Pathobiology of Early Arthritis Cohort (PEAC)

Lead Research Organisation: Queen Mary, University of London
Department Name: William Harvey Research Institute

Abstract

Rheumatoid arthritis (RA) is a diverse disease with some patients suffering from a mild disease while others develop a more aggressive course. At present it is impossible to predict from the outset the final disease outcome. Expert opinion favours the use of aggressive treatment in all patients with early RA including the use of the new biological agents (magic bullets). Given the high costs of these drugs (#10,000/year/patient) and their potential toxicity it is imperative to tailor early treatment to patients most at risk of poor outcome.

In some other inflammatory conditions such as kidney diseases specific treatments are guided by the severity of the tissue pathology determined following examination of the tissue under the microscope. We propose to validate and use the same concept to treat patients with RA. Patients would have a small piece of tissue (synovial biopsy) taken from the joint at disease outset that will be analysed for specific features that might give clues on the severity of the disease enabling doctors to target specific therapies to those most in need.

This together with studying biological markers in the blood and urine of these patients will enable scientist to investigate potential causes regarding the origin, evolution and treatment of arthritis.

It is hoped that the elucidation of key pathways involved in the perpetuation or resolution of inflammation will lead to the development of new drugs (and/or the testing currently available drugs in a better way) that will facilitate induction of remission in the majority of patients. This in turn will result in less joint damage and consequent disability with considerable alleviation of suffering for patients and their family as well as reduction of the health-economic burden on the NHS and society in general.

Technical Summary

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.

Publications

10 25 50
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Bombardieri M (2017) Ectopic lymphoid neogenesis in rheumatic autoimmune diseases. in Nature reviews. Rheumatology

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Corsiero E (2016) Ectopic Lymphoid Structures: Powerhouse of Autoimmunity. in Frontiers in immunology

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Dorris ER (2019) The Autoimmune Susceptibility Gene Regulates Macrophage-Mediated Resolution of Inflammation. in Journal of immunology (Baltimore, Md. : 1950)

 
Title Tate Exchange Programme (Jun 2019) 
Description Exhibition to demonstrate the 'Effect of Arthritis on Movement and Art' Gloves will be used to restrict movement and simulate the effects of arthritis Ultrasound machines will show delegates the inside of their joints Art from patients with arthritis (including Renoir ) will be displayed The role of research in the development of new medicines and the alleviation of symptoms will be highlighted 
Type Of Art Artistic/Creative Exhibition 
Year Produced 2019 
Impact Too early 
URL https://www.tate.org.uk/visit/tate-modern/tate-exchange
 
Description ACR/eular Exchange Program
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
 
Description AMP RA SLE Steering Committee
Geographic Reach North America 
Policy Influence Type Participation in a advisory committee
URL https://www.nih.gov/research-training/accelerating-medicines-partnership-amp
 
Description Addressing the grand challenges in Immune Mediated Inflammatory Diseases
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Annual EATC/EOTC Directors Meeting - Arthritis Research UK
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Arthritis Research UK and NIHR sponsored Experimental Musculoskeletal Medicine Conference - to explore the alignment and opportunities to maximise, improve and add to the UK musculoskeletal experimental medicine investment in order to accelerate the translation of innovations for the benefit of patients, the public and the healthcare system
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Development of immune tolerance therapies for the treatment of rheumatic diseases - THE INNOVATIVE MEDICINES INITIATIVE
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
URL http://www.imi.europa.eu
 
Description EULAR Synovitis Study Group
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
URL http://www.eular.org/investigative_rheumatology_study_groups.cfm
 
Description Influence on Funding Policy: MRC, NIHR, ARUK recognised need to fund Stratified Medicine Programmes in RA. PEAC has formed the platform for a suite of stratified Medicine programmes including MATURA and R4RA
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Influence on Industry drug development policy: Stratified Medicine for RA
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description TRC Strategy Review /Objectives Setting
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://www.nihr.ac.uk/life-sciences-industry/access-to-expertise-and-collaborations/collaborations-...
 
Description Training in Disease Activity Scores & Ultrasound Assessments of RA
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Greater consistency in evaluating and recording of measures of disease in RA
 
Description Translational Research Collaboration for Joint & related inflammatory diseases- Steering Committee Meeting
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL http://www.nihr.ac.uk/life-sciences-industry/access-to-expertise-and-collaborations/collaborations-f...
 
Description Ultrasound Guided Synovial Biopsy Courses
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.matura-mrc.whri.qmul.ac.uk/ultrasound_guided_synovial_biopsy_taking_a_biopsy.php
 
Description Versus Arthritis senior stakeholder meeting
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Abbvie
Amount £781,220 (GBP)
Funding ID PO 4200455030 
Organisation AbbVie Inc 
Sector Private
Country Global
Start 12/2015 
End 12/2017
 
Description Arthritis Research UK Clinical lecturer in experimental medicine and rheumatology
Amount £565,973 (GBP)
Funding ID 21890 
Organisation Versus Arthritis 
Start 01/2018 
End 01/2023
 
Description Arthritis Research UK Experimental Arthritis Treatment Centre
Amount £225,000 (GBP)
Funding ID 20022 
Organisation Versus Arthritis 
Start 07/2012 
End 06/2015
 
Description BMS
Amount £500,000 (GBP)
Funding ID IM006-030_Pitzalis 
Organisation Bristol-Myers Squibb 
Sector Private
Country United States
Start 10/2016 
End 10/2020
 
Description Clinical Trial - Arthritis Research UK ORBIT Trial- Biopsy driven sub-trial
Amount £993,924 (GBP)
Funding ID 18824 
Organisation Versus Arthritis 
Start 10/2010 
End 06/2014
 
Description Early Arthritis Referral Centre/Barts & the London Charity
Amount £498,438 (GBP)
Funding ID 523/819 
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 08/2015
 
Description Genentech
Amount £713,047 (GBP)
Funding ID PEAC 2 
Organisation Genentech, Inc 
Sector Private
Country United States
Start 05/2013 
End 08/2018
 
Description Immune-Mediated Inflammatory Disease Biobanks in the UK (IMIDBio-UK)
Amount £1,700,000 (GBP)
Funding ID MR/R014191/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 03/2021
 
Description Janssen
Amount £438,000 (GBP)
Funding ID PO 993320280 
Organisation Janssen Biotech, Inc. 
Sector Private
Country United States
Start 09/2014 
End 08/2019
 
Description LCRN service support costs and research nurse/North Thames CRN
Amount £234,612 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 11/2008 
End 03/2016
 
Description MICA Research Grant & MedImmune Ref: MR/K020250/1 Interleukin-21 (IL-21) in rheumatoid arthritis (RA): exploring its therapeutic potential for the development of a novel targeted biologic therapy.
Amount £252,663 (GBP)
Funding ID MR/K020250/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2013 
End 06/2016
 
Description MRC Stratified Medicines _ MATURA
Amount £4,985,662 (GBP)
Funding ID MR/K015346/1 
Organisation Medical Research Council (MRC) 
Department MRC Stratified Medicine
Sector Charity/Non Profit
Country United Kingdom
Start 03/2014 
End 03/2019
 
Description MRC project grant : Inflammation
Amount £363,277 (GBP)
Funding ID MR/K013068/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2013 
End 12/2016
 
Description NIHR Clinical Lectureship
Amount £310,937 (GBP)
Organisation Health Education England 
Sector Public
Country Unknown
Start 01/2019 
End 01/2023
 
Description NIHR EME funding for R4RA
Amount £1,002,635 (GBP)
Funding ID 11/100/76 
Organisation NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) 
Sector Academic/University
Country United Kingdom
Start 12/2012 
End 11/2018
 
Description NIHR/ NOCRI Translational Research Partnership (TRP) THERAPIST - Th17 Responses Evaluated in RA Patients on Inhibitors of TNFa
Amount £590,980 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2015 
End 12/2017
 
Description Pfizer Aspire
Amount £310,692 (GBP)
Funding ID 8502000364 
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 09/2018 
End 08/2020
 
Description Versus Arthritis Fellowship
Amount £219,113 (GBP)
Funding ID 22000 
Organisation Versus Arthritis 
Start 09/2018 
End 09/2020
 
