scholarly journals The baseline interferon signature predicts disease severity over the subsequent 5 years in systemic lupus erythematosus

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Lloyd Mai ◽  
Arundip Asaduzzaman ◽  
Babak Noamani ◽  
Paul R. Fortin ◽  
Dafna D. Gladman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Disease Severity ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Type I Interferons ◽  
Type I ◽  
Systemic Lupus ◽  
Increased Risk

Abstract Objectives Type I interferons (IFNs) play an important role in the pathophysiology of systemic lupus erythematosus (SLE). While cross-sectional data suggest an association between IFN-induced gene expression and SLE disease activity, interest in this as a biomarker of flare has been tempered by a lack of fluctuation with disease activity in the majority of patients. This led us to question whether IFN-induced gene expression might instead be a biomarker of overall disease severity, with patients with high levels spending more time in an active disease state. Methods Levels of five interferon-responsive genes were measured in the whole peripheral blood at baseline visit for 137 SLE patients subsequently followed for 5 years. Log transformed values were summed to yield a composite IFN5 score, and the correlation with various disease outcomes examined. Receiver operator characteristic analyses were performed for outcomes of interest. Kaplan-Meier curves were generated to compare the proportion of flare-free patients with high and low IFN5 scores over time. Results The baseline IFN5 score was positively correlated with the adjusted mean SLE disease activity index-2000, number of flares, adjusted mean prednisone dose, and number of new immunosuppressive medications over the subsequent 5 years. Optimal cut-offs for the IFN5 score were determined using Youden’s index and predicted more severe outcomes with 57–67% accuracy. A high baseline IFN5 level was associated with a significantly increased risk of subsequent flare. Conclusions Measurement of the type I IFN signature is a useful tool for predicting the subsequent disease activity course.

Cardiovascular Autonomic Nervous System Dysfunction in Patients with Systemic Lupus Erythematosus

QJM ◽  
2020 ◽  
Vol 113 (Supplement_1) ◽  
Author(s):  
D A Hussein ◽  
A B E Abdelaziz ◽  
A M Abdelmoteleb ◽  
M A Elserwy ◽  
S G Arafa
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Autonomic Neuropathy ◽  
Autonomic Dysfunction ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Tilt Table Test ◽  
Systemic Lupus ◽  
Tilt Table ◽  
Increased Risk

Abstract Background involvement of central and peripheral nervous systems are well-documented in SLE but literature on prevalence and pattern of autonomic neuropathy are few. Women with SLE have been found to have 5-8 fold increased risk of coronary heart disease. Autonomic dysfunction in the presence of structural cardiovascular disease is associated with adverse prognosis. Aim of the Work the purpose of this study is to evaluate the cardiovascular autonomic function in patients with Systemic lupus erythematosus, and to correlate it with SLE clinical features. Patients and Methods we conducted our study on one-hundred Egyptian SLE patients diagnosed according to SLICC classification criteria for SLE recruited from rheumatology outpatient clinic and inpatient department at Ain Shams University Hospitals. All the studied patients were subjected to history taking, clinical examination, and laboratory and radiological investigations related to SLE diagnosis and activity. SLE disease activity was assessed by SLE disease activity index-2000 (SLEDAI-2K).Tilt table test was used to assess for presence of cardiovascular autonomic neuropathy. Results we found that fifty (50%) of our SLE patients had symptoms suggestive for autonomic dysfunction, including orthostatic hypotension, palpitation and or Raynaud’s phenomenon. Regarding the result of tilt table test, sixty eight (68%) of the studied SLE patients were found to have positive tilt table responses. By doing the uni-variate analysis for predictors of SLE patients with positive tilt table test, we found that vasculitis, proteinuria, DNA, low TLC and complement levels, high SLEDAI, ESR and urinary P/C all were predictors for positivity of tilt table testing. Conclusion The prevalence of autonomic dysfunction was high among SLE patients.

scholarly journals Measuring Disease Activity and Damage with Validated Metrics: A Systematic Review on Mortality and Damage in Systemic Lupus Erythematosus

2018 ◽  
Vol 45 (10) ◽  
pp. 1448-1461 ◽  
Author(s):  
Stephanie O. Keeling ◽  
Ben Vandermeer ◽  
Jorge Medina ◽  
Trish Chatterley ◽  
Tatiana Nevskaya ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Damage Index ◽  
Disease Activity Index ◽  
Evaluation Methodology ◽  
Systemic Lupus ◽  
Increased Risk ◽  
Damage Accrual

