Optimizing methotrexate use for the management of chronic pediatric non-infectious uveitis

项目总结 儿童慢性非传染性葡萄膜炎(NIU)是一种炎症性眼病，有很大的风险 危及视力的并发症。甲氨蝶呤(MTX)是治疗所有亚型的首选一线全身疗法。 考虑到它的总体安全性和可负担性，NIU的安全性更高。然而，MTX故障高达50%。生物药物是 为未通过MTX的人保留。长时间等待疗效导致糖皮质激素时间延长 眼损伤的使用和持续增加。因为MTX可能不是治疗ALL的合适一线药物 NIU亚型，识别MTX反应性的预测因素将允许快速启动生物学 治疗。我们的长期目标是通过早期启动预防NIU儿童的视力威胁损害。 能迅速控制炎症的有效治疗。 这项调查是一项纵向翻译研究，是由以下专家组成的合作努力 风湿科、眼科、眼科、免疫学和生物统计学。本研究的目的是：1) 确定NIU患儿的基线人口学、临床、实验室和影像特征与之相关 对MTX的反应；2)评估增加定量成像手段以监测对MTX的反应的价值 甲氨蝶呤在患有NIU的儿童中的应用；3)发现预测应答和非应答的基因表达特征 NIU患儿对甲氨蝶呤的反应。共有120名儿童将开始在NIU的MTX将在所有 并在3个月和6个月时进行前瞻性随访。儿童将接受一系列临床眼科检查 以及眼前段光学相干断层扫描(AS-OCT)、超广域荧光素成像 血管造影术(UWFFA)和OCT评估MTX疗效。目标1将确定以下变量的组合 预测患者6个月后反应风险的基线。目标2将评估定量成像的使用 评估和监测MTX在6个月内的疗效。这些模式也将与临床上的 考试。在目标3中，20名儿童非葡萄膜炎对照也将包括在内。这一目标旨在发现 与基于临床和影像的MTX反应和非MTX反应相关的基因表达特征 回应。这项研究的成功将1)通过允许更早的启动来优化患有NIU的儿童的治疗 不太可能对MTX有反应的生物制剂，2)证明了定量成像的临床实用性 在治疗决策中，以及3)最终改变目前NIU的治疗标准，导致改善 儿童的眼睛健康。

PROJECT SUMMARY Pediatric chronic non-infectious uveitis (NIU) is an inflammatory ocular disease that has a substantial risk for sight-threatening complications. Methotrexate (MTX) is the preferred first line systemic treatment for all subtypes of NIU given its overall safety and affordability. However, MTX failure is as high as 50%. Biologic drugs are reserved for those who fail MTX. The long delays waiting for therapeutic effect leads to prolonged glucocorticoid use and continued accrual of ocular damage. As MTX may not be the appropriate first line treatment for all subtypes of NIU, identifying predictors of MTX responsiveness will allow expeditious initiation of biologic therapies. Our long-term goal is to prevent sight-threatening damage in children with NIU by initiating early effective treatment that controls inflammation quickly. This investigation is a longitudinal translational study that is a collaborative effort consisting of experts in rheumatology, ophthalmology, ocular imaging, immunology and biostatistics. The objectives of this study are: 1) To identify baseline demographic, clinical, laboratory, and imaging features in children with NIU that correlate with response to MTX; 2) To assess the value of adding quantitative imaging modalities to monitor response to MTX in children with NIU; and 3) To discover gene expression signatures that predict response and non- response to MTX in children with NIU. A total of 120 children who are starting MTX for NIU will be enrolled in all aims and followed prospectively at 3 and 6 months. Children will undergo serial clinical ophthalmic examinations and imaging by anterior segment optical coherence tomography (AS-OCT), ultrawide field fluorescein angiography (UWFFA), and OCT to assess MTX response. Aim 1 will identify the combination of variables at baseline that predict a patient’s risk of response by 6 months. Aim 2 will assess the use of quantitative imaging to evaluate and monitor MTX response over 6 months. These modalities will also be compared to the clinical examination. In Aim 3, 20 pediatric non-uveitic controls will also be included. This aim is designed to discover gene expression signatures that are associated with clinical and imaging based MTX response and non- response. The success of this study will 1) optimize treatment of children with NIU by allowing earlier initiation of biologics in those unlikely to respond to MTX, 2) demonstrate the clinical usefulness of quantitative imaging in therapeutic decision-making, and 3) eventually shift the current treatment standard of NIU leading to improved ocular health of children.