Diseases are traditionally managed within specific medical specialities, which often relate to parts of the body: rheumatology, dermatology, gastroenterology and so on. However, patients with disease in one organ often experience similar problems in another, suggesting a more holistic cross disease approach may be more effective. A patient with systemic lupus erythematosus, for example, may have to visit a number of medical specialists as they have symptoms in many organs.
Immune Mediated Inflammatory Diseases (IMIDs) are a common and growing problem for the NHS. They are often treated in very similar ways (combination therapy) with very similar drugs (steroids and anti-TNF biologics). This has led our patient partner groups to ask: if these diseases share so much in common, why are they not investigated in a common manner?
Through initiatives like the Human Cell Atlas, we know that some types of cells are found across all organs, while others are specific to an organ. We aim to identify a common set of cells that would allow us to target inflammation across all organs; as well as those cells that are unique to each organ.
We are testing the hypothesis that unravelling the common cellular and molecular basis of inflammation across four distinct but clinically related tissues in children and adults will lead to a new tissue-based, cellular understanding of inflammation. This will:
- Allow ‘basket trials’ over a range of IMIDs, where a drug is tested against two or more diseases.
- Link the cellular processes that underpin different diseases to new or repurposed drugs
- Enable us to carry out research studies to assess quickly how effective drugs are in tackling different diseases.
- Advance the concept of ‘precision pathology’ – using the right drug for the right IMID at the right dose.
Our approach builds on the previous success of the Kennedy Institute of Rheumatology, which developed the first anti-cytokine-based therapy. These anti-TNFs (tumour necrosis factor) therapies, a monoclonal antibody that helps stop inflammation, were initially used for rheumatoid arthritis, and are now used to treat a number of inflammatory conditions.
Sub-theme 1: Cohorts
Our first sub-theme is looking at clinical cohorts – both paediatric and adult, in Oxford and other UK centres – across seven diseases that reflect the full spectrum of autoimmune and auto inflammatory disease, covering a number of organs (skin, gut, joints, liver)
As part of the Arthritis Therapy Acceleration Programme (A-TAP), which involves a partnership with the University of Birmingham and a number of hospitals in the West Midlands, we have access to a significant cohort of patients.
We are also extending our successful True Colours online tool that has allowed large cohorts of people with ulcerative colitis to manage their own condition.
Sub-theme 2: Genes, microbiome and informatics
Our second sub-theme, Genes, microbiome and Informatics, is concerned with using genetic research to diagnose and predict IMIDs that are caused by variations in a single gene (Monogenic disorders).
A key element will be the work of Professor Holm Uhlig, who leads the NIHR BioResource aimed at investigating inflammatory bowel disease (IBD) in children. The Paediatric Inflammatory Bowel Disease (PIBD) BioResource is recruiting children with Crohn’s disease and ulcerative colitis to investigate the genetic factors driving these diseases.
Building on our research into how the microbiome can dictate how genetic variants lead to tissue maladaptation, we will integrate our IMID cohorts into the Inflammatory Arthritis Microbiome Consortium, which aims to manipulate microorganisms in the gut to treat inflammatory arthritis.
Sub-theme 3: Tissue biology
Our sub-theme, tissue biology, concerns the collection, transport, storage and processing of IMID tissue samples – vital for validating our approaches. We already have excellent processes as part of the partnership between Oxford and Birmingham within A-TAP.
Under the leadership of Professor Uhlig, we are also involved in the Cartography consortium, a major industry-academic collaboration with Janssen to develop a cellular map of the genes and proteins implicated across a range of IMIDs, with a view to better understanding how the disease works and so treat the right patients with the right medications – and inform the development of new therapies.
Working with colleagues in Birmingham, we have set up a new Inflammation and Advanced Cellular Therapy (I-ACT) trials team which will carry out early-phase experimental clinical trials in collabaptrion with our own Center for Clinical Therpaeutics led by Prof Duncan Richards. Clinical trials is our fourth sub-theme, with the aim of identifying new drug therapies for a range of inflammatory conditions using innovative trial designs
Our patient partners have played a major role in the overarching approach of our theme. We are keen to expand – and increase diversity of – participation in our trials and are using data to inform recruitment of patients from difficult to reach communities. Working with the centres involved in the A-TAP programme, we are increasing the number of patients from BAME backgrounds in our experimental medicine studies using virtual pre-screening consultations, which are now embedded in our True Colours strategy.