NIHRDataInsights/HRCSData huggingface dataset:
Title: A randomised controlled study of oral prednisolone in early diffuse cutaneous systemic sclerosis - PRedSS
Funder: Versus Arthritis

Abstract: Our aim is to test the hypothesis that moderate dose prednisolone confers symptomatic and functional benefit in patients with early diffuse cutaneous systemic sclerosis (dcSSc) and that these benefits outweigh any side effects. The main benefits are expected through anti-inflammatory effects in the skin and in the musculoskeletal system, thus reducing pain and disability and preventing late and irreversible complications such as digital contractures. Corticosteroid therapy in systemic sclerosis is currently controversial, because of concerns that corticosteroids are a risk factor for renal crisis (although relating mainly to high dose usage).


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Identification of disease specific phenotypes associated with clinical and patient reported long-term outcomes in rheumatoid arthritis patients with moderate disease activity - MODRAS
Funder: Versus Arthritis

Abstract: There is limited information about the long-term clinical and patient reported outcomes in rheumatoid arthritis (RA) patients with moderate disease activity (MDA) despite using synthetic Disease Modifying Anti-Rheumatic Drugs (sDMARDs). Latent class modelling is a relatively new statistical method used to better distinguish different patterns of disease outcome over time (e.g. steadily getting worse or better). These different changes over time are called trajectories. Identification of different disease specific phenotypes (based on baseline demographic, clinical and socio-economic factors) associated with membership of each trajectory would be useful in clinic for example to identify those patients on a worse trajectory and who may benefit from more intensive treatment earlier in the disease course.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Interactions between the Microbiome, Immunophenotype and Genome in PsA (IMIGPA).
Funder: Versus Arthritis

Abstract: Recent technological advances have enabled identification of interactions between humans and the microbial communities with which they have co-evolved. Such interactions influence immune homeostasis and pathogenesis of inflammatory diseases. Accordingly, we hypothesise, first, that alterations in skin or intestinal microbiota will contribute to PsA, in genetically susceptible individuals; and, second that comparison of changes in the immune response and in the skin and intestinal microbiota that occur following treatment of PsA will reveal mechanisms by which the microbiota act.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The significance of Staphylococcus aureus carriage and granulomatosis with polyangiitis: Pathophysiological alterations unravelled.
Funder: Versus Arthritis

Abstract: Abstract. Granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) is a multi-system autoimmune disorder. Genetic associations have been defined but unidentified environmental factors remain the major factors implicated in disease aetiopathogenesis. Nasal Staphylococcus aureus colonisation is frequent and investigations have shown an impaired antibody response towards Staphylococcus aureus. However, the exact mechanisms leading to adhesion and invasion of Staphylococcus aureus in GPA patients remain obscure. Musculoskeletal focus. Diverse manifestations of the disease portend diverse clinical phenotypes of the disease. However, most patients present with ENT-related symptoms, but generalised symptoms such as arthralgia, myalgia and constitutional symptoms occur. Objectives. We would like to explore the microbiome of patients with GPA and the shift of diversity during diverse disease states. We expect that 33% of patients who will discontinue immunosuppression will exhibit a relapse. Our focus relies on understanding the local changes prior to relapse and exploit the interplay between microbiome und epigenome. Network analysis and mathematical modelling will exploit novel associations of the disease aetiopathogenesis. Results. Our aim is to identify associations between microbiome and epigenome in GPA. With a further understanding of disease aetiopathogenesis using network analyses and mathematical modelling we aim to understand ENT-related disease onset and estimate relapse risk.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: MIMIC - Do parasitic worms and their secreted immunomodulators protect against musculosketal disease by impacting on the host microbiome?
Funder: Versus Arthritis

Abstract: Evolution of our immune system has been influenced by the colonisation of mucosa and tissues by other organisms including the bacterial microbiota and parasitic helminths (worms). Indeed, the Hygiene Hypothesis proposes that the recent eradication of microbial pathogens has generated hyper-activated, dysfunctional immune systems resulting in the well-documented rise in autoimmune diseases in industrialised countries. Consistent with this, parasitic helminths, via secreted immunomodulators, can protect against various autoimmune inflammatory disorders, and this is strikingly apparent with respect to the musculoskeletal disorder, Rheumatoid Arthritis (RA). In addition, they can modulate the microbiome and stabilise epithelial barrier integrity to limit tissue damage and also the systemic bacterial colonisation that results in the chronic, low-grade inflammation implicated in the aetiology of musculoskeletal disease. The core aim of this Pathfinder application is thus to establish MIMIC (Microbiome Impact on Muscoskeletal Immunomodulation Centre): MIMIC is designed to determine whether protective effects of helminths against autoimmune conditions reflect direct impact on the microbiome. It will encompass a multidisciplinary team of researchers, employing robust experimental models in concert with unique cohorts of musculoskeletal disease patients from helminth-endemic areas to address this issue with respect to diseases like RA prior to exploiting data generated for translational purposes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Role of pathobionts in dysbiosis and autoimmunity: An investigation in DMARD-NAÏVE early arthritis patients
Funder: Versus Arthritis

Abstract: Accumulating evidence links the human microbiome to autoimmunity in rheumatoid arthritis (RA), however the aetiopathology of this association and arthritis development remains unclear. Correlations of RA with periodontal disease and gut dysbiosis and the presence of antibodies specific for bacterial (auto)-antigens in newly-diagnosed RA patients have been reported. Furthermore, increased abundance of oral and gut pathobionts, P.gingivalis and P.copri, are observed in RA patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Towards functional correlates of microbiota, immune phenotype and RA
Funder: Versus Arthritis

Abstract: There is considerable interest in the notion that rheumatoid arthritis (RA) pathogenesis may result from microbiota dysbiosis. Evidence for this view encompasses the successful utilization of anti-microbial therapeutics, the impact of microbial environmental differences in RA models and evidence of microbial community differences in periodontal disease and gut microbiota correlating with RA. However, whether microbiota differences are cause or effect of disease remains unclear. We seek to develop collaborative capacity to start addressing key questions in this area, building on existing microbiota research in RA discordant twin pairs. We will establish research links between immunologists, microbiologists, bioinformaticians and rheumatologists, working together to build a dataset on the microbiota in UK RA patients. We will recruit further patients and controls for microbiota analysis, both RA-discordant twin pairs recruited through TwinsUK, recent onset RA cases (and controls) as well as patients with RA and bronchiectasis. We will generate and analyse a peripheral blood immune-subset phenotype and T cell receptor repertoire dataset, allowing investigation of mechanistic relationships between disease phenotype, gut microbiota complexity, phylotypes, common pathways and gene content. We would subsequently aim to transition to translational, therapeutic studies such as culture and investigation of implicated bacterial species in disease models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Determining the molecular mechanisms underlying IL-10 expression in human CD4+ T-cells following TNF blockade
Funder: Versus Arthritis

Abstract: Pro-inflammatory CD4+ T-cells are key contributors to the chronic joint inflammation in rheumatoid arthritis (RA), through their production of pro-inflammatory cytokines. Importantly, pro-inflammatory CD4+ T-cells can also produce the potent anti-inflammatory cytokine interleukin-10 (IL-10), thereby limiting excessive tissue damage. Detailed understanding how IL-10 is regulated is therefore scientifically and clinically important.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the role of regulatory B cells in healthy and in rheumatic diseases
Funder: Versus Arthritis

Abstract: B-cell depletion in autoimmunity has led to heterogeneous clinical responses in patients ranging from no effect to complete and sustained remission. These results have highlighted our limited understanding of the complexity of B-cell function in the context of autoimmune disorders. Conversely, B-cells can drive pathogenic responses by producing autoantibody and providing support for Th1, Th2 and Th17 responses. On the other hand regulatory B-cell (Breg) subsets can restrain inflammation, thorough production of anti-inflammatory cytokines such as IL-10, TGFbeta and IL-35. Currently, we have a rudimentary understanding of the biological mechanisms that control pathogenic and Breg function in autoimmune disease. Here we propose to refine this understanding by investigating Breg development, function, and fate in mice and human disease. In particular we will focus on the emerging role that gut-microbiota play in the development of experimental rheumatic diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Influence of the gut-microbiota on peripheral B cells responses in Juvenile Idiopathic Arthritis.
Funder: Versus Arthritis

Abstract: Juvenile idiopathic arthritis is a collective term encompassing a heterogeneous group of childhood arthritides. Autoimmune phenomena such as autoreactive T-cells and autoantibody-producing B-cells can be detected in both polyarticular and oligoarticular subtypes of JIA. While T-cell responses in JIA have been extensively studied, what causes abnormal B-cell responses and how this contributes to JIA pathology, remain unclear. Bacteria that colonize the gastrointestinal tract, collectively known as the microbiota, have been shown to control both arthritis development and peripheral B cell responses. This proposal aims to test the hypothesis that changes in the microbiota during early-life cause uncontrolled B-cell responses that contribute to JIA pathogenesis. Greater mechanistic understanding into biological pathways that control B-cell responses during childhood and autoimmunity may identify novel therapeutics targets for the treatment and/or prevention of paediatric arthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Granville Hugh King Foundation Fellowship - Elucidating the genetic mechanisms of disease-associated enhancer variants in rheumatoid arthritis
Funder: Versus Arthritis

Abstract: There has been tremendous success in determining the genetic component of susceptibility to rheumatoid arthritis (RA), with over 100 loci identified. For the majority, the causal variants and their target genes remain unknown. Over 80% of associated variants fall in non-coding regions with evidence of enrichment within cell-specific enhancer elements.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Measuring T cell activation thresholds and their role in susceptibility to autoimmune joint disease
Funder: Versus Arthritis

Abstract: For most complex autoimmune diseases including rheumatoid arthritis(RA), juvenile idiopathic arthritis(JIA) and systemic sclerosis(SSc) multiple genetic and environmental factors modulate disease risk. Genome-wide association studies demonstrate substantial sharing of susceptibility genes between diseases, suggesting common underlying elements which cluster into functional pathways. Many of these relate to T-cell activation, differentiation and function, where MHC-II, required for antigen presentation to T-cells, is the strongest genetic risk. Other loci outside of the MHC, identified as providing additional risk, affect T-cell activity including PTPN22, CD28, CTLA-4, TCR-zeta and IL-2RA. Accordingly, inappropriate control of T-cell activation is likely central in the development of autoimmunity. Despite progress in identifying genetic susceptibility little is known about how genetic variation alters immune function. Understanding which loci influence which functions and how these combine to generate significant functional changes is the next major challenge. By studying such relationships we will be able to better understand disease, inform patient treatment and stimulate development of new therapeutic strategies. In this proposal we tackle this roadblock at the interface of genetics and immune function by developing quantitative assays that measure variation in human T-cell activation thresholds and relate these to their underlying genetic influences.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of Myeloid Inhibitory C-type lectin-like receptor (MICL, CLEC12A) in Rheumatoid Arthritis
Funder: Versus Arthritis

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory syndrome whose underlying aetiology is immune mediated. We have discovered that a receptor called myeloid inhibitory C-type lectin (MICL, official name CLEC12A) plays an essential role in controlling inflammation during rheumatoid arthritis (RA). Notably, we have established that MICL is a target of auto-antibodies in patients with RA, and that the administration of such antibodies greatly exacerbates disease in experimental models. These data suggest an entirely novel mechanism underlying the severity and persistence of inflammatory synovitis, whereby myeloid cell activation can be modulated by autoantibody binding regulatory cell-surface receptors. These exciting insights have important diagnostic and therapeutic implications. Using the Scottish Early Rheumatoid Arthritis (SERA) cohort, relevant animal models, and our unique toolbox of human and mouse reagents (including the MICL-/- knockout mice), we will determine the expression, function and role of MICL and the effects of anti-MICL antibodies in RA. Importantly, we will correlate the presence of these antibodies with a variety of human disease parameters, and determine the underlying mechanisms by which they influence RA pathogenesis. In summary, these experiments will provide definitive insights into the mechanisms by which MICL and anti-MICL antibodies influence the progression of RA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Stratification of psoriasis patients at high risk of psoriatic arthritis using lifestyle, environmental and genetic factors
Funder: Versus Arthritis

Abstract: Detection of psoriatic arthritis (PsA) and appropriate rapid treatment was identified as a key area for research in the NICE guidelines for the care of psoriasis in 2012. There are currently no good predictors to determine which psoriasis patients will develop PsA. The proposal aims to identify PsA-specific genetic risk factors and develop a prediction model that includes lifestyle and environmental factors that has the potential to identify at high risk of PsA and help target preventative treatment. Unlike screening in other complex genetic diseases, the potential for identifying PsA risk factors is higher because it will be applied in psoriasis patients already at high risk (10-30%) of developing PsA. There are three objectives: 1) perform the largest comparative genetic analysis of PsA and psoriasis using extant data, 2) perform a gene-based pathway analysis 3) assess the predictive ability of known, and newly discovered genetic risk factors, in conjunction with known lifestyle and environmental factors using data from the UK BioBank. The ability to stratify psoriasis patients at high risk of PsA could prevent illness through preventative treatment, thus providing significant clinical benefits to this high need group.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Lessening the Impact of Fatigue: Therapies for Inflammatory Rheumatic Diseases (LIFT)
Funder: Versus Arthritis

Abstract: Fatigue is pervasive, disabling and challenging to manage across all inflammatory rheumatic diseases (IRDs). Addressing the burden of fatigue is central to Arthritis Research UK’s strategy. Their recent think tank identified a number of fundamental research priorities, several of which we now aim to investigate in this proposal.


Research activity codes: 6.7 PHYSICAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: SYNDECAN BASED ANTI-ANGIOGENIC THERAPEUTICS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
Funder: Versus Arthritis

Abstract: Angiogenesis is the formation of new blood vessels and is essential for the development of the vascular system. In adults this process is rare, however angiogenesis is a feature of a number of inflammatory pathologies including RA. Blockade of angiogenesis in rodent models of RA leads to an amelioration of symptoms and therefore makes this process an attractive target for therapeutic intervention. Although therapies to treat pathological angiogenesis are available their efficacy has not met expectations and there is a need to identify other therapeutic targets. One such group of molecules are the four member syndecan family of cell surface receptors. We have demonstrated that within the extracellular core proteins of syndecans are sequences which inhibit endothelial cell migration and as a result angiogenesis via their action on integrins. We propose that these sequences could be exploited to therapeutic effect and the aim of this project is to characterise the amino acid sequences and synthesize peptides to test whether their anti-angiogenic properties confer therapeutic benefit in murine models of RA. This project will provide an entirely novel set of anti-angiogenic therapeutics which could be used alone or in conjunction with other existing therapies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Dissecting the tripartite relationship of fatigue, autonomic dysfunction and immune dysregulation
Funder: Versus Arthritis

Abstract: Fatigue is a common and disabling problem in many chronic rheumatic conditions, but the underlying mechanisms of fatigue are unclear and no effective treatment is available. Immune dysregulation is frequently observed among fatigued subjects regardless of the underlying condition and pro-inflammatory cytokine blockade can dramatically improve fatigue in some patients with autoimmune rheumatic diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Sleep and Rheumatoid Arthritis health related quality of life: the Sleep-RA study
Funder: Versus Arthritis

Abstract: Background Disease severity is an important predictor of reduced health related quality of life (HRQoL) in people with Rheumatoid Arthritis (RA). RA-HRQoL is lower compared to people with other rheumatic diseases and the general population, even among those with controlled disease. Sleep disturbance is common among people with RA and may interact with pain, fatigue and low mood to reduce HRQoL. Aim The aim of this study is to determine the relative contributions of sleep and circadian parameters, pain, fatigue and mood to RA-HRQoL Method For 30 days participants will wear an actigraphy monitor that will assess their sleep patterns, and via a mobile app self-report their sleep, pain, fatigue and mood. The primary outcome is RA-HRQoL measured at days 0, 10, 30 and 60. State-of-the-art analytical methods (structural equation modelling and latent trajectory analysis) will test the relationship between disease severity and RA-HRQoL over time and the explanatory value of trajectories of sleep, pain, fatigue and mood using repeated measurements. Deliverables The first clear description of sleep disturbance in people with RA Data on pathways that explain the relationship between disease severity and RA-HRQoL Recommendations for targets for intervention development studies and future trials


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Behavioural and neural biomarkers of fatigue in inflammatory arthritis
Funder: Versus Arthritis

Abstract: Fatigue is a major cause of reduced quality of life in inflammatory arthritis, and primarily manifest as a reduction in motivation and drive. But the nature and causes of fatigue are little understood: in particular, how can fatigue be objectively measured, and how is it dependent on nociceptive (chronic pain) and immune (chronic inflammation) inputs to the brain? The aim of this clinical project is to establish both a behavioural and a brain-based biomarker for fatigue in inflammatory arthritis. We plan to utilise a novel behavioural task to measure fatigue, based on psychological and computational theories of 'effort discounting'. We then aim to measure task-related brain activity, and resting-state brain functional network imaging, to identify the specific neural connectivity signature of fatigue in patients (versus control subjects). We aim to identify how this signature is dependent on levels of co-incident pain, and circulating pro-inflammatory cytokines. Finally, we aim to identify translational biomarkers for fatigue and pain by co-analysis of data from a partner project using high-resolution brain network imaging in a rat model of inflammatory arthritis (in Japan). The results should provide a mechanistic and quantitative behavioural and neural biomarker for fatigue, laying a foundation for new therapeutic advances.


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