High insulin levels and increased low‐density lipoprotein oxidizability in pediatric patients with systemic lupus erythematosus

Objective

To examine low‐density lipoprotein (LDL) size, LDL susceptibility to oxidation, and plasma insulin levels in children with systemic lupus erythematosus (SLE).

Methods

Fifty‐nine SLE patients and 59 healthy, age‐matched control subjects were studied. LDL size was determined by gradient gel electrophoresis. LDL oxidizability was assessed by lag time for conjugated diene formation during copper incubation. Plasma levels of fasting insulin, glucose, lipids, lipoproteins, apolipoproteins B and A‐I, and fatty acids were also measured.

Results

Compared with control subjects, SLE patients showed significantly higher plasma insulin levels and increased susceptibility of LDLs to oxidation. Patients with active disease were more likely than patients with inactive disease or control subjects to have the following lipid characteristics: small, dense LDL subclass, elevated total cholesterol levels, elevated LDL cholesterol levels, elevated triglyceride levels, and low levels of high‐density lipoprotein cholesterol (HDL‐C). Statistically significant direct correlations were observed between disease activity and triglyceride levels and between disease activity and lag time, whereas significant inverse correlations were found between disease activity and HDL‐C levels and between disease activity and LDL size. Prednisone dosage explained only 15.6% of the variance in insulin levels.

Conclusion

SLE patients have higher plasma insulin levels and increased LDL oxidizability compared with healthy control subjects. These abnormalities may contribute to the accelerated atherosclerosis observed in patients with SLE.

     

Lipid and lipoprotein levels in premenopausal systemic lupus erythematosus patients

The purpose of this study was to assess the prevalence of dyslipoproteinemia and to analyze the clinical variables that are associated with it in a sample of premenopausal systemic lupus erythematosus (SLE) patients. We studied 53 premenopausal (34.5 y) SLE outpatients and 45 controls. Clinical variables studied included patient age, weight, height, body mass index (BMI), age at disease onset, disease duration, clinical activity of SLE, renal involvement and drug therapy. Total cholesterol (TC), high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), and triglycerides were measured using standard enzymatic techniques. Apolipoproteins (apo) A-I and B were determined by radial immunodiffusion. Twenty-nine patients (55%) and 14 controls (30%) had dyslipoproteinemia. An increase in TC, triglycerides, HDL3-C, apo A-I and apo B, and a decrease in HDL2-C and HDL-C/TC index was found in SLE patients in comparison with controls. TC (P = 0.007), apo B (P = 0.02), LDL-C (P = 0.03) and triglycerides (P = 0.0001) were significantly correlated with proteinuria. Patients on prednisone therapy had higher triglycerides levels (P = 0.03) than untreated patients. TC (P = 0.01), LDL-C (P = 0.006) and triglycerides (P = 0.04) were also correlated with the dose of prednisone. Dyslipoproteinemia is a common feature in adult SLE premenopausal patients which is characterized by an increase in TC, triglycerides and apo B, and an abnormal distribution of HDL subclasses. Corticosteroid therapy and proteinuria are the best predictors of dyslipoproteinemia in these patients.     

Association of biological markers of activity of systemic lupus erythematosus with levels of anti-oxidized low-density lipoprotein antibodies

OBJECTIVES: To study the levels of anti-oxidized low-density lipoprotein (LDL) antibodies in patients with systemic lupus erythematosus (SLE) at two different points during the disease, and evaluate their relation with markers of SLE activity in serial blood samples. To investigate the correlations at two points in time between anti-oxidized LDL antibodies and anti-beta2-glycoprotein-I antibodies, leucocytes, immunoglobulin G, anti-deoxyribonucleic acid, complement 3, complement 4 and the disease activity index. METHODS: A total of 49 patients with SLE according to ACR criteria were studied at two points, 3 to 4 months apart, Time 1 and Time 2. RESULTS: There were ostensible changes in levels of anti-oxidized LDL antibodies between Times 1 and 2, which correlated significantly with disease activity markers. The association between levels of anti-oxidized LDL antibodies and complement system activation remained after multiple regression analysis with stepwise adjustment. CONCLUSIONS: Antibody levels against oxidized LDL vary with time and are closely related to the degree of SLE activity. There is an association between levels of autoantibodies to oxidized LDL and complement system activation.     

