The oRAcle Study - Predicting the risk of infection in RA

oRAcle 研究 - 预测 RA 感染风险

• 批准号: MR/R001332/1
• 负责人: Katie Bechman
• 金额: $ 30.38万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 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%2FR001332%2F1
• 关键词: oRAcle; Study; Predicting; risk; infection

The backgroundRheumatoid Arthritis (RA) is a long-term, incurable condition, affecting 1% of the adult population. It causes joint pain and stiffness, which overtime can result in damage. In RA the body's immune system (which is designed to defend against infection) becomes too active and mistakenly attacks the body's own tissue. Drug therapies that treat RA do so by targeting the immune system. These are called disease-modifying antirheumatic drugs (DMARDs). The problemPatients with RA experience frequent and severe infections, with twice as many hospital admissions compared to people without the disease. Serious infections are the tip of the iceberg, with over 30% of patients reporting non-serious infections each year. When a patient has an infection, their clinician will stop their DMARDs. Without treatment for RA, disease activity worsens and the disease may 'flare'. Interrupted treatment regimens are associated worsening disease and increased joint damage. The research questionCurrent belief is that the increased risk of infection in patients with RA is a side effect of drug therapy. However, we propose that the active inflammatory process in RA is an important cause of susceptibility to infection. We believe that this is because chronic inflammation paradoxically suppresses the immune system, putting patients at greater risk of infection. This is supported by clinical experience where patients with more severe disease experience more infections. It is currently not known how much the disease state contributes to the body's ability to resist infection. We want to answer this question.Study aimOur research will address how much the disease state contributes to infection susceptibility. Our goal is to study the clinical and laboratory features of a large group of RA patients to identify which of these characteristics put them at greatest risk of infection, independent of drug therapy. Study planThe TACERA (Towards A Cure in RA) dataset has acquired extensive clinical information and blood samples on 270 patients with newly diagnosed RA prior to starting treatment. It is one of the richest datasets generated in recent years combining large amounts of clinical and laboratory data. Importantly, this is "real life" data because patients were treated as they would be in routine clinical practice. All infectious events have been captured throughout the study, and so the high risk group has already been identified. In this study we will compare the patients who have had an infection with those who did not. Initial work will identify any differences in their clinical characteristics (e.g. age, smoking, disease severity). The TACERA dataset has detailed analysis of the patients' blood samples prior to starting DMARDs, with the measurements of the expression of thousands of genes that control the way the immune system functions. We can look at this data and see if there are any specific differences between patients that developed infections compared to those who did not. This will help identify patterns associated with the risk of infection. We will then investigate changes in the blood after starting DMARDs, to identify changes in the immune system associated with an increased risk of infection. We will compare these patterns to those seen before therapy was started. This will enable us to assess the relative contribution of the drug and the disease on the risk of infection.Study impactWe anticipate being in a position to use a combination of blood test results with clinical features to determine for every patient their risk of developing an infection. This test may contribute to a scoring system that considers other risks factors for infection, and may be relevant to patients with many inflammatory disorders. In clinical practice this means we could identify high risk patients and personalise their care, preventing infection, improving safety of treatment, and optimising long-term outcomes.

