NIHRDataInsights/HRCSData huggingface dataset:
Title: Disease Duration & TNF-dependent Inflammation in Rheumatoid Arthritis- a programme to improve patient outcomes
Funder: Department of Health (England)

Abstract: Objectives: Rheumatoid Arthritis (RA) poses a significant health economic burden. More complete TNF-blockade response in early compared with later RA suggests a critical therapeutic window to derive maximal benefit. This study aims to develop a rational treatment algorithm in early RA. Hypothesis: i) Inflammation in true early RA is TNF-dependent but becomes increasingly TNF-independent over time ii) Failure to surpress inflammation early encourages development of alternative mediators and loss of response. Design: Pilot, open-label studies, dissecting extent of suppression of inflammation at different disease stages. understanding the drive for this and why response to TNF-blockade changes over time, with mode of action studies to overcome failure/response loss. Methods: 100 patients with true early, early and late RA will receive TNF-antagonistic therapy with longitudinal clinical phenotype, biomarker and Doppler ultrasound assessment. Synovial biopsy and peripheral blood will be acquired at baseline and if suggestion of persistent/increase in inflammation. Primary failure will be managed with tocilzumab and abatacept. Results: The multi-faceted approach will evaluate suppression of inflammation and residual inflammation, correlating with disease duration and linked with identification of alternative mediators responsible for rare true early failure, loss of response and poorer response in late RA. Suppression of inflammation with tocilzumab (downstream target, IL-6) and then abatacept (higher target in immunological hierarchy) will be evaluated in TNF-failures. Conclusion: This study will address an unmet need for development of a logical approach in early RA to improve patient outcome. The host institution is uniquely placed to provide the breadth of clinical and translational expertise needed


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Selecting the right biologic for the right patient in systemic lupus erythematosus (SLE): Personalised therapy based on immunopathogenesis.
Funder: Department of Health (England)

Abstract: Systemic lupus erythematosus (SLE) is a condition which affects the immune system. Patients with SLE have a variable response to treatment. The most commonly used “biologic” treatment is a drug called rituximab. It works by removing specific immune cells, called B cells. While this helps with symptoms in some patients, in others, it is ineffective particularly in patients who have a discoid rash. We aim to improve the use of rituximab by (i) investigating why B cells are not always completely removed in patients receiving rituximab (ii) using an alternative biologic drug specifically targeting the major drive for discoid rash.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Developing a novel biopsy-based diagnostic for patient stratification: A Randomised open labelled study in anti-TNFalpha inadequate responders to investigate the mechanisms for Response Resistance to Rituximab versus Tocilizumab in Rheumatoid Arthritis patients
Funder: Department of Health (England)

Abstract: RESEARCH DESIGN Open randomised clinical trial. Patients will be stratified according to their synovial B cell infiltrate (poor rich or germinal center) at inception and randomised to receive either Rituximab (RTX) or Tocilizumab (TCZ). Patients failing to respond clinically at 6 months will cross-over to the other treatment. STUDY POPULATION Inclusion Criteria: Active seropositive RA patients who have an inadequate to at least one anti-TNF agent. Exclusion Criteria: Contraindications to either therapy as listed in the summary of product characteristics or patients who have a recent change in therapy within the last 4 weeks.PLANNED INTERVENTIONS Randomization to RTX or TCZ following an ultrasound-guided synovial biopsy. Depending on clinical response measured by the DAS28-CRP (see Protocol) patients may continue on RTX or switched to TCZ for a subsequent 6 months. PROPOSED OUTCOME MEASURESPrimary outcome: The primary end point will be the mean change in the DAS28-CRP performed at 6 months from baseline by a blinded assessor. Secondary outcomes at 12 months: *Clinical: 1) Change in x- ray erosive score; 2) Percentage of patients with low disease activity; 3) Percentage of patients in remission; 4) Mean change in Health Assessment Questionnaire (HAQ) score; 5) Reduction in US 2D grey scale and power Doppler signal. *Pathobiology outcomes as described in the Protocol. ASSESSMENT AND FOLLOW UP Patient will be assessed monthly. Each visit will entail: clinical assessment of DAS28-CRP reporting of adverse events safety bloods. Clinical radiological & histological assessments will be performed as indicated by the secondary outcome measures. PROPOSED SAMPLE SIZE 128 patients randomised STATISTICAL ANALYSIS Fisher exact test for the difference in two proportions will be used to (i) compare randomised treatments in B cell poor patients; (ii) to compare B cell rich to B cell poor patients taking Rituximab. The interaction between treatment and B-cell status will be tested by logistic regression and using a two-sided Wald test for the interaction term (with one degree of freedom). PROJECT TIMETABLE Five milestones with go/no-go decisions: 1) Completion of Regulatory approvals; 2) Review of recruitment at 6 months (minimum 20 patients; 3) Preliminary analysis to confirm poorer 3 month clinical response in B cell poor compared to B cell rich patients treated with RTX 12 months after study start;4) Interim analysis of disease outcome measure at 3 months disease activity following therapy (18 months after study start) in B cell poor patients: potential early stopping. 25 months: recruitment completed. 31 months: 6 month follow-up completed. 5) Submission of final study report.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Innovative targets for circadian drug discovery: REV-ERBalpha and RORalpha
Funder: Engineering and Physical Sciences Research Council

Abstract: Humans are rhythmic beings, with daily sleep/wake cycles affecting almost every aspect of physiology and behaviour. Our master circadian clock is known to reside in the suprachiasmatic nuclei (SCN) of the hypothalamus. Via multiple pathways, output from the SCN synchronizes peripheral oscillators throughout the body. The discovery of the molecular components of the core clock has provided new insight into the link between circadian biology and chronic diseases, but has not been exploited for drug discovery. With this work we will prepare chemical probes for the clock proteins REV-ERBalpha and RORalpha, characterise their activity in models of inflammation, and deliver lead optimised molecules for clinical development.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Engineering a semi-biotic immune system
Funder: Engineering and Physical Sciences Research Council

Abstract: Synthetic biology is an emerging field that aims to engineer biological systems by utilising engineering principles, analytical technologies and increasing understanding from biological research. Some of the successes in this young field include bacterial production of the anti-malaria drug artemisinin and generation of significant private funding for basic research. We wish to move developments in Synthetic Biology from simple components towards integrated systems with higher functionalities. Specifically, our long-term goal is to design and fabricate a semi-biotic immune device. At its core, the device will use a consortium of engineered bacteria, composed of a group of detectors that monitor the host for signals of disease onset and responders, that await signals from the detecting bacteria, before initiating the production and release of the relevant small molecule treatment. The engineered bacteria will be interfaced with traditional electronic components that oversee, record and transmit the status of the unit. We envisage that this device will enable individual-specific, rapid and autonomic therapeutic intervention at the early stages of disease.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: An electronic-based ELISA combined with microfluidics
Funder: Engineering and Physical Sciences Research Council

Abstract: Our aim is to develop a low-cost real-time protein detection device to continuously monitor cytokines during in-vitro culture that could eventually expand in clinical practice. We will do this by exploiting discrete electronic components as chemical sensors that are compatible with unique microfluidic chips for minimising the overall cost of the device in combination with small size enzyme-linked immunosorbent assay (ELISA) chambers that minimise antibody requirements. We aspire achieving this by adapting well established manufacturing techniques, currently employed in fabricating printed-circuit boards (PCBs), that could effortlessly render bespoke functionalised electrodes coupled with um-scale fluidic channels/chambers.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Persisting inflammation following critical illness: prevalence, relationship to physical recovery, and exploration of defects in inflammatory resolution pathways.
Funder: Chief Scientist Office (Scotland)

Abstract: Intensive care (ICU) survivors are often severely disabled for many months. The reasons some patients’ recovery is slow and/or incomplete are poorly understood. Systemic inflammation is present in most patients during ICU care, but we do not know how long it persists after ICU discharge. We hypothesise that inflammation during the “recovery” period is important, because in many chronic diseases it causes similar problems to those present in ICU survivors. As part of a randomised trial exploring rehabilitation strategies after critical illness, we are collecting blood samples over the 3 months following ICU discharge. We request funding to use these samples to study the prevalence and patterns of systemic inflammation during this period, and how these relate to patient recovery. Using these data together with a further prospective study of inflammatory cell function, we will explore possible defects in the molecular and cellular events required for successful inflammation resolution.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The development of chemokines as novel, clinical grade, cell-sorting tools.
Funder: Chief Scientist Office (Scotland)

Abstract: We have previously received funding from CSO to examine the usefulness of chemokines as cell-sorting agents. We have hypothesised that chemokines will be able to specifically select for cells bearing their cognate receptors. As chemokine receptors are essential mediators of in vivo leukocyte migration, this will result in selection of cellular populations with enhanced tissue-specific homing capacity. We propose that such selection will be of particular importance in the context of cell-therapies where tissue-specific homing of therapeutic cells is required. We have fully realised the aims of the original grant and have demonstrated the utility of this approach with CCR7-expressing cells. We will now develop this technology for clinical use focusing on dendritic cells which require to migrate to lymph nodes for therapeutic effect. Thus we will optimise the technologies involved, produce novel optimised reagents and develop standard operating procedures for eventual translation to the clinic.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The use of polyomic analyses to direct biologic therapy in biologic-naive people with rheumatoid arthritis
Funder: Chief Scientist Office (Scotland)

Abstract: Rheumatoid Arthritis (RA) is associated with considerable morbidity and premature mortality. Targeted biologic therapies represent a major therapeutic advance. Partial or non-response to biologic agents is common, and only a minority of patients achieve remission. Several biologic modes of action are now available yet no tool exists to select those patients in whom one agent may confer advantage over another. Moreover, these drugs are expensive, costing NHS Scotland approximately £25-30M pa. Gene expression and metabolomic profiling shows promise in identifying predictive polyomic signatures to stratify treatment towards enriched responses. This project will utilise the biobank created in the ORBIT study, the first multi-centre RCT directly comparing TNF inhibitor and B-cell depletion therapy in biologic-naïve RA patients. Gene expression and metabolomic profiles will be generated and submitted for innovative polyomic, bioinformatic analysis to identify integrated signatures that predict drug response, and therefore could optimize biologic drug selection, avoiding unnecessary drug exposure and reducing costs.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A pilot study of oral melatonin in patients with sepsis
Funder: Chief Scientist Office (Scotland)

Abstract: Ex vivo studies have shown that under conditions mimicking sepsis, melatonin and its major metabolite 6-hydroxymelatonin reduce mitochondrial dysfunction and oxidative stress and attenuate pro-inflammatory cytokine responses. In animal models of sepsis, melatonin is effective in reducing organ dysfunction and mortality, even when administered after the onset of sepsis. We have undertaken a Phase I dose escalation study and found oral melatonin to be well tolerated at the doses which result in circulating levels of melatonin and 6-hydroxymelatonin which are effective ex vivo. We propose to determine the pharmacokinetics of oral melatonin in this target population to define the required dosing interval, followed by a double blind randomised pilot study to assess feasibility and safety with initial explorations of a range of biomarkers as potential markers of efficacy. The data from this study will provide key information to enable us to proceed to a larger multi-centre Phase II trial.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Scottish Early Rheumatoid Arthritis (SERA) bio-bank from an inception cohort of patients with newly diagnosed rheumatoid arthritis.
Funder: Chief Scientist Office (Scotland)

Abstract: Scottish patients with newly diagnosed undifferentiated polyarthritis (UP) and rheumatoid arthritis (RA) will be enrolled into an inception cohort, and carefully characterised in terms of clinical, laboratory and radiographic characteristics over 12 months. Samples of whole blood, serum, plasma, RNA, DNA and (where available) synovial fluid from the entire cohort will be stored at baseline, 6 and 12 month in a bio-repository at the Translational Medicine Research Institute (TMRI) in Dundee. A scientific steering committee will grant access to the clinical data and bio-repository samples according to scientific merit. In the long term, the SERA clinical database has the potential to be developed into a Scottish Clinical Information system for RA (SCI-RA) that would integrate information systems for the benefit of clinical care, audit and research.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A Population-based Ankylosing Spondylitis [PAS] cohort
Funder: Medical Research Council

Abstract: Ankylosing spondylitis (AS) is the second most common form of inflammatory arthritis. However, the natural history of AS is poorly understood with considerable variability in presentation and progression. In particular, there is a paucity of research on the cost of AS which has resulted in delayed NICE approval of new effective therapies for AS. The cost-effectiveness issue is further limited by the current inability to identify patients at risk of developing aggressive disease (who would benefit most from early aggressive therapy) and inability to predict which patients will fail to respond to these therapies. Identifying and recruiting AS patients, in a prompt and cost-effective manner, for genetic validation studies and clinical trials of new therapies is becoming increasingly difficult in the current fragmented NHS system. This proposal is for a population based cohort of people with AS, utilising disease-specific data (rheumatology database, radiology imaging) and patient-centred data (quality of life, work limitations, disease activity, function) linked with existing electronic data from disparate clinical, laboratory and administrative systems held by HIRU (GP records, out-patient and in-patient data, laboratory, A&E, social services datasets etc). All patients with AS (diagnosed by a rheumatologist) living in Wales will be approached to participate in this cohort, resulting in a well characterised cohort with robust clinical data at its base. The unique link with existing datasets will allow the cohort to be followed both prospectively and retrospectively. Therefore the cohort can be used to provide data on the natural history of AS, give an objective estimate of the cost of AS at each stage of the disease, identify early risk factors for severe disease, help identify potential interventions to prevent surgery and disability, in addition to facilitating patient identification and recruitment for genetic studies and clinical trials of new interventions. This study builds on existing UK resources and enhances the NHS?s ability to attract research. The cohort can also contribute to registers and post-marketing surveillance of new therapies. The use of routine data will ensure that this study will not suffer from the ?cohort effect? as all patients nationally can be included in the linking of routine data, and the use of rheumatology and GP clinical records will ensure the cohort will not date with time as it will include all new patients every year. Therefore this cohort, which can act as a pilot for other conditions, builds on and enhances existing UK resources and infrastructure.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Pathobiology of Early Arthritis Cohort (PEAC)
Funder: Medical Research Council

Abstract: Rheumatoid arthritis (RA) is one of the most important chronic inflammatory disorders in the UK. It affects approximately 1% of adults, causes considerable morbidity, reduces quality of life, increases mortality and results in large medical costs (over #1.2 billion/year). Importantly, RA behaves clinically as a heterogeneous condition with a variable clinical course and major differences in joint damage scores and consequent disability. Thus, it is crucial to tailor potentially toxic and expensive drugs (biologic #10k/year/patient/) to the individual patient?s needs as well as for targeting limited health care resources. Current prognostic algorithms are insufficiently sensitive at presentation to reliably identify individuals that will progress to destructive arthritis and hence functional and economic decline. The purpose of the application is to address this unmet clinical need by developing a prospective cohort of early inflammatory arthritis patients with the goal of creating a unique resource with high-density data including genotyping, biologic tissue characterisation, state?of-the-art 3/4D ultrasound-US/power-Doppler-PDU imaging, and detailed clinical phenotyping that will enable us to search for early predictors of disease evolution as well as to examine the role of multiple cellular and molecular pathways involved in joint destruction and therapeutic response. Thus, this cohort will represent an ideal platform for innovative clinical trials with stratified entry according to imaging, biologic and clinical profile that will be of major interest to academia, industry and government bodies. In particular, it is envisaged that time integrated US/PDU imaging will improve on currently employed composite clinical assessment tools permitting earlier evaluation of response to therapy and development of novel prognostic algorithms of structural damage progression. Equally, the comprehensive collection of samples (particularly synovial tissue through a US guided minimally invasive biopsy) will facilitate research in the fields of Genomics, Transcriptomics, Proteomics, Metabonomics, Cell and Humoral Biology enabling scientists to test and generate hypotheses on the disease origin, susceptibility and diverse outcome. Despite being a common disease there have been few cohorts in the UK that have systematically collected clinical, radiological, genetic and biological data. The Pathobiology of Early Arthritis Cohort (PEAC) will provide such a unified approach. It will lead to a step change in the way in which clinical, imaging and immune-pathologic data is collated and integrated in the UK, allowing UK rheumatologists to have a unique resource to compete within the EU arena, where complementary but distinct approaches in the Netherlands and Scandinavia have proven to be highly informative and successful.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM