Antibiotics, Juvenile Idiopathic Arthritis, and Antirheumatic Treatment Response

抗生素在儿科人群中被过度使用，暴露于抗生素的儿童可能会出现 肠道微生物群失衡（生态失调）数月至数年后。肠道微生物群发挥关键作用， 免疫发育和功能。相应地，生态失调和儿童早期抗生素暴露 已被认为是幼年特发性关节炎（JIA）的潜在原因。抗生素研究和 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检查。使用常规和 生物疾病缓解抗风湿药物（DMARDs）极大地改善了儿童的预后 但对特定药物的反应是可变的，难以预测。甲氨蝶呤（MTX），最 用于治疗JIA的普通DMARD对某些细菌是有毒的， 孩子与JIA此外，早期的证据表明，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年人可能有不同的肠道菌群， 响应者。我们迫切需要更好地了解一种潜在的可修饰因子--抗生素 糖尿病影响JIA发病率、表型和对DMARD治疗反应的变异性， 甲氨蝶呤，使儿童得到适当的，有效的药物。该项目的长期目标是确保 确保所有JIA儿童得到有效和安全的治疗，并确定JIA的新模式 治疗和预防。本提案的总体目标是了解抗生素如何影响 发生JIA的风险和对标准JIA治疗的反应。该项目将（1）测试如何 抗生素暴露模式与JIA事件和JIA表型有关，（2）确定最近是否 JIA患儿开始DMARD时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增加了JIA的风险，并损害了JIA的治疗效果。 对MTX的反应比对其他DMARD（如肿瘤坏死因子抑制剂）的反应更大。项目组 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， 在大量不同的一般儿科人群（目标1）和开始MTX治疗的JIA患者中的暴露量， 其他DMARD（目标2）。拟议的研究将产生关于 抗生素与最常见的儿科风湿性疾病和标准 抗风湿药这项研究将为潜在的潜在机制提供关键线索。 对特定DMARD的不同反应。此外，该项目将为以下方面奠定重要基础： 未来的干预措施，以限制儿童感染和不适当的抗生素使用， 操纵微生物群以治疗或预防JIA并促进DMARD的有效性和安全性。

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.