role in morbidity and mortality [4]. Systemic inflammation and autoimmune vascular damage are the main driving events behind cardiovascular disease (CVD) [5]. Chronic inflammation, antibody production and atherosclerotic risk factors such as hypertension, central obesity, dyslipidemia, and glucose intolerance contribute to the development of early atherosclerosis [6]. Some of these risk factors may be the result of corticosteroid use [7]. Clinical factors associated with coronary heart disease (CHD) in SLE include disease activity [8], nephritis, hypocomplementemia, anti-double
https://doi.org/10.1016/j.ejr.2020.02.010 1110-1164/Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Z. Rezaieyazdi, Z. Mirfeizi, M. Reza Hatef et al., The association between adipokines and stigmata of atherosclerosis in patients with systemic lupus erythematosus, The Egyptian Rheumatologist, https://doi.org/10.1016/j.ejr.2020.02.010
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stranded deoxyribonucleic acid (antidsDNA), antiphospholipid antibodies [9], oxidative stress, C-reactive protein (CRP)[11] and elevated homocysteine [10]. Insulin sensitivity, obesity, dyslipidemia and intima-media thickness (IMT) are altered in SLE patients, especially those with metabolic syndrome (MetS) with an associated increase in disease activity and damage as well as increased risk of atherosclerosis [11,12]. Even SLE patients without traditional major cardiovascular factors may have increased risk of future cardiac events [13]. The adipose tissue secretes a group of cytokines, including leptin and adiponectin [3,14], that have autocrine, paracrine and endocrine functions [4,15]. Leptin is related to adipose tissue mass and is higher in women [4]. It is related to vascular proliferation, plaque formation and decreased arterial dispensability which contribute to the progression of atherosclerosis [16]. Adiponectin, a protein derived from adipose tissue is reduced in obese patients [14] and plays an important role in the increased insulin sensitivity in skeletal muscles and the liver [4]. Due to anti-inflammatory and anti-thrombotic effects, it is important in protecting from atherosclerosis and MetS. Low levels of adiponectin are associated with insulin resistance, dyslipidemia, and increased coronary calcifications [17,18]. Since conventional cardiovascular risk factors and MetS partially account for the increased risk of CVDs in SLE, the role of inflammatory mediators such as adipokines in the acceleration of atherosclerosis has been suggested [19–21]. Cardiac complications of lupus are potentially serious eventhough the pathogenesis is incompletely justified [22]. The aim of the present study was to determine the serum levels of leptin and adiponectin and to assess their relation to atherosclerotic risk factors and disease activity in patients with SLE.
2. Patients and methods This cross-sectional study included 59 patients fulfilling the Systemic Lupus International Collaborating Clinics classification (SLICC) criteria for SLE [23] at the Rheumatology clinics of two University Hospitals (Ghaem and Imam Reza) in Mashhad, Iran, between 2013 and 2014. All patients were diagnosed with SLE at least 1 year prior to the study and those under the age of 16, pregnant, use estrogen or progesterone containing drugs, or have malignancy were excluded. 31 healthy age and sex matched healthy individuals were considered as controls. All subjects willingly filled out informed consent sheets and the study was approved by the Ethics Committee of the Mashhad University of Medical Sciences (Number: 88667). Parameters including age; sex; body mass index (BMI); diabetes; hypertension; hyperlipidemia; previous atherosclerotic disease such as ischemic heart disease, coronary bypass surgery or angioplasty, stroke, peripheral vascular disease, and claudication; premature ovarian failure; and history of drug consumption were recorded through careful observation, interview, and physical exam performed on every patient. The SLE disease activity index 2000 (SLEDAI-2k) was assessed [24] and patients were categorized into 3 groups with scores 4 (inactive), 5–9 (mild to moderate) and 10 (high). This stratification of SLEDAI was done arbitrarily. In patients, anti-dsDNA, C3, and C4 were measured using indirect immunofluorescence assay. The fasting blood glucose (FBG) and lipid profile were assessed. The high-sensitivity C-reactive protein (hs-CRP) ELISA kit (Parsazmoon, Iran), the human vascular cell adhesion molecule 1 (VCAM-1) ELISAkit (Cusabio, China), and the homocysteine enzyme immunoassay (EIA) (Axis-Shield, Scotland), were applied to quantify hs-CRP, VCAM1, and homocysteine levels, respectively. The sandwich enzyme-linked immunosorbent assay (ELISA) kits (Bio-Equip, China) and (Abnova, Tiawan) were used to determine serum leptin and adiponectin levels, respectively.