背景类风湿性关节炎(RA)是一种长期的、不可治愈的疾病，影响1%的成年人口。它会导致关节疼痛和僵硬，长时间使用会导致损伤。在类风湿性关节炎中，身体的免疫系统(旨在防御感染)变得过于活跃，错误地攻击身体自身的组织。治疗类风湿性关节炎的药物疗法是通过针对免疫系统来实现的。这些药物被称为抗风湿病药物(DMARD)。问题患有类风湿性关节炎的患者会经历频繁而严重的感染，与没有患上这种疾病的人相比，住院的人数是前者的两倍。严重感染只是冰山一角，每年报告非严重感染的患者超过30%。当患者感染时，他们的临床医生会停止他们的DMARDS。如果不对类风湿性关节炎进行治疗，疾病活跃度会恶化，疾病可能会“发作”。中断的治疗方案伴随着疾病的恶化和关节损伤的增加。目前的研究问题是，RA患者感染风险的增加是药物治疗的副作用。然而，我们认为RA中活跃的炎症过程是感染易感性的重要原因。我们认为，这是因为慢性炎症矛盾地抑制了免疫系统，使患者面临更大的感染风险。这一点得到了临床经验的支持，即病情越严重的患者感染越多。目前尚不清楚这种疾病状态对身体抵抗感染的能力有多大贡献。我们想要回答这个问题。研究目的我们的研究将解决疾病状态在多大程度上导致感染易感性。我们的目标是研究一大群RA患者的临床和实验室特征，以确定这些特征中的哪些特征使他们处于独立于药物治疗的最大感染风险。研究计划TACERA(治疗类风湿性关节炎)数据集在开始治疗之前已经获得了270名新诊断类风湿性关节炎患者的广泛临床信息和血液样本。它是近年来产生的最丰富的数据集之一，结合了大量的临床和实验室数据。重要的是，这是“真实生活”的数据，因为患者在常规临床实践中得到了应有的待遇。在整个研究过程中，所有感染事件都已被捕获，因此已经确定了高危人群。在这项研究中，我们将比较感染过和没有感染的患者。初步工作将确定他们的临床特征(例如，年龄、吸烟、疾病严重程度)的任何差异。TACERA数据集在开始DMARDS之前对患者的血液样本进行了详细的分析，并测量了控制免疫系统功能的数千个基因的表达。我们可以查看这些数据，看看发生感染的患者与没有感染的患者之间是否有任何具体的差异。这将有助于确定与感染风险相关的模式。然后，我们将调查启动DMARDS后血液的变化，以确定与感染风险增加相关的免疫系统变化。我们将把这些模式与治疗开始前看到的模式进行比较。这将使我们能够评估药物和疾病对感染风险的相对贡献。研究影响我们预计能够结合血液测试结果和临床特征来确定每个患者发展为感染的风险。这项测试可能有助于建立一个评分系统，该系统考虑感染的其他风险因素，并可能与许多炎症性疾病患者相关。在临床实践中，这意味着我们可以识别高危患者并对他们进行个性化护理，防止感染，提高治疗安全性，并优化长期结果。

项目成果

The infection risks of JAK inhibition.

• DOI: 10.1080/1744666x.2022.2014323
• 发表时间: 2022-03
• 期刊: Expert review of clinical immunology
• 影响因子: 4.4
• 作者: Adas MA;Alveyn E;Cook E;Dey M;Galloway JB;Bechman K
• 通讯作者: Bechman K

A systematic review of CXCL13 as a biomarker of disease and treatment response in rheumatoid arthritis.

• DOI: 10.1186/s41927-020-00154-3
• 发表时间: 2020-11-02
• 期刊: BMC rheumatology
• 影响因子: 2.2
• 作者: Bechman K;Dalrymple A;Southey-Bassols C;Cope AP;Galloway JB
• 通讯作者: Galloway JB

Inpatient COVID-19 mortality has reduced over time: Results from an observational cohort.

• DOI: 10.1371/journal.pone.0261142
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bechman K;Yates M;Mann K;Nagra D;Smith LJ;Rutherford AI;Patel A;Periselneris J;Walder D;Dobson RJB;Kraljevic Z;Teo JHT;Bernal W;Barker R;Galloway JB;Norton S
• 通讯作者: Norton S

Mental health, fatigue and function are associated with increased risk of disease flare following TNF inhibitor tapering in patients with rheumatoid arthritis: an exploratory analysis of data from the Optimizing TNF Tapering in RA (OPTTIRA) trial.

• DOI: 10.1136/rmdopen-2018-000676
• 发表时间: 2018
• 期刊: RMD open
• 影响因子: 6.2
• 作者: Bechman K;Sin FE;Ibrahim F;Norton S;Matcham F;Scott DL;Cope A;Galloway J
• 通讯作者: Galloway J

A systematic review and network meta-analysis of the safety of early interventional treatments in rheumatoid arthritis.

• DOI: 10.1093/rheumatology/keab429
• 发表时间: 2021-10-02
• 期刊: Rheumatology (Oxford, England)
• 作者: Adas MA;Allen VB;Yates M;Bechman K;Clarke BD;Russell MD;Rutherford AI;Cope AP;Norton S;Galloway JB
• 通讯作者: Galloway JB