Clinical features and antinuclear antibodies profile among adults with systemic lupus erythematosus and lupus nephritis: a cross-sectional study.
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ABSTRACT:
SUBMITTER: Ahmed N
PROVIDER: S-EPMC5554640 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:ObjectivesSerum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis.MethodsA total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non-commercial techniques.ResultsThe presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLE patients at low-medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0-12 months), and high levels at T0-1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLE patients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions.ConclusionNephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLE patients limited to the renal complication and other SLE patients.Trial registrationThe Zeus study was registered at https://clinicaltrials.gov, NCT02403115.
| S-EPMC8487649 | biostudies-literature
Project description:BACKGROUND:Cardiovascular disease is common in patients with systemic lupus erythematosis (SLE) and lupus nephritis (LN). Up to 80% of children with SLE develop kidney disease, which is also associated with increased risk for cardiovascular disease and death compared to those without renal involvement. Hepcidin is an iron-regulatory protein which may contribute to atherosclerosis and is elevated in autoimmune disease. Pulse wave velocity (PWV) is a validated indicator of arterial stiffness, an early marker of cardiovascular risk, and is increased in children with SLE versus healthy controls. Our objective was to quantify hepcidin and PWV in children with SLE and investigate if those with biopsy-proven LN have higher hepcidin levels and higher PWV compared to those without kidney disease. METHODS:Cross-sectional analysis with hepcidin was measured via ELISA assay in 16 children aged 10-21 years with SLE recruited from a single center. Subjects were classified as having LN if histologic evidence of the disease was documented on a clinical renal biopsy. Serum hepcidin was quantified using a validated competitive enzyme-linked immunoassay. Carotid-femoral PWV was measured using applanation tonometry. Wilcoxon rank sum testing was used to compare median levels of hepcidin, PWV, and other continuous variables by nephritis status. RESULTS:The cohort (n = 16) was 93.8% female and 68.8% African-American with mean (SD) 16 (3.6) years. 37.5% (n = 6) had LN. Overall median (IQR) hepcidin was 34.4 (18.9, 91.9) ng/ml, and PWV 4.4 (4, 4.6) meters/second. Although significance was limited by small sample size, both hepcidin and PWV were higher in the subjects with LN. Median (IQR) hepcidin in subjects with LN was 71.5 (26.4, 116.4) ng/ml compared to 27.9 (18.7, 59.7) ng/ml in those with SLE(p = 0.19). Similarly, median (IQR) PWV in those with LN was 4.4 (4.4, 4.9) meters/second compared to 3 (3.75, 4.55) meters/second in those with without kidney involvement (p = 0.10). CONCLUSION:PWV and serum hepcidin were higher in subjects with LN compared to those with SLE alone, suggesting that elevated hepcidin levels may be associated with morbid CV changes in children with LN. This association, along with identification of additional predictors of arterial stiffness in patients with LN, warrants further investigation.
| S-EPMC6440617 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is a polyclonal autoimmune syndrome directed against multiple nuclear autoantigens. Although RNA and DNA seem to have identical immunostimulatory effects on systemic and intrarenal inflammation, each seems to differ with regard to the propensity to induce mitogenic effects such as lymphoproliferation. To identify potential mechanisms by which DNA specifically contributes to the pathogenesis of lupus nephritis, we stimulated cells with immunostimulatory DNA or RNA in vitro and used microarray to compare the transcriptomes of RNA- and DNA-induced genes. Immunostimulatory DNA, but not RNA, induced Mdm2, which is a negative regulator of p53. In vivo, we observed greater expression and activation of Mdm2 in the spleen and kidneys in a mouse model of lupus (MRL-Fas(lpr) mice) than healthy controls. Treatment of MRL-Fas(lpr) mice with the Mdm2 inhibitor nutlin-3a prevented nephritis and lung disease and significantly prolonged survival. Inhibition of Mdm2 reduced systemic inflammation and abrogated immune complex disease by suppressing plasma cells and the production of lupus autoantibodies. In addition, nutlin-3a suppressed the abnormal expansion of all T cell subsets, including CD3(+)CD4(-)CD8(-) T cells, which associated with attenuated systemic inflammation. However, inhibiting Mdm2 did not cause myelosuppression or affect splenic regulatory T cells, neutrophils, dendritic cells, or monocytes. Taken together, these data suggest that the induction of Mdm2 promotes the expansion of plasma cells and CD3(+)CD4(-)CD8(-) T cells, which cause autoantibody production and immune complex disease in MRL-Fas(lpr) mice. Antagonizing Mdm2 may have therapeutic potential in lupus nephritis.
