NIHRDataInsights/HRCSData huggingface dataset:
Title: The Long-term Safety and Effectiveness of Biologic Therapies in Children with Rheumatic Diseases (BCRD)
Funder: Versus Arthritis

Abstract: Biologic therapies have significantly improved outcomes for children and young people (CYP) with severe juvenile idiopathic arthritis (JIA). However, their long-term effects remain understudied. A majority of data capture has focused on etanercept, the first biologic approved for JIA. Increasingly, other biologic drugs licensed only in adults are being used in CYP when etanercept may not be the best choice, such as in CYP with systemic arthritis or uveitis, or as subsequent biologic therapy following failure of etanercept. The response to these drugs and their long-term safety has not been well studied during routine clinical use. This study, launched in 2010, aims to prospectively recruit and follow a cohort of UK CYP receiving biologic agents other than etanercept to study their long-term effectiveness and safety. The rates of adverse events will be compared with a cohort of biologically-naive CYP starting methotrexate. In addition, a BioBank has been established, collecting biological samples from CYP receiving biologic therapies, in order that predictors of response, including genetics, can be studied.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Validating targets and defining clinical outcomes in enthesitis related arthritis
Funder: Versus Arthritis

Abstract: Enthesitis related arthritis (ERA) is a disease of late childhood and adolescence presenting with arthritis and enthesitis of the lower limb. Axial arthritis subsequently develops in around 60% of patients. Those patients often progress to a clinical phenotype that closely parallels adult-onset spondyloarthropathy. The pathogenesis and natural history of ERA has not been studied. Significant advances have improved understanding in the pathogenesis of adult-onset spondyloarthropathy leading to the identification of promising new treatment targets, including IL-23 and IL-17. It is unclear whether these discoveries will also apply in ERA, or certain sub-phenotypes within this group. This is important because almost all patients with ERA have arthritis that continues into adulthood and therefore require long-term treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: How do cytokines signalling through the transcription factors STAT1 and STAT3 determine the course of synovial inflammation?
Funder: Versus Arthritis

Abstract: Synovial histopathology in rheumatoid arthritis is highly diverse and complex. For example, tissue inflammation may display either a diffuse pattern of leukocyte infiltration or more organized structures arranged around lymphoid aggregates. Thus, various mechanisms must influence the clinical presentation of disease. We propose that cytokines (e.g., interferon-?, interleukin (IL)-6, IL-10, IL-21, IL-27) that signal via the latent transcription factors STAT1 and STAT3 contribute to the form of inflammation seen in rheumatoid patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Targeting c-Rel in systemic sclerosis-related fibrosis
Funder: Versus Arthritis

Abstract: Clinical Benefits: Systemic Scleroderma is a severe life threatening rheumatic disease in which progressive deposition of scar tissue affects the architecture and function of major organs including the skin, lungs, kidneys and heart. At present there is no clinically effective treatment that prevents or reverses fibrosis in scleroderma. A major reason for this lack of medicines is that we still understand relatively little about the mechanisms that drive the excessive deposition of extracellular matrix scar tissue in the affected tissues. Our lab specializes in studying mechanisms of fibrosis and has published key discoveries now laying the foundations for new drug discovery. With respect to the present application, we have discovered that a regulatory protein called c-Rel is required for fibrotic matrix deposition in the skin, heart and liver. We now wish to identify the cell type in which c-Rel plays this role and determine if inhibition of c-Rel will suppress fibrosis, this would inform future pre-clinical studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Exploring the links between intestinal inflammation and SpA
Funder: Versus Arthritis

Abstract: The pathophysiology and genetics of axial spondyloarthropathy (axSpA) are different from rheumatoid arthritis. Clinical, genetic and experimental evidence supports the hypothesis that intestinal inflammation contributes to axSpA pathogenesis in a significant proportion of patients. Data from animal models also indicate that intestinal inflammation drives systemic inflammation, leading to SpA-like disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the immune response to citrullinated antigen
Funder: Versus Arthritis

Abstract: RA aetiopathogenesis is incompletely understood. Individuals with a genetic pre-disposition develop disordered immunity that culminates in breach of self-tolerance and emergent clinical disease. Many identified genetic susceptibility loci associate with the pathways through which antigen presenting cells (APC) and T cells communicate. Ultimately, APC-T cell interactions determine T cell function, influence B cell help and class switching, and the subsequent generation of the anti-citrullinated peptide autoantibodies (ACPA) that are present in 70% of RA patients, and may be detectable prior to clinical disease onset. The MHC binding properties of citrullinated peptides have been investigated, and T cell responses to citrullinated residues identified in RA. However, factors regulating initiation and development of ACPAs remain poorly understood. Using a novel technique to study cellular interactions, we recently made the remarkable observation that citrullination of peptide may dramatically alter the nature, duration and consequence of the T cell-APC interaction. We thus hypothesise that presentation of citrullinated proteins generates an inappropriate immune response by altering the interaction between T cell and APC. Our goal is now to elucidate how T cells differentially respond to citrullinated forms of cognate antigen and determine the consequences of such altered T cell behavior for disease pathogenesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Mesenchymal Glucocorticoid Metabolism: Shaping Articular and Extra-articular Manifestations of Rheumatoid Arthritis via Wnt Mediated Pathways
Funder: Versus Arthritis

