Use and Effectiveness of Infection Prophylaxis Strategies in a National Cohort of Patients with ANCA Vasculitis

项目总结/摘要 降低感染风险是抗神经元胞质自身抗体（ANCA）患者的优先事项- 相关性血管炎（AAV），一组罕见的，危及生命的自身免疫性疾病，引起炎症 以及多个器官（最常见的是肾脏）的血管坏死。提供有效的， 积极的免疫抑制药物将AAV从快速致命的疾病转变为慢性， 复发缓解型疾病，但伴随着严重感染的高负担，这是现在的主要疾病。 AAV发病和死亡的原因。预防肺孢子虫机会性感染 肺炎（PJP），治疗指南建议使用甲氧苄啶/磺胺甲恶唑预防 (TMP/SMX）。然而，PJP在AAV中很少发生，即使在未接受预防的患者中也是如此。其他严重 感染是常见的并且可以通过替代的预防性抗微生物剂（例如， 氟喹诺酮类、多西环素、阿莫西林、抗真菌药），推荐用于非AAV免疫抑制 人口。有限的可用数据表明，建议的 和替代预防策略，但缺乏关于这种变化的驱动因素的可推广信息。在 此外，我们缺乏随机试验或严格的观察性研究的证据，以评估因果关系， 推荐和替代预防对AAV关键结局的影响，包括严重感染和 mortality.这项研究的长期目标是减少AAV感染相关的发病率和死亡率， 通过更好地了解患者使用预防性药物的决定因素， 推荐与替代预防的有效性。拟议的回顾性队列研究将使用 医疗索赔和处方药数据的国家队列的医疗保险受益人与AAV谁启动 2016-2017年免疫抑制治疗的新疗程。具体目标是：（1）确定诱发因素， 使能，和医疗需要（即，与使用TMP/SMX预防相关的临床）因素，替代 预防策略，或无预防;（2）评估抗菌预防的有效性 减少严重感染和死亡风险的战略。目标1分析将使用回归分析， 确定与使用指南推荐的TMP/SMX预防或替代治疗相关的因素 预防策略，与无预防相比。目标2将使用强有力的药物流行病学方法， 降低选择偏倚和混杂的可能性，包括活性对照药物、新用户设计和 先进的协变量平衡方法（即，熵平衡），以比较严重感染和死亡风险 在接受TMP/SMX与替代预防的患者中。这项研究将确定最有风险的患者， 接受推荐的预防，改善证据基础，为预防决策提供信息 在AAV中，并为未来比较有前途的替代品的比较有效性试验奠定基础 预防策略，以目前的标准治疗，在这个研究不足的人群。

PROJECT SUMMARY/ABSTRACT Reducing infection risk is a priority in patients with antineutrophil cytoplasmic autoantibody (ANCA) – associated vasculitis (AAV), a group of rare, life-threatening autoimmune diseases that cause inflammation and necrosis of blood vessels in multiple organs, most commonly the kidneys. The availability of effective, aggressive immunosuppressive medications transformed AAV from a rapidly fatal condition to a chronic, relapsing-remitting disease, but comes with a high burden of severe infections, which are now the leading cause of morbidity and mortality in AAV. To prevent opportunistic infection with Pneumocystis jirovecii pneumonia (PJP), treatment guidelines recommend prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX). However, PJP occurs very rarely in AAV, even in those not receiving prophylaxis. Other severe infections are common and may be effectively prevented by alternative prophylactic antimicrobials (e.g., fluoroquinolones, doxycycline, amoxicillin, antifungals) recommended for non-AAV immunosuppressed populations. Limited available data suggests under-utilization and widespread variation in use of recommended and alternative prophylaxis strategies, but generalizable information about drivers of this variation is lacking. In addition, we lack evidence from randomized trials or rigorous observational studies designed to assess causal effects of recommended and alternative prophylaxis on key outcomes in AAV, including severe infections and mortality. The long-term goal of this research is to reduce infection-related morbidity and mortality in AAV, through improved understanding of the determinants of patients’ use of prophylaxis and evidence regarding effectiveness of recommended vs. alternative prophylaxis. The proposed retrospective cohort study will use medical claims and prescription drug data for a national cohort of Medicare beneficiaries with AAV who initiate a new course of immunosuppressive therapy in 2016-2017. Specific aims are to (1) identify predisposing, enabling, and medical need (i.e., clinical) factors associated with use of TMP/SMX prophylaxis, alternative prophylaxis strategies, or no prophylaxis; and (2) assess the effectiveness of antimicrobial prophylaxis strategies in reducing risk of severe infections and mortality. Aim 1 analyses will use regression analyses to identify factors associated with use of guideline-recommended TMP/SMX prophylaxis or alternative prophylaxis strategies, versus no prophylaxis. Aim 2 will use powerful pharmacoepidemiologic methods to reduce potential for selection bias and confounding, including an active-comparator, new-user design and advanced covariate balancing methods (i.e., entropy balancing), to compare severe infection and mortality risk in those receiving TMP/SMX vs. alternative prophylaxis. This study will identify patients most at-risk for not receiving recommended prophylaxis, improve the evidence base to inform decision-making about prophylaxis in AAV, and build a foundation for future comparative effectiveness trials comparing promising alternative prophylaxis strategies to the current standard of care in this understudied population.