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.

项目概要 儿童慢性非感染性葡萄膜炎 (NIU) 是一种炎症性眼部疾病，具有显着的风险 甲氨蝶呤 (MTX) 是所有亚型的首选一线全身治疗方法。 然而，MTX 的失败率高达 50%。 为 MTX 失败的患者保留 等待治疗效果的时间过长导致糖皮质激素时间延长。 由于 MTX 可能不是适合所有人的一线治疗方法。 NIU 亚型，确定 MTX 反应性的预测因素将有助于迅速启动生物制剂 我们的长期目标是通过早期开始治疗来预防 NIU 儿童的视力损害。 快速控制炎症的有效治疗。 这项调查是一项纵向转化研究，是由以下领域的专家共同努力的结果： 风湿病学、眼科学、眼影像学、免疫学和生物统计学本研究的目的是：1) 确定与 NIU 儿童相关的基线人口统计学、临床、实验室和影像学特征 对 MTX 的反应；2) 评估添加定量成像方式来监测对 MTX 的反应的价值 MTX 用于 NIU 儿童；3) 发现预测反应和非反应的基因表达特征 NIU 儿童对 MTX 的反应 共有 120 名开始 MTX 治疗 NIU 的儿童将被纳入所有研究中。 目标并在 3 个月和 6 个月时进行前瞻性随访。 眼前节光学相干断层扫描 (AS-OCT)、超广角荧光素成像 血管造影 (UWFFA) 和 OCT 来评估 MTX 反应，目标 1 将确定变量的组合。 预测患者 6 个月内缓解风险的基线将评估定量成像的使用。 评估和监测 6 个月内的 MTX 反应。这些方式也将与临床进行比较。 在目标 3 中，还将包括 20 个儿童非葡萄膜炎对照。该目标旨在发现。 与基于临床和成像的 MTX 反应相关的基因表达特征和非 这项研究的成功将 1) 通过允许更早开始来优化 NIU 儿童的治疗。 生物制剂在不太可能对 MTX 产生反应的患者中的应用，2) 证明定量成像的临床用途 治疗决策，3）最终改变 NIU 目前的治疗标准，从而改善 儿童眼部健康。