NIHRDataInsights/HRCSData huggingface dataset:
Title: A systematic and qualitative review of the extent to which arthritis patient education interventions are accessible and relevant for people with lower-literacy levels.
Funder: Arthritis Research UK

Abstract: Effective and appropriate patient education is a key component in the care and management of arthritis. Currently, many patient education materials require literacy levels that are too high to be easily understood and acted upon by many patients. _x000D_ _x000D_ The goals of this proposal are to:_x000D_ _x000D_ _x000D_ Undertake a systematic review of research into the effectiveness of written, non-written and electronic health information, for patients with lower-literacy skills, with particular reference to arthritis patient education_x000D_ Carry out a review of qualitative research literature exploring the views of patients with lower literacy levels about written, non-written and electronic health information, using a specific approach known as ‘qualitative evidence synthesis’_x000D_ Explore the information needs, preferences and understandings about communication and management of arthritic conditions with lower-literacy patients with inflammatory arthritis, and with health professionals using a linguistic model.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The Educational Needs of Carers of People with Rheumatoid Arthritis (RA)
Funder: Arthritis Research UK

Abstract: A diagnosis of rheumatoid arthritis not only affects the patient, but can also have significant health, social, economic, and emotional impact on those around them. The limited research carried out regarding the experiences of informal carers consistently highlights their need for information and support which is different, and sometimes greater than for patients themselves. However, it may be difficult for them to obtain this, because at present information provision and education is directed primarily towards the patient. This multi-method, longitudinal qualitative research project aims to achieve a greater understanding of the educational needs of carers of people with RA, focusing on carers’ experiences of the educational resources which are currently available and the differences between the needs of patients and their carers. We are looking to highlight those areas where current provision does not meet carers’ needs, and suggest optimum methods to meet them.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: How should we educate young people to help them make decisions about biologic therapies?
Funder: Arthritis Research UK

Abstract: Young people, aged between 16 and 25, with a spectrum of inflammatory arthritis can have severe disease warranting biologic therapies. This comes at a time when they are undergoing a process of physical, cognitive, psychosocial, educational and vocational development and learning to take on more responsibility for their health care. It is important to understand the challenges they face when making such decisions, the developmentally appropriate resources and support they need to make an informed decision and how best these can be delivered. _x000D_ _x000D_ This multi-method qualitative research project aims to explore their educational needs. Through interviews, audio-recording consultations and focus group, we focus on the experiences of young people alongside parents/carers, partners, peers and health professionals. We will develop a robust conceptual model of the young peoples’ decision-making about biologic therapies.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Genetically determined ubiquitination in autoimmunity
Funder: Arthritis Research UK

Abstract: Ubiquitination critically controls cellular functions by targeting proteins for proteasomal degradation. Strong genetic evidence links the ubiquitin-conjugating enzyme UBE2L3 with systemic lupus erythematosus (SLE). Preliminary data suggests the risk allele increases UBE2L3 expression. Yeast two-hybrid studies have identified the E3 ligase binding partners of UBE2L3, of which c-Cbl and TRAF6 appear most likely to be implicated in autoimmunity: c-Cbl inhibits phagocytosis by downregulating Fcgamma receptors, thought to cause SLE through defective clearance of immune complexes. TRAF6 is a critical adaptor for endosomal TLR signals, activating NF-kB and IRF-5 leading to type I interferon responses, characteristic of SLE. My aims include fine-mapping the UBE2L3 gene, looking for novel variants by re-sequencing and/or mutants affecting the coding region, and examine whether UBE2L3 genotype correlates with transcript levels and splicing variant stability. UBE2L3 is predominantly expressed in monocytes and lymphocytes, so I will determine the relationship between UBE2L3 genotype and protein expression in these cells, isolated from SLE patients and healthy controls. I will also use these cells to examine whether UBE2L3 affects monocyte phagocytosis through c-Cbl, and is correlated with Fcgamma receptor downregulation. I will also investigate the effect of UBE2L3 genotype on IFN-alpha expression via the TRAF6 pathway.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Is elevated central sympathetic nerve activity a pathogenic feature of rheumatoid arthritis?
Funder: Arthritis Research UK

