Stratified Medicine in Primary Biliary Cirrhosis (PBC): Understanding Disease Mechanisms and Targeting Therapies (UK-PBC)

原发性胆汁性肝硬化（PBC）是一种慢性肝病，影响英国20，000名患者。我们项目的目的是改变我们治疗它的能力。问题是，尽管许多PBC患者对一种名为熊去氧胆酸（“urso”）的药物治疗反应良好，但约30%的患者反应不佳。我们现在知道，当人们对urso没有反应时，随着时间的推移，他们的肝脏疾病会有真实的风险，最终导致肝硬化及其所有并发症，唯一的治疗方法是肝移植。UK-PBC项目得到了英国各地学术中心、医生、患者团体和行业的支持，其目标是了解为什么有些人对urso没有反应，找到更好的方法来预测谁会和不会做出反应，并找出治疗那些没有反应的人的最佳方法（对于对urso无反应的人，已经建议使用一些药物作为合理的治疗方法，但目前我们不知道如何使用这些药物，也不知道对谁使用这些药物）。我们正在与患者团体合作，招募英国一半以上的无反应PBC患者（我们已经招募了三分之一），使这成为一项真正独特的研究。我们的预备性研究已经阐明了为什么人们有PBC的风险，并表明PBC在年轻患者和男性中对治疗反应的可能性较小。我们现在需要知道为什么，并知道我们可以做些什么。在第一部分，我们将与PBC基金会合作招募患者，并组织收集重要的临床信息和血液样本。临床信息将使我们能够确定是否有人对urso有反应（以及他们的症状有多严重）。血液样本将使我们了解人们组成的关键方面，包括他们的基因和他们的免疫系统的工作方式，以及对urso有反应和没有反应的人之间的组成差异。除了主要的患者组外，我们还将邀请一小部分对URSO无反应的高危患者（50岁以下被诊断为PBC的人），或尚未作出反应的人，参加一个更详细的研究，我们将在研究的第二部分探讨他们肝脏的实际损害。在我们研究的第二部分，我们将探讨对urso有反应和没有反应的人的PBC不同。这将使我们能够识别导致无反应的过程，并为无反应的人确定最好的治疗方法。PBC被认为是由免疫系统错误识别胆管细胞并试图排斥它们引起的。这会导致胆管损伤，从而损害胆汁流动。胆汁，这是有毒的，然后建立在肝脏造成更多的损害胆管，从而进一步胆管损伤。损伤最终导致瘢痕形成，并最终导致肝硬化。在第二个研究部分，我们将探讨对urso无反应的人是否比有反应的人有更积极的免疫反应，是否有更多的毒性胆汁，是否有对损伤反应不同的胆管细胞（应对能力较差），或者是否更容易形成肝脏疤痕。重要的是，所有这些潜在的原因都与现有的潜在治疗方法相匹配，或者可以快速开发新治疗方法的领域。在第三部分中，我们将与患者团体和行业合作伙伴合作，制定一种研究PBC新药的国家方法，使开发新药更容易，更具成本效益;这将鼓励公司开发最终使患者受益的新疗法。我们还开始制定一项全国性的PBC治疗方案，使所有患者都能从最佳治疗中受益，我们的目标就是改变我们对如何治疗这一重大疾病的认识

Primary Biliary Cirrhosis (PBC) is a chronic liver disease affecting 20,000 patients in the UK. The aim of our project is to transform our capacity to treat it. The problem is that whereas many PBC patients respond well to treatment with a drug called ursodeoxycholic acid ("urso") around 30% do not. We now know that when people don't respond to urso they run a real risk of their liver disease getting worse over time, leading ultimately to cirrhosis with all its complications and for which the only treatment is liver transplantation. The goal of the UK-PBC project, which is supported by academic centres, doctors, patient groups and industry throughout the UK, is to understand why it is that some people don't respond to urso, to find better ways of predicting who will and won't respond, and to identify the best way to treat people who don't respond (a number of drugs have been suggested as sensible treatments for people who don't respond to urso but at present we don't know how and in whom to use them). We are working with patient groups to recruit over half of all urso non-responding PBC patients in Britain (we have already recruited a third) making this a truly unique study. Our preparatory studies have already shed light on why people are at risk of PBC, and have shown that PBC is less likely to respond to treatment in young patients and in men. We now need to know why and to know what we can do about it.The UK-PBC study will be in 3 sections. In the 1st section we will work with the PBC Foundation to recruit patients and to organise to collect important clinical information, together with a blood sample. The clinical information will allow us to identify whether someone has responded to urso or not (as well as how bad their symptoms are). The blood samples will allow us to understand key aspects of people's make up, including their genes and the way their immune system works, and the differences in make up between people who do and don't respond to urso. In addition to the main group of patients we will invite a smaller group of patients who are at very high risk of not responding to urso (those in whom PBC was diagnosed below the age of 50), or who have already not responded, to take part in a more detailed study in which we explore the actual damage to their liver in the 2nd section of the study.In the 2nd section of our study we will explore what is different about PBC in people who do and don't respond to urso. This will allow us to identity the processes that cause non-response and to identify the best possible treatments for people who don't respond. It is thought that PBC is caused by the immune system mis-identifying the cells that line the bile duct and trying to reject them. This leads to damage to the bile ducts which impairs bile flow. Bile, which is toxic, then builds up in the liver causing more damage to the bile ducts and thus further bile duct injury. Injury eventually leads to scarring, and ultimately cirrhosis. In the second study section we will explore whether people who don't respond to urso have a more aggressive immune response than responders, have more toxic bile, have bile duct cells that react differently to injury (coping less well) or are more susceptible to liver scarring. Critically, all of these potential causes match up to existing potential treatments, or areas where new treatments can be developed rapidly. In the 3rd section we will work with patient groups and industry partners to develop a national approach to studying new drugs in PBC to make it easier and more cost-effective to explore new drugs; a step which will encourage companies to want to develop new treatments which will ultimately benefit patients. We also begin to develop a national approach to treatment of PBC so that all patients benefit from the best possible treatments.Our goal is nothing less than a transformation in our understanding of how to treat this significant disease