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 儿童慢性非感染性葡萄膜炎（NIU）是一种炎症性眼部疾病， 危及视力的并发症甲氨蝶呤（MTX）是所有亚型的首选一线全身治疗 考虑到其整体安全性和可负担性，然而，MTX失败率高达50%。生物药物是 为MTX失败的人保留。长时间等待治疗效果导致长期糖皮质激素 使用和眼损伤的持续累积。由于MTX可能不是所有患者的适当一线治疗， NIU亚型，确定MTX反应性的预测因子将允许快速启动生物制剂治疗。 治疗我们的长期目标是通过早期启动NIU治疗， 快速控制炎症的有效治疗方法。 这项调查是一项纵向转化研究，是由以下专家组成的合作努力： 风湿病学、眼科学、眼部成像学、免疫学和生物统计学。本研究的目的是：1） 确定NIU儿童的基线人口统计学、临床、实验室和影像学特征， 2）评估增加定量成像方式监测对MTX反应的价值。 MTX在NIU儿童中的作用; 3）发现预测反应和非反应的基因表达特征。 NIU患儿对MTX的反应总共将入组120名开始MTX治疗NIU的儿童， 目标，并在3个月和6个月进行前瞻性随访。儿童将接受一系列临床眼科检查 通过眼前节光学相干断层扫描（AS-OCT）、超宽视野荧光素 血管造影（UWFFA）和OCT评估MTX反应。目标1将确定变量的组合， 基线预测患者6个月的反应风险。目标2将评估定量成像的使用 评估和监测MTX反应超过6个月。这些模式也将与临床 考试在目标3中，还将纳入20例儿童非葡萄膜炎对照。这一目标旨在发现 与临床和基于成像的MTX应答相关的基因表达特征，以及非 反应这项研究的成功将1）通过允许早期开始，优化NIU儿童的治疗 生物制剂在那些不太可能对MTX有反应的患者中的应用，2）证明定量成像的临床实用性 在治疗决策中，3）最终改变NIU的当前治疗标准， 儿童的眼睛健康。