In order to screen for carotid plaques and determine the IMT every patient and control underwent right and left common carotid Doppler ultrasound examination (Medison-man 8000EX) with linear 10 MHz probe; a plaque was defined as a specific area with hyper-echogenicity or a focal elevation in to the lumenat least 50% of the artery circumference. The mean thickness of the sum of left and right sides was recorded. 2.1. Statistical analysis Data were statistically analyzed using the Statistical Package for the Social Sciences (SPSS) version 11.5. Implementing the Kolmogorov-Smirnov test, for the parametric data (independentsamples t-test and Pearson correlation coefficient) and for nonparametric (Mann-Whitney, Kruskal-Wallis, and Spearman rank correlation coefficient) were used. The results from the Kolmogorov-Smirnov test showed that the variables of age and BMI had a normal distribution. The receiver operating characterisitic (ROC) curves were determined. A p-value < 0.05 was regarded as significant. 3. Results This study was performed on 59 SLE patients; 54 (91.5%) were females and 5 (8.5%) males (F:M 10.8:1). Similarly in the control, 27 (87.1%) were female and 4 (12.9%) male (6.75:1) (p = 0.4). The mean age in SLE and control was 30.8 ± 9.9 and 34.2 ± 6.5 years, respectively (p = 0.06). The disease duration was 55.7 ± 59.3 month. The BMI was also comparable 23.9 ± 5.2 for patients and 24.1 ± 4. 1for control (p = 0.8). All patients (100%) received prednisolone, 57 (96.6%) received antimalarials and 11 (18.6%) received cyclophosphamide (CYC). 6 (10.7%) received mycophenolate mofetil (MMF), 15 (25.4%) received azathioprine (AZA), 7 (11.9%) received methotrexate (MTX) and 10 (16.9%) received statins. The cardiovascular system was involved in 9 (15.2%) patients; 3 (5%) pectoris angina, 5 (8.4%) had pericarditis and 1 (1.6%) had a cardiovascular intervention done; renal affection was present in 18 (30.5%) and neuropsychiatric in 5 (8.4%): 2 (3.3%) psychosis, 2 (3.3%) seizure and 1 (1.6%) cerebrovascular accident (CVA). 12 patients and 2 control had hypertension and were comparable (p = 0.07). Only 2 were diabetic. 5 patients had carotid plaque and the mean carotid IMT was 0.39 ± 0.08 and 0.36 ± 0.08 for patients and control, respectively (p = 0.07). Based on SLEDAI-2k, 29 were inactive, 13 had mild-moderate activity and 17 patients were highly active. The patients had a SLEDAI-2k score of 7.9 ± 7.3. The risk factors of atherosclerosis in the patients and control are presented in Table 1.
Table 1 Risk factors of atherosclerosis in the systemic lupus erythematosus patients and control. Variable mean ± SD
SLE patients (n = 59)
Control (n = 31)
p
BMI LDL (mg/dl) HDL (mg/dl) hs-CRP (mg/dl) Homocysteine (mmol/L) VCAM1 (ng/ml) Cholesterol (mg/dl) Triglycerides (mg/dl) WBC (103/mm3) Platelets (103/mm3) Adiponectin (ng/ml) Leptin (ng/ml) IMT (mm)
23.95 ± 5.2 121.7 ± 32.8 44.7 ± 9.3 2.5 ± 3.02 24.1 ± 8.1 853.3 ± 369.3 181.9 ± 43.4 135.6 ± 45.8 5.74 ± 2.6 230.3 ± 86.3 3.6 ± 0.4 20.1 ± 55.5 0.39 ± 08
24.1 ± 4.2 98.8 ± 37.9 47.13 ± 8.2 3.1 ± 11.8 12.4 ± 1.9 364.3 ± 175.5 184.1 ± 147.9 72 ± 34.7 5.6 ± 0.9 199.9 ± 76.2 3.9 ± 0.26 8.2 ± 7 0.36 ± 0.08
0.86 0.001 0.17 0.68 <0.001 <0.001 0.92 <0.001 <0.001 <0.001 <0.001 0.28 0.08
BMI: body mass index, LDL: low density lipoprotein, HDL: high density lipoprotein, hs-CRP: high sensitivity C-reactive protein, VCAM1: vascular cell adhesion molecule-1, WBC: white blood cells, IMT: intima media thickness.
Please cite this article as: Z. Rezaieyazdi, Z. Mirfeizi, M. Reza Hatef et al., The association between adipokines and stigmata of atherosclerosis in patients with systemic lupus erythematosus, The Egyptian Rheumatologist, https://doi.org/10.1016/j.ejr.2020.02.010
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The mean adiponectin level was significantly lower in patients (3.6 ± 0.4 ng/ml) compared to control (3.9 ± 0.3 ng/ml) (p < 0.001). The serum leptin in patients was 20.1 ± 55.5 ng/ml and 8.2 ± 7 ng/ml in control (p = 0.28) (Fig. 1). Serum adiponectin in females (3.6 ± 0.4 ng/ml) was significantly higher than in males (3.1 ± 0.5 ng/ml) (p = 0.02); for leptin, levels were 10.84 ± 11 ng/ml and 4.08 ± 2.3 ng/ml, respectively (p = 0.01). There was no significant difference in the serum levels of adiponectin (p = 0.4) and leptin (p = 0.5) between those with and without renal involvement. Serum adiponectin levels correlated with triglyceride (r = 0.3, p = 0.003) and high-density lipoprotein (HDL) (r = 0.27, p = 0.04). Serum leptin significantly correlated with the BMI and total cholesterol (r = 0.43, p = 0.002) and r = 0.3, p = 0.04 respectively) as well as with the anti-dsDNA (r = 0.2, p = 0.04). There was lack of a meaningful relationship between serum adiponectin and leptin levels and disease duration or risk factors such as hsCRP, VCAM, homocysteine and IMT as well as with the SLEDAI-2k, C3 or C4 (Table 2). In patients, leptin and adiponectin were not significantly correlated (r = 0.07, p = 0.6). The sensitivity and specificity of leptin and adiponectin in discriminating patients from control are presented (Table 3, Fig. 2).
Table 2 Correlation of serum adiponectin and leptin levels with traditional and new cardiovascular risk factors, disease activity and intima media thickness in systemic lupus erythematosus patients. Risk factors Rs (p)
Age Dis. Dur. BMI FBG TG LDL HDL Total Cho hs-CRP VCAM-1 Homocysteine C3 C4 Anti-dsDNA SLEDAI-2k IMT
SLE patients (n = 59) Adiponectin
Leptin
0.01 (0.92) 0.2 (0.15) 0.01 (0.94) 0.01 (0.94) 0.3 (0.003) 0.17 (0.2) 0.27 (0.04) 0.02 (0.86) 0.21 (0.13) 0.05 (0.74) 0.13 (0.36) 0.03 (0.80) 0.09 (0.52) 0.05 (0.74) 0.09 (0.51) 0.14 (0.32)
0.01 (0.93) 0.08 (0.57) 0.43 (0.002) 0.04 (0.76) 0.06 (0.67) 0.03 (0.84) 0.06 (0.69) 0.3 (0.04) 0.26 (0.07) 0.22 (0.13) 0.07 (0.62) 0.08 (0.61) 0.13 (0.39) 0.28 (0.04) 0.03 (0.84) 0.05 (0.73)
LDL = low-density lipoprotein, TG = triglyceride, HDL = high-density lipoprotein, FPG = fasting blood glucose. hsCRP = high-sensitivity C-reactive protein, VCAM1 = vascular cell adhesion molecule. Bold values are significant at p < 0.05
4. Discussion Adipokines alter metabolism via the production of cytokines that lead to the malfunctioning of the vascular endothelium, alteration of the lipid profile, hypertension and may rupture atherosclerotic plaques. They are potential risk factors for early atherosclerosis in SLE [5]. In this study, adiponectin and leptin levels showed no correlation with atherosclerosis as assessed by the carotid IMT in patients with SLE. The role of adipokines in MetS and disease activity in SLE has been investigated. An increase in the level of leptin in SLE patients has been reported [25,26]. Chung et al. demonstrated increased BMI with higher leptin levels in SLE patients and found a significant correlation with triglycerides and cholesterol levels [26]. The association between higher leptin levels and increased BMI has also been recognized by Xu et al. [27]. Scotece et al. have also investigated this relationship as a risk factor for CVD in patients with SLE [28]. Higher levels of leptin have been shown by Vadacca and coworkers to be significantly related to vascular compromise [19]. In the investigation by Viswanath et al., leptin was considered an important factor in the context of inflammation. The levels of leptin are higher in females in
Fig. 1. Serum adipokine and leptin levels in systemic lupus erythematosus patients and control.
Table 3 The receiver operating characteristic (ROC) for serum leptin and adiponectin in discriminating systemic lupus erythematosus patients. Characteristic
Sensitivity (%) Specificity (%) PPV (%) NPV (%) Cut-point (ng/ml) AUC p-value
SLE patients (n = 5) Adiponectin
Leptin
58.9 (45–71.9) 74.2 (55.4–88.1) 80.5 (65.1–91.2) 50 (34.9–65.1) 3.7 0.76 (0.65–0.85) <0.0001
26 (14.6–40.3) 93.1 (77.2–99.2) 86.7 (59.5–98.3) 42.2 (29.9–55.2) >19.3 0.57 (0.46–0.68) 0.27
SLE: systemic lupus erythematosus, PPV: positive predictive power, NPP: negative predictive power, AUC: area under the curve
Fig. 2. The receiver operating characteristic (ROC) for serum leptin and adiponectin in discriminating systemic lupus erythematosus patients.
Please cite this article as: Z. Rezaieyazdi, Z. Mirfeizi, M. Reza Hatef et al., The association between adipokines and stigmata of atherosclerosis in patients with systemic lupus erythematosus, The Egyptian Rheumatologist, https://doi.org/10.1016/j.ejr.2020.02.010
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comparison with males even after adjusting for BMI that has to be discussed in view of increased prevalence of autoimmune diseases in females. The leptin/adiponectin ratio was introduced as an independent risk factor for insulin resistance and CVD [29]. In the present study, leptin levels were not higher in patients than the control. BMI, however, significantly correlated with serum leptin levels. This is indicative of higher leptin levels in SLE patients with increased BMI during chronic inflammation and may be considered as an independent risk factor for premature atherosclerosis. The association between elevated leptin levels and increased BMI suggests the need for changes in lifestyle to decrease the morbidity and mortality resulting from cardiovascular events [30]. In the study of Diaz Rizo et al., comparing between SLE with and without nephritis, there were no significant differences in age, BMI and serum adipokines. It was remarked to inconsistency between inflammation and adipokines [31]. In this work, there was an association between leptin and total cholesterol levels. Elevated serum leptin levels during hyperlipidemia and insulin resistance were reported as independent risk factors for CVD [26,32]. Selzer et al. noted the causative effect of inflammatory cytokines on the development of atherosclerotic plaques [33]. It has been established that adiponectin decreases in SLE [28]. Serum adiponectin levels are inversely related to BMI and insulin resistance [26]. In line with the above, our findings demonstrated significantly lower serum adiponectin levels in patients with SLE than in control; this may be due to the effect of chronic inflammation. However, no meaningful relationship was observed between the serum levels of adiponectin and age, hypertension, cholesterol, LDL, FBG and BMI in SLE patients. Triglyceride and adiponectin levels negatively correlated, which is suggestive of the effect of MetS on the lowering of adiponectin and the secondary effect on atherosclerosis. Measuring hs-CRP is a useful marker of disease activity, increased IMT and subclinical atherosclerosis in SLE especially those with positive ds-DNA [13]. Adipokines correlated with CRP levels in the study of Chung et al., in disagreement to the findings in the present work. Low adiponectin levels have been introduced as a possible risk factor for CHD but not essentially with the degree of coronary calcification [26]. Shields et al. have demonstrated similar findings in the descending aorta [34]. Xu et al. demonstrated a lack of correlation between leptin levels and coronary calcification [27]. Yet, no correlation was found between adipokines and vascular IMT in another study [35]. The present study indicated a lack of association between serum leptin and adiponectin levels with the IMT in any of the carotid artery branches. In the present study, the relationship between leptin and adiponectin levels and SLEDAI was unremarkable. In agreement, serum leptin and adiponectin levels did not correlate with disease activity [4,26]. Shang et al. found high activity disease in SLE patients with a carotid atheroma plaque compared to those without [21]. In contrast, leptin but not adiponectin correlated with disease activity in SLE patients and SLEDAI showed no relation to vascular stiffness parameters [19]. A significant correlation was found between leptin and anti-dsDNA. In another study, SLE patients had elevated serum leptin levels that correlated significantly with BMI and total cholesterol but not with the SLEDAI [36]. On the contrary, SLE disease activity was found to affect the lipid level and its control would be helpful in treatment strategies. Likewise, control of hyerlipidemia can favourably affect SLE renal disease [37]. Although lower adiponectin levels and increased leptin were found in the SLE patients, no significant relation was found to exist with carotid atherosclerosis. Unknown risk factors may contribute to premature atherosclerosis in SLE and may confound the effect of adipokines. Other factors such as race and genetics may influence the inflammatory response and must be taken into account. Hereby, among the limitations to the present study is the cross-
