Angiogenic gene expression and vascular density are reflected in ultrasonographic features of synovitis in early Rheumatoid Arthritis: an observational study.

INTRODUCTION: Neovascularization contributes to the development of sustained synovial inflammation in the early stages of Rheumatoid Arthritis. Ultrasound (US) provides an indirect method of assessing synovial blood flow and has been shown to correlate with clinical disease activity in patients with Rheumatoid Arthritis. This study examines the relationship of US determined synovitis with synovial vascularity, angiogenic/lymphangiogenic factors and cellular mediators of inflammation in a cohort of patients with early Rheumatoid Arthritis (RA) patients prior to therapeutic intervention with disease modifying therapy or corticosteroids. METHODS: An ultrasound guided synovial biopsy of the supra-patella pouch was performed in 12 patients with early RA prior to treatment. Clinical, US and biochemical assessments were undertaken prior to the procedure. Ultrasound images and histological samples were obtained from the supra-patella pouch. Histological samples were stained for Factor VIII and a-SMA (a-smooth muscle actin). Using digital imaging analysis a vascular area score was recorded. QT-PCR (quantitative-PCR) of samples provided quantification of angiogenic and lymphangiogenic gene expression and immunohistochemistry stained tissue was scored for macrophage, T cell and B cell infiltration using an existing semi-quantitative score. RESULTS: Power Doppler showed a good correlation with histological vascular area (Spearman r--0.73) and angiogenic factors such as vascular endothelial growth factor-A (VEGF-A), Angiopoietin 2 and Tie-2. In addition, lymphangiogenic factors such as VEGF-C and VEGF-R3 correlated well with US assessment of synovitis. A significant correlation was also found between power Doppler and synovial thickness, pro-inflammatory cytokines and sub-lining macrophage infiltrate. Within the supra-patella pouch there was no significant difference in US findings, gene expression or inflammatory cell infiltrate between any regions of synovium biopsied. CONCLUSION: Ultrasound assessment of synovial tissue faithfully reflects synovial vascularity. Both grey scale and power Doppler synovitis in early RA patients correlate with a pro-angiogenic and lymphangiogenic gene expression profile. In early RA both grey scale and power Doppler synovitis are associated with a pro-inflammatory cellular and cytokine profile providing considerable validity in its use as an objective assessment of synovial inflammation in clinical practice

Gout incidence and management during the COVID-19 pandemic in England, UK: a nationwide observational study using OpenSAFELY

BackgroundGout is the most prevalent inflammatory arthritis, yet one of the worst managed. Our objective was to assess how the COVID-19 pandemic impacted incidence and quality of care for people with gout in England, UK.MethodsWith the approval of National Health Service England, we did a population-level cohort study using primary care and hospital electronic health record data for 17·9 million adults registered with general practices using TPP health record software, via the OpenSAFELY platform. The study period was from March 1, 2015, to Feb 28, 2023. Individuals aged 18–110 years were defined as having incident gout if they were assigned index diagnostic codes for gout, were registered with TPP practices in England for at least 12 months before diagnosis, did not receive prescriptions for urate-lowering therapy more than 30 days before diagnosis, and had not been admitted to hospital or attended an emergency department for gout flares more than 30 days before diagnosis. Outcomes assessed were incidence and prevalence of people with recorded gout diagnoses, incidence of gout hospitalisations, initiation of urate-lowering therapy, and attainment of serum urate targets (≤360 μmol/L).FindingsFrom a reference population of 17 865 145 adults, 246 695 individuals were diagnosed with incident gout. The mean age of individuals with incident gout was 61·3 years (SD 16·2). 66 265 (26·9%) of 246 695 individuals were female, 180 430 (73·1%) were male, and 189 035 (90·9%) of 208 050 individuals with available ethnicity data were White. Incident gout diagnoses decreased by 30·9% in the year beginning March, 2020, compared with the preceding year (1·23 diagnoses vs 1·78 diagnoses per 1000 adults). Gout prevalence was 3·07% in 2015–16, and 3·21% in 2022–23. Gout hospitalisations decreased by 30·1% in the year commencing March, 2020, compared with the preceding year (9·6 admissions vs 13·7 admissions per 100 000 adults). Of 228 095 people with incident gout and available follow-up, 66 560 (29·2%) were prescribed urate-lowering therapy within 6 months. Of 65 305 individuals who initiated urate-lowering therapy with available follow-up, 16 790 (25·7%) attained a serum urate concentration of 360 μmol/L or less within 6 months of urate-lowering therapy initiation. In interrupted time-series analyses, urate-lowering therapy prescribing improved modestly during the pandemic, compared with pre-pandemic, whereas urate target attainment was similar.InterpretationUsing gout as an exemplar disease, we showed the complexity of how health care was impacted during the COVID-19 pandemic. We observed a reduction in gout diagnoses but no effect on treatment metrics. We showed how country-wide, routinely collected data can be used to map disease epidemiology and monitor care quality

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 r4ra randomized trial

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

Background Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. Methods STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)–European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). Findings Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47–2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). Interpretation In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response

Alessandro Pasqualini im Dienste Karls V. und des Fürstbischofs Georg von Österreich : Tirlemont, Lüttich, Dinant und Bouillon (1538-1548)

Objective: Magnetic resonance imaging (MRI) has been increasingly recognized as a critical tool for the assessment of patients with rheumatoid arthritis (RA) and is able to reliably identify synovitis, bone marrow edema, bone erosion, and joint space narrowing (JSN)/cartilage loss. Understanding the exact relationship between each MRI feature and local synovial pathobiology is critical to dissect disease pathogenesis as well as develop future predictive models. Methods: A systematic review was performed of the current published literature examining the relationship between MRI abnormalities and synovial pathobiology in patients with RA. Results: Eighteen studies were identified; most focused on validation of MRI as a tool to detect and quantify synovitis, with a significant relationship demonstrated. Additionally, from the limited data available, a critical role seems likely for synovial pathways, at least in driving joint damage. However, there was a lack of data examining the relationship between synovial pathobiology and bone marrow abnormalities and JSN. Conclusion: Although understanding the interrelationship of these disease biomarkers offers the potential to enhance the predictive validity of modern imaging with concomitant synovial pathobiological analysis, further studies integrating MRI with synovial tissue analysis in well-controlled cohorts at distinct disease stages before and after therapeutic intervention are required to achieve this

Treatment-resistant synovitis and radiographic progression are increased in elderly-onset rheumatoid arthritis patients : findings from a prospective observational longitudinal early arthritis cohort study

© 2020 Elsevier Inc. All rights reservedBackground: Clinical outcomes in elderly-onset rheumatoid arthritis (EORA), starting after the age of 60, are conflicting. Thus, we aimed to investigate in a unique biopsy-driven, treatment-naïve early arthritis cohort, the relationship between synovial pathobiology of elderly- (EORA) and younger-onset rheumatoid arthritis (YORA) patients through clinical, imaging and treatment response outcome-measures. Methods: Patients (n = 140) with early RA (<12months) starting before (YORA, n = 99) or after (EORA, n = 41) age 60 had an ultrasound-guided synovial biopsy prior to conventional immunosuppressive therapy and after 6 months. Clinical, ultrasound and radiographic data were collected prospectively and compared between groups and against immunohistological features. Using multivariate logistic regression, we determined predictors of clinical response (disease activity score-28-erythrocyte sedimentation rate [DAS28-ESR]<3.2) at 6 months and radiographic progression ( 1-unit-increase in Sharp van der Heijde [SvdH] score) at 12 months. Results: EORA patients were more frequently male and presented most commonly with an abrupt, polymyalgia rheumatica-like onset and extra-articular features. Both before and after treatment, DAS28-ESR was similar but ultrasound synovial-thickening (p<0.05) and power-Doppler (p<0.01) synovitis and SvdH (p<0.001) scores were higher in EORA patients. EORA was independently associated with poor treatment response at 6 months (OR=0.28, p = 0.047) and radiographic progression at 12 months (OR=4.08, p = 0.029). Synovial pathotype, synovitis scores and cellular infiltration were similar before treatment, but a pauci-immune-fibroid pathotype tended to be more common in YORA at 6 months (p = 0.093). Moreover, YORA patients had a marked improvement of all synovitis parameters (p<0.001), whereas EORA presented only mild decreases in synovitis (p<0.05), sublining macrophage (p<0.05) and T cell scores (p<0.05), with no significant changes in lining macrophages, B cells or plasma cells. Conclusion: Early EORA presents differently and has a worse overall prognosis than YORA, with poorer clinical, histological, ultrasonographic and radiographic outcomes.This work was supported by the Medical Research Council (grant number 36661, to PEAC); Arthritis Research UK (now Versus Arthritis; Experimental Arthritis Treatment Centre Grant, number 20022, to Centre for Experimental Medicine and Rheumatology); Fundação para a Ciência e Tecnologia (Interno Doutorando Bursary reference SFRH/SINTD/95030/2013, to VCR); European League Against Rheumatism (EULAR Scientific Training Bursary 2014, to VCR); and Sociedade Portuguesa de Reumatologia (Fundo de Apoio à Investigação da SPR 2015, to VCR).info:eu-repo/semantics/publishedVersio

Incidence and management of inflammatory arthritis in England before and during the COVID-19 pandemic: a population-level cohort study using OpenSAFELY.

BACKGROUND: The impact of the COVID-19 pandemic on the incidence and management of inflammatory arthritis is not understood. Routinely captured data in secure platforms, such as OpenSAFELY, offer unique opportunities to understand how care for patients with inflammatory arthritis was impacted upon by the pandemic. Our objective was to use OpenSAFELY to assess the effects of the pandemic on diagnostic incidence and care delivery for inflammatory arthritis in England and to replicate key metrics from the National Early Inflammatory Arthritis Audit. METHODS: In this population-level cohort study, we used primary care and hospital data for 17·7 million adults registered with general practices using TPP health record software, to explore the following outcomes between April 1, 2019, and March 31, 2022: (1) incidence of inflammatory arthritis diagnoses (rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and undifferentiated inflammatory arthritis) recorded in primary care; (2) time to first rheumatology assessment; (3) time to first prescription of a disease-modifying antirheumatic drug (DMARD) in primary care; and (4) choice of first DMARD. FINDINGS: Among 17 683 500 adults, there were 31 280 incident inflammatory arthritis diagnoses recorded between April 1, 2019, and March 31, 2022. The mean age of diagnosed patients was 55·4 years (SD 16·6), 18 615 (59·5%) were female, 12 665 (40·5%) were male, and 22 925 (88·3%) of 25 960 with available ethnicity data were White. New inflammatory arthritis diagnoses decreased by 20·3% in the year commencing April, 2020, relative to the preceding year (5·1 vs 6·4 diagnoses per 10 000 adults). The median time to first rheumatology assessment was shorter during the pandemic (18 days; IQR 8-35) than before (21 days; 9-41). The proportion of patients prescribed DMARDs in primary care was similar before and during the pandemic; however, during the pandemic, fewer people were prescribed methotrexate or leflunomide, and more were prescribed sulfasalazine or hydroxychloroquine. INTERPRETATION: Inflammatory arthritis diagnoses decreased markedly during the early phase of the pandemic. The impact on rheumatology assessment times and DMARD prescribing in primary care was less marked than might have been anticipated. This study demonstrates the feasibility of using routinely captured, near real-time data in the secure OpenSAFELY platform to benchmark care quality on a national scale, without the need for manual data collection. FUNDING: None

Evaluation of Minimally Invasive, Ultrasound-guided Synovial Biopsy Techniques by the OMERACT Filter - Determining Validation Requirements

OBJECTIVE: Because limited data currently support the clinical utility of peripherally expressed biomarkers in guiding treatment decisions for patients with rheumatoid arthritis, the search has turned to the disease tissue. The strategic aim of the Outcome Measures in Rheumatology (OMERACT) synovitis working group over the years has been to develop novel diagnostic and prognostic synovial biomarkers. A critical step in this process is to refine and validate minimally invasive, technically simple, robust techniques to sample synovial tissue, for use both in clinical trials and routine clinical practice. The objective of the synovitis working group (SWG) at OMERACT 12 (2014) was to examine whether recently developed ultrasound (US)-guided synovial biopsy techniques could be validated according to the OMERACT filter for future clinical use recommendation. METHODS: The SWG examined whether current data reporting US-guided synovial biopsy of both large and small joints addressed the OMERACT filters of truth, discrimination, and feasibility. RESULTS: There are currently limited data examining the performance of US-guided synovial biopsy, mainly from observational studies. Thus, it remains critical to evaluate its performance, within the clinical trials context, against the current gold standard of arthroscopic biopsy, with particular reference to: (1) synovial tissue yield, (2) capacity to determine treatment response as measured by a validated synovial biomarker, and (3) tolerability of the procedure. CONCLUSION: We summarize the discrete work packages agreed to as requirements to validate US-guided synovial biopsy and therefore lead to a global consensus on the use of synovial biopsy for research and clinical practice