[NIHR CRN Portfolio Study ID: 5339]
The MRC funded Pathobiology of Early Arthritis Cohort (PEAC) was established through the contribution of a consortium of 5 independent, national centres of excellence, patient recruitment continues at Barts the lead site. This project has created an extensively phenotyped cohort of early inflammatory arthritis patients (362 to date) with linked, detailed pathobiological data.
The development of a prospective early arthritis cohort with high quality clinical and imaging data (state-of-the-art 3D/4D ultrasound-US / power-Doppler-PDU imaging) together with a comprehensive collection of biological samples (blood, urine and synovial tissue) is providing a unique resource to search for early predictors of disease evolution as well as to enable early proof of concept/mechanistic studies with stratified entry according to the imaging and immunological profile. This cohort has provided an ideal platform for novel clinical trials (see below).
“A randomised, open labelled study in anti-TNFa inadequate responders to investigate the mechanisms for Response - Resistance to Rituximab versus Tocilizumab in RA”
[NIHR CRN Portfolio Study ID: 14524]
Evidence from PEAC (see above), in which synovial biopsies have been taken from patients with early arthritis, indicate that there are at least three distinct histo-morphological subtypes. These are described as fibroblast (pauci-immune), lymphoid (B-cell rich, with or without germinal centre formation) and Myeloid (rich in monocytes but poor in B cells), which correspond to different transcriptomic signatures.
With these subsets in mind, the overarching hypothesis of this study is whether a diagnostic synovial biopsy showing a “B-cell rich / B- cell poor” pathotype can predict response and define certain disease responsive / resistance subsets for patients stratification and help to rationalize drug choice. The purpose of this study is to test the hypothesis that the presence or absence of specific synovial and molecular signatures (B-cells and B-cell associated signatures), assessed through obtaining tissue from a synovial biopsy, will enrich for response / non-response to Rituximab, and B-cell depleting anti-CD20 monoclonal antibody. Patients are eligible if they have failed anti-TNF therapy and will undergo a synovial biopsy baseline and then be randomised to receive Rituximab or Tocilizumab.
This is a multi-site, international clinical trial, 12 UK and 8 EU sites recruited 164 patients between February 2013 and November 2017. Patient follow-up is now complete and the results of this trial, the first biopsy driven RCT in RA, will be published in 2019.
This study is being funded by the National Institute of Health Research Efficacy and Mechanism Evaluation program (NIHR EME).
[NIHR CRN Portfolio Study ID: 18178]
“Stratification of Therapy for RA by Pathobiology”
Maximising Therapeutic Utility in Rheumatoid Arthritis (MATURA) is an ambitious research project jointly funded by MRC and Versus Arthritis to identify and test biomarkers predictive of response to therapy in rheumatoid arthritis (RA), thereby allowing the stratification of patients into groups according to the therapies that are most likely to be effective. The project comprises two work-streams: Workstream 1 is managed by Prof Costantino Pitzalis the Centre for Experimental Medicine and Rheumatology, and Workstream 2 is managed at The University of Manchester.
An important component of the Workstream 1 is the STRAP Trial, a randomised control trial which aims to test the utility of synovial histomorphology and B cell number together with specific molecular signatures as potential biomarkers to guide therapeutic decisions in patients failing DMARD therapy to improve on current response rates and identify patients more likely to respond. Patients are randomised to receive either Rituximab, Tocilizumab or Anti-TNF therapy following a baseline synovial biopsy.
This trial is open in 20 UK and 5 European centres, recruitment will close in May 2019 (target 219 patients) and the results will be available in 2020.
ISRCTN reference: ISRCTN 18262002
NIHR CRN Portfolio Study ID: 18893]
Preliminary data suggest that up-regulation of IL-17 and the ThH17 pathway occurs in patients with rheumatoid arthritis (RA) who have been treated with anti-tumor necrosis factor- alpha (anti-TNFα) therapy but demonstrate an incomplete clinical response. A deeper understanding of this is required in order to determine whether IL-17 or the ThH17 pathway is a valid target for intervention in this population to improve response outcome.
The main aim of this study is to examine the relationship of IL-17 expression within blood and synovium of subjects with RA as relates to clinical response or non-responses to anti-TNF therapy.
Clinical assessments, ultrasound assessments, synovial tissue bio-markers obtained from the ultrasound-guided synovial biopsy, and study specific blood sampling are being used to evaluate the pattern of activity shown in the Th17 pathway.
Recruitment of 57 patients took place in 10 NHS Trusts, results are now being analysed and will be published in 2019.
[NIHR CRN Portfolio Study ID: 31852]
There are many reports that strongly suggest that certain bacteria living in the mouth and in the intestines of RA patients may cause and/or worsen RA. The purpose of the IRMA study is to identify RA patients who also have periodontitis (inflammation in their gums caused by bacteria) and compare them to healthy individuals. We will compare the presence of bacteria in the mouth with the RA disease activity and severity and investigate whether the presence of periodontitis and certain bacteria are related to the inflammation in joints and severity of RA disease. The long term goal is to determine if treating periodontitis, caused by certain bacteria, may help to improve the outcomes for patients with RA.
This trial is recruiting patients at Barts.
This study is exploring the relationship between synovial and skin histological, molecular and gene profiles, and the evolution of clinical disease characteristics, in patients with psoriatic arthritis who have failed standard non-biologic therapy and are eligible for biologic treatment. We hypothesise that specific biomarkers exist which predict or correlate to the course of an individual’s disease. This study primarily aims to determine if levels of IL-23 in psoriatic synovium or skin correlate with clinical disease activity. Other cellular and molecular biomarkers will also be explored as secondary objectives. We aim to identify one or a panel of biomarkers that can facilitate patient stratification for disease severity and likely response to treatment.
This study is recruiting patients at Barts.
This study is in set-up.
The aim of the study is to investigate the hypothesis that the cytokine and phosphoproteomic profiles of RA synovial tissue determine response to Janus kinase (JAK) inhibition with tofacitinib and thus whether pre-treatment examination of joint tissue can help select patients most likely to respond to tofacitinib.
[NIHR CRN Portfolio Study ID: 37570]
CReMSIA is a research database that captures longitudinal data on inflammatory arthritis patients. The study cohort are patients previously studied as part of synovial biopsy based clinical trials within the centre for Experimental Medicine and Rheumatology at Barts Health NHS Trust. Upwards of 400 patients with inflammatory arthritis have been recruited to date within the organisation. This cohort of patients is relatively unique and the opportunity to track the progress of patients over the course of their disease gives a unique opportunity to determine the value of synovial tissue as a marker of response to therapy and disease progression. All patients entering clinical trials within the centre are invited to join the database to enable ongoing collection of data as part of routine follow up following exit from clinical trial. The database offers a unique opportunity to collect an integrated pathophysiological/clinical longitudinal dataset in a unique cohort of patients offering the opportunity to evaluate the progression, modulation and development of synovial pathobiology in line with disease progression and response/non-response to treatment.
The Centre of Experimental Medicine & Rheumatology (EMR) works in association with the Human Tissue Resource Centre (HTRC) at St Bartholomew’s Hospital to provide an HTA-approved biobank resource to support current and future research. EMR works with the HTRC to ensure full compliance with the Human Tissue Act 2004 and to enhance the research infrastructure of QMUL and the Trust.
Since registering as a biobank with the HTRC (site licence 12199), EMR has collected thousands of biological samples (tissues and bodily fluids), along with matched clinical data, to build this biobank/data resource from patients suffering from Arthritis (inflammatory/non-inflammatory), Sjogrens Syndrome and Lupus who have been recruited to various observational studies and clinical trials on-going in the department. All biological samples collected for storage and distribution for future research are anonymised, logged, tracked and monitored to ensure traceability from consent/collection to scientific output. Patient-matched clinical data is entered onto our secure clinical databases to ensure full compliance with the Data Protection Act.
For further information on the role of the HTRC within research please go to - http://www.jrmo.org.uk/performing-research/research-facilities/clinical-facilities/htrc/what-is-the-htrc/