Abstract: Rheumatoid Arthritis (RA) is a chronic, systemic inflammatory disorder which particularly affects synovial joints, but can also affect many other tissues and organs. Alarmingly, cardiovascular disease accounts for ~50% of the mortality in RA patients; however the underlying pathophysiological mechanisms remain incompletely understood. One potentially important factor is an over-activity of the sympathetic nervous system. Recent animal studies have demonstrated that elevations in central and blood-borne levels of pro-inflammatory cytokines can induce profound elevations in sympathetic nerve activity (SNA) and blood pressure, while many of the established pathological consequences of chronic elevations in SNA are prevalent in RA patients (e.g. hypertension, cardiac arrhythmias). In addition, high levels of SNA are known to be pro-inflammatory which could exacerbate RA disease severity. We wish to determine whether the chronic activation of pro-inflammatory cytokines in humans elicits pathogenic increases in SNA, by making the first direct intra-neural recordings of SNA in RA patients both before and after potent anti-inflammatory therapy (i.e. Tumour Necrosis Factor – TNFα inhibition). These studies may provide important new mechanistic insights into the pathophysiology of RA, and instigate the development of new strategies to reduce both cardiovascular risk and disease severity in RA patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of the Integrated Stress Response in joint inflammation
Funder: Arthritis Research UK

Abstract: IL-23 promotes the expansion of Th17 cells during antibacterial immune responses and is emerging as a key player in the pathogenesis of inflammatory diseases including arthritis. I have recently shown that the expression of IL-23 by dendritic cells is dependent on the activation of cellular stress pathways in addition to signals provided by pattern-recognition receptors (PRRs) or bacterial infection. I have identified that the stress induced transcription factor, CHOP, is a crucial factor that regulates IL-23 expression, and that PRR are able to induce CHOP. The primary aim of my fellowship is to determine whether CHOP, and molecules downstream of CHOP, play a crucial role in animal models of arthritis. Furthermore, I will identify the pathway that integrates PRR signals to induce the stress response. My final aim is to examine the interplay between PRR and stress responses and determine the role of PRR signals in fine tuning stress signalling pathways that effect the translation of pro-inflammatory cytokines. This programme of research will identify pathways that can then be exploited as therapeutic targets for the prevention and treatment of inflammation and arthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Functional analysis of genetic variants in ITGAM associated with systemic lupus erythematosus
Funder: Arthritis Research UK

Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component. Recent genome wide association studies have identified a robust association of the ITGAM gene with SLE. Although the genetic significance of ITGAM polymorphisms is now established, surprisingly little is known about how these gene polymorphisms contribute to disease._x000D_ _x000D_ ITGAM encodes for the CD11b protein, which pairs with CD18 to form a functional Mac-1 (CD11b/CD18) integrin, an important leukocyte adhesion receptor. The main disease associated variant of ITGAM encodes for a CD11b protein with an arginine/histidine substitution at position 77 (R77H) in the extracellular portion of the receptor. Our preliminary data now show that transfected cells expressing the R77H substituted Mac-1 integrin display drastically reduced cell adhesion to ICAM-ligands and the complement protein iC3b._x000D_ _x000D_ The aim of this study is to investigate the functional effects of naturally occurring ITGAM variants using in vitro model systems as well as isolated primary leukocytes. We will examine whether the R77H substitution in Mac-1 leads to defects in integrin-mediated leukocyte functions such as phagocytosis of apoptotic cells and leukocyte trafficking. Understanding why ITGAM polymorphisms predispose to SLE will help us understand the immune pathogenesis of disease and may identify novel therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: How does PTPN22/Lyp regulate T cell adhesion and migration?
Funder: Arthritis Research UK

Abstract: Cell migration is fundamental to embryonic development, wound healing and coordination of immune and inflammatory responses. A critical early step in leucocyte adhesion and migration is the activation of integrins such as LFA-1. Engagement by its counterligand ICAM-1 leads to a cascade of signalling events that permit cell spreading, cytoskeletal rearrangement, cell migration and proliferation. Among intermediates that regulate integrin activation are src kinases such as Lck. The protein tyrosine phosphatase Lyp has received particular attention in recent years following reports of a strong association between a missense single nucleotide polymorphism in the gene (PTPN22) and autoimmune diseases such as rheumatoid arthritis and lupus. While much work has focussed on the regulatory effects of Lyp on Lck activation during antigen T cell receptor signalling, no clear consensus has emerged as to whether the disease associated mutant is a gain or a loss-of-function phosphatase. Our recent data provide compelling evidence to suggest that the disease associated variant may in fact function as a loss-of-function regulator of integrin mediated adhesion and migration. Using PTPN22 mutant human and murine cells, this project will investigate precisely how Lyp mutants perturb leucocyte adhesion and migration.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Local and systemic T cell abnormalities in Primary Sjogren's Syndrome and their Response to B Cell Depletion
Funder: Arthritis Research UK

