Search

Abstract Objective Rheumatoid Arthritis (RA) often exhibits suboptimal treatment response despite early diagnosis and treatment. This study aimed to analyze Early Rheumatoid Arthritis (ERA) synovial biopsies through histology and immunohistochemistry (IHC) to identify predictive factors for treatment response to Methotrexate (MTX). Methods 140 ERA patients from the UCLouvain Arthritis Cohort underwent synovial biopsy and were monitored after initiating Disease-Modifying Antirheumatic Drug (DMARD) therapy. Histological features [Synovial Hyperplasia, Fibrinoid Necrosis (FN), Hypervascularization and Inflammatory Infiltrate] and IHC (CD3, CD20, CD138, CD68) were each semi-quantitatively assessed on a 0–3 scale with 7 levels. Results A strong association was observed between synovial CD68 and Fibrinoid Necrosis scores [r = 0.44 (0.27 − 0.56); p

Objectives To investigate if patients with early rheumatoid arthritis responding insufficiently to initial methotrexate (MTX) and bridging glucocorticoids (GCs) could benefit from early but temporary etanercept introduction as a second remission-induction attempt.Methods CareRA2020 (NCT03649061) was a 2-year, open-label, multicentre, pragmatic randomised controlled trial. Treatment-naïve patients started MTX and GC bridging (COBRA-Slim: CS). Within a time window from week (W) 8 until W32, early insufficient responders (28-joint Disease Activity Score – C-reactive Protein (DAS28-CRP) >3.2 between W8 and W32 or ≥2.6 at W32) were randomised to a Standard-CS strategy (adding leflunomide first) or Bio-induction-CS strategy (adding etanercept for 24 weeks). Additional treatment adaptations followed the treat-to-target principle. Longitudinal disease activity (DAS28-CRP) over 104 weeks (primary outcome), achievement of DAS28-CRP

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

Abstract Introduction This study sought to analyze the benefit of an early induction therapy with a biological disease-modifying anti-rheumatic drugs (bDMARD) during the first year of treatment with a 5-year follow-up in early rheumatoid arthritis (ERA). Methods We included ERA patients from the UCLouvain Brussels cohort who met the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 classification criteria and were naïve to DMARDs. ERA patients were divided into two groups according to whether they received an induction bDMARD therapy or a standard therapy with methotrexate (MTX). Clinical response after the induction treatment at 6 and 12 months followed by a MTX maintenance therapy at 36 and 60 months was evaluated. Results Data from 470 ERA patients were collected, 189 received a bDMARD and 281 initiated MTX alone. In the bDMARD group, disease activity and HAQ were higher at baseline. A total of 391 patients were followed up to 5 years. We then divided each group into two subgroups according to the last treatment they received at 5 years: bDMARD > MTX (n = 95), bDMARD > bDMARD (n = 59); MTX > MTX (n = 134), MTX > bDMARD (n = 103). During the induction, we observed a clinical response with a large number of patients achieving DAS28-CRP remission. According to a treat-to-target (T2T) approach, remission rate was stable on MTX monotherapy or rescued by the addition or prolongation of a bDMARD. Interestingly, bDMARD followed by a MTX maintenance therapy experienced a stable and sustained DAS28-CRP remission rate in 53% of the ERA patients at year 5. Conclusions Long-term remission is an achievable goal in ERA. Our results suggest that a bDMARD induction therapy followed by MTX maintenance therapy could be an interesting option.

This article contains microstructural characterization data related to the research article ‘Self-lubrication of Nuclear Graphite in Argon at High Temperature’, published in Tribology International. Digital, optical, and scanning electron micrographs are collected on the pebble and disk samples generated in the tribological tests and in their corresponding reference samples. Surface roughness measurements of the test and control samples are performed using the 3D-depth composition feature of the digital microscope. X-ray diffraction and Raman spectra of the test and reference samples are acquired and peak-fitted according to published literature on nuclear graphite characterization. Plots of the peak-fitted spectra are included in this article; the full list of peak-fitting parameters is provided in the linked data repository.

