Abstract
Objective. To study concentrations of adipokines in patients with systemic lupus erythematosus (SLE) and the relationship among adipokines, the metabolic syndrome (MeS), and cardiovascular disease (CVD) risk factors.
Methods. We enrolled 50 SLE patients and 26 controls, all women. Leptin, resistin, visfatin, and adiponectin were measured by commercial ELISA kits.
Results. MeS prevalence was increased among subjects with SLE. Leptin levels were higher in patients with SLE than controls. Among SLE patients, independent determinants of leptin were insulin levels (p < 0.0001), triglycerides (p = 0.03), body mass index (p = 0.02), corticosteroid dosage (p = 0.02), and SLE Disease Activity Index (p = 0.005). Other adipokines did not differ between SLE patients and controls.
Conclusion. Leptin was increased in SLE patients and could play a role in SLE-related cardiovascular diseases.
The role of cardiovascular diseases (CVD) has become increasingly important in the morbidity and mortality of patients with systemic lupus erythematosus (SLE), in particular among young fertile women1. Metabolic syndrome (MeS), a new independent CVD risk factor, characterized by insulin-resistance (IR), obesity, dyslipidemia, and hypertension, has been shown to be highly prevalent among SLE patients, increasing the interest in the role of adipose tissue in rheumatic diseases2,3. White adipose tissue (WAT) secretes a variety of bioactive peptides, called adipokines, including leptin, resistin, visfatin, and adiponectin. These molecules are involved in a wide spectrum of biological activity, playing a role in atherogenesis and modulating insulin sensitivity4,5. Further, a deregulation in adipokine concentrations has been demonstrated in numerous inflammatory and autoimmune diseases6–8. To date, it has not yet been clarified whether adipokine levels in SLE are related to metabolic alterations and/or to the inflammatory milieu. The aim of our study was to determine the adipokine levels in patients with SLE versus healthy subjects and to identify different cardiovascular and metabolic variables associated with adipokines in this population.
MATERIALS AND METHODS
Study population
Fifty eligible patients, who met the Hochberg modified American College of Rheumatology classification criteria for SLE9, and 26 control subjects were enrolled in this study. Patients and controls, all women, were stratified according to fertile or menopausal status. The study was approved by the Ethical Committee of “Campus Bio-Medico” University of Rome. All participants gave written informed consent.
For patients with SLE, disease activity was assessed at time of enrollment in the study using the SLE Disease Activity Index (SLEDAI) and the European Consensus Lupus Activity Measurement (ECLAM) index10.
Metabolic syndrome and CVD risk factors
All subjects were evaluated for CVD risk factors. To estimate 10-year CVD risk, we used an individual risk calculator according to the Italian Global Cardiovascular Risk Score (IGCRS/CUORE)11. The diagnosis of MeS was made according to the criteria of the World Health Organization (WHO)12 and the European Group for the study of Insulin-Resistance (EGIR)13.
Adipokines
Serum levels of leptin were determined by a commercial sandwich ELISA kit (DRG Instruments GmbH, Marburg, Germany). Serum resistin, visfatin, and adiponectin were measured by commercial ELISA kits (AdipoGen Inc., Seoul, Korea).
Statistical analysis
Data were analyzed with Prism 5.0 software (Prism Inc., San Diego, CA, USA). Comparisons of continuous variables among groups were performed by Mann-Whitney U test. The categorical variables were analyzed by Fisher F test. Correlations were calculated by Spearman tests. Multivariate analysis for leptin level independent determinants was performed by multiple regression, using a stepwise model. Two-sided p values < 0.05 were considered statistically significant.
RESULTS
Clinical characteristics, metabolic syndrome, and CVD risk factors
Forty (80%) and 10 (20%) patients with SLE versus 16 (61.5%) and 10 (38.5%) controls were fertile and menopausal, respectively (p = 0.10).
The overall prevalence of MeS by WHO definition was 28% in SLE and 7.7% in controls (p = 0.043). Moreover, 30% of SLE patients and 3.8% of controls met EGIR criteria (p = 0.007).
Compared to controls, SLE patients showed higher levels of fasting insulin (p = 0.004), HOMA-IR (homeostasis model assessment for insulin resistance; p = 0.03), body mass index (BMI; p = 0.04), waist circumference (p = 0.04), systolic blood pressure (p = 0.03), homocysteine (p < 0.0001), and C-reactive protein (p = 0.01). Other results are reported in Table 1.
Clinical characteristics, metabolic syndrome variables, and risk factors for cardiovascular disease. All patients and controls were female. Data are median (range).
Adipokines
Leptin was higher among SLE patients compared to controls in the group as a whole and in fertile subjects (p = 0.04 and p = 0.005, respectively; Figure 1). Among SLE patients, leptin correlated with insulin levels (r = 0.8, p < 0.0001), HOMA-IR (r = 0.8, p < 0.0001), MeS (r = 0.7, p < 0.0001), triglycerides (r = 0.4, p = 0.002), BMI (r = 0.8, p < 0.0001), weight to height (W/H) ratio (r = 0.6, p < 0.0001), systolic and diastolic blood pressure (r = 0.5, p < 0.0001; r = 0.4, p = 0.001, respectively), IGCRS/CUORE score (r = 0.4, p = 0.003), SLEDAI (r = 0.5, p < 0.0001), and ECLAM (r = 0.6, p < 0.0001). In stepwise multiple regression analysis of leptin levels among SLE patients, model R2 was 0.88 and adjusted R2 was 0.87 (p < 0.0001). Variables entered stepwise were insulin levels (p < 0.0001), triglycerides (p = 0.03), BMI (p = 0.02), corticosteroid dosage (p = 0.02), and SLEDAI (p = 0.005).
Leptin levels in patients with SLE and in controls (CTR) in the group as a whole and in fertile subjects.
Median resistin, visfatin, and adiponectin did not differ between SLE patients and controls. Regarding SLE patients, adiponectin levels were inversely correlated to plasma insulin (r = –0.3, p = 0.003), HOMA-IR (r = –0.3, p = 0.003), W/H ratio (r = –0.4, p = 0.006), triglycerides (r = –0.3, p = 0.02), and MeS diagnosis (r = –0.4, p = 0.007).
DISCUSSION
Adipokines have recently been implicated in insulin resistance, atherogenesis, and autoimmune diseases4,5,14. The aim of our study was to determine the adipokine levels in patients with SLE and to identify factors associated with adipokine levels in this population. Our results showed hyperexpression of leptin, notably, among fertile patients with SLE. In SLE, leptin correlated with insulin and HOMA-IR levels and with the MeS. Indeed, although the small sample size precluded adequate statistical power, our work represents the first evidence of an increased frequency of insulin resistance and MeS in an Italian SLE sample. Moreover, we found that leptin levels were related to CVD risk factors and to the IGCRS, a useful tool in evaluating the importance of CVD risk factors in an Italian population.
A few studies have been published regarding leptin levels and CVD in SLE; however, the West of Scotland Coronary Prevention Study15 showed that leptin is an independent risk factor for coronary heart disease in the general population. Leptin levels have been described as directly correlated with inflammatory markers and disease activity in patients with rheumatoid arthritis8. In analogy with these data, we found a positive correlation between leptin and SLE-specific disease activity indexes.
Although we did not find higher levels of adiponectin in SLE, our data confirmed results of Sada, et al that demonstrated an inverse correlation between levels of adiponectin and HOMA-IR in SLE patients7. A possible involvement of adiponectin in insulin resistance in SLE requires further investigation.
Our results suggest that leptin may play a role regarding CVD risk factors and MeS in women with SLE, above all in the fertile years. Further, leptin seems to be implicated in disease activity. Further studies are required to clarify the role of adipokines in SLE immuno-imbalance and in SLErelated cardiovascular involvement.
Footnotes
- Accepted for publication September 3, 2008.