| S-EPMC3279995 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by a loss of tolerance to self-antigens and the production of high titers of serum autoantibodies. Lupus nephritis can affect up to 74% of SLE patients, particularly those of Hispanic and African ancestries, and remains a major cause of morbidity and mortality. A genetic etiology in SLE is now well substantiated. Thanks to extensive collaborations, extraordinary progress has been made in the past few years and the number of confirmed genes predisposing to SLE has catapulted to approximately 30. Studies of other forms of genetic variation, such as copy number variants and epigenetic alterations, are emerging and promise to revolutionize our knowledge about disease mechanisms. However, to date little progress has been made on the identification of genetic factors specific to lupus nephritis. On the near horizon, two large-scale efforts, a collaborative meta-analysis of lupus nephritis based on all genome-wide association data in Caucasians and parallel scans in four other ethnicities, are poised to make fundamental discoveries in the genetics of lupus nephritis. Collectively, these findings will show that a broad array of pathways underlines the genetic heterogeneity of SLE and lupus nephritis, and provide potential avenues for the development of novel therapies.
| S-EPMC2847514 | biostudies-literature
Project description:Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis-predisposing loci. Through genotyping and imputation, >1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis and 1412 patients with lupus without nephritis). Tests of association were computed using logistic regression adjusting for population substructure. The strongest evidence for association was observed outside the MHC and included markers localized to 4q11-q13 (PDGFRA, GSX2; P=4.5×10(-7)), 16p12 (SLC5A11; P=5.1×10(-7)), 6p22 (ID4; P=7.4×10(-7)), and 8q24.12 (HAS2, SNTB1; P=1.1×10(-6)). Both HLA-DR2 and HLA-DR3, two well established lupus susceptibility loci, showed evidence of association with lupus nephritis (P=0.06 and P=3.7×10(-5), respectively). Within the class I region, rs9263871 (C6orf15-HCG22) had the strongest evidence of association with lupus nephritis independent of HLA-DR2 and HLA-DR3 (P=8.5×10(-6)). Consistent with a functional role in lupus nephritis, intra-renal mRNA levels of PDGFRA and associated pathway members showed significant enrichment in patients with lupus nephritis (n=32) compared with controls (n=15). Results from this large-scale genome-wide investigation of lupus nephritis provide evidence of multiple biologically relevant lupus nephritis susceptibility loci.
| S-EPMC4243339 | biostudies-literature
Project description:ObjectiveRetinoblastoma (Rb) protein is a nuclear protein with several important functions, including the ability to stabilize heterochromatin. Because antibodies against the nucleosome and chromatin are key in systemic lupus erythematosus (SLE), we sought to determine whether Rb was an autoantigen in SLE and to evaluate any associated clinical phenotypes.MethodsSera from 222 patients with SLE from the Hopkins longitudinal cohort were studied. Additional cohorts tested included sera from 100 patients with primary Sjögren syndrome (pSS) (disease controls) evaluated at the Johns Hopkins Jerome L. Greene Sjögren's Center and sera from 36 healthy individuals. Anti-Rb antibodies were assayed by immunoprecipitation of 35S-methionine-labeled Rb, which was generated by in vitro transcription/translation. Fisher's exact test was used for the univariate analysis. Multivariable exact logistic regression was used to model for the presence of proteinuria in patients with SLE.ResultsAnti-Rb antibodies were present in 15 of 222 (6.8%) patients with SLE, in 3 of 100 patients with pSS (3%), and in 0 of 36 healthy individuals. Among patients with SLE, Rb antibodies were strongly negatively associated with proteinuria (P = 0.0031), renal involvement (odds ratio [OR] = 0.11; P = 0.01), and anemia (OR = 0.05; P < 0.0001) and were positively associated with stroke (OR = 7.65; P = 0.05). The negative association with lupus nephritis held true in multivariate models (adjusted OR = 0.11; P = 0.01).ConclusionAnti-Rb antibodies are a novel specificity not previously described in SLE. These new data define a possible SLE subset that is protected against renal involvement, is positively associated with stroke, and is not associated with antiphospholipid antibodies.
| S-EPMC6857985 | biostudies-literature
Project description:We report a rare case of dengue fever triggering systemic lupus erythematosus and lupus nephritis. The patient presented herself during a large outbreak of dengue fever in December 2012 in Maharashtra, India. The diagnosis of dengue fever was confirmed by the presence of NS-1 antigen during the first few days of febrile illness. Eight weeks later, kidney tissue biopsy studies revealed evidence of lupus nephritis on microscopic examination and immunofluorescence. The report interpreted it as focal proliferative glomerulonephritis and segmental sclerosis (Stage IIIC). The case was also found positive for perinuclear antineutrophil cytoplasmic antibodies by indirect immunofluorescence assay. An active and effective management of a case essentially calls for clear perception of differentiating dengue-induced lupus flare, antineutrophil cytoplasmic antibody-related nephropathy, and/or dengue-induced de-novo lupus disease. Dengue viremia may be the trigger for immune complex formation in patients who are predisposed to developing autoimmune diseases. The present case explains the importance of considering the diagnosis of dengue-related lupus nephritis as an atypical occurrence in appropriate situations, as in this case. It would not be improper to regard this escalating disease as an expanded feature of dengue.
