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

类风湿性关节炎（RA）是一种关节炎症可引起疼痛、僵硬、持久损伤和残疾的疾病。据估计，英国有50万人患有这种疾病，并对他们的生活产生了重要影响。例如，在疾病发病的5年内，33%的人无法继续从事全职工作。近年来，类风湿性关节炎的治疗取得了显著进展。首先，一旦确诊为类风湿性关节炎，患者就会接受药物治疗，并迅速增加剂量，试图抑制所有关节炎症。最常用的药物是甲氨蝶呤（MTX）。其次，那些对甲氨蝶呤没有反应的人可以服用一种生物药物，之所以这么说，是因为它们抑制了与炎症有关的生物途径。可以使用的生物药物有很多；最常见的是，抗肿瘤坏死因子（TNF）疗法被用作首选的生物疗法。那些对这些药物没有反应的患者会转而尝试一种生物药物，这种药物通过清除循环中的B细胞起作用（利妥昔单抗，RTX）。最近，推荐使用一种通过阻断另一种炎症途径（il - 6途径）起作用的生物药物（tocilizumab， TOC）。虽然这些药物都被证明可以控制炎症，减缓或防止持久的关节损伤，但它们并不是对每个病人都有效。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都没有反应。目前，我们没有办法预测哪些病人对哪种药物的反应最好，所以这些药物都是在“试错”的基础上开出的。然而，我们知道，寻找有效治疗方法所需的时间越长，关节损伤就会累积越多，患者的长期前景也就越糟糕。因此，本研究的目的是确定MTX、抗tnf、RTX和TOC反应的预测因素，以便RA患者在确诊后立即给予他们最有可能反应的药物。反应预测因子可能是DNA、蛋白质或其他分子的变化，这些变化可以在血液样本或发炎的关节组织中检测到。在这个工作计划中，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患者关节处采集的组织样本，以及从大量接受这四种药物治疗的RA患者身上采集的血液样本。我们将研究基因变化、蛋白质水平和其他分子。我们将结合所获得的信息来测试组合标记是否比一次研究一种标记更好地预测反应。我们已经有证据表明，发炎关节组织中B细胞的数量可以预测患者是否可能对B细胞消耗疗法（RTX）有良好的反应。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，根据患者关节组织中B细胞浸润的水平，患者将被随机分配接受RTX或另一种生物疗法。这项研究的结果将是确定血液或组织标记物，以帮助对RA患者进行正确的治疗。这一点尤其重要，因为生物药物非常昂贵（每位患者每年8-1万英镑）。至关重要的是，由于NHS每年的生物制剂费用约为1.6亿英镑，在“盲”治疗之前确定30-40%的无反应者每年可能节省1300 - 1800万英镑，因为在英国每年大约有4000 - 5000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.