Plasma/Serum Oxidant Parameters in Systemic Lupus Erythematosus Patients: A Systematic Review and Meta-Analysis.

CXC ligand 13 (CXCL13) is known as B cell chemotactic factor (BLC), promoting the migration of B lymphocytes by communicating with its receptor CXCR5, which can be regarded as part of pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This meta-analysis was to evaluate the circulating CXCL13 levels in SLE and RA. All articles were respectively gathered from PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) (by the end of 10 April 2019). According to random effects model, standardized mean difference (SMD) and 95% confidence interval (CI) of CXCL13 levels in SLE and RA were calculated by Stata 12.0 software. Totally, 15 studies were selected (981 SLE patients and 380 healthy controls, 332 RA patients and 147 healthy controls). SLE and RA patients were significantly increased in circulating CXCL13 levels (SMD = 1.851, 95% CI 0.604-3.098; SMD = 1.801, 95% CI = 1.145-2.457). Subgroup analyses showed that SLE patients from the Chinese group and systemic lupus erythematosus disease activity index (SLEDAI) score ≥ 6 group had higher circulating CXCL13 levels (SMD = 2.182, 95% CI 0.135-4.229; SMD = 0.767, 95% CI 0.503-1.030). However, there were no significant changes in CXCL13 concentrations in SLE patients from the English and SLEDAI score < 6 group. Similarly, subgroup analyses presented that RA patients from different classifications showed higher circulating CXCL13 levels. There was no publication bias. This meta-analysis demonstrated increased circulating CXCL13 concentrations in SLE and RA patients. Circulating CXCL13 levels may act as biomarkers and therapy targets in the diagnosis and treatment of SLE and RA.Key Point• First, CXC ligand 13 (CXCL13) is closely related to the pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), Second, this study may provide novel therapeutic targets for the treatment of SLE and RA patients. This meta-analysis provides a comprehensive analysis of circulating CXCL13 levels in patients with SLE and RA and also explores related influencing factors.

studies have shown that high-mobility group box 1 (HMGB1) may play a role in the propagation of inflammatory response in infectious and autoimmune diseases. However, its utility in the differentiation between infections and disease flares in systemic lupus erythematosus (SLE) patients has not been investigated. we prospectively recruited 38 hospitalized patients from Taiwan with SLE. Among them, 13 patients suffered from superimposed bacterial infections while the other 25 patients experienced disease flares. SLE disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Serum levels of HMGB1 were measured by an enzyme-linked immunosorbent assay (ELISA). Additionally, serum levels of high-sensitivity C-reactive protein (hsCRP) were determined among 34 of the SLE patients. there was no significant difference between the serum HMGB1 levels in SLE patients with disease flares and patients with bacterial infections. Among SLE patients with disease flares, serum HMGB1 levels were significantly higher in patients with mild to moderate flares (3.53 ng/ml) compared to those with severe flares (1.72 ng/ml, p < 0.05). For identifying bacterial infections in patients with SLE, the area under the receiver operating characteristic (ROC) curve was 0.705 (95% CI: 0.524-0.848) for hsCRP and 0.497 (95% CI: 0.331-0.663) for HMGB1. The best cutoff value for hsCRP was 1.07 mg/dl for detection of bacterial infections in SLE patients, with a sensitivity of 75% and a specificity of 68%. the determination of serum HMGB1 level is not useful in the differentiation between disease flares and bacterial infections in SLE patients.

