Transcriptomic profiling of programmed cell death 1 (PD-1) expressing T cells in early rheumatoid arthritis identifies a decreased CD4 + PD-1 + signature post-treatment.

Programmed cell death protein 1 (PD-1)-expressing T cells are expanded in individuals with established rheumatoid arthritis (RA). However, little is known about their functional role in the pathogenesis of early RA. To address this, we investigated the transcriptomic profiles of circulating CD4 and CD8 PD-1 lymphocytes from patients with early RA (n = 5) using fluorescence activated cell sorting in conjunction with total RNA sequencing.

Differential expansion of T peripheral helper cells in early rheumatoid arthritis and osteoarthritis synovium.

Objectives: Programmed cell death protein 1 (PD-1)-expressing T cells are implicated in the pathogenesis of autoimmune inflammatory diseases such as rheumatoid arthritis. A subset of CXCR5 T cells, termed T peripheral helper (Tph) cells, which drive B cell differentiation, have been identified in ectopic lymphoid structures in established rheumatoid arthritis synovial tissue. Here, we aimed to characterise these in treatment-naïve, early rheumatoid arthritis to determine whether these cells accumulate prior to fully established disease.

Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resolution with synovial biopsy-guided therapy.

Background: Immune checkpoint inhibitors (ICIs) are associated with rheumatic and musculoskeletal immune-related adverse events (irAEs) in 5%-20% of patients. Currently, patients refractory to corticosteroids and conventional disease-modifying antirheumatic drugs (cDMARD) are treated with biological DMARDs (bDMARDs) targeting tumor necrosis factor α (TNFα) and interleukin-6, although without a clear biological rationale. Synovial tissue (ST) biopsy presents a valuable opportunity to investigate irAE pathogenesis and appropriately stratify bDMARD use in refractory irAE patients.

Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus.

Background: Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE.

Methods: RNA-sequencing analysis of synovial biopsies from various stages of RA disease progression, flow cytometry analysis of peripheral blood mononuclear cells (PBMC) from patients with RA or SLE and healthy donors, immunohistochemistry assessment (IHC) of synovial biopsies from patients with early RA, and ex vivo immune cell depletion assays using daratumumab (an anti-CD38 monoclonal antibody) were used to assess CD38 as a therapeutic target.

Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA.

Opposing effects of rheumatoid arthritis and low dose prednisolone on arginine metabolomics.

Background And Aims: The effects of low dose prednisolone on circulating markers of endothelial function, the arginine metabolites asymmetric dimethyl arginine (ADMA), mono methyl arginine (MMA), and homoarginine, are uncertain. We assessed whether patients with rheumatoid arthritis have perturbations in arginine metabolite concentrations that are reversed by low dose prednisolone.

Methods: Eighteen rheumatoid arthritis patients who had not taken prednisolone for >6 months (non-glucocorticoid (GC) users), 18 rheumatoid arthritis patients taking continuous oral prednisolone (6.

Triple DMARD treatment in early rheumatoid arthritis modulates synovial T cell activation and plasmablast/plasma cell differentiation pathways.

Objectives: This study sought to investigate the genome-wide transcriptional effects of a combination of disease modifying anti-rheumatic drugs (tDMARD; methotrexate, sulfasalazine and hydroxychloroquine) in synovial tissues obtained from early rheumatoid arthritis (RA) patients. While combination DMARD strategies have been investigated for clinical efficacy, very little data exists on the potential molecular mechanism of action. We hypothesized that tDMARD would impact multiple biological pathways, but the specific pathways were unknown.

Osteoclast-Associated Receptor (OSCAR) Distribution in the Synovial Tissues of Patients with Active RA and TNF-α and RANKL Regulation of Expression by Osteoclasts In Vitro.

Osteoclast-associated receptor (OSCAR) is a co-stimulatory receptor in osteoclastogenesis. Synovial tissues from active rheumatoid arthritis (RA) patients express higher levels of OSCAR compared with osteoarthritic and normal patients; however, the comparison of OSCAR levels in different regions of active RA synovium has not been reported. The regulation of OSCAR by TNF-α and receptor activator of NF kappa β ligand (RANKL) in pre-osteoclasts/osteoclasts in vitro is unclear.

CD40L-Dependent Pathway Is Active at Various Stages of Rheumatoid Arthritis Disease Progression.

The inflammatory CD40-CD40L pathway is implicated in various autoimmune diseases, but the activity status of this pathway in various stages of rheumatoid arthritis (RA) progression is unknown. In this study, we used gene signatures of CD40L stimulation derived from human immature dendritic cells and naive B cells to assess the expression of CD40-downstream genes in synovial tissues from anti-citrullinated protein Ab-positive arthralgia, undifferentiated arthritis (UA), early RA, and established RA cohorts in comparison with healthy donors. Interestingly, the expression of and active full-length was increased in the disease tissues, whereas that of a dominant-negative isoform was decreased.

A Treat-to-Target Strategy Preserves Work Capacity in a Rheumatoid Arthritis Inception Cohort Treated With Combination Conventional DMARD Therapy.

Objectives: Quantification of work disability in patients with early rheumatoid arthritis (RA) receiving conventional DMARDs according to a treat-to-target strategy.

Methods: This is a retrospective cohort analysis of RA patients who received combination conventional DMARDs, escalated to achieve DAS28(ESR) remission and completed an annual work and arthritis questionnaire. Random effect mixed modeling was used to assess associations between average hours worked per week (HWPW), and baseline prognostic factors.

Low dose prednisolone and insulin sensitivity differentially affect arterial stiffness and endothelial function: An open interventional and cross-sectional study.

Background And Aims: Glucocorticoids could impair vascular function directly, or indirectly by reducing insulin sensitivity. The aim of this study was to determine the direct and indirect effects of acute and chronic low dose prednisolone on arterial stiffness and endothelial function.

Methods: Twelve subjects with inflammatory arthritis, who had not taken oral glucocorticoids for ≥6 months, and 12 subjects with inflammatory arthritis, taking chronic (>6 months) low dose (6.

Arthroscopic guided synovial biopsy in rheumatology: current perspectives.

Synovial membrane (SM) pathology has provided valuable insights into our current understanding of immunopathological processes and treatment responses in the inflammatory arthritides. Amongst various methods of synovial biopsy, arthroscopic techniques remain the 'gold standard' owing to better sampling from sites of interest, particularly in patients with partially treated disease and from areas within joints that may be difficult to access using other techniques. Newer sophisticated techniques of SM membrane analyses allow assessment of differentially regulated pathways, the knowledge of which may help elucidate diagnostic and therapeutic targets in an attempt towards developing strategies for personalised medicine in the current era of targeted biologic therapies.

Active Foot Synovitis in Patients With Rheumatoid Arthritis: Unstable Remission Status, Radiographic Progression, and Worse Functional Outcomes in Patients With Foot Synovitis in Apparent Remission.

Objective: To determine whether foot synovitis is associated with adverse radiographic and functional outcomes after 3 years in an inception rheumatoid arthritis (RA) cohort receiving treat-to-target combination disease-modifying antirheumatic drug therapy.

Methods: Disease activity was assessed in early RA patients (n = 266) using the Disease Activity Score in 28 joints, Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI). Radiographic outcomes were assessed with annual hand and feet radiographs and quality of life with the Short Form 36 (SF-36).

Effects of prednisolone on energy and fat metabolism in patients with rheumatoid arthritis: tissue-specific insulin resistance with commonly used prednisolone doses.

Objective: Glucocorticoids can cause postprandial hyperglycaemia, but the effects on postprandial energy and fat metabolism are uncertain. We investigated the effects of acute and chronic low-dose prednisolone on fasting and postprandial energy expenditure and substrate metabolism.

Design: An open interventional and cross-sectional study was undertaken.

PTPN22 R620W minor allele is a genetic risk factor for giant cell arteritis.

Giant cell arteritis (GCA) is one of the commonest forms of vasculitis in the elderly, and may result in blindness and stroke. The pathogenesis of GCA is not understood, although environmental, infectious and genetic risk factors are implicated. One gene of interest is PTPN22, encoding lymphoid protein tyrosine phosphatase (Lyp), expressed exclusively in immune cells, which is proposed to be an 'archetypal non-HLA autoimmunity gene'.

Replication of association of the apolipoprotein A1-C3-A4 gene cluster with the risk of gout.

Objective: Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout.

Effect of acute and chronic glucocorticoid therapy on insulin sensitivity and postprandial vascular function.

Objective: Postprandial hyperglycaemia is associated with increased arterial stiffness and cardiovascular events. Low-dose prednisolone causes insulin resistance that typically manifests as postprandial hyperglycaemia. We investigated whether prednisolone causes postprandial vascular dysfunction in a cohort of patients with rheumatoid arthritis.

The X-Linked Inhibitor of Apoptosis Protein Inhibitor Embelin Suppresses Inflammation and Bone Erosion in Collagen Antibody Induced Arthritis Mice.

Objective: To investigate the effect of Embelin, an inhibitor of X-Linked Inhibitor of Apoptosis Protein (XIAP), on inflammation and bone erosion in a collagen antibody induced arthritis (CAIA) in mice.

Methods: Four groups of mice (n = 6 per group) were allocated: CAIA untreated mice, CAIA treated with Prednisolone (10 mg/kg/day), CAIA treated with low dose Embelin (30 mg/kg/day), and CAIA treated with high dose Embelin (50 mg/kg/day). Joint inflammation was evaluated using clinical paw score and histological assessments.

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.

Utility of arthroscopic guided synovial biopsy in understanding synovial tissue pathology in health and disease states.

The synovium is the soft tissue lining diarthrodial joints, tendon sheaths and bursae and is composed of intimal and subintimal layers. The intimal layer is composed of type A cells (macrophages) and type B cells (fibroblasts); in health, the subintima has few inflammatory cells. The synovium performs several homeostatic functions and is the primary target in several inflammatory arthritides.

Greater trochanteric pain syndrome: does imaging-identified pathology influence the outcome of interventions?

Aim: To assess the outcomes for patients seen in a rheumatology service presenting with features of the greater trochanteric pain syndrome (GTPS) and the impact of imaging results on the outcomes of treatment.

Methods: Retrospective audit, using a phone interview was performed to establish links between results of imaging undertaken in the diagnostic work-up of patients with lateral hip pain and clinical outcomes for these patients. Patient perceptions of the effectiveness of interventions were also assessed.

Effects of low-dose prednisolone on hepatic and peripheral insulin sensitivity, insulin secretion, and abdominal adiposity in patients with inflammatory rheumatologic disease.

Objective: The metabolic effects of low-dose prednisolone and optimal management of glucocorticoid-induced diabetes are poorly characterized. The aims were to investigate the acute effects of low-dose prednisolone on carbohydrate metabolism and whether long-term low-dose prednisolone administration increases visceral adiposity, amplifying metabolic perturbations.

Research Design And Methods: Subjects with inflammatory rheumatologic disease without diabetes mellitus were recruited.