NIHRDataInsights/HRCSData huggingface dataset:
Title: The safety of glucocorticoids in patients with inflammatory musculoskeletal conditions
Funder: Medical Research Council

Abstract: Aim To quantify the risk of single and multiple adverse events in patients with inflammatory musculoskeletal conditions treated with glucocorticoid (GC) therapy. Objectives To explore the association between time-varying GC dosage and route of administration of GC and outcome. To develop and validate a predictive tool to estimate likelihood of GC-associated adverse events. To address the influence of adherence upon risk estimates. To better understand the benefit/ harm balance of GC use. To improve risk communication through development of an electronic visual tool Design and Methodology The planned analyses will use databases that are established or in development. First, nested case-control and cohort studies, with modelling of time-varying GC exposure including dose, will be undertaken using respected UK primary care databases: the General Practice Research Database and The Health Improvement Network. Prediction modelling will be used to identify patients at risk of GC-associated adverse events (including infection, cardiovascular disease, diabetes, fractures), in one dataset with validation in the second dataset. In order to address the influence of factors captured only in secondary care, such as parenteral GC therapy and disease severity measures, further analysis will be undertaken in two additional databases under development, the arc Early Inflammatory Arthritis Information System and the NorthWest e-Health e-Labs project. Additional funding will be sought to develop and implement novel technology to capture patient reported outcome measures and adherence data, and to develop an electronic visual tool for risk communication. Scientific and medical opportunities It is not clear which GC treatment regimes place patients at risk of adverse events, what degree of risk is conferred, or what predisposes patients to such events. This makes accurate communication of risk difficult. The work described above will unpick some of the complexities of GC-associated adverse events. It will also move risk estimation towards personalised risk assessment, whereby patients can be informed of their individual risk of side effects given their profile, including demographics, disease characteristics and co-morbidity. Pharmacoepidemiology is currently limited by the scope of available datasets. These projects will improve capture of clinical data, both from clinicians and directly from patients. Although focussed on GC safety, the skills, techniques and visual tools developed in these projects will have wider application for investigating the safety of other medications.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Targeted Therapy for better patient outcomes in Musculoskeletal Diseases: Treat Smarter
Funder: Department of Health and Social Care

Abstract: Our aim is to apply P4 Medicine to musculoskeletal (MSK) diseases to introduce a ‘Treat Smarter’ approach by:  Preventing inflammatory arthritis (IA) where possible;  Where prevention is not possible, personalising care pathways through identification of biomarkers to select the most effective drug/intervention;  Predicting which of the promising novel therapeutic strategies will be effective in the wider patient population;  Working with patients, empowering them to participate in their own healthcare, thereby improving clinical outcomes. Short term (1-2 years)  Identify disease endotypes according to therapy response or outcome across inflammatory MSK conditions;  Develop behavioural interventions to improve self-management in juvenile idiopathic arthritis (JIA) and adherence to medication in IA. Medium term (3-4 years)  Develop and test algorithms to predict IA development and response to methotrexate (MTX) and anti-TNF biologics;  Translate genetic findings in JIA into establishing the feasibility of IL2 blockade for the treatment of a disease subgroup;  Re-classify connective tissue diseases (CTD) by molecular signatures related to phenotype/outcome and develop an algorithm to predict digital ulceration in systemic sclerosis;  Establish the feasibility of stem cell approaches to treat intervertebral disc degeneration and progress novel therapeutics into phase III trials in osteoarthritis (OA). Long term (5+ years)  Implement biomarker-driven, personalised therapy selection of interventions for MSK diseases;  Four novel therapeutics with evidence of efficacy from experimental medicine programmes, establish cost-effectiveness in phase III trials.


Research activity codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Arthritis Research UK Primary Care Centre of Excellence
Funder: Versus Arthritis

Abstract: Our mission is to conduct high quality research designed to improve the content and delivery of primary care and reduce the impact of chronic musculoskeletal pain and arthritis in individuals and populations.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Cells of the immune system direct inappropriate bone formation in arthritides
Funder: Versus Arthritis

Abstract: In inflammatory arthritis, systemic bone loss is a common feature however inappropriate new bone formation in the spine, hips and other joints is a major clinical problem in ankylosing spondylitis (AS) and psoriatic arthritis. New bone develops in areas of inflammation near cartilage or tendons. I have shown that the interaction between monocytes and mesenchymal stem cells increases osteoblast formation due to oncostatin M (OSM) production by monocytes. This results in STAT3 activation that induces a cascade of osteoblast-associated genes. There is a strong genetic association of AS with STAT3.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Arthritis Research UK Centre for Epidemiology
Funder: Versus Arthritis

Abstract: The proposed Arthritis Research UK Centre of Excellence in Epidemiology (CoEE), based at the Universities of Manchester and East Anglia, aims to


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating mesenchymal stem cells in joint health and disease
Funder: Versus Arthritis

Abstract: We recently identified in mouse synovium a population of label-retaining mesenchymal stromal/stem cells (MSCs) with a heterogeneous phenotype. We hypothesise that MSC heterogeneity reflects distinct ontogeny pathways; that a finely balanced synovial MSC heterogeneity is key to maintaining joint homeostasis; and that MSC lineage/clonal shifts are at the basis of joint homeostasis breakdown and development of joint disease. We will focus on two key cell populations in synovium: Progeny of Gdf5-expressing cells from the embryonic joint interzone and Nestin+ MSCs. We will determine (i) whether Nestin+ cells in synovium are a subset of joint interzone progeny or a distinct cell population; (ii) the rate of expansion of Nestin+ lineage during physiological turnover and following injury; (iii) a possible origin of Nestin+ cells from bone marrow; and (iv) which cell subsets contain MSC/FLS activity in vitro. Finally, we will employ in vivo clonal lineage tracing models to analyse dynamics of clonal lineage size and topography in the adult synovium during physiological turnover and following joint surface injury, in post-traumatic osteoarthritis and inflammatory arthritis. Such knowledge on MSC heterogeneity and dynamics in joint health and disease will be crucial for future therapeutic targeting of MSCs to maintain/restore joint homeostasis and prevent/treat arthritis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Harnessing the Chondroprotective Actions of Neutrophil Microparticles
Funder: Versus Arthritis

Abstract: A key feature of rheumatoid and osteoarthritis is cartilage erosion, but current therapy targeting this aspect of the disease is non-existent. A newly discovered mode of communication between cell types, in which cells release small “packages” of information known as microparticles, is potently chondroprotective during experimental models of arthritis. These small structures are capable of penetrating the cartilage matrix to reach chondrocytes, inducing cartilage matrix accumulation and reducing cytokine production and chondrocyte apoptosis. I aim to investigate how these microparticles act to protect and potentially heal cartilage damage. By determining whether mice deficient in neutrophil microparticles suffer exacerbation of joint erosion and assessing how microparticles penetrate the cartilage, I will seek to exploit these microparticles as potential therapeutic vectors. By enhancing the inherent capabilities of microparticles to protect the cartilage, we will pave the way to creating a totally new cell-based therapy for the treatment of cartilage erosion in joint disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Development of Individual Supported Employment work-placements to Improve the health-related Quality of Life of people with chronic pain who are unemployed (ISEIQoL)
Funder: Versus Arthritis

Abstract: Improving work participation within sick and disabled populations improves health outcomes and quality of life. Individual Placement Support (IPS) packages help people with mental health problems gain and retain work. We will adapt the IPS model for people with chronic musculoskeletal pain, exploring the feasibility of delivering the intervention with large employer partners providing work placements. Adapted IPS has the potential to improve quality of life and allow people with chronic pain to make useful contributions.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: HMGB1: a key damage mediator in tendinopathy
Funder: Versus Arthritis

Abstract: We have previously shown that damage associated molecules (DAMPs) are significantly altered in human tendon disease. In a hypothesis driven and mechanistic approach we demonstrated a novel inflammatory/matrix crosstalk involving the DAMP interleukin 33 (IL-33) in human tendinopathy. HMGB1 is a widely expressed, highly conserved nuclear protein involved in transcriptional regulation which plays principal roles in a variety of inflammatory responses and diseases. Importantly stress conditions which are considered key to the onset and perpetuation of tendinopathy result in HMGB1 secretion while its extracellular release induces proinflammatory cytokines, cell proliferation, and stromal cell matrix responses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Getting sustainable, person-centred musculoskeletal health intelligence from primary care electronic health record linkage and modelling: the PRELIM initiative
Funder: Versus Arthritis

Abstract: There is an urgent need to provide more effective and efficient means of maximising quality of life and independence for the growing number of people with common musculoskeletal conditions. Better health intelligence is needed for the common musculoskeletal conditions that cause the greatest amount of disability in the United Kingdom (UK). Primary care has a critical role in responding to this challenge and electronic health records (EHR) from this setting are increasingly recognised as an important driver for public health policy, clinical practice, and research. However there is also a need to move beyond processes of care to information on patient health-states, experiences and outcomes like the impact on work, function and quality of life. The ultimate purpose of our research is to harness primary care EHR and patient-reported data from the registered practice population as a sample frame for meaningful and sustainable surveillance of musculoskeletal health, illness, clinical care and outcomes in the UK. The ultimate purpose of our research is to contribute to a system that provides useful, timely, sustainable, trustworthy evidence on musculoskeletal health for policymakers, practitioners, and the public. Our aims cover the generation of substantive new evidence on musculoskeletal health in the UK population as well as methodological insights to inform the future direction of information-gathering and analysis in this field. Our focus will be on the most common musculoskeletal disorders, responsible for most attributable disability at the population level: osteoarthritis, low back pain, neck pain, and other regional musculoskeletal pains. Three sources of data will be used:


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Implementing the MSK-HQ to empower patients and improve services
Funder: Versus Arthritis

Abstract: New models of musculoskeletal (MSK) care are required that better reflect patients’ individual needs through care that is patient-centred, co-ordinated, and provides choice. The Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ) is a recently validated outcome measure to evaluate an individual’s MSK health-status across the clinical care pathway. The next step is to find useful ways to implement the MSK-HQ into routine practice.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Bringing MSK conditions in from the care planning cold - a feasibility study
Funder: Versus Arthritis

Abstract: This is a feasibility study to develop and test the practical processes, skills, systems and tools needed to embed collaborative care and support planning (CSP)[1] as normal care within general practice for people living with single MSK conditions or with MSK conditions as part of multi-morbidity; and to demonstrate how this links with specialist care and community support.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Molecular basis of arthritic pain: roles of HCN ion channels and AT2 receptors
Funder: Versus Arthritis

Abstract: The overall aim is to extend our understanding of the roles of the HCN2 ion channel and the angiotensin II – AT2 receptor pathway in arthritic pain. HCN2 has been shown to play an important role in both inflammatory and neuropathic pain, and the work will extend this to a study of the role of HCN2 in the pain of rheumatoid arthritis and osteoarthritis. Preliminary evidence from our group also shows that the peptide angiotensin II is a potent pro-inflammatory agent which acts via HCN2 ion channels, and together with other recent evidence that the AT2 receptor for angiotensin II in an important analgesic target, this work suggests that the angiotensin II-AT2-HCN2 pathway may be important in arthritic pain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Transient Receptor Potential Canonical 5 (TRPC5), a missing link in osteoarthritic pain and inflammation
Funder: Versus Arthritis

Abstract: The understanding of novel mechanisms involved in regulating pain associated with arthritis is key for the development of new treatments. Our group has discovered that TRPC5 knockout (TRPC5KO) mice exhibit exacerbated pain in an inflammatory arthritis model and that TRPC5 gene expression is reduced in human arthritic synovial tissue, highlighting a potentially conserved effect. We now present pilot evidence that TRPC5KO mice show enhanced nociception, gait and weight bearing irregularities in a model of chronic osteoarthritis (OA) following partial meniscectomy destabilization knee surgery . We hypothesise that TRPC5 protein expression and activity is important for limiting pain. Using mouse models, together with molecular, histological and pharmacological techniques, we propose to determine i) whether TRPC5 is active in protecting against pain at central, in addition to peripheral sites of action ii) how the enhanced pain correlates with the localisation of TRPC5 in the context of joint disease and markers of inflammation and joint degeneration; iii) the ability of TRC5 agonists to protect against pain and joint damage; iv) potential signalling systems. Finally, to build on these studies, we will utilise human naïve and OA synovial tissue and study a population of OA patients to investigate for TRPC5 and related genetic determinants.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Epidemiology of common hand conditions
Funder: Versus Arthritis

Abstract: The aim of this research is to establish a greater understanding of the pathophysiology of clinically significant hand osteoarthritis and carpal tunnel syndrome through the use of large-scale epidemiological study. The project focuses upon UK primary and secondary care data linked to prospective cohort studies UK Biobank and Million Women Study, with external validation between cohorts and through comparison to international datasets. Patients and lay advisors perceived treatment variation, prevention of progression, and greater understanding of disease prognosis as key priorities for the work, which is reflected in these aims:


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Increasing Physical Activity in Older People with Chronic Musculoskeletal Pain
Funder: Versus Arthritis

Abstract: Physical activity (PA) improves pain and quality of life and reduces risk of further chronic illness in those with musculoskeletal pain. While increasing PA levels is a public health priority, the mechanisms to achieve this in older adults with chronic musculoskeletal pain remain unclear. Walking is the most likely way all adults can achieve recommended levels of physical activity. However, there is a lack of research into the effectiveness of interventions to promote walking for older people with musculoskeletal pain.


Research activity codes: 6.7 PHYSICAL
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Multimorbidity in Arthritis and persistent musculoskeletal Pain (MAP) Study
Funder: Versus Arthritis

Abstract: Multimorbidity, the presence of =2 long-term conditions (LTCs), is an urgent healthcare challenge. Painful arthritis-related conditions are long-term in nature and often experienced alongside other LTCs. People with multimorbidity tend to experience increased levels of “work” or treatment burden when managing their LTCs. Yet, we know relatively little about the impact of multimorbidity on people living with persistent musculoskeletal pain and arthritis in terms of effects on: healthcare experiences, health related quality of life (HRQoL), general wellbeing, and health-related outcomes. Furthermore, it is unclear how the presence of multimorbidity in those with persistent musculoskeletal pain and arthritis influences healthcare professional (HCP) management approaches. This work will combine data science and qualitative methods to address these issues.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;2.4 SURVEILLANCE AND DISTRIBUTION;7.3 MANAGEMENT AND DECISION MAKING
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: The effect of calorie restriction on mouse haematopoetic and skeletal muscle stem cells.
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Defects in stem cells are implicated in the age-related decline in the function of many organ systems Skeletal muscle repair, maintenance and regeneration are mediated by satellite cells, muscle-specific stem/precursor cells. However, there are other stem cells present within skeletal muscle that can contribute to regeneration after grafting into host mice, but the relevance of these to routine muscle repair is not known. Despite the presence of stem cells in adult muscles, skeletal muscle mass and its ability to regenerate following injury are reduced with increasing age, but it is unclear whether this is due to a defect in muscle stem cells, the local or systemic environment, or a combination of these. Age-related changes in the haematopoietic system lead to increased incidence of leukemias, a decline in adaptive immunity, and greater tendency to anaemia. Haematopoietic stem cells (HSC) from old mice have altered homing and mobilization, reduced repopulating ability, increased capacity to give rise to myeloid and reduced capacity to give lymphoid progenitors. Calorie restriction has been shown to increase lifespan and reduce or delay the onset of many age-related defects. But there appears to be a mouse strain-specific difference in the response to calorie restriction, as it increases lifespan in C57BL/6, but not DBA/2, mice. However, the effect of calorie restriction on skeletal muscle stem cells and their regenerative ability is not known. As there is a differential response to calorific restriction between C57BL/6 and DBA/2 mice, we propose to investigate the effect of calorie restriction in both strains of mice on skeletal muscle histopathology and on the number and function of satellite and other stem cells present within skeletal muscle. Simultaneously, we will investigate the effects of calorie restriction on HSC frequency and functional output in these two contrasting mouse models.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM;BLOOD
Title: Comparing the immunological signatures of common inflammatory diseases, to identify potential therapeutic targets.
Funder: Chief Scientist Office (Scotland)

Abstract: Inflammatory bowel disease (IBD), ankylosing spondylitis (AS), psoriasis (Ps) and psoriatic arthritis (PsA) are common chronic inflammatory diseases with overlapping symptoms Recently, analyses of large numbers of patients have revealed that polymorphisms in genes involved with immune functions contribute significantly to all four diseases. Despite this knowledge, and many investigations of specific immunological pathways, even the best currently available treatments fail to treat the underlying damage caused by these conditions. A better understanding of the cellular pathways that lead to disease is vital for the development of improved therapeutics for these conditions. Thus we aim to use our recently-developed technology to characterise and compare the immunological signatures of patients with these conditions in unprecedented detail, to identify the common and unique immune pathways affected by each of these diseases. This information will be vital for the development of future therapeutics for IBS, AS, Ps and PsA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;INFLAMMATORY AND IMMUNE SYSTEM;SKIN;ORAL AND GASTROINTESTINAL