sectional design and not taking into consideration the medications received. In conclusion, there was a lack of association between adipokines and the risk factors of age, FPG, LDL, hs-CRP, VCAM-1 and homocysteine in patients with lupus. However, serum adiponectin levels inversely correlated with HDL. A significant correlation of leptin with BMI and total cholesterol was found in SLE. None of the two adipokines were associated with atherosclerosis as assessed with the carotid IMT. There was no signficant correlation between adipokines and disease activity. Conflict of interest The authors have declared no conflict of interest. Funding This work, originating from a medical thesis (N:T 2557), was supported by a grant from the Vice Chancellor of Research at Mashhad University of Medical Sciences. References [1] Azkalany GS, Gheita TA, Gaber W, Mohey A. Clinical significance of serum TNFa and -308 G/A promoter polymorphism and serum Il-6 and -174 G/C promoter polymorphism in systemic lupus erythematosus patients. Egyptian Rheumatologist 2012;34(3):119–25. [2] Hahn BH. Systemic Lupus Erythematosus. 18th ed. New York: McGrawHill; 2012. p. 2724–35. [3] Hahn BH, Tsao BP. Pathogenesis of systemic lupus erythematosus. 8th ed. Canada: Saunders Elsevier; 2012. p. 1233–310. [4] Al M, Ng L, Tyrrell P, Bargman J, Bradley T, Silverman E. Adipokines as novel biomarkers in paediatric systemic lupus erythematosus. Rheumatology 2009;48:497–501. [5] Lee AB, Godfrey T, Rowley KG, Karschimkus CS, Dragicevic G, Romas E, et al. Traditional risk factor assessment does not capture the extent of cardiovascular risk in systemic lupus erythematosus. Intern Med J 2006;36:237–43. [6] Hak AE, Karlson EW, Feskanich D, Stampfer MJ, Costenbader KH. Systemic lupus erythematosus and the risk of cardiovascular disease: results from the nurses’ health study. Arthritis Care Res (Hoboken) 2009;61:1396–402. [7] Gustafsson J, Gunnarsson I, Börjesson O, Pettersson S, Möller S, Fei GZ, et al. Predictors of the first cardiovascular event in patients with systemic lupus erythematosus—a prospective cohort study. Arthritis Res Ther 2009;11(6): R186. [8] Pons-Estel GJ, González LA, Zhang J, Burgos PI, Reveille JD, Vilá LM, et al. Predictors of cardiovascular damage in patients with systemic lupus erythematosus: data from LUMINA (LXVIII), a multiethnic US cohort. Rheumatology 2009;48:817–22. [9] Nojima J, Masuda Y, Iwatani Y, Kuratsune H, Watanabe Y, Suehisa E, et al. Arteriosclerosis obliterans associated with anti-cardiolipin antibody/beta2glycoprotein I antibodies as a strong risk factor for ischaemic heart disease in patients with systemic lupus erythematosus. Rheumatology 2008;47:684–9. [10] Manzi S, Selzer F, Sutton-Tyrrell K, Fitzgerald SG, Rairie JE, Tracy RP, et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum 1999;42:51–60. [11] Gheita TA, Raafat HA, Sayed S, El-Fishawy H, Nasrallah MM, Abdel-Rasheed E. Metabolic syndrome and insulin resistance comorbidity in systemic lupus erythematosus: effect on carotid intima-media thickness. Z Rheumatol. 2013;72(2):172–7. [12] Rizk A, Gheita TA, Nassef S, Abdallah A. The impact of obesity in systemic lupus erythematosus on disease parameters, quality of life, functional capacity and the risk of atherosclerosis. Int J Rheum Dis. 2012;15(3):261–7. [13] Gheita TA, El-Gazzar II, Azkalany G, El-Fishawy HS, El-Faramawy A. Highsensitivity C-reactive protein (hs-CRP) in systemic lupus erythematosus patients without cardiac involvement; relation to disease activity, damage and intima-media thickness. Egyptian Rheumatologist 2012;34(4):147–52. [14] Flier JS, Maratos-Flier E. Biology of Obesity. 18th ed. New York: McGrawHill; 2012. p. 622–9. [15] De Sanctis JB, Zabaleta M, Bianco NE, Garmendia JV, Rivas L. Serum adipokine levels in patients with systemic lupus erythematosus: brief definite report. Autoimmunity 2009;42:272–4. [16] Dubey L, Hesong Z. Role of leptin in atherogenesis. Exp Clin Cardiol 2006;11 (4):269–75. [17] Maahs DM, Ogden LG, Kinney GL, Wadwa P, Snell-Bergeon JK, Dabelea D, et al. Low plasma adiponectin levels predict progression of coronary artery calcification. Circulation 2005;111:747–53.
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Please cite this article as: Z. Rezaieyazdi, Z. Mirfeizi, M. Reza Hatef et al., The association between adipokines and stigmata of atherosclerosis in patients with systemic lupus erythematosus, The Egyptian Rheumatologist, https://doi.org/10.1016/j.ejr.2020.02.010