Jennifer Grossman

High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids

Background Patients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors. High levels of leptin and low levels of adiponectin are associated with both atherosclerosis and immunomodulatory functions in the general population. Objective To examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis. Methods Carotid ultrasonography was performed in 250 women with SLE and 122 controls. Plasma leptin and adiponectin levels were measured. Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed. Results Leptin levels were significantly higher in patients with SLE than in controls (23.7±28.0 vs 13.3±12.9 ng/ml, p<0.001). Leptin was also higher in the 43 patients with SLE with plaque than without plaque (36.4±32.3 vs 20.9±26.4 ng/ml, p=0.002). After multivariate analysis, the only significant factors associated with plaque in SLE were leptin levels in the highest quartile (≥29.5 ng/ml) (OR=2.8, p=0.03), proinflammatory HDL (piHDL) (OR=12.8, p<0.001), age (OR=1.1, p<0.001), tobacco use (OR=7.7, p=0.03) and hypertension (OR=3.0, p=0.01). Adiponectin levels were not significantly associated with plaque in our cohort. A significant correlation between leptin and piHDL function (p<0.001), Lp(a) (p=0.01) and OxPL/apoB100 (p=0.02) was also present. Conclusions High leptin levels greatly increase the risk of subclinical atherosclerosis in SLE, and are also associated with an increase in inflammatory biomarkers of atherosclerosis such as piHDL, Lp(a) and OxPL/apoB100. High leptin levels may help to identify patients with SLE at risk of atherosclerosis.

180 Plasma myeloperoxidase is inversely associated with future atherosclerosis progression and inflammatory hdl function in sle

Background and aims Women with SLE have increased atherosclerosis (ATH) that is not adequately explained by traditional risk factors. We previously discovered that a “high risk” score on a panel of biomarkers, PREDICTS, confers 28-fold increased odds for carotid plaque in SLE women. The biomarkers included in PREDICTS are sTWEAK, pro-inflammatory HDL (piHDL), homocysteine, leptin, age ≥48, and DMII. It is unknown, however, whether other biomarkers of oxidative stress also predict progression of ATH in SLE. The enzyme myeloperoxidase (MPO) catalyses formation of reactive oxygen species and generates piHDL. The aim of this study was to determine whether MPO levels might predict future progression of ATH in SLE. Methods B-mode and Doppler scanning of carotid arteries was performed at baseline and 24–36 months. Baseline plasma MPO levels were measured using ELISA. Results Repeat carotid ultrasounds and MPO measurements were completed on 202 SLE women. Plaque progression (defined as new or increased plaque) was seen in 42 subjects (21%). Baseline MPO levels were significantly lower in SLE patients with plaque progression vs. those without (p<0.001). Baseline MPO levels were also inversely correlated with piHDL function at follow-up (r=−0.33, p<0.001). Using logistic regression, the variables associated with plaque progression in SLE included high PREDICTS (OR 27.0 p<0.001), MPO levels in the lowest half (OR 4.2, p=0.005), and non-Caucasian ethnicity (OR 4.5, p=0.003). Conclusions Plasma MPO levels are inversely associated with plaque progression in SLE. Lower baseline MPO levels are also associated with future formation of inflammatory piHDL, suggesting that this could be one mechanism to explain the association.

