Extent of vascular plaque predicts future cardiovascular events in patients with systemic lupus erythematosus.

OBJECTIVE: Patients with SLE have increased prevalence of clinical cardiovascular disease (CVD) and subclinical atherosclerosis. Although 30-40% of patients with SLE have vascular plaque on ultrasound scanning, this study is the first to consider the relationship between total burden of plaque and subsequent CVD risk. METHODS: One hundred patients with SLE and without any previous clinical CVD underwent vascular ultrasound scans of both carotid and both common femoral bifurcations between 2011 and 2013. Clinical, serological, demographic and treatment data were collected at baseline. Patients were followed till 2020 to identify those who developed new onset coronary disease or stroke. Statistical analysis to identify factors associated with increased risk of developing CVD events was carried out. RESULTS: Thirty-six patients had plaque at baseline. During follow-up five patients (all had baseline plaque) developed coronary disease and two, without baseline plaque, developed lacunar strokes. Mean (s.d.) age of these patients was 46.5 (4.5) years. Patients with three or more baseline bifurcations with plaque were 10 times more likely to develop CVD than those with 0-2 bifurcations with plaques (OR 9.9, P = 0.009). TPA > 16mm2 was associated with six-fold increased risk of CVD (OR = 6.44, P = 0.028). Patients with disease duration > 14 years were more likely than those with disease duration < 14 years to develop CVD (OR 8.3 P = 0.043). CONCLUSIONS: The number of bifurcations with plaque and TPA in patients with SLE may be valuable in assessing risk of CVD and deciding on clinical measures to reduce this risk.

Serum Metabolomic Signatures Can Predict Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus.

[Figure: see text].

Total plaque area and plaque echogenicity are novel measures of subclinical atherosclerosis in patients with systemic lupus erythematosus.

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.

Atherosclerosis in systemic lupus erythematosus.

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.

Nitrated nucleosome levels and neuropsychiatric events in systemic lupus erythematosus; a multi-center retrospective case-control study.

BACKGROUND: In patients with systemic lupus erythematosus (SLE) there is no serological test that will reliably distinguish neuropsychiatric (NP) events due to active SLE from those due to other causes. Previously we showed that serum levels of nitrated nucleosomes (NN) were elevated in a small number of patients with NPSLE. Here we measured serum NN in samples from a larger population of patients with SLE and NP events to see whether elevated serum NN could be a marker for NPSLE. METHODS: We obtained serum samples from patients in the Systemic Lupus International Collaborative Clinics (SLICC) inception cohort. This included 216 patients with NP events and two matched controls with SLE but no NP events for each of these patients. For the NP patients we tested samples taken before, during and after the NP event. RESULTS: Twenty-six patients had events attributed to SLE according to the most stringent SLICC attribution rule. In these patients there was no association between onset of event and elevated serum NN. In 190 patients in whom events were not attributed to SLE by the SLICC rules, median serum NN was elevated at the onset of event (P = 0.006). The predominant clinical features in this group of 190 patients were headache, mood disorders and anxiety. CONCLUSIONS: Serum NN levels rise at the time of an NP event in a proportion of patients with SLE. Further studies are needed to determine the value of serum NN as a biomarker for NPSLE.

Cross-talk between iNKT cells and monocytes triggers an atheroprotective immune response in SLE patients with asymptomatic plaque.

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.

IgG anti-apolipoprotein A-1 antibodies in patients with systemic lupus erythematosus are associated with disease activity and corticosteroid therapy: an observational study.

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.

Serum nitrated nucleosome levels in patients with systemic lupus erythematosus: a retrospective longitudinal cohort study.

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.

Imaging assessment of cardiovascular disease in systemic lupus erythematosus.

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.

Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts.

OBJECTIVE: 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. METHODS: 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 albumin <0.5 g, and partial response (PR) as a >50% improvement in all renal parameters that were abnormal at baseline, with no deterioration in any parameter. RESULTS: 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, p<0.001) and protein/creatinine ratio (from 421.94 g/mmol baseline to 234.98 post-therapy, p<0.001) 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) (p<0.001 and p=0.024, respectively). CONCLUSION: 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.

Assessment of a lupus nephritis cohort over a 30-year period.

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 (1975-85, 1986-95 and 1996-2005) 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 Afro-caribbean (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.