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Contact activation products are new potential biomarkers to evaluate the risk of thrombotic events in systemic lupus erythematosus.

ABSTRACT: INTRODUCTION: Patients with systemic lupus erythematosus (SLE) have persistent platelet activation and an increased risk of thrombotic events, which cannot be accounted for by traditional cardiovascular risk factors. Factor (F)XII has a potentially important role in thrombus formation and is triggered by activated platelets. We therefore asked whether the contact system is involved in inflammation and vascular disease (VD) in SLE. METHODS: Fibrin clots were incubated with purified FXII or whole blood, and the activation and regulation of FXII were studied. Plasma from SLE patients with (n?=?31) or without (n?=?38) previous VD and from matched healthy controls (n?=?68) were analyzed for the presence of complexes formed between contact system enzymes and antithrombin (AT) or C1 inhibitor (C1INH) and evaluated with regard to clinical data and laboratory parameters. RESULTS: Fibrin clots elicited FXII activation and acted as co-factors for AT. In clotting plasma, the levels of FXIIa-AT increased, and FXIIa-C1INH decreased. A similar reciprocal relationship existed in SLE patients. FXIIa-AT was elevated in the SLE patients with a history of VD, while the corresponding levels of factor FXIIa-C1INH were significantly decreased. FXIIa-AT correlated strongly with platelet parameters. The odds ratio for VD among the SLE patients was 8.9 if they had low levels of FXIIa-C1INH, 6.1 for those with high levels of FXIIa-AT, and increased to 23.4 for those with both decreased levels of FXIIa-C1INH and increased levels of FXIIa-AT. CONCLUSIONS: Activation of FXII is elicited by fibrin during thrombotic reactions in vitro and in vivo, and fibrin acts as a heparin-like co-factor and regulates AT. Patients with SLE had altered levels of FXIIa-serpin complexes, supporting that the contact system is involved in this disease. FXIIa-serpin complexes are strongly associated with previous VD in SLE patients, suggesting that these complexes are potential biomarkers for monitoring and assessing the risk of thrombotic events in SLE.

SUBMITTER: Back J

PROVIDER: S-EPMC3979000 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Contact activation products are new potential biomarkers to evaluate the risk of thrombotic events in systemic lupus erythematosus.

Bäck Jennie J Lood Christian C Bengtsson Anders A AA Ekdahl Kristina Nilsson KN Nilsson Bo B

Arthritis research & therapy 20130101 6

<h4>Introduction</h4>Patients with systemic lupus erythematosus (SLE) have persistent platelet activation and an increased risk of thrombotic events, which cannot be accounted for by traditional cardiovascular risk factors. Factor (F)XII has a potentially important role in thrombus formation and is triggered by activated platelets. We therefore asked whether the contact system is involved in inflammation and vascular disease (VD) in SLE.<h4>Methods</h4>Fibrin clots were incubated with purified F ...[more]

