High-density lipoprotein cholesterol subfraction HDL2 is associated with improved endothelial function in systemic lupus erythematosus.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have increased risk of premature atherosclerosis but the exact mechanisms remains unclear. Flow-mediated dilatation (FMD) is an established non-invasive assessment of vascular endothelial function. Lipoprotein subfractions may be better predictors of FMD than conventional cholesterol measurements. We tested the hypothesis that lipoprotein subfractions are independently associated with FMD. METHODS: Forty-one consecutive adult patients with SLE without known cardiovascular risk factors or disease were recruited in this cross-sectional study. Endothelial function and early atherosclerosis were assessed by brachial FMD and common carotid artery (CCA) intima-media thickness (IMT). High-density lipoprotein (HDL)/low-density lipoprotein (LDL) subfractions were measured. Machine learning models were also constructed to predict FMD and CCA IMT. RESULTS: Median FMD was 4.48% (IQR 5.00%) while median IMT was 0.54 mm (IQR 0.12 mm). Univariate analysis showed lower LDL1 (r=-0.313, p<0.05) and higher HDL2 subfractions (r=0.313, p<0.05) were significantly associated with higher log-transformed FMD. In a multiple linear regression model, HDL2 (ß=0.024, SE=0.012, p<0.05) remained an independent predictor of higher FMD after adjusting for age, body mass index, LDL1 and systolic blood pressure. The machine learning model included parameters such as HDL2 (positive association), prednisolone dose, LDL cholesterol and LDL1 for prediction of FMD (r=0.433, p<0.01). Age, LDL cholesterol and systolic blood pressure were independently associated with higher CCA IMT after adjusting for body mass index and HDL2. CONCLUSIONS: HDL 2, a large HDL particle, was independently associated with greater FMD and may be a biomarker of vascular health in SLE.

Impact of glucocorticoids on the incidence of lupus-related major organ damage: a systematic literature review and meta-regression analysis of longitudinal observational studies.

OBJECTIVE: In systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence. METHODS: We conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966-October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with <5 years of follow-up, <50 patients, different outcomes and special populations were excluded. RESULTS: We selected 49 articles including 16 224 patients, 14 755 (90.9%) female with a mean age and disease duration of 35.1 years and of 37.1 months. The mean follow-up time was 104.9 months. For individual damage items, the average daily GC dose was associated with the occurrence of overall cardiovascular events and with osteoporosis with fractures. A higher average cumulative dose adjusted (or not)/number of follow-up years and a higher proportion of patients on GC were associated with the occurrence of osteonecrosis. CONCLUSIONS: We confirm associations of GC use with three specific damage items. In treating patients with SLE, our aim should be to maximise the efficacy of GC and to minimise their harms.

Global epidemiology of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with protean manifestations that predominantly affects young women. Certain ethnic groups are more vulnerable than others to developing SLE and experience increased morbidity and mortality. Reports of the global incidence and prevalence of SLE vary widely, owing to inherent variation in population demographics, environmental exposures and socioeconomic factors. Differences in study design and case definitions also contribute to inconsistent reporting. Very little is known about the incidence of SLE in Africa and Australasia. Identifying and remediating such gaps in epidemiology is critical to understanding the global burden of SLE and improving patient outcomes. Mortality from SLE is still two to three times higher than that of the general population. Internationally, the frequent causes of death for patients with SLE include infection and cardiovascular disease. Even without new therapies, mortality can potentially be mitigated with enhanced quality of care. This Review focuses primarily on the past 5 years of global epidemiological studies and discusses the regional incidence and prevalence of SLE and top causes of mortality.

CD34+CD133+CD309+ circulating angiogenic cell level is reduced but positively related to hydroxychloroquine use in SLE patients-a case-control study and meta-regression analysis.

OBJECTIVES: To identify and quantify the level of CD34+CD133+CD309+ circulating angiogenic cells (CAC) and explore factors associated with the level of CAC in patients with SLE. METHODS: The peripheral blood mononuclear cells of consecutive SLE patients and demographically matched healthy controls (HC) were extracted and identified, enumerated and compared for CAC levels by multi-colour flow cytometry based on the EULAR Scleroderma Trials and Research (EUSTAR) recommendation. Meta-analyses were performed by combining the current and previous case-control studies, aiming to increase the statistical power to discern the difference in CAC level between SLE patients and HC. Mixed-model meta-regression was conducted to explore potential demographic and clinical factors that were associated with CAC level. RESULTS: A lower level of CAC was found in 29 SLE patients compared with 24 HC [mean (s.d.) 10.76 (13.9) vs 24.58 (25.4) cells/ml, P = 0.015]. Random-effects meta-analyses of the current and six previously published case-control studies involving 401 SLE patients and 228 HC revealed a lower CAC level compared with HC (standardized mean difference = -2.439, P = 0.001). Meta-regression analysis demonstrated that HCQ use was associated with a more discrepant CAC level between both groups (P = 0.01115). CONCLUSION: SLE patients had a significantly lower CD34+CD133+CD309+ CAC level than HC, and HCQ use was associated with a more discrepant CAC level between SLE patients and HC. This study triggers further observational, interventional and mechanistic studies to address the beneficial impact of HCQ on the functionality of CAC in SLE patients.

Detection of putative autoantibodies in systemic lupus erythematous using a novel native-conformation protein microarray platform.

OBJECTIVE: Conventional immunoassays detect autoantibodies related to systemic lupus erythematosus (SLE) via recognition of epitopes on autoantigens expressed in their denatured rather than native conformational state, casting difficulty in evaluating the genuine pathogenicity of the autoantibodies. We aimed to use a novel high-throughput protein microarray platform to identify autoantibodies against native autoantigens in SLE sera. METHODS: Sera from SLE patients and those of gender-, age-, and ethnicity-matched healthy controls (HC) were screened against more than 1,600 immune-related antigens of native conformation. The relative fluorescent unit readout from post-assay imaging were subjected to bioinformatics pre-processing and composite normalization. A penetrance fold change (pFC) analysis between SLE and HC samples shortlisted 50 autoantigens that were subjected to an unsupervised cluster analysis. Correlations between the pFC of putative autoantigens and clinical parameters including SLE disease activity index (SLEDAI-2K) and recent SLE flares were explored. RESULTS: 381 autoantigens were identified when 15 SLE and 15 HC serum samples were compared. The top 20 autoantigens which elicited autoantibody responses in SLE sera filtered based on the highest pFC were further analyzed. Autoantigens which the putative autoantibodies reacted against are those involved in chromatin organization such as DEK, regulation of transcription activity including REOX4 and ELF4, and negative regulation of NFkB activity such as TRIB3. Additionally, the pFC of these autoantibodies significantly and positively correlated with SLEDAI-2K and recent SLE flares. CONCLUSION: A high-throughput protein microarray platform allows detection and quantification of putative lupus-related autoantibodies which are of potential pathophysiological and prognostic significance in SLE patients.

Deletion of CD137 Ligand Exacerbates Renal and Cutaneous but Alleviates Cerebral Manifestations in Lupus.

The CD137-CD137 ligand (CD137L) costimulatory system is a critical immune checkpoint with pathophysiological implications in autoimmunity. In this study, we investigated the role of CD137L-mediated costimulation on renal, cutaneous and cerebral manifestations in lupus and the underlying immunological mechanism. Lupus-prone C57BL/6lpr-/- (B6.lpr) mice were crossed to C57BL/6.CD137L-/- mice to obtain CD137L-deficient B6.lpr [double knock out (DKO)] mice. We investigated the extent of survival, glomerulonephritis, skin lesions, cerebral demyelination, immune deviation and long-term synaptic plasticity among the two mouse groups. Cytokine levels, frequency of splenic leukocyte subsets and phenotypes were compared between DKO, B6.lpr and B6.WT mice. A 22 month observation of 226 DKO and 137 B6.lpr mice demonstrated significantly more frequent proliferative glomerulonephritis, larger skin lesions and shorter survival in DKO than in B6.lpr mice. Conversely, microglial activation and cerebral demyelination were less pronounced while long-term synaptic plasticity, was superior in DKO mice. Splenic Th17 cells were significantly higher in DKO than in B6.lpr and B6.WT mice while Th1 and Th2 cell frequencies were comparable between DKO and B6.lpr mice. IL-10 and IL-17 expression by T cells was not affected but there were fewer IL-10-producing myeloid (CD11b+) cells, and also lower serum IL-10 levels in DKO than in B6.lpr mice. The absence of CD137L causes an immune deviation toward Th17, fewer IL-10-producing CD11b+ cells and reduced serum IL-10 levels which potentially explain the more severe lupus in DKO mice while leading to reduced microglia activation, lesser cerebral damage and less severe neurological deficits.

Endothelial dysfunction in systemic lupus erythematosus - a case-control study and an updated meta-analysis and meta-regression.