Objective: The objective is to characterize transcriptomic profiles and immune cell composition and distribution in juvenile idiopathic arthritis (JIA) synovial biopsies, assess for associations of these features with clinical parameters, and compare JIA and rheumatoid arthritis (RA) synovial features. Methods: RNA sequencing (RNASeq) was performed on 24 samples, with pathway analysis and inference of relative abundance of immune cell subsets based on gene expression data. Two multiplex fluorescence immunohistochemistry (IHC) panels were performed on 28 samples (including 13 on which RNASeq was performed), staining for CD206− classical and CD206+ nonclassical macrophages, and CD8+ and CD4+ T and B lymphocytes. Data were compared to a published series of early RA synovial biopsies. Results: Pathway analysis of the most variably expressed genes (n = 339) identified a B and plasma cell signature as the main driver of heterogeneity in JIA synovia, with strong overlap between JIA and RA synovitis. Multiplex IHC confirmed heterogeneity of immune cell infiltration. M1‐like macrophage–rich synovial lining was associated with greater lining hypertrophy and higher (CD45+) pan–immune cell and CD8+ T cell infiltration. Conclusion: Our study indicates significant similarities between JIA and RA synovitis. Similar to RA, JIA synovia may be broadly categorized into two groups: (1) those with an inflammatory/adaptive immune transcriptomic signature, M1‐like macrophage and CD8+ T cell infiltration, and thicker, M1‐like macrophage–rich synovial lining, and (2) those with an M2‐like macrophage transcriptomic signature, greater M2/M1‐like macrophage ratios, and thinner, M2‐like macrophage–rich synovial lining. Synovial features were not significantly associated with clinical parameters, likely because of group size and heterogeneity. [ABSTRACT FROM AUTHOR]

Abstract Background/purpose Studies have demonstrated that rheumatoid arthritis (RA) patients who achieve low disease activity or remission are able to taper biological disease-modifying antirheumatic drugs (bDMARDs). The aim of this study was to evaluate the proportion of patients in whom bDMARDs can be tapered in daily practice and to analyse the characteristics of these patients. Other objectives were to analyse which bDMARDs are more suitable for dose reduction and the cost savings. Results Data from 332 eligible RA patients from our Brussels UCLouvain cohort were retrospectively analysed; 140 patients (42.1%) received a tapered regimen, and 192 received stable doses of bDMARDs. The age at diagnosis (43.1 vs 38.7 years, p = 0.04), health assessment questionnaire (HAQ) score (1.3 vs 1.5, p = 0.048), RF positivity rate (83.3 vs 72.9%, p = 0.04) and disease duration at the time of bDMARD introduction (9.7 vs 12.1 years, p = 0.034) were significantly different between the reduced-dose and stable-dose groups. Interestingly, relatively more patients receiving a tapered dose were treated with a combination of bDMARDs and methotrexate (MTX) (86.7% vs 73.8%, p = 0.005). In our cohort, anti-TNF agents were the most commonly prescribed medications (68%). Only 15 patients experienced a flare during follow-up. Adalimumab, etanercept and rituximab were the most common bDMARDs in the reduced-dose group and were associated with the most important reductions in annual cost. Conclusion In daily practice, tapering bDMARDs in RA patients who have achieved low disease activity or remission is an achievable goal in a large proportion of patients, thereby reducing potential side effects and annual drug-associated costs. The combination of bDMARDs with MTX could improve the success of dose reduction attempts. Trial registration This retrospective non-interventional study was retrospectively registered with local ethics approval.

ObjectivesOur goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab.MethodsSynovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3+, CD20+, and CD68+ cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR.ResultsGene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders.ConclusionWe provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.