Atherosclerosis is an inflammatory disease and the major cause of cardiovascular disease (CVD) in general. Atherosclerotic plaques are characterized by the presence of activated immune competent cells, but antigens and underlying mechanisms causing this immune activation are not well defined. During recent years and with improved treatment of acute disease manifestations, it has become clear that the risk of CVD is very high in a prototypic autoimmune disease, systemic lupus erythematosus (SLE). SLE-related CVD and atherosclerosis are important clinical problems but may in addition also shed light on how immune reactions are related to premature atherosclerosis and atherothrombosis. A combination of traditional and nontraditional risk factors, including dyslipidaemia (and to a varying degree hypertension, diabetes and smoking), inflammation, antiphospholipid antibodies (aPL) and lipid oxidation are related to CVD in SLE. Premature atherosclerosis in some form leading to atherothrombosis is likely to be a major underlying mechanism, though distinctive features if any, of SLE-related atherosclerosis when compared with 'normal' atherosclerosis are not clear. One interesting possibility is that factors such as inflammation or aPL make atherosclerotic lesions in autoimmune disease more prone to rupture than in 'normal' atherosclerosis. Whether premature atherosclerosis is a general feature of SLE or only affects a subgroup of patients remains to be demonstrated. Treatment of SLE patients should also include a close monitoring of traditional risk factors for CVD. In addition, attention should also be paid to nontraditional risk factors such as inflammation and SLE-related factors such as aPL. Hopefully novel therapeutic principles will be developed that target the causes of the inflammation and immune reactions present in atherosclerotic lesions.

Systemic lupus erythematosus (SLE) patients have tendencies of accelerated atherosclerosis (AS) which can only partly be explained by traditional cardiovascular disease (CVD) risk factors. Imbalanced inflammation also plays a vital role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new therapeutic target for AS for its dual mechanisms in lipids and inflammation. We aimed to assess serum PCSK9 concentrations in SLE patients and its possible role in atherogenesis of SLE. Ninety SLE patients and 50 healthy controls were included. SLE patients were further divided into SLE-AS and SLE-NonAS subgroups, according to the carotid intima-media thickness (cIMT). Traditional CVD risk factors, inflammatory biomarkers and PCSK9 concentrations were compared between: (I) SLE patients and controls; (II) SLE-AS subgroup and SLE-NonAS subgroup; (III) SLE patients with and without lupus nephritis (LN). Correlational analysis, univariate and multivariate linear regression analysis were applied to analyze the association between PCSK9 levels and disease parameter in SLE patients. Effects on PCSK9 concentrations by monotherapy with hydroxychloroquine (HCQ), which is thought having protective effects against AS in SLE, were investigated by follow-up analysis in 15 SLE patients. We found that SLE patients had significantly elevated serum PCSK9 levels than controls, especially in SLE-As subgroup or those with LN, accompanied with higher ratio of cIMT thickening. Correlational analysis showed PCSK9 concentrations correlated with C-reactive protein (CRP) levels, age and erythrocyte sedimentation rate (ESR). Univariate and multivariate linear regression revealed that only CRP, but not age or ESR was positive predictors of PCSK9. Interestingly, monotherapy with HCQ for three months significantly reduced PCSK9 and CRP levels in inactive SLE patients. Our results suggested that elevated PCSK9 levels in SLE are probably associated with atherogenic inflammation in SLE. HCQ, which is thought having protective effects against AS in SLE, can effectively reduce PCSK9 levels in SLE patients.

BackgroundSequence variation in gene promoters is often associated with disease risk. In this study, we tested the hypothesis that common promoter variation in the APOM gene is associated with systemic lupus erythematosus (SLE) risk and SLE-related clinical phenotypes in a Chinese cohort. Meanwhile, we investigated the expression of apolipoprotein M (APOM) in the serum of patients with systemic lupus erythematosus (SLE) and its relationship with disease activity.MethodsWe used a case-control design and genotyped 52 SLE patients and 52 healthy controls for 19 APOM promoter single nucleotide polymorphism (SNP) (rs113947529, rs1143030, rs114826514, rs116715239, rs12525463, rs1266078, rs2273612, rs28432254, rs34490746, rs4947251, rs55880811, rs707921, rs74890500, rs75629491, rs76611345, rs76794541, rs805264, rs805297, rs9267528). Genotyping was done by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The blood serum concentration of APOM was measured by an enzyme-linked immunosorbent assay in SLE patients and controls.ResultsThe average concentration of APOM in serum was significantly lower in SLE patients compared to controls and APOM levels in SLE patients with positive anti-dsDNA antibodies were dramatically lower than that of patients with negative anti-dsDNA antibodies (P = 0.011). It was interesting that APOM levels correlated with systemic lupus erythematosus disease activity index (SLEDAI) scores (r = −0.396, P = 0.004). No association between APOM and SLE susceptibility was detected in our Han Chinese cohort.ConclusionsOur results demonstrated that lower APOM levels in SLE patients and correlated with disease activity.

Background: Fibromyalgia tender points (FMTP) have consistently reported higher number count in systemic lupus erythematosus (SLE) patients compared with the general population.Objective: The purpose of this study was to determine the association and impact of fibromyalgia tender points on disease activity in SLE patients.Methods: Sixty seven female SLE patients and equal number of asymptomatic, age and sex matched control subjects were enrolled in this observational study. The study was performed between April 2005 and October 2006. After fulfilling the certain inclusion criteria, obtained data were recorded in a structured questionnaire. 18 FMTP sites and 6 control sites were examined by standardized manual tender point survey system. Systemic lupus erythematosus disease activity index (SLEDAI) was used covering all 9 organs and 24 descriptors with pre assigned severity weights. The scores ranged from 0 ( no disease activity) to 105 ( maximum disease activity). Both the SLE cases and the control group were classified into two subgroups namely ‘0-10 FMTP’ having 10 or less FMTP and &gt;11 FMTP’ bearing 11or more tender points.Results: The age (mean ± SD) of the SLE patients and controls were 26.82 ± 8.02 and 29.67± 10.80 years respectively. No significant difference in age (p = 0.091) and in family income (p = 0.065) was observed but significant difference was observed in level of education ( p = 0.009) and in occupation ( p = 0.004) . At enrolment, the number of FMTP (mean ± SD) in SLE patients and control groups were 8.80±6.40 and 3.63±4.90 respectively. The difference was significant (p&lt;0.001). The SLEDAI score (mean ± SD) in SLE patients was 11.75±9.85. Further, the SLEDAI score of ‘0-10 FMTP’ and &gt;11FMTP’ subgroups of SLE were 8.49±7.34 and 17.58±11.17 respectively. The difference was again significant (p&lt;0.001). Hence the disease activity was positively correlated (r=+0.439, p&lt;0.001) with FMTPs in SLE patients. Meanwhile, no significant correlation was observed between disease duration (r= +0.085, p = 0.495) and SLEDAI and similarly no significant correlation was also observed in disease duration with FMTP; 0-10 and &gt;11FMTP groups of SLE (p = 0.605)Conclusions: SLE patients with higher number of FMTPs are significantly associated with increased scores of SLEDAI. Hence, it can be said that there is a linear correlation between the number of FMTPs and the disease activity in SLE patients. Interestingly, no significant correlation was observed between ‘disease duration and SLEDAI’ as well as between ‘disease duration and FMTP’.J Dhaka Medical College, Vol. 24, No.2, October, 2015, Page 99-107

Interleukin-15 (IL-15) has multiple biological properties, including the induction of other cytokine production and the inhibition of T cell apoptosis. Recently, IL-15 was reported to have a major role in synovial inflammation of rheumatoid arthritis, and that it provokes and amplifies the inflammatory process through the activation of TNF-alpha production. In systemic lupus erythematosus (SLE), the dysregulation of apoptosis and various cytokine production were observed and have been implicated in the pathogenesis of SLE. Thus, we tried to determine serum IL-15 levels in SLE patients and to assess the relationship among IL-15 levels, TNF-alpha levels and disease activity of SLE. Twenty SLE patients and 10 controls were studied. Paired serum samples were collected from all SLE patients at the time of presentation with active disease and at 4 weeks after institution of treatment. IL-15 levels were determined by ELISA and compared with the disease activity indices in SLE. The disease activity of SLE was measured using the SLE Disease Activity Index (SLEDAI) and laboratory parameters such as circulating immune complex (CIC), C3, C4, anti-DNA antibody, IgG, IgM, and IgA. The IL-15 levels in SLE patients were significantly higher than those of controls (5.38 +/- 4.89 vs. 1.04 +/- 1.26 pg/ml). However, elevated IL-15 levels did not correlate with the SLEDAI, nor did they correlate with other laboratory activity indices. The changes in serum IL-15 levels did not correlate with the changes in serum TNF-alpha in the disease course of SLE patients, whereas TNF-alpha reflected the changes in disease activity of SLE. Serum levels of IL-15 are elevated in SLE patients, but IL-15 did not correlate with the disease activity of SLE. TNF-alpha production in SLE patients was unlikely to be related with IL-15.