PMID: 24299152

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Project description:It has been postulated that advanced glycation end products (AGEs) and their soluble receptor (sRAGE) may play a relevant role as inducers in the chronic inflammatory pathway in various conditions, among them, in immune-mediated diseases such as systemic lupus erythematosus (SLE). However, previous studies show conflicting results about their association with SLE characteristics and their usefulness as disease biomarkers. We aimed to study the association of specific serum AGEs (pentosidine, Nξ-(carboxymethyl)lysine (CML), Nξ-(carboxyethyl)lysine (CEL)), sRAGE levels and AGEs (specific serum AGEs and skin AGEs) to sRAGE ratios with various disease parameters, in order to clarify their potential as new biomarkers in SLE and to study their relationship with cardiovascular disease (CVD). To this aim, serum pentosidine, CML, CEL and sRAGE were measured via ELISA, and skin AGEs levels were measured by skin autofluorescence. Correlations of pentosidine levels with demographic and clinical data, indexes of activity, accrual damage and patient-reported outcomes were analyzed through multiple linear regression models, while correlations of the rest of the AGEs, sRAGE and AGE to sRAGE ratios (non-normal) were analyzed using both an OLS regression model and a GML. All of the analyses were adjusted for confounders. A total of 119 SLE patients were recruited. Serum AGEs and sRAGEs were significantly associated with SLE activity indexes and/or demographic or disease characteristics: pentosidine with pulmonary manifestations; CML with anti-dsDNA antibodies, IL-6, disease duration and non-Caucasian ethnicities; CEL with anti-dsDNA antibodies, IL-6 and accumulated number of manifestations; and sRAGE with male gender, photosensitivity and being on specific immunosuppressants. These results suggest that the AGE-sRAGE axis may serve as a novel biomarker for managing and prognosticating this disease. Its correlation with certain antibodies, demographics and disease presentations may indicate a distinct clinical phenotype associated with varying levels of AGEs and/or sRAGE. The significance of specific AGE/sRAGE ratios, introduced in this study for the first time, warrants additional investigation in forthcoming research. Our study did not confirm the link between serum AGEs and CVD, which merits further exploration through studies designed for this specific purpose.

Project description:ObjectiveTo identify the correlation between thrombosis and atherosclerosis in systemic lupus erythematosus (SLE) patients with antiphospholipid antibodies (aPLs) (SLE/aPLs) through high-resolution magnetic resonance imaging (HR-MRI) of the carotid artery.MethodsA single-center, cross-sectional study was conducted. We collected consecutive patients with SLE/aPLs and healthy controls who underwent carotid HR-MRI examinations. The morphometric characteristics of the common carotid artery (CCA), internal carotid artery (ICA), external carotid artery (ECA), and carotid bulb (Sinus) were measured, and the differences in morphometric parameters between different groups were analyzed.ResultsA total of 144 carotid arteries were analyzed. Compared with the control group, the wall area, wall thickness (WT and WTmax), and normalized wall index of CCA, ICA, ECA, and Sinus were increased in patients with SLE/aPLs, and the total vascular area (TVA) of CCA, ICA, and Sinus, and the bifurcation angle (BIFA) of ICA-ECA were also increased. A negative lupus anticoagulant (LAC) (with or without positive anticardiolipin antibody (aCL) or anti-β2glycoprotein antibody (aβ2GPI)) contributed to illustrating lower increased TVA and thickened vessel walls of CCA and ICA in SLE/aPLs patients without thrombotic events. Logistic regression analysis showed that WTmaxSinus and WTmaxGlobal were independent risk factors for thrombotic events in SLE/aPLs patients. The receiver operator characteristic curve showed that the cut-off value of WTmaxSinus was 2.855 mm, and WTmaxGlobal was 3.370 mm.ConclusionHR-MRI ensures the complete and accurate measurement of carotid morphometric parameters. Compared with the control group, the carotid artery in patients with SLE/aPLs is mainly characterized by diffusely thickened vessel walls, and the patients with thrombotic events showed additional higher vascular area of CCA and ICA, and BIFA of ICA-ECA without significant change in lumen area. The carotid arteries of SLE/aPLs patients with thrombotic events exhibited significant vessel wall thickening in all segments except ECA compared to those without thrombotic events. LAC-negative and non-thrombotic events distinguish relatively early atherosclerosis in the carotid arteries in patients with SLE/aPLs. Patients with SLE/aPLs that possess circumscribed thickened carotid vessel walls (>3.370 mm), particularly thickened at the Sinus (>2.855 mm), may require management strategies for the risk of thrombotic events.

