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Objectives Patients with SLE have an increased risk of developing cardiovascular disease (CVD). Multiple studies have shown that these patients have increased numbers of carotid plaques and greater intima-media thickness (IMT) than healthy controls. Measures such as total plaque area (TPA) and plaque echogenicity may be more sensitive and more relevant to cardiovascular risk than presence of plaque and IMT alone. Our objective was to produce the first report of TPA and echogenicity in a population of patients with SLE. Methods One hundred patients with SLE and no history of clinical CVD were recruited. Clinical, serological and treatment variables were recorded and serum was tested for antibodies to apolipoprotein A-1 and high-density lipoprotein. Both carotid and both femoral artery bifurcations of each patient were scanned to determine IMT, TPA and echogenicity of plaques. Univariable and multivariable statistical analyses were carried out to define factors associated with each of these outcomes. Results Thirty-six patients had carotid and/or femoral plaque. Increasing age was associated with presence of plaque and increased IMT. Triglyceride levels were associated with presence of plaque. Mean (s.d.) TPA was 60.8 (41.6) mm2. Patients taking prednisolone had higher TPA. Most plaques were echolucent, but increased echogenicity was associated with prednisolone therapy and persistent disease activity. Conclusion TPA and plaque echogenicity in patients with SLE are associated with different factors than those associated with presence of plaque and IMT. Longitudinal studies may show whether these outcome measures add value in the management of cardiovascular risk in SLE.

Objective: Patients with systemic lupus erythematosus (SLE) have an increased risk of developing cardiovascular disease. Standard serum lipid measurements in clinical practice do not predict cardiovascular disease risk in patients with SLE. More detailed analysis of lipoprotein taxonomy could identify better predictors of cardiovascular disease risk in SLE. Approach and Results: Eighty women with SLE and no history of cardiovascular disease underwent carotid and femoral ultrasound scans; 30 had atherosclerosis plaques (patients with SLE with subclinical plaque) and 50 had no plaques (patients with SLE with no subclinical plaque). Serum samples obtained at the time of the scan were analyzed using a lipoprotein-focused metabolomics platform assessing 228 metabolites by nuclear magnetic resonance spectroscopy. Data were analyzed using logistic regression and 5 binary classification models with 10-fold cross validation. Patients with SLE had global changes in complex lipoprotein profiles compared with healthy controls despite having clinical serum lipid levels within normal ranges. In the SLE cohort, univariate logistic regression identified 4 metabolites associated with subclinical plaque; 3 subclasses of VLDL (very low-density lipoprotein; free cholesterol in medium and large VLDL particles and phospholipids in chylomicrons and extremely large VLDL particles) and leucine. Together with age, these metabolites were also within the top features identified by the lasso logistic regression (with and without interactions) and random forest machine learning models. Logistic regression with interactions differentiated between patients with SLE with subclinical plaque and patients with SLE with no subclinical plaque groups with the greatest accuracy (0.800). Notably, free cholesterol in large VLDL particles and age differentiated between patients with SLE with subclinical plaque and patients with SLE with no subclinical plaque in all models. Conclusions: Serum metabolites are promising biomarkers to uncover and predict multimetabolic phenotypes of subclinical atherosclerosis in SLE.