BackgroundDepression is one of the most commonly reported neuropsychiatric symptoms in systemic lupus erythematosus (SLE) patients. However, the prevalence of depression in relation to the general population and its relationship...

Nonstandard and adjunctive medical therapies for systemic lupus erythematosus

Higher serum adiponectin in systemic lupus erythematosus (SLE) patients mitigates the inflammatory response. Previous studies investigated serum adiponectin level in SLE patients compared with control subjects, yielding inconsistent results. The aim of this meta-analysis was to assess the difference between serum adiponectin levels in SLE patients compared with control subjects. MEDLINE, PubMed, EMBASE, and Web of Science were searched from inception to August 31, 2016, to identify all observational studies that examined the relationship between serum adiponectin levels and SLE. The study quality was assessed by the Newcastle-Ottawa Scale. Standard mean difference values and 95% confidence intervals were estimated and pooled using the meta-analysis methodology. The Cochrane Q test and I statistics were used to test heterogeneity. To assess publication bias, visual observations of a funnel plot were used. The Stata software (version 11.0) was used for statistical analysis. A total of 8 studies including 782 SLE patients and 550 control subjects were eligible for the meta-analysis. In overall random-effects model including all the studies, we found that patients with SLE had higher serum adiponectin levels than control subjects (eight studies; pooled standardized mean difference, 0.502 μg/mL; 95% confidence interval, 0.021-0.984; I = 94.0%; P < 0.001). In subgroup analyses, SLE patients with body mass index of 25 kg/m or greater had higher serum adiponectin levels compared with control subjects. Collectively, our results demonstrate that higher serum adiponectin level is significantly associated with SLE. Furthermore, they suggest that serum adiponectin levels in SLE patients are not correlated with Systemic Lupus Erythematosus Disease Activity Index scores. Imbalanced adiponectin levels might be associated with onset of other chronic diseases.

The global hypomethylation of CD4+ T cells in systemic lupus erythematosus (SLE) patients has been previously reported. However, potential influencing factors are unclear. This study aimed to uncover the potential influence of obese on hypomethylated CD4+ T cells in SLE patients. Obese SLE patients with Body Mass Index (BMI)>30 (N.=15) and normal weight SLE patients with 18<BMI<25 (N.=20) were included. SLEADI, antinuclear-ribonuclear-protein (nRNP) and dsDNA levels in them were detected. Methylation rate of CD4+ T cells isolated from SLE patients was assessed, as well as its correlation to BMI and Systemic Lupus Erythematosus Disease Activity Index (SLEADI) in SLE patients. Subsequently, relative level and catalytic activity of DNA (cytosine-5)-methyltransferase 1 (DNMT1) were examined. New Zealand black/white (NZB/W) mice were fed high-fat diet for generating obesity model or normal diet, followed by detection of antinuclear-ribonuclear-protein (nRNP) immunoglobulin G (IgG), antidouble-stranded (ds) DNA IgG, methylation rate of CD4+ T cells and DNMT1 level. SLEADI, nRNP and dsDNA levels were higher in obese SLE patients than normal weight cases. SLEADI was positively correlated to BMI in included SLE patients. Compared with normal weight SLE patients, methylation rate of CD4+ T cells was lower in obese patients. DNMT1 was downregulated in obese SLE patients, and its level was negatively correlated to BMI in SLE patients. Consistently, methylation rate of CD4+ T cells and DNMT1 level remained lower in obese SLE mice than those normally fed mice with SLE. Hypomethylated CD4+ T cells extensively occur in SLE patients, which are much more pronounced in obese cases. DNMT1 level is found to be negatively correlated to the methylation rate of CD4+ T cells in SLE patients.

