NIHRDataInsights/HRCSData huggingface dataset:
Title: Characterising the pro-resolution properties of immune complex-induced neutrophil apoptosis in rheumatoid arthritis
Funder: Versus Arthritis

Abstract: Neutrophils are key inflammatory effectors in rheumatoid arthritis (RA). Insoluble and soluble immune complexes (iICs and sICs) are abundant in synovial fluid. ICs are known to activate neutrophils to generate and extend inflammation. However, we recently reported that FcgammaR-PI3K-Cdc42-Pak-Mek-Erk signalling drives iIC induced neutrophil apoptosis; a process that is known to drive the resolution of inflammation. We observed also, that stimulation with iICs results in the uptake of the iICs by neutrophils. This suggests that neutrophils are involved in IC clearance, and that this in turn drives neutrophil apoptosis and the resolution of inflammation. The proposed work will characterise the molecular mechanism(s) that underpin these processes in unprimed and in inflammatory neutrophils, with the aim of identifying how to pharmacologically uncouple IC induced pro-inflammation and pro-resolution events. The project will moreover characterise which part(s) of this process are dysregulated in RA patients by systematically analysing patient neutrophils and patient derived ICs for their ability to undergo / induce IC-dependent neutrophil apoptosis. The proposed work will build the foundations to a potential therapeutic approach that takes advantage of IC-induced neutrophil apoptosis in an autoinflammatory condition that is characterised by abnormally high levels of ICs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Type 14 C-type lectins link endothelial cells and bone remodelling in inflammatory arthritis
Funder: Versus Arthritis

Abstract: Relevance: A key feature of arthritis is pathological bone destruction and new bone formation. The cumulative effects of this bone remodelling result in pain for patients and significant, often permanent, loss of function.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Using bioinformatics to link disease associations with epigenomic resources to uncover cell type specific rheumatoid arthritis risk
Funder: Versus Arthritis

Abstract: Although genome-wide association studies (GWAS) have been successful in identifying variants that increase the risk of disease, the translation of these findings to clinical benefit has proved more elusive. This is partially due to the, rather surprising, discovery that the vast majority of DNA changes associated with disease are found in ‘non-coding’ regions of the genome, often some distance from the nearest gene. These regions are therefore more likely to regulate gene expression which has been shown to vary across different cell types, stimuli and timepoints. Therefore, the next task to allow full utilisation of GWAS findings, is to determine how these non-coding regions increase the risk of disease. My projects key goals are to link GWAS findings in rheumatoid arthritis (RA) to the genes they regulate, the cell types where this regulation takes place and the mechanisms by which different genetic backgrounds increases the risk of disease. I am in a strong position to achieve this, given my skills, background in bioinformatics and the enormous wealth of data now available, both publicly in general cell types, and more specifically in cell types and conditions pertinent to RA, (e.g. patient T cells, fibroblasts, cartilage) which have been generated within the group. I will utilise both public and in-house generated epigenomic data (e.g. Hi-C, ChIP and ATAC-Seq), showing how regulatory regions of DNA are active in different cell types and conditions, link this to DNA interaction data, providing a physical indication of the genes that are regulated, and expression data to score enhancers for every RA region in each cell type. Overlaying our GWAS variants onto this model will provide the next, crucial step in assigning genetic risk of disease to genes, cell type and mechanism.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Balance between T follicular helper and T follicular regulatory cells in controlling ectopic germinal centre responses and response to B cell depletion in primary Sjogren’s syndrome
Funder: Versus Arthritis

Abstract: The formation of ectopic lymphoid structures (ELS) in the salivary glands of Sjögren’s syndrome (SS) with the development of functional germinal centres (GC) contribute to the perpetuation of autoimmunity and the evolution towards MALT lymphoma. Additionally, the persistence and disruption of ELS in the salivary glands following B cell depletion has been linked with resistance or response to Rituximab in small clinical studies. Follicular T-helper cells (Tfh) and follicular T regulatory cells (Tfr) are specialized CD4+ T-cells, which positively and negatively regulate, respectively, the magnitude of the GC response and the onset of autoimmunity in animal models, but their role in SS has not been investigated as yet. In preliminary work I have demonstrated a significant increase of infiltrating Tfh and Tfr in the ELS+ subset of SS patients. However, while Tfh localise within the ectopic GC a process of follicular exclusion seems to prevent Tfr from exerting their inhibitory role in controlling the GC response. Additionally, by analysing peripheral blood T cells in a small subset of ELS+ vs ELS- patients, I provided the preliminary observation that circulating Tfh are enriched in the ELS+ subset and may represent a surrogate biomarker of ectopic GC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Centre for Genetics and Genomics
Funder: Versus Arthritis

Abstract: We have established a Centre of Excellence in Genetics and Genomics of arthritic diseases with an international reputation for research identifying genetic markers of susceptibility to and outcomes of inflammatory arthritis and for training researchers of the future. We now plan to exploit that knowledge with two major programmes of research. In Translational Genetics we will translate the findings from susceptibility and outcome studies to prevent disease and it’s complications, predict treatment response and personalise treatment to the individual. In Functional Genomics, we will advance a programme of discovery science aimed at understanding exactly how genetic variants associated with inflammatory arthritis alter gene, protein and cellular function to cause dysregulation of the immune system; we believe that such a mechanistic understanding of arthritis causation is vital if we are ever to cure or prevent arthritis. By developing a pipeline to facilitate the interpretation of genome wide association studies, the impact of this programme, to inform patient stratification and personalised medicine and identify novel therapeutic targets, will reach beyond arthritis to other complex diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A randomised controlled trial of job retention vocational rehabilitation for employed people with inflammatory arthritis: the WORKWELL trial.
Funder: Versus Arthritis

Abstract: Background: Inflammatory arthritis (IA) causes work disability, absenteeism (sick leave) and presenteeism (reduced productivity) at high cost to individuals, employers and society. A trial of job retention vocational rehabilitation (VR) amongst people with IA in the US showed that VR reduced work disability. However, it is unknown whether this approach transfers to the UK with a different social and welfare structure. Previously, we modified the VR for the UK, funded by Arthritis Research UK (the WORKWELL programme) and demonstrated it to be deliverable and acceptable in a feasibility trial. Our aim now is to move to the definitive UK trial testing the effectiveness and cost-effectiveness of WORKWELL.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.7 PHYSICAL;7.1 INDIVIDUAL CARE NEEDS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Evaluating macrophage metabolism as a therapeutic target in immune complex- mediated autoimmune diseases
Funder: Versus Arthritis

Abstract: Background: IgG antibodies play an important role in defence against infection, but can also cause inflammation and organ damage in autoimmune diseases, for example, in lupus nephritis. Current treatments in systemic lupus erythematosus (SLE) and other autoantibody-mediated diseases do not adequately control disease activity and are associated with significant side-effects. Fcgamma receptors (Fc?Rs) mediate the cellular effector functions of IgG, and polymorphisms in the FCGR genes are associated with increased susceptibility to SLE, RA, and vasculitis. Macrophages are tissue-resident immune cells that express Fc?Rs and respond to local IgG immune complexes (IC) by producing pro-inflammatory mediators. We sought to investigate how macrophage metabolism changed following Fc?R cross-linking, and if this might inform therapeutic strategies in antibody-mediated autoimmunity. We found that macrophages undergo a switch to glycolysis in response to IgG IC stimulation. This metabolic reprogramming was required to generate pro-inflammatory cytokines, including IL1ß. Fc?R-associated glycolysis was dependent on hypoxia-inducible factor (HIF)1a.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Joint enterprise: the collaboration of synovial fibroblasts and macrophages to sustain inflammation
Funder: Versus Arthritis

Abstract: A fundamental feature of RA pathogenesis is hyperplasia of the synovial membrane and the formation of pannus, an aggressive and invasive tissue that progressively degrades both cartilage and bone, resulting in pain, loss of joint integrity and function. In order to better understand the pathogenesis of RA, many research groups have focused exclusively on the study of either synovial fibroblasts or synovial macrophages. In the new field of immunometabolism, exciting discoveries have been made concerning metabolic changes that occur in activated pro-inflammatory macrophages, or in synovial fibroblasts of the inflamed joint. The problem is that these studies tend to treat macrophages or fibroblasts as if they exist in isolation. In reality, the inflamed joint is a complex ecosystem, in which there is competition for nutrients and exchange of metabolites, both of which can profoundly influence cellular behaviour. These aspects of metabolic communication between cells are absent from models that investigate one cell type or the other in isolation. We have made a number of recent discoveries, collectively suggesting that communication between synovial macrophages and fibroblasts at the level of metabolism contributes to the establishment of chronic inflammation and the destructive properties of the pannus. In order to further investigate these mechanisms, we have assembled a unique team combining expertise in macrophage biology (Clark and Kurowska-Stolarska), expertise in synovial fibroblast biology (Buckley and Filer) and expertise in metabolism (Tennant, Falconer, Young).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Mapping physiology to function: an experimental medicine study of autologous tolerogenic dendritic cell therapy for rheumatoid arthritis, with a focus on route of delivery (AuToDeCRA 2)
Funder: Versus Arthritis

