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

优化甲氨蝶呤的使用以治疗慢性儿科非感染性葡萄膜炎

• 批准号: 10568202
• 负责人: Sheila Therese Angeles-Han
• 金额: $ 65.75万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568202
• 关键词: Adult; Anterior; Biological; Biological Products; Biological Response Modifier Therapy; Biometry; Blindness; Blood specimen; Cells; Child; Child Health; Childhood; Chronic; Chronic Childhood Arthritis; Clinical; Complement; Cystoid Macular Edema; Data; Decision Making; Diagnosis; Disease; Drops; Enrollment; Extravasation; Eye diseases; Failure; Fluorescein; Fluorescein Angiography; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genetic Transcription; Glucocorticoids; Goals; Image; Imaging Device; Immune; Immunologist; Immunology; Individual; Inflammation; Inflammatory; Investigation; Laboratories; Location; Methotrexate; Modality; Monitor; Nomenclature; Ophthalmologist; Ophthalmology; Optical Coherence Tomography; Oral; Outcome; Patient risk; Patients; Pharmaceutical Preparations; Prediction of Response to Therapy; Predictive Factor; Research; Rheumatism; Rheumatology; Risk; Risk Factors; Safety; Standardization; Systemic disease; Testing; Therapeutic; Therapeutic Effect; United States National Institutes of Health; Uveitis; Vision; Whole Blood; Work; anterior chamber; clinical examination; demographics; design; disease heterogeneity; effective therapy; experimental study; follow-up; gene discovery; high risk; imaging modality; improved; innovation; ocular imaging; ophthalmic examination; peripheral blood; personalized medicine; predicting response; predictive signature; prevent; prospective; quantitative imaging; response; rheumatologist; standard care; success; transcriptome sequencing; translational study; treatment optimization; treatment response; treatment strategy

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.

项目摘要 小儿慢性非感染葡萄膜炎（NIU）是一种炎症性眼疾病，具有很大的风险 危及视力并发症。甲氨蝶呤（MTX）是所有亚型的首选第一线系统治疗 NIU的总体安全性和负担能力。但是，MTX失败高达50％。生物药物是 保留给失败MTX的人。等待治疗效果的长延迟导致长期糖皮质激素 使用并继续口音眼损伤。因为MTX可能不是所有人的合适第一行处理 NIU的子类型，确定MTX响应能力的预测因子将允许迅速的生物学倡议 疗法。我们的长期目标是通过提早开始，以防止NIU儿童的视力危害 有效控制注射的有效治疗方法。 这项投资是一项纵向翻译研究，是一项合作努力，由专家组成 风湿病学，眼科，眼部成像，免疫学和生物统计学。这项研究的目标是：1） 确定NIU儿童的基线人口统计学，临床，实验室和成像特征 对MTX的响应； 2）评估添加定量成像方式的价值以监视对 NIU儿童的MTX； 3）发现基因表达特征，以预测反应和非 - NIU儿童对MTX的反应。总共有120名开始MTX的儿童将参加所有人 目标并在3个月和6个月中前瞻性。儿童将接受连续临床眼科检查 和前段光学相干断层扫描（AS-OCT），超消极场荧光素的成像 血管造影（UWFFA）和OCT评估MTX响应。 AIM 1将确定变量的组合 基线可以预测患者的反应风险6个月。 AIM 2将评估定量成像的使用 在6个月内评估和监视MTX响应。这些方式也将与临床进行比较 考试。在AIM 3中，还将包括20个儿科非割草机控制。这个目标旨在发现 与基于临床和成像的MTX反应和非 - 非基因表达特征 回复。这项研究的成功将通过允许较早的启动来优化NIU儿童的治疗 生物制剂中不太可能响应MTX的生物制剂，2）证明了定量成像的临床实用性 在热决策中，以及3）最终改变了NIU的当前治疗标准，从而改善了 儿童的眼部健康。