Developing new tests and treatments to enable prevention of osteoarthritis.

骨关节炎（OA）是最常见的关节炎，在英国影响着850万人。相关的医疗预算估计为20亿英镑，社会成本要高得多。除了昂贵的关节置换术，我们目前还没有预防、减缓或治愈OA的药物治疗方法。膝关节损伤是未来膝关节炎的最大危险因素。大约一半的膝关节损伤（如韧带撕裂）患者会发展为OA；手术治疗损伤并不能降低这种风险。这种类型的骨关节炎被称为“创伤后骨关节炎”（pta）。pta患者通常较年轻，但我们不知道这种形式是否与“通常”（特发性）OA相同。研究患有关节损伤和pta的人提供了一个无与伦比的机会来了解导致OA的过程，并通过测量和瞄准这些过程来预防OA。到目前为止，我们已经证明膝盖受伤后会有炎症反应，因人而异。这种最初的“关节损伤反应”与后来与OA相关的症状有关。初步发现，膝关节液（滑液）中的两种代表性“标志物”，损伤时关节内血液和液体的增加都是膝关节损伤患者预后较差的标志物。在英国生物银行的工作中，我们发现受伤时年龄较大和女性也会增加膝关节损伤后OA的风险。已知的“OA基因”并没有特别增加这种风险（尽管我们不能确定，直到我们完成更多的研究）。我们还发现了一种可能的新基因关联（以前没有发现与OA相关），需要进一步测试。我的总体目标是开发有利于患者和NHS的新知识，主要目的是能够对寻求预防OA的新疗法进行临床试验。这些试验重点关注的是经历过膝关节损伤的人或其他患膝关节OA的高危人群。有三个主要目的和相关目标：1。我将通过观察这两组个体关节液中的许多（数千）蛋白质，并比较数千个基因之间的遗传相似性和差异，来展示PTOA和特发性OA的相似或不同之处。我的目标是开发有用的方法，将这些信息结合起来，对关节损伤患者进行分组，例如挑选出具有特定风险的个体，或者那些具有特定治疗方法可能对他们更有效的标记的个体。这包括观察关节中是否存在血液，以及我们是否可以将其发展为一种准确而有用的风险评估测试。与此相关，我将使用包括核磁共振在内的扫描来测量血液或寻找其他预测结果的特征。我的目标是推动新的干预措施的临床试验，特别是药物，在toa和特发性OA。这将研究参与试验的人（患有关节损伤和膝关节OA的个人及其医疗保健专业人员）可交付和可接受的内容，与包括制药公司等利益相关者在内的国际社会合作，为该领域的试验制定指导方针，并使我们能够选择至少一种新的干预措施进行全面试验（将通过其他方式资助）。评估个人患OA风险的预测测试或工具将有很多好处：对个人来说，可以制定生活方式计划和治疗决策；为了推动这一领域新疗法的临床试验，挑选出那些风险最高或最有可能产生反应的人，将使试验更容易交付和接受。它也可以从更小的数字中给我们更准确的答案。这项工作的目的是加快开发新的治疗方法，为那些与toa和潜在的特发性OA。鉴于使用OA的人数越来越多，任何创新都可能使医疗保健和社会受益。

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.