Objective.To identify the effect of disease activity and damage, measured by validated indices, on mortality and damage accrual, in order to inform upcoming Canadian systemic lupus erythematosus (SLE) recommendations.Methods.Following GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology to fill in evidence-to-decision tables to create recommendations for “minimal investigations needed to monitor SLE patients at baseline and subsequent visits,” a systematic literature review was performed. The effect of disease activity and damage, measured by validated metrics, on mortality and damage was systematically reviewed, with metaanalyses performed when available.Results.A title/abstract screen of 5599 articles identified 816 articles for full paper review, with 102 meeting inclusion criteria and 53 with extractable data. Thirty-three articles describing outcomes related to disease activity and 20 articles related to damage were identified. Mortality was associated with higher SLE Disease Activity Index-2000 scores in 6 studies (HR 1.14, 95% CI 1.06–1.22) and higher Systemic Lupus International Collaborating Clinics/ACR Damage Index scores in 6 studies (HR 1.53, 95% CI 1.28–1.83). Higher SLE Activity Measure scores were associated with increased risk of damage in 3 studies (OR 1.06, 95% CI 1.04–1.08). British Isles Lupus Assessment Group was associated with mortality in 1 study with HR of 1.15.Conclusion.Active SLE disease and damage are associated with and predict greater mortality and damage. The use of validated disease activity and damage metrics is important in the assessment of disease activity and damage and will inform upcoming Canadian recommendations for the assessment of SLE.

The Potential Role of Interferon-regulatory Factor 7 Among Taiwanese Patients with Systemic Lupus Erythematosus

2011 ◽  
Vol 38 (9) ◽  
pp. 1914-1919 ◽  
Author(s):  
LI-HSIN LIN ◽  
PIN LING ◽  
MING-FEI LIU
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Clinical Manifestations ◽  
Control Group ◽  
Type I ◽  
Mrna Levels ◽  
Regulatory Factor ◽  
Systemic Lupus ◽  
Increased Risk

Objective.Type I interferons (IFN), especially IFN-α, have been proposed to underlie the pathogenesis of systemic lupus erythematosus (SLE). Members of the IFN regulatory factor (IRF) family, which regulate IFN expression, have been implicated as risk factors for SLE. Our aims were to investigate the expression of IRF7 and its correlation with disease activity and to explore the association in Taiwanese patients between 2 genetic single-nucleotide polymorphisms (SNP) of IRF7 and SLE.Methods.IRF7 messenger RNA (mRNA) levels were measured in peripheral blood mononuclear cells by real-time reverse transcription polymerase chain reaction in 51 adult patients with SLE and 65 age-matched and sex-matched controls. Their serum IFN-α levels were determined by ELISA and the clinical manifestations were recorded at the same time. Two IRF7 SNP, rs1061501 and rs1061502, were examined by genotyping across 92 patients with SLE and 92 age and sex-matched healthy control subjects.Results.Compared with controls, the expression of IRF7 mRNA was significantly increased in patients with SLE and was positively correlated with both the serum level of IFN-α and lupus disease activity. The distribution of SNP rs1061501 by genotype (CC, CT, and TT) and by allele (C, T) was significantly different between the SLE and the control group (p = 0.028 for genotype and p = 0.009 for allele). There were no significant differences for SNP rs1061502.Conclusion.The results suggest that dysregulation of IRF7 might mediate an excessive production of IFN-α, which then exerts a crucial effect on the pathogenesis of human SLE. The IRF7 SNP rs1061501 TT genotype and T allele are enriched in Taiwanese patients with SLE and thus would seem to be associated with an increased risk of developing SLE.

Cardiovascular Disease in Systemic Lupus Erythematosus: Recent Data on Epidemiology, Risk Factors and Prevention

2020 ◽  
Vol 18 (6) ◽  
pp. 549-565 ◽  
Author(s):  
Myrto Kostopoulou ◽  
Dionysis Nikolopoulos ◽  
Ioannis Parodis ◽  
George Bertsias
Keyword(s):  
Risk Factors ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Statin Treatment ◽  
Type I Interferons ◽  
Type I ◽  
Lifestyle Modifications ◽  
Systemic Lupus ◽  
Increased Risk ◽  
Atherogenic Dyslipidaemia