BackgroundPatients with systemic lupus erythematosus (SLE) have an increased risk of developing cardiovascular disease (CVD) and 30-40% have sub-clinical atherosclerosis on vascular ultrasound scanning. Standard measurements of serum lipids in clinical practice do not predict CVD risk in patients with SLE. We hypothesise that more detailed analysis of lipoprotein taxonomy could identify better predictors of CVD risk in SLE.MethodsEighty patients with SLE and no history of CVD underwent carotid and femoral ultrasound scans; 30 had atherosclerosis plaques (SLE-P) and 50 had no plaques (SLE-NP). Serum samples obtained at the time of the scan were analysed using a lipoprotein-focused metabolomics platform assessing 228 metabolites by nuclear magnetic resonance spectroscopy. Data was analysed using logistic regression and five binary classification models with 10-fold cross validation; decision tree, random forest, support vector machine and lasso (Least Absolute Shrinkage and Selection Operator) logistic regression with and without interactions.ResultsUnivariate logistic regression identified four metabolites associated with the presence of sub-clinical plaque; three subclasses of very low density lipoprotein (VLDL) (percentage of free cholesterol in medium and large VLDL particles and percentage of phospholipids in chylomicrons and extremely large VLDL particles) and Leucine. Together with age, these metabolites were also within the top features identified by the lasso logistic regression (with and without interactions) and random forest machine learning models. Logistic regression with interactions differentiated between SLE-P and SLE-NP with greatest accuracy (0.800). Notably, percentage of free cholesterol in large VLDL particles and age were identified by all models as being important to differentiate between SLE-P and SLE-NP patients.ConclusionSerum metabolites are a promising biomarker for prediction of sub-clinical atherosclerosis development in SLE patients and could provide novel insight into mechanisms of early atherosclerosis development.

Background Patients with SLE have 5-10-fold increased risk of developing CVD compared to age and sex-matched controls. The average age of developing a first CVD event in patients with SLE is only 49. In this study we aimed to describe the rate and determinants of carotid plaque progression in a cohort of SLE patients who were asymptomatic of CVD at baseline. Methods We carried out vascular ultrasound studies of 100 patients with SLE asymptomatic of CVD at baseline. Sixty-nine patients were rescanned over a median of 5 years of follow up. Ninety-four percent who were re-scanned were women and the mean overall age was 46 years (SD 11). Clinical and CVD risk was assessed at baseline and follow up. The same protocol for assessment at baseline using B-mode Doppler ultrasound to measure intimal media thickness and plaque was used at follow up to assess progression. We also assessed total plaque area (TPA), a more sensitive measure of plaque, and echolucency expressed as gray scale median (GSM) which is linked to plaque lipid content. Results Of the 100 patients with a baseline scan, 69 patients had a second scan at a median of 5 years follow up. New plaque developed in 9% and 26% had an increase in plaque number. The mean overall IMT (0.111 vs 0.064, p < 0.01) and common carotid IMT (0.065 vs 0.055, p < 0.01) were significantly raised in plaque vs non-plaque patients. In a multi -variable analysis CIMT at follow-up was independently associated with age (beta 0.415, p < 0.001) and diastolic blood pressure (beta 0.285, p < 0.021). Independent predictors of plaque at follow-up scan on multi-variable analysis were age at scan>52 years (OR 10.41, CI 2.66-40.80) and systolic BP > 133 (OR 5.26, CI 1.396 - 19.862). In contrast, total cholesterol was negatively correlated with TPA (beta = -1.167, p = 0.002) and with GSM (beta = -0.513, p = 0.012). Conclusion Amongst these 69 patients, 26% had increased plaque and none had decreased plaque over a median of five years follow-up. Measurement of novel ultrasound variables such as TPA and echolucency may identify more modifiable risk factors that can be used to improve CVD outcomes in patients with SLE. Disclosures J. Bakshi: None. M. Griffin: None. S. Croca: None. F. Farhina: None. D. Isenberg: None. A. Nicolaides: None. A. Rahman: None.

Background Cardiovascular disease is a significant burden on SLE patients, and no satisfactory markers exist to predict atherosclerotic development in patients. This study utilised an orthogonal approach to develop a marker of cardiovascular progression with predictive value in SLE patients. Methods The earliest available sample from a cohort of 92 SLE patients was tested for anti-Domain I (aDI), anti Beta-2-Glycoprotein-I, and anti-Cardiolipin antibodies. Persistent positivity was not assessed. These patients then had vascular ultrasound scans (carotid and femoral arteries) (mean 10 years later) to assess subclinical atherosclerotic plaque. A range of demographic, clinical and serological markers were recorded at the time of the scan. Predictors of plaque presence were investigated using binary logistic regression. Results A total of 34 patients from the cohort of 92 had atherosclerotic plaque (37%). A total of 32 patients had aDI positivity, of which 20 (62.5%) also had Plaque, this is reflected by the significantly higher levels of aDI antibodies seen in Plaque patients (p < 0.01). Anti-DI positivity was predictive of the development of plaque in the future (Odds Ratio (OR) 5.476, p < 0.001). No association was seen for any other antibody tested. Multiple binary logistic regression showed aDI positivity had as much predictive value as triglyceride levels on the day of the scan (OR 3.5 vs 3.9, Table 1) for predicting plaque in patients. Age at scan was a third independent variable associated with atherogenic plaque. Conclusion Early aDI positivity may be a good marker of atherogenesis in SLE patients in the long term. Disclosures T.C.R. McDonnell: Other; I am an inventor on the patent for Domain I. F. Farinha: None. C. Pericleous: Other; This Author is an Inventor on the Patent for Domain I. M. Griffin: None. A. Nicolaides: None. S. Croca: None. I. Giles: Other; This Author is an Inventor on the Domain I Patent. A. Rahman: Other; This Author is an Inventor on the Domain I Patent..

Background Cardiovascular disease is a significant burden on SLE patients and no satisfactory markers exist to predict atherosclerotic development in patients. This study utilised an orthogonal approach to develop a marker of cardiovascular progression with predictive value in SLE patients. Methods The earliest available sample from a cohort of 92 SLE patients was tested for anti-Domain I (aDI), anti Beta-2-Glycoprotein-I, and anti-Cardiolipin antibodies. Persistent positivity was not assessed. These patients then had vascular ultrasound scans (carotid and femoral arteries) (mean 10 years later) to assess subclinical atherosclerotic plaque. A range of demographic, clinical and serological markers were recorded at the time of the scan. Predictors of plaque presence were investigated using binary logistic regression. Results A total of 34 patients from the cohort of 92 had atherosclerotic plaque (37%). A total of 32 patients had aDI positivity, of which 20 (62.5%) also had Plaque, this is reflected by the significantly higher levels of aDI antibodies seen in Plaque patients (p Conclusions Early aDI positivity may be a good marker of atherogenesis in SLE patients in the long term.

Background SLE patients have 5–10-fold increased risk of developing CVD compared to controls.1,2 In this study we aimed to describe the rate and determinants of carotid plaque progression in a cohort of SLE patients who were asymptomatic of CVD at baseline. Methods Vascular ultrasound studies of 100 patients with SLE asymptomatic of CVD was carried out at baseline. Sixty-nine patients were rescanned (94% female, mean overall age 46 years (SD 11)) over a median of 5 years of follow up. Clinical and CVD risk was assessed at baseline and follow up. B-mode Doppler ultrasound was used to measure intimal media thickness and plaque to assess progression. Total plaque area (TPA), a more sensitive measure of plaque, and echolucency expressed as gray scale median (GSM), linked to plaque lipid content were assessed. Results Of the 100 patients with a baseline scan, 69 patients had a second scan at a median of 5 years follow up. New plaque developed in 9% and 26% had an increase in plaque number. The mean overall IMT (0.111 vs 0.064, p 52 years (OR 10.41, CI 2.66–40.80) and systolic BP>133 (OR 5.26, CI 1.396 – 19.862). In contrast, total cholesterol was negatively correlated with TPA (beta =-1.167, p=0.002) and with GSM (beta =-0.513, p=0.012). Conclusions Amongst these 69 patients, 26% had progression and none had decreased plaque over a median of five years follow-up. Measurement of novel ultrasound variables such as TPA and echolucency may identify more modifiable risk factors that can be used to improve CVD outcomes in patients with SLE. Acknowledgements Rosetrees Trust References Bruce IN. ‘Not only...but also’: factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus erythematosus. Rheumatology(Oxford, England) 2005;44(12);1492–502. Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997;145(5);408–15.

Cardiovascular disease (CVD), comprising coronary heart disease and stroke, is one of the most important causes of death in patients with systemic lupus erythematosus (SLE). The risks of developing both clinical CVD and sub-clinical atherosclerosis are increased in patients with SLE. This increase is not fully explained by traditional cardiovascular risk factors such as smoking, hypertension and elevated cholesterol, and it is believed that immune dysfunction also contributes to CVD risk in SLE. In particular, recent studies have shown that abnormalities in both serum lipid profile and the autoantibody and T lymphocyte response to lipids may play a role in development of atherosclerosis. The standard CVD risk calculation algorithms based on traditional risk factors underestimate the risk of developing CVD in patients with SLE. Thus, novel algorithms incorporating new biomarkers such as pro-inflammatory high-density lipoprotein and use of imaging techniques such as carotid ultrasound scanning may become increasingly valuable.

Accelerated atherosclerosis is a complication of the autoimmune rheumatic disease systemic lupus erythematosus (SLE). We questioned the role played by invariant natural killer T (iNKT) cells in this process because they not only are defective in autoimmunity but also promote atherosclerosis in response to CD1d-mediated lipid antigen presentation. iNKT cells from SLE patients with asymptomatic plaque (SLE-P) had increased proliferation and interleukin-4 production compared with those from SLE patients with no plaque. The anti-inflammatory iNKT cell phenotype was associated with dyslipidemia and was driven by altered monocyte phospholipid expression and CD1d-mediated cross-talk between iNKT cells and monocytes but not B cells. Healthy iNKT cells differentiated in the presence of healthy monocytes and SLE-P serum polarized macrophages toward an anti-inflammatory M2 phenotype. Conversely, patients with clinical cardiovascular disease had unresponsive iNKT cells and increased proinflammatory monocytes. iNKT cell function could link immune responses, lipids, and cardiovascular disease in SLE patients and, together with serum lipid taxonomy, help predict preclinical atherosclerosis in SLE patients.

Introduction IgG anti-apolipoprotein A-1 (IgG anti-apoA-1) antibodies are present in patients with systemic lupus erythematosus (SLE) and may link inflammatory disease activity and the increased risk of developing atherosclerosis and cardiovascular disease (CVD) in these patients. We carried out a rigorous analysis of the associations between IgG anti-apoA-1 levels and disease activity, drug therapy, serology, damage, mortality and CVD events in a large British SLE cohort. Methods Serum IgG anti-apoA-1 levels were measured in 100 healthy controls to define a cut-off for positivity. In 499 patients with SLE we obtained the earliest stored serum sample from their disease course and measured IgG anti-apoA-1 level. We then examined associations between IgG anti-apoA-1 positivity in early disease and the development of damage, CVD or death over a mean follow-up period of 12.1 years in these patients. In a separate study, we measured IgG anti-apoA-1 levels in 397 samples taken longitudinally from 49 patients with SLE over a mean period of 89 months of fluctuating disease activity and carried out multi-variable analysis to examine the demographic, serological, disease activity and treatment factors associated with IgG anti-apoA-1 level over time. Results In the longitudinal study, IgG anti-apoA-1 levels were significantly higher in patients with persistently active disease, those on high dose corticosteroid and those not taking hydroxychloroquine. Of the 499 subjects who had early disease IgG anti-apoA-1 levels measured, 135 (27%) were positive. However, we found no convincing associations between early IgG anti-apoA-1 positivity and development of damage, mortality or CVD. Conclusions IgG anti-apoA-1 developed early in a quarter of our patients with SLE, but this had no major impact on subsequent clinical outcomes. However, levels of IgG anti-apoA-1 vary over time and are associated with disease activity, treatment with high dose corticosteroid and not taking hydroxychloroquine.