Title EMR Biobank 
Description EMR biobank containing over 800 synovial biopsies supports multiple projects and each research project adds to the samples and information available Synovial biopsies are linked to tight clinical databases including ultrasound synovitis assessments 
Type Of Material Biological samples 
Year Produced 2015 
Provided To Others? Yes  
Impact Supports academic and industry collaborations 
 
Title Pathobiology of Early Arthritis Cohort (PEAC) 
Description Blood, urine and synovial tissue coupled with detailed clinical phenotyping 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact The PEAC biomedical resource will enable to examine the role of multiple cellular and molecular pathways involved in arthritis susceptibility, heterogeneous outcome and treatment response. 
URL http://www.peac-mrc.mds.qmul.ac.uk/
 
Title Clinical Records Management System for Inflammatory Arthritis database (CReMSIA) 
Description Currently upwards of 400 patients suffering from inflammatory arthritis (predominantly Rheumatoid and Psoriatic arthritis) have been recruited primarily to synovial biopsy based studies led by the centre for Experimental Medicine and Rheumatology at Barts Health NHS Trust. Patients within the cohort have been recruited at varying disease stages including at disease onset (PEAC, Pathobiology of Early Arthritis cohort), following failure to respond to traditional disease modifying anti-rheumatic drugs (DMARDs) (THERAPIST, STRAP) and following the failure on first line biologic therapy (R4RA study). The CReMSIA database proposed intends to act as a central repository for all clinical data collected within clinical trials within the department of Rheumatology, Barts Health NHS Trust led by Experimental Medicine and Rheumatology for which QMUL is the study sponsor. The intention would be to continue to follow these patients on their return to routine NHS rheumatology clinic, collecting data recorded within routine follow up visits. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? No  
Impact Too early 
 
Title PEAC Study Database 
Description Study specific Electronic Data Capture (EDC) system for PEAC. This includes a electronic Case Record Form (eCRF) as well as a Study Management system linking clinical data to pathobiology data. The EDC system is designed to follow the order of the study assessments and include all the clinical data (incl. Medication history, lifestyle factors questionnaire, DAS28 etc) submission to the database is via an encrypted and password protected link dedicated to each individual centre. This database is designed to provide an online facility to monitor registration, transport and processing of PEAC samples, from the clinic to the microscope. Further, this application allows the clinician at a remote centre, to view histopathology reports and representative micrographs of submitted samples as soon as they are prepared at the central repository. Additionally, a PEAC Website Tutorial Manual has been constructed and disseminated to the participating PEAC centres. This manual details online access to the PEAC Bio-bank and tracking of the samples provided to PEAC. 
Type Of Material Data handling & control 
Year Produced 2008 
Provided To Others? Yes  
Impact High quality data for PEAC cohort now supporting many studies 
URL https://www.peac.whri.qmul.ac.uk
 
Title Synovial RNA-sequence transcriptomic database 
Description The first comprehensive synovial RNA-sequence transcriptomic database 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact Work ongoing 
 
Description AbbVie: Targeting synovial tissue pathways in RA patients resistant to conventional DMARDs: screening AbbVie development pipeline. 
Organisation AbbVie Inc
Country Global 
Sector Private 
PI Contribution Analysis of samples
Collaborator Contribution Financial support & pipeline compounds
Impact Work ongoing
Start Year 2016
 
Description Humanitas PEAC 
Organisation Humanitas University
PI Contribution Provided serum samples with clinical data
Collaborator Contribution Partner to analyse for PTX3 expression
Impact Too early - publication anticipated
Start Year 2018
 
Description Janssen / J&J: Genetic and genomic profiling of RA early arthritis patients 
Organisation Janssen Biotech, Inc.
Country United States 
Sector Private 
PI Contribution Analysis of samples in PEAC cohort
Collaborator Contribution Financial support
Impact Work ongoing
Start Year 2014
 
Description MedImmune / AZ: MRC/MICA Targeting IL-21 in specific synovial tissue pathotypes 
Organisation MedImmune
Country United States 
Sector Private 
PI Contribution Analysis of synovial samples
Collaborator Contribution Financial support
Impact Work ongoing
Start Year 2013
 
