Antibiotics, Juvenile Idiopathic Arthritis, and Antirheumatic Treatment Response

抗生素、幼年特发性关节炎和抗风湿治疗反应

基本信息

批准号：
10442518
负责人：
Daniel Benjamin Horton
金额：
$ 46.63万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442518
关键词：
Adult Affect Age Anti-Bacterial Agents Antibiotics Antirheumatic Agents Bacteria Bacteroidetes Biological Child Childhood Chronic Childhood Arthritis Clindamycin Clinical effectiveness Country Data Databases Development Diagnosis Diet Disease Disease-Modifying Second-Line Drugs Dose Drug usage Drug user Effectiveness Ensure European Firmicutes Foundations Funding Future Goals Immune Immune System Diseases Impairment Incidence Infection Intervention Intervention Studies Macrolides Measures Mediating Medicaid Medicine Methotrexate Modality Pathogenesis Patients Pattern Pharmaceutical Preparations Pharmacoepidemiology Pharmacotherapy Phenotype Play Population Population Heterogeneity Prevention Probiotics Proteobacteria Proxy Psoriasis Research Research Infrastructure Retrospective cohort study Rheumatoid Arthritis Rheumatology Risk Risk Factors Role Safety Symptoms TNF gene Testing Time Translating Translational Research Treatment Effectiveness United States National Institutes of Health base commensal bacteria critical period dysbiosis early childhood fecal transplantation gut bacteria gut microbiota improved outcome inhibitor insight microbiota novel pediatric rheumatic diseases prevent response standard care treatment response

项目摘要

Antibiotics are overprescribed in pediatric populations, and antibiotic-exposed children can have signs of gut microbiota imbalance (dysbiosis) for months to years afterwards. Gut microbiota play key roles in immune development and function. Correspondingly, dysbiosis and early childhood antibiotic exposure have been implicated as potential causes of juvenile idiopathic arthritis (JIA). Studies on antibiotics and JIA have been restricted to two European populations of mostly young children, and their findings need replication and deeper examination in broader, more diverse populations. The use of conventional and biologic disease-modifying antirheumatic drugs (DMARDs) has vastly improved outcomes for children with JIA, but response to specific drugs is variable and difficult to predict. Methotrexate (MTX), the most common DMARD used to treat JIA, is toxic to certain commensal bacteria found in higher abundance in children with JIA. Moreover, early evidence suggests that certain gut microbiota can metabolize MTX, and adults with rheumatoid arthritis who respond poorly to MTX may have different gut microbiota from responders. There is a critical need to understand better how a potentially modifiable factor—antibiotic exposure—affects variability in JIA incidence, phenotype, and therapeutic response to DMARDs such as MTX so that children receive appropriate, effective medicines. This project's long-term goal is to ensure that all children with JIA receive effective and safe treatment and to identify new modalities for JIA treatment and prevention. The overall objective of this proposal is to understand how antibiotics affect the risk of developing JIA and the response to standard JIA treatments. This project will (1) test how patterns of antibiotic exposure relate to incident JIA and JIA phenotype and (2) determine whether recent antibiotic exposure in children with JIA starting DMARDs is associated with early changes in therapy. The central hypothesis is that antibiotic exposure increases the risk of JIA and impairs the therapeutic response to MTX more than to other DMARDs, such as tumor necrosis factor inhibitors. The project team will use administrative claims data to conduct retrospective cohort studies on the effects of antibiotic exposure in large, diverse general pediatric populations (Aim 1) and in patients with JIA starting MTX and other DMARDs (Aim 2). The proposed research will yield novel and important information about the potential risks of antibiotics in relation to the most common pediatric rheumatic disease and standard antirheumatic drugs. This research will produce critical clues about underlying mechanism for potentially differential responses to specific DMARDs. Furthermore, this project will lay important foundations for future interventions to limit infections and inappropriate antibiotic use in children and potentially to manipulate microbiota in order to treat or prevent JIA and promote DMARD effectiveness and safety.

儿科人群过度使用抗生素，接触抗生素的儿童可能会出现以下症状肠道微生物群失衡（生态失调）在数月至数年内发挥着关键作用。相应地，免疫发育和功能失调和儿童早期抗生素暴露。抗生素和研究已被认为是幼年特发性关节炎（JIA）的潜在原因。 JIA 仅限于两个主要是幼儿的欧洲人群，他们的发现需要在更广泛、更多样化的人群中进行复制和更深入的研究。生物疾病缓解抗风湿药 (DMARD) 极大地改善了儿童的预后与 JIA 相关，但对特定药物的反应是可变的且难以预测，其中甲氨蝶呤 (MTX) 是最常见的。用于治疗 JIA 的常见 DMARD 对某些在体内含量较高的共生细菌具有毒性。此外，早期证据表明某些肠道微生物群可以代谢 MTX，对 MTX 反应不佳的类风湿性关节炎成人可能具有与其他患者不同的肠道微生物群迫切需要更好地了解潜在的可改变因素——抗生素。暴露——影响 JIA 发病率、表型和对 DMARD 的治疗反应，例如让儿童获得MTX适当、有效的药物是这个项目的长期目标。所有患有幼年特发性关节炎的儿童都接受有效和安全的治疗，并确定治疗幼年特发性关节炎的新方法该提案的总体目标是了解抗生素如何影响。罹患幼年特发性关节炎的风险以及对标准幼年特发性关节炎治疗的反应该项目将 (1) 测试如何进行治疗。抗生素暴露的事件模式与 JIA 和 JIA 表型相关，并且 (2) 确定最近是否开始使用 DMARD 的 JIA 儿童的抗生素暴露与治疗的早期改变有关。中心假设是抗生素暴露会增加幼年特发性关节炎的风险并损害治疗效果项目团队对 MTX 的反应高于其他 DMARD，例如肿瘤坏死因子抑制剂。将使用行政索赔数据对抗生素的影响进行回顾性队列研究在大量、多样化的普通儿科人群（目标 1）以及开始 MTX 和 JIA 的患者中暴露其他 DMARD（目标 2）。拟议的研究将产生有关该疾病的新颖且重要的信息。抗生素与最常见的儿科风湿病相关的潜在风险和标准这项研究将为潜在机制提供重要线索。此外，该项目将为具体的 DMARD 的不同反应奠定重要基础。未来采取干预措施限制儿童感染和抗生素的不当使用，并有可能操纵微生物群以治疗或预防 JIA 并提高 DMARD 的有效性和安全性。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Validation of new medication use algorithms as proxies for worsening disease activity in patients with juvenile idiopathic arthritis.

新药物的验证使用算法作为幼年特发性关节炎患者疾病活动恶化的代理。

DOI：
发表时间：
2024-05
期刊：
影响因子：
2.6
作者：
Saito, Kyoko;Gabbeta, Avinash;Mulvihill, Evan;Al;Beukelman, Timothy;Lewis, James D;Rose, Carlos D;Strom, Brian L;Horton, Daniel B
通讯作者：
Horton, Daniel B

Real-World Evidence for Assessing Treatment Effectiveness and Safety in Pediatric Populations.

评估儿科人群治疗有效性和安全性的真实世界证据。