Developing new tests and treatments to enable prevention of osteoarthritis.

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Osteoarthritis (OA) is the commonest form of arthritis, affecting 8.5 million people in the UK. It has an associated healthcare budget estimated at £2 billion, with much greater societal cost. Other than expensive joint replacement, we currently have no drug treatments that prevent, slow or cure OA. Knee joint injuries are the biggest risk factor for future knee OA. About half of all people with knee injuries such as ligament tears will develop OA; surgery to treat the injury does not reduce this risk. This type of OA is known as 'post-traumatic osteoarthritis' (PTOA). Individuals with PTOA are often younger, but we don't know if this form is otherwise the same as 'usual' (idiopathic) OA. Studying people with joint injury and with PTOA gives an unrivalled opportunity to understand the processes which cause OA, and to aim to prevent OA by measuring and targeting these processes.So far we have shown that there is an inflammation response in the knee to injury which varies considerably between people. This initial 'joint injury response' is linked to later symptoms associated OA. Initial findings are that two representative 'markers' in knee joint fluid (synovial fluid), increased blood and increased fluid in the joint at the time of injury all act as markers of worse outcome in those with knee injury. In UK Biobank work, we showed that being older at the time of injury and being female also increase risk of OA after knee injury. Known 'OA genes' did not particularly add to this risk (though we cannot be sure until we finish studies in bigger numbers). We also found a possible new gene association (not previously seen with OA) which will need to be tested further.My overall goal is to develop new knowledge that will benefit patients and the NHS, with the main aim of being able to run clinical trials of new treatments that seek to prevent OA. These trials importantly focus on people who have experienced knee joint injury or in other high risk groups for developing knee OA.There are three main aims and related objectives:1. I will aim to show how similar or different PTOA and idiopathic OA are, by looking at many (thousands) of proteins in the joint fluid of individuals in these two groups and also comparing genetic similarities and differences across thousands of genes.2. I will aim to develop useful ways to combine this information to subgroup people with joint injury, for example picking out individuals at particular risk or those with markers that mean particular treatments may work better for them. This includes looking at the presence of blood in the joint and whether we can develop it as an accurate and useful test to assess risk. Related to this, I will use scans including MRI to measure blood or look for other features that predict outcome.3. I will aim to drive clinical trials of new interventions, particular drugs, in PTOA and in idiopathic OA. This will look at what is deliverable and acceptable to those taking part in trials (individuals with joint injury and with knee OA and their healthcare professionals), work with the international community including stakeholders like drug companies to develop guidance for trials in the area and enable us to select at least one new intervention to take forward to testing in a full trial (which will be funded by other means).A predictive test or tool which rates an individual's risk of OA would have a number of advantages: to the individual, enabling lifestyle planning and decisions around treatments; and to drive clinical trials of new treatments in this area - picking out those at highest risk or most likely to respond would make trials more deliverable and acceptable. It may also give us more accurate answers from smaller numbers. This work aims to speed up the development of new treatments for those with PTOA and potentially also idiopathic OA. Given the high and growing numbers with OA, any innovation is likely to benefit healthcare and society.