Oxidized low-density lipoprotein and beta2-glycoprotein I in patients with systemic lupus erythematosus and increased carotid intima-media thickness: implications in autoimmune-mediated atherosclerosis

Oxidative stress and LDL modification (oxLDL) are early pro-atherogenic events. OxLDL binds beta2GPI producing immunogenic oxLDL/beta2GPI complexes. Antibodies to these complexes have been associated with arterial thrombosis in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Circulating oxLDL/beta2GPI complexes, IgG and IgM antibodies to these complexes were measured by ELISA in 30 SLE patients asymptomatic for cardiovascular disease (mean age 31 years) and 27 age/sex matched healthy controls. Carotid intima-media thickness (IMT) was measured by ultrasound in all patients and controls. Forty-seven percent of SLE presented plaques (median IMT of 0.65 +/- 0.12 mm) while only 7% of the controls had plaques (median IMT of 0.50 +/- 0.04 mm, P < 0.001). Median optical density (OD450nm) for oxLDL/beta2GPI complexes in SLE was 0.244 +/- 0.07, higher than controls (0.174 +/- 0.09, P < 0.001). Median OD for IgG anti-oxLDL/beta2GPI antibodies was also higher in SLE (0.297 +/- 0.26) compared to controls (0.194 +/- 0.07, P < 0.001) while the median OD for IgM antibodies in SLE (0.444 +/- 0.46) was not different than controls (0.326 +/- 0.22, P = 0.267). There was no correlation between IMT and oxLDL/beta2GPI complexes, IgG or IgM antibodies, possibly reflecting the complex interrelationship between these serologic elements and tissue factors in the arterial wall. These results support the hypothesis that oxLDL/beta2GPI complexes and IgG (not IgM) anti-oxLDL/beta2GPI antibodies contribute to the development of autoimmune-mediated atherosclerosis.     

Altered levels of adipocytokines in association with insulin resistance in patients with systemic lupus erythematosus

OBJECTIVE: The metabolic syndrome, closely associated with cardiovascular disease, is characterized by increased insulin resistance (IR). Although accelerated atherosclerosis is frequently observed in systemic lupus erythematosus (SLE), the prevalence and significance of IR remain to be elucidated. We evaluated IR in association with plasma concentrations of adipocytokines in patients with SLE. METHODS: Outpatients with SLE (n = 37) and healthy controls (n = 80) were studied. A value of the homeostasis model assessment index (HOMA-IR) > 2.0 was considered to be IR. Plasma concentrations of adiponectin and tumor necrosis factor-a (TNF-a) were measured by ELISA and leptin by radioimmunoassay. RESULTS: HOMA-IR indices of the SLE patients were significantly higher than those of controls (2.3 +/- 2.3 vs 1.3 +/- 1.0, respectively; p < 0.01), although both groups exhibited a similar body mass index. The prevalence of hypertension and diabetes mellitus was significantly higher in patients with SLE compared with controls (48.6% vs 8.8% and 10.8% vs 0%). Twelve SLE patients (32%) with IR exhibited significantly higher incidence of hypertension and current proteinuria than SLE patients without IR. Plasma leptin, TNF-a, and, unexpectedly, adiponectin levels were higher in SLE patients than controls (adiponectin, 13.7 +/- 5.0 vs 9.5 +/- 3.9 microg/ml). Among the SLE patients, patients with IR showed significantly lower adiponectin levels than patients without IR (10.9 +/- 4.6 vs 15.4 +/- 4.4 microg/ml). Serum levels of adiponectin were significantly correlated inversely with HOMA-IR in SLE patients. CONCLUSIONS: Elevated levels of adiponectin in SLE, despite inverse correlation with IR, suggest the possible involvement of adiponectin in IR and alterations in its effect on insulin sensitivity.     

Serum interferon levels in patients with systemic lupus erythematosus

Levels of interferon (IFN) were measured in 81 serum samples from 23 patients with systemic lupus erythematosus (SLE) by a plaque-reduction method and correlated retrospectively with clinical records of disease activity, anti-DNA binding, and serum complement measurements. IFN titers were found to correlate with both clinical disease activity and anti-DNA binding, but no relation was found to serum complement. Most (76.6%, 31 of 41) serum samples obtained during periods of active disease contained measureable amounts of IFN, but only 9.1% (2 of 22) of results of tests on samples obtained during periods of disease quiescence were positive (P less than 0.005). Of samples with clearly elevated anti-DNA binding (greater than 40%), 69.7% (23 of 33) had positive results for IFN, but 57.1% (8 of 14) had negative results when the anti-DNA binding was normal (less than 20%) (P less than 0.005). Measurement of serum IFN titers in patients with SLE, therefore, provides another serologic marker of disease activity. Contrary to the findings of previous studies, the IFN found in the present study was characterized as IFN-alpha, or Type I IFN, on the basis of acid stability and neutralization by antibody to IFN-alpha. Of interest are the questions raised about the origin of IFN in the sera of patients with SLE and what role IFN might have in the pathogenesis of the autoimmune disease in view of the many documented immunomodulating effects of IFN.     

Serum L-ficolin levels in patients with systemic lupus erythematosus

Abstract

Objective L-ficolin plays an important role in innate immunity and is involved in apoptosis. The objective of this study was to investigate the relationship between serum L-ficolin levels and clinical manifestations in patients with systemic lupus erythematosus (SLE).

Methods Serum L-ficolin levels were determined by enzyme-linked immunosorbent assay in 66 SLE patients and 50 healthy controls.

Results Median serum L-ficolin levels were 5.0 and 8.7 μg/ml in SLE patients and controls, respectively (p = 0.0001). There were no significant differences in serum L-ficolin levels between the active disease group [SLE Disease Activity Index (SLEDAI) > 6] and the inactive disease group (SLEDAI < 5). Decreased serum L-ficolin levels were associated with thrombocytopenia (median of with vs. without thrombocytopenia 3.4 vs. 5.3 μg/ml, p = 0.008). There were no correlations between serum L-ficolin levels and SLEDAI, serum C3, or serum C4 levels.

Conclusion The association between L-ficolin and thrombocytopenia suggests a pathogenic role for L-ficolin in thrombocytopenia in SLE.     

Serum L-ficolin levels in patients with systemic lupus erythematosus

Objective

L-ficolin plays an important role in innate immunity and is involved in apoptosis. The objective of this study was to investigate the relationship between serum L-ficolin levels and clinical manifestations in patients with systemic lupus erythematosus (SLE).

Methods

Serum L-ficolin levels were determined by enzyme-linked immunosorbent assay in 66 SLE patients and 50 healthy controls.

Results

Median serum L-ficolin levels were 5.0 and 8.7?μg/ml in SLE patients and controls, respectively (p?=?0.0001). There were no significant differences in serum L-ficolin levels between the active disease group [SLE Disease Activity Index (SLEDAI) >6] and the inactive disease group (SLEDAI <5). Decreased serum L-ficolin levels were associated with thrombocytopenia (median of with vs. without thrombocytopenia 3.4 vs. 5.3?μg/ml, p?=?0.008). There were no correlations between serum L-ficolin levels and SLEDAI, serum C3, or serum C4 levels.

Conclusion

The association between L-ficolin and thrombocytopenia suggests a pathogenic role for L-ficolin in thrombocytopenia in SLE.     

Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid-lowering effect

The influence of antimalarials on lipids in systemic lupus erythematosus (SLE) has been identified in several studies but not in many prospective cohorts. The aim of this study was to longitudinally determine the effect of antimalarials on the lipoprotein profile in SLE. Patients and methods: Fasting total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low-density lipoprotein cholesterol (LDL) plasma levels were determined at entry and after 3 months of hydroxychloroquine (HCQ) treatment in a longitudinal evaluation of 24 patients with SLE. Results: a significant decrease in TC (198?±?33.7 vs. 183?±?30.3?mg/dl, p?=?0.023) and LDL levels (117?±?31.3 vs. 101?±?26.2?mg/dl, p?=?0.023) were detected after the 3 months of HCQ therapy. The reduction of 7.6% in TC (p?=?0.055) and 13.7% in LDL levels (p?=?0.036) determined a significant decrease in the frequency of dyslipidemia (26% vs. 12.5%, p?=?0.013) after HCQ therapy. Conclusion: This longitudinal study demonstrated the beneficial effect of antimalarials on lipids in SLE since this therapy induced a reduction of atherogenic lipoproteins.     

Epicardial adipose tissue is increased in patients with systemic lupus erythematosus

ObjectiveMorbidity and mortality secondary to premature cardiovascular disease (CVD) in systemic lupus erythematosus (SLE) remain significant issues. The pathogenesis of CVD in SLE patients has not been fully explored. Epicardial adipose tissue (EAT) is believed to contribute to atherosclerosis development, through a paracrine and systemic inflammatory effect. We measured EAT volume in 162 SLE patients and 86 matched controls to assess the association of EAT with markers of atherosclerosis, cardiovascular risk and immunoactivation.MethodsClinical and laboratory characteristics collected included anthropomorphic measures, disease activity and damage indices, blood pressure measurement, lipid profile, inflammatory indices, adipokine levels and measures of adiposity. Coronary artery calcium (CAC) and EAT volume were measured using non-contrast cardiac computed tomography.ResultsEAT volume was greater in patients with SLE [(mean ± SD) 96.8 ± 45.9 cm³] than controls (78.2 ± 40.7 cm³; P = 0.001). The EAT volume was 31% larger (95% CI, 16.5%–47.4%) in SLE patients than controls (P < 0.001 adjusted for age, sex, and race; after additional adjustment for waist circumference P = 0.007). Within SLE patients, after adjusting for age, race, sex, and waist circumference, EAT volume was associated with cumulative corticosteroid dose (P = 0.007), current corticosteroid use (P < 0.001), HDL cholesterol (P = 0.033), and triglycerides (P = 0.005). EAT was significantly correlated with CAC score (P < 0.001), but the association was attenuated after adjustment for Framingham risk score (P = 0.051).ConclusionThe increased EAT volume seen in SLE patients is associated with corticosteroid use. Corticosteroids could have adverse cardiovascular effects in SLE via an increase in EAT volume, a marker of risk in the general population.     

QT-interval parameters are increased in systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) patients have increased cardiovascular morbidity and mortality. QT-interval parameters are presumed markers of cardiovascular risk and have not been previously evaluated in SLE. Standard 12-lead ECGs were obtained from 140 female SLE outpatients and 37 age and body mass index-matched controls. QT interval was measured in each lead and heart rate-corrected maximum QT-interval duration (QTcmax) and QT-interval dispersion (QTd) were calculated. Risk factors for cardiovascular disease and lupus clinical features, disease treatment, disease activity and damage index were recorded. SLE patients have increased QT-interval parameters when compared to controls (QTcmax: 427.91 +/- 31.53 ms(1/2) versus 410.05 +/- 15.45 ms(1/2), P < 0.001; QTd: 52.38 +/- 22.21 ms versus 37.12 +/- 12.88 ms, P < 0.001). These differences persisted after excluding those patients with arterial hypertension, diabetes and with ECG abnormalities (QTcmax: 419.90 +/- 28.78 ms(1/2) versus 409.15 +/- 15.85 ms(1/2), P = 0.041; QTd: 54.74 +/- 26.00 ms versus 37.96 +/- 13.05 ms, P = 0.001). Multivariate linear regression for factors associated with QTcmax selected the presence of electrocardiographic left ventricular hypertrophy (ECG-LVH) (P = 0.003), nonspecific ST-T-wave abnormalities (P = 0.022) and left atrial enlargement (P = 0.044). Multivariate associates with QTd were age (P = 0.018), ECG-LVH (P = 0.022) and ST-T abnormalities (P = 0.031). In conclusion, SLE patients have increased QT interval parameters when compared to controls. This prolongation may lead to an increased cardiovascular risk. This finding might be due to subclinical atherosclerotic cardiovascular disease.     

Raised serum APRIL levels in patients with systemic lupus erythematosus

OBJECTIVE: To determine whether serum levels of a proliferation-inducing ligand (APRIL) are raised in patients with systemic lupus erythematosus (SLE) and correlate with autoantibody titres or disease activity, or both. METHODS: Serum samples from 48 patients with SLE, 41 normal healthy subjects, and 21 patients with rheumatoid arthritis (RA) were assayed for APRIL by enzyme linked immunosorbent assay. Medical charts were retrospectively reviewed for autoantibody titres and immunoglobulin levels. Disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) index. RESULTS: The APRIL levels in the serum samples from patients with SLE were significantly higher than in those from healthy controls and those from patients with RA. Serum APRIL levels did not correlate with serum IgG and IgM levels, but had a tendency to correlate with anti-double stranded DNA antibody titres. Moreover, serum APRIL levels correlated significantly with musculoskeletal manifestations among patients with SLE when assessed by the BILAG index. CONCLUSION: APRIL may be an important factor in raised autoantibody titres and musculoskeletal disease in patients with SLE. Patients with raised serum APRIL levels may be ideal candidates for therapeutic targeting of APRIL.     

Dyslipoproteinemia in pediatric systemic lupus erythematosus

Patients with systemic lupus erythematosus are at increased risk for premature atherosclerosis. We examined one possible etiologic factor, dyslipoproteinemia, both before and after corticosteroid therapy. We identified 2 distinct patterns of dyslipoproteinemia. One is attributable to active disease; the other is attributable, in part, to corticosteroid therapy. The dyslipoproteinemia of active disease consists of depressed high density lipoprotein cholesterol and apoprotein A-I with elevated very low density lipoprotein cholesterol and triglyceride, while the dyslipoproteinemia after corticosteroid therapy consists of increased total cholesterol, very low density lipoprotein cholesterol, and triglyceride. The possible pathophysiologic mechanisms responsible for these patterns, as well as the possible roles in premature atherosclerosis seen in systemic lupus erythematosus patients, are discussed.     

Body composition, lipid and lipoprotein levels in childhood-onset systemic lupus erythematosus

OBJECTIVES: Systemic inflammation, corticosteroid therapy, and reduced physical activity are risk factors for altered body composition in patients with systemic lupus erythematosus (SLE). The aim of this study was to assess whether body composition differs between childhood-onset SLE patients and healthy controls, and to investigate the impact of disease characteristics and lifestyle factors on body fat mass, serum lipids, and lipoproteins. METHODS: Fat mass and lean tissue mass were measured in a cross-sectional study of 68 childhood-onset SLE patients and 68 matched healthy controls by dual-energy X-ray absorptiometry (DXA). The influence of disease, glucocorticosteroids, disease activity and severity, physical activity, and dietary intake on fat mass was evaluated by multiple linear regression analysis. Serum lipid and lipoprotein levels were measured. RESULTS: Patients had a significantly higher fat mass [mean (SD) 35.3 (10.8) vs. 30.9 (11.1)%; p = 0.024] and lower lean mass [39.7 (9.8) vs. 44.4 (1.5) kg; p = 0.003] than controls. Corticosteroid use and the disease itself were significant independent predictors of greater fat mass, while disease activity, physical activity, and dietary intake had only a minor influence. Mean high density lipoprotein (HDL) cholesterol and apolipoprotein A1 (apo A1) levels were significantly lower (p<0.001), and the mean apo B/apo A1 ratio significantly higher (p = 0.004), in patients than in controls. CONCLUSION: Childhood-onset SLE patients had a higher fat mass and lower lean mass than healthy controls and corticosteroid use was an independent predictor of increased fat mass. Patients had a more proatherogenic lipid profile, which will contribute to the increased risk of coronary heart disease in SLE patients.     

Nitric oxide synthesis is increased in patients with systemic lupus erythematosus

Nitric oxide (NO) is believed to have a role in the inflammatory process. NO production was measured in 26 patients with systemic lupus erythematosus (SLE) and 20 healthy volunteers, using spectrophotometrically determined serum nitrite and citrulline as surrogate markers. Both nitrite and citrulline levels were significantly higher in patients with SLE than in controls (P<0.001). Twelve and 10 patients, respectively, with SLE had nitrite and citrulline levels that were two standard deviations higher than the mean level of controls. These patients had a significantly higher measure of disease activity (SLE Disease Activity Index). These data show that there is increased NO production in SLE and that it may serve as a marker for disease activity. Received: 24 July 1997 / Accepted: 31 March 1998     

Platelet bound IgG levels in patients with systemic lupus erythematosus

Platelet bound IgG (PBIgG) measured by antiglobulin consumption assay was compared with indices of clinical and laboratory disease activity in 37 nonthrombocytopenic patients with systemic lupus erythematosus. There was no correlation with clinical disease activity. When patients with a PBIgG level over 50 ng/10(7) platelets were compared to those with normal PBIgG levels (less than 20 ng/10(7) platelets), however, they had a significantly higher DNA binding level (p less than 0.05). In 17 patients there was no correlation between PBIgG levels and circulating immune complexes as measured by the Raji cell assay. Ten patients with PBIgG levels over 50 ng/10(7) platelets were followed for a mean of 23 months (5-26 months). None developed thrombocytopenia.     

Elevated apolipoprotein-B levels in corticosteroid-treated patients with systemic lupus erythematosus

Patients treated with corticosteroids often have a dyslipoproteinemia characterized by elevated plasma levels of triglyceride and low density lipoprotein cholesterol and/or decreased levels of the high density lipoprotein2 fraction of high density lipoprotein cholesterol. This study was undertaken to determine if such patients also have elevated apolipoprotein-B (apoB) levels and/or abnormalities of the activities of the triglyceride lipases in postheparin plasma. Plasma lipoprotein levels and the postheparin activities of hepatic lipase and lipoprotein lipase were measured in 28 women with systemic lupus erythematosus (SLE) who were treated with prednisone, 10 women with SLE not treated with prednisone, and 15 normal women. The prednisone-treated group had higher mean plasma levels of triglyceride [2.06 +/- 1.3 (+/- SD) vs. 1.15 +/- 0.35 and 0.95 +/- 0.46 mmol/L; P less than 0.01], low density lipoprotein cholesterol [3.41 +/- 1.4 (+/- SD) vs. 2.79 +/- 0.67 and 2.84 +/- 0.70 mmol/L; P less than 0.01], and apoB [1.16 +/- 0.35 (+/- SD) vs. 0.82 +/- 0.13 and 0.76 +/- 0.22 g/L] than the other 2 groups. Forty-three percent of the prednisone-treated group had apoB levels of 1.20 g/L or more compared to 7% of normal subjects and none of the untreated SLE group (P less than 0.05). However, of the 12 prednisone-treated patients with elevated plasma apoB levels 5 had normal plasma lipid levels. There were no differences in the postheparin lipase activities among the 3 groups. These data indicate that corticosteroid-treated patients have elevations in apoB as well as hyperlipidemia. The lipoprotein abnormalities may explain the increased risk of atherosclerosis reported in these patients.