Description Metabolic analysis in serum and urine of patients with early arthritis 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided samples and data from the PEAC cohort
Collaborator Contribution Metabolomic analysis of samples to identify biomarkers in early arthritis
Impact Work ongoing
Start Year 2016
 
Description NIH Accelerated Medicines Partnership 
Organisation North Shore Long Island Jewish Medical Center
Department Feinstein Institute for Medical Research
Country United States 
Sector Academic/University 
PI Contribution Contributed skills in synovial biopsy, sample processing and storage Samples provided for analysis
Collaborator Contribution Single-cell analysis
Impact Improved methods Publications
Start Year 2015
 
Description Optimal Treatment of RA Patients Requiring Biologic Therapy (ORBIT). 
Organisation NHS Greater Glasgow and Clyde (NHSGGC)
Department Rheumatology NHSGGC
Country United Kingdom 
Sector Public 
PI Contribution Arthritis research UK has also funded a randomised clinical trial in which patients with RA that require commencement of a biologic agent by virtue of current disease activity will receive either a B cell depleting agent or a TNF blocking agent: Optimal Treatment of RA Patients Requiring Biologic Therapy (ORBIT). The PEAC investigators are part of this wider study and have nested within it an exploratory evaluation (PEAC 2) in which synovial biopsies will be used to determine whether the synovial pathotype, in particular that containing either an inflammatory or B cell dominant phenotype, enriches subsequent responsiveness to either biologic intervention. This study will capitalize upon the unique resource created by PEAC in that responses can be compared with the wider natural progression of RA patients on conventional therapy.
Collaborator Contribution Expanded the opportunity of translational research by facilitating the clinical utility of synovial biopsy in a clinical trial.
Impact Results to be published
Start Year 2009
 
Description PEAC Consortium 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution The PEAC Initiative was led and coordinated by Professor Costantino Pitzalis with the support of the members of the PEAC consortium, the PEAC Steering Committee and the PEAC Scientific Advisory Board. In order to ensure effective and efficient administration of the PEAC project, the following administrative infrastructure was installed: Project Management: to ensure optimal coordination and administration of this programme together with timely and high quality data collection and analysis. Technical Assistance: A highly experience and able Research Assistant, Miss Rebecca Hands was appointed to ensure efficient processing, storing and high fidelity archiving of PEAC biological samples. Data Management: A website was created to act as a central repository for all the PEAC project samples and their related data. Over 300 patients were recruited for the study at Bart's
Collaborator Contribution Partners provided samples to generate this unique bio-medical resource with high-density data including gene expression profiling, proteomics, metabolomics, genotyping, serum and synovial fluid cyotokine & chemokine analysis, biological tissue characterisation, state-of-the-art ultrasound imaging, and detailed clinical phenotyping. This resource continues to enable assessment of the role of a spectrum of molecular and cellular pathways that may be involved in disease susceptibility, heterogeneity and treatment response.
Impact Multiple publications, which are continuing to be generated. Additional academic and industry partnerships Additional grant funding secured Additional industry funding secured Change in policy regarding support for research on stratified medicines Patents pending
Start Year 2008
 
Description PEAC Consortium 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution The PEAC Initiative was led and coordinated by Professor Costantino Pitzalis with the support of the members of the PEAC consortium, the PEAC Steering Committee and the PEAC Scientific Advisory Board. In order to ensure effective and efficient administration of the PEAC project, the following administrative infrastructure was installed: Project Management: to ensure optimal coordination and administration of this programme together with timely and high quality data collection and analysis. Technical Assistance: A highly experience and able Research Assistant, Miss Rebecca Hands was appointed to ensure efficient processing, storing and high fidelity archiving of PEAC biological samples. Data Management: A website was created to act as a central repository for all the PEAC project samples and their related data. Over 300 patients were recruited for the study at Bart's
Collaborator Contribution Partners provided samples to generate this unique bio-medical resource with high-density data including gene expression profiling, proteomics, metabolomics, genotyping, serum and synovial fluid cyotokine & chemokine analysis, biological tissue characterisation, state-of-the-art ultrasound imaging, and detailed clinical phenotyping. This resource continues to enable assessment of the role of a spectrum of molecular and cellular pathways that may be involved in disease susceptibility, heterogeneity and treatment response.
Impact Multiple publications, which are continuing to be generated. Additional academic and industry partnerships Additional grant funding secured Additional industry funding secured Change in policy regarding support for research on stratified medicines Patents pending
Start Year 2008
 
Description PEAC Consortium 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution The PEAC Initiative was led and coordinated by Professor Costantino Pitzalis with the support of the members of the PEAC consortium, the PEAC Steering Committee and the PEAC Scientific Advisory Board. In order to ensure effective and efficient administration of the PEAC project, the following administrative infrastructure was installed: Project Management: to ensure optimal coordination and administration of this programme together with timely and high quality data collection and analysis. Technical Assistance: A highly experience and able Research Assistant, Miss Rebecca Hands was appointed to ensure efficient processing, storing and high fidelity archiving of PEAC biological samples. Data Management: A website was created to act as a central repository for all the PEAC project samples and their related data. Over 300 patients were recruited for the study at Bart's
Collaborator Contribution Partners provided samples to generate this unique bio-medical resource with high-density data including gene expression profiling, proteomics, metabolomics, genotyping, serum and synovial fluid cyotokine & chemokine analysis, biological tissue characterisation, state-of-the-art ultrasound imaging, and detailed clinical phenotyping. This resource continues to enable assessment of the role of a spectrum of molecular and cellular pathways that may be involved in disease susceptibility, heterogeneity and treatment response.
Impact Multiple publications, which are continuing to be generated. Additional academic and industry partnerships Additional grant funding secured Additional industry funding secured Change in policy regarding support for research on stratified medicines Patents pending
Start Year 2008
 
Description PEAC Consortium 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution The PEAC Initiative was led and coordinated by Professor Costantino Pitzalis with the support of the members of the PEAC consortium, the PEAC Steering Committee and the PEAC Scientific Advisory Board. In order to ensure effective and efficient administration of the PEAC project, the following administrative infrastructure was installed: Project Management: to ensure optimal coordination and administration of this programme together with timely and high quality data collection and analysis. Technical Assistance: A highly experience and able Research Assistant, Miss Rebecca Hands was appointed to ensure efficient processing, storing and high fidelity archiving of PEAC biological samples. Data Management: A website was created to act as a central repository for all the PEAC project samples and their related data. Over 300 patients were recruited for the study at Bart's
Collaborator Contribution Partners provided samples to generate this unique bio-medical resource with high-density data including gene expression profiling, proteomics, metabolomics, genotyping, serum and synovial fluid cyotokine & chemokine analysis, biological tissue characterisation, state-of-the-art ultrasound imaging, and detailed clinical phenotyping. This resource continues to enable assessment of the role of a spectrum of molecular and cellular pathways that may be involved in disease susceptibility, heterogeneity and treatment response.
Impact Multiple publications, which are continuing to be generated. Additional academic and industry partnerships Additional grant funding secured Additional industry funding secured Change in policy regarding support for research on stratified medicines Patents pending
Start Year 2008
 
Description PEAC Genotypic analysis of Methotrexate responsiveness 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided DNA samples from MTX responders and non-responders for analysis
Collaborator Contribution Genetic analysis including methylation studies
Impact Work ongoing
Start Year 2015
 
Description Pfizer: Screening Pfizer immunology pipeline against synovial tissue in early RA 
Organisation Pfizer Inc
Country United States 
Sector Private 
PI Contribution Analysis of samples from the PEAC cohort
Collaborator Contribution Financial support, pipeline compounds
Impact Work ongoing
Start Year 2013
 
Description Roche/Genentech: RA synovial tissue multi-biomic profiling in early arthritis patients 
Organisation Genentech, Inc
Country United States 
Sector Private 
PI Contribution Analysis of samples from PEAC cohort
Collaborator Contribution Financial support
Impact Work ongoing
Start Year 2012
 
Description University of California 
Organisation University of California
Country United States 
Sector Academic/University 
PI Contribution Provided formalin fixed slides of synovial tissue from RA patients of known pathotype, treatment and response to treatment
Collaborator Contribution Analysis of expression of protein tyrosine phosphatases in the samples
Impact Too early - publication anticipated
Start Year 2018
 
Title A Randomised, open labelled study in anti-TNFa inadequate responders to investigate the mechanisms for Response - Resistance to Rituximab versus Tocilizumab in RA 
Description Full Title: A Randomised, open labelled study in anti-TNFa inadequate responders to investigate the mechanisms for Response - Resistance to Rituximab versus Tocilizumab in RA EudraCT reference: 2012-002535-28 R4-RA is a biopsy-driven, multicentre, international, open-label randomised controlled trial. This trial will aim to develop a diagnostic tool (immunohistochemical analysis of synovial tissue) for patient stratification into responsive / non-responsive categories with respect to Rituximab therapy in patients who have had an inadequate response to anti-TNF therapy. Specifically, it aims to determine whether a diagnostic synovial biopsy showing a B-cell "rich/poor pathotype" defines specific disease responsive/resistant subsets for patient stratification and helps rationalize biologic drug choice. Patients will undergo a synovial biopsy which will stratify them in to 3 pathotype groups (B Cell Poor, B Cell Rich, Germinal Centres (GC) Rich) according to the B-cell score from the biopsy tissues, and in each stratum they will be randomised into two therapeutic arms, Rituximab and Tocilizumab (1:1). Primary Endpoint is treatment response assessed using the Clinical Disease Activity Index (CDAI) at 16 weeks. Patients deemed treatment failures at 16 weeks will be switched to the other therapeutic option. The trial involves 48 weeks treatment period, followed by further 48 weeks follow-up period. Both Rituximab and Tocilizumab have marketing authorisation. Whilst Rituximab is a NICE approved treatment option for patients following anti-TNF therapy, Tocilizumab is not currently a NICE approved pathway. The trial is funded by NIHR EME Programme. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Market authorisation
Year Development Stage Completed 2006
Development Status Under active development/distribution
Impact The significant impact is expected from the outcome of this trial, which has a potential to change clinical practice and therapeutic algorithms for biologic therapies in Rheumatoid Arthritis (RA). This trial aims to develop of a diagnostic synovial tissue biopsy for patient stratification into responsive / non-responsive categories (treatment algorithm) to the depleting anti-CD20 monoclonal antibody: Rituximab (RTX). As approximately half of the RA patients have very few B-cells in the joint, the hypothesis of this trial is that these patients are less likely to respond to RTX and that, by examining a small piece of synovial tissue (biopsy) for the presence or absence of B cells prior to treatment with RTX, clinicians will be able to predict likelihood of response and inform drug choice. This would: a) provide better care by preventing delay in starting a potentially more effective biologic drug; b) prevent unnecessary exposure to a potentially seriously toxic drug such as RTX and c) avoid wasting £6-8 million to the NHS. The development of the technology may also lead to protectable IP. In addition, transcriptomic and next generation sequencing analysis may lead to the identification of specific pathways, "known or unknown", associated with clinical response to therapeutic intervention with biologic agents. The discovery of such pathways would lead to patentable inventions. 
 
Title ORBIT (Biopsy study) 
Description Synovial biopsy technique to obtain disease tissue from most patients and any joints (large and small), through a minimally invasive, well-tolerated ultrasound-guided approach. Synovial biopsy B-cell Biomarker as a diagnostic tool to be validated in clinical trials for patient stratification into responsive / non-responsive categories. (Trained over 20 EU and 15 USA Fellow Rheumatologists The diagnostic tool emerging from analysing diseased tissue can be adapted for execution in all NHS accredited clinical pathology units 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2014
Development Status Actively seeking support
Clinical Trial? Yes
Impact Applied to numerous clinical studies for stratification of RA 
 