| S-EPMC3818025 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) and lupus nephritis (LN) disproportionately affect individuals who are members of racial/ethnic minority groups and individuals of lower socioeconomic status (SES). This study was undertaken to investigate the epidemiology and sociodemographics of SLE and LN in the low-income US Medicaid population.We utilized Medicaid Analytic eXtract data, with billing claims from 47 states and Washington, DC, for 23.9 million individuals ages 18-65 years who were enrolled in Medicaid for >3 months in 2000-2004. Individuals with SLE (?3 visits >30 days apart with an International Classification of Diseases, Ninth Revision [ICD-9] code of 710.0) and with LN (?2 visits with an ICD-9 code for glomerulonephritis, proteinuria, or renal failure) were identified. We calculated SLE and LN prevalence and incidence, stratified by sociodemographic category, and adjusted for number of American College of Rheumatology (ACR) member rheumatologists in the state and SES using a validated composite of US Census variables.We identified 34,339 individuals with SLE (prevalence 143.7 per 100,000) and 7,388 (21.5%) with LN (prevalence 30.9 per 100,000). SLE prevalence was 6 times higher among women, nearly double in African American compared to white women, and highest in the US South. LN prevalence was higher among all racial/ethnic minority groups compared to whites. The areas with lowest SES had the highest prevalence; areas with the fewest ACR rheumatologists had the lowest prevalence. SLE incidence was 23.2 per 100,000 person-years and LN incidence was 6.9 per 100,000 person-years, with similar sociodemographic trends.In this nationwide Medicaid population, there was sociodemographic variation in SLE and LN prevalence and incidence. Understanding the increased burden of SLE and its complications in this low-income population has implications for resource allocation and access to subspecialty care.
| S-EPMC3733212 | biostudies-literature
Project description:ObjectiveTo validate clinical indices of lupus nephritis activity and damage when used in children against the criterion standard of kidney biopsy findings.MethodsIn 83 children requiring kidney biopsy, the Systemic Lupus Erythematosus Disease Activity Index renal domain (SLEDAI-R), British Isles Lupus Assessment Group index renal domain (BILAG-R), Systemic Lupus International Collaborating Clinics (SLICC) renal activity score (SLICC-RAS), and SLICC Damage Index renal domain (SDI-R) were measured. Fixed effects and logistic models were calculated to predict International Society of Nephrology/Renal Pathology Society (ISN/RPS) class; low-to-moderate versus high lupus nephritis activity (National Institutes of Health [NIH] activity index [AI]) score: ≤10 versus >10; tubulointerstitial activity index (TIAI) score: ≤5 versus >5; or the absence versus presence of lupus nephritis chronicity (NIH chronicity index) score: 0 versus ≥1.ResultsThere were 10, 50, and 23 patients with ISN/RPS class I/II, III/IV, and V, respectively. Scores of the clinical indices did not differentiate among patients by ISN/RPS class. The SLEDAI-R and SLICC-RAS but not the BILAG-R differed with lupus nephritis activity status defined by NIH-AI scores, while only the SLEDAI-R scores differed between lupus nephritis activity status based on TIAI scores. The sensitivity and specificity of the SDI-R to capture lupus nephritis chronicity was 23.5% and 91.7%, respectively. Despite being designed to measure lupus nephritis activity, SLICC-RAS and SLEDAI-R scores significantly differed with lupus nephritis chronicity status.ConclusionCurrent clinical indices of lupus nephritis fail to discriminate ISN/RPS class in children. Despite its shortcomings, the SLEDAI-R appears best for measuring lupus nephritis activity in a clinical setting. The SDI-R is a poor correlate of lupus nephritis chronicity.
| S-EPMC4720587 | biostudies-literature
Project description:ObjectiveTo examine the epidemiology of serious infections, a significant cause of morbidity and mortality in systemic lupus erythematosus (SLE), in a nationwide cohort of SLE and lupus nephritis (LN) patients.MethodsUsing the Medicaid Analytic eXtract database for the years 2000-2006, we identified patients ages 18-64 years who had SLE and the subset who had LN. We ascertained cases of serious hospitalized infections using validated algorithms, and we determined 30-day mortality rates. Poisson regression was used to calculate infection incidence rates and multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) for the first infection, adjusted for sociodemographic variables, medication use, and an SLE-specific risk adjustment index.ResultsWe identified 33,565 patients with SLE, 7,113 of whom had LN. There were 9,078 serious infections in 5,078 SLE patients and 3,494 infections in 1,825 LN patients. The infection incidence rate per 100 person-years was 10.8 in the SLE cohort and 23.9 in the LN subcohort. In adjusted models for the SLE cohort, we observed increased risks of infection in men as compared to women (HR 1.33 [95% confidence interval (95% CI) 1.20-1.47]), in blacks as compared to whites (HR 1.14 [95% CI 1.06-1.21]), and in users of glucocorticoids (HR 1.51 [95% CI 1.43-1.61]) and immunosuppressive drugs (HR 1.11 [95% CI 1.03-1.20]) as compared to never users. Hydroxychloroquine users had a reduced risk of infection as compared to never users (HR 0.73 [95% CI 0.68-0.77]). The 30-day mortality rate per 1,000 person-years among those hospitalized with infections was 21.4 in the SLE cohort and 38.6 in the LN subcohort.ConclusionIn this diverse, nationwide cohort of SLE patients, we observed a substantial burden of serious infections with many subsequent deaths, particularly among those with LN.
| S-EPMC4446132 | biostudies-literature