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Find video protocols related to scientific articles indexed in Pubmed.
An integrated extrapolation of long-term outcomes in systemic lupus erythematosus: analysis and simulation of the Hopkins Lupus Cohort.
Rheumatology (Oxford)
PUBLISHED: 09-20-2014
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The aim of this study was to develop an SLE disease model that simulates long-term outcomes of SLE to estimate the long-term effectiveness and cost-effectiveness of SLE treatments.
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The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
Hum. Mol. Genet.
PUBLISHED: 09-08-2014
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Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
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Apolipoprotein-containing lipoprotein subclasses and subclinical atherosclerosis In systemic lupus erythematosus (SLE).
Arthritis Care Res (Hoboken)
PUBLISHED: 08-25-2014
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Objectives: Traditional classification of hyperlipidemia using HDL, LDL and VLDL does not provide information on lipoprotein function. Apolipoproteins, (which are protein components of plasma lipoproteins including A, B, C, D, E) with their different composition, metabolic and atherogenic properties, provide insight on lipoprotein functioning. In particular, the ApoB/A-1 ratio is associated with atherogenic LDL and development of cardiovascular disease. We explored the baseline association between these non-traditional risk factors with subclinical measures of atherosclerosis (coronary artery calcium and carotid intima-media thickness) in SLE. Methods: 58 SLE patients (97% female, 58% Caucasian, 40% African-American, 2% other, mean age 44±11 yrs) had measurement of apolipoprotein and lipoproteins by immunoturbidimetric procedures, electroimmunoassays and immunoprecipitation. Coronary artery calcium was measured by helical CT and carotid intima-media thickness by carotid duplex. This study was based on the baseline assessment of subclinical atherosclerosis in the LAPS study. The measurement of the lipoproteins was made on sera collected at the same time. Results: There was no association between cardioprotective apoliporoteins (apoA-I, LpA-I, LpA-I:AII) and coronary artery calcium (p<0.15,0.41,0.39) or carotid intima-media thickness (p<0.97,0.53,0.76). Coronary artery calcium and carotid intima-media thickness did not associate with atherogenic apolipoproteins either, including LpB:E+LpB:C:E, apoB, LpB, LpB:C, apoC-III, apoC-III-HS, apoC-III-HP, CIII-R, LpA-II:B:C:D:E and apoB/apoA-I. Measures of disease activity, including physician's global assessment and SLEDAI, were not associated with coronary artery calcium or carotid intima-media thickness. Conclusion: Neither cardioprotective nor atherogenic lipoproteins were associated with measures of subclinical atherosclerosis in this series of SLE patients. Further studies with larger sample size are warranted to confirm our findings. © 2014 American College of Rheumatology.
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Myocardial T2 mapping by cardiovascular magnetic resonance reveals subclinical myocardial inflammation in patients with systemic lupus erythematosus.
Int J Cardiovasc Imaging
PUBLISHED: 08-18-2014
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To evaluate whether T2 mapping techniques can detect myocardial edema in patients with systemic lupus erythematosus (SLE). Twenty-four patients (mean age 54 ± 9 years) with SLE and twelve controls (mean age 50 ± 7 years) underwent cardiac MRI at 1.5 T. Standard cine images were obtained. Single-slice T2 maps and non-contrast T1 maps were acquired in a mid-cavity short-axis plane. Late gadolinium enhancement (LGE) images were obtained 15 min after 0.2 mmol/kg of contrast. SLE patients had low disease activity (mean SLE disease activity index score 0.71 ± 0.8). There were no differences in LV size or function between SLE patients and controls. No subjects had LGE. T2 times were higher in SLE patients (58.2 ± 5.6 vs. 52.8 ± 4.4 ms, p = 0.009). On multivariate analysis including demographic and LV parameters, only the diagnosis of SLE was associated with T2 time (p = 0.01). T1 times trended lower in SLE patients, (981.6 ± 65.5 vs. 963.9 ± 32.5), however, differences were not significant (p = 0.3). Repeated measures were highly correlated by linear regression for both inter- and intraobserver analysis (both R = 0.95, p < 0.001). Inter- and intraobserver bias and limits of agreement were -0.4 ± 3.8 and 1.0 ± 3.3 ms, respectively. T2-mapping identifies increased myocardial T2 times in SLE patients, likely due to subclinical myocardial edema. These findings suggest that even in SLE patients with inactive disease and normal cardiac function, low grade myocardial inflammation can be detected by this novel quantitative and highly reproducible technique.
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Predictors of incident depression in systemic lupus erythematosus.
J. Rheumatol.
PUBLISHED: 08-15-2014
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Findings from previous studies of predictors of depression among patients with systemic lupus erythematosus (SLE) have been inconsistent. The aim of our study was to identify risk factors that preceded incident depression based on a large, closely followed longitudinal cohort.
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Lupus Nephritis Susceptibility Loci in Women with Systemic Lupus Erythematosus.
J. Am. Soc. Nephrol.
PUBLISHED: 06-12-2014
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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.
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Risk factors for cataracts in systemic lupus erythematosus (SLE).
Rheumatol. Int.
PUBLISHED: 05-07-2014
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Cataract is the most common ocular damage in systemic lupus erythematosus (SLE). We analyzed data from the Hopkins Lupus Cohort longitudinally to identify the factors that predict onset of cataract prior to 60 years of age. The Hopkins Lupus Cohort is a clinical cohort of patients with SLE seen quarterly. This analysis was based on the follow-up experience prior to age 60 of 2,109 SLE patients who had not had a cataract prior to cohort entry. Patients saw their ophthalmologist every 6 months. Cataract was defined by the SLICC/American College of Rheumatology Damage Index. The rate of incident cataract was calculated in subsets of the follow-up defined by patient characteristics and history. Multivariable logistic regression models were fit to identify predictors of cataract while controlling for potential confounding variables. The analysis was based on 11,887 persons-years of follow-up, with median follow-up time of 4.1 years per patient. The incidence of cataract was 13.2/1,000 persons-years. Adjusting for other predictors, a cumulative prednisone dose equivalent to 10 mg/day for 10 years was a strong predictor of cataract (RR = 2.9, P = 0.0010). Disease activity measured by SELENA-SLEDAI (P = 0.0004) and higher systolic blood pressure (P = 0.0003) were associated with cataract. Duration of SLE, diabetes mellitus, smoking, cholesterol, renal involvement, immunological profile and medication history other than prednisone were not associated with cataract. Cataract development in SLE patients is multifactorial with prednisone, systolic blood pressure and disease activity all playing a role.
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Fc? receptor IIIa single-nucleotide polymorphisms and haplotypes affect human IgG binding and are associated with lupus nephritis in African Americans.
PUBLISHED: 05-01-2014
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To investigate whether the Fc? receptor IIIa-66L/R/H (Fc?RIIIa-66L/R/H) polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by Fc?RIIIa-66L/R/H and Fc?RIIIa-176F/V, as well as copy number variation (CNV), confer risk of developing systemic lupus erythematosus (SLE) and lupus nephritis.
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Belimumab pregnancy registry: prospective cohort study of pregnancy outcomes.
Obstet Gynecol
PUBLISHED: 04-29-2014
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Systemic lupus erythematosus (SLE) is an autoimmune disorder typically affecting women of childbearing age, making it important to understand how underlying disease and treatments affect pregnancy outcomes. Belimumab, a biologic, received regulatory approval in 2011. Given that the agent has been used for a short time, there is little information about its use in pregnancy. Belimumab Pregnancy Registry objectives are to evaluate pregnancy and infant outcomes in women with SLE exposed to commercially supplied belimumab within the 4 months before or during pregnancy or both.
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14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends.
Autoimmun Rev
PUBLISHED: 04-15-2014
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Current classification criteria for definite Antiphospholipid Syndrome (APS) require the use of three laboratory assays to detect antiphospholipid antibodies (aCL, anti-?2GPI and LA) in the presence of at least one of the two major clinical manifestations (i.e. thrombosis or pregnancy morbidity) of the syndrome. However, several other autoantibodies shown to be directed to other proteins or their complex with phospholipids have been proposed to be relevant to APS but their clinical utility and their diagnostic value remains elusive. This report summarizes the findings, conclusions and recommendations of the "APS Task Force 3-Laboratory Diagnostics and Trends" meeting that took place during the 14th International Congress on Antiphospholipid Antibodies (APLA 2013, September 18-21, Rio de Janeiro, RJ, Brazil).
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Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.
Am. J. Hum. Genet.
PUBLISHED: 03-12-2014
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Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.
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A polymorphism in TLR2 is associated with arterial thrombosis in a multiethnic population of patients with systemic lupus erythematosus.
PUBLISHED: 02-18-2014
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Thrombosis is a serious complication of systemic lupus erythematosus (SLE). Studies that have investigated the genetics of thrombosis in SLE are limited. We undertook this study to assess the association of previously implicated candidate genes, particularly Toll-like receptor (TLR) genes, with pathogenesis of thrombosis.
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End-stage renal disease in African Americans with lupus nephritis is associated with APOL1.
PUBLISHED: 02-08-2014
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Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.
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Prevention and management of co-morbidities in SLE.
Presse Med
PUBLISHED: 01-29-2014
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The prognosis and survival of patients with systemic lupus erythematosus (SLE) have improved over the past few decades. The major cause of death is no longer active lupus, but instead cardiovascular disease, complications of renal failure, and malignancy. Co-morbid factors, including both traditional and non-traditional cardiovascular risk factors, can be targeted according to accepted guidelines. We will emphasize the deleterious effect of corticosteroids in contributing to cardiovascular risk and the need to shift maintenance prednisone doses to a much lower threshold.
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25-hydroxyvitamin D and cardiovascular disease in patients with systemic lupus erythematosus: data from a large international inception cohort.
Arthritis Care Res (Hoboken)
PUBLISHED: 01-21-2014
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An association between 25-hydroxyvitamin D (25[OH]D; vitamin D) deficiency and increased cardiovascular (CV) risk factors and CV disease (CVD) has been shown in general population studies. Vitamin D deficiency has been noted in systemic lupus erythematosus (SLE), and CVD is a major cause of morbidity and mortality in SLE. The objectives of this study were to estimate the associations of 25(OH)D levels with CV risk factors and to determine whether low baseline 25(OH)D levels predict future CV events in patients participating in an international inception cohort.
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Electrocardiographic findings in systemic lupus erythematosus: Data from an international inception cohort.
Arthritis Care Res (Hoboken)
PUBLISHED: 01-20-2014
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Objective: To estimate the early prevalence of various electrocardiographic (ECG) abnormalities in patients with SLE and to evaluate possible associations between repolarization changes (increased corrected QT, QTc, and QT dispersion, QTd) and clinical and laboratory variables, including the anti-Ro/SSA level and specificity (52 or 60KDa). Methods: We studied adult SLE patients from 19 centers participating in the Systemic Lupus International Collaborating Clinics (SLICC) Inception Registry. Demographics, disease activity (SLEDAI-2K), disease damage (SLICC/ACR DI), and laboratory data from the baseline or first follow-up visit were assessed. Multivariate logistic and linear regression models were used to asses for any cross-sectional associations between anti-Ro/SSA and ECG repolarization abnormalities. Results: For the 779 patients included, mean age (SD) was 35.6 years (13.8), 88.4% were women, and mean disease duration was 10.5 months (14.4). Mean SLEDAI-2K was 5.4 (5.6) and mean SLICC/ACR DI was 0.5 (1.0). ECG abnormalities were frequent and included non-specific ST-T changes (30.9%), possible left ventricular hypertrophy (5.4%) and supraventricular arrhythmias (1.3%). A QTc ? 440ms was found in 15.3%, while QTc ? 460ms was found in 5.3%. Mean (SD) QTd was 34.2ms (14.7) and QTd ? 40ms was frequent (38.1%). Neither the specificity, nor the level of anti-Ro/SSA was associated with QTc duration or QTd, although confidence intervals were wide. Total DI was significantly associated with a QTc interval exceeding 440 ms (OR 1.38 95% CI 1.06, 1.79). Conclusion: A substantial proportion of recent-onset SLE patients exhibit repolarization abnormalities although severe abnormalities were rare. © 2014 American College of Rheumatology.
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Incidence of lymphoma associated with underlying lupus: lessons learned from observational studies.
Curr Opin Rheumatol
PUBLISHED: 01-15-2014
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The increased risk of overall malignancy in systemic lupus erythematosus (SLE) is well established. Cohort studies have shown a significant association of non-Hodgkin's lymphoma with SLE. This review will focus on the associated risk factors, the role of immunology, immunosuppressive medications and secondary Sjogren's syndrome in the development of lymphoma in SLE.
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Lymphotoxin-LIGHT Pathway Regulates the Interferon Signature in Rheumatoid Arthritis.
PLoS ONE
PUBLISHED: 01-01-2014
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A subset of patients with autoimmune diseases including rheumatoid arthritis (RA) and lupus appear to be exposed continually to interferon (IFN) as evidenced by elevated expression of IFN induced genes in blood cells. In lupus, detection of endogenous chromatin complexes by the innate sensing machinery is the suspected driver for the IFN, but the actual mechanisms remain unknown in all of these diseases. We investigated in two randomized clinical trials the effects on RA patients of baminercept, a lymphotoxin-beta receptor-immunoglobulin fusion protein that blocks the lymphotoxin-??/LIGHT axis. Administration of baminercept led to a reduced RNA IFN signature in the blood of patients with elevated baseline signatures. Both RA and SLE patients with a high IFN signature were lymphopenic and lymphocyte counts increased following baminercept treatment of RA patients. These data demonstrate a coupling between the lymphotoxin-LIGHT system and IFN production in rheumatoid arthritis. IFN induced retention of lymphocytes within lymphoid tissues is a likely component of the lymphopenia observed in many autoimmune diseases. ClinicalTrials.gov NCT00664716.
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Clinical, laboratory and health-related quality of life correlates of Systemic Lupus Erythematosus Responder Index response: a post hoc analysis of the phase 3 belimumab trials.
Lupus Sci Med
PUBLISHED: 01-01-2014
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Correlates of systemic lupus erythematosus (SLE) Responder Index (SRI) response with clinical trial end points were examined using pooled data from the Study of Belimumab in Subjects with SLE (BLISS) trials (N=1684).
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The SLE transcriptome exhibits evidence of chronic endotoxin exposure and has widespread dysregulation of non-coding and coding RNAs.
PLoS ONE
PUBLISHED: 01-01-2014
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Gene expression studies of peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE) have demonstrated a type I interferon signature and increased expression of inflammatory cytokine genes. Studies of patients with Aicardi Goutières syndrome, commonly cited as a single gene model for SLE, have suggested that accumulation of non-coding RNAs may drive some of the pathologic gene expression, however, no RNA sequencing studies of SLE patients have been performed. This study was designed to define altered expression of coding and non-coding RNAs and to detect globally altered RNA processing in SLE.
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Allelic-dependent expression of an activating fc receptor on B cells enhances humoral immune responses.
Sci Transl Med
PUBLISHED: 12-20-2013
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B cells are pivotal regulators of acquired immune responses, and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can substantially alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. Fc?RIIb (CD32B), the only recognized Fc? receptor on B cells, provides immunoglobulin G (IgG)-mediated negative modulation through a tyrosine-based inhibition motif, which down-regulates B cell receptor-initiated signaling. These properties make Fc?RIIb a promising target for antibody-based therapy. We report the discovery of allele-dependent expression of the activating Fc?RIIc on B cells. Identical to Fc?RIIb in the extracellular domain, Fc?RIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and B cells from mice transgenic for human Fc?RIIc, Fc?RIIc expression counterbalances the negative feedback of Fc?RIIb and enhances humoral responses to immunization in mice and to BioThrax vaccination in a human anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. Fc?RIIc expression on B cells challenges the prevailing paradigm of unidirectional negative feedback by IgG immune complexes via the inhibitory Fc?RIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell-targeted antibody-based therapy.
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Epratuzumab for patients with moderate to severe flaring SLE: health-related quality of life outcomes and corticosteroid use in the randomized controlled ALLEVIATE trials and extension study SL0006.
Rheumatology (Oxford)
PUBLISHED: 11-22-2013
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Objective. To evaluate health-related quality of life (HRQOL) and corticosteroid use in patients with moderate to severely active SLE enrolled in two international, multicentre, randomized controlled trials of epratuzumab (ALLEVIATE-1 and -2) and a long-term extension study (SL0006).Methods. Ninety ALLEVIATE patients (43% BILAG A, mean BILAG score 13.2) were randomized to receive 360 mg/m(2) (n = 42) or 720 mg/m(2) (n = 11) epratuzumab or placebo (n = 37), plus standard of care, in 12-week cycles. Corticosteroid use, patient and physician global assessments of disease activity (PtGA and PGA) and 36-item Medical Outcomes Survey Short Form (SF-36) results were recorded at baseline and every 4 weeks. Both trials were prematurely discontinued due to a drug supply interruption; patients followed for ?6 months were analysed. Twenty-nine patients continued in SL0006, with interim analysis at a median exposure of 120 (range 13-184) weeks.Results. At week 12, proportions of patients with a PGA ?20% above baseline or with a PtGA improvement greater than or equal to the minimum clinically important difference were higher in the epratuzumab arms than the placebo arm. PGA and PtGA improvements were sustained but did not reach statistical significance. At week 24, mean cumulative corticosteroid doses with epratuzumab 360 and 720 mg/m(2) were 1051 and 1973 mg less than placebo (P = 0.034 and 0.081, respectively). At week 48, SF-36 scores approached or exceeded US age- and gender-matched norms in five domains with the 360 mg/m(2) treatment. Improvements were maintained in SL0006 over ?2 years.Conclusion. Epratuzumab treatment produced clinically meaningful and sustained improvements in PGA, PtGA and HRQOL and reductions in corticosteroid doses.
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Managing lupus patients during pregnancy.
Best Pract Res Clin Rheumatol
PUBLISHED: 11-19-2013
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Systemic lupus erythematosus (SLE) is an auto-immune disease, primarily affecting young females. Pregnancy in a woman with SLE remains a high-risk situation with higher maternal and foetal mortality and morbidity. Although live births are achieved in majority of the pregnancies, active disease and major organ involvement can negatively affect the outcomes. A higher risk of foetal loss, pre-term birth, intra-uterine growth restriction (IUGR) and neonatal lupus syndromes (NLSs) are major foetal issues. Mothers are faced with disease flares, pre-eclampsia and other complications. Disease flares during SLE pregnancy pose the unique issue of recognition and differentiation between physiologic changes and disease state. Similarly, pre-eclampsia and lupus nephritis may lead to diagnostic confusion. Treatment choices during pregnancy are limited to a few safe drugs, further restricting the options. Refractory pregnancy loss associated with anti-phospholipid antibodies (aPLs) and complete heart block associated with anti-Ro antibodies remain unresolved issues. A multidisciplinary approach, with close monitoring, is essential for optimal outcomes.
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Disease Control and Safety of Belimumab Plus Standard Therapy Over 7 Years in Patients with Systemic Lupus Erythematosus.
J. Rheumatol.
PUBLISHED: 11-01-2013
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To evaluate the efficacy/safety of belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing).
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Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression.
PLoS Genet.
PUBLISHED: 10-01-2013
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Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P?=?2.7×10??, OR?=?1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
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Impaired health status and the effect of pain and fatigue on functioning in clinical trial patients with systemic lupus erythematosus.
J. Rheumatol.
PUBLISHED: 10-01-2013
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Our study evaluated the impaired health status of clinical trial patients with systemic lupus erythematosus (SLE) and explored the relationship between changes in fatigue and pain and their effect on overall health status.
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Diffuse lymphadenopathy as the presenting manifestation of systemic lupus erythematosus.
J Clin Rheumatol
PUBLISHED: 09-20-2013
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We report the case of a 27-year-old African American man who presented with 6 months of generalized lymphadenopathy and nothing in his history or examination to suggest systemic lupus erythematosus (SLE). He was thought to have lymphoma, syphilis, or tuberculosis, and an extensive workup was done. Laboratory investigation finally revealed leukopenia (4.0), proteinuria (1.87 g), antinuclear antibodies (640 speckled), anti-double-stranded DNA (640), anticardiolipin immunoglobulins G and M, anti-Smith, Coombs, anti-Ro, anti-La, CK (531 U/L), aldolase (8.5 U/L), high erythrocyte sedimentation rate (130 mm/h), and low complement (C3 15 mg/dL and C4 3 mg/dL). A kidney biopsy showed diffuse proliferative glomerulonephritis, International Society of Nephrology class IV. Generalized lymphadenopathy as the first and only manifestation for 6 months made the diagnosis of SLE challenging. Generalized diffuse lymphadenopathy has been associated with SLE but is much less frequent now than in the past. The differential diagnosis of lymphadenopathy relevant to rheumatologists includes Kikuchi histiocytic necrotizing lymphadenitis, Castleman disease, syphilis, tuberculosis, sarcoidosis, and lymphoma.
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Progression of coronary artery atherosclerosis in rheumatoid arthritis: comparison with participants from the Multi-Ethnic Study of Atherosclerosis.
Arthritis Res. Ther.
PUBLISHED: 09-11-2013
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In cross-sectional studies, patients with rheumatoid arthritis (RA) have higher coronary artery calcium (CAC) than controls. However, their rate of progression of CAC and the predictors of CAC progression have heretofore remained unknown.
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ABIN1 dysfunction as a genetic basis for lupus nephritis.
J. Am. Soc. Nephrol.
PUBLISHED: 08-22-2013
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The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-?B is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-?B and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases of systemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-?B and mitogen-activated protein kinase activity.
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Vitamin D deficiency does not predict progression of coronary artery calcium, carotid intima-media thickness or high-sensitivity C-reactive protein in systemic lupus erythematosus.
Rheumatology (Oxford)
PUBLISHED: 08-16-2013
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Vitamin D deficiency is common in SLE. Cardioprotective effects of vitamin D have been postulated due to modulation of inflammatory cytokines. However, the effects of vitamin D supplementation on inflammatory cytokines in trials have been inconsistent. We determined whether levels of vitamin D at baseline were associated with subclinical measures of atherosclerosis, or with changes in subclinical measures over 2 years.
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Value of Isolated IgA Anti-?2 -Glycoprotein I Positivity in the Diagnosis of the Antiphospholipid Syndrome.
Arthritis Rheum.
PUBLISHED: 08-06-2013
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To examine the prevalence of isolated IgA anti-?2 -glycoprotein I (anti-?2 GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of ?2 GPI, with clinical manifestations of the antiphospholipid syndrome (APS) in 3 patient groups and to evaluate the pathogenicity of IgA anti-?2 GPI in a mouse model of thrombosis.
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2013 update: Hopkins lupus cohort.
Curr Rheumatol Rep
PUBLISHED: 07-27-2013
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The Hopkins lupus cohort is a longitudinal cohort study of over 2,000 systemic lupus erythematosus (SLE) patients, who are seen quarterly. This review covers ten important clinically-relevant studies of the cohort. These studies include the function of prednisone in atherosclerosis and thrombosis, the preventive function of hydroxychloroquine, new insights into rare neurological manifestations, and treatment of flares with bursts of steroids rather than maintenance steroids.
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Atherosclerosis in systemic lupus erythematosus.
J. Cardiovasc. Pharmacol.
PUBLISHED: 06-25-2013
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Accelerated atherosclerosis and its long-term sequelae are a major cause of late mortality among patients with systemic lupus erythematosus (SLE). Traditional Framingham risk factors such as hypertension, hypercholesterolemia, diabetes, and smoking do not account in entirety for this risk. SLE specific factors like disease activity and duration, use of corticosteroids, presence of antiphospholipid antibodies, and others are important risk factors. SLE is considered a coronary heart disease; equivalent and aggressive management of all traditional risk factors is recommended. Despite their role in primary and secondary prevention in the general population, statins seem to have no effect on cardiovascular outcomes in adult or pediatric SLE populations. The use of hydroxychloroquine has a cardioprotective effect, and mycophenolate mofetil may reduce cardiovascular events based on basic science data and data from the transplant population. The role of vitamin D supplementation and treatment of hyperhomocysteinemia remain controversial, but due to the safety of therapy and the potential benefit, they remain as optional therapies.