Title Stratification of Therapy for Rheumatoid Arthritis by Pathobiology (STRAP) Clinical Trial 
Description This study will aim to test the utility of synovial histopathology and cell type as a potential biomarker to guide therapeutic decisions in RA patients failing DMARD therapy and started on Rituximab, Tocilizumab or Etanercept therapy. Specifically, can a diagnostic synovial biopsy showing a B-cell "rich/poor pathotype" define specific disease responsive/resistant subsets for patient stratification and help rationalise biologic drug choice? The trial is currently under review by the REC and MHRA and is jointly funded by the MRC and ARUK. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2019
Development Status Under active development/distribution
Impact The aim is to provide a tailored approach to treatment decisions in patients at this stage of their disease, in order to maximise their potential response to therapy. The following are notable impacts arising from trial development: 1. STRAP Protocol complete and patient related documents review by Queen Mary patient advisory group. 3. Clinical Database: testing underway. 4. REC and MHRA submitted. REC meeting 13th Nov 5. 5. TMG formed and convenes frequently TSC will be in line with timelines. 6. STRAP website launched. 7. Investigators Meeting 17th September 2014. 
URL http://www.matura-mrc.whri.qmul.ac.uk
 
Title Therapist 
Description Though anti-TNFa therapy has transformed the treatment of rheumatoid arthritis (RA), 30-40% patients don't respond to this treatment. Currently, there are no tests capable of predicting response and the mechanisms of non-response remain unknown. This leaves a major unmet need and a considerable health and economic burden. In the UK alone, RA drugs cost the NHS £560 million, while RA total annual economic impact is estimated £4.2 billion (NAO). The THERAPIST study aims to address this major unmet need by exploring the capacity of disease tissue (synovium) and peripheral blood biomarkers to predict response prior to anti-TNFa therapy initiation and to understand the mechanisms of response/nonresponse. In addition THERAPIST will characterise the role of IL17/ Th17 pathway (primary hypothesis) & , through a powerful hypothesis-free discovery investigation, potentially unveil new therapeutic targets. 50 RA patients requiring anti-TNFa therapy after failure of conventional Disease Modifying Anti Rheumatic Drugs, e.g. methotrexate, according to NICE guidelines, will be recruited to the study following informed consent. Clinical responses will be assessed by standard/validated tools such as 28 tender-swollen joint count integrated into the Disease Activity Score (DAS28), as well as objective ultrasound joint imaging. Biological responses are measured in the disease tissue (synovial biopsy substudy) in 20 patients consenting to an ultrasound-guided, minimally invasive, well-tolerated procedure, as we described (Kelly et al. Ann Rheum Disease 2013) and in peripheral blood of all 50 patients as comparators. The biopsy substudy is essential to provide disease tissue for the proposed investigation, as 30 years of research looking for peripheral blood predictive biomarkers have proven unsuccessful. It is clear that direct sampling of the diseased tissue can provide fundamental evidence to inform therapeutic decision-making (e.g. Tamoxifen in ER+ve breast cancer). 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Provide evidence to evidence to inform therapeutic decision-making so improving health outcomes and reducing the economic burden of RA 
URL http://www.isrctn.com/ISRCTN18262002
 
Title BioT-App 
Description Application developed for patients to monitor disease activity using the DAS28 outcome measure Patients report joint swelling & tenderness, measures of well being and adverse events, this information is captured centrally 
Type Of Technology Software 
Year Produced 2018 
Impact Too early , will be applied to future clinical trials to enable real time monitoring of patients , providing more accurate information and potentially reducing the costs of running trials by reducing the number of unperson visits required. 
 
Description Arthritis stand at the Bart's & QMUL Science Festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact The festival, aimed at secondary schools and young people interested in a career in science and medicine, was held at QMUL's Mile End campus on the 21 June .
Students from schools across London attended the seventh edition of the festival which was supported by the National Institute for Health Research (NIHR), the Biomedical Research Centre (Barts BRC), the NHS Trust and Trials Connect. EMR coordinated a stand to provide children with an opportunity to learn more about arthritis, this included; Posters on the difference between RA & OA; simulation gloves to mimic the effect of arthritis on dexterity , ultrasound scans so that children could 'see inside their joints'. Members of NRAS & ARUK helped on the day with the exhibition.
Year(s) Of Engagement Activity 2017,2018
URL http://www.qmul.ac.uk/media/news/items/smd/198594.html
 
Description MUTURA article in NRAS Magazine spring 2017 & spring 2018 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Article in NRAS magazine purpose was to engage RA patients and carers in the potential of stratified medicines. Resulted in enquiries about the clinical trial, STRAP, and in patients volunteering to join the MATURA patient advisory group
Year(s) Of Engagement Activity 2017,2018
URL https://www.nras.org.uk/data/files/Membership/Members%20Area/27642%20NRAS%20Magazine%20Spring%202017...
 
Description Meet the Researcher Event QMUL 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Patients and carers invited to visit laboratories to meet researchers and see their work, this also allowed laboratory researchers to meet patients . Researchers also manned stands to educate patients and carers on research projects . MATURA patient advisory group manned a stand that allowed researchers to meet them and to try on gloves that simulate having arthritis. Followed by a BBQ to allow informal conversations and greater insights for both groups.
Year(s) Of Engagement Activity 2017,2018
URL http://www.qmul.ac.uk/citi/patient-and-public-engagement/
 
Description PEAC Consortium - Operational 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Regular communication to inform partners, monitor progress and to stimulate discussion on future research projects. This included teleconferences, meetings an symposia
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012
 
Description PEAC Website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The PEAC Website provides information on the background and objectives of the study. Details of participating centres are included and the sources made available to researchers/industry as a result of the study.
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012
URL http://www.peac-mrc.mds.qmul.ac.uk/resource.php
 
Description Precision Medicine UK 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact NOCRI joined UK leaders in the research, development and commercialisation of precision medicine for a one-day event this week designed to encourage new partnerships and highlight new opportunities in the field. The Precision Medicine UK: Collaboration Nation event at De Vere Holborn Bars, London, on 9 December was organised on behalf of the Stratified Medicine Innovation Platform by Innovate UK,, National Institute for Health Research, Cancer Research UK,Medical Research Council, Invest Northern Ireland, Health and Care Research Wales and the Knowledge Transfer Network, with the NIHR Office for Clinical Research Infrastructure (NOCRI) coordinating the NIHR's involvement. The day formed part of a programme to make the UK a world leader in precision medicine and provided real-world examples of the discovery and development of precision medicine solutions, through talks, panel discussions, workshops and exhibitions with the opportunity to arrange one-to-one partnering meetings. Precision medicine is an emerging approach to the treatment and diagnosis of disease that takes into account variations in a patient's genes, environment and lifestyle. It aims to better target treatments to an individual's circumstances to improve outcomes for patients. Representatives from across the NIHR were involved in the day and presented on a range of projects and funding programmes. Professor Bryan Williams of NIHR UCLH Biomedical Research Centre joined the first panel of the day which highlighted UK investments in the invention and evaluation phase of research. Professor Williams' highlighted key NIHR's investments in this space and provided examples of exciting precision medicine projects from UCLH BRC. In addition, a number of NIHR precision medicine projects were presented during the disease area specific showcase sessions. This included Professor Costantino Pitzalis who presented the THERAPIST study on behalf of the NIHR Translational Research Partnership, Professor Simon Mead's who presented a project at NIHR Queen's Square Biomedical Research Unit on the "dementia chip" and Professor Tariq Sadiq's who presented on Capacity Building and Delivery of Precision Medicine in Sexual Health, through NIHR Funding. Mark Samuels, Managing Director of NOCRI, also chaired a discussion panel themed 'Enabling Collaboration', which highlighted the value of collaborative working between companies, academics, charities and patients. The event saw the launch by the chief executive of Innovate UK, Dr Ruth McKernan, of a new map of the precision medicine landscape. A whole range of organisations, including charities, health bodies and devolved administrations are coordinating their work under the umbrella of Innovate UK's Stratified Medicine Innovation Platform, with NOCRI representing the NIHR.
Year(s) Of Engagement Activity 2015
 
Description Video of patient describing synovial biopsy procedure 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Video produced of patient being interviewed about the experience of having a synovial biopsy. Purpose - to answer patient (RA) questions and concerns about undergoing a synovial biopsy for a research study. Video posted on STRAP and R4RA websites and used widely in outpatient clinic waiting rooms where a screen is available
Year(s) Of Engagement Activity 2017
URL http://www.matura-mrc.whri.qmul.ac.uk/ultrasound_guided_synovial_biopsy_taking_a_biopsy.php