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

MICA：限制类风湿性关节炎持续缓解的生物因素（BIO-FLARE 研究）

• 批准号: MR/N026977/1
• 负责人: John Isaacs
• 金额: $ 363.05万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN026977%2F1
• 关键词: MICA; BIOlogical; Factors; Limit; sustAined

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.

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。想象一下，例如，当开始一份新工作或即将开始一个期待已久的假期时，这种事件的影响。关节炎症也会导致关节损伤，进而导致残疾，以及导致心脏病和中风等疾病。因此，每一次爆发都增加了对长期健康的潜在后果。尽管对类风湿关节炎病因的了解有所进展，但我们对导致疾病“爆发”（复发的替代术语）的原因几乎一无所知。有几种可能性。RA是一种所谓的自身免疫性疾病，其中身体的免疫系统转向内部并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，只是再次被触发导致复发。有许多不同的白色血细胞有助于免疫系统，其中一些可能与耀斑有关。虽然一些白色血细胞是破坏性的，但其他细胞可以调节免疫反应，这两种类型的细胞之间的平衡似乎在RA等疾病中至关重要。此外，一些“坏”细胞产生自身抗体（可以破坏组织的蛋白质），这些自身抗体的变化可能引发耀斑。或者，我们现在了解到关节中的细胞（滑膜成纤维细胞）可以影响免疫系统的活性，因此在确定何时发生耀斑时可能很重要。就像免疫细胞一样，成纤维细胞本身也可以以“好”和“坏”的形式存在。最后，上述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，并决定了特定基因的开启或关闭。我们认为，表观遗传学是一个重要的决定因素，一个人是否发展为RA，也是如何严重的疾病是。同样，表观遗传学的变化也会影响患者是否会发作，因为发作的发生是不可预测的，所以很难进行科学研究。然而，我们已经开发了一个人类“模型”，这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，可持续数月或数年。许多患者然后问他们是否可以停止他们的药物，如果他们这样做，大约一半的耀斑和其余的保持良好，在不同的时间段-虽然目前我们不能告诉哪些患者将耀斑。我们将询问缓解期RA患者是否愿意停药。如果他们这样做，并且他们同意参加我们的研究，我们将在停止治疗后的6个月内对他们进行评估-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，如果他们再次发作，我们也会要求在不需要住院的简单程序中采集他们发炎关节的衬里样本。我们将使用我们收集的样本来解决上面列出的各种可能性。通过比较发作患者和未发作患者的样本，我们将能够更好地了解触发发作的途径。从长远来看，这将使我们能够开发预防或中断发作的治疗方法，并预测最有可能发作的患者，停止治疗的安全性较低。我们相信，这可能会为这些患者带来新的治疗方法，提高他们的生活质量和长期健康。

项目成果

The interferon gene signature as a clinically relevant biomarker in autoimmune rheumatic disease

• DOI: 10.1016/s2665-9913(21)00254-x
• 发表时间: 2021-12-23
• 期刊: LANCET RHEUMATOLOGY
• 影响因子: 25.4
• 作者: Cooles, Faye A. H.;Isaacs, John D.
• 通讯作者: Isaacs, John D.

Single-cell insights into immune dysregulation in rheumatoid arthritis flare versus drug-free remission.

单细胞洞察类风湿性关节炎发作与无药物缓解中的免疫失调。

• DOI: 10.1038/s41467-024-45213-2
• 发表时间: 2024
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Baker KF

Distinct fibroblast subsets drive inflammation and damage in arthritis

• DOI: 10.1038/s41586-019-1263-7
• 发表时间: 2019-06-13
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Croft, Adam P.;Campos, Joana;Buckley, Christopher D.
• 通讯作者: Buckley, Christopher D.

SP0065 To taper or not to taper non biological dmards in ra remission?

SP0065 在 RA 缓解期间逐渐减少还是不逐渐减少非生物药物？

• DOI: 10.1136/annrheumdis-2018-eular.7678
• 发表时间: 2018
• 作者: Baker K

Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs and Disease Flare in Patients With Rheumatoid Arthritis.

半剂量与稳定剂量传统合成疾病缓解抗风湿药物和类风湿关节炎患者的疾病发作。

• DOI: 10.1001/jama.2021.10648
• 发表时间: 2021
• 期刊: JAMA
• 作者: Baker KF