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，在英国影响着2万名患者。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%的患者效果不佳。我们现在知道，当人们对urso没有反应时，他们的肝病确实有可能随着时间的推移而恶化，最终导致肝硬化及其所有并发症，而唯一的治疗方法是肝移植。英国-PBC项目得到了英国各地的学术中心、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有反应，并找出治疗没有反应的人的最佳方法(一些药物被建议作为对urso没有反应的人的合理治疗方法，但目前我们不知道如何使用它们，以及在谁身上使用它们)。我们正在与患者团体合作，招募英国一半以上的URSO无反应PBC患者(我们已经招募了三分之一)，这使这项研究真正成为一项独特的研究。我们的前期研究已经阐明了为什么人们有患PBC的风险，并表明PBC对年轻患者和男性患者的治疗反应较小。我们现在需要知道为什么，并知道我们能做些什么。英国-PBC的研究将分为三个部分。在第一部分中，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以及血液样本。临床信息将使我们能够识别某人是否对URSO有反应(以及他们的症状有多严重)。血液样本将让我们了解人们构成的关键方面，包括他们的基因和免疫系统的工作方式，以及对URSO有反应和没有反应的人在组成上的差异。除了主要的患者组外，我们还将邀请一小部分对URSO无反应的高风险患者(那些PBC被诊断为50岁以下的人)或已经没有反应的患者参加更详细的研究，在研究的第二部分，我们将探索他们肝脏的实际损害。在我们的研究的第二部分，我们将探索对URSO有反应和无反应的人的PBC的不同之处。这将使我们能够识别导致无应答的过程，并确定对无应答的人进行最佳可能的治疗。据认为，PBC是由免疫系统错误识别排列在胆管内的细胞并试图排斥它们引起的。这会导致胆管受损，从而影响胆汁流动。胆汁是有毒的，然后在肝脏中积聚，对胆管造成更大的损害，从而进一步损害胆管。损伤最终会导致疤痕形成，最终导致肝硬变。在第二个研究部分，我们将探索那些对urso没有反应的人是否比有反应的人有更具侵略性的免疫反应，有更多的有毒胆汁，有对损伤反应不同的胆管细胞(应对能力较差)，或者更容易受到肝脏疤痕的影响。关键的是，所有这些潜在的原因都与现有的潜在治疗方法相匹配，或者是可以迅速开发新的治疗方法的领域。在第三部分中，我们将与患者团体和行业合作伙伴合作，制定在PBC研究新药的全国性方法，使探索新药变得更容易、更具成本效益；这一步骤将鼓励公司希望开发最终将使患者受益的新疗法。我们还开始开发一种全国性的方法来治疗PBC，以便所有患者都能从尽可能好的治疗中受益。我们的目标无非是改变我们对如何治疗这种重大疾病的理解

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