Abstract: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterised by synovitis, joint destruction, systemic osteoporosis and muscle wasting that affects 1-2% of the global population. I have demonstrated that the glucocorticoid activating enzyme 11ß-HSD1 is significantly up-regulated within mesenchymal derived cell populations in response to inflammation, where it increases anti-anabolic inhibitors of Wnt signalling. I hypothesise that in RA, increased 11ß-HSD1 in mesenchymal cell populations results in persistently elevated levels of endogenous glucocorticoids within joints, muscle and bone. This underpins destruction and wasting in these tissues via anti-anabolic Wnt pathways. Glucocorticoid and Wnt signalling pathways will be assessed in biopsies from joints, muscle and bone in RA patients and normal controls. Functional consequences of 11ß-HSD1 activity will be examined in primary mesenchymal derived cell populations isolated from them. The influence of 11ß-HSD1 on anti-anabolic Wnt signalling and articular/extra-articular manifestations of inflammation will be explored in vivo using mice models of inflammatory arthritis in mesenchymal 11ß-HSD1 null mice. A protective role for pharmaceutical inhibitors of 11ß-HSD1 will subsequently be explored in these models. This pre-clinical study aims to identify mechanisms, which underpin articular and extra-articular manifestations of RA, examining a role for 11ß-HSD1 inhibitors and Wnt modifying agents in their management.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Integrin-mediated regulation of leukocytes in autoimmunity
Funder: Versus Arthritis

Abstract: Leukocyte beta2 integrins perform both pro-inflammatory and immunomodulatory functions in the immune system by mediating cell-cell interactions and cellular migration. Indeed, the duration, frequency, and intensity of leukocyte interactions profoundly influence the nature of immune responses, but the detailed molecular mechanisms regulating these cellular interactions in vivo remain unclear. The key goal of my research is to examine the contributions of beta2 integrin family members to the fundamental functions of dendritic cells (DCs), and the subsequent impact on in vivo Rheumatoid Arthritis (RA). Specifically, I will measure the adhesive strengths of integrin alpha chain (CD11a/b/c/d) and beta2 (CD18) knockout DCs to ligands and to T cells, and visualise and quantify DC-T cell contact dynamics in vivo. Importantly, I aim to unravel the roles of these integrin alpha subunits in the modulation of DC signalling and activation. Using mouse models of RA I aim to dissect out the molecular mechanisms that govern beta2 integrin-mediated suppression of autoimmunity in vivo. My findings will advance our basic understanding of integrin function in leukocytes under homeostatic and inflammatory conditions. Only by fully understanding the diverse mechanisms of integrin functions can more specific integrin-targeted therapeutics be generated for the treatment of autoimmune disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Linking inflammation and autoimmunity in RA: fine specificity and functional characterization of anti-NET antibodies derived from single synovial B-cells
Funder: Versus Arthritis

Abstract: RA is characterised by breach of self-tolerance and production of anti-citrullinated peptide/protein antibodies (ACPA). Up to 50% of RA patients display synovial ectopic lymphoid structures (ELS) supporting functional B-cell follicles and local ACPA production. However, the nature of the main (auto)antigenic reactivity of synovial B-cells is unknown. Recently, I identified and patented (P102082GB) recombinant monoclonal antibodies derived from highly mutated, locally differentiated B-cells from RA ELS+ synovium that display high-frequency/strong immunoreactivity towards citrullinated histones (H2A/H2B) exposed during neutrophil-NETosis. Thus, synovial neutrophil-NET emerge as major antigenic force driving in-situ autoreactive B-cell activation/selection/differentiation within ELS sustaining local autoimmunity within RA joints. However, three main areas remains to be elucidated: 1) the antigenic epitopes of citrullinated histones exposed in NET that drives autoimmunity; 2) the functionality/pathogenicity of anti-NET antibodies in driving RA joint inflammation/autoimmunity and destruction; 3) the fine specificity of intra-synovial antibody autoimmune response at single patient level. Therefore, the key goal of my fellowship proposal is to address these three areas in three world-class laboratories that will deliver high-quality scientific training and original insights in RA pathogenesis. This may lead to developing novel diagnostic/prognostic tests in early RA and innovative therapeutic approaches encompassing vaccination/tolerogenic strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Safety and efficacy of BElimumab After B cell depleTion therapy in systemic LUPUS erythematosus - BEAT LUPUS
Funder: Versus Arthritis

Abstract: Biologic therapies for systemic lupus erythematosus (SLE) have shown promise but have yet to make a substantial impact. We and other investigators have pioneered B cell depletion therapy using rituximab for patients with SLE but randomised controlled trials have failed to prove efficacy. Our most recent biomarker data demonstrated that relapse following rituximab is associated with an increase in the B cell cytokine BAFF and rising anti-DNA antibodies (a biomarker of disease activity). We hypothesise that rising BAFF levels limit rituximab’s efficacy by precipitating flares and that this could be countered by the anti-BAFF therapeutic belimumab. We will randomise 50 lupus patients two months after BCDT to receive belimumab or placebo plus standard of care. This sequential strategy has not been tested before in lupus patients, nor reported in humans. Therefore we have designed a double-blind early phase clinical trial to assess the safety and effectiveness (change in anti-DNA antibodies) of belimumab after rituximab and generate blood-based immunologic biomarkers of clinical response to glean mechanistic insight. This pilot study will inform the design of a larger clinical trial to determine whether belimumab administered post rituximab can prevent flares from occurring more effectively than standard of care in patients with SLE.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Web-based physiotherapy for people with axial spondyloarthritis: a cohort study - WEB-PASS
Funder: Versus Arthritis

Abstract: Regular exercise is a core component of the long-term management of people with axial spondyloarthritis (axial SpA). However, delivering long term exercise programmes is unrealistic and unsustainable using traditional NHS services. We have developed web-based physiotherapy, a possible alternative service model to support people with axial SpA to exercise regularly however long term compliance to the programme (12 months) needs to be established. The aim of this prospective cohort study is to assess the feasibility, sustainability and acceptability of a 12 month individualised web-based physiotherapy programme in people with axial SpA. Forty people with established axial SpA, will receive 12 months of individualised, remotely monitored, web-based physiotherapy. The primary outcome will be compliance to the programme measured every four weeks. Secondary outcomes (baseline, 6 and 12 months) are function (BASFI), disease activity (BASDAI), spinal mobility (BASMI), quality of life (ASQoL), exercise capacity, health status (EQ5D), Work, Productivity and Activity Impairment (WPAI) and physical activity (activPAL activity monitor). The number of interactions with health care professionals and changes in medication will be documented. A subsample of the cohort will be interviewed at 6 and 12 months to gather participants’ views of the web-based physiotherapy programme and factors affecting compliance.


Research activity codes: 6.7 PHYSICAL
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: IFN-lambda: novel biologics for controlling neutrophil-mediated pathology in rheumatic diseases?
Funder: Versus Arthritis

Abstract: Neutrophils emerge as key immune cells in the initiation and perpetuation of immune responses in autoimmune diseases. They display marked abnormalities in phenotype and function in various autoimmune diseases, including systemic vasculitis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These neutrophils are characterised by an extended life span, increased capacity to produce reactive oxygen species, active gene expression and release of extracellular traps. Consequently, there is a need for better understanding of neutrophil phenotype and functions in these conditions, as well as for identifying molecules capable of specifically manipulating neutrophil function. We have recently discovered that IFN-?s, aka IL-28/29, class II cytokines with previously studied anti-viral biological functions, specifically suppress neutrophil infiltration and IL-1ß production and thereby, halt and reverse the development of collagen induced arthritis (CIA). We propose to further investigate the cellular and molecular mechanisms behind this suppression and examine the translational potential of our finding by examining the IFN-? receptor expression and function in neutrophils isolated from the blood of healthy donors and rheumatic patients (early RA and vasculitis).


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Ion channels underlying arthritic pain
Funder: Versus Arthritis

Abstract: In rheumatoid arthritis, joint sensory neurones are bathed in an acidic inflammatory soup, which excites sensory neurones and evokes pain. Many substances contained in the inflammatory soup also influence gene expression and sensitise neuronal responses to stimulation, e.g. innocuous stimuli can evoke pain. Noxious stimuli activate sensory neurones primarily by activating ion channels, but lack of joint sensory neurone characterisation means that it is currently unclear which ion channels mediate arthritic pain. We will use the complete Freund’s adjuvant-induced mouse arthritis model and conduct fluorescence-activated cell sorting to isolate joint sensory neurones labelled with retrograde tracers. We will conduct RNA-Seq of sorted neurones to measure changes in ion channel expression during arthritis, are specific ion channels upregulated? We will also use in vivo imaging to measure how joint pH and lactic acid levels change during arthritis. RNA-Seq and in vivo imaging results will guide subsequent electrophysiological examination of identified joint sensory neurone function. Finally, siRNA knock down of candidate ion channels and gait analysis will be conducted to measure their contribution to arthritic pain. We will thus interrogate joint sensory neurone function using multiple methods to identify ion channels that underlie arthritic pain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A transdermal micro needle delivery system for methotrexate treatment in paediatric rheumatic disease: Production and evaluation
Funder: Versus Arthritis

