Large-scale analysis of tumor necrosis factor α levels in systemic lupus erythematosus.

PubMed

Weckerle, Corinna E; Mangale, Dorothy; Franek, Beverly S; Kelly, Jennifer A; Kumabe, Marissa; James, Judith A; Moser, Kathy L; Harley, John B; Niewold, Timothy B

2012-09-01

Systemic lupus erythematosus (SLE) disease manifestations are highly variable among patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum tumor necrosis factor α (TNFα) levels are elevated in some SLE patients and may play a role in disease pathogenesis. The aim of this study was to look for associations between serum TNFα levels, clinical manifestations of SLE, autoantibodies, and serum interferon-α (IFNα) levels in a large multiancestral SLE cohort. We studied serum TNFα levels in 653 SLE patients (214 African Americans, 298 European Americans, and 141 Hispanic Americans). TNFα was measured using an enzyme-linked immunosorbent assay, and IFNα was measured with a functional reporter cell assay. Stratified and multivariate analyses were used to detect associations in each ancestral background separately, with meta-analysis when appropriate. Serum TNFα levels were significantly higher in SLE patients than in non-autoimmune disease controls (P < 5.0 × 10(-3) for each ancestral background). High serum TNFα levels were positively correlated with high serum IFNα levels when tested in the same sample across all ancestral backgrounds (odds ratio range 1.76-1.86, P = 4.8 × 10(-3) by Fisher's combined probability test). While serum TNFα levels alone did not differ significantly among SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high levels of TNFα and IFNα was highest in African Americans and lowest in European Americans (P = 5.0 × 10(-3) ). Serum TNFα levels were not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at the time of sampling. Serum TNFα levels are high in many SLE patients, and we observed a positive correlation between serum TNFα and IFNα levels. These data support a role for TNFα in the pathogenesis of SLE across all ancestral backgrounds and suggest important cytokine subgroups within the disease. Copyright © 2012 by the American College of Rheumatology.

The correlational research among serum CXCL13 levels, circulating plasmablasts and memory B cells in patients with systemic lupus erythematosus: A STROBE-compliant article.

PubMed

Fang, Chenglong; Luo, Tingting; Lin, Ling

2017-12-01

We investigated whether serum CXC ligand 13 protein (CXCL13) levels correlate with the circulating plasmablasts and memory B-cells alteration in systemic lupus erythematosus (SLE) patients. The diagnostic use of CXCL13 concentrations in active lupus was also analyzed.A total of 36 SLE patients and 18 healthy controls were included. Serum CXCL13 levels were examined by enzyme-linked immunosorbent assay. The frequency and absolute count of circulating plasmablasts and memory B cells were analyzed by flow cytometry. Receiver operating characteristic curves (ROC curves) were generated to analyze the utility of serum CXCL13 level and plasmablasts frequency as tools for the recognition of active SLE.Elevation of serum CXCL13 levels, higher plasmablasts frequency, and reduction of memory B-cells count were observed in SLE patients, compared with healthy controls. Interestingly, correlational analyses showed not only significantly positive association between CXCL13 levels and SLE Disease Activity Index (SLEDAI) or plasmablasts frequency, but an inverse correlation between CXCL13 concentration and memory B-cell count. ROC curves showed that serum CXCL13 level and plasmablasts frequency were practical in identifying active disease from overall SLE patients, with considerable accuracy.Serum CXCL13 levels correlate with the alteration of plasmablasts and memory B cells in SLE. CXCL13 may be used as a practical tool in judgment of active SLE.

C-reactive protein +1444CT (rs1130864) genetic polymorphism is associated with the susceptibility to systemic lupus erythematosus and C-reactive protein levels.

PubMed

Delongui, Francieli; Lozovoy, Marcell Allyson Batisti; Iriyoda, Tatiana Mayiumi Veiga; Costa, Neide Tomimura; Stadtlober, Nicole Perugini; Alfieri, Daniela Frizon; Flauzino, Tamires; Dichi, Isaias; Simão, Andréa Name Colado; Reiche, Edna Maria Vissoci

2017-08-01

The T rare allele of +1444CT (rs1130864) polymorphism of C-reactive protein (CRP) has been associated with increased CRP levels in some inflammatory conditions, but its role on systemic lupus erythematosus (SLE) susceptibility and on CRP levels in SLE patients remains uncertain. The objective of the study was to evaluate the association between the rs1130864 CRP polymorphism with SLE susceptibility, disease activity, and CRP levels in SLE Brazilian patients. The study enrolled 176 SLE patients and 137 controls. SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI). The rs1130864 CRP polymorphism was determined using polymerase chain reaction and restriction fragment length polymorphism. SLE patients presented higher body mass index (p = 0.046) and CRP levels (p = 0.017) than controls. The genotype and allele frequencies of patients differed from controls [CC vs. CT = odds ratio (OR) 1.730, 95% confidence interval (CI) 1.068-2.803, p = 0.035; CC vs. TT = OR 3.667, 95% CI 1.410-9.533, p = 0.009; C vs. T = OR 1.883, 95% CI 1.299-2.728, p = 0.001)]. Patients carrying the T allele presented higher CRP levels (p = 0.009), were more frequent Caucasians (p = 0.018), and with no use of immunosuppressive treatment (p = 0.004) than those carrying the C allele. However, the SLEDAI and anti-double-stranded DNA positivity did not differ from those carrying T vs. C allele (p = 0.595 and p = 0.243, respectively). The rs1130864 CRP polymorphism was associated with SLE susceptibility and CRP levels, but not with disease activity, suggesting that this polymorphism may play a role in the pathophysiology of SLE through increasing the CRP that, probably, plays an inflammatory role in SLE pathophysiology.

Leptin and adiponectin in patients with systemic lupus erythematosus: clinical and laboratory correlations.

PubMed

Barbosa, Vitalina de Souza; Francescantônio, Paulo Luiz; Silva, Nílzio Antônio da

2015-01-01

To evaluate the serum levels of leptin and adiponectin in patients with systemic lupus erythematosus (SLE) and correlate their levels with disease activity, presence of autoantibodies and clinical manifestations. 52 women with SLE and 33 healthy women were evaluated. The patients were divided into two groups, the first with active SLE and the second with inactive SLE. Patients with SLEDAI ≥3 were considered active. Serum levels of leptin (ng/ml) and adiponectin (μg/ml) were measured by enzyme immunoassay. There was a significant difference in leptin levels between SLE and controls (20.7 ± 17.1 vs. 8.0 ± 5.0 ng/mL, P <0.001), but no significant difference in adiponectin levels (87.5 ± 69.7 vs. 118.1 ± 70.6 pg/ml, P = 0.053). No significant difference in levels of leptin and adiponectin was noted between inactive and active SLE groups. There was a significant association between low levels of leptin and positivity for anticardiolipin (aCL) (P = 0.025) and lupus anticoagulant (LA) (p = 0.003) and a significant association between high levels of leptin and the presence of renal disease (p <0.001). However, there was no association between adiponectin levels with autoantibodies and clinical features in SLE patients. Patients with SLE had elevated leptin levels, with association with renal involvement. Leptin and adiponectin were not correlated with disease activity. Low levels of leptin have been associated with the presence of LA and aCL. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

Towards developing high-fidelity simulated learning environment training modules in audiology.

PubMed

Dzulkarnain, A A; Rahmat, S; Mohd Puzi, N A F; Badzis, M

2017-02-01

This discussion paper reviews and synthesises the literature on simulated learning environment (SLE) from allied health sciences, medical and nursing in general and audiology specifically. The focus of the paper is on discussing the use of high-fidelity (HF) SLE and describing the challenges for developing a HF SLE for clinical audiology training. Through the review of the literature, this paper discusses seven questions, (i) What is SLE? (ii) What are the types of SLEs? (iii) How is SLE classified? (iv) What is HF SLE? (v) What types of SLEs are available in audiology and their level of fidelity? (vi) What are the components needed for developing HF SLE? (vii) What are the possible types of HF SLEs that are suitable for audiology training? Publications were identified by structured searches from three major databases PubMed, Web of Knowledge and PsychInfo and from the reference lists of relevant articles. The authors discussed and mapped the levels of fidelity of SLE audiology training modules from the literature and the learning domains involved in the clinical audiology courses. The discussion paper has highlighted that most of the existing SLE audiology training modules consist of either low- or medium-fidelity types of simulators. Those components needed to achieve a HF SLE for audiology training are also highlighted. Overall, this review recommends that the combined approach of different levels and types of SLE could be used to obtain a HF SLE training module in audiology training.

Association between Vitamin D level and/or deficiency, and systemic lupus erythematosus: a meta-analysis.

PubMed

Bae, Sang-Cheol; Lee, Young Ho

2018-01-31

This study aimed to evaluate the relationship between the level of 25-hydroxyvitamin D [25(OH)D] and systemic lupus erythematosus (SLE). We searched the PUBMED, EMBASE, and Cochrane databases and performed a meta-analysis examining the vitamin D level and/or deficiency in patients with SLE, compared with that in healthy controls. In total, 18 studies consisting of 1,083 patients with SLE and 1,273 controls were included. Vitamin D level was significantly lower in the SLE group than in the control group (standardized mean difference [SMD] = -0.938, 95% CI = -1.352 to -0.524, p = 9.0 × 10-6). Stratification by ethnicity showed a significantly decreased vitamin D level in the SLE group in the European and Arab populations (SMD = -1.485, 95% CI = -2.427 to -0.543, p = 0.002; SMD = -1.067, 95% CI = -1.251 to -0.883, p < 1.0 × 10-8), and an association tendency between decreased vitamin D level and SLE in the Asian population (SMD = -0.874, 95% CI = -2.073 to -0.324, p = 0.153). Subgroup analysis by sample size showed a significantly lower vitamin D level in the SLE group in small- (n ≤ 100) and large-sample (n > 100) populations (SMD = -1.008, 95% CI = -1.672 to -0.344, p = 0.003; SMD = -0.863, 95% CI = -1.444 to -0.293, p = 0.003). Meta-analysis revealed a significant association between SLE and vitamin D deficiency (RR = 2.321, 95% CI = 1.361-3.960, p = 0.002). Stratification by ethnicity showed a significant association between SLE and vitamin D deficiency in European and Arab populations (RR = 2.182, 95% CI = 1.024-4.648, p = 0.043; RR = 4.550, 95% CI = 3.471-5.965, p < 1.0 × 10-8). Our meta-analysis demonstrates that compared with controls, patients with SLE show significantly low serum levels of vitamin D, and that a deficiency of vitamin D is associated with SLE.

[Expression and Clinical Significance of Semaphorin 3A in serum and mononuclear cells in patients with systemic lupus erythematosus].

PubMed

Gao, H; Ma, X X; Guo, Q; Zou, Y D; Zhong, Y C; Xie, L F; Shao, M; Zhang, X W

2017-02-07

Objective: To determine the expression of Sema3A in serum and peripheral blood mononuclear cells (PBMC) of patients with systemic lupus erythematosus (SLE), to analysis the correlation of Sema3A expression and SLE clinical manifestations and laboratory indexes, and to evaluate the diagnostic value of Sema3A in patients with SLE. Methods: The concentration of serum Sema3A was detected by enzyme-linked immuno sorbent assay (ELISA) in patients with SLE, healthy controls (HC) and diseases controls. In addition, the mRNA expression level of Sema3A was examined in PBMC by real-time polymerase chain reaction. The correlation of serum Sema3A level and clinical and laboratory features of SLE patients were analyzed. Unpaired t test, Kruskal-Wallis test, Mann-Whitney U test, χ(2) test, Pearson and Spearman correlation analysis were used to statistical analysis by using SPSS 13.0. Results: (1) Serum Sema3A concentration in patients with SLE was significantly lower than that in HC groups ( P <0.01). (2) Consistent with the serum level, the Sema3A mRNA level in SLE was lower than that in HC ( P =0.001). And the mRNA expression of Nrp-1 in SLE was also lower than that in HC ( P <0.01). (3) The serum Sema3A level in patients with SLE was positively correlated with haemoglobin (HGB) ( r =0.271, P <0.013), platelet (PLT) ( r =0.600, P <0.011), complement 3 (C3) ( r =0.234, P =0.0027) and complement 4 (C4) ( r =0.159, P =0.434) levels. Whereas, the expression of Sema3A was negatively correlated with SLE disease activity index (SLEDAI) ( r =-0.286, P =0.036). (4) Area under curve illustrated by ROC curve was 0.876 (95% CI: 0.846-0.906). The best cut-off value for the diagnosis of SLE was 6.31 μg/L, with the sensitivity of 80.6% and the specificity of 77.5%. The Youden index was 0.581. Above results indicated good validity of Sema3A as a diagnostic marker for SLE. (5) The HGB, PLT, C3 and C4 levels in the group of Sema3A- positiveSLE patients (≤6.31 μg/L) were lower than that in negative group (>6.31 μg/L), while CRP level and SLEDAI of positive group was higher than that in negative group( P <0.05). In addition, the positive rate of antinuclear antibodies ( P =0.046) and anticardiolipin antibody ( P =0.018) in the Sema3A-negative group were also significantly higher than that of negative group. Conclusions: Sema3A and Nrp-1 was both decreased in serum and PBMC of SLE patients, suggesting that the circulating expression of Sema3A and Nrp-1 was seriously defected in SLE. Circulating Sema3A was significantly correlated with disease activity and blood damage in patients with SLE. The result of ROC curve showed that Sema3A had the potential to be a new diagnostic biomarker in SLE.

CXCL13 is an activity marker for systemic, but not cutaneous lupus erythematosus: a longitudinal cohort study.

PubMed

Niederkorn, Anna; Frühauf, Julia; Schwantzer, Gerold; Wutte, Nora; Painsi, Clemens; Werner, Stefan; Stradner, Martin; Berghold, Andrea; Hermann, Josef; Aberer, Elisabeth

2018-05-04

Serum levels of the IFN-regulated cytokine CXCL13 have been found to correlate with SLEDAI and renal involvement in systemic lupus erythematosus. This study investigates whether CXCL13 can also be a marker of disease activity in patients with subacute cutaneous or chronic cutaneous lupus erythematosus (SCLE, CCLE). We analysed CXCL13 levels in 60 patients' sera (18 SLE, 19 SCLE, 23 CCLE) at five time points within 1 year and correlated these levels with disease activity scores and laboratory markers. Clinical scores with no/mild, moderate or high/severe disease activity were categorized by SLEDAI in SLE, by CLASI in SCLE/CCLE. CXCL13 levels were significantly higher in SLE (median 122.5, IQR 88.0-239.0 pg/ml) than in CCLE patients (median 69.0, IQR 60.0-102.0 pg/ml) (p = 0.006). CXCL13 levels were elevated in 59% (41/70) of SLE patient visits with mild or no disease activity, but in 90% (9/10) with high disease activity. CXCL13 levels correlated with ECLAM, dsDNA-antibodies, and inversely with complement factors C3 and C4 in SLE, and with IgA and ESR in SCLE. In CCLE CXCL13 did not correlate with CLASI or laboratory markers. One SCLE and two CCLE patients with CXCL13 levels > 500 pg/ml had conversion to SLE or an underlying autoimmune disease. CXCL13 seems to be a useful marker of disease activity in SLE, but not in SCLE and CCLE. Conversion from normal to elevated CXCL13 may indicate a flare of SLE. Whether high CXCL13 levels in cutaneous LE indicate the development of SLE should be further investigated.

Influenza A/H1N1 vaccination of patients with SLE: can antimalarial drugs restore diminished response under immunosuppressive therapy?

PubMed

Borba, Eduardo F; Saad, Carla G S; Pasoto, Sandra G; Calich, Ana L G; Aikawa, Nadia E; Ribeiro, Ana C M; Moraes, Julio C B; Leon, Elaine P; Costa, Luciana P; Guedes, Lissiane K N; Silva, Clovis A A; Goncalves, Celio R; Fuller, Ricardo; Oliveira, Suzimara A; Ishida, Maria A; Precioso, Alexander R; Bonfa, Eloisa

2012-06-01

To assess the efficacy and safety of pandemic 2009 influenza A (H1N1) in SLE under different therapeutic regimens. A total of 555 SLE patients and 170 healthy controls were vaccinated with a single dose of a non-adjuvanted preparation. According to current therapy, patients were initially classified as SLE No Therapy (n = 75) and SLE with Therapy (n = 480). Subsequent evaluations included groups under monotherapy: chloroquine (CQ) (n = 105), prednisone (PRED) ≥20 mg (n = 76), immunosuppressor (IS) (n = 95) and those with a combination of these drugs. Anti-H1N1 titres and seroconversion (SC) rate were evaluated at entry and 21 days post-vaccination. The SLE with Therapy group had lower SC compared with healthy controls (59.0 vs 80.0%; P < 0.0001), whereas the SLE No Therapy group had equivalent SC (72 vs 80.0%; P = 0.18) compared with healthy controls. Further comparison revealed that the SC of SLE No Therapy (72%) was similar to the CQ group (69.5%; P = 0.75), but it was significantly reduced in PRED ≥20 mg (53.9%; P = 0.028), IS (55.7%; P = 0.035) and PRED ≥20 mg + IS (45.4%; P = 0.038). The concomitant use of CQ in each of these later regimens was associated with SC responses comparable with SLE No Therapy group (72%): PRED ≥20 mg + CQ (71.4%; P = 1.00), IS + CQ (65.2%; P = 0.54) and PRED ≥20 mg + IS + CQ (57.4%; P = 0.09). Pandemic influenza A H1N1/2009 vaccine response is diminished in SLE under immunosuppressive therapy and antimalarials seems to restore this immunogenicity. Trial registration. www.clinicaltrials.gov, NCT01151644.

Therapeutic Potential for Targeting the Suppressor of Cytokine Signaling-1 pathway for the treatment of SLE

PubMed Central

Sukka-Ganesh, Bhagyalaxmi; Larkin, Joseph

2016-01-01

Although the specific events dictating systemic lupus erythematosus (SLE) pathology remain unclear, abundant evidence indicates a critical role for dysregulated cytokine signaling in disease progression. Notably, the suppressor of cytokine signaling (SOCS) family of intracellular proteins, in particular the kinase inhibitory region (KIR) bearing SOCS1 and SOCS3, play a critical role in regulating cytokine signaling. To assess a relationship between SOCS1/SOCS3 expression and SLE, the goals of this study were to: 1) evaluate the time kinetics of SOCS1/SOCS3 message and protein expression based on SLE associated stimulations, 2) compare levels of SOCS1 and SOCS3 present in SLE patients and healthy controls by message and protein, 3) relate SOCS1/SOCS3 expression to inflammatory markers in SLE patients, and 4) correlate SOCS1/SOCS3 levels to current treatments. We found that SOCS1 and SOCS3 were most abundant in murine splenic samples at 48 hours subsequent to stimulation by anti-CD3, LPS, or interferon gamma. In addition, significant reductions in SOCS1 and SOCS3 were present within PMBC’s of SLE patients compared to controls by both mRNA and protein expression. We also found that decreased levels of SOCS1 in SLE patients were correlated to enhanced levels of inflammatory markers and up-regulated expression of MHC class II. Finally, we show that patients receiving steroid treatment possessed higher levels SOCS1 compared to SLE patient counterparts, and that steroid administration to human PBMCs up-regulated SOCS1 message in a dose and time dependent manner. Together, these results suggest that therapeutic strategies focused on SOCS1 signaling may have efficacy in the treatment of SLE. PMID:27781323

Soluble Mediators and Clinical Features Discern Risk of Transitioning to Classified Disease in Relatives of Systemic Lupus Erythematosus Patients

PubMed Central

Munroe, Melissa E.; Young, Kendra A.; Kamen, Diane L.; Guthridge, Joel M.; Niewold, Timothy B.; Costenbader, Karen H.; Weisman, Michael H.; Ishimori, Mariko L.; Wallace, Daniel J.; Gilkeson, Gary S.; Karp, David R.; Harley, John B.; Norris, Jill M.; James, Judith A.

2016-01-01

Objective Systemic lupus erythematosus (SLE) and other autoimmune diseases cause significant morbidity. Identifying populations at risk of developing SLE is essential to curtail irreversible inflammatory damage. The objective of this study was to identify factors associated with transition to classified disease that inform SLE risk. Methods Previously identified lupus patient blood relatives with < 4 American College of Rheumatology SLE classification criteria at baseline (n=409) were enrolled in this follow-up study. Participants provided detailed family, demographic, and clinical information, including the SLE-specific portion of the Connective Tissue Disease Screening Questionnaire (SLE-CSQ). Plasma samples were tested for the presence of lupus-associated autoantibodies and 52 soluble mediators. Generalized estimating equations (GEE) were applied to identify factors anticipating disease transition. Results Forty-five relatives (11%) transitioned to classified SLE during follow-up (mean time=6.4 years). Relatives who transitioned displayed more lupus-associated autoantibody specificities and higher SLE-CSQ scores (p<0.0001) at baseline than non-transitioned relatives. Importantly, they also had elevated baseline plasma levels of inflammatory mediators, including B-lymphocyte stimulator (BLyS), stem cell factor (SCF), and interferon-associated chemokines (p≤0.02), with concurrent decreases in levels of regulatory mediators, tumor growth factor (TGF)-β and interleukin (IL)-10 (p≤0.03). GEE revealed that baseline SLE-CSQ or ACR scores and plasma levels of SCF and TGF-β (p≤0.03), but not autoantibodies, were significant and independent predictors of SLE transition. Conclusions Altered levels of soluble mediators anticipate transition to classified disease in lupus relatives. Thus, immune perturbations precede SLE classification and can help identify high-risk relatives for rheumatology referral and potential enrollment in prevention trials. PMID:27863174

Inflammation associated anemia and ferritin as disease markers in SLE

PubMed Central

2012-01-01

Introduction In a recent screening to detect biomarkers in systemic lupus erythematosus (SLE), expression of the iron storage protein, ferritin, was increased. Given that proteins that regulate the storage, transfer and release of iron play an important role in inflammation, this study aims to determine the serum and urine levels of ferritin and of the iron transfer protein, transferrin, in lupus patients and to correlate these levels with disease activity, inflammatory cytokine levels and markers of anemia. Methods A protein array was utilized to measure ferritin expression in the urine and serum of SLE patients and healthy controls. To confirm these results as well as the role of the iron transfer pathway in SLE, ELISAs were performed to measure ferritin and transferrin levels in inactive or active SLE patients and healthy controls. The relationship between ferritin/transferrin levels and inflammatory markers and anemia was next analyzed. Results Protein array results showed elevated ferritin levels in the serum and urine of lupus patients as compared to controls, which were further validated by ELISA. Increased ferritin levels correlated with measures of disease activity and anemia as well as inflammatory cytokine titers. Though active SLE patients had elevated urine transferrin, serum transferrin was reduced. Conclusion Urine ferritin and transferrin levels are elevated significantly in SLE patients and correlate with disease activity, bolstering previous reports. Most importantly, these changes correlated with the inflammatory state of the patients and anemia of chronic disease. Taken together, altered iron handling, inflammation and anemia of chronic disease constitute an ominous triad in SLE. PMID:22871034

Serum 25-OH vitamin D level in treatment-naïve systemic lupus erythematosus patients: Relation to disease activity, IL-23 and IL-17.

PubMed

Shahin, D; El-Farahaty, R M; Houssen, M E; Machaly, S A; Sallam, M; ElSaid, T O; Neseem, N O

2017-08-01

Objectives The aim of this study was to assess the vitamin D status in treatment-naïve SLE patients and its association with clinical and laboratory markers of disease activity, including serum levels of IL-17 and IL-23. Methods Fifty-seven treatment-naïve SLE patients along with 42 matched controls were included. SLEDAI score was used to estimate disease activity. Serum levels of 25(OH) D, IL-17 and IL-23 were measured. Results The median level of 25(OH) D in SLE patients (40.8; 4-70 ng/ml) was significantly lower than in the controls (47; 25-93 ng/ml) ( P = 0.001). A total of 38.6% of SLE cases had 25 (OH) D levels < 30 ng/ml (hypovitaminosis D) vs. 4.8% of the controls ( P < 0.0001). Apart from thrombocytopenia, vitamin D was not associated with clinical signs of SLE. There were negative correlations between serum 25(OH) D and serum levels of IL-17, IL-23 and ANA (rho = -0.5, -0.8, -0.5, P ≤ 0.05) in SLE patients. Conclusion Hypovitaminosis D is prevalent in treatment naïve SLE patients. It contributes to ANA antibody production and is associated with high serum levels of IL-23 and IL-17; thus they may trigger the inflammatory process in SLE.

[Role of anti c-mpl antibody in systemic lupus erythematosus with thrombocytopenia].

PubMed

Yang, Tuo; Huang, Ci Bo; Lai, Bei; Zhao, Li Ke; Chen, Ying Juan; Zhao, Yue Tao; Zhang, Chun Mei; Zeng, Xiao Feng

2012-04-18

To determine whether anti-thrompoietin receptor (TPO-R, c-mpl) antibody contributes to thrombocytopenia in systemic lupus erytematosus (SLE) and explore the pathogenic role of this antibody. Sera from 24 SLE patients with thrombocytopenia, 27 SLE patients having normal platelet counts with a history of thrombocytopenia, 18 SLE patients with neither thrombocytopenia nor post thrombocytopenia and 18 healthy controls were collected. Anti c-mpl antibodies were detected by an indirected ELISA assay. The serum TPO levels were measured by an ELISA assay. Clinical findings, autoantibody profiles, and SLEDAI were evaluated. Serum anti c-mpl antibodies were detected in 18.8% of the SLE patientis. The frequency of this antibody in SLE with thrombocytopenia, SLE with a history of thrombocytopenia and SLE without thrombocytopenia were of no difference (P=0.600). In the patients with anti c-mpl antibodies, their platelet counts were decreased(P=0.025) and serum TPO levels elevated(P=0.038) than those in the patients without, while there were no differences between the two groups in C3, C4, ESR, CRP level, the frequency of ANA, dsDNA, ANCA and SLEDAI. Anti c-mpl antibody contributes to SLE-associated thrombocytopenia by functionally blocking an interaction between thrombopoietin and c-mpl, which might inhibit TPO-dependent megakaryocyte proliferation and differentiation.

S100β is associated with cognitive impairment in childhood-onset systemic lupus erythematosus patients.

PubMed

Lapa, A T; Postal, M; Sinicato, N A; Bellini, B S; Fernandes, P T; Marini, R; Appenzeller, S

2017-04-01

Objective To investigate serologic S100β protein levels in childhood-onset SLE patients (cSLE) and to elucidate their association with disease activity and neuropsychiatric (NP) manifestations. Methods We included 71 cSLE patients (67 females; median age 18 years; range 9-37 and 53 (47 females; median age of 20 years; range 6-29) age and sex matched healthy controls. Neurological manifestations were analysed according to the American College of Rheumatology (ACR) criteria. Cognitive evaluation was performed in all participants using Wechsler Intelligence Scale for Children (WISC-III) and Wechsler Adult Intelligence Scale (WAIS), according to age, and validated in Portuguese. SLE patients were further assessed for clinical and laboratory SLE manifestations, disease activity (SLE Disease Activity Index (SLEDAI)), damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)) and current drug exposures. Sera S100β protein levels were measured by enzyme-linked immunosorbent assay using commercial kits. Results The median S100β protein level was 116.55 pg/mL (range 1.53-468.50) in cSLE and 54.98 pg/mL (range 0.69-181.00) in healthy controls ( p < 0.001). An association was observed between S100β protein and NP manifestations ( p = 0.03). The S100β protein levels was associated with cognitive impairment in cSLE patients ( p = 0.006). Conclusions S100β protein levels are increased in cSLE with cognitive impairment. S100β may be considered a potential biomarker that underlies central nervous system (CNS) dysfunction, especially cognitive impairment.

Decreased interleukin 35 and CD4+EBI3+ T cells in patients with active systemic lupus erythematosus.

PubMed

Ouyang, Han; Shi, Yong-Bing; Liu, Zhi-Chun; Wang, Zhi; Feng, Sheng; Kong, Shu-Min; Lu, Ying

2014-08-01

Interleukin 35 (IL-35) is likely to contribute to the development of autoimmune diseases, as the Epstein-Barr virus-induced gene protein 3 (EBI3) is the specificity subunit of IL-35. Nevertheless, until recently, no studies have evaluated its role in systemic lupus erythematosus (SLE) in humans. The objective of this study was to investigate the serum IL-35 level and the percentage of CD4EBI3 T cells in the peripheral blood of patients with SLE and explore the roles of double-positive T cells and IL-35 in the pathogenesis of SLE and the effects of glucocorticoid on these roles. Fifty-five hospitalized patients with SLE were recruited, and 20 volunteers were enrolled as healthy controls. Serum IL-35 levels were measured by enzyme-linked immunosorbent assay, and the percentage of CD4EBI3 T cells was analyzed by flow cytometry. The serum IL-35 level and the percentage of CD4EBI3 T cells were significantly decreased in patients with active SLE compared with healthy controls and patients with inactive SLE. The serum IL-35 level and the percentage of CD4EBI3 T cells were negatively correlated with the SLE disease activity index. The percentages of CD4EBI3 T cells and serum IL-35 levels in 10 untreated patients with active SLE were increased at days l, 3, and 7 after the treatment with methylprednisolone (0.8 mg·kg·d) compared with the percentages before the treatment. These results demonstrate that abnormalities in IL-35 and CD4EBI3 T cells may play important roles in the pathogenesis of SLE; the percentage of double-positive T cells and the level of IL-35 are parameters for the evaluation of SLE activity and severity.

Anti-müllerian hormone and ovarian reserve in systemic lupus erythematosus.

PubMed

Martins, Nádia Filipa Esteves; Seixas, Maria Inês; Pereira, Joaquim Polido; Costa, Maria Manuela; Fonseca, João Eurico

2017-12-01

Systemic lupus erythematosus (SLE) is a chronic immune-mediated inflammatory disease that affects predominantly females during childbearing age (Lateef and Petri Best Pract Res Clin Rheumatol 27(3):435-447, 2013). Fertility in SLE patients is considered to be normal (Clowse et al. Arthritis Care Res (Hoboken) 64(5):668-674, 2012; Ekblom-Kullberg et al. Scand J Rheumatol 38:375-380, 2009) but several known factors may negatively influence fertility. Immune mechanisms are also thought to be an important cause of premature ovarian senescence, characterized by reduced ovarian reserve markers such as anti-Müllerian hormone (AMH) (Oktem et al. Obstet Gynecol Surv 70(3):196-210, 2015; Bermas and Sammaritano Fertil Res Pract 1:13, 2015; Østensen Int J Clin Rheumtol 8(1):27-37, 2013; Ulug et al. Am J Reprod Immunol 72(1):85-88, 2014; Lawrenz et al. Lupus 20(11):1193-1197, 2011). We evaluated the ovarian reserve of women in reproductive age with SLE, by measuring AMH levels and we compared it to that of non-SLE women. We also analyzed the association of SLE disease characteristics with AMH levels. AMH levels were decreased in this population of SLE women, accounting for a high proportion of women with criteria for low ovarian reserve. Age and SLE damage were associated with abnormally lower AMH levels in our SLE patients. In this way, SLE may have a negative influence on the ovarian reserve.

Fragmented QRS in patients with systemic lupus erythematosus.

PubMed

Demır, Kenan; Avcı, Ahmet; Yılmaz, Sema; Demır, Tarık; Ersecgın, Ahmet; Altunkeser, Bulent Behlul

2014-08-01

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a variety of clinical features. Cardiac involvement is present in more than half of the patients with SLE. Fragmentation of QRS (fQRS) is presumed marker of cardiovascular risk and has not been previously evaluated in SLE. A total of 56 women previously diagnosed with SLE were recruited. In addition, a control group consisting of 51 healthy people was formed. QRS complexes were also evaluated in terms of fragmentations. All patients with SLE and control subjects underwent transthoracic echocardiographic examination. Erythrocyte sedimentation rate and C-reactive protein levels were also obtained. Frequency of fQRS was higher in patients with SLE (41% vs. 21%, p = 0.03). Left ventricular posterior wall thickness and mass index were higher in the patients with SLE. CRP levels and age were significantly higher, and disease duration was significantly longer in the fQRS(+) group (p = 0.02, 0.01, and 0.006, respectively). A careful cardiovascular evaluation and follow-up is essential to continuously improve survival in SLE. For this purpose, fQRS may be used for the early detection in patients with SLE.

Antibodies against C1q Are a Valuable Serological Marker for Identification of Systemic Lupus Erythematosus Patients with Active Lupus Nephritis

PubMed Central

Chi, Shuhong; Yu, Yunxia; Shi, Juan; Zhang, Yurong; Yang, Jijuan; Yang, Lijuan; Liu, Xiaoming

2015-01-01

Objective. An early diagnosis of lupus nephritis (LN) has an important clinical implication in guiding treatments of systemic lupus erythematosus (SLE) in clinical settings. In this study, the diagnostic values of circulating autoantibodies to C1q alone or in combination with other markers for accessing active SLE and LN were evaluated. Methods. The diagnostic value of anti-C1q autoantibodies for identification of patients with active SLE disease and LN was evaluated by analyzing the level of anti-C1q antibodies in sera from 95 SLE patients, 40 non-SLE patients, and 34 healthy cohorts. Results. The prevalence of anti-C1q antibodies was significantly higher in patients with SLE (50/95, 52.6%), active SLE (40/51, 78.4%), and LN (30/35, 85.7%) in comparison with non-SLE patient controls, patients with inactive SLE, and non-LN, respectively. A combination of anti-C1q with anti-dsDNA and/or levels of complements C3 and C4 exhibited an increased specificity but a decreased sensitivity for identification of patients with active SLE and LN diseases relative to each of these markers alone. Conclusion. Anti-C1q antibodies were strongly associated with disease activity and LN in SLE patients, suggesting that it may be a reliable serological marker for identification of SLE patients with active LN and active SLE disease. PMID:26549923

Serum levels of P-glycoprotein and persistence of disease activity despite treatment in patients with systemic lupus erythematosus.

PubMed

Perez-Guerrero, Edsaul Emilio; Gamez-Nava, Jorge Ivan; Muñoz-Valle, Jose Francisco; Cardona-Muñoz, Ernesto German; Bonilla-Lara, David; Fajardo-Robledo, Nicte Selene; Nava-Zavala, Arnulfo Hernan; Garcia-Cobian, Teresa Arcelia; Rincón-Sánchez, Ana Rosa; Murillo-Vazquez, Jessica Daniela; Cardona-Müller, David; Vazquez-Villegas, Maria Luisa; Totsuka-Sutto, Sylvia Elena; Gonzalez-Lopez, Laura

2018-02-01

Around 25% of patients with systemic lupus erythematosus (SLE) could be refractory to conventional therapies. P-glycoprotein expression on cell surface has been implied on drug resistance, however, to date, it is unknown if P-gp serum levels are associated with SLE disease activity. Evaluate the association of serum P-gp levels and SLE with disease activity despite treatment. A cross-sectional study was conducted on 93 female SLE patients, all receiving glucocorticoids at stable doses for the previous 6 months before to baseline. SLE patients were classified into two groups: (a) patients with active disease [SLE disease activity index (SLEDAI) ≥ 3] despite treatment, and (b) patients with inactive disease (SLEDAI < 3) after treatment. Forty-three healthy females comprised the control group. Serum P-gp, anti-DNA, and both anti-nucleosome antibody levels were measured using ELISA. Active-SLE patients despite treatment had higher P-gp levels compared with inactive-SLE after treatment (78.02 ng/mL ± 114.11 vs. 33.75 ng/mL ± 41.11; p = 0.018) or versus reference group subjects (30.56 ng/mL ± 28.92; p = 0.011). P-gp levels correlated with the scores of SLEDAI (r = 0.26; p = 0.01), Mexican-SLEDAI (MEX-SLEDAI) (r = 0.32; p = 0.002), SLICC/ACR damage index (r = 0.47; p < 0.001), and with prednisone doses (r = 0.33; p = 0.001). In the multivariate model, the high P-gp levels were associated with SLICC/ACR score (p = 0.001), and SLEDAI score (p = 0.014). Our findings support a relationship between serum P-gp levels and SLE with disease activity despite treatment, but it requires further validation in longitudinal studies.

Type I Interferon-Mediated Skewing of the Serotonin Synthesis Is Associated with Severe Disease in Systemic Lupus Erythematosus

PubMed Central

Lood, Christian; Tydén, Helena; Gullstrand, Birgitta; Klint, Cecilia; Wenglén, Christina; Nielsen, Christoffer T.; Heegaard, Niels H. H.; Jönsen, Andreas; Kahn, Robin; Bengtsson, Anders A.

2015-01-01

Serotonin, a highly pro-inflammatory molecule released by activated platelets, is formed by tryptophan. Tryptophan is also needed in the production of kynurenine, a process mediated by the type I interferon (IFN)-regulated rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO). The aim of this study was to investigate levels of serotonin in patients with the autoimmune disease systemic lupus erythematosus (SLE), association to clinical phenotype and possible involvement of IDO in regulation of serotonin synthesis. Serotonin levels were measured in serum and plasma from patients with SLE (n=148) and healthy volunteers (n=79) by liquid chromatography and ELISA, as well as intracellularly in platelets by flow cytometry. We found that SLE patients had decreased serotonin levels in serum (p=0.01) and platelets (p<0.0001) as compared to healthy individuals. SLE patients with ongoing type I IFN activity, as determined by an in-house reporter assay, had decreased serum levels of serotonin (p=0.0008) as well as increased IDO activity (p<0.0001), as determined by the kynurenine/tryptophan ratio measured by liquid chromatography. Furthermore, SLE sera induced IDO expression in WISH cells in a type I IFN-dependent manner (p=0.008). Also platelet activation contributed to reduce overall availability of serotonin levels in platelets and serum (p<0.05). Decreased serum serotonin levels were associated with severe SLE with presence of anti-dsDNA antibodies and nephritis. In all, reduced serum serotonin levels in SLE patients were related to severe disease phenotype, including nephritis, suggesting involvement of important immunopathological processes. Further, our data suggest that type I IFNs, present in SLE sera, are able to up-regulate IDO expression, which may lead to decreased serum serotonin levels. PMID:25897671

Analysis of Serum Interleukin (IL)-1β and IL-18 in Systemic Lupus Erythematosus.

PubMed

Mende, Rachel; Vincent, Fabien B; Kandane-Rathnayake, Rangi; Koelmeyer, Rachel; Lin, Emily; Chang, Janet; Hoi, Alberta Y; Morand, Eric F; Harris, James; Lang, Tali

2018-01-01

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by biological and clinical heterogeneity. The interleukin (IL)-1 superfamily is a group of innate cytokines that contribute to pathogenesis in many autoimmune diseases. IL-1β and IL-18 are two members that have been shown to play a role in murine lupus-like models, but their role in human SLE remains poorly understood. Here, IL-1β and IL-18 were quantified by enzyme-linked immunosorbent assay in the serum of healthy controls (HCs) and SLE patients from a prospectively followed cohort. Disease activity and organ damage were assessed using SLE disease activity index 2000 (SLEDAI-2K) and SLE damage index scores (SDI), respectively. 184 SLE patients (mean age 44.9 years, 91% female, 56% double-stranded deoxyribonucleic acid positive) were compared to 52 HC. SLE patients had median [IQR] SLEDAI-2K of 4 [2,6], and SDI of 1 [0-2]. Serum IL-18 levels were statistically significantly higher in SLE patients compared to HCs. Univariable linear regression analyses showed that patients with active renal disease or irreversible organ damage had statistically significantly elevated serum IL-18 levels. The association between serum IL-18 and active renal disease was confirmed in multivariable analysis after adjusting for ethnicity and organ damage. High baseline serum IL-18 levels were associated with organ damage at the subsequent visit. Serum IL-1β levels were not significantly elevated in SLE patients when compared to HCs and had no association with overall or organ-specific disease activity or organ damage in cross-sectional and longitudinal analyses. Our data suggest that serum IL-18 and IL-1β have different clinical implications in SLE, with IL-18 being potentially associated with active renal disease.

Reticulocytes bearing C4d as biomarkers of disease activity for systemic lupus erythematosus.

PubMed

Liu, Chau-Ching; Manzi, Susan; Kao, Amy H; Navratil, Jeannine S; Ruffing, Margie J; Ahearn, Joseph M

2005-10-01

There is an urgent need for biomarkers with which to monitor disease activity in patients with systemic lupus erythematosus (SLE). We recently showed that abnormal levels of C4d, an activation-derived fragment of complement component C4, are deposited on the surface of erythrocytes from patients with SLE. This study focused on reticulocytes, the youngest and shortest-lived erythrocytes (lifespan 24-48 hours), with the objective of testing our hypothesis that when reticulocytes emerge from the bone marrow, they are immediately exposed to and acquire C4d at levels proportionate to the extent of complement activation at that time, thereby reflecting disease activity in SLE. We conducted a cross-sectional study of 156 patients with SLE, 140 patients with other diseases, and 159 healthy controls. Levels of C4d on the surface of reticulocytes were examined using a 2-color flow cytometric assay. The results were analyzed for correlations with SLE disease activity. A wide range of increased levels of reticulocyte C4d was specifically detected in SLE patients. These levels fluctuated in SLE patients and correlated with clinical disease activity, as determined by the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus Activity Measure (SLAM). Specifically, in cross-sectional analyses, patients with reticulocyte C4d levels in the highest quartile compared with those in the lowest quartile had significantly higher SELENA-SLEDAI (P = 0.00002) and SLAM (P = 0.02) scores. Longitudinal observation demonstrated that the reticulocyte C4d levels changed in relation to the clinical course in individual patients. These findings support our hypothesis that C4d-bearing reticulocytes may serve as biomarkers of disease activity in patients with SLE.

Plasma DNA aberrations in systemic lupus erythematosus revealed by genomic and methylomic sequencing

PubMed Central

Chan, Rebecca W. Y.; Jiang, Peiyong; Peng, Xianlu; Tam, Lai-Shan; Liao, Gary J. W.; Li, Edmund K. M.; Wong, Priscilla C. H.; Sun, Hao; Chan, K. C. Allen; Chiu, Rossa W. K.; Lo, Y. M. Dennis

2014-01-01

We performed a high-resolution analysis of the biological characteristics of plasma DNA in systemic lupus erythematosus (SLE) patients using massively parallel genomic and methylomic sequencing. A number of plasma DNA abnormalities were found. First, aberrations in measured genomic representations (MGRs) were identified in the plasma DNA of SLE patients. The extent of the aberrations in MGRs correlated with anti-double–stranded DNA (anti-dsDNA) antibody level. Second, the plasma DNA of active SLE patients exhibited skewed molecular size-distribution profiles with a significantly increased proportion of short DNA fragments. The extent of plasma DNA shortening in SLE patients correlated with the SLE disease activity index (SLEDAI) and anti-dsDNA antibody level. Third, the plasma DNA of active SLE patients showed decreased methylation densities. The extent of hypomethylation correlated with SLEDAI and anti-dsDNA antibody level. To explore the impact of anti-dsDNA antibody on plasma DNA in SLE, a column-based protein G capture approach was used to fractionate the IgG-bound and non–IgG-bound DNA in plasma. Compared with healthy individuals, SLE patients had higher concentrations of IgG-bound DNA in plasma. More IgG binding occurs at genomic locations showing increased MGRs. Furthermore, the IgG-bound plasma DNA was shorter in size and more hypomethylated than the non–IgG-bound plasma DNA. These observations have enhanced our understanding of the spectrum of plasma DNA aberrations in SLE and may provide new molecular markers for SLE. Our results also suggest that caution should be exercised when interpreting plasma DNA-based noninvasive prenatal testing and cancer testing conducted for SLE patients. PMID:25427797

Decreased SAP expression in T cells from patients with SLE contributes to early signaling abnormalities and reduced IL-2 production

PubMed Central

Karampetsou, Maria P.; Comte, Denis; Kis-Toth, Katalin; Terhorst, Cox; Kyttaris, Vasileios C.; Tsokos, George C.

2016-01-01

T cells from patients with systemic lupus erythematosus (SLE) display a number of functions including increased early signaling events following engagement of the T cell receptor (TCR). Signaling lymphocytic activation molecule family (SLAMF) cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating immune response. Here we present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and 3 men with SLE independently of disease activity. In SLE T cells the SAP protein is also subject to increased degradation by a caspase-3. Forced expression of SAP in SLE T cells simultaneously heightened IL-2 production, calcium (Ca2+) responses and tyrosine phosphorylation of a number of proteins. Exposure of normal T cells to SLE serum IgG, known to contain anti-CD3/TCR antibodies, resulted in SAP downregulation. We conclude that SLE T cells display reduced levels of the adaptor protein SAP probably as a result of continuous T cell activation and degradation by caspase-3. Restoration of SAP levels in SLE T cells corrects the overexcitable lupus T cell phenotype. PMID:27183584

High occurrence of in vitro apoptosis of lymphocytes induced by serum from systemic lupus erythematosus patients is associated with increased serum levels of anti-C1q autoantibodies.

PubMed

Hasan, Siti Idayu; Mohd Ashari, Noor Suryani; Mohd Daud, Kamaliah; Che Husin, Che Maraina

2013-08-01

The ethiopathogenesis of increased apoptosis of lymphocytes in systemic lupus erythematosus (SLE) is still incompletely understood but anti-C1q autoantibodies have been shown to induce apoptosis in lymphocytes from healthy donors and certain cell lines. This study was undertaken to investigate the relationship between peripheral lymphocyte apoptosis and serum levels of anti-C1q autoantibodies in SLE patients. The sera of 124 patients with SLE involving 62 active SLE and 62 inactive SLE, fulfilling America College of Rheumatology (ACR) classification criteria for SLE (1997) were incubated with peripheral blood lymphocytes of healthy donors. The results were compared with 124 sex- and age-matched normal controls. Apoptotic lymphocytes (AL) were detected by flow cytometry using annexin V and propidium iodide binding. Anti-C1q autoantibodies were detected by an enzyme-linked immunoassay kit for all SLE patients. Results demonstrated that the percentage of AL in the peripheral blood of active SLE patients was significantly higher (n = 62, 34.95 ± 12.78%) than that of the inactive SLE patients (n = 62, 30.69 ± 10.13%, P = 0.042, 95%CI = 0.16-8.36) and normal controls (n = 124, 27.92 ± 10.22%, P = 0.001, 95%CI = 3.33-10.73). The percentage of AL significantly correlated with serum levels of anti-C1q autoantibodies in the active SLE patients (r = 0.263, P = 0.039) but not in the inactive SLE patients (r = 0.170, P = 0.185). The results of this study suggest that increased serum levels of anti-C1q autoantibodies are responsible for apoptosis and may play a pathogenic role in SLE patients, especially in active disease. © 2013 The Authors International Journal of Rheumatic Diseases © 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Differences of serum procalcitonin levels between bacterial infection and flare in systemic lupus erythematosus patients

NASA Astrophysics Data System (ADS)

Patrick, J.; Marpaung, B.; Ginting, Y.

2018-03-01

Differentiate bacterial infections from flare in SLE patients is difficult to do because clinical symptoms of infection is similar to flare. SLE patients with infection require antibiotic therapy with decreased doses of immunosuppressant while in flare diseases require increased immunosuppressant. Procalcitonin (PCT), a biological marker, increased in serum patients with bacterial infections and expected to be a solution of problem. The aim of this study was to examine the function of PCT serum as marker to differentiate bacterial infection and flare in SLE patients. This cross-sectional study was conducted in Adam Malik Hospital from January-July 2017. We examined 80 patients SLE flare (MEX-SLEDAI>5), screen PCT and culture according to focal infection. Data were statistically analyzed. 80 SLE patients divided into 2 groups: bacterial infection group (31 patients) and non-infection/flare group (49 patients). Median PCT levels of bacterial infection group was 1.66 (0.04-8.45)ng/ml while flare group was 0.12 (0.02-0.81)ng/ml. There was significant difference of serum Procalcitonin level between bacterial infection and flare group in SLE patients (p=0.001). Procalcitonin serum levels can be used as a biomarker to differentiate bacterial infections and flare in SLE patients.

Pentraxin-3 levels are associated with vasculitis and disease activity in childhood-onset systemic lupus erythematosus.

PubMed

Sahin, S; Adrovic, A; Barut, K; Durmus, S; Gelisgen, R; Uzun, H; Kasapcopur, O

2017-09-01

Objectives Childhood-onset systemic lupus erythematosus (cSLE) is a multisystemic autoimmune disease characterized by inflammatory organ damage by means of vasculitis. Pentraxin-3 (PTX3) is expressed locally at the sites of inflammatory processes, predominantly from endothelial cells. In adult studies, PTX3 has shown to be an indicator of active vasculitis both in large-vessel and small-vessel vasculitides, as well as in SLE. Moreover, in SLE it has found to be correlated with disease activity, and with some of the clinical manifestations and laboratory parameters. We aimed to ascertain if PTX3 might be a significant mediator in cSLE and if it might indicate active vasculitis during the course of the disease. Methods Serum PTX3 levels were measured in 76 patients with cSLE and 41 healthy subjects. We have investigated its relation with disease activity, damage, clinical features, laboratory parameters and medications. Results Serum levels of PTX3 were found to be increased in cSLE compared to healthy controls (mean ± SD; 10.6 ± 8.2 ng/mL vs 2.7 ± 1.3 ng/mL, p < 0.001). PTX3 concentrations were also in correlation with SLEDAI-2K ( r = 0.57, p < 0.001). When viewed from the clinical perspective, serum PTX3 levels were significantly higher only in patients with active vasculitis ( p < 0.001), Raynaud phenomenon ( p = 0.006) and mucocutaneous manifestations ( p < 0.001). However, an association between PTX3 and age, age at disease onset, disease duration, complement levels, PedSDI score (pediatric version of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), ESR, CRP, procalcitonin levels, anti-ds DNA antibody, anticardiolipin antibodies was not detected. Conclusions Patients with cSLE have increased levels of serum PTX3 compared to healthy controls. Thus, serum PTX-3 level might be a significant mediator in cSLE. Apart from these, the results support that PTX3 reflects active cutaneous vasculitis in cSLE and correlates with disease activity.

Partial construction of apoptotic pathway in PBMC obtained from active SLE patients and the significance of plasma TNF-alpha on this pathway.

PubMed

Pitidhammabhorn, Dhanesh; Kantachuvesiri, Surasak; Totemchokchyakarn, Kitti; Kitiyanant, Yindee; Ubol, Sukathida

2006-09-01

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that affects various organs and systems. Increased apoptosis, together with defects in the uptake of apoptotic bodies, are thought to have a pathogenic role in SLE. By detection of chromatin condensation, 30% of apoptosis was detected in peripheral blood mononuclear cells (PBMC) from Thai patients with active SLE. Therefore, understanding of the molecular processes in PBMC apoptosis may allow us to gain insight into pathophysiology of SLE. Thus, genes involved in the apoptosis of PBMC from these patients were investigated ex vivo by cDNA array analysis. Seventeen apoptosis-related genes were stimulated in active SLE, more than twofold higher than in inactive SLE. These genes are classified into six groups, namely death receptors, death ligands, caspases, bcl-family, and neutral proteases and genes involved in endoplasmic reticulum stress-mediated apoptosis, such as caspase-4 and GADD153. Among those stimulated genes, tumor necrosis factor (TNF) and the TNF-receptor family were drastically up-regulated 60- and 19-fold higher than in healthy controls, respectively. Moreover, the degree of apoptosis correlated with the level of TNF-alpha in plasma, suggesting that the TNF family plays a role in the induction of apoptosis in SLE. To verify this hypothesis, PBMC from healthy individuals were treated with plasma from active SLE patients in the presence or absence of etanercept, a TNF inhibitor. In the presence of etanercept, active SLE plasma reduced the level of apoptosis to 26.43%. In conclusion, massive apoptotic death of PBMC occurred during the active stage of SLE. The molecular pathway of SLE-PBMC apoptosis was mediated at least via TNF/TNFR signaling pathway, which was confirmed by functional test of TNF-alpha in SLE patients' plasma.

[Diagnostic significance of anti-collectin 11 in systemic lupus erythematosus].

PubMed

Deng, X L; Zhong, L J; Sun, L; Li, C H; Liu, X Y

2016-12-18

To analyze the role of anti-collectin 11 in the diagnosis of systemic lupus erythematosus (SLE) and in the evaluation of disease activity. This was a cross-sectional study. Five groups of patients were enrolled: SLE active (SLE disease activity index-2000,SLEDAI-2000≥9), SLE remission (SLEDAI-2000≤4 and there was no organ involvement), rheumatoid arthritis (RA), primary Sjogren Syndrome (SS) and healthy control (HC). Serum anti-collectin 11 was detected in all the groups by ELISA. One-way ANOVA analysis and LSD-t-test as post-hoc analysis were used to compare the levels of anti-collectin 11 among all the groups. Receiver operating characteristic (ROC) curve and the area under curve (AUC) were used to analyze the value of anti-collectin 11 in the diagnosis of SLE. In the study, 30 patients were enrolled in each group, including 13 males and 137 females with an average age of (34±14) years (18-77 years). The age and gender of the other three groups were comparable to the two SLE groups. The difference of serum anti-collectin 11 between the SLE active group and SLE remission group was not statistically significant (88.8±16.8 vs. 89.7±24.7, P=0.896). The level of serum anti-collectin 11 was significantly higher in SLE group (as a whole) (89.1±19.4) than in RA group (49.1±22.0), SS group (56.9±30.1) and HC group (72.7±24.6) (P<0.001, P<0.001, P=0.007, respectively). The AUC was 0.806 for the diagnosis of SLE by serum anti-collectin 11. Further descriptive analysis showed that the positive rate of anti-collectin 11 was very high in the patients of SLE in whom both anti-double-stranded DNA (dsDNA) and Sm antibody were negative. The nervous system and gastrointestinal system involvement were the most common in the patients with positive anti-collectin 11. The level of serum anti-collectin 11 was significantly higher in SLE than in RA, SS and HC. anti-collectin 11 antibody had a relatively high value in the diagnosis of SLE and it might have some complementary function in the diagnosis of SLE. It might be a relatively specific autoantibody for SLE.

Cognitive dysfunction in antiphospholipid antibody (aPL)-negative systemic lupus erythematosus (SLE) versus aPL-positive non-SLE patients.

PubMed

Kozora, Elizabeth; Erkan, Doruk; Zhang, Lening; Zimmerman, Robert; Ramon, Glendalee; Ulug, Aziz M; Lockshin, Michael D

2014-01-01

The aim of this study was to compare the cognitive function of antiphospholipid antibody (aPL)-negative systemic lupus erythematosus (SLE) and aPL-positive non-SLE patients. Twenty aPL-negative SLE and 20 aPL-positive non-SLE female patients with no history of overt neuropsychiatric manifestations took standardised cognitive tests of learning and memory, attention and working memory, executive functions, verbal fluency, visuoconstruction, and motor function. The primary outcome measure was an established global cognitive impairment index (CII). Cranial magnetic resonance imaging (MRI) was also obtained on all patients. Twelve of 20 (60%) of the SLE and 8/20 (40%) of the aPL-positive patients had global cognitive impairment on CII; there were no group differences on CII or on individual measures. Cognitive impairment was not associated with duration of disease, level of disease activity, or prednisone use. No correlations were found between clinical disease factors and cognitive impairment, and neither group showed an association between incidental or major MRI abnormalities and cognitive dysfunction. Both aPL-negative SLE and aPL-positive non-SLE patients, without other overt neuropsychiatric disease, demonstrated high levels of cognitive impairment. No clinical, serologic, or radiologic characteristics were associated with cognitive impairment. Cognitive dysfunction is common in APS and in SLE, but its mechanisms remain unknown.

Genetic Variation near IRF8 is Associated with Serologic and Cytokine Profiles in Systemic Lupus Erythematosus and Multiple Sclerosis

PubMed Central

Chrabot, Beverly S.; Kariuki, Silvia N.; Zervou, Maria I.; Feng, Xuan; Arrington, Jasmine; Jolly, Meenakshi; Boumpas, Dimitrios T.; Reder, Anthony T.; Goulielmos, George N.; Niewold, Timothy B.

2013-01-01

Alleles of IRF8 are associated with susceptibility to both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). While high type I interferon (IFN) is thought to be causal in SLE, type I IFN is used as a therapy in MS. We investigated whether IRF8 alleles were associated with type I IFN levels or serologic profiles in SLE and MS. Alleles which have been previously associated with SLE or MS were genotyped in SLE and MS patients. The MS-associated rs17445836G allele was associated with anti-dsDNA autoantibodies in SLE patients (meta-analysis OR=1.92). The same allele was associated with decreased serum IFN activity in SLE patients with anti-dsDNA antibodies, and with decreased type I IFN-induced gene expression in PBMC from anti-dsDNA negative SLE patients. In secondary progressive MS patients, rs17445836G was associated with decreased serum type I IFN. Rs17445836G was associated with increased IRF8 expression in SLE patient B cells. In summary, IRF8 rs17445836G is associated with human autoimmune disease characterized by low type I IFN levels, and this may have pharmacogenetic relevance as type I IFN is modulated in SLE and MS. The association with autoantibodies and increased IRF8 expression in B cells supports a role for rs17445836G in humoral tolerance. PMID:23965942

Elevated Concentrations of Serum Immunoglobulin Free Light Chains in Systemic Lupus Erythematosus Patients in Relation to Disease Activity, Inflammatory Status, B Cell Activity and Epstein-Barr Virus Antibodies

PubMed Central

Draborg, Anette H.; Lydolph, Magnus C.; Westergaard, Marie; Olesen Larsen, Severin; Nielsen, Christoffer T.; Duus, Karen; Jacobsen, Søren; Houen, Gunnar

2015-01-01

Objective In this study, we examined the concentration of serum immunoglobulin free light chains (FLCs) in systemic lupus erythematosus (SLE) patients and investigated its association with various disease parameters in order to evaluate the role of FLCs as a potential biomarker in SLE. Furthermore, FLCs’ association with Epstein-Barr virus (EBV) antibodies was examined. Methods Using a nephelometric assay, κFLC and λFLC concentrations were quantified in sera from 45 SLE patients and 40 healthy controls. SLE patients with renal insufficiency were excluded in order to preclude high concentrations of serum FLCs due to decreased clearance. Results Serum FLC concentrations were significantly elevated in SLE patients compared to healthy controls (p<0.0001) also after adjusting for Ig levels (p<0.0001). The concentration of serum FLCs correlated with a global disease activity (SLE disease activity index (SLEDAI)) score of the SLE patients (r = 0.399, p = 0.007). Furthermore, concentrations of FLCs correlated with titers of dsDNA antibodies (r = 0.383, p = 0.009), and FLC levels and SLEDAI scores correlated in the anti-dsDNA-positive SLE patients, but not in anti-dsDNA-negative SLE patients. Total immunoglobulin (IgG and IgA) concentrations correlated with FLC concentrations and elevated FLC levels were additionally shown to associate with the inflammatory marker C-reactive protein and also with complement consumption determined by low C4 in SLE patients. Collectively, results indicated that elevated serum FLCs reflects increased B cell activity in relation to inflammation. SLE patients had an increased seropositivity of EBV-directed antibodies that did not associate with elevated FLC concentrations. An explanation for this could be that serum FLC concentrations reflect the current EBV activity (reactivation) whereas EBV-directed antibodies reflect the extent of previous infection/reactivations. Conclusion SLE patients have elevated concentrations of serum FLCs that correlate with global disease activity scores and especially serologic markers for active disease. These findings are suggestive of circulating FLCs having potential as a new supplementary serologic biomarker in SLE. PMID:26402865

Visceral leishmaniasis mimicking systemic lupus erythematosus: Case series and a systematic literature review.

PubMed

Santana, Iuri Usêda; Dias, Blenda; Nunes, Eduardo Araújo Santana; Rocha, Francisco Airton Castro da; Silva, Francisco Saraiva; Santiago, Mittermayer Barreto

2015-06-01

Systemic lupus erythematosus (SLE) is an autoimmune disease that may present manifestations that resemble other diseases. Visceral leishmaniasis (VL) is a parasitic infection whose hallmarks may mimic SLE symptoms. Here, we report a case series and evaluate the published, scientific evidence of the relationship between SLE and VL infection. To assess original studies reporting cases of VL-infected patients presenting manifestations that are capable of leading to inappropriate suspicions of SLE or mimicking an SLE flare, we performed an extensive search in several scientific databases (MEDLINE, LILACS, SciELO, and Scopus). Two authors independently screened all citations and abstracts identified by the search strategy to identify eligible studies. Secondary references were additionally obtained from the selected articles. The literature search identified 53 eligible studies, but only 17 articles met our criteria. Among these, 10 lupus patients with VL mimicking an SLE flare and 18 cases of VL leading to unappropriated suspicions of SLE were described. The most common manifestations in patients infected with VL were intermittent fever, pancytopenia, visceromegaly, and increased serum level of acute phase reactants. The most frequent autoantibodies were antinuclear antibodies, rheumatoid factor, and direct Coombs' test. In endemic areas for VL, the diagnosis of SLE or its exacerbation may be a clinical dilemma. Hepatosplenomegaly or isolated splenomegaly was identified in the majority of the reported cases where VL occurred, leading to unappropriated suspicions of SLE or mimicking an SLE flare. Furthermore, the lack of response to steroids, the normal levels of complement proteins C3 and C4, and the increased level of transaminases suggest a possible infectious origin. Copyright © 2015 Elsevier Inc. All rights reserved.

The relationship between increased levels of Anti-dsDNA with clinical manifestation in patients with SLE in Haji Adam Malik General Hospital Medan

NASA Astrophysics Data System (ADS)

Marpaung, B.; Patrick, J.

2018-03-01

Systemic Lupus Erythematosus (SLE) is an autoimmune rheumatic disease characterized by widespread inflammation and affects any organism the body. Many autoimmune diseases result in autoantibody production, but Anti-dsDNA antibodies are highly specific to SLE. Previous study found that Anti-dsDNA antibodies are associated with severe clinical manifestations of lupus. The aim of this study was to examine the relationship between anti-dsDNA level with clinical features and laboratory findings in SLE patients. This cross-sectional study was conducted in Hospital Haji Adam Malik Medan in May-October 2016.We examine anti-dsDNA, clinical features and kidney laboratory profile in all patient. Data were statistically analyzed.81 SLE patients with median level of anti-dsDNA 294 (6.1-1317). There was no significant relationship between increased level of Anti-dsDNA with clinical manifestations (p>0.05). There were significant relationships between increased level of Anti-dsDNA with renal impairment (p=0.049), urea level (p=0.016), urine protein (p=0.042) and hematology disorder (p=0.005). Arthritis is the most frequent clinical manifestation (96.3%) followed by malar rash (77.8%). Elevated anti-dsDNA level was not related with clinical manifestations but there was significant relationship with hematology disorder, urea, creatinine, and proteinuria in SLE patents.

Altered cellular and humoral immunity to varicella-zoster virus in patients with autoimmune diseases.

PubMed

Rondaan, Christien; de Haan, Aalzen; Horst, Gerda; Hempel, J Cordelia; van Leer, Coretta; Bos, Nicolaas A; van Assen, Sander; Bijl, Marc; Westra, Johanna

2014-11-01

Patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and granulomatosis with polyangiitis (Wegener's) (GPA) have a 3-20-fold increased risk of herpes zoster compared to the general population. The aim of this study was to evaluate if susceptibility is due to decreased levels of cellular and/or humoral immunity to the varicella-zoster virus (VZV). A cross-sectional study of VZV-specific immunity was performed in 38 SLE patients, 33 GPA patients, and 51 healthy controls. Levels of IgG and IgM antibodies to VZV were measured using an in-house glycoprotein enzyme-linked immunosorbent assay (ELISA). Cellular responses to VZV were determined by interferon-γ (IFNγ) enzyme-linked immunospot (ELISpot) assay and carboxyfluorescein succinimidyl ester (CFSE) dye dilution proliferation assay. Levels of IgG antibodies to VZV were increased in SLE patients as compared to healthy controls, but levels of IgM antibodies to VZV were not. Antibody levels in GPA patients did not differ significantly from levels in healthy controls. In response to stimulation with VZV, decreased numbers of IFNγ spot-forming cells were found among SLE patients (although not GPA patients) as compared to healthy controls. Proliferation of CD4+ T cells in response to stimulation with VZV was decreased in SLE patients but not GPA patients. SLE patients have increased levels of IgG antibodies against VZV, while cellular immunity is decreased. In GPA patients, antibody levels as well as cellular responses to VZV were comparable to those in healthy controls. These data suggest that increased prevalence of herpes zoster in SLE patients is due to a poor cellular response. Vaccination strategies should aim to boost cellular immunity against VZV. Copyright © 2014 by the American College of Rheumatology.

Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort

PubMed Central

Willis, R; Seif, AM; McGwin, G; Martinez-Martinez, LA; González, EB; Dang, N; Papalardo, E; Liu, J; Vilá, LM; Reveille, JD; Alarcón, GS; Pierangeli, SS

2013-01-01

Objective We sought to determine the effect of hydroxychloroquine therapy on the levels proinflammatory/prothrombotic markers and disease activity scores in patients with systemic lupus erythematosus (SLE) in a multiethnic, multi-center cohort (LUMINA). Methods Plasma/serum samples from SLE patients (n=35) were evaluated at baseline and after hydroxychloroquine treatment. Disease activity was assessed using SLAM-R scores. Interferon (IFN)-α2, interleukin (IL)-1β, IL-6, IL-8, inducible protein (IP)-10, monocyte chemotactic protein-1, tumor necrosis factor (TNF)-α and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Anticardiolipin antibodies were evaluated using ELISA assays. Thirty-two frequency-matched plasma/serum samples from healthy donors were used as controls. Results Levels of IL-6, IP-10, sCD40L, IFN-α and TNF-α were significantly elevated in SLE patients versus controls. There was a positive but moderate correlation between SLAM-R scores at baseline and levels of IFN-α (p=0.0546). Hydroxychloroquine therapy resulted in a significant decrease in SLAM-R scores (p=0.0157), and the decrease in SLAM-R after hydroxychloroquine therapy strongly correlated with decreases in IFN-α (p=0.0087). Conclusions Hydroxychloroquine therapy resulted in significant clinical improvement in SLE patients, which strongly correlated with reductions in IFN-α levels. This indicates an important role for the inhibition of endogenous TLR activation in the action of hydroxychloroquine in SLE and provides additional evidence for the importance of type I interferons in the pathogenesis of SLE. This study underscores the use of hydroxychloroquine in the treatment of SLE. PMID:22343096

IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus

PubMed Central

Zhao, Ming; Zhou, Yin; Zhu, Bochen; Wan, Mengjie; Jiang, Tingting; Tan, Qiqun; Liu, Yan; Jiang, Juqing; Luo, Shuaihantian; Tan, Yixin; Wu, Haijing; Renauer, Paul; Gutiérrez, Maria del Mar Ayala; Palma, Maria Jesús Castillo; Castro, Rafaela Ortega; Fernández-Roldán, Concepción; Raya, Enrique; Faria, Raquel; Carvalho, Claudia; Alarcón-Riquelme, Marta E; Xiang, Zhongyuan; Chen, Jinwei; Li, Fen; Ling, Guanghui; Zhao, Hongjun; Liao, Xiangping; Lin, Youkun; Sawalha, Amr H; Lu, Qianjin

2016-01-01

Objective Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease with limited reliable diagnostic biomarkers. We investigated whether gene methylation could meet sensitivity and specificity criteria for a robust biomarker. Methods IFI44L promoter methylation was examined using DNA samples from a discovery set including 377 patients with SLE, 358 healthy controls (HCs) and 353 patients with rheumatoid arthritis (RA). Two independent sets including 1144 patients with SLE, 1350 HCs, 429 patients with RA and 199 patients with primary Sjögren’s syndrome (pSS) were used for validation. Results Significant hypomethylation of two CpG sites within IFI44L promoter, Site1 (Chr1: 79 085 222) and Site2 (Chr1: 79 085 250; cg06872964), was identified in patients with SLE compared with HCs, patients with RA and patients with pSS. In a comparison between patients with SLE and HCs included in the first validation cohort, Site1 methylation had a sensitivity of 93.6% and a specificity of 96.8% at a cut-off methylation level of 75.5% and Site2 methylation had a sensitivity of 94.1% and a specificity of 98.2% at a cut-off methylation level of 25.5%. The IFI44L promoter methylation marker was also validated in an European-derived cohort. In addition, the methylation levels of Site1 and Site2 within IFI44L promoter were significantly lower in patients with SLE with renal damage than those without renal damage. Patients with SLE showed significantly increased methylation levels of Site1 and Site2 during remission compared with active stage. Conclusions The methylation level of IFI44L promoter can distinguish patients with SLE from healthy persons and other autoimmune diseases, and is a highly sensitive and specific diagnostic marker for SLE. PMID:26787370

IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus.

PubMed

Zhao, Ming; Zhou, Yin; Zhu, Bochen; Wan, Mengjie; Jiang, Tingting; Tan, Qiqun; Liu, Yan; Jiang, Juqing; Luo, Shuaihantian; Tan, Yixin; Wu, Haijing; Renauer, Paul; Del Mar Ayala Gutiérrez, Maria; Castillo Palma, Maria Jesús; Ortega Castro, Rafaela; Fernández-Roldán, Concepción; Raya, Enrique; Faria, Raquel; Carvalho, Claudia; Alarcón-Riquelme, Marta E; Xiang, Zhongyuan; Chen, Jinwei; Li, Fen; Ling, Guanghui; Zhao, Hongjun; Liao, Xiangping; Lin, Youkun; Sawalha, Amr H; Lu, Qianjin

2016-11-01

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease with limited reliable diagnostic biomarkers. We investigated whether gene methylation could meet sensitivity and specificity criteria for a robust biomarker. IFI44L promoter methylation was examined using DNA samples from a discovery set including 377 patients with SLE, 358 healthy controls (HCs) and 353 patients with rheumatoid arthritis (RA). Two independent sets including 1144 patients with SLE, 1350 HCs, 429 patients with RA and 199 patients with primary Sjögren's syndrome (pSS) were used for validation. Significant hypomethylation of two CpG sites within IFI44L promoter, Site1 (Chr1: 79 085 222) and Site2 (Chr1: 79 085 250; cg06872964), was identified in patients with SLE compared with HCs, patients with RA and patients with pSS. In a comparison between patients with SLE and HCs included in the first validation cohort, Site1 methylation had a sensitivity of 93.6% and a specificity of 96.8% at a cut-off methylation level of 75.5% and Site2 methylation had a sensitivity of 94.1% and a specificity of 98.2% at a cut-off methylation level of 25.5%. The IFI44L promoter methylation marker was also validated in an European-derived cohort. In addition, the methylation levels of Site1 and Site2 within IFI44L promoter were significantly lower in patients with SLE with renal damage than those without renal damage. Patients with SLE showed significantly increased methylation levels of Site1 and Site2 during remission compared with active stage. The methylation level of IFI44L promoter can distinguish patients with SLE from healthy persons and other autoimmune diseases, and is a highly sensitive and specific diagnostic marker for SLE. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

The effect of acute physical exercise on cytokine levels in patients with systemic lupus erythematosus.

PubMed

da Silva, A E; dos Reis-Neto, E Torres; da Silva, N P; Sato, E I

2013-12-01

Acute exercise increases IL-6, IL-10 and TNF-α levels in healthy subjects. There is no study evaluating the effect of exercise on cytokines level in systemic lupus erythematosus (SLE) patients. Our aim was to assess IL-10, IL-6 and TNF-α levels at baseline and after acute physical exercise in patients with SLE. In total, 27 female SLE patients and 30 healthy controls were evaluated. Serum levels of IL-10, IL-6 and TNF-α at baseline and soon after the ergospirometric test were measured by ELISA test. Student's t-tests and Mann-Whitney test were used for intra- and inter-group comparisons; p values <0.05 were considered significant. Patients with SLE presented worse ergospirometric parameters compared with controls: VO2max (25.78 ± 5.51 vs. 32.74 ± 5.85 ml/kg/min, p < 0.001); maximum heart rate (174.18 ± 12.36 vs. 185.15 ± 2.07 bpm, p = 0.001); maximum ventilation (65.51 ± 15.68 vs. 80.48 ± 18.98 l/min, p = 0.001) and maximum speed (7.70 ± 1.24 vs. 9.40 ± 1.22 km/h, p < 0.001). At baseline, SLE patients presented higher levels of IL-6 (2.38 ± 1.70 vs. 1.71 ± 0.29 pg/ml, p = 0.035) and IL-10 (1.09 ± 1.55 vs. 0.30 ± 0.11 pg/ml, p = 0.037) than controls. Acute exercise in controls increased IL-6 level (1.71 ± 0.29 vs. 2.01 ± 0.27 pg/ml, p = 0.003) without change in IL-10 and TNF-α levels. However, no significant change in cytokine levels was observed in SLE patients after acute exercise. This is the first study evaluating the effect of acute exercise on cytokine levels in patients with SLE. In contrast to healthy controls, acute physical exercise did not increase the levels of IL-6 in patients with SLE, and seems to be safe in those patients with inactive or mild active disease.

Associations of B cell-activating factor (BAFF) and anti-BAFF autoantibodies with disease activity in multi-ethnic Asian systemic lupus erythematosus patients in Singapore.

PubMed

Howe, H S; Thong, B Y H; Kong, K O; Chng, H H; Lian, T Y; Chia, F L; Tay, K S S; Lau, T C; Law, W G; Koh, E T; Leung, B P

2017-09-01

To measure the levels of B cell-activating factor (BAFF) and endogenous anti-BAFF autoantibodies in a cohort of multi-ethnic Asian systemic lupus erythematosus (SLE) patients in Singapore, to determine their correlation with disease activity. Serum samples from 121 SLE patients and 24 age- and sex-matched healthy controls were assayed for BAFF and anti-BAFF immunoglobulin (Ig)G antibody levels by enzyme-linked immunosorbent assay (ELISA). The lowest reliable detection limit for anti-BAFF-IgG antibody levels was defined as 2 standard deviations (s.d.) from blank. Correlation of serum BAFF and anti-BAFF IgG levels with disease activity [scored by SLE Activity Measure revised (SLAM-R)], and disease manifestations were determined in these 121 patients. SLE patients had elevated BAFF levels compared to controls; mean 820 ± 40 pg/ml and 152 pg ± 45/ml, respectively [mean ± standard error of the mean (s.e.m.), P < 0·01], which were correlated positively with anti-dsDNA antibody levels (r = 0·253, P < 0·03), and SLAM-R scores (r = 0·627, P < 0·01). In addition, SLE patients had significantly higher levels of anti-BAFF IgG, which were correlated negatively with disease activity (r = -0·436, P < 0·01), levels of anti-dsDNA antibody (r = -0·347, P < 0·02) and BAFF (r = -0·459, P < 0·01). The majority of patients in this multi-ethnic Asian SLE cohort had elevated levels of BAFF and anti-BAFF antibodies. Anti-BAFF autoantibody levels correlated negatively with clinical disease activity, anti-dsDNA and BAFF levels, suggesting that they may be disease-modifying. Our results provide further information about the complexity of BAFF pathophysiology in different SLE disease populations and phenotypes, and suggest that studies of the influence of anti-cytokine antibodies in different SLE populations will be required when selecting patients for trials using targeted anti-cytokine therapies. © 2017 British Society for Immunology.

Increased serum levels of S100A8/A9 and S100A12 are associated with cardiovascular disease in patients with inactive systemic lupus erythematosus.

PubMed

Tydén, Helena; Lood, Christian; Gullstrand, Birgitta; Jönsen, Andreas; Nived, Ola; Sturfelt, Gunnar; Truedsson, Lennart; Ivars, Fredrik; Leanderson, Tomas; Bengtsson, Anders A

2013-11-01

Patients with SLE have an increased morbidity and mortality from cardiovascular disease (CVD). The reason for this is not entirely understood, but is believed to be partly related to the long-lasting inflammatory process seen in SLE. The aim of the present study was to investigate whether there is an association between CVD and serum levels of the proinflammatory proteins S100A8/A9 and S100A12 in SLE. Serum levels of S100A8/A9 and S100A12 were measured with ELISA in 237 SLE patients with clinically inactive disease and without infections, as well as in 100 healthy individuals. Cardiovascular manifestations were defined according to the SLICC/ACR Damage Index (SLICC/ACR-DI). Serum levels of S100A8/A9 were elevated in our inactive SLE patients as compared with healthy individuals (P < 0.0001), which was not seen for S100A12 (P = 0.12). SLE patients with a history of CVD had increased serum levels of both S100A8/A9 and S100A12 compared with patients with no CVD or venous thromboembolism (P = 0.003 and P = 0.006, respectively). The presence of organ damage according to SLICC/ACR-DI was associated with an increase in both S100A8/A9 and S100A12 serum levels (P = 0.001 and P = 0.006, respectively). Elevated serum levels of S100A8/A9 and S100A12 may be used as an indicator of severe disease and CVD in SLE, suggesting that SLE patients with elevated serum S100A8/A9 and S100A12 concentrations may benefit from more intense cardiovascular primary preventive strategies and possibly also from more intense and early immunosuppressive treatment.

Hypothalamic-mediated model for systemic lupus erythematosis: relation to hemispheric chemical dominance.

PubMed

Kurup, Ravi Kumar; Kurup, Parameswara Achutha

2003-11-01

The isoprenoid pathway including endogenous digoxin was assessed in systemic lupus erythematosis (SLE). All the patients with SLE were right-handed/left hemispheric dominant by the dichotic listening test. This was also studied for comparison in patients with right hemispheric and left hemispheric dominance. The isoprenoid pathway was upregulated with increased digoxin synthesis in patients with SLE and in those with right hemispheric dominance. In this group of patients (i) the tryptophan catabolites were increased and the tyrosine catabolites reduced, (ii) the dolichol and glycoconjugate levels were elevated, (iii) lysosomal stability was reduced, (iv) ubiquinone levels were low and free radical levels increased, and (v) the membrane cholesterol:phospholipid ratios were increased and membrane glycoconjugates reduced. On the other hand, in patients with left hemispheric dominance the reverse patterns were obtained. The biochemical patterns obtained in SLE is similar to those obtained in left-handed/right hemispheric chemically dominant individuals. But all the patients with SLE were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. SLE occurs in right hemispheric chemically dominant individuals, and is a reflection of altered brain function. The role of the isoprenoid pathway in the pathogenesis of SLE and its relation to hemispheric dominance is discussed.

Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production.

PubMed

Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin; Terhorst, Cox; Kyttaris, Vasileios C; Tsokos, George C

2016-06-15

T cells from patients with systemic lupus erythematosus (SLE) display a number of abnormalities, including increased early signaling events following engagement of the TCR. Signaling lymphocytic activation molecule family cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating the immune response. We present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and three men with SLE, independent of disease activity. In SLE T cells, SAP protein is also subject to increased degradation by caspase-3. Forced expression of SAP in SLE T cells normalized IL-2 production, calcium (Ca(2+)) responses, and tyrosine phosphorylation of a number of proteins. Exposure of normal T cells to SLE serum IgG, known to contain anti-CD3/TCR Abs, resulted in SAP downregulation. We conclude that SLE T cells display reduced levels of the adaptor protein SAP, probably as a result of continuous T cell activation and degradation by caspase-3. Restoration of SAP levels in SLE T cells corrects the overexcitable lupus T cell phenotype. Copyright © 2016 by The American Association of Immunologists, Inc.

Autoantigen microarrays reveal autoantibodies associated with proliferative nephritis and active disease in pediatric systemic lupus erythematosus.

PubMed

Haddon, D James; Diep, Vivian K; Price, Jordan V; Limb, Cindy; Utz, Paul J; Balboni, Imelda

2015-06-17

Pediatric systemic lupus erythematosus (pSLE) patients often initially present with more active and severe disease than adults, including a higher frequency of lupus nephritis. Specific autoantibodies, including anti-C1q, anti-DNA and anti-alpha-actinin, have been associated with kidney involvement in SLE, and DNA antibodies are capable of initiating early-stage lupus nephritis in severe combined immunodeficiency (SCID) mice. Over 100 different autoantibodies have been described in SLE patients, highlighting the need for comprehensive autoantibody profiling. Knowledge of the antibodies associated with pSLE and proliferative nephritis will increase the understanding of SLE pathogenesis, and may aid in monitoring patients for renal flare. We used autoantigen microarrays composed of 140 recombinant or purified antigens to compare the serum autoantibody profiles of new-onset pSLE patients (n = 45) to healthy controls (n = 17). We also compared pSLE patients with biopsy-confirmed class III or IV proliferative nephritis (n = 23) and without significant renal involvement (n = 18). We performed ELISA with selected autoantigens to validate the microarray findings. We created a multiple logistic regression model, based on the ELISA and clinical information, to predict whether a patient had proliferative nephritis, and used a validation cohort (n = 23) and longitudinal samples (88 patient visits) to test its accuracy. Fifty autoantibodies were at significantly higher levels in the sera of pSLE patients compared to healthy controls, including anti-B cell-activating factor (BAFF). High levels of anti-BAFF were associated with active disease. Thirteen serum autoantibodies were present at significantly higher levels in pSLE patients with proliferative nephritis than those without, and we confirmed five autoantigens (dsDNA, C1q, collagens IV and X and aggrecan) by ELISA. Our model, based on ELISA measurements and clinical variables, correctly identified patients with proliferative nephritis with 91 % accuracy. Autoantigen microarrays are an ideal platform for identifying autoantibodies associated with both pSLE and specific clinical manifestations of pSLE. Using multiple regression analysis to integrate autoantibody and clinical data permits accurate prediction of clinical manifestations with complex etiologies in pSLE.

Whole-genome transcription and DNA methylation analysis of peripheral blood mononuclear cells identified aberrant gene regulation pathways in systemic lupus erythematosus.

PubMed

Zhu, Honglin; Mi, Wentao; Luo, Hui; Chen, Tao; Liu, Shengxi; Raman, Indu; Zuo, Xiaoxia; Li, Quan-Zhen

2016-07-13

Recent achievement in genetics and epigenetics has led to the exploration of the pathogenesis of systemic lupus erythematosus (SLE). Identification of differentially expressed genes and their regulatory mechanism(s) at whole-genome level will provide a comprehensive understanding of the development of SLE and its devastating complications, lupus nephritis (LN). We performed whole-genome transcription and DNA methylation analysis in PBMC of 30 SLE patients, including 15 with LN (SLE LN(+)) and 15 without LN (SLE LN(-)), and 25 normal controls (NC) using HumanHT-12 Beadchips and Illumina Human Methy450 chips. The serum proinflammatory cytokines were quantified using Bio-plex Human Cytokine 27-plex assay. Differentially expressed genes and differentially methylated CpG were analyzed with GenomeStudio, R, and SAM software. The association between DNA methylation and gene expression were tested. Gene interaction pathways of the differentially expressed genes were analyzed by IPA software. We identified 552 upregulated genes and 550 downregulated genes in PBMC of SLE. Integration of DNA methylation and gene expression profiling showed that 334 upregulated genes were hypomethylated, and 479 downregulated genes were hypermethylated. Pathway analysis on the differential genes in SLE revealed significant enrichment in interferon (IFN) signaling and toll-like receptor (TLR) signaling pathways. Nine IFN- and seven TLR-related genes were identified and displayed step-wise increase in SLE LN(-) and SLE LN(+). Hypomethylated CpG sites were detected on these genes. The gene expressions for MX1, GPR84, and E2F2 were increased in SLE LN(+) as compared to SLE LN(-) patients. The serum levels of inflammatory cytokines, including IL17A, IP-10, bFGF, TNF-α, IL-6, IL-15, GM-CSF, IL-1RA, IL-5, and IL-12p70, were significantly elevated in SLE compared with NC. The levels of IL-15 and IL1RA correlated with their mRNA expression. The upregulation of IL-15 may be regulated by hypomethylated CpG sites in the promotor region of the gene. Our study has demonstrated that significant number of differential genes in SLE were involved in IFN, TLR signaling pathways, and inflammatory cytokines. The enrichment of differential genes has been associated with aberrant DNA methylation, which may be relevant to the pathogenesis of SLE. Our observations have laid the groundwork for further diagnostic and mechanistic studies of SLE and LN.

Association between circulating transforming growth factor-β1 level and polymorphisms in systemic lupus erythematosus and rheumatoid arthritis: A meta-analysis.

PubMed

Lee, Y H; Bae, S-C

2017-02-22

This study systemically reviewed evidence regarding the relationship between circulating blood transforming growth factor-β1 (TGF-β1) levels and systemic lupus erythematous (SLE) and rheumatoid arthritis (RA), and associations between TGF-β1 polymorphisms and susceptibility to SLE and RA.  We conducted a meta-analysis on the serum/plasma TGF-β1 levels in SLE and RA patients and healthy controls, and the associations between TGF-β1 +869 T/C, +915 C/G, and -509 T/C polymorphisms and SLE or RA risk. Twenty-eight studies were considered in this meta-analysis. Circulating TGF-β1 levels were significantly lower in the SLE group than in controls (SMD = -1.164, 95% CI = -2.257 - -0.070, P = 0.037). Serum/plasma TGF-β1 levels were not significantly different between RA and control groups (SMD = 0.699, 95% CI = -0.379 - 1.717, p = 0.211). No association between TGF-β1 +869 T/C polymorphism and SLE was found. However, meta-analysis showed an association between the TGF-β1 +869 T allele and RA in all subjects (OR = 1.282, 95% CI = 1.118-1.470, P = 3.8 x 10-4). Analysis after stratification by ethnicity indicated that the T allele was significantly associated with RA in Asians and Arabs (OR = 1.429, 95% CI = 1.179-1.733, P = 2.9 x 10-4; OR = 1.352, 95% CI = 1.097-1.668, P = 0.005), but not Europeans. However, no association was found between TGF-β1 +915 G/C or -509 C/T polymorphisms and RA or SLE. Meta-analysis revealed a significantly lower circulating TGF-β1 level in SLE patients, and a significant association between TGF-β1 +869 T/C polymorphism and RA development.

Measurement of interleukin-1 receptor antagonist in patients with systemic lupus erythematosus could predict renal manifestation of the disease.

PubMed

Brugos, Boglarka; Kiss, Emese; Dul, Csaba; Gubisch, Wolfgang; Szegedi, Gyula; Sipka, Sandor; Zeher, Margit

2010-09-01

Interleukin-1 receptor antagonist (IL-1Ra) is a good indicator of disease activity in patients with systemic lupus erythematosus (SLE). Glucocorticosteroids are the most frequently used drugs in SLE. Our goal was to compare IL-1Ra activity in SLE patients with and without renal involvement and to determine the effect of different dosage of glucocorticosteroids used in 17 patients with active SLE without nephritis, 7 patients with inactive lupus nephritis (LN), and 8 patients with active LN, along with 10 healthy controls. IL-1Ra levels were measured in the serum of SLE patients by Human Luminex [100] analyzer. Both in patients with active SLE without nephritis and in patients with LN, serum levels of IL-1Ra (p<0.001) were significantly higher compared with those in the controls. IL-1Ra was significantly higher in patients with active LN than in patients with inactive LN (p = 0.028). The use of methylprednisolone was significantly higher in the active LN group compared with the inactive LN group (p = 0.013). SLE patients with higher IL-1Ra are at lower risk for developing nephritis. The higher doses of glucocorticosteroids needed in active LN could be due to steroid resistance and IL-1Ra polymorphism. Measurement of IL-1Ra levels in SLE patients could help to predict future renal involvement. Copyright 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Evaluation of ovarian reserve tests in women with systemic lupus erythematosus.

PubMed

Ulug, Pasa; Oner, Gokalp; Kasap, Burcu; Akbas, Emin Murat; Ozcicek, Fatih

2014-07-01

Impact of systemic lupus erythematosus (SLE) on fertility may be negative, and ovarian function can be also reduced by autoimmune oophoritis. In this article, we evaluated the ovarian reserve of pre-menopausal women firstly diagnosed with systemic lupus erythematosus (SLE). This was a prospective controlled study which included twenty women with SLE and twenty healthy women as controls in the reproductive age. Basal levels of FSH, estradiol (E2), and LH on cycle day 3 were measured. All participants underwent transvaginal ultrasonographic examination on the third day of their menstrual periods for the determination of ovarian volume (OV) and total antral follicle count (AFC). A significant difference in FSH, LH, and E2 levels was observed between women with SLE and healthy controls. There was a statistically significant reduction in total AFC and OV in SLE group. Age was associated negatively with AFC, whereas positively with FSH and LH. Menstrual irregularity was significantly higher in SLE patients than control. AFC was the most reliable test to show the menstrual irregularity and negatively correlated each other in women with SLE. In this preliminary study, the first in SLE patients, we illustrated that women with SLE had lower ovarian reserves and higher menstrual irregularity compared with healthy controls according to hormonal and ultrasonographical evaluation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Characteristics of pleural effusions in systemic lupus erythematosus: differential diagnosis of lupus pleuritis.

PubMed

Choi, B Y; Yoon, M J; Shin, K; Lee, Y J; Song, Y W

2015-03-01

We investigated the clinical characteristics of pleural effusion in systemic lupus erythematosus (SLE). A prospective analysis of 17 SLE patients with pleural effusion (seven lupus pleuritis, eight transudative effusions and two parapneumonic effusions) was performed. Thirty non-SLE patients with pleural effusion were recruited as controls. A pleural fluid ANA titer ≥1:160 was found in 8/17 (47.1%) SLE patients and none of the 30 non-SLE patients (p = 0.0001). Pleural fluid to serum C3 ratios were significantly lower in SLE than in non-SLE (median (minimum-maximum) 0.29 (0.03-0.43) versus 0.52 (0.26-0.73), p = 0.0002). Among SLE patients, pleural fluid ANA titers ≥1:160 were more frequently found in patients with lupus pleuritis than in those with pleural effusion from causes other than lupus itself (85.7% versus 20.0%, p = 0.0152). Serum CRP levels were significantly increased in patients with lupus pleuritis compared with SLE patients with transudative pleural effusion (2.30 (0.30-5.66) versus 0.7 (0.12-1.47) mg/dl, p = 0.0062). In conclusion, pleural fluid ANA titer and serum CRP levels are significantly increased in lupus pleuritis. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus

PubMed Central

2013-01-01

Introduction Osteopontin (OPN) has been implicated as a mediator of Th17 regulation via type I interferon (IFN) receptor signaling and in macrophage activity at sites of tissue repair. This study assessed whether increased circulating plasma OPN (cOPN) precedes development of organ damage in pediatric systemic lupus erythematosus (pSLE) and compared it to circulating plasma neutrophil gelatinase-associated lipocalin (cNGAL), a predictor of increased SLE disease activity. Methods cOPN and cNGAL were measured in prospectively followed pSLE (n = 42) and adult SLE (aSLE; n = 23) patients and age-matched controls. Time-adjusted cumulative disease activity and disease damage were respectively assessed using adjusted-mean SLE disease activity index (SLEDAI) (AMS) and SLICC/ACR damage index (SDI). Results Compared to controls, elevated cOPN and cNGAL were observed in pSLE and aSLE. cNGAL preceded worsening SLEDAI by 3-6 months (P = 0.04), but was not associated with increased 6-month AMS. High baseline cOPN, which was associated with high IFNalpha activity and expression of autoantibodies to nucleic acids, positively correlated with 6-month AMS (r = 0.51 and 0.52, P = 0.001 and 0.01 in pSLE and aSLE, respectively) and was associated with SDI increase at 12 months in pSLE (P = 0.001). Risk factors for change in SDI in pSLE were cOPN (OR 7.5, 95% CI [2.9-20], P = 0.03), but not cNGAL, cumulative prednisone, disease duration, immunosuppression use, gender or ancestry using univariate and multivariate logistic regression. The area under the curve (AUC) when generating the receiver-operating characteristic (ROC) of baseline cOPN sensitivity and specificity for the indication of SLE patients with an increase of SDI over a 12 month period is 0.543 (95% CI 0.347-0.738; positive predictive value 95% and negative predictive value 38%). Conclusion High circulating OPN levels preceded increased cumulative disease activity and organ damage in SLE patients, especially in pSLE, and its value as a predictor of poor outcome should be further validated in large longitudinal cohorts. PMID:23343383

Serum levels of pregnenolone and 17-hydroxypregnenolone in patients with rheumatoid arthritis and systemic lupus erythematosus: relation to other adrenal hormones.

PubMed

Vogl, Daniela; Falk, Werner; Dorner, Monika; Schölmerich, Jürgen; Straub, Rainer H

2003-02-01

In patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), low levels of adrenal steroids have been repeatedly demonstrated, but the site of alteration has not been exactly described because measurements of serum pregnenolone and 17-hydroxypregnenolone (17OHPreg) together with other adrenal steroids have never been performed. We measured serum levels of adrenal hormones such as pregnenolone, 17OHPreg, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), progesterone (P), 17-hydroxyprogesterone (17OHP), androstenedione (ASD), and cortisol in 24 healthy controls, 24 patients with RA, and 24 patients with SLE. Serum levels of pregnenolone were similar in RA and SLE patients as compared to healthy controls irrespective of prior prednisolone therapy. In all RA and SLE patients (including those with prior prednisolone treatment), serum levels of all measured hormones except pregnenolone were significantly lower as compared to controls. In RA patients without prior prednisolone treatment, serum levels of 17OHPreg, DHEA, cortisol, and ASD were similar to controls, and serum levels of P, 17OHP, and DHEAS were significantly lower as compared to controls. In SLE patients without prior prednisolone treatment, serum levels of 17OHPreg and cortisol were similar, and serum levels of P, 17OHP, ASD, DHEA, and DHEAS were significantly lower as compared to controls. The primary hormone of the adrenal steroid cascade, pregnenolone, is almost normal in RA and SLE irrespective of corticosteroid treatment. In patients with RA, we believe that there is a near normal P450scc reaction and a normal double step P450c17 reaction. In SLE patients, the P450scc reaction also seems normal but the second step of the P450c17 reaction seems to be inhibited. In both diseases, cortisol levels remain relatively stable at the expense of other adrenal hormones. This study revealed distinct changes of steroid pathways that are related to the disease entities.

[Serum levels of vitamin D in systemic lupus erythematosus patients (SLE) and their relationship with disease activity: longitudinal study].

PubMed

García-Carrasco, Mario; Mendoza-Pinto, Claudia; Ayón-Aguilar, Jorge; Soto-Santillán, Pamela; Rodríguez-Gallegos, Alma; Escamilla-Márquez, Marco Antonio; Méndez-Martínez, Socorro

2016-10-01

To determine changes over time of serum levels of 25-hydroxy vitamin D (25(OH)D) in Mexican patients with SLE and their relationship with disease activity. Longitudinal and observational study. Women with SLE were included. Serum levels of 25(OH)D were measured at baseline and after two years; the disease activity was measured with MEX-SLEDAI. Patients with initial suboptimal levels of 25(OH)D received supplements or increased doses of calcitriol. 105 women with SLE were included, mean age 49.4 ± 11 years. Serum levels of 25(OH)D were higher at two years (baseline 20 ± 6.8 vs. follow-up 22.7 ± 7.7; p = < 0.001). There were no differences between disease activity scores at baseline and two years (baseline 1.7 ± 1.9 vs. follow-up 1.1 ± 1.7; p = 0.7). Serum levels of 25(OH)D did not correlate with disease activity during the follow up, p = 0.7. No correlation was found between changes in MEX-SLEDAI scores and serum levels of 25(OH)D, p = 0.87. Mexican women with SLE had increased serum levels of 25(OH)D. No correlation between serum levels of 25(OH)D and disease activity was found.

Serum interleukin-17 in Egyptian children with systemic lupus erythematosus: is it related to pulmonary affection?

PubMed

Hammad, A; Osman, E; Mosaad, Y; Wahba, M

2017-04-01

Objective Pulmonary involvement in paediatric systemic lupus erythematosus (pSLE) is not an uncommon finding; however, subclinical affection occurs more frequently. Many studies have reported that cytokine dysregulation as interleukin-17 (IL-17) over-expression plays a key role in the pathogenesis of systemic lupus erythematosus (SLE). We aim to assess serum levels of IL-17 A and their association with pulmonary involvement in children with SLE. Methods Serum IL-17A levels - determined by solid phase sandwich ELISA - were assessed in forty-two pSLE patients and compared to 45 age-matched healthy controls. All patients were subjected to pulmonary function tests to detect subclinical pulmonary affection. High-resolution CT (HRCT) chest scan was carried out in patients with abnormal pulmonary function tests (PFTs) and those with chronic respiratory symptoms. Results Abnormal PFTs were found in 73% of patients; of them, only 25% had abnormal findings in HRCT chest. Serum levels of IL-17 A were significantly elevated in pSLE patients as compared to healthy controls ( p < 0.001). The serum levels of IL-17 A had a highly significant positive correlation with SLEDAI ( r = 0.811 and p < 0.001) Strong negative correlation was found between serum levels of IL-17A with both FEV1 and FVC ( p < 0.05). Conclusions Serum IL-17A is elevated in pSLE patients, which correlates with disease activity. IL-17 seems to have a possible role in the pathogenesis of subclinical lung affection. Abnormal PFTS may be found in pSLE patients even with normal radiology.

Autoantibodies associated with RNA are more enriched than anti-dsDNA antibodies in circulating immune complexes in SLE.

PubMed

Ahlin, E; Mathsson, L; Eloranta, M-L; Jonsdottir, T; Gunnarsson, I; Rönnblom, L; Rönnelid, J

2012-05-01

To what extent different autoantibodies accumulate in systemic lupus erythematosus (SLE) immune complexes (ICs), and whether such accumulation is associated with disease activity has been investigated. ICs were isolated from SLE sera by both polyethylene glycol (PEG) precipitation and C1q-binding. Autoantibody specificities were determined using a lineblot assay quantified by densitometry. To compare the relative levels of autoantibodies, levels were normalized to the total levels of IgG measured by ELISA in sera and parallel ICs. Samples were investigated both in a cross-sectional design as well as in a paired design with samples obtained during both active and inactive SLE. All investigated autoantibody specificities except anti-dsDNA were enriched in circulating ICs as compared with parallel sera. The group of antibodies against RNA-associated antigens (anti-RNP/Sm, anti-Sm, anti-SSA/Ro60, anti-SSA/Ro52, anti-SSB/La) all exhibited higher median enrichment than the DNA-associated (anti-dsDNA, anti-histones, anti-nucleosomes) or cytoplasmic (anti-ribosomal P) antigens. In particular autoantibodies against RNP/Sm and SSA/Ro52 had the highest degree of enrichment in SLE PEG precipitates. These findings were corroborated by analysis of autoantibody content in C1q-bound ICs. There was no difference in degree of IC accumulation of the investigated autoantibodies during active and inactive SLE. Our findings demonstrate a difference in enrichment between autoantibodies against RNA- and DNA-associated autoantigens in isolated SLE IC, suggesting that the RNA-associated autoantibodies are more prone to form circulating ICs in SLE, in contrast to antibodies against DNA-associated autoantigens such as dsDNA. These finding have implications in understanding mechanisms of differential autoantibody accumulation in target organs in SLE.

Clinical significance of nailfold capillaroscopy in systemic lupus erythematosus: correlation with endothelial cell activation markers and disease activity.

PubMed

Kuryliszyn-Moskal, A; Ciolkiewicz, M; Klimiuk, P A; Sierakowski, S

2009-01-01

To evaluate whether nailfold capillaroscopy (NC) changes are associated with the main serum endothelial cell activation markers and the disease activity of systemic lupus erythematosus (SLE). Serum levels of vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), soluble E-selectin (sE-selectin), and soluble thrombomodulin (sTM) were determined by an enzyme-linked immunosorbent assay (ELISA) in 80 SLE patients and 33 healthy controls. Nailfold capillary abnormalities were seen in 74 out of 80 (92.5%) SLE patients. A normal capillaroscopic pattern or mild changes were found in 33 (41.25%) and moderate/severe abnormalities in 47 (58.75%) of all SLE patients. In SLE patients a capillaroscopic score >1 was more frequently associated with the presence of internal organ involvement (p < 0.001) as well as with immunosuppressive therapy (p < 0.01). Significant differences were found in VEGF (p < 0.001), ET-1 (p < 0.001), sE-selectin (p < 0.01), and sTM (p < 0.001) serum concentrations between SLE patients with a capillaroscopic score > 1 and controls. SLE patients with severe/moderate capillaroscopic abnormalities showed significantly higher VEGF serum levels than patients with mild changes (p < 0.001). Moreover, there was a significant positive correlation between the severity of capillaroscopic changes and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (p < 0.005) as well as between capillaroscopic score and VEGF serum levels (p < 0.001). Our findings confirm the usefulness of NC as a non-invasive technique for the evaluation of microvascular involvement in SLE patients. A relationship between changes in NC, endothelial cell activation markers and clinical features of SLE suggest an important role for microvascular abnormalities in clinical manifestation of the disease.

