MICA: BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study)

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。尽管对类风湿性关节炎病因的了解有所进步，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。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。有许多不同的白血球对免疫系统有贡献，其中几个可能与火焰有关。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。或者，我们现在了解到关节中有一些细胞(滑膜成纤维细胞)可以影响免疫系统的活动，因此这些细胞在确定耀斑发生的时间方面可能是重要的。就像免疫细胞一样，成纤维细胞本身也可以“好”和“坏”的形式存在。最后，上面提到的所有细胞都可以进行表观遗传修饰。这是一个影响细胞中DNA活性的过程，并决定特定基因的开启或关闭。我们认为，表观遗传学是决定某人是否患上类风湿性关节炎的重要因素，也决定了他们的疾病有多严重。类似地，表观遗传变化可能会影响患者是否出现红斑，因为红斑的发生是不可预测的，因此很难进行科学研究。然而，我们已经开发了一个人类模型，它将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。我们将询问缓解期的类风湿关节炎患者，他们是否愿意停止服药。如果他们这样做了，并且他们同意参与我们的研究，我们将在停止治疗后的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。当他们最初停止服药时，如果他们再次发炎，我们也会要求对他们发炎的关节衬里进行采样，这是一个简单的程序，不需要住院。我们将使用我们收集的样本来处理上面列出的各种可能的发炎情况。通过比较红斑患者和非红斑患者的样本，我们将能够更好地了解引发红斑的途径。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 for longterm 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. 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 white blood cells 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 cell 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. Alternatively, we now understand that there are cells in the joint (synovial fibroblasts) that can influence the activity of the immune system, and which therefore could be important in determining when a flare happens. Just like the immune cells, fibroblasts themselves can also exist in 'good' and 'bad' forms. Lastly, all of the cells mentioned above can undergo 'epigenetic' modification. This is a process that influences the activity of the DNA in a cell and determines whether a particular gene is switched on or off. We believe that epigenetics is an important determinant of whether someone develops RA, and also of how severe their disease is. Similarly, epigenetic changes could influence whether or not a patient flares.Because flares occur unpredictably they are difficult to study scientifically. However, we have developed a human 'model' which will allow 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. We will ask patients with RA, in remission, whether they would like to stop their medicines. If they do, and they agree to take part in our research, we will assess them at intervals for 6 months after stopping treatment - initially fortnightly, then less frequently. Each time we see them we will take a blood sample for analysis in the laboratory. When they initially stop their medicines, and again if they flare, we will also ask to take a sample of the lining of their inflamed joint in a simple procedure which does not require admission to hospital.We will use the samples we have collected to address the various possibilities for flare listed above. By comparing samples from patients who flare and those who don't we will be able to gain a better understanding of the pathways that trigger 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.