Abstract: Background. We are developing a treatment to reset immune tolerance in patients with rheumatoid arthritis (RA). We recently completed a phase 1 study of autologous tolerogenic dendritic cells (tolDC), manufactured from peripheral blood monocytes (AuToDeCRA). AuToDeCRA was designed to provide a robust safety signal: tolDC were loaded with autologous synovial fluid as a source of autoantigen and injected directly into an inflamed joint.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Identification of immune cell types predicting response to treatment with biologics in rheumatoid arthritis
Funder: Versus Arthritis

Abstract: Background: Pathogenic immune cell types and functions have not been identified yet in rheumatoid arthritis (RA). This is explained by the limited number of immune markers tested so far and by the fact that disease heterogeneity decreases study power – different immune cell types might be involved in the pathogenesis of different RA endotypes. Our lack of understanding of RA pathophysiology results in a trial and error in the prescription of biologic drugs with 30% of patients failing to respond to the first drug prescribed. This approach leads to prolonged inflammation and decreased quality of life for many patients. It is currently not possible to predict which patient will respond to which treatment.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The RA Standard Study: Reducing Variation in Early Arthritis Care
Funder: Versus Arthritis

Abstract: Inflammatory arthritis, of which rheumatoid arthritis (RA) is the commonest form, is an incurable condition with significant morbidity and mortality. It accounts for £660 million a year in direct healthcare costs. Research has shown that early treatment reduces severity of the disease, and increases the likelihood of drug free remission. This is reflected in the seven quality statements that have been published by NICE for newly diagnosed RA.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding the long-term outcomes of PMR: Long-term Follow-up of the PMR Cohort Study
Funder: Versus Arthritis

Abstract: Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatological condition of older people. Symptoms include pain and stiffness in the hip and shoulder girdles, with significant impact reported on daily activities, work and quality of life. Most patients are diagnosed and managed exclusively in primary care. The mainstay of treatment is oral glucocorticoids, with guidelines suggesting that treatment is often required for around 2 years. However, our in-depth work with patient groups (including the charity PMRGCAuk) and general practitioners suggests that this is not always the case. Medical record studies confirm that 34% of PMR patients are treated with glucocorticoids for more than 2 years, and many people experience periods of flare and relapse beyond this time period. This is of concern not only because of impact on patients’ lives but also because of the potential adverse effects related to prolonged glucocorticoid treatment. To date there is limited data on the long-term outcomes of PMR and we are not yet able to predict which patients are likely to have a prolonged course or experience adverse treatment effects.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Utilizing the epoxygenase pathway to promote tolerogenic dendritic cell maturation and function in man
Funder: Versus Arthritis

Abstract: Leukocytes are implicated in the aetiology of rheumatoid arthritis (RA) with myeloid cells being either pathogenic or protective. The transition of immunogenic to tolerogenic dendritic cells (DCs) is one key determinant in the development of protective cell types with pro-resolution pathways, shown by us, to play a role in this process (Blood, 2014). Therefore, strategies that promote resolution and the development of tolerogenic DCs are potential therapeutic avenues to treat RA. The CYP450 epoxygenase-soluble epoxide hydrolase pathway is protective in models of inflammatory disease. Our recent publication (PNAS, 2016) showed, for the first time, a critical role for epoxygenase products in the regulation of innate immunity and inflammatory resolution in mice. Epoxygenase products in particular regulate the recruitment and activity of cells of the monocyte/ macrophage lineage including dendritic cells. The recruited cells where endogenous epoxygenases were inhibited were highly pro-inflammatory and poorly phagocytic resembling the phenotype observed in RA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Delineating the immunological links between periodontitis and RA
Funder: Versus Arthritis

Abstract: Since the start of the last century links between periodontitis and rheumatoid arthritis (RA) pathology have been proposed. Yet most research examining how periodontitis contributes to RA pathogenesis has focused on the roles of periodontal pathogens, with little insight into how immune cells activated in periodontitis could drive inflammation in RA. This is surprising given that the same immune mediators are key drivers of pathology in both diseases. In particular Th17-cells, CD4+ T-cells producing IL-17, are crucial mediators of disease in both RA and periodontitis. In this research proposal we will test the hypothesis that generation of Th17-cells during periodontitis contributes to joint pathology in settings of RA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Harnessing the anti-inflammatory properties of neutrophil-derived microvesicles
Funder: Versus Arthritis

