Inflammatory Mechanisms Affecting the Lipid Profile in Patients with Systemic Lupus Erythematosus CECILIA P. CHUNG, ANNETTE OESER, JOSEPH SOLUS, INGRID AVALOS, TEBEB GEBRETSADIK, AYUMI SHINTANI, MacRAE F. LINTON, SERGIO FAZIO, and C. MICHAEL STEIN ABSTRACT. Objective. Increased low density lipoprotein (LDL) cholesterol and triglycerides, and decreased high density lipoprotein (HDL) cholesterol concentrations are associated with adverse cardiovascular risk in the general population. Patients with systemic lupus erythematosus (SLE) have an altered lipid profile characterized by increased triglycerides and decreased HDL cholesterol concentrations. We examined the relationships between lipid concentrations, cytokines, and inflammatory markers in patients with SLE. Methods. Fasting lipid concentrations, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were measured in 110 patients with SLE. Disease activity was quantified by the SLE Disease Activity Index (SLEDAI), and disease damage by the Systemic Lupus International Collaborating Clinics (SLICC) score. Concentrations of circulating tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and insulin were measured and insulin sensitivity calculated. Results. Lower concentrations of HDL cholesterol were independently associated with higher ESR (p < 0.001), IL-6 (p = 0.02), SLEDAI (p = 0.04), and TNF-α (p = 0.04) after adjustment for age, sex, race, body mass index, insulin sensitivity, and current use of corticosteroids or hydroxychloroquine. Triglyceride concentrations were associated with higher CRP concentrations (p = 0.02) and SLICC score (p = 0.04). Conclusion. Deleterious changes in lipid profile are independently associated with higher concentra- tions of markers and mediators of inflammation and disease activity and damage in patients with SLE. (First Release July 15 2007; J Rheumatol 2007;34:1849–54) Key Indexing Terms: CHOLESTEROL TRIGLYCERIDES CYTOKINES SYSTEMIC LUPUS ERYTHEMATOSUS INFLAMMATION Systemic lupus erythematosus (SLE) is an inflammatory dis- tions of high density lipoprotein (HDL) cholesterol are major ease leading to accelerated atherosclerosis1,2. Epidemiological independent cardiovascular risk factors6; high concentrations data indicate that young women with SLE have a cardiovas- of triglycerides are also associated with increased risk of car- cular risk several times higher than that of an age-matched diovascular disease6, particularly in women7. In patients with control population3. Concordantly, patients with SLE have an SLE, lipid profiles are altered; concentrations of HDL choles- increased prevalence of atherosclerosis and increased risk of terol are lower8,9, and triglycerides higher, than those of con- hospitalization due to myocardial infarction4,5. trol subjects8-10. Further, oxidative modification of LDL cho- In the general population high concentrations of total and lesterol including ß2-glycoprotein I ox-LDL complexes are low density lipoprotein (LDL) cholesterol, and low concentra- associated with arterial thrombosis11. In addition to the dele- terious effect on the cardiovascular system, dyslipidemia may From the Departments of Medicine, Molecular Physiology and also contribute to noncardiovascular risk in patients with Biophysics, Biostatistics, Pathology, and Pharmacology, Vanderbilt lupus. For example, higher cholesterol concentrations are University, Nashville, Tennessee, USA. associated with increased mortality and a greater risk of Supported by grants HL04012, HL65082, and GM5M01-RR00095 from adverse renal outcomes in patients with SLE12. Therefore, a the National Institutes of Health and by a grant from the Lupus Foundation of America, Nashville Chapter. Dr. Avalos is supported in part better understanding of the mechanisms that lead to a decrease by a grant from the American College of Rheumatology. in HDL and an increase in triglyceride and LDL cholesterol C.P. Chung, MD, MPH; A. Oeser, BS; I. Avalos, MD, Department of concentrations in patients with SLE is of interest. Medicine; M.F. Linton, MD; C.M. Stein, MD, Departments of Medicine and Pharmacology; S. Fazio, MD, PhD, Departments of Medicine and Diet and heredity are known to be major determinants of Pathology; J. Solus, PhD, Departments of Molecular Physiology and lipid concentrations, but the role of inflammation is less well Biophysics and Pharmacology; T. Gebretsadik, MPH; A. Shintani, MPH, recognized. In animal models, concentrations of tumor necro- PhD, Department of Biostatistics, Vanderbilt University. sis factor-α (TNF-α) are associated with increased serum cho- Address reprint requests to Dr. C.P. Chung, Rheumatology Division, 13 Vanderbilt University School of Medicine, T-3219 MCN, 1161 21st Ave., lesterol and decreased HDL cholesterol concentrations , and Nashville, TN 37232, USA. E-mail: [email protected] in humans, inflammation during infection is associated with Accepted for publication April 25, 2007. increased triglyceride concentrations14. Further, in patients Personal non-commercial use only. The Journal of Rheumatology Copyright © 2007. All rights reserved. Chung, et al: Lipids and inflammation in lupus 1849 Downloaded on October 1, 2021 from www.jrheum.org with human immunodeficiency virus infection, inflammatory The study was approved by the Institutional Review Committee at Vanderbilt University and all subjects gave written informed consent. mediators such as interferon and TNF-α are associated with an increase in triglyceride and a decrease in HDL concentra- Laboratory tests. Blood was drawn from participants after an overnight fast- tions15. SLE induces cytokine activation. Some cytokines, ing period and glucose, total cholesterol, HDL, triglycerides, Lp (a) lipopro- tein, and homocysteine concentrations were measured, and LDL concentra- including TNF-α and IL-6, may be not only biomarkers of tions calculated. Plasma samples, stored at –70°C, were analyzed by ELISA 16 disease activity , but also a link between inflammation and (Linco Research) to measure concentrations of TNF-α, IL-6, and insulin. A dyslipidemia. Recent data suggest that TNF-α is associated HOMA index was calculated as a measure of insulin sensitivity. with lower HDL cholesterol and higher triglyceride concen- Statistical methods. Demographic characteristics are presented for continuous 17 variables as means and standard deviations or medians and interquartile trations in patients with SLE . However, TNF-α also pro- motes insulin resistance18, and insulin sensitivity is decreased ranges (IQR) based on their distribution and as frequencies and percentages 19 for categorical variables. The analyses were performed in 2 phases. First, in patients with SLE and is related to cholesterol concentra- Spearman’s correlation coefficients were calculated to examine the bivariate 20 tions . Further, medications such as corticosteroids and association between HDL and LDL cholesterol, and triglycerides with disease hydroxychloroquine8,21 may affect lipid concentrations. There activity and damage, markers of inflammation, insulin sensitivity, cytokine is little information available about the relationship between concentrations, and medication use. In addition, lipid concentrations were inflammation and the lipid profile of patients with SLE, inde- compared in patients with and without antiphospholipid antibodies. Second, multiple linear regressions models were applied to assess whether these asso- pendent of other factors such as medications and insulin ciations were independent of age, sex, race, BMI, insulin sensitivity, and use sensitivity. of corticosteroids and antimalarials. These covariates were chosen a priori for Previous work in this cohort of patients suggested there adjustment based on their clinical relevance. Residuals of the multiple linear might be a relationship between alterations in lipid concentra- regressions were assessed to ensure model assumptions. We performed box- tion and inflammation in patients with lupus22. Our study Cox transformation of the outcome variables to obtain normality of the regression residuals to ensure model assumption. For continuous independent builds on this observation and specifically addresses the variables nonlinear effect was assessed by using restricted cubic splines32. All hypothesis raised: it examines the relationship between HDL, analyses used a 2-sided level of significance of 5% and were performed with LDL, and triglyceride concentrations and other clinical vari- R 2.1.0 (www.r-project.org). ables and takes into account potential confounders such as body mass index (BMI), comedications, and insulin sensitivity RESULTS that could have accounted for the initial correlations observed. Patient characteristics. Patients with lupus were 40 ± 12 years Thus, we set out to examine the relationship between triglyc- old, 90.9% women, and 69.1% Caucasian. Sixty percent were erides, HDL and LDL cholesterol, and markers of inflamma- taking corticosteroids and 62.7% antimalarials (Table 1). tion, independent of the effect of traditional cardiovascular risk Their median (IQR) disease duration was 7 (3–12) years, and factors, insulin sensitivity, and medications. the median SLEDAI score was 4 (1–6) and current corticos- teroid dose 5 (0–7) mg of prednisone or equivalent per day. MATERIALS AND METHODS The mean concentration of HDL cholesterol was 47.6 ± 14.7 Outpatients older than 18 years of age, who met the classification criteria of mg/dl, LDL cholesterol 102.8 ± 37.9 mg/dl, and triglycerides 23 SLE and had disease duration longer