Maximising Therapeutic Utility for Rheumatoid Arthritis using genetic and genomic tissue responses to stratify medicines.

风湿性关节炎（RA）是一种关节炎症可导致疼痛、僵硬、持久损伤和残疾的疾病。它影响了英国约50万人，并对他们的生活产生了重要影响。例如，在疾病发作的5年内，33%的人无法继续从事全职工作。近年来，RA的治疗取得了巨大进展。首先，患者一旦被诊断患有RA就立即接受药物治疗，并迅速增加剂量以抑制所有关节炎症。最常用的药物是甲氨蝶呤（MTX）。第二，可以给那些对MTX没有反应的人一种生物药物，所谓的生物药物是因为它们抑制了与炎症有关的生物途径。有许多生物药物可以使用;最常见的是，抗肿瘤坏死因子（TNF）疗法被用作首选生物制剂。那些对这些药物没有反应的患者则转而尝试一种生物药物，这种药物通过从循环中清除B细胞（利妥昔单抗，RTX）来起作用。最近，推荐使用一种通过阻断另一种炎症途径（IL 6途径）发挥作用的生物药物（托珠单抗，TOC）。虽然这些药物中的每一种都已被证明可以控制炎症，减缓或预防持久的关节损伤，但它们并不适用于每一个患者。因此，45%的患者对MTX没有反应，而30-40%的患者对每种生物药物没有反应。目前，我们无法预测哪些患者对哪种药物的反应最好，因此药物是在“试错”的基础上开的。然而，我们知道，找到有效治疗方法所需的时间越长，关节损伤累积得越多，患者的长期前景就越差。因此，本研究的目的是确定对MTX，抗TNF，RTX和TOC反应的预测因子，以便RA患者一旦被诊断，就可以给予他们最有可能反应的药物。反应预测因子可以是DNA、蛋白质或其他分子的变化，并且这些变化可以在血液样本或发炎的关节组织中检测到。在这项工作计划中，我们计划进行一系列全面的实验来研究这一点。我们将研究从RA患者关节采集的组织样本以及从接受4种待研究药物治疗的大量RA患者采集的血液样本。我们将研究基因变化，蛋白质水平和其他分子。我们将联合收割机获得的信息，以测试是否组合的标志物预测反应更好地比研究一个标志物的时间。我们已经有证据表明，炎症关节组织中B细胞的数量可以预测患者是否可能对B细胞耗竭疗法（RTX）反应良好。因此，我们还计划通过进行随机临床试验来测试这种方法在实践中的效果如何。根据关节组织中观察到的B细胞浸润水平，患者将被随机分配接受RTX或其他生物治疗。这项研究的结果将是确定血液或组织标记物，以帮助针对RA患者进行正确的治疗。这一点特别重要，因为生物药物非常昂贵（每位患者每年8- 10，000英镑）。至关重要的是，由于NHS每年的生物制剂成本约为1.6亿英镑，因此在“盲”治疗之前识别30-40%的无应答者每年可能节省1300 - 1800万英镑，因为英国每年约有4- 5，000名患者开始抗TNF治疗。

Rheumatoid arthritis (RA) is a disease in which inflammation of joints can cause pain, stiffness, lasting damage and disability. It affects an estimated 500,000 people in the UK and has important impacts on their lives. For example, within 5 years of diseases onset, 33% people are unable to remain in full-time work. There have been dramatic advances in treatment of RA in recent years. First, patients are treated with drugs as soon as they are diagnosed with RA and the dose is increased quickly to try and suppress all joint inflammation. The most common drug used is called methotrexate (MTX). Second, those people who fail to respond to MTX can be given a biologic drug, so-called because they inhibit a biological pathway involved in inflammation. There are a number of biologic drugs that can be used; most commonly, anti-tumour necrosis factor (TNF) therapies are used as the first choice biologic. Patients who fail to respond to those are then switched to try a biologic drug that acts by removing B cells from the circulation (rituximab, RTX). More recently, a biologic drug that acts by blocking another inflammatory pathway, the IL6 pathway, has been recommended for use (tocilizumab, TOC). Whilst each of these drugs has been proven to control inflammation and slow or prevent lasting joint damage, they don't work for every patient. Thus, 45% patients fail to respond to MTX whilst 30-40% fail to respond to each of the biologic drugs. At the moment, we have no means of predicting which patients will respond best to which drug and so the drugs are prescribed on a 'trial and error' basis. However, we know that the longer it takes to find an effective therapy, the more joint damage accumulates and the worse the long-term outlook is for patients. Therefore, the aim of this study is to identify predictors of response to MTX, anti-TNF, RTX and TOC so that patients with RA can be given the drug that they are most likely to respond to, as soon as they are diagnosed. The response predictors may be changes in DNA, proteins or other molecules and these changes may be detectable in blood samples or in the joint tissues that are inflamed. In this program of work, we plan a comprehensive series of experiments to investigate this. We will study both tissue samples taken from the joints of patients with RA as well as blood samples collected from large numbers of RA patients treated with each of the 4 drugs to be investigated. We will study genetic changes, protein levels and other molecules. We will combine the information obtained to test whether combinations of markers predict response better than studying one marker at a time. We already have evidence to suggest that the number of B cells in the inflamed joint tissue can predict whether patients are likely to respond well to the B cell depleting therapy, RTX. Therefore, we also plan to test how well this works in practice by performing a randomized clinical trial whereby patients will be randomly assigned to receive RTX or another biologic therapy based on the level of B cell infiltration seen in their joint tissue.The outcome of this study will be the identification of blood or tissue markers that help to target the right treatments to the right patients with RA. This is particularly important because the biologic drugs are very expensive (£8-10,000 per patient per year). Crucially, as the annual cost of biologics to the NHS is ~£160 million, the identification of the 30-40% of non-responders prior to "blind" therapy would potentially save £13-18 million annually because approximately 4-5,000 patients start anti-TNF therapy each year in the UK.