Theme Lead Prof Ann Morgan
Musculoskeletal diseases (MSKD) are the commonest cause of chronic disability and one of the most expensive to treat, costing NHS England >£10B annually. MSKD can broadly be divided into immune-mediated inflammatory diseases (IMIDs) and osteoarthritis (OA). Affecting 1 in 4 people in the UK, the global burden of MSKD has increased by 25% over the past decade.
Underpinned by accurate detection, early diagnosis and identification of novel therapeutic targets, enabled by interdisciplinary collaborations we aim to:
- Identify people at risk of developing IMID to prevent inflammation onset and complications
- Reduce glucocorticoid toxicity burden, multi-morbidity and frailty
- Develop individually-targeted, cost-effective therapies for common/impactful MSKD
This Theme builds on excellence in translational research across MSKD, which has underpinned our BRU/C since 2008; for which Leeds is internationally recognised. We bring a depth of talent to drive forward this work: second most highly cited rheumatology group in Europe; most highly cited rheumatologist globally (Emery); five NIHR SI (Conaghan, Emery, Keenan, Morgan, Redmond); largest international academic facility for pre-clinical testing of joint replacements.
Research Hypotheses and Innovation Opportunities
We will capitalise on our highly characterised BRC cohorts and capabilities in imaging, data science, health technologies and bioengineering and national investments in genomic/digital medicine, including UK Biobank, NIHR BioResource, Our Future Health and the cross-BRC PRS Initiative. This will harness the power of genomics and imaging ‘omics to improve diagnostic services, risk prediction and validation of emerging therapeutic targets.
MSKD Workstreams and Academic Leads
Based on our translational pipeline, diverse population demographics – in partnership with our PPIEP group, to ensure our research follows patient need – the MSK workstreams will address the following grand challenges:
Grand challenge: for those at risk of RA, provide validated stratification permitting preventative intervention. RA is the commonest autoimmune disease, requires long-term therapy and has a pre-clinical phase where intervention may delay/prevent arthritis without accepted management principles. Leeds is a national centre for identifying at-risk individuals and has pioneered risk stratification. Our next challenges are to identify key risk factors (including microbiome and polygenic risk scores (PRS)) studying their relationship over time and investigating the effect of risk factor intervention on clinical outcome.
Grand challenge: characterize the in-depth phenotype of psoriasis populations “at-risk” of developing PsA and identify innovative targets and remission induction strategies. PsA impacts physical and mental health with no cure and significant economic burden. Psoriasis presents a decade before joint involvement in >90% of PsA patients adding to multi-morbidity and polypharmacy. Building on existing BRC cohorts, we will develop diagnostic and treatment algorithms (including PRS) and validate imaging/progression biomarkers with academic/industry partners, linking the immunobiology of the normal enthesis and investigating the impact of novel pharmacological strategies to modify risk factors and prevent progression from psoriasis to PsA.
Grand challenge: translate discoveries on prediction of onset and severity of autoimmune CTD into validated diagnostics and therapeutics. CTDs are a complex spectrum of, often-severe, IMIDs. Therapeutic advances are limited by clinical and immune heterogeneity, late diagnosis and early damage. We will build on BRC cohorts, capitalising on NIHR BioResource and Our Future Health, to: predict CTD onset; identify preventative interventions; improve diagnostic pathways with stratification for early intensive therapy; use demographics, imaging, biomarkers to classify established CTD for basket trials; work with NIHR MICs to progress biomarkers into NHS-ready diagnostics.
Grand challenge: glucocorticoid-free treatment reducing long-term disease burden and treatment complications. Giant cell arteritis (GCA) is the commonest vasculitis exclusively affecting older adults with a challenging diagnostic pathway. There is considerable morbidity due to disease (blindness, aortic aneurysm) or treatment complications (86% experience glucocorticoid toxicity). Exploiting Leeds-led national cohorts and consortia, we will develop diagnostic/treatment algorithms, stratified by molecular diagnostics (including PRS). With Industry, we will develop a target validation platform and support NHS adoption through the development of a GCA-specific, industry-standard health economic assessment tool (G-HEAT).
Grand challenge: alleviate the “Cushingoid” phenotype in glucocorticoid-treated PMR, and retain therapeutic efficacy. PMR affects 2% of the over-55’s, but the only licensed therapy is long-term glucocorticoids, which cause multimorbidity, polypharmacy and frailty. We will develop integrated prognostic-decision models for safer glucocorticoid treatment to reduce frailty and other important adverse outcomes. In parallel we will recruit a new cohort of patients with PMR with deep phenotyping to validate steroid sparing therapeutic targets to be tested in separately-funded trials, thereby improving clinical outcomes in PMR with potential translation to other IMIDs
WS6; Prof Philip Conaghan: Osteoarthritis stratification for targeted intervention
Grand challenge: reduce the burden of OA pain for individuals with multimorbidities, leading to improved quality-of-life, and reduced NHS burden. OA is the single most common cause of disability in older adults, affecting 250M people worldwide. Building on our advances in quantitative imaging biomarkers, understanding of structural pathology, targeted intervention studies and unique cohorts, we stratify for intervention by: elucidating relationships between weight-bearing 3D-imaging and pain; identifying key structural transition points from pre-OA to symptomatic disease; defining relationship of systemic inflammation associated with multimorbidity (metabolic syndrome) and joint pain.
Grand challenge: deliver optimum treatment for every patient requiring joint replacement in the most cost-effective way. Pre-COVID, 250,000 joint replacements were performed each year in the UK, increasing to 400,000 by 2035, with a 15% rise in revision surgery over the last 5 years. Young, active and obese patients place greater demands on implants. We will build on our unique capabilities in experimental simulation and computational modelling, incorporating individual patient data from biomechanical measurements and imaging, enriched for at-risk cohorts. We will generate new pre-clinical evidence and validate through clinical data (retrievals, patient outcomes), to identify measurement approaches to address key factors negatively impacting performance.