Identifying therapeutic targets to treat and prevent disease flare in rheumatoid arthritis

确定治疗和预防类风湿关节炎疾病发作的治疗靶点

• 批准号: MR/X005003/1
• 负责人: John Isaacs
• 金额: $ 39.02万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX005003%2F1
• 关键词: Identifying; therapeutic; targets; treat; prevent

Diseases such as rheumatoid arthritis (RA) relapse and remit. In other words, symptoms come and go unpredictably. This adds to the physical and psychological burden for patients because, even when they are well, they face the prospect of a sudden deterioration in their health. Imagine, for example, the impact of such an event when starting a new job or when about to go on a long-awaited vacation. Joint inflammation also causes joint damage which in turn causes disability, as well as contributing to conditions such as heart disease and stroke. So every flare has added potential consequences forlong-term health. Despite advances in understanding of the causes of RA, we understand almost nothing about what leads to disease 'flare' (an alternative term for relapse). There are a number of possibilities, one of which involves the white blood cells. RA is a so-called autoimmune disease in which the body's immune system turns inwards and starts to attack the joints and other tissues. So, when the disease is inactive the immune system may revert back to the normal state, only to become triggered again leading up to relapse. There are a number of different types of white blood cell that contribute to the immune system, several of which could be implicated in a flare. Although some white blood cells are damaging, others can regulate the immune response, and the balance between these two types of cells appears to be critical in diseases such as RA. Also, some of the 'bad' cells produce autoantibodies (proteins that can damage the tissues), and changes in these autoantibodies could trigger flares. Because flares occur unpredictably they are difficult to study scientifically. However, we have developed a human 'model' which allows us to study the underlying processes. As already implied, up to a third of patients with RA enter periods of remission, which can last for months or years. Many patients then ask whether they can stop their medicines and, if they do, about a half flare and the remainder remain well, for variable periods of time - although currently we cannot tell which patients will flare. In a recently completed study we asked 118 patients with RA, in remission, whether they would like to stop their medicines. If they did, and they agreed to take part in our research, we assessed them at intervals for 6 months after stopping treatment - initially fortnightly, then less frequently. Each time we saw them we took a blood sample for analysis in the laboratory. Now, by comparing samples from patients who flared and those who remained in remission we will be able to gain a better understanding of the immune reactions that trigger flare. In the proposed work we will use the samples we have collected from ten patients who remained in remission after stopping treatment with samples from ten patients who flared, to look for differences in their white blood cells at different timepoints. We only plan to look at a selection of patients at first because the tests we employ are sophisticated and will provide highly detailed information on the proteins that are on the surface of each blood cell, as well as the genes that are switched on inside each cell, and the proteins on their surface that are responsible for recognising and discriminating 'self' from the outside world of bugs etc - mistakes in which underlie the autoimmune attack. If this work proves to be informative then we will seek funding to extend the analysis to samples from a broader set of patients. We hope this work will help us to understand the mechanisms that underpin flare. In the longer term this should allow us to develop treatments that prevent or interrupt flare, as well as to predict the patients who are most likely to flare, in whom it is less safe to stop treatment. We believe that this could lead to new treatment approaches for such patients, enhancing their quality of life and long-term health.

类风湿性关节炎（RA）等疾病的复发和缓解。换句话说，症状的出现和消失是不可预测的。这增加了病人的生理和心理负担，因为即使他们身体健康，他们也面临着健康突然恶化的前景。例如，想象一下，当开始一份新工作或即将开始一个期待已久的假期时，这样的事件会产生什么影响。关节炎症还会导致关节损伤，进而导致残疾，还会导致心脏病和中风等疾病。因此，每次耀斑都增加了长期健康的潜在后果。尽管对类风湿性关节炎病因的了解有所进展，但我们对导致疾病“发作”（复发的另一种说法）的原因几乎一无所知。有许多可能性，其中之一与白细胞有关。类风湿性关节炎是一种所谓的自身免疫性疾病，在这种疾病中，身体的免疫系统转向内部，开始攻击关节和其他组织。因此，当疾病处于不活跃状态时，免疫系统可能会恢复到正常状态，只是再次被触发导致复发。有许多不同类型的白细胞对免疫系统有贡献，其中一些可能与耀斑有关。虽然有些白细胞具有破坏性，但其他白细胞可以调节免疫反应，这两种细胞之间的平衡似乎对类风湿关节炎等疾病至关重要。此外，一些“坏”细胞会产生自身抗体（一种可以损害组织的蛋白质），这些自身抗体的变化可能会引发耀斑。因为耀斑的发生是不可预测的，所以很难进行科学的研究。然而，我们已经开发了一个人类“模型”，使我们能够研究潜在的过程。如前所述，多达三分之一的RA患者进入缓解期，持续数月或数年。许多患者随后询问他们是否可以停药，如果停药，大约有一半会发作，其余的则会在不同的时间内保持良好状态——尽管目前我们还不能确定哪些患者会发作。在最近完成的一项研究中，我们询问了118名缓解期RA患者是否愿意停药。如果他们这样做了，并且他们同意参加我们的研究，我们会在停止治疗后的6个月内对他们进行评估——最初是两周，然后减少频率。每次见到他们，我们都会取血样到实验室进行分析。现在，通过比较爆发和缓解期患者的样本，我们将能够更好地了解引发爆发的免疫反应。在提议的工作中，我们将使用我们从10名停止治疗后仍处于缓解期的患者和10名爆发患者的样本中收集的样本，来寻找他们在不同时间点的白细胞差异。我们一开始只计划挑选一些病人，因为我们采用的测试是复杂的，将提供每个血细胞表面蛋白质的非常详细的信息，以及每个细胞内打开的基因，以及它们表面负责识别和区分“自我”与外部世界的细菌等的蛋白质——这些错误是自身免疫攻击的基础。如果这项工作被证明是有益的，那么我们将寻求资金将分析扩展到更广泛的患者样本。我们希望这项工作将帮助我们理解支撑耀斑的机制。从长远来看，这将使我们能够开发出预防或中断急性发作的治疗方法，并预测最可能发生急性发作的患者，对这些患者停止治疗不太安全。我们相信，这可能会为这类患者带来新的治疗方法，提高他们的生活质量和长期健康。