Abstract: Cartilage erosion is a key feature of rheumatoid arthritis occurring as a result of the pro-inflammatory milieu generated by cells such as macrophages and fibroblast-like synoviocytes in the invading pannus. Current therapies target key pro-inflammatory mechanisms but there is a paucity of drugs targeting cartilage erosion. Microvesicles are small “packages” of information released by all cells and they are believed to be a mechanism of intercellular communication delivering proteins, lipids and nucleic acids from the parent cell to a recipient cell. We have shown that neutrophil-derived microvesicles can penetrate cartilage matrix and that their contents are taken up by chondrocytes resulting in increased matrix accumulation and reduced cytokine production. With this studentship we will investigate how microvesicles enter cartilage and exert these protective effects. Endogenous generation of microvesicles in arthritic mice will also be characterised from both synovial fluid and plasma. We seek to exploit these vesicles as potential therapeutic vectors paving the way to creating a totally new cell-based therapy for the treatment of cartilage erosion in joint disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Abnormal iron metabolism and mitochondrial dysfunction: investigating a novel mechanism for the pathogenesis of fatigue in systemic lupus erythematosus
Funder: Versus Arthritis

Abstract: There have been significant recent advances in the treatment of systemic lupus erythematosus (SLE) yet patients often describe high levels of debilitating fatigue, which has severely detrimental effects on quality of life. This symptom is difficult to manage with no reliable evidence-based treatments available. Recent studies have found links between fatigue and altered iron homeostasis in a number of chronic conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The Development of a Continuous and Remote Disease Activity Monitoring System in Inflammatory Myopathies to Improve Management and Treatment
Funder: Versus Arthritis

Abstract: Purpose The idiopathic inflammatory myopathies (IIMs) are a group of diseases characterised by muscle inflammation. Clinical decision making is limited by the inability to remotely and continuously measure disease activity. Previous studies have developed smartphone-based apps for patient reported outcome measurement (PROM) entry ("PROM apps"). The muscles of the thighs that allow hip flexion are particularly affected in the IIMs, resulting in predictable changes of gait. Accelerometers incorporated into user-friendly devices can remotely measure gait patterns. Changes of PROMs and gait patterns follow IIM disease activity. Aim This study aims to develop, test and evaluate a novel system that can continuously and remotely measure a patient’s IIM disease activity through daily submission of PROMs and continuous assessment of gait pattern. Study design Stage 1: An IIM patient participant group will inform changes to the initial design and capability of an already designed PROM app template and the proposed use of an accelerometer "patch" system. Stage 2: The system will be trialled in 30-40 participants with an IIM over a 90 day period. Each day participants will be requested to complete a panel of PROMs through the developed PROM app. Participants will also continuously wear an accelerometer patch on the lateral aspect of their thigh for continuous collection of gait data. Stage 3: Analysis will employ machine learning techniques to identify PROM and gait variables associated with changes in disease activity. A novel “disease activity score” algorithm will be developed, which will allow IIM disease activity to be measured (through daily PROM submission and gait pattern analysis) for clinical purposes. Stage 4: The clinical utility of the novel system will be explored through focus groups with IIM-specialist clinicians. Application Patient care will be improved through the ability to remotely identify worsening IIM disease activity, thus preventing irreversible muscle damage and disability.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Elucidating the clinical phenotype of sero-negative rheumatoid arthritis through synovial pathobiology and advanced classification modelling
Funder: Versus Arthritis

Abstract: The prognosis and selection of appropriate therapy for patients with ACPA-ve RA remains a significant unmet need. Patients are frequently left with an uncertain prognosis and a variable treatment plan. Increasing evidence suggests that ACPA-ve RA is a disease distinct from ACPA+ve RA although its pathophysiological relationship to other sero negative inflammatory arthritidies such as PsA or SpA at disease onset remains largely unknown. Preliminary data from the pathobiology of early arthritis cohort (PEAC) http://www.peac-mrc.mds.qmul.ac.uk/ indicates that the clinical outcome and therapeutic response of RA can be defined through synovial pathobiological signatures. However, to date there has been limited examination of the synovial pathobiology in refining diagnostic subgroups within the ACPA-ve cohort (through for example a comparative analysis with ACPA+ve RA, PsA and SpA) and/or in defining outcome and/or response to therapy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM