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，在英国影响了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%的患者却没有反应。我们现在知道，当人们对urso没有反应时，他们的肝脏疾病会随着时间的推移而恶化，最终导致肝硬化及其并发症，唯一的治疗方法就是肝移植。UK-PBC项目的目标,这是在学术中心的支持下,医生、病人团体和行业在英国,是理解为什么有些人不应对urso,找到更好的方法来预测谁会和不会回应,并确定最好的方法来治疗那些不回应(许多药物被认为是合理的治疗那些不应对urso但目前我们不知道和谁使用它们)。我们正在与患者团体合作，招募英国超过一半的无反应PBC患者（我们已经招募了三分之一），这是一项真正独特的研究。我们的前期研究已经阐明了人们有PBC风险的原因，并表明PBC在年轻患者和男性中对治疗的反应较小。我们现在需要知道原因，知道我们能做些什么。英国- pbc研究将分为三个部分。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，以及血液样本。临床信息将使我们能够确定某人是否对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组成的关键方面，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方面的差异。除了主要患者组外，我们还将邀请一组对urso无反应风险非常高的患者（那些被诊断为PBC的患者年龄在50岁以下）或已经没有反应的患者参加更详细的研究，我们将在研究的第二部分探索他们肝脏的实际损害。在我们研究的第二部分中，我们将探讨对urso有反应和没有反应的人的PBC有什么不同。这将使我们能够确定导致无反应的过程，并为无反应的人确定最佳的治疗方法。人们认为PBC是由免疫系统错误识别胆管内的细胞并试图排斥它们引起的。这会导致胆管受损，从而阻碍胆汁流动。胆汁是有毒的，然后在肝脏中积聚，对胆管造成更大的损害，从而进一步损伤胆管。损伤最终会导致疤痕，最终导致肝硬化。在第二个研究部分，我们将探讨是否对urso没有反应的人比反应者有更积极的免疫反应，有更多的毒性胆汁，胆管细胞对损伤的反应不同（应对能力较差）或更容易产生肝脏疤痕。至关重要的是，所有这些潜在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，我们将与患者群体和行业合作伙伴合作，开发一种全国性的PBC新药研究方法，使新药开发更容易，成本效益更高；这一举措将鼓励制药公司开发新的治疗方法，最终使患者受益。我们还开始制定一种全国性的PBC治疗方法，以便所有患者都能从最好的治疗中受益。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