Glucocorticoid use and osteonecrosis in chronic pediatric inflammatory diseases

糖皮质激素在儿科慢性炎症性疾病中的使用和骨坏死

• 批准号: 8784410
• 负责人: Daniel Benjamin Horton
• 金额: $ 7.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-21 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784410
• 关键词: Accounting; Adolescent; Adult; Adverse effects; Affect; Age; Anti-Inflammatory Agents; Arthritis; Asthma; Award; Bone Diseases; Bone necrosis; British; Cessation of life; Child; Childhood; Childhood Leukemia; Chronic; Chronic Childhood Arthritis; Chronic Disease; Clinic; Clinical Investigator; Clinical Research; Cohort Studies; Complication; Data; Databases; Development; Diagnosis; Disease; Dose; Foundations; Fracture; Future; Glucocorticoids; Grant; Immunosuppressive Agents; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Joints; Knowledge; Lead; Learning; Legg-Perthes Disease; Literature; Lupus; Medical; Medical Records; Mentors; Methods; Modeling; Modification; Monitor; National Research Service Awards; Necrosis; Newly Diagnosed; Oncology; Operative Surgical Procedures; Oral; Osteoporosis; Outcome; Pain; Patients; Pattern; Pediatrics; Pharmaceutical Preparations; Pharmacoepidemiology; Population; Postdoctoral Individual National Research Service Award; Process; Psoriasis; Publishing; Regimen; Regression Analysis; Replacement Arthroplasty; Reporting; Research; Research Design; Research Personnel; Research Training; Rheumatology; Risk; Role; Safety; Series; Steroids; Subgroup; Systemic Lupus Erythematosus; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Training; Training Programs; Transplantation; United Kingdom; Ursidae Family; Validation; Weight-Bearing state; bone; career; clinical practice; cohort; comparative effectiveness; disability; disabling disease; disease diagnosis; dosage; hazard; high risk; insight; leukemia; medical specialties; population based; prevent; public health relevance; skeletal; skills; treatment duration; treatment strategy

DESCRIPTION (provided by applicant): Glucocorticoids (GCs) are widely used medications for many chronic pediatric inflammatory diseases. Among the many toxicities attributed to GCs, osteonecrosis (ON, also called avascular necrosis) is one of the more serious, leading in some individuals to severe pain, disability, and the need for surgical joint replacement. Despite a long described association with high-dose GC exposure for diseases such as pediatric leukemia, the risk for ON in association with these commonly used medications in the broader pediatric population is still not well understood. Additional questions remain about whether certain inflammatory diseases affect the risk of ON independent of GC dosage, and whether this association changes with age. The proposed project aims to expand understanding of the relationship between GC use and ON through the following broad objectives: 1) examine how different patterns of GC exposure affect the development of ON in children and adolescents; 2) determine whether age and underlying inflammatory disease modify the association between GCs and ON; 3) train the applicant in methods of pharmacoepidemiology as they apply to treatments of disorders of chronic inflammation; and 4) support the applicant's development as an independent clinical investigator. The applicant will leverage a large medical records database from the United Kingdom to achieve the stated objectives. This database contains extensive demographic, medical, and therapeutic information and has been used successfully for prior pharmacoepidemiologic research. Cohorts with and without GC exposure will be assembled from a population of children and adolescents with diverse inflammatory diseases. Through a series of different models to represent GC use, the association between GCs and newly diagnosed, clinically apparent ON will be evaluated through Cox proportional hazards regression. These models will then be used as a foundation to test for effect modification by age and disease diagnosis. If appropriate, subgroup analysis will be performed. The applicant will complete these objectives with the help of directed one-on-one mentoring from a senior investigator and a team of participating co-mentors and collaborators, as part of ongoing participation in a rigorous clinical research training program. As a result of the support from the NRSA, the applicant will develop and refine the skills necessary to conduct further research in the pharmacoepidemiology of antiinflammatory and immunosuppressant medications as part of a K23/K08 award. Moreover, the results of the project supported by this F32 award will contribute valuably to multiple fields of pediatrics, by quantifying the risk of serious bone diseae from a widely prescribed medication, and by evaluating some of the key factors that might modify this risk. Insights from this study may eventually lead to better strategies for treating, monitoring for, and preventing ON in the future.

描述（由申请人提供）：糖皮质激素（GC）是广泛用于治疗许多慢性儿科炎症性疾病的药物。在 GC 引起的众多毒性中，骨坏死（ON，也称为股骨头缺血性坏死）是最严重的毒性之一，导致一些人出现严重疼痛、残疾，并需要进行关节置换手术。尽管很长一段时间 描述了高剂量 GC 暴露与儿童白血病等疾病的关联，但在更广泛的儿科人群中与这些常用药物相关的 ON 风险仍不清楚。其他问题仍然是，某些炎症性疾病是否会独立于 GC 剂量影响 ON 风险，以及这种关联是否随着年龄而变化。拟议项目旨在通过以下广泛目标扩大对 GC 使用与 ON 之间关系的理解：1）研究不同的 GC 暴露模式如何影响儿童和青少年 ON 的发展； 2) 确定年龄和潜在炎症性疾病是否改变 GC 和 ON 之间的关联； 3) 对申请人进行药物流行病学方法方面的培训，因为这些方法适用于慢性炎症疾病的治疗； 4) 支持申请人作为独立临床研究者的发展。申请人将利用英国的大型医疗记录数据库来实现既定目标。该数据库包含广泛的人口统计、医学和治疗信息，并已成功用于先前的药物流行病学研究。有和没有GC暴露的队列将从患有多种炎症性疾病的儿童和青少年群体中组装而成。通过一系列不同的模型来代表 GC 的使用，GC 与新诊断的、临床上明显的 ON 之间的关联将通过 Cox 比例风险回归进行评估。然后，这些模型将用作测试年龄和疾病诊断影响的基础。如果合适，将进行亚组分析。申请人将在高级研究员以及参与的共同导师和合作者团队的定向一对一指导的帮助下完成这些目标，作为持续参与严格的临床研究培训计划的一部分。由于得到了各方面的支持 作为 K23/K08 奖项的一部分，NRSA 申请人将开发和完善在抗炎和免疫抑制药物的药物流行病学方面进行进一步研究所需的技能。此外，F32 奖项支持的项目结果将通过量化广泛使用的药物引起严重骨疾病的风险，并评估一些可能改变这种风险的关键因素，为儿科的多个领域做出宝贵贡献。这项研究的见解最终可能会在未来带来更好的治疗、监测和预防 ON 的策略。