179 Biomarkers of atherosclerosis in sle improve after treatment with mycophenolate mofetil

Background and aims Women with SLE have an increased risk of atherosclerosis that is not adequately explained by traditional risk factors. We previously discovered that a “high risk” score on a panel of biomarkers, PREDICTS, confers 28-fold increased odds for carotid plaque in SLE women, and is also associated with IMT progression. The biomarkers included are pro-inflammatory HDL, sTWEAK ≥373 pg/mL, homocysteine ≥12 mmol/L, leptin ≥34 ng/dL, age ≥48 years, and DMII. It is unknown, however, whether these biomarkers are modifiable by SLE disease modifying agents. Methods This prospective observational study included UCLA cohort patients started on new immunosuppressive agents. Plasma samples were taken at baseline and 12 weeks. HDL antioxidant function was measured by changes in fluorescence intensity of a substrate incubated with LDL and patient HDL. Plasma leptin and sTWEAK were measured using ELISA. Homocysteine was measured in the UCLA clinical labs. Results 16 subjects started mycophenolate mofetil (MMF), 18 azathioprine (AZA), and 25 hydroxychloroquine (HCQ). In MMF treated subjects, HDL function (p=0.009, paired t-test) and sTWEAK (p=0.05) significantly improved after 12 weeks, while leptin and homocysteine did not significantly change. In HCQ treated subjects, HDL function improved (p=0.05). In the AZA group there were no significant changes in any of the biomarkers. Overall, the mean number of PREDICTS biomarkers at week 12 significantly decreased in the MMF group (p=0.03). Conclusions The mean number of “high-risk” cardiac biomarkers significantly improved after initiation of MMF. Further longitudinal studies will determine whether changes in biomarkers reflect decreased cardiovascular events.

SAT0304 Coagulation Factor XIII Might Be A Promising Marker for Predicting Atherosclerosis in SLE

Background Several traditional and non-traditional risk have been implicated in the development of atherosclerosis in systemic lupus erythematosus (SLE). However, while growing evidence demonstrates that blood coagulation factor XIII (FXIII) may play an essential role in atherothrombotic disease in patients with primary antiphospholipid syndrome, the role of this coagulation factor in atherothrombotic disease and overall disease activity in patients with SLE is still poorly understood. Plasma FXIII cross-links fibrin with itself and with the endothelium, making clots resistant to fibrinolysis. Intracellular FXIII in monocytes also cross-links Type I angiotensin receptor dimer, which increases monocyte adhesion to endothelial cells and accelerates atherosclerosis. We investigated whether FXIII was associated with intima media thickness (IMT) of carotid arteries or disease activity in patients with SLE. Objectives to evaluate clinical significance of FXIII in SLE. Methods the study involved 50 consecutive patients with SLE enrolled in a longitudinal study on atherosclerosis biomarker from 2008 through 2015 at UCLA. Plasma FXIII activity (FXIIIa) was measured in the blood samples by ELISA. B-mode and Doppler Scanning was performed to measure IMT at baseline and 24–36 month. Results Table1 shows the correlation with plasma level of FXIIIa and variables that were independently associated with SLE activity and atherosclerosis. There was a strong inverse correlation with the SLE Disease Activity Index (SLEDAI), physician global assessment (PGA), and dsDNA antibody, whereas there was a significant positive correlation between FXIIIa and C3 and IMT at the follow-up ultrasound (Figure1). In patients with high plasma FXIIIa (>143%), the mean SLEDAI was significantly lower, (2.17± 3.7 vs. 4.1 ± 3.2, p=0.009) and IMT at follow-up was significantly higher (0.61 ± 0.17 vs. 0.51 ± 0.14, p=0.009).Table 1. Correlations between FXIII and variables in SLE Variable Plasma level of XIII activity Correlation P-value (Spearmans) SLEDAI −0.378 0.007** PGA −0.311 0.028* ds DNA antibody −0.361 0.014* C3 0.440 0.002** C4 0.294 0.050 Diagnosis of APS −0.021 0.914 Positive aCL −0.118 0.463 Hypertension 0.110 0.466 Diabetes 0.255 0.090 Dyslipidemia 0.142 0.354 Tobacco 0.286 0.046* IMT at follow up 0.400 0.010* **p<0.01 (2-tailed), *p<0.05 (2-tailed). Conclusions Although further confirmatory testing is underway, FXIII might be a novel marker for increased IMT in SLE. References McMahon M, Skaggs BJ, Grossman JM, Sahakian L, Fitzgerald J, Wong WK, et al. A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus erythematosus. Arthritis Rheumatol. 2014;66(1):130–9. Ames PR, Iannaccone L, Alves JD, Margarita A, Lopez LR, Brancaccio V. Factor XIII in primary antiphospholipid syndrome. The Journal of rheumatology. 2005;32(6):1058–62. Muszbek L, Bereczky Z, Bagoly Z, Shemirani AH, Katona E. Factor XIII and atherothrombotic diseases. Seminars in thrombosis and hemostasis. 2010;36(1):18–33. Disclosure of Interest None declared