Abstract Background Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD) and blood pressure (BP) or hypertension. Many of these loci are not linked to traditional risk factors, nor do they include obvious candidate genes, complicating their functional characterization. We hypothesize that many GWAS loci associated with vascular diseases modulate endothelial functions. Endothelial cells play critical roles in regulating vascular homeostasis, such as roles in forming a selective barrier, inflammation, hemostasis, and vascular tone, and endothelial dysfunction is a hallmark of atherosclerosis and hypertension. To test this hypothesis, we generate an integrated map of gene expression, open chromatin region, and 3D interactions in resting and TNFα-treated human endothelial cells. Results We show that genetic variants associated with CAD and BP are enriched in open chromatin regions identified in endothelial cells. We identify physical loops by Hi-C and link open chromatin peaks that include CAD or BP SNPs with the promoters of genes expressed in endothelial cells. This analysis highlights 991 combinations of open chromatin regions and gene promoters that map to 38 CAD and 92 BP GWAS loci. We validate one CAD locus, by engineering a deletion of the TNFα-sensitive regulatory element using CRISPR/Cas9 and measure the effect on the expression of the novel CAD candidate gene AIDA. Conclusions Our data support an important role played by genetic variants acting in the vascular endothelium to modulate inter-individual risk in CAD and hypertension.

ObjectivesWe explored histological and transcriptomic profiles of paired synovial biopsies from rheumatoid arthritis (RA) patients, in order to assess homogeneity in synovial tissue at the individual level.MethodsSynovial biopsies were performed simultaneously in one small and one large joint per patient using needle-arthroscopy for the knee and ultrasound-guided biopsy for the hand or wrist. Synovium from individuals with osteoarthritis was used as controls. Paraffin-embedded samples were stained for CD3, CD20, and CD68. Total RNA was hybridized on high-density microarrays. TCRB variable sequences were obtained from synovial and blood RNA samples.ResultsTwenty paired biopsies from 10 RA patients with active disease were analyzed. Semi-quantification of histological markers showed a positive correlation for synovial hyperplasia, inflammatory infiltrates and CD3-positive T cells between pairs. Pairwise comparison of transcriptomic profiles showed similar expression of RA-related molecular pathways (TCR signaling, T cell costimulation and response to TNFα). T cells clonotypes were enriched in all but one joints compared to blood, regardless of the magnitude of T cell infiltration. Enriched clonotypes were shared between pairs (23–100%), but this was less the case in pairs of joints displaying weaker T cell signatures and more pronounced germinal center-like transcriptomic profiles.ConclusionCellular and molecular alterations in RA synovitis are similar between small and large joints from the same patient. Interindividual differences in magnitude of T cell infiltrates and distribution of enriched T cell clonotypes support the concept of distinct synovial pathotypes in RA that are associated with systemic versus local antigen-driven activation of T cells.

Abstract Background The aim of this global collaboration was to develop a consensual set of items for the analysis of synovial biopsies in clinical practice and translational research through the EULAR Synovitis Study Group (ESSG) and OMERACT Synovial Tissue Biopsy Group. Methods Participants were consulted through a modified Delphi method. Three sequential rounds occurred over 12 months. Members were sent a written questionnaire containing items divided into two parts. Items were identified and formulated based on a scoping review. The first part of the questionnaire referred to synovial biopsies in clinical practice including five subsections, and the second part to translational research with six subsections. Every participant was asked to score each item on a 5-point Likert scale. Items with a median score above 3.5 and a ≥ 70% agreement were selected for the next round. The last round was conducted orally at EULAR in June 2017. Results Twenty-seven participants from 19 centers were contacted by email. Twenty participants from 17 centers answered. Response rates for next rounds were 100%. For the first part relating to clinical practice, 20/44 items (45.5%) were selected. For the second part relating to translational research, 18/43 items (41.9%) were selected for the final set. Conclusions We herein propose a consensual set of analysis items to be used for synovial biopsies conducted in clinical practice and translational research.