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    ABSTRACT: RA (rheumatoid arthritis) is a chronic rheumatic condition hallmarked by joint inflammation and destruction by self-reactive immune responses. Clinical management of RA patients is often hampered by its heterogeneous nature in both clinical presentation and outcome, thereby highlighting the need for new predictive biomarkers. In this sense, several studies have recently revealed a role for type I IFNs (interferons), mainly IFNα, in the pathogenesis of a subset of RA patients. Genetic variants associated with the type I IFN pathway have been linked with RA development, as well as with clinical features. Moreover, a role for IFNα as a trigger for RA development has also been described. Additionally, a type I IFN signature has been associated with the early diagnosis of RA and clinical outcome prediction in patients undergoing biological drug treatment, two challenging issues for decision-making in the clinical setting. Moreover, these cytokines have been related to endothelial damage and vascular repair failure in different autoimmune disorders. Therefore, together with chronic inflammation and disease features, they could probably account for the increased cardiovascular disease morbidity and mortality of these patients. The main aim of the present review is to provide recent evidence supporting a role for type I IFNs in the immunopathology of RA, as well as to analyse their possible role as biomarkers for disease management.
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    ABSTRACT: Objective: We performed whole-blood transcriptomic profiling for patients with rheumatoid arthritis (RA) who received rituximab (RTX). We aimed to identify a molecular signature that could predict the clinical response to RTX and transcriptomic changes after RTX therapy.Methods: We performed a microarray assay of the whole human genome with RNA from a peripheral blood sample taken before the first RTX cycle from 68 patients included in the SMART study (24 EULAR non-responders and 44 responders at week 24). The transcriptomic profile was also assessed 24 weeks after the first RTX administration, and Ingenuity Interactive Pathways Analysis (IPA) was used to identify molecular pathways modified by RTX therapy according to the clinical response. Quantitative PCR was performed to confirm microarray results.Results: At baseline, 198 genes showed significant differential expression between RTX responders and non-responders. This molecular signature could be reduced to 143 genes, which allowed for classifying 89% of patients by EULAR response status at week 24, with 100% classification of non-responders. The signature for response featured up-regulation of inflammatory genes centered on NF-kB, including interleukin 33 and signal transducer and activator of transcript 5A, and down-regulation of the interferon pathway. As expected, at week 24 post-RTX therapy, genes involved in B-cell development and functions were the strongest downregulated genes without any difference between both groups.Conclusion: Whole-blood transcriptomic analyses may accurately identify patients with RA who will not respond to RTX therapy and open new perspectives to tailor RA management. © 2014 American College of Rheumatology.
    04/2014; DOI:10.1002/art.38671
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    ABSTRACT: IFIH1 (Interferon Induced with Helicase C domain 1) gene encodes a sensor of double-stranded RNA, which initiates antiviral activity. Recent studies have indicated the association of rare and common IFIH1 variants with type 1 diabetes mellitus (T1D). The aim of this study was to investigate whether polymorphisms in the IFIH1 locus are a risk factor for T1D in Caucasian patients from Poland. We genotyped 514 T1D patients and 713 healthy control individuals for rs3747517, rs1990760, rs2111485 and rs13422767 variants. Cumulative genetic risk score (CGRS) was calculated using unweighted and weighted approaches. We also examined the expression of IFIH1 gene in a cohort of 90 T1D patients. All studied polymorphisms showed significant association with type 1 diabetes. The risk alleles G of rs3747517, rs2111485, rs13422767 and A of rs1990760 were observed more frequently in T1D group with P values and allelic odds ratio OR (95%CI) <0.0001, 1.742 (1.428-2.126); 0.001, 1.336 (1.125-1.588); <0.0001, 1.799 (1.416-2.285); 0.0005, 1.359 (1.144-1.616), respectively. The risk for type 1 diabetes increased with the growing number of the risk alleles. OR (95%CI) for carriers of ≥6 risk alleles reached 2.387 (1.552-3.670) for unweighted CGRS and 3.132 (1.928-5.089) for weighted CGRS. Furthermore, IFIH1 gene expression levels in unstimulated peripheral blood mononuclear cells of T1D patients were significantly higher compared to healthy individuals (mean±SEM mRNA copy number 163.8±15.7 vs. 117.8±7.2; P=0.046). This study confirms the association of the IFIH1 locus with susceptibility to T1D in the Polish population. The cumulative effect of rs3747517, rs1990760, rs2111485 and rs13422767 variants on type 1 diabetes risk was observed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Diabetes Research and Clinical Practice 12/2014; 107(2). DOI:10.1016/j.diabres.2014.11.008 · 2.54 Impact Factor