Abstract: Primary Sjögren's Syndrome (PSS) is an autoimmune exocrinopathy; some patients develop systemic manifestations and secondary malignancy. Preliminary studies have confirmed known and uncovered novel T-cell abnormalities in PSS. The response of T-cell abnormalities in PSS to biological therapy remains unknown, as does the ability of such responses to predict clinical efficacy. Here, we will study circulating and infiltrating T-cells of PSS patients with systemic manifestations enrolled in TRACTISS, an ARUK-funded randomised trial of Rituximab. Markers of CD4+ and CD8+ T-cell activation, proliferation, memory/effector subsets, inflammatory recruitment, and T/B-cell collaboration will be quantified in TRACTISS patients' PBMCs before and after Rituximab or placebo treatment, and compared to healthy controls. Transcriptional profiling of blood CD4+ and CD8+ T cells purified from cryopreserved PBMCs will be performed at 0 and 4 months. Where feasible, immunophenotypes and transcriptional activity will also be analysed in situ, in minor salivary gland biopsies. T-cell transcriptomes and immunophenotypes will be compared to controls and correlated with disease activity, and blood/tissue relationships explored. Comparing pre-/post-treatment samples and Rituximab vs. placebo will reveal T-cell remodelling after B-cell depletion and its relationship to efficacy. Given the efficacy of Rituximab in other autoimmune diseases, the studies will have relevance beyond PSS.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Nottingham Gout Treatment Trial. Phase 2: Two Year Randomised Controlled Trial Of A Nurse Led Package Of Care
Funder: Arthritis Research UK

Abstract: In Phase 1: (a) qualitative work is informing development of a nurse-delivered package of care reflecting current management guidelines for gout, and (b) a “proof-of concept” hospital clinic is demonstrating successful management (serum uric acid (SUA) <360 µmol/L) in >70% of gout patients. Phase 2 involves a questionnaire to gout patients in general practices. Of those reporting acute attacks within the last year, 724 will be randomised to receive the nurse-led intervention for 2 years (individualised management and follow-up), or a single visit with the nurse for a booklet and continuation of their GP standard care (SC). Primary outcome: the number with reduction in frequency of attacks in the 2nd year. Secondary outcomes at study end: SUA <360µmol/L and quality of life (QoL) (SF36, gout assessment questionnaire). Additionally, an observational group, also identified from the questionnaire, will have a repeat questionnaire after 2 years and a sample (up to 600 with, and 600 without, attacks in the previous year) will have SUA measured at baseline and 2 years (to determine any effect of the nurse visit/booklet in the SC group and any change in SC during the study; also to increase numbers for QoL comparison between good versus suboptimal outcomes).


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Estimating the Risk of Rheumatoid Arthritis: Modeling Genetic, Environmental, Epidemiological and Serological Factors
Funder: Arthritis Research UK

Abstract: Preventing common high cost, long-term diseases like Rheumatoid Arthritis (RA) is a key strategic research goal. This fellowship focuses on the crucial first step - identifying individuals at high risk of developing RA._x000D_ _x000D_ RA occurs when genetically predisposed individuals are exposed to environmental risks. Genome-wide association studies are defining its genetic architecture. Epidemiological studies are evaluating environmental risks like smoking. Each factor confers small risks, but in combination they will be highly informative._x000D_ _x000D_ This fellowship will develop a robust model combining genetic, environmental, epidemiological and serological factors to predict individuals’ risks of developing RA. Underpinning initial developmental research will systematically collect risk factors from original peer-reviewed papers and mathematically combine them in an RA prediction model._x000D_ _x000D_ Subsequent research spans three strands. Firstly the model will be validated using contemporary data from large UK and US RA population studies. Secondly, original data from 623 active RA patients enrolled in two recently-completed trials will evaluate the impact of disease severity on the prediction model. Finally, its performance in a cohort of 400 UK RA patients of African descent, who may have different genetic risks, will be examined as the prediction model will be developed using data from patients of European ancestry.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Validation of the new ACR/EULAR rheumatoid arthritis classification criteria with special emphasis on the role of anti-citrullinated protein antibodies
Funder: Arthritis Research UK

Abstract: The new American College of Rheumatology/European League Against Rheumatism classification criteria promise to revolutionise the study of rheumatoid arthritis (RA) by providing a clear definition of the disease in its early stages. However it remains to be seen whether these criteria can accurately identify all patients who would, in the absence of appropriate treatment, go on to develop the chronic erosive arthritis classically seen in RA. This study aims to evaluate the new criteria in the context of two large cohorts of patients with inflammatory polyarthropathy which cover both recent onset (The Norfolk Arthritis Register) and established (The British Society for Rheumatology Biologics Register) disease. In particular it will focus on elucidating the role of anti-citrullinated peptide antibodies in predicting prognosis for these patients.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Does the failure of mechanisms to maintain FOXP3 expression in T regulatory cells contribute to the development of severe disease in childhood arthritis?
Funder: Arthritis Research UK

Abstract: Childhood arthritis has a wide spectrum of outcomes, ranging from complete remission, through to severe destructive joint inflammation. One factor which has been shown to correlate with clinical severity is the number of FOXP3+ regulatory T cells (Treg) at the inflamed site and their relationship to Th17 cells. I hypothesise that bioavailability of key factors in the joint can contribute to the stability of Treg. Such factors include the cytokine TGFβ, and the vitamin A derivative all-trans retinoic acid (ATRA), which may be lacking in children destined to develop severe disease. If so, these two pathways could offer novel avenues for drug intervention, through signaling pathway modulation, and/or vitamin supplementation._x000D_ _x000D_ The key goals of this fellowship are four-fold:_x000D_ _x000D_ 1. To define availability of bioactive TGFβ and all-trans retinoic acid in the joint in JIA and relate these data to clinical severity _x000D_ _x000D_ 2. To determine the epigenetic profile of synovial Treg and how TGFβ and retinoic acid affect these marks_x000D_ _x000D_ 3. To investigate whether Treg stability can be manipulated in vitro in order to model the possible effects of therapeutic intervention eg with Vitamin A_x000D_ _x000D_ 4 To establish my own career as an independent scientist and translational immunologist.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Functional characterisation of Fc gamma RIIa with respect to both rheumatoid arthritis pathogenesis and as a potential therapeutic target
Funder: Arthritis Research UK

Abstract: Genetic association studies have recently implicated FcγRIIa in the susceptibility to RA. This receptor not only functions as a ligand for IgG, but has a dual role in recognising pentraxins, including C-reactive protein (CRP). Structural and functional studies on FcgRIIa have described competition between CRP and IgG for their shared binding domains. However, recent data have suggested a modified monomeric form of CRP may play a role in the development of cardiovascular disease. In addition to the well-recognised coding variant modulating IgG binding, my recent genetic work has identified a coding polymorphism in FCGR2A (the gene encoding FcγRIIa), encoding an amino acid substitution, predicted to alter the interaction of CRP with FcγRIIa. The aims of this project are to (i) evaluate the impact of this coding polymorphism on the competitive binding of IgG and CRP in both its conformational forms, thereby testing the hypothesis that the balance of CRP and IgG binding to FcγRIIa is crucial to the development of autoimmunity, (ii) use in silico modelling to design small molecule inhibitors with high specificity for FcγRIIa, (iii) experimentally evaluate potential small molecules as antagonists in the IgG-FcγRIIa interaction, (iv) counter-screen selected small molecules against homologous FcγRs to check FcγRIIa specificity.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Can altered patterns of cytokine signalling predict the course of inflammatory arthritis?
Funder: Arthritis Research UK

Abstract: Early therapeutic intervention remains the most effective strategy for treating inflammatory arthritis. However determining the most appropriate biologic therapy for an individual patient is restricted by current clinical assessments. Indeed, clinical criteria alone are often inadequate at determining whether patients will enter remission or progress to inflammatory arthritis. We hypothesise that signalling crosstalk between the transcription factors STAT1 and STAT3 may influence the transition from inflammatory resolution to chronic joint disease. These factors often oppose each other and recent cancer research indicates that signatures of STAT3 signalling act as prognostic biomarkers. We suggest that a similar approach might aid the clinical assessment and treatment of early arthritis patients._x000D_ _x000D_ _x000D_ _x000D_ Specifically, clinical and experimental approaches will: Assess crosstalk between STAT1 and STAT3 in vivo (AIM-1), Identify biomarker signatures that reflect changes in STAT1/STAT3 crosstalk in synovial fibroblasts and T-cells (AIM-2 & 3) and conduct a longitudinal screen of STAT1/STAT3 signatures in early-undifferentiated arthritis patients (AIM-4). The characterisation of STAT1/STAT3 pathway signatures in early arthritis will help predict the course of disease and aid clinical decisions relating to personalised care. Targeting newer biologics to patients most likely to show favourable efficacy will reduce the incidence of adverse responses and treatment cost.


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