[Soluble interleukin 2 receptor as activity parameter in serum of systemic and discoid lupus erythematosus].

PubMed

Blum, C; Zillikens, D; Tony, H P; Hartmann, A A; Burg, G

1993-05-01

The evaluation of disease activity in systemic lupus erythematosus (SLE) is important for selection of the appropriate therapeutic regimen. In addition to the clinical picture, various laboratory parameters are taken into account. However, no validated criteria for the evaluation of the disease activity in SLE have yet been established. Recently, serum levels of soluble interleukin-2 receptor (sIL-2R) have been proposed as a potential parameter for disease activity in SLE. However, the studies reported on this subject so far have focused mainly on certain subsets of the disease, and the evaluation of the disease activity was based on a very limited number of parameters. In the present study, we determined serum levels of sIL-2R in 23 patients with SLE and 30 patients with discoid LE (DLE). Evaluation of disease activity in SLE was based on a comprehensive scale which considered numerous clinical signs and laboratory parameters. In SLE, serum levels of sIL-2R showed a better correlation with disease activity than all the other parameters investigated, including proteinuria, erythrocyte sedimentation rate, serum globulin concentration, titre of antibodies against double-stranded DNA, serum albumin concentration, serum complement levels and white blood cell count. For the first time, we report on elevated serum levels of sIL-2R in DLE, which also correlated with disease activity.

Cross-sectional analysis of adverse outcomes in 1,029 pregnancies of Afro-Caribbean women in Trinidad with and without systemic lupus erythematosus

PubMed Central

Molokhia, Mariam; Maconochie, Noreen; Patrick, Alan Leslie; Doyle, Pat

2007-01-01

The objective of the study was to examine pregnancy outcomes in women with systemic lupus erythematosus (SLE) and population controls in Trinidad. We performed a cross-sectional analysis of adverse outcomes in pregnancies of Afro-Caribbean women with SLE and without SLE. One hundred and twenty-two female adult cases of SLE and 203 neighbourhood age-matched women without SLE were interviewed concerning details of their reproductive history, and the anticardiolipin antibody (ACL) status was established for women with SLE. A total of 1,029 pregnancies were reported (356 by women with SLE, 673 by women without SLE). In women with ≥ 1 pregnancy the total number of pregnancies was similar in women with a diagnosis of SLE and women without; however, a lower proportion of women with SLE had ever been pregnant compared with women without SLE (80% versus 91%, P = 0.002). In multivariate logistic regression analyses adjusted for maternal age, district of residence, pregnancy order and smoking, SLE pregnancies were more than twice as likely to end in foetal death than non-SLE pregnancies (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2–4.7). This effect was driven by a large increase in the odds of stillbirth (OR, 8.5; 95% CI, 2.5–28.8). The odds of early miscarriage (OR, 1.4; 95% CI, 0.6–3.1) and of mid-trimester miscarriage (OR, 1.9; 95% CI, 0.4–9.5) were higher, but were not statistically significantly different, in SLE pregnancies than in non-SLE pregnancies. The odds of ectopic pregnancy (OR, 7.5; 95% CI, 0.9–62.5) and of preterm birth (OR, 3.4; 95% CI, 1.2–10.0) were higher in SLE pregnancies conceived after diagnosis than in non-SLE pregnancies. There was no evidence of raised levels of IgG or IgM ACL among the majority (93/97 women, 96%) of SLE cases who reported sporadic mid-trimester miscarriage or stillbirth, although there was evidence of high levels of IgM and IgG ACL among women reporting three or more miscarriages and three consecutive miscarriages, and of raised IgG ACL among those experiencing ectopic pregnancy. In conclusion, we found evidence for a large increase in risk of stillbirth in the pregnancies of Afro-Caribbean Trinidadian women with SLE (not accounted for by high ACL status). There was some evidence of an increased risk of preterm delivery and ectopic pregnancy in pregnancies conceived after a diagnosis of maternal SLE. PMID:18042277

Engraftment of PBMC from SLE and APS Donors into BALB-Rag2−/−IL2Rgc−/− Mice: a Promising Model for Studying Human Disease

PubMed Central

Andrade, Danieli; Redecha, Patricia B.; Vukelic, Milena; Qing, Xiaoping; Perino, Giorgio; Salmon, Jane E.; Koo, Gloria C.

2011-01-01

Purpose To construct a humanized SLE mouse that resembles the human disease to define pathophysiology and targeted for treatments. Methods We infused peripheral blood mononuclear cells (PBMC) from SLE patients into BALB-Rag2−/−IL2Rgc−/−mice (DKO), which lack T, B and NK cells. PBMC from 5 SLE patients and 4 normal donors (ND) at 3–5×106/mouse were infused IV/IP to non-irradiated 4–5 weeks old mice. We evaluated the engraftment of human CD45+cells and monitored the plasma human IgG, anti-dsDNA, anti-cardiolipin (aCL) antibodies, proteinuria, and kidney histology. Results We found 100% successful engraftment of 40 DKO mice infused with human PBMC. In both SLE-DKO and ND-DKO mice, 50–80% human CD45+ cells were observed in PBMC fraction 4–6 weeks post engraftment, with 70–90% CD3+ cells. There were fewer CD3+4+cells (5.5±2.1%) and more CD3+8+cells (79.4±3.6%) in the SLE-DKO mice, as in the SLE patients. CD19+B cells and CD11c+Monocytic cells were found in the spleen, lung, liver and bone marrow. There was no significant difference in plasma human IgG levels and anti-dsDNA antibodies between SLE-DKO and ND-DKO mice. Levels of aCL antibody were significantly higher in all SLE-DKO mice infused with PBMC from a SLE patient with high titers of aCL antibodies. SLE-DKO mice had proteinuria, human IgG deposits in the kidneys and shorter life span. In SLE- DKO mice engrafted from the aCL-positive patient, we found micro-thrombi and infiltration of CD3+, CD8+ and CD19+ cells in the glomeruli, recapitulating APS in these mice. Conclusion A novel humanized SLE-DKO mouse is established, exhibiting many characteristics of immunologic and clinical features of SLE. PMID:21560114

Leptin levels in patients with systemic lupus erythematosus inversely correlate with regulatory T cell frequency.

PubMed

Wang, X; Qiao, Y; Yang, L; Song, S; Han, Y; Tian, Y; Ding, M; Jin, H; Shao, F; Liu, A

2017-11-01

Leptin levels are increased in patients with systemic lupus erythematosus (SLE) but little is known on how this correlates with several disease characteristics including the frequency of regulatory T cells (Tregs). Here we compared serum leptin levels with frequency of circulating Tregs in 47 lupus patients vs. 25 healthy matched controls. Correlations with lupus disease activity were also analyzed, as well as Treg proliferation potential. It was found that leptin was remarkably increased in SLE patients as compared to controls, particularly in SLE patients with moderate and severe active SLE, and the increase correlated with disease activity. Importantly, increased leptin in lupus patients inversely correlated with the frequency of Tregs but not in controls, and leptin neutralization resulted in the expansion of Tregs ex vivo. Thus, hyperleptinemia in lupus patients correlates directly with disease activity and inversely with Treg frequency. The finding that leptin inhibition expands Tregs in SLE suggests possible inhibition of this molecule for an enhanced Treg function in the disease.

Circulating FABP4 is a marker of metabolic and cardiovascular risk in SLE patients.

PubMed

Parra, S; Cabré, A; Marimon, F; Ferré, R; Ribalta, J; Gonzàlez, M; Heras, M; Castro, A; Masana, L

2014-03-01

The aim of this study is to determine if circulating fatty acid-binding protein 4 (FABP4) plasma levels are a possible marker of metabolic risk in SLE patients. Circulating levels of adipose FABP4 are associated with adiposity, insulin resistance (IR), metabolic syndrome, diabetes and cardiovascular diseases. Patients affected by systemic lupus erythematosus (SLE) show an accelerated atherosclerosis that cannot be entirely explained by traditional cardiovascular risk factors. Sixty consecutive patients with SLE and 34 non-SLE age-matched controls were recruited for the study. Total plasma lipids and circulating FABP4 were determined. Subclinical atherosclerosis was evaluated by measuring carotid intimae-media thickness (c-IMT) by sonography, and the distribution of lipoprotein subclasses was analysed by nuclear magnetic resonance (NMR) spectroscopy. In the SLE group, FABP4 was associated with IR, atherogenic dyslipidaemia, as measured by NMR, and the presence of subclinical atherosclerosis. In multivariate analyses FABP4 was associated with increased c-IMT independent of the inflammatory state of the patient. In sum, circulating FABP4 is involved in the metabolic disturbances of SLE affecting lipid metabolism and IR, and it could be a biomarker of atherosclerosis in this population.

Adolescent onset of lupus results in more aggressive disease and worse outcomes: results of a nested matched case-control study within LUMINA, a multiethnic US cohort (LUMINA LVII).

PubMed

Tucker, L B; Uribe, A G; Fernández, M; Vilá, L M; McGwin, G; Apte, M; Fessler, B J; Bastian, H M; Reveille, J D; Alarcón, G S

2008-04-01

The objective of this study is to examine the clinical features and outcomes of patients with systemic lupus erythematosus (SLE) whose disease began in adolescence [juvenile-onset SLE (jSLE)] compared with adult-onset patients [adult-onset SLE (aSLE)] from a large multiethnic cohort. Systemic lupus erythematosus patients of African-American, Caucasian, or Hispanic ethnicity and >or=1 year follow-up were studied in two groups: jSLE (diagnosed at

Utility of TWEAK to assess neuropsychiatric disease activity in systemic lupus erhytematosus.

PubMed

Fragoso-Loyo, H; Atisha-Fregoso, Y; Nuñez-Alvarez, C A; Llorente, L

2016-04-01

The purpose of this study was to assess the utility of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) in serum and cerebrospinal fluid (CSF) as a biomarker in neuropsychiatric systemic lupus erythematosus (NPSLE). Thirty three NPSLE patients were evaluated at hospitalization and six months later. As controls, five SLE patients with septic meningitis, 51 hospitalized SLE patients without a history of neuropsychiatric (NP) manifestations and without infections, 16 SLE patients without NP manifestations (surgical-SLE), four patients with primary neuropsychiatric disorders, and 25 patients with non-autoimmune diseases were also studied. Serum and CSF samples were drawn at hospitalization, except non-NPSLE patients, in whom only serum was studied, and six months later in 19 NPSLE and 27 non-NPSLE patients. Serum and CSF TWEAK levels were measured by ELISA; values are expressed in pg/mL. The mean ± SD age of NPSLE patients was 31 ± 13.1 years, which was similar across study groups (p = 0.54). TWEAK levels in serum were not different across the study groups. In CSF, TWEAK levels were higher in NPSLE, surgical-SLE and primary neuropsychiatric groups than in non-autoimmune patients: median (IQR) 159.2 (94.1-374.9), 172.3 (125.3-421.9), 371.3 (143-543) vs. 122.1 (76.1-212.4), respectively; all p < 0.05. Six months later, when the neuropsychiatric manifestations were clinically in remission, serum or CSF TWEAK did not vary from baseline in NPSLE patients. TWEAK levels are slightly elevated in CSF in SLE patients compared with non-autoimmune controls, irrespective of the presence of NP manifestations. TWEAK levels in serum and CSF do not seem to be a useful biomarker of CNS involvement in SLE. © The Author(s) 2015.

B Lymphocyte Stimulator Levels in Systemic Lupus Erythematosus: Higher Circulating Levels in African American Patients and Increased Production after Influenza Vaccination in Patients with Low Baseline Levels

PubMed Central

Ritterhouse, Lauren L.; Crowe, Sherry R.; Niewold, Timothy B.; Merrill, Joan T.; Roberts, Virginia C.; Dedeke, Amy B.; Neas, Barbara R.; Thompson, Linda F.; Guthridge, Joel M.; James, Judith A.

2011-01-01

Objective Examine the relationship between circulating B lymphocyte stimulator (BLyS) levels and humoral responses to influenza vaccination in systemic lupus erythematosus (SLE) patients, as well as the effect of vaccination on BLyS levels. Clinical and serologic features of SLE that are associated with elevated BLyS levels will also be investigated. Methods Clinical history, disease activity measurements and blood specimens were collected from sixty SLE patients at baseline and after influenza vaccination. Sera were tested for BLyS levels, lupus-associated autoantibodies, serum IFN-α activity, 25-hydroxyvitamin D, and humoral responses to influenza vaccination. Results Thirty percent of SLE patients had elevated BLyS levels, with African American patients having higher BLyS levels than European American patients (p=0.006). Baseline BLyS levels in patients were not correlated with humoral responses to influenza vaccination (p=0.863), and BLyS levels increased post-vaccination only in the subset of patients in the lowest quartile of BLyS levels (p=0.0003). Elevated BLyS levels were associated with increased disease activity as measured by SLEDAI, PGA, and SLAM in European Americans (p=0.035, p=0.016, p=0.018, respectively), but not in African Americans. Elevated BLyS levels were also associated with anti-nRNP (p=0.0003) and decreased 25(OH)D (p=0.018). Serum IFN-α activity was a significant predictor of elevated BLyS in a multivariate analysis (p=0.002). Conclusion African American SLE patients have higher BLyS levels regardless of disease activity. Humoral response to influenza vaccination is not correlated with baseline BLyS levels in SLE patients and only those patients with low baseline BLyS levels demonstrate an increased BLyS response after vaccination. PMID:22127709

Urinary Angiostatin - A Novel Putative Marker of Renal Pathology Chronicity in Lupus Nephritis*

PubMed Central

Wu, Tianfu; Du, Yong; Han, Jie; Singh, Sandeep; Xie, Chun; Guo, Yuyuan; Zhou, Xin J.; Ahn, Chul; Saxena, Ramesh; Mohan, Chandra

2013-01-01

There is a critical need to identify biomarkers for Systemic Lupus Erythematosus (SLE) which has a high prevalence of renal failure. When urine from patients with lupus nephritis was recently screened for the levels of ∼280 molecules using an exploratory array-based proteomic platform, elevated angiostatin levels were noted. Angiostatin is a bioactive fragment of plasminogen, and has been known to have modulatory function in angiogenesis and inflammation. The significant elevation in urinary angiostatin was next validated in an independent cohort of SLE patients (n = 100) using ELISA. Among patients with SLE, urine angiostatin was significantly increased in active SLE compared with inactive SLE, correlating well with the SLEDAI disease activity index and SLICC renal activity score (r = 0.66, p < 0.0001). ROC curve analysis further confirmed that urinary angiostatin had the capacity to discriminate patients with active SLE from those with inactive disease. Patients with Class IV lupus nephritis exhibited the highest levels of urinary angiostatin. Immunohistochemistry staining localized angiostatin expression to the renal tubular cells in these patients. Finally, when paired urine-kidney samples procured concurrently from patients with LN were next examined, urine angiostatin levels correlated strongly with the renal pathology chronicity index, but not with the activity index. Given that Class IV lupus nephritis and renal pathology chronicity changes forebode poor renal and patient survival, urinary angiostatin emerges as a novel noninvasive marker of renal disease in SLE. Longitudinal studies are in progress to further assess the disease-predictive potential of urinary angiostatin. PMID:23345539

Mild and moderate Mannose Binding Lectin deficiency are associated with systemic lupus erythematosus and lupus nephritis in Brazilian patients.

PubMed

Perazzio, Sandro Félix; Silva, Neusa Pereira da; Carneiro-Sampaio, Magda; Andrade, Luis Eduardo Coelho

2016-01-01

The potential association of mannose binding lectin (MBL) deficiency and systemic lupus erythematosus (SLE) has been investigated in several studies, but results have been mixed. One explanation for the conflicting results could be differences in ethnic background of study subjects. In this study we investigated the association of MBL deficiency and SLE in a large cohort of Brazilian SLE patients and controls. Serum MBL and Complement levels were determined for 286 Brazilian adult SLE patients and 301 healthy Brazilian adults as controls. MBL deficiency was classified as mild (<1000 and ≥500μg/L), moderate (<500 and ≥100μg/L) or severe (<100μg/L). SLE patients presented higher frequency of mild and moderate MBL deficiency compared to controls. SLE patients with MBL deficiency presented higher frequency of lupus nephritis compared to those without MBL deficiency. MBL deficiency was not associated with any other clinical manifestation, use of immunosuppressant therapy, disease activity, disease severity serum or Complement levels. This study shows that an association between MBL deficiency and SLE does exist in the Brazilian population. We also found an association between MBL deficiency and lupus nephritis. These findings support the hypothesis that MBL deficiency contributes to the development of SLE and lupus nephritis. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

Neutrophil CD64 expression, procalcitonin and presepsin are useful to differentiate infections from flares in SLE patients with SIRS.

PubMed

Echeverri, A; Naranjo-Escobar, J; Posso-Osorio, I; Aguirre-Valencia, D; Zambrano, D; Castaño, G L; Martínez, J D; Cañas, C A; Tobón, G J

2018-06-01

Background/Objective Differentiating systemic lupus erythematosus (SLE) activity from infections in febrile patients is difficult because of similar initial clinical presentation. The aim of this study is to evaluate the usefulness of a number of biomarkers for differentiating infections from activity in SLE patients admitted with systemic inflammatory response (SIRS). Methods Patients with SLE and SIRS admitted to the emergency room were included in this study. Measurements of different markers including procalcitonin, neutrophil CD64 expression and presepsin, were performed. Infection was considered present when positive cultures and/or polymerase chain reaction were obtained. Sensitivity and specificity were calculated for all biomarkers. Results Twenty-seven patients were admitted, 23 women (82.5%), mean age 33.2 years. An infectious disease was confirmed in 12 cases. Markers for SLE activity including anti-DNA titers by IIF ( p = 0.041) and enzyme-linked immunosorbent assay ( p = 0.009) were used for differentiating SLE flares from infection. On the contrary, increased procalcitonin ( p = 0.047), neutrophil CD64 expression by flow cytometry ( p = 0.037) and presepsin ( p = 0.037) levels were observed in infected SLE patients. Conclusions High neutrophil CD64 expression, presepsin and procalcitonin levels are useful to differentiate infections from activity in SLE patients. In most cases, a positive bioscore that includes these three markers demonstrate the presence of an infectious disease.

[Determination of 25(OH)D serum levels in children with systemic lupus erythematosus and juvenile idiopathic arthritis].

PubMed

Rosiles, Vanessa Hernández; Salazar, Carolina Duarte; Velazquez, Rocío Maldonado; Ruiz, Rodolfo Rivas; Clark, Patricia

It is well recognized that vitamin D has a direct effect in bone and muscle and has been associated as well with some rheumatologic diseases. Reports in children are scarce. The aim of this study was to determine the concentration level of 25(OH)D in a group of patients with systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA) and compare them with healthy controls. Vitamin D (25(OH)D) was measured with isotope-dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS), PTH with immunoradiometric assay (IRMA), calcium, phosphorus and alkaline phosphatase by colorimetric assay in 37 patients with SLE, 37 patients with JIA and 79 healthy controls. Mean 25(OH)D concentration levels were as follows: SLE 18.9±7.92ng/ml, JIA 21.97±5.55ng/ml and 23.6±3.07ng/ml in healthy controls. There was a significant difference between SLE patients vs. healthy controls (p <0.05); 29.7% of SLE patients, 35.1% of JIA patients and 31.6% of healthy controls had deficient levels of vitamin D. One third of the total sample of children in this study had deficient levels of vitamin D. Patients with SLE presented a significant difference compared with healthy controls. Copyright © 2015 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression

PubMed Central

Kelly, Jennifer A.; Brown, Elizabeth E.; Harley, John B.; Bae, Sang-Cheol; Alarcόn-Riquelme, Marta E.; Edberg, Jeffrey C.; Kimberly, Robert P.; Ramsey-Goldman, Rosalind; Petri, Michelle A.; Reveille, John D.; Vilá, Luis M.; Alarcón, Graciela S.; Kaufman, Kenneth M.; Vyse, Timothy J.; Jacob, Chaim O.; Gaffney, Patrick M.; Sivils, Kathy Moser; James, Judith A.; Kamen, Diane L.; Gilkeson, Gary S.; Niewold, Timothy B.; Merrill, Joan T.; Scofield, R. Hal; Criswell, Lindsey A.; Stevens, Anne M.; Boackle, Susan A.; Kim, Jae-Hoon; Choi, Jiyoung; Pons-Estel, Bernardo A.; Freedman, Barry I.; Anaya, Juan-Manuel; Martin, Javier; Yu, C. Yung; Chang, Deh-Ming; Song, Yeong Wook; Langefeld, Carl D.; Chen, Weiling; Grossman, Jennifer M.; Cantor, Rita M.; Hahn, Bevra H.; Tsao, Betty P.

2013-01-01

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 = 2.7×10−8, 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. PMID:24130510

Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression.

PubMed

Sakurai, Daisuke; Zhao, Jian; Deng, Yun; Kelly, Jennifer A; Brown, Elizabeth E; Harley, John B; Bae, Sang-Cheol; Alarcόn-Riquelme, Marta E; Edberg, Jeffrey C; Kimberly, Robert P; Ramsey-Goldman, Rosalind; Petri, Michelle A; Reveille, John D; Vilá, Luis M; Alarcón, Graciela S; Kaufman, Kenneth M; Vyse, Timothy J; Jacob, Chaim O; Gaffney, Patrick M; Sivils, Kathy Moser; James, Judith A; Kamen, Diane L; Gilkeson, Gary S; Niewold, Timothy B; Merrill, Joan T; Scofield, R Hal; Criswell, Lindsey A; Stevens, Anne M; Boackle, Susan A; Kim, Jae-Hoon; Choi, Jiyoung; Pons-Estel, Bernardo A; Freedman, Barry I; Anaya, Juan-Manuel; Martin, Javier; Yu, C Yung; Chang, Deh-Ming; Song, Yeong Wook; Langefeld, Carl D; Chen, Weiling; Grossman, Jennifer M; Cantor, Rita M; Hahn, Bevra H; Tsao, Betty P

2013-01-01

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 = 2.7×10⁻⁸, 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.

Longitudinal analysis of varicella-zoster virus-specific antibodies in systemic lupus erythematosus: No association with subclinical viral reactivations or lupus disease activity.

PubMed

Rondaan, C; van Leer, C C; van Assen, S; Bootsma, H; de Leeuw, K; Arends, S; Bos, N A; Westra, J

2018-07-01

Systemic lupus erythematosus (SLE) patients are at high risk of herpes zoster. Previously, we found increased immunoglobulin (Ig)G levels against varicella-zoster virus (VZV) in SLE patients compared to controls, while antibody levels against diphtheria and cellular immunity to VZV were decreased. We aimed to test our hypothesis that increased VZV-IgG levels in SLE result from subclinical VZV reactivations, caused by stress because of lupus disease activity or immunosuppressive drug use. Methods Antibody levels to VZV (IgG, IgA, IgM), total IgG and VZV-DNA were longitudinally determined in the serum of 34 SLE patients, using enzyme-linked immunosorbent assay and polymerase chain reaction. Clinical data were retrieved from medical records. Reactivation of VZV was defined as an at least fivefold rise in VZV-IgG or presence of VZV-IgM or VZV-DNA. Generalized estimating equations (GEE) were used to longitudinally analyse associations between antibody levels, lupus disease activity and medication use. Systemic Lupus Erythematosus Disease Activity Index, anti-double-stranded DNA and complement levels were used as indicators of lupus disease activity. Results A VZV reactivation was determined in 11 patients (33%). In at least five of them, herpes zoster was clinically overt. No association between SLE disease activity or medication use and VZV-specific antibody levels was found. There was a weak association between total IgG and VZV-IgG. Conclusions Our results indicate that increased VZV-IgG levels in SLE do not result from frequent subclinical VZV reactivations, and are not associated with lupus disease activity. Increased VZV-IgG can only partially be explained by hypergammaglobulinaemia.

The NZM2410-derived lupus susceptibility locus Sle2c1 increases TH17 polarization and induces nephritis in Fas-deficient mice

PubMed Central

Xu, Zhiwei; Cuda, Carla M.; Croker, Byron P.; Morel, Laurence

2010-01-01

Objective Sle2 is a lupus susceptibility locus that has been linked toglomerulonephritis in the NZM2410mouse. Byitself, Sle2 does not induce any autoimmune pathology, but results into the accumulation of B1a cells. This study was designed to assess the contribution of Sle2 to autoimmune pathogenesis. Methods Sle2 or its sub-congenic intervals (Sle2a, Sle2b and Sle2c) were bred to Fas-deficient B6.lpr mice. Lymphoid phenotypes, focused on T cells, were assessed by flow cytometry, and histopathology was compared between cohorts of B6.Sle2.lpr congenics and B6.lpr mice aged up to 6 mo old. Results Sle2 synergized with lpr, resulting in a greatly accelerated lymphadenopathy that largely targeted T cells, and mapped to the Sle2c1 locus. This locus has been identified as the main contributor to B1a cell expansion. Further analyses showed that Sle2c1 expression skewed the differentiation and polarization of Fas-deficient T cells, with a reduction of the CD4+ CD25+ Foxp3+ regulatory T cell subset and an expansion of the TH17 cells. This was associated with a high level of T cell infiltrates that promoted severe nephritis and dermatitis in the B6.Sle2c1.lpr mice. Conclusion These results show that Sle2c1 contributes to lupus pathogenesis by affecting T cell differentiation in combination with other susceptibility loci such as lpr. The significance of the co-segregation of this phenotype and B1a cell expansion in Sle2c1-expressing mice for lupus pathogenesis is discussed. PMID:21360506

Mitochondrial DNA damage is associated with damage accrual and disease duration in patients with Systemic Lupus Erythematosus

PubMed Central

López-López, Linnette; Nieves-Plaza, Mariely; Castro, María del R.; Font, Yvonne M.; Torres-Ramos, Carlos; Vilá, Luis M.; Ayala-Peña, Sylvette

2014-01-01

Objective To determine the extent of mitochondrial DNA (mtDNA) damage in systemic lupus erythematosus (SLE) patients compared to healthy subjects and to determine the factors associated with mtDNA damage among SLE patients. Methods A cross-sectional study was performed in 86 SLE patients (per American College of Rheumatology classification criteria) and 86 healthy individuals matched for age and gender. Peripheral blood mononuclear cells (PBMCs) were collected from subjects to assess the relative amounts of mtDNA damage. Quantitative polymerase chain reaction assay was used to measure the frequency of mtDNA lesions and mtDNA abundance. Socioeconomic-demographic features, clinical manifestations, pharmacologic treatment, disease activity, and damage accrual were determined. Statistical analyses were performed using t test, pairwise correlation, and Pearson’s chi-square test (or Fisher’s exact test) as appropriate. Results Among SLE patients, 93.0% were women. The mean (SD) age was 38.0 (10.4) years and the mean (SD) disease duration was 8.7 (7.5) years. SLE patients exhibited increased levels of mtDNA damage as shown by higher levels of mtDNA lesions and decreased mtDNA abundance as compared to healthy individuals. There was a negative correlation between disease damage and mtDNA abundance and a positive correlation between mtDNA lesions and disease duration. No association was found between disease activity and mtDNA damage. Conclusion PBMCs from SLE patients exhibited more mtDNA damage compared to healthy subjects. Higher levels of mtDNA damage were observed among SLE patients with major organ involvement and damage accrual. These results suggest that mtDNA damage have a potential role in the pathogenesis of SLE. PMID:24899636

Mitochondrial DNA damage is associated with damage accrual and disease duration in patients with systemic lupus erythematosus.

PubMed

López-López, L; Nieves-Plaza, M; Castro, M del R; Font, Y M; Torres-Ramos, C A; Vilá, L M; Ayala-Peña, S

2014-10-01

To determine the extent of mitochondrial DNA (mtDNA) damage in systemic lupus erythematosus (SLE) patients compared to healthy subjects and to determine the factors associated with mtDNA damage among SLE patients. A cross-sectional study was performed in 86 SLE patients (per American College of Rheumatology classification criteria) and 86 healthy individuals matched for age and gender. Peripheral blood mononuclear cells (PBMCs) were collected from subjects to assess the relative amounts of mtDNA damage. Quantitative polymerase chain reaction assay was used to measure the frequency of mtDNA lesions and mtDNA abundance. Socioeconomic-demographic features, clinical manifestations, pharmacologic treatment, disease activity, and damage accrual were determined. Statistical analyses were performed using t test, pairwise correlation, and Pearson's chi-square test (or Fisher's exact test) as appropriate. Among SLE patients, 93.0% were women. The mean (SD) age was 38.0 (10.4) years and the mean (SD) disease duration was 8.7 (7.5) years. SLE patients exhibited increased levels of mtDNA damage as shown by higher levels of mtDNA lesions and decreased mtDNA abundance as compared to healthy individuals. There was a negative correlation between disease damage and mtDNA abundance and a positive correlation between mtDNA lesions and disease duration. No association was found between disease activity and mtDNA damage. PBMCs from SLE patients exhibited more mtDNA damage compared to healthy subjects. Higher levels of mtDNA damage were observed among SLE patients with major organ involvement and damage accrual. These results suggest that mtDNA damage have a potential role in the pathogenesis of SLE. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Expression of autophagy related genes mTOR, Becline-1, LC3 and p62 in the peripheral blood mononuclear cells of systemic lupus erythematosus.

PubMed

Wu, Zhen-Zhen; Zhang, Jun-Jun; Gao, Cong-Cong; Zhao, Man; Liu, Sheng-Yun; Gao, Guan-Min; Zheng, Zhao-Hui

2017-01-01

To determine the expression of mTOR, Becline-1, LC3 and p62 in the peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) and assess their relationship with disease activity and immunologic features. The expression of mTOR, Becline-1, LC3 and p62 was detected by RT-PCR in 81 SLE subjects and 86 age- and sex-matched healthy controls. Data regarding demographics and clinical parameters were collected. Disease activity of SLE was evaluated according to the SLE Disease Activity Index (SLEDAI) score. Independent sample t-test was used to analyze the expression of mTOR, Becline-1, LC3, and p62 in the two groups. Pearson's or Spearman's correlation was performed to analyze their relationship with disease activity and immunologic features. The mean levels of Becline-1, LC3 and p62 mRNA were significantly higher in SLE patients than the controls (9.96×10 -4 vs 7.38×10 -4 for Becline-1 with P <0.001; 4.04×10 -5 vs 2.62×10 -5 for LC3 with P <0.001; 9.51×10 -4 vs 7.59×10 -4 for p62 with P =0.008). However, the levels of mTOR mRNA in SLE patients were not significantly different from that in controls. Correlation analysis showed that Becline-1, LC3 and p62 mRNA levels correlated positively with SLEDAI, IgG and ds-DNA, negatively with C3. Our results suggested that autophagosomes formation were activated and their degradation were blocked in SLE. Moreover, the maintenance of autophagy balance can improve disease activity and immune disorders in SLE patients.

Protective Role of Myeloid Cells Expressing a G-CSF Receptor Polymorphism in an Induced Model of Lupus.

PubMed

Sivakumar, Ramya; Abboud, Georges; Mathews, Clayton E; Atkinson, Mark A; Morel, Laurence

2018-01-01

The genetic analysis of the lupus-prone NZM2410 mouse has identified a suppressor locus, Sle2c2 , which confers resistance to spontaneous lupus in combination with NZM2410 susceptibility loci, or in the chronic graft-versus-host disease (cGVHD) induced model of lupus in the B6. Sle2c2 congenic strain. The candidate gene for  Sle2c2 , the Csf3r gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R/CD114), was validated when cGVHD was restored in B6. Sle2c2 mice after treatment with G-CSF. The goal of the project reported herein was to investigate the myeloid cells that confer resistance to cGVHD and to ascertain if the mechanism behind their suppression involves the G-CSF pathway. We showed that despite expressing the highest levels of G-CSF-R, neutrophils play only a modest role in the autoimmune activation induced by cGVHD. We also found reduced expression levels of G-CSF-R on the surface of dendritic cells (DCs) and a differential distribution of DC subsets in response to cGVHD in B6. Sle2c2 versus B6 mice. The CD8α + DC subset, known for its tolerogenic phenotype, was expanded upon induction of cGVHD in B6. Sle2c2 mice. In addition, the deficiency of CD8α + DC subset enhanced the severity of cGVHD in B6. Batf3 -/- and B6 .Sle2c2 mice, confirming their role in suppression of cGVHD. B6. Sle2c2 DCs presented lowered activation and antigen presentation abilities and expressed lower levels of genes associated with DC activation and maturation. Exposure to exogenous G-CSF reversed the majority of these phenotypes, suggesting that tolerogenic DCs maintained through a defective G-CSF-R pathway mediated the resistance to cGVHD in B6. Sle2c2 mice.

A/H1N1 influenza vaccination in patients with systemic lupus erythematosus: safety and immunity.

PubMed

Lu, Chun-Chi; Wang, Yeau-Ching; Lai, Jenn-Haung; Lee, Tony Szu-Hsien; Lin, Hui-Tsu; Chang, Deh-Ming

2011-01-10

To determine the safety of and immunogenicity induced by A/H1N1 influenza vaccination in patients with systemic lupus erythematosus (SLE). The study population comprised 21 SLE patients and 15 healthy control subjects who underwent split-virion, inactivated monovalent A/H1N1 vaccination between December 2009 and January 2010. Sera were obtained before, three weeks after, and six months after vaccination. SLE disease activity index (SLEDAI) scores and autoantibodies were measured at every visit in SLE patients. Haemagglutination inhibition and the serum immunoglobulin G (IgG) level were calculated using the World Health Organization (WHO) procedure to evaluate the antibody responses. We also recorded current medications and past seasonal influenza vaccinations to analyse the interactions between vaccinations and the autoimmunity of SLE patients. The mean age of the enrolled population was 34.3 years for SLE patients and 39.4 years for control subjects. The average SLEDAI score for SLE patients was 4.1 at vaccination, 4.5 at three weeks, and 4.3 at six months. The seroprotection rate at three weeks was 76.2% in SLE patients and 80.0% in healthy control subjects; by six months, the seroprotection rate was 66.7% in SLE patients and 60% in healthy control subjects. The seroconversion rate was 76.2% in SLE patients and 80% in healthy controls at three weeks; by six months, the seroconversion rate was 52.4% in SLE patients and 53.3% in healthy controls. The response in SLE patients met the criteria of the European Committee for Proprietary Medicinal Products guidelines at three weeks, while the percentage of seroprotection did not at six months. The clinical disease activity and SLEDAI scores did not differ significantly from before to after vaccination in SLE patients, although the level of anticardiolipin IgG increased at three weeks after vaccination, but with no apparent clinical manifestations. The A/H1N1 influenza vaccine is safe and effective in SLE patients and has no obvious adverse clinical effects. Treatment with a single immunosuppressive agent or combination therapy also leads to effective humoral immunity in these patients. Copyright © 2010 Elsevier Ltd. All rights reserved.

Initial Benchmarking of the Quality of Medical Care in Childhood-Onset Systemic Lupus Erythematosus.

PubMed

Mina, Rina; Harris, Julia G; Klein-Gitelman, Marisa S; Appenzeller, Simone; Centeville, Maraisa; Eskra, Diane; Huggins, Jennifer L; Johnson, Anne L; Khubchandani, Raju; Khandekar, Prachi; Lee, Jiha; Liu, Hai Mei; Pendl, Joshua D; Silva, Clovis A; Silva, Marco F; Zaal, Ahmad I; DeWitt, Esi Morgan; Ardoin, Stacy P; Brunner, Hermine I

2016-02-01

To assess the quality of medical care in childhood-onset systemic lupus erythematosus (SLE) at tertiary pediatric rheumatology centers as measured by observance of SLE quality indicators (SLE-QIs). International consensus has been achieved for childhood-onset SLE-QIs capturing medical care provision in 9 domains: diagnostic testing, education of cardiovascular (CV) risk and lifestyles, lupus nephritis (LN), medication management, bone health, ophthalmologic surveillance, transition, pregnancy, and vaccination. Using medical record information, the level of performance of these childhood-onset SLE-QIs was assessed in childhood-onset SLE populations treated at 4 tertiary pediatric rheumatology centers in the US, 2 in Brazil, and 1 center in India. A total of 483 childhood-onset SLE patients were assessed. Care for the 310 US patients differed markedly for childhood-onset SLE-QIs addressing LN, bone health, vaccinations, education on CV risk, and transition planning. Performance of safety blood testing for medications was high at all centers. Despite often similar performance on the childhood-onset SLE-QI, access to kidney biopsies was lower in Brazil than in the US. Irrespective of the country of practice, larger centers tended to meet the childhood-onset SLE-QIs more often than smaller centers. The childhood-onset SLE-QIs, evidence-based minimum standards of medical care, are not consistently met in the US or some other countries outside the US. This has the potential to contribute to suboptimal childhood-onset SLE outcomes. © 2016, American College of Rheumatology.

Initial Benchmarking of the Quality of Medical Care of Childhood-Onset Systemic Lupus Erythematosus

PubMed Central

Mina, Rina; Harris, Julia G.; Klein-Gitelman, Marisa S.; Appenzeller, Simone; Centeville, Maraisa; Eskra, Diane; Huggins, Jennifer L.; Johnson, Anne L.; Khubchandani, Raju; Khandekar, Prachi; Lee, Jiha; Liu, HaiMei; Pendl, Joshua D.; Silva, Clovis A.; Silva, Marco F.; Zaal, Ahmad I.; DeWitt, Esi Morgan; Ardoin, Stacy P.; Brunner, Hermine I.

2015-01-01

Objective To assess the quality of medical care in childhood-onset systemic lupus erythematosus (cSLE) at tertiary pediatric rheumatology centers as measured by observance cSLE quality indicators (cSLE-QI). Methods International consensus has been achieved for cSLE-QI (Hollander et al. Arthritis Care & Research, 2013) capturing medical care provision in nine domains: diagnostic testing, education of cardiovascular (CV) risk and lifestyles, lupus nephritis (LN), medication management, bone health, ophthalmological surveillance, transition, pregnancy and vaccination. Using medical record information, the level of performance these cSLE-QI was assessed in cSLE populations treated at four tertiary pediatric rheumatology centers in the U.S, two in Brazil, and one center in India. Results A total of 483 cSLE patients were assessed. Care for the 310 U.S. patients differed markedly for cSLE-QI addressing LN, bone health, vaccinations, education on CV risk, and transition planning. Performance of safety blood testing for medications was high at all centers. Despite often similar performance on the cSLE-QI, access to kidney biopsies was lower in Brazil than in the U.S. Irrespective of country of practice, larger centers tended to meet the cSLE-QI more often than smaller centers. Conclusions The cSLE-QI, evidence based minimum standards of medical care, are not consistently met in the U.S. or some other countries outside the U.S. This has the potential to contribute to suboptimal cSLE outcomes. PMID:26219749

Reduced response to Epstein–Barr virus antigens by T-cells in systemic lupus erythematosus patients

PubMed Central

Draborg, Anette Holck; Jacobsen, Søren; Westergaard, Marie; Mortensen, Shila; Larsen, Janni Lisander; Houen, Gunnar; Duus, Karen

2014-01-01

Objective Epstein–Barr virus (EBV) has for long been associated with systemic lupus erythematosus (SLE). In this study, we investigated the levels of latent and lytic antigen EBV-specific T-cells and antibodies in SLE patients. Methods T cells were analyzed by flow cytometry and antibodies were analyzed by enzyme-linked immunosorbent assay. Results SLE patients showed a significantly reduced number of activated (CD69) T-cells upon ex vivo stimulation with EBV nuclear antigen (EBNA) 1 or EBV early antigen diffuse (EBV-EA/D) in whole blood samples compared with healthy controls. Also, a reduced number of T-cells from SLE patients were found to produce interferon-γ upon stimulation with these antigens. Importantly, responses to a superantigen were normal in SLE patients. Compared with healthy controls, SLE patients had fewer EBV-specific T-cells but higher titres of antibodies against EBV. Furthermore, an inverse correlation was revealed between the number of lytic antigen EBV-specific T-cells and disease activity of the SLE patients, with high-activity SLE patients having fewer T-cells than low-activity SLE patients. Conclusions These results indicate a limited or a defective EBV-specific T-cell response in SLE patients, which may suggest poor control of EBV infection in SLE with an immune reaction shift towards a humoral response in an attempt to control viral reactivation. A role for decreased control of EBV as a contributing agent in the development or exacerbation of SLE is proposed. PMID:25396062

[Effect of corticosteroids on the balance of Th cytokines in patients with systemic lupus erythematosus].

PubMed

Xie, Hong-fu; Li, Jie; Shi, Wei

2002-12-28

To investigate the levels of Th cell-derived cytokines and the effect of corticosteroids on the balance of Th1/Th2 cytokines in patients with systemic lupus erythematosus (SLE). Fifty-eight SLE patients were treated with corticosteroids. Their IFN-gamma, IL-4 and IL-10 levels were detected by ELISA before and after the treatment with corticosteroids respectively; and the SLEDAI scores of the patients were compared before and after the treatment. Before the treatment, the serum levels of IFN-gamma, IL-4 and IL-10 were higher than those of the healthy controls (P < 0.05). After the treatment with corticosteroids, the elevated levels of IFN-gamma, IL-4 and IL-10 in the SLE patients were all significantly reduced than those before the treatment (P < 0.05). At the same time, the SLEDAI scores were significantly lower than those before the treatment (P < 0.01). The serum level of IFN-gamma was significantly decreased in the patients with SLE compared with the healthy controls (P < 0.05). By contrast, the levels of IL-4 and IL-10 of the patients with SLE were significantly increased compared with the healthy controls (P < 0.05). Corticosteroids may induce a shift from the Th1 to Th2 profile of cytokine secretion. This may be one aspect of the mechanisms for corticosteroids treatment.

Activation status of mucosal-associated invariant T cells reflects disease activity and pathology of systemic lupus erythematosus.

PubMed

Chiba, Asako; Tamura, Naoto; Yoshikiyo, Kazunori; Murayama, Goh; Kitagaichi, Mie; Yamaji, Ken; Takasaki, Yoshinari; Miyake, Sachiko

2017-03-14

Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes constituting a large proportion of peripheral blood T cells expressing αβ T-cell receptor in humans. In this study, we aimed to investigate their involvement in systemic lupus erythematosus (SLE). Peripheral blood MAIT cells from patients with SLE were assessed for their frequency, activation markers, and cell death by flow cytometry. The correlation between plasma cytokine levels and CD69 expression on MAIT cells was analyzed. The major histocompatibility complex class I-related protein MR1-restricted antigen-presenting capacity of antigen-presenting cells was investigated. Cytokine-mediated activation of MAIT cells in the absence of exogenous antigens was also examined. The frequency of MAIT cells was markedly reduced in SLE. The reduced number of MAIT cells was not attributable to the downregulation of surface markers, but it was partially due to the enhanced cell death of MAIT cells, possibly by activation-induced cell death. The CD69 expression levels on MAIT cells in SLE correlated with disease activity. Moreover, monocytes from patients with SLE exhibited increased ability to induce MAIT cell activation. The plasma concentration of interleukin (IL)-6, IL-18, and interferon (IFN)-α positively correlated with the expression levels of CD69 on MAIT cells in SLE. MAIT cells were activated by cytokines, including IFN-α, IL-15, and IL-12 plus IL-18, in the absence of exogenous antigens. These results suggest that MAIT cells reflect the pathological condition of SLE and that their activated status correlates with presence of disease.

An update on diet and nutritional factors in systemic lupus erythematosus management.

PubMed

Aparicio-Soto, Marina; Sánchez-Hidalgo, Marina; Alarcón-de-la-Lastra, Catalina

2017-06-01

Systemic lupus erythematosus (SLE) is a chronic inflammatory and autoimmune disease characterised by multiple organ involvement and a large number of complications. SLE management remains complicated owing to the biological heterogeneity between patients and the lack of safe and specific targeted therapies. There is evidence that dietary factors can contribute to the geoepidemiology of autoimmune diseases such as SLE. Thus, diet therapy could be a promising approach in SLE owing to both its potential prophylactic effects, without the side effects of classical pharmacology, and its contribution to reducing co-morbidities and improving quality of life in patients with SLE. However, the question arises as to whether nutrients could ameliorate or exacerbate SLE and how they could modulate inflammation and immune function at a molecular level. The present review summarises preclinical and clinical experiences to provide the reader with an update of the positive and negative aspects of macro- and micronutrients and other nutritional factors, including dietary phenols, on SLE, focusing on the mechanisms of action involved.

Lower vitamin D levels are associated with higher systemic lupus erythematosus activity, but not predictive of disease flare-up

PubMed Central

Schoindre, Yoland; Jallouli, Moez; Tanguy, Marie-Laure; Ghillani, Pascale; Galicier, Lionel; Aumaître, Olivier; Francès, Camille; Le Guern, Véronique; Lioté, Frédéric; Smail, Amar; Limal, Nicolas; Perard, Laurent; Desmurs-Clavel, Hélène; Thi Huong, Du Le; Asli, Bouchra; Kahn, Jean-Emmanuel; Sailler, Laurent; Ackermann, Félix; Papo, Thomas; Sacré, Karim; Fain, Olivier; Stirnemann, Jérôme; Cacoub, Patrice; Leroux, Gaëlle; Cohen-Bittan, Judith; Hulot, Jean-Sébastien; Lechat, Philippe; Musset, Lucile; Piette, Jean-Charles; Amoura, Zahir; Souberbielle, Jean-Claude; Costedoat-Chalumeau, Nathalie

2014-01-01

Objectives Growing evidence suggests that vitamin D plays a key role in the pathogenesis and progression of autoimmune diseases, including systemic lupus erythematosus (SLE). Recent studies have found an association between lower serum 25-hydroxyvitamin D (25(OH)D) levels and higher SLE activity. We studied the relationship between 25(OH)D levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and we assessed for the first time the role of vitamin D in predicting SLE flare-ups. Methods Serum 25(OH)D levels were measured in 170 patients with SLE who were prospectively followed up for 6 months (Plaquenil LUpus Systemic study, ClinicalTrials.gov number NCT00413361). Results The mean SLEDAI score was 2.03±2.43 and 12.3% patients had active disease (SLEDAI ≥6). The mean 25(OH)D level was 20.6±9.8 ng/mL. Deficiency (25(OH)D <10 ng/mL) was observed in 27 (15.9%), insufficiency (10≤25(OH)D<30) in 112 (65.9%) and optimal vitamin D status (25(OH)D≥30) in 31 (18.2%) patients. In multivariate analysis, female gender (p=0.018), absence of defined antiphospholipid syndrome (p=0.002) and higher creatinine clearance (p=0.004) were predictive of lower 25(OH)D levels. In multivariate analysis, lower 25(OH)D levels were associated with high SLE activity (p=0.02). Relapse-free survival rate was not statistically different according to the vitamin D status during the 6-month follow-up (p=0.22). Conclusions We found a low vitamin D status in the majority of patients with SLE, and a modest association between lower 25(OH)D levels and high disease activity. There was no association between baseline 25(OH)D levels and relapse-free survival rate. PMID:25379192

Lower vitamin D levels are associated with higher systemic lupus erythematosus activity, but not predictive of disease flare-up.

PubMed

Schoindre, Yoland; Jallouli, Moez; Tanguy, Marie-Laure; Ghillani, Pascale; Galicier, Lionel; Aumaître, Olivier; Francès, Camille; Le Guern, Véronique; Lioté, Frédéric; Smail, Amar; Limal, Nicolas; Perard, Laurent; Desmurs-Clavel, Hélène; Le Thi Huong, Du; Asli, Bouchra; Kahn, Jean-Emmanuel; Sailler, Laurent; Ackermann, Félix; Papo, Thomas; Sacré, Karim; Fain, Olivier; Stirnemann, Jérôme; Cacoub, Patrice; Leroux, Gaëlle; Cohen-Bittan, Judith; Hulot, Jean-Sébastien; Lechat, Philippe; Musset, Lucile; Piette, Jean-Charles; Amoura, Zahir; Souberbielle, Jean-Claude; Costedoat-Chalumeau, Nathalie

2014-01-01

Growing evidence suggests that vitamin D plays a key role in the pathogenesis and progression of autoimmune diseases, including systemic lupus erythematosus (SLE). Recent studies have found an association between lower serum 25-hydroxyvitamin D (25(OH)D) levels and higher SLE activity. We studied the relationship between 25(OH)D levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and we assessed for the first time the role of vitamin D in predicting SLE flare-ups. Serum 25(OH)D levels were measured in 170 patients with SLE who were prospectively followed up for 6 months (Plaquenil LUpus Systemic study, ClinicalTrials.gov number NCT00413361). The mean SLEDAI score was 2.03±2.43 and 12.3% patients had active disease (SLEDAI ≥6). The mean 25(OH)D level was 20.6±9.8 ng/mL. Deficiency (25(OH)D <10 ng/mL) was observed in 27 (15.9%), insufficiency (10≤25(OH)D<30) in 112 (65.9%) and optimal vitamin D status (25(OH)D≥30) in 31 (18.2%) patients. In multivariate analysis, female gender (p=0.018), absence of defined antiphospholipid syndrome (p=0.002) and higher creatinine clearance (p=0.004) were predictive of lower 25(OH)D levels. In multivariate analysis, lower 25(OH)D levels were associated with high SLE activity (p=0.02). Relapse-free survival rate was not statistically different according to the vitamin D status during the 6-month follow-up (p=0.22). We found a low vitamin D status in the majority of patients with SLE, and a modest association between lower 25(OH)D levels and high disease activity. There was no association between baseline 25(OH)D levels and relapse-free survival rate.

On lupus, vitamin D and leukopenia.

PubMed

Simioni, Juliana A; Heimovski, Flavia; Skare, Thelma L

2016-01-01

Immune regulation is among the noncalcemic effects of vitamin D. So, this vitamin may play a role in autoimmune diseases such as systemic lupus erythematosus (SLE). To study the prevalence of vitamin D deficiency in SLE and its association with clinical, serological and treatment profile as well as with disease activity. Serum OH vitamin D3 levels were measured in 153 SLE patients and 85 controls. Data on clinical, serological and treatment profile of lupus patients were obtained through chart review. Blood cell count and SLEDAI (SLE disease activity index) were measured simultaneously with vitamin D determination. SLE patients have lower levels of vitamin D than controls (p=0.03). In univariate analysis serum vitamin D was associated with leukopenia (p=0.02), use of cyclophosphamide (p=0.007) and methotrexate (p=0.03). A negative correlation was verified with prednisone dose (p=0.003). No association was found with disease activity measured by SLEDAI (p=0.88). In a multiple regression study only leukopenia remained as an independent association (B=4.04; p=0.02). A negative correlation of serum vitamin level with granulocyte (p=0.01) was also found, but not with lymphocyte count (p=0.33). SLE patients have more deficiency of vitamin D than controls. This deficiency is not associated with disease activity but with leucopenia (granulocytopenia). Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

Prolactin, dendritic cells, and systemic lupus erythematosus.

PubMed

Jara, Luis J; Benitez, Gamaliel; Medina, Gabriela

2008-01-01

Dendritic cells (DC) play a central role in the induction of autoimmunity in T and B cells. DC express a high level of the major histocompatibility complex that interact with the receptors on T cells. Immature DC present antigens efficiently. Prolactin (PRL) participates in DC maturation. Systemic lupus erythematosus (SLE) is characterized by a loss of tolerance to self-antigens and persistent production of autoantibodies. Serum from SLE patients induces normal monocytes to differentiate into DC in correlation with disease activity depending on the actions of interferon-alpha, immune complexes, PRL, etc. High serum PRL levels have been found in a subset of SLE patients associated with active disease and organ involvement. It is possible that PRL interacts with DC, skewing its function from antigen presentation to a proinflammatory phenotype with high interferon-alpha production. Therefore, SLE is characterized by deficiency of DC functions and abnormal PRL secretion. The relationships between PRL and DC may have a role in the pathogenesis of SLE.

The SLE transcriptome exhibits evidence of chronic endotoxin exposure and has widespread dysregulation of non-coding and coding RNAs.

PubMed

Shi, Lihua; Zhang, Zhe; Yu, Angela M; Wang, Wei; Wei, Zhi; Akhter, Ehtisham; Maurer, Kelly; Costa Reis, Patrícia; Song, Li; Petri, Michelle; Sullivan, Kathleen E

2014-01-01

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. Purified monocytes from eight healthy age/gender matched controls and nine SLE patients (with low-moderate disease activity and lack of biologic drug use or immune suppressive treatment) were studied using RNA-seq. Quantitative RT-PCR was used to validate findings. Serum levels of endotoxin were measured by ELISA. We found that SLE patients had diminished expression of most endogenous retroviruses and small nucleolar RNAs, but exhibited increased expression of pri-miRNAs. Splicing patterns and polyadenylation were significantly altered. In addition, SLE monocytes expressed novel transcripts, an effect that was replicated by LPS treatment of control monocytes. We further identified increased circulating endotoxin in SLE patients. Monocytes from SLE patients exhibit globally dysregulated gene expression. The transcriptome is not simply altered by the transcriptional activation of a set of genes, but is qualitatively different in SLE. The identification of novel loci, inducible by LPS, suggests that chronic microbial translocation could contribute to the immunologic dysregulation in SLE, a new potential disease mechanism.

CCL21 and IP-10 as blood biomarkers for pulmonary involvement in systemic lupus erythematosus patients.

PubMed

Odler, B; Bikov, A; Streizig, J; Balogh, C; Kiss, E; Vincze, K; Barta, I; Horváth, I; Müller, V

2017-05-01

Biomarkers for pulmonary manifestations in systemic lupus erythematosus (SLE) are missing. Plasma samples of nine SLE patients with known pulmonary involvement (SLE pulm ) and nine SLE patients without pulmonary involvement (SLE) were tested by multiplex microarray analysis for various cyto- and chemokines. Significantly decreased lung function paramters for forced vital capacity (FVC), total lung capacity (TLC), diffusion capacity for carbon monoxide (DL CO ) and diffusion of CO corrected on lung volume (KL CO ) were observed in SLE pulm as compared to SLE patients. CC chemokine ligand 21 (CCL21) and interferon gamma-induced protein 10 (IP-10) levels were significantly higher in SLE pulm , than in patients without pulmonary manifestations. CCL21 correlated negatively with DL CO ( r = -0.73; p < 0.01) and KL CO ( r = -0.62; p < 0.01), while IP-10 with FVC and forced expiratory volume one second. Receiver Operating Characteristics (ROC) analysis confirmed high sensitivity and specificity for the separation of SLE patients with and without pulmonary involvement for the chemokines CCL21 (Area Under Curve (AUC): 0.85; sensitivity%: 88.90; specificity%: 75.00; p < 0.01) and IP-10 (AUC: 0.82; sensitivity%: 66.67, specificity%: 100; p < 0.01). Pleuropulmonary manifestations in SLE patients associated with lung functional and DL CO /KL CO changes and were associated with significant increase in CCL21 and IP-10. These chemokines might serve as potential biomarkers of lung involvement in SLE patients.

Dysregulation of Innate and Adaptive Serum Mediators Precedes Systemic Lupus Erythematosus Classification and Improves Prognostic Accuracy of Autoantibodies

PubMed Central

Guthridge, Joel M.; Bean, Krista M.; Fife, Dustin A.; Chen, Hua; Slight-Webb, Samantha R.; Keith, Michael P.; Harley, John B.; James, Judith A.

2016-01-01

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a poorly understood preclinical stage of immune dysregulation and symptom accrual. Accumulation of antinuclear autoantibody (ANA) specificities is a hallmark of impending clinical disease. Yet, many ANA-positive individuals remain healthy, suggesting that additional immune dysregulation underlies SLE pathogenesis. Indeed, we have recently demonstrated that interferon (IFN) pathways are dysregulated in preclinical SLE. To determine if other forms of immune dysregulation contribute to preclinical SLE pathogenesis, we measured SLE-associated autoantibodies and soluble mediators in samples from 84 individuals collected prior to SLE classification (average timespan = 5.98 years), compared to unaffected, healthy control samples matched by race, gender, age (± 5 years), and time of sample procurement. We found that multiple soluble mediators, including interleukin (IL)-5, IL-6, and IFN-γ, were significantly elevated in cases compared to controls more than 3.5 years pre-classification, prior to or concurrent with autoantibody positivity. Additional mediators, including innate cytokines, IFN-associated chemokines, and soluble tumor necrosis factor (TNF) superfamily mediators increased longitudinally in cases approaching SLE classification, but not in controls. In particular, levels of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were comparable in cases and controls until less than 10 months pre-classification. Over the entire pre-classification period, random forest models incorporating ANA and anti-Ro/SSA positivity with levels of IL-5, IL-6, and the IFN-γ-induced chemokine, MIG, distinguished future SLE patients with 92% (± 1.8%) accuracy, compared to 78% accuracy utilizing ANA positivity alone. These data suggest that immune dysregulation involving multiple pathways contributes to SLE pathogenesis. Importantly, distinct immunological profiles are predictive for individuals who will develop clinical SLE and may be useful for delineating early pathogenesis, discovering therapeutic targets, and designing prevention trials. PMID:27338520

Inhibition of aberrant circulating Tfh cell proportions by corticosteroids in patients with systemic lupus erythematosus.

PubMed

Feng, Xuebing; Wang, Dandan; Chen, Jingjing; Lu, Lin; Hua, Bingzhu; Li, Xia; Tsao, Betty P; Sun, Lingyun

2012-01-01

To observe the proportion of peripheral T follicular helper (Tfh) cells in patients with systemic lupus erythematosus (SLE) and to assess the role of steroids on Tfh cells from SLE patients. Peripheral blood mononuclear cells (PBMCs) from 42 SLE patients and 22 matched healthy subjects were collected to assess proportions of circulating CXCR5(+)PD1(+)/CD4(+) T cells (Tfh), CD4(+)CCR6(+) T cells (Th17-like) and CD19(+)CD138(+) plasma cells by flow cytometry. 8 of the patients had their blood redrawn within one week after receiving methylprednisolone pulse treatment. Disease activity was evaluated by SLE disease activity index. To test the effect of IL-21 and corticosteroids on Tfh cells in vitro, PBMCs harvested from another 15 SLE patients were cultured with medium, IL-21, or IL-21+ dexamethasone for 24 hours and 72 hours. PBMCs from an independent 23 SLE patients were cultured with different concentrations of dexamethasone for 24 hours. Compared to normal controls, percentages of circulating Tfh cells, but not Th17 cells, were elevated in SLE patients and correlated with disease activity. Proportions of Tfh cells in SLE patients were positively correlated with those of plasma cells and serum levels of antinuclear antibodies. After methylprednisolone pulse treatment, both percentages and absolute numbers of circulating Tfh cells were significantly decreased. In vitro cultures showed an increase of Tfh cell proportion after IL-21 stimulation that was totally abolished by the addition of dexamethasone. Both 0.5 and 1 µM dexamethasone decreased Tfh cells dose dependently (overall p = 0.013). We demonstrated that elevated circulating Tfh cell proportions in SLE patients correlated with their disease activities, and circulating levels of plasma cells and ANA. Corticosteroids treatment down-regulated aberrant circulating Tfh cell proportions both in vivo and in vitro, making Tfh cells a new treatment target for SLE patients.

Impaired Cytokine Responses to Epstein-Barr Virus Antigens in Systemic Lupus Erythematosus Patients

PubMed Central

Draborg, Anette Holck; Sandhu, Noreen; Larsen, Nanna; Lisander Larsen, Janni; Jacobsen, Søren; Houen, Gunnar

2016-01-01

We analyzed cytokine responses against latent and lytic Epstein-Barr virus (EBV) antigens in systemic lupus erythematosus (SLE) patients and healthy controls (HCs) to obtain an overview of the distinctive immune regulatory response in SLE patients and to expand the previously determined impaired EBV-directed T-cell response. The concentrations of 14 cytokines (IL2, IL4, IL5, IL6, IL10, IL12, IL17, IL18, IL1β, IFNγ, TNFα, TNFβ, TGFβ, and GM-CSF) were quantified upon stimulation of whole blood with latent state antigen EBNA1, lytic cycle antigen EBV-EA/D, and the superantigen SEB. To avoid results affected by lack of lymphocytes, we focused on SLE patients with normal levels. Decreased induction of IL12, IFNγ, IL17, and IL6 upon EBNA1 stimulation and that of IFNγ, IL6, TNFβ, IL1β, and GM-CSF upon EBV-EA/D stimulation were detected in SLE patients compared to HCs. IFNγ responses, especially, were shown to be reduced. Induction of several cytokines was furthermore impaired in SLE patients upon SEB stimulation, but no difference was observed in basic levels. Results substantiate the previously proposed impaired regulation of the immune response against latent and lytic cycle EBV infection in SLE patients without lymphopenia. Furthermore, results indicate general dysfunction of leukocytes and their cytokine regulations in SLE patients. PMID:27110576

Antigen-specific antibody response in juvenile-onset SLE patients following routine immunization with tetanus toxoid.

PubMed

Kashef, Sara; Ghazizadeh, Farid; Derakhshan, Ali; Farjadian, Shirin; Alyasin, Soheila

2008-09-01

Infection is now the most common cause of morbidity in Systemic Lupus Erythematosus (SLE). There is lack of information regarding the specific antibody formation in response to vaccines in young SLE patients. To determine the efficacy of anti-tetanus antibody response in young patients with SLE. Forty SLE patients with mean age of 14.1 years (range: 7-21) and 60 age and sex matched normal controls were enrolled in this study over a period of one year. Diagnosis was made according to the ACR criteria and disease activity was determined based on SLE Disease Activity Index (SLEDAI). All patients and controls had received the complete schedule of tetanus vaccinations consisting of three primary doses and two boosters by the age of six. Serum immunoglobulins and anti-tetanus antibody titers were determined by Nephelometry and ELISA. Anti-tetanus antibody levels greater than 0.1 IU/ml have been suggested as protective. In all of the patients and controls anti-tetanus antibody titer was > 0.1 IU/ml. IgG, IgA, and IgM levels were in the normal range for their age. Mean disease activity score was 4.9 (range: 0-16). There was no association between SLEDAI score and anti-tetanus antibody response. School age onset and immunosuppressive therapy does not seem to interfere with development of consistent immunity to tetanus vaccine in young SLE patients.

High level of reactive oxygen species impaired mesenchymal stem cell migration via overpolymerization of F-actin cytoskeleton in systemic lupus erythematosus.

PubMed

Shi, D; Li, X; Chen, H; Che, N; Zhou, S; Lu, Z; Shi, S; Sun, L

2014-12-01

Some lines of evidence have demonstrated abnormalities of bone marrow mesenchymal stem cells (MSCs) in systemic lupus erythematosus (SLE) patients, characterized by defective phenotype of MSCs and slower growth with enhanced apoptosis and senescence. However, whether SLE MSCs demonstrate aberrant migration capacity or abnormalities in cytoskeleton are issues that remain poorly understood. In this study, we found that MSCs from SLE patients did show impairment in migration capacity as well as abnormalities in F-actin cytoskeleton, accompanied by a high level of intracellular reactive oxygen species (ROS). When normal MSCs were treated in vitro with H2O2, which increases intracellular ROS level as an oxidant, both reorganization of F-actin cytoskeleton and impairment of migration capability were observed. On the other hand, treatment with N-acetylcysteine (NAC), as an exogenous antioxidant, made F-actin more orderly and increased migration ratio in SLE MSCs. In addition, oral administration of NAC markedly reduced serum autoantibody levels and ameliorated lupus nephritis (LN) in MRL/lpr mice, partially reversing the abnormalities of MSCs. These results indicate that overpolymerization of F-actin cytoskeleton, which may be associated with high levels of ROS, causes impairment in the migration capacity of SLE MSCs and that oral administration of NAC may have potential therapeutic effects on MRL/lpr mice. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Hypogammaglobulinemia in pediatric systemic lupus erythematosus.

PubMed

Lim, E; Tao, Y; White, A J; French, A R; Cooper, M A

2013-11-01

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease typically associated with elevated serum immunoglobulin G (IgG). Hypogammaglobulinemia in SLE patients has been attributed to immunosuppressive treatment or a transient effect associated with nephrotic syndrome. We retrospectively reviewed pediatric SLE patients from a single institution to identify patients with hypogammaglobulinemia and risk factors for hypogammaglobulinemia. A total of 116 pediatric SLE cases from 1997 to 2011 were reviewed and patients with hypogammaglobulinemia (IgG < 500 mg/dl) were identified. The two cohorts were evaluated for association with age, sex, presence of lupus nephritis at SLE diagnosis, disease activity at diagnosis, initial IgG level, and drug treatment. Eighty-six patients were included in our study, with a median age of 15 years and a median follow-up of 39.5 months. Seven percent (six of 86) of patients had hypogammaglobulinemia with a median onset of 27 months (0-72 months) after SLE diagnosis. Significant associations were noted for white race (p value 0.029), male sex (p value 0.009), and the presence of lupus nephritis at SLE diagnosis (p value 0.004). Use of immunosuppressive treatment did not show a statistical association with hypogammaglobulinemia, although two of the patients with hypogammaglobulinemia did receive rituximab. Most patients with hypogammaglobulinemia received intravenous immunoglobulin (IVIG) replacement therapy because of infections and/or concern for infection. Measurement of immunoglobulin levels during treatment in SLE could help identify patients with hypogammaglobulinemia who might require more aggressive follow-up to monitor for increased risk of infection and need for IVIG treatment. A prospective study is needed to validate associated risk factors identified in this study.

IFN-γ, CXCL16, uPAR: potential biomarkers for systemic lupus erythematosus.

PubMed

Wen, Si; He, Fang; Zhu, Xuejing; Yuan, Shuguang; Liu, Hong; Sun, Lin

2018-01-01

IFN-γ, CXCL16 and uPAR have recently been regarded as potential biomarkers in systemic lupus erythematosus (SLE). However, few researches have focused on the comparison of these three markers in SLE. We conducted this study to evaluate their role as biomarkers of disease activity and renal damage. We enrolled 50 SLE patients with or without lupus nephritis (LN) and 15 healthy control subjects. The levels of IFN-γ, CXCL16, uPAR in serum, urine and renal tissues were detected by ELISA or immunohistochemistry. Relevant clinical and laboratory features were recorded. Serum and urine IFN-γ, CXCL16 and suPAR levels in SLE patients were significantly higher than that in healthy controls. Moreover, LN patients had higher levels than non-LN patients. A positive correlation was observed between these markers, and disease activity and suPAR had a stronger association with disease activity. The expression of these biomarkers in renal tissues was significantly higher in LN patients and was also associated with the activity of pathological lesions. IFN-γ, CXCL16 and uPAR are promising as effective biomarkers of disease activity, renal damage, and the activity of pathological lesions in SLE.

Association of large intergenic noncoding RNA expression with disease activity and organ damage in systemic lupus erythematosus.

PubMed

Wu, Yanfang; Zhang, Feifei; Ma, Jianyang; Zhang, Xiaoyan; Wu, Lingling; Qu, Bo; Xia, Shiwei; Chen, Shunle; Tang, Yuanjia; Shen, Nan

2015-05-21

Despite growing evidence that large intergenic noncoding RNAs (lincRNAs) can regulate gene expression and widely take part in normal physiological and disease conditions, our knowledge of systemic lupus erythematosus (SLE)-related lincRNAs remains limited. The aim of this study was to detect the levels of four lincRNAs (ENST00000500949: linc0949, ENST00000500597: linc0597, ENST00000501992: linc1992, and ENST00000523995: linc3995) involved in innate immunity in the peripheral blood mononuclear cells (PBMCs) of patients with SLE and correlate these lincRNA levels with disease activity, organ damage, clinical features and medical therapies. PBMCs were obtained from 102 patients with SLE, 54 patients with rheumatoid arthritis (RA) and 76 healthy donors. lincRNA expression levels were measured by real-time quantitative polymerase chain reaction. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, and organ damage was evaluated with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. linc0949 and linc0597 were significantly decreased in patients with SLE compared with patients with RA and healthy control subjects. linc0949 was correlated with SLEDAI-2K score (r = -0.329, P = 0.0007), as well as with complement component C3 level (r = 0.348, P = 0.0003). The level of linc0949 was also reduced in patients with SLE who had the presence of cumulative organ damage. In addition, decreasing expression of linc0949 was associated with lupus nephritis. linc0949 expression significantly increased after treatment, whereas neither disease activity nor organ damage correlated with linc0597 expression. Our results provide novel empirical evidence that linc0949 could be a potential biomarker for diagnosis, disease activity and therapeutic response in SLE.

Anti-Müllerian hormone in reproductive age women with systemic lupus erythematosus.

PubMed

Velarde-Ochoa, María Del Carmen; Esquivel-Valerio, Jorge Antonio; Vega-Morales, David; Skinner-Taylor, Cassandra Michele; Galarza-Delgado, Dionicio Ángel; Garza-Elizondo, Mario Alberto

2015-01-01

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune systemic and chronic disease. Fertility in SLE patients is considered normal; factors that have been associated in these patients with ovarian failure are: disease activity, autoantibodies, and the use of cytotoxic agents. The anti-Müllerian hormone (AMH) is a marker that helps to determine the follicular reserve. Determinate the objective was to determine AMH levels in women of reproductive age with SLE. We included 65 women with SLE classified according to the 1997 ACR criteria, 18- to 40-years old. We obtained demographic, clinical, obstetric, and gynecological characteristics as well as serum levels of AMH. We performed a bivariate analysis among patients with low ovarian reserve and those with normal ovarian reserve. We also performed a correlation analysis between activity and damage index and between the cumulative cyclophosphamide dose and AMH levels. We found a median of serum AMH in SLE patients of .61 ng/mL. The prevalence of low ovarian reserve in our study was 3.07%. We found a median MEX-SLEDAI score of 1 point and the median SLICC score was 2 points. Twenty-five patients (38.4%) had used cyclophosphamide and their cumulative average dose was 7.5 grams. We found a median of AMH of .61 ng/mL in our population. The prevalence of low ovarian reserve in SLE patients was 3.07%. We did not find a correlation between AMH levels, the use of cyclophosphamide, and disease activity. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Reduction of nitric oxide and DNA/RNA oxidation products are associated with active disease in systemic lupus erythematosus patients.

PubMed

Iriyoda, T M V; Stadtlober, N; Lozovoy, M A B; Delongui, F; Costa, N T; Reiche, E M V; Dichi, I; Simão, A N C

2017-09-01

The aims of the present study were to evaluate biomarkers of oxidative and nitrosative stress in systemic lupus erythematosus (SLE) patients, in particular products of DNA/RNA oxidative damage and their correlation with disease activity. This study included 188 controls and 203 patients; 153 with inactive SLE (SLEDAI < 6) and 50 with active SLE (SLEDAI ≥ 6) without renal impairment. Oxidative stress was assessed by tert-butyl hydroperoxide-initiated by chemiluminescence, advanced oxidation protein products (AOPP), total radical-trapping antioxidant parameter (TRAP), nitric oxide metabolites (NOx), and DNA/RNA oxidation products. Patients with SLE showed increased oxidative stress, as demonstrated by the augmentation of lipid hydroperoxides ( p < 0.0001) and AOPP ( p < 0.001) and reduced total antioxidant capacity ( p < 0.0001), without differences between patients with active disease and in remission. NOx levels and DNA/RNA oxidation products were inversely and independently associated with disease activity ( p < 0.0001 and p = 0.021, respectively), regardless of BMI and prednisone use. The linear regression analysis showed that about 5% of the SLEDAI score can be explained by the levels of DNA/RNA oxidation products ( r 2 :0.051; p = 0.002) and about 9% of this score by the levels of NOx ( r 2 :0.091; p < 0.0001). This study provides evidence for an inverse association between serum NOx levels and DNA/RNA oxidation products and SLE disease activity, suggesting that oxidative/nitrosative stress markers may be useful in evaluating SLE disease activity and progression of the disease.

Diminished IL-17A levels may protect filarial-infected individuals from development of rheumatoid arthritis and systemic lupus erythematosus.

PubMed

Panda, A K; Das, B K

2017-04-01

Nematode infections have been observed to inversely correlate with autoimmune disorders. Recently, we have shown the absence of filarial infection in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who live in filarial-endemic areas. The mechanism(s) by which filarial-infected individuals are protected against the development of RA or SLE are unknown. In mice CIA, an experimental model for RA, ES-62, an execratory product of rodent filarial nematode , has been shown to improve arthritis through suppression of the IL-17 pathway. A total of 160 individuals, 40 each of endemic normal, filarial-infected cases, SLE and RA patients, from filarial-endemic areas, were enrolled in the study. Plasma levels of IL17-A, IFN-α and TNF-α were quantified by enzyme-linked immunosorbent assay (ELISA). RA and SLE patients displayed significantly higher plasma IL-17A, IFN-α and TNF-α levels compared to endemic normal and infected individuals. Furthermore, IL-17A levels were significantly low in participants with filarial infection compared to endemic controls ( p < 0.05). Interestingly, plasma IL-17A levels correlated inversely with circulating filarial antigen (CFA) ( p = 0.004, Spearman r = -0.51). Filarial infection was associated with low plasma IL-17A levels, a mechanism by which it possibly protects individuals in filarial-endemic areas from the development of autoimmune disorders like RA and SLE.

Role of vitamin D deficiency in systemic lupus erythematosus incidence and aggravation.

PubMed

Hassanalilou, Tohid; Khalili, Leila; Ghavamzadeh, Saeid; Shokri, Ali; Payahoo, Laleh; Bishak, Yaser Khaje

2017-12-26

Vitamin D is one of the main groups of sterols; playing an important role in phospho-calcic metabolism. The conversion of 7-dehydrocholesterol to pre- vitamin D3 in the skin, through solar ultraviolet B radiation, is the main source of vitamin D. Since lupus patients are usually photosensitive, the risk of developing vitamin D deficiency in is high in this population. Although evidences showed the connotation between systemic lupus erythematosus (SLE) and vitamin D through which SLE can lead to lower vitamin D levels, it is also important to consider the possibility that vitamin D deficiency may have a causative role in SLE etiology. This paper analyzes existing data from various studies to highlight the role of vitamin D deficiency in SLE occurrence and aggravation and the probable efficacy of vitamin D supplementation on SLE patients. We searched "Science Direct" and "Pub Med" using "Vitamin D" and "SLE" for finding the studies focusing on the association between vitamin D deficiency and SLE incidence and consequences. Evidences show that vitamin D plays an important role in the pathogenesis and progression of SLE and vitamin D supplementation seems to ameliorate inflammatory and hemostatic markers; so, can improve clinical subsequent.

Social Determinants of Health, the Chronic Care Model, and Systemic Lupus Erythematosus

PubMed Central

Williams, Edith M.; Ortiz, Kasim; Browne, Teri

2014-01-01

Systemic lupus erythematosus (SLE) is a chronic inflammatory rheumatic disease that disproportionately affects African Americans and other minorities in the USA. Public health attention to SLE has been predominantly epidemiological. To better understand the effects of this cumulative disadvantage and ultimately improve the delivery of care, specifically in the context of SLE, we propose that more research attention to the social determinants of SLE is warranted and more transdisciplinary approaches are necessary to appropriately address identified social determinants of SLE. Further, we suggest drawing from the chronic care model (CCM) for an understanding of how community-level factors may exacerbate disparities explored within social determinant frameworks or facilitate better delivery of care for SLE patients. Grounded in social determinants of health (SDH) frameworks and the CCM, this paper presents issues relative to accessibility to suggest that more transdisciplinary research focused on the role of place could improve care for SLE patients, particularly the most vulnerable patients. It is our hope that this paper will serve as a springboard for future studies to more effectively connect social determinants of health with the chronic care model and thus more comprehensively address adverse health trajectories in SLE and other chronic conditions. PMID:26464854

Genetic variation in C-reactive protein (CRP) gene may be associated with risk of systemic lupus erythematosus and CRP concentrations.

PubMed

Shih, P Betty; Manzi, Susan; Shaw, Penny; Kenney, Margaret; Kao, Amy H; Bontempo, Franklin; Barmada, M Michael; Kammerer, Candace; Kamboh, M Ilyas

2008-11-01

The gene coding for C-reactive protein (CRP) is located on chromosome 1q23.2, which falls within a linkage region thought to harbor a systemic lupus erythematosus (SLE) susceptibility gene. Recently, 2 single-nucleotide polymorphisms (SNP) in the CRP gene (+838, +2043) have been shown to be associated with CRP concentrations and/or SLE risk in a British family-based cohort. Our study was done to confirm the reported association in an independent population-based case-control cohort, and also to investigate the influence of 3 additional CRP tagSNP (-861, -390, +90) on SLE risk and serum CRP concentrations. DNA from 337 Caucasian women who met the American College of Rheumatology criteria for definite (n = 324) or probable (n = 13) SLE and 448 Caucasian healthy female controls was genotyped for 5 CRP tagSNP (-861, -390, +90, +838, +2043). Genotyping was performed using restriction fragment length polymorphism-polymerase chain reaction, pyrosequencing, or TaqMan assays. Serum CRP levels were measured using ELISA. Association studies were performed using the chi-squared distribution, Z-test, Fisher's exact test, and analysis of variance. Haplotype analysis was performed using EH software and the haplo.stats package in R 2.1.2. While none of the SNP were found to be associated with SLE risk individually, there was an association with the 5 SNP haplotypes (p < 0.001). Three SNP (-861, -390, +90) were found to significantly influence serum CRP level in SLE cases, both independently and as haplotypes. Our data suggest that unique haplotype combinations in the CRP gene may modify the risk of developing SLE and influence circulating CRP levels.

Functional polymorphisms of the coagulation factor II gene (F2) and susceptibility to systemic lupus erythematosus (SLE)

PubMed Central

Demirci, F. Yesim K.; Dressen, Amy S.; Kammerer, Candace M.; Barmada, M. Michael; Kao, Amy H.; Ramsey-Goldman, Rosalind; Manzi, Susan; Kamboh, M. Ilyas

2011-01-01

Objective Two F2 functional polymorphisms, rs1799963 (G20210A) and rs3136516 (A19911G), are known to be associated with elevated prothrombin (encoded by F2) levels/activity and thrombosis risk. Since systemic lupus erythematosus (SLE) patients have high risk of thrombosis and accelerated atherosclerosis and also high prevalence of anti-prothrombin antibodies, we hypothesized that these two F2 polymorphisms could affect SLE risk. Methods We investigated these polymorphisms in 627 women with SLE (84% Caucasian Americans, 16% African Americans) and 657 female controls (78% Caucasian Americans, 22% African Americans). Results While the rs1799963 A allele was almost absent in African Americans, it was present at ~2% frequency in Caucasian Americans and showed no significant association with SLE. The rs3136516 G allele frequency was significantly higher in Caucasian SLE cases than controls (48.4% vs. 43.7%) with a covariate-adjusted odds ratio (OR) of 1.22 (95%CI: 1.03–1.46; P = 0.023). The association was replicated in African Americans (rs3136516 G allele frequency: 91.2% in cases vs. 82.2% in controls) with an adjusted OR of 1.96 (95%CI: 1.08–3.58; P = 0.022). Stratification of Caucasian SLE patients based on the presence or absence of cardiac and vascular events (CVE) revealed stronger association with the CVE-positive SLE subgroup than the CVE-negative SLE subgroup (OR: 1.42 vs. 1.20). Prothrombin activity measurements in a subset of SLE cases demonstrated higher activity in the carriers of the rs3136516 G allele. Conclusion Our results suggest a potential role for prothrombin and the crosstalk between hemostatic and immune/inflammatory systems in SLE and SLE-associated cardiovascular events, which warrant further investigation in independent samples. PMID:21239755

Prevalence and correlates of suicidal ideation in SLE inpatients: Chinese experience.

PubMed

Xie, Lun-Fang; Chen, Pei-Ling; Pan, Hai-Feng; Tao, Jin-Hui; Li, Xiang-Pei; Zhang, Yu-Jing; Zhai, Yu; Ye, Dong-Qing

2012-09-01

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs. Because of double damages of body and mind, SLE patients are in a potential risk of suicide. Many factors may contribute to the occurrence of suicide in SLE: socioeconomic factors, medical factors, mental health, family support and coping style. This study aims to investigate the prevalence and correlates of suicidal ideation in SLE inpatients in China in order to determine whether they had risk of suicide, and if so, what factors should be paid more attention to prevent suicide in wards. A total of 285 SLE patients were interviewed with questionnaires on suicidal ideation and socio-demographic characteristics, Beck Depression Inventory (BDI), Family APGAR and Trait Coping Style Questionnaire (TCSQ). Disease activity was assessed with SLE Disease Activity Index. The other medical information was collected from the patients' medical records. In total, 34.4% of SLE patients had current suicidal ideation. Significant individual risk factors for current suicidal ideation in SLE patients included having religious belief, heavy self-reported financial burdens, long duration of SLE, low level of family functioning and negative coping style. And in the presence of these risk factors, being separated, divorced or widowed, having premorbid suicidal ideation and depression were independent predictors of suicidal ideation. In summary, the rate of suicidal ideation in SLE patients in China is higher than that in other countries. Factors that contribute to risk of suicidal ideation include social and cultural domains and physical and psychological health. Although the association of suicidal ideation to religions and medical factors is still to be investigated, these findings may give some references to suicide prevention efforts for SLE patients in China.

Epstein-Barr virus-associated infectious mononucleosis and risk of systemic lupus erythematosus.

PubMed

Ulff-Møller, Constance J; Nielsen, Nete M; Rostgaard, Klaus; Hjalgrim, Henrik; Frisch, Morten

2010-09-01

Elevated levels of serological markers of EBV infection in patients with SLE and observations that infectious mononucleosis (IM) may precede some cases of SLE suggest a possible role of EBV in the aetiology of SLE. We evaluated the relationship between EBV-associated IM and subsequent risk of SLE in a population-based cohort study. We followed cohorts of Danes tested serologically for IM using the Paul-Bunnell (PB) heterophile antibody test between 1939 and 1989, and patients hospitalized with IM between 1977 and 2007 for subsequent first hospitalizations with SLE in the period 1977-2008. Standardized incidence ratios (SIRs) with 95% CI served as measures of relative risk. Risk of SLE was not increased either in individuals with a positive PB test (SIR = 1.1; 95% CI 0.8, 1.6; n = 27) or in individuals hospitalized with IM (SIR = 1.3; 95% CI 0.7, 2.2; n = 12). However, SLE risk in PB-negative individuals was significantly increased (SIR = 2.6; 95% CI 2.1, 3.2; n = 82), a risk that was particularly high 1-4 years after the PB test (SIR = 6.6; 95% CI 3.3, 13.2) and remained significantly elevated for >25 years. EBV-associated IM does not seem to be a risk factor for SLE. The temporal pattern of increased SLE risk in individuals with a negative PB test suggests that some patients who go on to develop SLE may present with unspecific symptoms, for which they may be tested for IM, long in advance of their SLE diagnosis.

Regional and national differences in stressful life events: The role of cultural factors, economic development, and gender.

PubMed

Vázquez, José Juan; Panadero, Sonia; Martín, Rosa M

2015-07-01

The study analyzed differences in the risk of experiencing stressful life events (SLE) according to cultural factors, the level of economic development of the region inhabited, and gender. Information was gathered on the number and nature of SLE experienced by a sample of 604 undergraduates from 3 regions with very different levels of economic development: Madrid (Spain), León (Nicaragua), and Bilwi (Nicaragua). The results indicated a greater risk of experiencing SLE among undergraduates from Nicaragua, but few differences attributed to the undergraduates' gender or the level of economic development in the region they inhabit within the same country. (c) 2015 APA, all rights reserved).

Coagulation cascade and complement system in systemic lupus erythematosus

PubMed Central

Liang, Yan; Xie, Shang-Bo; Wu, Chang-Hao; Hu, Yuan; Zhang, Qin; Li, Si; Fan, Yin-Guang; Leng, Rui-Xue; Pan, Hai-Feng; Xiong, Hua-Bao; Ye, Dong-Qing

2018-01-01

This study was conducted to (1) characterize coagulation cascade and complement system in systemic lupus erythematosus (SLE); (2) evaluate the associations between coagulation cascade, complement system, inflammatory response and SLE disease severity; (3) test the diagnostic value of a combination of D-dimer and C4 for lupus activity. Transcriptomics, proteomics and metabolomics were performed in 24 SLE patients and 24 healthy controls. The levels of ten coagulations, seven complements and three cytokines were measured in 112 SLE patients. Clinical data were collected from 2025 SLE patients. The analysis of multi-omics data revealed the common links for the components of coagulation cascade and complement system. The results of ELISA showed coagulation cascade and complement system had an interaction effect on SLE disease severity, this effect was pronounced among patients with excess inflammation. The analysis of clinical data revealed a combination of D-dimer and C4 provided good diagnostic performance for lupus activity. This study suggested that coagulation cascade and complement system become ‘partners in crime’, contributing to SLE disease severity and identified the diagnostic value of D-dimer combined with C4for lupus activity. PMID:29599912

Schramm-Loewner evolution and perimeter of percolation clusters of correlated random landscapes.

PubMed

de Castro, C P; Luković, M; Pompanin, G; Andrade, R F S; Herrmann, H J

2018-03-27

Motivated by the fact that many physical landscapes are characterized by long-range height-height correlations that are quantified by the Hurst exponent H, we investigate the statistical properties of the iso-height lines of correlated surfaces in the framework of Schramm-Loewner evolution (SLE). We show numerically that in the continuum limit the external perimeter of a percolating cluster of correlated surfaces with H ∈ [-1, 0] is statistically equivalent to SLE curves. Our results suggest that the external perimeter also retains the Markovian properties, confirmed by the absence of time correlations in the driving function and the fact that the latter is Gaussian distributed for any specific time. We also confirm that for all H the variance of the winding angle grows logarithmically with size.

Two Independent Functional Risk Haplotypes in TNIP1 are Associated with Systemic Lupus Erythematosus

PubMed Central

Adrianto, Indra; Wang, Shaofeng; Wiley, Graham B.; Lessard, Christopher J.; Kelly, Jennifer A.; Adler, Adam J.; Glenn, Stuart B.; Williams, Adrienne H.; Ziegler, Julie T.; Comeau, Mary E.; Marion, Miranda C.; Wakeland, Benjamin E.; Liang, Chaoying; Kaufman, Kenneth M.; Guthridge, Joel M.; Alarcón-Riquelme, Marta E.; Alarcón, Graciela S.; Anaya, Juan-Manuel; Bae, Sang-Cheol; Kim, Jae-Hoon; Joo, Young Bin; Boackle, Susan A.; Brown, Elizabeth E.; Petri, Michelle A.; Ramsey-Goldman, Rosalind; Reveille, John D.; Vilá, Luis M.; Criswell, Lindsey A.; Edberg, Jeffrey C.; Freedman, Barry I.; Gilkeson, Gary S.; Jacob, Chaim O.; James, Judith A.; Kamen, Diane L.; Kimberly, Robert P.; Martin, Javier; Merrill, Joan T.; Niewold, Timothy B.; Pons-Estel, Bernardo A.; Scofield, R. Hal; Stevens, Anne M.; Tsao, Betty P.; Vyse, Timothy J.; Langefeld, Carl D.; Harley, John B.; Wakeland, Edward K.; Moser, Kathy L.; Montgomery, Courtney G.; Gaffney, Patrick M.

2012-01-01

Objective Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified more than 30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting the NF-κB signaling. In order to better understand the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway, we analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog, TNIP2, in case-control sets of diverse ethnic origins. Methods We fine-mapped TNIP1, TNIP2, and TAX1BP1 in a total of 8372 SLE cases and 7492 healthy controls from European-ancestry, African-American, Hispanic, East Asian, and African-American Gullah populations. Levels of TNIP1 mRNA and ABIN1 protein were analyzed using quantitative RT-PCR and Western blotting, respectively, in EBV-transformed human B cell lines. Results We found significant associations between genetic variants within TNIP1 and SLE but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified two independent risk haplotypes within TNIP1 in individuals of European-ancestry that were also present in African-American and Hispanic populations. These risk haplotypes produced lower levels of TNIP1 mRNA and ABIN1 protein suggesting they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. Conclusion Our results confirmed the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis. PMID:22833143

Prevalence, severity, and clinical features of acute and chronic pancreatitis in patients with systemic lupus erythematosus.

PubMed

Wang, Qiang; Shen, Min; Leng, Xiaomei; Zeng, Xiaofeng; Zhang, Fengchun; Qian, Jiaming

2016-10-01

Pancreatitis is a rare, life-threatening complication of systemic lupus erythematosus (SLE). This study aimed to describe the clinical features of acute pancreatitis (AP) and chronic pancreatitis (CP) in patients with SLE. Data of patients who fulfilled the revised criteria of the American Rheumatism Association for diagnosis of SLE were retrospectively analyzed. SLE activity was graded according to the SLE Disease Activity Index. Logistic regression analysis was conducted to find out independent associations. Survival rates were estimated by using Kaplan-Meier plots. This study included 5665 SLE patients admitted between January 1983 and January 2014, of whom 52 patients were diagnosed with pancreatitis. Pancreatitis prevalence in SLE patients was 0.92 % (52/5665). AP (0.8 %, 46/5665) was more prevalent than CP (0.1 %, 6/5665), presented mostly during active SLE, and affected more organs. Hypertriglyceridemia occurred in 76.9 % of AP patients and in none of the CP patients. AP patients were divided into severe (n = 10) or mild (n = 20) cases. The average triglyceride level in severe AP cases was higher than that in mild AP cases (P = 0.006), and the mortality rate of lupus-associated AP was 32.6 % (15/46). Concomitant infections and thrombocytopenia were independently associated with poor prognosis (P < 0.001, P = 0.028, respectively). There were significant differences in the clinical manifestations of AP and CP. Patients with severe AP were found to have a higher incidence of concomitant infection and serum triglyceride levels. Concomitant infections and thrombocytopenia were independent risk factors for poor prognosis.

Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus.

PubMed

Julià, Antonio; López-Longo, Francisco Javier; Pérez Venegas, José J; Bonàs-Guarch, Silvia; Olivé, Àlex; Andreu, José Luís; Aguirre-Zamorano, Mª Ángeles; Vela, Paloma; Nolla, Joan M; de la Fuente, José Luís Marenco; Zea, Antonio; Pego-Reigosa, José María; Freire, Mercedes; Díez, Elvira; Rodríguez-Almaraz, Esther; Carreira, Patricia; Blanco, Ricardo; Taboada, Víctor Martínez; López-Lasanta, María; Corbeto, Mireia López; Mercader, Josep M; Torrents, David; Absher, Devin; Marsal, Sara; Fernández-Nebro, Antonio

2018-05-30

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with a complex genetic inheritance. Genome-wide association studies (GWAS) have significantly increased the number of significant loci associated with SLE risk. To date, however, established loci account for less than 30% of the disease heritability and additional risk variants have yet to be identified. Here we performed a GWAS followed by a meta-analysis to identify new genome-wide significant loci for SLE. We genotyped a cohort of 907 patients with SLE (cases) and 1524 healthy controls from Spain and performed imputation using the 1000 Genomes reference data. We tested for association using logistic regression with correction for the principal components of variation. Meta-analysis of the association results was subsequently performed on 7,110,321 variants using genetic data from a large cohort of 4036 patients with SLE and 6959 controls of Northern European ancestry. Genetic association was also tested at the pathway level after removing the effect of known risk loci using PASCAL software. We identified five new loci associated with SLE at the genome-wide level of significance (p < 5 × 10 - 8 ): GRB2, SMYD3, ST8SIA4, LAT2 and ARHGAP27. Pathway analysis revealed several biological processes significantly associated with SLE risk: B cell receptor signaling (p = 5.28 × 10 - 6 ), CTLA4 co-stimulation during T cell activation (p = 3.06 × 10 - 5 ), interleukin-4 signaling (p = 3.97 × 10 - 5 ) and cell surface interactions at the vascular wall (p = 4.63 × 10 - 5 ). Our results identify five novel loci for SLE susceptibility, and biologic pathways associated via multiple low-effect-size loci.

Serum osteopontin and vitronectin levels in systemic sclerosis.

PubMed

Gundogdu, Baris; Yolbas, Servet; Yilmaz, Musa; Aydin, Suleyman; Koca, Sulayman Serdar

2017-11-01

Osteopontin a matricellular protein has pro-fibrotic effects and binds integrin such as αvβ1 and αvβ3. Vitronectin is one of the integrin αvβ3 ligands and is a multifunctional glycoprotein. The aim of the present study was to evaluate serum osteopontin and vitronectin levels in a cohort of patients with systemic sclerosis (SSc). Eighty-six patients with SSc, 46 patients with systemic lupus erythematosus (SLE), and 38 healthy controls (HC) were enrolled in the study. Serum osteopontin, vitronectin, IL-6, and TGF-β levels were analyzed. Serum osteopontin levels were higher in the SSc and SLE groups compared to the HC group (p < 0.01 and p < 0.001, respectively). However, it was not correlated with disease activity and severity scores in the SSc group. On the other hand, serum vitronectin levels were lower in the SSc group than in the SLE and HC groups (p < 0.001 for both). These results may suggest that osteopontin levels may be increased due to the inflammatory process and osteopontin has not a specific role on fibrosis in SSc. On the other hand, serum vitronectin levels decrease in SSc in contrast to SLE. It may be concluded that the one cause of decreased serum vitronectin levels in SSc may be its accumulation in fibrotic area.

SER consensus statement on the use of biologic therapy for systemic lupus erythematosus.

PubMed

Calvo-Alén, Jaime; Silva-Fernández, Lucía; Úcar-Angulo, Eduardo; Pego-Reigosa, José María; Olivé, Alejandro; Martínez-Fernández, Carmen; Martínez-Taboada, Víctor; Luis Marenco, José; Loza, Estíbaliz; López-Longo, Javier; Gómez-Reino, Juan Jesús; Galindo-Izquierdo, María; Fernández-Nebro, Antonio; Cuadrado, María José; Aguirre-Zamorano, María Ángeles; Zea-Mendoza, Antonio; Rúa-Figueroa, Iñigo

2013-01-01

To provide a reference to rheumatologists and other physicians involved in the treatment of systemic lupus erythematosus (SLE) who are using, or about to use biologic therapies. Recommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and degree of recommendation were classified according to a model proposed by the Center for Evidence Based Medicine at Oxford. The level of agreement was established through a Delphi technique. We have produced recommendations on the use of belimumab, the only biological agent with approved indications for SLE, and other biological agents without an indication for SLE. The objective of treatment is to achieve a complete clinical response, taken as the absence of perceived or evident disease activity. Nuances regarding the use of biologic therapies in SLE were reviewed as well, such as the evaluation that should be performed prior to administration and the follow up of patients undergoing these therapies. We present the SER recommendations for the use of biological therapies in patients with SLE. Copyright © 2013 Elsevier España, S.L. All rights reserved.

High ACSL5 Transcript Levels Associate with Systemic Lupus Erythematosus and Apoptosis in Jurkat T Lymphocytes and Peripheral Blood Cells

PubMed Central

2011-01-01

Background Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease in which increased apoptosis and decreased apoptotic cells removal has been described as most relevant in the pathogenesis. Long-chain acyl-coenzyme A synthetases (ACSLs) have been involved in the immunological dysfunction of mouse models of lupus-like autoimmunity and apoptosis in different in vitro cell systems. The aim of this work was to assess among the ACSL isoforms the involvement of ACSL2, ACSL4 and ACSL5 in SLE pathogenesis. Findings With this end, we determined the ACSL2, ACSL4 and ACSL5 transcript levels in peripheral blood mononuclear cells (PBMCs) of 45 SLE patients and 49 healthy controls by quantitative real time-PCR (q-PCR). We found that patients with SLE had higher ACSL5 transcript levels than healthy controls [median (range), healthy controls = 16.5 (12.3–18.0) vs. SLE = 26.5 (17.8–41.7), P = 3.9×10 E-5] but no differences were found for ACSL2 and ACSL4. In in vitro experiments, ACSL5 mRNA expression was greatly increased when inducing apoptosis in Jurkat T cells and PBMCs by Phorbol-Myristate-Acetate plus Ionomycin (PMA+Io). On the other hand, short interference RNA (siRNA)-mediated silencing of ACSL5 decreased induced apoptosis in Jurkat T cells up to the control levels as well as decreased mRNA expression of FAS, FASLG and TNF. Conclusions These findings indicate that ACSL5 may play a role in the apoptosis that takes place in SLE. Our results point to ACSL5 as a potential novel functional marker of pathogenesis and a possible therapeutic target in SLE. PMID:22163040

Coronary calcification in SLE: comparison with the Multi-Ethnic Study of Atherosclerosis.

PubMed

Kiani, Adnan N; Magder, Laurence S; Post, Wendy S; Szklo, Moyses; Bathon, Joan M; Schreiner, Pam J; O'Leary, Daniel; Petri, Michelle

2015-11-01

Accelerated atherosclerosis is a major cause of morbidity and death in SLE. The purpose of this study was to determine whether the prevalence and extent of coronary artery calcium (CAC) is higher in female SLE patients compared with a non-SLE sample from the Multi-Ethnic Study of Atherosclerosis (MESA). CAC was measured in 80 female SLE patients and 241 female MESA controls from the Baltimore Field Centre, ages 45-64 years, without evidence of clinical cardiovascular disease. Binary regression was used to estimate the ratio of CAC prevalence in SLE vs MESA controls, controlling for demographic and cardiovascular risk factors. To compare the groups with respect to the quantity of CAC among those with non-zero Agatston scores, we used linear models in which the outcome was a log-transformed Agatston score. The prevalence of CAC was substantially higher in SLE. The differences were most pronounced and statistically significant in those aged 45-54 years (58% vs 20%, P < 0.0001), but were still observed among those aged 55-65 years (57% vs 36%, P = 0.069). After controlling for age, ethnicity, education, income, diabetes mellitus, hypertension, hyperlipidaemia, high-density lipoprotein levels, smoking, education and BMI, SLE patients still had a significantly higher prevalence of CAC than controls. Among those with CAC, the mean log Agatston score did not differ significantly between SLE and MESA participants. Women with SLE have a higher prevalence of CAC than comparable women without SLE, even after adjusting for traditional cardiovascular risk factors, especially among those aged 45-54 years. Published by Oxford University Press 2015. This work is written by US Government employees and is in the public domain in the US.

Functional polymorphisms of the coagulation factor II gene (F2) and susceptibility to systemic lupus erythematosus.

PubMed

Demirci, F Yesim K; Dressen, Amy S; Kammerer, Candace M; Barmada, M Michael; Kao, Amy H; Ramsey-Goldman, Rosalind; Manzi, Susan; Kamboh, M Ilyas

2011-04-01

Two F2 functional polymorphisms, rs1799963 (G20210A) and rs3136516 (A19911G), are known to be associated with elevated levels/activity of prothrombin (encoded by F2) and risk of thrombosis. Since patients with systemic lupus erythematosus (SLE) have high risk of thrombosis and accelerated atherosclerosis and also high prevalence of anti-prothrombin antibodies, we hypothesized that these two F2 polymorphisms could affect risk of SLE. We investigated these polymorphisms in 627 women with SLE (84% Caucasian Americans, 16% African Americans) and 657 female controls (78% Caucasian Americans, 22% African Americans). While the rs1799963 A allele was almost absent in African Americans, it was present at ~2% frequency in Caucasian Americans and showed no significant association with SLE. The rs3136516 G allele frequency was significantly higher in Caucasian SLE cases than in controls (48.4% vs 43.7%, respectively) with a covariate-adjusted odds ratio (OR) of 1.22 (95% CI 1.03-1.46, p = 0.023). The association was replicated in African Americans (rs3136516 G allele frequency 91.2% in cases vs 82.2% in controls) with an adjusted OR of 1.96 (95% CI 1.08-3.58, p = 0.022). Stratification of Caucasian SLE patients based on the presence or absence of cardiac and vascular events (CVE) revealed stronger association with the CVE-positive SLE subgroup than the CVE-negative SLE subgroup (OR 1.42 vs 1.20). Prothrombin activity measurements in a subset of SLE cases demonstrated higher activity in the carriers of the rs3136516 G allele. Our results suggest a potential role for prothrombin and the crosstalk between hemostatic and immune/inflammatory systems in SLE and SLE-associated cardiovascular events, which warrants further investigation in independent samples.

Targeting the RhoA-ROCK Pathway to Reverse T Cell Dysfunction in SLE

PubMed Central

Rozo, Cristina; Chinenov, Yurii; Maharaj, Reena Khianey; Gupta, Sanjay; Leuenberger, Laura; Kirou, Kyriakos A.; Bykerk, Vivian P.; Goodman, Susan M.; Salmon, Jane E.; Pernis, Alessandra B.

2018-01-01

Objectives Deregulated production of IL-17 and IL-21 contributes to the pathogenesis of autoimmune disorders like SLE and RA. Production of IL-17 and IL-21 can be regulated by ROCK2, one of the two Rho kinases. Increased ROCK activation was previously observed in an SLE cohort. Here, we evaluated ROCK activity in a new SLE cohort, an RA cohort, and assessed the ability of distinct inhibitors of the ROCK pathway to suppress production of IL-17 and IL-21 by SLE T cells or human Th17 cells. Methods ROCK activity in PBMCs from 29 SLE patients, 31 RA patients, and 28 healthy controls was determined by ELISA. SLE T cells or in vitro-differentiated Th17 cells were treated with Y27632 (a pan-ROCK inhibitor), KD025 (a selective ROCK2 inhibitor), or simvastatin (which inhibits RhoA, a major ROCK activator). ROCK activity, IL-17, and IL-21 production were assessed. The transcriptional profile altered by ROCK inhibitors was evaluated by NanoString technology. Results ROCK activity levels were significantly higher in SLE and RA patients than healthy controls. Th17 cells exhibited high ROCK activity that was inhibited by Y276327, KD025, or simvastatin; each also decreased IL-17 and IL-21 production by purified SLE T cells or Th17 cells. Immune profiling revealed both overlapping and distinct effects of the different ROCK inhibitors. Conclusions ROCK activity is elevated in PBMCs from SLE and RA patients. Production of IL-17 and IL-21 by SLE T cells or Th17 cells can furthermore be inhibited by targeting the RhoA-ROCK pathway via both non-selective and selective approaches. PMID:28283529

Influence of psychological stress on headache in patients with systemic lupus erythematosus.

PubMed

Vargas-Hitos, José Antonio; Sabio, José Mario; Martínez-Egea, Isabel; Jiménez-Jáimez, Enrique; Rodríguez-Guzmán, Manuel; Navarrete-Navarrete, Nuria; López-Lozano, Esther; Romero-Alegría, Ángela; de la Calle, Cristina; Jáimez-Gámiz, Laura; Baños-Piñero, Pilar; Nebrera-Navarro, Fernando; Fidalgo, Alba; Caminal, Luis; de Ramón Garrido, Enrique; Ortego-Centeno, Norberto; Expósito, Manuela; Zamora-Pasadas, Mónica; Jiménez-Alonso, Juan

2014-03-01

To compare the prevalence and disability of headache in patients with systemic lupus erythematosus (SLE) with the general population and to assess the role of chronic psychological stress (CPS) in headache development. One hundred seventy patients with SLE and 102 control subjects matched for age, sex, and level of education were included in this multicenter, cross-sectional study. CPS, headache-related disability, and chronic analgesic intake (CAI) were evaluated in all participants. No statistical differences in the prevalence of headache between both groups were observed but headache disability was significantly higher in patients with SLE. In addition, a higher average score in the Cohen Perceived Stress Scale (CPSS) and a higher prevalence of patients with CAI were observed in patients with SLE. In multivariate analysis, CPSS score was positively (OR 1.09; 95% CI: 1.03-1.14; p = 0.001) and CAI negatively (OR 0.43; 95% CI: 0.19-0.99; p = 0.049) associated with headache in patients with SLE. Despite the prevalence of headache in patients with SLE and the general population being similar, headache-related disability may be higher in patients with SLE. Moreover, CPS might play a role in the pathogenesis of SLE headache, whereas CAI might have a protective effect against it.

Extended Antiphospholipid Antibodies Screening in Systemic Lupus Erythematosus Patients.

PubMed

Dima, Alina; Caraiola, Simona; Jurcut, C; Balanescu, Eugenia; Balanescu, P; Ramba, Doina; Badea, Camelia; Pompilian, V; Ionescu, R; Baicus, Anda; Baicus, C; Dan, G A

2015-01-01

The antiphospholipid syndrome (APS) is one of the most encountered autoimmunity in systemic lupus erythematosus (SLE) patients and pathogenesis of these two seems to be intricate. To investigate the association of antiphospholipid antibodies (APLAs) titer with the presence of secondary APS diagnosis in SLE patients. 65 patients fulfilling the 2012 Systemic Lupus Collaborating International Clinics (SLICC) SLE's criteria were included. The APS diagnosis was sustained according to the 2006 Sydney APS's criteria. Three groups of patients were defined: SLE patients with secondary APS, SLE with history of positive "criteria" APLAs but without APS clinical features, respectively SLE patients without positive APLAs or clinical APS criteria. An extended APLAs panel was searched in all cases: both IgM and IgG of anticardiolipin antibodies (aCL), anti-P2 glycoprotein I antibodies (aβ2GPI), antiphosphatidylethanolamine antibodies (aPE), antiphosphatidylserine antibodies (aPS), respectively antiprothrombin antibodies (aPT). Results. Only the aβ2GPI, both IgM and IgG serotypes, had significantly higher titers in patients with SLE and secondary APS compared to no APS (with/ without positive APLAs): median (min; max) 7.0 (0.0-300.0) vs. 1.0 (0.0-28.0) vs. 1.0 (0.0-12.0), respectively 3.0 (0.0-79.0) vs. 1.0 (0.0-3.0) vs. 1.0 (0.0-12.0) (p<0.001, Kruskal-Wallis test)]. Also, in regression logistic models, only the aβ2 GPI (IgG and IgM ) were identified as risk factors for secondary APS diagnosis in the SLE patients: OR(95%CI) 5.9 (2.2-15.7), respectively 1.3 (1.1-1.5). In regard with the SLE markers, the IgG serotypes of the "non-criteria" APLAs analyzed (aPS, aPT, aPE) were correlated with the antiDNA titers while the IgM serotypes inversely associated with the complement C3 levels. IgG aβ2 GPI are accompanied by almost 6-fold increase risk of secondary APS when screening SLE patients. On the contrary, the "non-criteria" APLAs do not seem associated with the APS diagnosis in SLE patients. Some correlates of the "non-criteria" APLAs with the antiDNA and complement C3 levels were also observed.

Overview and Assessment of Antarctic Ice-Sheet Mass Balance Estimates: 1992-2009

NASA Technical Reports Server (NTRS)

Zwally, H. Jay; Giovinetto, Mario B.

2011-01-01

Mass balance estimates for the Antarctic Ice Sheet (AIS) in the 2007 report by the Intergovernmental Panel on Climate Change and in more recent reports lie between approximately ?50 to -250 Gt/year for 1992 to 2009. The 300 Gt/year range is approximately 15% of the annual mass input and 0.8 mm/year Sea Level Equivalent (SLE). Two estimates from radar altimeter measurements of elevation change by European Remote-sensing Satellites (ERS) (?28 and -31 Gt/year) lie in the upper part, whereas estimates from the Input-minus-Output Method (IOM) and the Gravity Recovery and Climate Experiment (GRACE) lie in the lower part (-40 to -246 Gt/year). We compare the various estimates, discuss the methodology used, and critically assess the results. We also modify the IOM estimate using (1) an alternate extrapolation to estimate the discharge from the non-observed 15% of the periphery, and (2) substitution of input from a field data compilation for input from an atmospheric model in 6% of area. The modified IOM estimate reduces the loss from 136 Gt/year to 13 Gt/year. Two ERS-based estimates, the modified IOM, and a GRACE-based estimate for observations within 1992 2005 lie in a narrowed range of ?27 to -40 Gt/year, which is about 3% of the annual mass input and only 0.2 mm/year SLE. Our preferred estimate for 1992 2001 is -47 Gt/year for West Antarctica, ?16 Gt/year for East Antarctica, and -31 Gt/year overall (?0.1 mm/year SLE), not including part of the Antarctic Peninsula (1.07% of the AIS area). Although recent reports of large and increasing rates of mass loss with time from GRACE-based studies cite agreement with IOM results, our evaluation does not support that conclusion

Immunogenicity of 23-Valent Pneumococcal Vaccine in Children with Systemic Lupus Erythematosus.

PubMed

Alyasin, Soheila; Adab, Marzieh; Hosseinpour, Asieh; Amin, Reza; Babaei, Maryam

2016-09-01

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease which is characterized by B-cell abnormality and auto-antibody generation. Since bacterial infections are the most important causes of mortality in these patients, pneumococcal vaccination is recommended for children with SLE. To investigate humoral immunity and specific-antibody formation in response to a 23-valent polysaccharide pneumococcal vaccination in SLE children and asthmatic control group. The case and control groups consisted of 30 children with the mean age of 13 years who were matched by sex and age. Anti-pneumococcal antibody titers were determined using Enzyme-Linked Immunosorbent Assay (ELISA) before the vaccination with the 23-valent pneumococcal vaccine and 3 weeks later in both groups. Also the correlation between anti-pneumococcal antibody titer and different factors including age, sex, lupus activity, disease duration, medications, history of recurrent infections, and laboratory data were investigated. Both groups showed significant increases in anti-pneumococcal antibody level after vaccination (p≤0.001). The increase in antibody level were almost the same in both groups (p≥0.05) such that 77.7% of SLE children and 86.2% of control children showed at least 2-fold increase in anti-pneumococcal antibody titer following immunization. Significant correlations were seen between the level of post-immunization anti-pneumococcal antibody with the age of children with SLE (p=0.02) and their age of disease onset (p=0.02). It is concluded that pneumococcal vaccination is generally immunogenic in children with SLE. However, a small group of patients show impaired response to the vaccine.

miR-125b is downregulated in systemic lupus erythematosus patients and inhibits autophagy by targeting UVRAG.

PubMed

Cao, Wenting; Qian, Ge; Luo, Wen; Liu, Xin; Pu, Yunjing; Hu, Guilan; Han, Lulu; Yuan, Limei; A, Xiao; Deng, Danqi

2018-03-01

Systemic lupus erythematosus (SLE) is a severe autoimmune disease and the pathogenesis remains incompletely understood. This study aimed to investigate the role of miR-125b in the pathogenesis of SLE and explore the underlying mechanism. Compared to healthy controls, the expression of miR-125b decreased in peripheral blood mononuclear cells (PBMCs) of SLE patients. In addition, PBMCs exposed to ultraviolet B had lower miR-125b level compared to those unexposed to radiation. We identified UV radiation resistance associated gene (UVRAG) as a target of miR-125b. Jurkat cells treated with miR-125b-5p agomir showed reduced levels of ATG7, Beclin-1 and LC3 II and decreased autophagy. In contrast, Jurkat cells treated with miR-125b-5p antagomir showed increased levels of ATG7, Beclin-1 and LC3 II and increased autophagy. Furthermore, Jurkat cells transfected with UVRAG expression vector showed higher expression of ATG7, Beclin-1 and LC3 II and increased autophagy. Conversely, cells transfected with UVRAG siRNA had lower expression of ATG7, Beclin-1 and LC3 II and decreased autophagy. Taken together, our data demonstrate that Ultraviolet B radiation can downregulate miR-125b-5p and increase UVRAG expression and autophagy activity in PBMCs of SLE patients. These findings help explain how ultraviolet B exacerbates SLE and suggest that UVRAG is a potential therapeutic target for SLE. Copyright © 2018. Published by Elsevier Masson SAS.

Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis

PubMed Central

Munroe, Melissa E.; Pezant, Nathan; Brown, Michael A.; Fife, Dustin A.; Guthridge, Joel M.; Kelly, Jennifer A.; Wiley, Graham; Gaffney, Patrick M.; James, Judith A.; Montgomery, Courtney G.

2017-01-01

Antiviral defenses are inappropriately activated in systemic lupus erythematosus (SLE) and association between SLE and the antiviral helicase gene, IFIH1, is well established. We sought to extend the previously reported association of pathogenic soluble mediators and autoantibodies with mouse Mda5 to its human ortholog, IFIH1. To better understand the role this gene plays in human lupus, we assessed association of IFIH1 variants with soluble mediators and autoantibodies in 357 European-American SLE patients, first-degree relatives, and unrelated, unaffected healthy controls. Association between each of 135 genotyped SNPs in IFIH1 and four lupus-associated plasma mediators, IL-6, TNF-α, IFN-β, and IP-10, were investigated via linear regression. No significant associations were found to SNPs orthologous to those identified in exon 13 of the mouse. However, outside of this region there were significant associations between IL-6 and rs76162067 (p = 0.008), as well as IP-10 and rs79711023 (p = 0.003), located in a region of IFIH1 previously shown to directly influence MDA-5 mediated IP-10 and IL-6 secretion. SLE patients and FDRs carrying the minor allele for rs79711023 demonstrated lower levels of IP-10, while only FDRs carrying the minor allele for rs76162067 demonstrated an increased level of IL-6. This would suggest that the change in IP-10 is genotypically driven, while the change in IL-6 may be reflective of SLE transition status. These data suggest that IFIH1 may contribute to SLE pathogenesis via altered inflammatory mechanisms. PMID:28234905

Protective and ameliorative effect of sea buckthorn leaf extract supplementation on lead induced hemato-biochemical alterations in Wistar rats.

PubMed

Zargar, Rizwana; Raghuwanshi, Pratiksha; Rastogi, Ankur; Koul, Aditi Lal; Khajuria, Pallavi; Ganai, Aafreen Wahid; Kour, Sumeet

2016-09-01

To evaluate the protective and ameliorative effect of aqueous sea buckthorn leaf extract (SLE) on hemato-biochemical profile in lead intoxicated Wistar rats. An experiment was conducted for 60 days. 36 adult male Wistar rats with a mean body weight of 177.8±12.6 g were divided into five groups and were subjected to various daily oral treatment regimens. Group I served as a negative control receiving only feed and water, Group II (positive control for lead) received lead acetate at 250 ppm in drinking water, and Group III (positive control for SLE) received SLE at 100 mg/kg b.wt. Animals in Group IV received a combination of lead acetate at 250 ppm in drinking water for the first 45 days and SLE at 100 mg/kg b.wt. throughout the experimental period of 60-day, and in Group V for the last 15 days of the trial after the administration of lead acetate until the first 45 days of the trial to study the protective and ameliorating effects of SLE, respectively. Blood samples were collected from retro-orbital fossa of each rat on 0 th , 45 th , and 60 th day of the experiment for hemato-biochemical analysis including hemoglobin (Hb), packed cell volume (PCV), serum total protein, albumin, globulin, albumin:globulin ratio, cholesterol, urea, and creatinine. Significantly (p<0.01) lower levels of serum total proteins and albumin, and a significantly (p<0.01) higher serum cholesterol, urea and creatinine levels were observed in Group II (lead intoxicated group) in comparison to Group I (negative control). Administration of SLE at 100 mg/kg body wt. to lead intoxicated Wistar rats resulted in normalization of almost all the biochemical parameters studied in both the treatment Groups, i.e., IV and V (protective and ameliorative). However, the effects were more pronounced in the protective group. No effects of SLE supplementation were observed on Hb levels. PCV levels improved in protective groups, but no effect was observed in ameliorative group in comparison to lead intoxicated groups. SLE administration at 100 mg/kg b.wt. to lead intoxicated Wistar rats may be used to protect/ameliorate lead induced biochemical alterations in Wistar rats.

Usefulness of neutrophil-to-lymphocyte ratio as a biomarker for diagnosing infections in patients with systemic lupus erythematosus.

PubMed

Kim, Hyoun-Ah; Jung, Ju-Yang; Suh, Chang-Hee

2017-11-01

Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) have been investigated as disease activity markers for systemic lupus erythematosus (SLE). Hence, we investigated the clinical significance of these parameters in diagnosing infection in patients with SLE. In total, 120 patients with SLE, who were admitted to hospital due to disease flares or infection, were recruited for the study. Of the 120 patients, 60 had a concurrent infection (SLE with infection), while the remaining 60 patients were admitted with a flare without any evidence of infection (SLE with flare). NLR was higher in the patients with SLE with infection, compared to patients with SLE with flare (14.2 ± 15.4 versus 3.3 ± 2.2, p < 0.001). Additionally, PLR was higher in the SLE with infection group than in the SLE with flare group (357.7 ± 350.1 versus 231.7 ± 152.9, p = 0.012), but not MLR. In the SLE with infection group, C-reactive protein (CRP) levels positively correlated with NLR and PLR. NLR with a cut-off value of 5.70 and an area under the curve (AUC) of 0.872 indicated good sensitivity (75%) and specificity (90%), for the diagnosis of SLE with infection. CRP with a cut-off value of 1.28 mg/dL (AUC 0.942) showed the sensitivity (93.3%) and specificity (91.7%). NLR with a cut-off value of 5.70 and CRP with a cut-off value of 1.28 mg/dL showed the increased specificity (98.3%) than only CRP, but not significant. NLR could be a good additive marker for diagnosing infection in patients with SLE.

How compelling are the data for Epstein-Barr virus being a trigger for systemic lupus and other autoimmune diseases?

PubMed

Draborg, Anette; Izarzugaza, Jose M G; Houen, Gunnar

2016-07-01

Systemic lupus erythematosus (SLE) is caused by a combination of genetic and acquired immunodeficiencies and environmental factors including infections. An association with Epstein-Barr virus (EBV) has been established by numerous studies over the past decades. Here, we review recent experimental studies on EBV, and present our integrated theory of SLE development. SLE patients have dysfunctional control of EBV infection resulting in frequent reactivations and disease progression. These comprise impaired functions of EBV-specific T-cells with an inverse correlation to disease activity and elevated serum levels of antibodies against lytic cycle EBV antigens. The presence of EBV proteins in renal tissue from SLE patients with nephritis suggests direct involvement of EBV in SLE development. As expected for patients with immunodeficiencies, studies reveal that SLE patients show dysfunctional responses to other viruses as well. An association with EBV infection has also been demonstrated for other autoimmune diseases, including Sjögren's syndrome, rheumatoid arthritis, and multiple sclerosis. Collectively, the interplay between an impaired immune system and the cumulative effects of EBV and other viruses results in frequent reactivation of EBV and enhanced cell death, causing development of SLE and concomitant autoreactivities.

EBV and systemic lupus erythematosus: a new perspective.

PubMed

Gross, Andrew J; Hochberg, Donna; Rand, William M; Thorley-Lawson, David A

2005-06-01

We have proposed that EBV uses mature B cell biology to access memory B cells as a site of persistent infection. A central feature of this model is that EBV adapts its gene expression profile to the state of the B cell it resides in and that the level of infection is stable over time. This led us to question whether changes in the behavior or regulation of mature B cells would alter the state of EBV persistence. To investigate this, we studied the impact of systemic lupus erythematosus (SLE), a disease characterized by immune dysfunction, on EBV infection. We show that patients with SLE have abnormally high frequencies of EBV-infected cells in their blood, and this is associated with the occurrence of SLE disease flares. Although patients with SLE have frequencies of infected cells comparable to those seen in immunosuppressed patients, in SLE the effect was independent of immunosuppressive therapy. Aberrant expression of viral lytic (BZLF1) and latency (latency membrane proteins 1 and 2a) genes was also detected in the blood of SLE patients. We conclude that the abnormal regulation of EBV infection in SLE patients reflects the sensitivity of the virus to perturbation of the immune system.

High Affinity Antibodies against Influenza Characterize the Plasmablast Response in SLE Patients After Vaccination

PubMed Central

Kaur, Kaval; Zheng, Nai-Ying; Smith, Kenneth; Huang, Min; Li, Lie; Pauli, Noel T.; Henry Dunand, Carole J.; Lee, Jane-Hwei; Morrissey, Michael; Wu, Yixuan; Joachims, Michelle L.; Munroe, Melissa E.; Lau, Denise; Qu, Xinyan; Krammer, Florian; Wrammert, Jens; Palese, Peter; Ahmed, Rafi; James, Judith A.; Wilson, Patrick C.

2015-01-01

Breakdown of B cell tolerance is a cardinal feature of systemic lupus erythematosus (SLE). Increased numbers of autoreactive mature naïve B cells have been described in SLE patients and autoantibodies have been shown to arise from autoreactive and non-autoreactive precursors. How these defects, in the regulation of B cell tolerance and selection, influence germinal center (GC) reactions that are directed towards foreign antigens has yet to be investigated. Here, we examined the characteristics of post-GC foreign antigen-specific B cells from SLE patients and healthy controls by analyzing monoclonal antibodies generated from plasmablasts induced specifically by influenza vaccination. We report that many of the SLE patients had anti-influenza antibodies with higher binding affinity and neutralization capacity than those from controls. Although overall frequencies of autoreactivity in the influenza-specific plasmablasts were similar for SLE patients and controls, the variable gene repertoire of influenza-specific plasmablasts from SLE patients was altered, with increased usage of JH6 and long heavy chain CDR3 segments. We found that high affinity anti-influenza antibodies generally characterize the plasmablast responses of SLE patients with low levels of autoreactivity; however, certain exceptions were noted. The high-avidity antibody responses in SLE patients may also be correlated with cytokines that are abnormally expressed in lupus. These findings provide insights into the effects of dysregulated immunity on the quality of antibody responses following influenza vaccination and further our understanding of the underlying abnormalities of lupus. PMID:25951191

Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort.

PubMed

Ardoin, S P; Schanberg, L E; Sandborg, C; Yow, E; Barnhart, H X; Mieszkalski, K l; Ilowite, N T; von Scheven, E; Eberhard, A; Levy, D M; Kimura, Y; Silverman, E; Bowyer, S L; Punaro, L; Singer, N G; Sherry, D D; McCurdy, D; Klein-Gitelman, M; Wallace, C; Silver, R; Wagner-Weiner, L; Higgins, G C; Brunner, H I; Jung, L K; Imundo, L; Soep, J B; Reed, A M

2010-10-01

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

Autoimmune hemolytic anemia in systemic lupus erythematosus at diagnosis: differences between pediatric and adult patients.

PubMed

Gormezano, N W S; Kern, D; Pereira, O L; Esteves, G C X; Sallum, A M E; Aikawa, N E; Pereira, R M R; Silva, C A; Bonfá, E

2017-04-01

Objective To determine the overall prevalence of autoimmune hemolytic anemia (AIHA), and to compare clinical and laboratory features in a large population of children and adult lupus patients at diagnosis. Methods This retrospective study evaluated the medical charts of 336 childhood-onset systemic lupus erythematosus (cSLE) and 1830 adult SLE (aSLE) patients followed in the same tertiary hospital. Demographic data, clinical features and disease activity were recorded. AIHA was defined according to the presence of anemia (hemoglobin <10 g/dL) and evidence of hemolysis (reticulocytosis and positive direct antiglobulin test (DAT)/Coombs test) at SLE diagnosis. Evans syndrome (ES) was defined by the combination of immune thrombocytopenia (platelet count <100,000/mm 3 ) and AIHA. Results The frequency of AIHA at diagnosis was significantly higher in cSLE patients compared to aSLE (49/336 (14%) vs 49/1830 (3%), p = 0.0001), with similar frequency of ES (3/336 (0.9%) vs 10/1830 (0.5%), p = 0.438). The median of hemoglobin levels was reduced in cSLE vs aSLE patients (8.3 (2.2-10) vs 9.5 (6.6-10) g/dL, p = 0.002) with a higher frequency of multiple hemorrhagic manifestations (41% vs 7%, p = 0.041) and erythrocyte transfusion due to bleeding (24% vs 5%, p = 0.025). cSLE patients also had more often constitutional involvement (84% vs 31%, p < 0.001), fever (65% vs 26%, p < 0.001), weight loss > 2 kg (39% vs 6%, p < 0.001), reticuloendothelial manifestations (48% vs 8%, p < 0.001), hepatomegaly (25% vs 2%, p < 0.001) and splenomegaly (21% vs 2%, p = 0.004). Other major organ involvements were common but with similar frequencies in cSLE and aSLE ( p > 0.05). Median systemic lupus erythematosus disease activity index 2000 (SLEDAI-2 K) was comparable in cSLE and aSLE (p = 0.161). Conclusions We identified that AIHA was not a common condition in cSLE and aSLE, with distinct features characterized by a higher prevalence/severity in children and concomitant constitutional symptoms in the majority of them.

Effects of Arsenic Trioxide on INF-gamma Gene Expression in MRL/lpr Mice and Human Lupus.

PubMed

Hu, Hongye; Chen, Enjiu; Li, Yongji; Zhu, Xiaochun; Zhang, Ting; Zhu, Xiaofang

2017-11-20

Arsenic trioxide (As2O3; ATO), a traditional Chinese medicine, is used to treat patients with acute promye-locytic leukemia, while its application for treatment of systemic lupus erythematosus (SLE) is still under evaluation. The high expression of INF-gamma (INF-γ) is a primary pathogenic factor in SLE. It is found that ATO can reduce INF-γ expression levels in lupus-prone mice, whereas it is not clear whether ATO has the same effect on SLE patients. Therefore, this study was to investigate the underlying mechanism of the effects of ATO on the expression of INF-γ in splenocytes of MRL/lpr mice and PBMCs of human lupus. The mRNA and protein expression levels of INF-γ were assessed by real-time RT-PCR and ELISA, respectively. The histone acetylation status of the INF-γ promoter and the binding of RNA polymerase II (RNA Pol II) to the INF-γ promoter were detected using a chromatin immunoprecipitation (ChIP) technique. The mRNA and protein expression levels of INF-γ decreased in both splenocytes of MRL/lpr mice and PBMCs of SLE patients with ATO treatment, which were accompanied by reduced histone H4 and H3 acetylation in INF-γ promoter and decreased combination of RNA Pol II to the INF-γ promoter. Therefore, ATO may reduce the expression level of the INF-γ by altering the levels of INF-γ promoter acetylation and the combination of RNA Pol II to the INF-γ promoter in splenocytes of MRL/lpr mice and PBMCs of SLE patients.

Adjusted neutropenia is associated with early serious infection in systemic lupus erythematosus.

PubMed

Lee, Sang-Won; Park, Min-Chan; Lee, Soo-Kon; Park, Yong-Beom

2013-05-01

The susceptibility to infection increases in systemic lupus erythematosus (SLE) patients with neutropenia, but the link between infection risk and the cutoff neutrophil count still remains controversial. In this study, we investigated a valuable parameter associated with early serious infection in SLE patients during the first follow-up year. We reviewed the medical records of 160 patients with SLE. The initial levels were defined as the mean of the results of the first two consecutive tests. The adjusted levels were defined as the results of the accumulated area under the curve divided by interval follow-up days. Patients were divided into two groups according to early serious infection and initial and adjusted neutropenia and were then compared. Immunosuppressive-naïve SLE patients with early serious infection more frequently had initial, latest, and adjusted leukopenia and neutropenia (<2,500/mm(3)) and hypocomplementemia than those without. Adjusted neutropenia was the only independent predictive value for early serious infection [odds ratio (OR 11.366)]. Initial neutropenia was the independent predictive value for adjusted neutropenia (OR 6.504). We suggest that adjusted neutropenia is useful for predicting early serious infection in SLE patients during the first follow-up year.

IgE Inhibits Toll-like Receptor 7- and Toll-like Receptor 9-Mediated Expression of Interferon-α by Plasmacytoid Dendritic Cells in Patients With Systemic Lupus Erythematosus.

PubMed

Khoryati, Liliane; Augusto, Jean-François; Shipley, Emilie; Contin-Bordes, Cécile; Douchet, Isabelle; Mitrovic, Stéphane; Truchetet, Marie-Elise; Lazaro, Estibaliz; Duffau, Pierre; Couzi, Lionel; Jacquemin, Clément; Barnetche, Thomas; Vacher, Pierre; Schaeverbeke, Thierry; Blanco, Patrick; Richez, Christophe

2016-09-01

Plasmacytoid dendritic cells (PDCs) play a central role in pathogenesis of systemic lupus erythematosus (SLE) through their unique ability to produce large amounts of type I interferon (IFN) upon Toll-like receptor 7 (TLR-7) and TLR-9 triggering. PDCs express specific surface regulatory receptors involved in negative regulation of IFNα secretion. These receptors use the γ-chain of high-affinity Fc receptor (FcR) for IgE, FcɛRI. We undertook this study to test our hypothesis that IgE engagement of FcɛRI on PDCs may impact IFNα production in SLE patients. Serum levels of total IgE were measured in healthy volunteers, SLE patients, and patients with IgE-dependent allergic disorders. FcɛRI expression on PDCs from SLE patients was evaluated by flow cytometry. Purified PDCs were incubated with monoclonal IgE for 24 hours, then stimulated for 18 hours with TLR agonists or immune complexes (ICs). IFNα production by PDCs was detected by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. Expression of TLR-7, TLR-9, and IFN regulatory factor 7 (IRF-7) in PDCs was quantified by quantitative real-time PCR. We observed significantly higher IgE levels in SLE patients with quiescent disease than in those with active disease. In SLE patients, IgE levels correlated inversely with disease activity. IgE levels were not associated with the presence of antinuclear IgE. Purified PDCs treated for 24 hours with monoclonal IgE up-regulated FcɛRI expression in an IgE dose-dependent manner. IgE-treated PDCs significantly decreased IFNα secretion and down-regulated CCR7 expression upon stimulation with TLR-7 and TLR-9 ligands and ICs from lupus patients. IgE treatment down-regulated expression of TLR-9 and IRF-7. Our results support the notion that IgE plays a protective role in SLE pathogenesis through the modulation of inflammatory response by PDCs. © 2016, American College of Rheumatology.

Is Identification of Lupus Erythematosus Cells Still Useful? A Case Report.

PubMed

Xu, Min; MacNeal, Lucinda A; Wittman, Brenda J; Rutledge, Joe C

A 13-year-old girl presented with significant weight loss, depression, anemia, and neutropenia. The preliminary diagnosis was anorexia nervosa combined with depression. Due to peripheral cytopenia, a bone marrow biopsy was performed to rule out leukemia. Lupus erythematosus (LE) cells were found in the bone marrow aspirate, which prompted autoantibody testing, although clinically it was not suspected the patient had systemic lupus erythematosus (SLE). Further testing demonstrated very high levels of antinuclear antibodies (ANA) (>12 U) and anti-double strand DNA (dsNDA) (>1000 IU/mL), which confirmed the diagnosis of SLE. The patient was treated with steroids for SLE, and symptoms improved quickly. In conclusion, although the identification of LE cells as one of the diagnostic criteria for SLE has been obsolete, careful examination of bone marrow to identify LE cells is still very important in the diagnosis of unsuspected SLE.

Serum neuron specific enolase - a novel indicator for neuropsychiatric systemic lupus erythematosus?

PubMed

Hawro, T; Bogucki, A; Krupińska-Kun, M; Maurer, M; Woźniacka, A

2015-12-01

Neuropsychiatric (NP) lupus, a common manifestation of systemic lupus erythematosus (SLE), is still insufficiently understood, in part, because of the lack of specific biomarkers. Neuron specific enolase (NSE), an important neuronal glycolytic enzyme, shows increased serum levels following acute brain injury, and decreased serum levels in several chronic disorders of the nervous system, including multi infarct dementia, multiple sclerosis and depression. The aim of the study was to evaluate serum NSE levels in SLE patients with and without nervous system involvement, and in healthy controls, and to assess the correlation of NSE serum levels of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) with clinical parameters. The study comprised 47 SLE patients and 28 controls. SLE activity was assessed using the Systemic Lupus Activity Measure (SLAM). A neurologist and a psychiatrist examined all patients. NP involvement was diagnosed according to strict NPSLE criteria proposed by Ainiala and coworkers, as modification to American College of Rheumatology (ACR) nomenclature and case definitions. NSE serum levels were determined by use of an immunoassay. Mean NSE serum concentrations in patients with NPSLE were significantly lower than in non-NPSLE patients (6.3 ± 2.6 µg/L vs. 9.7 ± 3.3 µg/L, p < 0.01) and in controls (8.8 ± 3.3 µg/L, p < 0.05). There were significant negative correlations between NSE serum levels and SLE activity (r = -0.42, p < 0.05) and the number of NPSLE manifestations diagnosed (-0.37; p = 0.001). Decreased serum concentrations of NSE may reflect chronic neuronal damage with declined metabolism of the nervous tissue in patients with NPSLE. © The Author(s) 2015.

Differences in subclinical cardiovascular disease between African American and Caucasian women with systemic lupus erythematosus.

PubMed

Rhew, Elisa Y; Manzi, Susan M; Dyer, Alan R; Kao, Amy H; Danchenko, Natalya; Barinas-Mitchell, Emma; Sutton-Tyrrell, Kim; McPherson, David D; Pearce, William; Edmundowicz, Daniel; Kondos, George T; Ramsey-Goldman, Rosalind

2009-02-01

Racial differences exist in disease rates and mortality in both cardiovascular disease (CVD) and systemic lupus erythematosus (SLE). The objective of this cross-sectional study was to compare the frequency and risk factors for subclinical CVD in African American (AA) and Caucasian women with SLE and no prior CVD events. Traditional CVD risk factors and SLE-related factors were assessed in 309 SLE women. Subclinical CVD was assessed by carotid ultrasound to measure intimamedial thickness (IMT) and plaque, and electron beam computed tomography (EBCT) was used to measure coronary artery calcium (CAC). AA women had less education and higher levels of body mass index, blood pressure, lipoprotein(a), C-reactive protein (CRP), fibrinogen, and erythrocyte sedimentation rate (ESR). However, AA women had lower albumin, more and longer duration of corticosteroid use, higher SLE disease activity and damage, and more dsDNA antibodies compared with Caucasian women after adjustment for age and study site. More AA women had carotid plaque (adjusted odds ratio [OR], 1.94; 95% confidence interval [CI], 1.03-3.65) and higher carotid IMT (0.620 vs 0.605 mm, P = 0.07) but similar CAC compared with Caucasians. A multivariate analysis revealed that the following risk factor variables were significantly different between the racial groups and associated with plaque: blood pressure, current corticosteroid use, SLE disease activity, and SLE damage. All factors contributed to the result, but no individual risk factor fully accounted for the association between race and plaque. In conclusion, the presence of carotid plaque was higher in AA compared with Caucasian women with SLE, in contrast to studies of non-SLE subjects, in which AA have similar or less plaque than Caucasians. A combination of SLE-related and traditional CVD risk factors explained the racial difference in plaque burden.

Assessment of Antarctic Ice-Sheet Mass Balance Estimates: 1992 - 2009

NASA Technical Reports Server (NTRS)

Zwally, H. Jay; Giovinetto, Mario B.

2011-01-01

Published mass balance estimates for the Antarctic Ice Sheet (AIS) lie between approximately +50 to -250 Gt/year for 1992 to 2009, which span a range equivalent to 15% of the annual mass input and 0.8 mm/year Sea Level Equivalent (SLE). Two estimates from radar-altimeter measurements of elevation change by European Remote-sensing Satellites (ERS) (+28 and -31 Gt/year) lie in the upper part, whereas estimates from the Input-minus-Output Method (IOM) and the Gravity Recovery and Climate Experiment (GRACE) lie in the lower part (-40 to -246 Gt/year). We compare the various estimates, discuss the methodology used, and critically assess the results. Although recent reports of large and accelerating rates of mass loss from GRACE=based studies cite agreement with IOM results, our evaluation does not support that conclusion. We find that the extrapolation used in the published IOM estimates for the 15 % of the periphery for which discharge velocities are not observed gives twice the rate of discharge per unit of associated ice-sheet area than the 85% faster-moving parts. Our calculations show that the published extrapolation overestimates the ice discharge by 282 Gt/yr compared to our assumption that the slower moving areas have 70% as much discharge per area as the faster moving parts. Also, published data on the time-series of discharge velocities and accumulation/precipitation do not support mass output increases or input decreases with time, respectively. Our modified IOM estimate, using the 70% discharge assumption and substituting input from a field-data compilation for input from an atmospheric model over 6% of area, gives a loss of only 13 Gt/year (versus 136 Gt/year) for the period around 2000. Two ERS-based estimates, our modified IOM, and a GRACE-based estimate for observations within 1992 to 2005 lie in a narrowed range of +27 to - 40 Gt/year, which is about 3% of the annual mass input and only 0.2 mm/year SLE. Our preferred estimate for 1992-2001 is - 47 Gt/year for West Antarctica, + 16 Gt/year for East Antarctica, and -31 Gt/year overall (+0.1 mm/year SLE), not including part of the Antarctic Peninsula (1.07 % of the AIS area)

Observationally constrained projections of Antarctic ice sheet instability

NASA Astrophysics Data System (ADS)

Edwards, Tamsin; Ritz, Catherine; Durand, Gael; Payne, Anthony; Peyaud, Vincent; Hindmarsh, Richard

2015-04-01

Large parts of the Antarctic ice sheet lie on bedrock below sea level and may be vulnerable to a positive feedback known as Marine Ice Sheet Instability (MISI), a self-sustaining retreat of the grounding line triggered by oceanic or atmospheric changes. There is growing evidence MISI may be underway throughout the Amundsen Sea Embayment (ASE) of West Antarctica, induced by circulation of warm Circumpolar Deep Water. If this retreat is sustained the region could contribute up to 1-2 m to global mean sea level, and if triggered in other areas the potential contribution to sea level on centennial to millennial timescales could be two to three times greater. However, physically plausible projections of Antarctic MISI are challenging: numerical ice sheet models are too low in spatial resolution to resolve grounding line processes or else too computationally expensive to assess modelling uncertainties, and no dynamical models exist of the ocean-atmosphere-ice sheet system. Furthermore, previous numerical ice sheet model projections for Antarctica have not been calibrated with observations, which can reduce uncertainties. Here we estimate the probability of dynamic mass loss in the event of MISI under a medium climate scenario, assessing 16 modelling uncertainties and calibrating the projections with observed mass losses in the ASE from 1992-2011. We project losses of up to 30 cm sea level equivalent (SLE) by 2100 and 72 cm SLE by 2200 (95% credibility interval: CI). Our results are substantially lower than previous estimates. The ASE sustains substantial losses, 83% of the continental total by 2100 and 67% by 2200 (95% CI), but in other regions losses are limited by ice dynamical theory, observations, or a lack of projected triggers.

An unusual case of crescentic lupus nephritis presenting with normal renal function.

PubMed

Manohar, Sandhya; Subramanian, Chamundeswari; Lakshmi, Kameswari

2015-11-01

Lupus nephritis is a life-threatening manifestation of systemic lupus erythematosus (SLE). This is commonly suspected when lupus patients present with elevated serum creatinine levels. But it is important to be aware that even patients with advanced disease in the kidney from SLE can have normal renal function, thus requiring a high index of suspicion. We present the case of a patient who presented with nonspecific musculoskeletal symptoms and was diagnosed with SLE. He also had nephrotic range proteinuria but his serum creatinine was normal. A renal biopsy revealed diffuse proliferative crescentic lupus nephritis. We have reviewed the literature for correlation between crescents; a sign of severe glomerular damage and creatinine levels.

CpG DNA: A pathogenic factor in systemic lupus erythematosus?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krieg, A.M.

1995-11-01

Systemic lupus erythematosus (SLE) is a multifactorial disease of unknown etiology. Characteristic features of SLE include (1) polyclonal B cell activation, (2) overexpression of the immune stimulatory cytokine interleukin-6 (IL-6), (3) defective tolerance to self antigens, and (4) production of anti-DNA antibodies (Ab). Bacterial infection has been suspected as a triggering factor for lupus. Bacterial DNA differs from vertebrate DNA in the frequency and methylation of CpG dinucleotides. These CpG motifs in bacterial DNA induce a variety of immune effects, including (1) polyclonal activation of murine and human B cells, (2) IL-6 secretion, and (3) resistance to apoptosis, thereby potentiallymore » allowing the survival of autoreactive cells. These results suggest that microbial DNA could therefore be a pathogenic factor in SLE. SLE patients have elevated levels of circulating plasma DNA which is reportedly enriched in hypomethylated CpGs. Genomic DNA is also hypomethylated in SLE. The purpose of this review is to summarize the immune effects of CpG motifs and to present the evidence for their possible involvement in the pathogenesis of SLE. 77 refs.« less

Semaphorin 3A - a marker for disease activity and a potential putative disease-modifying treatment in systemic lupus erythematosus.

PubMed

Vadasz, Z; Toubi, E

2012-10-01

Semaphorin 3A (sema3A) and neuropilin-1 (NP-1) play a regulatory role in immune responses and have a demonstrated effect on the course of collagen-induced arthritis. Sema3A was also found to be involved in other immune-mediated diseases, e.g. psoriasis and allergic rhinitis. In this review we concentrated on the involvement of sema3A and NP-1 in the pathogenesis of systemic lupus erythematosus (SLE) and on the specific effect of sema3A on the auto-reactive properties of B cells in SLE patients. We demonstrated the expression of sema3A in renal biopsies from lupus glomerulonephritis patients. This expression was found to be inversely correlated with proteinuria and kidney function tests. Sema3A serum levels in SLE patients were found to be significantly lower than in RA patients (disease control) and lower yet than in normal individuals. Altered serum sema3A levels were found to be in inverse correlation with SLE disease activity, mainly with renal damage and the presence of anti-cardiolipin antibodies. The expression of both sema3A and NP-1 on B cells from SLE patients was significantly different in comparison with normal healthy individuals. Finally, we demonstrated that when sema3A was co-cultured with CpG-ODN-stimulated memory B cells of SLE patients, their TLR-9 expression was significantly reduced by almost 50% (p = 0.001). These findings, along with the observation of sema3A being reduced in SLE patients in correlation with disease severity and autoimmunity, and memory B cells being beneficially responsive to sema3A, suggest this regulatory molecule may be considered as a potential therapy for SLE. Such focused therapies will help in achieving the maintenance of self-tolerance and alter pro-inflammatory status in lupus.

Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus.

PubMed

Adrianto, Indra; Wang, Shaofeng; Wiley, Graham B; Lessard, Christopher J; Kelly, Jennifer A; Adler, Adam J; Glenn, Stuart B; Williams, Adrienne H; Ziegler, Julie T; Comeau, Mary E; Marion, Miranda C; Wakeland, Benjamin E; Liang, Chaoying; Kaufman, Kenneth M; Guthridge, Joel M; Alarcón-Riquelme, Marta E; Alarcón, Graciela S; Anaya, Juan-Manuel; Bae, Sang-Cheol; Kim, Jae-Hoon; Joo, Young Bin; Boackle, Susan A; Brown, Elizabeth E; Petri, Michelle A; Ramsey-Goldman, Rosalind; Reveille, John D; Vilá, Luis M; Criswell, Lindsey A; Edberg, Jeffrey C; Freedman, Barry I; Gilkeson, Gary S; Jacob, Chaim O; James, Judith A; Kamen, Diane L; Kimberly, Robert P; Martín, Javier; Merrill, Joan T; Niewold, Timothy B; Pons-Estel, Bernardo A; Scofield, R Hal; Stevens, Anne M; Tsao, Betty P; Vyse, Timothy J; Langefeld, Carl D; Harley, John B; Wakeland, Edward K; Moser, Kathy L; Montgomery, Courtney G; Gaffney, Patrick M

2012-11-01

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway. We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis. Copyright © 2012 by the American College of Rheumatology.

Systemic lupus erythematosus patients in the low-latitude plateau of China: altitudinal influences.

PubMed

Qian, G; Ran, X; Zhou, C X; Deng, D Q; Zhang, P L; Guo, Y; Luo, J H; Zhou, X H; Xie, H; Cai, M

2014-12-01

The current study was to investigate the features of hospitalized patients with systemic lupus erythematosus (SLE) at different altitudes. The correlation between SLE activity and altitudinal variations was also explored. Medical records of 1029 patients were retrospectively reviewed. Activity of SLE in each organ system was recorded using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). There was no significant correlation between SLE activity and altitudes (r = 0.003, p = 0.159). Age at onset for SLE patients at high altitudes was significantly younger than that at low and moderate altitudes (p = 0.022 and p = 0.004, respectively). Age at SLE admission at low altitudes was significant older than those at moderate and high altitudes (p = 0.011 and p < 0.001, respectively). Patients at high altitudes had shorter duration from disease onset to admission than those at moderate altitudes (p = 0.009). Incidence of Sm antibodies-positive for resident patients at high altitudes was 36.4%, which were higher than that at moderate altitudes (p = 0.003). We found increasing trends of CNS activity in active patients; immunological and renal activities in inactive patients were correlated with elevated altitudes (p = 0.024, p = 0.004, p = 0.005), while arthritis scores in active patients showed the tendency of decreasing with the rise of elevation (p = 0.002). Hemoglobin level, red blood cell and platelet counts at high altitudes were significantly lower than those at low altitudes (p < 0.05, respectively). There was no significant difference in hemoglobin level between moderate- and low-altitude groups (p > 0.05). No significant difference in platelet counts between moderate- and high-altitude groups was observed (p > 0.05). Our findings suggest that some clinical features, laboratory tests and activity of main organs in SLE are influenced by altitudes. Furthermore, organ activities of active and inactive SLE patients have different patterns of altitudinal variations. These distinctive variations likely reveal that peculiar environmental factors at high altitudes can affect the development of SLE. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Distinct Subtypes of Microparticle-containing Immune Complexes Are Associated with Disease Activity, Damage, and Carotid Intima-media Thickness in Systemic Lupus Erythematosus.

PubMed

Fortin, Paul R; Cloutier, Nathalie; Bissonnette, Vincent; Aghdassi, Ellie; Eder, Lihi; Simonyan, David; Laflamme, Nathalie; Boilard, Eric

2016-11-01

Microparticles (MP) are small extracellular vesicles present in body fluids. MP originate from different cellular lineages, principally from platelets in blood, and may expose phosphatidylserine (PS). In systemic lupus erythematosus (SLE), MP harbor immunoglobulin G (IgG), thereby forming MP-containing immune complexes (mpIC). We aimed to verify an association between SLE disease activity, damage, and surrogate markers of atherosclerosis and MP harboring IgG, taking into account the platelet origin and PS exposure of MP. MP expressing surface IgG, platelet antigen (CD41+), and PS were quantified using flow cytometry in plasma of 191 women with SLE. Carotid ultrasounds (US) were available in 113 patients. Spearman correlation analysis was used to analyze whether levels of MP were associated with the following outcomes: SLE Disease Activity Index 2000 (SLEDAI-2K), Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), and carotid US plaques and intima-media thickness (CIMT) as surrogates for vascular damage. We found CD41+ MP harboring IgG present in SLE. A positive correlation was found between SLEDAI-2K and levels of CD41+ MP harboring IgG and exposing (p = 0.027) and non-exposing PS (p = 0.001). Conversely, SDI (p = 0.024) and CIMT (p = 0.016) correlated with concentrations of CD41- MP harboring IgG and exposing PS. Associations were independent of low-density lipoprotein cholesterol level, body mass index, and antimalarial drug use. Different subtypes of mpIC are produced in SLE and are associated with distinct clinical characteristics such as disease activity and vascular damage. The assessment of MP subtypes might serve for the design of predictive markers of disease activity and vascular damage in patients.

Circulating Angiogenic Factors and the Risk of Preeclampsia in Systemic Lupus Erythematosus Pregnancies.

PubMed

Leaños-Miranda, Alfredo; Campos-Galicia, Inova; Berumen-Lechuga, María Guadalupe; Molina-Pérez, Carlos José; García-Paleta, Yolanda; Isordia-Salas, Irma; Ramírez-Valenzuela, Karla Leticia

2015-07-01

To investigate whether angiogenic factors are associated with risk of developing preeclampsia in pregnant women with systemic lupus erythematosus (SLE). We performed a nested case-control study within a cohort of SLE women with singleton pregnancies. The study included 42 patients with SLE who eventually developed preeclampsia and 75 normal SLE pregnancies. Serum samples were collected at 4-week intervals (from weeks 12 to 36). Serum samples were analyzed for soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng). Women destined to develop preeclampsia had lower PlGF levels and higher sFlt-1 and sEng levels, and a higher sFlt-1/PlGF ratio than normal pregnancies. These changes became significant at 12 weeks in patients destined to develop either early onset (< 34 weeks, p ≤ 0.003) or late-onset preeclampsia (≥ 34 weeks, p ≤ 0.02). The risk to develop preeclampsia was higher among patients with PlGF concentration values in the lowest quartile or with sFlt-1 and sEng levels, and sFlt-1/PlGF ratio, in the highest quartile of the normal SLE pregnancies distribution. The OR were higher and appeared earlier in patients destined to develop early onset preeclampsia (OR ≥ 16.2, from Week 12 onward) than in patients who presented preeclampsia later (OR ≥ 8.9, from Week 24 onward). Changes in circulating concentrations of sFlt-1, PlGF, sEng, and the sFlt-1/PlGF ratio precede the onset of preeclampsia in SLE pregnancies. The risk profile of circulating angiogenic factors for developing preeclampsia distinctly evolves depending on whether this condition is manifested earlier or later.

Feasibility of measurement of bone turnover markers in female patients with systemic lupus erythematosus.

PubMed

Bogaczewicz, Jaroslaw; Karczmarewicz, Elzbieta; Pludowski, Pawel; Zabek, Jakub; Kowalski, Jan; Lukaszkiewicz, Jacek; Wozniacka, Anna

2015-01-01

To investigate the feasibility of bone turnover markers (BTMs) for the assessment of bone metabolism in patients with systemic lupus erythematosus (SLE), according to the guidelines of the International Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine. The study included 43 female SLE patients. Serum procollagen type I N propeptide (PINP), C-terminal telopeptide of type I collagen (CTX), osteocalcin, PTH, 25(OH)D, anti-cardiolipin, anti-dsDNA, and anti-nucleosome levels were measured. PINP and CTX levels were elevated in SLE patients aged > 45 in comparison to those aged < 45, although with borderline significance (p = 0.05, respectively). Correlations were found between BTMs: the strongest being between PINP and osteocalcin (τ = 0.69, p < 0.05). PINP and osteocalcin were found to be associated with PTH (τ = 0.3, τ = 0.29, respectively, p < 0.05). Age correlated with PINP (τ = 0.23, p < 0.05). Elevated PINP was found more frequently than elevated osteocalcin or CTX, both in patients aged < 45 (p = 0.001) and > 45 (p < 0.001). No significant difference in PINP, osteocalcin or CTX levels was found with respect to season, neither in the entire SLE group, nor in the under-45 or over-45 groups. Previous glucocorticoid treatment was not associated with difference in BTMs. Increased BTMs in SLE appear to predominantly reflect the pattern of bone remodeling related to age. Increased PINP is expected to be the most frequent outcome among BTMs. Better diagnoses of bone disturbances with BTMs performed in accordance with international reference standards need to be included in the approach to SLE patients, in addition to bone mineral density assessment. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

Reduced ADAMTS13 activity is associated with thrombotic risk in systemic lupus erythematosus.

PubMed

Martin-Rodriguez, S; Reverter, J C; Tàssies, D; Espinosa, G; Heras, M; Pino, M; Escolar, G; Diaz-Ricart, M

2015-10-01

Severe deficiency of ADAMTS13 activity leads to von Willebrand factor (VWF) ultralarge multimers with high affinity for platelets, causing thrombotic thrombocytopenic purpura. Other pathological conditions with moderate ADAMTS13 activity exhibit a thrombotic risk. We examined the ADAMTS13 activity in systemic lupus erythematosus (SLE) and its value as a thrombotic biomarker. ADAMTS13 activity, VWF antigen and multimeric structure, and vascular cell adhesion molecule 1 (VCAM-1) were measured in plasma samples from 50 SLE patients and 50 healthy donors. Disease activity (systemic lupus erythematosus disease activity index; SLEDAI) and organ damage (systemic lupus international collaborating clinics) scores, thrombotic events, antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPLs) were registered. SLE patients showed decreased ADAMTS13 activity and high VWF levels compared with controls (66 ± 27% vs. 101 ± 8%, P < 0.01, and 325 ± 151% vs. 81 ± 14%, P < 0.001). VCAM-1 levels were higher in SLE patients (P < 0.05). Considering three groups of SLE patients depending on ADAMTS13 activity (>60%, 60-40% and <40%), comparative analysis showed significant association between ADAMTS13 activity and SLEDAI (P < 0.05), presence of aPLs (P < 0.001), APS (P < 0.01) and thrombotic events (P < 0.01). Reduced ADAMTS13 activity together with increased VWF levels were especially notable in patients with active disease and with aPLs. ADAMTS13 activity, in combination with other laboratory parameters, could constitute a potential prognostic biomarker of thrombotic risk in SLE. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Comprehensive approach to study complement C4 in systemic lupus erythematosus: Gene polymorphisms, protein levels and functional activity.

PubMed

Tsang-A-Sjoe, M W P; Bultink, I E M; Korswagen, L A; van der Horst, A; Rensink, I; de Boer, M; Hamann, D; Voskuyl, A E; Wouters, D

2017-12-01

Genetic variation of the genes encoding complement component C4 is strongly associated with systemic lupus erythematosus (SLE), a chronic multi-organ auto-immune disease. This study examined C4 and its isotypes on a genetic, protein, and functional level in 140 SLE patients and 104 healthy controls. Gene copy number (GCN) variation, silencing CT-insertion, and the retroviral HERV-K(C4) insertion) were analyzed with multiplex ligation-dependent probe amplification. Increased susceptibility to SLE was found for low GCN (≪2) of C4A. Serositis was the only clinical manifestation associated with low C4A GCN. One additional novel silencing mutation in the C4A gene was found by Sanger sequencing. This mutation causes a premature stop codon in exon 11. Protein concentrations of C4 isoforms C4A and C4B were determined with ELISA and were significantly lower in SLE patients compared to healthy controls. To study C4 isotypes on a functional level, a new C4 assay was developed, which distinguishes C4A from C4B by its binding capacity to amino or hydroxyl groups, respectively. This assay showed high correlation with ELISA and detected crossing over of Rodgers and Chido antigens in 3.2% (8/244) of individuals. The binding capacity of available C4 to its substrates was unaffected in SLE. Our study provides, for the first time, a complete overview of C4 in SLE from genetic variation to binding capacity using a novel test. As this test detects crossing over of Rodgers and Chido antigens, it will allow for more accurate measurement of C4 in future studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Contrasting genetic association of IL2RA with SLE and ANCA-associated vasculitis.

PubMed

Carr, Edward J; Clatworthy, Menna R; Lowe, Christopher E; Todd, John A; Wong, Andrew; Vyse, Timothy J; Kamesh, Lavanya; Watts, Richard A; Lyons, Paul A; Smith, Kenneth G C

2009-03-05

Autoimmune diseases are complex and have genetic and environmental susceptibility factors. The objective was to test the genetic association of systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibody (ANCA) - associated systemic vasculitis (AAV) with SNPs in the IL2RA region and to correlate genotype with serum levels of IL-2RA. Using a cohort of over 700 AAV patients, two SLE case-control studies and an SLE trio collection (totalling over 1000 SLE patients), and a TaqMan genotyping approach, we tested 3 SNPs in the IL2RA locus, rs11594656, rs2104286 & rs41295061, each with a prior association with autoimmune disease; rs11594656 and rs41295061 with type 1 diabetes (T1D) and rs2104286 with multiple sclerosis (MS) and T1D. We show that SLE is associated with rs11594656 (P = 3.87 x 10-7) and there is some evidence of association of rs41295061 with AAV (P = 0.0122), which both have prior association with T1D. rs2104286, an MS and T1D - associated SNP in the IL2RA locus, is not associated with either SLE or AAV. We have confirmed a previous suggestion that the IL2RA locus is associated with SLE and showed some evidence of association with AAV. Soluble IL-2RA concentrations correlate with rs11594656 genotype in quiescent disease in both AAV and SLE. Differential association of autoimmune diseases and SNPs within the IL2RA locus suggests that the IL2RA pathway may prove to play differing, as yet undefined, roles in each disease.

The effects of corticosteroids on cognitive flexibility and decision-making in women with lupus.

PubMed

Montero-López, E; Santos-Ruiz, A; Navarrete-Navarrete, N; Ortego-Centeno, N; Pérez-García, M; Peralta-Ramírez, M I

2016-11-01

The aim of this study was to investigate the possible effects of corticosteroids in women with systemic lupus erythematosus (SLE) in two processes of executive function: cognitive flexibility and decision-making. To that end, we evaluated 121 women divided into three groups: 50 healthy women, 38 women with SLE not receiving corticosteroid treatment and 33 women with SLE receiving corticosteroid treatment. Cognitive flexibility was measured with the Trail Making Tests A and B; decision-making was measured with the Iowa Gambling Task. Additionally, demographic (age and education level), clinical (SLE Disease Activity Index (SLEDAI), Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI) and disease duration) and psychological characteristics (stress vulnerability, perceived stress and psychopathic symptomatology) were evaluated. The results showed that both SLE groups displayed poorer decision-making than the healthy women ( p = 0.006) and also that the SLE group receiving corticosteroid treatment showed lower cognitive flexibility than the other two groups ( p = 0.030). Moreover, SLE patients showed poorer scores than healthy women on the following SCL-90-R subscales: somatisation ( p = 0.005), obsessions and compulsions ( p = 0.045), depression ( p = 0.004), hostility ( p = 0.013), phobic anxiety ( p = 0.005), psychoticism ( p = 0.016) and positive symptom total ( p = 0.001). In addition, both SLE groups were more vulnerable to stress ( p = 0.000). These findings help to understand the effects of corticosteroid treatment on cognitive flexibility and decision-making, in addition to the disease-specific effects suffered by women with SLE.

[A clinical analysis of 15 children with systemic lupus erythematosus accompanied by pulmonary hypertension].

PubMed

Li, Ji; Ma, Jing-Ran; Sun, Zhi-Xing; Jiang, Jing-Jing; Dong, Yan-Qing; Wang, Qian; Song, Hong-Mei

2017-06-01

To evaluate the clinical features, laboratory findings, diagnosis and treatment, and prognosis of children with systemic lupus erythematosus (SLE) accompanied by pulmonary hypertension (PH). The clinical symptoms, laboratory findings, echocardiographic features, SLE disease activity index, and treatment outcome of 15 hospitalized children with SLE accompanied by PH were retrospectively analyzed. Among the 15 patients, the median interval from diagnosis of SLE to diagnosis of PH was 0.1 year (range: 0-6.5 years). Aside from PH-related symptoms, Raynaud's phenomenon was observed in 6 (40%) of the 15 patients. There was no significant difference in SLE disease activity (evaluated by complements 3 and 4 levels, erythrocyte sedimentation rate, and positive rate of anti-double-stranded DNA) between patients with mild-to-moderate PH and those with severe PH (P<0.05). As for treatment, 13 patients received immunosuppressive therapy with glucocorticoids, and among them 2 patients received PH-targeted therapy. During a median follow-up of 8.0 years (range: 0.5-18.1 years) since the diagnosis of PH, 2 deaths were noted with class III or IV cardiac function (World Health Organization), while the other patients were in a stable condition. Raynaud's phenomenon is a common clinical manifestation in children with SLE accompanied by pulmonary hypertension (PH). PH severity is not significantly associated with SLE disease activity, and thus greater focus should be placed upon early screening of pulmonary arterial pressure in SLE patients. Early diagnosis and early treatment can improve the prognosis of children with SLE.

Endothelial dysfunction is associated with activation of the type I interferon system and platelets in patients with systemic lupus erythematosus

PubMed Central

Tydén, Helena; Lood, Christian; Gullstrand, Birgitta; Nielsen, Christoffer Tandrup; Heegaard, Niels H H; Kahn, Robin; Jönsen, Andreas; Bengtsson, Anders A

2017-01-01

Objectives Endothelial dysfunction may be connected to cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Type I interferons (IFNs) are central in SLE pathogenesis and are suggested to induce both endothelial dysfunction and platelet activation. In this study, we investigated the interplay between endothelial dysfunction, platelets and type I IFN in SLE. Methods We enrolled 148 patients with SLE and 79 sex-matched and age-matched healthy controls (HCs). Type I IFN activity was assessed with a reporter cell assay and platelet activation by flow cytometry. Endothelial dysfunction was assessed using surrogate markers of endothelial activation, soluble vascular cell adhesion molecule-1 (sVCAM-1) and endothelial microparticles (EMPs), and finger plethysmograph to determine Reactive Hyperaemia Index (RHI). Results In patients with SLE, type I IFN activity was associated with endothelial activation, measured by high sVCAM-1 (OR 1.68, p<0.01) and elevated EMPs (OR 1.40, p=0.03). Patients with SLE with high type I IFN activity had lower RHI than HCs (OR 2.61, p=0.04), indicating endothelial dysfunction. Deposition of complement factors on platelets, a measure of platelet activation, was seen in patients with endothelial dysfunction. High levels of sVCAM-1 were associated with increased deposition of C4d (OR 4.57, p<0.01) and C1q (OR 4.10, p=0.04) on platelets. High levels of EMPs were associated with C4d deposition on platelets (OR 3.64, p=0.03). Conclusions Endothelial dysfunction was associated with activation of platelets and the type I IFN system. We suggest that an interplay between the type I IFN system, injured endothelium and activated platelets may contribute to development of CVD in SLE. PMID:29119007

A prospective functional MRI study for executive function in patients with systemic lupus erythematosus without neuropsychiatric symptoms.

PubMed

Mak, Anselm; Ren, Tao; Fu, Erin Hui-yun; Cheak, Alicia Ai-cia; Ho, Roger Chun-man

2012-06-01

To study the functional brain activation signals before and after sufficient disease control in patients with systemic lupus erythematosus (SLE) without clinical neuropsychiatric symptoms. Blood-oxygen-level-dependent signals during event-related functional magnetic resonance imaging brain were recorded, while 14 new-onset SLE patients and 14 demographically and intelligence quotient matched healthy controls performed the computer-based Wisconsin card sorting test for assessing executive function, which probes strategic planning and goal-directed task performance during feedback evaluation (FE) and response selection (RS), respectively. Composite beta maps were constructed by a general linear model to identify regions of cortical activation. Blood-oxygen-level-dependent functional magnetic resonance imaging signals were compared between (1) new-onset SLE patients and healthy controls and (2) SLE patients before and after sufficient control of their disease activity. During RS, SLE patients demonstrated significantly higher activation than healthy controls in both caudate bodies and Brodmann area (BA) 9 to enhance event anticipation, attention, and working memory, respectively, to compensate for the reduced activation during FE in BA6, 13, 24, and 32, which serve complex motor planning and decision-making, sensory integration, error detection, and conflict processing, respectively. Despite significant reduction of SLE activity, BA32 was activated during RS to compensate for reduced activation during FE in BA6, 9, 37, and 23/32, which serve motor planning, response inhibition and attention, color processing and word recognition, error detection, and conflict evaluation, respectively. Even without clinically overt neuropsychiatric symptoms, SLE patients recruited additional pathways to execute goal-directed tasks to compensate for their reduced strategic planning skill despite clinically sufficient disease control. Copyright © 2012 Elsevier Inc. All rights reserved.

Targeting the RhoA-ROCK pathway to reverse T-cell dysfunction in SLE.

PubMed

Rozo, Cristina; Chinenov, Yurii; Maharaj, Reena Khianey; Gupta, Sanjay; Leuenberger, Laura; Kirou, Kyriakos A; Bykerk, Vivian P; Goodman, Susan M; Salmon, Jane E; Pernis, Alessandra B

2017-04-01

Deregulated production of interleukin (IL)-17 and IL-21 contributes to the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Production of IL-17 and IL-21 can be regulated by ROCK2, one of the two Rho kinases. Increased ROCK activation was previously observed in an SLE cohort. Here, we evaluated ROCK activity in a new SLE cohort, and an RA cohort, and assessed the ability of distinct inhibitors of the ROCK pathway to suppress production of IL-17 and IL-21 by SLE T cells or human Th17 cells. ROCK activity in peripheral blood mononuclear cells (PBMCs) from 29 patients with SLE, 31 patients with RA and 28 healthy controls was determined by ELISA. SLE T cells or in vitro-differentiated Th17 cells were treated with Y27632 (a pan-ROCK inhibitor), KD025 (a selective ROCK2 inhibitor) or simvastatin (which inhibits RhoA, a major ROCK activator). ROCK activity and IL-17 and IL-21 production were assessed. The transcriptional profile altered by ROCK inhibitors was evaluated by NanoString technology. ROCK activity levels were significantly higher in patients with SLE and RA than healthy controls. Th17 cells exhibited high ROCK activity that was inhibited by Y27632, KD025 or simvastatin; each also decreased IL-17 and IL-21 production by purified SLE T cells or Th17 cells. Immune profiling revealed both overlapping and distinct effects of the different ROCK inhibitors. ROCK activity is elevated in PBMCs from patients with SLE and RA. Production of IL-17 and IL-21 by SLE T cells or Th17 cells can furthermore be inhibited by targeting the RhoA-ROCK pathway via both non-selective and selective approaches. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Fatigue and cognitive function in systemic lupus erythematosus: associations with white matter microstructural damage. A diffusion tensor MRI study and meta-analysis.

PubMed

Wiseman, S J; Bastin, M E; Hamilton, I F; Hunt, D; Ritchie, S J; Amft, E N; Thomson, S; Belch, J F F; Ralston, S H; Wardlaw, J M

2017-05-01

Objective The objective of this study was to investigate fatigue and cognitive impairments in systemic lupus erythematous (SLE) in relation to diffuse white matter microstructural brain damage. Methods Diffusion tensor MRI, used to generate biomarkers of brain white matter microstructural integrity, was obtained in patients with SLE and age-matched controls. Fatigue and cognitive function were assessed and related to SLE activity, clinical data and plasma biomarkers of inflammation and endothelial dysfunction. Results Fifty-one patients with SLE (mean age 48.8 ± 14.3 years) were included. Mean diffusivity (MD) was significantly higher in all white matter fibre tracts in SLE patients versus age-matched healthy controls ( p < 0.0001). Fatigue in SLE was higher than a normal reference range ( p < 0.0001) and associated with lower MD ( ß = -0.61, p = 0.02), depression ( ß = 0.17, p = 0.001), anxiety ( ß = 0.13, p = 0.006) and higher body mass index ( ß = 0.10, p = 0.004) in adjusted analyses. Poorer cognitive function was associated with longer SLE disease duration ( p = 0.003) and higher MD ( p = 0.03) and, in adjusted analysis, higher levels of IL-6 ( ß = -0.15, p = 0.02) but not with MD. Meta-analysis (10 studies, n = 261, including the present study) confirmed that patients with SLE have higher MD than controls. Conclusion Patients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. The association between raised IL-6 and worse current cognitive function in SLE should be explored in larger datasets.

Th17 responses and natural IgM antibodies are related to gut microbiota composition in systemic lupus erythematosus patients

PubMed Central

López, Patricia; de Paz, Banesa; Rodríguez-Carrio, Javier; Hevia, Arancha; Sánchez, Borja; Margolles, Abelardo; Suárez, Ana

2016-01-01

Intestinal dysbiosis, characterized by a reduced Firmicutes/Bacteroidetes ratio, has been reported in systemic lupus erythematosus (SLE) patients. In this study, in vitro cultures revealed that microbiota isolated from SLE patient stool samples (SLE-M) promoted lymphocyte activation and Th17 differentiation from naïve CD4+ lymphocytes to a greater extent than healthy control-microbiota. Enrichment of SLE-M with Treg-inducing bacteria showed that a mixture of two Clostridia strains significantly reduced the Th17/Th1 balance, whereas Bifidobacterium bifidum supplementation prevented CD4+ lymphocyte over-activation, thus supporting a possible therapeutic benefit of probiotics containing Treg-inducer strains in order to restore the Treg/Th17/Th1 imbalance present in SLE. In fact, ex vivo analyses of patient samples showed enlarged Th17 and Foxp3+ IL-17+ populations, suggesting a possible Treg-Th17 trans-differentiation. Moreover, analyses of fecal microbiota revealed a negative correlation between IL-17+ populations and Firmicutes in healthy controls, whereas in SLE this phylum correlated directly with serum levels of IFNγ, a Th1 cytokine slightly reduced in patients. Finally, the frequency of Synergistetes, positively correlated with the Firmicutes/Bacteroidetes ratio in healthy controls, tended to be reduced in patients when anti-dsDNA titers were increased and showed a strong negative correlation with IL-6 serum levels and correlated positively with protective natural IgM antibodies against phosphorylcholine. PMID:27044888

Fingerprinting sea-level variations in response to continental ice loss: a benchmark exercise

NASA Astrophysics Data System (ADS)

Barletta, Valentina R.; Spada, Giorgio; Riva, Riccardo E. M.; James, Thomas S.; Simon, Karen M.; van der Wal, Wouter; Martinec, Zdenek; Klemann, Volker; Olsson, Per-Anders; Hagedoorn, Jan; Stocchi, Paolo; Vermeersen, Bert

2013-04-01

Understanding the response of the Earth to the waxing and waning ice sheets is crucial in various contexts, ranging from the interpretation of modern satellite geodetic measurements to the projections of future sea level trends in response to climate change. All the processes accompanying Glacial Isostatic Adjustment (GIA) can be described solving the so-called Sea Level Equation (SLE), an integral equation that accounts for the interactions between the ice sheets, the solid Earth, and the oceans. Modern approaches to the SLE are based on various techniques that range from purely analytical formulations to fully numerical methods. Here we present the results of a benchmark exercise of independently developed codes designed to solve the SLE. The study involves predictions of current sea level changes due to present-day ice mass loss. In spite of the differences in the methods employed, the comparison shows that a significant number of GIA modellers can reproduce their sea-level computations within 2% for well defined, large-scale present-day ice mass changes. Smaller and more detailed loads need further and dedicated benchmarking and high resolution computation. This study shows how the details of the implementation and the inputs specifications are an important, and often underappreciated, aspect. Hence this represents a step toward the assessment of reliability of sea level projections obtained with benchmarked SLE codes.

Serum free light chains, interferon-alpha, and interleukins in systemic lupus erythematosus.

PubMed

Jolly, M; Francis, S; Aggarwal, R; Mikolaitis, R A; Niewold, T B; Chubinskaya, S; Block, J A; Scanzello, C; Sequeira, W

2014-08-01

Interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-alpha (IFN-α), and free light chains (FLCs: lambda, kappa) have all been noted to be of importance in systemic lupus erythematosus (SLE). Herein, we quantified and explored the relationship between these inflammatory mediators and disease activity in SLE; and stratified by their current anti-dsDNA antibody status. Seventy-seven SLE patients underwent assessment of disease activity using the SLE disease activity index (SLEDAI). Serum FLC (lambda, kappa, and total), IL-6, IL-10, and IFN-α were quantified. Demographics of disease characteristics were determined by chart reviews. Statistical analyses included Mann-Whitney test, chi square, and linear regression analyses. Mean (SD) age of the patients was 44.9 ± 12.7 years; SLEDAI (mean ± SD) was 3.4 ± 4.0. Serum lambda FLC levels had a moderate correlation (r = 0.46 with physician global assessment, 0.44 with SLEDAI) and the strongest correlation with disease activity as compared with other inflammatory mediators including current dsDNA antibody status. After adjusting for prednisone use, the correlation of lambda FLC with PGA (r = 0.48) and SLEDAI (r = 0.52) was better than of current dsDNA antibody status with PGA (r = 0.33) and adjusted SLEDAI (r = 0.24), respectively. IL-10 and IFN-α activity did not correlate with disease activity. Serum FLC and IL-6 levels could differentiate between active and inactive SLE patients. Serum lambda FLC and IL-6 levels differed significantly among patients with and without current dsDNA antibodies. Serum lambda FLC levels accounted for 31% of variance in SLEDAI scores. Serum FLC and IL-6 are potentially useful biomarkers of disease activity in SLE. Further studies, with larger study sample and longitudinal design, are indicated. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity.

PubMed

Nakayama, Yumi; Kosek, Jolanta; Capone, Lori; Hur, Eun Mi; Schafer, Peter H; Ringheim, Garth E

2017-10-01

BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27 + memory and memory-like CD27 - IgD - double-negative (DN) B cells, but not CD27 - IgD + naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27 + memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines. Copyright © 2017 by The American Association of Immunologists, Inc.

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

PubMed Central

Nakayama, Yumi; Kosek, Jolanta; Capone, Lori; Schafer, Peter H.

2017-01-01

BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines. PMID:28848067

Association of objectively measured physical activity and sedentary time with arterial stiffness in women with systemic lupus erythematosus with mild disease activity.

PubMed

Morillas-de-Laguno, Pablo; Vargas-Hitos, José A; Rosales-Castillo, Antonio; Sáez-Urán, Luis Manuel; Montalbán-Méndez, Cristina; Gavilán-Carrera, Blanca; Navarro-Mateos, Carmen; Acosta-Manzano, Pedro; Delgado-Fernández, Manuel; Sabio, José M; Ortego-Centeno, Norberto; Callejas-Rubio, José L; Soriano-Maldonado, Alberto

2018-01-01

To examine the association of objectively measured physical activity (PA) intensity levels and sedentary time with arterial stiffness in women with systemic lupus erythematosus (SLE) with mild disease activity and to analyze whether participants meeting the international PA guidelines have lower arterial stiffness than those not meeting the PA guidelines. The study comprised 47 women with SLE (average age 41.2 [standard deviation 13.9]) years, with clinical and treatment stability during the 6 months prior to the study. PA intensity levels and sedentary time were objectively measured with triaxial accelerometry. Arterial stiffness was assessed through pulse wave velocity, evaluated by Mobil-O-Graph® 24h pulse wave analysis monitor. The average time in moderate to vigorous PA in bouts of ≥10 consecutive minutes was 135.1±151.8 minutes per week. There was no association of PA intensity levels and sedentary time with arterial stiffness, either in crude analyses or after adjusting for potential confounders. Participants who met the international PA guidelines did not show lower pulse wave velocity than those not meeting them (b = -0.169; 95% CI: -0.480 to 0.143; P = 0.280). Our results suggest that PA intensity levels and sedentary time are not associated with arterial stiffness in patients with SLE. Further analyses revealed that patients with SLE meeting international PA guidelines did not present lower arterial stiffness than those not meeting the PA guidelines. Future prospective research is needed to better understand the association of PA and sedentary time with arterial stiffness in patients with SLE.

Correlation between IL-17A/F, IL-23, IL-35 and IL-12/-23 (p40) levels in peripheral blood lymphocyte cultures and disease activity in Behcet's patients.

PubMed

Sonmez, Cemile; Yucel, Aysegul Atak; Yesil, Turan Hilmi; Kucuk, Hamit; Sezgin, Berna; Mercan, Ridvan; Yucel, Ahmet Eftal; Demirel, Gulderen Yanikkaya

2018-03-20

Behcet's disease is a chronic multisystemic disease with remissions and relapses. Several studies have shown that immune mechanisms play an important role in the development of the disease. In order to assess the association of disease activity with IL-17A/F, IL-23, IL-12/23 (p40) and IL-35 expression, we aimed to investigate production of these cytokines in peripheral blood mononuclear cells (PBMCs) from Behcet's patients and normal controls. Furthermore, we included Systemic Lupus Erythematosus (SLE) as disease control to evaluate the specificity of our data for immunopathogenesis of BD. Totally 15 active, 15 inactive Behcet's patients, 12 active and 12 inactive SLE patients and 12 healthy volunteers were enrolled in the study. Peripheral blood mononuclear cells were separated, lymphocyte cultures were performed and IL-17A/F, IL-12/23 p(40), IL-23, IL-35 cytokine levels were measured by ELISA in culture supernatants in the presence or absence of phytohemagglutinin (PHA) on time-dependent manner. IL-17 A/F levels increased parallel to IL-23 levels in Behcet's and SLE patients. Compared to healthy controls, IL-17 A/F levels were higher in active Behcet's and SLE patients; on the contrary, levels of IL-35 were lower. IL-17A/F, IL-12/23 (p40) and IL-23 levels were detectable most frequently in active Behcet's patients followed by active SLE patients. Our results indicate that IL-17 A/F, IL-23 and IL-12/23 (p40) may play role in the immunopathogenesis of BD so as Th17 and Th1 cell responses. Since IL-35 levels were lower in active Behcet's patients compared to inactive patients and healthy controls, there may be a plasticity between Th17 and Treg cells according to the state of disease activity.

Serum Vascular Endothelial Growth Factor (VEGF) as a Biomarker for Disease Activity in Lupus Nephritis.

PubMed

Ghazali, Wan Syamimee Wan; Iberahim, Rahimah; Ashari, Noor Suryani Mohd

2017-10-01

Previous studies have shown that serum VEGF levels were elevated in patients with active systemic lupus erythematosus (SLE), especially in those with lupus nephritis (LN). In this case control study, we aimed to compare serum levels of VEGF in SLE patients between LN, non-LN and healthy participants to determine the association between serum VEGF levels and the activity and histological classes of lupus nephritis. Blood samples were obtained from 92 SLE patients (46 LN and 46 non-LN) and 26 controls. Data were collected from medical records. Serum VEGF assays were performed by specific, enzyme-linked immunosorbent assay kits (ELISA). Laboratory investigations included urinalysis, urine protein-creatinine ratio, serum creatinine, albumin and VEGF levels. Blood pressure, renal biopsy result and treatment were recorded. LN activity was evaluated using the renal subscale of the British Isles Lupus Assessment Group (rBILAG, 2004). The rBILAG measures blood pressure (diastolic and systolic), urine protein, serum creatinine, calculated glomerular filtration rate (GFR), presence of active urinary sediments and histological evidence of active nephritis. Serum VEGF was elevated in SLE patients with LN compared with the non-LN group and healthy controls. The levels found were significantly higher in the sera of patients with active nephritis compared to those with quiescent nephritis ( P = 0.024). The study did not find a statistically significant relationship between serum VEGF levels and histological classes of LN. There was no significant difference of serum VEGF level between LN and non-LN SLE groups and between the non-LN group and healthy controls. However, there were increased levels of serum VEGF in the LN group, especially in patients with active nephritis as compared to quiescent nephritis group. This reflects the role of VEGF in the pathogenesis of lupus nephritis, however the clinical potential of this biomarker needs further study.

Characteristics and long-term outcome of 15 episodes of systemic lupus erythematosus-associated hemophagocytic syndrome.

PubMed

Lambotte, Olivier; Khellaf, Mehdi; Harmouche, Hicham; Bader-Meunier, Brigitte; Manceron, Véronique; Goujard, Cécile; Amoura, Zahir; Godeau, Bertrand; Piette, Jean-Charles; Delfraissy, Jean-François

2006-05-01

Reactive hemophagocytic syndrome (HS) occurs mainly in the setting of serious infections and lymphomas. HS can occur in the course of 2 active systemic diseases, without simultaneous infection: adult Still disease and systemic lupus erythematosus (SLE). Observations of specific lupus-associated HS are rare, and the long-term outcome of these patients with active SLE is unknown. We retrospectively studied 15 episodes of SLE-associated HS in 12 patients (10 women, 2 men) and noted the long-term outcome. HS occurred at a mean age of 25 years. All patients were febrile with >or=2 cytopenias, and bone marrow aspiration indicated hemophagocytosis. HS revealed SLE in 9 patients and recurred in 3. The main features of SLE-associated HS were a low frequency of hepatosplenomegaly, a high frequency of heart involvement (5 pericarditis, 4 myocarditis requiring transfer to intensive care unit), and a low C-reactive protein level (mean, 15 mg/L). Cutaneous-mucous symptoms of SLE, arthritis, and nephritis were present respectively in 8 (53%), 6 (40%), and 4 (27%) episodes, but symptoms of SLE were absent in 4 episodes at admission. All patients had anti-nuclear antibodies when the HS occurred. Anti-double-stranded DNA antibodies were present in 12 episodes. Treatment was steroids in 14 cases but cyclophosphamide was the only treatment able to control HS in 2 cases. All the cases of SLE-associated HS were controlled by the immunosuppressive regimen. Intravenous immunoglobulins seemed poorly effective. No infectious agent was found. Clinical presentations of the 23 patients with SLE-associated HS described in the literature were reviewed and were similar to those of the current series. The mean follow-up was 88 months (range, 7-240 mo). One patient died at 15 months (sepsis). Among the 5 patients with a follow-up >8 years, 4 always had active disease. During the follow-up of SLE, immunosuppressive drugs were added in 8 patients (cyclophosphamide in 7, azathioprine in 3, mycophenolate mofetil in 2) with significant adverse drug reactions. In the long-term, SLE-associated HS seems to define a severe SLE form with frequent flares, possible HS recurrences, and the need for prolonged immunosuppression.

Genetic Analysis of the Pathogenic Molecular Sub-phenotype Interferon Alpha Identifies Multiple Novel Loci Involved in Systemic Lupus Erythematosus

PubMed Central

Kariuki, Silvia N.; Ghodke-Puranik, Yogita; Dorschner, Jessica M.; Chrabot, Beverly S.; Kelly, Jennifer A.; Tsao, Betty P.; Kimberly, Robert P.; Alarcón-Riquelme, Marta E.; Jacob, Chaim O.; Criswell, Lindsey A.; Sivils, Kathy L.; Langefeld, Carl D.; Harley, John B.; Skol, Andrew D.; Niewold, Timothy B.

2014-01-01

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, greatly reducing the power of case-control studies in SLE. Elevated circulating interferon alpha (IFN-α) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. 40–50% of patients have high IFN-α, and high levels correspond with clinical differences. To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high vs. low IFN-α in over 1550 SLE cases, including GWAS and replication cohorts. In meta-analysis, the top associations in European ancestry were PRKG1 rs7897633 (PMeta=2.75 × 10−8) and PNP rs1049564 (PMeta=1.24 × 10−7). We also found evidence for cross-ancestral background associations with the ANKRD44 and PLEKHF2 loci. These loci have not been previously identified in case-control SLE genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN-α production in SLE. As case-control studies of heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic subphenotypes becomes an attractive strategy for genetic discovery in complex disease. PMID:25338677

Cause-effect relations between 55 kD soluble TNF receptor concentrations and specific and unspecific symptoms in a patient with mild SLE disease activity: an exploratory time series analysis study.

PubMed

Schubert, Christian; Haberkorn, Julia; Ocaña-Peinado, Francisco M; König, Paul; Sepp, Norbert; Schnapka-Köpf, Mirjam; Fuchs, Dietmar

2015-09-21

This integrative single-case study investigated the 12 h-to-12 h cause-effect relations between 55 kD soluble tumor necrosis factor receptor type 1 (sTNF-R55) and specific and unspecific symptoms in a 52-year-old Caucasian woman with mild systemic lupus erythematosus (SLE) disease activity. The patient collected her entire urine for 56 days in 12 h-intervals to determine sTNF-R55/creatinine and protein/creatinine levels (ELISA, HPLC). Additionally, twice a day, she took notes on oral ulceration and facial rash; answered questionnaires (VAS) on fatigue, weakness, and joint pain; and measured body temperature orally. Time series analysis consisted of ARIMA modeling and cross-correlational analyses (significance level = p < 0.05). Time series analysis revealed both a circadian and a circasemiseptan rhythm in the urinary sTNF-R55 data. Moreover, several significant lagged correlations between urinary sTNF-R55 concentrations and SLE symptoms in both directions of effect were identified. Specifically, increased urinary sTNF-R55 concentrations preceded decreased urinary protein levels by 36-48 h (r = -0.213) and, in the opposite direction of effect, increased protein levels preceded increased sTNF-R55 concentrations by 24-36 h (r = +0.202). In addition, increased urinary sTNF-R55 levels preceded increased oral ulcers by 36-48 h (r = +0.277) and, conversely, increased oral ulceration preceded decreased sTNF-R55 levels by 36-48 h (r = -0.313). Moreover, increased urinary sTNF-R55 levels preceded decreased facial rash by 36-48 h (r = -0.223) and followed increased body temperature after 36-48 h (r = +0.209). Weakness, fatigue and joint pain were not significantly correlated with urinary sTNF-R55 levels. This study gathered first evidence of real-life, long-term feedback loops between cytokines and SLE symptoms in mild SLE disease activity. Such insights into the potential role of sTNF-R55 in SLE would not have been possible had we applied a pre-post design group study. These findings require replication before firm conclusions can be drawn.

A Systems Biology-Based Investigation into the Pharmacological Mechanisms of Sheng-ma-bie-jia-tang Acting on Systemic Lupus Erythematosus by Multi-Level Data Integration.

PubMed

Huang, Lin; Lv, Qi; Liu, Fenfen; Shi, Tieliu; Wen, Chengping

2015-11-12

Sheng-ma-bie-jia-tang (SMBJT) is a Traditional Chinese Medicine (TCM) formula that is widely used for the treatment of Systemic Lupus Erythematosus (SLE) in China. However, molecular mechanism behind this formula remains unknown. Here, we systematically analyzed targets of the ingredients in SMBJT to evaluate its potential molecular mechanism. First, we collected 1,267 targets from our previously published database, the Traditional Chinese Medicine Integrated Database (TCMID). Next, we conducted gene ontology and pathway enrichment analyses for these targets and determined that they were enriched in metabolism (amino acids, fatty acids, etc.) and signaling pathways (chemokines, Toll-like receptors, adipocytokines, etc.). 96 targets, which are known SLE disease proteins, were identified as essential targets and the rest 1,171 targets were defined as common targets of this formula. The essential targets directly interacted with SLE disease proteins. Besides, some common targets also had essential connections to both key targets and SLE disease proteins in enriched signaling pathway, e.g. toll-like receptor signaling pathway. We also found distinct function of essential and common targets in immune system processes. This multi-level approach to deciphering the underlying mechanism of SMBJT treatment of SLE details a new perspective that will further our understanding of TCM formulas.

[Prevention of infections in adults and adolescents with systemic lupus erythematosus: Guidelines for the clinical practice based on the literature and expert opinion].

PubMed

Mathian, A; Arnaud, L; Adoue, D; Agard, C; Bader-Meunier, B; Baudouin, V; Belizna, C; Bonnotte, B; Boumedine, F; Chaib, A; Chauchard, M; Chiche, L; Daugas, E; Ghali, A; Gobert, P; Gondran, G; Guettrot-Imbert, G; Hachulla, E; Hamidou, M; Haroche, J; Hervier, B; Hummel, A; Jourde-Chiche, N; Korganow, A-S; Kwon, T; Le Guern, V; Le Quellec, A; Limal, N; Magy-Bertrand, N; Marianetti-Guingel, P; Martin, T; Martin Silva, N; Meyer, O; Miyara, M; Morell-Dubois, S; Ninet, J; Pennaforte, J-L; Polomat, K; Pourrat, J; Queyrel, V; Raymond, I; Remy, P; Sacre, K; Sibilia, J; Viallard, J-F; Viau Brabant, A; Hanslik, T; Amoura, Z

2016-05-01

To develop French recommendations about the management of vaccinations, the screening of cervical cancer and the prevention of pneumocystis pneumonia in systemic lupus erythematosus (SLE). Thirty-seven experts qualified in internal medicine, rheumatology, dermatology, nephrology and pediatrics have selected recommendations from a list of proposition based on available data from the literature. For each recommendation, the level of evidence and the level of agreement among the experts were specified. Inactivated vaccines do not cause significant harm in SLE patients. Experts recommend that lupus patient should receive vaccinations accordingly to the recommendations and the schedules for the general public. Pneumococcal vaccination is recommended for all SLE patients. Influenza vaccination is recommended for immunosuppressed SLE patients. Live attenuated vaccines should be avoided in immunosuppressed patients. Yet, recent works suggest that they can be considered in mildly immunosuppressed patients. Experts have recommended a cervical cytology every year for immunosuppressed patients. No consensus was obtained for the prevention of pneumocystis pneumonia. These recommendations can be expected to improve clinical practice uniformity and, in the longer term, to optimize the management of SLE patients. Copyright © 2016 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid-lowering effect.

PubMed

Cairoli, E; Rebella, M; Danese, N; Garra, V; Borba, E F

2012-10-01

The influence of antimalarials on lipids in systemic lupus erythematosus (SLE) has been identified in several studies but not in many prospective cohorts. The aim of this study was to longitudinally determine the effect of antimalarials on the lipoprotein profile in SLE. Fasting total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low-density lipoprotein cholesterol (LDL) plasma levels were determined at entry and after 3 months of hydroxychloroquine (HCQ) treatment in a longitudinal evaluation of 24 patients with SLE. a significant decrease in TC (198 ± 33.7 vs. 183 ± 30.3 mg/dl, p = 0.023) and LDL levels (117 ± 31.3 vs. 101 ± 26.2 mg/dl, p = 0.023) were detected after the 3 months of HCQ therapy. The reduction of 7.6% in TC (p = 0.055) and 13.7% in LDL levels (p = 0.036) determined a significant decrease in the frequency of dyslipidemia (26% vs. 12.5%, p = 0.013) after HCQ therapy. This longitudinal study demonstrated the beneficial effect of antimalarials on lipids in SLE since this therapy induced a reduction of atherogenic lipoproteins.

Complement system studies in systemic lupus erythematosus (SLE)

PubMed

Teisberg, P

1975-01-01

Complement system involvement has been studied in 16 patients with systemic lupus erythematosus (SLE). Circulating conversion products of C3 were observed in 4 cases. Low mean values of C4 and C3 were found, while C3 proactivator (properdin factor B) levels were low in only a few of the patients. The levels of C4, C3 and C3 proactivator were not lower in the 4 patients in whom C3 conversion products could be demonstrated than in the others. It is concluded that the low complement values found in SLE may be caused mainly by deficient synthesis. Signs of complement activation are in this patient material demonstrated early in the disease, and chiefly in patients not receiving immunosuppressive therapy.

Free fatty acids are associated with metabolic syndrome and insulin resistance but not inflammation in systemic lupus erythematosus.

PubMed

Ormseth, M J; Swift, L L; Fazio, S; Linton, M F; Raggi, P; Solus, J F; Oeser, A; Bian, A; Gebretsadik, T; Shintani, A; Stein, C M

2013-01-01

Free fatty acids (FFAs) are implicated in the pathogenesis of insulin resistance and atherosclerosis. Inflammatory cytokines promote lipolysis and increase FFAs, a cause of endothelial dysfunction and increased atherosclerosis risk. We hypothesized that increased inflammation is associated with increased FFAs, resulting in insulin resistance and atherosclerosis in patients with systemic lupus erythematosus (SLE). We measured clinical variables, serum FFAs, homeostasis model assessment for insulin resistance (HOMA), inflammatory cytokines, markers of endothelial activation, cholesterol concentrations and coronary artery calcium in 156 patients with SLE and 90 controls. We compared FFAs in patients with SLE and controls using Wilcoxon rank sum tests and further tested for the independent association between FFAs and disease status with adjustment for age, race and sex using multivariable regression models. We assessed the relationship between FFAs and continuous variables of interest using Spearman correlation and multivariable regression analysis. Levels of FFAs were higher in patients with SLE than controls (0.55 mmol/l (0.37-0.71) vs 0.44 mmol/l (0.32-0.60), P = 0.02). Levels of FFAs remained significantly higher among patients with SLE after adjustment for age, race and sex (P = 0.03) but not after further adjustment for body mass index (P = 0.13). FFA levels did not differ according to the usage of current immunosuppressive medications in univariate and adjusted analysis (all P > 0.05). Among patients with SLE, concentrations of FFAs were higher among those with metabolic syndrome compared to those without (0.66 mmol/l (0.46-0.81) vs 0.52 mmol/l (0.35-0.66), P < 0.001). FFAs were positively correlated with insulin resistance (HOMA) (rho = 0.23, P = 0.004, P adjusted = 0.006) and triglyceride levels (rho = 0.22, P = 0.01, P adjusted = 0.004). FFAs were not associated with inflammatory cytokines (IL-6, TNF-α) (all P > 0.05) but were positively associated with levels of E-selectin (rho = 0.33, P = < 0.001, P adjusted = 0.001) and ICAM-1 (rho = 0.35, P < 0.001, P adjusted = 0.001). FFAs were correlated with coronary artery calcium score (rho = 0.20, P = 0.01) but this was attenuated after adjustment for age, race and sex (P = 0.33). From our study we concluded that FFAs are elevated in patients with SLE, particularly those with metabolic syndrome. FFAs in patients with SLE are not associated with markers of generalized inflammation but are associated with insulin resistance and markers of endothelial activation.

Retrospective analysis on the impact of tuberculosis on patients with systemic lupus erythematosus (SLE).

PubMed

Zhang, Chang-Ran; Niu, Yuan-Yuan; Lin, Jian-Cong; Wu, Wen-Hui; Li, Ming; Li, Jian-Feng

2013-01-01

Up to now, there have been few reports concerning changes in lupus activity and immune indices of tuberculosis in patients with systemic lupus erythematosis (SLE). A retrospective investigation was given to survey the case data of SLE patients companied with tuberculosis that were treated in our hospital from 2001 to 2010 and compared with that of sex- and age-matched patients with single SLE. Changes in autoantibodies, lupus activity, inflammatory indices, positive rates of tuberculin (PPD) test and tuberculosis antibody (TB-Ab) of both groups were observed. It was indicated by results that ANA antibody level and positive rates of anti-Sm, anti-SSA and anti-SSB antibodies were significantly lower in the TB group than those in the control group (P < 0.05); C3 and C4 levels were significantly higher in the TB group than those in the control group; damage of hematological system (predominantly platelet) was less severe in the TB group than that in the control group (P < 0.05); no significant differences in IgG, IgM and IgA were noted between two groups (P > 0.05); ESR, C-reactive protein and LDH levels were significantly higher in the TB group than those in the control group (P < 0.05); PPD-IgG were significantly higher in the TB group than those in the control group (P < 0.05). These results suggested that after SLE patients were infected with tuberculosis, immune function was altered and lupus activity was inhibited as well.

Impaired contraction of blood clots as a novel prothrombotic mechanism in systemic lupus erythematosus.

PubMed

Le Minh, Giang; Peshkova, Alina D; Andrianova, Izabella A; Sibgatullin, Timur B; Maksudova, Adelia N; Weisel, John W; Litvinov, Rustem I

2018-01-31

The aim of this work was to examine a possible role of clot contraction/retraction in thrombotic complications of systemic lupus erythematosus (SLE). Using a novel automated method, we investigated kinetics of clot contraction in the blood of 51 SLE patients and 60 healthy donors. The functionality of platelets in the SLE patients was assessed using flow cytometry by expression of P-selectin and fibrinogen-binding capacity. The rate and degree of clot contraction were significantly reduced in SLE patients compared with healthy subjects, especially in the patients with higher blood levels of anti-dsDNA antibodies. The reduced platelet contractility correlated with partial refractoriness of platelets isolated from the blood of SLE patients to stimulation induced by the thrombin receptor activating peptide. To test if the anti-dsDNA autoantibodies cause continuous platelet activation, followed by exhaustion and dysfunction of the cells, we added purified exogenous anti-dsDNA autoantibodies from SLE patients to normal blood before clotting. In support of this hypothesis, the antibodies first enhanced clot contraction and then suppressed it in a time-dependent manner. Importantly, a direct correlation of clot contraction parameters with the disease severity suggests that the reduced compactness of intravascular clots and thrombi could be a pathogenic factor in SLE that may exaggerate the impaired blood flow at the site of thrombosis. In conclusion, autoantibodies in SLE can affect platelet contractility, resulting in reduced ability of clots and thrombi to shrink in volume, which increases vessel obstruction and may aggravate the course and outcomes of thrombotic complications in SLE. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Multidimensional Single Cell Based STAT Phosphorylation Profiling Identifies a Novel Biosignature for Evaluation of Systemic Lupus Erythematosus Activity

PubMed Central

Huang, Xinfang; Guo, Yanzhi; Bao, Chunde; Shen, Nan

2011-01-01

Introduction Dysregulated cytokine action on immune cells plays an important role in the initiation and progress of systemic lupus erythematosus (SLE), a complex autoimmune disease. Comprehensively quantifying basal STATs phosphorylation and their signaling response to cytokines should help us to better understand the etiology of SLE. Methods Phospho-specific flow cytometry was used to measure the basal STAT signaling activation in three immune cell types of peripheral-blood mononuclear cells from 20 lupus patients, 9 rheumatoid arthritis (RA) patients and 13 healthy donors (HDs). A panel of 27 cytokines, including inflammatory cytokines, was measured with Bio-Plex™ Human Cytokine Assays. Serum Prolactin levels were measured with an immunoradiometric assay. STAT signaling responses to inflammatory cytokines (interferon α [IFNα], IFNγ, interleukin 2 [IL2], IL6, and IL10) were also monitored. Results We observed the basal activation of STAT3 in SLE T cells and monocytes, and the basal activation of STAT5 in SLE T cells and B cells. The SLE samples clustered into two main groups, which were associated with the SLE Disease Activity Index 2000, their erythrocyte sedimentation rate, and their hydroxychloroquine use. The phosphorylation of STAT5 in B cells was associated with cytokines IL2, granulocyte colony-stimulating factor (G-CSF), and IFNγ, whereas serum prolactin affected STAT5 activation in T cells. The responses of STAT1, STAT3, and STAT5 to IFNα were greatly reduced in SLE T cells, B cells, and monocytes, except for the STAT1 response to IFNα in monocytes. The response of STAT3 to IL6 was reduced in SLE T cells. Conclusions The basal activation of STATs signaling and reduced response to cytokines may be helpful us to identify the activity and severity of SLE. PMID:21799742

Bone mineral density and vertebral fractures in patients with systemic lupus erythematosus: A systematic review and meta-regression.

PubMed

Mendoza-Pinto, Claudia; Rojas-Villarraga, Adriana; Molano-González, Nicolás; Jiménez-Herrera, Erick A; León-Vázquez, María de la Luz; Montiel-Jarquín, Álvaro; García-Carrasco, Mario; Cervera, Ricard

2018-01-01

Observational studies have indicated a high but heterogeneous prevalence of low bone mineral density (BMD) and vertebral fractures (VF) in patients with systemic lupus erythematosus (SLE). Therefore, the objectives of this systematic review and meta-regression were: 1) to compare BMD between SLE patients and healthy controls and 2) to evaluate the relationship between BMD and glucocorticoid therapy and VF in SLE patients. Articles were identified from electronic databases (PubMed, Embase, VHL, SciELO and the Cochrane Library). Prospective longitudinal and cross-sectional studies were considered for review. We evaluated the quality of the evidence included using the Oxford Centre for evidence-based medicine (EBM) Levels of Evidence. In total, 38 articles were identified and analyzed (3442 SLE cases and 6198 controls) in the analysis of BMD (9232 women and 408 men). There were significant differences in mean BMD between SLE patients and controls. BMD mean difference in cases/controls: -0.0566 95% CI (-0.071, -0.0439; p = < 0.0001). When only SLE patients were analyzed, the BMD did not significantly differ between patients who had or had not received glucocorticoid (GCT) therapy. 694 SLE patients were included in the analysis of VF (189 with VF vs. 505 without VF). Patients with VF had lower BMD than patients without VF (BMD mean difference without VF/with VF: 0.033 (95%CI: 0.006-0.060); p-value: 0.0156). Patients with SLE had lower BMD than healthy controls. Moreover, SLE patients with VF had lower BMD than patients without VF. However, our data did not show that GCT therapy had an impact on BMD.

SLE syndrome, probably induced by labetalol

PubMed Central

Brown, R. C.; Cooke, J.; Losowsky, M. S.

