NIHRDataInsights/HRCSData huggingface dataset:
Title: Is vascular endothelial growth factor a possible new treatment target in inflammatory arthritis?
Funder: Arthritis Research UK

Abstract: The novel variant of vascular endothelial growth factor, VEGF165b is analgesic in experimental arthritis, nerve injury and diabetic neuropathy. It is also anti-inflammatory and anti-angiogenic. In contrast, VEGF165a, the VEGF isoform commonly upregulated in for example solid tumours and inflammation, is algesic and pro-angiogenic. Pre-mRNA splicing controls relative VEGF isoform expression levels. In many normal tissues VEGF165b predominates, whereas in most pathological conditions e.g. tumours, VEGF165a predominates. The amounts of VEGF165a and VEGF165b in inflammatory arthritis are unknown, as all previous studies used antibodies that bind both isoforms and therefore did not assay VEGF165a and VEGF165b independently. As VEGF165b is analgesic and anti-inflammatory, increasing intra-articular VEGF165b by altering pre-RNA splicing to favour VEGF165b expression, by expressing native protein in the joint, or by removing VEGF165a from the joint with a specific antibody, is a potential new therapy for inflammatory arthritis. Using an experimental arthritis, we will determine the effect of VEGF165b on: nociceptive behaviour; synovial content of VEGF isoforms and key inflammatory mediators; articular angiogenesis and vascular integrity; and synoviocyte proliferation/apoptosis. We will determine whether VEGF165b has analgesic and anti-arthritic actions in arthritis, as a first step in the development of VEGF165b as a novel treatment for this condition.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Epigenetic regulation of IL23R in ankylosing spondylitis
Funder: Arthritis Research UK

Abstract: Genome-wide association studies (GWAS) have revealed over 41 susceptibility loci for ankylosing spondylitis (AS). The next challenge is to identify the corresponding functional genetic variants, the molecular mechanisms by which they act, and the cellular pathways they modulate. Most single nucleotide polymorphisms (SNPs) associated with AS are not in exons and are therefore more likely to have regulatory rather than protein coding effects. In this project we shall assess the function of regulatory genetic variants near IL23R and RUNX3, which have been implicated strongly in the pathogenesis of AS (IL23R p=5x10-21; RUNX3 p=2.6x10-15) and other related inflammatory conditions. We have integrated genetic and epigentic data to identify candidate regulatory SNPs and will test which of these disrupt gene expression in AS patients. We will go on to define the precise epigenetic mechanisms through which SNPs alter transcription and identify the cellular effects of altered gene regulation in AS patients. This type of genetic-bioinformatic-epigenetic methodology can also be applied to other associated loci in the future. This research will highlight specific functional alterations in the immune system of AS patients and will identify the specific cell types involved, findings that have translational potential for drug development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of the MSK-CREB axis in IL-23 production and initiation of arthritis.
Funder: Arthritis Research UK

Abstract: Th17 cells have increasingly become recognized as one of the key cell types that drive pathogenesis in autoimmune disorders including inflammatory arthritis. The production of IL-23 by antigen presenting cells is necessary to promote Th17 function, and blocking IL-23 production or function represents a promising new therapeutic strategy. We have found that the production of IL-23 in macrophages and dendritic cells can be regulated by an MSK1/2-CREB dependent signaling pathway. Additionally we find that MSK1/2 knockout reduces T cell dependent antibody production in vivo. We therefore propose that MSK1/2-CREB dependent signaling plays a role in mediating the interface between the innate and adaptive immune systems, and that blocking this pathway may protect against the development of arthritis. In the current proposal we will characterize the signaling controlling IL-23 transcription in dendritic cells. We will also examine the contribution of MSK1/2-CREB signaling to Th17 polarization both in vitro and in vivo and assess the mechanisms by which MSKs regulate antibody production. Finally we will examine the effect of MSK1/2 knockout on the development of arthritis in mice. Together this should provide a better understanding of IL-23 regulation and validate the MSK1/2-CREB pathway as a therapeutic target for autoimmune disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Development of an Internationally agreed Minimal Dataset for Juvenile Dermatomyositis (JDM); a rare but severe, potentially life-threatening, childhood rheumatological condition.
Funder: Arthritis Research UK

Abstract: This study will develop an internationally agreed minimal dataset for juvenile dermatomyositis (JDM), critical for delivery of future clinical trials, that can be used within clinical care, directly informing practice, improving disease understanding, aiding collaboration and enabling prioritisation of interventional trials. Large patient cohorts (achievable through uniform data collection and international collaboration) are vital to elucidate impact of novel genetic or antibody discoveries on pathogenesis, phenotype and outcome of JDM. Two overlapping but distinct research ‘JDM core sets,’ including many time-consuming tools (unfeasible for clinical use) exist in America and Europe, without international agreement._x000D_ A provisional dataset, formulated through structured processes by a representative group of JDM experts, will be scrutinised by modified Delphi exercises, using electronic software, distributed via international organisations. Participants will rate validity, feasibility and rank-order of variables over two web-based surveys. An international meeting of JDM experts will determine, by nominal group consensus, feasibility, validity, acceptability, format, definition and glossary of variables within the proposed minimal dataset. Participating clinicians (non-experts) will test this dataset by submitting clinical cases to established web-based registries. Completion rate and accuracy of data entry will be examined. Finally, a refined minimal dataset will be presented and endorsed through established international collaborations.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Identify Egr-2 and -3 regulatory program in B and T cells that controls the self-immune responses for the development of bio-markers and potential therapeutics for rheumatoid arthritis and lupus
Funder: Arthritis Research UK

Abstract: The mechanism that controls autoimmune responses of B and T cells is largely unknown. We have discovered an overlapping function of Egr-2 and -3 in B and T cells to be essential for the control of inflammatory responses of B and T cells. Deficiency of Egr-2 and -3 in B and T cells results in severe systemic autoimmune diseases which resemble closely to that from rheumatoid arthritis and lupus patients. Our findings have published in immunity recently (PMID: 23021953). In this proposal, using our unique models of Egr-2 and -3 deficient, Egr-2 transgenic and Egr-2GFP knockin mice, our goals are; to analyze the Egr-2 and -3 regulatory program for the control of self-tolerance and expression of inflammatory cytokines in B and T cells; to validate the findings in human B and T cells; to investigate changes of this regulatory program in B and T cells from patients; and to investigate the therapeutic potential of Egr-2 in lupus models. The findings will not only define the function of Egr-2 and -3 in prevention of the development of rheumatoid arthritis and lupus, but also lead to the development of bio-markers and therapeutic target molecules used for clinical applications.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Optimisation of a novel magnetic resonance imaging-based scoring system for assessing disease activity in children with juvenile dermatomyositis
Funder: Arthritis Research UK

Abstract: With a UK and Ireland incidence of 1.9/million children, juvenile dermatomyositis (JDM) is the commonest childhood inflammatory myopathy. Current diagnostic criteria require identification of the presence of a characteristic “heliotrope” rash, proximal myopathy, raised muscle enzymes, a myopathic electromyogram and histopathological confirmation of a myopathy. JDM is diagnosed in the presence of the rash plus 3 or 4 other parameters. Limitations to this diagnostic approach are the invasivness of some parameters and failure to represent current clinical practice because magnetic resonance imaging (MRI) is not included. Although non-invasive and clearly depicting muscle oedema and wasting (associated with active and chronic disease respectively), easily applicable, objective, reliable and validated MRI parameters do not exist. This project aims to refine a novel MRI-based classification system for recording disease activity in JDM._x000D_ _x000D_ We recently introduced a novel MRI-based scoring system and showed it to be reliable when employed by a single reader on more than one occasion. The system however performed less reliably between 2 readers._x000D_ _x000D_ In this current study, we shall optimise the scoring system using multiple readers, thereby developing an objective tool for diagnosis, clinical management, prognostication and assessment of response to therapy in both the clinical and research domains.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Lighting the way for digital ulcers in systemic sclerosis: the development of local treatments and outcome measures of efficacy.
Funder: Arthritis Research UK

Abstract: Background: Much of the pain and disability of systemic sclerosis (SSc) is caused by digital ulcers, which can severely compromise hand function and negatively impact on quality of life. Digital ulcers are important also for another reason: they are often the primary endpoint in clinical trials of SSc-related digital vasculopathy. Yet many questions regarding digital ulcers remain unanswered, specifically how best to define, measure and treat them. Goals: To investigate the definition, objective measurement of interval change, pathophysiology and local (as opposed to systemic) treatments of SSc-related digital ulcers. Methods: Four studies of SSc-related digital ulceration will be undertaken: 1.A web-based study aimed at improving ulcer definition (rheumatologists will grade photographs of digital lesions with and without contextual clinical information). 2. A four-week longitudinal study using high-frequency ultrasound to measure change in digital ulcer status i.e. healing or progression. 3. A mechanistic study of topical glyceryl trinitrate versus placebo ointment (to elucidate the microvascular component to pathophysiology) 4. A study of light-based therapy. Conclusion: The proposed programme of research will address key unanswered questions relating to SSc-related digital ulcers and will inform/facilitate future clinical trials. In addition, it will provide training in the design, conduct and analysis of clinical studies.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;5.1 PHARMACEUTICALS;8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding the variability in clinical response to B-cell depletion therapy in Rheumatoid Arthritis and Systemic Lupus Erythematosus
Funder: Arthritis Research UK

Abstract: Inadequate clinical response to rituximab-induced B-cell depletion therapy (BCDT) in Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) is associated with incomplete depletion of B cells and early reconstitution with memory B cells. In this proposed study, we aim to explore the underlying mechanisms by which B cells evade rituximab-induced cytotoxicity. Our preliminary data indicated that B cells from patients with RA and SLE can internalise rituximab, but not BHH2 (GA101-like, GA101 is in Phase III study-stage for lymphoma), which may reduce serum rituximab levels and impair antibody-dependent cell-cytotoxicity. Further, we found that BHH2 was at least twice as efficient at killing both RA- and SLE-B cells in vitro. We will also investigate whether non-depleted B cells retain the ability to proliferate, differentiate into antibody-secreting cells and co-stimulate T cells. Further, we will explore the potential of B cell related biomarkers (B cell phenotype, expression of CD20, CD32 and serum soluble CD23 levels) to predict biological and/or clinical response to rituximab. We expect that the results of this study will provide crucial information on how to optimise the use of B-cell depleting agents to improve cost-effectiveness and improve outcomes for patients with RA and SLE.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Identifying the current knowledge and confidence of rheumatology nurses in providing advice on pain management
Funder: Arthritis Research UK

Abstract: People with rheumatoid arthritis have identified pain as a dominant symptom of their condition and the rheumatology nurse as the key member of the team who can provide advice on managing pain. Previous research on role activities of rheumatology nurses have not focused on pain management and there is evidence to suggest rheumatology nurses may not have the knowledge or confidence to provide advice on managing pain._x000D_ _x000D_ We will conduct a national electronic survey of rheumatology nurses who are members of the Royal College of Nursing Rheumatology Forum to identify the current knowledge and confidence of rheumatology nurses in providing pain management to people with rheumatoid arthritis._x000D_ _x000D_ The findings from the survey will identify areas of pain management advice that can be enhanced through appropriate education.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The practical management of fatigue by people with arthritis: the impact of Arthritis Research UK written information
Funder: Arthritis Research UK

Abstract: Fatigue is a common and debilitating symptom for people with arthritis, and effective management strategies are in their infancy. Biotherapies may be ineffective for fatigue, while self-management programmes are not available for all patients, and many choose not to attend. Health professionals struggle to support patients with fatigue, and the Arthritis Research UK booklet provides an accessible and rigorously developed resource. This study addresses the practical management of fatigue across three forms of arthritis: rheumatoid arthritis, ankylosing spondylitis and primary Sjogren’s syndrome. It employs serial qualitative interviews before and after receiving the Arthritis Research UK booklet. Our key goals are: to explore how people with arthritis practically manage fatigue and attempt to reduce its impact on their life; to determine how the booklet on fatigue connects with the lived experience of fatigue and influences patients; and to evaluate and suggest changes to the booklet in the light of these findings.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Better arthritis care in the community; assessing the educational needs of nurses & AHPs
Funder: Arthritis Research UK

Abstract: To ensure people with arthritis receive the care they need and consistent self-management and life style messages it is important that all health providers they may have contact with are familiar with arthritis, its impact, diagnosis and management. Arthritis is a common presenting problem and co-morbidity and an increased competency amongst health workers who are not specialists in rheumatology will enable any clinical encounter to be used for the maximum benefit and well-being of the patient. The aim of this project is to assess what education community based nurses and allied health professionals need to enable them to provide the appropriate assessment, care and management to patients with arthritis. The project outcomes will be:_x000D_ _x000D_ A set of teaching objectives and education topics for the training of community based nurses and AHPs in arthritis assessment, management and care;_x000D_ _x000D_ An understanding of the barriers and facilitators to delivery of this training.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Non-specific Mechanisms in Orthodox and CAM management of back pain (MOCAM)
Funder: Arthritis Research UK

Abstract: Components other than the active ingredients of treatment can have substantial effects on pain and disability. There are five domains of "non-specific" components: the therapeutic relationship, the healthcare environment, superficial treatment characteristics, patients' beliefs, and practitioners' beliefs. Complementary and alternative medicines like acupuncture have particularly powerful non-specific components. However, existing evidence is based primarily on studies of single components, in single treatments, in isolation from pain theories. This project investigates multiple non-specific components in three treatments and relates them to pain theories. We aim to:_x000D_ Identify the most powerful non-specific treatment components. Compare their effects on patient outcomes across three treatments. Develop a deeper understanding of the pathways through which they generate positive patient outcomes. We will recruit a cohort of 1548 adults with back pain attending acupuncturists, physiotherapists, and osteopaths in private and NHS clinics. A quantitative longitudinal questionnaire-based study will use advanced statistical techniques (multi-level modelling) to test hypothesised relationships between five domains of non-specific components, key theoretically-derived mediators (e.g. behaviour change, self-efficacy), and patient outcomes (e.g. disability). A randomised sample of 63 consultations (21 per treatment) will be audio-recorded and analysed using the quantitative Roter Interactional Analysis System and inductive qualitative analysis, to identify treatment-enhancing communication practices.


Research activity codes: 5.7 PHYSICAL;5.8 COMPLEMENTARY
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Determining the causal genes in genetically associated rheumatoid arthritis regions
Funder: Arthritis Research UK

Abstract: Although genome wide association studies (GWAS) have been used with great effect to detect variants associated with many diseases, they generally do not pinpoint the causal gene or causal variant. Indeed, the majority of lead GWAS genetic variants map outside gene regions, with more than half residing a significant distance from the nearest gene. In order to progress these findings towards novel drug discovery, patient stratification and ultimately cure, it is necessary to determine the genes implicated by GWAS findings._x000D_ _x000D_ The disease associated variants that map outside gene regions are likely to act by influencing gene regulation. This long-distance regulation is thought to act through physical contact with target genes. Here we will use a novel chromosome conformation capture technique to interrogate all known GWAS associated regions for rheumatoid arthritis (RA), to detect long range physical interactions and thus determine the genes regulated by RA associated variants. This approach has the advantage of potentially highlighting causal variants in regions where genetic analysis does not have the sensitivity to distinguish between a number of highly correlated association signals. The identification of causal genes and potential regulatory mechanisms for each GWAS associated region will be a significant step forward for RA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A Genome-Wide Association Study in anti-PR3-ANCA Vasculitis
Funder: Arthritis Research UK

Abstract: Anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis (AAV) is a severe systemic autoimmune disease characterised by vascular inflammation. It often presents with pulmonary haemorrhage or acute renal failure, and has substantial morbidity and mortality. We recently performed the first genome-wide association study (GWAS) in AAV, which found it was comprised of two genetically distinct subsets, each best characterised by ANCA-specificity for either anti-proteinase 3 (PR3) (a group overlapping the clinical syndrome Granulomatosis with Polyangiitis, formerly Wegener’s granulomatosis) or myeloperoxidase. Three significant associations were found in the anti-PR3 AAV group, implicating autoimmunity to PR3 as a central driver of disease. Many other associations failed to reach statistical significance due to the small size of the subgroup. We therefore propose the first GWAS in anti-PR3-associated AAV. Importantly, this GWAS involves a collaboration between the only two major international vasculitis genetics consortia, in Europe and North America. Our preliminary data indicates the study should produce novel genetic variants associated with PR3 ANCA disease. It will also assist in the search for genetic variation associated with AAV as a whole, and may confirm data suggesting that there are genetic associations with subgroups with different organ involvement.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Granulomatosis with Polyangiitis (Wegener’s Granulomatosis): Defining the risk of infection associated with the disease and the treatment
Funder: Arthritis Research UK

Abstract: Granulomatosis with Polyangiitis (GPA) (formerly known as Wegener’s Granulomatosis) is a relatively rare immune disorder causing inflammation of the respiratory tract and kidneys. Untreated it is life-threatening. Treatment of this disease involves immunosuppressive drugs which in turn put the patient at risk of infection. It is likely that the inflammation and scarring caused by the disease also increases the risk of infection in these patients. It is also now established that infection is the major cause of illness (including death) complicating the disease and its treatment._x000D_ _x000D_ The problem with defining the risk of infection in patients with GPA is a consequence of the rarity of the disorder, meaning it has been difficult to gather data on enough patients to draw robust conclusions._x000D_ _x000D_ Previous work in multi-national studies has documented mainly severe infections which have required hospitalisation. It is likely that these patients are experiencing many other infections causing significant illness and affecting quality of life. We aim in this national study to accurately describe the risk of infection in this population and potentially identify risk factors which contribute, including drug treatment. We will also assess whether vaccination and long-term antibiotic use appear effective at reducing the risk of infection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM