Leeds BRC has a broad portfolio of translational research in musculoskeletal disease. This is focussed on developing early identification and early stratified intervention with the aim of:
- Preventing disease and disability in immune-mediated inflammatory diseases (through preclinical diagnosis and prevention, disease phenotyping and precise delivery of targeted therapy)
- Improving the treatment for osteoarthritis, enabling “50 active years after 50” (through molecular/physical therapy, autologous stem cells, acellular scaffolds and joint replacement)
Our Research Themes and Workstreams
Our research is undertaken through the following two Research Themes and seven Workstreams:
- Optimal treatment and preventing disability in immune-mediated inflammatory diseases (Workstream one to four)
- Improving the treatment of osteoarthritis (Workstream five to seven)
One: At risk of developing rheumatoid arthritis
Early detection and optimal management of immune mediated inflammatory diseases.
Lead: Prof Paul Emery
Work stream 1: At Risk of Developing RA
Aim: In individuals at risk of developing rheumatoid arthritis (RA), we will expand our local investigations to nationally validate biomarkers, develop risk models, and using stratified populations, develop proof of concept studies to prevent disease progression.
- Establish a sustainable national referral primary care network from primary care of individuals with imminent RA with the aim of developing regional treatment centres for the at-risk population across England.
- Establish prospective cohort of first-degree relatives (FDRs, already in progress) and phenotype using clinical features, prevalence of RA related autoantibodies and specific markers of genetic risk (HLA-DRB1 shared epitope).
- Undertake proof of concept studies across this network to demonstrate reduced progression in at risk individuals to clinical disease.
- Test preventive strategies in FDRs at high risk of developing systemic autoimmunity.
Year 5 +
- Develop and secure external funding for a multi-centre randomised, controlled clinical trial to reduce progression of disease.
Two: Immunotherapies in rheumatoid arthritis
Lead: Prof Maya Buch
Aim: In early and established RA, we will aim for disease cure and remission respectively through the precise use of immunotherapies; by accurate phenotyping of response, identification of response predictors and understanding of refractory RA. Our objectives are to:
- Accurately phenotype heterogeneous treatment responses using imaging techniques.
- Establish a cohort of RA individuals refractory to multiple biologic therapies for cellular and molecular phenotyping.
- Deliver effective mechanistic studies that integrate clinical, imaging, cellular and molecular datasets to identify treatment-responsive disease strata and patient phenotypes.
- Deliver proof of concept and novel stratified intervention studies to achieve cure in early disease and remission in established disease respectively.
Three: Interventions based on stratified prognosis
Lead: Prof Dennis McGonagle
Co-Lead: Associate Prof Francesco del Galdo
Aim: Develop intervention studies through stratified prognosis at different disease stages, with the aims of disease prevention in autoantibody-mediated diseases or disease remission/cure for those with established disease in two areas: systemic sclerosis (SSc) and psoriatic arthritis (PsA).
- Establish a sustainable national referral network from primary care of inception PsA and individuals with higher risk of SSc.
- Validate additional prognostic factors of early progression to SSc for stratification/inclusion criteria of prevention trials.
- Explore the immunological profile of a pre-clinical PsA cohort with novel imaging biomarkers (nail imaging and ultrasound) to determine a risk model for developing PsA.
- Explore the biomarker profile of a preclinical SSc cohort with imaging ( OCT and MRI), serum ( IFN Score and ELF) and skin biopsy biomarkers.
- Undertake proof of concept studies to demonstrate reduced progression in at risk individuals to clinical disease.
Year 5 +
- Develop and secure external funding for a multi-centre randomised, controlled clinical trial to delay onset of PsA and SSc and/or its severe clinical manifestations.
- Electronic Medical Record evaluation of psoriasis therapy on PsA prevention with international partners in Israel and Italy.
Four: Drug repurposing and treatment toxicity
Lead: Prof Ann Morgan
Aim: Improve the management of established IMID through accurate molecular phenotyping applying knowledge of pathogenesis, drug mechanisms and treatment toxicities, particularly infections and those associated with glucocorticoids.
- molecular diagnostics informing selection of biologics and/or opportunities for drug repurposing.
- novel outcome measures and imaging/molecular biomarkers that can be used to evaluate IMID and alleviate glucocorticoid toxicity.
- Informatics platform and methodology to interrogate large datasets, to evaluate clinical, biochemical and molecular predictors.
- health economic models that demonstrate commercial space for new technologies and therapies.
Five: Longer lasting joint replacements
Lead: Prof John Fisher
Aim: Improve durability of hip, knee and ankle joint replacement through enhanced pre-clinical testing, and simulation methods, and development of international standards for industry testing by stratifying for population needs, addressing the inherent variability in patient anatomy and disease state and in surgical delivery. Working with industry partners we will apply enhanced simulation methods to reduce the variability and improve function, reliability and patient outcomes in hip, knee and ankle joint replacement.
- Develop new preclinical experimental simulation and test methods which can evaluate the effect of variability of surgical positioning in all six degrees of freedom for different kinematic conditions on the function of prostheses and collaboratively apply them with industry partners.
- Develop novel computational models to predict effect of surgical positioning on prostheses function and translate.
- Translate with industry partners through preclinical design and development.
Six: Acellular scaffolds and regenerative devices for treatment of OA
Lead: Prof Eileen Ingham
Aim: To develop biological acellular scaffolds which can be matched as closely as possible to the properties of the natural tissue to be replaced and develop and apply robust pre-clinical stratified simulation test methods for biological scaffolds in natural joints.
Short/medium term (1-4 years):
- To progress pre-clinical studies on acellular human bone patellar tendon bone graft for anterior cruciate ligament reconstruction.
- To progress pre-clinical evaluation of acellular osteochondral grafts
- Clinical testing of a novel patented “synovial brush” that increases stem cell mobilisation into the synovial fluid
- Development of novel pre-clinical experimental simulation methods for the evaluation of surgical interventions in the knee
- Develop deeper understanding of the role of multipotential mesenchymal stromal cells in the regeneration process in the knee joint especially after knee joint distraction procedures.
Longer term (5+ years):
- Implementation of novel pre-clinical simulation methods for stratification of acellular interventions in the knee
- In collaboration with industrial partners, progress towards first clinical studies of acellular human bone patellar tendon bone and acellular osteochondral grafts in the knee.
- Advance treatments in combination with minimally manipulated multipotential mesenchymal stromal cells and develop deeper understanding of the regeneration process.
Seven: Non-surgical treatments for OA
Lead: Prof Philip Conaghan
Aim: To use our extensive imaging experience, facilities and unique statistical shape modelling image analysis capabilities to understand temporal and spatial relationships of OA pathologies so we can define early OA phenotypes for novel pathology-targeted therapies
- Complete development and assess metric properties of individual OA tissues.
- Understand relevant pathology (bone, synovium and cartilage) responsiveness and predictive validity from ongoing intervention trials.
- Develop temporal models from the earliest phases of disease initiation involving all OA knee pathologies and symptom relationship.
- Develop novel knee subchondroplasty intervention.
- Develop hip OA imaging pathology quantification.
- Test novel subchondroplasty intervention in bone marrow lesion (BML) positive patients.