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

儿童关节炎，归类于青少年特发性关节炎（JIA），及其相关的眼部炎症，JIA-葡萄膜炎，对儿童和家庭都是毁灭性的，并对社会造成重大的长期经济负担。尽管JIA的管理有所改善，新药物的可得性也有所增加，但许多儿童仍然长期接受多种药物治疗，而这些药物可能不起作用，使他们面临无法控制的炎症、副作用和疾病的破坏性影响，其中包括残疾、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jia -葡萄膜炎转化为更好的长期结果和经济效益。然而，目前的JIA分类并不能为大多数儿童的药物选择提供依据，也没有经过验证的临床或生物学工具来预测病程、选择治疗或预测反应。允许医生在正确的时间为每个孩子选择正确的药物（“分层药物”）的有效策略将增加早期缓解率，减少痛苦，改善长期结果并避免使用无效药物治疗多年。为了开始解决这些未满足的需求，我们在4个大型英国JIA队列研究中建立了合作伙伴关系，即儿童关节炎治疗反应（CHART）联盟，代表5000名JIA患儿，提供临床信息、生物样本和新数据。在我们成功的基础上，并在重要的新队列和研究者的加强下，我们现在提出一个雄心勃勃的联盟CLUSTER，汇集国际公认的儿童关节炎和JIA-葡萄膜炎的领导者，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、免疫学和统计科学方面的多学科专业知识，其中包括英国在儿科风湿病学和眼科学方面的领先专家，以及设计和提供JIA及其相关葡萄膜炎临床试验的专家。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），更准确地反映可能的治疗反应和疾病病程，并与儿童中可行的生物标志物相关联，以便做出有针对性的治疗决策。我们将采用P4（预测、预防、个性化、参与）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“生物标志物”（临床、遗传、蛋白质、基因表达或免疫因子），以便更有针对性地选择药物并防止不良的长期结果；2 .明确JIA患儿患葡萄膜炎的预测因素（临床、遗传、自身抗体），完善筛查方案，预防视力下降；3 .利用血液和炎症关节标本，对JIA进行细胞、蛋白和基因表达的最新分析，明确治疗反应机制和不同疾病类型，寻找新的治疗方法；整合和探索所有CLUSTER数据，共同定义JIA的内源性类型，预测疾病类型或治疗反应，以及可测量的相关标记物，以实现个性化治疗并促进患者/家长参与治疗选择；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儿童关节炎和葡萄膜炎的未来试验。我们的工作规划将加快为JIA患儿引入“分层”药物。早期控制炎症和减少接触副作用将使儿童能够恢复教育和全面的体育和家庭生活活动，防止终身残疾和失明，并减少保健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.