Systemic lupus erythematosus is a multisystem, autoimmune disease known to be one of the strongest risk factors for atherosclerosis. Patients with SLE have an excess cardiovascular risk compared with the general population, leading to increased cardiovascular morbidity and mortality. Although the precise explanation for this is yet to be established, it seems to be associated with the presence of an accelerated atherosclerotic process, arising from the combination of traditional and lupus-specific risk factors. Moreover, cardiovascular-disease associated mortality in patients with SLE has not improved over time. One of the main reasons for this is the poor performance of standard risk stratification tools on assessing the cardiovascular risk of patients with SLE. Therefore, establishing alternative ways to identify patients at increased risk efficiently is essential. With recent developments in several imaging techniques, the ultimate goal of cardiovascular assessment will shift from assessing symptomatic patients to diagnosing early cardiovascular disease in asymptomatic patients which will hopefully help us to prevent its progression. This review will focus on the current status of the imaging tools available to assess cardiac and vascular function in patients with SLE.

To present a pooled analysis of the efficacy of rituximab from European cohorts diagnosed with biopsy-proven lupus nephropathy (LN) who were treated with rituximab.Consecutive patients with biopsy-proven LN treated with rituximab in European reference centers were included. Complete response (CR) was defined as normal serum creatinine with inactive urinary sediment and 24-hour urinary albumin0.5 g, and partial response (PR) as a50% improvement in all renal parameters that were abnormal at baseline, with no deterioration in any parameter.164 patients were included (145 women and 19 men, with a mean age of 32.3 years). Rituximab was administered in combination with corticosteroids (162 patients, 99%) and immunosuppressive agents in 124 (76%) patients (cyclophosphamide in 58 and mycophenolate in 55). At 6- and 12-months, respectively, response rates were 27% and 30% for CR, 40% and 37% for PR and 33% for no response. Significant improvement in 24-h proteinuria (4.41 g. baseline vs 1.31 g. post-therapy, p=0.006), serum albumin (28.55 g. baseline to 36.46 g. post-therapy, p0.001) and protein/creatinine ratio (from 421.94 g/mmol baseline to 234.98 post-therapy, p0.001) at 12 months was observed. A better response (CR+PR) was found in patients with type III LN in comparison with those with type IV and type V (p=0.007 and 0.03, respectively). Nephrotic syndrome and renal failure at the time of rituximab administration predicted a worse response (no achievement of CR at 12 months) (p0.001 and p=0.024, respectively).Rituximab is currently being used to treat refractory systemic autoimmune diseases. Rituximab may be an effective option for patients with lupus nephritis, especially those refractory to standard treatment or who experience a new flare after intensive immunosuppressive treatment.

Objective. LN is a common and potentially severe complication of SLE. Our aim was to characterize a LN cohort followed at a single centre for 30 years and assess its evolution over time. Methods. Between 1975 and 2005, 156 LN patients were followed up at University College Hospital London. We divided them into three groups depending on the date of recognition of renal involvement (197585, 198695 and 19962005) and compared them in terms of clinical, demographic and serological characteristics and disease outcome. Results. Clinical characteristics were comparable between groups; however, the proportion of Afrocaribbean (AC) patients and the prevalence of anti-ENA antibodies rose significantly over time. The 5-year mortality rate decreased by 60% between the first and second decades, remaining stable over the third decade. The 5-year end-stage renal disease (ESRD) rate remained constant. An increasing number of renal transplants (RTx) was performed with encouraging results. AC origin was associated with a poorer overall prognosis. Conclusion. LN, a common complication of SLE, is associated with increased mortality and morbidity, particularly among AC patients. Despite encouraging results for RTx, once ESRD is established the prognosis is relatively poor and no improvement in preventing its development was achieved. Moreover, although a significant decrease in mortality was observed, it has remained stable for 10 years. These results suggest that we have maximized the benefits of conventional therapies and if further improvement is to be achieved, novel drug regimens must be developed.