Abstract: Methotrexate is the only disease modifying drug used in the treatment of JIA, other than biologics. It is clinically effective with very good long term safety. However its oral absorbtion is variable, and nausea and vomiting frequent, resulting in discontinuation. Regular subcutaneous injections are painful and very stressful for children causing considerable anxiety.Our transdermal microneedle system is minimally-invasive, pain and blood free and should enable the controlled delivery of MTX.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the role of miRNAs in inflammatory arthritis
Funder: Versus Arthritis

Abstract: MicroRNAs (miRNAs) are genomically encoded small RNA molecules that are present in all multi-cellular organisms and are involved developmental and cellular processes through posttranscriptional regulation of target mRNA transcripts. In humans, over 2,500 miRNAs have been identified, and dysregulated expression of miRNAs has been reported in disease, including rheumatoid arthritis (RA). The consequences of dysregulated miRNA expression in RA pathogenesis remain to be mostly defined however. Our data show that CD14+ cells (monocytes and macrophages) from the RA joint have increased expression of miRNAs, including miR-155 and miR-210, compared to peripheral blood monocytes. We also have evidence that synovial CD14+ cells are potent drivers of pro-inflammatory T-cell responses, have an activated phenotype and are resistant to apoptosis. We hypothesise that miRNAs regulate monocyte/macrophage activation and survival resulting in enhanced T-helper cell polarization and inflammation. The key goals of this project are: (1) to investigate the individual and synergistic roles of miR-155 and miR-210 in monocyte/macrophage function, phenotype and survival; (2) to unravel the underlying molecular mechanism by studying key target genes of these miRNAs; and (3) to determine the regulation of these miRNAs in the context of inflammation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: IRF5 Activation and its contribution to inflammatory arthritis
Funder: Versus Arthritis

Abstract: Macrophages are critical cells for setting up inflammatory environment and development of rheumatoid arthritis. Our laboratory has recently discovered that the transcription factor IRF5 is a key regulator of the inflammatory macrophage phenotype both in vitro and in vivo. Given the importance of IRF5 function in physiology and disease, IRF5 represents a new target for therapeutic intervention. This project is set to understand how IRF5 activity is controlled in macrophages. One way of controlling IRF5 function is targeting the molecular events that lead to its activation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Activating people with inflammatory arthritis to engage in collaborative healthcare
Funder: Versus Arthritis

Abstract: Activation refers to patients’ ability and willingness to take on the role of managing their health and healthcare. The concept of activation focuses on skills and knowledge required to address the impact of disease; including unpredictable fluctuations in symptoms such as pain and fatigue, complex medications, and the associated emotional effects. Increased patient activation can lead to better self-management, which is a major focus of national healthcare policy and is recommended in rheumatology treatment guidelines. Patients able to self-manage their disease report better healthcare experiences and outcomes than patients with lower levels of activation. Evidence suggests that activation is amenable to intervention, but no research has been conducted to determine whether or how we can activate patients with inflammatory arthritis. This PhD will use mixed methods to achieve three goals:


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of galectin-1 in neutrophil recruitment and clearance in the arthritic joint.
Funder: Versus Arthritis

Abstract: The persistant recruitment of neutrophils to the arthritic joint and their prolonged survival within synovial fluid is a major factor in the pathogenesis of Rheumatoid arthritis. As such, agents that modulate either of these parameters are of potential therapeutic value. Galectin-1 is a glycan binding protein with a specific preference for the dissacharide N-acetyllactosamine. It has many recognised immune-regulatory and anti-inflammatory properties. We have shown that galectin-1 inhibits neutrophil recruitment and oedema formation in acute inflammation and it also possesses the ability to induce phosphatidylserine exposure, a well-recognised “eat-me” signal on the surface of neutrophils. With this studentship we will challenge the hypothesis that the anti-inflammatory properties of galectin-1 are mediated through its ability to inhibit neutrophil recruitment and potentiate neutrophil clearance. Effects on neutrophil recruitment will be studied in a murine model of Rheumatoid arthritis that is neutrophil-dependent whilst apoptosis and efferocytosis assays will be used to assess its effects on neutrophil clearance. In the final part of the project we will assess the impact of the arthritic response on the availability of glycans required for galectin-1 binding


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM