MICA: Childhood arthritis and its associated uveitis: stratification through endotypes and mechanism to deliver benefit; the CLUSTER Consortium.

儿童关节炎被归类为幼年特发性关节炎(JIA)及其相关的眼部炎症JIA-葡萄膜炎，对儿童和家庭都可能是毁灭性的，并给社会带来重大的长期经济负担。尽管JIA的管理得到了改善，新药的供应也越来越多，但许多儿童仍在接受多种可能无效的长期药物治疗，使他们面临无法控制的炎症、副作用和疾病的破坏性影响，包括残疾、视力丧失、生活质量下降和就业机会减少。早期控制儿童关节炎和葡萄膜炎可转化为更好的长期结果和经济效益。然而，目前的JIA分类并没有为大多数儿童提供药物选择的信息，也没有经过验证的临床或生物工具来预测病程、选择治疗方法或预测反应。有效的战略使医生能够在正确的时间为每个儿童选择正确的药物(“分层药物”)，这将提高早期缓解率，减少痛苦，改善长期结果，并避免多年使用无效药物治疗。为了开始解决这些未得到满足的需求，我们在4项英国JIA队列研究、儿童关节炎治疗反应(CHART)联盟之间建立了合作伙伴关系，该联盟代表5000名JIA儿童，提供临床信息、生物样本和新数据。在我们成功的基础上，以及重要的新队列和研究人员的加强，我们现在提议成立一个雄心勃勃的联盟，集群，将国际公认的儿童关节炎和葡萄膜炎领域的领导者聚集在一起，与新的合作者和行业合作伙伴一起为JIA提供分层药物。CLUSTER将包括临床、分子、遗传学、免疫学和统计学方面的多学科专业知识，英国在儿科风湿学和眼科领域处于领先地位，以及那些在JIA及其相关葡萄膜炎方面设计和提供临床试验的人。CLUSTER的总体目标是定义儿童关节炎和JIA-葡萄膜炎的“内型”(基于潜在疾病机制的亚组)，这些内型更准确地反映可能的治疗反应和病程，与可在儿童中测量的生物标记物相关联，以便做出有针对性的治疗决定。我们将采用P4(预测、预防、个性化、参与性)方法；我们的主要科学目标是：1.确定有助于预测JIA治疗反应的生物标记物(临床、遗传、蛋白质、基因表达或免疫因素)，以便更有针对性地选择药物并防止不良的长期结果；2.确定JIA儿童患葡萄膜炎的预测因素(临床、遗传、自身抗体)，以改进筛查方案，防止视力丧失；3.使用血液和炎症关节的样本，对JIA中的细胞、蛋白质和基因表达进行最先进的分析，以确定对治疗和不同疾病类型的反应机制，并确定新的治疗方法；4.整合和探索所有集群数据，以确定JIA中的内型，预测疾病类型或治疗反应，以及可测量的相关标记，以实现个性化治疗，促进患者/父母参与治疗选择；5.与业界和国际合作伙伴建立合作协议，以确保高质量的生物样本收集和分层设计用于未来儿童关节炎和葡萄膜炎的试验。我们的工作计划将加快为患有JIA的儿童引入“分层”药物。及早控制炎症和减少副作用的暴露将使儿童能够重返他们的教育和充分的体育和家庭生活，防止终身残疾和失明，并降低卫生服务和整个社会的成本。

Childhood arthritis, classified under the umbrella term juvenile idiopathic arthritis, JIA, and its associated eye inflammation, JIA-uveitis, can be devastating for both child and family, and impose significant long-term economic burden on society. Despite improvements in the management of JIA, and increasing availability of new medicines, many children still undergo prolonged treatment with multiple drugs that may not work, leaving them exposed to uncontrolled inflammation, side effects, and the damaging effects of disease, which include disability, vision loss, lower quality of life and reduced chances of employment. Early control of childhood arthritis and JIA-uveitis translates to better longterm outcomes and economic benefit. However, current JIA classification does not inform choice of drug for most children, and there are no verified clinical or biological tools with which to predict disease course, select treatment or predict response. Effective strategies allowing doctors to choose the right medicine, at the right time for each child ('stratified medicine'), would increase early remission rates, reduce suffering, improve long-term outcomes and avoid years of treatment with ineffective drugs. To start to address these unmet needs, we established a partnership between 4 large UK JIA cohort studies, the Childhood Arthritis Response to Treatment (CHART) Consortium, representing 5000 children with JIA, with clinical information, biological samples, and new data. Building on our success, and strengthened by important new cohorts and investigators, we now propose an ambitious consortium, CLUSTER, bringing together internationally recognised leaders in childhood arthritis and JIA-uveitis, with new collaborators and industry partners to deliver stratified medicine for JIA. CLUSTER will include multidisciplinary expertise in clinical, molecular, genetic, immunological, and statistical sciences, with UK leaders in paediatric rheumatology and ophthalmology, and those designing and delivering clinical trials in JIA and its associated uveitis.The overall goal of CLUSTER is to define 'endotypes' (subgroups based on underlying disease mechanism) of childhood arthritis and JIA-uveitis, which more accurately reflect likely treatment response and disease course, linked to biomarkers that are feasible to measure in children, to allow targeted treatment decisions. We will adopt a P4 (predict, prevent, personalise, participatory) approach; our key scientific aims are to: 1. Identify 'biomarkers' (clinical, genetic, protein, gene expression or immune factor) that help predict treatment response in JIA, to allow a more targeted approach to medicine choices and prevent poor long-term outcomes;2. Identify predictors (clinical, genetic, auto-antibody) of getting uveitis for children with JIA, to improve screening protocols and prevent vision loss;3. Using specimens from both blood and inflamed joints, undertake state of the art analysis of cells, proteins and gene expression in JIA to define mechanisms of response to treatment and different disease types, and identify new treatments;4. Integrate and explore all CLUSTER data together to define endotypes in JIA, that predict disease type or treatment response, with associated markers that can be measured, to enable personalised treatment and facilitate patient/parent participation in treatment choices; 5. Establish collaborative agreements with Industry and international partners to ensure that high-quality bio-sample collection and stratification design are used in future trials in childhood arthritis and uveitis.Our programme of work will speed up the introduction of 'stratified' medicine for children with JIA. Earlier control of inflammation and reduced exposure to side effects will allow children to return to their education and full sporting and family life activities, prevent life long disability and blindness, and reduce costs to the health service and society as a whole.