Clinical Rheumatology
Rheumatic and musculoskeletal diseases are extremely common conditions, representing up to 30% of all consultations in primary care. They are a major cause of morbidity and frequently associated with significant comorbidities, further impacting on wellbeing and function.
The clinical rheumatology group undertakes translational, clinical, laboratory and epidemiological research into rheumatic diseases, with a focus on inflammatory conditions. These include rheumatoid arthritis, axial spondyloarthritis and ankylosing spondylitis, myositis, systemic sclerosis and Behçet’s syndrome. Large cohorts of well-characterised patients are available at Aintree University Hospital, with clinical care led by members of the group. Our research integrates seamlessly with clinical care, of which much is delivered from the context of national or supra-regional services.
Our group hosts the EULAR Centre of Excellence for Rheumatology Research 2015-2020 and the UK Behçet’s Syndrome Centre of Excellence. We are also part of the MRC-Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing (CIMA) and Arthritis Research UK/MRC Centre for Musculoskeletal Health and Work.
The rheumatology group undertakes programmes of work designed to:
- study the role of neutrophils at the cellular and molecular level in disease
- discover and evaluate biomarkers to predict treatment response
- elucidate the potential interaction between arthritis and co-morbidities (such as cardiovascular disease) on disease, response to treatment and other important outcomes such as work,
- explore the pathophysiology of muscle and inflammatory lung disease with a particular interest in the association of autoantibodies with clinical sub-type and outcome
- study pathophysiological aspects of connective tissue diseases such as systemic sclerosis
- study the effect of lifestyle factors (obesity and smoking) on disease activity and treatment response in inflammatory rheumatic disease
- evaluate the clinical utility and potential mechanisms of action of novel drugs for osteoarthritis
The group is based in the Clinical Sciences Centre at Aintree University Hospital and the William Henry Duncan Building on the University of Liverpool main campus.
The Clinical Sciences Centre has laboratory and clinical research facilities under the same roof on the site of a large hospital that provides care for well-characterised cohorts of patients with rheumatological disorders, under the care of leaders of the group. Patients are referred not only from the locality, but also from around the region and nationally. The laboratories support molecular immunology work, including primary and secondary cell culture, cell and tissue storage, flow cytometry and various PCR technologies. The clinical research suite provides facilities for clinical assessment, including joint aspiration and injection, together with phlebotomy on both healthy people and patients.
Research Group Projects
Clinical Trials
As well as a number of commercial clinical trials, the Clinical Rheumatology group runs clinical trials which incorporate translational laboratory research into the trial protocol.
A Phase I and Phase II study to evaluate the role of APPA in osteoarthritis of the knee (AKL Research & Development) (Moots)
Utilising the Phase I facilities of the Royal Liverpool University Hospital and the Liverpool Clinical Trials Unit, this comprises the first in human pharmacokinetics study and first in patients Phase II study to examine safety and potential effectiveness for APPA, a promising drug to treat osteoarthritis of the knee.
See here for a report on this project.
The interaction between IL-17, inhibition of IL-17 and neutrophils with exploratory study of the role of Vitamin D in psoriatic arthritis: SATURN (Novartis) (Moots/Edwards/Goodson/Wright)
The potential cellular and molecular interactions between IL-17 and neutrophils are being examined in detail, within the context of a clinical trial of the IL-17 inhibitor, secukinumab. This includes an exploratory study of the potential role of vitamin D status on response to drug and function of neutrophil.
Key people
Collaborators
Professor S.W. Edwards (University of Liverpool)
Biomarkers
Rheumatoid arthritis (RA) is the most common cause of inflammatory arthritis and affects over half a million people in the UK. Behçet’s syndrome and Myositis are very rare and affect only around a few thousand people in the UK. However, RA, Behçet’s syndrome and Myositis can be difficult to treat, because not all patients with the same disease diagnosis respond to the same drugs. Our group is working to identify clinical biomarkers that could help stratify patients with RA, Behçet’s syndrome and Myositis onto the most appropriate therapy. As well as treating the diseases with an appropriate drug much more quickly, this personalised medicine approach will reduce the unnecessary exposure of patients to potentially toxic, unhelpful drugs, and reduce the cost to the NHS of prescribing these drugs to patients who will not respond (approximately £12M/year).
Biomarker discovery for biologic therapies in RA (ARUK/MRC/Illix Predictive Diagnostics) (Wright/Moots/Edwards)
A recently completed transcriptomics analysis of neutrophils in patients with RA has identified promising biomarkers able to predict clinical response or non-response to TNF inhibitors, the more widely used class of biologic drugs. These are now being evaluated for use in the routine clinical setting.
BIO BEHÇET’S: Optimal utilisation of biologic drugs in Behçet’s Disease: a randomised controlled trial of infliximab vs alpha interferon, with genotyping and metabolomic profiling, towards a stratified medicines approach to treatment (NIHR/MRC) (Moots)
This is the first randomised head-to-head trial of the two most widely used biologics for Behçet’s syndrome worldwide. It also involves an integrated biomarker discovery program and is resulting in cost saving of £600,000 to the NHS.
MYOPROSP: a prospective longitudinal cohort study in myositis (MRC) (Chinoy/Cooper)
Prospective study collecting blood, muscle biopsies and imaging for research purposes to measure a number of biomarkers for the assessment of diagnostic accuracy and clinical utility evaluation. This is an ongoing longitudinal mechanistic study in myositis aiming to discover new biomarkers and their associations, with a long-term aim to improve treatment outcomes.
UK BILD: biomarkers in interstitial lung disease (ILD) (Cooper)
This collaboration aims to develop a strategy that correlates ILD genotypes with ILD serotypes and phenotypes. Recruitment to the study (co-ordinated via the University of Liverpool) is across 38 centres and the patient cohort is currently 3,000.
Key People:
Professor R.G. Cooper
Collaborators:
Professor S.W. Edwards (University of Liverpool)
Professor Sir M. Pirmohammed (University of Liverpool)
Dr H. Chinoy (University of Manchester)
Molecular Biology
We are particularly interested in the role that neutrophils play in inflammation and inflammatory diseases such as rheumatoid arthritis (RA), lupus (SLE/JSLE) and vasculitis via:
(i) production of reactive oxygen species (ROS) and proteases, implicated in damage to host tissues (e.g. cartilage, vascular tissue) and activation of neighbouring cells;
(ii) secretion of cytokines and chemokines which regulate the activity of both innate and adaptive immune systems;
(iii) production of neutrophil extracellular traps (NETs), implicated in exposure of neo-epitopes (citrullinated proteins in RA, double-stranded DNA in SLE) to the immune system;
(iv) exposure of auto-antigens (MPO, PR3) that cause generation of anti-neutrophil cytoplasmic antibodies (ANCA) in vasculitis.
We are investigating in how dysregulated neutrophil function contributes to disease pathophysiology and how neutrophil activation can be modified by drug therapies.
Find out more about our neutrophil research here (video produced by Dr E Chapman & Dr A Hackett).
The effect of JAK inhibition on neutrophil killing, NETosis and metabolism in rheumatoid arthritis (Pfizer) (Wright/Moots)
JAK inhibitors are a new, highly effective treatment for rheumatoid arthritis, but patients often suffer from infections. This project investigates the effect of JAK inhibitors on normal neutrophil functions associated with bacterial killing and host defence.
Molecular control of neutrophil extracellular trap (NET) production in rheumatoid arthritis (Wellcome Trust) (Wright/Moots)
NETs are structures of DNA chromatin and proteins released by neutrophils during inflammation. This project is using quantitative proteomics and fluorescence microscopy to identify the proteins present on NETs from patients with RA and understand the signalling pathways leading to NET production in RA.
Evaluation of novel mechanisms for inhibiting rheumatoid arthritis (AKL Research & Development) (Moots/Edwards/Wright/Cross)
This project will determine the effects of the drug APPA, and its constituent parts apocynin (AP) and paeonol (PA) on neutrophil functions regulated by exogenous and endogenous mTNFα, in cells with and without re-modelled chromatin.
Role of neutrophils in osteoarthritis and rheumatoid arthritis (Chulalongkorn University Bangkok and University of Liverpool joint PhD programme in Musculoskeletal Biology) (Moots/Edwards/Wright)
This project will investigate the effect of neutrophil-derived microvesicles on synovial fibroblasts and joint inflammation in osteoarthritis and rheumatoid arthritis.
Investigating non-immune cell mediated muscle weakness induction in myositis (Cooper/Lightfoot)
This is a lab-based collaboration with Manchester Metropolitan University, testing the effects of up-regulation of ER-stress and its effects on ROS generation and muscle cell damage.
Key People:
Professor R.G.Cooper
Mr D. Zhan
Collaborators:
Professor S.W. Edwards (University of Liverpool)
Professor H. Sittisak (Chulalongkorn University, Bangkok)
Dr H. Chinoy (University of Manchester)
Dr. A Lightfoot (Manchester Metropolitan University)
Epidemiology
Rheumatic diseases and their co-morbidities place a severe burden on the quality of life of patients and their families. It is estimated that 40% of patients with rheumatoid arthritis (RA) of working age lose their job within 5 years of diagnosis, as a direct result of RA. Our epidemiological research accesses large, regional and national datasets of patients to explore the impact of lifestyle choices (such as smoking) on the severity of musculoskeletal disease, including response to therapies and the ability of patients to remain in work.
Elucidate the potential interaction between arthritis, co-morbidities (such as cardiovascular disease) on disease, response to treatment and other important outcomes such as work (MRC/ARUK) (Moots/Goodson)
Analysing the HEAF (Health and Employment After Fifty) database to explore potential interactions between joint problems, co-morbidities and ability to work.
Exploration of the impact of smoking on axial spondyloarthritis disease activity and response to TNF inhibitors (NHS) (Goodson/Moots)
Utilising large observational cohorts from the British Society for Rheumatology Biologics Register for Axial Spondyloarthritis (BSRBR-AS) and the Aintree axial spondyloarthritis registry. This project will inform more personalised management of disease by recognising individual variations in disease activity and treatment response.
The epidemiology of Behçet’s syndrome (NIHR) (Moots)
Investigation into the impact of Behçet’s syndrome and the ability to undertake work, including a systematic review of the role of human stem cell transplantation in Behçet’s syndrome and an investigation into the relationship between geography on distribution and phenotype of Behçet’s syndrome.
UK MYONET: Myositis Network across 80 UK Centres (co-ordinated via Manchester University) (Cooper)
Prospective cross-sectional recruitment of patients with myositits across the myositis spectrum. This is allowing ongoing mechanistic research and correlation of myositis genetics and genotypes with myositis serotypes and phenotypes.
Key People:
Professor R.G. Cooper
Dr L. Chadwick
Dr S. Duffield
Collaborators:
Professor W. Ollier (University of Manchester)
Dr H. Chinoy (University of Manchester)
Dr J. Lamb (University of Manchester)
Dr A. Lightfoot (Manchester Metropolitan University)
Dr Z. Betteridge (University of Bath)
Professor N. McHugh (University Bath)
UK MYONET (80 collaborating centres)
UK BILD (38 collaborating centres)
Omics
Omics technologies have transformed the way we study complex diseases such as rheumatoid arthritis (RA). In our group, we have applied transcriptomics, proteomics and 1H NMR metabolomics to the study of neutrophil biology in inflammatory disease. We were the first group to publish analysis of neutrophils using RNA-seq transcriptomics, and using this approach we have identified neutrophil-derived gene biomarkers of response to drug therapy in RA.
Computational modelling and functional investigation of neutrophil plasticity in inflammatory disease (ARUK) (Wright)
This project will develop a computational model of neutrophil activation in inflammatory disease by combining data from RA neutrophils (clinically-characterised) and healthy neutrophils treated with inflammatory mediators. It will use advanced machine-learning to construct a model to predict regulators of inflammation in sub-groups of patients (disease responders/non-responders; early/severe disease). This information will be used to develop strategies for stratification of patients to therapy and development of new therapies.
Proteomic analysis of neutrophil extracellular traps (NETs) in rheumatoid arthritis (Wellcome Trust) (Wright/Moots)
NETs are structures of DNA chromatin and proteins released by neutrophils during inflammation. This project is using quantitative proteomics and fluorescence microscopy to identify the proteins present on NETs from patients with RA and whether NETs may be a source of auto-antigens in auto-immune disease.
Effect of JAK inhibitors on neutrophil metabolism (Pfizer) (Wright/Moots)
JAK inhibitors are a new, highly effective treatment for rheumatoid arthritis, but patients often suffer from infections. This project investigates the effect of JAK inhibitors on the intracellular metabolite profile of neutrophils using 1H NMR spectroscopy.
Effect of chromatin remodelling on neutrophil gene expression (Edwards/Wright/Moots)
This project will offer important new insights into the complexity of the heterogeneous immune responses in RA patients and how this is regulated by changes in gene expression caused by chromatin remodelling.
In vivo modelling of epigenetic regulation of neutrophil phenotype in musculoskeletal ageing (CIMA) (Renshaw/Wright/Edwards)
This CIMA-funded PhD studentship will confirm observations of epigenetic gene regulation in RA patient neutrophils in a tractable in vivo model system using zebrafish, investigating the role of epigenetic regulation on neutrophil gene expression and function in vivo.
Key People:
Collaborators:
Professor S.W. Edwards (University of Liverpool)
Professor R. Beynon (University of Liverpool)
Professor S. Renshaw (University of Sheffield)
Dr M. Phelan (University of Liverpool)
Dr P. Antczak (University of Liverpool)
