B lymphocyte stimulator levels in systemic lupus erythematosus: Higher circulating levels in African American patients and increased production after influenza vaccination in patients with low baseline levels

AB0620 B lymphocyte stimulator(BLYS) levels are higher in younger caucasian patients with SLE

To determine the association of plasma B lymphocyte stimulator (BLyS) levels, immunosuppressive therapy, and other clinical parameters with disease activity in systemic lupus erythematosus (SLE). Two hundred forty-five SLE patients were evaluated prospectively over a 2-year period at 4 centers. Assessments were performed every 3-6 months. Univariate analysis was used to determine the association among the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, serum anti-double-stranded DNA (anti-dsDNA), and plasma BLyS levels. A multivariate repeated-measures model incorporating immunosuppressive therapy was utilized. Ninety-two percent of the patients were female. Sixty-seven percent were white, 31% African American, and 2% Asian (all of these groups may include Hispanic). Mean values at baseline were as follows: age 41.5 years, disease duration 8.1 years, SELENA-SLEDAI 3.3 (median 2, range 0-18), BLyS 5.57 ng/ml, IgG 1,439 mg/dl, C3 104.4 mg/dl, and C4 21.3 mg/dl; among those positive for anti-dsDNA, the median titer was 1:40 (range 1:10-1:1,280). Univariate analysis showed that plasma BLyS levels were associated with anti-dsDNA titers (P = 0.0465) and SELENA-SLEDAI scores (P = 0.0002). In multivariate analyses, a greater increase in the SELENA-SLEDAI score from the previous visit was associated with higher BLyS levels at the previous visit (P = 0.0042) and with a greater increase in the BLyS level from the previous visit (P = 0.0007). The findings of association between a greater increase in the BLyS level from the previous visit and a greater increase in the SELENA-SLEDAI score at the subsequent visit, and between an elevated BLyS level at the previous visit and a greater SELENA-SLEDAI score at the subsequent visit, demonstrate a relationship between circulating BLyS levels and SLE disease activity. These results lend support to the notion that BLyS is a candidate for therapeutic targeting in SLE.

The overall aim of this study is to identify clinical and serological features that are associated with B lymphocyte stimulator (BLyS) elevation in a homogeneous Caucasian SLE population and thereby identify patients who are most likely to benefit from BLyS blockade. Patients with SLE (as per ACR criteria) were recruited. Clinical history, disease activity measures and laboratory measures of disease were recorded. BLyS levels were determined by ELISA. BLyS elevation was defined as being higher than the 95th percentile of BLyS levels measured in controls. Patients were divided into two groups: those with elevated BLyS levels (group 1, n = 23) and those with normal BLyS levels (group 2, n = 22). Elevated BLyS levels were significantly associated with patients of younger age and shorter disease duration. In keeping with previous reports, patients with elevated BLyS levels had more active disease (SLEDAI 5.1 vs 0.86, P < 0.001); however, our analysis also demonstrates that BLyS elevation was significantly associated with increased organ damage at 5-year follow-up [Systemic Lupus International Collaborating Clinics/ACR Damage Index (SLICC/ACR DI) 0.53 vs 0.13, P = 0.012]. Furthermore, the presence of Sm autoantibody significantly predicted elevated BLyS levels in a Caucasian population. BLyS levels were significantly higher in those with musculoskeletal involvement, malar rash, renal disease and evidence of immunological activity. BLyS blockade may be most beneficial if introduced early in the course of disease in young Caucasian patients presenting with renal, musculoskeletal and skin disease in an effort to reduce long-term damage.

To determine whether serum levels of B lymphocyte stimulator (BLyS) are elevated in patients with systemic immune-based rheumatic diseases and correlate with serum Ig levels and/or autoantibody titers. Sera from 185 patients with various systemic immune-based rheumatic diseases (95 with systemic lupus erythematosus [SLE], 67 with rheumatoid arthritis [RA], 23 with other diagnoses) were assayed for BLyS and Ig. In 7 patients who required arthrocentesis of a swollen knee, coincident serum and synovial fluid samples were assayed for BLyS. Medical charts were retrospectively reviewed for elevated autoantibody titers and proteinuria within a 1-month period before or after collection of sera for BLyS and Ig determination. Sera concurrently collected from 48 normal healthy subjects served as controls. Serum BLyS levels were elevated in 38 of 185 patients (21%) and correlated significantly with serum IgG levels. Serum BLyS levels did not correlate with the patients' age, sex, race, or medications, but correlated positively with anti-double-stranded DNA antibody titers among SLE patients and with rheumatoid factor titers among seropositive RA patients. In contrast, serum BLyS levels correlated inversely with nephrotic-range proteinuria among SLE patients. In every case tested, BLyS levels in clinically inflamed synovial fluids were greater than those in simultaneously obtained sera. BLyS may be an important factor in driving polyclonal hypergammaglobulinemia and elevated autoantibody titers in patients with systemic immune-based rheumatic diseases. Local production of BLyS in the joints may contribute to joint pathology. Patients with elevated serum BLyS levels may be ideal candidates for therapeutic targeting of BLyS.