Systemic Lupus Erythematosus (SLE) is associated with increased risk for accelerated atherosclerosis and cardiovascular (CV) events including coronary heart disease, cerebrovascular and peripheral artery disease. CV events occur both early and late during the disease course, with younger patients being at much higher risk than age-matched counterparts. The risk cannot be fully accounted for by the increased prevalence of traditional atherosclerotic factors and may be due to pathophysiologic intermediates such as type I interferons and other inflammatory cytokines, oxidative stress, activated granulocytes and production of extracellular chromatin traps, antiphospholipid and other autoantibodies causing dysfunction of lipoproteins, altogether resulting in endothelial injury and pro-atherogenic dyslipidaemia. These mechanisms may be further aggravated by chronic intake of prednisone (even at doses <7.5 mg/day), whereas immunomodulatory drugs, especially hydroxychloroquine, may exert antiatherogenic properties. To date, there is a paucity of randomized studies regarding the effectiveness of preventative strategies and pharmacological interventions specifically in patients with SLE. Nevertheless, both the European League Against Rheumatism recommendations and extrapolated evidence from the general population emphasize that SLE patients should undergo regular monitoring for atherosclerotic risk factors and calculation of the 10-year CV risk. Risk stratification should include diseaserelated factors and accordingly, general (lifestyle modifications/smoking cessation, antihypertensive and statin treatment, low-dose aspirin in selected cases) and SLE-specific (control of disease activity, minimization of glucocorticoids, use of hydroxychloroquine) preventive measures be applied as appropriate. Further studies will be required regarding the use of non-invasive tools and biomarkers for CV assessment and of risk-lowering strategies tailored to SLE.

scholarly journals High disease activity status suggests more severe disease and damage accrual in systemic lupus erythematosus

2020 ◽  
Vol 7 (1) ◽  
pp. e000372
Author(s):  
Rachel Koelmeyer ◽  
Hieu Tri Nim ◽  
Mandana Nikpour ◽  
Ying B Sun ◽  
Amy Kao ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Disease Severity ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Severe Disease ◽  
High Disease Activity ◽  
Physician Global Assessment ◽  
Systemic Lupus ◽  
Damage Accrual

ObjectiveDisease severity in SLE is an important concept related to disease activity, treatment burden and prognosis. We set out to evaluate if high disease activity status (HDAS), based on ever attainment of a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) disease activity score of ≥10, is an indicator for disease severity in SLE.MethodsUsing prospectively collected data, we assessed the association of HDAS with sociodemographic and disease characteristics and adverse clinical outcomes using logistic regression or generalised estimating equations.ResultsOf 286 patients with SLE, who were observed for a median (range) of 5.1 years (1–10.8 years), 43.7% experienced HDAS at least once during the observational period. Autoantibody positivity, particularly anti-dsDNA and anti-Sm positivity, were associated with increased likelihood of HDAS. Age ≥45 years at diagnosis was associated with reduced likelihood of HDAS (p=0.002). Patients with HDAS had higher Physician Global Assessment score (>1: OR 8.1, p<0.001) and were more likely to meet criteria for flare (mild/moderate flare: OR 4.4, p<0.001; severe flare: OR 17.2, p<0.001) at the time of experiencing HDAS. They were also more likely to have overall higher disease activity, as defined by time-adjusted mean SLEDAI-2K score in the highest quartile (OR 11.7, 95% CI 5.1 to 26.6; p>0.001), higher corticosteroid exposure (corticosteroid dose in highest quartile: OR 7.7, 95% CI 3.9 to 15.3; p<0.001) and damage accrual (OR 2.3, 95% CI 1.3 to 3.9; p=0.003) when compared with non-HDAS patients.ConclusionsHDAS is associated with more severe disease, as measured by higher disease activity across time, corticosteroid exposure and damage accrual. The occurrence of HDAS may be a useful prognostic marker in the management of SLE.

Association between toxic organochlorine levels in human serum and systemic lupus erythematosus

Lupus ◽  
2021 ◽  
pp. 096120332110519
Author(s):  
Manar A Helmy ◽  
Amal Saad-Hussein ◽  
Heba Allah Abd E Rahman ◽  
Rasha S Shemies ◽  
Mona Elhelaly ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Severity ◽  
Lupus Erythematosus ◽  
Clinical Laboratory ◽  
Activity Index ◽  
Disease Activity Index ◽  
B Value ◽  
Systemic Lupus ◽  
Cross Sectional ◽  
Increased Risk

Organochlorines (OCs) are groups of highly toxic pesticides with known immunotoxicity. The present work aimed to study the potential association between serum residues of OCs and the risk of developing systemic lupus erythematosus (SLE) as well as correlating to the clinical-laboratory manifestations in a sample of Egyptian SLE patients. A cross-sectional study was conducted on 132 patients environmentally exposed to OCs. Patients were diagnosed as SLE based on the American College of Rheumatology (ACR) revised criteria. Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score was calculated to stratify the disease severity. Blood and urine samples were collected to measure the levels of OCs, serological markers, and urinary protein. The most frequently detected OCs were p,p’-DDE; lindane; and hexachlorobenzene (HCB). The risk of developing SLE was significantly associated with detected p,p’-DDE and HCB (B value 7.704 and 14.33, respectively). Hexachlorobenzene, in addition, was significantly associated with increased SLEDAI-2K score and polycythemia. Lindane was significantly associated with hypocomplementemia, cardiac manifestations of SLE, anemia, and leucopenia. In conclusion, the detected OCs p,p’-DDE and HCB are associated with increased risk of SLE in Egyptian patients and correlates to the manifestations of disease severity.