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Predictors of self-reported health-related quality of life in systemic lupus erythematosus.
Rheumatology (Oxford)
PUBLISHED: 05-16-2013
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The Medical Outcomes Short Form-36 Survey (SF-36) has been widely used as a measure of health-related quality of life (HRQOL) in different populations. SLE patients have consistently reported lower scores compared with the general population. The objective of our study was to identify predictors of HRQOL using SF-36 among patients with SLE enrolled in a 2-year randomized controlled trial (RCT).
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Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry.
J. Rheumatol.
PUBLISHED: 05-01-2013
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Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate-related genes biological candidates for disease susceptibility. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry.
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Baseline predictors of systemic lupus erythematosus flares: data from the combined placebo groups in the phase III belimumab trials.
Arthritis Rheum.
PUBLISHED: 04-24-2013
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To identify predictors of moderate-to-severe systemic lupus erythematosus (SLE) flare in 562 patients treated with standard therapy alone in phase III belimumab trials, and to evaluate the impact of standard therapies on preventing flares.
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Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus: results from two randomized, double-blind, placebo-controlled, multicentre studies (ALLEVIATE) and follow-up.
Rheumatology (Oxford)
PUBLISHED: 03-28-2013
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To evaluate epratuzumab treatment in patients with moderately-to-severely active SLE in two international, randomized, controlled trials (ALLEVIATE-1 and -2) and an open-label extension study (SL0006).
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Improvements in health-related quality of life with belimumab, a B-lymphocyte stimulator-specific inhibitor, in patients with autoantibody-positive systemic lupus erythematosus from the randomised controlled BLISS trials.
Ann. Rheum. Dis.
PUBLISHED: 03-22-2013
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OBJECTIVE: Assess the effects of belimumab treatment plus standard systemic lupus erythematosus (SLE) therapy on health-related quality of life (HRQOL) in patients with active, autoantibody-positive SLE. METHODS: Patients received standard therapy plus placebo or belimumab 1 or 10 mg/kg in two multicentre, randomised controlled trials of 52 (BLISS-52; N=865) and 76 (BLISS-76; N=819) weeks duration. Responders were evaluated by SLE Responder Index at week 52. Patient-reported outcome assessments included SF-36, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, and EQ-5D. RESULTS: Mean SF-36 Physical Component Summary (PCS) scores at week 24 was a major secondary endpoint. Baseline SF-36 scores were 1.5 SDs below age-/sex-matched US norms with similar improvement at week 24 across treatment groups. Mean changes from baseline in PCS scores were significantly (p<0.05) greater with belimumab 1 mg/kg (4.20) and 10 mg/kg (4.18) versus placebo (2.96) in BLISS-52, week 52. In BLISS-76, significantly (p<0.05) greater improvements were seen with belimumab 1 mg/kg in PCS (belimumab 1 mg/kg=4.37, 10 mg/kg=3.41 vs placebo=2.85) and Mental Component Summary (MCS) scores (belimumab 1 mg/kg=3.14, 10 mg/kg=2.70 vs placebo=1.40) at week 52, and in MCS score at week 76 (belimumab 1 mg/kg=3.05, 10 mg/kg=2.28 vs placebo=1.36). In pooled analysis, significantly greater improvements in PCS, SF-36 vitality domain, and FACIT-Fatigue scores at week 52 were evident with both belimumab doses. CONCLUSIONS: The clinically meaningful improvements in HRQOL in autoantibody-positive patients with active SLE treated with belimumab and standard therapy are consistent with the reductions in disease activity observed in these trials. CLINICALTRIALS.GOV NUMBER: NCT00424476, NCT00410384.
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Vitamin D in systemic lupus erythematosus: modest association with disease activity and the urine protein-to-creatinine ratio.
Arthritis Rheum.
PUBLISHED: 03-21-2013
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To investigate whether an increase in vitamin D levels in patients with systemic lupus erythematosus (SLE) was associated with improvement in disease activity.
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Brief Report: Single-nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in Asians.
Arthritis Rheum.
PUBLISHED: 03-19-2013
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The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single-nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects.
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Omega-3 in SLE: a double-blind, placebo-controlled randomized clinical trial of endothelial dysfunction and disease activity in systemic lupus erythematosus.
Rheumatol. Int.
PUBLISHED: 02-19-2013
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Accelerated atherosclerosis remains a major cause of death in late systemic lupus erythematosus (SLE). Omega-3 has been reported to have benefit for endothelial dysfunction, one of the earliest stages of atherosclerosis, and to reduce disease activity in SLE. We performed a randomized, double-blind placebo-controlled trial to examine the effect of Omega-3 on endothelial function, disease activity, inflammatory markers and lipids in SLE. SLE patients (n = 85, mean age 47, 55% Caucasian, 38% African-American, 94% female) were randomly assigned to 3 g of Omega-3 (Lovaza, GSK) versus placebo for 12 weeks. Endothelial function was measured at baseline and at 12 weeks using flow-mediated dilation, calculated using high-resolution B-mode ultrasound of the brachial artery diameter in response to vasoactive stimuli (hyperemia). Disease activity was measured using the physician global assessment and SELENA-SLEDAI score. Inflammatory markers (sICAM-1, sVCAM-1, IL-6) and fasting lipid profile were done at baseline and 12-week follow-up. There was no difference between the treatment groups with respect to changes in flow-mediated dilation parameters or disease activity. An average increase in LDL cholesterol of 3.11 mg/dL (±21.99) was found with Omega-3 versus a decrease of 1.87 mg/dL (±18.29) with placebo (p = 0.0266). In this trial, Omega-3 did not improve endothelial function, disease activity, nor reduce inflammatory markers in SLE. Longer trials might be required if there are delayed clinical effects. There was evidence that Omega-3 may increase LDL cholesterol, but not the LDL/HDL ratio.
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Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.
PLoS Genet.
PUBLISHED: 02-18-2013
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Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
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Sifalimumab, a human anti-interferon-? monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study.
Arthritis Rheum.
PUBLISHED: 02-13-2013
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To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE).
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Utility of antiphosphatidylserine/prothrombin and IgA antiphospholipid assays in systemic lupus erythematosus.
J. Rheumatol.
PUBLISHED: 02-01-2013
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Currently, 3 antiphospholipid assays are widely used clinically [lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-ß2-glycoprotein I (anti-ß2-GPI)]. LAC is the most specific assay, conferring the highest risk of thrombosis and pregnancy loss, but it cannot be validly performed in an anticoagulated patient. We investigated the usefulness of antiphosphatidylserine/prothrombin (anti-PS/PT) and its association with thrombosis. Anti-PS/PT is strongly associated with the presence of LAC. We also studied the association of IgA antiphospholipid isotypes and specific domains of ß2-GPI with thrombosis in systemic lupus erythematosus (SLE).
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Lupus enteritis: an uncommon manifestation of systemic lupus erythematosus.
J Clin Rheumatol
PUBLISHED: 02-01-2013
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We report the case of a 25-year-old Iraqi woman who had multiple hospitalizations at an outside hospital for abdominal pain, nausea, and diarrhea without any evidence of systemic lupus erythematosus. Laboratory investigations finally showed a positive antinuclear antibody (1280), positive anti-dsDNA, anti-?2 glycoprotein I, low complement, positive Coombs tests, and leukopenia. A kidney biopsy showed ISN class II lupus nephritis. An ileal biopsy and angiogram were unremarkable. A computed tomography showed marked and dramatic bowel edema involving the small and large bowel ("target sign"), dilatation of intestinal segments, engorgement of mesenteric vessels ("comb sign"), and increased attenuation of mesenteric fat. These cardinal signs on computed tomography scan led to the correct diagnosis of lupus enteritis. Treatment was commenced with high-dose corticosteroids followed by mycophenolate mofetil, hydroxychloroquine, and then oral cyclophosphamide, but failed. The patient was eventually treated with the Euro-Lupus intravenous cyclophosphamide regimen, which resulted in significant clinical and radiological resolution.
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Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study.
Ann. Rheum. Dis.
PUBLISHED: 01-12-2013
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To identify a suitable dosing regimen of the CD22-targeted monoclonal antibody epratuzumab in adults with moderately to severely active systemic lupus erythematosus (SLE).
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MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus.
PLoS Genet.
PUBLISHED: 01-08-2013
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We previously reported that the G allele of rs3853839 at 3untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P?=?6.5×10(-10), odds ratio (OR) (95%CI)?=?1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta?=?7.5×10(-11), OR?=?1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R(2)?=?0.255, P?=?0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3UTR segment bearing the C allele (P?=?0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta ?=?2.0×10(-19), OR?=?1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
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PTPN22 association in systemic lupus erythematosus (SLE) with respect to individual ancestry and clinical sub-phenotypes.
PLoS ONE
PUBLISHED: 01-01-2013
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Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7 × 10(-9), OR = 1.40 (95% CI = 1.25-1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67-0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7 × 10(-5), OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.
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A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.
Arthritis Rheum.
PUBLISHED: 12-01-2011
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To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE).
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Lupus and pregnancy.
