Temporal and regional variation in the use of biologic and targeted synthetic DMARDs for rheumatoid arthritis: a nationwide cohort study.

Objective: To evaluate temporal and regional variation in biologic and targeted synthetic DMARD (b/tsDMARD) initiation for rheumatoid arthritis (RA) in England and Wales.

Methods: An observational cohort study was conducted for people with RA enrolled in the National Early Inflammatory Arthritis Audit (NEIAA) between May 2018 and April 2022 who had 12-month follow-up data. Temporal trends in escalation to b/tsDMARDs within 12 months of initial rheumatology assessment were explored, including comparisons before and after publication (July 2021) of national guidelines that lowered the threshold for b/tsDMARD initiation to include moderate-severity RA.

Therapeutic interception in individuals at risk of rheumatoid arthritis to prevent clinically impactful disease.

Multiple clinical trials for rheumatoid arthritis (RA) prevention have been completed. Here, we set out to report on the lessons learnt from these studies. Researchers who conducted RA prevention trials shared the background, rationale, approach and outcomes and evaluated the lessons learnt to inform the next generation of RA prevention trials.

Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial.

Background: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept.

Methods: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands.

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

Background: Gout 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.

Methods: With 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.

Efficacy and safety of baricitinib or ravulizumab in adult patients with severe COVID-19 (TACTIC-R): a randomised, parallel-arm, open-label, phase 4 trial.

Background: From early in the COVID-19 pandemic, evidence suggested a role for cytokine dysregulation and complement activation in severe disease. In the TACTIC-R trial, we evaluated the efficacy and safety of baricitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2, and ravulizumab, a monoclonal inhibitor of complement C5 activation, as an adjunct to standard of care for the treatment of adult patients hospitalised with COVID-19.

Methods: TACTIC-R was a phase 4, randomised, parallel-arm, open-label platform trial that was undertaken in the UK with urgent public health designation to assess the potential of repurposing immunosuppressants for the treatment of severe COVID-19, stratified by a risk score.

Implementing treat-to-target urate-lowering therapy during hospitalizations for gout flares.

Objectives: To evaluate a strategy designed to optimize care and increase uptake of urate-lowering therapy (ULT) during hospitalizations for gout flares.

Methods: We conducted a prospective cohort study to evaluate a strategy that combined optimal in-hospital gout management with a nurse-led, follow-up appointment, followed by handover to primary care. Outcomes, including ULT initiation, urate target attainment and re-hospitalization rates, were compared between patients hospitalized for flares in the 12 months post-implementation and a retrospective cohort of hospitalized patients from 12 months pre-implementation.

Extracellular matrix rigidity modulates physical properties of subcapsular sinus macrophage-B cell immune synapses.

Subcapsular sinus macrophages (SSMs) play a key role in immune defense by forming immunological barriers that control the transport of antigens from lymph into lymph node follicles. SSMs participate in antibody responses by presenting antigens directly to naive B cells and by supplying antigens to follicular dendritic cells to propagate germinal center reactions. Despite the prominent roles that SSMs play during immune responses, little is known about their cell biology because they are technically challenging to isolate and study in vitro.

Rheumatoid arthritis prevention in arthralgia: fantasy or reality?

The concept of a 'window of opportunity' in treating a disease assumes the existence of a time frame during which the trajectory of the disease can be effectively and permanently modified. In rheumatoid arthritis (RA), optimal timing of this period is presumed to be during the phase before arthritis is clinically apparent and disease is diagnosed. Several proof-of-concept trials of treatment during the 'arthralgia' phase of RA have been completed in the past 4 years, with the underlying notion that temporary treatment at this stage could prevent the development of RA or induce a sustained reduction in the burden of disease.

JAK inhibitors and the risk of malignancy: a meta-analysis across disease indications.

Objectives: To estimate the association of Janus kinase inhibitors (JAKi) with the incidence of malignancy, compared with placebo, tumour necrosis factor (TNF)-α inhibitors (TNFi) and methotrexate.