Project description:BackgroundB lymphocytes (B cells) are essential in humoral response, and their activation is an important first step for the production of antibodies. However, aberrant B-cell activation is common in the development and progression of autoimmune diseases including systemic lupus erythematosus (SLE), which is characterized by the generation of superfluous autoantibodies. SLE exhibits clinical manifestation such as excessive inflammation and tissue damage. This review aims to summarize the recent emerging studies on aberrant B-cell activation and the associated concurrent therapeutic targets in SLE.SummaryAberrant B-cell activation is closely associated with the pathogenesis of SLE. Among a variety of mechanisms, dysregulations of B-cell receptor (BCR), toll-like receptor (TLR), and B-cell activating factor receptor (BAFF-R) pathways are the common and dominating factors involved in aberrant B-cell activation. These aberrant signaling transductions play diverse and integrated roles in the development and the pathogenesis of SLE. Therapies targeting aberrant B-cell activation have shown promising efficacy in achieving the clinical alleviation of SLE, suggesting the discovery of new drug targets from these aberrant signaling pathways is imminent. Here, an integrated survey or review of published high-throughput sequencing database covering RNAs of B cells from SLE versus criteria-matched healthy controls highlights that reported signaling molecules in BCR pathway (VAV2, PLC-γ2), TLR pathway (TLR9, P105, IRF7, TAB1), and BAFF-R pathway (SDF-1α) are attitudinally upregulated in SLE patients. This review thus suggests the concurrent and future therapeutic targets and potential biomarkers in both basic and clinical studies of SLE.Key messagesThis review focuses on core B-cell signaling pathways, discussing the progress in the role of aberrant B-cell activation during the pathogenesis of SLE. This review also highlights the signaling molecules from published studies and database for the possible prevention and treatment targets serving the future clinical treatments of SLE.

Project description:ImportanceSystemic lupus erythematosus (SLE) predisposes individuals to early cardiovascular (CV) events. While hydroxychloroquine is thought to mitigate CV risk factors, its protective role against CV events, particularly arterial ones, remains to be confirmed.ObjectiveTo evaluate the association between hydroxychloroquine and the risk of myocardial infarction (MI), stroke, and other thromboembolic events (OTEs) in patients with SLE.Design, setting, and participantsThis cohort study using a nested case-control design was conducted within the National French Healthcare Database (SNDS), which represents 99% of the French population, from 2010 to 2020. Participants were the cohort of all patients with SLE recorded in the SNDS. Patients with SLE experiencing CV events during the study period were the case group; those without CV events were controls. The analysis period was from February 2022 to September 2023.ExposuresHydroxychloroquine use within 365 days prior to the index date, defined as current (within 90 days), remote (91-365 days), or no exposure within the previous 365 days.Main outcomes and measuresOutcomes of interest were MI, stroke, and OTE, analyzed individually and as a composite outcome (primary analysis). Controls were matched to patients with CV events by age, sex, time since SLE onset and entry into the SNDS database, index date, prior antithrombotic and CV medication, chronic kidney disease, and hospitalization. Multivariable conditional logistic regression was performed using hydroxychloroquine exposure as the main independent variable.ResultsThe SLE cohort included 52 883 patients (mean [SD] age, 44.23 [16.09] years; 45 255 [86.6%] female; mean [SD] follow-up, 9.01 [2.51] years), including 1981 patients with eligible CV events and 16 892 matched control patients. There were 669 MI events, 916 stroke events, and 696 OTEs in the individual outcome studies. For current exposure to hydroxychloroquine, the adjusted odds were lower for composite CV events (odds ratio [OR], 0.63; 95% CI, 0.57-0.69) as well as for MI (OR, 0.72; 95% CI, 0.60-0.85), stroke (OR, 0.69; 95% CI, 0.60-0.81), and OTEs (OR, 0.58; 95% CI, 0.49-0.69) individually compared with no hydroxychloroquine exposure within 365 days.Conclusions and relevanceIn this nationwide cohort study of patients with SLE, a protective association was found between the current use of hydroxychloroquine and the occurrence of CV events, but not between remote use of hydroxychloroquine and CV outcomes, highlighting the value of continuous hydroxychloroquine treatment in patients with SLE.

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Contact activation products are new potential biomarkers to evaluate the risk of thrombotic events in systemic lupus erythematosus.

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Contact activation products are new potential biomarkers to evaluate the risk of thrombotic events in systemic lupus erythematosus.

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