PBC Predict: Prediction models and predictive biomarkers for primary biliary cholangitis

原发性胆管炎(PBC)是一种自身免疫性肝病，身体自身免疫系统会损害肝脏内的小胆管，最终导致肝硬变(肝脏疤痕形成)。目前关于PBC治疗的指导方针建议采用“循序渐进”的治疗方法，这意味着所有患者开始治疗时都要服用一种名为熊去氧胆酸(UDCA)的药物，这种药物只有一定的疗效，但副作用很小。如果这种疾病不是只在UDCA上起作用，就会增加更有效的药物-但也更有可能引起副作用。这种方法的明显问题是，需要更有效治疗的患者(即那些患有更具侵袭性疾病的患者)最终等待接受治疗的时间更长。另一方面，“逐级”治疗，即每个人都从更有效的药物开始，会导致许多患者暴露在不必要的副作用中。在许多PBC患者中，目前可用的任何药物都无法控制这种疾病。这些患者患上肝硬变和需要肝移植的风险增加。因此，PBC是与肝病相关的主要死亡原因，也是在英国进行肝脏移植的主要原因之一。因此，对于对目前可用药物无效的患者需要新的药物--需要准确的方法(例如新的血液测试)来尽早预测哪个患者需要更有效的药物，以及哪种药物对该患者效果最好。这就是精准医学的本质：在正确的时间给正确的患者正确的药物。英国-PBC是大学、制药公司和NHS之间雄心勃勃的合作，旨在为PBC开发精确医学。它是在医学研究委员会(MRC)的资助下开始的。作为UK-PBC的一部分，我的团队建立了UK-PBC研究队列(‘Cohort’)，该队列已经由6000多名PBC患者组成，每个患者都提供DNA样本，并同意从任何NHS组织收集临床信息。我们以前曾使用队列中患者的临床信息来开发统计模型，以预测对UDCA一线治疗的反应，或未来对肝移植的需求。我们已经使用关于队列的遗传信息进行了大规模的基因研究，这些研究强调了目前用于治疗其他自身免疫性疾病的药物，这些药物可能也适用于PBC。在拟议的项目中，在我们之前成功的基础上，我们将把队列扩大到10,000多名PBC患者。我们将从一系列NHS组织收集大量关于这些患者的临床信息。我们将利用这些临床信息来提高预测治疗反应或未来肝移植需求的统计模型的准确性，然后将其用于临床实践，以定制对PBC患者的治疗。我们将结合临床和遗传信息，确定决定治疗反应或未来肝移植需求的遗传因素，并开发包含临床和遗传信息的统计模型。我们将测量精心挑选的一组新诊断患者的血液免疫细胞中的基因调节和基因表达，并利用这些测量来开发新的血液测试，以尽早预测哪些患者将需要更有效的药物治疗。最后，我们将结合临床和遗传信息，以及对基因调控和基因表达的测量，确定导致PBC的基因，这将有助于我们确定可能对这种情况有效的新药。

Primary biliary cholangitis (PBC) is an autoimmune liver disease in which the body's own immune system causes damage to the small bile ducts inside the liver, eventually leading to cirrhosis (scarring of the liver). Current guidelines on the management of PBC recommend a 'step-up' approach to treatment, meaning that all patients start treatment with a medication called ursodeoxycholic acid (UDCA), which is only moderately effective but has few side effects. If the disease does not settle on UDCA alone, medication is added that is more effective - but also more likely to cause side effects. The obvious problem with this approach is that patients who need more effective treatment (i.e. those with more aggressive disease) end up waiting longer to receive it. On the other hand, 'step-down' treatment, in which everyone starts with more effective medication, would cause many patients to have unnecessary exposure to side effects. In many patients with PBC, the disease is not controlled by any of the medications that are currently available. These patients have increased risk of developing cirrhosis and needing a liver transplant. PBC is therefore a major cause of death related to liver disease, and one of the main reasons for having a liver transplant in the UK. Thus, new medications are needed for patients who do not respond to currently available medications - and accurate methods (e.g. new blood tests) are needed to predict, at the earliest possible stage, which patient will need more effective medication, and which medication will work best in that patient. This is the essence of precision medicine: to give the right medication to the right patient at the right time. UK-PBC is an ambitious collaboration between Universities, Drug Companies and the NHS to develop precision medicine for PBC. It was started with funding from the Medical Research Council (MRC). As part of UK-PBC, my team established the UK-PBC Research Cohort ('Cohort'), which already consists of more than 6,000 patients with PBC, each providing a DNA sample and consenting for clinical information to be collected from any NHS organisation. We have previously used clinical information about patients in the Cohort to develop statistical models that predict response to first-line treatment with UDCA, or future need for liver transplantation. We have used genetic information about the Cohort for large-scale genetic studies that have highlighted drugs, currently used for treatment of other autoimmune conditions, that might also work in PBC. In the proposed project, building on our previous success, we will expand the Cohort to more than 10,000 patients with PBC. We will collect large amounts of clinical information about these patients from a range of NHS organisations. We will use this clinical information to improve the accuracy of statistical models that predict response to treatment or future need for liver transplantation, which may then be used in clinical practice to tailor the treatment of PBC patients. We will combine clinical and genetic information to identify the genetic factors that determine response to treatment or future need for liver transplantation, and develop statistical models incorporating clinical and genetic information. We will measure gene regulation and gene expression in blood-based immune cells from a carefully selected group of newly diagnosed patients, and use these measurements to develop new blood tests that predict, at the earliest possible stage, which patients will need more effective medication. Finally, we will combine clinical and genetic information with measurements of gene regulation and gene expression to pinpoint the genes involved in causing PBC, which will help us to identify new medications that might work in this condition.