Most published results have revealed variations in the association of serum/plasma levels of malondialdehyde (MDA), apolipoprotein B (ApoB), and oxidized low-density lipoprotein (OxLDL) and systemic lupus erythematosus (SLE). This study was performed to establish MDA, ApoB, and OxLDL levels in systemic lupus erythematosus (SLE) patients. Electronic databases were searched for the included articles up to 27th February 2023. The meta-analysis included 48 articles with 2358 SLE patients and 2126 healthy controls considered for MDA, ApoB, and OxLDL levels. There were significantly higher MDA, ApoB, and OxLDL levels in SLE patients than those in the control groups. Subgroup analysis indicated that European/American SLE patients and patients of both ages <36 and ≥36 exhibited higher MDA, ApoB, and OxLDL levels. Arab and Asian SLE patients had higher ApoB and MDA/OxLDL levels. African SLE patients recorded higher OxLDL levels than the control groups. SLE patients with a body mass index (BMI) of ≥23 and a disease duration of <10 recorded significantly higher MDA, ApoB, and OxLDL levels. Patients with systemic lupus erythematosus disease activity index (SLEDAI) ≥8 of SLE had higher MDA and ApoB levels, whereas SLE patients with SLEDAI <8 showed significantly higher ApoB levels. Patients with BMI <23 of SLE had higher MDA and OxLDL levels. This study established significantly higher MDA, ApoB, and OxLDL levels in SLE patients, suggesting a possible role of MDA, ApoB, and OxLDL in the disease.

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.

Systemic lupus erythematosus (SLE) is an autoimmune disorder in which cytokine balance is disturbed. Glucocorticoids (GCs) are shown to balance immune response by transcriptional regulation of glucocorticoid receptor target genes such as Glucocorticoid-induced leucine zipper (GILZ) which has been introduced as an endogenous anti-inflammatory mediator. In the present study, we assessed the expression of GILZ in association with interferon-γ (IFN-γ), interleukine-10 (IL-10), and B lymphocyte stimulator (BLyS) plasma levels in SLE patients. A total of 40 female patients (18 under treatment and 22 newly diagnosed) were recruited in this study. Real-time RT PCR was conducted to quantify the mRNA expression of GILZ. The plasma levels of IFN-γ, IL-10, and BLyS were evaluated using ELISA method. GILZ was overexpressed among under treatment SLE patients. The mRNA expression of GILZ was significantly correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. IFN-γ and BLyS were downregulated in response to therapies with negative correlations to GILZ. Moreover, IL-10 was upregulated among treated patients. The levels of IFN-γ and BLyS were correlated with the severity of disease, while IL-10 was negatively correlated with SLEDAI score. GILZ could be introduced as one of the acting molecules in mediating the regulatory effects of GCs on producing pro- and anti-inflammatory cytokines in SLE.

To assess the overexpression of B lymphocyte stimulator (BLyS) over time in patients with systemic lupus erythematosus (SLE). Sixty-eight SLE patients were followed up longitudinally for a median 369 days. At each physician encounter, disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index, and blood was collected for determination of the serum BLyS level, blood BLyS messenger RNA (mRNA) level, and cell surface BLyS expression. Twenty normal control subjects underwent similar laboratory evaluations. In contrast to the uniformly normal serum BLyS and blood BLyS mRNA phenotypes in control subjects, SLE patients displayed marked heterogeneity, with 50% and 61% of patients manifesting persistently or intermittently elevated serum BLyS and blood BLyS mRNA phenotypes, respectively. Surface BLyS expression by SLE peripheral blood mononuclear cells was also often increased. Treatment of patients who had elevated serum BLyS levels with intensive courses of high-dose corticosteroids resulted in marked reductions in serum BLyS levels, and tapering of the corticosteroid dosage often resulted in increases in serum BLyS levels. Serum BLyS levels generally correlated with anti-double-stranded DNA (anti-dsDNA) titers (in those with detectable anti-dsDNA titers), but changes in serum BLyS levels did not correlate with changes in disease activity in individual patients. Serum BLyS phenotype did not associate with specific organ system involvement. Dysregulation of BLyS over extended periods of time is common in patients with SLE. Neutralization of BLyS activity with an appropriate BLyS antagonist may be therapeutically beneficial.

Serum B-lymphocyte stimulator (BLyS) levels have been found to be elevated in a number of immune disease models. Therefore, we sought to establish whether BLyS levels were elevated in patients with B-cell lymphoproliferative disorders and to determine whether elevated BLyS levels correlated with clinical characteristics of the disease. Specimens were collected from the peripheral blood of individuals diagnosed with B-cell chronic lymphocytic leukemia (B-CLL; n = 70) or from age- and sex-matched patients seen at the same institution (n = 41). Serum BLyS levels were determined by enzyme-linked immunosorbent assay, and sequencing of the BLyS promoter was performed by conventional methods and confirmed by restriction fragment length polymorphism analysis. We found that elevated BLyS levels were more common in patients with familial B-CLL than individuals with sporadic B-CLL or normal controls. Because of this association, we sequenced the BLyS promoter in patients with B-CLL and normal controls and identified a polymorphic site, -871 C/T. We found that the wild-type sequence was significantly underrepresented in patients with familial B-CLL (4%) compared with patients with sporadic B-CLL (30%; P = .01) or controls (24%; P = .04). Furthermore, using a luciferase reporter under control of the BLyS promoter containing either a C or a T at position -871, we found that the reporter construct containing a T at -871 had a 2.6-fold increase in activity (P = .004). Our data suggest serum BLyS levels are elevated in patients with familial B-CLL and that elevated BLyS levels correlate with the presence of a T at -871 in the BLyS promoter.

Considerable evidence points to a role for B lymphocyte stimulator (BLyS) overproduction in murine and human systemic lupus erythematosus (SLE). Nevertheless, the correlation between circulating levels of BLyS protein and disease activity in human SLE is modest at best. This may be due to an inadequacy of the former to reflect endogenous BLyS overproduction faithfully, in that steady-state protein levels are affected not just by production rates but also by rates of peripheral utilization and excretion. Increased levels of BLyS mRNA may better reflect increased in vivo BLyS production, and therefore they may correlate better with biologic and clinical sequelae of BLyS overexpression than do circulating levels of BLyS protein. Accordingly, we assessed peripheral blood leukocyte levels of BLyS mRNA isoforms (full-length BLyS and ΔBLyS) and plasma BLyS protein levels in patients with SLE, and correlated these levels with laboratory and clinical features. BLyS protein, full-length BLyS mRNA, and ΔBLyS mRNA levels were greater in SLE patients (n = 60) than in rheumatoid arthritis patients (n = 60) or normal control individuals (n = 30). Although full-length BLyS and ΔBLyS mRNA levels correlated significantly with BLyS protein levels in the SLE cohort, BLyS mRNA levels were more closely associated with serum immunoglobulin levels and SLE Disease Activity Index scores than were BLyS protein levels. Moreover, changes in SLE Disease Activity Index scores were more closely associated with changes in BLyS mRNA levels than with changes in BLyS protein levels among the 37 SLE patients from whom repeat blood samples were obtained. Thus, full-length BLyS and ΔBLyS mRNA levels are elevated in SLE and are more closely associated with disease activity than are BLyS protein levels. BLyS mRNA levels may be a helpful biomarker in the clinical monitoring of SLE patients.

Nonstandard and adjunctive medical therapies for systemic lupus erythematosus

Increasing evidence has demonstrated the association between UBASH3A gene and multiple autoimmune diseases (ADs). The aim of our study was to explore the potential effect of UBASH3A messenger RNA (mRNA) expression and its role in the pathogenesis of systemic lupus erythematosus (SLE). UBASH3A mRNA levels were detected by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) in total RNA, isolated from the peripheral blood mononuclear cells (PBMCs) of 32 SLE patients and 30 healthy donors with TRIzol Reagent. The expression level of UBASH3A mRNA was significantly reduced in PBMCs from SLE patients when compared with healthy controls (p = 0.002). UBASH3A mRNA expression levels in lower active SLE were significantly lower than that in inactive SLE groups (p = 0.000). There was a negative association between mRNA levels of hyper-active and lower-active SLE patients (p = 0.000). Moreover, a significant negative correlation between UBASH3A mRNA expression and the onset age of SLE patients was found (p = 0.044). A negative correlation was found between UBASH3A mRNA expression and SLEDAI (p = 0.049). Nevertheless, no significant difference was found between patients with lupus nephritis (LN) and those without LN (p = 0.392). The presence of leukopenia, positive for anti-dsDNA antibody and anti-SSB antibody were associated with UBASH3A mRNA levels in SLE patients (all p < 0.05). The dysregulation of UBASH3A mRNA levels in SLE patients and their correlations with experimental parameters suggested that UBASH3A may involve in the pathogenesis of SLE.

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.

Autoantibodies and auto-reactive B cells participate in the pathogenesis of systemic lupus erythematosus (SLE), affecting various organs and tissues, including the nervous system, referred to as neuropsychiatric SLE (NPSLE).The cytokine B-lymphocyte stimulator (BLyS), which induces B cell proliferation and survival, may play an important role in neuropsychiatric manifestations (NPM).Here, we examine BLyS levels in SLE patients with well-defined NPSLE symptoms as compared to SLE patients without NPSLE and individuals with depression and cognitive impairment and healthy controls. CONCLUSIONSLE patients with depression and cognitive impairment had higher BLyS levels when compared to SLE patients without NPM and control with NP.BLyS may play a role in NPSLE pathogenesis.

OP0298 PCSK9 IN ATHEROSCLEROTIC INFLAMMATION OF LUPUS PATIENTS AND MURINE MODEL OF LUPUS WITH ATHEROSCLEROSIS