Obstet Gynecol Surv
PUBLISHED: 11-25-2011
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Systemic lupus erythematosus (SLE) disproportionately affects women in their reproductive age years. Pregnancy in this systemic autoimmune disease has long been associated with poor obstetric outcomes. However, the frequency of pregnancy loss in lupus has dropped to a level commensurate with that of the general US population. The outcomes of lupus pregnancies are better if conception is delayed until the disease has been inactive for at least 6 months, and the medication regimen has been adjusted in advance. Pregnancy in lupus is prone to complications, including flares of disease activity during pregnancy or in the postpartum period, preeclampsia, miscarriage, stillbirth, intrauterine growth retardation, and preterm birth. Active lupus nephritis poses the greatest risk. The recognition of a lupus flare during pregnancy may be difficult because the signs and symptoms may mimic those of normal pregnancy. Monitoring should include baseline and monthly laboratory tests, serial ultrasonography, fetal surveillance tests, and fetal m-mode echocardiography for mothers with SS-A (Ro) or SS-B (La) antibodies. In the absence of any signs or symptoms of active SLE, affected patients require no specific treatment during pregnancy. If hydroxychloroquine was in use before conception, it should be maintained throughout pregnancy. If a woman with SLE has antiphospholipid antibodies, prophylactic treatment with aspirin and/or low-molecular weight heparin is indicated to prevent fetal loss. Lupus flares during pregnancy are generally treated with hydroxychloroquine, low-dose prednisone, pulse intravenous methylprednisolone, and azathioprine. High-dose prednisone and cyclophosphamide are reserved for severe lupus complications but are associated with significant pregnancy-related complications and poor obstetrical outcomes.
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Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus.
Ann. Rheum. Dis.
PUBLISHED: 11-21-2011
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Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci.
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IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus.
Ann. Rheum. Dis.
PUBLISHED: 11-16-2011
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High serum interferon ? (IFN?) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFN? production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease.
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Longitudinal predictors of progression of carotid atherosclerosis in rheumatoid arthritis.
Arthritis Rheum.
PUBLISHED: 10-04-2011
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To explore predictors of change in measures of carotid atherosclerosis among rheumatoid arthritis (RA) patients without known cardiovascular disease (CVD) at baseline.
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Predictors of progression in atherosclerosis over 2 years in systemic lupus erythematosus.
Rheumatology (Oxford)
PUBLISHED: 08-28-2011
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Cardiovascular disease remains the major cause of death in SLE. We assessed the degree to which cardiovascular risk factors (CVRFs) and disease activity were associated with 2-year changes in measures of subclinical atherosclerosis.
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Identification of novel genetic susceptibility loci in African American lupus patients in a candidate gene association study.
Arthritis Rheum.
PUBLISHED: 07-28-2011
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Candidate gene and genome-wide association studies have identified several disease susceptibility loci in lupus patients. These studies have largely been performed in lupus patients who are Asian or of European ancestry. This study was undertaken to examine whether some of these same susceptibility loci increase lupus risk in African American individuals.
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Identification of urinary metabolites that distinguish membranous lupus nephritis from proliferative lupus nephritis and focal segmental glomerulosclerosis.
Arthritis Res. Ther.
PUBLISHED: 06-24-2011
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Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease, and kidney involvement with SLE, a.k.a. lupus nephritis (LN), is a frequent and severe complication of SLE that increases patient morbidity and mortality. About 50% of patients with SLE encounter renal abnormalities which, if left untreated, can lead to end-stage renal disease. Kidney biopsy is considered the criterion standard for diagnosis and staging of LN using the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification, which was developed to help predict renal outcomes and assist with medical decision-making. However, kidney biopsy-based classification of LN is highly invasive and impractical for real-time monitoring of LN status. Here, nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling was used to identify urinary metabolites that discriminated between proliferative and pure membranous LN as defined by the ISN/RPS classification, and between LN and primary focal segmental glomerulosclerosis (FSGS).
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Neuroimaging evidence of white matter inflammation in newly diagnosed systemic lupus erythematosus.
Arthritis Rheum.
PUBLISHED: 05-28-2011
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Central nervous system (CNS) involvement occurs frequently in systemic lupus erythematosus (SLE) and frequently results in morbidity. The primary pathophysiology of CNS involvement in SLE is thought to be inflammation secondary to autoantibody-mediated vasculitis. Neuroimaging studies have shown hypometabolism (representing impending cell failure) and atrophy (representing late-stage pathology), but not inflammation. The purpose of this study was to detect the presence and regional distribution of inflammation (hypermetabolism) and tissue failure, apoptosis, or atrophy (hypometabolism).
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Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients.
Curr Rheumatol Rep
PUBLISHED: 05-26-2011
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Hydroxychloroquine is used extensively in the treatment of systemic lupus erythematosus, not only for its benefit for cutaneous and musculoskeletal lupus, but also for its role in preventing flares, preventing renal and central nervous system lupus, and improving survival rates. Hydroxychloroquine also has known benefits in reducing some traditional cardiovascular risk factors, such as hyperlipidemia and diabetes mellitus. This article reviews its possible role as an antithrombotic drug in the general population, in systemic lupus erythematosus, and in patients with antiphospholipid antibodies.
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Association of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups.
Arthritis Rheum.
PUBLISHED: 05-19-2011
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T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin-2 (IL-2). Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac.
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