Deregulated NLRP3 and NLRP1 Inflammasomes and Their Correlations with Disease Activity in Systemic Lupus Erythematosus

2013 ◽  
Vol 41 (3) ◽  
pp. 444-452 ◽  
Author(s):  
Qingrui Yang ◽  
Chengcheng Yu ◽  
Zhaowen Yang ◽  
Qing Wei ◽  
Kun Mu ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Activity Index ◽  
Type I ◽  
Healthy Controls ◽  
Systemic Lupus ◽  
Glucocorticoid Treatment ◽  
Peripheral Blood Mononuclear

Objective.NOD-like receptor family, pyrin domain containing 3 and 1 (NLRP3 and NLRP1) inflammasomes are molecular platforms that sense the damage or danger signals of cells. We investigated whether NLRP3/NLRP1 inflammasomes are involved in the pathogenesis and progression of systemic lupus erythematosus (SLE).Methods.Expressions of inflammasome components at the mRNA and protein levels in the peripheral blood mononuclear cells (PBMC) from patients with SLE and healthy controls were investigated by quantitative real-time transcription PCR and Western blot, respectively. Correlations between NLRP3/NLRP1 inflammasome components’ expression and clinical disease progression were investigated. Expressions of NLRP3/NLRP1 inflammasomes before and after treatment in the patients with SLE were also analyzed and compared.Results.Our data showed that expressions of NLRP3/NLRP1 inflammasomes were significantly downregulated in PBMC from patients with SLE compared with PBMC from healthy controls. Further, expressions of NLRP3/NLRP1 inflammasomes were negatively correlated with the SLE Disease Activity Index, and regular glucocorticoid treatment significantly corrected this deregulation of these inflammasomes. Further analysis showed that type I interferon (IFN) level was significantly negatively correlated with expression of NLRP3/NLRP1 inflammasomes, which indicated that enhanced IFN-I level in patients with SLE was responsible, at least to a great degree, for the deregulation of inflammasomes.Conclusion.These results indicated deregulation of NLRP3/NLRP1 inflammasomes in patients with SLE, and suggested an important role for inflammasomes in the pathogenesis and progression of SLE.

Impact of markers of endothelial injury and hypercoagulability on systemic lupus erythematosus

Lupus ◽  
2020 ◽  
Vol 29 (2) ◽  
pp. 182-190
Author(s):  
W Batista Cicarini ◽  
R C Figueiredo Duarte ◽  
K Silvestre Ferreira ◽  
C de Mello Gomes Loures ◽  
R Vargas Consoli ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Disease Activity Index ◽  
Endothelial Injury ◽  
Control Group ◽  
Systemic Lupus ◽  
Low Concentrations ◽  
The Relationship

We have explored the relationship between possible hemostatic changes and clinical manifestation of the systemic lupus erythematosus (SLE) as a function of greater or lesser disease activity according to Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) criteria. Endothelial injury and hypercoagulability were investigated in patients with SLE by measuring thrombomodulin (TM), D-dimer (DDi) and thrombin generation (TG) potential. A total of 90 participants were distributed into three groups: 1) women with SLE presenting with low disease activity (laSLE) (SLEDAI-2K ≤ 4), 2) women with SLE presenting with moderate to high disease activity (mhaSLE) (SLEDAI-2K > 4), and 3) a control group comprising healthy women. Levels of TM and DDi were higher both in the laSLE and mhaSLE groups compared to controls and in mhaSLE compared to the laSLE group. With respect to TG assay, lagtime and endogen thrombin potential, low concentrations of tissue factor provided the best results for discrimination among groups. Analysis of these data allow us to conclude that TM, DDi and TG are potentially useful markers for discriminating patients with very active from those with lower active disease. Higher SLE activity may cause endothelial injury, resulting in higher TG and consequently a hypercoagulability state underlying the picture of thrombosis common in this inflammatory disease.

scholarly journals OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 4-5
Author(s):  
A. Aue ◽  
F. Szelinski ◽  
S. Weißenberg ◽  
A. Wiedemann ◽  
T. Rose ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
B Cell Subsets

Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen

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