Endothelium-dependent flow-mediated dilation (ED-FMD), a biophysical marker of endothelial dysfunction, is apparently impaired in patients with systemic lupus erythematosus (SLE) but such observation is inconsistent. Here, we assessed and compared the brachial artery ED-FMD (baED-FMD) using ultrasonography between SLE patients without cardiovascular disease and healthy controls (HC) matched for age, gender and body mass index. We then performed a comprehensive meta-analysis of case-control studies which compared baED-FMD between SLE patients and HC by determining the effect size of baED-FMD as standardized mean difference (SMD). Factors associated with the effect size were explored by mixed-model meta-regression. Seventy one SLE patients and 71 HC were studied. SLE patients had lower baED-FMD than HC (3.72 ± 2.8% vs 4.63 ± 3.1%, p = 0.032). Meta-analysis of 25 case-control studies involving 1,313 SLE patients and 1,012 HC with the random effects model revealed lower baED-FMD in SLE patients compared to HC (SMD -1.077, p < 0.001). The presence of diabetes mellitus (p = 0.04747), higher diastolic blood pressure (p = 0.044), renal involvement (p = 0.027) and aspirin use (p = 0.001) were associated with more discrepant baED-FMD between both groups. In conclusion, SLE patients naïve of cardiovascular disease have impaired endothelial function. Diabetes mellitus, renal disease and diastolic hypertension are major contributors of endothelial dysfunction in SLE patients.

The pathology of T cells in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoantibodies. Thus, the condition was traditionally classified as a "B-cell disease". Compelling evidence has however shown that without the assistance of the helper T lymphocytes, it is indeed difficult for the "helpless" B cells to become functional enough to trigger SLE-related inflammation. T cells have been recognized to be crucial in the pathogenicity of SLE through their capabilities to communicate with and offer enormous help to B cells for driving autoantibody production. Recently, a number of phenotypic and functional alterations which increase the propensity to trigger lupus-related inflammation have been identified in lupus T cells. Here, potential mechanisms involving alterations in T-cell receptor expressions, postreceptor downstream signalling, epigenetics, and oxidative stress which favour activation of lupus T cells will be discussed. Additionally, how regulatory CD4+, CD8+, and γδ T cells tune down lupus-related inflammation will be highlighted. Lastly, while currently available outcomes of clinical trials evaluating therapeutic agents which manipulate the T cells such as calcineurin inhibitors indicate that they are at least as efficacious and safe as conventional immunosuppressants in treating lupus glomerulonephritis, larger clinical trials are undoubtedly required to validate these as-yet favourable findings.

Imbalance between endothelial damage and repair: a gateway to cardiovascular disease in systemic lupus erythematosus.

Atherosclerosis is accelerated in patients with systemic lupus erythematosus (SLE) and it leads to excessive cardiovascular complications in these patients. Despite the improved awareness of cardiovascular disease and advent of clinical diagnostics, the process of atherogenesis in most patients remains clinically silent until symptoms and signs of cardiovascular complications develop. As evidence has demonstrated that vascular damage is already occurring before clinically overt cardiovascular disease develops in lupus patients, intervention at the preclinical stage of atherogenesis would be plausible. Indeed, endothelial dysfunction, one of the earliest steps of atherogenesis, has been demonstrated to occur in lupus patients even when they are naïve for cardiovascular disease. Currently known "endothelium-toxic" factors including type 1 interferon, proinflammatory cytokines, inflammatory cells, immune complexes, costimulatory molecules, neutrophils extracellular traps, lupus-related autoantibodies, oxidative stress, and dyslipidemia, coupled with the aberrant functions of the endothelial progenitor cells (EPC) which are crucial to vascular repair, likely tip the balance towards endothelial dysfunction and propensity to develop cardiovascular disease in lupus patients. In this review, altered physiology of the endothelium, factors leading to perturbed vascular repair contributed by lupus EPC and the impact of proatherogenic factors on the endothelium which potentially lead to atherosclerosis in lupus patients will be discussed.

Costimulatory pathways: physiology and potential therapeutic manipulation in systemic lupus erythematosus.

System lupus erythematosus (SLE) is an immune-complex-mediated autoimmune condition with protean immunological and clinical manifestation. While SLE has classically been advocated as a B-cell or T-cell disease, it is unlikely that a particular cell type is more pathologically predominant than the others. Indeed, SLE is characterized by an orchestrated interplay amongst different types of immunopathologically important cells participating in both innate and adaptive immunity including the dendritic cells, macrophages, neutrophils and lymphocytes, as well as traditional nonimmune cells such as endothelial, epithelial, and renal tubular cells. Amongst the antigen-presenting cells and lymphocytes, and between lymphocytes, the costimulatory pathways which involve mutual exchange of information and signalling play an essential role in initiating, perpetuating, and, eventually, attenuating the proinflammatory immune response. In this review, advances in the knowledge of established costimulatory pathways such as CD28/CTLA-4-CD80/86, ICOS-B7RP1, CD70-CD27, OX40-OX40L, and CD137-CD137L as well as their potential roles involved in the pathophysiology of SLE will be discussed. Attempts to target these costimulatory pathways therapeutically will pave more potential treatment avenues for patients with SLE. Preliminary laboratory and clinical evidence of the potential therapeutic value of manipulating these costimulatory pathways in SLE will also be discussed in this review.