Antibiotics, Juvenile Idiopathic Arthritis, and Antirheumatic Treatment Response

抗生素在儿科人群中处方过多，接触抗生素的儿童可能出现 之后几个月到几年的肠道微生物区系失衡(生物失调)。肠道微生物区系在 免疫发育和功能。相应地，生态失调和儿童早期接触抗生素 已被认为是幼年特发性关节炎(JIA)的潜在原因。抗菌素和抗生素的研究进展 贾被限制在两个欧洲人群中，其中大部分是年幼的儿童，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。使用常规的和 修改生物疾病的抗风湿药物(DMARDS)极大地改善了儿童的预后 对于JIA，但对特定药物的反应是可变的，很难预测。甲氨蝶呤(MTX)，最多 用于治疗JIA的常见DMARD对某些共生细菌有毒性，这些细菌在 患有JIA的儿童。此外，早期证据表明，某些肠道微生物群可以代谢MTX， 而对MTX反应不佳的类风湿性关节炎患者的肠道微生物区系可能与 响应者。迫切需要更好地了解一种潜在的可改变因素--抗生素 暴露-影响JIA发病率、表型和对DMARDS的治疗反应的变异性，例如 甲氨蝶呤，使儿童获得适当、有效的药物。这个项目的长期目标是确保 确保所有患有JIA的儿童得到有效和安全的治疗，并确定治疗JIA的新方法 治疗和预防。这项提案的总体目标是了解抗生素是如何影响 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 抗生素暴露的模式与事件JIA和JIA表型有关，并且(2)决定最近 JIA启动DMARDS的儿童接触抗生素与治疗的早期变化有关。 中心假设是，接触抗生素会增加患JIA的风险，并损害治疗 对MTX的反应比对其他DMARD，如肿瘤坏死因子抑制剂更有效。项目团队 将使用行政索赔数据对抗生素的效果进行回顾性队列研究 在广大、多样化的普通儿科人群(目标1)和JIA患者中暴露于开始使用MTX和 其他DMARDS(目标2)。这项拟议的研究将产生关于 抗生素与最常见的儿科风湿病和标准相关的潜在风险 抗风湿药。这项研究将产生关于潜在的潜在机制的关键线索 对特定DMARDS的不同反应。此外，该项目将为以下项目奠定重要基础 未来的干预措施，以限制儿童感染和不适当使用抗生素，并可能 操纵微生物区系，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.