Background Systemic lupus erythematosus (SLE) patients have tendencies of accelerated atherosclerosis (AS), which is refractory to statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new therapeutic target for AS for its dual mechanisms in lipids metabolism and inflammation. PCSK9 inhibitors had proved to be highly promising cardiovascular disease (CVD) drugs [1]. Our previous study suggested that Toll-like recetor 4(TLR4) signal participates in the atherosclerotic inflammation of murine model of lupus with AS [2]. Objectives To investigate the role of PCSK9 in atherosclerotic process of lupus and the association between TLR4 and PCSK9 in athergenic inflammation of murine model of lupus with AS. Methods 90 SLE patients and 50 healthy controls were included. According to carotid intima-media thickness (cIMT), SLE patients were further divided into SLE-AS and SLE-NonAS subgroups (cut-off point: 1.0mm). Traditional CVD risk factors, inflammatory biomarkers and PCSK9 concentrations were compared between: (I) SLE patients and controls; (II) SLE-AS subgroup and SLE-NonAS subgroup. Correlational analysis and multivariate linear regression analysis were applied to analyze the association between PCSK9 levels and disease parameter, and the predictors of PCSK9 levels in SLE patients. Effects on PCSK9 concentrations by monotherapy with hydroxychloroquine (HCQ), which is thought having protective effects against CVD in SLE, were investigated by follow-up analysis in 15 SLE patients with inactive disease (SLEDAI=2). In animal experiment, murine model of SLE with AS was set up by intraperitoneally injection of lipopolysaccharides (LPS) in ApoE-/- mice. 30 female ApoE-/- mice were respectively administrated with LPS (SLE+AS group, n=10), saline (AS group, n=10) and LPS plus injection of lentiviruse-PCSK9 small hairpin RNA targeting the mouse PCSK9 gene into the tail vein to interfere PCSK9 expression (SLE+AS+PCSK9i group, n=10). 10 female C57BL/6 mice were included as controls. Serum concentrations of PCSK9 and inflammatory biomarkers including TNF-α and IL-1β, atherosclerotic lesion, lipids parameters, expression of PCSK9, TLR4 and NF-κB p65 in atherosclerotic plaque were assessed. Results Characteristics of SLE patients and controls were listed in Table 1. SLE patients had significantly elevated serum PCSK9 levels than controls, especially in SLE-AS subgroup, accompanied with higher ratio of cIMT thickening. Correlational analysis showed PCSK9 concentrations correlated with C-reactive protein (CRP) levels, age and erythrocyte sedimentation rate (ESR), but not lipids parameters. Univariate and multivariate linear regression revealed that only CRP, but not age or ESR was positive predictors of PCSK9. Monotherapy with HCQ for 3 months significantly reduced PCSK9 levels in inactive SLE patients (Table 2, Figure 1). Mice in SLE+AS group had significantly higher serum PCSK9 concentrations than mice in AS group and C57BL/6 mice. Immunohistochemistry showed that PCSK9 overexpression was observed in SLE+AS mice than those in AS group and SLE+AS+PCSK9i group. Mice in SLE+AS+PCSK9i group exhibited decreased inflammatory cell infiltration in atherosclerotic plaque, alleviated atherosclerotic lesion, lower serum TNF-α and IL-1β levels and attenuated expression of TLR4 and NF-κB p65 in atherosclerotic plaque than SLE+AS group. PCSK9 silencing had no significant effects on lipids parameters in SLE+AS mice (Figure 2). Conclusion PCSK9 participates in atherogenic inflammation in SLE patients and murine model of SLE with AS. This process is associated with TLR4-NF-κB pathway, probably independent of lipids parameters alteration. HCQ can effectively reduce PCSK9 levels in SLE patients.

