Developing new tests and treatments to enable prevention of osteoarthritis.

骨关节炎(OA)是最常见的关节炎形式，在英国有850万人受到影响。它有一个相关的医疗预算，估计为20亿英镑，社会成本要高得多。除了昂贵的关节置换，我们目前还没有预防、减缓或治愈骨性关节炎的药物治疗。膝关节损伤是未来膝关节骨性关节炎的最大危险因素。所有膝盖受伤的人中，大约有一半会患上骨性关节炎；治疗这种损伤的手术并不能降低这种风险。这种类型的骨性关节炎被称为“创伤后骨性关节炎”(PTOA)。患有PTOA的人通常更年轻，但我们不知道这种形式在其他方面是否与通常的(特发性)OA相同。研究关节损伤和PTOA患者提供了一个无与伦比的机会来了解导致OA的过程，并旨在通过测量和靶向这些过程来预防OA。到目前为止，我们已经表明，膝关节对损伤的炎症反应在人与人之间有很大的不同。这种最初的“关节损伤反应”与后来的与骨性关节炎相关的症状有关。初步发现，膝关节积液(滑液)中的两个具有代表性的“标志物”，受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。在英国生物库的研究中，我们发现，受伤时年龄较大和女性也会增加膝盖受伤后发生骨性关节炎的风险。已知的‘OA基因’并没有特别增加这种风险(尽管我们在完成更大数量的研究之前不能确定)。我们还发现了一种可能的新基因关联(以前没有见过)，需要进一步测试。我的总体目标是开发新的知识，使患者和NHS受益，主要目的是能够对试图预防OA的新疗法进行临床试验。这些试验的重点是那些经历过膝关节损伤或在其他高危人群中患上膝关节骨质疏松症的人。有三个主要目的和相关目标：1.我的目的是通过观察这两个群体中个人关节液中的许多(数千)蛋白质，并比较数千个基因的遗传相似性和差异性，来展示PTOA和特发性骨性关节炎的相似或不同之处。我的目标是开发有用的方法，将这些信息结合起来，对关节损伤的人进行分组，例如挑选出有特殊风险的人，或者那些具有意味着特定治疗可能对他们更有效的标记的人。这包括观察关节中血液的存在，以及我们是否可以将其发展为评估风险的准确和有用的测试。与此相关，我将使用包括MRI在内的扫描来测量血液或寻找其他可以预测结果的特征。我将致力于推动新干预措施的临床试验，特别是药物，用于PTOA和特发性骨关节炎。这将考察什么是可交付的，哪些是那些参与试验的人(关节损伤和膝关节炎患者及其医疗专业人员)可以接受的，与包括制药公司等利益相关者在内的国际社会合作，为该地区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，以便在全面试验中进行测试(这将由其他方式资助)。对个人来说，预测测试或工具将有许多优势：对个人来说，使生活方式规划和治疗决策成为可能；在这一领域推动新疗法的临床试验--挑选风险最高或最有可能起效的药物，将使试验更具可操作性和可接受性。它还可能从较小的数字中给出更准确的答案。这项工作旨在加快为PTOA和潜在的特发性OA患者开发新的治疗方法。鉴于办公自动化的人数很高，而且还在不断增长，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.