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

类风湿性关节炎(RA)等疾病会复发和缓解。换句话说，症状来来去去是不可预测的。这增加了患者的身体和心理负担，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，在开始一份新工作或即将开始期待已久的假期时，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，并导致心脏病和中风等疾病。因此，每一次耀斑都会增加对长期健康的潜在后果。尽管人们对类风湿性关节炎的病因有了进一步的了解，但我们对导致疾病“复发”(复发的另一种说法)的原因几乎一无所知。有很多种可能性，其中一种涉及到白细胞。类风湿关节炎是一种所谓的自身免疫性疾病，在这种疾病中，身体的免疫系统向内转，开始攻击关节和其他组织。因此，当疾病处于非活动状态时，免疫系统可能会恢复到正常状态，但最终会再次触发，导致复发。有许多不同类型的白细胞对免疫系统有贡献，其中几种可能与火焰有关。虽然一些白血球是有害的，但其他白血球可以调节免疫反应，而这两种细胞之间的平衡在RA等疾病中似乎是至关重要的。此外，一些“坏”细胞会产生自身抗体(可以破坏组织的蛋白质)，这些自身抗体的变化可能会引发疾病。由于耀斑的发生是不可预测的，因此很难对它们进行科学研究。然而，我们已经开发出一种人类‘模型’，使我们能够研究潜在的过程。正如已经暗示的那样，多达三分之一的RA患者进入缓解期，缓解期可能持续数月或数年。然后，许多患者会问他们是否可以停止服药，如果他们这样做了，大约一半的患者会在不同的时间段内保持良好--尽管目前我们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名缓解期的RA患者，他们是否愿意停止服药。如果他们这样做了，并且他们同意参加我们的研究，我们在停止治疗后的6个月内每隔6个月对他们进行评估-最初每两周一次，然后减少频率。每次我们看到他们，我们都会抽取血液样本，在实验室进行分析。现在，通过比较红斑患者和缓解期患者的样本，我们将能够更好地了解引发红斑的免疫反应。在拟议的工作中，我们将使用我们从停止治疗后仍处于缓解状态的10名患者身上收集的样本，以及从10名突发事件患者身上收集的样本，来寻找他们在不同时间点的白细胞的差异。我们只计划首先观察一些患者，因为我们使用的测试是复杂的，将提供关于每个血细胞表面的蛋白质的非常详细的信息，以及每个细胞内部开启的基因，以及它们表面负责识别和区分细菌等外部世界的“自我”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信息的，那么我们将寻求资金，将分析扩展到更广泛的患者组的样本。我们希望这项工作将有助于我们理解耀斑的机制。从长远来看，这将使我们能够开发出预防或中断红斑的治疗方法，并预测最有可能红肿的患者，对他们停止治疗不太安全。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。

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.