BackgroundDyslipidemia is prevalent in Systemic Lupus Erythematosus (SLE) patients and associated with lupus nephritis. Non-thyroidal illness syndrome (NTIS) frequently occurs in some autoimmune diseases. The incidence of dyslipidemia and NTIS...

To examine the relationship between circulating B lymphocyte stimulator (BLyS) levels and humoral responses to influenza vaccination in systemic lupus erythematosus (SLE) patients, as well as the effect of vaccination on BLyS levels, and to investigate clinical and serologic features of SLE that are associated with elevated BLyS levels. Clinical history, disease activity measurements, and blood specimens were collected from 60 SLE patients at baseline and after influenza vaccination. Sera were tested for BLyS levels, lupus-associated autoantibodies, serum interferon-α (IFNα) activity, 25-hydroxyvitamin D (25[OH]D), and humoral responses to influenza vaccination. Thirty percent of the SLE patients had elevated BLyS levels, with African American patients having higher BLyS levels than white patients (P = 0.006). Baseline BLyS levels in patients were not correlated with humoral responses to influenza vaccination (P = 0.863), and BLyS levels increased postvaccination only in the subset of patients with BLyS levels in the lowest quartile (P = 0.0003). Elevated BLyS levels were associated with increased disease activity, as measured by the SLE Disease Activity Index, physician's global assessment, and Systemic Lupus Activity Measure in white patients (P = 0.035, P = 0.016, and P = 0.018, respectively), but not in African Americans. Elevated BLyS levels were also associated with anti-nuclear RNP (P = 0.0003) and decreased 25(OH)D (P = 0.018). Serum IFNα activity was a significant predictor of elevated BLyS in a multivariate analysis (P = 0.002). Our findings indicate that African American patients with SLE have higher BLyS levels regardless of disease activity. Humoral response to influenza vaccination is not correlated with baseline BLyS levels in SLE patients, and only those patients with low baseline BLyS levels demonstrate an increased BLyS response after vaccination.

Objective To determine the levels of vitamin D in the peripheral blood of patients with systemic lupus erythematosus(SLE).Methods Seventy-eight cases of SLE were selected as SLE group,42 cases of chronic nephritis (CN) were as CN group,and 40 cases of healthy persons were as control group.Vitamin D levels were detected by enzyme-linked immunosorbant assay.The correlation of vitamin D levels in patients with SLE and 24 h urinary protein excretion,SLE disease activity (SLEDAI) score,anti-ds-DNA antibodies,complement C3 were analyzed,and the relationships between vitamin D levels and kidney damage were estimated.Results The vitamin D levels in SLE group were (13.3 ± 6.2) μ g/L,significantly lower than those in CN group [(21.4 ± 9.7) μ g/L] and control group [(20.8 ± 9.5) μ g/L] (P ＜ 0.05),and the difference was not statistically significant between CN group and control group (P ＞ 0.05).The vitamin D levels in SLE and lupus nephritis (LN) patients were significantly lower than those in SLE and non-LN patients [(9.8 ±6.1) μg/L vs.(15.9 ±7.8) μg/L,P ＜0.05].Vitamin D levels in SLE patients were negatively correlated with SLEDAI score,anti-ds-DNA antibodies and 24 h urinary protein excretion (r =-0.712,-0.682,-0.769,P ＜ 0.05),and were positively correlated with complement C3(r =0.608,P ＜ 0.05).Conclusions The vitamin D levels in SLE patients decrease significantly and have close relationship with disease activity.It can not only reflect disease activity,but also act as a useful marker to predict visceral involvement. Key words: Lupus erythematosns,systemic; Vitamin D; Relationship