Background Variability in rituximab-induced B cell depletion (BCD) occurs in a significant number of patients with Systemic Lupus Erythematosus (SLE) and to a lesser extent in patients with Rheumatoid Arthritis (RA). A failure to adequately deplete (CD19+ B cells Objectives To determine the serum levels of rituximab at 1 and 3 months post-rituximab in SLE and RA in conjunction with the measurement of absolute number of peripheral CD19+ B cells. Methods A total of 16 patients with SLE were included and 23 with RA. All patients were treated with rituximab (2 x 1g doses given 2 week apart). Rituximab levels at 1 and 3 months post treatment were measured with a capture ELISA using sera diluted at a concentration of 1/40,000. CD19 counts were determined by flow cytometry. Adequate depletion was defined as CD19+ count below 5cells/ml. Data were compared using the Mann Whitney U test for non-parametric data and the Spearman Rank for correlation. Results At 1 month, 6 of 15 (40%) patients with SLE and 6 of 23 (26%) patients with RA had CD19 counts >5 cells/ml. The median CD19 count in these patients was 0.02cells/μl and 0.008cells/μl for SLE and RA, respectively. The levels of rituximab were significantly lower in SLE when compared with RA, at both 1 and 3 months after rituximab treatment. The median rituximab level at 1 month for SLE was 43.07μg/ml (range 0-777) and for RA, 391.9μg/ml (range 1.3-2500) (p=0.0008). The median rituximab level at 3 months was 0μg/ml (range 0-54) for SLE and 2.6μg/ml (range 0-1153) for RA (p=0.008). Amongst patients who had depleted well, rituximab levels were significantly lower in patients with SLE when compared with patients who have RA at 1 month (p=0.003) and also at 3 months (p=0.008). No such difference was found in patients who did not deplete well. Six patients with SLE had lupus nephritis (LN) and the presence of LN did not influence the levels of rituximab or the degree of BCD, in this small group of patients. The levels of rituximab correlated inversely with the absolute numbers of CD19+ B cells in patients with RA at 1 month (r2=0.69) and in patients with SLE at 3 months (r2=0.51). Conclusions Our data indicated that patients with SLE had markedly (>9 fold at 1 month) lower serum levels than RA patients at both 1 and 3 months. However, a higher proportion of patients with SLE depleted less well with significantly higher residual CD19+ B cells due to factors involved in the clearance of rituximab such as impaired recycling through FcRn, internalisation and destruction by target B cells. Disclosure of Interest None Declared

Introduction Circulating nucleosomes released from apoptotic cells are important in the pathogenesis of systemic lupus erythematosus (SLE). Both nucleosomes and anti-nucleosome antibodies are deposited in inflamed tissues in patients with SLE. Active inflammation promotes nitration of tyrosine residues on serum proteins. Our hypothesis was that levels of nitrated nucleosomes would be elevated in patients with SLE and could be associated with disease activity. We therefore carried out a retrospective longitudinal study to investigate factors affecting levels of nitrated nucleosomes (NN) in patients with SLE. Methods A novel serum ELISA was developed to measure serum NN and modified to measure serum nitrated albumin (NA). Levels of both NN and NA were measured in 397 samples from 49 patients with SLE followed through periods of disease flare and remission for a mean of 89 months. Anti-nucleosome antibody (anti-nuc) levels were measured in the same samples. The effects of 24 different clinical, demographic and serological variables on NN, NA and anti-nuc levels were assessed by univariable and multivariable analysis. Results Patients with SLE had higher mean NN than healthy controls or patients with other autoimmune rheumatic diseases (P =0.01). Serum samples from 18 out of 49 (36.7%) of SLE patients were never positive for NN. This group of 18 patients was characterized by lower anti-double stranded DNA antibodies (anti-dsDNA), disease activity and use of immunosuppressants. In the remaining 63.3%, NN levels were variable. High NN was significantly associated with anti-Sm antibodies, vasculitis, immunosuppressants, hydroxychloroquine and age at diagnosis. NN levels were raised in neuropsychiatric flares. NN levels did not completely parallel NA results, thus providing additional information over measuring nitration status alone. NN levels were not associated with anti-nuc levels. Conclusions NN are raised in a subset of patients with SLE, particularly those who are anti-Sm positive. Elevated NN may be a marker of vascular activation and neuropsychiatric flares in these patients.