Clinical, genetic and immune determinants of drug immunogenicity in psoriasis

为什么需要在这个领域进行研究？牛皮癣很常见，每100人中就有2人患病。在这种情况下，皮肤细胞的生长和脱落比平时更快。患者可能会有红色鳞片状的皮肤斑块，他们会感到尴尬、瘙痒和疼痛。这会极大地影响生活质量——就像患心脏病或癌症一样。严重的牛皮癣现在可以使用强力注射生物制剂治疗（每位患者每年花费约1万英镑）。虽然许多人一开始对生物治疗反应良好，但有些人不幸地看到他们的皮肤再次恶化。事实上，几乎三分之一的患者在三年内停止使用生物制剂，因为它们不再起作用。我们认为，这主要是由于患者的免疫系统攻击药物分子（一种抗药物反应），随着时间的推移，药物的效果会降低。抗药反应是一个普遍的问题，影响着人们在许多不同的情况下服用生物制剂，但我们对此知之甚少。特别是，目前还不清楚为什么有些人的免疫系统会对生物药物发起攻击，而另一些人却不会。这项研究的目的是什么？我们的目标是确定特定的因素，可以帮助预测哪些患者产生抗药物反应的风险增加。这些知识将使我们能够采取措施尽可能地降低风险，同时在为每位患者选择最佳生物制剂时权衡其他因素。采取这种个性化的方法将最大限度地提高患者从治疗中获得持久益处的机会。例如，如果患者有很高的抗药物反应风险，他们的医生可能会建议开始使用那些似乎在更少的人中导致抗药物反应的生物制剂。医生也可以考虑在服用生物制剂的同时服用一片药片，以稳定免疫系统，或者改变生物制剂本身的剂量和频率。另一方面，如果患者出现抗药反应的风险较低，医生可以向他们保证，这种生物制剂可能会继续起作用。生物制剂的高成本使得了解哪些患者将从它们的使用中获得持久的益处变得尤为重要。虽然这项研究关注的是牛皮癣患者，但潜在的影响是广泛的。目前，开具生物制剂处方是基于不断的试验和错误，但使用个性化的方法将帮助患有多种不同疾病的患者更好地控制自己的健康，同时为NHS节省资金。在基本层面上，我们可能对抗药物反应是如何以及为什么产生的，以及更广泛地了解免疫系统是如何工作的有了基本的了解。这项研究将如何进行？使用超过3000名牛皮癣患者的独特英国数据库，我们计划测试对最常见的生物阿达木单抗（品牌名Humira）产生抗药反应的患者与无抗药反应的患者之间是否存在以下因素的差异：-临床因素，通过分析参与者的年龄和性别等信息-遗传因素，通过分析DNA样本-免疫因素，通过分析白细胞在第一阶段；我们将把重要的临床和遗传因素结合成一个风险评分，以预测某人是否可能产生抗药物反应。我们还将在服用另一种名为ustekinumab（品牌名为Stelara）的生物制剂的人群，以及服用其他免疫相关疾病（如类风湿关节炎和炎症性肠病）生物制剂的人群中测试这种风险评分。在第二阶段，我们将非常详细地研究白细胞，寻找产生抗药物反应的人与没有产生抗药物反应的人之间的差异。谁将进行这项研究，在哪里进行？该项目将由伦敦国王学院的皮肤科医生兼研究员Teresa Tsakok博士领导。她的工作将得到牛皮癣、遗传学和免疫系统专家团队的支持。

Why is research needed in this area?Psoriasis is common, affecting around 2 in every 100 people. In this condition, skin cells grow and shed more rapidly than usual. Patients may have red scaly patches of skin that they find embarrassing, itchy and painful. This can hugely affect quality of life - as much as having heart disease or cancer. Severe psoriasis can now be treated using powerful injectable biologics (costing around £10,000 per year, per patient). Although many people at first respond well to biologic treatment, some unfortunately see their skin worsen again. In fact, almost a third of patients discontinue biologics within 3 years because they no longer work. We believe that this is mostly due to a patient's immune system attacking the drug molecules (an anti-drug response), which reduces the drug's effect over time. The anti-drug response is a common problem affecting people taking biologics for many different conditions, but we know surprisingly little about it. In particular, it is unclear why some people's immune systems launch an attack on biologic drugs, whereas others do not. What does this research aim to achieve?We aim to identify specific factors that could help predict which patients are at increased risk of developing an anti-drug response. This knowledge would allow us to take steps to reduce the risk as much as possible, whilst weighing up other factors to consider when choosing the best biologic for each patient. Taking this personalised approach would maximise patients' chances of having lasting benefit from treatment. For instance, if a patient is at high risk of an anti-drug response, their doctor could suggest starting biologics that appear to result in anti-drug responses in fewer people. Doctors could also consider giving a tablet alongside the biologic that settles the immune system, or changing the dose and frequency of the biologic itself. On the other hand, if a patient is at low risk of an anti-drug response, doctors could reassure them that the biologic will likely continue to work. The high cost of biologics makes it especially important to understand which patients will have lasting benefit from their use. Although this research focuses on people with psoriasis, the potential impact is widespread. Prescribing biologics is currently based on trial and error, but using a personalised approach would help patients with many different conditions maintain better control of their health, as well as saving money for the NHS. On a fundamental level, we may gain basic insight into how and why the anti-drug response develops, and more generally into how the immune system works. How will this research be conducted?Using a unique UK database of more than 3000 people with psoriasis, we plan to test whether or not the following factors differ between those who develop an anti-drug response to the commonest biologic adalimumab (brand name Humira), compared to those who do not:- Clinical factors, by analysing information about participants such as age and gender- Genetic factors, by analysing DNA samples- Immune factors, by analysing white blood cellsIn the first stage, we will combine important clinical and genetic factors into a risk score to predict whether someone is likely to develop an anti-drug response. We will also test this risk score in people taking a different biologic called ustekinumab (brand name Stelara), and in people on biologics for other immune-related conditions such as rheumatoid arthritis and inflammatory bowel disease. In the second stage, we will study white blood cells in great detail, looking for differences between people who develop an anti-drug response, compared to those who do not. Who will carry out the research and where will it take place?This project will be led by Dr Teresa Tsakok, a dermatologist and researcher at King's College London. Her work will be supported by a team of experts in psoriasis, genetics, and the immune system.