Splicing machinery is impaired in rheumatoid arthritis, associated with disease activity and modulated by anti-TNF therapy.

Objectives: To characterise splicing machinery (SM) alterations in leucocytes of patients with rheumatoid arthritis (RA), and to assess its influence on their clinical profile and therapeutic response.

Methods: Leucocyte subtypes from 129 patients with RA and 29 healthy donors (HD) were purified, and 45 selected SM elements (SME) were evaluated by quantitative PCR-array based on microfluidic technology (Fluidigm). Modulation by anti-tumour necrosis factor (TNF) therapy and underlying regulatory mechanisms were assessed.

Expression of DDX11 and DNM1L at the 12p11 Locus Modulates Systemic Lupus Erythematosus Susceptibility.

Objectives: This study employed genetic and functional analyses using OASIS meta-analysis of multiple existing GWAS and gene-expression datasets to identify novel SLE genes.

Methods: Four hundred and ten genes were mapped using SNIPPER to 30 SLE GWAS loci and investigated for expression in three SLE GEO-datasets and the Cordoba GSE50395-dataset. Blood eQTL for significant SNPs in SLE loci and STRING for functional pathways of differentially expressed genes were used.

Therapeutic Potential and Immunomodulatory Role of Coenzyme Q and Its Analogues in Systemic Autoimmune Diseases.

Coenzyme Q (CoQ) is a mitochondrial electron carrier and a powerful lipophilic antioxidant located in membranes and plasma lipoproteins. CoQ is endogenously synthesized and obtained from the diet, which has raised interest in its therapeutic potential against pathologies related to mitochondrial dysfunction and enhanced oxidative stress. Novel formulations of solubilized CoQ and the stabilization of reduced CoQ (ubiquinol) have improved its bioavailability and efficacy.

Integrative Clinical, Molecular, and Computational Analysis Identify Novel Biomarkers and Differential Profiles of Anti-TNF Response in Rheumatoid Arthritis.

This prospective multicenter study developed an integrative clinical and molecular longitudinal study in Rheumatoid Arthritis (RA) patients to explore changes in serologic parameters following anti-TNF therapy (TNF inhibitors, TNFi) and built on machine-learning algorithms aimed at the prediction of TNFi response, based on clinical and molecular profiles of RA patients. A total of 104 RA patients from two independent cohorts undergoing TNFi and 29 healthy donors (HD) were enrolled for the discovery and validation of prediction biomarkers. Serum samples were obtained at baseline and 6 months after treatment, and therapeutic efficacy was evaluated.

Comparison of real world and core laboratory lupus anticoagulant results from the Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) clinical database and repository.

Background: Variability remains a challenge in lupus anticoagulant (LA) testing.

Objective: To validate LA test performance between Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) Core laboratories and examine agreement in LA status between Core and local/hospital laboratories contributing patients to this prospective registry.

Methods: Five Core laboratories used the same reagents, analyzer type, protocols, and characterized samples for LA validation.

Early restoration of immune and vascular phenotypes in systemic lupus erythematosus and rheumatoid arthritis patients after B cell depletion.

This translational multi-centre study explored early changes in serologic variables following B lymphocyte depletion by rituximab (RTX) treatment in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients and investigated in vitro effects on the activity of other immune cells and the vascular endothelium. Eighty-five SLE patients, seventy-five RA patients and ninety healthy donors were enrolled. Two additional cohorts of selected SLE and RA patients were treated with RTX for 3 months.

Pregnancy outcomes in mixed connective tissue disease: a multicentre study.

Objectives: In this study we aimed to investigate foetal and maternal pregnancy outcomes from a large multicentre cohort of women diagnosed with MCTD and anti-U1RNP antibodies.

Methods: This multicentre retrospective cohort study describes the outcomes of 203 pregnancies in 94 consecutive women ever pregnant who fulfilled the established criteria for MCTD with confirmed U1RNP positivity.

Results: The foetal outcomes in 203 pregnancies were as follows: 146 (71.

New Biomarkers for Atherothrombosis in Antiphospholipid Syndrome: Genomics and Epigenetics Approaches.

Antiphospholipid Syndrome (APS) is an autoimmune disorder, characterized by pregnancy morbidity and/or a hyper coagulable state involving the venous or the arterial vasculature and associated with antiphospholipid antibodies (aPL), including anti-cardiolipin antibodies (aCL), anti-beta2-glycoprotein I (anti-ß2GPI), and Lupus anticoagulant (LA). In recent years there have been many advances in the understanding of the molecular basis of vascular involvement in APS. APS is of multifactorial origin and develops in genetically predisposed individuals.

Circulating microRNAs as biomarkers of disease and typification of the atherothrombotic status in antiphospholipid syndrome.

We aimed to identify the plasma miRNA profile of antiphospholipid syndrome (APS) patients and to investigate the potential role of specific circulating miRNAs as non-invasive disease biomarkers. Ninety APS patients and 42 healthy donors were recruited. Profiling of miRNAs by PCR-array in plasma of APS patients identified a set of miRNAs differentially expressed and collectively involved in clinical features.

Ubiquinol Effects on Antiphospholipid Syndrome Prothrombotic Profile: A Randomized, Placebo-Controlled Trial.

Objective: Antiphospholipid syndrome (APS) leukocytes exhibit an oxidative perturbation, directly linked to alterations in mitochondrial dynamics and metabolism. This disturbance is related to the patients' prothrombotic status and can be prevented by in vitro treatment with coenzyme Q10. Our aim was to investigate short-term effects of in vivo ubiquinol (reduced coenzyme Q [Q]) supplementation on markers related to inflammation and thrombosis in APS through a prospective, randomized, crossover, placebo-controlled trial.

Oxidative stress in the pathogenesis of atherothrombosis associated with anti-phospholipid syndrome and systemic lupus erythematosus: new therapeutic approaches.

Atherothrombosis is a recurrent complication in APS and SLE patients. Oxidative stress has been suggested as a key player underlying this process. Autoantibodies have been pointed to as the main contributors to abnormality in the oxidative status observed in APS and SLE patients, promoting the increased production of oxidant species and the reduction of antioxidant molecules.

Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFα.

Introduction: The advent of anti-tumor necrosis factor alpha (anti-TNFα) drugs has considerably improved medical management in rheumatoid arthritis (RA) patients, although it has been reported to be ineffective in a fraction of them. MicroRNAs (miRNAs) are small, non-coding RNAs that act as fine-tuning regulators of gene expression. Targeting miRNAs by gain or loss of function approaches have brought therapeutic effects in various disease models.

Anticyclic citrullinated protein antibodies are implicated in the development of cardiovascular disease in rheumatoid arthritis.

Objective: Previous studies have suggested a relationship between anticyclic citrullinated protein (CCP) levels and development of cardiovascular disease in rheumatoid arthritis (RA). However, a limited number of studies have demonstrated an involvement of anti-CCPs in those processes. This study was aimed to define the specific role of these auto-antibodies in the pro-oxidative, inflammatory, and proatherogenic profile observed in leukocytes from RA patients.

Atherosclerosis and cardiovascular disease in systemic lupus erythematosus: effects of in vivo statin treatment.

Objective: Statins may have beneficial vascular effects in systemic lupus erythematosus (SLE) beyond their cholesterol-lowering action, although the mechanisms involved are not completely understood. We investigated potential mechanisms involved in the efficacy of fluvastatin in preventing atherothrombosis in SLE.

Methods: Eighty-five patients with SLE and 62 healthy donors were included in the study.

Gene profiling reveals specific molecular pathways in the pathogenesis of atherosclerosis and cardiovascular disease in antiphospholipid syndrome, systemic lupus erythematosus and antiphospholipid syndrome with lupus.

Objective: To identify shared and differential molecular pathways involved in the pathogenesis of atherosclerosis (AT) and cardiovascular disease (CVD) in systemic lupus erythematosus (SLE), primary antiphospholipid syndrome (APS) and APS associated with SLE (APS plus SLE).

Methods: 129 patients (42 APS, 31 APS plus SLE and 56 SLE) and 61 healthy donors were included. Microarray expression profiling was performed in monocytes.

Mitochondrial dysfunction in antiphospholipid syndrome: implications in the pathogenesis of the disease and effects of coenzyme Q(10) treatment.

The exact mechanisms underlying the role of oxidative stress in the pathogenesis and the prothrombotic or proinflammatory status of antiphospholipid syndrome (APS) remain unknown. Here, we investigate the role of oxidative stress and mitochondrial dysfunction in the proatherothrombotic status of APS patients induced by IgG-antiphospholipid antibodies and the beneficial effects of supplementing cells with coenzyme Q(10) (CoQ(10)). A significant increase in relevant prothrombotic and inflammatory parameters in 43 APS patients was found compared with 38 healthy donors.

Potential use of statins in the treatment of antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a disorder characterized by the association of arterial or venous thrombosis and/or pregnancy morbidity with the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant antibodies, and/or anti-β2-glycoprotein I antibodies). Several studies have contributed to uncovering the basis of antiphospholipid antibody pathogenicity, including the targeted cellular components, affected systems, involved receptors, intracellular pathways used, and the effector molecules that are altered in the process. Therapy for thrombosis traditionally has been based on long-term oral anticoagulation; however, bleeding complications and recurrence despite high-intensity anticoagulation can occur.

Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome.

Objective: Numerous mechanisms have been proposed to explain the thrombotic/proinflammatory tendency of antiphospholipid syndrome (APS) patients. Prothrombotic monocyte activation by antiphospholipid antibodies involves numerous proteins and intracellular pathways. The anti-inflammatory, anticoagulant and immunoregulatory effects of statins have been aimed as a therapeutic tool in APS patients.

Accelerated atherosclerosis in systemic lupus erythematosus: role of proinflammatory cytokines and therapeutic approaches.

Systemic lupus erythematosus (SLE), a chronic multisystem autoimmune disease with a broad range of clinical manifestations, is associated with accelerated atherosclerosis (AT) and increased risk of cardiovascular complications. Relevant factors directly influencing the development of AT comprise immune complex generation, complement activation, and changes in the production and activity of a complex network of cytokines, including type I and II interferons, B lymphocyte stimulator (BLyS), TNFα, IL-6, IL-17 and migration macrophage inhibitor (MIF). Autoantibodies, also responsible for cytokine expression and activation, play a supplementary key role in the development of AT.

Differential expression of protease-activated receptors in monocytes from patients with primary antiphospholipid syndrome.

Objective: To investigate the expression of protease-activated receptors (PARs), their potential regulation by anticardiolipin antibodies (aCL), and their association with the expression of other molecules relevant to thrombosis in monocytes obtained from 62 patients with primary antiphospholipid syndrome (APS).

Methods: Monocytes were isolated from peripheral blood mononuclear cells by magnetic depletion of nonmonocytes. Expression of tissue factor (TF) and PARs 1-4 genes was measured by quantitative real-time reverse transcription-polymerase chain reaction.

Proteomic analysis in monocytes of antiphospholipid syndrome patients: deregulation of proteins related to the development of thrombosis.

Objective: Antiphospholipid antibodies (aPL) are closely related to the development of thrombosis, but the exact mechanism(s) leading to thrombotic events remains unknown. In this study, using proteomic techniques, we evaluated changes in protein expression of monocytes from patients with antiphospholipid syndrome (APS) related to the pathophysiology of the syndrome.

Methods: Fifty-one APS patients were included.

Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF-kappaB/Rel proteins via the p38 mitogen-activated protein kinase pathway, and of the MEK-1/ERK pathway.

Objective: Antiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid antibodies (aPL). In patients with primary APS, expression of tissue factor (TF) on the surface of monocytes is increased, which may contribute to thrombosis in these patients. However, the intracellular mechanisms involved in aPL-mediated up-regulation of TF on monocytic cells are not understood.