1981-01-01

A 45-year-old woman developed polyarthralgia and muscle tenderness after 6 months' therapy with labetalol 1800 mg daily. A raised ANF titre but normal DNA binding levels suggested a drug-induced SLE syndrome. Both symptoms and ANF titre improved when therapy was changed from labetalol to propranolol. PMID:6977135

The role and diagnostic value of cell-free DNA in systemic lupus erythematosus.

PubMed

Truszewska, Anna; Foroncewicz, Bartosz; Pączek, Leszek

2017-01-01

Cell-free DNA (cfDNA) represents a small fraction of total DNA pool that circulates freely in the blood both in normal and pathological conditions. Data indicate that cfDNA plays an important role in the pathogenesis of systemic lupus erythematosus (SLE) and hypomethylation may be crucial for its immunogenic properties. Although differences in quantification methodology hinder the comparison of results between the studies, it appears that levels of cfDNA are abnormally elevated in SLE patients and correlate with various antibody titers, but not with disease activity. Increased cfDNA concentration, however, may be associated with active lupus nephritis. Most of the studies confirmed apoptosis as the major cfDNA release mechanism in various conditions, but formation of neutrophil extracellular traps may significantly contribute to the cfDNA generation in SLE patients. In this review, we summarise current knowledge about the role and possible origin of cfDNA in SLE patients, and discuss why cfDNA testing for diagnostic and prognosis of SLE remains questionable.

Correlation between clinical severity of central nervous system (CNS) lupus and findings on single photon emission computed tomographic (SPECT) images of the brain; preliminary results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Silverman, I.E.; Zeit, R.M.; Von Feldt, J.M.

1994-05-01

Systemic Lupus Erythematosis (SLE) commonly causes significant neuropsychiatric disorders. The purpose of this study was to review the brain SPECT studies of SLE patients with clinical evidence of CNS involvement and determine whether there is a correlation between the findings on SPECT images and the clinical manifestations of this serious phase of the disease. We enrolled 19 SLE patients and 12 normal controls in this study. The level of each patient`s disease activity was determined by the SLE Disease Activity Index (SLEDAI), an established method of scoring disease severity which is heavily weighted toward neuropsychiatric symptomatology, for 15 of themore » 19 SLE patients. The SLEDAI was calculated within a 10 day window of the date when the SPECT scan was obtained. SPECT scans were performed 30 minutes following the intravenous administration of 99mTc-HMPAO. Results are discussed.« less

Predictors of preterm birth in patients with mild systemic lupus erythematosus.

PubMed

Clowse, Megan E B; Wallace, Daniel J; Weisman, Michael; James, Andra; Criscione-Schreiber, Lisa G; Pisetsky, David S

2013-09-01

While increased disease activity is the best predictor of preterm birth in women with systemic lupus erythematosus (SLE), even women with low disease activity are at increased risk of this complication. Biomarkers that would identify at-risk pregnancies could allow interventions to prevent preterm birth. Measures of SLE activity, inflammation, placental health and renal function between 20 and 28 weeks gestation (mid-gestation) were correlated to preterm birth and gestational age at delivery in a prospective cohort of pregnant women with SLE. Of the 40 pregnancies in 39 women, all with mild-moderate SLE disease, 9 (23.7%) of the 38 live births were delivered preterm. Low C4 was the only marker of SLE activity associated with younger gestational age at delivery. Elevated ferritin and lower oestradiol correlated with younger gestational age at delivery. Renal function remained normal during all pregnancies at mid-gestation and did not correlate with preterm birth. Higher serum uric acid, however, correlated with younger gestational age at delivery. In women with SLE with mild-moderate disease activity, ferritin, oestradiol and uric acid levels at mid-gestation may predict preterm birth. These markers may prove to be clinically useful in identifying pregnancies at particularly high risk for adverse outcomes.

CD(+)(4)CD(+)(25) Treg cells in thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus patients.

PubMed

Huang, Hongdong; Sun, Weiming; Liang, Yumei; Long, Xi-Dai; Peng, Youming; Liu, Zhihua; Wen, Xiaojun; Jia, Meng

2014-09-01

CD(+)(4)CD(+)(25) Treg cells are of critical importance for maintenance of tolerance. The purpose of the this study was to observe the number of CD(+)(4)CD(+)(25) Treg cells in the patients with thrombotic thrombocytopenic purpura (TTP) associated with systemic lupus erythematosus (SLE), and to study pathogenesis of TTP with SLE. Seven patients with TTP associated with SLE and seven healthy volunteers were studied. The CD(+)(4)CD(+)(25) Treg cells were examined by flow cytometry. Clinical and laboratory data, such as urinary protein, serum creatinine, endothelial markers and immunologic serologics, were obtained from each patient and healthy volunteer. Glomerular injury was assessed by histopathology. Serum IL-2, IL-4, IL-6 and anti-endothelial cell antibody were analyzed by ELISA and anti-ADAMTS13 antibody were detected by Western blotting. CD(+)(4)CD(+)(25) Treg cells significantly decreased in TTP with SLE patients compared with controls (p < 0.05). CD(+)(4)CD(+)(25) Treg cells are negatively correlated with blood urea nitrogen, serum uric acid, supernatant IL-4, and proteinuria, and positively with estimated glomerular filtration rate (eGFR) in TTP with SLE patients. [Formula: see text] Treg cells gradually decreased as the severity of renal histology increased. Serum IL-2, IL-6, supernatant IL-4, anti-endothelial cell antibody, and anti-ADAMTS13 antibody significantly increased in TTP with SLE patients compared to those of the control groups (all p < 0.05). In contrast, serum levels of C3 were significantly decreased in TTP with SLE patients compared to those of the control groups (p < 0.05). CD(+)(4)CD(+)(25) Treg cells are not only lower in TTP with SLE patients, but also are correlated with disease severity in TTP with SLE patients.CD(+)(4)CD(+)(25)Treg cells may play an important role in the pathogenesis of TTP with SLE.

The role of the transcription factor Ets1 in lupus and other autoimmune diseases

PubMed Central

Garrett-Sinha, Lee Ann; Kearly, Alyssa; Satterthwaite, Anne B.

2017-01-01

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by excess B and T cell activation, the development of autoantibodies against self-antigens including nuclear antigens, and immune complex deposition in target organs which triggers an inflammatory response and tissue damage. The genetic and environmental factors that contribute to development of SLE have been extensively studied in both humans and mouse models of the disease. One of the important genetic contributions to SLE development is an alteration in the expression of the transcription factor Ets1, which regulates the functional differentiation of lymphocytes. Here we review the genetic, biochemical and immunological studies that have linked low levels of Ets1 to aberrant lymphocyte differentiation and to the pathogenesis of SLE. PMID:28845756

Soluble thrombomodulin levels in plasma of multiple sclerosis patients and their implication.

PubMed

Festoff, Barry W; Li, Chaoyang; Woodhams, Barry; Lynch, Sharon

2012-12-15

Thrombomodulin (TM) on the cell-surface of cerebrovascular endothelial cells (CECs) is released into blood upon CEC damage. TM promotes activation of protein C (APC), an anticoagulant, anti-inflammatory, neuroprotective molecule that protects CECs and impedes inflammatory cell migration across the blood-brain barrier (BBB). Multiple sclerosis (MS) is associated with CEC damage and BBB dysfunction. We evaluated soluble TM (sTM) levels as a biomarker of BBB integrity and whether glatiramer acetate (GA) influenced sTM levels in MS patients. sTM levels quantified by 2-site ELISA from sera of healthy controls and systemic lupus erythematosus (SLE) patients (CEC-damage positive control) were compared with levels from patients with relapsing-remitting (RRMS) or secondary-progressive MS (SPMS), stratified as: RRMS/GA/no relapse, RRMS/GA/in relapse, RRMS no GA/no relapse, RRMS/no GA/in relapse; and SPMS/no GA. Additionally, soluble endothelial protein C receptor (sEPCR) levels were assessed in the non-stratified MS group, SLE patients, and controls. sTM levels were highest in RRMS patients taking GA with or without relapse, followed in decreasing order by SLE, RRMS/no GA/in relapse, SPMS, RRMS/no GA/no relapse, healthy controls. sEPCR levels were highest in MS patients, then SLE, then controls. sTM may be a useful biomarker of BBB integrity in RRMS patients. Further evaluation of sEPCR is needed. The finding that the highest sTM levels were in RRMS patients taking GA is interesting and warrants further investigation. Published by Elsevier B.V.

Bone marrow analysis of immune cells and apoptosis in patients with systemic lupus erythematosus.

PubMed

Park, J W; Moon, S Y; Lee, J H; Park, J K; Lee, D S; Jung, K C; Song, Y W; Lee, E B

2014-09-01

To examine the immune cell profile in the bone marrow of systemic lupus erythematosus (SLE) patients and to assess its clinical relevance. Sixteen bone marrow samples from 14 SLE patients were compared with seven healthy control samples. The numbers of immune cells and apoptotic cells in the bone marrow were examined by immunohistochemistry. The association between immune cell subsets and clinical features was investigated. CD4+ T cells, macrophages and plasma cells were more common in the bone marrow of SLE patients than in healthy controls (p=0.001, p=0.004 and p<0.001, respectively). Greater numbers of CD4+ T cells and macrophages were associated with high-grade bone marrow damage. The percentage of apoptotic cells in bone marrow of SLE patients was significantly higher than that in controls (p<0.001) and was positively correlated with the number of plasmacytoid dendritic cells (p=0.013). Increased number of plasma cells along with high interleukin-6 expression was correlated with anti-double stranded DNA antibody levels and the SLE disease activity index (p=0.031 and 0.013, respectively). Bone marrow from SLE patients showed a distinct immune cell profile and increased apoptosis. This, coupled with a correlation with disease activity, suggests that the bone marrow may play a critical role in the pathogenesis of SLE. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Association Between Stressful Life Events and Depression; Intersection of Race and Gender.

PubMed

Assari, Shervin; Lankarani, Maryam Moghani

2016-06-01

Although stressful life events (SLEs) and depression are associated, we do not know if the intersection of race and gender modifies the magnitude of this link. Using a nationally representative sample of adults in the USA, we tested if the association between SLE and major depressive episode (MDE) depends on the intersection of race and gender. Data came from the National Survey of American Life (NSAL), 2003, a cross-sectional survey that enrolled 5899 adults including 5008 Blacks (African-Americans or Caribbean Blacks), and 891 Non-Hispanic Whites. Logistic regression was used for data analysis. Stressful life events (past 30 days) was the independent variable, 12-month MDE was the dependent variable, and age, educational level, marital status, employment, and region of country were controls. In the pooled sample, SLE was associated with MDE above and beyond all covariates, without the SLE × race interaction term being significant. Among men, the SLE × race interaction was significant, suggesting a stronger association between SLE and MDE among White men compared to Black men. Such interaction between SLE × race could not be found among women. The association between SLE and depression may be stronger for White men than Black men; however, this link does not differ between White and Black women. More research is needed to better understand the mechanism behind race by gender variation in the stress-depression link.

PKK deficiency in B cells prevents lupus development in Sle lupus mice

PubMed Central

Oleksyn, D.; Zhao, J.; Vosoughi, A.; Zhao, JC.; Misra, R; Pentland, AP; Ryan, D.; Anolik, J.; Ritchlin, C.; Looney, J.; Anandarajah, AP.; Schwartz, G.; Calvi, LM; Georger, M; Mohan, C.; Sanz, I.; Chen, L

2018-01-01

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can result in damage to multiple organs. It is well documented that B cells play a critical role in the development of the disease. We previously showed that protein kinase C associated kinase (PKK) is required for B1 cell development as well as for the survival of recirculating mature B cells and B- lymphoma cells. Here, we investigated the role of PKK in lupus development in a lupus mouse model. We demonstrate that the conditional deletion of PKK in B cells prevents lupus development in Sle1Sle3 mice. The loss of PKK in Sle mice resulted in the amelioration of multiple classical lupus-associated phenotypes and histologic features of lupus nephritis, including marked reduction in the levels of serum autoantibodies, proteinuria, spleen size, peritoneal B-1 cell population and the number of activated CD4 T cells. In addition, the abundance of autoreactive plasma cells normally seen in Sle lupus mice was also significantly decreased in the PKK-deficient Sle mice. Sle B cells deficient in PKK display defective proliferation responses to BCR and LPS stimulation. Consistently, B cell receptor-mediated NF-κB activation, which is required for the survival of activated B cells, was impaired in the PKK-deficient B cells. Taken together, our work uncovers a critical role of PKK in lupus development and suggests that targeting the PKK-mediated pathway may represent a promising therapeutic strategy for lupus treatment. PMID:28274793

Association of objectively measured physical activity and sedentary time with arterial stiffness in women with systemic lupus erythematosus with mild disease activity

PubMed Central

Vargas-Hitos, José A.; Gavilán-Carrera, Blanca; Navarro-Mateos, Carmen; Acosta-Manzano, Pedro; Delgado-Fernández, Manuel; Sabio, José M.; Ortego-Centeno, Norberto; Callejas-Rubio, José L.; Soriano-Maldonado, Alberto

2018-01-01

Objectives To examine the association of objectively measured physical activity (PA) intensity levels and sedentary time with arterial stiffness in women with systemic lupus erythematosus (SLE) with mild disease activity and to analyze whether participants meeting the international PA guidelines have lower arterial stiffness than those not meeting the PA guidelines. Methods The study comprised 47 women with SLE (average age 41.2 [standard deviation 13.9]) years, with clinical and treatment stability during the 6 months prior to the study. PA intensity levels and sedentary time were objectively measured with triaxial accelerometry. Arterial stiffness was assessed through pulse wave velocity, evaluated by Mobil-O-Graph® 24h pulse wave analysis monitor. Results The average time in moderate to vigorous PA in bouts of ≥10 consecutive minutes was 135.1±151.8 minutes per week. There was no association of PA intensity levels and sedentary time with arterial stiffness, either in crude analyses or after adjusting for potential confounders. Participants who met the international PA guidelines did not show lower pulse wave velocity than those not meeting them (b = -0.169; 95% CI: -0.480 to 0.143; P = 0.280). Conclusions Our results suggest that PA intensity levels and sedentary time are not associated with arterial stiffness in patients with SLE. Further analyses revealed that patients with SLE meeting international PA guidelines did not present lower arterial stiffness than those not meeting the PA guidelines. Future prospective research is needed to better understand the association of PA and sedentary time with arterial stiffness in patients with SLE. PMID:29694382

International multi-center evaluation of a novel chemiluminescence assay for the detection of anti-dsDNA antibodies.

PubMed

Bentow, C; Lakos, G; Martis, P; Wahl, E; Garcia, M; Viñas, O; Espinosa, G; Cervera, R; Sjöwall, C; Carmona-Fernandes, D; Santos, M J; Hanly, J G; Mahler, M

2016-07-01

Anti-double stranded desoxyribonucleic acid (anti-dsDNA) antibodies are considered fairly specific for systemic lupus erythematosus (SLE) and their quantification is useful for the clinical management of SLE patients. We assessed the diagnostic performance of the QUANTA Flash dsDNA chemiluminescent immunoassay (CIA) in comparison to an ELISA, using patients from five participating countries. The main focus was to evaluate the correlation between anti-dsDNA antibody results from the CIA and global SLE disease activity, as measured by the SLE Disease Activity Index 2000 (SLEDAI-2K). A total of 1431 samples (SLE, n = 843; disease controls, n = 588) from five countries (Canada, USA, Portugal, Sweden and Spain) were tested with QUANTA Flash dsDNA (Inova Diagnostics, San Diego, CA, USA). Data obtained with the QUANTA Lite dsDNA SC ELISA (Inova Diagnostics) were available for samples from three sites (Canada, USA and Sweden, n = 566). The SLEDAI-2K scores were available for 805 SLE patients and a cut-off of > 4 was used to define active disease. QUANTA Flash dsDNA had a sensitivity of 54.3% for the diagnosis of SLE, combined with 89.8% specificity. Anti-dsDNA antibody levels were significantly higher (p < 0.0001) in active SLE (SLEDAI-2K > 4; n = 232; median value 83.0 IU/mL) versus the inactive patients (n = 573; median value 22.3 IU/mL), and the SLEDAI-2K scoring correlated with their dsDNA antibody levels (Spearman's rho = 0.44, p < 0.0001). Similar but less pronounced findings were also found for the ELISA, in relation to disease activity. The QUANTA Flash dsDNA assay showed good clinical performance in a large international multi-center study. Additionally, the strong correlation between anti-dsDNA antibody results and SLEDAI-2K scores supported the potential utility of QUANTA Flash dsDNA for monitoring disease activity. © The Author(s) 2016.

Association of interleukin-10 promoter haplotypes with disease susceptibility and IL-10 levels in Mexican patients with systemic lupus erythematosus.

PubMed

Palafox-Sánchez, Claudia Azucena; Oregon-Romero, Edith; Salazar-Camarena, Diana Celeste; Valle, Yeminia Maribel; Machado-Contreras, Jesús René; Cruz, Alvaro; Orozco-López, Mariana; Orozco-Barocio, Gerardo; Vázquez-Del Mercado, Mónica; Muñoz-Valle, José Francisco

2015-11-01

Systemic lupus erythematosus (SLE) is the prototype autoimmune rheumatic disease. The etiology of this disease is incompletely understood; however, environmental factors and genetic predisposition are involved. Cytokine-mediated immunity plays a crucial role in the pathogenesis of SLE. We investigate the association of interleukin-10 (IL-10) promoter polymorphisms and their haplotypes in SLE patients from the western Mexico. One hundred and twenty-five SLE patients fulfilling the 1997 ACR criteria and 260 unrelated healthy subjects (HS), both Mexican mestizos, were genotyped for IL-10 -1082A>G, -819C>T, and -592C>A polymorphisms. Haplotypes were inferred using the expectation-maximization algorithm, then allele and haplotype distributions were compared between patients and HS, as well as patients with different clinical variables. We identified at -1082, -819, and -592 four predominant haplotypes ACC (43.70 % in patients vs 46.55 % in HS), ATA (21.45 vs 22.97 %), GCC (16.28 vs 14.21 %), and GTA (14.12 vs 14.12 %). The ATC haplotype was more frequent in SLE respect to HS, suggesting a risk effect (3.23 vs 1.05 %; OR 3.55, CI 1.14-11.11; p = 0.0293). SLE patient carriers of -592 CC genotype as well as the dominant model of inheritance showed higher sIL-10 respect to AA genotype, suggesting that -592 C allele is associated with increased production of the cytokine (p < 0.05). The ACC haplotype had higher IL-10 serum levels and higher values of Mexican version of the Systemic Lupus Erythematosus Disease Activity Index compared with the other haplotype carriers; however, no association was found regarding autoantibodies. Our data suggest that the IL-10 promoter haplotypes play an important role in the risk of developing SLE and influence the production of IL-10 in Mexican population. Nevertheless, further studies are required to analyze the expression of mRNA as well as to investigate the interacting epigenetic factors that could help to define the true contribution of this marker in SLE pathogenesis.

Predictors of intestinal pseudo-obstruction in systemic lupus erythematosus complicated by digestive manifestations: data from a Southern China lupus cohort.

PubMed

Huang, Q; Lai, W; Yuan, C; Shen, S; Cui, D; Zhao, J; Lin, J; Ren, H; Yang, M

2016-03-01

To determine factors that may predict intestinal pseudo-obstruction (IpsO) in systemic lupus erythematosus (SLE) patients complicated by digestive manifestations. SLE patients with digestive manifestations (n = 135) were followed at Southern Medical University affiliated Nanfang Hospital from 2000 until 2013. Demographic variables, clinical features, and laboratory data were compared between the two groups. Univariate and multivariate logistic regression models were used to establish factors that predispose to IpsO in these patients. At the end of the study period, 32 (23.7%) patients had developed IpsO. Mortality (9 patients) was infrequent and the cause of death was unrelated to IpsO. Independent predictors of IpsO in SLE were ureterectasia, anti-U1 RNP(+), peritonitis, and low C3 levels. Regular abdominal X-ray examinations are recommended in SLE patients with ureterectasia, anti-U1 RNP(+), peritonitis, or low C3 levels, as early diagnosis and therapy may prevent unnecessary surgical intervention and improve the disease course. © The Author(s) 2015.

Serum levels of adiponectin and leptin as biomarkers of proteinuria in lupus nephritis.

PubMed

Diaz-Rizo, Valeria; Bonilla-Lara, David; Gonzalez-Lopez, Laura; Sanchez-Mosco, Dalia; Fajardo-Robledo, Nicte S; Perez-Guerrero, Edsaul E; Rodriguez-Jimenez, N Alejandra; Saldaña-Cruz, A Miriam; Vazquez-Villegas, M Luisa; Gomez-Bañuelos, Eduardo; Vazquez-Del Mercado, Monica; Cardona-Muñoz, E German; Cardona-Muller, David; Trujillo, Xochitl; Huerta, Miguel; Salazar-Paramo, Mario; Gamez-Nava, Jorge I

2017-01-01

There are controversial results about the role of serum leptin and adiponectin levels as biomarkers of the severity of proteinuria in lupus nephritis. The aim of this study was to evaluate the relationship between serum leptin and adiponectin levels with severity of proteinuria secondary to lupus nephritis (LN). In a cross-sectional study, 103 women with systemic lupus erythematosus (SLE) were evaluated for kidney involvement. We compared 30 SLE patients with LN, all of them with proteinuria, versus 73 SLE patients without renal involvement (no LN). A comprehensive set of clinical and laboratory variables was assessed, including serum levels of leptin and adiponectin by ELISA. Multivariate analyses were used to adjust for potential confounders associated with proteinuria in LN. We found higher adiponectin levels in the LN group compared with the no LN group (20.4 ± 10.3 vs 15.6 ± 7.8 μg/mL; p = 0.02), whereas no differences were observed in leptin levels (33.3 ± 31.4 vs 22.5 ± 25.5 ng/mL; p = 0.07). Severity of proteinuria correlated with an increase in adiponectin levels (r = 0.31; p = 0.001), but no correlation was observed with leptin. Adiponectin levels were not related to anti-dsDNA or anti-nucleosome antibodies. In the logistic regression, adiponectin levels were associated with a high risk of proteinuria in SLE (OR = 1.06; 95% CI 1.01-1.12; p = 0.02). Instead, leptin was not associated with LN. These findings indicate that adiponectin levels are useful markers associated with proteinuria in LN. Further longitudinal studies are required to identify if these levels are predictive of renal relapse.

Serum levels of adiponectin and leptin as biomarkers of proteinuria in lupus nephritis

PubMed Central

Sanchez-Mosco, Dalia; Fajardo-Robledo, Nicte S.; Perez-Guerrero, Edsaul E.; Rodriguez-Jimenez, N. Alejandra; Saldaña-Cruz, A. Miriam; Vazquez-Villegas, M. Luisa; Gomez-Bañuelos, Eduardo; Vazquez-Del Mercado, Monica; Cardona-Muñoz, E. German; Cardona-Muller, David; Trujillo, Xochitl; Huerta, Miguel; Salazar-Paramo, Mario

2017-01-01

Introduction There are controversial results about the role of serum leptin and adiponectin levels as biomarkers of the severity of proteinuria in lupus nephritis. Objective The aim of this study was to evaluate the relationship between serum leptin and adiponectin levels with severity of proteinuria secondary to lupus nephritis (LN). Methods In a cross-sectional study, 103 women with systemic lupus erythematosus (SLE) were evaluated for kidney involvement. We compared 30 SLE patients with LN, all of them with proteinuria, versus 73 SLE patients without renal involvement (no LN). A comprehensive set of clinical and laboratory variables was assessed, including serum levels of leptin and adiponectin by ELISA. Multivariate analyses were used to adjust for potential confounders associated with proteinuria in LN. Results We found higher adiponectin levels in the LN group compared with the no LN group (20.4 ± 10.3 vs 15.6 ± 7.8 μg/mL; p = 0.02), whereas no differences were observed in leptin levels (33.3 ± 31.4 vs 22.5 ± 25.5 ng/mL; p = 0.07). Severity of proteinuria correlated with an increase in adiponectin levels (r = 0.31; p = 0.001), but no correlation was observed with leptin. Adiponectin levels were not related to anti-dsDNA or anti-nucleosome antibodies. In the logistic regression, adiponectin levels were associated with a high risk of proteinuria in SLE (OR = 1.06; 95% CI 1.01–1.12; p = 0.02). Instead, leptin was not associated with LN. Conclusion These findings indicate that adiponectin levels are useful markers associated with proteinuria in LN. Further longitudinal studies are required to identify if these levels are predictive of renal relapse. PMID:28898254

Autoimmune response of IgE antibodies to cellular self-antigens in systemic Lupus Erythematosus.

PubMed

Atta, Ajax Mercês; Santiago, Mittermayer Barreto; Guerra, Fernanda Garcia; Pereira, Mariana Menezes; Sousa Atta, Maria Luiza B

2010-01-01

Systemic lupus erythematosus (SLE) patients may exhibit high total IgE and antinuclear IgE antibodies (ANA-IgE). Here, we investigated the specificity of ANA-IgE in SLE patients and the involvement of cytokines in this immune response. Sera from 92 SLE patients and 68 healthy controls were evaluated for the presence of antinuclear IgE antibodies by immunoperoxidase with HEp-2,000(R) cells and immunoblotting with IgG-depleted sera. Total IgE, IgE specific to allergens, and serum cytokine levels were determined by ELISA. Antinuclear IgE antibodies were detected only in SLE patients (29/92, 31.5%). High total IgE was associated with ANA-IgE (p < 0.0001), but was not associated with IgE antibodies to allergens. In the immunoblotting, ANA-IgE reacted with nucleosomes (23/29, 79.3%), dsDNA (14/29, 48.3%), SS-A/Ro (14/29, 48.3%), SS-B/La (2/29, 18.7%), Sm (14/29, 48.3%) and RNP (18/29, 62.1%). Patients with ANA-IgE had very low serum IL-4, less IL-5 than controls (p < 0.05), more IL-10 than seronegative patients (p < 0.05), and unaltered IFN-gamma levels. The IL-5/IL-10 ratio was lower in ANA-IgE seropositive patients in comparison with either seronegative patients (p < 0.05) or healthy controls (p = 0.001). Controls displayed higher IL-5/IFN-gamma ratios than either SLE patients with ANA-IgE (p < 0.05) or patients without these immunoglobulins (p < 0.01). We conclude that IgE antibodies against cell autoantigens involved in protein expression, cellular proliferation, and cell death are present in patients with SLE. Interleukin-10 seems to down-regulate this IgE autoimmune response in SLE. Copyright 2010 S. Karger AG, Basel.

Intravenous Immunoglobulin in the Therapeutic Armamentarium of Systemic Lupus Erythematosus: A Systematic Review and Meta-Analysis

PubMed Central

Sakthiswary, Rajalingham; D’Cruz, David

2014-01-01

Abstract Prepared from the plasma of thousands of blood donors, therapeutic intravenous immunoglobulin (IVIg) mostly consists of human polyspecific immunoglobulin G (IgG). The use of IVIg in systemic lupus erythematosus (SLE) is still considered experimental without any clear indications. The purpose of this systematic review is, therefore, to evaluate the available evidence to determine the therapeutic role of IVIg in SLE. A comprehensive, computerised search was performed in the MEDLINE (Pubmed), Scopus, EMBASE, and Cochrane controlled trials. The study eligibility criteria were randomized controlled trials, and prospective and retrospective observational studies that examined the efficacy of IVIg in adult patients with SLE who were considered the participants. IVIg therapy was the mode of intervention in these patients. Data abstracted included the study design, study population, changes in the disease activity scores (Systemic Lupus Erythematosus Disease Activity Index, Systemic Lupus Activity Measure, and Lupus Activity Index-Pregnancy), steroid dose, complement levels, autoantibodies, and renal function. Thereafter, data analysis established statistical procedures for meta-analysis. Thirteen studies (including 3 controlled and 10 observational) were eligible for inclusion. There was significant reduction in the SLE disease activity scores with IVIg therapy with a standard mean difference of 0.584 (P = 0.002, 95% confidence interval [CI] 0.221–0.947). In terms of rise in complement levels, the response rate was 30.9% (P = 0.001, 95 CI 22.1–41.3). The effects of IVIg on other clinical outcome measures including anti-double-stranded DNA, antinuclear antibody, average steroid dose, and renal function could not be determined because of the limited numbers of trials. The limitations of this review were lack of well-designed controlled trials with adequate sample size on the use of IVIg in SLE. In conclusion, the use of IVIg is associated with significant reduction in SLE disease activity and improvement in complement levels. PMID:25310743

Intravenous immunoglobulin in the therapeutic armamentarium of systemic lupus erythematosus: a systematic review and meta-analysis.

PubMed

Sakthiswary, Rajalingham; D'Cruz, David

2014-10-01

Prepared from the plasma of thousands of blood donors, therapeutic intravenous immunoglobulin (IVIg) mostly consists of human polyspecific immunoglobulin G (IgG). The use of IVIg in systemic lupus erythematosus (SLE) is still considered experimental without any clear indications. The purpose of this systematic review is, therefore, to evaluate the available evidence to determine the therapeutic role of IVIg in SLE. A comprehensive, computerised search was performed in the MEDLINE (Pubmed), Scopus, EMBASE, and Cochrane controlled trials. The study eligibility criteria were randomized controlled trials, and prospective and retrospective observational studies that examined the efficacy of IVIg in adult patients with SLE who were considered the participants.IVIg therapy was the mode of intervention in these patients. Data abstracted included the study design, study population, changes in the disease activity scores (Systemic Lupus Erythematosus Disease Activity Index, Systemic Lupus Activity Measure, and Lupus Activity Index-Pregnancy), steroid dose, complement levels, autoantibodies, and renal function. Thereafter, data analysis established statistical procedures for meta-analysis. Thirteen studies (including 3 controlled and 10 observational) were eligible for inclusion. There was significant reduction in the SLE disease activity scores with IVIg therapy with a standard mean difference of 0.584 (P = 0.002, 95% confidence interval [CI] 0.221-0.947). In terms of rise in complement levels, the response rate was 30.9% (P = 0.001, 95 CI 22.1-41.3). The effects of IVIg on other clinical outcome measures including anti-double-stranded DNA, antinuclear antibody, average steroid dose, and renal function could not be determined because of the limited numbers of trials. The limitations of this review were lack of well-designed controlled trials with adequate sample size on the use of IVIg in SLE. In conclusion, the use of IVIg is associated with significant reduction in SLE disease activity and improvement in complement levels.

Histone demethylase JMJD3 regulates CD11a expression through changes in histone H3K27 tri-methylation levels in CD4+ T cells of patients with systemic lupus erythematosus.

PubMed

Yin, Heng; Wu, Haijing; Zhao, Ming; Zhang, Qing; Long, Hai; Fu, Siqi; Lu, Qianjin

2017-07-25

Aberrant CD11a overexpression in CD4+ T cells induces T cell auto-reactivity, which is an important factor for systemic lupus erythematosus (SLE) pathogenesis. Although many studies have focused on CD11a epigenetic regulation, little is known about histone methylation. JMJD3, as a histone demethylase, is capable of specifically removing the trimethyl group from the H3K27 lysine residue, triggering target gene activation. Here, we examined the expression and function of JMJD3 in CD4+ T cells from SLE patients. Significantly decreased H3K27me3 levels and increased JMJD3 binding were detected within the ITGAL (CD11a) promoter locus in SLE CD4+ T cells compared with those in healthy CD4+ T cells. Moreover, overexpressing JMJD3 through the transfection of pcDNA3.1-JMJD3 into healthy donor CD4+ T cells increased JMJD3 enrichment and decreased H3K27me3 enrichment within the ITGAL (CD11a) promoter and up-regulated CD11a expression, leading to T and B cell hyperactivity. Inhibition of JMJD3 via JMJD3-siRNA in SLE CD4+ T cells showed the opposite effects. These results demonstrated that histone demethylase JMJD3 regulates CD11a expression in lupus T cells by affecting the H3K27me3 levels in the ITGAL (CD11a) promoter region, and JMJD3 might thereby serve as a potential therapeutic target for SLE.

Comparison of the Farr radioimmunoassay, 3 commercial enzyme immunoassays and Crithidia luciliae immunofluorescence test for diagnosis and activity assessment of systemic lupus erythematosus.

PubMed

Launay, David; Schmidt, Jean; Lepers, Sébastien; Mirault, Tristan; Lambert, Marc; Kyndt, Xavier; Reumaux, Dominique; Duhamel, Alain; Hachulla, Eric; Hatron, Pierre-Yves; Prin, Lionel; Dubucquoi, Sylvain

2010-07-04

Among anti-double-strand (ds)DNA antibody assays, Farr radioimmunoassay is decreasingly used because it requires radioactive material and is labor intensive. We evaluated the performance of Farr, three commercial enzyme immunoassays (EIAs) and the Crithidia luciliae immunofluorescence test (CLIFT) in systemic lupus erythematosus (SLE). Anti-dsDNA antibodies were determined in 99 SLE patients, 101 healthy subjects, and 53 patients with autoimmune rheumatic diseases. Farr performed better than the 3 EIAs and CLIFT for the diagnosis of SLE at the manufacturer's cut off and at the cut off set to achieve a specificity of 95%. To achieve a similar level of specificity, some EIAs had a decrease in sensitivity which was dramatic for some tests. Farr was also the best at distinguishing patients with quiescent to mildly active disease from patients with more active disease at the cut off value of 93 IU/ml. Using manufacturer's cut off did not allow distinguishing between patients with quiescent and active SLE. Farr was the best global test to assess the level of anti-dsDNA antibodies for both diagnosis and disease activity evaluation in SLE with adequately determined cut off values. Some EIA had low performances limiting their use in decision-making regarding diagnosis and/or treatment. Copyright 2010 Elsevier B.V. All rights reserved.

Lactobacillus paracasei GMNL-32 exerts a therapeutic effect on cardiac abnormalities in NZB/W F1 mice

PubMed Central

Rajendran, Peramaiyan; Tzang, Bor-Show; Yeh, Yu-Lan; Shen, Chia-Yao; Chen, Ray-Jade; Ho, Tsung-Jung; Vijaya Padma, Viswanadha

2017-01-01

Systemic lupus erythematosus (SLE) is a disease that mostly affects women. Accelerated atherosclerosis is a high-risk factor associated with SLE patients. SLE associated with cardiovascular disease is one of the most important causes of death. In this study, we demonstrated that Lactobacillus paracasei GMNL-32 (GMNL-32), a probiotic species, exhibits anti-fibrosis and anti-apoptotic effects on the cardiac tissue of NZB/WF1 mice. Female NZB/W F1 mice, a well-known and commonly used lupus-prone mouse strain, were treated with or without GMNL-32 administration for 12 weeks. Oral administration of GMNL-32 to NZB/WF1 mice significantly increased the ventricular thickness when compared to that of NZB/WF1 mice. Administration of GMNL-32 significantly attenuated the cardiac cell apoptosis that was observed in exacerbate levels in the control NZB/WF1 mice. Further, the cellular morphology that was slightly distorted in the NZB/WF1 was effectively alleviated in the treatment group mice. In addition, GMNL-32 reduced the level of Fas death receptor-related pathway of apoptosis signaling and enhanced anti-apoptotic proteins. These results indicate that GMNL-32 exhibit an effective protective effect on cardiac cells of SLE mice. Thus, GMNL-32 may be a potential therapeutic strategy against SLE associated arthrosclerosis. PMID:28934296

Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor. alpha. : Relevance to genetic predisposition to systemic lupus erythematosus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jacob, C.O.; Fronek, Z.; Koo, M.

1990-02-01

The authors report on the production of tumor necrosis factor (TNF)-{alpha} and TNF-{beta} by mitogen-activated peripheral blood lymphocytes or enriched monocyte subpopulations from human leukocyte antigen (HLA)-typed healthy subjects. The results indicate that HLA-DR2- and DQw1-positive donors frequently exhibit low production of TNF-{alpha}, whereas DR3- and DR4-positive subjects show high levels of TNF-{alpha} production. No correlation between TNF-{alpha} levels and HLA-A, -B, and -C genotype was found. The relevance of this quantitative polymorphism to the genetic predisposition to lupus nephritis in systemic lupus erythematosus (SLE) patients was investigated. DR2, DQw1-positive SLE patients show low levels of TNF-{alpha} inducibility; this genotypemore » is also associated with an increased incidence of lupus nephritis. DR3-positive SLE patients, on the other hand, are not predisposed to nephritis, and these patients have high TNF-{alpha} production. DR4 haplotype is associated with high TNF-{alpha} inducibility and is negatively correlated with lupus nephritis. These data may help explain the strong association between HLA-DR2, DQw1 in SLE patients and their susceptibility to nephritis.« less

Space Link Extension (SLE) Emulation for High-Throughput Network Communication

NASA Technical Reports Server (NTRS)

Murawski, Robert W.; Tchorowski, Nicole; Golden, Bert

2014-01-01

As the data rate requirements for space communications increases, significant stress is placed not only on the wireless satellite communication links, but also on the ground networks which forward data from end-users to remote ground stations. These wide area network (WAN) connections add delay and jitter to the end-to-end satellite communication link, effects which can have significant impacts on the wireless communication link. It is imperative that any ground communication protocol can react to these effects such that the ground network does not become a bottleneck in the communication path to the satellite. In this paper, we present our SCENIC Emulation Lab testbed which was developed to test the CCSDS SLE protocol implementations proposed for use on future NASA communication networks. Our results show that in the presence of realistic levels of network delay, high-throughput SLE communication links can experience significant data rate throttling. Based on our observations, we present some insight into why this data throttling happens, and trace the probable issue back to non-optimal blocking communication which is sup-ported by the CCSDS SLE API recommended practices. These issues were presented as well to the SLE implementation developers which, based on our reports, developed a new release for SLE which we show fixes the SLE blocking issue and greatly improves the protocol throughput. In this paper, we also discuss future developments for our end-to-end emulation lab and how these improvements can be used to develop and test future space communication technologies.

Space Link Extension (SLE) Emulation for High-Throughput Network Communication

NASA Technical Reports Server (NTRS)

Murawski, Robert; Tchorowski, Nicole; Golden, Bert

2014-01-01

As the data rate requirements for space communications increases, signicant stressis placed not only on the wireless satellite communication links, but also on the groundnetworks which forward data from end-users to remote ground stations. These wide areanetwork (WAN) connections add delay and jitter to the end-to-end satellite communicationlink, eects which can have signicant impacts on the wireless communication link. It isimperative that any ground communication protocol can react to these eects such that theground network does not become a bottleneck in the communication path to the satellite.In this paper, we present our SCENIC Emulation Lab testbed which was developed to testthe CCSDS SLE protocol implementations proposed for use on future NASA communica-tion networks. Our results show that in the presence of realistic levels of network delay,high-throughput SLE communication links can experience signicant data rate throttling.Based on our observations, we present some insight into why this data throttling happens,and trace the probable issue back to non-optimal blocking communication which is sup-ported by the CCSDS SLE API recommended practices. These issues were presented aswell to the SLE implementation developers which, based on our reports, developed a newrelease for SLE which we show xes the SLE blocking issue and greatly improves the pro-tocol throughput. In this paper, we also discuss future developments for our end-to-endemulation lab and how these improvements can be used to develop and test future spacecommunication technologies.

Microparticles (CD146) and Arterial Stiffness Versus Carotid Intima Media Thickness as an Early Predictors of Vascular Affection in Systemic Lupus Patients.

PubMed

Nassef, Sahar; El Guindey, Hala; Fawzy, Mary; Nasser, Amal; Reffai, Rasha; Shemiy, Doa

2016-03-01

This study aims to evaluate cluster of differentiation 146 (CD146) and pulse wave velocity (PWV) as non-invasive methods for prediction of early vascular affection in systemic lupus erythematosus (SLE) patients without symptoms of vascular disease, to detect the outcome and reproducibility of these methods, and to correlate CD146 and PWV with lipid profile, intima media thickness (IMT), and ankle brachial index. Thirty female SLE patients (mean age 26.6±6.6 years; range 15 to 35 years) fulfilling the American College of Rheumatology 1997 revised criteria for SLE classification, and 15 age and sex matched healthy controls were included. All participants were performed full clinical assessments including measurement of Systemic Lupus Erythematosus Disease Activity Index, lipid profile, CD146, carotid IMT, PWV, and rise time as an indication of how fast the waveform rises. Cluster of differentiation 146 levels were elevated in patients with SLE compared to controls (p<0.001). There was a statistically significant difference between patients and controls in the femoral, lower thigh, and ankle rise time. There was a statistically significant correlation between IMT and ages of patients, Systemic Lupus Erythematosus Disease Activity Index, and brachial-below knee PWV, while there was no correlation between IMT and disease duration, lipid profile, brachial-femoral PWV, and brachial-ankle PWV. There was statistically significant correlations between brachial-femoral PWV and serum cholesterol level, and between brachial-ankle PWV and low density lipoprotein cholesterol. Our results showed that SLE vascular affection is more pronounced in small arteries. Also, elevated CD146 and brachial-femoral PWV are useful early markers of vascular affection in SLE as well as rise time may be a marker for arterial stiffness.

TLR9 deficiency breaks tolerance to RNA-associated antigens and upregulates TLR7 protein in Sle1 mice.

PubMed

Celhar, Teja; Yasuga, Hiroko; Lee, Hui-Yin; Zharkova, Olga; Tripathi, Shubhita; Thornhill, Susannah I; Lu, Hao K; Au, Bijin; Lim, Lina H K; Thamboo, Thomas P; Akira, Shizuo; Wakeland, Edward K; Connolly, John E; Fairhurst, Anna-Marie

2018-04-24

Toll-like receptors (TLRs) 7 and 9 are important innate signaling molecules with opposing roles in the development and progression of Systemic Lupus Erythematosus (SLE). While multiple studies support a dependency on TLR7 for disease development, genetic ablation of TLR9 results in severe disease with glomerulonephritis (GN) by a largely unknown mechanism. The present study was designed to examine the suppressive role of TLR9 in the development of severe lupus. We crossed Sle1 lupus-prone mice with TLR9-deficient mice to generate Sle1TLR9 -/- . These mice were aged and evaluated for severe autoimmunity by assessing splenomegaly, GN, immune cell populations, autoantibody and total immunoglobulin profiles, kidney dendritic cell (DC) function and TLR7 protein expression. Young mice were used for functional B cell studies, immunoglobulin profiling and TLR7 expression. Sle1TLR9 -/- mice developed severe disease similar to TLR9-deficient MRL and Nba2 models. Sle1TLR9 -/- B cells produced more class-switched antibodies and the autoantibody repertoire was skewed towards RNA-containing antigens. GN in these mice was associated with DC infiltration and purified Sle1TLR9 -/- renal DCs were more efficient at TLR7-dependent antigen presentation and expressed higher levels of TLR7 protein. Importantly, this increase in TLR7 expression occurred prior to disease development, indicating a role in the initiation stages of tissue destruction. The increase in TLR7-reactive immune complexes (IC) and the concomitant enhanced expression of their receptor, promotes inflammation and disease in Sle1TLR9 -/- mice. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Roles of germination-specific lytic enzymes CwlJ and SleB in Bacillus anthracis.

PubMed

Heffron, Jared D; Orsburn, Benjamin; Popham, David L

2009-04-01

The structural characteristics of a spore enable it to withstand stresses that typically kill a vegetative cell. Spores remain dormant until small molecule signals induce them to germinate into vegetative bacilli. Germination requires degradation of the thick cortical peptidoglycan by germination-specific lytic enzymes (GSLEs). Bacillus anthracis has four putative GSLEs, based upon sequence similarities with enzymes in other species: SleB, CwlJ1, CwlJ2, and SleL. In this study, the roles of SleB, CwlJ1, and CwlJ2 were examined. The expression levels of all three genes peak 3.5 h into sporulation. Genetic analysis revealed that, similar to other known GSLEs, none of these gene products are individually required for growth, sporulation, or triggering of germination. However, later germination events are affected in spores lacking CwlJ1 or SleB. Compared to the wild type, germinating spores without CwlJ1 suffer a delay in optical density loss and cortex peptidoglycan release. The absence of SleB also causes a delay in cortex fragment release. A double mutant lacking both SleB and CwlJ1 is completely blocked in cortex hydrolysis and progresses through outgrowth to produce colonies at a frequency 1,000-fold lower than that of the wild-type strain. A null mutation eliminating CwlJ2 has no effect on germination. High-performance liquid chromatography and mass spectroscopy analysis revealed that SleB is required for lytic transglycosylase activity. CwlJ1 also clearly participates in cortex hydrolysis, but its specific mode of action remains unclear. Understanding the lytic germination activities that naturally diminish spore resistance can lead to methods for prematurely inducing them, thus simplifying the process of treating contaminated sites.

Noncanonical autophagy inhibits the auto-inflammatory, lupus-like response to dying cells

PubMed Central

Martinez, Jennifer; Cunha, Larissa D.; Park, Sunmin; Yang, Mao; Lu, Qun; Orchard, Robert; Li, Quan-Zhen; Yan, Mei; Janke, Laura; Guy, Cliff; Linkermann, Andreas; Virgin, Herbert W.; Green, Douglas R.

2016-01-01

Defects in dying cell clearance are postulated to underlie the pathogenesis of systemic lupus erythematosus (SLE)1. Mice lacking molecules associated with dying cell clearance develop SLE-like disease2, and phagocytes from SLE patients often display defective clearance and increased inflammatory cytokine production when exposed to dying cells in vitro. Previously, we3–6 and others7 described a form of noncanonical autophagy called “LC3-associated phagocytosis” (LAP), wherein phagosomes containing engulfed particles, including dying cells3,4,7, recruit elements of the autophagy pathway to facilitate phagosome maturation and digestion of cargo. Genome-wide association studies have identified polymorphisms in atg58 and possibly atg79, involved in both canonical autophagy and LAP3–7, as predisposition markers for SLE. Here, we describe the consequences of defective LAP in vivo. Mice lacking any of several components of the LAP pathway display elevated serum inflammatory cytokines, autoantibodies, glomerular immune complex deposition, and evidence of kidney damage. Dying cells, injected into LAP-deficient animals, are engulfed but not efficiently degraded, and trigger acute elevation of pro-inflammatory cytokines but not the anti-inflammatory interleukin (IL)-10. Repeated injection of dying cells into LAP-deficient, but not LAP-sufficient animals accelerated SLE-like disease, including increased serum levels of autoantibodies. In contrast, animals deficient for genes required for canonical autophagy but not LAP do not display defective dead cell clearance, inflammatory cytokine production, or SLE-like disease, and like wild-type animals, produce IL-10 in response to dying cells. Therefore, defects in LAP, rather than canonical autophagy, can cause SLE-like phenomena, and may contribute to the pathogenesis of SLE. PMID:27096368

Activation-induced necroptosis contributes to B-cell lymphopenia in active systemic lupus erythematosus

PubMed Central

Fan, H; Liu, F; Dong, G; Ren, D; Xu, Y; Dou, J; Wang, T; Sun, L; Hou, Y

2014-01-01

B-cell abnormality including excessive activation and lymphopenia is a central feature of systemic lupus erythematosus (SLE). Although activation threshold, auto-reaction and death of B cells can be affected by intrinsical and/or external signaling, the underlying mechanisms are unclear. Herein, we demonstrate that co-activation of Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) pathways is a core event for the survival/dead states of B cells in SLE. We found that the mortalities of CD19+CD27- and CD19+IgM+ B-cell subsets were increased in the peripheral blood mononuclear cells (PBMCs) of SLE patients. The gene microarray analysis of CD19+ B cells from active SLE patients showed that the differentially expressed genes were closely correlated to TLR7, BCR, apoptosis, necroptosis and immune pathways. We also found that co-activation of TLR7 and BCR could trigger normal B cells to take on SLE-like B-cell characters including the elevated viability, activation and proliferation in the first 3 days and necroptosis in the later days. Moreover, the necroptotic B cells exhibited mitochondrial dysfunction and hypoxia, along with the elevated expression of necroptosis-related genes, consistent with that in both SLE B-cell microarray and real-time PCR verification. Expectedly, pretreatment with the receptor-interacting protein kinase 1 (RIPK1) inhibitor Necrostatin-1, and not the apoptosis inhibitor zVAD, suppressed B-cell death. Importantly, B cells from additional SLE patients also significantly displayed high expression levels of necroptosis-related genes compared with those from healthy donors. These data indicate that co-activation of TLR7 and BCR pathways can promote B cells to hyperactivation and ultimately necroptosis. Our finding provides a new explanation on B-cell lymphopenia in active SLE patients. These data suggest that extrinsic factors may increase the intrinsical abnormality of B cells in SLE patients. PMID:25210799

Comparison of clinical and serological differences among juvenile-, adult-, and late-onset systemic lupus erythematosus in Korean patients.

PubMed

Choi, J H; Park, D J; Kang, J H; Yim, Y R; Lee, K E; Lee, J W; Wen, L; Kim, T J; Park, Y W; Lee, J K; Lee, S S

2015-10-01

We investigated whether systemic lupus erythematosus (SLE) patients could be distinguished based on the time of disease onset and, if so, whether the groups differed in their clinical and laboratory features in ethnically homogeneous Korean patients. We enrolled 201 SLE patients with available clinical data at the time of onset of SLE from the lupus cohort at Chonnam National University Hospital. Sociodemographic, clinical, and laboratory data, including autoantibodies, and concomitant diseases were found at the time of diagnosis of SLE by reviewing patient charts. We divided SLE patients according to age at SLE diagnosis into three groups: juvenile-onset SLE (JSLE, diagnosed at ≤ 18 years), adult-onset SLE (ASLE, diagnosed at 19-50 years), and late-onset SLE (LSLE, diagnosed at >50 years), and compared baseline demographic, clinical, and relevant laboratory findings. Of the 201 patients, 27 (14.4%), 149 (74.1%), and 25 (12.4%) were JSLE, ASLE, and LSLE patients, respectively. Fever, oral ulcers, nephritis, anemia, and thrombocytopenia were more common in JSLE patients than ASLE or LSLE patients (p < 0.05, < 0.05, 0.001, < 0.05, and < 0.05, respectively). However, Sjögren's syndrome was more frequent in LSLE patients than JSLE or ASLE patients (p < 0.05). Disease activity was significantly higher in JSLE patients than in ASLE or LSLE patients (p < 0.001). Anti-dsDNA and anti-nucleosome antibodies were found more frequently in JSLE patients and less frequently in LSLE patients (p < 0.05 and 0.005, respectively) and decreased complement levels were more common in JSLE patients and less common in LSLE patients (p < 0.001, 0.001, and < 0.05, respectively). Our results indicate that SLE patients present with different clinical and serological manifestations according to age at disease onset. JSLE patients have more severe disease activity and more frequent renal involvement and LSLE patients have milder disease activity, more commonly accompanied by Sjögren's syndrome, at disease onset. © The Author(s) 2015.

Sclerostin serum levels in patients with systemic autoimmune diseases

PubMed Central

Fernández-Roldán, Concepción; Genre, Fernanda; López-Mejías, Raquel; Ubilla, Begoña; Mijares, Verónica; Cano, Daniel Sánchez; Robles, Concepción López; Callejas-Rubio, José Luis; Fernández, Raquel Ríos; Ruiz, Manuela Expósito; González-Gay, Miguel Á; Centeno, Norberto Ortego

2016-01-01

Systemic autoimmune diseases (SADs) are associated with lower bone mass and an increased risk of fractures. Sclerostin has a pivotal role in bone metabolism. Available data on circulating sclerostin levels in healthy subjects are limited, whereas those in SAD patients are absent. Our objective was to determine circulating sclerostin concentrations in systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Crohn's disease (CD) patients, and to analyze the factors associated with sclerostin concentrations. In this cross-sectional case–control study, serum sclerostin levels were measured in 38 SLE patients, 20 CD patients, 8 SSc patients and 20 healthy controls using a sclerostin ELISA. The mean values of the sclerostin (95% confidence interval) were 35.36 pmol l−1 (12–101) in patients and 33.92 pmol l−1 (2.31–100) in control subjects. The mean sclerostin value was 36.4 pmol l−1 (22.1–48.5) in SLE patients, 26.7 pmol l−1 (17.3–36.3) in CD patients and 51.8 pmol l−1 (26.5–77.1) in SSc patients (P=0.001). Serum sclerostin levels were positively correlated with age (P<0.001), body mass index (BMI) (P=0.01) and lumbar spine Z-score (P=0.001) and negatively with creatinine clearance (P=0.001). Glucocorticoid treatment did not affect sclerostin levels. Sclerostin levels seem to have a heterogeneous pattern in different autoimmune diseases. SLE and SSc patients did not differ from healthy controls regarding sclerostin levels. The CD group had significantly lower values compared with SSc patients. Factors associated with sclerostin levels in autoimmune diseases seem to be the same than in the general population. PMID:26909149

Sclerostin serum levels in patients with systemic autoimmune diseases.

PubMed

Fernández-Roldán, Concepción; Genre, Fernanda; López-Mejías, Raquel; Ubilla, Begoña; Mijares, Verónica; Cano, Daniel Sánchez; Robles, Concepción López; Callejas-Rubio, José Luis; Fernández, Raquel Ríos; Ruiz, Manuela Expósito; González-Gay, Miguel Á; Ortego Centeno, Norberto

2016-01-01

Systemic autoimmune diseases (SADs) are associated with lower bone mass and an increased risk of fractures. Sclerostin has a pivotal role in bone metabolism. Available data on circulating sclerostin levels in healthy subjects are limited, whereas those in SAD patients are absent. Our objective was to determine circulating sclerostin concentrations in systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Crohn's disease (CD) patients, and to analyze the factors associated with sclerostin concentrations. In this cross-sectional case-control study, serum sclerostin levels were measured in 38 SLE patients, 20 CD patients, 8 SSc patients and 20 healthy controls using a sclerostin ELISA. The mean values of the sclerostin (95% confidence interval) were 35.36 pmol l(-1) (12-101) in patients and 33.92 pmol l(-1) (2.31-100) in control subjects. The mean sclerostin value was 36.4 pmol l(-1) (22.1-48.5) in SLE patients, 26.7 pmol l(-1) (17.3-36.3) in CD patients and 51.8 pmol l(-1) (26.5-77.1) in SSc patients (P=0.001). Serum sclerostin levels were positively correlated with age (P<0.001), body mass index (BMI) (P=0.01) and lumbar spine Z-score (P=0.001) and negatively with creatinine clearance (P=0.001). Glucocorticoid treatment did not affect sclerostin levels. Sclerostin levels seem to have a heterogeneous pattern in different autoimmune diseases. SLE and SSc patients did not differ from healthy controls regarding sclerostin levels. The CD group had significantly lower values compared with SSc patients. Factors associated with sclerostin levels in autoimmune diseases seem to be the same than in the general population.

Systemic Lupus Erythematosus in Primary Care: An Update and Practical Messages for the General Practitioner

PubMed Central

Gergianaki, Irini; Bertsias, George

2018-01-01

Systemic Lupus Erythematosus (SLE) is a complex chronic autoimmune disease that manifests a wide range of organ involvement. Traditionally, the diagnosis and management of SLE is provided at secondary and tertiary centers to ensure prompt initiation of treatment, adequate control of flares and prevention of irreversible organ damage. Notwithstanding, the role of primary care in SLE is also emerging as there are still significant unmet needs such as the diagnostic delay at the community level and the high burden of therapy- and disease-related comorbidities. In the present review, we summarize practical messages for primary care physicians and general practitioners (GPs) concerning early diagnosis and proper referral of patients with SLE. In addition, we discuss the main comorbidities complicating the disease course and the recommended preventative measures, and we also provide an update on the role and current educational needs of GPs regarding the disease. PMID:29896474

The Role of CXC Chemokines in Pulmonary Fibrosis of Systemic Lupus Erythematosus Patients.

PubMed

Nielepkowicz-Goździńska, Agnieszka; Fendler, Wojciech; Robak, Ewa; Kulczycka-Siennicka, Lilianna; Górski, Paweł; Pietras, Tadeusz; Brzeziańska, Ewa; Pietrusińska, Małgorzata; Antczak, Adam

2015-12-01

The inflammatory process in systemic lupus erythematosus (SLE) affects many organs including the lungs. CXC chemokines are suggested to play an important role in the pathogenesis of SLE and pulmonary fibrosis. To estimate the concentrations of CXCL9, CXCL10, CXCL11 in bronchoalveolar lavage fluid (BALF) of patients with and without pulmonary involvements of SLE to evaluate CXC chemokines role in the pathogenesis of pulmonary fibrosis in SLE. Twenty-six SLE patients and 31 healthy controls were evaluated using high-resolution computed tomography (HRCT), pulmonary function tests, the SLE Disease Activity Index (SLEDAI), assessing CXCL9, CXCL11, CXCL10 level in BALF (an enzyme-immunosorbent assay kit). The mean CXCL9 and CXCL11 concentrations in BALF were higher in SLE patients compared to healthy controls (34.09 ± 102.34 vs 10.98 ± 14.65 pg/mL, p < 0.001; 72.65 ± 112.89 vs 16.12 ± 83.75 pg/mL, p = 0.012, respectively). The disease activity scored by SLEDAI and the concentration of CXCL10 in BALF were significantly higher in the SLE patients with pulmonary fibrosis when compared with patients with normal HRCT (8.23 ± 3.19 vs 5.01 ± 2.41; 73.45 ± 34.12 vs 40.76 ± 41.65, respectively, in both p < 0.05). In SLE patients positive correlations were found between SLEDAI and the percentage of lymphocytes in BALF (r = 0.51, p < 0.05); CXCL9 and CXCL10 concentrations in BALF (r = 0.65, p < 0.001); CXCL9 and CXCL11 concentrations in BALF (r = 0.69, p < 0.001). In lupus patients with pulmonary manifestations positive correlations were found between CXCL11 concentration in BALF and SLEDAI (r = 0.55, p < 0.05), CXCL11 concentration and the percentage of neutrophils in BALF (r = 0.69, p < 0.05), CXCL10 concentration and the percentage of neutrophils in BALF (r = 0.57, p < 0.05). Our observations indicate that CXCL9 and CXCL11 play an important role in the pathogenesis of SLE but it needs further studies. These results suggest that CXCL10 and CXCL11 are associated with neutrophils accumulation in the alveolar space of SLE patients with pulmonary fibrosis and should be considered as potential factor of interstitial fibrosis.

Th17-Related Cytokines in Systemic Lupus Erythematosus Patients with Dilated Cardiomyopathies: A Possible Linkage to Parvovirus B19 Infection

PubMed Central

Chen, Der-Yuan; Chen, Yi-Ming; Lan, Joung-Liang

2014-01-01

Dilated cardiomyopathies (DCM) are a major cause of mortality in patients with systemic lupus erythematosus (SLE). Immune responses induced by human parvovirus B19 (B19) are considered an important pathogenic mechanism in myocarditis or DCM. However, little is known about Th17-related cytokines in SLE patients with DCM about the linkage with B19 infection. IgM and IgG against B19 viral protein, and serum levels of Th17-related cytokines were determined using ELISA in eight SLE patients with DCM and six patients with valvular heart disease (VHD). Humoral responses of anti-B19-VP1u and anti-B19-NS1 antibody were assessed using Western blot and B19 DNA was detected by nested Polymerase Chain Reaction (PCR). Levels of interleukin (IL)-17, IL-6, IL-1β, and tumor necrosis factor (TNF)-α were significantly higher in SLE patients with DCM (mean ± SEM, 390.99±125.48 pg/ml, 370.24±114.09 pg/ml, 36.01±16.90 pg/ml, and 183.84±82.94 pg/ml, respectively) compared to healthy controls (51.32±3.04 pg/ml, p<0.001; 36.88±6.64 pg/ml, p<0.001; 5.39±0.62 pg/ml, p<0.005; and 82.13±2.42 pg/ml, p<0.005, respectively). Levels of IL-17 and IL-6 were higher in SLE patients with DCM versus those with VHD (both p<0.01). Five (62.5%) of DCM patients had detectable anti-B19-NS1 IgG and four (50.0%) of them had anti-B19-VP1u IgG, whereas only one (16.7%) of VHD patients had detectable anti-B19-NS1 IgG and anti-B19-VP1u IgG. Serum levels of IL-17, IL-6 and IL-1β were markedly higher in SLE patients with anti-B19-VP1u IgG and anti-B19-NS1 IgG compared to those without anti-B19-VP1u IgG or anti-B19-NS1 IgG, respectively. These suggest a potential association of B19 with DCM and Th17-related cytokines implicated in the pathogenesis of DCM in SLE patients. PMID:25462010

Time trend and risk factors of avascular bone necrosis in patients with systemic lupus erythematosus.

PubMed

Tse, Sau Mei; Mok, Chi Chiu

2017-06-01

Objectives The objective of this paper is to study the time trend and risk factors of avascular bone necrosis (AVN) in patients with systemic lupus erythematosus (SLE). Methods Between 1999 and 2014, patients who fulfilled the ACR criteria for SLE and developed symptomatic AVN were identified from our cohort database and compared with those without AVN, matched for age, sex and SLE duration. The standardized incidence ratios (SIRs) of AVN in different SLE age groups were calculated from data derived from our hospital registry and population census. Risk factors for AVN were studied by logistic regression, adjusted by a propensity score for ever use of high-dose glucocorticoids (GCs). Results Fifty-five SLE patients with AVN and 220 SLE patients without AVN were studied. There were 104 AVN sites involved, with the hips being most commonly affected (82%). The point prevalence of AVN in our SLE cohort was 7.4%. The SIRs of AVN in our SLE patients were 131 (86.6-199; p < 0.001) and 56.0 (34.3-91.4; p < 0.001), respectively, in the periods 1995-2004 and 2005-2014. In both decades, the age-stratified SIR was highest in the youngest age group (<19 years). AVN patients were more likely to be treated with GCs and had received a significantly higher cumulative dose of prednisolone since SLE diagnosis (16.5 vs 10.7 grams; p = 0.001). The SLE damage score (excluding AVN) was also significantly higher in AVN than non-AVN patients (2.5 vs 0.4; p < 0.001). Logistic regression revealed that preceding septic arthritis of the involved joint (odds ratio (OR) 17.7 (1.5-205); p = 0.02), cushingoid body habitus (OR 2.4 (1.1-5.2); p = 0.04), LDL cholesterol level (OR 1.4 (1.0-1.9); p = 0.04), maximum daily dose of prednisolone (OR 6.4 (1.2-33.3); p = 0.03) and cumulative dose of prednisolone received in the first six months of the first lupus flare (OR 1.3 (1.0-1.8); p = 0.046) were independently associated with AVN. Conclusions AVN is prevalent in SLE, particularly in younger patients. The use of GCs remains the strongest independent risk factor. A trend of reduction in the SIR of AVN in our SLE patients is observed over the past two decades.

B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design.

PubMed

Reddy, Venkat; Jayne, David; Close, David; Isenberg, David

2013-01-01

B cells are believed to be central to the disease process in systemic lupus erythematosus (SLE), making them a target for new therapeutic intervention. In recent years there have been many publications regarding the experience in SLE of B-cell depletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells,reporting promising results in uncontrolled open studies and in routine clinical use. However, the two large randomised controlled trials in extra-renal lupus (EXPLORER study) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints. Based on the clinical experience with rituximab this failure was somewhat unexpected and raised a number of questions and concerns, not only into the true level of benefit of B-cell depletion in a broad population but also how to test the true level of effectiveness of an investigational agent as we seek to improve the design of therapeutic trials in SLE. A better understanding of what went wrong in these trials is essential to elucidate the underlying reasons for the disparate observations noted in open studies and controlled trials. In this review, we focus on various factors that may affect the ability to accurately and confidently establish the level of treatment effect of the investigational agent, in this case rituximab, in the tw studies and explore hurdles faced in the randomised controlled trials investigating the efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based on the lessons learned from the clinical trials, we make suggestions that could be implemented in future clinical trial design to overcome the hurdles faced.

TH1/TH2 cytokine profile, metalloprotease-9 activity and hormonal status in pregnant rheumatoid arthritis and systemic lupus erythematosus patients

PubMed Central

MUÑOZ-VALLE, J F; VÁZQUEZ-DEL MERCADO, M; GARCÍA-IGLESIAS, T; OROZCO-BAROCIO, G; BERNARD-MEDINA, G; MARTÍNEZ-BONILLA, G; BASTIDAS-RAMÍREZ, B E; NAVARRO, A D; BUENO, M; MARTÍNEZ-LÓPEZ, E; BEST-AGUILERA, C R; KAMACHI, M; ARMENDÁRIZ-BORUNDA, J

2003-01-01

During the course of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), several immune and neuroendocrine changes associated with pregnancy may exert positive (amelioration) or negative (exacerbation) effects on the clinical outcome. In order to shed light on the mechanisms underlying these responses, we performed a prospective longitudinal study in RA and SLE pregnant women, including healthy pregnant women as a control group. Cytokine messenger RNA (mRNA) expression assessed by quantitative competitive polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMC), cytokine levels and lymphocyte proliferation responses (LPR) following phytohaemagglutinin (PHA) stimulation of PBMC, plasma metalloprotease-9 activity (MMP-9) and hormonal status during pregnancy were determined. TNFa was the most abundant cytokine mRNA expressed in PBMC in all groups studied (healthy pregnant women, RA and SLE pregnant patients). However, a general TH2 response reflected by high IL-10 levels was found in RA, as well as SLE, patients. A significant change in IFN-γ was observed in RA patients but only during the first trimester of pregnancy. This compared with a major TH1 response in healthy pregnant women. Interestingly, our study showed a homogeneous hormonal pattern in RA and SLE patients. Although decreased cortisol levels were observed in all patients studied, this is possibly related to the remission of disease activity status brought about by steroid treatment before and during pregnancy. In summary, we suggest that complex immune and hormonal networks are involved in pregnancy and that rheumatic diseases are very dynamic immune processes that cannot be described with a clear-cut cytokine profile. Furthermore, the observations in this study may reflect treatment-related immune effects more than those associated with disease. PMID:12562402

Adherence to treatment in patients with systemic lupus erythematosus.

PubMed

Prados-Moreno, Sebastián; Sabio, José Mario; Pérez-Mármol, José Manuel; Navarrete-Navarrete, Nuria; Peralta-Ramírez, María Isabel

2018-01-12

Non-adherence to treatment is usually a clinical problem in patients with systemic lupus erythematosus (SLE). Increasing the knowledge of predictors of treatment adherence can be meaningful in the clinical setting. The main objective of the present study was to analyse the influence of sociodemographic, clinical and psychological variables on the degree of treatment adherence in a sample of Spanish women with SLE. This is an observational-transversal study. All participants were evaluated for the degree of treatment adherence, their clinical status, psychopathological manifestations, the level of perceived stress and self-efficacy. The sample was divided into two groups (adherent vs non-adherent). The factors associated with a lack of adherence in this sample were analysed by means of logistic regression. This study comprises 72 women with SLE (average age=36.72±12.2 years). Almost 64% of patients with SLE were non-adherent to treatment. The results showed that a low educational level, being unemployed, living with a partner and alcohol abuse were associated with low treatment adherence. There were significant mean differences between groups in psychopathological subscales of somatisation, obsession-compulsion and general psychopathological indices. There were also mean differences between groups for the level of perceived stress. The use of non-steroidal anti-inflammatory drugs, suffering arthrosis and scoring higher in dimensions of psychopathology were significant predictors of treatment adherence, explaining between 35% and 47% of its variability. Including the clinical and psychopathological manifestations as important aspects in the clinical reasoning of health professionals could improve the adherence to treatment of patients with SLE. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

46-Year Trends in Systemic Lupus Erythematosus Mortality in the United States, 1968 to 2013: A Nationwide Population-Based Study.

PubMed

Yen, Eric Y; Shaheen, Magda; Woo, Jennifer M P; Mercer, Neil; Li, Ning; McCurdy, Deborah K; Karlamangla, Arun; Singh, Ram R

2017-12-05

No large population-based studies have been done on systemic lupus erythematosus (SLE) mortality trends in the United States. To identify secular trends and population characteristics associated with SLE mortality. Population-based study using a national mortality database and census data. United States. All U.S. residents, 1968 through 2013. Joinpoint trend analysis of annual age-standardized mortality rates (ASMRs) for SLE and non-SLE causes by sex, race/ethnicity, and geographic region; multiple logistic regression analysis to determine independent associations of demographic variables and period with SLE mortality. There were 50 249 SLE deaths and 100 851 288 non-SLE deaths from 1968 through 2013. Over this period, the SLE ASMR decreased less than the non-SLE ASMR, with a 34.6% cumulative increase in the ratio of the former to the latter. The non-SLE ASMR decreased every year starting in 1968, whereas the SLE ASMR decreased between 1968 and 1975, increased between 1975 and 1999, and decreased thereafter. Similar patterns were seen in both sexes, among black persons, and in the South. However, statistically significant increases in the SLE ASMR did not occur among white persons over the 46-year period. Females, black persons, and residents of the South had higher SLE ASMRs and larger cumulative increases in the ratio of the SLE to the non-SLE ASMR (31.4%, 62.5%, and 58.6%, respectively) than males, other racial/ethnic groups, and residents of other regions, respectively. Multiple logistic regression showed independent associations of sex, race, and region with SLE mortality risk and revealed significant racial/ethnic differences in associations of SLE mortality with sex and region. Underreporting of SLE on death certificates may have resulted in underestimates of SLE ASMRs. Accuracy of coding on death certificates is difficult to ascertain. Rates of SLE mortality have decreased since 1968 but remain high relative to non-SLE mortality, and significant sex, racial, and regional disparities persist. None.

Functional anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies in patients with systemic lupus erythematosus.

PubMed

Hagberg, Niklas; Theorell, Jakob; Hjorton, Karin; Spee, Pieter; Eloranta, Maija-Leena; Bryceson, Yenan T; Rönnblom, Lars

2015-04-01

Recently we serendipitously identified a patient with systemic lupus erythematosus (SLE) who was positive for autoantibodies to CD94/natural killer receptor group 2A (NKG2A). The present study was undertaken to investigate the occurrence and function of autoantibodies targeting lectin-like NK cell receptors in SLE. Sera from 203 SLE patients and 90 healthy individuals were analyzed, by flow cytometry, for Ig binding to Ba/F3 cells transfected with CD94/NKG2A, CD94/NKG2C, or NKG2D. Autoantibodies identified were characterized with regard to interference with HLA-E binding, effect on NK cell activation in response to HLA-E-transfected K562 cells, and capacity to facilitate antibody-dependent cell-mediated cytotoxicity (ADCC). Levels of autoantibodies were determined in longitudinally sampled sera, and correlations with disease activity (SLE Disease Activity Index 2000) and severity (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) were investigated. Anti-CD94/NKG2A autoantibodies were identified in 7 SLE patients. The autoantibodies from 6 patients inhibited binding of HLA-E to CD94/NKG2A, whereas those from the seventh patient augmented this binding. Autoantibodies from 2 patients also reacted with the activating receptor CD94/NKG2C, with inhibition of the binding of HLA-E to CD94/NKG2C observed in 1 case and enhancement of this binding in the other. None of the sera contained anti-NKG2D autoantibodies. The levels of anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies correlated with disease activity and with a more severe SLE phenotype. Mechanistically, anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies both interfered with HLA-E-mediated regulation of NK cell activation and facilitated the elimination of target cells expressing CD94/NKG2A or CD94/NKG2C through ADCC. Anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies occur in a subset of patients with clinically active SLE. Given their capacity to deplete certain NK cell subsets and interfere with particular NK cell function, such autoantibodies may promote the pathogenesis of SLE. Copyright © 2015 by the American College of Rheumatology.

Mean platelet volume as an indicator of disease activity in juvenile SLE.

PubMed

Yavuz, Sevgi; Ece, Aydin

2014-05-01

The aim of the study was to assess mean platelet volume (MPV) in children with systemic lupus erythematosus (SLE) at the active and inactive stages. Twenty children with SLE and 30 age- and gender-matched controls were enrolled. Demographic data, SLE disease activity index (SLEDAI), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), MPV, complement 3 (C3), complement 4 (C4), urine protein (Up), and urine creatinine (Ucr) values upon reactivation and remission phases were recorded. MPV was statistically higher in patients than in controls and significantly increased in active phase compared to inactive phase (p = 0.001). A MPV level of 8.4 fL was determined as predictive cutoff value of activation of SLE (sensitivity 75 %, specificity 90 %). MPV was positively correlated with SLEDAI (p = 0.01, r = 0.55), ESR (p = 0.01, r = 0.45), CRP (p = 0.04, r = 0.24), and Up/Ucr (p = 0.01, r = 0.45) and negatively correlated with C3 (p = 0.02, r = -0.36), albumin (p = 0.01, r = -0.63), and Hb (p = 0.01, r = -0.48). There was not any significant association between MPV and the histological classification of lupus nephritis (p = 0.65). MPV might be used as an early indicator of reactivation in children with SLE. MPV seemed to be more accurate than ESR, CRP, and C3 for monitoring the disease activity in SLE.

JAK inhibitor has the amelioration effect in lupus-prone mice: the involvement of IFN signature gene downregulation.

PubMed

Ikeda, Keigo; Hayakawa, Kunihiro; Fujishiro, Maki; Kawasaki, Mikiko; Hirai, Takuya; Tsushima, Hiroshi; Miyashita, Tomoko; Suzuki, Satoshi; Morimoto, Shinji; Tamura, Naoto; Takamori, Kenji; Ogawa, Hideoki; Sekigawa, Iwao

2017-08-22

We previously reported that JAK-STAT-pathway mediated regulation of IFN-regulatory factor genes could play an important role in SLE pathogenesis. Here, we evaluated the efficacy of the JAK inhibitor tofacitinib (TOFA) for controlling IFN signalling via the JAK-STAT pathway and as a therapeutic for SLE. We treated NZB/NZW F1 mice with TOFA and assessed alterations in their disease, pathological, and immunological conditions. Gene-expression results obtained from CD4 + T cells (SLE mice) and CD3 + T cells (human SLE patients) were measured by DNA microarray and qRT-PCR. TOFA treatment resulted in reduced levels of anti-dsDNA antibodies, decreased proteinuria, and amelioration of nephritis as compared with those observed in control animals. Moreover, we observed the rebalance in the populations of naïve CD4 + T cells and effector/memory cells in TOFA-treated mice; however, treatment with a combination of TOFA and dexamethasone (DEXA) elicited a stronger inhibitory effect toward the effector/memory cells than did TOFA or DEXA monotherapy. We also detected decreased expression of several IFN-signature genes Ifit3 and Isg15 in CD4 + from SLE-prone mice following TOFA and DEXA treatment, and IFIT3 in CD3 + T cells from human patients following immunosuppressant therapy including steroid, respectively. Modulation of type I IFN signalling via JAK-STAT inhibition may exert a beneficial effect in SLE patients, and our results suggest that TOFA could be utilised for the development of new SLE-specific therapeutic strategies.

Altered lipid raft–associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus

PubMed Central

Jury, Elizabeth C.; Kabouridis, Panagiotis S.; Flores-Borja, Fabian; Mageed, Rizgar A.; Isenberg, David A.

2004-01-01

Systemic lupus erythematosus (SLE) is characterized by abnormalities in T lymphocyte receptor–mediated signal transduction pathways. Our previous studies have established that lymphocyte-specific protein tyrosine kinase (LCK) is reduced in T lymphocytes from patients with SLE and that this reduction is associated with disease activity and parallels an increase in LCK ubiquitination independent of T cell activation. This study investigated the expression of molecules that regulate LCK homeostasis, such as CD45, C-terminal Src kinase (CSK), and c-Cbl, in lipid raft domains from SLE T cells and investigated the localization of these proteins during T cell receptor (TCR) triggering. Our results indicate that the expression of raft-associated ganglioside, GM1, is increased in T cells from SLE patients and LCK may be differentially regulated due to an alteration in the association of CD45 with lipid raft domains. CD45 tyrosine phosphatase, which regulates LCK activity, was differentially expressed and its localization into lipid rafts was increased in T cells from patients with SLE. Furthermore, T cells allowed to “rest” in vitro showed a reversal of the changes in LCK, CD45, and GM1 expression. The results also revealed that alterations in the level of GM1 expression and lipid raft occupancy cannot be induced by serum factors from patients with SLE but indicated that cell-cell contact, activating aberrant proximal signaling pathways, may be important in influencing abnormalities in T cell signaling and, therefore, function in patients with SLE. PMID:15085197

Plasma Cell Depletion Attenuates Hypertension in an Experimental Model of Autoimmune Disease.

PubMed

Taylor, Erin B; Barati, Michelle T; Powell, David W; Turbeville, Hannah R; Ryan, Michael J

2018-04-01

Numerous studies show a direct relation between circulating autoantibodies, characteristic of systemic autoimmune disorders, and primary hypertension in humans. Whether these autoantibodies mechanistically contribute to the development of hypertension remains unclear. Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by aberrant immunoglobulin production, notably pathogenic autoantibodies, and is associated with prevalent hypertension, renal injury, and cardiovascular disease. Because plasma cells produce the majority of serum immunoglobulins and are the primary source of autoantibodies in SLE, we hypothesized that plasma cell depletion using the proteasome inhibitor bortezomib would lower autoantibody production and attenuate hypertension. Thirty-week-old female SLE (NZBWF1) and control (NZW [New Zealand White]) mice were injected IV with vehicle (0.9% saline) or bortezomib (0.75 mg/kg) twice weekly for 4 weeks. Bortezomib treatment significantly lowered the percentage of bone marrow plasma cells in SLE mice. Total plasma IgG and anti-dsDNA IgG levels were higher in SLE mice compared with control mice but were lowered by bortezomib treatment. Mean arterial pressure (mm Hg) measured in conscious mice by carotid artery catheter was higher in SLE mice than in control mice, but mean arterial pressure was significantly lower in bortezomib-treated SLE mice. Bortezomib also attenuated renal injury, as assessed by albuminuria and glomerulosclerosis, and reduced glomerular immunoglobulin deposition and B and T lymphocytes infiltration into the kidneys. Taken together, these data show that the production of autoantibodies by plasma cells mechanistically contributes to autoimmune-associated hypertension and suggests a potential role for patients with primary hypertension who have increased circulating immunoglobulins. © 2018 American Heart Association, Inc.

IgG and IgM autoantibody differences in discoid and systemic lupus patients.

PubMed

Chong, Benjamin F; Tseng, Lin-chiang; Lee, Thomas; Vasquez, Rebecca; Li, Quan Z; Zhang, Song; Karp, David R; Olsen, Nancy J; Mohan, Chandra

2012-12-01

Systemic lupus erythematosus (SLE) patients with discoid lupus erythematosus (DLE) were reported to have milder disease. To test this observation, we used sandwich arrays containing 98 autoantigens to compare autoantibody profiles of SLE subjects without DLE (DLE-SLE+) (N=9), SLE subjects with DLE (DLE+SLE+) (N=10), DLE subjects without SLE (DLE+SLE-) (N=11), and healthy controls (N=11). We validated differentially expressed autoantibodies using immunoassays in DLE-SLE+ (N=18), DLE+SLE+ (N=17), DLE+SLE- (N=23), and healthy subjects (N=22). Arrays showed 15 IgG autoantibodies (10 against nuclear antigens) and 4 IgM autoantibodies that were differentially expressed (q-value<0.05). DLE-SLE+ subjects had higher IgG autoantibodies against double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), double-stranded RNA (dsRNA), histone H2A and H2B, and SS-A (52 kDa) compared with all other groups including DLE+SLE+ subjects (P<0.05). Immunoassays measuring anti-dsDNA, -ssDNA, and -SS-A (52 kDa) IgG autoantibodies showed similar trends (P<0.05). Healthy and DLE+SLE- subjects expressed higher IgM autoantibodies against alpha beta crystallin, lipopolysaccharide, heat-shock cognate 70, and desmoglein-3 compared with DLE+SLE+ and DLE-SLE+ subjects. IgG:IgM ratios of autoantibodies against nuclear antigens progressively rose from healthy to DLE-SLE+ subjects. In conclusion, lower IgG autoantibodies against nuclear antigens in DLE+SLE+ versus DLE-SLE+ subjects suggest that DLE indicates lower disease severity. Higher IgM autoantibodies against selected antigens in healthy and DLE+SLE- subjects may be nonpathogenic.

Anticardiolipin antibodies in patients from Malaysia with systemic lupus erythematosus.

PubMed

Jones, H W; Ireland, R; Senaldi, G; Wang, F; Khamashta, M; Bellingham, A J; Veerapan, K; Hughes, G R; Vergani, D

1991-03-01

Systemic lupus erythematosus (SLE) is highly prevalent in Malaysia, which has a mixed population of Malays, Chinese, and Indians. A quantitative enzyme linked immunosorbent assay (ELISA) was used to determine anticardiolipin antibody (aCL) levels (total immunoglobulin, IgG, and IgM) in 200 patients with SLE (164 Chinese, 26 Malay, and 10 Indian) attending the University Hospital of Kuala Lumpur, Malaysia, and 103 matched controls. Only 33 (16.5%) of the patients had raised aCL levels; 26 had raised IgG aCL, five IgM aCL, and two both IgG and IgM aCL. There was a low prevalence of raised levels of aCL in the population studied, which was seen in conjunction with a rare occurrence of thrombosis. The classical association of high aCL levels with thrombocytopenia and recurrent abortions was noted, though not with cerebral disease. The low prevalence of aCL in this study population of mixed racial origin contrasts with findings in European patients with SLE and lends support to the influence of local factors, be they genetic or environmental, on the clinical manifestations of this disease.

Naja naja atra Venom Protects against Manifestations of Systemic Lupus Erythematosus in MRL/lpr Mice.

PubMed

Zhu, Jiali; Cui, Kui; Kou, Jianqun; Wang, Shuzhi; Xu, Yinli; Ding, Zhihui; Han, Rong; Qin, Zhenghong

2014-01-01

Systemic lupus erythematosus (SLE) is an autoimmune disease and effective therapy for this pathology is currently unavailable. We previously reported that oral administration of Naja naja atra venom (NNAV) had anti-inflammatory and immune regulatory actions. We speculated that NNAV may have therapeutic effects in MRL/lpr SLE mice. Twelve-week-old MRL/lpr mice received oral administration of NNAV (20, 40, and 80 μg/kg) or Tripterygium wilfordii polyglycosidium (10 mg/kg) daily for 16 weeks. The effects of NNAV on SLE manifestations, including skin erythema, proteinuria, and anxiety-like behaviors, were assessed with visual inspection and Multistix 8 SG strips and open field test, respectively. The pathology of spleen and kidney was examined with H&E staining. The changes in autoimmune antibodies and cytokines were determined with ELISA kits. The results showed that NNAV protected against the manifestation of SLE, including skin erythema and proteinuria. In addition, although no apparent histological change was found in liver and heart in MRL/lpr SLE mice, NNAV reduced the levels of glutamate pyruvate transaminase and creatine kinase. Furthermore, NNAV increased serum C3 and reduced concentrations of circulating globulin, anti-dsDNA antibody, and inflammatory cytokines IL-6 and TNF-α. NNAV also reduced lymphadenopathy and renal injury. These results suggest that NNAV may have therapeutic values in the treatment of SLE by inhibiting autoimmune responses.

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

PubMed Central

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J.; Isenberg, David A.; Magee, Anthony I.; Butters, Terry; Jury, Elizabeth C.

2014-01-01

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft–associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE. PMID:24463447

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients.

PubMed

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J; Isenberg, David A; Magee, Anthony I; Butters, Terry; Jury, Elizabeth C

2014-02-01

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft-associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE.

Interleukin-6 promotes systemic lupus erythematosus progression with Treg suppression approach in a murine systemic lupus erythematosus model.

PubMed

Mao, Xiaoli; Wu, Yunyun; Diao, Huitian; Hao, Jianlei; Tian, Gaofei; Jia, Zhenghu; Li, Zheng; Xiong, Sidong; Wu, Zhenzhou; Wang, Puyue; Zhao, Liqing; Yin, Zhinan

2014-11-01

Our aim is to reveal the role of interleukin 6 (IL-6) in the pathogenesis of systemic lupus erythematosus (SLE) in a murine model of SLE. Normal female C57BL/6 mice were immunized with syngeneic-activated lymphocyte-derived DNA (ALD-DNA) to induce SLE. Non-immunized mice were used as control. SLE-associated markers, including anti-double-stranded DNA (anti-dsDNA) Abs, urine protein, and kidney histopathology, were assayed to ensure the induction of the disease. Compared with control mice, ALD-DNA immunized mice exhibited high levels of anti-dsDNA Abs, IL-6 expression in vivo and in vitro. We also found that IL-6 knockout (IL-6KO) mice were resistant to ALD-DNA-induced SLE. The activation of CD4(+) T cells in immunized IL-6KO mice was lower than in immunized wild-type (Wt) mice. Intracellular cytokine staining showed that Foxp3 expression in immunized IL-6KO mice was higher than in immunized Wt mice, which might be associated with the disease severity. We further discovered that ALD-DNA-stimulated dendritic cells supernatants could result in higher IL-6 and TNF-α expression and could suppress Foxp3 expression. In addition, blocking IL-6 could up-regulate Foxp3 expression. Therefore, our findings show that IL-6 promotes the progression of SLE via suppressing Treg differentiation.

Levels of uric acid may predict the future development of pulmonary hypertension in systemic lupus erythematosus: a seven-year follow-up study.

PubMed

Castillo-Martínez, D; Marroquín-Fabián, E; Lozada-Navarro, A C; Mora-Ramírez, M; Juárez, M; Sánchez-Muñoz, F; Vargas-Barrón, J; Sandoval, J; Amezcua-Guerra, L M

2016-01-01

The objective of this paper is to assess whether pulmonary hypertension (PH) may be detected at one point in time or longitudinally predicted by serum uric acid (sUA) levels in systemic lupus erythematosus (SLE). We conducted a post-hoc analysis of a long-term followed cohort of Mexican SLE patients. Echocardiography-based definitions of PH by the ESC/ERS/ISHLT and its associations with clinical and laboratory data on enrollment were studied. Especially, the impact that sUA levels at baseline may have on the future development of PH in patients with normal pulmonary artery systolic pressure (PASP) was explored. Out of the 156 SLE patients originally enrolled in the cohort, 44 met the inclusion criteria for the present study and were grouped as having (n =10) or not having (n = 34) PH. At baseline, sUA levels of 5.83 ± 1.79 and 5.82 ± 1.97 mg/dl (p = ns) were found in patients with and without PH, respectively. No association between PASP and other markers was found. In patients with normal PASP, the presence of sUA ≥ 7 mg/dl at baseline predicted future development of PH (relative risk 8.5, 1.0009 to 72; p = 0.04). In SLE, sUA levels at one point in time are useless to detect PH. However, steady hyperuricemia may predict the future development of PH in patients with normal PASP at baseline. © The Author(s) 2015.

Response to belimumab among patients with systemic lupus erythematosus in clinical practice settings: 24-month results from the OBSErve study in the USA

PubMed Central

Collins, C E; Dall'Era, M; Kan, H; Macahilig, C; Molta, C; Koscielny, V; Chang, D J

2016-01-01

Objective To examine disease activity and clinical outcomes, and describe overall patterns of systemic lupus erythematosus (SLE) care in patients who received belimumab in a real-world clinical setting. Methods This observational cohort study was conducted in US clinical practices. Rheumatologists (n=92) identified adults with SLE who had received ≥8 infusions of belimumab plus standard of care (SoC). Physicians assessed disease outcomes at 6-month intervals using patient medical charts, for up to 24 months. The primary outcome was physician-assessed change in SLE disease. Other outcomes included change in steroid use, laboratory tests and healthcare resource utilisation (HCRU). Results Of 501 patients (intent-to-treat population (ITT)), 446 were female, mean age was 43.3 years and 98% had moderate/severe disease activity at baseline (first dose of belimumab). Data for 277 patients who completed 24 months of belimumab treatment were available. Among the ITT, a ≥50% improvement in overall clinical response between baseline and month 6 was reported for 48.7% of patients; continued improvement was seen at all subsequent 6-month intervals relative to the previous timepoint. The percentage of patients with moderate/severe disease also decreased at each timepoint. At baseline, 77.0% of patients received steroids at a mean (SD) prednisone equivalent dose of 19.9 (14.39) mg/day, which decreased to 8.4 (7.35) mg/day at month 6 and 6.1 (9.31) mg/day at month 24. Abnormal laboratory values typically associated with SLE also demonstrated improvements at month 6, which continued through 24 months. HCRU decreased over the duration of the study. Conclusions Patients with SLE who received belimumab plus SoC for up to 24 months demonstrated improvements in disease severity and laboratory values and a reduction in steroid use and HCRU as early as month 6. Improvements continued through 24 months, providing evidence of reduced disease activity among patients taking belimumab in real-world clinical practice. PMID:26835146

Glucocorticoid-induced leucine zipper expression is associated with response to treatment and immunoregulation in systemic lupus erythematosus.

PubMed

Mohammadi, Saeed; Ebadpour, Mohammad Reza; Sedighi, Sima; Saeedi, Mohsen; Memarian, Ali

2017-08-01

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

Erythrocyte-bound C4d in combination with complement and autoantibody status for the monitoring of SLE.

PubMed

Merrill, Joan T; Petri, Michelle A; Buyon, Jill; Ramsey-Goldman, Rosalind; Kalunian, Kenneth; Putterman, Chaim; Conklin, John; Furie, Richard A; Dervieux, Thierry

2018-01-01

We examined the usefulness of erythrocyte-bound C4d (EC4d) to monitor disease activity in SLE. Data and blood samples were collected from three different studies, each of which included longitudinal evaluations using the Physicians Global Assessment (PGA) of disease activity and the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE Disease Activity Index (SLEDAI), which was assessed without anti-double-stranded DNA (dsDNA) and low complement C3/C4 (clinical SELENA-SLEDAI). EC4d levels were determined using flow cytometry; other laboratory measures included antibodies to dsDNA, C3 and C4 proteins. Relationships between clinical SELENA-SLEDAI, PGA and the laboratory measures were analysed using linear mixed effect models. The three studies combined enrolled 124 patients with SLE (mean age 42 years, 97% women, 31% Caucasians and 34% African-Americans) followed for an average of 5 consecutive visits (range 2-13 visits). EC4d levels and low C3/C4 status were significantly associated the clinical SELENA-SLEDAI or PGA in each of the three study groups (p<0.05). Multivariate analysis revealed that EC4d levels (estimate=0.94±0.28) and low complement C3/C4 (estimate=1.24±0.43) were both independently and significantly associated with the clinical SELENA-SLEDAI (p<0.01) and PGA. EC4d levels were also associated with the clinical SELENA-SLEDAI (estimate: 1.20±0.29) and PGA (estimate=0.19±0.04) among patients with chronically low or normal C3/C4 (p<0.01). Anti-dsDNA titres were generally associated with disease activity. These data support the association of EC4d with disease activity regardless of complement C3/C4 status and its usefulness in monitoring SLE disease. Additional studies will be required to support these validation data.

Brief Report: The Euro-Lupus Low-Dose Intravenous Cyclophosphamide Regimen Does Not Impact the Ovarian Reserve, as Measured by Serum Levels of Anti-Müllerian Hormone.

PubMed

Tamirou, Farah; Husson, Séverine Nieuwland; Gruson, Damien; Debiève, Frédéric; Lauwerys, Bernard R; Houssiau, Frédéric A

2017-06-01

The Euro-Lupus regimen of low-dose intravenous cyclophosphamide (IV CYC) (cumulative dose of 3 gm) was developed to reduce gonadal toxicity. To address the possibility of a marginal effect on the ovarian reserve, we measured serum titers of anti-Müllerian hormone (AMH) in patients with systemic lupus erythematosus (SLE) treated with the Euro-Lupus regimen and compared them with those measured in patients who were treated with higher doses of IV CYC or were never treated with IV CYC. Serum AMH levels were measured by enzyme-linked immunosorbent assay in a cohort of 155 premenopausal SLE patients; 30 of these patients had been treated with the Euro-Lupus regimen, and 24 had received higher doses of IV CYC. None had received oral CYC. AMH levels were age-adjusted using a slope computed from levels measured across the group of SLE patients who had not been treated with IV CYC. Demographic and clinical data were collected. Serum titers of AMH measured in SLE patients treated with the Euro-Lupus IV CYC regimen (median dose 1.46 ng/ml) did not differ from those measured in patients never treated with the cytotoxic drug (median 1.85 ng/ml). As expected, patients given >6 gm of IV CYC had significantly lower serum titers of AMH (median 0.83 ng/ml) compared with those never treated with IV CYC (P = 0.047). Median serum AMH titers did not change before (1.24 ng/ml) and after (2.50 ng/ml) treatment with the Euro-Lupus IV CYC regimen in the subset of patients for whom paired samples could be tested (P = 0.43). The Euro-Lupus regimen of low-dose IV CYC does not impact the ovarian reserve of SLE patients and can therefore be proposed as treatment in patients seeking to become pregnant. © 2017, American College of Rheumatology.

Analysis of correlations between selected endothelial cell activation markers, disease activity, and nailfold capillaroscopy microvascular changes in systemic lupus erythematosus patients.

PubMed

Ciołkiewicz, Mariusz; Kuryliszyn-Moskal, Anna; Klimiuk, Piotr Adrian

2010-02-01

The aim of the study was to evaluate the correlation between selected serum endothelial cell activation markers such as vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), soluble thrombomodulin (sTM), soluble E-selectin (sE-selectin), disease activity, and microvascular changes determined by nailfold capillaroscopy in patients with systemic lupus erythematosus (SLE). Serum levels of VEGF, ET-1, sTM, and sE-selectin were determined by an enzyme-linked immunosorbent assay in 80 SLE patients. The disease activity was measured with Systemic Lupus Erythematosus Disease Activity Index score. Nailfold capillaroscopy was performed in all patients. Positive correlation was found between VEGF and both ET-1 (r = 0.294, p < 0.01) and sE-selectin (r = 0.274, p < 0.05) serum levels as well as between sTM and ET-1 (r = 0.273, p < 0.05) serum concentrations. We noticed also positive correlation between VEGF (r = 0.224, p < 0.05) and ET-1 (r = 0.471, p < 0.001) serum levels and disease activity, and also between VEGF serum concentration and grade of morphological changes observed by nailfold capillaroscopy (r = 0.458, p < 0.001). There was also positive correlation between capillaroscopic score and disease activity (r = 0.339, p < 0.01). Our data suggest that correlation between VEGF and both ET-1 and E-selectin serum levels as well as between sTM and ET-1 serum concentrations may reflect their participation in the pathogenesis of SLE. VEGF seems to reflect changes in microcirculation in the course of SLE, visualised by nailfold capillaroscopy. The relationship between changes in nailfold capillaroscopy, endothelial cell activation markers, and the clinical activity of SLE points to an important role of microvascular abnormalities in the clinical manifestation of the disease.

Evaluation of ATG5 polymorphisms in Italian patients with systemic lupus erythematosus: contribution to disease susceptibility and clinical phenotypes.

PubMed

Ciccacci, C; Perricone, C; Alessandri, C; Latini, A; Politi, C; Delunardo, F; Pierdominici, M; Conti, F; Novelli, G; Ortona, E; Borgiani, P

2018-01-01

Systemic lupus erythematosus (SLE) is a common heterogeneous autoimmune disease that is caused by the involvement both of genetic and environmental factors. There is evidence that autophagy is involved in several aspects of SLE pathogenesis. In particular, polymorphisms in the ATG5 gene have been observed to be associated with disease susceptibility. Our aim was to verify if ATG5 polymorphisms are involved in the susceptibility to disease and its clinical phenotypes in an Italian cohort of SLE patients. This study involved 315 SLE patients and 265 healthy controls. Three polymorphisms in the ATG5 gene (rs573775, rs6568431 and rs2245214) were investigated by allelic discrimination assay. A case-control association study, a genotype/phenotype correlation analysis and a haplotype study were performed. Moreover, an expression study was conducted in peripheral blood mononuclear cells from 15 SLE patients to verify a possible effect of the three SNPs on the expression of ATG5. Among the three investigated SNPs, only the rs573775 SNP was significantly associated with disease susceptibility with the variant allele conferring a higher risk of developing SLE (OR = 1.50, p = 0.018 and OR = 1.48, p = 0.007 at the genotypic and allelic level, respectively). The variant allele of rs6568431 SNP was more present in patients with anemia (OR = 1.86, p = 0.009) and renal involvement (OR = 1.63, p = 0.06), while the variant allele of rs2245214 SNP was significantly associated with a higher risk of producing anti-DNA autoantibodies (OR = 1.66, p = 0.04). Carriers of the rs6568431 variant allele showed higher messenger RNA levels compared to the carriers of the wild-type allele, suggesting also a potential variant allele dose-dependent effect on gene expression. In conclusion, our study confirms a role for ATG5 polymorphisms both in disease susceptibility and in the modulation of clinical phenotypes in an Italian SLE cohort. These results further suggest that genetic variations in autophagy genes could play a role in autoimmune diseases susceptibility and are worth further investigation.

Very delayed lupus nephritis: a report of three cases and literature review.

PubMed

Alexandre, André R; Carreira, Pedro L; Isenberg, David A

2018-01-01

Lupus nephritis (LN) affects up to 50% of patients with Systemic Lupus Erythematosus (SLE) and is associated with a worse prognosis. LN usually develops within the first 5 years of the onset of the disease. We report three patients with very delayed LN (DLN) diagnosed after 15 or more years after SLE diagnosis. The three patients were non-Caucasian women with adolescent or adult-onset SLE. Each had antinuclear, anti-dsDNA and anti-Ro antibodies. Hydroxychloroquine was prescribed for each. Their disease courses were characterised by sporadic non-renal flares controlled by steroids and, in two cases, by one cycle of rituximab. Unexpectedly, they developed proteinuria, haematuria and lowering of estimated glomerular filtration rate with clinical signs of renal disease. LN was confirmed by renal biopsy. Reviewing them, each showed serological signs of increasing disease activity (rising levels of anti-dsDNA antibodies and fall in C3) that predated clinical or laboratory signs of LN by 1-3 years. Reviewing the literature, we found a lack of knowledge about DLN starting more than 15 years after SLE diagnosis. With the increasing life expectancy of patients with SLE it is likely that more cases of very DLN will emerge.

Pre-B cell leukemia homeobox 1 is associated with lupus susceptibility in mice and humans

PubMed Central

Cuda, Carla M.; Li, Shiwu; Liang, Shujuan; Yin, Yiming; Potula, Hari Hara S.K.; Xu, Zhiwei; Sengupta, Mayami; Chen, Yifang; Butfiloski, Edward; Baker, Henry; Chang, Lung-Ji; Dozmorov, Igor; Sobel, Eric S.; Morel, Laurence

2011-01-01

Sle1a.1 is part of the Sle1 susceptibility locus, which has the strongest association with lupus nephritis in the NZM2410 mouse model. Here we show that Sle1a.1 results in the production of activated and autoreactive CD4+ T cells. In addition, Sle1a.1 expression reduces the peripheral regulatory T cell (Treg) pool, as well as induces a defective response of CD4+ T cells to the retinoic acid (RA) expansion of TGFβ-induced Tregs. At the molecular level, Sle1a.1 corresponds to an increased expression of a novel splice isoform of Pbx1, Pbx1-d. Pbx1-d over-expression is sufficient to induce an activated/inflammatory phenotype in Jurkat T cells, and to decrease their apoptotic response to RA. PBX1-d is expressed more frequently in the CD4+ T cells from lupus patients than from healthy controls, and its presence correlates with an increased central memory T cell population. These findings indicate that Pbx1 is a novel lupus susceptibility gene that regulates T cell activation and tolerance. PMID:22180614

Induction of a systemic lupus erythematosus-like disease in mice by a common human anti-DNA idiotype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mendlovic, S.; Brocke, S.; Meshorer, A.

1988-04-01

Systemic lupus erythematosus (SLE) is considered to be the quintessential autoimmune disease. It has not been possible to induce SLE in animal models by DNA immunization or by challenge with anti-DNA antibodies. The authors report a murine model of SLE-like disease induced by immunization of C3H.SW female mice with a common human monoclonal anti-DNA idiotype (16/6 idiotype). Following a booster injection with the 16/6 idiotype, high levels of murine anti-16/6 and anti-anti-16/6 antibodies (associated with anti-DNA activity) were detected in the sera of the immunized mice. Elevated titers of autoantibodies reacting with DNA, poly(I), poly(dT), ribonucleoprotein, autoantigens (Sm, SS-A (Ro),more » and SS-B (La)), and cardiolipin were noted. The serological findings were associated with increased erythrocyte sedimentation rate, leukopenia, proteinuria, immune complex deposition in the glomerular mesangium, and sclerosis of the glomeruli. The immune complexes in the kidneys were shown to contain the 16/6 idiotype. This experimental SLE-like model may be used to elucidate the mechanisms underlying SLE.« less

Understanding and Managing Pregnancy in Patients with Lupus

PubMed Central

de Jesus, Guilherme Ramires; Mendoza-Pinto, Claudia; de Jesus, Nilson Ramires; dos Santos, Flávia Cunha; Klumb, Evandro Mendes; Carrasco, Mario García; Levy, Roger Abramino

2015-01-01

Systemic lupus erythematosus (SLE) is a chronic, multisystemic autoimmune disease that occurs predominantly in women of fertile age. The association of SLE and pregnancy, mainly with active disease and especially with nephritis, has poorer pregnancy outcomes, with increased frequency of preeclampsia, fetal loss, prematurity, growth restriction, and newborns small for gestational age. Therefore, SLE pregnancies are considered high risk condition, should be monitored frequently during pregnancy and delivery should occur in a controlled setting. Pregnancy induces dramatic immune and neuroendocrine changes in the maternal body in order to protect the fetus from immunologic attack and these modifications can be affected by SLE. The risk of flares depends on the level of maternal disease activity in the 6–12 months before conception and is higher in women with repeated flares before conception, in those who discontinue useful medications and in women with active glomerulonephritis at conception. It is a challenge to differentiate lupus nephritis from preeclampsia and, in this context, the angiogenic and antiangiogenic cytokines are promising. Prenatal care of pregnant patients with SLE requires close collaboration between rheumatologist and obstetrician. Planning pregnancy is essential to increase the probability of successful pregnancies. PMID:26246905

The mediational role of helplessness in psychological outcomes in systemic lupus erythematosus.

PubMed

Mills, S D; Azizoddin, D; Gholizadeh, S; Racaza, G Z; Nicassio, P M

2018-06-01

Objective Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can result in disability and psychological distress. Although pain has been associated with depressive symptomatology and stress in SLE, a paucity of theoretical models have been used to explain the relationship between pain and psychological distress in this population. Thus, the present study examined helplessness as a mediator of the relationship between pain and psychological distress among patients with SLE. Methods Multiple mediation analysis was used to examine the hypothesis that learned helplessness mediates the relationship between pain and symptoms of anxiety, depression, and stress in a sample of patients with SLE ( N = 136) receiving medical care at Cedars Sinai Medical Center. Results The mean score on the Helplessness subscale was 14.5 ( SD = 5.4). Helplessness fully mediated the relationship between pain vitality and symptoms of anxiety (BCa 95% CI (-0.073, -0.015)), depression (BCa 95% CI (-0.502, -0.212)), and stress (BCa 95% CI (-0.063, -0.027)). Conclusion Participants reported a high level of perceived inability to control one's disease. Helplessness fully mediated the relationship between pain and measures of anxiety, depression, and perceived stress among patients with SLE.

Anti-pentraxin 3 auto-antibodies might be protective in lupus nephritis: a large cohort study.

PubMed

Yuan, Mo; Tan, Ying; Pang, Yun; Li, Yong-Zhe; Song, Yan; Yu, Feng; Zhao, Ming-Hui

2017-11-01

Anti-pentraxin 3 (PTX3) auto-antibodies were found to be associated with the absence of renal involvement in systemic lupus erythematosus (SLE). This study is to investigate the prevalence of anti-PTX3 auto-antibodies and their clinical significance based on a large Chinese lupus nephritis cohort. One hundred and ninety-six active lupus nephritis patients, 150 SLE patients without clinical renal involvement, and 100 healthy controls were enrolled. Serum anti-PTX3 auto-antibodies and PTX3 levels were screened by enzyme-linked immunosorbent assay (ELISA). The associations between anti-PTX3 auto-antibodies and clinicopathological parameters in lupus nephritis were further analyzed. Anti-PTX3 auto-antibodies were less prevalent in active lupus nephritis patients compared with SLE without renal involvement (19.4% (38/196) versus 40.7% (61/150), p < .001). The serum levels of anti-PTX3 auto-antibodies were negatively correlated with proteinuria in lupus nephritis (r = -.143, p = .047). The levels of proteinuria, serum creatinine, and the prevalence of thrombotic microangiopathy were significantly higher in patients with higher PTX3 levels (≥3.207 ng/ml) and without anti-PTX3 auto-antibodies compared with patients with lower PTX3 levels (<3.207 ng/ml) and with anti-PTX3 auto-antibodies (4.79 (3.39-8.28) versus 3.95 (1.78-7.0), p = .03; 168.84 ± 153.63 versus 101.44 ± 47.36, p = .01; 34.1% (14/41) versus 0% (0/9), p = .04; respectively). Anti-PTX3 auto-antibodies were less prevalent in active lupus nephritis patients compared with SLE without renal involvement and associated with less severe renal damage, especially with the combined evaluation of serum PTX3 levels.

A benchmark study of the sea-level equation in GIA modelling

NASA Astrophysics Data System (ADS)

Martinec, Zdenek; Klemann, Volker; van der Wal, Wouter; Riva, Riccardo; Spada, Giorgio; Simon, Karen; Blank, Bas; Sun, Yu; Melini, Daniele; James, Tom; Bradley, Sarah

2017-04-01

The sea-level load in glacial isostatic adjustment (GIA) is described by the so called sea-level equation (SLE), which represents the mass redistribution between ice sheets and oceans on a deforming earth. Various levels of complexity of SLE have been proposed in the past, ranging from a simple mean global sea level (the so-called eustatic sea level) to the load with a deforming ocean bottom, migrating coastlines and a changing shape of the geoid. Several approaches to solve the SLE have been derived, from purely analytical formulations to fully numerical methods. Despite various teams independently investigating GIA, there has been no systematic intercomparison amongst the solvers through which the methods may be validated. The goal of this paper is to present a series of benchmark experiments designed for testing and comparing numerical implementations of the SLE. Our approach starts with simple load cases even though the benchmark will not result in GIA predictions for a realistic loading scenario. In the longer term we aim for a benchmark with a realistic loading scenario, and also for benchmark solutions with rotational feedback. The current benchmark uses an earth model for which Love numbers have been computed and benchmarked in Spada et al (2011). In spite of the significant differences in the numerical methods employed, the test computations performed so far show a satisfactory agreement between the results provided by the participants. The differences found can often be attributed to the different approximations inherent to the various algorithms. Literature G. Spada, V. R. Barletta, V. Klemann, R. E. M. Riva, Z. Martinec, P. Gasperini, B. Lund, D. Wolf, L. L. A. Vermeersen, and M. A. King, 2011. A benchmark study for glacial isostatic adjustment codes. Geophys. J. Int. 185: 106-132 doi:10.1111/j.1365-

Clinical and immunological aspects and outcome of a Brazilian cohort of 414 patients with systemic lupus erythematosus (SLE): comparison between childhood-onset, adult-onset, and late-onset SLE.

PubMed

das Chagas Medeiros, M M; Bezerra, M Campos; Braga, F N Holanda Ferreira; da Justa Feijão, M R Melo; Gois, A C Rodrigues; Rebouças, V C do Rosário; de Carvalho, T M Amorim Zaranza; Carvalho, L N Solon; Ribeiro, Át Mendes

2016-04-01

The clinical expression of systemic lupus erythematosus (SLE) is influenced by genetic and environmental factors and therefore varies between ethnicities. Information on the epidemiology of SLE in Brazil is scarce and practically limited to studies conducted in socioeconomically developed regions (South and Southeast). The objective of this study was to describe the clinical and immunological aspects and outcome of a cohort of patients with SLE treated at a university hospital in northeastern Brazil and compare patterns related to age at onset: childhood (cSLE), adult (aSLE), and late (lSLE). A random sample of 414 records (women: 93.5%) were reviewed. The mean age at SLE onset and the mean disease duration were 28.9 ± 10.9 years and 10.2 ± 6.6 years, respectively. Most patients had aSLE (n = 338; 81.6%), followed by cSLE (n = 60; 14.5%) and lSLE (n = 16; 3.9%). The female/male ratio was 6.5:1 in cSLE and 16.8:1 in aSLE; in lSLE, all patients were female (p = 0.05). During follow-up, the cSLE group presented higher rates of nephritis (70% vs. 52.9% vs. 12.5%; p = 0.0001) and leuko/lymphopenia (61.7% vs. 43.8% vs. 56.2%; p = 0.02). No significant differences were found for anti-dsDNA, anti-Sm, and antiphospholipid antibodies. Treatment with immunosuppressants was significantly more common, and higher doses of prednisone were used, in cSLE. The prevalence of cardiovascular diseases were more frequent in lSLE (p = 0.03). No significant differences were found between the three groups with regard to mean damage accrual (SDI), remission, and mortality. Although cSLE presented higher rates of nephritis and leuko/lymphopenia, more frequent use of immunosuppressants and higher prednisone doses than aSLE and lSLE, the three groups did not differ significantly with regard to damage accrual, remission, and mortality. © The Author(s) 2015.

The exaggerated inflammatory response in Behçet's syndrome: identification of dysfunctional post-transcriptional regulation of the IFN-γ/CXCL10 IP-10 pathway

PubMed Central

Ambrose, N; Khan, E; Ravindran, R; Lightstone, L; Abraham, S; Botto, M; Johns, M; Haskard, D O

2015-01-01

The mechanisms underlying the exaggerated inflammatory response in Behçet's syndrome (BS) remain poorly understood. We investigated the response of CD14+ blood monocytes to interferon (IFN)-γ, focusing on the chemokine CXCL10. Chemokine synthesis and release were analysed at a protein and mRNA level following stimulation with IFN-γ. Findings in BS patients were compared with 25 healthy controls (HC), 15 rheumatoid arthritis (RA) and 15 systemic lupus erythematosus (SLE) disease control patients. BS monocytes produced significantly more CXCL10 protein than HC monocytes from 2 h following IFN-γ stimulation, despite equivalent quantities of mRNA, suggesting more efficient translation. This was significantly more pronounced in BS with high disease activity and in those with ocular and neurological clinical manifestations. The imbalance between CXCL10 protein and mRNA expression was not observed in either RA or SLE patients, and was not seen with other chemokines studied (CXCL9, CXCL11 and CCL2). Furthermore, BS monocytes treated with an alternative stimulant (LPS) did not show abnormal tumour necrosis factor (TNF)-α release. Sucrose density gradients to segregate monocyte CXCL10 mRNA into free RNA or polysome-associated RNA showed equal proportions in BS and HC samples, suggesting that the difference between BS and HC may be due to reduced negative control of CXCL10 translation in BS at a post-initiation level. We conclude that BS monocytes have dysfunctional post-transcriptional regulation of CXCL10 mRNA, resulting in over-expression of CXCL10 protein upon IFN-γ stimulation. As CXCL10 is a chemokine that recruits mononuclear cells, this abnormality may contribute to the exaggerated inflammatory responses that characterizes BS. PMID:25982097

The exaggerated inflammatory response in Behçet's syndrome: identification of dysfunctional post-transcriptional regulation of the IFN-γ/CXCL10 IP-10 pathway.

PubMed

Ambrose, N; Khan, E; Ravindran, R; Lightstone, L; Abraham, S; Botto, M; Johns, M; Haskard, D O

2015-09-01

The mechanisms underlying the exaggerated inflammatory response in Behçet's syndrome (BS) remain poorly understood. We investigated the response of CD14(+) blood monocytes to interferon (IFN)-γ, focusing on the chemokine CXCL10. Chemokine synthesis and release were analysed at a protein and mRNA level following stimulation with IFN-γ. Findings in BS patients were compared with 25 healthy controls (HC), 15 rheumatoid arthritis (RA) and 15 systemic lupus erythematosus (SLE) disease control patients. BS monocytes produced significantly more CXCL10 protein than HC monocytes from 2 h following IFN-γ stimulation, despite equivalent quantities of mRNA, suggesting more efficient translation. This was significantly more pronounced in BS with high disease activity and in those with ocular and neurological clinical manifestations. The imbalance between CXCL10 protein and mRNA expression was not observed in either RA or SLE patients, and was not seen with other chemokines studied (CXCL9, CXCL11 and CCL2). Furthermore, BS monocytes treated with an alternative stimulant (LPS) did not show abnormal tumour necrosis factor (TNF)-α release. Sucrose density gradients to segregate monocyte CXCL10 mRNA into free RNA or polysome-associated RNA showed equal proportions in BS and HC samples, suggesting that the difference between BS and HC may be due to reduced negative control of CXCL10 translation in BS at a post-initiation level. We conclude that BS monocytes have dysfunctional post-transcriptional regulation of CXCL10 mRNA, resulting in over-expression of CXCL10 protein upon IFN-γ stimulation. As CXCL10 is a chemokine that recruits mononuclear cells, this abnormality may contribute to the exaggerated inflammatory responses that characterizes BS. © 2015 British Society for Immunology.

Clinical associations of proinflammatory cytokines, oxidative biomarkers and vitamin D levels in systemic lupus erythematosus.

PubMed

Willis, R; Smikle, M; DeCeulaer, K; Romay-Penabad, Z; Papalardo, E; Jajoria, P; Harper, B; Murthy, V; Petri, M; Gonzalez, E B

2017-12-01

Background The abnormal biological activity of cytokines plays an important role in the pathophysiology of both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Several studies have highlighted the association of vitamin D and certain pro-inflammatory cytokines with disease activity in SLE. However, there are limited data on the association of vitamin D and antiphospholipid antibodies (aPL) with various proinflammatory biomarkers in these patients and their relative impact on clinical outcomes. Methods The serum levels of several aPL, 25-hydroxy-vitamin D, pro-inflammatory cytokines including IFNα, IL-1β, IL-6, IL-8, IP10, sCD40L, TNFα and VEGF were measured in 312 SLE patients from the Jamaican ( n = 45) and Hopkins ( n = 267) lupus cohorts using commercial Milliplex and ELISA assays. Oxidized LDL/β2glycoprotein antigenic complexes (oxLβ2Ag) and their associated antibodies were also measured in the Jamaican cohort. Healthy controls for oxidative marker and cytokine testing were used. Results Abnormally low vitamin D levels were present in 61.4% and 73.3% of Hopkins and Jamaican SLE patients, respectively. Median concentrations of IP10, TNFα, sCD40L and VEGF were elevated in both cohorts, oxLβ2Ag and IL-6 were elevated in the Jamaican cohort, and IFNα, IL-1β and IL-8 were the same or lower in both cohorts compared to controls. IP10 and VEGF were independent predictors of disease activity, aPL, IP10 and IL-6 were independent predictors of thrombosis and IL-8, and low vitamin D were independent predictors of pregnancy morbidity despite there being no association of vitamin D with pro-inflammatory cytokines. Conclusions Our results indicate that aPL-mediated pro-inflammatory cytokine production is likely a major mechanism of thrombus development in SLE patients. We provide presumptive evidence of the role IL-8 and hypovitaminosis D play in obstetric pathology in SLE but further studies are required to characterize the subtle complexities of vitamin D's relationship with cytokine production and disease activity in these patients.

[The association of fibromyalgia and systemic lupus erythematosus change the presentation and severity of both diseases?].

PubMed

de Araújo, Ana Luiza P Kasemodel; Paliares, Isabella Cristina; de Araújo, Maria Izabel P Kasemodel; Novo, Neil Ferreira; Cadaval, Ricardo Augusto M; Martinez, José Eduardo

2015-01-01

The association of fibromyalgia (FM) and systemic lupus erythematosus (SLE) have been investigated, with conflicting results regarding the impact of a condition on the other. To determine the frequency of FM in a sample of patients with SLE treated at the Hospital Complex of Sorocaba (CHS) and the impact of FM in SLE activity and quality of life, as well as of SLE in FM. Descriptive and correlational study. Patients who met the American College of Rheumatology (ACR) criteria for SLE and/or FM were included. The total sample was divided into three groups: FM/SLE (patients with association of SLE and FM), SLE (SLE patients only) and FM (FM patients only). The following variables were used: Fibromyalgia Impact Questionnaire (FIQ), activity index of SLE (SLEDAI), Indices of Diagnostic Criteria for Fibromyalgia 2010 (SSI end GPI) and SF-36. The prevalence of patients with FM among SLE patients was 12%. FIQ showed no difference between groups, indicating that SLE did not affect the impact caused by FM alone. The presence of FM in SLE patients did not influence the clinical activity of this disease. A strong impact of FM on the quality of life in patients with SLE was observed; the opposite was not observed. The prevalence of FM observed in SLE patients is 12%. The presence of FM adversely affects the quality of life of patients with SLE. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

[Anti-Müllerian hormone levels as a predictor of ovarian reserve in systemic lupus erythematosus patients: a review].

PubMed

Gasparin, Andrese Aline; Chakr, Rafael Mendonça da Silva; Brenol, Claiton Viegas; Palominos, Penélope Ester; Xavier, Ricardo Machado; Souza, Lucian; Brenol, João Carlos Tavares; Monticielo, Odirlei André

2015-01-01

The anti-Müllerian hormone (AMH) is secreted from granulosa cells of growing ovarian follicles and appears to be the best endocrine marker capable of estimating ovarian reserve. Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women of reproductive age and may negatively affect their fertility due to disease activity and the treatments used. Recently, several studies assessed AMH levels to understand the real impact of SLE and its treatment on fertility. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

Phase I, randomized, double-blind, placebo-controlled, multiple intravenous, dose-ascending study of sirukumab in cutaneous or systemic lupus erythematosus.

PubMed

Szepietowski, Jacek C; Nilganuwong, Surasak; Wozniacka, Anna; Kuhn, Annegret; Nyberg, Filippa; van Vollenhoven, Ronald F; Bengtsson, Anders A; Reich, Adam; de Vries, Dick E; van Hartingsveldt, Bart; Robinson, Donald W; Gordon, Robert; Hsu, Benjamin

2013-10-01

We undertook a 2-part, phase I, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of multiple intravenous infusions of sirukumab, a human anti-interleukin-6 monoclonal antibody, in patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE). In part A, patients with histologically confirmed CLE were randomized to 4 infusions of placebo or 1, 4, or 10 mg/kg sirukumab every 2 weeks. In part B, SLE patients diagnosed according to American College of Rheumatology criteria with a score of 5-12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index were randomized to 4 infusions of placebo or 10 mg/kg sirukumab every 2 weeks. We treated 31 CLE patients (23 with sirukumab, 8 with placebo) and 15 SLE patients (10 with sirukumab, 5 with placebo). Adverse events (AEs) occurred more often with sirukumab than placebo in CLE patients (91% versus 63%) and in SLE patients (90% versus 80%). Sirukumab led to sustained, dose-independent decreases in white blood cell counts, absolute neutrophil counts (neutropenia), and platelet counts (thrombocytopenia) and to minor elevations in total cholesterol levels. The majority of infections were mild respiratory infections. which were reported similarly across CLE cohorts but more often in sirukumab-treated than in placebo-treated SLE patients. Two serious AEs of infection occurred (pneumonia in the 10 mg/kg-treated group and iatrogenic wound infection in the 4 mg/kg-treated group). Sirukumab showed linear pharmacokinetics in CLE patients. Systemic exposure and half-life were comparable between CLE and SLE patients. No patient developed antibodies to sirukumab through 22 weeks. C-reactive protein and serum amyloid A mean concentrations were suppressed with sirukumab from week 1 to week 14. Treatment with intravenous sirukumab infusions was generally well tolerated in both CLE and SLE patients with mild, stable, active disease. Sirukumab demonstrated linear pharmacokinetics over the dose range studied and comparable systemic exposure and half-life in CLE and SLE patients. Copyright © 2013 by the American College of Rheumatology.

Urinary angiostatin, CXCL4 and VCAM-1 as biomarkers of lupus nephritis.

PubMed

Mok, Chi Chiu; Soliman, Samar; Ho, Ling Yin; Mohamed, Fatma A; Mohamed, Faten Ismail; Mohan, Chandra

2018-01-11

The aim was to study urinary angiostatin, CXC chemokine ligand 4 (CXCL4) and vascular cell adhesion molecule-1 (VCAM-1) as biomarkers of renal disease in systemic lupus erythematosus (SLE). Patients who fulfilled ≥ 4 American College of Rheumatology (ACR) criteria for SLE with active renal, active non-renal or inactive disease, and a group of healthy controls were studied. Urine samples were assayed for angiostatin, CXCL4 and VCAM-1 by ELISA, and normalized by creatinine. Receiver operating characteristic analysis was performed to obtain the best cutoff values to calculate the performance of these markers in differentiating the different groups of patients as compared to anti-double-stranded DNA (anti-dsDNA) and complement C3. Correlation between these urinary biomarkers and various renal parameters was also tested. Patients with SLE (n = 227; 80 with inactive SLE, 67 with active non-renal disease and 80 with active renal disease; 94% women; age 39.2 ± 13.8 years) and 53 controls (96% women) were studied. All were ethnic Chinese. Urinary angiostatin, CXCL4 and VCAM-1 (normalized for creatinine) were significantly higher in patients with active renal disease than in patients with active non-renal disease, patients with inactive SLE and controls. These markers correlated significantly with total SLE disease activity index (SLEDAI) and renal SLEDAI scores, and with the urinary protein-to-creatinine ratio. Urine angiostatin exhibited higher specificity and sensitivity in differentiating active renal from active non-renal SLE (area under the curve (AUC) 0.87) than serum anti-dsDNA/C3. Urine CXCL4 (AUC 0.64) and VCAM-1 (AUC 0.73), on the other hand, performed similarly to anti-dsDNA/C3. All three markers performed comparably to anti-dsDNA/C3 in distinguishing active from inactive SLE. In a subgroup of 68 patients with paired renal biopsy, the urinary levels of these proteins did not differ significantly between the proliferative and non-proliferative types of lupus nephritis. Urinary CXCL4 and VCAM-1 correlated significantly with the histologic activity score, and urinary angiostatin correlated significantly with proteinuria in this subgroup. Urinary angiostatin, CXCL4 and VCAM-1 are potential biomarkers for SLE, in particular lupus nephritis. Further longitudinal studies are necessary to delineate the performance of these markers in predicting renal flares and prognosis in SLE patients.

Differences in Long-Term Disease Activity and Treatment of Adult Patients With Childhood-and Adult-Onset Systemic Lupus Erythematosus

PubMed Central

Hersh, Aimee O.; von Scheven, Emily; Yazdany, Jinoos; Panopalis, Pantelis; Trupin, Laura; Julian, Laura; Katz, Patricia; Criswell, Lindsey A.; Yelin, Edward

2009-01-01

Objective To compare differences in long-term outcome between adults with childhood-onset (age at diagnosis <18 years) systemic lupus erythematosus (SLE) and with adult-onset SLE. Methods Data were derived from the University of California Lupus Outcomes Study, a longitudinal cohort of 885 adult subjects with SLE (90 childhood-onset [cSLE], 795 adult-onset [aSLE]). Baseline and 1-year followup data were obtained via structured 1-hour telephone interviews conducted between 2002 and 2006. Using self-report data, differences in organ involvement and disease morbidity, current disease status and activity, past and current medication use, and number of physician visits were compared, based on age at diagnosis of SLE. Results Average disease duration for the cSLE and aSLE subgroups was 16.5 and 13.4 years, respectively, and mean age at followup was 30.5 and 49.9 years, respectively. When compared with aSLE subjects, cSLE subjects had a higher frequency of SLE-related renal disease, whereas aSLE subjects were more likely to report a history of pulmonary disease. Rates of clotting disorders, seizures, and myocardial infarction were similar between the 2 groups. At followup, cSLE subjects had lower overall disease activity, but were more likely to be taking steroids and other immunosuppressive therapies. The total number of yearly physician visits was similar between the 2 groups, although cSLE subjects had a higher number of nephrology visits. Conclusion This study demonstrates important differences in the outcomes of patients with cSLE and aSLE, and provides important prognostic information about long-term SLE disease activity and treatment. PMID:19116979

Association between Secondary and Primary Sjögren's Syndrome in a Large Collection of Lupus Families.

PubMed

Aggarwal, Rachna; Anaya, Juan-Manuel; Koelsch, Kristi A; Kurien, Biji T; Scofield, R Hal

2015-01-01

Objective. Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) share clinical and immunogenetic features and may occur together. We undertook this study to determine the risk of primary SS among SLE-unaffected relatives of SLE patients and whether or not primary and secondary SS tended to occur in the same families. Methods. We collected clinical and serological data on 2694 SLE patients, 7390 SLE-unaffected relatives of the SLE patients, and 1470 matched controls. Results. Of the 2694 subjects with SLE, 548 had secondary SS, while 71 of their 7390 SLE-unaffected relatives had primary SS. None of the 1470 controls had SS as defined herein (p = 5 × 10(-5) compared to SLE-unaffected relatives). Of the 71 SLE-unaffected relatives with primary SS, 18 (25.3%) had an SLE-affected family member with secondary SS, while only 530 of the 7319 (7.2%) SLE-unaffected relatives without SS did so (p = 1 × 10(-8)). Conclusion. Among families identified for the presence of SLE, primary and secondary SS tend to occur within the same families. These results highlight the commonalities between these two forms of SS, which in fact correspond to the same disease.

Clinical and Serologic Features in Patients With Incomplete Lupus Classification Versus Systemic Lupus Erythematosus Patients and Controls.

PubMed

Aberle, Teresa; Bourn, Rebecka L; Munroe, Melissa E; Chen, Hua; Roberts, Virginia C; Guthridge, Joel M; Bean, Krista; Robertson, Julie M; Sivils, Kathy L; Rasmussen, Astrid; Liles, Meghan; Merrill, Joan T; Harley, John B; Olsen, Nancy J; Karp, David R; James, Judith A

2017-12-01

Incomplete lupus erythematosus (ILE) involves clinical and/or serologic manifestations consistent with but insufficient for systemic lupus erythematosus (SLE) classification. Because the nature of ILE is poorly understood and no treatment recommendations exist, we examined the clinical manifestations, medication history, and immunologic features in a diverse collection of ILE and SLE patients. Medical records of subjects enrolled in the Lupus Family Registry and Repository were reviewed for medication history and American College of Rheumatology (ACR) classification criteria to identify ILE patients (3 ACR criteria; n = 440) and SLE patients (≥4 ACR criteria; n = 3,397). Participants completed the Connective Tissue Disease Screening Questionnaire. Anticardiolipin and plasma B lymphocyte stimulator (BLyS) were measured by enzyme-linked immunosorbent assay, antinuclear antibodies (ANAs) by indirect immunofluorescence, and 13 autoantibodies by bead-based assays. On average, ILE patients were older than SLE patients (46.2 years versus 42.0 years; P < 0.0001), and fewer ILE patients were African American (23.9% versus 32.2%; P < 0.001). ILE patients exhibited fewer autoantibody specificities than SLE patients (1.3 versus 2.6; P < 0.0001) and were less likely to have ANA titers ≥1:1,080 (10.5% versus 19.5%; P < 0.0001). BLyS levels were intermediate in ILE patients (controls < ILE; P = 0.016; ILE < SLE; P = 0.008). Pericarditis, renal, or neurologic manifestations occurred in 12.5% of ILE patients and were associated with non-European American race/ethnicity (P = 0.012). Hydroxychloroquine use increased over time, but was less frequent in ILE than SLE patients (65.2% versus 83.1%; P < 0.0001). Although usually characterized by milder symptoms, ILE manifestations may require immunomodulatory treatments. Longitudinal studies are necessary to understand how ILE affects organ damage and future SLE risk, and to delineate molecular pathways unique to ILE. © 2017, American College of Rheumatology.

Differences in quality of life determinants according to the presence of fibromyalgia in middle-aged female patients with systemic lupus erythematosus: a multicenter, cross-sectional, single-ethnicity cohort.

PubMed

Moon, Su-Jin; Kang, Kwi Young; Kwok, Seung-Ki; Ju, Ji Hyeon; Hong, Yeon-Sik; Park, Sung-Hwan; Jeon, Chan Hong; Choi, Sang Tae; Song, Jung-Soo; Min, Jun-Ki

2018-06-01

The purpose of this study was to identify whether determinants of health-related quality of life (HRQoL) in middle-aged female patients with systemic lupus erythematosus (SLE) differed according to the presence or absence of fibromyalgia. One hundred and fifty-two patients with SLE and 139 healthy controls (HCs) completed the Medical Outcomes Study 36-Item Short Form (SF-36) and EuroQol EQ-5D questionnaires about HRQoL. Disease activity and cumulative disease damage were assessed with standard indices. Sleep quality was assessed using the Korean version of the Pittsburgh Sleep Quality Index (K-PSQI). The mean EQ-5D and physical and mental components of SF-36 were lower in SLE patients with fibromyalgia (n = 41) than in those without fibromyalgia (n = 111) and HCs. The scores in all eight domains of the SF-36 were lower in SLE patients with fibromyalgia than in patients without fibromyalgia and HCs. Poor sleep (defined as a K-PSQI > 5) was reported by 85% of SLE patients with fibromyalgia, by 51% of patients without fibromyalgia, and by 33% of HCs. Multivariate logistic regression analysis showed that lower educational level, cumulative organ damage severity and poor sleep quality were independent determinants of HRQoL in SLE patients with fibromyalgia, whereas disease activity, sleep quality and depressive mood were independent determinants of HRQoL in those without fibromyalgia. Poor sleep quality is the common independent risk factor for poor HRQoL in both middle-aged SLE patients with fibromyalgia and without fibromyalgia. Sleep quality improvement may improve HRQoL in female SLE patients, even in those without fibromyalgia. © 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Prevalence of premature ovarian failure in systemic lupus erythematosus patients treated with immunosuppressive agents in Thailand.

PubMed

Akawatcharangura, P; Taechakraichana, N; Osiri, M

2016-04-01

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects most women of reproductive age. The prevalence of premature ovarian failure (POF) in SLE patients is higher than that in the general population. However, the data on this condition are limited in Asian countries. To determine the prevalence and associated factors of POF in SLE patients who received immunosuppressive therapy. Women aged 18-40 years who were diagnosed with SLE according to the 1997 revised criteria for the classification of SLE or patients with biopsy-proven lupus nephritis were evaluated. All patients had received at least one of the following immunosuppressive agents: cyclophosphamide (CYC), azathioprine, mycophenolate mofetil, chlorambucil or cyclosporine for more than six months. POF was diagnosed in those who had sustained amenorrhea for more than six consecutive months, with a level of estradiol ≤ 110 pmol/L (30 pg/mL) and follicle stimulating hormone ≥40 IU/L. Ninety two SLE patients were included in this study. Mean age at enrollment was 30 ± 6.9 years and disease duration was 103 ± 67.5 months. The mean Systemic Lupus International Collaborating Clinics/ American College of Rheumatology (SLICC/ACR) damage index was 1.7 ± 1.7. Seventy five patients (82%) had lupus nephritis. Sixty four patients (70%) received CYC. Eleven patients (12%) with POF were observed. For the binary logistic regression model, CYC cumulative dosage of more than 10 g was the only independent risk factor of POF (hazard ratio 17.0, 95% CI 1.96-147.72, p = 0.01). From our data, 12% of SLE patients developed POF. A cumulative dose of CYC of more than 10 g was the only risk factor for POF. To prevent these events, systematic evaluation and early recognition of POF should be promoted in the care of SLE patients. © The Author(s) 2015.

European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus

PubMed Central

Chung, Sharon A.; Tian, Chao; Taylor, Kimberly E.; Lee, Annette T.; Ortmann, Ward A.; Hom, Geoffrey; Graham, Robert R.; Nititham, Joanne; Kelly, Jennifer A.; Morrisey, Jean; Wu, Hui; Yin, Hong; Alarcón-Riquelme, Marta E.; Tsao, Betty P.; Harley, John B.; Gaffney, Patrick M.; Moser, Kathy L.; Manzi, Susan; Petri, Michelle; Gregersen, Peter K.; Langefeld, Carl D.; Behrens, Timothy W.; Seldin, Michael F.; Criswell, Lindsey A.

2009-01-01

Objective To determine whether genetic substructure in European-derived populations is associated with specific manifestations of systemic lupus erythematosus (SLE), including mucocutaneous phenotypes, autoantibody production, and renal disease. Methods SLE patients of European descent (n=1754) from 8 case collections were genotyped for over 1,400 ancestry informative markers that define a north/south gradient of European substructure. Based on these genetic markers, we used the STRUCTURE program to characterize each SLE patient in terms of percent northern (vs. southern) European ancestry. Non-parametric methods, including tests of trend, were used to identify associations between northern European ancestry and specific SLE manifestations. Results In multivariate analyses, increasing levels of northern European ancestry were significantly associated with photosensitivity (ptrend=0.0021, OR for highest quartile of northern European ancestry compared to lowest quartile 1.64, 95% CI 1.13–2.35) and discoid rash (ptrend=0.014, ORhigh-low 1.93, 95% CI 0.98–3.83). In contrast, northern European ancestry was protective for anticardiolipin (ptrend=1.6 × 10−4, ORhigh-low 0.46, 95% CI 0.30–0.69) and anti-dsDNA (ptrend=0.017, ORhigh-low 0.67, 95% CI 0.46–0.96) autoantibody production. Conclusions This study demonstrates that specific SLE manifestations vary according to northern vs. southern European ancestry. Thus, genetic ancestry may contribute to the clinical heterogeneity and variation in disease outcomes among SLE patients of European descent. Moreover, these results suggest that genetic studies of SLE subphenotypes will need to carefully address issues of population substructure due to genetic ancestry. PMID:19644962

Preliminary Criteria for Global Flares in Childhood-Onset Systemic Lupus Erythematosus

PubMed Central

Brunner, Hermine I.; Mina, Rina; Pilkington, Clarissa; Beresford, Michael W.; Reiff, Andreas; Levy, Deborah M.; Tucker, Lori B.; Eberhard, B. Anne; Ravelli, Angelo; Schanberg, Laura E.; Saad-Magalhaes, Claudia; Higgins, Gloria C.; Onel, Karen; Singer, Nora G.; von Scheven, Emily; Itert, Lukasz; Klein-Gitelman, Marisa S.; Punaro, Marilynn; Ying, Jun; Giannini, Edward H.

2011-01-01

Objectives To develop widely acceptable preliminary criteria of global flare for childhood-onset SLE (cSLE). Methods Pediatric rheumatologists (n=138) rated a total of 358 unique patient profiles (PP) with information about the cSLE flare descriptors (cSLE-FD) from two consecutive visits: patient global assessment of well-being, physician global assessment of disease activity (MD-global), health-related quality of life, anti-dsDNA antibodies, disease activity index score, protein/creatinine (P/C) ratio, complement levels and ESR. Based on 2996 rater responses about the course of cSLE (baseline vs. follow-up) the accuracy (sensitivity, specificity, area under the receiver operating characteristic curve) of candidate flare criteria was assessed. An international consensus conference was held to rank these candidate flare criteria as per the ACR-recommendations for the development and validation of criteria sets. Results The highest ranked candidate criteria considered absolute changes (Δ) of the SLEDAI or BILAG, MD-global, P/C ratio, and ESR; Flare scores can be calculated [0.5 × ΔSLEDAI + 0.45 × ΔP/C ratio + 0.5 × ΔMD-global + 0.02 × ΔESR], where values ≥ 1.04 are reflective of a flare. Similarly, BILAG-based flare scores [0.4 × ΔBILAG + 0.65 × ΔP/C ratio + 0.5 × ΔMD-global + 0.02 × ΔESR] of ≥ 1.15 were diagnostic of a flare. Flare scores increase with flare severity. Conclusions Consensus has been reached on preliminary criteria for global flares in cSLE. Further validation studies are needed to confirm the usefulness of the cSLE flare criteria in research and for clinical care. PMID:21618452

Serological and molecular analysis of parvovirus B19 infection in Mayan women with systemic lupus erythematosus in Mexico.

PubMed

Valencia Pacheco, Guillermo; Nakazawa Ueji, Yumi E; Rodríguez Dzul, Edwin A; Angulo Ramírez, Angélica V; López Villanueva, Ricardo F; Quintal Ortiz, Irma G; Rosado Paredes, Elsy P

2017-09-30

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that mainly affects women, characterized by the production of autoantibodies. Its causal agent is unknown, but the combination of environmental, hormonal and genetic factors may favor the development of the disease. Parvovirus B19 has been associated with the development of SLE, since it induces the production of anti-single stranded DNA antibodies. It is unknown whether PV-B19 infection is an environmental factor that trigger or reactivate SLE in the Mexican Mayan population. A preliminary serological and molecular study of PV-B19 infection in Mayan women with established SLE was done. IgG and IgM anti PV-B19 were evaluated in 66 SLE patients and 66 control subjects, all women of Mayan origin. Viral DNA and viral load were analyzed by qPCR. Insignificant levels of IgM were observed in 14.3% (4/28) of the patients and 11.4% (4/35) of control subjects. IgG was detected in 82.1% (23/28) of the patients and 82.9% (29/35) of control subjects, but were significantly higher in patients. Viral DNA was found in 86.0% (57/66) of the patients and 81.0% (54/66) of control subjects. Viral load, quantified in 28/66 patients and 31/66 controls which were positive for IgM and IgG, was significantly higher in controls. The high prevalence of PV-B19 in Yucatan, and the presence of IgM, IgG, and viral load in Mayan women with established SLE suggest that PV-B19 infection could be an environmental factor to trigger or reactivate SLE.

Serological and molecular analysis of parvovirus B19 infection in Mayan women with systemic lupus erythematosus in Mexico

PubMed Central

Nakazawa Ueji, Yumi E; Rodríguez Dzul, Edwin A; Angulo Ramírez, Angélica V; López Villanueva, Ricardo F; Quintal Ortiz, Irma G; Rosado Paredes, Elsy P

2017-01-01

Abstract Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that mainly affects women, characterized by the production of autoantibodies. Its causal agent is unknown, but the combination of environmental, hormonal and genetic factors may favor the development of the disease. Parvovirus B19 has been associated with the development of SLE, since it induces the production of anti-single stranded DNA antibodies. It is unknown whether PV-B19 infection is an environmental factor that trigger or reactivate SLE in the Mexican Mayan population. Aim: A preliminary serological and molecular study of PV-B19 infection in Mayan women with established SLE was done. Methods: IgG and IgM anti PV-B19 were evaluated in 66 SLE patients and 66 control subjects, all women of Mayan origin. Viral DNA and viral load were analyzed by qPCR. Results: Insignificant levels of IgM were observed in 14.3% (4/28) of the patients and 11.4% (4/35) of control subjects. IgG was detected in 82.1% (23/28) of the patients and 82.9% (29/35) of control subjects, but were significantly higher in patients. Viral DNA was found in 86.0% (57/66) of the patients and 81.0% (54/66) of control subjects. Viral load, quantified in 28/66 patients and 31/66 controls which were positive for IgM and IgG, was significantly higher in controls. Conclusion: The high prevalence of PV-B19 in Yucatan, and the presence of IgM, IgG, and viral load in Mayan women with established SLE suggest that PV-B19 infection could be an environmental factor to trigger or reactivate SLE. PMID:29213152

Role of YpeB in Cortex Hydrolysis during Germination of Bacillus anthracis Spores

PubMed Central

Bernhards, Casey B.

2014-01-01

The infectious agent of the disease anthrax is the spore of Bacillus anthracis. Bacterial spores are extremely resistant to environmental stresses, which greatly hinders spore decontamination efforts. The spore cortex, a thick layer of modified peptidoglycan, contributes to spore dormancy and resistance by maintaining the low water content of the spore core. The cortex is degraded by germination-specific lytic enzymes (GSLEs) during spore germination, rendering the cells vulnerable to common disinfection techniques. This study investigates the relationship between SleB, a GSLE in B. anthracis, and YpeB, a protein necessary for SleB stability and function. The results indicate that ΔsleB and ΔypeB spores exhibit similar germination phenotypes and that the two proteins have a strict codependency for their incorporation into the dormant spore. In the absence of its partner protein, SleB or YpeB is proteolytically degraded soon after expression during sporulation, rather than escaping the developing spore. The three PepSY domains of YpeB were examined for their roles in the interaction with SleB. YpeB truncation mutants illustrate the necessity of a region beyond the first PepSY domain for SleB stability. Furthermore, site-directed mutagenesis of highly conserved residues within the PepSY domains resulted in germination defects corresponding to reduced levels of both SleB and YpeB in the mutant spores. These results identify residues involved in the stability of both proteins and reiterate their codependent relationship. It is hoped that the study of GSLEs and interacting proteins will lead to the use of GSLEs as targets for efficient activation of spore germination and facilitation of spore cleanup. PMID:25022853

Murine Lupus Susceptibility Locus Sle1a Requires the Expression of two Subloci to Induce Inflammatory T Cells

PubMed Central

Cuda, Carla M.; Zeumer, Leilani; Sobel, Eric S.; Croker, Byron P.; Morel, Laurence

2010-01-01

The NZM2410-derived Sle1a lupus susceptibility locus induces activated autoreactive CD4+ T cells and reduces the number and function of Foxp3+ regulatory T cells. In this study, we first showed that Sle1a contributes to autoimmunity by increasing anti-nuclear antibody production when expressed on either NZB or NZW heterozygous genomes, and by enhancing the chronic graft vs. host disease response indicating an expansion of the autoreactive B cell pool. Screening two non-overlapping recombinants, the Sle1a.1 and Sle1a.2 intervals that cover the entire Sle1a locus, revealed that both Sle1a.1 and Sle1a.2 were necessary for the full Sle1a phenotype. Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4+ T cell activation as well as Treg differentiation and function. Sle1a.2 also increased the production of autoreactive B cells. Since the Sle1a.1 and Sle1a.2 intervals contain only one and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells. These results also demonstrate that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the co-expression of multiple genetic variants with individual weak effects. PMID:20445563

Murine Lupus Susceptibility Locus Sle2 Activates DNA-Reactive B Cells through Two Sub-Loci with Distinct Phenotypes

PubMed Central

Zeumer, Leilani; Sang, Allison; Niu, Haitao; Morel, Laurence

2010-01-01

The NZM2410-derived Sle2 lupus susceptibility locus induces an abnormal B cell differentiation which most prominently leads to the expansion of autoreactive B1a cells. We have mapped the expansion of B1a cells to three Sle2 sub-loci, Sle2a, Sle2b, and Sle2c. Sle2 also enhances the breach of B cell tolerance to nuclear antigens in the 56R anti-DNA immunoglobulin transgenic (Tg) model. This study used the Sle2 sub-congenic strains to map the activation of 56R Tg B cells. Sle2c strongly sustained the breach of tolerance and the activation of anti-DNA B cells. The production of Tg-encoded anti-DNA antibodies was more modest in Sle2a expressing mice, but Sle2a was responsible for the recruitment for Tg B cells to the marginal zone, a phenotype that has been found for 56R Tg B cells in mice expressing the whole Sle2 interval. In addition, Sle2a promoted the production of endogenously encoded anti-DNA antibodies. Overall, this study showed that at least two Sle2 genes are involved in the activation of anti-DNA B cells, and excluded more than two-thirds of the Sle2 interval from contributing to this phenotype. This constitutes an important step toward the identification of novel genes that play a critical role in B cell tolerance. PMID:21270826

Elevated serum BAFF levels in patients with localized scleroderma in contrast to other organ-specific autoimmune diseases.

PubMed

Matsushita, Takashi; Hasegawa, Minoru; Matsushita, Yukiyo; Echigo, Takeshi; Wayaku, Takamasa; Horikawa, Mayuka; Ogawa, Fumihide; Takehara, Kazuhiko; Sato, Shinichi

2007-02-01

Serum levels of B-cell activating factor belonging to the tumor necrosis factor family (BAFF), a potent B-cell survival factor, are elevated in patients with systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis and systemic sclerosis (SSc). The objective of this study was to determine serum BAFF levels and relate the results to the clinical features in patients with organ-specific autoimmune diseases of the skin, such as localized scleroderma and autoimmune bullous diseases. Serum BAFF levels were examined by enzyme-linked immunosorbent assay in 44 patients with localized scleroderma, 20 with pemphigus vulgaris/pemphigus foliaceus, 20 with bullous pemphigoid and 30 healthy controls. Twenty patients with SSc and 20 with SLE were also examined as disease controls. Serum BAFF levels were elevated in localized scleroderma patients compared with healthy controls. Concerning localized scleroderma subgroups, patients with generalized morphea, the severest form of localized scleroderma, had higher serum BAFF levels than linear scleroderma or morphea patients. The BAFF levels of generalized morphea were comparable with those of SSc or SLE. Furthermore, serum BAFF levels correlated positively with antihistone antibody levels and the severity of skin lesion as well as the number of skin lesions. By contrast, serum BAFF levels were not significantly elevated in patients with pemphigus or pemphigoid. These results suggest that BAFF may be contributing to autoimmunity and disease development in localized scleroderma.

C1q complement component and -antibodies reflect SLE activity and kidney involvement.

PubMed

Horák, P; Hermanová, Z; Zadrazil, J; Ciferská, H; Ordeltová, M; Kusá, L; Zurek, M; Tichý, T

2006-07-01

The role of the complement system in the pathogenesis of systemic diseases is very ambivalent. In systemic lupus erythematosus (SLE), many abnormalities in the activation of the complement system have been reported. The most important antibodies formed against the complement system in SLE are the ones associated with the C1q component. The aim of this study was to assess separately the anti-C1q antibodies and C1q component in the serum from 65 patients with SLE, then in individuals with (n=33) and without (n=32) lupus nephritis and with active (n=36) and nonactive (n=29) form of the disease (European Consensus Lupus Activity Measurement, ECLAM>3, ECLAM

Neurocognitive Dysfunction in Systemic Lupus Erythematosus: Association with Antiphospholipid Antibodies, Disease Activity and Chronic Damage

PubMed Central

Conti, Fabrizio; Alessandri, Cristiano; Perricone, Carlo; Scrivo, Rossana; Rezai, Soheila; Ceccarelli, Fulvia; Spinelli, Francesca Romana; Ortona, Elena; Marianetti, Massimo; Mina, Concetta; Valesini, Guido

2012-01-01

Introduction Systemic lupus erythematosus (SLE) is characterized by frequent neuropsychiatric involvement, which includes cognitive impairment (CI). We aimed at assessing CI in a cohort of Italian SLE patients by using a wide range of neurocognitive tests specifically designed to evaluate the fronto-subcortical dysfunction. Furthermore, we aimed at testing whether CI in SLE is associated with serum autoantibodies, disease activity and chronic damage. Methods Fifty-eight consecutive patients were enrolled. Study protocol included data collection, evaluation of serum levels of ANA, anti-dsDNA, anti-cardiolipin, anti-β2-glycoprotein I, anti-P ribosomal, anti-endothelial cell, and anti-Nedd5 antibodies. SLEDAI-2000 and SLICC were used to assess disease activity and chronic damage. Patients were administered a test battery specifically designed to detect fronto-subcortical dysfunction across five domains: memory, attention, abstract reasoning, executive function and visuospatial function. For each patient, the raw scores from each test were compared with published norms, then transformed into Z scores (deviation from normal mean), and finally summed in the Global Cognitive Dysfunction score (GCDs). Results Nineteen percent of patients had mild GCDs impairment (GCDs 2–3), 7% moderate (GCDs 4–5) and 5% severe (GCDs≥6). The visuospatial domain was the most compromised (MDZs = −0.89±1.23). Anti-cardiolipin IgM levels were associated with visuospatial domain impairment (r = 0.331, P = 0.005). SLEDAI correlated with GCDs, and attentional and executive domains; SLICC correlated with GCDs, and with visuospatial and attentional domains impairment. Conclusions Anti-phospholipids, disease activity, and chronic damage are associated with cognitive dysfunction in SLE. The use of a wide spectrum of tests allowed for a better selection of the relevant factors involved in SLE cognitive dysfunction, and standardized neuropsychological testing methods should be used for routine assessment of SLE patients. PMID:22461897

Incidence and risk factors of thromboembolism in systemic lupus erythematosus: a comparison of three ethnic groups.

PubMed

Mok, Chi Chiu; Tang, Sandy Shuk Kuen; To, Chi Hung; Petri, Michelle

2005-09-01

To compare the incidence and risk factors for thromboembolic events in systemic lupus erythematosus (SLE) patients of different ethnic backgrounds. SLE patients who were newly diagnosed or were referred within 6 months of diagnosis between 1996 and 2002 were prospectively followed up for the occurrence of thromboembolic events. Cumulative hazard and risk factors for thromboembolism were evaluated and compared among patients of different ethnic origins. We studied 625 patients who fulfilled the American College of Rheumatology criteria for SLE (89% women): 258 Chinese, 140 African Americans, and 227 Caucasians. The mean +/- SD age at SLE diagnosis was 35.7 +/- 14 years. After a followup of 3,094 patient-years, 48 arterial events and 40 venous events occurred in 83 patients. The overall incidence of arterial and venous thromboembolism was 16/1,000 patient-years and 13/1,000 patient-years, respectively. The cumulative hazard of arterial events at 60 months after the diagnosis of SLE was 8.5%, 8.1%, and 5.1% for the Chinese, African Americans, and Caucasians, respectively. The corresponding cumulative risk of venous events was 3.7%, 6.6%, and 10.3%, respectively (P = 0.008 for Chinese versus Caucasians, by log rank test). Smoking, obesity, antiphospholipid antibodies, and use of antimalarial agents and exogenous estrogens were less frequent in the Chinese patients. In Cox regression models, low levels of high-density lipoprotein (HDL) cholesterol, Chinese ethnicity, oral ulcers, and serositis predicted arterial events, whereas male sex, low levels of HDL cholesterol, antiphospholipid antibodies, non-Chinese ethnicity, obesity, renal disease, and hemolytic anemia predicted venous events. There are ethnic differences in the incidence of arterial and venous thromboembolism in patients with SLE that cannot be fully explained by the clinical factors studied. Further evaluation of other genetic and immunologic factors is warranted.

Clinical profile and direct medical cost of care of adults presenting with systemic lupus erythematosus in Italy.

PubMed

Doria, Andrea; Iaccarino, Luca; La Montagna, Giovanni; Mathieu, Alessandro; Piga, Matteo; Galeazzi, Mauro; Iuliano, Annamaria; Maurel, Frédérique B; Garofano, Anna M; Perna, Alessandra G; Porcasi, Rolando E

2015-01-01

To determine the clinical profile and estimate the annual direct medical cost of care of adult patients with active, autoantibody positive systemic lupus erythematosus (SLE) in Italy. A two-year, retrospective, multicentre, observational study was conducted from January to May 2011. Patients' characteristics, SLE disease activity and severity, rate of flares, healthcare consumption (e.g. medications, etc.) were evaluated. Medical costs were assessed from the Italian National Health Insurance perspective. Four centres enrolled 96 eligible patients, including 85.4% women. Patients were equally stratified per disease severity (severe SLE: 51%). The mean (SD) age was 42.9 (13.8) years. At baseline, SLE duration was 12.6 (7.2) years. The mean (SD) SELENA-SLEDAI score was higher in severe than in non-severe patients 9.2 (6.4) vs. 3.3 (3.1) (p<0.001). The mean (SD) SLICC/ACR index score was similar in the two subgroups: 0.4 (0.8) vs. 0.3 (0.8). Over the study period, severe patients experienced on average 0.73 (0.56) flares/year and non-severe patients 0.57 (0.63). The annual medical cost was 1.6 times higher in severe than in non-severe patients (€2,101 vs. €1,320; p=0.031). The cost of medications was also 2.5 times higher in severe patients (€1101 vs. €445, p=0.007). Low C3/C4 complement levels and each severe flare incremented the annual cost of €550 (p=0.011) and €465 (p=0.02), respectively. The medical cost of SLE in Italy is related to disease severity and flares. Medications identified as the main cost drivers, and low C3/C4 complement levels and severe flares as the main cost predictors, increased significantly the cost of SLE management.

Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B-cell subsets with clinical manifestations in systemic lupus erythematosus.

PubMed

Salazar-Camarena, D C; Ortiz-Lazareno, P C; Cruz, A; Oregon-Romero, E; Machado-Contreras, J R; Muñoz-Valle, J F; Orozco-López, M; Marín-Rosales, M; Palafox-Sánchez, C A

2016-05-01

B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) signaling pathways regulate B-cell survival through interactions with their receptors BAFF-R, TACI and BCMA. We evaluated the association of these ligands/receptors on B-cell subsets according to clinical manifestations of systemic lupus erythematosus (SLE). BAFF and APRIL serum concentrations were measured in 30 SLE patients by enzyme-linked immunosorbent assay. The BAFF-R, TACI and BCMA expression was analyzed on each B cell subset (CD19 + CD27-CD38-/ + naïve; CD19 + CD27 + CD38-/ + memory; CD19 + CD27-CD38 + + immature and CD19 + CD27 + CD38 + + plasma cells) by flow cytometry, and compared among patients with different clinical manifestations as well as healthy controls (HCs). Serum BAFF and APRIL levels were high in SLE patients and correlated with the Mex-SLEDAI disease activity index (r = 0.584; p = 0.001 and r = 0.456; p = 0.011, respectively). The SLE patients showed an increased proportion of memory and plasma B cells (p < 0.05). BAFF-R, TACI and BCMA expression in SLE patients was decreased in almost all B cell subsets compared to HCs (p < 0.05). A lower BCMA expression was associated with severe disease activity, glomerulonephritis, serositis and hemolytic anemia (p < 0.01). BCMA expression showed a negative correlation with Mex-SLEDAI score (r = -0.494, p = 0.006). Decreased BCMA expression on peripheral B cells according to severe disease activity suggests that BCMA plays an important regulating role in B-cell hyperactivity and immune tolerance homeostasis in SLE patients. © The Author(s) 2015.

Hemorrhagic Tamponade as Initial Manifestation of Systemic Lupus with Subsequent Refractory and Progressive Lupus Myocarditis Resulting in Cardiomyopathy and Mitral Regurgitation.

PubMed

Marijanovich, Nicole; Halalau, Alexandra

2018-01-01

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a wide range of clinical and serological manifestations. Cardiac disease among patients with SLE is common and can involve the pericardium, myocardium, valves, conduction system, and coronary arteries. We are reporting a case of SLE in a young woman that is unique is unique in that initial symptoms consisted of pericarditis and hemorrhagic tamponade which remained progressive and resistant to aggressive immunosuppressive treatment and led to severe cardiomyopathy (ejection fraction of 25%) and severe (+4) mitral regurgitation. Her immunosuppressive treatment included hydroxychloroquine, high-dose steroids, intravenous immunoglobulins, azathioprine, and mycophenolate mofetil. Her disease progression was felt to be due to underlying uncontrolled SLE because the complement levels remained persistently low throughout the entire course and PET Myocardial Perfusion and Viability study showed stable persistent active inflammation. Eventually, she was treated with cyclophosphamide which led to improvement in ejection fraction to 55% with only mild mitral regurgitation.

Hemorrhagic Tamponade as Initial Manifestation of Systemic Lupus with Subsequent Refractory and Progressive Lupus Myocarditis Resulting in Cardiomyopathy and Mitral Regurgitation

PubMed Central

Marijanovich, Nicole

2018-01-01

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a wide range of clinical and serological manifestations. Cardiac disease among patients with SLE is common and can involve the pericardium, myocardium, valves, conduction system, and coronary arteries. We are reporting a case of SLE in a young woman that is unique is unique in that initial symptoms consisted of pericarditis and hemorrhagic tamponade which remained progressive and resistant to aggressive immunosuppressive treatment and led to severe cardiomyopathy (ejection fraction of 25%) and severe (+4) mitral regurgitation. Her immunosuppressive treatment included hydroxychloroquine, high-dose steroids, intravenous immunoglobulins, azathioprine, and mycophenolate mofetil. Her disease progression was felt to be due to underlying uncontrolled SLE because the complement levels remained persistently low throughout the entire course and PET Myocardial Perfusion and Viability study showed stable persistent active inflammation. Eventually, she was treated with cyclophosphamide which led to improvement in ejection fraction to 55% with only mild mitral regurgitation. PMID:29610699

First Real-World Insights into Belimumab Use and Outcomes in Routine Clinical Care of Systemic Lupus Erythematosus in Germany: Results from the OBSErve Germany Study.

PubMed

Schwarting, Andreas; Schroeder, Johann O; Alexander, Tobias; Schmalzing, Marc; Fiehn, Christoph; Specker, Christof; Perna, Alessandra; Cholmakow-Bodechtel, Constanze; Koscielny, Volker B; Carnarius, Heike

2016-12-01

OBSErve Germany was the first observational study of belimumab as add-on treatment for systemic lupus erythematosus (SLE) in routine clinical care in Germany, retrospectively collecting data from 102 SLE patients, 6 months before and after belimumab initiation. Most patients had moderate or severe SLE and several SLE manifestations. After 6 months of belimumab treatment, 78% of patients showed an improvement in overall disease activity of at least 20% in their physician's judgment and for 42% of patients the improvement was at least 50%. Similar results were observed for the most common manifestations: arthritis, fatigue, rash, alopecia, increased anti-dsDNA antibody levels, and low complement. The SLE Disease Activity Index (SLEDAI/SELENA-SLEDAI) decreased from 10.6 to 5.6 (n = 65), with other indices also showing improvement. A notable dose reduction was seen for concomitant oral corticosteroids, from 13.7 to 7.6 mg/day overall (n = 91), and from 17.5 to 8.6 mg/day in patients with a high corticosteroid dose at belimumab initiation (≥7.5 mg; n = 63). Six patients discontinued belimumab therapy within 6 months. Overall, belimumab showed promising results for SLE patients in real-world settings. After 6 months of belimumab treatment, disease activity and corticosteroid use were reduced. The discontinuation rate was low and belimumab appeared to be well tolerated. Funding GlaxoSmithKline UK.

I too, am America: a review of research on systemic lupus erythematosus in African-Americans

PubMed Central

Williams, Edith M; Bruner, Larisa; Adkins, Alyssa; Vrana, Caroline; Logan, Ayaba; Kamen, Diane; Oates, James C

2016-01-01

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder that can cause significant morbidity and mortality. A large body of evidence has shown that African-Americans experience the disease more severely than other racial-ethnic groups. Relevant literature for the years 2000 to August 2015 were obtained from systematic searches of PubMed, Scopus, and the EBSCOHost platform that includes MEDLINE, CINAHL, etc. to evaluate research focused on SLE in African-Americans. Thirty-six of the 1502 articles were classified according to their level of evidence. The systematic review of the literature reported a wide range of adverse outcomes in African-American SLE patients and risk factors observed in other mono and multi-ethnic investigations. Studies limited to African-Americans with SLE identified novel methods for more precise ascertainment of risk and observed novel findings that hadn't been previously reported in African-Americans with SLE. Both environmental and genetic studies included in this review have highlighted unique African-American populations in an attempt to isolate risk attributable to African ancestry and observed increased genetic influence on overall disease in this cohort. The review also revealed emerging research in areas of quality of life, race-tailored interventions, and self-management. This review reemphasizes the importance of additional studies to better elucidate the natural history of SLE in African-Americans and optimize therapeutic strategies for those who are identified as being at high risk. PMID:27651918

Educational and vocational outcomes of adults with childhood- and adult-onset systemic lupus erythematosus: 9 years of follow-up

PubMed Central

Lawson, Erica F.; Hersh, Aimee O.; Trupin, Laura; von Scheven, Emily; Okumura, Megumi J.; Yazdany, Jinoos; Yelin, Edward H.

2014-01-01

Objective To compare educational and vocational outcomes among adults with childhood-onset SLE (cSLE) and adult-onset SLE (aSLE). Methods Data derive from the 2002–2010 cycles of the Lupus Outcomes Study, a longitudinal cohort of 1204 adult subjects with SLE. Subjects age 18–60 living in the U.S. (N=929) were included in the analysis, and were classified as cSLE if age at diagnosis was <18 years (N=115). Logistic regression was used to assess the unadjusted and adjusted effect of cSLE, gender, race/ethnicity, baseline age, urban or rural location and U.S. region on the likelihood of completing a bachelor’s degree. Generalized estimating equations were used to assess the effect of cSLE, demographics, education, and disease-related factors on the odds of employment, accounting for multiple observations over the study period. Results Subjects with cSLE were on average younger (29±10 versus 44±9 years), with longer disease duration (15±10 versus 11±8 years). Subjects with aSLE and cSLE subjects were equally likely to complete a bachelor’s degree. However, subjects with cSLE were significantly less likely to be employed, independent of demographic and disease characteristics (OR 0.62, 95% CI 0.42–0.91). Conclusion While subjects with SLE are just as likely as those with aSLE to complete college education, cSLE significantly increases the risk of not working in adulthood, even when controlling for disease and demographic factors. Exploring reasons for low rates of employment and providing vocational support may be important to maximize long-term functional outcomes in patients with cSLE. PMID:24877200

MCP-1 in urine as biomarker of disease activity in Systemic Lupus Erythematosus.

PubMed

Barbado, Julia; Martin, Debora; Vega, Luisa; Almansa, Raquel; Gonçalves, Lisbeth; Nocito, Mercedes; Jimeno, Antonio; Ortiz de Lejarazu, Raúl; Bermejo-Martin, Jesus F

2012-11-01

Conventional clinical parameters are not sensitive or specific enough for detecting ongoing disease activity in the Systemic Lupus Erythematosus (SLE). Measurement of cytokines in urine is an encouraging approach to detection of early flares in this disease. Here we have profiled 27 different cytokines, chemokines and celular growth factors in the urine of 48 patients previously diagnosed of SLE as potential biomarkers of disease activity. Correlation analysis with Bonferroni correction showed that MCP-1 was the only immune mediator which levels in urine correlated directly with the SLE Disease Activity Index 2000 (SLEDAI-2K) score (correlation coefficient, p): MCP-1 (0.45,0.003). MCP-1 correlated inversely with levels of C3 complement protein in serum (-0.50,0.001). MCP-1 showed significant higher levels in patients with severe disease activity in comparison with those exhibiting mild activity. Levels of this chemokine were also higher in patients with severe disease activity in comparison with patients with inactive disease and healthy controls. Areas under receiver operating characteristic curves (AUROC) for detection of severe disease (SLEDAI⩾8) was as follows for MCP-1: [AUROC, (IC95%), p]: [0.81 (0.65-0.96) 0.003]. In addition, MCP-1 showed a good result in the AUROC analysis for detecting renal involvement [0.70 (0.52-0.87) 0.050]. When correlation analysis were repeated excluding those patients with active renal disease (n=14), levels of MCP-1 in urine kept on showing a significant positive association with SLEDAI-2K score. In conclusion, multiplex-based cytokine profiling in urine demonstrated the superiority of MCP-1 over a wide range of cytokines as biomarker of disease activity in SLE. Copyright © 2012 Elsevier Ltd. All rights reserved.

Urine β2-microglobulin is associated with clinical disease activity and renal involvement in female patients with systemic lupus erythematosus.

PubMed

Choe, J-Y; Park, S-H; Kim, S-K

2014-12-01

We investigated the association of serum and urine β2-microglobulin (β2MG) with renal involvement and clinical disease activity in systemic lupus erythematosus (SLE). Sixty-four female patients with SLE were enrolled. We assessed SLE disease activity (SLEDAI)-2K and measured serum and urine β2MG levels, as well as complement (C3 and C4) and anti-dsDNA levels. According to the SLEDAI scores, two groups were categorized: low (0-5 of SLEDAI) and high (6-19 of SLEDAI) disease activity groups. The presence of renal involvement was determined by renal SLEDAI score. Statistical analysis was performed using Spearman's correlation analysis, Mann-Whitney U test, multivariate regression analysis, and logistic regression analysis. Urine β2MG levels were significantly different between low and high SLEDAI groups (p = 0.001), but not for serum β2MG levels (p = 0.579). Patients with renal involvement showed higher urine β2MG levels compared to those without renal involvement (p < 0.001), but again there was not a difference in serum β2MG levels (p = 0.228). Urine β2MG was closely associated with SLEDAI (r = 0.363, p = 0.003), renal SLEDAI (r = 0.479, p < 0.001), urine protein/Cr (r = 0.416, p = 0.001), and ESR (r = 0.347, p = 0.006), but not serum β2MG (r = 0.245, p = 0.051). Urine β2MG level was identified as a surrogate for renal involvement (p = 0.009, OR = 1.017, 95% CI 1.004-1.030) and overall disease activity (p = 0.009, OR = 1.020, 95% CI 1.005-1.036). We demonstrated that urine β2MG levels are associated with renal involvement and overall clinical disease activity in SLE. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Disease-specific definitions of vitamin D deficiency need to be established in autoimmune and non-autoimmune chronic diseases: a retrospective comparison of three chronic diseases.

PubMed

Broder, Anna R; Tobin, Jonathan N; Putterman, Chaim

2010-01-01

We compared the odds of vitamin D deficiency in three chronic diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 2 diabetes (T2DM), adjusting for medications, demographics, and laboratory parameters, common to all three diseases. We also designed multivariate models to determine whether different factors are associated with vitamin D deficiency in different racial/ethnic groups. We identified all patients with non-overlapping diagnoses of SLE, RA, and T2DM, with 25-hydroxyvitamin D (25OHD) levels measured between 2000 and 2009. Vitamin D deficiency was defined as 25OHD levels <20 ng/ml, based on previously established definitions. Race/ethnicity was analyzed as African-American non-Hispanic (African-American), Hispanic non-African-American (Hispanic), and Other based on self report. We included 3,914 patients in the final analysis: 123 SLE, 100 RA, and 3,691 T2DM. Among African-Americans the frequency of vitamin D deficiency was 59% in SLE, 47% in RA, and 67% in T2DM. Among Hispanics the frequency of vitamin D deficiency was 67% in SLE, 50% in RA, and 59% in T2DM. Compared with the SLE group, the adjusted odds ratio of vitamin D deficiency was 1.1, 95% CI (0.62, 2.1) in the RA group, and 2.0, 95% CI (1.3, 3.1) in the T2DM group. In the multivariate analysis, older age, higher serum calcium and bisphosphonate therapy were associated with a lower odds of vitamin D deficiency in all three racial/ethnic groups: 1,330 African-American, 1,257 Hispanic, and 1,100 Other. T2DM, serum creatinine, and vitamin D supplementation were associated with vitamin D deficiency in some, but not all, racial/ethnic groups. Vitamin D deficiency is highly prevalent in our patients with SLE, RA, and T2DM. While the odds of vitamin D deficiency are similar in RA and SLE patients in a multivariate analysis, T2DM patients have much higher odds of being vitamin D deficient. Different demographic and laboratory factors may be associated with vitamin D deficiency within different racial/ethnic groups. Therefore, disease-specific and race/ethnicity-specific definitions of vitamin D deficiency need to be established in future studies in order to define goals of vitamin D replacement in patients with autoimmune and non-autoimmune chronic diseases.

Juvenile- and adult-onset systemic lupus erythematosus: a comparative study in a large cohort from the Spanish Society of Rheumatology Lupus Registry (RELESSER).

PubMed

Torrente-Segarra, Vicenç; Salman Monte, Tarek Carlos; Rúa-Figueroa, Iñigo; Sánchez-Alonso, Fernando; López-Longo, Francisco Javier; Galindo-Izquierdo, María; Calvo-Alén, Jaime; Olivé-Marqués, Alejandro; Ibañez-Ruán, Jesús; Horcada, Loreto; Sánchez-Atrio, Ana; Montilla, Carlos; Melero González, Rafael Benito; Díez-Álvarez, Elvira; Martinez-Taboada, Victor; Andreu, José Luis; Fernández-Berrizbeitia, Olaia; Hernández-Beriain, José Ángel; Gantes, Marian; Hernández-Cruz, Blanca; Pecondón-Español, Ángela; Marras, Carlos; Bonilla, Gema; Pego-Reigosa, José M

2017-01-01

We aimed to describe juvenile-onset systemic lupus erythematosus (jSLE) features and to establish its differences compared to adult-onset SLE (aSLE) from a large national database. Data from patients (≥4 ACR criteria) included in Spanish Society of Rheumatology Lupus Registry (RELESSER) were analysed. Sociodemographic, clinical, serological, activity, treatment, cumulative damage, comorbidities and severity data were collected. Patients with disease onset <18 years were described and compared to those with disease onset ≥18 years. We reviewed 3,428 aSLE patients (89.6% women) and 484 jSLE patients (89.8% girls), 93% Caucasian (both groups). Mean age at diagnosis was 38.1±14 and 16.6±6.3 years (p<0.001) and mean age at the end of follow-up was 48.8±14.3 and 31.5±30 years (p<0.001), respectively. jSLE showed significantly more clinical (including lymphadenopathy, fever, malar rash, mucosal ulcers, pericarditis, pleuritis, Raynaud's phenomenon, lupus nephritis, recurrent nephritis, histologic nephritis changes, thrombocytopenia, haemolytic anaemia, thrombotic thrombocytopenic purpura, seizures, lupus headache and organic brain syndrome) and immunological (a-dsDNA and a-Sm antibodies, hypocomplementaemia) involvement than did aSLE, except for secondary Sjögren's syndrome, a-Ro antibodies, fibromyalgia and osteoporosis. jSLE also showed more SLE family history, longer diagnosis delay, higher SLEDAI and Katz scores, but lower Charlson scores than aSLE. Several specific domains were more frequently involved in SLICC/ACR DI in jSLE. jSLE patients more frequently underwent all SLE-related treatment and procedures, as well as dialysis and kidney transplantations. jSLE shares many clinical and serological features with aSLE. However, jSLE patients typically manifested more activity, severity, cumulative damage in certain areas, than their aSLE counterparts.

Altered CD19/CD22 balance in Egyptian children and adolescents with systemic lupus erythematosus.

PubMed

El-Sayed, Zeinab A; Ragab, Seham M; Khalifa, Khaled A; El Ashmawy, Ramy A

2009-01-01

B cells from systemic lupus erythematosus (SLE) patients display signalling defects that may underlie disease pathogenesis activity.CD19 and CD22 play a major role as regulators of B-cell response. The aim of this study was to clarify the relationship between B cell surface markers namely CD19, CD20 and CD22 expression and clinical and laboratory indices of SLE activity. The study included 33 SLE patients and 20 healthy children and adolescents as controls. Flowcytometric assay of dual markers, CD19/CD20, and CD20/CD22 was done. SLE disease activity was assessed by SLEDAI score. CD22% was significantly higher while CD20% was significantly lower in the study compared to the control group. No significant difference was observed in both groups with respect to CD19% or CD19/CD22% ratio. The level of CD22 expression was significantly lower in high and very high active cases than in mild and moderate cases and negatively correlated with SLDEAI score and ESR. Results obtained showed that, B cell surface receptors CD20 and CD22 are significantly affected in patients with SLE, pointing to their possible involvement in the aetiopathogenesis of the disease and in the regulatory mechanisms in response to the immune disturbance.

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

PubMed Central

Günther, Claudia; Kind, Barbara; Reijns, Martin A.M.; Berndt, Nicole; Martinez-Bueno, Manuel; Wolf, Christine; Tüngler, Victoria; Chara, Osvaldo; Lee, Young Ae; Hübner, Norbert; Bicknell, Louise; Blum, Sophia; Krug, Claudia; Schmidt, Franziska; Kretschmer, Stefanie; Koss, Sarah; Astell, Katy R.; Ramantani, Georgia; Bauerfeind, Anja; Morris, David L.; Cunninghame Graham, Deborah S.; Bubeck, Doryen; Leitch, Andrea; Ralston, Stuart H.; Blackburn, Elizabeth A.; Gahr, Manfred; Witte, Torsten; Vyse, Timothy J.; Melchers, Inga; Mangold, Elisabeth; Nöthen, Markus M.; Aringer, Martin; Kuhn, Annegret; Lüthke, Kirsten; Unger, Leonore; Bley, Annette; Lorenzi, Alice; Isaacs, John D.; Alexopoulou, Dimitra; Conrad, Karsten; Dahl, Andreas; Roers, Axel; Alarcon-Riquelme, Marta E.; Jackson, Andrew P.; Lee-Kirsch, Min Ae

2014-01-01

Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2–associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage–associated pathways in the initiation of autoimmunity. PMID:25500883

High sensitive detection of double-stranded DNA autoantibodies by a modified Crithidia luciliae immunofluorescence test.

PubMed

Conrad, Karsten; Ittenson, Annelore; Reinhold, Dirk; Fischer, Richard; Roggenbuck, Dirk; Büttner, Thomas; Bosselmann, Hans-Peter; Steinbach, Jörg; Schössler, Werner

2009-09-01

Anti-double-stranded (ds)DNA antibodies are serological markers of systemic lupus erythematosus (SLE). Of all anti-dsDNA antibody detection methods, the Crithidia luciliae immunofluorescence test (CLIFT) is thought to have the highest specificity for SLE. However, the clinical application is hampered by the low diagnostic sensitivity. A CLIFT with modified assay buffer (mCLIFT) was developed and compared with conventional CLIFT, using sera from 110 patients with SLE, 89 anti-dsDNA ELISA-positive patients with other diseases (non-SLE group A), 157 non-SLE patients with undetectable anti-dsDNA antibodies by ELISA (non-SLE group B), 77 disease controls (non-SLE group C), and 50 healthy blood donors. Out of the 110 anti-dsDNA antibody ELISA-positive SLE patients, 84 (76.4%) demonstrated a positive kinetoplast staining, using the mCLIFT, compared to only 42.3%, using the conventional CLIFT. The diagnostic specificity of mCLIFT was 100% with healthy blood donors and 98.1% with the non-SLE group C (anti-nuclear antibodies negative; no signs or symptoms of an autoimmune disease) included. In the non-SLE groups A and B with various other autoimmune diseases or symptoms of a possible autoimmune disease, positive mCLIFT results were obtained in 33.7% and 3.2%, respectively. In conclusion, by modification of the assay buffer, a significant increase in sensitivity of the CLIFT could be observed while retaining the high specificity for SLE. Further investigation is required to check whether the CLIFT-positive non-SLE patients develop SLE and whether anti-dsDNA antibodies detected by the mCLIFT represent a pathogenetic and diagnostic subgroup of autoantibodies that may improve the early diagnosis of SLE or SLE-overlap syndromes.

Effects of Obesity on Health-Related Quality of Life in Juvenile-Onset Systemic Lupus Erythematosus

PubMed Central

Mina, Rina; Klein-Gitelman, Marisa S.; Nelson, Shannen; Eberhard, B. Anne; Higgins, Gloria; Singer, Nora G.; Onel, Karen; Tucker, Lori; O' Neil, Kathleen M.; Punaro, Marilynn; Levy, Deborah M.; Haines, Kathleen; Ying, Jun; Brunner, Hermine I.

2014-01-01

Objective Evaluate the effects of obesity on health-related quality of life (HRQOL) measures in juvenile-onset SLE (jSLE). Methods Obesity was defined as a body mass index (BMI) ≥ 95th% according to the sex-specific Center for Disease Control body mass index-for-age charts and determined in a multicenter cohort of jSLE patients. In this secondary analysis, the domain and summary scores of the Pediatric Quality of Life (PedsQL) Inventory and the Child Health Questionnaire (CHQ) of obese jSLE patients were compared to those of non-obese jSLE patients as well as historical obese and non-obese healthy controls. Mixed-effects modeling was performed to evaluate the relationship between obesity and HRQOL measures. Results Among the 202 jSLE patients, 25% (n=51) were obese. Obesity had a significant negative impact on HRQOL in jSLE, even after adjusting for differences in current corticosteroid use, disease activity, disease damage, gender, and race between groups. Obese jSLE patients had lower physical functioning compared to non-obese jSLE patients, and to non-obese and obese healthy controls. Compared to their non-obese counterparts, obese jSLE patients also had worse school functioning, more pain, worse social functioning, and emotional functioning. Parents of obese jSLE patients worry more. The CHQ scores for obese jSLE patients were also worse compared to non-obese jSLE patients in several other domains Conclusion Our study demonstrates the detrimental effects of obesity on patient-reported outcomes in jSLE. This supports the importance of weight management for the therapeutic plan of jSLE. PMID:25335488

Dimension of the SLE Light Cone, the SLE Fan, and {SLE_κ(ρ)} for {κ \\in (0,4)} and {ρ \\in} {\\big[{κ}/{2} -4,-2\\big)}

NASA Astrophysics Data System (ADS)

Miller, Jason

2018-06-01

Suppose that h is a Gaussian free field (GFF) on a planar domain. Fix {κ \\in (0,4)}. The {SLE_κ} light cone L {(θ)} of h with opening angle {θ \\in [0,π]} is the set of points reachable from a given boundary point by angle-varying flow lines of the (formal) vector field {e^{ih/χ}}, {χ = {2}/{√{κ}} - {√{κ}}/{2}}, with angles in {[-{θ}/{2}, {θ}/{2}]}. We derive the Hausdorff dimension of L {(θ)}. If {θ =0} then L {(θ)} is an ordinary {SLE_{κ}} curve (with {κ < 4}); if {θ = π} then L {(θ)} is the range of an {SLE_{κ'}} curve ({κ' = 16/κ > 4}). In these extremes, this leads to a new proof of the Hausdorff dimension formula for {SLE}. We also consider {SLE_κ(ρ)} processes, which were originally only defined for {ρ > - 2}, but which can also be defined for {ρ ≤ -2} using Lévy compensation. The range of an {SLE_κ(ρ)} is qualitatively different when {ρ ≤ -2}. In particular, these curves are self-intersecting for {κ < 4} and double points are dense, while ordinary {SLE_κ} is simple. It was previously shown (Miller and Sheffield in Gaussian free field light cones and {SLE_κ(ρ)}, 2016) that certain {SLE_κ(ρ)} curves agree in law with certain light cones. Combining this with other known results, we obtain a general formula for the Hausdorff dimension of {SLE_κ(ρ)} for all values of {ρ}. Finally, we show that the Hausdorff dimension of the so-called {SLE_κ} fan is the same as that of ordinary {SLE_κ}.

Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus

PubMed Central

Ritterhouse, Lauren L; Crowe, Sherry R; Niewold, Timothy B; Kamen, Diane L; Macwana, Susan R; Roberts, Virginia C; Dedeke, Amy B; Harley, John B; Scofield, R Hal; Guthridge, Joel M; James, Judith A

2011-01-01

Objectives Vitamin D deficiency is widespread and has been associated with many chronic diseases, including autoimmune disorders. A study was undertaken to explore the impact of low vitamin D levels on autoantibody production in healthy individuals, as well as B cell hyperactivity and interferon α (IFNα) activity in patients with systemic lupus erythematosus (SLE). Methods Serum samples from 32 European American female patients with SLE and 32 matched controls were tested for 25-hydroxyvitamin D (25(OH)D) levels, lupus-associated autoantibodies and serum IFNα activity. Isolated peripheral blood mononuclear cells were tested for intracellular phospho-ERK 1/2 as a measure of B cell activation status. Results Vitamin D deficiency (25(OH)D <20 ng/ml) was significantly more frequent among patients with SLE (n=32, 69%) and antinuclear antibody (ANA)-positive controls (n=14, 71%) compared with ANA-negative controls (n=18, 22%) (OR 7.7, 95% CI 2.0 to 29.4, p=0.003 and OR 8.8, 95% CI 1.8 to 43.6, p=0.011, respectively). Patients with high B cell activation had lower mean (SD) 25(OH)D levels than patients with low B cell activation (17.2 (5.1) vs 24.2 (3.9) ng/ml; p=0.009). Patients with vitamin D deficiency also had higher mean (SD) serum IFNα activity than patients without vitamin D deficiency (3.5 (6.6) vs 0.3 (0.3); p=0.02). Conclusions The observation that ANA-positive healthy controls are significantly more likely to be deficient in vitamin D than ANA-negative healthy controls, together with the finding that vitamin D deficiency is associated with certain immune abnormalities in SLE, suggests that vitamin D plays an important role in autoantibody production and SLE pathogenesis. PMID:21586442

Levels and temporal trends (1988-1999) of polybrominated diphenyl ethers in beluga whales (Delphinapterus leucas) from the St. Lawrence Estuary, Canada.

PubMed

Lebeuf, Michel; Gouteux, Bruno; Measures, Lena; Trottier, Steve

2004-06-01

Polybrominated diphenyl ethers (PBDEs) were determined in blubber samples of 54 stranded adult beluga whales (Delphinapterus leucas) collected between 1988 and 1999 in the St. Lawrence Estuary (SLE), Quebec, Canada. Summed concentrations of 10 PBDE congeners (sigmaPBDEs) measured in beluga samples varied between 20 and almost 1000 ng/g wet weight. According to the PBDE concentrations in marine mammals reported in the scientific literature, SLE belugas appear to be relatively lightly contaminated. Only a few predominant congeners (namely, PBDE-47, -99, and -100) represent on average more than 75% of sigmaPBDEs in SLE belugas. The accumulation of sigmaPBDEs in both male and female belugas showed significant exponential increase throughout the 1988-1999 time period. The time necessary for beluga to double their blubber concentration of the most prevalent PBDE congeners was no longer than 3 years. The PBDE temporal changes reported in this study are generally faster but in agreement with the trend observed in other organisms collected in Canada, such as lake trout (Salvelinus namaycush) from the Great Lakes, ringed seal (Phoca hispida), and beluga whale from the Canadian Arctic. Some changes in the pattern of PBDEs in belugas were also observed during the time period investigated. The recent and important increase of PBDE levels in SLE belugas could explain the unexpected lack of statistical difference in PBDE contamination between males and females. This suggests that to date PBDEs tend to be accumulated by both male and female belugas, masking the elimination of PBDEs by females through post-natal transfer to their offspring. This study confirms that the growing use of PBDEs as flame retardants has resulted in rising contamination of Canadian aquatic environments. Additional studies are needed to assess the toxicological implications of the PBDE tissue levels found in SLE belugas.

The effects of rituximab on the lipid profile of patients with active systemic lupus erythematosus: results from a nationwide cohort in Spain (LESIMAB).

PubMed

Fernández-Nebro, A; Marenco, J L; López-Longo, F; Galindo, M; Hernández-Cruz, B E; Narváez, J; Rúa-Figueroa, I; Raya-Alvarez, E; Zea, A; Freire, M; Sánchez-Atrio, A I; García-Vicuña, R; Pego-Reigosa, J M; Manrique-Arija, S; Nieves-Martín, L; Carreño, L

2014-09-01

Patients with systemic lupus erythematosus (SLE) have increased cardiovascular risk related to lipid changes induced by inflammatory activity, proteinuria and treatments. Our objective was to analyse lipid changes in a cohort of patients with SLE resistant to standard treatments who were treated with rituximab. The study population comprised a retrospective multicentre, national cohort of patients with SLE resistant to standard treatments who were treated with rituximab. The basic lipid profile, concomitant treatment and disease activity were analysed at the start of the treatment, 24 weeks later, and at the end of the follow-up period. The effects of the main lupus variables and therapy on the lipid changes were analysed. Seventy-nine patients with active lupus treated with rituximab were assessed during 149.3 patient-years. Prior to the treatment, 69% had dyslipidaemia. The most frequent abnormalities were a low-density lipoprotein (LDL) level of ≥100 mg/dl (34%) and a high-density lipoprotein (HDL) level of <50 mg/dl (27%). Baseline total cholesterol (TC) and LDL levels correlated with the degree of proteinuria, while the concentration of triglycerides (TGs) correlated with the SLE Disease Activity Index (SLEDAI). TGs were reduced at short- and long-term follow-up after rituximab treatment. A multiple linear regression analysis identified that the reduction of the lupus inflammatory activity, particularly changes in proteinuria, was the only independent variable that was positively associated with the reduction in TGs after 24 weeks (p=0.001) and with TC (p=0.005) and TGs (p<0.001) at the end of the follow-up period. Our results suggest that rituximab may improve the long-term lipid profile of patients with SLE refractory to standard treatment, mainly by reducing inflammatory activity. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Definition and initial validation of a Lupus Low Disease Activity State (LLDAS).

PubMed

Franklyn, Kate; Lau, Chak Sing; Navarra, Sandra V; Louthrenoo, Worawit; Lateef, Aisha; Hamijoyo, Laniyati; Wahono, C Singgih; Chen, Shun Le; Jin, Ou; Morton, Susan; Hoi, Alberta; Huq, Molla; Nikpour, Mandana; Morand, Eric F

2016-09-01

Treating to low disease activity is routine in rheumatoid arthritis, but no comparable goal has been defined for systemic lupus erythematosus (SLE). We sought to define and validate a Lupus Low Disease Activity State (LLDAS). A consensus definition of LLDAS was generated using Delphi and nominal group techniques. Criterion validity was determined by measuring the ability of LLDAS attainment, in a single-centre SLE cohort, to predict non-accrual of irreversible organ damage, measured using the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Consensus methodology led to the following definition of LLDAS: (1) SLE Disease Activity Index (SLEDAI)-2K ≤4, with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, fever) and no haemolytic anaemia or gastrointestinal activity; (2) no new lupus disease activity compared with the previous assessment; (3) a Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (scale 0-3) ≤1; (4) a current prednisolone (or equivalent) dose ≤7.5 mg daily; and (5) well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents. Achievement of LLDAS was determined in 191 patients followed for a mean of 3.9 years. Patients who spent greater than 50% of their observed time in LLDAS had significantly reduced organ damage accrual compared with patients who spent less than 50% of their time in LLDAS (p=0.0007) and were significantly less likely to have an increase in SDI of ≥1 (relative risk 0.47, 95% CI 0.28 to 0.79, p=0.005). A definition of LLDAS has been generated, and preliminary validation demonstrates its attainment to be associated with improved outcomes in SLE. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

[Long-term effects of hydroxychloroquine on metabolism of serum lipids and left ventricular structure and function in patients of systemic lupus erythematosus].

PubMed

Meng, Juan; Lu, Yuewu; Dong, Xin; Liu, Hongyan

2014-04-08

To observe the long-term effects of hydroxychloroquine treatment on blood lipids and left ventricular function of systemic lupus erythematosus (SLE) patients. A total of 72 SLE patients were randomly divided into 2 groups of hydroxychloroquine treatment (n = 36) and non-hydroxychloroquine (n = 36). The serum level of lipids, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), fractional shortening rate (FS), left ventricular ejection fraction (LVEF) and E/A ratio were measured before, 6 month, 12 month and 2 years after treatment. After long-term use of hydroxychloroquine, there were statistically differences in the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). And LVEDD, LVWPT and E/A were statistically different (P < 0.05) before and after hydroxychloroquine dosing. The long-term use of hydroxychloroquine may improve lipid metabolism and left ventricular function in SLE patients.

Neuropsychiatric systemic lupus erythematosus is associated with imbalance in interleukin 10 promoter haplotypes

PubMed Central

Rood, M; Keijsers, V; van der Linden, M W; Tong, T; Borggreve, S; Verweij, C; Breedveld, F; Huizinga, T

1999-01-01

OBJECTIVE—To investigate the association of interleukin 10 (IL10) promoter polymorphisms and neuropsychiatric manifestations of systemic lupus erythematosus (SLE).
METHODS—IL10 haplotypes of 11 healthy volunteers were cloned to confirm that in the Dutch population, only the three common haplotypes (-1082/-819/-592) GCC, ACC and ATA exist. The IL10 promoter polymorphisms of 92 SLE patients and 162 healthy controls were determined. The medical records of the SLE patients were screened for the presence of neuropsychiatric involvement.
RESULTS—All cloned haplotypes were either GCC, ACC or ATA. Forty two SLE patients had suffered from neuropsychiatric manifestations (NP-SLE). In NP-SLE patients, the frequency of the ATA haplotype is 30% versus 18% in the controls and 17% in the non-NP-SLE group (odds ratios 1.9, p=0.02, and 2.1, p=0.04, respectively), whereas the GCC haplotype frequency is lower in the NP-SLE group compared with controls and non-NP-SLE patients (40% versus 55% and 61%, odds ratios 0.6, p=0.02 and 0.4 p=0.006). The odds ratio for the presence of NP-SLE is inversely proportional to the number of GCC haplotypes per genotype when the NP-SLE group is compared with non-NP-SLE patients.
CONCLUSIONS—The IL10 locus is associated with neuropsychiatric manifestations in SLE. This suggests that IL10 is implicated in the immunopathogenesis of neuropsychiatric manifestations in SLE.

 Keywords: systemic lupus erythematosus; neuropsychiatric manifestations; genetics; interleukin 10 promoter haplotypes PMID:10343522

Association between antiphospholipid antibodies and all-cause mortality among end-stage renal disease patients with and without SLE: a retrospective cohort study

PubMed Central

Mowrey, Wenzhu B.; Kim, Mimi; Murakhovskaya, Irina; Billett, Henny; Neugarten, Joel; Costenbader, Karen H.; Putterman, Chaim

2016-01-01

Objective. To investigate the association between the presence of aPL and/or LA and all-cause mortality among end-stage renal disease (ESRD) patients with and without SLE. Methods. We included ESRD patients >18 years old followed at an urban tertiary care centre between 1 January 2006 and 31 January 2014 who had aPL measured at least once after initiating haemodialysis. All SLE patients met ACR/SLICC criteria. APL/LA+ was defined as aCL IgG or IgM >40 IU, anti-β2glycoprotein1 IgG or IgM >40 IU or LA+. Deaths as at 31 January 2014 were captured in the linked National Death Index data. Time to death was defined from the first aPL measurement. Results. We included 34 SLE ESRD and 64 non-SLE ESRD patients; 30 patients died during the study period. SLE ESRD patients were younger [40.4 (12.5) vs 51.9 (18.1) years, P = 0.001] and more were women (88.2% vs 54.7%, P < 0.001) vs non-SLE ESRD patients. The frequency of aPL/LA+ was 24% in SLE and 13% in non-SLE ESRD (P = 0.16). Median (inter-quartile range) follow-up time was 1.6 (0.3–3.5) years in SLE and 1.4 (0.4–3.2) years in non-SLE, P = 0.74. The adjusted hazard ratio (HR) for all-cause mortality for SLE patients who were aPL/LA+ vs aPL/LA− was 9.93 (95% CI 1.33, 74.19); the adjusted HR for non-SLE aPL/LA+ vs aPL/LA− was 0.77 (95% CI 0.14, 4.29). Conclusion. SLE ESRD patients with aPL/LA+ had higher all-cause mortality risk than SLE ESRD patients without these antibodies, while the effects of aPL/LA on mortality were comparable among non-SLE ESRD patients. PMID:26705328

Evaluating the cost-effectiveness of laryngeal examination after elective total thyroidectomy.

PubMed

Lang, Brian Hung-Hin; Wong, Carlos K H; Tsang, Raymond K Y; Wong, Kai Pun; Wong, Birgitta Y H

2014-10-01

Although routine laryngeal examination (RLE) after thyroidectomy may cost more than selective laryngeal examination (SLE), it permits earlier detection and treatment of vocal cord palsy (VCP) and so may be cost-saving in the longer term. We compared the 2-year cost-effectiveness between RLE and SLE with RLE performed at 2 weeks (SLE-2w), 1 month (SLE-1m), and 3 months (SLE-3m) after thyroidectomy in the institution's perspective. Our case definition was a hypothetical 50-year-old woman who underwent an elective total thyroidectomy for a benign multinodular goiter. A decision-analytic model was constructed to compare the estimated cost-effectiveness between RLE, SLE-2w, SLE-1m, and SLE-3m after a 2-year period. Outcome probabilities, utilities, and costs were estimated from the literature. The threshold for cost-effectiveness was set at US$50,000/quality-adjusted life-year. Sensitivity and threshold analyses were used to examine model uncertainty. RLE was not cost-effective because its incremental cost-effectiveness ratio to SLE-2w, SLE-1m, and SLE-3m were US$302,755, US$227,883 and US$247,105, respectively. RLE was only cost-effective when the temporary VCP rate increased >42.7 % or when the cost of RLE equaled zero. Similarly, SLE-2w was only cost-effective to SLE-3m when dysphonia for temporary VCP at 3 months increased >39.13 %, dysphonia for permanent VCP at 3 months increased >50.29 %, or dysphonia without VCP at 3 months increased >42.69 %. However, none of these scenarios appeared clinically likely. In the institution's perspective, RLE was not cost-effective against the other three SLE strategies. Regarding to the optimal timing of SLE, SLE-3m appears to be a reasonable and acceptable strategy because of its relative low overall cost.

Comprehensive description of clinical characteristics of a large systemic lupus erythematosus cohort from the Spanish Rheumatology Society Lupus Registry (RELESSER) with emphasis on complete versus incomplete lupus differences.

PubMed

Rúa-Figueroa, Íñigo; Richi, Patricia; López-Longo, Francisco Javier; Galindo, María; Calvo-Alén, Jaime; Olivé-Marqués, Alejandro; Loza-Santamaría, Estíbaliz; Vicente, Sabina Pérez; Erausquin, Celia; Tomero, Eva; Horcada, Loreto; Uriarte, Esther; Sánchez-Atrio, Ana; Rosas, José; Montilla, Carlos; Fernández-Nebro, Antonio; Rodríguez-Gómez, Manuel; Vela, Paloma; Blanco, Ricardo; Freire, Mercedes; Silva, Lucía; Díez-Álvarez, Elvira; Ibáñez-Barceló, Mónica; Zea, Antonio; Narváez, Javier; Martínez-Taboada, Víctor; Marenco, José Luis; de Castro, Mónica Fernández; Fernández-Berrizbeitia, Olaia; Hernández-Beriain, José Ángel; Gantes, Marian; Hernández-Cruz, Blanca; Pérez-Venegas, José J; Pecondón, Ángela; Marras, Carlos; Carreira, Patricia; Bonilla, Gema; Torrente, Vicente; Castellví, Iván; Alegre, Juan; Moreno, Mireia; Raya, Enrique; de la Peña, Paloma García; Vázquez, Tomás; Aguirre, Ángeles; Quevedo, Víctor; Pego-Reigosa, José M

2015-01-01

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement and pronounced racial and ethnic heterogeneity. The aims of the present work were (1) to describe the cumulative clinical characteristics of those patients included in the Spanish Rheumatology Society SLE Registry (RELESSER), focusing on the differences between patients who fulfilled the 1997 ACR-SLE criteria versus those with less than 4 criteria (hereafter designated as incomplete SLE (iSLE)) and (2) to compare SLE patient characteristics with those documented in other multicentric SLE registries.RELESSER is a multicenter hospital-based registry, with a collection of data from a large, representative sample of adult patients with SLE (1997 ACR criteria) seen at Spanish rheumatology departments. The registry includes demographic data, comprehensive descriptions of clinical manifestations, as well as information about disease activity and severity, cumulative damage, comorbidities, treatments and mortality, using variables with highly standardized definitions.A total of 4.024 SLE patients (91% with ≥4 ACR criteria) were included. Ninety percent were women with a mean age at diagnosis of 35.4 years and a median duration of disease of 11.0 years. As expected, most SLE manifestations were more frequent in SLE patients than in iSLE ones and every one of the ACR criteria was also associated with SLE condition; this was particularly true of malar rash, oral ulcers and renal disorder. The analysis-adjusted by gender, age at diagnosis, and disease duration-revealed that higher disease activity, damage and SLE severity index are associated with SLE [OR: 1.14; 95% CI: 1.08-1.20 (P < 0.001); 1.29; 95% CI: 1.15-1.44 (P < 0.001); and 2.10; 95% CI: 1.83-2.42 (P < 0.001), respectively]. These results support the hypothesis that iSLE behaves as a relative stable and mild disease. SLE patients from the RELESSER register do not appear to differ substantially from other Caucasian populations and although activity [median SELENA-SLEDA: 2 (IQ: 0-4)], damage [median SLICC/ACR/DI: 1 (IQ: 0-2)], and severity [median KATZ index: 2 (IQ: 1-3)] scores were low, 1 of every 4 deaths was due to SLE activity.RELESSER represents the largest European SLE registry established to date, providing comprehensive, reliable and updated information on SLE in the southern European population.

Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial).

PubMed

Isenberg, David; Gordon, Caroline; Licu, Daiana; Copt, Samuel; Rossi, Claudia Pena; Wofsy, David

2015-11-01

Despite advances in systemic lupus erythematosus (SLE) treatment, many patients suffer from the disease and side effects. Atacicept is a fusion protein that blocks B-lymphocyte stimulator and a proliferation-inducing ligand, which are increased in patients with SLE. In this double-blind, placebo-controlled study, patients with moderate-to-severe SLE were randomised to atacicept 75 mg or atacicept 150 mg administered subcutaneously, or placebo twice-weekly for 4 weeks, then weekly for 48 weeks. Primary and secondary efficacy measures were the proportion of patients experiencing at least one flare of British Isles Lupus Assessment Group A or B, and time to first flare, respectively. Enrolment in the atacicept 150 mg arm was discontinued prematurely due to two deaths. In the intention-to-treat population (n=461), there was no difference in flare rates or time to first flare between atacicept 75 mg and placebo. Analysis of patients treated with atacicept 150 mg suggested beneficial effect versus placebo in flare rates (OR: 0.48, p=0.002) and time to first flare (HR: 0.56, p=0.009). Both atacicept doses were associated with reductions in total Ig levels and anti-dsDNA antibodies, and increases in C3 and C4 levels. Most treatment-emergent adverse events were mild or moderate. There was no difference between atacicept 75 mg and placebo for flare rate or time to first flare. Analysis of atacicept 150 mg suggested benefit. EudraCT: 2007-003698-13; NCT00624338. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus.

PubMed

Alonso-Perez, Elisa; Suarez-Gestal, Marian; Calaza, Manuel; Blanco, Francisco J; Suarez, Ana; Santos, Maria Jose; Papasteriades, Chryssa; Carreira, Patricia; Pullmann, Rudolf; Ordi-Ros, Josep; Marchini, Maurizio; Skopouli, Fotini N; Bijl, Marc; Barrizone, Nadia; Sebastiani, Gian Domenico; Migliaresi, Sergio; Witte, Torsten; Lauwerys, Bernard R; Kovacs, Attila; Ruzickova, Sarka; Gomez-Reino, Juan J; Gonzalez, Antonio

2014-06-19

We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE. Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRS(s)). Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRS(s). GRS(s) were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10(-16)) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10(-7)), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results. Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women.

Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus

PubMed Central

2014-01-01

Introduction We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE. Methods Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRSs). Results Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRSs. GRSs were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10−16) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10−7), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results. Conclusion Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women. PMID:24946689

Myeloid leukaemia in systemic lupus erythematosus--a nested case-control study based on Swedish registers.

PubMed

Löfström, Björn; Backlin, Carin; Sundström, Christer; Hellström-Lindberg, Eva; Ekbom, Anders; Lundberg, Ingrid E

2009-10-01

To assess the risk factors for leukaemic transformation and myeloid leukaemia in patients with SLE. A national SLE cohort identified through SLE discharge diagnoses in the Swedish hospital discharge register during 1964 to 1995 (n = 6438) was linked to the national cancer register. A nested case-control study in SLE patients who developed acute or chronic myeloid leukaemia was performed with SLE patients without malignancy as controls. Medical records from cases and controls were reviewed and bone marrow specimens were re-evaluated. A Medline search of previously published cases of SLE and myeloid leukaemia was performed. After confirmation of SLE diagnosis according to the ACR criteria, eight patients with SLE and myeloid leukaemia and 18 SLE controls were included in the study. Preceding leucopenia was significantly associated with leukaemia development, whereas other SLE manifestations were not. Two cases had a preceding bone marrow confirming myelodysplastic syndrome (MDS). Only two cases were significantly treated with cyclophosphamide or AZA. A Medline search resulted in only 15 previously published cases of coincident SLE and myeloid leukaemia. Preceding MDS was reported in five of these, whereas only eight had been treated with cytotoxic drugs. Low-dose chemotherapy was not a major cause of myeloid malignancy in our population-based cohort of SLE patients nor in the reported cases from literature. Leucopenia was a risk factor for myeloid leukaemia development and an MDS was frequently seen. Therefore bone marrow investigation should be considered in SLE patients with long-standing leucopenia and anaemia.

Urinary vitamin D-binding protein, a novel biomarker for lupus nephritis, predicts the development of proteinuric flare.

PubMed

Go, D J; Lee, J Y; Kang, M J; Lee, E Y; Lee, E B; Yi, E C; Song, Y W

2018-01-01

Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE). Conventional biomarkers for assessing renal disease activity are imperfect in predicting clinical outcomes associated with LN. The aim of this study is to identify urinary protein biomarkers that reliably reflect the disease activity or predict clinical outcomes. A quantitative proteomic analysis was performed to identify protein biomarker candidates that can differentiate between SLE patients with and without LN. Selected biomarker candidates were further verified by enzyme-linked immunosorbent assay using urine samples from a larger cohort of SLE patients ( n = 121) to investigate their predictive values for LN activity measure. Furthermore, the association between urinary levels of a selected panel of potential biomarkers and prognosis of LN was assessed with a four-year follow-up study of renal outcomes. Urinary vitamin D-binding protein (VDBP), transthyretin (TTR), retinol binding protein 4 (RBP4), and prostaglandin D synthase (PTGDS) were significantly elevated in SLE patients with LN, especially in patients with active LN ( n = 21). Among them, VDBP well correlated with severity of proteinuria (rho = 0.661, p < 0.001) and renal SLE Disease Activity Index (renal SLEDAI) (rho = 0.520, p < 0.001). In the four-year follow-up, VDBP was a significant risk factor (hazard ratio 9.627, 95% confidence interval 1.698 to 54.571, p = 0.011) for the development of proteinuric flare in SLE patients without proteinuria ( n = 100) after adjustments for multiple confounders. Urinary VDBP correlated with proteinuria and renal SLEDAI, and predicted the development of proteinuria.

Muscle Strength and Changes in Physical Function in Women With Systemic Lupus Erythematosus.

PubMed

Andrews, James S; Trupin, Laura; Schmajuk, Gabriela; Barton, Jennifer; Margaretten, Mary; Yazdany, Jinoos; Yelin, Edward H; Katz, Patricia P

2015-08-01

Cross-sectional studies have observed that muscle weakness is associated with worse physical function among women with systemic lupus erythematosus (SLE). The present study examines whether reduced upper and lower extremity muscle strength predict declines in function over time among adult women with SLE. One hundred forty-six women from a longitudinal SLE cohort participated in the study. All measures were collected during in-person research visits approximately 2 years apart. Upper extremity muscle strength was assessed by grip strength. Lower extremity muscle strength was assessed by peak knee torque of extension and flexion. Physical function was assessed using the Short Physical Performance Battery (SPPB). Regression analyses modeled associations of baseline upper and lower extremity muscle strength with followup SPPB scores controlling for baseline SPPB, age, SLE duration, SLE disease activity (Systemic Lupus Activity Questionnaire), physical activity level, prednisone use, body composition, and depression. Secondary analyses tested whether associations of baseline muscle strength with followup in SPPB scores differed between intervals of varying baseline muscle strength. Lower extremity muscle strength strongly predicted changes over 2 years in physical function even when controlling for covariates. The association of reduced lower extremity muscle strength with reduced physical function in the future was greatest among the weakest women. Reduced lower extremity muscle strength predicted clinically significant declines in physical function, especially among the weakest women. Future studies should test whether therapies that promote preservation of lower extremity muscle strength may prevent declines in function among women with SLE. © 2015, American College of Rheumatology.

Integrative analysis of long non-coding RNAs and messenger RNA expression profiles in systemic lupus erythematosus.

PubMed

Luo, Qing; Li, Xue; Xu, Chuxin; Zeng, Lulu; Ye, Jianqing; Guo, Yang; Huang, Zikun; Li, Junming

2018-03-01

Thousands of long noncoding RNAs (lncRNAs) have been reported and represent an important subset of pervasive genes associated with a broad range of biological functions. Abnormal expression levels of lncRNAs have been demonstrated in multiple types of human disease. However, the role of lncRNAs in systemic lupus erythematosus (SLE) remains poorly understood. In the present study, the expression patterns of lncRNAs and messenger RNAs (mRNAs) were investigated in peripheral blood mononuclear cells (PBMCs) in SLE using Human lncRNA Array v3.0 (8x60 K; Arraystar, Inc., Rockville, MD, USA). The microarray results indicated that 8,868 lncRNAs (3,657 upregulated and 5,211 downregulated) and 6,876 mRNAs (2,862 upregulated and 4,014 downregulated) were highly differentially expressed in SLE samples compared with the healthy group. Gene ontology (GO) analysis of lncRNA target prediction indicated the presence of 474 matched lncRNA‑mRNA pairs for 293 differentially expressed lncRNAs (fold change, ≥3.0) and 381 differentially expressed mRNAs (fold change, ≥3.0). The most enriched pathways were 'Transcriptional misregulation in cancer' and 'Valine, leucine and isoleucine degradation'. Furthermore, reverse transcription‑quantitative polymerase chain reaction data verified six abnormal lncRNAs and mRNAs in SLE. The results indicate that the lncRNA expression profile in SLE was significantly changed. In addition, a range of SLE‑associated lncRNAs were identified. Thus, the present results provide important insights regarding lncRNAs in the pathogenesis of SLE.

Regulation and Characterization of a Newly Deduced Cell Wall Hydrolase Gene (cwlJ) Which Affects Germination of Bacillus subtilis Spores

PubMed Central

Ishikawa, Shu; Yamane, Kunio; Sekiguchi, Junichi

1998-01-01

The predicted amino acid sequence of Bacillus subtilis ycbQ (renamed cwlJ) exhibits high similarity to those of the deduced C-terminal catalytic domain of SleBs, the specific cortex-hydrolyzing enzyme of B. cereus and the deduced one of B. subtilis. We constructed a cwlJ::lacZ fusion in the B. subtilis chromosome. The β-galactosidase activity and results of Northern hybridization and primer extension analyses of the cwlJ gene indicated that it is transcribed by EςE RNA polymerase. cwlJ-deficient spores responded to both l-alanine and AGFK, the A580 values of spore suspensions decreased more slowly than in the case of the wild-type strain, and the mutant spores released less dipicolinic acid than did those of the wild-type strain during germination. However, the mutant spores released only slightly less hexosamine than did the wild-type spores. In contrast, B. subtilis sleB spores did not release hexosamine at a significant level. While cwlJ and sleB spores were able to germinate, CJSB (cwlJ sleB) spores could not germinate but exhibited initial germination reactions, e.g., partial decrease in A580 and slow release of dipicolinic acid. CJSB spores became slightly gray after 6 h in the germinant, but their refractility was much greater than that of sleB mutant spores. The roles of the sleB and cwlJ mutations in germination and spore maturation are also discussed. PMID:9515903

Anti-dsDNA, anti-nucleosome and anti-C1q antibodies as disease activity markers in patients with systemic lupus erythematosus.

PubMed

Zivković, Valentina; Stanković, Aleksandra; Cvetković, Tatjana; Mitić, Branka; Kostić, Svetislav; Nedović, Jovan; Stamenković, Bojana

2014-01-01

In spite of the growing number of reports on the study of anti-nucleosome and anti-C1q antibodies, there are still controversies on their significance as disease activity markers in patients with systemic lupus erythematosus (SLE) and their use in everyday clinical practice. Our aim was to assess the presence of anti-dsDNA, anti-nucleosome and anti-C1q antibodies in SLE patients, as well as to establish their sensitivity, specificity, positive and negative predictive value, and their correlation with SLE and lupus nephritis clinical activity. The study enrolled 85 patients aged 45.3 +/- 9.7 years on the average, with SLE of average duration 10.37 +/- 7.99 years, hospitalized at the Institute,,Niska Banja" during 2011, and 30 healthy individuals as controls. Disease activity was assessed using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). In all examinees the levels of anti-dsDNA, anti-nucleosome and anti-C1q antibodies were measured using the ELISA method with Alegria Test Strips Orgentec (Germany). Patients with active lupus nephritis had a higher presence of anti-C1q antibodies and higher co-positivity of anti-dsDNA, anti-nucleosome, and anti-C1q antibodies compared to those with inactive lupus nephritis (77.77% vs. 21.74%; p < 0.01). SLE patients with SLEDAI > or = 11 had a higher presence of antinucleosome (93.75% vs. 64.15%; p < 0.01) and anti-C1q antibodies (46.87% vs. 22.64%; p<0.05), as well as a higher mean level of anti-nucleosome antibodies (107.79 +/- 83.46 U/ml vs. 57.81 +/- 63.15 U/ml; p < 0.05), compared to those with SLEDAI of 0-10. There was a positive correlation between the SLEDAI and the level of anti-dsDNA (r=0.290; p<0.01), anti-nucleosome (r = 0.443; p < 0.001), and anti-C1q antibodies (r = 0.382; p < 0.001). Only anti-C1q antibodies demonstrated correlation with proteinuria (r = 0.445; p < 0.001). Anti-nucleosome and anti-C1q antibodies demonstrated association with SLE and lupus nephritis activity, suggesting their potential usefulness in making predictions about lupus nephritis and assessment of disease activity.

Diagnosis of systemic lupus erythematosus in an unusual presentation: what a primary care physician should know.

PubMed

Pramanik, Bimalendu

2014-01-01

Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease affecting millions of people worldwide. It can affect any organ systems of the body. However, all systems may not be involved initially rather than they may be affected gradually, sometimes over years. Diagnosis depends on characteristic clinical features and laboratory test results. Some features such as skin rash, joint symptoms and oral ulcers are common in SLE. But initial presentation of many patients is unusual because either they do not have these common features of the disease or the presentation mimics other illnesses. As a result, delayed diagnosis and misdiagnosis are common. Therefore, high index of initial suspicion of SLE is critical. In clinical practice, SLE should be suspected in any patient presenting with an unexplained disease process involving two or more organ systems. To make a diagnosis in an unusual presentation, thorough clinical evaluation with details history of both present and past illnesses as well as laboratory tests for SLE should be performed. Usually primary-care physicians first evaluate SLE patients; but there is no single article, where all the information on when to suspect SLE in an unusual presentation, is available in an integrated form. In this article, a list of conditions, when SLE should be suspected in an unusual presentation, has been given and some relatively common areas with diagnostic challenges of SLE have been briefly described. To prepare this manuscript, most articles have been identified through 'Pubmed' search using keywords-atypical/ unusual presentation of SLE, case reports on SLE, gastrointestinal manifestations of SLE, neuropsychiatric SLE, diagnostic challenges with SLE, etc. Selected most articles are from currently medline-indexed journals.

Osteoporotic fractures in patients with systemic lupus erythematosus and end stage renal disease.

PubMed

Le, B; Waller, J L; Radhakrishnan, R; Oh, S J; Kheda, M F; Nahman, N S; Carbone, L

2018-01-01

Background The incidence of end stage renal disease (ESRD) in patients with systemic lupus erythematosus (SLE) is rising. However, the relationship between osteoporotic fractures and SLE in the setting of ESRD remains uninvestigated. The purpose of this study was to compare the frequency of incident osteoporotic fractures in patients with ESRD with and without SLE, to identify risk factors for fractures in patients with SLE and ESRD, and to examine the contribution of these fractures to mortality. Methods Retrospective cohort study of patients with SLE ( n = 716) and a 5% random sample of controls without SLE ( n = 4176) in the United States Renal Data System (USRDS) from years 2006-2008 enrolled in Medicare Part D. Results Fractures occurred in 10.6% ( n = 76) of patients with SLE and ESRD and 12.1% ( n = 507) of patients with ESRD without SLE ( p = 0.24). Older age (adjusted relative risk 1.02, 95% confidence interval 1.01-1.04) was associated with an increased risk for fracture in patients with SLE and ESRD. In multivariable analyses, vertebral and hip fractures more than doubled the risk for mortality. Conclusions The frequency of osteoporotic fractures in patients with SLE and ESRD is similar to the general population of patients with ESRD. Vertebral and hip fractures are significant contributors to mortality in patients with SLE and ESRD. Fracture prevention, in particular, for elderly patients with SLE and ESRD, should be considered. Summary SLE is not an independent risk factor for fractures in patients with ESRD. However, among patients with SLE and ESRD, vertebral and hip fractures are significant contributors to mortality.

Effects of obesity on health-related quality of life in juvenile-onset systemic lupus erythematosus.

PubMed

Mina, R; Klein-Gitelman, M S; Nelson, S; Eberhard, B A; Higgins, G; Singer, N G; Onel, K; Tucker, L; O'Neil, K M; Punaro, M; Levy, D M; Haines, K; Ying, J; Brunner, H I

2015-02-01

This study evaluated the effects of obesity on health-related quality of life (HRQOL) measures in juvenile-onset systemic lupus erythematosus (jSLE). Obesity was defined as a body mass index (BMI) ≥ 95 th percentile according to the Sex-specific Center for Disease Control BMI-For-Age Charts and determined in a multicenter cohort of jSLE patients. In this secondary analysis, the domain and summary scores of the Pediatric Quality of Life (PedsQL) Inventory and the Child Health Questionnaire (CHQ) of obese jSLE patients were compared to those of non-obese jSLE patients as well as historical obese and non-obese healthy controls. Mixed-effects modeling was performed to evaluate the relationship between obesity and HRQOL measures. Among the 202 jSLE patients, 25% (n = 51) were obese. Obesity had a significant negative impact on HRQOL in jSLE, even after adjusting for differences in current corticosteroid use, disease activity, disease damage, gender and race between groups. Obese jSLE patients had lower physical functioning compared to non-obese jSLE patients, and to non-obese and obese healthy controls. Compared to their non-obese counterparts, obese jSLE patients also had worse school functioning, more pain, worse social functioning and emotional functioning. Parents of obese jSLE patients worry more. The CHQ scores for obese jSLE patients were also worse compared to non-obese jSLE patients in several other domains. Our study demonstrates the detrimental effects of obesity on patient-reported outcomes in jSLE. This supports the importance of weight management for the therapeutic plan of jSLE. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Clinical association between Kikuchi׳s disease and systemic lupus erythematosus: A systematic literature review.

PubMed

Sopeña, Bernardo; Rivera, Alberto; Chamorro, Antonio; Freire, Mayka; Alende, Vanessa; Seco, Elena; González-Gay, Miguel A; González-Quintela, Arturo

2017-08-01

To perform a systematic review of all cases of the association between Kikuchi's disease (KD) and systemic lupus erythematosus (SLE), and to ascertain the clinical and laboratory characteristics of this association (KD-SLE). We conducted a systematic search of the scientific literature until 31 January 2016. For study purposes, only patients aged >14 years, with histologically proven KD, definite SLE and adequate clinical data were included. To compare KD-SLE against isolated KD and SLE, we selected 2 large series of patients with KD and 4 series of SLE patients. The search found 158 adults with proven KD-SLE. Of these, 113 with sufficient clinical information were included; 86 were women (female:male ratio = 5.0); mean age at diagnosis was 34 years (range: 14-56 years); and an ethnic distribution of 50.5% Asian, 34% Caucasian, and 15% other. KD-SLE patients differed significantly from patients with isolated KD, presenting with a higher frequency of high fever (90%), severe KD (88%), and extranodal manifestations. When compared to patients with SLE, those with KD-SLE presented with a higher frequency of fever and systemic symptoms and a lower frequency of lupus nephritis (22%). SLE had been diagnosed before KD in 18% of cases, simultaneously in 51%, and after KD in 31%. No significant differences were found in terms of time of diagnosis. While KD-SLE patients share many clinical and laboratory manifestations with SLE, they differ in a lower frequency of lupus nephritis. The relative time of diagnosis of each disease did not affect the clinical expression of KD-SLE. Copyright © 2017 Elsevier Inc. All rights reserved.

Novel insights of microRNAs in the development of systemic lupus erythematosus.

PubMed

Le, Xiong; Yu, Xiang; Shen, Nan

2017-09-01

To provide a brief overview of recent progress in microRNA biogenesis and homeostasis, its function in immune system and systemic lupus erythematosus (SLE), as well as successful microRNA-based therapy in vivo. Stepwise microRNA biogenesis is elaborately regulated at multiple levels, ranging from transcription to ultimate function. Mature microRNAs have inhibitory effects on various biological molecules, which are crucial for stabilizing and normalizing differentiation and function of immune cells. Abnormality in microRNA expression contributes to dysfunction of lupus immune cells and resident cells in local tissues. Manipulation of dysregulated microRNAs in vivo through microRNA delivery or targeting microRNA might be promising for SLE treatment. Recent advances highlight that microRNAs are important in immunity, lupus autoimmunity and as potential therapy target for SLE.

Annual incidence and standardized incidence ratio of cerebrovascular accidents in patients with systemic lupus erythematosus.

PubMed

Mok, C C; Ho, L Y; To, C H

2009-01-01

To study the annual incidence and standardized incidence ratio (SIR) of cerebrovascular accident (CVA) in patients with systemic lupus erythematosus (SLE). The annual incidence of CVA from 1999 to 2007 in a longitudinal cohort of SLE patients was calculated each year and compared with that of the regional population within the same study period. Age-specific SIRs and outcome of CVA in SLE patients were also studied. In 2007, there were 490 SLE patients in our cohort. The mean annual incidence of CVA between 1999 and 2007 was 6.45/1000 patients and no obvious trend over time was observed. Of the 20 CVAs in patients with SLE, 18 (90%) were ischaemic stroke whereas two (10%) were haemorrhagic stroke. The mean SIR of all types of CVA in SLE patients was 2.02 [95% confidence interval (CI) 1.30-3.81; p = 0.002]. The SIR of ischaemic stroke decreased with age and the stroke incidence was no longer significantly higher than that of the population in patients aged >or= 60 years. Haemorrhagic stroke occurred mainly in younger SLE patients. The duration of hospitalization and the mortality rate for CVA was non-significantly higher in SLE than in non-SLE patients. The incidence of CVA in SLE remained constant over the 8 years between 1999 and 2007. Younger SLE patients are at substantially increased risk of CVA compared to age-matched population. The duration of hospitalization and the mortality rate for CVA are similar in SLE and non-SLE patients.

Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti–dsDNA Autoantibody Production

PubMed Central

Chung, Sharon A.; Taylor, Kimberly E.; Graham, Robert R.; Nititham, Joanne; Lee, Annette T.; Ortmann, Ward A.; Jacob, Chaim O.; Alarcón-Riquelme, Marta E.; Tsao, Betty P.; Harley, John B.; Gaffney, Patrick M.; Moser, Kathy L.; Petri, Michelle; Demirci, F. Yesim; Kamboh, M. Ilyas; Manzi, Susan; Gregersen, Peter K.; Langefeld, Carl D.; Behrens, Timothy W.; Criswell, Lindsey A.

2011-01-01

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti–dsDNA autoantibody positive (anti–dsDNA +, n = 811) and anti–dsDNA autoantibody negative (anti–dsDNA –, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti–dsDNA + SLE. Far fewer and weaker associations were observed for anti–dsDNA – SLE. For example, rs7574865 in STAT4 had an OR for anti–dsDNA + SLE of 1.77 (95% CI 1.57–1.99, p = 2.0E-20) compared to an OR for anti–dsDNA – SLE of 1.26 (95% CI 1.12–1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti–dsDNA + SLE and were not associated with anti–dsDNA – SLE. In conclusion, we identified differential genetic associations with SLE based on anti–dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti–dsDNA – SLE. PMID:21408207

Preliminary study of a traditional Chinese medicine formula in systemic lupus erythematosus patients to taper steroid dose and prevent disease flare-up.

PubMed

Liao, Yen-Nung; Liu, Ching-Shen; Tsai, Tong-Rong; Hung, Yu-Chiang; Chang, Shun-Jen; Lin, Hong-Long; Chen, Ying-Chou; Lai, Han-Ming; Yu, Shan-Fu; Chen, Chung-Jen

2011-07-01

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease. Prolonged complete remission is rare. Most patients with SLE need long-term treatment with glucocorticoid and immunomodulators. However, side effects because of the above medications are common. We evaluated the effect of adding-on Dan-Chi-Liu-Wei combination (DCLWC) on SLE patients with conventional therapy in tapering steroid and preventing disease flare-up. This was a double-blind and randomized controlled trial. Sixty-six SLE patients were recruited into this study and 53 patients who fulfilled the 1997 revised criteria for the classification of SLE with an SLE disease activity index (SLEDAI) score of 2-12 and a steroid (measured with prednisolone) daily dose of less than 20mg/d were enrolled. The patients were randomized into either an experimental or control group. We checked the urine analysis, hemogram, liver function, renal function, C3, C4, erythrocyte sedimentation rate, and anti-dsDNA, evaluated the SLEDAI score, and recorded the steroid dose at 0 months, 3 months, and 6 months, respectively. After 6 months of study, the C4 and blood urea nitrogen level revealed a statistically significant difference in either group. There was a tendency toward a decreased SLEDAI score in the experimental group (p=0.083) but not in the control group (p=0.867). The steroid dose was not statistically significant in either group. Renal function and liver function revealed no statistically significant statistics changes in either group. Adding-on DCLWC to conventional therapy for the treatment of SLE was safe and might have a borderline effect in decreasing disease activity, but it was not possible to taper the dosage of steroid after 6 months of clinical trial. Therefore, a long-term follow-up and a large-scale study are necessary to confirm the effect of DCLWC. Copyright © 2011 Elsevier Taiwan LLC. All rights reserved.

Low dynamic muscle strength and its associations with fatigue, functional performance, and quality of life in premenopausal patients with systemic lupus erythematosus and low disease activity: a case–control study

PubMed Central

2013-01-01

Background The purpose of the present study was to compare dynamic muscle strength, functional performance, fatigue, and quality of life in premenopausal systemic lupus erythematosus (SLE) patients with low disease activity versus matched-healthy controls and to determine the association of dynamic muscle strength with fatigue, functional performance, and quality of life in SLE patients. Methods We evaluated premenopausal (18–45 years) SLE patients with low disease activity (Systemic lupus erythematosus disease activity index [SLEDAI]: mean 1.5 ± 1.2). The control (n = 25) and patient (n = 25) groups were matched by age, physical characteristics, and the level of physical activities in daily life (International Physical Activity Questionnaire IPAQ). Both groups had not participated in regular exercise programs for at least six months prior to the study. Dynamic muscle strength was assessed by one-repetition maximum (1-RM) tests. Functional performance was assessed by the Timed Up and Go (TUG), in 30-s test a chair stand and arm curl using a 2-kg dumbbell and balance test, handgrip strength and a sit-and-reach flexibility test. Quality of life (SF-36) and fatigue were also measured. Results The SLE patients showed significantly lower dynamic muscle strength in all exercises (leg press 25.63%, leg extension 11.19%, leg curl 15.71%, chest press 18.33%, lat pulldown 13.56%, 1-RM total load 18.12%, P < 0.001-0.02) compared to the controls. The SLE patients also had lower functional performance, greater fatigue and poorer quality of life. In addition, fatigue, SF-36 and functional performance accounted for 52% of the variance in dynamic muscle strength in the SLE patients. Conclusions Premenopausal SLE patients with low disease activity showed lower dynamic muscle strength, along with increased fatigue, reduced functional performance, and poorer quality of life when compared to matched controls. PMID:24011222

A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS).

PubMed

van Vollenhoven, Ronald; Voskuyl, Alexandre; Bertsias, George; Aranow, Cynthia; Aringer, Martin; Arnaud, Laurent; Askanase, Anca; Balážová, Petra; Bonfa, Eloisa; Bootsma, Hendrika; Boumpas, Dimitrios; Bruce, Ian; Cervera, Ricard; Clarke, Ann; Coney, Cindy; Costedoat-Chalumeau, Nathalie; Czirják, László; Derksen, Ronald; Doria, Andrea; Dörner, Thomas; Fischer-Betz, Rebecca; Fritsch-Stork, Ruth; Gordon, Caroline; Graninger, Winfried; Györi, Noémi; Houssiau, Frédéric; Isenberg, David; Jacobsen, Soren; Jayne, David; Kuhn, Annegret; Le Guern, Veronique; Lerstrøm, Kirsten; Levy, Roger; Machado-Ribeiro, Francinne; Mariette, Xavier; Missaykeh, Jamil; Morand, Eric; Mosca, Marta; Inanc, Murat; Navarra, Sandra; Neumann, Irmgard; Olesinska, Marzena; Petri, Michelle; Rahman, Anisur; Rekvig, Ole Petter; Rovensky, Jozef; Shoenfeld, Yehuda; Smolen, Josef; Tincani, Angela; Urowitz, Murray; van Leeuw, Bernadette; Vasconcelos, Carlos; Voss, Anne; Werth, Victoria P; Zakharova, Helena; Zoma, Asad; Schneider, Matthias; Ward, Michael

2017-03-01

Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE. An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%. The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life. The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Effect of ventriculectomy versus ventriculocordectomy on upper airway noise in draught horses with recurrent laryngeal neuropathy.

PubMed

Cramp, P; Derksen, F J; Stick, J A; Nickels, F A; Brown, K E; Robinson, P; Robinson, N E

2009-11-01

Little is known about the efficacy of bilateral ventriculectomy (VE) or bilateral ventriculocordectomy (VCE) in draught horses. To compare the effect of VE and VCE on upper airway noise in draught horses with recurrent laryngeal neuropathy (RLN) by use of quantitative sound analysis techniques. In competitive draught horses with grade 4 RLN, VE and VCE reduce upper airway noise during exercise, but VCE is more effective. Thirty competitive hitch or pulling draught horses with grade 4 RLN were evaluated for upper airway sound during exercise. Respiratory rate (RR), inspiratory (Ti) and expiratory time (Te), the ratio between Ti and Te (Ti/Te), inspiratory (Sli) and expiratory sound levels (Sle), the ratio between Sli and Sle (Sli/Sle), and peak sound intensity of the second formant (F2) were calculated. Eleven horses were treated with VE and 19 with VCE. After 90 days of voice and physical rest and 30 days of work, the horses returned for post operative upper airway sound evaluation and resting videoendoscopy. VE significantly reduced Ti/Te, Sli, Sli/Sle and the sound intensity of F2. Respiratory rate, Ti, Te and Sle were unaffected by VE. VCE significantly reduced Ti/Te, Ti, Te, Sli, Sli/Sle and the sound intensity of F2, while RR and Sle were unaffected. The reduction in sound intensity of F2 following VCE was significantly greater than following VE. After VE and VCE, 7/11 (64%) and 15/18 (83%) owners, respectively, concluded that the surgery improved upper airway sound in their horses sufficiently for successful competition. VE and VCE significantly reduce upper airway noise and indices of airway obstruction in draught horses with RLN, but VCE is more effective than VE. The procedures have few post operative complications. VCE is recommended as the preferred treatment for RLN in draught horses. Further studies are required to evaluate the longevity of the procedure's results.

Assessment of premature atherosclerosis in systemic lupus erythematosus patients with and without nephritis.

PubMed

Sharma, S K; Rathi, M; Sahoo, S; Prakash, M; Dhir, V; Singh, S

2016-04-01

Risk of subclinical atherosclerosis is increased in patients with systemic lupus erythematosus (SLE). We correlated carotid intima media thickness (CIMT) and endothelial dysfunction through flow-mediated dilation (FMD) in SLE patients with the SLE Disease Activity Index (SLEDAI). This single-centre cross-sectional study recruited 100 consenting SLE outpatients (ACR 1997 criteria) out of which 50 had nephritis, with disease duration of ≥2 years for SLE and ≥6 months for lupus nephritis. We measured baseline laboratory levels, CIMT and FMD (after brachial BP cuff inflation up to 200 mmHg for five minutes), and calculated SLEDAI. Mean age was 29.88 ± 6.53 years; 95/100 were female. CIMT showed positive correlation (p = 0.037; rho = 0.209), and FMD showed inverse correlation with patient's age (p = 0.011; rho = -0.252). CIMT and FMD were more deranged in patients aged ≥25 years (p < 0.05). CIMT was not significantly different between SLE patients with and without nephritis (p > 0.05), whereas SLEDAI and FMD were more deranged in nephritis patients (p < 0.05). In patients without nephritis, FMD showed significant inverse correlation with disease duration (p = 0.043; rho = -0.288) and urine albumin (p = 0.045; rho = -0.285). In nephritis patients, the correlation between age of the patient was significantly positive with CIMT (p = 0.001; rho = 0.441) and significantly inverse with FMD (p = 0.028; rho = -0.312). SLE patients with nephritis are at a higher risk to develop arterial stiffening, leading to early end-organ damage. Early aggressive treatment may prevent endothelial dysfunction. FMD using vascular ultrasonography on the brachial artery represents a non-invasive, repeatable and useful method for the assessment of endothelial dysfunction. © The Author(s) 2015.

Hypothyroidism among SLE patients: Case-control study.

PubMed

Watad, Abdulla; Mahroum, Naim; Whitby, Aaron; Gertel, Smadar; Comaneshter, Doron; Cohen, Arnon D; Amital, Howard

2016-05-01

The prevalence of hypothyroidism in SLE patients varies considerably and early reports were mainly based on small cohorts. To investigate the association between SLE and hypothyroidism. Patients with SLE were compared with age and sex-matched controls regarding the proportion of hypothyroidism in a case-control study. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services. The study included 5018 patients with SLE and 25,090 age and sex-matched controls. The proportion of hypothyroidism in patients with SLE was increased compared with the prevalence in controls (15.58% and 5.75%, respectively, P<0.001). In a multivariate analysis, SLE was associated with hypothyroidism (odds ratio 2.644, 95% confidence interval 2.405-2.908). Patients with SLE have a greater proportion of hypothyroidism than matched controls. Therefore, physicians treating patients with SLE should be aware of the possibility of thyroid dysfunction. Copyright © 2016 Elsevier B.V. All rights reserved.

Mountain Glaciers and Ice Caps

USGS Publications Warehouse

Ananichheva, Maria; Arendt, Anthony; Hagen, Jon-Ove; Hock, Regine; Josberger, Edward G.; Moore, R. Dan; Pfeffer, William Tad; Wolken, Gabriel J.

2011-01-01

Projections of future rates of mass loss from mountain glaciers and ice caps in the Arctic focus primarily on projections of changes in the surface mass balance. Current models are not yet capable of making realistic forecasts of changes in losses by calving. Surface mass balance models are forced with downscaled output from climate models driven by forcing scenarios that make assumptions about the future rate of growth of atmospheric greenhouse gas concentrations. Thus, mass loss projections vary considerably, depending on the forcing scenario used and the climate model from which climate projections are derived. A new study in which a surface mass balance model is driven by output from ten general circulation models (GCMs) forced by the IPCC (Intergovernmental Panel on Climate Change) A1B emissions scenario yields estimates of total mass loss of between 51 and 136 mm sea-level equivalent (SLE) (or 13% to 36% of current glacier volume) by 2100. This implies that there will still be substantial glacier mass in the Arctic in 2100 and that Arctic mountain glaciers and ice caps will continue to influence global sea-level change well into the 22nd century.

Non-scarring patchy alopecia in patients with systemic lupus erythematosus differs from that of alopecia areata.

PubMed

Ye, Y; Zhao, Y; Gong, Y; Zhang, X; Caulloo, S; Zhang, B; Cai, Z; Yang, J; McElwee, K J; Zhang, X

2013-12-01

Non-scaring patchy alopecia associated with systematic lupus erythematosus (SLE) is sometimes mis-diagnosed as alopecia areata (AA). Our aim was to differentiate non-scarring patchy SLE alopecia features from patchy AA. Clinical, dermatoscopic and histopathological data from 21 SLE patients with patchy alopecia were compared with data from 21 patients with patchy AA. Incomplete alopecia was common in SLE alopecia patches, while AA patches exhibited complete alopecia. Exclamation-mark hairs, black dots, broken hair and yellow dots were common to AA, while hair shaft thinning and hypopigmentation, angiotelectasis, peripilar sign, perifollicular red dots, white dots and honeycomb pigment patterns were more common in SLE. Interfollicular polymorphous vessels were the most common angiotelectasis presentation in the SLE alopecia patches, but interfollicular arborizing vessels were significantly more common in non-hair-loss-affected SLE regions and in AA hair-loss regions. During follow-up, increased vellus hair was the earliest feature that emerged after treatment both in SLE and AA, while the earliest feature that disappeared was hair shaft hypopigmentation in SLE and broken hair in AA. After treatment, no SLE patients had relapse of alopecia, while 41.7% of AA patients did. Distinct clinical, dermatoscopic and histopathological features were found in SLE-associated alopecia regions, which were different from those of AA. Serological autoantibody tests are of value to confirm the differential diagnosis. Local angiotelectasis and vasculitis close to hair follicles may be involved in the pathogenesis of alopecia in SLE.

Can SLE classification rules be effectively applied to diagnose unclear SLE cases?

PubMed Central

Mesa, Annia; Fernandez, Mitch; Wu, Wensong; Narasimhan, Giri; Greidinger, Eric L.; Mills, DeEtta K.

2016-01-01

Summary Objective Develop a novel classification criteria to distinguish between unclear SLE and MCTD cases. Methods A total of 205 variables from 111 SLE and 55 MCTD patients were evaluated to uncover unique molecular and clinical markers for each disease. Binomial logistic regressions (BLR) were performed on currently used SLE and MCTD classification criteria sets to obtain six reduced models with power to discriminate between unclear SLE and MCTD patients which were confirmed by Receiving Operating Characteristic (ROC) curve. Decision trees were employed to delineate novel classification rules to discriminate between unclear SLE and MCTD patients. Results SLE and MCTD patients exhibited contrasting molecular markers and clinical manifestations. Furthermore, reduced models highlighted SLE patients exhibit prevalence of skin rashes and renal disease while MCTD cases show dominance of myositis and muscle weakness. Additionally decision trees analyses revealed a novel classification rule tailored to differentiate unclear SLE and MCTD patients (Lu-vs-M) with an overall accuracy of 88%. Conclusions Validation of our novel proposed classification rule (Lu-vs-M) includes novel contrasting characteristics (calcinosis, CPK elevated and anti-IgM reactivity for U1-70K, U1A and U1C) between SLE and MCTD patients and showed a 33% improvement in distinguishing these disorders when compare to currently used classification criteria sets. Pending additional validation, our novel classification rule is a promising method to distinguish between patients with unclear SLE and MCTD diagnosis. PMID:27353506

Voice disorder in systemic lupus erythematosus

PubMed Central

de Macedo, Milena S. F. C.; da Silva Filho, Manoel

2017-01-01

Systemic lupus erythematosus (SLE) is a chronic disease characterized by progressive tissue damage. In recent decades, novel treatments have greatly extended the life span of SLE patients. This creates a high demand for identifying the overarching symptoms associated with SLE and developing therapies that improve their life quality under chronic care. We hypothesized that SLE patients would present dysphonic symptoms. Given that voice disorders can reduce life quality, identifying a potential SLE-related dysphonia could be relevant for the appraisal and management of this disease. We measured objective vocal parameters and perceived vocal quality with the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale in SLE patients and compared them to matched healthy controls. SLE patients also filled a questionnaire reporting perceived vocal deficits. SLE patients had significantly lower vocal intensity and harmonics to noise ratio, as well as increased jitter and shimmer. All subjective parameters of the GRBAS scale were significantly abnormal in SLE patients. Additionally, the vast majority of SLE patients (29/36) reported at least one perceived vocal deficit, with the most prevalent deficits being vocal fatigue (19/36) and hoarseness (17/36). Self-reported voice deficits were highly correlated with altered GRBAS scores. Additionally, tissue damage scores in different organ systems correlated with dysphonic symptoms, suggesting that some features of SLE-related dysphonia are due to tissue damage. Our results show that a large fraction of SLE patients suffers from perceivable dysphonia and may benefit from voice therapy in order to improve quality of life. PMID:28414781

Genetic Ancestry, Serum Interferon-α Activity, and Autoantibodies in Systemic Lupus Erythematosus

PubMed Central

Ko, Kichul; Franek, Beverly S.; Marion, Miranda; Kaufman, Kenneth M.; Langefeld, Carl D.; Harley, John B.; Niewold, Timothy B.

2012-01-01

Objective To investigate and refine the relationships among systemic lupus erythematosus (SLE) and related autoantibodies, interferon-α (IFN-α), and various ancestral backgrounds. Methods We investigated quantitatively defined genetic ancestry through principal component analysis in place of self-reported ancestry. Results African ancestry was found to be associated with presence of anti-RNP antibody (p = 0.0026), and anti-RNP was correlated with high levels of IFN-α (p = 2.8 × 10−5). Conclusion Our data support a model in which African ancestry increases the likelihood of SLE-associated autoantibody formation, which subsequently results in higher levels of serum IFN-α. PMID:22505704

[Clinical practice guidelines for systemic lupus erythematosus: Recommendations for general clinical management].

PubMed

Trujillo-Martín, María M; Rúa-Figueroa Fernández de Larrinoa, Iñigo; Ruíz-Irastorza, Guillermo; Pego-Reigosa, José María; Sabio Sánchez, José Mario; Serrano-Aguilar, Pedro

2016-05-06

Systemic lupus erythematosus (SLE) is a complex rheumatic multisystemic disease of autoimmune origin with significant potential morbidity and mortality. It is one of the most common autoimmune diseases with an estimated prevalence of 20-150 cases per 100,000 inhabitants. The clinical spectrum of SLE is wide and variable both in clinical manifestations and severity. This prompted the Spanish Ministry of Health, Social Services and Equality to promote and fund the development of a clinical practice guideline (CPG) for the clinical care of SLE patients within the Programme of CPG in the National Health System which coordinates GuiaSalud. This CPG is is intended as the reference tool in the Spanish National Health System in order to support the comprehensive clinical management of people with SLE by all health professionals involved, regardless of specialty and level of care, helping to standardize and improve the quality of clinical decisions in our context in order to improve the health outcomes of the people affected. The purpose of this document is to present and discuss the rationale of the recommendations on the general management of SLE, specifically, clinical follow-up, general therapeutic approach, healthy lifestyles, photoprotection, and training programmes for patients. These recommendations are based on the best available scientific evidence, on discussion and the consensus of expert groups. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Methyl salicylate 2-O-β-d-lactoside alleviates the pathological progression of pristane-induced systemic lupus erythematosus-like disease in mice via suppression of inflammatory response and signal transduction

PubMed Central

He, Yang-Yang; Yan, Yu; Zhang, Hui-Fang; Lin, Yi-Huang; Chen, Yu-Cai; Yan, Yi; Wu, Ping; Fang, Jian-Song; Yang, Shu-Hui; Du, Guan-Hua

2016-01-01

Systemic lupus erythematosus (SLE), with a high incidence rate and insufficient therapy worldwide, is a complex disease involving multiple organs characterized primarily by inflammation due to deposition of immunocomplexes formed by production of autoantibodies. The mechanism of SLE remains unclear, and the disease still cannot be cured. We used pristane to induce SLE in female BALB/c mice. Methyl salicylate 2-O-β-d-lactoside (MSL; 200, 400, and 800 mg/kg) was orally administered 45 days after pristane injection for 4.5 months. The results showed that MSL antagonized the increasing levels of multiple types of antibodies and cytokines in lupus mice. MSL was found to suppress joint swelling and have potent inhibitory effect on arthritis-like symptoms. MSL also significantly decreased the spleen index and expression of inflammatory markers in the lupus mice. MSL protected the kidneys of lupus mice from injury through inhibiting the expression of inflammatory cytokines and reducing the IgG and C3 immunocomplex deposits. Further Western blot assays revealed that the downregulation of the intracellular inflammatory signals of NFκB and JAK/STAT3 might be the potential molecular mechanisms of the pharmacological activity of MSL against SLE in vivo. These findings may demonstrate that MSL has the potential to be a useful and highly effective treatment for SLE. PMID:27729775

Lupus erythematosus cell phenomenon in synovial and peritoneal fluids in systemic lupus erythematosus: smoking guns, crime scenes and a twist.

PubMed

Tay, Sen Hee; Nga, Min En; Koh, Dow-Rhoon; Mak, Anselm

2015-01-01

The presence of the lupus erythematosus (LE) phenomenon has been generally conceptualized as an in vitro occurrence where numerous damaged cells are present and substantial nucleo-phagocytosis has occurred. In systemic lupus erythematosus (SLE), the positive LE cell phenomenon has been shown to indicate active disease with major organ involvement which potentially warrants prompt and heavy immunosuppressive therapy. We report a 36-year-old woman with a known history of SLE who presented with fever, left knee effusion, polyserositis, pancytopenia, low complement and high anti-dsDNA antibody levels whose immunosuppressive treatment was escalated in view of the clinically and serologically active SLE, accompanied by the presence of LE cells in her inflammatory yet sterile left knee synovial fluid. Within 3 days of immunosuppressant escalation, her ascites worsened. While microscopic examination of the ascitic fluid also revealed LE cells, culture of the ascitic fluid later grew Candida parapsilosis. The patient subsequently responded to the addition of anti-fungal therapy into her augmented immunosuppressive regime. Coexistence of the LE cell phenomenon and infection in SLE patients has hitherto not been described. This case illustrates that infection remains to be meticulously excluded despite the presence of the LE phenomenon in the context of clinically and serologically active SLE. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Optimal management of fatigue in patients with systemic lupus erythematosus: a systematic review

PubMed Central

Yuen, Hon K; Cunningham, Melissa A

2014-01-01

Among the host of distressing pathophysiological and psychosocial symptoms, fatigue is the most prevalent complaint in patients with systemic lupus erythematosus (SLE). This review is to update the current findings on non-pharmacological, pharmacological, and modality strategies to manage fatigue in patients with SLE and to provide some recommendations on optimal management of fatigue based on the best available evidence. We performed a systematic literature search of the PubMed and Scopus databases to identify publications on fatigue management in patients with SLE. Based on the studies reported in the literature, we identified nine intervention strategies that have the potential to alleviate fatigue in patients with SLE. Of the nine strategies, aerobic exercise and belimumab seem to have the strongest evidence of treatment efficacy. N-acetylcysteine and ultraviolet-A1 phototherapy demonstrated low-to-moderate levels of evidence. Psychosocial interventions, dietary manipulation (low calorie or glycemic index diet) aiming for weight loss, vitamin D supplementation, and acupuncture all had weak evidence. Dehydroepiandrosterone is not recommended due to a lack of evidence for its efficacy. In addition to taking treatment efficacy and side effects into consideration, clinicians should consider factors such as cost of treatment, commitments, and burden to the patient when selecting fatigue management strategies for patients with SLE. Any comorbidities, such as psychological distress, chronic pain, sleep disturbance, obesity, or hypovitaminosis D, associated with fatigue should be addressed. PMID:25328393

Immunoserological parameters in SLE: high-avidity anti-dsDNA detected by ELISA are the most closely associated with the disease activity.

PubMed

Andrejevic, Sladjana; Jeremic, Ivica; Sefik-Bukilica, Mirjana; Nikolic, Milos; Stojimirovic, Biljana; Bonaci-Nikolic, Branka

2013-11-01

We assessed the relationship between the serum levels of antibodies against double-stranded DNA (dsDNA), C1q, nucleosomes, histones, C3 and C4 complement components with one another, with organ involvement and overall disease activity in patients with systemic lupus erythematosus (SLE). One hundred seventy-five sera from 99 patients with SLE, 31 sera of patients with other connective tissue diseases, and 20 sera from healthy blood donors were tested. SLE disease activity was assessed by modified SLEDAI-2K (M-SLEDAI-2K), not including complement and anti-dsDNA descriptors. Anti-dsDNA antibodies were measured by indirect immunofluorescence on Crithidia luciliae (CLIFT), standard enzyme-linked immunosorbent assay (ELISA) and ELISA for high-avidity antibodies. The most significant risk factor for renal involvement were anti-C1q antibodies (OR = 3.88, p < 0.05), high-avidity anti-dsDNA antibodies for polyserositis (OR = 7.99, p < 0.01), anti-histone antibodies for joint involvement (OR = 2.75, p < 0.05), and low C3 for cytopenia (OR = 11.96, p < 0.001) and mucocutaneous lesions (OR = 3.32, p < 0.01). Multiple linear regression analysis showed that disease activity in SLE could be predicted by the levels of antibodies against dsDNA determined by standard (p < 0.05) and high-avidity (p < 0.001) ELISA, and inversely associated with concentration of C3 (p < 0.001). Using stepwise method, high-avidity anti-dsDNA antibodies were found to be in the closest association to M-SLEDAI-2K. Moreover, positive test for high-avidity anti-dsDNA antibodies appeared as an independent risk factor for moderately to severely active disease (M-SLEDAI-2K>5) (OR = 5.5, p < 0.01). The presence of high-avidity anti-dsDNA antibodies represented a risk for renal, joint, and most importantly for serosal involvement. Our results suggest that simple and reliable ELISA for high-avidity anti-dsDNA antibodies is the test of good clinical utility for the assessment of global SLE activity.

Penile anthropometry in systemic lupus erythematosus patients.

PubMed

Vecchi, A P; Borba, E F; Bonfá, E; Cocuzza, M; Pieri, P; Kim, C A; Silva, C A

2011-04-01

The aim of this study was to evaluate penile anthropometry in systemic lupus erythematosus (SLE) patients compared with healthy controls and the possible relevant pubertal, clinical, hormonal and treatment factors that could influence penile dimensions. Twenty-five consecutive SLE patients were assessed by urological examination, sexual function, testicular ultrasound, hormones, sperm analysis, genetic analysis, clinical features and treatment. The control group included 25 age-matched healthy males. SLE patients had a lower median penis length and circumference [8 (7.5-10) vs. 10 (8-13) cm, p = 0.0001; 8 (7-10) vs. 10 (7-11) cm, p = 0.001; respectively], lower median testicular volume by right and left Prader [15 (10-25) vs. 20 (12-25) ml, p = 0.003; 15 (10-25) vs. 20 (12-25) ml, p = 0.006; respectively], higher median of follicle-stimulating hormone [5.8 (2.1-25) vs. 3.3 (1.9-9) IU/l, p = 0.002] and lower morning total testosterone levels (28% vs. 0%, p = 0.009) compared with controls. In spite of that, erectile dysfunction was not observed in patients or controls. Analyses of lupus patients revealed that the median penis circumference was lower in patients with disease onset before first ejaculation compared with those with disease onset after first ejaculation [7.8 (7-10) vs. 9.0 (7.5-10) cm, p = 0.026]. No differences were observed in the median penile anthropometry regarding sexual dysfunction (p = 0.610), lower morning total testosterone levels (p = 0.662), oligo/azoospermia (p = 0.705), SLE Disease Activity Index ≥ 4 (p = 0.562), Systemic Lupus International Collaborating Clinics/ACR Damage Index ≥ 1 (p = 0.478), prednisone cumulative dose (p = 0.789) and intravenous cyclophosphamide therapy (p = 0.754). Klinefelteŕs syndrome (46XY/47XXY) was diagnosed in one (4%) SLE patient with decreased penile size whereas Y-chromosomal microdeletions was absent in all of them. In conclusion, we have identified reduced penile dimensions in SLE patients with no deleterious effect in erectile function. Disease onset before first ejaculation seems to affect penis development in pre-pubertal lupus.

Intravenous cyclophosphamide pulse therapy in Japanese children with systemic lupus erythematosus.

PubMed

Igarashi, Toru; Igarashi, Tsutomu; Shimizu, Akira; Itoh, Yasuhiko

2013-01-01

Intravenous cyclophosphamide (IVCY) pulse therapy has been used for lupus nephritis since the latter half of the 1980s; it has been shown to be effective for lupus nephritis and vasculitis and has become a standard therapy for the diffuse proliferative type of lupus nephritis in adults. IVCY therapy has also come to be used in children. This paper reports the long-term outcomes of IVCY therapy in children. Six female patients (age range, 13 to 18 years) with systemic lupus erythematosus (SLE) were enrolled in this retrospective study. Three patients had lupus nephritis (World Health Organization class IIb, IVa, IVc), 2 had central nervous system (CNS) lupus, and 1 had neither lupus nephritis nor CNS lupus. The mean pretreatment SLE disease activity index (SLEDAI) score was 18.8 ± 4.6. Cyclophosphamide (initial dose, 500 mg/m(2)) was administered intravenously each month for 6 months and then given every 3 months for maintenance. Prednisolone was given in dosages ranging from 5 to 60 mg/day, adjusted according to laboratory data and clinical symptoms. Levels of C3, C4, CH50, and creatinine; the SLEDAI score; and the SLE responder index were monitored and evaluated. The SLE responder index was considered to have improved if the SLEDAI score had decreased by 4 points or more after 52 weeks. Prednisolone doses were reduced in all patients. Because methylprednisolone pulse therapy was administered before IVCY therapy, some patients had low titers of immunoglobin G antibodies against double-stranded DNA at the start of IVCY therapy. All patients had low serum creatinine levels. Proteinuria resolved in 1 of the 3 patients with lupus nephritis. The SLEDAI scores improved after 52 weeks in 5 of 6 patients (mean, 5.2 ± 2.6). No patients had severe bone marrow suppression or hemorrhagic cystitis during IVCY pulse therapy. IVCY pulse therapy for SLE in children achieved good long-term outcomes with no serious adverse effects, such as digestive symptoms, bone marrow suppression, infection, and hemorrhagic cystitis. IVCY pulse therapy for children with SLE has recently been approved by the Ministry of Health, Labour and Welfare. Accordingly, this paper might become a guideline for this treatment.

Enhanced IFN-α production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus.

PubMed

Murayama, Goh; Furusawa, Nanako; Chiba, Asako; Yamaji, Ken; Tamura, Naoto; Miyake, Sachiko

2017-10-19

Interferon-α (IFN-α) is increased and plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) are the main producer of IFN-α, but their IFN-α producing capacity has been shown to be unchanged or reduced when stimulated with a Toll-like receptor 9 (TLR9) agonist in patients with SLE compared to in healthy individuals. In this study, we investigated the IFN-α-producing capacity of lupus pDCs under different stimulation. pDCs from patients with SLE and healthy controls (HC) were stimulated with TLR9 or TLR7 agonist, and their IFN-α producing capacity was examined by intracellular cytokine staining and flow cytometry. The correlation of IFN-α-producing capacity with serum IFN-α levels and disease activity was assessed. The effect of in vitro IFN-α exposure on IFN-α production by pDCs was examined. Localization of TLR7 in cellular compartments in pDCs was investigated. The IFN-α producing capacity of pDCs was reduced after TLR9 stimulation, but increased when stimulated with a TLR7 agonist in SLE compared to in HC. IFN-α production by pDCs upon TLR9 stimulation was reduced and the percentage of IFN-α + pDC was inversely correlated with disease activity and serum IFN-α levels. However, the TLR7 agonist-induced IFN-α producing capacity of lupus pDCs was enhanced and correlated with disease activity and serum IFN-α. Exposure to IFN-α enhanced IFN-α production of TLR7-stimulated pDCs, but reduced that of pDCs activated with a TLR9 agonist. TLR7 localization was increased in late endosome/lysosome compartments in pDCs from SLE patients. These findings indicate that enhanced TLR7 responses of lupus pDCs, owing to TLR7 retention in late endosome/lysosome and exposure to IFN-α, are associated with the pathogenesis of SLE.

Serum from patients with SLE instructs monocytes to promote IgG and IgA plasmablast differentiation

PubMed Central

Joo, HyeMee; Coquery, Christine; Xue, Yaming; Gayet, Ingrid; Dillon, Stacey R.; Punaro, Marilynn; Zurawski, Gerard; Banchereau, Jacques; Pascual, Virginia

2012-01-01

The development of autoantibodies is a hallmark of systemic lupus erythematosus (SLE). SLE serum can induce monocyte differentiation into dendritic cells (DCs) in a type I IFN–dependent manner. Such SLE-DCs activate T cells, but whether they promote B cell responses is not known. In this study, we demonstrate that SLE-DCs can efficiently stimulate naive and memory B cells to differentiate into IgG- and IgA-plasmablasts (PBs) resembling those found in the blood of SLE patients. SLE-DC–mediated IgG-PB differentiation is dependent on B cell–activating factor (BAFF) and IL-10, whereas IgA-PB differentiation is dependent on a proliferation-inducing ligand (APRIL). Importantly, SLE-DCs express CD138 and trans-present CD138-bound APRIL to B cells, leading to the induction of IgA switching and PB differentiation in an IFN-α–independent manner. We further found that this mechanism of providing B cell help is relevant in vivo, as CD138-bound APRIL is expressed on blood monocytes from active SLE patients. Collectively, our study suggests that a direct myeloid DC–B cell interplay might contribute to the pathogenesis of SLE. PMID:22689824

Hyperthyroidism association with SLE, lessons from real-life data--A case-control study.

PubMed

Watad, Abdulla; Cohen, Arnon D; Comaneshter, Doron; Tekes-Manova, Dorit; Amital, Howard

2016-01-01

Despite the frequently encountered association between thyroid disease and systemic lupus erythematosus (SLE) is well known, it is of surprise that only several reports compromised of small population size support this observation. To investigate the association of comorbid SLE and hyperthyroidism. Using the database of the largest health maintenance organization (HMO) in Israel, the Clalit Health Services, we searched for the co-existence of SLE and hyperthyroidism. Patients with SLE were compared with age- and sex-matched controls regarding the prevalence of hyperthyroidism in a case-control study. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis. The study included 5018 patients with SLE and 25,090 age- and sex- matched controls. The prevalence of hyperthyroidism in patients with SLE was increased compared with the prevalence in controls (2.59% and 0.91%, respectively, p < 0.001). In a multivariate analysis, SLE was associated with hyperthyroidism (odds ratio 2.52, 95% confidence interval 2.028-3.137). Patients with SLE have a greater prevalence of hyperthyroidism than matched controls. Therefore, physicians treating patients with SLE should be aware of this possibility of this thyroid dysfunction.

Fibromyalgia prevalence and related factors in a large registry of patients with systemic lupus erythematosus.

PubMed

Torrente-Segarra, Vicenç; Salman-Monte, Tarek C; Rúa-Figueroa, Íñigo; Pérez-Vicente, Sabina; López-Longo, Francisco J; Galindo-Izquierdo, María; Calvo-Alén, Jaime; Olivé-Marqués, Alejandro; Ibañez-Ruán, Jesus; Horcada, Loreto; Sánchez-Atrio, Ana; Montilla, Carlos; Rodríguez-Gómez, Manuel; Díez-Álvarez, Elvira; Martinez-Taboada, Victor; Andreu, José L; Fernández-Berrizbeitia, Olaia; Hernández-Beriain, José A; Gantes, Marian; Hernández-Cruz, Blanca; Pecondón-Español, Ángela; Marras, Carlos; Bonilla, Gema; Pego-Reigosa, José M

2016-01-01

The objective of this study is to determine the prevalence of fibromyalgia (FM) in systemic lupus erythematosus (SLE) patients and to study its relationship to depression and other SLE-related factors. A cross-sectional data analysis from the RELESSER-Transversal Spanish Registry, which includes SLE patients in a national multicentre retrospective charts review, was performed. patients who fulfilled ≥4 ACR 1997 SLE criteria. Main variables were disease duration, depression, sociodemographics, comorbidities, SLE activity symptoms, serological findings, therapies and different disease status indices. Statistical analyses included a descriptive, associative and logistic regression analyses. A literature review was performed. 3,591 SLE patients were included, 90.1% women, 34.6 years of age at diagnosis (SD 14.6 years) and 93.1% Caucasians. FM prevalence was 6.2%. SLE patients with disease duration >5 years showed more FM than those with duration <5 years: 6.9% vs. 4.0%, respectively (p<0.05). SLE-FM patients showed higher prevalence of depression compared to non-FM-SLE patients: 53.1% vs. 14.6%, respectively (p<0.001). After adjusting by risk factors, the OR (CI) of suffering depression in FM-SLE patients was 6.779 (4.770-9.636), p<0.001. The OR of having secondary Sjögren's 2.447 (1.662-3.604), p<0.001, photosensitivity 2.184 (1.431-3.334), p<0.001, and oral ulcers 1.436 (1.005-2.051), p=0.047. Prevalence of FM in Caucasian SLE patients was high compared to the general population, and was significantly higher in those in later stages of disease. SLE patients with depression showed a strong risk of developing FM. Photosensitivity, oral ulcers and secondary Sjögren's were the only SLE-related factors associated with FM.

Arterial stiffening, wave reflection, and inflammation in habitually exercising systemic lupus erythematosus patients.

PubMed

Barnes, Jill N; Nualnim, Nantinee; Sugawara, Jun; Sommerlad, Shawn M; Renzi, Christopher P; Tanaka, Hirofumi

2011-11-01

Chronic systemic inflammation has been implicated in the pathogenesis of hypertension and cardiovascular disease. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic inflammation and an increased risk for cardiovascular disease. Currently few studies have evaluated the potential cardiovascular benefits of exercise in SLE. It is unknown whether the favorable effect of habitual exercise on arterial stiffness observed in healthy adults can be extended to SLE. Therefore, as an initial step, we determined the association between habitual exercise, inflammatory markers, central arterial compliance, and aortic wave reflection in healthy adults and SLE patients. We studied 41 adults, aged 33 ± 11 years (15 healthy controls, 12 sedentary SLE, and 14 physically active SLE patients). Age, body mass index, and metabolic risk factors were not different between the three groups. Carotid arterial compliance was lower whereas augmentation index (AI) and inflammatory markers (C-reactive protein (CRP), interleukin (IL)-12, tumor necrosis factor-α (TNF-α)) were higher in sedentary SLE patients compared with healthy controls, but were not different between physically active SLE patients and healthy controls. Cardiac ejection fraction was lower in sedentary SLE than physically active SLE or healthy controls. In the pooled population, carotid arterial compliance was inversely associated with TNF-α (r = -0.38; P < 0.01), and AI was positively associated with both CRP (r = 0.33; P < 0.05) and intercellular adhesion molecule-1 (r = 0.28; P < 0.05). SLE-associated stiffening of the central artery and wave reflection were not observed in habitually exercising adults with SLE. Furthermore, greater arterial stiffness was associated with higher inflammatory markers, suggesting that need for studies on inflammation and SLE-associated arterial stiffening.

Female polysomy-X and systemic lupus erythematosus.

PubMed

Slae, Mordechai; Heshin-Bekenstein, Merav; Simckes, Ari; Heimer, Gali; Engelhard, Dan; Eisenstein, Eli M

2014-02-01

Systemic lupus erythematosus (SLE) occurs more commonly in females than in males. Recent evidence suggests that genetic factors transmitted by the X-chromosome may confer increased risk for autoimmune disease in general, and for SLE in particular. It is therefore possible that X-chromosome polysomy might confer further increased risk for lupus. In addition to describing the clinical and immunologic features of a young woman with polysomy-X and SLE, we sought to review all other published cases associating female or male polysomy-X with SLE or other forms of autoimmunity. We report a case of a prepubertal girl with polysomy-X and SLE. We performed a systemic literature review for cases of polysomy-X and SLE and summarize previously published cases. In addition, we reviewed reports concerning the possible association between SLE and other connective tissue diseases and male polysomy-X. An 11-year-old girl with tetrasomy-X (48 XXXX karyotype) presented with prolonged fever. Workup led to the diagnosis of SLE, and subsequent renal biopsy revealed mild diffuse mesangial proliferative glomerulonephritis. Two additional cases of SLE in women with 47 XXX and one of 48 XXXX karyotype were found in a literature review and compared to the present case. We identified studies that found X-chromosome polysomy to be over-represented in male patients with SLE and case descriptions of connective tissue diseases occurring in patients with polysomy-X. No consistent pattern of disease was observed in female polysomy patients with SLE. Taken together with the data concerning the frequency of polysomy-X among males with SLE, our findings provide additional support for the hypothesis that X-chromosome polysomy may confer increased susceptibility to SLE. Molecular mechanisms that might account for this phenomenon are discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

Educational and vocational outcomes of adults with childhood- and adult-onset systemic lupus erythematosus: nine years of followup.

PubMed

Lawson, Erica F; Hersh, Aimee O; Trupin, Laura; von Scheven, Emily; Okumura, Megumi J; Yazdany, Jinoos; Yelin, Edward H

2014-05-01

To compare educational and vocational outcomes among adults with childhood-onset systemic lupus erythematosus (SLE) and adult-onset SLE. We used data derived from the 2002–2010 cycles of the Lupus Outcomes Study, a longitudinal cohort of 1,204 adult subjects with SLE. Subjects ages 18–60 years living in the US (n = 929) were included in the analysis and were classified as childhood-onset SLE if age at diagnosis was <18 years (n = 115). Logistic regression was used to assess the unadjusted and adjusted effect of childhood-onset SLE, sex, race/ethnicity, baseline age, urban or rural location, and US region on the likelihood of completing a bachelor's degree. Generalized estimating equations were used to assess the effect of childhood-onset SLE, demographics, education, and disease-related factors on the odds of employment, accounting for multiple observations over the study period. Subjects with childhood-onset SLE were on average younger (mean ± SD 29 ± 10 years versus 44 ± 9 years), with longer disease duration (mean ± SD 15 ± 10 years versus 11 ± 8 years). Subjects with adult-onset SLE and childhood-onset SLE subjects were equally likely to complete a bachelor's degree. However, subjects with childhood-onset SLE were significantly less likely to be employed, independent of demographic and disease characteristics (odds ratio 0.62, 95% confidence interval 0.42–0.91). While subjects with SLE are just as likely as those with adult-onset SLE to complete college education, childhood-onset SLE significantly increases the risk of not working in adulthood, even when controlling for disease and demographic factors. Exploring reasons for low rates of employment and providing vocational support may be important to maximize long-term functional outcomes in patients with childhood-onset SLE.

Pregnancy outcomes and contraceptive use in patients with systemic lupus Erythematosus, rheumatoid arthritis and women without a chronic illness: a comparative study.

PubMed

Galappatthy, Priyadarshani; Jayasinghe, Jayan D D; Paththinige, Sampath C; Sheriff, Rezvi M H; Wijayaratne, Lalith S

2017-06-01

To compare the pregnancy outcomes and contraceptive practices in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and women with no chronic illness (WNCI) in a tertiary care referral center in Colombo, Sri Lanka. Patients with SLE satisfying American College of Rheumatology criteria for diagnosis and history of pregnancies were recruited from university lupus clinic, National Hospital of Sri Lanka (NHSL). Age-matched women with history of pregnancy and RA were recruited from the rheumatology clinic, NHSL and WNCI from a surgical clinic. In 71 patients with SLE, 79 pregnancies occurred in 38 patients. The number of total pregnancies in SLE, RA and WNCI (79, 80 and 85 respectively) were not significantly different (P > 0.05), but most occurred before diagnosis of SLE and RA. Pregnancies occurring after diagnosis were significantly higher in SLE compared to RA (P = 0.013, χ 2 = 6.169). Mean age at diagnosis was higher (P < 0.01) in RA (35 years) than in SLE (26 years). Percentage live births after diagnosis was significantly lower (P < 0.01) in SLE (9/20; 45%) compared to RA (6/8; 75%) and WNCI (77/85; 91%). Adverse fetal outcomes (fetal loss, pre-maturity, low birth weight) and assisted deliveries were significantly more (P < 0.001) in SLE than in WNCI. Unplanned pregnancies were significantly higher (P < 0.01) in SLE (80%) compared to RA (25%) and in WNCI (9.4%). Contraceptive usage was lower in patients with SLE (25.6%) and RA (33%) compared to WNCI (56.4%). Disease exacerbations occurred in 20% of SLE patients during pregnancy. More pregnancies occur in SLE than in RA after diagnosis of illness. Unplanned pregnancies and adverse pregnancy outcomes need to be addressed more in SLE than in RA or in WNCI. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Antiphospholipid antibodies and non-thrombotic manifestations of systemic lupus erythematosus.

PubMed

İlgen, U; Yayla, M E; Ateş, A; Okatan, İ E; Yurteri, E U; Torgutalp, M; Keleşoğlu, A B D; Turgay, T M; Kınıklı, G

2018-04-01

Objectives The aim of this study was to investigate the association between antiphospholipid antibodies and non-thrombotic and non-gestational manifestations of systemic lupus erythematosus. Methods Systemic lupus erythematosus patients with persistently positive antiphospholipid antibodies or lupus anticoagulant were identified and grouped as systemic lupus erythematosus with antiphospholipid syndrome (SLE-APS), systemic lupus erythematosus with positive antiphospholipid antibodies/lupus anticoagulant without antiphospholipid syndrome (SLE-aPL), and systemic lupus erythematosus with negative aPLs (SLE-No aPL). Groups were compared in terms of non-thrombotic systemic lupus erythematosus manifestations and laboratory features retrospectively. Results A total of 150 systemic lupus erythematosus patients, 26 with SLE-APS, 25 with SLE-aPL, and 99 with SLE-No aPL, were identified. Livedo reticularis, neurologic involvement, and thrombocytopenia were more common in antiphospholipid antibody positive systemic lupus erythematosus cases. Malar rash, arthritis, and pleuritis were more common in the SLE-No aPL, SLE-APS, and SLE-aPL groups, respectively. Positivity rates and titers of specific antiphospholipid antibodies did not differ between the SLE-APS and SLE-aPL groups. Conclusions Presence of antiphospholipid syndrome or persistent antiphospholipid antibodies may be related to non-thrombotic and non-gestational systemic lupus erythematosus manifestations. Patients with systemic lupus erythematosus plus antiphospholipid syndrome and persistent antiphospholipid antibodies without antiphospholipid syndrome also differ in terms of systemic lupus erythematosus manifestations.

Retinal nerve fiber layer and macular thinning in systemic lupus erythematosus: an optical coherence tomography study comparing SLE and neuropsychiatric SLE.

PubMed

Liu, G Y; Utset, T O; Bernard, J T

2015-10-01

Due to the lack of reliable biomarkers in diagnosing and monitoring neuropsychiatric systemic lupus erythematosus (NPSLE), the aim of this study was to examine the utility of measurements obtained through spectral domain optical coherence tomography (SD-OCT) as a biomarker for NP involvement in SLE. Retinal nerve fiber layer (RNFL) and macula scans were performed using SD-OCT on 15 NPSLE patients, 16 SLE patients without NP symptoms (non-NP SLE), and 16 healthy controls. Macular volume and thickness of the central macula and peripapillary RNFL were compared between the groups and to scores on two validated cognitive tests. NPSLE patients did not differ significantly from non-NP SLE patients in retinal thickness or macular volume. However, SLE patients as a whole showed significant RNFL and macular thinning compared to controls. Scores on the Trail Making Test B, a test of complex attention, showed significant correlation to temporal superior and temporal inferior RNFL thickness. Our results demonstrate RNFL thinning in SLE, and confirm the previous finding of high incidence of abnormal brain scans in SLE. These findings suggest that OCT measurements may be indicative of neurodegeneration in SLE and may be a useful biomarker for early cognitive impairment in SLE. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

The Real Culprit in Systemic Lupus Erythematosus: Abnormal Epigenetic Regulation

PubMed Central

Wu, Haijing; Zhao, Ming; Chang, Christopher; Lu, Qianjin

2015-01-01

Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and the presence of anti-nuclear antibodies. The pathogenesis of SLE has been intensively studied but remains far from clear. B and T lymphocyte abnormalities, dysregulation of apoptosis, defects in the clearance of apoptotic materials, and various genetic and epigenetic factors are attributed to the development of SLE. The latest research findings point to the association between abnormal epigenetic regulation and SLE, which has attracted considerable interest worldwide. It is the purpose of this review to present and discuss the relationship between aberrant epigenetic regulation and SLE, including DNA methylation, histone modifications and microRNAs in patients with SLE, the possible mechanisms of immune dysfunction caused by epigenetic changes, and to better understand the roles of aberrant epigenetic regulation in the initiation and development of SLE and to provide an insight into the related therapeutic options in SLE. PMID:25988383

Assessment of fatigue in routine care on a Multidimensional Health Assessment Questionnaire (MDHAQ): a cross-sectional study of associations with RAPID3 and other variables in different rheumatic diseases.

PubMed

Castrejon, Isabel; Nikiphorou, Elena; Jain, Ruchi; Huang, Annie; Block, Joel A; Pincus, Theodore

2016-01-01

To characterise associations of fatigue with other variables within a multidimensional health assessment questionnaire (MDHAQ) in routine care of patients with different rheumatic diagnoses. All patients complete MDHAQ, which includes fatigue on a 0-10 visual analogue scale (VAS), and routine assessment of patient index data (RAPID3), a composite of function, pain, and patient global. Physicians complete a RheuMetric checklist which includes 4 VAS for overall global status (DOCGL), inflammation, damage, and distress. Median score for fatigue and other MDHAQ and RheuMetric scores were compared in 4 diagnosis groups: rheumatoid arthritis (RA), osteoarthritis (OA), systemic lupus erythematosus (SLE), and fibromyalgia (FM), using a Kruskall-Wallis test. Associations of fatigue with other variables were analysed using Spearman correlations and multivariate regressions. 612 patients were included: 173 RA, 199 with OA, 146 with SLE, and 94 with FM. Median fatigue was significantly higher in FM (7) than in RA (4), OA (5), and SLE (5). Fatigue was correlated significantly with all other MDHAQ scores, at higher levels in RA and SLE versus OA and FM. Fatigue was correlated significantly with DOCGL in RA, OA, SLE, but not FM. In multivariate analyses, fatigue scores were explained independently by higher pain and symptom number in RA; lower age and higher symptom number in OA; only higher pain in SLE; and none of the variables in FM. Fatigue is common in rheumatic diseases and strongly associated with higher pain and number of symptoms. The MDHAQ provides a useful tool to assess fatigue in clinical settings.

The Tie2 receptor antagonist angiopoietin-2 in systemic lupus erythematosus: its correlation with various disease activity parameters.

PubMed

Salama, Maysa K; Taha, Fatma M; Safwat, Miriam; Darweesh, Hanan E A; Basel, Mohamed El

2012-01-01

Systemic lupus erythematosus is one of the autoimmune diseases characterized by multisystem involvement associated with autoantibody and immune complex vasculitis along with endothelial cell damage. to study the possible role of Angiopoietin- 2 (Ang-2) as a recently highlighted inflammatory and angiogenic mediator in the pathogenesis of SLE and its correlation with the state of another inflammatory marker, P-Selectin, as well as with various markers of the disease activity. The present study included 3 main groups: active SLE patients (group I), inactive SLE patients (group II) and healthy normal control subjects (group III). Groups I and II were subjected to disease activity assessment using the SLEDAI scoring system and measurement of plasma Ang-2 and P-Selectin by ELISA in addition to various laboratory investigations to assess disease activity as: Complete blood count, ESR, serum creatinine, C3, C4 and 24-h urinary proteins. The mean level of Plasma Ang-2 and P-selectin showed a high significant increase in active group compared to inactive SLE patients and control subjects (p < 0.001).There was a significant positive correlation between Ang-2, P-Selectin, and each of SLEDAI score and 24-h urinary proteins in all SLE patients as well as in the active group, and Ang-2 was a significant independent marker for proteinuria. A significant negative correlation was found between Ang-2, P-Selectin and each of C3, C4. Ang-2 and P-Selectin showed a high sensitivity and specificity in the patients with SLE. Our study suggests that Ang-2 may be a more useful marker than P-Selectin, C3 and C4 in the assessment of disease activity.

Clinical Significance of Anti-Ribosomal P Protein Antibodies in Patients with Lupus Nephritis.

PubMed

Sarfaraz, Sabahat; Anis, Sabiha; Ahmed, Ejaz; Muzaffar, Rana

2018-04-09

Systemic lupus erythematosus (SLE) is achronic inflammatory disorder affecting multiplesystems of the body. Clinical features show wide variations in patients with different ethnic background. Renal involvement is a predictor of poor prognosis. Immunological workup is an integral part of SLE diagnostic criteria. Anti-ribosomal P Protein (anti-P) antibodies are highly specific for SLE. They may be present inantinuclear antibodies (ANA) negative SLE patients. Their role in lupus nephritis (LN) is under debate, some researchers found them associated with poor prognosiswhereasothers found favorable effect of these antibodies on renal disease. In this study we investigated frequency of anti-P antibodies and the effect of these antibodies on renal functions in LN patients. A total of 133SLE patientswere enrolled in this study. All patients had ANA in their sera. Anti-P antibodies along with other autoantibodiesagainstextractable nuclearantigens (anti-Sm, anti-SS-A, anti-SS-B, anti-histones and anti-RNP) were detected by Immunoblot assay. Anti-dsDNA antibodies were detected by indirect immunofluorescence assay (IFA). We found anti-P antibodies in 10.5% LN patients. Interestingly their presence in association with anti-dsDNA was associated with improved renal functions in comparison to those who had anti-dsDNA antibodies in isolation (serum creatinine: 1.3 ± 0.8 mg/dl vs. 3.0 ± 3.0; P= 0.091). Anti-dsDNA antibodies are directly involved in renal pathology in SLE patients. As these antibodies are nephrotoxic, concomitant occurrence of anti-P antibodies seems to offer a shielding effect on renal functions, which was evident by normal serum creatinine levels. Therefore anti-P antibodies may be considered as a good prognostic marker in these patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Association between polymorphisms in the promoter region of miR-17-92 cluster and systemic lupus erythematosus in a Chinese population.

PubMed

Wang, Rong; Wang, Chun-Fang; Qin, Hai-Mei; Lu, Yu-Lan; Wei, Gui-Jiang; Huang, Hua-Tuo; Xiang, Yang; Wang, Jun-Li; Lan, Yan; Wei, Ye-Sheng

2018-05-16

The aim of this study was to investigate the association of genetic polymorphisms in the promoter region of miR-17-92 with systemic lupus erythematosus (SLE). The gene polymorphism was analysed using SNaPshot in 312 SLE patients and 396 controls. Relative expression of miR-17-92 was measured by quantitative real-time PCR. Association was found between rs9515692 and a decreased risk of SLE (CT vs CC: OR = 0.65, 95%CI, 0.46-0.92, P = .014; CT+TT vs CC: OR = 0.64, 95%CI, 0.46-0.90, P = .009; T vs C: OR = 0.69, 95%CI, 0.52-0.92, P = .010, respectively). Haplotype analysis showed that C-G-G, C-A-A haplotypes were associated with an increased SLE risk (OR=4.46, 95%CI, 2.17-9.17, P < 0.001; OR=2.33, 95%CI, 1.44-3.76, P < 0.001, respectively). T allele and CT+TT genotypes in rs9515692 were associated with decreased risk of anti-dsDNA in SLE (CT+TT vs CC: OR = 0.42, 95%CI = 0.24-0.72, P = .002; T vs A: OR = 0.49, 95%CI = 0.31-0.79, P = .003). Moreover, rs9515692 CT+TT genotypes had a higher level of miR-17 as compared to CC genotype (P = .017). These findings suggest that the rs9515692 CT+TT genotypes were a protective factor for the susceptibility of SLE, probably by increasing the expression of miR-17. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Parental history of lupus and rheumatoid arthritis and risk in offspring in a nationwide cohort study: does sex matter?

PubMed

Somers, Emily C; Antonsen, Sussie; Pedersen, Lars; Sørensen, Henrik Toft

2013-04-01

To examine the familial risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), including juvenile rheumatoid/idiopathic arthritis (JRA), in a population-based setting; and to determine whether patterns of transmission differ according to the sex of the parent or offspring, in order to provide insight into the potential impact of X-chromosomal factors on sex disparities in these autoimmune diseases. A population-based cohort of parent-offspring triads from Denmark (1977-2010) was established. SLE and RA incidence rates among offspring were calculated, and Cox regression was performed to assess the sex-specific risk of disease in offspring according to maternal or paternal disease history. Among 3 513 817 parent-offspring triads, there were 1258 SLE cases among offspring (1095 female, 163 male) and 9118 cases of RA/JRA (6086 female, 3032 male). Among female offspring, SLE risk was nearly the same according to maternal (HR 14.1) or paternal (HR 14.5) history (p=NS); likewise among male offspring, risk according to maternal (HR 5.5) and paternal (no cases) history were similar (p=NS). For RA, all risk estimates were similar, regardless of the sex of the offspring or parent (HR 2.6-2.9; p=NS). The authors quantified the familial risk of SLE and RA in a nationwide cohort study. For both diseases, transmission was comparable among both female and male offspring of maternal and paternal cases. These data provide evidence at the population level that X-chromosomal factors do not play a major role in sex disparities associated with the risk of SLE and RA.

Disease characterization of systemic lupus erythematosus (SLE) patients in Quebec.

PubMed

Ng, R; Bernatsky, S; Rahme, E

2017-08-01

Objective Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by an array of organ manifestations that can appear during flares and disappear during remissions. The objectives of this study were: (i) to examine SLE manifestation groups longitudinally in an SLE cohort; and (ii) to assess the association between early antimalarial treatment and renal manifestations. Methods Seven SLE manifestation groups-cutaneous, hematologic, lung, musculoskeletal, neuropsychiatric, serositis, renal-were tracked using Kaplan-Meier survival curves in an incident SLE cohort from Quebec health administrative data ( n = 2010). A subgroup with provincial drug insurance coverage was followed over time to examine the association between early antimalarial treatment (within three months after SLE diagnosis) and renal manifestations using a Cox proportional hazards survival model. Results Cutaneous manifestations was the most common manifestation at SLE diagnosis (30.0%, 95% CI: 27.7-32.2%). About two-thirds (66.2%, 95% CI: 63.4-68.9%) of patients had evidence of at least one SLE manifestation at diagnosis, which increased to 87.2% (95% CI: 84.2-90.3%) by the end of follow-up. After adjusting for age, sex, early concomitant systemic steroid therapy, Charlson comorbidity index, primary care visits in the year prior and other SLE manifestations at baseline, no statistically significant association was established between antimalarial therapy and renal manifestations. Conclusion This study provides insight regarding organ manifestations within a population-based sample. Most patients identified with SLE had other diagnostic evidence that supports an underlying diagnosis of SLE. No protective effects for antimalarial agents against renal manifestations could be established in this population-based cohort.

Chicken or the egg: anorexia nervosa and systemic lupus erythematosus in children and adolescents.

PubMed

Toulany, Alene; Katzman, Debra K; Kaufman, Miriam; Hiraki, Linda T; Silverman, Earl D

2014-02-01

Systemic lupus erythematosus (SLE) frequently has neuropsychiatric involvement including affective disorders, psychosis, and cognitive dysfunction. Evidence suggests that anorexia nervosa (AN) in adolescents with SLE may be triggered by steroid-induced changes in weight and body shape. We propose that AN may be another manifestation of neuropsychiatric SLE and should be considered in this patient population. A retrospective chart review identified 7 children/adolescents diagnosed with SLE and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria for AN, restrictive subtype, at the Hospital for Sick Children in Toronto between January 1989 and January 2011. One patient developed AN 15 months after being diagnosed with SLE that was attributed to prednisone-induced weight gain and cushingoid appearance. Of the remaining 6 patients, the median age at onset of AN symptoms was 12.2 years and diagnosis of AN was 13.6 years. The median age at SLE diagnosis was 14.2 years with median time after onset of AN symptoms of 20 months (7.5-32 months). All patients had evidence of joint symptoms and a positive antinuclear antibody, and 50% had lymphopenia at the time of SLE diagnosis. Treatment of SLE resulted in improvement of AN in all patients. The timing of the clinical presentation of AN in relation to the diagnosis of SLE and response to SLE treatment suggests that AN may be a novel presentation of neuropsychiatric SLE. Patients with AN who present with or develop joint symptoms, a positive antinuclear antibody, or lymphopenia should be investigated and followed for possible SLE.

Estrogen in cardiovascular disease during systemic lupus erythematosus.

PubMed

Gilbert, Emily L; Ryan, Michael J

2014-12-01

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension. PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed. The potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against cardiovascular risk factors in adulthood. In addition, increasing evidence suggests that estrogen may have distinct temporal effects on cardiovascular risk factors during SLE. Data from experimental models of lupus suggest that estrogens may have an important permissive role for developing SLE early in life. However, their role in adulthood remains unclear, particularly for the effect on cardiovascular disease and its risk factors. Additional work is needed to understand the effect of estrogens in human SLE, and preclinical studies in experimental models of SLE may contribute important mechanistic insight to further advance the field. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Estrogen in Cardiovascular Disease during Systemic Lupus Erythematosus

PubMed Central

Gilbert, Emily L.; Ryan, Michael J.

2015-01-01

Purpose Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension. Methods PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed. Findings The potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against cardiovascular risk factors in adulthood. In addition, increasing evidence suggests that estrogen may have distinct temporal effects on cardiovascular risk factors during SLE. Implications Data from experimental models of lupus suggest that estrogens may have an important permissive role for developing SLE early in life. However, their role in adulthood remains unclear, particularly for the effect on cardiovascular disease and its risk factors. Additional work is needed to understand the effect of estrogens in human SLE, and preclinical studies in experimental models of SLE may contribute important mechanistic insight to further advance the field. PMID:25194860

The management of pediatric systemic lupus erythematosus.

PubMed

Ardoin, Stacy P; Schanberg, Laura E

2005-12-01

Most children and adolescents with systemic lupus erythematosus (SLE) now survive into adulthood, leading the pediatric rheumatology community to focus on preventing long-term complications of SLE, including atherosclerosis, obesity, and osteoporosis, and their treatment. Unfortunately, because of the paucity of data in pediatric SLE, little is known about epidemiology, long-term outcome, and optimal treatment. Most research focuses on adults with SLE, but pediatric SLE differs significantly from adult SLE in many aspects, including disease expression, approaches to pharmacologic intervention, management of treatment toxicity, and psychosocial issues. Children and adolescents with SLE require specialized, multidisciplinary care. Treatment can be optimized by early recognition of disease flares and complications, minimizing medication toxicity, educating families about prevention, promoting school performance, addressing concerns about reproductive health, and negotiating the transition to adult-centered medical care. Developmentally appropriate concerns about pain, appearance, and peers often affect treatment adherence and must be addressed by the health-care team. Research in pediatric SLE is desperately needed and provides a unique opportunity to understand how developmental immunology and the hormonal changes associated with puberty affect the pathophysiology of SLE.

Serological and Genetic Evidence for Altered Complement System Functionality in Systemic Lupus Erythematosus: Findings of the GAPAID Consortium.

PubMed

Prechl, József; Papp, Krisztián; Hérincs, Zoltán; Péterfy, Hajna; Lóránd, Veronika; Szittner, Zoltán; Estonba, Andone; Rovero, Paolo; Paolini, Ilaria; Del Amo, Jokin; Uribarri, Maria; Alcaro, Maria Claudia; Ruiz-Larrañaga, Otsanda; Migliorini, Paola; Czirják, László

2016-01-01

Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, complement deposition on tested protein and lipid autoantigens showed positive correlation with C4 levels. Genetic analysis revealed that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) had lower levels of dsDNA specific IgM among SLE patients. Both the non-synonymous variant rs1143679 and the high ratio of nucleic acid specific IgG/IgM were associated with multiple organ involvement. In summary, secondary complement deficiency in SLE does not impair opsonization of nucleic-acid-containing autoantigens but does affect other antigens and potentially other complement dependent processes. Dysfunction of the receptor recognizing complement opsonized immune complexes promotes the development of class-switched autoantibodies targeting nucleic acids.

The potential protective role of hepatitis B virus infection in pristane-induced lupus in mice.

PubMed

Liu, X; Jiao, Y; Cui, B; Gao, X; Xu, J; Zhao, Y

2016-10-01

The objective of this study was to investigate whether hepatitis B virus (HBV) infection plays a role in the regulation of autoimmunity for systemic lupus erythematosus (SLE). A total of 21 female BALB/c mice and 21 female HBV transgenic BALB/c mice aged two months were randomly divided into four groups: BALB/c mice, HBV(Tg) mice, pristane-injected BALB/c mice, and pristane-injected HBV(Tg) mice. BALB/c mice and HBV(Tg) mice were given an intraperitoneal injection of 0.5 ml normal saline, and the mice in the other two groups were given an intraperitoneal injection of 0.5 ml pristane. ANA and anti-dsDNA levels in serum were detected by indirect immunofluorescence. Interleukin 2 (IL-2), IL-4, IL-6, IL-17, and TNF-α were measured by Luminex technology. The serum BAFF level was measured using an Elisa kit. Twenty-four weeks after pristane administration, kidneys were removed, dissected, and stained with hematoxylin and eosin and periodic-acid Schiff. At six months after injecting, the ANA titers in pristane-injected HBV(Tg) mice were significantly lower than pristane-injected BALB/c mice. IL-17, TNF-α, and BAFF levels were significantly higher in pristane-injected BALB/c mice than BALB/c mice and pristane-injected HBV(Tg) mice. IL-2, IL-4, and IL-6 levels were much higher in pristane-injected HBV(Tg) mice than pristane-injected BALB/c mice. In pristane-injected HBV(Tg) mice and HBV(Tg) mice, fewer glomerulonephritis changes were found in the kidneys. Our results showed that the incidence of SLE was much lower in HBV(Tg) mice, and that HBV infection helped the SLE mice survive high levels of inflammatory cytokines and severe renal damage. All these findings demonstrated the protective role of HBV in SLE patients via the immunoregulatory networks of the cytokines. © The Author(s) 2016.

ACADEMIC OUTCOMES IN CHILDHOOD-ONSET SYSTEMIC LUPUS ERYTHEMATOSUS

PubMed Central

Zelko, Frank; Beebe, Dean; Baker, Aimee; Nelson, Shannen M; Ali, Aisha; Cedeno, Adlin; Dina, Blair; Klein-Gitelman, Marisa S; Ying, Jun; Brunner, Hermine I

2012-01-01

Objective To explore academic outcomes in childhood-onset systemic lupus erythematosus (cSLE) and their relationship to variables such as demographic and socioeconomic status, neurocognitive functioning, behavioral/emotional adjustment, and cSLE disease status. Methods Forty pairs of children diagnosed with cSLE and healthy best-friend controls were rated by parents on a standardized scale of school competence. Information about participants’ demographic and socioeconomic status was obtained, along with measures of cSLE disease activity and damage. All participants received formal neurocognitive testing and were also rated on standardized scales of behavioral/emotional adjustment and executive functioning. Results Compared to healthy controls, school competence was rated as lower in the cSLE group, although the groups did not differ significantly on indices of cognitive, behavioral, emotional, or executive functioning. School competence ratings were correlated with reading and mathematics achievement test scores in both groups, and with ratings of mental self-regulation in the cSLE group. School competence ratings were correlated with measures of cSLE disease activity and treatment intensity. Conclusion cSLE is associated with inferior parent-rated academic outcomes compared to those noted in demographically-matched peers, despite similar neurocognitive function. The adverse academic outcomes which distinguish children with cSLE from their demographically-matched peers appear to be mediated by SLE disease activity and treatment. PMID:22807373

Greenland ice sheet surface mass-balance modeling in a 131-year perspective, 1950-2080

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mernild, Sebastian Haugard; Liston, Glen; Hiemstra, Christopher

2009-01-01

Fluctuations in the Greenland Ice Sheet (GrIS) surface mass-balance (SMB) and freshwater influx to the surrounding oceans closely follow climate fluctuations and are of considerable importance to the global eustatic sea level rise. SnowModel, a state-of-the-art snow-evolution modeling system, was used to simulate variations in the GrIS melt extent, surface water balance components, changes in SMB, and freshwater influx to the ocean. The simulations are based on the IPCC scenario AlB modeled by the HIRHAM4 RCM (using boundary conditions from ECHAM5 AOGCM) from 1950 through 2080. In-situ meteorological station (GC-Net and WMO DMI) observations from inside and outside the GrISmore » were used to validate and correct RCM output data before it was used as input for SnowModel. Satellite observations and independent SMB studies were used to validate the SnowModel output and confirm the model's robustness. We simulated a {approx}90% increase in end-of-summer surface melt extent (0.483 x 10{sup 6} km{sup 2}) from 1950 to 2080, and a melt index (above 2,000-m elevation) increase of 138% (1.96 x 10{sup 6} km{sup 2} x days). The greatest difference in melt extent occured in the southern part of the GrIS, and the greatest changes in the number of melt days was seen in the eastern part of the GrIS ({approx}50-70%) and was lowest in the west ({approx}20-30%). The rate of SMB loss, largely tied to changes in ablation processes, lead to an enhanced average loss of 331 km{sup 3} from 1950 to 2080, an average 5MB level of -99 km{sup 3} for the period 2070-2080. GrIS surface freshwater runoff yielded an eustatic rise in sea level from 0.8 {+-} 0.1 (1950-1959) to 1.9 {+-} 0.1 mm (2070-2080) sea level equivalent (SLE) y{sup -1}. The accumulated GrIS freshwater runoff contribution from surface melting equaled 160 mm SLE from 1950 through 2080.« less

Migraine is frequent in patients with systemic lupus erythematosus: a case-control study.

PubMed

Tjensvoll, Anne B; Harboe, Erna; Gøransson, Lasse G; Beyer, Mona K; Greve, Ole J; Herigstad, Anita; Kvaløy, Jan T; Omdal, Roald

2011-03-01

The objective of this study was to compare the prevalence of primary headaches in systemic lupus erythematosus (SLE) versus healthy subjects, and to determine whether headaches in SLE are associated with MRI- or cerebrospinal fluid (CSF) abnormalities. The case-control study included MRI- and CSF investigations. Headache was classified according to the International Classification of Headache Disorders. Depression and fatigue were measured with Beck Depression Inventory (BDI) and Fatigue Severity Scale (FSS) respectively. Twenty-four out of 67 SLE patients and 13 out of 67 age- and gender matched healthy subjects had migraine (36% vs 19%, P = 0.03). Nine (13%) SLE patients had migraine with aura vs 4 (6%) in healthy subjects, P = 0.14. The prevalence of tension type headache was equal (60% in patients vs 58% in controls). There was no association between migraine and SLE disease activity, biochemical or immunological markers, cerebral white matter hyperintensities, interleukin-6 in CSF, impairment of the blood-brain barrier, or intrathecal immunoglobulin production. SLE patients had higher BDI- and FSS scores compared with healthy control subjects, and SLE patients with migraine had higher BDI scores than lupus patients without migraine. Migraine is more prevalent in SLE patients, associated with depression like in the general population, but not associated with disease activity or abnormalities detected on cerebral MRI, in CSF, or any SLE characteristics except from SLE photosensitivity. The inclusion of the migraine item in SLE disease activity instruments remains questionable.

An evidence-based approach to pre-pregnancy counselling for patients with systemic lupus erythematosus.

PubMed

Teng, Y K Onno; Bredewold, Edwin O W; Rabelink, Ton J; Huizinga, Tom W J; Eikenboom, H C Jeroen; Limper, Maarten; Fritsch-Stork, Ruth D E; Bloemenkamp, Kitty W M; Sueters, Marieke

2017-11-20

Patients with SLE are often young females of childbearing age and a pregnancy wish in this patient group is common. However, SLE patients are at high risk for adverse pregnancy outcomes that require adequate guidance. It is widely acknowledged that pre-pregnancy counselling is the pivotal first step in the management of SLE patients with a wish to become pregnant. Next, management of these patients is usually multidisciplinary and often requires specific expertise from the different physicians involved. Very recently a EULAR recommendation was published emphasizing the need for adequate preconception counselling and risk stratification. Therefore the present review specifically addresses the issue of pre-pregnancy counselling for SLE patients with an evidence-based approach. The review summarizes data retrieved from recently published, high-quality cohort studies that have contributed to a better understanding and estimation of pregnancy-related risks for SLE patients. The present review categorizes risks from a patient-oriented point of view, that is, the influence of pregnancy on SLE, of SLE on pregnancy, of SLE on the foetus/neonate and of SLE-related medication. Lastly, pre-pregnancy counselling of SLE patients with additional secondary APS is reviewed. Collectively these data can guide clinicians to formulate appropriate preventive strategies and patient-tailored monitoring plans during pre-pregnancy counselling of SLE patients. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Emerging therapies in systemic lupus erythematous: from clinical trial to the real life.

PubMed

Zhang, Huza; Chambers, William; Sciascia, Savino; Cuadrado, Maria J

2016-01-01

Systemic lupus erythematous (SLE) is a chronic autoimmune disease characterised by multisystem involvement and a relapsing remitting course. SLE is a highly heterogeneous condition, with wide variations in both the presentation and severity of disease and the biological markers identified. The use of biologics in SLE has lagged behind that of other rheumatological conditions such as rheumatoid arthritis, in part due to the diverse clinical manifestations of SLE, making it difficult to design appropriate trials for novel treatments. As such, broad immunosuppressive treatment regimens are still widely used in SLE. Nevertheless, in recent years, elucidation of some aspects of SLE pathogenesis have allowed the development of therapies targeted at molecular mediators of SLE. This review provides an update of biological available therapies and those currently under development.

Tofacitinib ameliorates murine lupus and its associated vascular dysfunction

PubMed Central

Furumoto, Yasuko; Smith, Carolyne K.; Blanco, Luz; Zhao, Wenpu; Brooks, Stephen R.; Thacker, Seth G; Abdalrahman, Zarzour; Sciumè, Giuseppe; Tsai, Wanxia L.; Trier, Anna M.; Nunez, Leti; Mast, Laurel; Hoffmann, Victoria; Remaley, Alan T.; O'Shea, John J.

2016-01-01

Objectives Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. To date, no drug targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a Janus kinase (JAK) inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and on its associated vascular pathology remains to be characterized. Methods MRL/lpr lupus-prone mice received tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum autoantibody levels and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular trap (NET) release, endothelium-dependent vasorelaxation and endothelial differentiation were compared in treated and untreated mice. Results Treatment with tofacitinib led to significant improvement in measures of disease activity including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of pro-inflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated NET formation and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective as both preventive and therapeutic strategies. Conclusions Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage. PMID:27429362

Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction.

PubMed

Furumoto, Yasuko; Smith, Carolyne K; Blanco, Luz; Zhao, Wenpu; Brooks, Stephen R; Thacker, Seth G; Abdalrahman, Zarzour; Sciumè, Giuseppe; Tsai, Wanxia L; Trier, Anna M; Nunez, Leti; Mast, Laurel; Hoffmann, Victoria; Remaley, Alan T; O'Shea, John J; Kaplan, Mariana J; Gadina, Massimo

2017-01-01

Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. No drug to date targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a JAK inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and the associated vascular pathology remains to be characterized. MRL/lpr lupus-prone mice were administered tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum levels of autoantibodies and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular traps (NETs) release, endothelium-dependent vasorelaxation, and endothelial differentiation were compared in treated and untreated mice. Treatment with tofacitinib led to significant improvement in measures of disease activity, including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of proinflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated the formation of NETs and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective in both preventive and therapeutic strategies. Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus, and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage. © 2016, American College of Rheumatology.

Levels and temporal trends of toxaphene congeners in beluga whales (Delphinapterus leucas) from the St. Lawrence Estuary, Canada.

PubMed

Gouteux, Bruno; Lebeuf, Michel; Muir, Derek C G; Gagné, Jean-Pierre

2003-10-15

Environmentally relevant toxaphene congeners were determined in blubber samples of stranded beluga whales (Delphinapterus leucas) from the St. Lawrence Estuary (SLE), Canada. The purpose of this study was to evaluate the levels and the temporal trends (1988-1999) of a suite of six chlorobornanes (P26, P40/41, P44, P50, and P62) in the SLE belugas. P26 and P50 mean concentrations were in the same range as those reported for animals living in the Arctic environment suggesting that the atmospheric transport represents the main input of toxaphene to the SLE. A general exponential decline of chlorobornane concentrations in belugas was observed, except for P26 and P50 in males. On average, concentrations decreased by a factor of two in 8.5 years during the 1988-1999 time period. This rate of decline is similar to the reduction of toxaphene emission from agricultural soils in the southern United States reported over the same time period. Some differences in decline rates were observed among the studied CHB congeners. For instance, P62 decreased more rapidly than P26 and P50 in both male and female belugas. Several hypotheses were advanced to explain these differences such as selective metabolism of specific chlorobornanes by SLE belugas or their prey. However, a most likely explanation is the selective degradation of the technical product in soils and atmosphere in the source region.

Lupus Band Test in Patients with Borderline Systemic Lupus Erythematosus with Discoid Lesions.

PubMed

Akarsu, Sevgi; Ozbagcivan, Ozlem; Ilknur, Turna; Semiz, Fatma; Lebe, Banu; Fetil, Emel

2017-04-01

Patients with lupus erythematosus (LE) that have discoid lesions who fulfill the four diagnostic criteria of systemic lupus erythematosus (SLE) with only mucocutaneous findings and antinuclear antibody (ANA) positivity were classified as borderline SLE in the literature. Objective of this study was to determine the place of borderline SLE with discoid lesions on the LE spectrum according to the lupus band test (LBT). Lesional and sun-protected non-lesional (SPNL) skin LBTs of 94 patients with LE that had discoid lesions were retrospectively evaluated. Firstly, patients were divided into two main groups: discoid LE (DLE; group A) and SLE (Group B); three subgroups were then classified as DLE (Group A), borderline SLE (Group B1) and SLE (Group B2) using another method. Each group had its own comparisons. Immunoreactant (IR) deposition was observed on the lesional skin in all patients and on the SPNL skin in 42 (44.7%). In patients with borderline SLE, the deposition of IgM was lower on the lesional LBTs, whereas isolated IgG was higher than SLE; thus, it shows similarity with DLE. Additionally, it was also closer to DLE because of the low deposition of C3, multiple IRs, and a double conjugate of IRs on the SPNL skin. However, it showed similarity with SLE in the high percentage of LBT positivity and more immunoglobulin M (IgM) and immunoglobulin G (IgG) deposition on the SPNL skin. The deposition of multiple conjugates on SPNL skin in patients with LE with discoid lesions may reflect systemic involvement. Despite the fact that LBT positivity on SPNL skin in borderline SLE was higher than DLE, less deposition of multiple conjugates compared to SLE indicates that the classification of borderline SLE with discoid lesions in the LE spectrum is questionable.

Suicide attempts in patients with systemic lupus erythematosus: a single-center experience and literature review.

PubMed

Tang, Kuo-Tung; Hsieh, Chia-Wei; Hsieh, Tsu-Yi; Lan, Joung-Liang; Chen, Yi-Hsing; Chen, Der-Yuan

2015-01-01

Suicide is a global health issue, and an increase in suicide risk has been found in patients with systemic lupus erythematosus (SLE) when compared with the general population. However, only a few studies have described suicide attempts in patients with SLE in detail. The aim of this study is to describe the suicide attempts in patients with SLE in a tertiary hospital in Taiwan. A total of 8 patients with SLE, 7 women and 1 man, with 12 suicide attempts among them were identified among 2469 patients visiting a tertiary medical center in Taiwan, from March 1, 2003 to November 30, 2013. Their demographic data, lupus manifestations throughout their disease course, laboratory data, and details of their suicide attempts were retrospectively documented. We also searched the MEDLINE database and found 4 articles in English describing suicide attempts in 14 patients with SLE. The median age of the 8 patients with SLE in our hospital who attempted suicide was 33 years (range: 19-77 years). Neuropsychiatric SLE developed in 5 (63%) of these patients before the attempts, and psychiatric disorders were diagnosed in 5 (63%) of them. We also observed a high prevalence of neuropsychiatric SLE (71%) and psychiatric disorders (86%) in patients with SLE in the literature who had attempted suicide. We demonstrated that previous neuropsychiatric SLE and comorbid psychiatric disorders are prevalent in patients with SLE who attempt suicide. If a rheumatologist suspects that a patient with SLE has a psychiatric disorder, he or she should refer the patient to a psychiatrist. Copyright © 2015 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Evidence for the Detection of Subclinical Retinal Involvement in Systemic Lupus Erythematosus and Sjögren Syndrome: A Potential Association with Therapies.

PubMed

Conigliaro, Paola; Triggianese, Paola; Draghessi, Gianluca; Canofari, Claudia; Aloe, Gianluca; Chimenti, Maria Sole; Valeri, Claudia; Nucci, Carlo; Perricone, Roberto; Cesareo, Massimo

2018-06-14

Retinal involvement in systemic lupus erythematosus (SLE) and Sjögren syndrome (SS) may be subclinical and thus underdiagnosed. We aimed at evaluating morphological and functional visual abnormalities in a cohort of SLE and SS patients in the absence of an overt clinical visual impairment. We also investigated potential associations between retinal disorders and disease activity, organ involvement, and treatment with steroid and/or hydroxychloroquine. The study comprised 42 SLE and 36 primary SS patients and 76 healthy controls (HC). Ophthalmological examination, standard automated perimetry, spectral-domain optical coherence tomography, and fundus perimetry were performed. Retinal thickness of the posterior pole was not different between SLE and HC groups, but it was reduced in the SS group compared with both the HC and the SLE group. In SLE and SS patients, mean defect and pattern standard deviation by standard automated perimetry were higher than in HC. Visual field index values were lower in both SLE and SS patients than in HC. SLE patients with nephritis displayed increased mean defect and pattern standard deviation and reduced visual field index values compared to patients without nephritis. In SLE and SS patients, fundus perimetry differential sensitivity was reduced, and mean defect values were higher than in HC. Disturbances in fundus perimetry in the SLE group were more prevalent in steroid-naïve patients and in SS patients who received a cumulative hydroxychloroquine dose > 1,000 g. Functional eye impairment was demonstrated in SLE patients, possibly associated with kidney involvement. In SLE, corticosteroids might exert a protective role. Morphological alterations and functional impairment were detected in SS patients, which may be linked to hydroxychloroquine toxicity. © 2018 S. Karger AG, Basel.

Validation of Systemic Lupus Erythematosus Diagnosis as the Primary Cause of Renal Failure in the US Renal Data System.

PubMed

Broder, Anna; Mowrey, Wenzhu B; Izmirly, Peter; Costenbader, Karen H

2017-04-01

Using American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC) criteria for systemic lupus erythematosus (SLE) classification as gold standards, we determined sensitivity, specificity, positive and negative predictive values (PPV and NPV) of having SLE denoted as the primary cause of end-stage renal disease (ESRD) in the US Renal Data System (USRDS). ESRD patients were identified by International Classification of Diseases, Ninth Revision codes in electronic medical records of 1 large tertiary care center, Montefiore Hospital, from 2006 to 2012. Clinical data were extracted and reviewed to establish SLE diagnosis. Data were linked by social security number, name, and date of birth to the USRDS, where primary causes of ESRD were ascertained. Of 7,396 ESRD patients at Montefiore, 97 met ACR/SLICC SLE criteria, and 86 had SLE by record only. Among the 97 SLE patients, the attributed causes of ESRD in the USRDS were 77 SLE and 12 with other causes (unspecified glomerulonephritis, hypertension, scleroderma), and 8 missing. Sensitivity, specificity, PPV, and NPV for SLE in the USRDS were 79%, 99.9%, 93%, and 99.7%, respectively. Of the 60 patients with biopsy-proven lupus nephritis, 44 (73%) had SLE as primary ESRD cause in the USRDS. Attribution of the primary ESRD causes among SLE patients with ACR/SLICC criteria differed by race, ethnicity, and transplant status. The diagnosis of SLE as the primary cause of ESRD in the USRDS has good sensitivity, and excellent specificity, PPV, and NPV. Nationwide access to medical records and biopsy reports may significantly improve sensitivity of SLE diagnosis. © 2016, American College of Rheumatology.

The role of dietary sodium intake on the modulation of T helper 17 cells and regulatory T cells in patients with rheumatoid arthritis and systemic lupus erythematosus

PubMed Central

Massaro, Laura; Barbati, Cristiana; Vomero, Marta; Ceccarelli, Fulvia; Spinelli, Francesca Romana; Riccieri, Valeria; Spagnoli, Alessandra; Alessandri, Cristiano; Desideri, Giovambattista; Conti, Fabrizio

2017-01-01

We aimed at investigating whether the frequency and function of T helper 17 (Th17) and regulatory T cells (Treg) are affected by a restriction of dietary sodium intake in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We enrolled RA and SLE patients not receiving drugs known to increase urinary sodium excretion. Patients underwent a dietary regimen starting with a restricted daily sodium intake followed by a normal-sodium daily intake. The timepoints were identified at baseline (T0), after 3 weeks of low-sodium dietary regimen (T3), after 2 weeks of normal-sodium dietary regimen (T5). On these visits, we measured the 24-hour urinary sodium excretion, the frequency and function of Th17 and Treg cells in the peripheral blood, the serum levels of cytokines. Analysis of urinary sodium excretion confirmed adherence to the dietary regimen. In RA patients, a trend toward a reduction in the frequencies of Th17 cells over the low-sodium dietary regimen followed by an increase at T5 was observed, while Treg cells exhibited the opposite trend. SLE patients showed a progressive reduction in the percentage of Th17 cells that reached a significance at T5 compared to T0 (p = 0.01) and an increase in the percentage of Treg cells following the low-sodium dietary regimen at both T1 and T3 compared to T0 (p = 0.04 and p = 0.02, respectively). No significant apoptosis or proliferation modulation was found. In RA patients, we found a reduction at T5 compared to T0 in serum levels of both TGFβ (p = 0.0016) and IL-9 (p = 0.0007); serum IL-9 levels were also reduced in SLE patients at T5 with respect to T0 (p = 0.03). This is the first study investigating the effects of dietary sodium intake on adaptive immunity. Based on the results, we hypothesize that a restricted sodium dietary intake may dampen the inflammatory response in RA and SLE patients. PMID:28877244

The role of dietary sodium intake on the modulation of T helper 17 cells and regulatory T cells in patients with rheumatoid arthritis and systemic lupus erythematosus.

PubMed

Scrivo, Rossana; Massaro, Laura; Barbati, Cristiana; Vomero, Marta; Ceccarelli, Fulvia; Spinelli, Francesca Romana; Riccieri, Valeria; Spagnoli, Alessandra; Alessandri, Cristiano; Desideri, Giovambattista; Conti, Fabrizio; Valesini, Guido

2017-01-01

We aimed at investigating whether the frequency and function of T helper 17 (Th17) and regulatory T cells (Treg) are affected by a restriction of dietary sodium intake in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We enrolled RA and SLE patients not receiving drugs known to increase urinary sodium excretion. Patients underwent a dietary regimen starting with a restricted daily sodium intake followed by a normal-sodium daily intake. The timepoints were identified at baseline (T0), after 3 weeks of low-sodium dietary regimen (T3), after 2 weeks of normal-sodium dietary regimen (T5). On these visits, we measured the 24-hour urinary sodium excretion, the frequency and function of Th17 and Treg cells in the peripheral blood, the serum levels of cytokines. Analysis of urinary sodium excretion confirmed adherence to the dietary regimen. In RA patients, a trend toward a reduction in the frequencies of Th17 cells over the low-sodium dietary regimen followed by an increase at T5 was observed, while Treg cells exhibited the opposite trend. SLE patients showed a progressive reduction in the percentage of Th17 cells that reached a significance at T5 compared to T0 (p = 0.01) and an increase in the percentage of Treg cells following the low-sodium dietary regimen at both T1 and T3 compared to T0 (p = 0.04 and p = 0.02, respectively). No significant apoptosis or proliferation modulation was found. In RA patients, we found a reduction at T5 compared to T0 in serum levels of both TGFβ (p = 0.0016) and IL-9 (p = 0.0007); serum IL-9 levels were also reduced in SLE patients at T5 with respect to T0 (p = 0.03). This is the first study investigating the effects of dietary sodium intake on adaptive immunity. Based on the results, we hypothesize that a restricted sodium dietary intake may dampen the inflammatory response in RA and SLE patients.

Vitamin D insufficiency and deficiency in mexican patients with systemic lupus erythematosus: Prevalence and relationship with disease activity.

PubMed

García-Carrasco, Mario; Mendoza-Pinto, Claudia; Etchegaray-Morales, Ivet; Soto-Santillán, Pamela; Jiménez-Herrera, Erick Alejandro; Robles-Sánchez, Viridiana; Rodríguez-Gallegos, Alma; Ramos-Varela, Araceli; Muñoz-Guarneros, Margarita; Ruiz-Argüelles, Alejandro

To determine and compare the prevalence of vitamin D insufficiency and deficiency in patients with systemic lupus erythematosus (SLE) with and without disease activity. We made a comparative, observational, cross-sectional, prospective study of 137 women with SLE according to American College of Rheumatology criteria. Patients with chronic kidney disease, cancer, hyperparathyroidism, pregnancy, and lactation were excluded. Disease activity was assessed using the MEX-SLEDAI score: a score of ≥3 was considered as disease activity. Data were collected on diabetes mellitus, the use of corticosteroids, chloroquine, and immunosuppressants, photoprotection and vitamin D supplementation. Vitamin D levels were measured by chemiluminescent immunoassay: insufficiency was defined as serum 25-hydroxyvitamin D <30ng/ml and deficiency as <10ng/ml. 137 women with SLE (mean age 45.9±11.6 years, disease duration 7.7±3.4 years) were evaluated. Mean disease activity was 2 (0-8): 106 patients had no disease activity and 31 had active disease (77.4% versus 22.6%). Vitamin D insufficiency and deficiency was found in 122(89.0%) and 4 (2.9%) patients, respectively. There was no significant difference in vitamin D levels between patients with and without active disease (19.3±4.5 versus 19.7±6.8; P=.75). No correlation between the MEX-SLEDAI score (P=.21), photosensitivity, photoprotection, prednisone or chloroquine use and vitamin D supplementation was found. Women with SLE had a high prevalence of vitamin D insufficient. No association between vitamin D levels and disease activity was found. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Elastic and inelastic light scattering from single bacterial spores in an optical trap allows the monitoring of spore germination dynamics

PubMed Central

Peng, Lixin; Chen, De; Setlow, Peter; Li, Yong-qing

2009-01-01

Raman scattering spectroscopy and elastic light scattering intensity (ESLI) were used to simultaneously measure levels of Ca-dipicolinic acid (CaDPA) and changes in spore morphology and refractive index during germination of individual B. subtilis spores with and without the two redundant enzymes (CLEs), CwlJ and SleB, that degrade spores’ peptidoglycan cortex. Conclusions from these measurements include: 1) CaDPA release from individual wild-type germinating spores was biphasic; in a first heterogeneous slow phase, Tlag, CaDPA levels decreased ∼15% and in the second phase ending at Trelease, remaining CaDPA was released rapidly; 2) in L-alanine germination of wild-type spores and spores lacking SleB: a) the ESLI rose ∼2-fold shortly before Tlag at T1; b) following Tlag, the ESLI again rose ∼2-fold at T2 when CaDPA levels had decreased ∼50%; and c) the ESLI reached its maximum value at ∼Trelease and then decreased; 3) in CaDPA germination of wild-type spores: a) Tlag increased and the first increase in ESLI occurred well before Tlag, consistent with different pathways for CaDPA and L-alanine germination; b) at Trelease the ESLI again reached its maximum value; 4) in L-alanine germination of spores lacking both CLEs and unable to degrade their cortex, the time ΔTrelease (Trelease–Tlag) for excretion of ≥75% of CaDPA was ∼15-fold higher than that for wild-type or sleB spores; and 5) spores lacking only CwlJ exhibited a similar, but not identical ESLI pattern during L-alanine germination to that seen with cwlJ sleB spores, and the high value for ΔTrelease. PMID:19374431

The use of laboratory tests in the diagnosis of SLE.

PubMed

Egner, W

2000-06-01

ANA IIF is an effective screening assay in patients with clinical features of SLE and will detect most anti-ssDNA, anti-dsDNA, ENAs, and other autoantibodies. False positives are common. The clinical importance cannot be extrapolated from the ANA titre or pattern, although higher titres (> 1/160) are more likely to be important. HEp-2 cells are the most sensitive substrate for ANA detection, but this must be balanced against an increased incidence of insignificant positivity. ANA positive samples should be subjected to more specific assays for the diagnosis of SLE. A combination of ENA (Ro/La/Sm/RNP) and dsDNA assays will detect most patients with SLE as long as the characteristics of the assays used are well understood. ESR and CRP measurements provide useful additional information. Sjogren's syndrome and MCTD will produce overlapping serology with SLE, and anti-dsDNA titres are sometimes seen in autoimmune hepatitis and rheumatoid arthritis. All results should be reported in the light of the clinical details, by an experienced immunologist. A suggested diagnostic protocol is outlined in fig 1. The type of assay used crucially influences the predictive value of the tests. ELISA technology dominates routine laboratory practice, but tends to produce more false positive and true weak positive results, which may reduce the PPV of the test. This can be minimised by using IgG specific conjugates and careful assay validation. The NPV for SLE [figure: see text] is high for most assays but the PPV varies. Where necessary, laboratories should use crithidia or Farr dsDNA assays to confirm dubious ELISA dsDNA results, and ID/IB to confirm dubious ENA results. For monitoring, a precise, quantitative assay is required. It is unclear whether the detection of IgM or low affinity antibodies has a role here. A combination of anti-dsDNA, C3, C4, CRP, and ESR assays provides the most useful clinical information. Anti-ssDNA assays are likely to be useful, and are potentially more robust than anti-dsDNA assays, but require more validation. Local validation of individual assays and EQA participation is essential. Not all assays that apparently measure the same antibody specificities have equal clinical relevance, even within a single technology. Insufficient international or national reference preparations are currently available for many antibody specificities to enable effective standardisation. Quality assurance schemes reveal large differences in units reported by different assays for some analytes, even when calibrated against an IRP or equivalent reference preparation. Serial results can therefore only be compared from the same laboratory at present. Most autoantibodies increase during active disease, but few prospective data are currently available to justify treatment on the basis of rising titres. Further randomised prospective studies are required to examine the importance of antibody isotype and affinity in the monitoring of SLE by individual assay methods. The most important aspect of the appropriate use of laboratory assays is to become familiar with the limitations of the technology currently in use in your local laboratory, and to consult with your clinical immunologist in cases of doubt, preferably before commencing serological screening.

RNA-seq Analysis Reveals Unique Transcriptome Signatures in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Specificities

PubMed Central

Rai, Richa; Chauhan, Sudhir Kumar; Singh, Vikas Vikram; Rai, Madhukar; Rai, Geeta

2016-01-01

Systemic lupus erythematosus (SLE) patients exhibit immense heterogeneity which is challenging from the diagnostic perspective. Emerging high throughput sequencing technologies have been proved to be a useful platform to understand the complex and dynamic disease processes. SLE patients categorised based on autoantibody specificities are reported to have differential immuno-regulatory mechanisms. Therefore, we performed RNA-seq analysis to identify transcriptomics of SLE patients with distinguished autoantibody specificities. The SLE patients were segregated into three subsets based on the type of autoantibodies present in their sera (anti-dsDNA+ group with anti-dsDNA autoantibody alone; anti-ENA+ group having autoantibodies against extractable nuclear antigens (ENA) only, and anti-dsDNA+ENA+ group having autoantibodies to both dsDNA and ENA). Global transcriptome profiling for each SLE patients subsets was performed using Illumina® Hiseq-2000 platform. The biological relevance of dysregulated transcripts in each SLE subsets was assessed by ingenuity pathway analysis (IPA) software. We observed that dysregulation in the transcriptome expression pattern was clearly distinct in each SLE patients subsets. IPA analysis of transcripts uniquely expressed in different SLE groups revealed specific biological pathways to be affected in each SLE subsets. Multiple cytokine signaling pathways were specifically dysregulated in anti-dsDNA+ patients whereas Interferon signaling was predominantly dysregulated in anti-ENA+ patients. In anti-dsDNA+ENA+ patients regulation of actin based motility by Rho pathway was significantly affected. The granulocyte gene signature was a common feature to all SLE subsets; however, anti-dsDNA+ group showed relatively predominant expression of these genes. Dysregulation of Plasma cell related transcripts were higher in anti-dsDNA+ and anti-ENA+ patients as compared to anti-dsDNA+ ENA+. Association of specific canonical pathways with the uniquely expressed transcripts in each SLE subgroup indicates that specific immunological disease mechanisms are operative in distinct SLE patients’ subsets. This ‘sub-grouping’ approach could further be useful for clinical evaluation of SLE patients and devising targeted therapeutics. PMID:27835693

Follicular T helper cells and IL-21 in rheumatic diseases.

PubMed

Rasmussen, Tue Kruse

2016-10-01

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are lifelong diseases with increased mortality and chronic pains. They are both characterized by immunological imbalances causing the immune system attack and destroy the bodies own tissues (called autoimmune disease). The best treatment, we are currently able to offer these patients, cause significant side-effects and can not prevent significant loss of quality of life. At the heart of the disease mechanisms in RA and SLE are subsets of immune cells called T and B cells. These cell types produce proteins (called antibodies), which under normal circumstances protect the body against disease. In RA and SLE these cells produce antibodies that are directed at the bodies own tissues (called autoantibodies), causing inflammation and tissue damage. The cause of this loss of tolerance is still unknown. Interleukin 21 (IL-21) is thought to exert key functions in controlling and directing the T and B cell responses leading to formation of antibodies and autoantibodies alike. IL-21 is a signaling molecule secreted by a subpopulation of T cells called follicular T helper (Tfh) cells. IFNα is another signaling molecule of key importance in autoimmune disease. Stratification of SLE patients by their responsiveness to IFNα has proven a crucial tool in stratifying patients in terms of disease development and treatment response. The aim of this PhD study is to investigate the role of IL-21 and IFNα, and their effects on Tfh cells and B cells and the formation of autoantibodies in RA and SLE. The first part of this study addresses whether plasma levels of IL-21 influence disease activity in rheumatic disease. We further investigate the distribution of IL-21-producing Tfh cells in these patients. We find that IL-21 plasma levels correlate to disease activity and radiological progression in RA, and that the IL-21-producing Tfh cell are increased in the blood and synovial fluid of these patients. These findings support the idea that IL-21 and Tfh cells are linked to the development and perpetuation of these diseases. In the second part of this we investigate how small RNA molecules, called microRNAs, can regulate immunological processes. We find that microRNA-155 can regulate IL-21's capacity to signal, while microRNA-21 is important for survival of T cells. The third, and last part of this, concerns IFNα signaling and its impact on the development of SLE and the formation of autoantibodies. We find that IFNα signaling is altered in a murine model of SLE, and that inhibition of this signaling pathway leads to severe kidney disease. The latter is of key importance as inhibition of IFNα is currently in early trial as a new treatment form for SLE patients. In SLE patients, we find that IFNα responsiveness, as measured by a so-called IFN signature, is crucial in terms of development of the disease as well as serious complications such as kidney disease and involvement of the central nervous system. Interferon alpha does this by affecting intracellular signaling responses and the formation of autoantibodies. The data presented in this thesis supports that IL-21 and Tfh cells have a key role in the disease processes characterizing RA and SLE. We further describe a novel mechanism for microRNA-155 and microRNA-21 in regulating immunological processes in these diseases. Finally we show, that IFNα has important functions in the formation of autoantibodies in SLE. In conclusion, this thesis adds new and important knowledge on the interplay between Tfh cells and B cells and their formation of autoantibodies in rheumatic disease. This knowledge will guide and further the development of new treatment strategies to better patient outcome.

The pathophysiology of hypertension in systemic lupus erythematosus.

PubMed

Ryan, Michael J

2009-04-01

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that predominantly affects women during their reproductive years. Although SLE can affect any organ system, the kidneys are prominently involved in the form of immune complex glomerulonephritis. In addition, in women with SLE, risk for the development of cardiovascular disease is dramatically increased. Hypertension is a major risk factor for cardiovascular disease and is highly prevalent in women with SLE. Nevertheless, there has been little exploration of the pathophysiological mechanisms that promote SLE hypertension. This review discusses the role of several mechanisms, with an emphasis on the kidney, in SLE hypertension. These mechanisms include the renin-angiotensin system, endothelin, oxidative stress, sex steroids, metabolic changes, peroxisome proliferator-activated receptor-gamma, and, perhaps most importantly, chronic inflammation and cytokines. Growing evidence suggests a link between chronic inflammation and hypertension. Therefore, elucidation of mechanisms that promote SLE hypertension may be of significant value not only for patients with SLE, but also for a better understanding of the basis for essential hypertension.

Increased Arterial Stiffness in Systemic Lupus Erythematosus (SLE) Patients at Low Risk for Cardiovascular Disease: A Cross-Sectional Controlled Study

PubMed Central

Sacre, Karim; Escoubet, Brigitte; Pasquet, Blandine; Chauveheid, Marie-Paule; Zennaro, Maria-Christina; Tubach, Florence; Papo, Thomas

2014-01-01

Cardiovascular disease (CVD) is a major cause of death in systemic lupus erythematosus (SLE) patients. Although the risk for cardiovascular events in patients with SLE is significant, the absolute number of events per year in any given cohort remains small. Thus, CVD risks stratification in patients with SLE focuses on surrogate markers for atherosclerosis at an early stage, such as reduced elasticity of arteries. Our study was designed to determine whether arterial stiffness is increased in SLE patients at low risk for CVD and analyze the role for traditional and non-traditional CVD risk factors on arterial stiffness in SLE. Carotid-femoral pulse wave velocity (PWV) was prospectively assessed as a measure of arterial stiffness in 41 SLE patients and 35 controls (CTL). Adjustment on age or Framingham score was performed using a logistic regression model. Factors associated with PWV were identified separately in SLE patients and in controls using Pearson's correlation coefficient for univariate analysis and multiple linear regression for multivariate analysis. SLE patients and controls displayed a low 10-year risk for CVD according to Framingham score (1.8±3.6% in SLE vs 1.6±2.8% in CTL, p = 0.46). Pulse wave velocity was, however, higher in SLE patients (7.1±1.6 m/s) as compared to controls (6.3±0.8 m/s; p = 0.01, after Framingham score adjustment) and correlated with internal carotid wall thickness (p = 0.0017). In multivariable analysis, only systolic blood pressure (p = 0.0005) and cumulative dose of glucocorticoids (p = 0.01) were associated with PWV in SLE patients. Interestingly, the link between systolic blood pressure (SBP) and arterial stiffness was also confirmed in SLE patients with normal systolic blood pressure. In conclusion, arterial stiffness is increased in SLE patients despite a low risk for CVD according to Framingham score and is associated with systolic blood pressure and glucocorticoid therapy. PMID:24722263

Antinucleosome antibodies as a marker of active proliferative lupus nephritis.

PubMed

Bigler, Cornelia; Lopez-Trascasa, Margarita; Potlukova, Eliska; Moll, Solange; Danner, Doris; Schaller, Monica; Trendelenburg, Marten

2008-04-01

Antinucleosome autoantibodies were previously described to be a marker of active lupus nephritis. However, the true prevalence of antinucleosome antibodies at the time of active proliferative lupus nephritis has not been well established. Therefore, the aim of this study is to define the prevalence and diagnostic value of autoantibodies against nucleosomes as a marker for active proliferative lupus nephritis. Prospective multicenter diagnostic test study. 35 adult patients with systemic lupus erythematosus (SLE) at the time of the renal biopsy showing active class III or IV lupus nephritis compared with 59 control patients with SLE. Levels of antinucleosome antibodies and anti-double-stranded DNA (anti-dsDNA) antibodies. Kidney biopsy findings of class III or IV lupus nephritis at the time of sampling in a study population versus clinically inactive or no nephritis in a control population. Increased concentrations of antinucleosome antibodies were found in 31 of 35 patients (89%) with active proliferative lupus nephritis compared with 47 of 59 control patients (80%) with SLE. No significant difference between the 2 groups with regard to number of positive patients (P = 0.2) or antibody concentrations (P = 0.2) could be found. The area under the receiver operating characteristic curve as a marker of the accuracy of the test in discriminating between proliferative lupus nephritis and inactive/no nephritis in patients with SLE was 0.581 (95% confidence interval, 0.47 to 0.70; P = 0.2). Increased concentrations of anti-dsDNA antibodies were found in 33 of 35 patients (94.3%) with active proliferative lupus nephritis compared with 49 of 58 control patients (84.5%) with SLE (P = 0.2). In patients with proliferative lupus nephritis, significantly higher titers of anti-dsDNA antibodies were detected compared with control patients with SLE (P < 0.001). The area under the receiver operating characteristic curve in discriminating between proliferative lupus nephritis and inactive/no nephritis in patients with SLE was 0.710 (95% confidence interval, 0.60 to 0.82; P < 0.001). Antinucleosome antibodies have a high prevalence in patients with severe lupus nephritis. However, our data suggest that determining antinucleosome antibodies is of limited help in the distinction of patients with active proliferative lupus nephritis from patients with SLE without active renal disease.

Galectin-3 binding protein links circulating microparticles with electron dense glomerular deposits in lupus nephritis.

PubMed

Nielsen, C T; Østergaard, O; Rekvig, O P; Sturfelt, G; Jacobsen, S; Heegaard, N H H

2015-10-01

A high level of galectin-3-binding protein (G3BP) appears to distinguish circulating cell-derived microparticles in systemic lupus erythematosus (SLE). The aim of this study is to characterize the population of G3BP-positive microparticles from SLE patients compared to healthy controls, explore putative clinical correlates, and examine if G3BP is present in immune complex deposits in kidney biopsies from patients with lupus nephritis. Numbers of annexin V-binding and G3BP-exposing plasma microparticles from 56 SLE patients and 36 healthy controls were determined by flow cytometry. Quantitation of microparticle-associated G3BP, C1q and immunoglobulins was obtained by liquid chromatography tandem mass spectrometry (LC-MS/MS). Correlations between microparticle-G3BP data and clinical parameters were analyzed. Co-localization of G3BP with in vivo-bound IgG was examined in kidney biopsies from one non-SLE control and from patients with class IV (n = 2) and class V (n = 1) lupus nephritis using co-localization immune electron microscopy. Microparticle-G3BP, microparticle-C1q and microparticle-immunoglobulins were significantly (P < 0.01) increased in SLE patients by LC-MS/MS. Three G3BP-exposing microparticle populations could be discerned by flow cytometry, including two subpopulations that were significantly increased in SLE samples (P = 0.01 and P = 0.0002, respectively). No associations of G3BP-positive microparticles with clinical manifestations or disease activity were found. Immune electron microscopy showed co-localization of G3BP with in vivo-bound IgG in glomerular electron dense immune complex deposits in all lupus nephritis biopsies. Both circulating microparticle-G3BP numbers as well as G3BP expression are increased in SLE patients corroborating G3BP being a feature of SLE microparticles. By demonstrating G3BP co-localized with deposited immune complexes in lupus nephritis, the study supports cell-derived microparticles as a major autoantigen source and provides a new understanding of the origin of immune complexes occurring in lupus nephritis. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Illness intrusiveness explains race-related quality-of-life differences among women with systemic lupus erythematosus.

PubMed

Devins, G M; Edworthy, S M

2000-01-01

Our objective was to investigate whether quality of life in systemic lupus erythematosus (SLE) differs across ethnoracial groups and to identify factors that may explain race-related differences. Self-administered questionnaire data from 335 White, 40 Black, and 30 Asian women with SLE were obtained from a multi-center database. Measures assessed illness intrusiveness, psychological well-being, depressive symptoms, musculoskeletal pain, and learned helplessness. Extent of SLE disease activity was indexed by self-reported functional-system involvement. Educational attainment was indicated by number of years in school. Principal-components analysis reduced the four psychosocial measures to a single factor score. This represented psychosocial well-being In path analysis. Psychosocial well-being differed significantly across the three groups, with Whites reporting the highest, and Blacks the lowest, levels. Path analysis indicated that illness intrusiveness accounted for this race-related difference. Although disease activity was significantly associated with psychosocial well-being, it did not differ across ethnoracial groups. Illness intrusiveness and educational attainment emerged as independent mediators of the race-related difference in psychosocial well-being. We conclude that race-related quality-of-life differences exist among women with SLE and are mediated independently by illness intrusiveness and educational attainment.

[A case of anti-LKM 1 positive autoimmune hepatitis accompanied by systemic lupus erythematosus].

PubMed

Choi, Dae Han; Kim, Hae Kyung; Park, Tae Il; John, Byung Min; Kang, Sung Hwan; Lee, Yoon Serk; Kim, Tae Hyun; Lee, Uh Joo; Lee, Tae Seung; Yoon, Gwi Ok

2008-03-01

Overlap of autoimmune hepatitis and systemic lupus erythematosus (SLE) is a comparatively rare condition. Although both autoimmune hepatitis and SLE can share common autoimmune features such as polyarthralgia, hypergammaglobulinemia and positive ANA, it has been considered as two different entities. We report a case of anti-LKM1 positive autoimmune hepatitis who developed SLE two years later. The presence of interface hepatitis with lymphoplasma cell infiltrates and rosette formation points to the autoimmune hepatitis rather than SLE hepatitis. Autoimmune hepatitis is infrequently accompanied by SLE, therefore, it could be recommended to investigate for SLE in patients with autoimmune hepatitis.

Human papilloma virus and lupus: the virus, the vaccine and the disease.

PubMed

Segal, Yahel; Calabrò, Michele; Kanduc, Darja; Shoenfeld, Yehuda

2017-07-01

Systemic lupus erythematosus (SLE) is a well known, widespread autoimmune disease, involving multiple organ systems, with a multifaceted, widely unmapped etiopathogenesis. Recently, a new aspect of morbidity has been described among SLE patients: infection with human papilloma virus (HPV). We set out to review data regarding the intricate relationship between the two and attempt to determine whether HPV may pose as a contributing factor to the development of SLE. We relate to epidemiological, molecular and clinical data. We have found evidence in all these fields suggesting HPV to be involved in the pathogenesis of SLE: increased prevalence of HPV infection among SLE patients; vast molecular homology between viral peptides and human proteins associated with SLE; several reports of SLE development post-HPV vaccination. Our findings suggest a possible involvement of HPV infection in the induction of SLE, via a mechanism of immune cross-reaction due to molecular homology. We review clinical, epidemiological and molecular data suggesting involvement of HPV infection in the pathogenesis of SLE. We suggest that these findings may justify the development of new HPV vaccines containing viral peptides that bear no homology to the human proteome, in order to avoid possible adverse immune cross-reactivity.

Pregnancy in women with systemic lupus erythematosus.

PubMed

Kiss, Emese; Bhattoa, Harjit P; Bettembuk, Peter; Balogh, Adam; Szegedi, Gyula

2002-03-10

Systemic lupus erythematosus (SLE) is an autoimmune disorder which may be affected by hormonal changes, such as those of pregnancy. Women with SLE have increased adverse pregnancy outcomes. A retrospective analysis of the gynecologic and immunologic case history of 140 women with SLE and the outcome of 263 pregnancies in 99 women with SLE. In patients diagnosed with SLE, the proportion of pregnancies ending with live birth at term decreased to one-third compared with three quarters in those without a diagnosis of SLE and the incidence of pre-term deliveries and spontaneous abortions increased by 6.8 and 4.7 times, respectively. When SLE was associated with secondary antiphospholipid (APL) syndrome, and lupus anticoagulant (LA) or beta2-glycoprotein antibodies were present, a further increase in the incidence of pregnancy loss was observed. Pregnancy did not cause a flare-up of SLE in all cases, the disease remained stable in about 30% of the patients. Lupus was mild in the majority of the women who carried out their pregnancy to term. We also observed mothers with active SLE who successfully carried out pregnancies to term. These findings accord with previous literature and should inform rheumatologists, obstetricians and neonatologists who guide patients in their reproductive decisions.

Noncalcified coronary plaque in systemic lupus erythematosus.

PubMed

Kiani, Adnan N; Vogel-Claussen, Jens; Magder, Laurence S; Petri, Michelle

2010-03-01

To study noncalcified coronary plaque (NCP) in systemic lupus erythematosus (SLE). Sixty-four-slice coronary multidetector computed tomography (MDCT) was performed in 39 consecutive patients with SLE. MDCT scans were evaluated semiquantitatively by a radiologist using dedicated software. The presence or absence of NCP in each coronary artery was assessed. Patients with mixed plaque (calcified and noncalcified portions) were included in the NCP group. The patient group was 90% women, 64% Caucasian, 31% African American, 5% other; mean age 50.5 +/- 9.6 years. Fifty-four percent (21/39) had NCP. Seventy-six percent (16/21) of those with NCP also had coronary calcium (range 0.7 to 1264.1 Agatston units). In univariate analysis, NCP was associated with age (p = 0.01), current nonsteroidal antiinflammatory drug (NSAID) use (p = 0.04), hormone replacement therapy (p = 0.02), current use of immunosuppressive drugs (p = 0.02), current low serum C3 level (p = 0.07), current physician's global assessment of activity (PGA; p = 0.05), and low-density lipoprotein cholesterol (p = 0.04). NCP was not associated with other risk factors for atherosclerosis, including total serum cholesterol, high sensitivity C-reactive protein, and lipoprotein(a). Unlike coronary calcium, which is not associated with SLE activity measures or with active serologies, NCP is more common in patients with SLE with current, 3-, and 6-month activity by PGA. NCP was also associated with the need for current NSAID or immunosuppressive therapy. NCP is an important part of the total atherosclerotic burden in SLE.

Factor Xa Mediates Calcium Flux in Endothelial Cells and is Potentiated by Igg From Patients With Lupus and/or Antiphospholipid Syndrome.

PubMed

Artim-Esen, Bahar; Smoktunowicz, Natalia; McDonnell, Thomas; Ripoll, Vera M; Pericleous, Charis; Mackie, Ian; Robinson, Eifion; Isenberg, David; Rahman, Anisur; Ioannou, Yiannis; Chambers, Rachel C; Giles, Ian

2017-09-07

Factor (F) Xa reactive IgG isolated from patients with antiphospholipid syndrome (APS) display higher avidity binding to FXa with greater coagulant effects compared to systemic lupus erythematosus (SLE) non APS IgG. FXa signalling via activation of protease-activated receptors (PAR) leads to increased intracellular calcium (Ca 2+ ). Therefore, we measured alterations in Ca 2+ levels in human umbilical vein endothelial cells (HUVEC) following FXa-mediated PAR activation and investigated whether FXa reactive IgG from patients with APS or SLE/APS- alter these responses. We observed concentration-dependent induction of Ca 2+ release by FXa that was potentiated by APS-IgG and SLE/APS- IgG compared to healthy control subjects' IgG, and FXa alone. APS-IgG and SLE/APS- IgG increased FXa mediated NFκB signalling and this effect was fully-retained in the affinity purified anti-FXa IgG sub-fraction. Antagonism of PAR-1 and PAR-2 reduced FXa-induced Ca 2+ release. Treatment with a specific FXa inhibitor, hydroxychloroquine or fluvastatin significantly reduced FXa-induced and IgG-potentiated Ca 2+ release. In conclusion, PAR-1 and PAR-2 are involved in FXa-mediated intracellular Ca 2+ release in HUVEC and FXa reactive IgG from patients with APS and/or SLE potentiate this effect. Further work is required to explore the potential use of IgG FXa reactivity as a novel biomarker to stratify treatment with FXa inhibitors in these patients.

Replication of the BANK1 genetic association with systemic lupus erythematosus in a European-Derived Population

PubMed Central

Guo, Ling; Deshmukh, Harshal; Lu, Rufei; Vidal, Gabriel S; Kelly, Jennifer A; Kaufman, Kenneth M; Dominguez, Nicolas; Klein, Wendy; Kim-Howard, Xana; Bruner, Gail R; Scofield, R Hal; Moser, Kathy L; Gaffney, Patrick M; Dozmorov, Igor M; Gilkeson, Gary S; Wakeland, Edward K; Li, Quan-Zhen; Langefeld, Carl D; Marion, Miranda C; Williams, Adrienne H; Divers, Jasmin; Alarcón, Graciela S; Brown, Elizabeth E; Kimberly, Robert P; Edberg, Jeffery C; Ramsey-Goldman, Rosalind; Reveille, John D; McGwin, Gerald; Vilá, Luis M; Petri, Michelle A; Vyse, Timothy J; Merrill, Joan T; James, Judith A; Nath, Swapan K; Harley, John B; Guthridge, Joel M

2009-01-01

Systemic lupus erythematosus (SLE) is an autoimmune disease with highly variable clinical presentation. Patients suffer from immunological abnormalities that target T cell, B cell and accessory cell functions. B cells are hyperactive in SLE patients. An adaptor protein expressed in B cells called BANK1 (B-cell scaffold protein with ankyrin repeats) was reported in a previous study to be associated with SLE in a European population. The objective of this study is to assess the BANK1 genotype-phenotype association in an independent replication sample. We genotyped 38 single nucleotide polymorphisms (SNPs) in BANK1 on 1892 European-derived SLE patients and 2652 European-derived controls. The strongest associations with SLE and BANK1 were at rs17266594 (corrected p-value=1.97 × 10−5, OR=1.22, 95% C.I.(1.12–1.34)) and rs10516487 (corrected p-value=2.59 × 10−5, OR=1.22, 95% C.I.(1.11–1.34)). Our findings suggest that the association is explained by these two SNPs, confirming previous reports that these polymorphisms contribute to the risk of developing lupus. Analysis of patient subsets enriched for hematological, immunological and renal ACR criteria or the levels of autoantibodies, such as anti-RNP A and anti-SmRNP, uncovers additional BANK1 associations. Our results suggest that BANK1 polymorphisms alter immune system development and function to increase the risk for developing lupus. PMID:19339986

Annexin A5 anticoagulant activity in children with systemic lupus erythematosus and the association with antibodies to domain I of β2-glycoprotein I

PubMed Central

Wahezi, Dawn M.; Ilowite, Norman T.; Wu, Xiao Xuan; Pelkmans, Leonie; de Laat, Bas; Schanberg, Laura E.; Rand, Jacob H.

2014-01-01

Children with systemic lupus erythematosus (SLE) have a high prevalence of antiphospholipid (aPL) antibodies and are at increased risk for aPL-related thrombosis. We investigated the association between annexin A5 anticoagulant activity and antibodies to the domain I portion of β2-glycoprotein I (anti-DI antibodies), and propose a potential mechanism for the pathogenesis of aPL-related thrombosis. Using samples from 183 children with SLE collected during the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, we examined resistance to the anticoagulant effects of annexin A5, using the annexin A5 resistance (A5R) assay, and evaluated for anti-DI IgG antibodies. Children with SLE had higher frequency of anti-D1 antibodies (p=0.014) and significantly reduced A5R compared to pediatric controls: mean A5R = 172 ± 30 % versus 242 ± 32 % (p<0.0001). Children with SLE and positive anti-DI antibodies had significantly lower mean A5R levels compared to those with negative anti-DI antibodies: mean A5R = 155 ± 24 % versus 177 ± 30% (p<0.0001). In multivariate analysis, anti-DI antibodies (p=0.013) and lupus anticoagulant (LA) (p=0.036) were both independently associated with reduced A5R. Children with SLE have significantly reduced annexin A5 anticoagulant activity that is associated with the presence of LA and anti-DI antibodies. PMID:23690366

Expression of TLR-7, MyD88, NF-kB, and INF-α in B Lymphocytes of Mayan Women with Systemic Lupus Erythematosus in Mexico.

PubMed

Pacheco, Guillermo Valencia; Novelo Noh, Irene B; Velasco Cárdenas, Rubí M-H; Angulo Ramírez, Angélica V; López Villanueva, Ricardo F; Quintal Ortiz, Irma G; Alonso Salomón, Ligia G; Ruz, Norma Pavía; Rivero Cárdenas, Nubia A

2016-01-01

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease involving multiple organs. It is currently accepted that several genetic, environmental, and hormonal factors are contributing to its development. Innate immunity may have a great influence in autoimmunity through Toll-like receptors. TLR-7 recognizing single-strand RNA has been involved in SLE. Its activation induces intracellular signal with attraction of MyD88 and NF-kBp65, leading to IFN-α synthesis which correlate with disease activity. To assess the expression of TLR-7, MyD88, and NF-kBp65 in B lymphocytes of Mayan women with SLE. One hundred patients with SLE and 100 healthy controls, all of them Mayan women, were included. TLR-7 was analyzed on B and T lymphocytes, and MyD88 and NF-kB only in B lymphocytes. Serum INF-α level was evaluated by ELISA. Significant expression (p < 0.0001) of TLR-7 in B and T lymphocytes and serum IFN-α increased (p = 0.034) was observed in patients. MyD88 and NF-kBp65 were also increased in B lymphocytes of patients. TLR-7 and NF-kBp65 expression correlated, but no correlation with INF-α and disease activity was detected. Data support the role of TLR-7 and signal proteins in the pathogenesis of SLE in the Mayan population of Yucatán.

Effects of oral Lactobacillus administration on antioxidant activities and CD4+CD25+forkhead box P3 (FoxP3)+ T cells in NZB/W F1 mice.

PubMed

Tzang, Bor-Show; Liu, Chung-Hsien; Hsu, Kuo-Ching; Chen, Yi-Hsing; Huang, Chih-Yang; Hsu, Tsai-Ching

2017-09-01

Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by a dysregulation of the immune system, which causes inflammation responses, excessive oxidative stress and a reduction in the number of cluster of differentiation (CD)4+CD25+forkhead box P3 (FoxP3)+ T cells. Supplementation with certain Lactobacillus strains has been suggested to be beneficial in the comprehensive treatment of SLE. However, little is known about the effect and mechanism of certain Lactobacillus strains on SLE. To investigate the effects of Lactobacillus on SLE, NZB/W F1 mice were orally gavaged with Lactobacillus paracasei GMNL-32 (GMNL-32), Lactobacillus reuteri GMNL-89 (GMNL-89) and L. reuteri GMNL-263 (GMNL-263). Supplementation with GMNL-32, GMNL-89 and GMNL-263 significantly increased antioxidant activity, reduced IL-6 and TNF-α levels and significantly decreased the toll-like receptors/myeloid differentiation primary response gene 88 signalling in NZB/W F1 mice. Notably, supplementation with GMNL-263, but not GMNL-32 and GMNL-89, in NZB/W F1 mice significantly increased the differentiation of CD4+CD25+FoxP3+ T cells. These findings reveal beneficial effects of GMNL-32, GMNL-89 and GMNL-263 on NZB/W F1 mice and suggest that these specific Lactobacillus strains can be used as part of a comprehensive treatment of SLE patients.

Systemic lupus erythematosus.

PubMed

Kaul, Arvind; Gordon, Caroline; Crow, Mary K; Touma, Zahi; Urowitz, Murray B; van Vollenhoven, Ronald; Ruiz-Irastorza, Guillermo; Hughes, Graham

2016-06-16

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.

Effect of Xuebijing injection on systemic lupus erythematosus in mice.

PubMed

Wang, Yan-bo; Wang, Qiang; Yao, Yong-ming; Sheng, Zhi-yong; Liu, Yu-feng

2013-09-01

To observe the effects of Xuebijing injection on dendritic cells (DCs) and T lymphocytes, and the potential mechanisms of its therapeutic effect on systemic lupus erythematosus (SLE). A widely used mouse model, SLE-prone BLLF1 mice aged 8-10 weeks, was employed. Mice were randomly divided into 4 groups: a normal group, a model group and two treatment groups treated with Xuebijing Injection with a dose of 6.4 mL/kg via intraperitoneal administration for SLE-prone BLLF1 mice aged 8 weeks (treatment A group) and 10 weeks (treatment B group). Renal tissue sections were stained with Masson's trichrome and periodic acid-silver methenamine. Histopathological changes in the kidney were evaluated by a light microscopy. The capacity of the DCs isolated from the spleen to stimulate the T cell proliferation in response to concanavalin A (Con A) was determined. Compared with the model group, levels of anti-dsDNA antibodies in the two treatment groups decreased remarkablly (P<0.01, P<0.05), and levels of serum creatinine and blood urea nitrogen increased (P<0.01, P<0.05). Pathological changes were found in the kidney in the model group. Histopathological abnormalities were alleviated in the two treatment groups. Treatment with Xuebijing injection also significantly upregulated the expression of CD80, CD86 and major histocompatibility class II by DCs compared with the model group (P<0.05). When splenic T lymphocytes from BLLF1 mice were co-cultured with DCs at ratios of 1:100, 1:150 and 1:200 for 3 and 5 days, the proliferation of T lymphocytes was suppressed compared with the normal group (P<0.05), but this was restored by Xuebijing Injection under the same conditions. In the model group, levels of tumor necrosis factor (TNF)-α in supernatants were significantly elevated compared with the normal group (P<0.01), interleukin-2 levels decreased (P<0.05), while these changes were significantly alleviated in the Xuebijing treatment groups. Xuebijing Injection alleviated renal injury in SLE-prone BLLF-1 mice. The mechanism might be through influencing T cell polarization mediated by DCs, and Xuebijing Injection might be a potential drug that suppresses immune dysfunction in patients with SLE.

IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus

PubMed Central

Niewold, Timothy B; Kelly, Jennifer A; Kariuki, Silvia N; Franek, Beverly S; Kumar, Akaash A; Kaufman, Kenneth M; Thomas, Kenaz; Walker, Daniel; Kamp, Stan; Frost, Jacqueline M; Wong, Andrew K; Merrill, Joan T; Alarcón-Riquelme, Marta E; Tikly, Mohammed; Ramsey-Goldman, Rosalind; Reveille, John D; Petri, Michelle A; Edberg, Jeffrey C; Kimberly, Robert P; Alarcón, Graciela S; Kamen, Diane L; Gilkeson, Gary S; Vyse, Timothy J; James, Judith A; Gaffney, Patrick M; Moser, Kathy L; Crow, Mary K; Harley, John B

2012-01-01

Objective High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα 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. Methods 1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African–American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay. Results In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR > 2.56, p >003C; 1.9×10−14 for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained > 70% of the genetic risk of SLE due to IRF5. In African–American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African–American subjects and absent in African patients with SLE. Conclusions The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements. SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population.1 These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness2 and are likely pathogenic in SLE.34 PMID:22088620

Systemic lupus erythematosus with Sjögren's syndrome and renal tubular acidosis presenting as nephrogenic diabetes insipidus.

PubMed

Parrey, Ashaq Hussain; Ahmad, Fayaz; Ahmad, Mushtaq; Basher, Adil

2018-01-01

Systemic lupus erythematosus (SLE) presenting as diabetes insipidus (DI) is a rare association; there is a case report of neurogenic DI in patients of SLE; however, SLE and nephrogenic DI has not been reported in literature. We present a case of SLE presenting as nephrogenic DI. We report a case who presented with DI (nephrogenic) and fulfilled criteria for SLE and Sjögren's syndrome with renal tubular acidosis.

Pregnancy Outcomes in Chinese Patients with Systemic Lupus Erythematosus (SLE): A Retrospective Study of 109 Pregnancies

PubMed Central

Ku, Ming; Guo, Shuiming; Shang, Weifeng; Li, Qing; Zeng, Rui; Han, Min; Ge, Shuwang; Xu, Gang

2016-01-01

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that primarily affects women during their reproductive years. The interaction between SLE and pregnancy remains debated. The objective of this study was to analyze the fetal and maternal outcomes of Chinese women with SLE. A total of 109 pregnancies in 83 SLE patients from June 2004 to June 2014 at a tertiary university hospital were reviewed retrospectively. Patients’ characteristics, clinical and laboratory data during pregnancy were obtained from electronic medical records. After exclusion of elective abortions, the live birth rate was 61.5%. Significantly, APS (antiphospholipid syndrome), disease activity, hypertension, hypocomplementemia, thrombocytopenia, and anemia during pregnancy were more commonly observed in fetal loss pregnancies than in live birth pregnancies. Compared to the 64 women with a history of SLE, 19 women with new-onset lupus during pregnancy had worse pregnancy outcome. Furthermore, the 64 patients with a history of SLE were divided into lupus nephritis group and SLE group (non-renal involvement). We found that the lupus nephritis group had worse maternal outcome than the SLE group. We conclude that new-onset lupus during pregnancy predicts both adverse maternal and fetal outcomes, while a history of lupus nephritis predicts adverse maternal outcomes. It is essential to provide SLE women with progestational counseling and regular multispecialty care during pregnancy. PMID:27442513

Aggregation behavior of sodium lauryl ether sulfate with a positively bicharged organic salt and effects of the mixture on fluorescent properties of conjugated polyelectrolytes.

PubMed

Tang, Yongqiang; Liu, Zhang; Zhu, Linyi; Han, Yuchun; Wang, Yilin

2015-02-24

The aggregation behavior of anionic single-chain surfactant sodium lauryl ether sulfate containing three ether groups (SLE3S) with positively bicharged organic salt 1,2-bis(2-benzylammoniumethoxy)ethane dichloride (BEO) has been investigated in aqueous solution, and the effects of the BEO/SLE3S aggregate transitions on the fluorescent properties of anionic conjugated polyelectrolyte MPS-PPV with a larger molecular weight and cationic conjugated oligoelectrolyte DAB have been evaluated. Without BEO, SLE3S does not affect the fluorescent properties of MPS-PPV and only affects the fluorescent properties of DAB at a higher SLE3S concentration. With the addition of BEO, SLE3S and BEO form gemini-like surfactant (SLE3S)2-BEO. When the BEO/SLE3S molar ratio is fixed at 0.25, with increasing the BEO/SLE3S concentration, the BEO/SLE3S mixture forms large, loosely arranged aggregates and then transforms to closely packed spherical aggregates and finally to long thread-like micelles. The photoluminescence (PL) intensity of MPS-PPV varies with the morphologies of the BEO/SLE3S aggregates, while the PL intensity of DAB is almost independent of the aggregate morphologies. The results demonstrate that gemini-like surfactants formed through intermolecular interactions can effectively adjust the fluorescent properties of conjugated polyelectrolytes.

Rheumatologists' perception of systemic lupus erythematosus quality indicators: significant interest and perceived barriers.

PubMed

Casey, Carolyn; Chung, Cecilia P; Crofford, Leslie J; Barnado, April

2017-01-01

Differences in quality of care may contribute to health disparities in systemic lupus erythematosus (SLE). Studies show low physician adherence rates to the SLE quality indicators but do not assess physician perception of SLE quality indicators or quality improvement. Using a cross-sectional survey of rheumatologists in the southeastern USA, we assessed the perception and involvement of rheumatologists in quality improvement and the SLE quality indicators. Using electronic mail, an online survey of 32 questions was delivered to 568 rheumatologists. With a response rate of 19% (n = 106), the majority of participants were male, Caucasian, with over 20 years of experience, and seeing adult patients in an academic setting. Participants had a positive perception toward quality improvement (81%) with a majority responding that the SLE quality indicators would significantly impact quality of care (54%). While 66% of respondents were familiar with the SLE quality indicators, only 18% of respondents reported using them in everyday practice. The most commonly reported barrier to involvement in quality improvement and the SLE quality indicators was time. Rheumatologists had a positive perception of the SLE quality indicators and agreed that use of the quality indicators could improve quality of care in SLE; however, they identified time as a barrier to implementation. Future studies should investigate methods to increase use of the SLE quality indicators.

Academic outcomes in childhood-onset systemic lupus erythematosus.

PubMed

Zelko, Frank; Beebe, Dean; Baker, Aimee; Nelson, Shannen M; Ali, Aisha; Cedeno, Adlin; Dina, Blair; Klein-Gitelman, Marisa S; Ying, Jun; Brunner, Hermine I

2012-08-01

To explore academic outcomes in childhood-onset systemic lupus erythematosus (cSLE) and their relationship to variables such as demographic and socioeconomic status, neurocognitive functioning, behavioral/emotional adjustment, and cSLE disease status. Forty pairs of children diagnosed with cSLE and healthy best friend controls were rated by parents on a standardized scale of school competence. Information about participants' demographic and socioeconomic status was obtained, along with measures of cSLE disease activity and damage. All of the participants received formal neurocognitive testing and were also rated on standardized scales of behavioral/emotional adjustment and executive functioning. Compared to healthy controls, school competence was rated as lower in the cSLE group, although the groups did not differ significantly on indices of cognitive, behavioral, emotional, or executive functioning. School competence ratings were correlated with reading and mathematics achievement test scores in both groups, and with ratings of mental self-regulation in the cSLE group. School competence ratings were correlated with measures of cSLE disease activity and treatment intensity. cSLE is associated with inferior parent-rated academic outcomes compared to those noted in demographically-matched peers, despite similar neurocognitive function. The adverse academic outcomes that distinguish children with cSLE from their demographically-matched peers appear to be mediated by SLE disease activity and treatment. Copyright © 2012 by the American College of Rheumatology.

The feet in systemic lupus erythematosus; are we underestimating their involvement and functional impact?

PubMed

Morales-Lozano, Rosario; Martínez-Barrio, Julia; González-Fernández, María Luz; López-Longo, Francisco Javier; Ovalles-Bonilla, Juan Gabriel; Valor, Lara; Janta, Iustina; Nieto, Juan Carlos; Hernández-Flórez, Diana; González, Carlos M; Monteagudo, Indalecio; Garrido, Jesús; Carreño, Luis; Naredo, Esperanza

2016-01-01

To evaluate biomechanical and ultrasound (US) abnormalities in SLE patients as compared with controls and to assess the relationship between these abnormalities and SLE activity. Fifty-four consecutive female patients with SLE with and without foot pain and 60 female controls (30 with foot pain and 30 without foot pain) were recruited. SLE activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). SLE patients and controls blindly underwent a comprehensive podiatric, biomechanical and US evaluation of the feet. US assessment included detection of B-mode synovitis, tenosynovitis, enthesopathy, bone changes and synovial, tenosynovial and entheseal power Doppler (PD) signal. Thirty-one (57.4%) SLE patients had bilateral foot pain and 5 (9.3%) had unilateral foot pain. Metatarsalgia was the most common location for pain but without significant difference between groups (p=0.284). Toe joint deformities were significantly more common in SLE feet as compared with control feet (p<0.0005). SLE feet showed significantly more biomechanical abnormalities than control feet (p<0.05). B-mode synovitis in the tibiotalar joint was strongly associated with having SLE (p<0.0005) and the presence of synovial PD signal in the MTP joints was found only in painful feet of SLE patients. SLEDAI was significantly higher in patients with foot pain than in those with painless feet (p=0.008). However, SLEDAI did not discriminate between patients with and without biomechanical or US abnormalities. SLE patients showed more biomechanical and US abnormalities in the feet than controls, which were not captured by standardised assessment of the disease activity.

Hematoxylin Bodies in Pediatric Bone Marrow Aspirates and Their Utility in the Diagnosis of Systemic Lupus Erythematosus.

PubMed

Xu, Min; Chisholm, Karen M; Fan, Guang; Stevens, Anne M; Rutledge, Joe C

2017-01-01

In our recent case report, the finding of lupus erythematosus (LE) cells in a bone marrow aspirate led to the diagnosis of systemic lupus erythematosus (SLE) and appropriate treatment, although the patient was not clinically suspected to have SLE. To determine whether LE cells are present in the bone marrow aspirates of SLE patients, but overlooked in routine bone marrow morphology review, bone marrow aspirates from 30 pediatric patients (15 with SLE and 15 with other diagnoses) evaluated by rheumatologists were reviewed. LE cells were found in the bone marrow aspirates of only 1 SLE patient and none in non-SLE patients. However, hematoxylin bodies were identified in 53% (8/15) of SLE patients. Neither hematoxylin bodies nor LE cells were found in the aspirates from patients with other disorders. Three additional pediatric patients identified prospectively were found to have hematoxylin bodies in the bone marrow aspirates. Although the diagnosis was not initially suspected, 2 of the 3 patients were subsequently diagnosed with SLE. All patients with hematoxylin bodies and SLE had antinuclear antibody titers ≥1:640 with a homogeneous staining pattern. In addition, bone marrow aspirates of 9 adult patients were reviewed, and neither LE cells nor hematoxylin bodies were identified. In summary, hematoxylin bodies were present in the bone marrow aspirates of many pediatric SLE patients, while LE cells were rare. The finding of hematoxylin bodies in pediatric bone marrow aspirates is a helpful and specific diagnostic clue that may lead to the diagnosis of SLE when other clinical features are nonspecific.

Use of Atorvastatin in Systemic Lupus Erythematosus in Children and Adolescents

PubMed Central

Schanberg, L. E.; Sandborg, C.; Barnhart, H. X.; Ardoin, S. P.; Yow, E.; Evans, G. W.; Mieszkalski, K. L.; Ilowite, N. T.; Eberhard, A.; Imundo, L. F.; Kimura, Y.; von Scheven, E.; Silverman, E.; Bowyer, S. L.; Punaro, M.; Singer, N. G.; Sherry, D. D.; McCurdy, D.; Klein-Gitelman, M.; Wallace, C.; Silver, R.; Wagner-Weiner, L.; Higgins, G. C.; Brunner, H. I.; Jung, L.; Soep, J. B.; Reed, A. M.; Provenzale, J.; Thompson, S. D.

2014-01-01

Objective Statins reduce atherosclerosis and cardiovascular morbidity in the general population, but their efficacy and safety in children and adolescents with systemic lupus erythematosus (SLE) are unknown. This study was undertaken to determine the 3-year efficacy and safety of atorvastatin in preventing subclinical atherosclerosis progression in pediatric-onset SLE. Methods A total of 221 participants with pediatric SLE (ages 10–21 years) from 21 North American sites were enrolled in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus study, a randomized double-blind, placebo-controlled clinical trial, between August 2003 and November 2006 with 36-month followup. Participants were randomized to receive atorvastatin (n = 113) or placebo (n = 108) at 10 or 20 mg/day depending on weight, in addition to usual care. The primary end point was progression of mean-mean common carotid intima-media thickening (CIMT) measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures, lipid profile, high-sensitivity C-reactive protein (hsCRP) level, and SLE disease activity and damage outcomes. Results Progression of mean-mean common CIMT did not differ significantly between treatment groups (0.0010 mm/year for atorvastatin versus 0.0024 mm/year for placebo; P = 0.24). The atorvastatin group achieved lower hsCRP (P = 0.04), total cholesterol (P < 0.001), and low-density lipoprotein (P < 0.001) levels compared with placebo. In the placebo group, CIMT progressed significantly across all CIMT outcomes (0.0023–0.0144 mm/year; P < 0.05). Serious adverse events and critical safety measures did not differ between groups. Conclusion Our results indicate that routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients; however, further analyses may suggest subgroups that would benefit from targeted statin therapy. Atorvastatin was well tolerated without safety concerns. PMID:22031171

A Novel Epitope from CD22 Regulates Th1 and Th17 Cell Function in Systemic Lupus Erythematosus

PubMed Central

Chen, Xiao; Zhang, Li-Hua; Song, You; Cheng, Xiang; Zhou, Zi-Hua; Wang, Min; Guo, He-Ping; Du, Rong; Liao, Yu-Hua

2013-01-01

The published antibodies (Abs) against CD22 on B cells including Epratuzumab could inhibit B cell activation mainly through binding to C2-set Ig domain of CD22, but they are rarely reported to modulate the pathogenic CD4+ T cell function in systemic lupus erythematosus (SLE). Recently, it was proved that the extracellular amino-terminal V-set Ig domain of CD22 might mediate the interaction of B and T cells, but for now the exact effect of this domain on CD4+ T cell biology have not been identified. Thus, in this study, we screened out a peptide termed B2285 from this V-set Ig domain, developed the novel specific anti-B2285 Abs in rabbits, and investigated their effects in MRL/lpr mice with spontaneous SLE. The results showed that anti-B2285 Abs could ameliorate the disease severity obviously in spontaneous SLE mice with the decreased differentiations of Th1 and Th17 cells and no changes of Th2 and Treg cells. In co-cultured B cells and CD4+ T cells, this specific anti-CD22 Abs was observed to inhibit the anti-dsDNA Abs production, CD4+ T cells proliferation, the protein levels of T-bet and RORγt, and the mRNA levels of TNF-α, IFN-γ, IL-6 and IL-17 in CD4+ T cells. Moreover, the expression of CD45RO on CD4+ T cells could be also apparently diminished by this novel Abs. The data suggested that anti-B2285 Abs could slow SLE progression significantly by regulating Th1 and Th17 cells function via B-T cell interaction and the cytokine network regulation. The treatment against V-set Ig domain of CD22 would be a valuable therapeutic method for SLE and other autoimmune diseases. PMID:23704998

A novel epitope from CD22 regulates Th1 and Th17 cell function in systemic lupus erythematosus.

PubMed

Yuan, Jing; Yu, Miao; Cao, Ai-Lin; Chen, Xiao; Zhang, Li-Hua; Song, You; Cheng, Xiang; Zhou, Zi-Hua; Wang, Min; Guo, He-Ping; Du, Rong; Liao, Yu-Hua

2013-01-01

The published antibodies (Abs) against CD22 on B cells including Epratuzumab could inhibit B cell activation mainly through binding to C2-set Ig domain of CD22, but they are rarely reported to modulate the pathogenic CD4(+) T cell function in systemic lupus erythematosus (SLE). Recently, it was proved that the extracellular amino-terminal V-set Ig domain of CD22 might mediate the interaction of B and T cells, but for now the exact effect of this domain on CD4(+) T cell biology have not been identified. Thus, in this study, we screened out a peptide termed B2285 from this V-set Ig domain, developed the novel specific anti-B2285 Abs in rabbits, and investigated their effects in MRL/lpr mice with spontaneous SLE. The results showed that anti-B2285 Abs could ameliorate the disease severity obviously in spontaneous SLE mice with the decreased differentiations of Th1 and Th17 cells and no changes of Th2 and Treg cells. In co-cultured B cells and CD4(+) T cells, this specific anti-CD22 Abs was observed to inhibit the anti-dsDNA Abs production, CD4(+) T cells proliferation, the protein levels of T-bet and RORγt, and the mRNA levels of TNF-α, IFN-γ, IL-6 and IL-17 in CD4(+) T cells. Moreover, the expression of CD45RO on CD4(+) T cells could be also apparently diminished by this novel Abs. The data suggested that anti-B2285 Abs could slow SLE progression significantly by regulating Th1 and Th17 cells function via B-T cell interaction and the cytokine network regulation. The treatment against V-set Ig domain of CD22 would be a valuable therapeutic method for SLE and other autoimmune diseases.

Antibodies to histones in systemic lupus erythematosus: prevalence, specificity, and relationship to clinical and laboratory features.

PubMed Central

Cohen, M G; Pollard, K M; Webb, J

1992-01-01

Antibodies to histones (AHA) are commonly found in patients with systemic lupus erythematosus (SLE). However, the full profile of AHA and their clinical associations remains unclear. A total of 111 patients with SLE were studied, including 13 patients in whom multiple serum samples were available over several years. IgM, IgG, and IgA antibodies to total core histones, histone complexes, and individual histones were determined by highly sensitive enzyme linked immunosorbent assays (ELISAs). Antibodies to histones were detected in 74% of serum samples, though only at low levels in half of these. Antibodies to each of the individual histones (H1, H2A, H2B, H3, H4) occurred with similar frequencies except for IgG and IgA antibodies to H4, which were uncommon. In contrast, antibodies to the histone complexes H2A-H2B and H3-H4 were detected in only two serum samples and thus do not appear to be a feature of SLE. All three major isotypes of AHA were common and usually occurred with similar frequencies to one another for the various histone specificities. There were few clinical or laboratory associations with AHA; the strongest was between IgG antibodies to total core histones and antibodies to native DNA. Similarly, there was no association between the presence of AHA and disease activity. However, for the patients as a group and in one patient alone, periods of SLE disease activity were associated with higher levels of AHA. Although the profile of antibodies to individual histones varied with time, no profile was identified that corresponded with any specific disease manifestations. It is concluded from this study that although AHA are common in patients with SLE, their clinical value in this syndrome must, at present, be considered limited. PMID:1540040

Serum calcification propensity is independently associated with disease activity in systemic lupus erythematosus

PubMed Central

Chalikias, George; Tziakas, Dimitrios; Chizzolini, Carlo; Ribi, Camillo; Trendelenburg, Marten; Eisenberger, Ute; Hauser, Thomas; Pasch, Andreas; Huynh-Do, Uyen; Arampatzis, Spyridon

2018-01-01

Background Systemic lupus erythematosus (SLE) is associated with severe cardiovascular complications. The T50 score is a novel functional blood test quantifying calcification propensity in serum. High calcification propensity (or low T50) is a strong and independent determinant of all-cause mortality in various patient populations. Methods A total of 168 patients with ≥ 4 American College of Rheumatology (ACR) diagnostic criteria from the Swiss Systemic lupus erythematosus Cohort Study (SSCS) were included in this analysis. Serum calcification propensity was assessed using time-resolved nephelometry. Results The cohort mainly consisted of female (85%), middle-aged (43±14 years) Caucasians (77%). The major determinants of T50 levels included hemoglobin, serum creatinine and serum protein levels explaining 43% of the variation at baseline. Integrating disease activity (SELENA-SLEDAI) into this multivariate model revealed a significant association between disease activity and T50 levels. In a subgroup analysis considering only patients with active disease (SELENA-SLEDAI score ≥4) we found a negative association between T50 and SELENA-SLEDAI score at baseline (Spearman’s rho -0.233, P = 0.02). Conclusions Disease activity and T50 are closely associated. Moreover, T50 levels identify a subgroup of SLE patients with ongoing systemic inflammation as mirrored by increased disease activity. T50 could be a promising biomarker reflecting SLE disease activity and might offer an earlier detection tool for high-risk patients. PMID:29364894

Pitfalls in lupus.

PubMed

Schneider, M

2016-11-01

"The objective of Pitfall!™ is to guide Harry through a maze of jungle scenes, jumping over or avoiding many deadly dangers… Harry has three lives in each game." If you exchange Harry's adventures with "Life with SLE," patients have to be guided through the jungle having just one life and the deadly dangers are flares, organ manifestations, and, e.g., consequences of immunosuppressive medications, especially glucocorticoids. Monitoring and treatment in line with recommendations and guidelines may be supportive to survive the first 3 to 5 levels in most cases, but for higher levels of the reality game, creativity is needed and life becomes more risky. The aim of this reflection is to identify common pitfalls and to stimulate further research and collaboration in specific areas of the lupus jungle. Topics like "Hidden Power Unit," "Looks similar …," "Rev Meter for SLE," "Flare Prediction," "Level 2: Eminence Based," "Lupus=Lifelong Immunosuppression?!," "Glucocorticoids," "Antimalarials Are Contraindicated," "It Is All About Immunosuppression," "Prediction of Damage," and "Patient Global Assessment (PGA) versus Physician Global Assessment (PhGA)" are addressed. Raised ideas and thoughts are by no means complete or exclusive, but if taken up, they may hopefully lead to another approach in daily care and trials in SLE. Copyright © 2016 Elsevier B.V. All rights reserved.

Pseudo-pseudo Meigs' syndrome in a patient with systemic lupus erythematosus.

PubMed

Dalvi, S R; Yildirim, R; Santoriello, D; Belmont, H M

2012-11-01

Pseudo-pseudo Meigs' syndrome (PPMS) is a rare manifestation of patients with systemic lupus erythematosus (SLE), defined by the presence of ascites, pleural effusions and an elevated CA-125 level. We describe a patient with longstanding lupus who presented with localized lymphadenopathy and subsequently developed massive chylous ascites with marked hypoalbuminemia. A brief historical overview of Meigs' syndrome and related entities is presented, along with a discussion of the differential diagnosis of hypoalbuminemia and ascites in an SLE patient. In addition, we speculate on the optimal therapeutic intervention in such a patient.

[NEUROPSYCHIATRIC MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS].

PubMed

Stryjer, Rafael; Shriki Tal, Liron; Gizunterman, Alex; Amital, Daniela; Amital, Howard; Kotler, Moshe

2017-12-01

This review deals with the neuropsychiatric disorders resulting from systemic lupus erythematosus (SLE). SLE is a chronic autoimmune disease that impacts all systems in the human body, including the central nervous system. Neuropsychiatric symptoms in SLE are a common complication of the disease. This complication has significant implications for the severity of the illness. In most cases no thorough psychiatric assessment is performed during initial evaluation of the disease and no protocol or clear guidelines for treating the psychiatric symptoms in SLE are available. Early diagnosis of the psychiatric symptoms in SLE is critical since absence of treatment may result in severe psychiatric complications. Clinical pharmacological studies are needed in order to develop guidelines for treating psychiatric symptoms in SLE.

Interferon regulatory factor 1 and histone H4 acetylation in systemic lupus erythematosus

PubMed Central

Leung, Yiu Tak; Shi, Lihua; Maurer, Kelly; Song, Li; Zhang, Zhe; Petri, Michelle; Sullivan, Kathleen E

2015-01-01

Histone acetylation modulates gene expression and has been described as increased in systemic lupus erythematosus (SLE). We investigated interferon regulatory factor 1 (IRF1) interactions that influence H4 acetylation (H4ac) in SLE. Intracellular flow cytometry for H4 acetylated lysine (K) 5, K8, K12, and K16 was performed. Histone acetylation was defined in monocytes and T cells from controls and SLE patients. RNA-Seq studies were performed on monocytes to look for an imbalance in histone acetyltransferases and histone deacetylase enzyme expression. Expression levels were validated using real-time quantitative RT-PCR. IRF1 induction of H4ac was evaluated using D54MG cells overexpressing IRF1. IRF1 protein interactions were studied using co-immunoprecipitation assays. IRF1-dependent recruitment of histone acetyltransferases to target genes was examined by ChIP assays using p300 antibody. Flow cytometry data showed significantly increased H4K5, H4K8, H4K12, and H4K16 acetylation in SLE monocytes. HDAC3 and HDAC11 gene expression were decreased in SLE monocytes. PCAF showed significantly higher gene expression in SLE than controls. IRF1-overexpressing D54MG cells were associated with significantly increased H4K5, H4K8, and H4K12 acetylation compared to vector-control D54MG cells both globally and at specific target genes. Co-immunoprecipitation studies using D54MG cells revealed IRF1 protein-protein interactions with PCAF, P300, CBP, GCN5, ATF2, and HDAC3. ChIP experiments demonstrated increased p300 recruitment to known IRF1 targets in D54MG cells overexpressing IRF1. In contrast, p300 binding to IRF1 targets decreased in D54MG cells with IRF1 knockdown. SLE appears to be associated with an imbalance in histone acetyltransferases and histone deacetylase enzymes favoring pathologic H4 acetylation. Furthermore, IRF1 directly interacts with chromatin modifying enzymes, supporting a model where recruitment to specific target genes is mediated in part by IRF1. PMID:25611806

Cutaneous Manifestations of Systemic Lupus Erythematosus

PubMed Central

Uva, Luís; Miguel, Diana; Pinheiro, Catarina; Freitas, João Pedro; Marques Gomes, Manuel; Filipe, Paulo

2012-01-01

Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease of unknown etiology with many clinical manifestations. The skin is one of the target organs most variably affected by the disease. The American College of Rheumatology (ACR) established 11 criteria as a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be used to diagnose individuals and do not do well in that capacity. Cutaneous lesions account for four of these 11 revised criteria of SLE. Skin lesions in patients with lupus may be specific or nonspecific. This paper covers the SLE-specific cutaneous changes: malar rash, discoid rash, photosensitivity, and oral mucosal lesions as well as SLE nonspecific skin manifestations, their pathophysiology, and management. A deeper thorough understanding of the cutaneous manifestations of SLE is essential for diagnosis, prognosis, and efficient management. Thus, dermatologists should cooperate with other specialties to provide optimal care of SLE patient. PMID:22888407

Estradiol targets T cell signaling pathways in human systemic lupus.

PubMed

Walters, Emily; Rider, Virginia; Abdou, Nabih I; Greenwell, Cindy; Svojanovsky, Stan; Smith, Peter; Kimler, Bruce F

2009-12-01

The major risk factor for developing systemic lupus erythematosus (SLE) is being female. The present study utilized gene profiles of activated T cells from females with SLE and healthy controls to identify signaling pathways uniquely regulated by estradiol that could contribute to SLE pathogenesis. Selected downstream pathway genes (+/- estradiol) were measured by real time polymerase chain amplification. Estradiol uniquely upregulated six pathways in SLE T cells that control T cell function including interferon-alpha signaling. Measurement of interferon-alpha pathway target gene expression revealed significant differences (p= 0.043) in DRIP150 (+/- estradiol) in SLE T cell samples while IFIT1 expression was bimodal and correlated moderately (r= 0.55) with disease activity. The results indicate that estradiol alters signaling pathways in activated SLE T cells that control T cell function. Differential expression of transcriptional coactivators could influence estrogen-dependent gene regulation in T cell signaling and contribute to SLE onset and disease pathogenesis.

Prevalence and genetic diversity of torque teno virus in patients with systemic lupus erythematosus in a reference service in Mato Grosso do Sul.

PubMed

Costa, Márcio Reis da; Costa, Izaias Pereira da; Devalle, Sylvie; Castro, Ana Rita Coimbra Motta de; Freitas, Solange Zacalusni

2012-01-01

Recent studies on the torque teno virus (TTV), genus Anellovirus, have allowed formulating the hypothesis that TTV may trigger autoimmune rheumatic diseases or have some pathogenic role in them. To determine the frequency of TTV infection in patients with systemic lupus erythematosus (SLE), the genetic diversity of TTV, the correlation between TTV infection and SLE clinical manifestations, and SLE clinical course and serological profile. Serum samples were obtained from 46 SLE patients treated at the University-Affiliated Hospital of Campo Grande (NHU/FAMED/UFMS), Brazil. For controls, serum samples were obtained from 46 healthy volunteer blood donors. Viral DNA was extracted from samples using the QIAamp DNA Blood Mini Kit (QIAGEN, Hilden, Germany) and amplified using nested PCR. Positivity for TTV was found in 17 (37%) of SLE patients and in only seven (15.2%) of the controls (z test, P = 0.03). There was no correlation between TTV infection, SLE clinical manifestations, SLE clinical course, and the serological profile of the patients evaluated. Further studies on the presence of TTV in SLE patients are required.

A volcanic explosion of autoantibodies in systemic lupus erythematosus: a diversity of 180 different antibodies found in SLE patients.

PubMed

Yaniv, Gal; Twig, Gilad; Shor, Dana Ben-Ami; Furer, Ariel; Sherer, Yaniv; Mozes, Oshry; Komisar, Orna; Slonimsky, Einat; Klang, Eyal; Lotan, Eyal; Welt, Mike; Marai, Ibrahim; Shina, Avi; Amital, Howard; Shoenfeld, Yehuda

2015-01-01

Recent research in systemic lupus erythematosus (SLE) yielded new antigens and antibodies in SLE patients. We describe the various autoantibodies that can be detected in patients with SLE. A literature review, using the terms “autoantibody” and “systemic lupus erythematosus”, was conducted to search for articles on autoantibodies in SLE, their target antigens, association with disease activity and other clinical manifestations. One hundred and eighty autoantibodies were so far described in SLE patients. These include autoantibodies that target nuclear antigens, cytoplasmic antigens, cell membrane antigens, phospholipid-associated antigens, blood cells, endothelial cells, and nervous system antigens, plasma proteins, matrix proteins, and miscellaneous antigens. The target of an autoantibody, the autoantigen properties, autoantibody frequencies in SLE, as well as clinical associations, and correlation with disease activity are described for all 180 autoantibodies. SLE is so far the autoimmune disease with the largest number of detectable autoantibodies. Their production could be antigen-driven, the result of a polyclonal B cell activation, impaired apoptotic pathways, or the outcome of an idiotypic network dysregulation. Copyright © 2014 Elsevier B.V. All rights reserved.

Episodic memory impairment in systemic lupus erythematosus: involvement of thalamic structures.

PubMed

Zimmermann, Nicolle; Corrêa, Diogo Goulart; Netto, Tania Maria; Kubo, Tadeu; Pereira, Denis Batista; Fonseca, Rochele Paz; Gasparetto, Emerson Leandro

2015-02-01

Episodic memory deficits in systemic lupus erythematosus (SLE) have been frequently reported in the literature; however, little is known about the neural correlates of these deficits. We investigated differences in the volumes of different brain structures of SLE patients with and without episodic memory impairments diagnosed by the Rey Auditory Verbal Learning Test (RAVLT). Groups were paired based on age, education, sex, Mini Mental State Examination score, accumulation of disease burden (SLICC), and focused attention dimension score. Patients underwent magnetic resonance imaging (MRI). Cortical volumetric reconstruction and segmentation of the MR images were performed with the FreeSurfer software program. SLE patients with episodic memory deficits presented shorter time of diagnosis than SLE patients without episodic memory deficits. ANOVA revealed that SLE patients with episodic memory deficits had a larger third ventricle volume than SLE patients without episodic memory deficits and controls. Additionally, covariance analysis indicated group effects on the bilateral thalamus and on the third ventricle. Our findings indicate that episodic memory may be impaired in SLE patients with normal hippocampal volume. In addition, the thalamus may undergo volumetric changes associated with episodic memory loss in SLE.

British isles lupus assessment group 2004 index is valid for assessment of disease activity in systemic lupus erythematosus

PubMed Central

Yee, Chee-Seng; Farewell, Vernon; Isenberg, David A; Rahman, Anisur; Teh, Lee-Suan; Griffiths, Bridget; Bruce, Ian N; Ahmad, Yasmeen; Prabu, Athiveeraramapandian; Akil, Mohammed; McHugh, Neil; D'Cruz, David; Khamashta, Munther A; Maddison, Peter; Gordon, Caroline

2007-01-01

Objective To determine the construct and criterion validity of the British Isles Lupus Assessment Group 2004 (BILAG-2004) index for assessing disease activity in systemic lupus erythematosus (SLE). Methods Patients with SLE were recruited into a multicenter cross-sectional study. Data on SLE disease activity (scores on the BILAG-2004 index, Classic BILAG index, and Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K]), investigations, and therapy were collected. Overall BILAG-2004 and overall Classic BILAG scores were determined by the highest score achieved in any of the individual systems in the respective index. Erythrocyte sedimentation rates (ESRs), C3 levels, C4 levels, anti–double-stranded DNA (anti-dsDNA) levels, and SLEDAI-2K scores were used in the analysis of construct validity, and increase in therapy was used as the criterion for active disease in the analysis of criterion validity. Statistical analyses were performed using ordinal logistic regression for construct validity and logistic regression for criterion validity. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Results Of the 369 patients with SLE, 92.7% were women, 59.9% were white, 18.4% were Afro-Caribbean and 18.4% were South Asian. Their mean ± SD age was 41.6 ± 13.2 years and mean disease duration was 8.8 ± 7.7 years. More than 1 assessment was obtained on 88.6% of the patients, and a total of 1,510 assessments were obtained. Increasing overall scores on the BILAG-2004 index were associated with increasing ESRs, decreasing C3 levels, decreasing C4 levels, elevated anti-dsDNA levels, and increasing SLEDAI-2K scores (all P < 0.01). Increase in therapy was observed more frequently in patients with overall BILAG-2004 scores reflecting higher disease activity. Scores indicating active disease (overall BILAG-2004 scores of A and B) were significantly associated with increase in therapy (odds ratio [OR] 19.3, P < 0.01). The BILAG-2004 and Classic BILAG indices had comparable sensitivity, specificity, PPV, and NPV. Conclusion These findings show that the BILAG-2004 index has construct and criterion validity. PMID:18050213

Microparticles in the blood of patients with systemic lupus erythematosus (SLE): phenotypic characterization and clinical associations

PubMed Central

Mobarrez, Fariborz; Vikerfors, Anna; Gustafsson, Johanna T.; Gunnarsson, Iva; Zickert, Agneta; Larsson, Anders; Pisetsky, David S.; Wallén, Håkan; Svenungsson, Elisabet

2016-01-01

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by circulating autoantibodies and the formation of immune complexes. In these responses, the selecting self-antigens likely derive from the remains of dead and dying cells, as well as from disturbances in clearance. During cell death/activation, microparticles (MPs) can be released to the circulation. Previous MP studies in SLE have been limited in size and differ regarding numbers and phenotypes. Therefore, to characterize MPs more completely, we investigated 280 SLE patients and 280 individually matched controls. MPs were measured with flow cytometry and phenotyped according to phosphatidylserine expression (PS+/PS−), cellular origin and inflammatory markers. MPs, regardless of phenotype, are 2–10 times more abundant in SLE blood compared to controls. PS− MPs predominated in SLE, but not in controls (66% vs. 42%). Selectively in SLE, PS− MPs were more numerous in females and smokers. MP numbers decreased with declining renal function, but no clear association with disease activity was observed. The striking abundance of MPs, especially PS− MPs, suggests a generalized disturbance in SLE. MPs may be regarded as “liquid biopsies” to assess the production and clearance of dead, dying and activated cells, i.e. pivotal events for SLE pathogenesis. PMID:27777414

Deciphering systemic lupus erythematosus-associated serum biomarkers reflecting apoptosis and disease activity.

PubMed

Delfani, P; Sturfelt, G; Gullstrand, B; Carlsson, A; Kassandra, M; Borrebaeck, C A K; Bengtsson, A A; Wingren, C

2017-04-01

Systemic lupus erythematosus (SLE) is a severe chronic inflammatory autoimmune connective tissue disease. Despite major efforts, SLE remains a poorly understood disease with unpredictable course, unknown etiology and complex pathogenesis. Apoptosis combined with deficiency in clearing apoptotic cells is an important etiopathogenic event in SLE, which could contribute to the increased load of potential autoantigen(s); however, the lack of disease-specific protein signatures deciphering SLE and the underlying biological processes is striking and represents a key limitation. In this retrospective pilot study, we explored the immune system as a specific sensor for disease, in order to advance our understanding of SLE. To this end, we determined multiplexed serum protein expression profiles of crude SLE serum samples, using antibody microarrays. The aim was to identify differential immunoprofiles, or snapshots of the immune response modulated by the disease, reflecting apoptosis, a key process in the etiology of SLE and disease activity. The results showed that multiplexed panels of SLE-associated serum biomarkers could be decoded, in particular reflecting disease activity, but potentially the apoptosis process as well. While the former biomarkers could display a potential future use for prognosis, the latter biomarkers might help shed further light on the apoptosis process taking place in SLE.

Baseline predictors of systemic lupus erythematosus flares: data from the combined placebo groups in the phase III belimumab trials.

PubMed

Petri, Michelle A; van Vollenhoven, Ronald F; Buyon, Jill; Levy, Roger A; Navarra, Sandra V; Cervera, Ricard; Zhong, Z John; Freimuth, William W

2013-08-01

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. Post hoc analysis assessed baseline demographics, disease activity, and biomarkers in patients with and those without flare at treatment weeks 24 and 52. Severe flare was defined by the modified SLE Flare Index (SFI) and the development of any new British Isles Lupus Assessment Group (BILAG) A domain score. Severe and moderate flare was defined by development of 1 new BILAG A domain score or 2 new BILAG B domain scores. Baseline characteristics associated with a ≥10% absolute difference or a ≥50% increase in flare rates were considered predictive. Frequencies of flares over 52 weeks according to the SFI, any new BILAG A domain score, and 1 new BILAG A domain score or 2 new BILAG B domain scores were 23.7%, 23.1%, and 32.0%, respectively. Flare predictors by univariate analysis on all 3 indices at weeks 24 and 52 were a score ≥12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI); anti-double-stranded DNA (anti-dsDNA) positivity; proteinuria (≥0.5 gm/24 hours); BILAG renal, vasculitic, and hematologic scores; elevated C-reactive protein levels; and B lymphocyte stimulator (BLyS) levels ≥2 ng/ml. Independent predictors by multivariate analysis at week 52 were SELENA-SLEDAI and/or BILAG renal involvement and anti-dsDNA ≥200 IU/ml (on all 3 indices); SELENA-SLEDAI and/or BILAG neurologic and vasculitic involvement (on 2 indices: any new BILAG A domain score and 1 new BILAG A domain score or 2 new BILAG B domain scores); BLyS levels ≥2 ng/ml (on 2 indices: the SFI and 1 new BILAG A domain score or 2 new BILAG B domain scores); and low C3 level (on the SFI). Baseline medications did not significantly decrease or increase moderate-to-severe SLE flare risk. Patients who were receiving standard SLE therapy and had renal, neurologic, or vasculitic involvement, elevated anti-dsDNA or BLyS levels, or low C3 had increased risk of clinically meaningful flare over 1 year. Hydroxychloroquine use was not predictive. Copyright © 2013 by the American College of Rheumatology.

Anti-Myeloperoxidase Antibodies Associate with Future Proliferative Lupus Nephritis

PubMed Central

Lee, J. J.; Poirier, M.; Little, D. J.; Prince, L. K.; Baker, T. P.; Edison, J. D.; Abbott, K. C.

2017-01-01

Background The subclinical pathophysiology of proliferative lupus nephritis (PLN) has not been fully elucidated. Myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) is associated with PLN, but prediagnostic levels have not been reported. Methods We performed a retrospective case-control Department of Defense Serum Repository (DoDSR) study comparing MPO-ANCA levels in longitudinal prediagnostic serum samples for 23 biopsy confirmed proliferative lupus nephritis (PLN) patients to DoDSR identified age, sex, race, and age of serum matched healthy and SLE without LN disease controls. We also compared the temporal relationship of MPO-ANCA to anti-double stranded DNA antibodies (dsDNAab). Results A greater proportion of PLN patients had prediagnostic MPO-ANCA levels above ≥3 U/mL and ≥6 U/mL compared to SLE without LN (91% versus 43%, p < 0.001; 57% versus 5%, p < 0.001, resp.). In subgroup analysis, the MPO-ANCA threshold of ≥3 U/mL was significant at <1 year (88% versus 39%, p = 0.007) and 1–4 years (87% versus 38%, p = 0.009) prior to diagnosis. Statistically significant subclinical MPO-ANCA levels (≥3 U/mL) occurred prior to statistically significant dsDNAab ≥ 3 IU/ml (89% versus 11%, p = 0.003). Conclusions Subclinical MPO-ANCA levels could distinguish future PLN from SLE without LN. MPO-ANCA manifests prior to clinical disease and subclinical dsDNAab to suggest that it may contribute directly to PLN pathogenicity. PMID:29435367

Heterogeneity of peripheral blood monocytes, endothelial dysfunction and subclinical atherosclerosis in patients with systemic lupus erythematosus.

PubMed

Mikołajczyk, T P; Osmenda, G; Batko, B; Wilk, G; Krezelok, M; Skiba, D; Sliwa, T; Pryjma, J R; Guzik, T J

2016-01-01

Systemic lupus erythematosus (SLE) is characterized by increased cardiovascular morbidity and mortality. SLE patients have increased prevalence of subclinical atherosclerosis, although the mechanisms of this observation remain unclear. Considering the emerging role of monocytes in atherosclerosis, we aimed to investigate the relationship between subclinical atherosclerosis, endothelial dysfunction and the phenotype of peripheral blood monocytes in SLE patients. We characterized the phenotype of monocyte subsets defined by the expression of CD14 and CD16 in 42 patients with SLE and 42 non-SLE controls. Using ultrasonography, intima-media thickness (IMT) of carotid arteries and brachial artery flow-mediated dilation (FMD) as well as nitroglycerin-induced dilation (NMD) were assessed. Patients with SLE had significantly, but only modestly, increased IMT when compared with non-SLE controls (median (25th/75th percentile) 0.65 (0.60/0.71) mm vs 0.60 (0.56/0.68) mm; p < 0.05). Importantly, in spite of early atherosclerotic complications in the studied SLE group, marked endothelial dysfunction was observed. CD14dimCD16+proinflammatory cell subpopulation was positively correlated with IMT in SLE patients. This phenomenon was not observed in control individuals. Interestingly, endothelial dysfunction assessed by FMD was not correlated with any of the studied monocyte subsets. Our observations suggest that CD14dimCD16+monocytes are associated with subclinical atherosclerosis in SLE, although the mechanism appears to be independent of endothelial dysfunction. © The Author(s) 2015.

Squared ligament of the elbow: anatomy and contribution to forearm stability.

PubMed

Otayek, Salma; Tayeb, Abd-el-Kader Ait; Assabah, Bouchra; Viard, Brice; Dayan, Romain; Lazure, Thierry; Soubeyrand, Marc

2016-03-01

The present study describes the macroscopic and microscopic features of the squared ligament of the elbow (SLE). In addition, the SLE biomechanical behavior and contribution to the forearm stability were also examined. Ten forearms from freshly frozen cadavers were used for this work. Each forearm was mounted in an experimental frame for quantification of longitudinal and transverse stability. Macroscopic features and biomechanical behavior were analyzed on dynamic videos obtained during forearm rotation. Then, the SLE was harvested from the 10 forearms for microscopic analysis on histological slices stained with hematoxylin-eosin-saffron. Two main SLE configurations were identified. One in which the SLE had three distinct bundles (anterior, middle, posterior) and another in which it was homogeneous. The anterior part of the SLE had a mean length of 11.2 mm (±2.4 mm) and a mean width of 1.2 mm (±0.2 mm) while the posterior part had a mean length of 9.9 mm (±2.2 mm) and a mean width of 1 mm (±0.2 mm). Microscopic examination showed that the SLE is composed of a thin layer of arranged collagen fibers. During forearm rotation, the SLE progressively tightens upon pronation and supination by wrapping around the radial neck. Tightening of the SLE during forearm rotation provides transverse and longitudinal stability to the forearm, mainly in maximal pronation and supination. The SLE is a true ligament and provides forearm stability when it is stretched in pronation and supination.

Subgingival microbiota dysbiosis in systemic lupus erythematosus: association with periodontal status.

PubMed

Corrêa, Jôice Dias; Calderaro, Débora Cerqueira; Ferreira, Gilda Aparecida; Mendonça, Santuza Maria Souza; Fernandes, Gabriel R; Xiao, E; Teixeira, Antônio Lúcio; Leys, Eugene J; Graves, Dana T; Silva, Tarcília Aparecida

2017-03-20

Periodontitis results from the interaction between a subgingival biofilm and host immune response. Changes in biofilm composition are thought to disrupt homeostasis between the host and subgingival bacteria resulting in periodontal damage. Chronic systemic inflammatory disorders have been shown to affect the subgingival microbiota and clinical periodontal status. However, this relationship has not been examined in subjects with systemic lupus erythematosus (SLE). The objective of our study was to investigate the influence of SLE on the subgingival microbiota and its connection with periodontal disease and SLE activity. We evaluated 52 patients with SLE compared to 52 subjects without SLE (control group). Subjects were classified as without periodontitis and with periodontitis. Oral microbiota composition was assessed by amplifying the V4 region of 16S rRNA gene from subgingival dental plaque DNA extracts. These amplicons were examined by Illumina MiSeq sequencing. SLE patients exhibited higher prevalence of periodontitis which occurred at a younger age compared to subjects of the control group. More severe forms of periodontitis were found in SLE subjects that had higher bacterial loads and decreased microbial diversity. Bacterial species frequently detected in periodontal disease were observed in higher proportions in SLE patients, even in periodontal healthy sites such as Fretibacterium, Prevotella nigrescens, and Selenomonas. Changes in the oral microbiota were linked to increased local inflammation, as demonstrated by higher concentrations of IL-6, IL-17, and IL-33 in SLE patients with periodontitis. SLE is associated with differences in the composition of the microbiota, independently of periodontal status.

Epstein–Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti-DNA

PubMed Central

Fattal, Ittai; Shental, Noam; Molad, Yair; Gabrielli, Armando; Pokroy-Shapira, Elisheva; Oren, Shirly; Livneh, Avi; Langevitz, Pnina; Pauzner, Rachel; Sarig, Ofer; Gafter, Uzi; Domany, Eytan; Cohen, Irun R

2014-01-01

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities – anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein–Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease. PMID:24164500

[The role of elective neck dissection during salvage laryngectomy - a retrospective analysis].

PubMed

Hussain, Timon; Kanaan, Oliver; Höing, Benedikt; Dominas, Nina; Lang, Stephan; Mattheis, Stefan

2018-05-16

Elective neck dissection of the N0-neck is routinely performed during salvage laryngectomy (SLE) for recurrent cancer of the larynx or hypopharynx. The therapeutic benefit of additional neck dissection must be weighed against the risk of increased morbidity. In this retrospective analysis, we assessed oncologic parameters of patients who underwent SLE with concurrent bilateral neck dissection for recurrent laryngeal or hypopharyngeal cancer. We compared these data with patients who underwent primary laryngectomy (LE) with bilateral neck dissection for laryngeal and hypopharyngeal cancer.19 patients who had undergone SLE and 83 patients after LE were included in the analysis. The majority of patients had advanced stage tumors prior to LE or primary radiation therapy, as well as advanced stage recurrent tumors prior to SLE. Prior to SLE, 5 % of all patients (n = 1) had clinically pathologic lymph nodes, compared to 47 % (n = 39) prior to LE. 17 % (n = 14) of patients with LE and bilateral neck dissection had occult lymph node metastases, compared to 5 % (n = 1) of patients who underwent SLE with bilateral neck dissection. Overall, 55 % (n = 44) of patients who underwent LE had positive cervical lymph nodes, compared to 10 % (n = 2) of SLE patients. Lymph node yield was higher in patients with LE than in SLE-patients (37.3 vs. 18.7, p < 0.001). 5-year OS was 50 % after LE and 33 % after SLE. Cervical lymph node metastases are rare in patients who undergo SLE for recurrent cancers of the larynx of hypopharynx. However, occult metastases do occur. Therefore, since SLE is the final curative therapy, additional neck dissection should be taken into consideration. © Georg Thieme Verlag KG Stuttgart · New York.

HLA Association in SLE patients from Lahore-Pakistan

PubMed Central

Hussain, Nageen; Jaffery, Ghazala; Sabri, Anjum Nasim; Hasnain, Shahida

2011-01-01

The first genetic factors to be identified as important in the pathogenesis of Systemic lupus erythematosus (SLE) were those of the major histocompatibility complex (MHC) on chromosome 6. It is now widely accepted that MHC genes constitute a part of the genetic susceptibility to SLE. The study population comprised 61 SLE patients fulfilling at least four of the American college of Rheumatology criteria for SLE and 61 healthy blood donors as controls. SLE female versus male ratio was approximately 9:1. Mean age at diagnosis was 30.35 ± 1.687 (12-68 years). DNA-based HLA Typing for HLA-A, HLA-B, and HLA-DRB1 was carried out by Polymerase chain reaction with sequence specific primers using genomic DNA obtained from blood samples. A total of 22 alleles have been studied at locus A, 37 alleles at locus B and 17 DRB1 alleles. The allelic frequencies of HLA-A, HLA-B, and HLA-DRB1 antigens in SLE patients from Pakistan were compared with the controls. A significant increase was observed in the frequency of HLA-A*01, A*03, A*11, A*23, A*26 A*69, HLA-B*27, B*40, B*49, B*51, B*52, B*53, B*54, B*95, HLA-DRBI*01, DRBI*03, DRBI*11, DRBI*14 among SLE patients indicating a positive association of these alleles with SLE. HLA-A*24, A*29, A*31, A*34, A*68, A*92, HLA-B*18, HLA-DRB1*12, were found to be decreased in the patient group as compared to controls indicating a negative association of these alleles with SLE. Thus from this study we can conclude that SLE is associated with certain MHC alleles in Pakistani population. PMID:21342137

HLA association in SLE patients from Lahore-Pakistan.

PubMed

Hussain, Nageen; Jaffery, Ghazala; Sabri, Anjum Nasim; Hasnain, Shahida

2011-02-01

The first genetic factors to be identified as important in the pathogenesis of Systemic lupus erythematosus (SLE) were those of the major histocompatibility complex (MHC) on chromosome 6. It is now widely accepted that MHC genes constitute a part of the genetic susceptibility to SLE. The study population comprised 61 SLE patients fulfilling at least four of the American college of Rheumatology criteria for SLE and 61 healthy blood donors as controls. SLE female versus male ratio was approximately 9:1. Mean age at diagnosis was 30.35 ± 1.687 (12-68 years). DNA-based HLA Typing for HLA-A, HLA-B, and HLA-DRB1 was carried out by Polymerase chain reaction with sequence specific primers using genomic DNA obtained from blood samples. A total of 22 alleles have been studied at locus A, 37 alleles at locus B and 17 DRB1 alleles. The allelic frequencies of HLA-A, HLA-B, and HLA-DRB1 antigens in SLE patients from Pakistan were compared with the controls. A significant increase was observed in the frequency of HLA-A*01, A*03, A*11, A*23, A*26 A*69, HLA-B*27, B*40, B*49, B*51, B*52, B*53, B*54, B*95, HLA-DRBI*01, DRBI*03, DRBI*11, DRBI*14 among SLE patients indicating a positive association of these alleles with SLE. HLA-A*24, A*29, A*31, A*34, A*68, A*92, HLA-B*18, HLA-DRB1*12, were found to be decreased in the patient group as compared to controls indicating a negative association of these alleles with SLE. Thus from this study we can conclude that SLE is associated with certain MHC alleles in Pakistani population.

Genetic Analyses of Interferon Pathway-Related Genes Reveals Multiple New Loci Associated with Systemic Lupus Erythematosus (SLE)

PubMed Central

Ramos, Paula S.; Williams, Adrienne H.; Ziegler, Julie T.; Comeau, Mary E.; Guy, Richard T.; Lessard, Christopher J.; Li, He; Edberg, Jeffrey C.; Zidovetzki, Raphael; Criswell, Lindsey A.; Gaffney, Patrick M.; Graham, Deborah Cunninghame; Graham, Robert R.; Kelly, Jennifer A.; Kaufman, Kenneth M.; Brown, Elizabeth E.; Alarcón, Graciela S.; Petri, Michelle A.; Reveille, John D.; McGwin, Gerald; Vilá, Luis M.; Ramsey-Goldman, Rosalind; Jacob, Chaim O.; Vyse, Timothy J.; Tsao, Betty P.; Harley, John B.; Kimberly, Robert P.; Alarcón-Riquelme, Marta E.; Langefeld, Carl D.; Moser, Kathy L.

2011-01-01

Objective The overexpression of interferon (IFN)-inducible genes is a prominent feature of SLE, serves as a marker for active and more severe disease, and is also observed in other autoimmune and inflammatory conditions. The genetic variations responsible for sustained activation of IFN responsive genes are unknown. Methods We systematically evaluated association of SLE with a total of 1,754 IFN-pathway related genes, including IFN-inducible genes known to be differentially expressed in SLE patients and their direct regulators. We performed a three-stage design where two cohorts (total n=939 SLE cases, 3,398 controls) were analyzed independently and jointly for association with SLE, and the results were adjusted for the number of comparisons. Results A total of 16,137 SNPs passed all quality control filters of which 316 demonstrated replicated association with SLE in both cohorts. Nine variants were further genotyped for confirmation in an average of 1,316 independent SLE cases and 3,215 independent controls. Association with SLE was confirmed for several genes, including the transmembrane receptor CD44 (rs507230, P = 3.98×10−12), cytokine pleiotrophin (PTN) (rs919581, P = 5.38×10−04), the heat-shock DNAJA1 (rs10971259, P = 6.31×10−03), and the nuclear import protein karyopherin alpha 1 (KPNA1) (rs6810306, P = 4.91×10−02). Conclusion This study expands the number of candidate genes associated with SLE and highlights the potential of pathway-based approaches for gene discovery. Identification of the causal alleles will help elucidate the molecular mechanisms responsible for activation of the IFN system in SLE. PMID:21437871

Differences in disease features between childhood-onset and adult-onset systemic lupus erythematosus patients presenting with acute abdominal pain.

PubMed

Tu, Yu-Ling; Yeh, Kuo-Wei; Chen, Li-Chen; Yao, Tsung-Chieh; Ou, Liang-Shiou; Lee, Wen-I; Huang, Jing-Long

2011-04-01

Abdominal pain in systemic lupus erythematosus (SLE) patients has rarely been analyzed in pediatric populations. We planned to investigate the potential differences between childhood-onset and adult-onset SLE patients who were hospitalized because of acute abdominal pain. A retrospective study including 23 childhood-onset SLE patients with 38 admissions and 88 adult-onset SLE patients with 108 admissions from 1999 to 2008 were conducted in our hospital. All of them had the chief complaint of diffuse abdominal pain. The etiologies of acute abdominal pain in adult-onset SLE patients were more diverse than childhood-onset SLE patients. The most common cause of acute abdominal pain in SLE patients was lupus mesenteric vasculitis (LMV) (18.5%), followed by acute gastroenteritis (14.4%), pancreatitis (10.3%), appendicitis (7.5%), and cholecystitis (6.2%). Compared with adults, children were admitted more often due to LMV (31.6% versus 13.9%; P = 0.016), had more frequently recurrent episodes (39.1% versus 14.8%; P = 0.009), and were more often treated with immunosuppressive agents (31.6% versus 7.4%; P < 0.001) at the time of admission. The overall case fatality rate of acute abdomen in SLE patients was 9.4%. The extra-gastrointestinal symptoms, laboratory evaluation, disease activity, and organ damage measured by the SLE Disease Activity Index and outcomes were comparable between children and adults. Various etiologies of acute abdominal pain should be considered in SLE patients. LMV is the most common cause of acute abdomen in childhood-onset SLE patients with low mortality and morbidity provided by prompt diagnosis and timely administration of high-dose intravenous corticosteroids after excluding real surgical abdomen. Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

Carotid intima-media thickness and arterial stiffness in pediatric systemic lupus erythematosus.

PubMed

Su-Angka, N; Khositseth, A; Vilaiyuk, S; Tangnararatchakit, K; Prangwatanagul, W

2017-08-01

Objectives The carotid intima-media thickness (CIMT) and carotid arterial stiffness index (CASI) act as the surrogate markers of atherosclerosis. We aim to assess CIMT and CASI in pediatric systemic lupus erythematosus (SLE). Methods Patients ≤ 20 years old fulfilling diagnostic criteria for SLE were enrolled. Patients with active smoking, coronary heart disease, cerebrovascular disease, arterial thrombosis, family history of hypercholesterolemia, chronic liver disease, or other chronic severe diseases were excluded. The patients were categorized into four groups: active SLE, age- and sex-matched control (control A), inactive SLE, and age- and sex-matched control (control I), according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). All subjects underwent ultrasound of carotid arteries to evaluate CIMT and CASI. Results One hundred and two SLE patients (26 active and 76 inactive) and one hundred and three healthy controls (26 control A and 77 control I) were enrolled. The median CIMT in all groups were not significantly different (0.43, 0.41-0.44; 0.43, 0.41-0.44; 0.42, 0.41-0.43; and 0.42, 0.41-0.43 mm, respectively).The CASI in active SLE (13.5, 11.4-17.3) was significantly higher than in control A (8.2, 7.2-9.2) ( p < 0.0001), whereas CASI in inactive SLE (12.7, 10.9-15.7) was significantly higher than in control I (8.9, 7.6-9.8). However, the CASI in active and inactive SLE was not significantly different. Conclusions The higher CASI in active and inactive pediatric SLE, implying functional change of carotid arteries, may be early evidence of increased atherosclerosis in pediatric SLE. This functional dysfunction has been found both in inactive and active SLE.

Epstein-Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti-DNA.

PubMed

Fattal, Ittai; Shental, Noam; Molad, Yair; Gabrielli, Armando; Pokroy-Shapira, Elisheva; Oren, Shirly; Livneh, Avi; Langevitz, Pnina; Pauzner, Rachel; Sarig, Ofer; Gafter, Uzi; Domany, Eytan; Cohen, Irun R

2014-02-01

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities - anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease. © 2013 John Wiley & Sons Ltd.

Cytomegalovirus in pediatric systemic lupus erythematosus: prevalence and clinical manifestations.

PubMed

Rozenblyum, E V; Levy, D M; Allen, U; Harvey, E; Hebert, D; Silverman, E D

2015-06-01

Cytomegalovirus (CMV) is a beta-herpesvirus and antibodies to this virus are common in patients with systemic lupus erythematosus (SLE). However, few studies have examined the relationship between CMV infection and SLE. Our objectives were: 1) to determine the prevalence of CMV infection at the time of SLE diagnosis, and 2) to determine the risk factors for CMV infection. A database review of 670 patients with pediatric SLE (pSLE) seen over a 20-year period identified seven patients with a CMV infection detected at the time of diagnosis of SLE. CMV was diagnosed by serology, urine and bronchoalveolar lavage. Clinical manifestations, laboratory findings, virology studies and treatments were reviewed. CMV infection was detected in seven patients at the time of SLE diagnosis (1.04% of total cohort): six were female: mean age was 13 years. Predominant features included non-Caucasian ethnicity (p < 0.01 as compared to total SLE cohort), persistent fevers on prednisone in seven and nephrotic syndrome in four. Laboratory findings included: anemia in seven, lymphopenia in five, elevated liver enzymes in four, with anti-dsDNA and anti-RNP antibodies present in six and five, respectively. Six patients received ganciclovir and CMV hyperimmune globulin (Cytogam®) with the continuation of prednisone during CMV treatment. Six of seven fully recovered without sequelae (one without treatment) but one patient died with active CMV infection. There were 1.04% of patients with pSLE who developed CMV infection. All were of non-Caucasian ethnicity. Persistent fever despite prednisone, with concomitant anemia, may be additional clues to CMV infection in pSLE. We suggest all patients have routine testing for CMV immunity at initial presentation of pSLE. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Association between glutathione S-transferase M1, P1, and NFKB1 polymorphisms and systemic lupus erythematosus susceptibility: a meta-analysis.

PubMed

Lee, Y H; Song, G G

2016-09-30

This study aimed to determine whether Glutathione S-transferase M1 (GSTM1), P1 (GSTT1), NFKB1 polymorphisms confer susceptibility to systemic lupus erythematosus (SLE). We performed a meta-analysis on the associations between GSTM1 and GSTT1 null genotypes, and NFKB1 -94 ins/delATTG polymorphisms and SLE. In total, seven studies were considered for this meta-analysis, which comprised 2,119 SLE patients and 3,014 healthy controls. Meta-analysis of the GSTM1 null polymorphism in 869 SLE and 1,544 control subjects revealed an association between SLE and the GSTM1 null genotype (OR = 1.321, 95% CI = 1.103-1.583, p = 0.002). Stratification by ethnicity indicated an association between the GSTM1 null genotype and SLE in Asians (OR = 1.334, 95% CI = 1.096-1.623, p = 0.004). However, meta-analysis of the GSTT1 null polymorphism, comprising 717 SLE and 1,008 control subjects, revealed no association between SLE and the GSTT1 null genotype overall (OR = 0.850, 95% CI = 0.687-1.051, p = 0.113) or in an Asian population (OR = 0.794, 95% CI = 0.594-1.061, p = 0.119). Meta-analysis of the NFKB1 -94 ins/delATTG polymorphism, comprising 1,250 SLE and 1,127 control subjects, revealed an association between SLE and the NFKB1 D allele (OR = 1.127, 95% CI = 1.011-1.257, p = 0.031). Ethnicity-specific meta-analysis revealed an association between the NFKB1 D allele and SLE in Asians (OR = 1.155, 95% CI = 1.026-1.300, p = 0.017). This meta-analysis demonstrates that the functional GSTM1 and NFKB1 polymorphisms are associated with the SLE risk in Asians.

Systemic lupus erythematosus and thyroid disease - Experience in a single medical center in Taiwan.

PubMed

Liu, Yu-Chuan; Lin, Wen-Ya; Tsai, Ming-Chin; Fu, Lin-Shien

2017-06-28

To investigate the association of systemic lupus erythematosus (SLE) with thyroid diseases in a medical center in central Taiwan. This is a retrospective cohort of 2796 SLE patients in a tertiary referral medical center from 2000 to 2013. We screened SLE by catastrophic illness registration from national insurance bureau; and thyroid diseases by ICD 9 codes, then confirmed by thyroid function test, auto-antibody, medical and/or surgical intervention. We compared the rate of hyperthyroidism, hypothyroidism and autoimmune thyroid disease (AITD) in SLE patients and the 11,184 match controls. We calculated the rate of these thyroid diseases and positive antibodies to thyroglobulin (ATGAb), thyroid peroxidase (TPOAb) in SLE patients grouped by the presence of overlap syndrome and anti-dsDNA antibody. We also compared the association of thyroid diseases to severe SLE conditions, including renal, central nervous system (CNS) involvement, and thrombocytopenia. Compared to the matched controls, the cumulative incidence of thyroid disease, including hyperthyroidism, hypothyroidism and AITD, were all higher in SLE patients (p < 0.0001). The average age of SLE patients with thyroid diseases patients were older than those without thyroid diseases (p = 0.002). Those had euthyroid AITD were younger than other patients with thyroid diseases (p = 0.02). Up to 30.3% SLE patients had overlap syndrome and had higher relative risk of thyroid diseases than those without overlap syndrome, in terms of hypothyroidism and AITD, but not hyperthyroidism. SLE patients with thyroid diseases also carry higher risk for severe complications such as renal involvement (p = 0.024) central nervous system involvement (p < 0.0001). SLE patients had significantly higher rate of hyperthyroidism, hypothyroidism, and AITD than the matched control. Among lupus patients, the risks of thyroid diseases are even higher in the presence of overlap syndrome. SLE patients with thyroid diseases had higher risk of renal and CNS involvement. Copyright © 2017. Published by Elsevier B.V.

Impact of Disease Duration on Vascular Surrogates of Early Atherosclerosis in Childhood-Onset Systemic Lupus Erythematosus.

PubMed

Barsalou, Julie; Bradley, Timothy J; Tyrrell, Pascal N; Slorach, Cameron; Ng, Lawrence W K; Levy, Deborah M; Silverman, Earl D

2016-01-01

To determine whether longer disease duration negatively impacts carotid intima-media thickness (CIMT), flow-mediated dilation (FMD), and pulse wave velocity (PWV) in a cohort of patients with childhood-onset systemic lupus erythematosus (SLE), and to compare CIMT, FMD, and PWV in patients with childhood-onset SLE with those in healthy children and explore determinants of vascular test results in childhood-onset SLE. Cross-sectional analysis was performed in a prospective longitudinal cohort of patients with childhood-onset SLE at the latest followup visit. Clinical and laboratory data were collected for patients with childhood-onset SLE. CIMT, FMD, and PWV were measured using standardized protocols in patients with childhood-onset SLE and healthy children. Correlations between disease duration and results of the 3 vascular tests were performed. Vascular data in patients with childhood-onset SLE were compared with those in healthy children. Multivariable linear regression was used to identify determinants of CIMT, FMD, and PWV in childhood-onset SLE. Patients with childhood-onset SLE (n = 149) and healthy controls (n = 178) were enrolled. The median age of the patients was 17.2 years (interquartile range [IQR] 15.7-17.9 years), and their median disease duration was 3.2 years (IQR 1.8-4.9 years). The median age of the healthy children was 14.7 years (IQR 13.1-15.9 years). Longer disease duration correlated with worse FMD (r = -0.2, P = 0.031) in patients with childhood-onset SLE. Patients with childhood-onset SLE had smaller (better) CIMT, higher (better) FMD, and similar PWV compared with healthy controls. Linear regression analysis explained <24% of the variation in vascular test results in patients with childhood-onset SLE, suggesting that other variables should be explored as important determinants of CIMT, FMD, and PWV. In this cohort of 149 patients with childhood-onset SLE, patients did not have worse CIMT, FMD, or PWV than did healthy controls. Longer disease duration was associated with worse FMD, suggesting progressive endothelial dysfunction over time. © 2016, American College of Rheumatology.

Clinical, serologic, and immunogenetic characterization (HLA-DRB1) of late-onset lupus erythematosus in a Colombian population.

PubMed

Peñaranda-Parada, E; Quintana, G; Yunis, J J; Mantilla, R; Rojas, W; Panqueva, U; Caminos, J E; Garces, M F; Sanchez, E; Rondón-Herrera, F; de Jesús Iglesias-Gamarra, A

2015-10-01

Late-onset systemic lupus erythematosus (SLE) represents a specific subgroup that is defined as onset after 50 years of age. Late-onset lupus may have a different clinical course and serological findings, which may delay diagnosis and timely treatment. The objective of this paper is to determine the clinical, serologic, and immunogenetic differences among Colombian patients with late-onset SLE versus conventional SLE patients. This was a cross-sectional study in a Colombian population. Patients and their medical records were analyzed from the services of Rheumatology in Bogotá and met the criteria for SLE, according to the American College of Rheumatology (ACR) revised criteria for the classification of SLE.In a reference group of late-onset SLE patients (98 participants, with an onset after 50 years of age) and a group of conventional SLE patients (72 participants, with an onset of age of 49 years or less), multiple clinical variables (age, clinical criteria for lupus, alopecia, weight loss, fever, Raynaud's phenomenon) and multiple serological variables (blood count, blood chemistry profile, autoantibodies) were analyzed. Additionally, the HLA class II (DRB1) of all the patients was genotyped, including an additional group of patients without the autoimmune disease. Statistical analysis was performed using the STATA 10.0 package. In the group of late-onset lupus, there was a higher frequency of pleurisy (p = 0.002), pericarditis (p = 0.026), dry symptoms (p = 0.029), lymphopenia (p = 0.007), and higher titers of rheumatoid factor (p = 0.001) compared with the group of conventional SLE. Late-onset SLE patients had a lower seizure frequency (p = 0.019), weight loss (p = 0.009), alopecia (p < 0.001), and Raynaud's phenomenon (p = 0.013) compared to the conventional SLE group. In late-onset SLE, HLA DR17 (DR3) was found more frequently compared with individuals without autoimmune disease (OR 3.81, 95% CI 1.47 to 10.59) (p = 0.0016). In the Colombian SLE population analyzed, there may be a probable association of several clinical and serologic variants, which would allow the differentiation of variables in the presentation of the disease among patients with late-onset SLE vs. conventional SLE. © The Author(s) 2015.

High prevalence of immunoglobulin A antibody against Epstein-Barr virus capsid antigen in adult patients with lupus with disease flare: case control studies.

PubMed

Chen, Chung-Jen; Lin, Kuei-Hsiang; Lin, Shih-Chang; Tsai, Wen-Chan; Yen, Jeng-Hsien; Chang, Shun-Jen; Lu, Sheng-Nan; Liu, Hong-Wen

2005-01-01

Systemic lupus erythematosus (SLE) is a severe autoimmune disease with rare remission and recurrent flare. Epstein-Barr virus (EBV) infection has been reported to be strongly associated with SLE in the United States, but with an inconclusive role in Asia. We investigated the role of EBV infection in patients with SLE in Taiwan, with one of the highest population densities in Asia. We conducted case-control studies to test whether EBV infection was associated with adult SLE in Taiwan. In the first study, 36 adults with SLE and 36 sex and age matched controls were enrolled for examination of serum IgG, IgM, and IgA antibody against EBV-virus capsid antigen (EBV-VCA). In the second study, another 36 adult lupus cases and 36 matched controls were enrolled to confirm the high prevalence of IgA antibody against EBV-VCA found in the first study. Further, both groups of SLE patients were combined to analyze the association between the existence of IgA antibody against EBV-VCA and disease activity (determined by SLEDAI score) and disease flare in patients with SLE. In the first study, IgA antibody against EBV-VCA was the only marker with significantly higher prevalence in adults with SLE compared to healthy adults (36.1% vs 5.6%; p < 0.005). In the second study, we confirmed that the prevalence of IgA antibody against EBV-VCA was indeed higher in adults with SLE (38.9% vs 2.8%; p < 0.001). With further analysis (pooling analysis), adult SLE patients with IgA antibody against EBV-VCA had higher disease activity compared to SLE patients without IgA antibody against EBV-VCA (SLEDAI 7.8 +/- 6.6 vs 3.3 +/- 2.1; p < 0.001). SLE patients with flare showed much higher prevalence of IgA antibody against EBV-VCA compared to those without flare (81.3% vs 25.0%; p < 0.001). This is the first evidence that IgA antibody against EBV-VCA is strongly associated with disease flare in SLE patients. It suggests that EBV reactivation may contribute toward the disease flare of SLE.

Nonrenal and renal activity of systemic lupus erythematosus: a comparison of two anti-C1q and five anti-dsDNA assays and complement C3 and C4.

PubMed

Julkunen, Heikki; Ekblom-Kullberg, Susanne; Miettinen, Aaro

2012-08-01

Associations of different assays for antibodies to C1q (anti-C1q) and to dsDNA (anti-dsDNA) and of complements C3 and C4 with disease activity in patients with systemic lupus erythematosus (SLE) were studied. The clinical manifestations of 223 SLE patients were recorded, and the disease activity was assessed by the SLEDAI score. Anti-C1q were determined by two enzyme-linked immunosorbent assays (ELISA) and anti-dsDNA by a radioimmunoassay (RIA), a Crithidia immunofluorescence (IF) assay and three ELISA assays using human telomere DNA, plasmid DNA circles, or calf thymus DNA as antigens, respectively. Complement C3 and C4 were determined by nephelometry. Control sera were obtained from 98 blood donors. In patients with SLE, the prevalence of anti-C1q was 17-18% and that of anti-dsDNA was 36-69%. Anti-C1q, anti-dsDNA, and complement C3 and C4 correlated well with the overall activity of SLE (r = 0.323-0.351, 0.353-0.566, and -0.372-0.444, respectively; P < 0.001). Sensitivity, specificity, positive predictive value, and negative predictive value for active lupus nephritis among SLE patients were 40-44, 92, 29, and 91-92% for anti-C1q and 48-68, 29-66, 11-16, and 86-91% for anti-dsDNA, respectively. Patients with active nephritis had higher levels of anti-C1q and lower levels of C3 and C4 than patients with inactive nephritis (P = 0.003-0.018). The corresponding associations of anti-dsDNA were somewhat weaker (P = 0.023-0.198). Hematological parameters reflecting disease activity correlated clearly better with anti-dsDNA and complement C3 and C4 than with anti-C1q. Anti-C1q is inferior to anti-dsDNA as a diagnostic test in SLE and in the evaluation of overall clinical activity of the disease. Anti-C1q together with complement C3 and C4 may offer useful additional information to monitor lupus nephritis activity. There are no practical differences between different assays for anti-C1q and anti-dsDNA.

Heart failure in a woman with SLE, anti-phospholipid syndrome and Fabry’s disease

PubMed Central

Nandagudi, A; Alonzi, D; Butters, TD; Hughes, S; Isenberg, DA

2013-01-01

We describe a female patient with systemic lupus erythematosus (SLE) also diagnosed with Fabry’s disease and anti-phospholipid antibody syndrome (APS). SLE and Fabry’s disease are both systemic diseases with variable clinical presentations. Recent studies have shown a relatively high incidence of late onset Fabry’s disease in female heterozygous individuals, suggesting that this condition could be under-diagnosed. We discuss a possible association between SLE and Fabry’s disease and consider the role of lipid abnormalities in the pathogenesis of SLE. PMID:23864039

An Investigation into the Scale and Impact of Self-Reported Foot Problems Associated with Systemic Lupus Erythematosus: A Study Protocol and Survey Questionnaire Development.

PubMed

Williams, Anita Ellen; Cherry, Lindsey; Blake, Alison; Alcacer-Pitarch, Begonya; Edwards, Christopher; Hopkinson, Neil; Vital, Edward; Teh, Lee-Suan

2016-06-01

Systemic lupus erythematosus (SLE) can manifest with arthralgia and myalgia, and, in severe cases, disorganization of the joints and tendon rupture. Further, Raynaud's phenomenon and other circulatory problems such as vasculitis have been reported, and may be associated with loss of sensation and ulcers. Associated with impaired peripheral neurovascular function there is the potential for changes in tissue viability leading to thinning of the skin or callus formation. In addition, resistance to infections may be reduced, such as fungal infection of the skin and nails, bacterial infection associated with wounds and viral infections such as verruca. There is a dearth of evidence for the effects of SLE in the foot, the prevalence of foot problems in SLE and the impact of these on the individual. In addition, it is not known if people with SLE and foot problems have access to specialist care through foot health services. Hence, there is a need to investigate the scale of foot problems associated with SLE. In order to achieve this, a questionnaire needs to be developed in order to carry out a national survey in England. The items required for the questionnaire were generated using a focus group, which comprised patient advisers with SLE, consultants who specialized in SLE, specialist rheumatology podiatrists and specialist rheumatology nurses. From this consensus approach to the item generation, the draft questionnaire was developed with agreement on themes, question format and overall structure. Additionally, the Manchester Pain and Disability Questionnaire was included in order to capture levels of pain and associated disability. An iterative process followed, with feedback from the focus group reducing the number of other items from 53, until the penultimate version of questionnaire was produced with 50 items. Following on from this, a process of cognitive debriefing was used with two people with SLE who were naïve to the questionnaire. Minor changes to two questions and the layout was required before a final version of the questionnaire was produced. The questionnaire will be used for a study which aims to identify the frequency of patients' self-reported foot problems, the impact of foot problems on their lives and the status of foot care provision. This will be achieved through a survey of people with SLE across six clinical sites and interviews with some people in order to explore their experience of foot problems. The results from the present study will provide the information required to inform further research. In addition, it could potentially inform the design and delivery of foot health information and services to this patient group. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Managing hypertriglyceridemia in children with systemic lupus erythematosus: Two sides of the same coin.

PubMed

Basu, Biswanath; Babu, Binu George; Bhattacharyya, Suman

Hypertriglyceridemia is common in children with systemic lupus erythematosus (SLE). A retrospective analysis of the baseline clinical-pathological presentation and treatment outcome (status of lipid profiles) was performed in two children with SLE, who presented with extreme hypertriglyceridemia over a follow-up period of four weeks. The children were treated with prednisolone, mycophenolate mofetil (MMF), hydroxychloroquine and hypolipidemic agents, depending on their disease status. On serial follow-up, the first child showed a significantly raised serum triglyceride level after receiving one week of oral prednisolone therapy. Anti-lipoprotein-lipase (LPL) autoantibody was absent. Lipid profile levels of this child gradually improved after replacing oral prednisolone with another immunosuppressant, namely MMF. The second child presented with extreme hypertriglyceridemia with positive anti-LPL autoantibody. She responded to plasmapheresis followed by increasing the dose of immunosuppressant. So, extreme hypertriglyceridemia in children with SLE may be steroid induced or due to presence of anti-LPL auto antibody. Management should be individualized depending on the etiology. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

[Hyperuricemia in systemic lupus erythematosus: is it associated with the neuropsychiatric manifestations of the disease?

PubMed

Sheikh, Mahdi; Movassaghi, Shafieh; Khaledi, Mohammad; Moghaddassi, Maryam

2015-07-17

To assess the association between hyperuricemia and different neuropsychiatric manifestations and stroke risk factors in systematic lupus erythematosus (SLE) patients. This study was conducted on 204 SLE patients who were admitted to a tertiary referral center. A standardized questionnaire was completed for all the participants and the medical records were reviewed regarding the occurrence of arterial or venous thrombotic events, stroke, seizure, depression, headache, psychosis, and peripheral neuropathy. In addition blood samples were drawn to obtain serum uric acid, triglyceride (TG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and total cholesterol levels. Hyperuricemia (serum uric acid ≥ 6mg/dl for women and ≥ 7mg/dl for men) was detected in 16.1% of SLE patients and was significantly associated with the occurrence of stroke (OR, 2.38; 95%CI, 1.2-7.24), and peripheral neuropathy (OR, 3.49; 95% CI, 1.52-12.23), independent of hypertension and hyperlipidemia. Hyperuricemia was also significantly associated with hypertension (OR, 7.76; 95% CI, 2.72-15.76), hyperlipidemia (OR, 5.05; 95% CI, 1.59-11.32), and history of arterial thrombosis (OR, 4.95; 95% CI, 1.98-15.34), independent of age and body mass index. Hyperuricemia in SLE patients is independently associated with the occurrence of stroke and peripheral neuropathy. It is also independently associated with hypertension, hyperlipidemia, and history of arterial thrombosis, which are the major stroke and myocardial infarction risk factors in SLE patients. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

Hyperuricemia in systemic lupus erythematosus: is it associated with the neuropsychiatric manifestations of the disease?

PubMed

Sheikh, Mahdi; Movassaghi, Shafieh; Khaledi, Mohammad; Moghaddassi, Maryam

To assess the association between hyperuricemia and different neuropsychiatric manifestations and stroke risk factors in systematic lupus erythematosus (SLE) patients. This study was conducted on 204 SLE patients who were admitted to a tertiary referral center. A standardized questionnaire was completed for all the participants and the medical records were reviewed regarding the occurrence of arterial or venous thrombotic events, stroke, seizure, depression, headache, psychosis, and peripheral neuropathy. In addition blood samples were drawn to obtain serum uric acid, triglyceride (TG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and total cholesterol levels. Hyperuricemia (serum uric acid ≥6mg/dl for women and ≥7mg/dl for men) was detected in 16.1% of SLE patients and was significantly associated with the occurrence of stroke (OR, 2.38; 95%CI, 1.2-7.24), and peripheral neuropathy (OR, 3.49; 95% CI, 1.52-12.23), independent of hypertension and hyperlipidemia. Hyperuricemia was also significantly associated with hypertension (OR, 7.76; 95% CI, 2.72-15.76), hyperlipidemia (OR, 5.05; 95% CI, 1.59-11.32), and history of arterial thrombosis (OR, 4.95; 95% CI, 1.98-15.34), independent of age and body mass index. Hyperuricemia in SLE patients is independently associated with the occurrence of stroke and peripheral neuropathy. It is also independently associated with hypertension, hyperlipidemia, and history of arterial thrombosis, which are the major stroke and myocardial infarction risk factors in SLE patients. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

Bone mineral density among systemic lupus erythematosus patient age 5-18 years with glucocorticoid treatment in child and adolescent outpatient clinic, Cipto Mangunkusumo Hospital, Jakarta

NASA Astrophysics Data System (ADS)

Indriyani, N.; Tridjaja, B.; Medise, B. E.; Kurniati, N.

2017-08-01

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting children; its morbidity and mortality rates are significant. One risk factor for morbidity is chronic corticosteroid use. The aim of this study is to determine the occurrence rate of low bone mineral density; discuss the characteristics, including cumulative and daily doses of corticosteroid, body mass index, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), calcium, and vitamin D intake; and assess bone metabolism laboratory parameters, including serum calcium, vitamin D, alkaline phosphatase (ALP), phosphorus, and cortisol among children with SLE receiving corticosteroids. This was a descriptive, cross-sectional study involving 16 children with SLE attending the child and adolescent outpatient clinic at Cipto Mangunkusumo Hospital in November-December 2016. Low bone mineral density occurred among 7/16 patients. The mean total bone mineral density was 0.885 ± 0.09 g/cm2. Children with SLE receiving corticosteroid had low calcium (8.69 ± 0.50 mg/dl), vitamin D (19.3 ± 5.4 mg/dl), ALP (79.50 [43.00-164.00] U/l), and morning cortisol level (1.20 [0.0-10.21] ug/dl), as well as calcium (587.58 ± 213.29 mg/d) and vitamin D (2.9 [0-31.8] mcg/d) intake. The occurrence of low bone mineral density was observed among children with SLE receiving corticosteroid treatment. Low bone mineral density tends to occur among patients with higher cumulative doses and longer duration of corticosteroid treatments.

Elevated Psychosocial Stress at Work in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis.

PubMed

Richter, Jutta G; Muth, Thomas; Li, Jian; Brinks, Ralph; Chehab, Gamal; Koch, Tobias; Siegrist, Johannes; Angerer, Peter; Huscher, Dörte; Schneider, Matthias

2018-02-01

Psychosocial stress at work not only affects the healthy working population, but also workers with chronic diseases. We aimed to investigate the psychosocial work stress levels in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). A cross-sectional study applied the Effort-Reward Imbalance (ERI) questionnaire - an internationally established instrument that measures work stress - to patients with SLE and RA who were capable of work and to a group of controls without these diseases. Participants were recruited through rheumatologists in private practices, hospitals, and from self-help groups by personal communication, paper-based flyers, and online advertisements. Because very few studies tested the ERI's applicability in patient groups, with a lack of evidence in patients with inflammatory rheumatic diseases, internal consistency and construct validity of the ERI measure were evaluated. Data came from 270 patients with RA and 247 with SLE, and 178 controls. Patients showed elevated psychosocial stress at work compared to controls. Across the total sample and all groups, satisfactory internal consistencies of the scales effort, reward, and overcommitment were obtained (Cronbach's alpha coefficients > 0.70), and confirmatory factor analysis replicated the theoretical structure of the ERI model (goodness-of-fit index > 0.80). We found elevated psychosocial stress at work in patients with SLE and RA compared to controls by applying the ERI model. Despite some heterogeneity in the sample, we achieved satisfactory psychometric properties of the ERI questionnaire. Our results suggest that the ERI questionnaire is a psychometrically useful tool to be implemented in epidemiological studies of employed patients with SLE and RA.

Anti-DNase I antibodies in systemic lupus erythematosus: diagnostic value and share in the enzyme inhibition.

PubMed

Trofimenko, A S; Gontar, I P; Zborovsky, A B; Paramonova, O V

2016-04-01

Diagnostic accuracy of anti-DNase I antibodies measurement in a differentiation between SLE and other autoimmune rheumatic diseases was evaluated. The share of anti-DNase I and actin in the DNase I activity decrease in SLE was established. Serum samples were obtained from 54 patients with verified SLE, 52 control patients with other autoimmune rheumatic diseases, and 44 healthy persons. Anti-DNase I concentrations were measured by ELISA. Free and actin inhibited DNase I activities were evaluated in the fresh serum samples. The appraisal of antibodies and actin effects on DNase I activity was made using multiple regression. Anti-DNase I antibodies were positive in 35 SLE and 8 control patients, without significant difference between the mean antibody concentrations. Sensitivity of this test was 64.81 %, and specificity-84.62 %. Mean free DNase I activity in SLE was somewhat lower than in the control group as a result of augmented frequency of extremely low enzyme activities. On the contrary, after the exclusion of the latter cases we have revealed elevated mean free DNase I activity in the other SLE patients comparing to the similar control subgroup. Unlike the controls, low serum DNase I activity in SLE arose not only from actin and antibody action, but also, in half of the cases, from unidentified factor, related to active SLE. The accuracy of the anti-DNase I antibodies measurement is approximate to the present reference standard of SLE diagnostics. We first demonstrated that neither antibodies nor actin caused DNase I activity decrease in SLE.

17-β Estradiol reduces atherosclerosis without exacerbating lupus in ovariectomized systemic lupus erythematosus-susceptible LDLr(-/-) mice.

PubMed

Shelton, K A; Cline, J M; Cann, J A

2013-04-01

To test the hypothesis that estrogen treatment in a radiation chimera mouse model of systemic lupus erythematosus (SLE) and atherosclerosis will increase SLE-associated atherosclerosis by increasing autoantibody production and inflammation. We used a radiation chimera mouse model in which bone marrow from the polygenic B6.Sle1.2.3 model of SLE was transferred to the low density lipoprotein receptor knock out (LDLr(-/-)) model of atherosclerosis on a C57BL/6 background (Sle/LDLr(-/-)). Ovariectomized chimeric mice were treated for 10 weeks with either 5.6 μg/day of 17β-estradiol or placebo; outcomes included atherosclerosis plaque size, anti-dsDNA autoantibody production and renal pathology. Mean atherosclerosis plaque size was 67.4 ± 7.6% smaller in the estrogen treated group (p < 0.0001). Estrogen treated Sle/LDLr(-/-) mice had no significant difference in serum cholesterol concentration, lipoprotein distribution, anti-dsDNA autoantibody concentration, antibody isotype concentration and renal histopathology score compared to placebo. However, they had significantly lower mean urine protein to urine creatinine ratio (UP:UC). There was no correlation between atherosclerosis lesion size and either the renal histology score or UP:UC ratio in Sle/LDLr(-/-) mice. These results indicate that 17β-estradiol is atheroprotective within the context of murine SLE independent of changes in serum cholesterol concentration, autoantibody concentration, or renal pathology. The SLE phenotype in Sle/LDLr(-/-) mice is not exacerbated by exogenous 17β-estradiol administration, and the reduced UP:UC ratio suggests a protective effect against lupus nephritis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus.

PubMed

Hughes, Travis; Adler, Adam; Merrill, Joan T; Kelly, Jennifer A; Kaufman, Kenneth M; Williams, Adrienne; Langefeld, Carl D; Gilkeson, Gary S; Sanchez, Elena; Martin, Javier; Boackle, Susan A; Stevens, Anne M; Alarcón, Graciela S; Niewold, Timothy B; Brown, Elizabeth E; Kimberly, Robert P; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Petri, Michelle; Reveille, John D; Criswell, Lindsey A; Vilá, Luis M; Jacob, Chaim O; Gaffney, Patrick M; Moser, Kathy L; Vyse, Timothy J; Alarcón-Riquelme, Marta E; James, Judith A; Tsao, Betty P; Scofield, R Hal; Harley, John B; Richardson, Bruce C; Sawalha, Amr H

2012-05-01

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. A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10-8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.

Education, employment, absenteeism, and work disability in women with systemic lupus erythematosus.

PubMed

Ekblom-Kullberg, S; Kautiainen, H; Alha, P; Leirisalo-Repo, M; Julkunen, H

2015-01-01

To study education, employment, absenteeism, and work disability (WD) in women with systemic lupus erythematosus (SLE) compared to population controls. The study included 181 women of working age with SLE (mean age 44.0 years, disease duration 12.7 years) and 549 female population controls matched for age living in the same metropolitan area of Helsinki. Data regarding education, employment, absenteeism, and WD in patients and controls were obtained by questionnaire and personal interview. Basic education, vocational, or academic degrees and occupational categories in patients with SLE were similar to those in controls. In total, 62% of the patients were employed, compared to 77% of the controls (p < 0.001). During the preceding 12 months, employed SLE patients had been on sick leave for 25.4 days vs. 10.2 days in controls (p < 0.001). Subjective work ability regarding physical and mental demands of the job were lower in SLE patients than in controls (p < 0.001 and p = 0.036, respectively). The rate of permanent WD, defined as receiving disability benefits, was 34.3% in SLE patients vs. 10.3% in controls (p < 0.001). Cumulative WD due to SLE 5, 10, and 20 years after the clinical diagnosis was 13, 22, and 47%, respectively. SLE does not seem to affect educational achievements and the employment rate for SLE patients is reasonably high. Absenteeism and work disability are, however, 2-3 times more common than in controls. Less than half of the patients were on permanent disability pension due to SLE 20 years after diagnosis of the disease.

17-β Estradiol reduces atherosclerosis without exacerbating lupus in ovariectomized systemic lupus erythematosus-susceptible LDLr−/− mice

PubMed Central

Shelton, KA; Cline, JM; Cann, JA

2013-01-01

Objective To test the hypothesis that estrogen treatment in a radiation chimera mouse model of systemic lupus erythematosus (SLE) and atherosclerosis will increase SLE-associated atherosclerosis by increasing autoantibody production and inflammation. Methods We used a radiation chimera mouse model in which bone marrow from the polygenic B6.Sle1.2.3 model of SLE was transferred to the low density lipoprotein receptor knock out (LDLr−/−) model of atherosclerosis on a C57BL/6 background (Sle/LDLr−/−). Ovariectomized chimeric mice were treated for 10 weeks with either 5.6 ug/day of 17β-estradiol or placebo; outcomes included atherosclerosis plaque size, anti-dsDNA autoantibody production and renal pathology. Results Mean atherosclerosis plaque size was 67.4 ± 7.6% smaller in the estrogen treated group (p<0.0001). Estrogen treated Sle/LDLr−/− mice had no significant difference in serum cholesterol concentration, lipoprotein distribution, anti-dsDNA autoantibody concentration, antibody isotype concentration and renal histopathology score compared to placebo. However, they had significantly lower mean urine protein to urine creatinine ratio (UP:UC). There was no correlation between atherosclerosis lesion size and either the renal histology score or UP:UC ratio in Sle/LDLr−/− mice. Conclusion These results indicate that 17β-estradiol is atheroprotective within the context of murine SLE independent of changes in serum cholesterol concentration, autoantibody concentration, or renal pathology. The SLE phenotype in Sle/LDLr−/− mice is not exacerbated by exogenous 17β-estradiol administration, and the reduced UP:UC ratio suggests a protective effect against lupus nephritis. PMID:23395521

Subjective life expectancy and actual mortality: results of a 10-year panel study among older workers.

PubMed

van Solinge, Hanna; Henkens, Kène

2018-06-01

This research examined the judgemental process underlying subjective life expectancy (SLE) and the predictive value of SLE on actual mortality in older adults in the Netherlands. We integrated theoretical insights from life satisfaction research with existing models of SLE. Our model differentiates between bottom-up (objective data of any type) and top-down factors (psychological variables). The study used data from the first wave of the Netherlands Interdisciplinary Demographic Institute Work and Retirement Panel. This is a prospective cohort study among Dutch older workers. The analytical sample included 2278 individuals, assessed at age 50-64 in 2001, with vital statistics tracked through 2011. We used a linear regression model to estimate the impact of bottom-up and top-down factors on SLE. Cox proportional hazard regression was used to determine the impact of SLE on the timing of mortality, crude and adjusted for actuarial correlates of general life expectancy, family history, health and trait-like dispositions. Results reveal that psychological variables play a role in the formation of SLE. Further, the results indicate that SLE predicts actual mortality, crude and adjusted for socio-demographic, biomedical and psychological confounders. Education has an additional effect on mortality. Those with higher educational attainment were less likely to die within the follow-up period. This SES gradient in mortality was not captured in SLE. The findings indicate that SLE is an independent predictor of mortality in a pre-retirement cohort in the Netherlands. SLE does not fully capture educational differences in mortality. Particularly, higher-educated individuals underestimate their life expectancy.

Chinese SLE Treatment and Research group (CSTAR) registry VII: prevalence and clinical significance of serositis in Chinese patients with systemic lupus erythematosus.

PubMed

Zhao, J; Bai, W; Zhu, P; Zhang, X; Liu, S; Wu, L; Ma, L; Bi, L; Zuo, X; Sun, L; Huang, C; Tian, X; Li, M; Zhao, Y; Zeng, X

2016-05-01

To investigate both the prevalence and clinical characteristics of serositis in Chinese patients with systemic lupus erythematosus (SLE) in a large cohort in the Chinese SLE Treatment and Research group (CSTAR) database. A prospective cross-sectional study of patients with SLE was conducted based on the data from the CSTAR registry. Serositis was defined according to the 1999 revised American College of Rheumatology (ACR) criteria for SLE - that is, pleuritis/pleural effusion and/or pericarditis/pericardial effusion detected by echocardiography, chest X-ray or chest computerized tomography (CT) scan. Peritonitis/peritoneal effusion were confirmed by abdominal ultrasonography. We analysed the prevalence and clinical associations of serositis with demographic data, organ involvements, laboratory findings and SLE disease activity. Of 2104 patients with SLE, 345 were diagnosed with serositis. The prevalence of lupus nephritis (LN), interstitial lung disease and pulmonary arterial hypertension, as well as the presence of leukocytopenia, thrombocytopenia, hypocomplementemia and anti-dsDNA antibodies was significantly higher in patients with serositis (P < 0.05). Significantly higher SLE disease activity scores were found in patients with serositis compared to those patients without serositis (P < 0.05). Lupus-related peritonitis had similar clinical manifestations and laboratory profiles as serositis caused by SLE. There is a significant association of nephropathy, interstitial lung disease, pulmonary arterial hypertension, hypocomplementemia, leukocytopenia, thrombocytopenia and elevated anti-dsDNA antibodies with serositis. The results suggest that higher SLE disease activity contributes to serositis development, and should be treated aggressively. © The Author(s) 2016.

Stressful life events and cognitive decline in late life: moderation by education and age. The Cache County Study.

PubMed

Tschanz, Joann T; Pfister, Roxane; Wanzek, Joseph; Corcoran, Chris; Smith, Ken; Tschanz, Brian T; Steffens, David C; Østbye, Truls; Welsh-Bohmer, Kathleen A; Norton, Maria C

2013-08-01

Stressful life events (SLE) have been associated with increased dementia risk, but their association with cognitive decline has been inconsistent. In a longitudinal population-based study of older individuals, we examined the association between SLE and cognitive decline, and the role of potential effect modifiers. A total of 2665 non-demented participants of the Cache County Memory Study completed an SLE questionnaire at Wave 2 and were revisited 4 and 7 years later. The events were represented via several scores: total number, subjective rating (negative, positive, and unexpected), and a weighted summary based on their impact. Cognition was assessed at each visit with the modified Mini-Mental State Exam. General linear models were used to examine the association between SLE scores and cognition. Effect modification by age, education, and APOE genotype was tested. Years of formal education (p = 0.006) modified the effect of number of SLE, and age (p = 0.009) modified the effect of negative SLE on the rate of cognitive decline. Faster decline was observed among those with fewer years of education experiencing more SLE and also among younger participants experiencing more negative SLE. There was no association between other indicators of SLE and cognitive decline. APOE genotype did not modify any of the aforementioned associations. The effects of SLE on cognition in late life are complex and vary by individual factors such as age and education. These results may explain some of the contradictory findings in the literature. Copyright © 2012 John Wiley & Sons, Ltd.

Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity

PubMed Central

2013-01-01

Introduction Growth arrest-specific gene 6 protein (GAS6) and protein S (ProS) are vitamin K-dependent proteins present in plasma with important regulatory functions in systems of response and repair to damage. They interact with receptor tyrosine kinases of the Tyro3, Axl and MerTK receptor tyrosine kinase (TAM) family, involved in apoptotic cell clearance (efferocytosis) and regulation of the innate immunity. TAM-deficient mice show spontaneous lupus-like symptoms. Here we tested the genetic profile and plasma levels of components of the system in patients with systemic lupus erythematosus (SLE), and compare them with a control healthy population. Methods Fifty SLE patients and 50 healthy controls with matched age, gender and from the same geographic area were compared. Genetic analysis was performed in GAS6 and the TAM receptor genes on SNPs previously identified. The concentrations of GAS6, total and free ProS, and the soluble forms of the three TAM receptors (sAxl, sMerTK and sTyro3) were measured in plasma from these samples. Results Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded. Those parameters correlated with SLE disease activity index (SLEDAI) score, GAS6 being higher in the most severe cases, while free and total ProS were lower. All 3 soluble receptors increased its concentration in plasma of lupus patients. Conclusions The present study highlights that the GAS6/ProS-TAM system correlates in several ways with disease activity in SLE. We show here that this correlation is affected by common polymorphisms in the genes of the system. These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE. PMID:23497733

Disease activity and transition outcomes in a childhood-onset systemic lupus erythematosus cohort.

PubMed

Son, M B; Sergeyenko, Y; Guan, H; Costenbader, K H

2016-11-01

Objective The chronicity and severity of childhood-onset systemic lupus erythematosus (cSLE) necessitate effective transition from pediatric to adult providers. We studied transition outcomes in a cSLE cohort. Methods We identified patients at an adult lupus clinic diagnosed with SLE ≤ 18 years who had been followed by a pediatric rheumatologist. Data extracted from the first three years in adult care ("post-transition period") included: sociodemographics, depression, anxiety, SLE manifestations, SLE Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics/ACR Damage Index for SLE (SLICC) scores, non-adherence, and gaps in care (no appointments in the recommended time frame). Multivariable logistic regression analyses for predictors of: (1) time between pediatric and adult providers, (2) gaps in care, (3) unscheduled utilization (emergency department visits and admissions) (4) depression and/or anxiety were performed, as was a multivariable Poisson regression analysis for number of missed appointments. Results In 50 patients, SLEDAI scores were stable (mean 5.7 ± 5.0 at start vs. 4.7 ± 4.8 at year 3, p = 0.2), but SLICC scores increased (0.46 ± 0.84, vs. 0.78 ± 1.25, p = 0.01). Depression and anxiety increased significantly (10% vs. 26%, p = 0.02). Mean time from last pediatric to first adult provider visit was almost nine months (253 ± 392 days). Nearly 75% of patients had ≥ 1 gap in care. White race, low education level and non-adherence were significantly associated with missed appointments. Conclusion Despite moderate disease activity in this cSLE transition cohort, prolonged time between pediatric and adult providers and gaps in care in the post-transition period occurred. Anxiety and depression were frequently reported. Future work should identify methods to improve transition.

Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity.

PubMed

Recarte-Pelz, Pedro; Tàssies, Dolors; Espinosa, Gerard; Hurtado, Begoña; Sala, Núria; Cervera, Ricard; Reverter, Joan Carles; de Frutos, Pablo García

2013-03-12

Growth arrest-specific gene 6 protein (GAS6) and protein S (ProS) are vitamin K-dependent proteins present in plasma with important regulatory functions in systems of response and repair to damage. They interact with receptor tyrosine kinases of the Tyro3, Axl and MerTK receptor tyrosine kinase (TAM) family, involved in apoptotic cell clearance (efferocytosis) and regulation of the innate immunity. TAM-deficient mice show spontaneous lupus-like symptoms. Here we tested the genetic profile and plasma levels of components of the system in patients with systemic lupus erythematosus (SLE), and compare them with a control healthy population. Fifty SLE patients and 50 healthy controls with matched age, gender and from the same geographic area were compared. Genetic analysis was performed in GAS6 and the TAM receptor genes on SNPs previously identified. The concentrations of GAS6, total and free ProS, and the soluble forms of the three TAM receptors (sAxl, sMerTK and sTyro3) were measured in plasma from these samples. Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded. Those parameters correlated with SLE disease activity index (SLEDAI) score, GAS6 being higher in the most severe cases, while free and total ProS were lower. All 3 soluble receptors increased its concentration in plasma of lupus patients. The present study highlights that the GAS6/ProS-TAM system correlates in several ways with disease activity in SLE. We show here that this correlation is affected by common polymorphisms in the genes of the system. These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE.

Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups.

PubMed

Kaufman, Kenneth M; Zhao, Jian; Kelly, Jennifer A; Hughes, Travis; Adler, Adam; Sanchez, Elena; Ojwang, Joshua O; Langefeld, Carl D; Ziegler, Julie T; Williams, Adrienne H; Comeau, Mary E; Marion, Miranda C; Glenn, Stuart B; Cantor, Rita M; Grossman, Jennifer M; Hahn, Bevra H; Song, Yeong Wook; Yu, Chack-Yung; James, Judith A; Guthridge, Joel M; Brown, Elizabeth E; Alarcón, Graciela S; Kimberly, Robert P; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Petri, Michelle A; Reveille, John D; Vilá, Luis M; Anaya, Juan-Manuel; Boackle, Susan A; Stevens, Anne M; Freedman, Barry I; Criswell, Lindsey A; Pons Estel, Bernardo A; Lee, Joo-Hyun; Lee, Ji-Seon; Chang, Deh-Ming; Scofield, R Hal A; Gilkeson, Gary S; Merrill, Joan T; Niewold, Timothy B; Vyse, Timothy James; Bae, Sang-Cheol; Alarcón-Riquelme, Marta E; Jacob, Chaim O; Moser Sivils, Kathy; Gaffney, Patrick M; Harley, John B; Sawalha, Amr H; Tsao, Betty P

2013-03-01

The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE. We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups. Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p<5×10(-8) with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p(meta )= 1.3×10(-27), OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064). These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.

Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus.

PubMed

Hutcheson, Jack; Vanarsa, Kamala; Bashmakov, Anna; Grewal, Simer; Sajitharan, Deena; Chang, Betty Y; Buggy, Joseph J; Zhou, Xin J; Du, Yong; Satterthwaite, Anne B; Mohan, Chandra

2012-11-08

Systemic lupus erythematosus is a chronic autoimmune disease characterized by an abundance of autoantibodies against nuclear antigens. Bruton's tyrosine kinase (Btk) is a proximal transducer of the BCR signal that allows for B-cell activation and differentiation. Recently, selective inhibition of Btk by PCI-32765 has shown promise in limiting activity of multiple cells types in various models of cancer and autoimmunity. The aim of this study was to determine the effect of Btk inhibition by PCI-32765 on the development of lupus in lupus-prone B6.Sle1 and B6.Sle1.Sle3 mice. B6.Sle1 or B6.Sle1.Sle3 mice received drinking water containing either the Btk inhibitor PCI-32765 or vehicle for 56 days. Following treatment, mice were examined for clinical and pathological characteristics of lupus. The effect of PCI-32765 on specific cell types was also investigated. In this study, we report that Btk inhibition dampens humoral autoimmunity in B6.Sle1 monocongenic mice. Moreover, in B6.Sle1.Sle3 bicongenic mice that are prone to severe lupus, Btk inhibition also dampens humoral and cellular autoimmunity, as well as lupus nephritis. These findings suggest that partial crippling of cell signaling in B cells and antigen presenting cells (APCs) may be a viable alternative to total depletion of these cells as a therapeutic modality for lupus.

The African Lupus Genetics Network (ALUGEN) registry: standardized, prospective follow-up studies in African patients with systemic lupus erythematosus.

PubMed

Hodkinson, B; Mapiye, D; Jayne, D; Kalla, A; Tiffin, N; Okpechi, I

2016-03-01

The prevalence and severity of systemic lupus erythematosus (SLE) differs between ethnic groups and geographical regions. Although initially reported as rare, there is growing evidence that SLE is prevalent and runs a severe course in Africa. There is a paucity of prospective studies on African SLE patients. The African Lupus Genetics Network (ALUGEN) is a multicentred framework seeking to prospectively assess outcomes in SLE patients in Africa. Outcomes measured will be death, hospital admission, disease activity flares, and SLE-related damage. We will explore predictors for these outcomes including clinical, serological, socio-demographic, therapeutic and genetic factors. Further, we will investigate comorbidities and health-related quality of life amongst these patients. Data of patients recently (≤ 5 yrs) diagnosed with SLE will be collected at baseline and annual follow-up visits, and captured electronically. The ALUGEN project will facilitate standardized data capture for SLE cases in Africa, allowing participating centres to develop their own SLE registries, and enabling collaboration to enrich our understanding of inter-ethnic and regional variations in disease expression. Comprehensive, high-quality multi-ethnic data on African SLE patients will expand knowledge of the disease and inform clinical practice, in addition to augmenting research capacity and networking links and providing a platform for future biomarker and interventional studies. © The Author(s) 2015.

Inverse Association of Parkinson Disease With Systemic Lupus Erythematosus: A Nationwide Population-based Study.

PubMed

Liu, Feng-Cheng; Huang, Wen-Yen; Lin, Te-Yu; Shen, Chih-Hao; Chou, Yu-Ching; Lin, Cheng-Li; Lin, Kuen-Tze; Kao, Chia-Hung

2015-11-01

The effects of the inflammatory mediators involved in systemic lupus erythematous (SLE) on subsequent Parkinson disease have been reported, but no relevant studies have focused on the association between the 2 diseases. This nationwide population-based study evaluated the risk of Parkinson disease in patients with SLE.We identified 12,817 patients in the Taiwan National Health Insurance database diagnosed with SLE between 2000 and 2010 and compared the incidence rate of Parkinson disease among these patients with that among 51,268 randomly selected age and sex-matched non-SLE patients. A Cox multivariable proportional-hazards model was used to evaluate the risk factors of Parkinson disease in the SLE cohort.We observed an inverse association between a diagnosis of SLE and the risk of subsequent Parkinson disease, with the crude hazard ratio (HR) being 0.60 (95% confidence interval 0.45-0.79) and adjusted HR being 0.68 (95% confidence interval 0.51-0.90). The cumulative incidence of Parkinson disease was 0.83% lower in the SLE cohort than in the non-SLE cohort. The adjusted HR of Parkinson disease decreased as the follow-up duration increased and was decreased among older lupus patients with comorbidity.We determined that patients with SLE had a decreased risk of subsequent Parkinson disease. Further research is required to elucidate the underlying mechanism.

The cost of care of systemic lupus erythematosus (SLE) in the UK: annual direct costs for adult SLE patients with active autoantibody-positive disease.

PubMed

Khamashta, M A; Bruce, I N; Gordon, C; Isenberg, D A; Ateka-Barrutia, O; Gayed, M; Donatti, C; Guillermin, A-L; Foo, J; Perna, A

2014-03-01

The aim of the Systemic LUpus Erythematosus Cost of Care In Europe (LUCIE) study was to evaluate the annual direct medical costs of managing adults with active autoantibody-positive disease on medication for SLE in secondary care. This paper presents the UK analyses only. A cost-of-illness study was conducted from the perspective of the National Health Service. Health resource utilization data were retrieved over a two-year period from four centres in England and unit cost data were taken from published sources. At baseline, 86 patients were included, 38 (44.2%) had severe SLE and 48 (55.8%) had non-severe SLE. The mean (SD) SELENA-SLEDAI score was 7.7 (5.7). The mean (SD) annual direct medical cost of was estimated at £3231 (£2333) per patient and was 2.2 times higher in patients with severe SLE compared with patients with non-severe SLE (p < 0.001). Multivariate model analyses showed that renal disease involvement (p = 0.0016) and severe flares (p = 0.0001) were associated with higher annual direct costs. Improvement of the overall stability of SLE and early intervention to minimize the impact of renal disease may be two approaches to mitigate the long-term direct cost of managing SLE patients in the UK.

Mass Changes of the Greenland and Antarctic Ice Sheets and Shelves and Contributions to Sea-level Rise: 1992-2002

NASA Technical Reports Server (NTRS)

Zwally, H. Jay; Giovinetto, Mario B.; Li, Jun; Cornejo, Helen G.; Beckley, Matthew A.; Brenner, Anita C.; Saba, Jack L.; Yi, Donghui

2005-01-01

Changes in ice mass are estimated from elevation changes derived from 10.5 years (Greenland) and 9 years (Antarctica) of satellite radar altimetry data from the European Remote-sensing Satellites ERS-1 and -2. For the first time, the dH/dt values are adjusted for changes in surface elevation resulting from temperature-driven variations in the rate of fun compaction. The Greenland ice sheet is thinning at the margins (-42 plus or minus 2 Gta(sup -1) below the equilibrium line altitude (ELA)) and growing inland (+53 plus or minus 2 Gt a(sup -1)above the ELA) with a small overall mass gain (+11 plus or minus 3 Gt a(sup -1); -0.03 mm a(sup -1) SLE (sea level equivalent)). The ice sheet in West Antarctica (WA) is losing mass (-47 (dot) 4 GT a(sup -1) and the ice sheet in East Antarctica (EA) shows a small mass gain (+16 plus or minus 11 Gt a(sup -1) for a combined net change of -31 plus or minus 12 Gt a(sup -1) (+0.08 mm a(sup -1) SLE)). The contribution of the three ice sheets to sea level is +0.05 plus or minus 0.03 mm a(sup -1). The Antarctic ice shelves show corresponding mass changes of -95 (dot) 11 Gt a(sup -1) in WA and +142 plus or minus 10 Gt a(sup -1) in EA. Thinning at the margins of the Greenland ice sheet and growth at higher elevations is an expected response to increasing temperatures and precipitation in a warming climate. The marked thinnings in the Pine Island and Thwaites Glacier basins of WA and the Totten Glacier basin in EA are probably ice-dynamic responses to long-term climate change and perhaps past removal of their adjacent ice shelves. The ice growth in the southern Antarctic Peninsula and parts of EA may be due to increasing precipitation during the last century.

Cross-talk between iNKT cells and monocytes triggers an atheroprotective immune response in SLE patients with asymptomatic plaque.

PubMed

Smith, Edward; Croca, Sara; Waddington, Kirsty E; Sofat, Reecha; Griffin, Maura; Nicolaides, Andrew; Isenberg, David A; Torra, Ines Pineda; Rahman, Anisur; Jury, Elizabeth C

2016-12-02

Accelerated atherosclerosis is a complication of the autoimmune rheumatic disease systemic lupus erythematosus (SLE). We questioned the role played by invariant natural killer T (iNKT) cells in this process because they not only are defective in autoimmunity but also promote atherosclerosis in response to CD1d-mediated lipid antigen presentation. iNKT cells from SLE patients with asymptomatic plaque (SLE-P) had increased proliferation and interleukin-4 production compared with those from SLE patients with no plaque. The anti-inflammatory iNKT cell phenotype was associated with dyslipidemia and was driven by altered monocyte phospholipid expression and CD1d-mediated cross-talk between iNKT cells and monocytes but not B cells. Healthy iNKT cells differentiated in the presence of healthy monocytes and SLE-P serum polarized macrophages toward an anti-inflammatory M2 phenotype. Conversely, patients with clinical cardiovascular disease had unresponsive iNKT cells and increased proinflammatory monocytes. iNKT cell function could link immune responses, lipids, and cardiovascular disease in SLE patients and, together with serum lipid taxonomy, help predict preclinical atherosclerosis in SLE patients. Copyright © 2016, American Association for the Advancement of Science.

The role of antimalarial agents in the treatment of SLE and lupus nephritis.

PubMed

Lee, Senq-J; Silverman, Earl; Bargman, Joanne M

2011-10-18

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that affects various organs. Lupus nephritis is one of the most common, and most important, serious manifestations of SLE. Antimalarial agents are part of the immunomodulatory regimen used to treat patients with SLE; however, their role in the treatment of patients with lupus nephritis in particular is less well recognized, especially by nephrologists. Not all antimalarial agents have been used in the treatment of lupus; this Review will focus on studies using chloroquine and hydroxychloroquine. In addition, this Review will briefly describe the history of antimalarial drug use in patients with SLE, the theorized mechanisms of action of the agents chloroquine and hydroxychloroquine, their efficacy in patients with SLE and those with lupus nephritis, their use in pregnancy, and potential adverse effects. The Review will also cover the latest recommendations regarding monitoring for hydroxychloroquine-associated or chloroquine-associated retinopathy. Overall, antimalarial drugs have numerous beneficial effects in patients with SLE and lupus nephritis, and have a good safety profile.

An intriguing association of Turner syndrome with severe nephrotic syndrome: searching for a diagnosis.

PubMed

Minzala, G; Ismail, G

2016-10-01

Systemic lupus erythematosus (SLE) is a chronic disease caused by an aberrant autoimmune response, with a large spectrum of clinical manifestations. It strikingly affects women. Recent papers reveal that the men with Klinefelter syndrome (47, XXY) have a higher incidence of lupus than the men in the general population, similar with that of genotypic females. On the other hand, there is a great lack of information regarding the association of SLE with Turner syndrome, but it seems to be a lower risk for females with Turner to develop SLE. We present a rare association of a Turner syndrome with SLE, with negative immunology for SLE and with diagnosis made on renal biopsy. These data suggest that the presence of two X chromosomes may predispose to SLE, the ligand (CD40 ligand) for one of the genes that contributes to the pathogenesis of SLE being located on the X chromosome. © The Author(s) 2016.

Update on B-cell targeted therapies for systemic lupus erythematosus.

PubMed

Mok, Chi Chiu

2014-06-01

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by flares and remission, leading to accrual of organ damage over time as a result of persistent tissue inflammation and treatment-related complications. Novel therapies aiming at better treatment response and fewer adverse effects are being tested in the pipeline. This review summarizes the B-cell abnormalities observed in patients with SLE, and updates recent data on the efficacy and safety of B-cell targeted therapies in the treatment of SLE. The pitfalls of clinical trial design and future directions of the development of SLE therapeutics are discussed. The variability of clinical response to treatment in SLE reflects the clinical and immunological heterogeneity of the disease. The treatment plan for patients with SLE should be individualized with the aim of eradicating disease activity, preventing flares and minimizing treatment-related complications. Despite the disappointment of recent clinical trials, B-cell remains the promising target of future SLE therapies. Results from ongoing clinical trials on B-cell targeted biological agents are eagerly awaited.

Environmental Exposures and the Development of Systemic Lupus Erythematosus

PubMed Central

Barbhaiya, Medha; Costenbader, Karen H.

2016-01-01

Purpose of Review This review examines evidence relating environmental factors to the development of systemic lupus erythematosus (SLE). Recent findings The strongest epidemiologic evidence exists for the associations of silica, cigarette smoking, oral contraceptives, postmenopausal hormone therapy, and endometriosis, with SLE incidence. Recent studies have also provided robust evidence of the association between alcohol consumption and decreased SLE risk. There are preliminary, conflicting or unsubstantiated data that other factors, including air pollution, ultraviolet light, infections, vaccinations, solvents, pesticides, and heavy metals such as mercury, are related to SLE risk. Biologic mechanisms linking environmental exposures and SLE risk include increased oxidative stress, systemic inflammation and inflammatory cytokine upregulation, and hormonal triggers, as well as epigenetic modifications resulting from exposure that could lead to SLE. Summary Identifying the environmental risk factors related to risk of SLE is essential as it will lead to increased understanding of pathogenesis of this complex disease and will also make risk factor modification possible for those at increased risk. PMID:27428889

Murine Models of Systemic Lupus Erythematosus

PubMed Central

Perry, Daniel; Sang, Allison; Yin, Yiming; Zheng, Ying-Yi; Morel, Laurence

2011-01-01

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder. The study of diverse mouse models of lupus has provided clues to the etiology of SLE. Spontaneous mouse models of lupus have led to identification of numerous susceptibility loci from which several candidate genes have emerged. Meanwhile, induced models of lupus have provided insight into the role of environmental factors in lupus pathogenesis as well as provided a better understanding of cellular mechanisms involved in the onset and progression of disease. The SLE-like phenotypes present in these models have also served to screen numerous potential SLE therapies. Due to the complex nature of SLE, it is necessary to understand the effect specific targeted therapies have on immune homeostasis. Furthermore, knowledge gained from mouse models will provide novel therapy targets for the treatment of SLE. PMID:21403825

Clinical guidelines for the management of acute viral infections in patients with systemic lupus erythematosus.

PubMed

Ramos-Casals, M; Cuadrado, M J; Alba, P; Sanna, G; Brito-Zerón, P; Bertolaccini, L; Babini, A; Moreno, A; D'Cruz, D; Khamashta, M A

2009-12-01

In recent decades, many research groups have focused on the role of viral infections in the etiopathogenesis of systemic lupus erythematosus (SLE), the so-called "viral hypothesis". The main candidates are herpes viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), which have a high seroprevalence in the general population. However, a viral causal agent of SLE has not yet been discovered, although many interesting clinical findings on the complex interactions between viruses and SLE have been made. This review analyzes 88 cases of acute viral infections in adult patients with SLE and identifies situations in which viral infections influenced the diagnosis, prognosis or treatment of SLE. We also propose clinical guidelines for the management of these infections in patients with SLE.

Simultaneous presentation of acute disseminated encephalomyelitis (ADEM) and systemic lupus erythematosus (SLE) after enteroviral infection: can ADEM present as the first manifestation of SLE?

PubMed

Kim, J-M; Son, C-N; Chang, H W; Kim, S-H

2015-05-01

Central Nervous System (CNS) involvement of Systemic Lupus Erythematosus (SLE) includes a broad range of neuropsychiatric syndromes. Acute Disseminated Encephalomyelitis (ADEM) is a demyelinating CNS disorder characterized by encephalopathy and multifocal lesions predominantly involving the white matter on brain magnetic resonance imaging. ADEM associated with SLE has been only rarely reported. We report an unusual case of a 17-year-old girl who developed ADEM after enteroviral infection as the first manifestation of SLE. The authors emphasize that the patient's illness was preceded by enteroviral infection and that ADEM occurred before any other symptoms of SLE, which makes this case unique. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors.

PubMed

Omdal, R; Brokstad, K; Waterloo, K; Koldingsnes, W; Jonsson, R; Mellgren, S I

2005-05-01

To determine whether neuropsychiatric manifestations in patients with systemic lupus erythematosus (SLE) are influenced by antibodies against the human N-methyl-D-aspartate (NMDA) receptor types NR2a or NR2b. A decapeptide was synthesized containing a sequence motif present in the extracellular ligand-binding domain of NMDA receptors NR2a and NR2b, bound by the monoclonal murine anti-DNA antibody R4A. In an ELISA with the murine monoclonal R4v as positive control, plasma samples of 57 patients with SLE were examined for the anti-peptide (anti-NR2) antibody after the patients had been subjected to comprehensive psychological and cognitive testing. Poor performance on the Visual Paired Associates test (immediate), the Grooved Pegboard test, as well as high scores on the Beck Depression Inventory, and scales D-2 (depression), Pd-4 (psychopathic deviate), Sc-8 (schizophrenia), and Ma-9 (hypomania) of the MMPI-2 were significantly associated with elevated levels of anti-NR2 antibodies. The findings in several domains indicate an association between anti-NR2 antibodies and depressed mood in addition to decreased short-time memory and learning. Antibodies to NMDA receptors thus may represent one of several mechanisms for cerebral dysfunction in patients with SLE.

Anti-DNA antibodies--quintessential biomarkers of SLE.

PubMed

Pisetsky, David S

2016-02-01

Antibodies that recognize and bind to DNA (anti-DNA antibodies) are serological hallmarks of systemic lupus erythematosus (SLE) and key markers for diagnosis and disease activity. In addition to common use in the clinic, anti-DNA antibody testing now also determines eligibility for clinical trials, raising important questions about the nature of the antibody-antigen interaction. At present, no 'gold standard' for serological assessment exists, and anti-DNA antibody binding can be measured with a variety of assay formats, which differ in the nature of the DNA substrates and in the conditions for binding and detection of antibodies. A mechanism called monogamous bivalency--in which high avidity results from simultaneous interaction of IgG Fab sites with a single polynucleotide chain--determines anti-DNA antibody binding; this mechanism might affect antibody detection in different assay formats. Although anti-DNA antibodies can promote pathogenesis by depositing in the kidney or driving cytokine production, they are not all alike, pathologically, and anti-DNA antibody expression does not necessarily correlate with active disease. Levels of anti-DNA antibodies in patients with SLE can vary over time, distinguishing anti-DNA antibodies from other pathogenic antinuclear antibodies. Elucidation of the binding specificities and the pathogenic roles of anti-DNA antibodies in SLE should enable improvements in the design of informative assays for both clinical and research purposes.

Primary Sjögren's syndrome with diffuse cystic lung changes developed systemic lupus erythematosus: a case report and literature review.

PubMed

Liu, Xiao; Li, Hao; Yin, Yunhong; Ma, Dedong; Qu, Yiqing

2017-05-23

Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease that can occur as a unique existence (primary Sjögren's syndrome) or merge with other systemic diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis or systemic sclerosis (secondary Sjögren's syndrome). Data on the two diseases occurrence order are inadequate. Primary Sjögren's syndrome (pSS) may relatively uncommonly lead to diffuse cystic lung changes. We represent a female who was diagnosed pSS with diffuse cystic lung alterations developed SLE two years later. SS was diagnosed on account of the existence of dryness of eye and mouth, Schirmer's test, biopsy of the minor salivary glands of her lip, positive anti-SSA and anti-SSB antibody in the serum. Chest computed tomography image showed bilateral diffuse cystic changes with a wide variation in cyst size and distribution. SLE was finally diagnosed based on bilateral lower limb skin rash, gonarthritis and omarthritis, low level of complement, antinuclear antibody 1:640 and positive antibodies to double-stranded DNA. Improvement was achieved with therapy of corticosteroids, hydroxychloroquine and antibiotics. This report provides us clinical, diagnosis and treatment perception of SS-onset SLE as patient presenting diffuse cystic lung changes.

Insomnia symptoms, perceived stress and coping strategies in patients with systemic lupus erythematosus.

PubMed

Palagini, L; Mauri, M; Faraguna, U; Carli, L; Tani, C; Dell'Osso, L; Mosca, M; Riemann, D

2016-08-01

The aim of this study is to evaluate perceived stress and coping strategies in individuals with systemic lupus erythematosus (SLE) according to the presence of insomnia symptoms, using a set of variables that include anxiety and depressive symptoms evaluation. Ninety SLE women were evaluated in a cross-sectional study using the Perceived Stress Scale (PSS), Brief COPE, Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Beck Depression Inventory (BDI) and Self-rating Anxiety Scale (SAS). Individuals with insomnia symptoms (n = 57, 66%) presented higher PSS (p < 0.001), PSQI (p < 0.0001), BDI, (p < 0.0001) scores and showed less-effective coping strategies such as the use of behavioral disengagement (p = 0.04), self-blame (p = 0.02) and emotional-focused coping (p = 0.001). In a multi-regression model ISI was the independent determinant of high PSS and of behavioral disengagement; PSQI was the only determinant of self-blame (p = 0.02) and emotional-focused coping. SLE individuals with insomnia symptoms show high levels of perceived stress and more frequent use of disengaging and emotional-focused coping strategies. This body of evidence suggests that individuals with SLE and comorbid insomnia symptoms may therefore require additional interventions for insomnia. © The Author(s) 2016.

Lots of autoantibodies equal lupus?

PubMed Central

2013-01-01

Autoantibodies may be found years before an autoimmune disease becomes clinically apparent. For systemic lupus erythematosus (SLE), those to RNA-binding proteins, to phospholipids, and to double-stranded DNA, in particular, have been found in sera of SLE patients years before the diagnosis was made. New data now show in an unbiased way that, in patients with early SLE, no single antibody class or specificity is associated with progression to SLE. Rather, an increasing number of autoantibody specificities, such as to thyroid antigens, was observed in patients progressing. This points to more generalized B cell autoreactivity during progression to SLE, underlying lupus disease manifestations. PMID:23347779

[Clinical characteristics of Pneumocystis carinii pneumonia in children with systemic lupus erythematosus].

PubMed

Tang, Xiao-yan; Li, Ji; Dong, Fen; Song, Hong-mei

2013-12-01

To identify the risk factors which will indicate the Pneumocystis carinii (Pc) infection in children with systemic lupus erythematosus (SLE) and investigate the clinical features and to elevate the level to find out the high-risk patients and make early diagnosis and treatment. The characteristics, clinical features, laboratory examinations, treatment and prognosis of Pneumocystis carinii pneumonia (PCP) in children with SLE under 18 years of age treated in our hospital between January 2000 and January 2013 were prospectively reviewed. A comparison was made with the 26 cases of SLE children without PCP who were matched for gender, age and course, and a literature review was made. (1) Five cases were enrolled, 3 were male and 2 female. Their age range was 13-17 (14.0 ± 1.6) years. All the children had kidney involvement. The courses were from 3 months to 4.5 years. All patients were receiving daily glucocorticoid therapy and immunosuppressive drugs before the diagnosis of PCP.Four patients were in the inactive phase of SLE (SLEDAI 2-4 points), and the fifth case was in active phase (SLEDAI 8, low complement 2 points, anti-dsDNA antibody positive 2 points, urine-protein 4 points). (2) Besides the clinical manifestations of SLE, most patients had progressive dyspnea, fever and dry cough at onset of PCP. Two children accepted mechanical ventilation because of respiratory failure. The mean duration of the symptoms to diagnosis was 10-30 (17.6 ± 7.8) days. Lactose dehydrogenase (LDH) was elevated more or less, median was (700 ± 263) U/L. Lymphocyte count were (0.3-1.4)×10(9)/L (median 0.5×10(9)/L), and three children had CD4 T lymphocyte count <0.3×10(9)/L. Arterial blood gas analyses showed severe hypoxemia. Chest radiographs showed in all cases diffuse interstitial infiltration. Pc was positive in the sputum. All patients were treated with trimethoprim-sulfamethoxazole and corticosteroids. When SLE children are treated with corticosteroids and immunosuppressive drugs, low lymphocyte count is the risk factor for Pc infection.It is essential to monitor lymphocyte count.We should pay more attention to fever, dry cough and hypoxemia. Chest radiologic examination may help diagnose the PCP in SLE children.It may be helpful for SLE children whose CD4T lymphocyte was below 0.3×10(9)/L to take trimethoprim-sulfamethoxazole for PCP prophylaxis.

The Effects of Age at Drinking Onset and Stressful Life Events on Alcohol Use in Adulthood: A Replication and Extension Using a Population-Based Twin Sample

PubMed Central

Lee, Lewina O.; Young Wolff, Kelly C.; Kendler, Kenneth S.; Prescott, Carol A.

2012-01-01

Background A study by Dawson and colleagues (Alcohol Clin Exp Res 2007; 31:69) using data from National Epidemiologic Survey on Alcohol and Related Condition found earlier drinking onset age, and higher levels of past-year stressful life events (SLE) were associated with higher past-year alcohol consumption. The aims of our study were as follows: (i) to attempt to replicate this interaction; (ii) to extend it by examining sex and event dependence as potential moderators of the effect; and (iii) to estimate the roles of genetic and environmental factors in mediating the overlap of early drinking onset and SLE in their relations with alcohol consumption. Methods Data were from 1,382 female and 2,218 male drinkers interviewed as part of the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Regression models were used to evaluate the main and interactive effects of early drinking onset and moderate or severe past-year SLE on past-year drinking density (PYDD), a weighted quantity-frequency measure of alcohol consumption. Analyses adjusted for demographic covariates and were stratified by sex and whether SLE were independent or dependent on the person’s actions, as rated by interviewers. Structural twin models were used to estimate the degree to which early drinking onset, SLE, and their interaction accounted for additive genetic, common environmental and individual-specific variance in PYDD. Results We replicated the prior finding of a main effect of higher alcohol consumption among individuals reporting earlier drinking onset. Age at drinking onset accounted for about 5% of the variation in PYDD, and this association was mostly attributable to overlapping genetic influences. Evidence for an interaction between onset age and SLE was generally weak, possibly because of lower power and other methodological differences from Dawson and colleagues’ study. However, there was some evidence consistent with an interaction of higher PYDD among early drinking men who experienced independent SLE and early drinking women with dependent SLE. Conclusions We confirmed prior findings of an association between early age at drinking onset with higher past-year drinking among young- and middle-aged adults and found limited evidence supporting a replication for higher stress-related drinking among early-onset drinkers. The association is consistent with early onset and stress-related drinking being attributable to overlapping genetic liability. Among early drinkers, our results suggest sex differences in consumption with regard to event dependence. PMID:21895722

Platelet-Derived S100A8/A9 and Cardiovascular Disease in Systemic Lupus Erythematosus.

PubMed

Lood, Christian; Tydén, Helena; Gullstrand, Birgitta; Jönsen, Andreas; Källberg, Eva; Mörgelin, Matthias; Kahn, Robin; Gunnarsson, Iva; Leanderson, Tomas; Ivars, Fredrik; Svenungsson, Elisabet; Bengtsson, Anders A

2016-08-01

Levels of S100A8/A9, a proinflammatory and prothrombotic protein complex, are increased in several diseases, and high levels predispose to cardiovascular disease (CVD). Recently, platelet S100A8/A9 synthesis was described in mice and humans in relation to CVD. The aim of this study was to investigate the role of platelet S100A8/A9 in systemic lupus erythematosus (SLE), a disease with markedly increased cardiovascular morbidity, as well as the exact platelet distribution of the S100A8/A9 proteins. The occurrence and distribution of platelet S100A8/A9 protein were detected by enzyme-linked immunosorbent assay, electron microscopy, Western blotting, and flow cytometry in healthy controls (n = 79) and in 2 individual cohorts of SLE patients (n = 148 and n = 318, respectively) and related to cardiovascular morbidity. We observed that human platelets expressed S100A8/A9 proteins, and that these were localized in close proximity to intracellular membranes and granules as well as on the cell surface upon activation with physiologic and pathophysiologic stimuli. Interestingly, S100A8/A9 was enriched at sites of membrane interactions, indicating a role of S100A8/A9 in cell-cell communication. S100A8/A9 levels were highly regulated by interferon-α, both in vivo and in vitro. Patients with SLE had increased platelet S100A8/A9 content compared with healthy individuals. Increased levels of platelet S100A8/A9 were associated with CVD, particularly myocardial infarction (odds ratio 4.8, 95% confidence interval 1.5-14.9, P = 0.032 [adjusted for age, sex, and smoking]). Platelets contain S100A8/A9 in membrane-enclosed vesicles, enabling rapid cell surface deposition upon activation. Furthermore, platelet S100A8/A9 protein levels were increased in SLE patients, particularly in those with CVD, and may be a future therapeutic target. © 2016, American College of Rheumatology.

Risk and predictors of work disability in Chinese patients with systemic lupus erythematosus.

PubMed

Mok, C C; Cheung, M Y; Ho, L Y; Yu, K L; To, C H

2008-12-01

The aim of this study is to determine the risk and predictive factors for work disability in patients with SLE. A cross-sectional questionnaire study was performed to evaluate the employment status of a sample of consecutive Chinese patients with SLE. Demographic, socioeconomic data (age, gender, marital status, years of education and household income), employment status, self-reported fatigue score and disease characteristics (SLE duration, organ damage and disease activity) were collected. Work disability was defined by the failure to work due to SLE. The cumulative incidence of work disability since the time of SLE diagnosis was studied by a Kaplan Meier's plot, and factors predictive of work disability were studied by Cox regression. A total of 147 patients with SLE were studied (mean age = 39.4 +/- 11.3 years; 95% women). Among 105 patients who were working at the time of SLE diagnosis, 39 (37%) lost their ability to work as a result of SLE after a mean disease duration of 10.0 +/- 6.1 years. Twenty-two (56%) patients lost their work ability within 2 years of diagnosis of SLE. The self-reported reasons for job loss were musculoskeletal pain (87%), skin disease (26%), renal problem (21%), fatigue (85%), memory deterioration (51%), anxiety or depressive symptoms (74%), too frequent sick leave (10%) and long-term hospitalisation (10%). The cumulative risk of work disability was 36% at 5 years after SLE diagnosis. In a Cox regression model, age (HR = 1.06 [1.02-1.11] per year; P = 0.008), self-reported fatigue score (HR = 1.06 [1.01-1.10] per point; P = 0.01) and mean disease activity score in the preceding two years (HR = 1.20 [1.02-1.42] per point; P = 0.03) were independently associated with working disability. In all, 37% of this group of patients with SLE lost their work ability after having the disease for 10 years. More than 50% of these patients developed work disability within the first 2 years of SLE diagnosis. Older age, fatigue and more active disease were independent predictors of work disability.

Strong viral associations with SLE among Filipinos

PubMed Central

Vista, Evan S; Weisman, Michael H; Ishimori, Mariko L; Chen, Hua; Bourn, Rebecka L; Bruner, Ben F; Hamijoyo, Laniyati; Tanangunan, Robelle D; Gal, Noga J; Robertson, Julie M; Harley, John B; Guthridge, Joel M; Navarra, Sandra V; James, Judith A

2017-01-01

Objectives Epstein-Barr virus (EBV) is considered an important environmental factor in SLE aetiology, but the relationship between SLE and EBV in the Filipino population is unknown. We tested associations between SLE, lupus-associated autoantibodies and seropositivity for EBV and other herpes viruses in the Filipino population. Methods Sera from Filipino patients with SLE (n=233), unaffected first-degree relatives (FDRs, n=543) and unrelated controls (n=221) were tested for antibodies against EBV, cytomegalovirus (CMV) and herpes simplex viruses (HSV-1 and HSV-2) by standardised ELISAs. Humoral specificity against EBV nuclear antigen (EBNA)-1 was compared by solid-phase epitope mapping. Autoantibodies were detected by a bead-based multiplex assay. Results were analysed by Fisher's exact test, Student's t-test, χ2 test and one-way analysis of variance, as appropriate for the question. Results Filipino patients with SLE had increased seroprevalence and elevated antibody concentrations against EBV viral capsid antigen (EBV-VCA), CMV, HSV-1 and HSV-2 compared with unrelated controls (p<0.05). Seropositivity for anti-EBV early antigen (EA), a marker of EBV reactivation, was dramatically increased in patients with SLE compared with unrelated controls (92.3% vs 40.4%; OR 17.15(95% CI 10.10, 30.66), p<0.0001) or unaffected FDRs (49.4%; OR 12.04(7.42, 20.74), p<0.0001), despite similar seroprevalence of EBV-VCA in patients and FDRs. In patients with SLE, EBV-EA seropositivity correlated with lupus-associated autoantibodies (p<0.001), most notably with autoantibodies against dsDNA, chromatin, Sm, SmRNP and RNP A (p<0.01). Patient and unrelated control sera reacted to the highly repetitive glycine and alanine domain of EBNA-1. An epitope spanning EBNA-1410-420 was identified in sera of patients with SLE and showed limited binding by FDR and control sera. Conclusions Filipino patients with SLE have elevated prevalence and concentrations of antibodies against EBV, CMV, HSV-1 and HSV-2 antigens, along with altered anti-EBNA-1 specificities. EBV reactivation is more common among Filipino patients with SLE compared with healthy Filipinos and may contribute to SLE pathogenesis in this population. PMID:29214036

Correlation between systemic lupus erythematosus and cytomegalovirus infection detected by different methods.

PubMed

Chen, Jing; Zhang, Huidi; Chen, Peirong; Lin, Qiaoai; Zhu, Xiaochun; Zhang, Lifang; Xue, Xiangyang

2015-04-01

Human cytomegalovirus (HCMV), a β-herpes virus subfamily member, leads to a lifelong, latent infection in most humans, but the correlation between HCMV infection and systemic lupus erythematosus (SLE) remains controversial. We analyzed the relevance of HCMV infection in SLE by analyzing the peripheral blood leukocytes (PBLs) and serum samples of 60 patients with SLE and 111 healthy individuals. HCMV genes UL55 and UL138 were detected in PBLs by polymerase chain reaction (PCR), and HCMV-specific serum IgG and IgM antibodies were investigated by enzyme-linked immunosorbent assay. The relationship between cellular HCMV infection in PBLs and common clinical indicators of SLE was further explored. Data indicated that the frequency of positive IgG and IgM anti-CMV antibodies was not significantly different in SLE patients and controls. However, compared to the healthy controls, the titers of IgG and IgM anti-CMV antibodies in SLE patients were significantly higher. The detection of cellular HCMV infection showed that almost all subjects were positive for UL138 gene in PBLs, but the positivity for UL55 gene was lower in PBLs. HCMV UL138 detection in PBLs was highly consistent with the frequency of the HCMV-specific IgG test and did not show significant difference in SLE patients and healthy controls. However, compared with that in healthy people, the positivity rate for cellular HCMV UL55 detection was significantly higher in SLE patients (P < 0.001). In addition, cellular HCMV UL55 with positive detection in PBLs was associated with significantly different clinical characteristics of SLE than that with negative detection. In conclusion, our data confirmed that the HCMV infection was related to the development of SLE. Especially, some clinical strains or substrains of HCMV, such as containing the UL55 gene in HCMV's genome, might play a vital role in the development of SLE.

Predicting Sjögren's syndrome in patients with recent-onset SLE.

PubMed

Hernández-Molina, Gabriela; Zamora-Legoff, Tatiana; Romero-Díaz, Juanita; Nuñez-Alvarez, Carlos A; Cárdenas-Velázquez, Francisco; Hernández-Hernández, Carlos; Calderillo, Maria Luisa; Marroquín, Martha; Recillas-Gispert, Claudia; Ávila-Casado, Carmen; Sánchez-Guerrero, Jorge

2013-08-01

To determine the prevalence of SS in a cohort of recent-onset SLE patients and evaluate the clinical and immunological variables that may identify SLE patients prone to develop SS. A total of 103 patients participating in a prospective cohort of recent-onset SLE were assessed for fulfilment of the American European Consensus Group criteria for SS using a three-phase approach: screening (European questionnaire, Schirmer-I test and wafer test), confirmation (fluorescein staining test, non-stimulated whole-salivary flow and anti-Ro/La antibodies) and lip biopsy. Anti-Ro/SSA and anti-La/SSB antibodies and RF were measured at entry into the cohort and at SS assessment. Ninety-three females and 10 males were included. Mean age at lupus diagnosis was 25.9 ± 8.9 years, and lupus duration at SS assessment was 30.9 ± 9.1 years. SS was diagnosed in 19 (18.5%) patients, all female, and the patients were older at SLE diagnosis than patients without SS (30.8 ± 9.3 vs 24 ± 8.8 years, P = 0.004). Anti-Ro/SSA antibody was more common in SLE-SS patients (84% vs 55%, P = 0.02, LR + 1.53, 95% CI 1.14, 2.04). In the multivariate analysis, age ≥25 years and anti-Ro/SSA antibodies at SLE diagnosis were identified as predictors of SLE-SS, while the absence of anti-Ro/SSA, anti-La/SSB and RF seems to be protective (LR- 0.14, 95% CI 0.02, 0.95). The overlap of SLE and SS occurs in almost one-fifth of SLE patients and presents early during its evolution. SLE onset at age ≥25 years plus the presence of anti-Ro/SSA antibody at diagnosis are useful predictors, while the absence of anti-Ro/SSA, anti-La/SSB and RF identifies patients at lowest risk.

A Comparitive Study of Anticardiolipin Antibodies among Systemic Lupus Erythematosus Patients from Western and Eastern India.

PubMed

Doley, D; Kakati, S; Saikia, L; Rajadhyaksha, A; Nadkar, Milind; Khadilkar, P; Patwardhan, M; Pradhan, V

2017-03-01

Anti-phospholipid antibodies (APA) like anticardiolipin antibodies (ACA) are important cause of venous and arterial thrombosis and other occlusive vascular diseases. Prevalence of these antibodies in SLE patients at the time of diagnosis is not known in Indian SLE patients. This study was conducted to evaluate the prevalence of ACA in SLE patients from Eastern and Western India and to correlate them with disease activity. Seventy SLE patients from Assam Medical College, Dibrugarh, Assam and 85 SLE patients from Rheumatology Department, KEM Hospital, Mumbai were studied. SLE disease activity was evaluated by SLE Disease Activity Index (SLEDAI) score at the time of evaluation. All patients studied were in an active stage of disease. Demographic data showed significant variations in the clinical manifestations of SLE between two regions. Renal manifestations were higher (42.9%) among SLE patients from Eastern region as compared with 37.6% patients from Western region. These patients were categorized as Lupus Nephritis (LN) and patients that did not show any renal manifestations were categories as non-LN. ACA to IgG and IgM subclasses were tested by ELISA. IgGACA positivity was 20%, 12.9% and IgM-ACA positivity was 18.6%, 12.9% where asIgG + IgM ACA positivity as found in 12.9%, 3.5% patients respectively among SLE patients from Eastern and Western India. ACA positivity was higher among LN patients from Eastern India whereas the same was higher among non-LN patients from Western India. Hence detection of ACA alongwith associated clinical manifestations were helpful to evaluate their possible association with disease severity in SLE patients. A long term follow up of patients having ACA antibodies without thrombotic event is needed to detect their possible thrombotic event in future along with their clinical presentation from these two different geographic regions from India.

Common Marker Genes Identified from Various Sample Types for Systemic Lupus Erythematosus.

PubMed

Bing, Peng-Fei; Xia, Wei; Wang, Lan; Zhang, Yong-Hong; Lei, Shu-Feng; Deng, Fei-Yan

2016-01-01

Systemic lupus erythematosus (SLE) is a complex auto-immune disease. Gene expression studies have been conducted to identify SLE-related genes in various types of samples. It is unknown whether there are common marker genes significant for SLE but independent of sample types, which may have potentials for follow-up translational research. The aim of this study is to identify common marker genes across various sample types for SLE. Based on four public microarray gene expression datasets for SLE covering three representative types of blood-born samples (monocyte; peripheral blood mononuclear cell, PBMC; whole blood), we utilized three statistics (fold-change, FC; t-test p value; false discovery rate adjusted p value) to scrutinize genes simultaneously regulated with SLE across various sample types. For common marker genes, we conducted the Gene Ontology enrichment analysis and Protein-Protein Interaction analysis to gain insights into their functions. We identified 10 common marker genes associated with SLE (IFI6, IFI27, IFI44L, OAS1, OAS2, EIF2AK2, PLSCR1, STAT1, RNASE2, and GSTO1). Significant up-regulation of IFI6, IFI27, and IFI44L with SLE was observed in all the studied sample types, though the FC was most striking in monocyte, compared with PBMC and whole blood (8.82-251.66 vs. 3.73-74.05 vs. 1.19-1.87). Eight of the above 10 genes, except RNASE2 and GSTO1, interact with each other and with known SLE susceptibility genes, participate in immune response, RNA and protein catabolism, and cell death. Our data suggest that there exist common marker genes across various sample types for SLE. The 10 common marker genes, identified herein, deserve follow-up studies to dissert their potentials as diagnostic or therapeutic markers to predict SLE or treatment response.

Brain unidentified bright objects ("UBO") in systemic lupus erythematosus: sometimes they come back. A study of microembolism by cMRI and Transcranial Doppler ultrasound.

PubMed

Bortoluzzi, A; Padovan, M; Azzini, C; De Vito, A; Trotta, F; Govoni, M

2016-02-01

The objectives of this report are to assess the occurrence of microembolic signals (MES) detected by transcranial Doppler ultrasound (TCD) in systemic lupus erythematosus (SLE) patients with (NPSLE) and without (SLE) neuropsychiatric involvement, and to verify the correlation between MES, clinical characteristics, especially the patent foramen ovale (PFO), and the presence of punctuate T2-hyperintense white matter lesions (WMHLs) detected by conventional magnetic resonance imaging (cMRI). A TCD registration to detect MES from the middle cerebral artery was carried out in SLE and NPSLE patients after exclusion of aortic and/or carotid atheromatous disease. In all patients conventional brain magnetic resonance imaging (cMRI) and transesophageal echocardiography were performed. Patients were stratified in two groups, with and without WMHLs, and compared. Twenty-three SLE patients (16 NPSLE and seven SLE) were enrolled in the study. Overall MES were detected in 12 patients (52.1%), WHMLs were detectable in 15 patients (13 NPSLE and two SLE) while eight patients had normal cMRI (three NPSLE and five SLE). Matching TCD ultrasound and neuroimaging data, MES were detected in 10 (nine NPSLE and one SLE) out of 15 patients with WHMLs and in only two out of eight patients (two NPSLE and six SLE) with normal cMRI, both with NP involvement. A PFO was confirmed in all cases of MES detection. MES are frequent findings in SLE patients, especially in those with focal WMHLs detected by cMRI and correlating with PFO. These findings should be taken into account and suggest caution in the interpretation of cMRI pictures along with a careful evaluation of MES in patients with cMRI abnormalities that should be included in the workup of SLE patients. © The Author(s) 2015.

Phagocyte activity in the peripheral blood of pregnant women with systemic lupus erythematosus and in the cord blood of their newborns.

PubMed

Sukhikh, Gennady T; Safronova, Valentina G; Vanko, Ludmila V; Matveeva, Nataliya K; Belyaeva, Anastasiya S; Fedorova, Ekaterina V; Nikolaeva, Marina A; Klimenchenko, Nataliya I; Krechetova, Lyubov V

2017-05-01

To detect faults in phagocytosis in peripheral blood cells of pregnant women with systemic lupus erythematosus (SLE) and in cord blood of their newborns. Pregnant women fulfilled ≥ 4 American College of Rheumatology criteria for SLE and their newborns were recruited. Pregnant women without SLE and their newborns constituted controls. Phagocytosis and respiratory burst were measured using PHAGOTEST and BURSTTEST kits (Biotechnology GmbH, Germany) on FACSCalibur™ flow cytometer. Expression of CD11b was estimated with antibodies (BD Biosciences, San Jose, CA, USA). Mann-Whitney rank-sum test was used to compare SLE group and controls. Phagocytosis and respiratory burst were estimated in blood of 31 SLE women (29.5 ± 3.3 years) and in cord blood of 26 newborns. Controls were 21 health women (29.8 ± 2.8 years) and their 21 babies. Median reactive oxygen species (ROS) production was reduced in the SLE group versus controls (arbitrary units): women, 2315 versus 3316 (P = 0.034); babies, 1051 versus 1791 (P = 0.041), respectively. Proportion of ROS-producing granulocytes decreased in the SLE group: women, 72.5% versus 94.0% (P = 0.025); babies, 46.8% versus 90.7% (P = 0.008). Proportion of phagocytes which engulfed Escherichia coli and bacteria number per phagocyte also decreased in SLE women. Monocyte activity was suppressed in newborns from the SLE group (RLU): 224 versus 507 (P = 0.022). CD11b expression was reduced in SLE women (RLU): granulocytes, 588 versus 1448.5 (P < 0.001); monocytes, 1017 versus 1619 (P = 0.002). Pregnant SLE women have low ingesting capacity of phagocytes. Suppression of phagocytosis in their newborns is mainly due to reduced number of cells producing ROS. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Activated Platelets Induce Endothelial Cell Activation via an Interleukin-1β Pathway in Systemic Lupus Erythematosus.

PubMed

Nhek, Sokha; Clancy, Robert; Lee, Kristen A; Allen, Nicole M; Barrett, Tessa J; Marcantoni, Emanuela; Nwaukoni, Janet; Rasmussen, Sara; Rubin, Maya; Newman, Jonathan D; Buyon, Jill P; Berger, Jeffrey S

2017-04-01

Systemic lupus erythematosus (SLE) is associated with the premature development of cardiovascular disease. The platelet-endothelium interaction is important in the pathogenesis of cardiovascular disease. In this study, we investigated the platelet phenotype from patients with SLE and matched controls, and their effect on endothelial cells. Platelet aggregability was measured in 54 SLE subjects off antiplatelet therapy (mean age 40.1±12.8 years; 82% female; 37% white) with age- and sex-matched controls. Platelets were coincubated with human umbilical vein endothelial cells (HUVECs) and changes to gene expression assessed by an RNA array and quantitative reverse transcription polymerase chain reaction. SLE disease activity index ranged from 0 to 22 (mean 5.1±3.9). Compared with controls, patients with SLE had significantly increased monocyte and leukocyte-platelet aggregation and platelet aggregation in response to submaximal agonist stimulation. An agnostic microarray of HUVECs cocultured with SLE platelets found a platelet-mediated effect on endothelial gene pathways involved in cell activation. Sera from SLE versus control subjects significantly increased (1) activation of control platelets; (2) platelet adhesion to HUVECs; (3) platelet-induced HUVEC gene expression of interleukin-8, and intercellular adhesion molecule 1; and (4) proinflammatory gene expression in HUVECs, mediated by interleukin-1β-dependent pathway. Incubation of SLE-activated platelets with an interleukin-1β-neutralizing antibody or HUVECs pretreated with interleukin-1 receptor antibodies attenuated the platelet-mediated activation of endothelial cells. Platelet activity measurements and subsequent interleukin-1β-dependent activation of the endothelium are increased in subjects with SLE. Platelet-endothelial interactions may play a role in the pathogenesis of cardiovascular disease in patients with SLE. © 2017 American Heart Association, Inc.

Activated Platelets Induce Endothelial Cell Activation via an Interleukin-1β Pathway in Systemic Lupus Erythematosus

PubMed Central

Nhek, Sokha; Clancy, Robert; Lee, Kristen A.; Allen, Nicole M.; Barrett, Tessa J.; Marcantoni, Emanuela; Nwaukoni, Janet; Rasmussen, Sara; Rubin, Maya; Newman, Jonathan D.; Buyon, Jill P.; Berger, Jeffrey S.

2017-01-01

Objective Systemic lupus erythematosus (SLE) is associated with the premature development of cardiovascular disease. The platelet–endothelium interaction is important in the pathogenesis of cardiovascular disease. In this study, we investigated the platelet phenotype from patients with SLE and matched controls, and their effect on endothelial cells. Approach and Results Platelet aggregability was measured in 54 SLE subjects off antiplatelet therapy (mean age 40.1±12.8 years; 82% female; 37% white) with age- and sex-matched controls. Platelets were coincubated with human umbilical vein endothelial cells (HUVECs) and changes to gene expression assessed by an RNA array and quantitative reverse transcription polymerase chain reaction. SLE disease activity index ranged from 0 to 22 (mean 5.1±3.9). Compared with controls, patients with SLE had significantly increased monocyte and leukocyte–platelet aggregation and platelet aggregation in response to submaximal agonist stimulation. An agnostic microarray of HUVECs cocultured with SLE platelets found a platelet-mediated effect on endothelial gene pathways involved in cell activation. Sera from SLE versus control subjects significantly increased (1) activation of control platelets; (2) platelet adhesion to HUVECs; (3) platelet-induced HUVEC gene expression of interleukin-8, and intercellular adhesion molecule 1; and (4) proinflammatory gene expression in HUVECs, mediated by interleukin-1β–dependent pathway. Incubation of SLE-activated platelets with an interleukin-1β–neutralizing antibody or HUVECs pretreated with interleukin-1 receptor antibodies attenuated the platelet-mediated activation of endothelial cells. Conclusions Platelet activity measurements and subsequent interleukin-1β–dependent activation of the endothelium are increased in subjects with SLE. Platelet–endothelial interactions may play a role in the pathogenesis of cardiovascular disease in patients with SLE. PMID:28153882

Tumor necrosis factor gene polymorphisms are associated with systemic lupus erythematosus susceptibility or lupus nephritis in Mexican patients.

PubMed

Ramírez-Bello, Julian; Cadena-Sandoval, Daniel; Mendoza-Rincón, Jorge Flavio; Barbosa-Cobos, Rosa Elda; Sánchez-Muñoz, Fausto; Amezcua-Guerra, Luis M; Sierra-Martínez, Mónica; Jiménez-Morales, Silvia

2018-04-02

The TNF -238G/A (rs361525) and -308G/A (rs1800629) polymorphisms have consistently been associated with systemic lupus erythematosus (SLE) in several populations; however, these findings have not been verified in all populations. Here, we aimed to examine whether the TNF -238G/A, -308G/A, -376G/A (rs1800750), and -1031T/C (rs1799964) polymorphisms confer SLE or lupus nephritis (LN) susceptibility in a Mexican population. Our study included 442 patients with SLE and 495 controls. For genotyping, we used the TaqMan 5' allele discrimination assay. The TNF -238G/A and -1031T/C polymorphisms were associated with SLE susceptibility (odds ratio (OR) 2.1, p = 0.0005 and OR 1.4, p = 0.003, respectively). Gender stratification showed a strong association between TNF -238G/A and SLE in women (OR 2.2, p = 0.00006), while TNF -1031T/C had an OR of 1.5 (p = 0.007). With regard to the TNF -376G/A polymorphism, this also showed association with SLE susceptibility (OR 1.95, p = 0.036) and LN (OR 3.5, p = 0.01). In conclusion, our study provides the first demonstration of association between the TNF -376G/A polymorphism and SLE and LN susceptibility. In addition, our study is the second documenting an association of TNF -1031T/C with SLE susceptibility. We also observed a strong association between TNF -238G/A and SLE susceptibility. The TNF 308G/A polymorphism was not associated with SLE or LN.

GABAergic transmission facilitates ictogenesis and synchrony between CA3, hilus, and dentate gyrus in slices from epileptic rats

PubMed Central

Gafurov, Boris

2013-01-01

The impact of regional hippocampal interactions and GABAergic transmission on ictogenesis remain unclear. Cortico-hippocampal slices from pilocarpine-treated epileptic rats were compared with controls to investigate associations between seizurelike events (SLE), GABAergic transmission, and neuronal synchrony within and between cortico-hippocampal regions. Multielectrode array recordings revealed more prevalent hippocampal SLE in epileptic tissue when excitatory transmission was enhanced and GABAergic transmission was intact [removal of Mg2+ (0Mg)] than when GABAergic transmission was blocked [removal of Mg2+ + bicuculline methiodide (0Mg+BMI)]. When activity within individual regions was analyzed, spectral and temporal slow oscillation/SLE correlations and cross-correlations were highest within the hilus of epileptic tissue during SLE but were similar in 0Mg and 0Mg+BMI. GABAergic facilitation of spectral “slow” oscillation and ripple correlations was most prominent within CA3 of epileptic tissue during SLE. When activity between regions was analyzed, slow oscillation and ripple coherence was highest between the hilus and dentate gyrus as well as between the hilus and CA3 of epileptic tissue during SLE and was significantly higher in 0Mg than 0Mg+BMI. High 0Mg-induced SLE cross-correlations between the hilus and dentate gyrus as well as between the hilus and CA3 were reduced or abolished in 0Mg+BMI. SLE cross-correlation lag measurements provided evidence for a monosynaptic connection from the hilus to the dentate gyrus during SLE. Findings implicate the hilus as an oscillation generator, whose impact on other cortico-hippocampal regions is mediated by GABAergic transmission. Data also suggest that GABAA receptor-mediated transmission facilitates back-propagation from CA3/hilus to the dentate gyrus and that this back-propagation augments SLE in epileptic hippocampus. PMID:23615549