Methods: Systematic searches of databases were performed, to December 2022, to identify phase II/III/IV randomised clinical trials (RCTs) and long-term extension (LTE) studies of JAKi (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib) compared with placebo, TNFi or methotrexate, in adults with rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease or atopic dermatitis. Network and pairwise meta-analyses were performed to estimate incidence rate ratios (IRRs) for malignancy between JAKi and comparators.

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.

Treat-to-target urate-lowering therapy and hospitalizations for gout: results from a nationwide cohort study in England.

Objective: To investigate associations between treat-to-target urate-lowering therapy (ULT) and hospitalizations for gout.

Methods: Using linked Clinical Practice Research Datalink and NHS Digital Hospital Episode Statistics data, we described the incidence and timing of hospitalizations for flares in people with index gout diagnoses in England from 2004-2020. Using Cox proportional hazards and propensity models, we investigated associations between ULT initiation, serum urate target attainment, colchicine prophylaxis, and the risk of hospitalizations for gout.

Management of gout following 2016/2017 European (EULAR) and British (BSR) guidelines: An interrupted time-series analysis in the United Kingdom.

Background: Following studies reporting sub-optimal gout management, European (EULAR) and British (BSR) guidelines were updated to encourage the prescription of urate-lowering therapy (ULT) with a treat-to-target approach. We investigated whether ULT initiation and urate target attainment has improved following publication of these guidelines, and assessed predictors of these outcomes.

Methods: We used the Clinical Practice Research Datalink to assess attainment of the following outcomes in people ( = 129,972) with index gout diagnoses in the UK from 2004-2020: i) initiation of ULT; ii) serum urate ≤360 µmol/L and ≤300 µmol/L; iii) treat-to-target urate monitoring.

Humoral and cellular immunogenicity to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: a longitudinal cohort study.

Background: COVID-19 vaccines have robust immunogenicity in the general population. However, data for individuals with immune-mediated inflammatory diseases who are taking immunosuppressants remains scarce. Our previously published cohort study showed that methotrexate, but not targeted biologics, impaired functional humoral immunity to a single dose of COVID-19 vaccine BNT162b2 (Pfizer-BioNTech), whereas cellular responses were similar.

The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual "window of treatment success" in RA patients.

Background: There is a need for biomarker to identify patients "at risk" for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers.

Methods: Using protein macroarray and ELISA, epitope recognition against hnRNP-DL was analysed in sera from different developed RA disease and diagnosed SLE patients. Toll-like receptor (TLR) 7/9 and myeloid differentiation primary response gene 88 (MyD88)-dependency were studied in sera from murine disease models.

EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis.

Background: Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA).

Methods: An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements.

LFA-1 in T cell priming, differentiation, and effector functions.

The integrin LFA-1 is crucial for T cell entry into mammalian lymph nodes and tissues, and for promoting interactions with antigen-presenting cells (APCs). However, it is increasingly evident that LFA-1 has additional key roles beyond the mere support of adhesion between T cells, the endothelium, and/or APCs. These include roles in homotypic T cell-T cell (T-T) communication, the induction of intracellular complement activity underlying Th1 effector cell polarization, and the support of long-lasting T cell memory.

The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study.

Background: Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose.

A systematic review and network meta-analysis of the safety of early interventional treatments in rheumatoid arthritis.

Objectives: To evaluate the safety of treatment strategies in patients with early RA.

Methods: Systematic searches of MEDLINE, EMBASE and PubMed were conducted up to September 2020. Double-blind randomized controlled trials (RCTs) of licensed treatments conducted on completely naïve or MTX-naïve RA patients were included.

Endothelin antagonism and sodium glucose Co-transporter 2 inhibition. A potential combination therapeutic strategy for COVID-19.

The novel coronavirus 2019 (COVID-19) infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global pandemic that requires a multi-faceted approach to tackle this unprecedent health crisis. Therapeutics to treat COVID-19 are an integral part of any such management strategy and there is a substantial unmet need for treatments for individuals most at risk of severe disease. This perspective review provides rationale of a combined therapeutic regimen of selective endothelin-A (ET-A) receptor antagonism and sodium glucose co-transporter-2 (SGLT-2) inhibition to treat COVID-19.