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

MICA：儿童关节炎及其相关葡萄膜炎：通过内型和机制进行分层以提供益处；

• 批准号: MR/R013926/1
• 负责人: Lucy Wedderburn
• 金额: $ 518.85万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR013926%2F1
• 关键词: MICA; Childhood; arthritis; its; associated

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.

儿童关节炎被归类为幼年特发性关节炎 (JIA) 及其相关眼部炎症 (JIA 葡萄膜炎)，对儿童和家庭来说可能是毁灭性的，并给社会带来巨大的长期经济负担。尽管幼年特发性关节炎的管理有所改善，并且新药的供应不断增加，但许多儿童仍然接受多种可能不起作用的药物的长期治疗，使他们面临不受控制的炎症、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。儿童关节炎和幼年特发性葡萄膜炎的早期控制可以转化为更好的长期结果和经济效益。然而，目前的 JIA 分类并未告知大多数儿童的药物选择，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。有效的策略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”），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满足的需求，我们在英国 4 项大型 JIA 队列研究之间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 儿童，并提供临床信息、生物样本和新数据。在我们成功的基础上，并通过重要的新队列和研究人员的加强，我们现在提出一个雄心勃勃的联盟，CLUSTER，汇集了儿童关节炎和幼年特发性葡萄膜炎领域国际公认的领导者，以及新的合作者和行业合作伙伴，为幼年特发性关节炎提供分层医学。 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，以及英国儿科风湿病学和眼科领域的领导者，以及设计和实施 JIA 及其相关葡萄膜炎临床试验的人员。CLUSTER 的总体目标是定义儿童关节炎和相关疾病的“内型”（基于潜在疾病机制的亚组）。 JIA-葡萄膜炎能够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志物相关，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. 识别有助于预测幼年特发性关节炎治疗反应的“生物标志物”（临床、遗传、蛋白质、基因表达或免疫因子），以便采取更有针对性的药物选择方法并防止不良的长期结果；2.确定幼年特发性关节炎儿童患葡萄膜炎的预测因素（临床、遗传、自身抗体），以改进筛查方案并预防视力丧失；3.使用血液和发炎关节的标本，对幼年特发性关节炎的细胞、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，以定义 JIA 的内型，预测疾病类型或治疗反应，以及可测量的相关标记，以实现个性化治疗并促进患者/家长参与治疗选择； 5. 与行业和国际合作伙伴建立合作协议，确保在未来的儿童关节炎和葡萄膜炎试验中使用高质量的生物样本采集和分层设计。我们的工作计划将加快针对幼年特发性关节炎儿童推出“分层”药物。及早控制炎症和减少副作用将使儿童能够重返教育、充分的体育和家庭生活活动，防止终身残疾和失明，并降低医疗服务和整个社会的成本。

项目成果

Discontinuing adalimumab in patients with controlled juvenile idiopathic arthritis-associated uveitis (ADJUST-Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Stopping Trial): study protocol for a randomised controlled trial.

在受控少年性特发性关节炎相关的葡萄膜炎的患者中停止使用adalimimab（少年特发性关节炎相关的葡萄膜炎停止试验中的调节型氨基肌）：一项随机对照试验的研究方案。

• DOI: 10.1186/s13063-020-04796-z
• 发表时间: 2020-10-27
• 期刊: Trials
• 影响因子: 2.5
• 作者: Acharya NR;Ebert CD;Kelly NK;Porco TC;Ramanan AV;Arnold BF;ADJUST Research Group
• 通讯作者: ADJUST Research Group

Development and implementation of 'A guide to PPIE-Early Integration into Research Proposals' in a multi-disciplinary consortium.

在多学科联盟中制定和实施“PPIE 早期融入研究计划指南”。

• DOI: 10.1093/rheumatology/kead482
• 发表时间: 2023
• 期刊: Rheumatology (Oxford, England)
• 作者: Beesley R

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

• DOI: 10.1056/nejmoa2035790
• 发表时间: 2021-11-11
• 期刊: The New England journal of medicine
• 作者: 100,000 Genomes Project Pilot Investigators;Smedley D;Smith KR;Martin A;Thomas EA;McDonagh EM;Cipriani V;Ellingford JM;Arno G;Tucci A;Vandrovcova J;Chan G;Williams HJ;Ratnaike T;Wei W;Stirrups K;Ibanez K;Moutsianas L;Wielscher M;Need A;Barnes MR;Vestito L;Buchanan J;Wordsworth S;Ashford S;Rehmström K;Li E;Fuller G;Twiss P;Spasic-Boskovic O;Halsall S;Floto RA;Poole K;Wagner A;Mehta SG;Gurnell M;Burrows N;James R;Penkett C;Dewhurst E;Gräf S;Mapeta R;Kasanicki M;Haworth A;Savage H;Babcock M;Reese MG;Bale M;Baple E;Boustred C;Brittain H;de Burca A;Bleda M;Devereau A;Halai D;Haraldsdottir E;Hyder Z;Kasperaviciute D;Patch C;Polychronopoulos D;Matchan A;Sultana R;Ryten M;Tavares ALT;Tregidgo C;Turnbull C;Welland M;Wood S;Snow C;Williams E;Leigh S;Foulger RE;Daugherty LC;Niblock O;Leong IUS;Wright CF;Davies J;Crichton C;Welch J;Woods K;Abulhoul L;Aurora P;Bockenhauer D;Broomfield A;Cleary MA;Lam T;Dattani M;Footitt E;Ganesan V;Grunewald S;Compeyrot-Lacassagne S;Muntoni F;Pilkington C;Quinlivan R;Thapar N;Wallis C;Wedderburn LR;Worth A;Bueser T;Compton C;Deshpande C;Fassihi H;Haque E;Izatt L;Josifova D;Mohammed S;Robert L;Rose S;Ruddy D;Sarkany R;Say G;Shaw AC;Wolejko A;Habib B;Burns G;Hunter S;Grocock RJ;Humphray SJ;Robinson PN;Haendel M;Simpson MA;Banka S;Clayton-Smith J;Douzgou S;Hall G;Thomas HB;O'Keefe RT;Michaelides M;Moore AT;Malka S;Pontikos N;Browning AC;Straub V;Gorman GS;Horvath R;Quinton R;Schaefer AM;Yu-Wai-Man P;Turnbull DM;McFarland R;Taylor RW;O'Connor E;Yip J;Newland K;Morris HR;Polke J;Wood NW;Campbell C;Camps C;Gibson K;Koelling N;Lester T;Németh AH;Palles C;Patel S;Roy NBA;Sen A;Taylor J;Cacheiro P;Jacobsen JO;Seaby EG;Davison V;Chitty L;Douglas A;Naresh K;McMullan D;Ellard S;Temple IK;Mumford AD;Wilson G;Beales P;Bitner-Glindzicz M;Black G;Bradley JR;Brennan P;Burn J;Chinnery PF;Elliott P;Flinter F;Houlden H;Irving M;Newman W;Rahman S;Sayer JA;Taylor JC;Webster AR;Wilkie AOM;Ouwehand WH;Raymond FL;Chisholm J;Hill S;Bentley D;Scott RH;Fowler T;Rendon A;Caulfield M
• 通讯作者: Caulfield M

Outcome of adalimumab monotherapy in paediatric non-infectious uveitis.

• DOI: 10.1186/s12969-023-00794-y
• 发表时间: 2023-03-02
• 期刊: Pediatric rheumatology online journal

IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis.

• DOI: 10.1002/art.40498
• 发表时间: 2018-08
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Arthur VL;Shuldiner E;Remmers EF;Hinks A;Grom AA;Foell D;Martini A;Gattorno M;Özen S;Prahalad S;Zeft AS;Bohnsack JF;Ilowite NT;Mellins ED;Russo R;Len C;Oliveira S;Yeung RSM;Rosenberg AM;Wedderburn LR;Anton J;Haas JP;Rösen-Wolff A;Minden K;Szymanski AM;INCHARGE Consortium;Thomson W;Kastner DL;Woo P;Ombrello MJ
• 通讯作者: Ombrello MJ