Improving the Management of Rheumatoid Arthritis-Associated Lung Disease in Veterans Using Real-World Data

类风湿性关节炎(RA)是一种慢性自身免疫性疾病，在美国有130万人患病，导致 身体残疾、生活质量下降、过早死亡和巨大的医疗费用。退伍军人与 RA死于呼吸系统疾病的比率是普通人群的三倍。这其中的大部分过剩 影响退伍军人RA的呼吸道死亡可归因于间质性肺疾病(ILD)，这种疾病有 预后和许多癌症一样差。尽管过去20年来类风湿性关节炎的治疗取得了进展， 采用新的治疗方法和更积极的治疗策略，RA-ILD的最佳管理是 未知。有效管理患有RA-ILD的退伍军人的两个关键限制是：1)无法识别 患有进展性RA-ILD的退伍军人--那些最有可能从抗纤维化或侵袭性疾病中受益的人 免疫调节疗法和2)缺乏关于疾病的相对有效性和安全性的数据- 修改这一人群中的类风湿性关节炎疗法。因此，该项目的总体目标是利用 退伍军人健康管理局(VHA)内独特的潜在RA-ILD队列和数据联系 1)确定RA-ILD的预后血清和遗传生物标记物；2)比较其有效性和安全性 在患有RA-ILD的退伍军人中使用RA治疗。我们的中心假设是血清和遗传生物标记物 独立关联并准确预测RA-ILD进展，并选择RA治疗方法 以不同的方式延缓ILD的进展并提高相关生存率。在目标1中，我们将使用预期的RA-ILD 确定预后血清和遗传生物标记物的队列，并得出进展性RA-ILD预测模型。 我们假设来自RA-ILD病理生理域的生物标记物-新的疾病相关 自身抗体、遗传标记、促炎细胞因子和基质金属蛋白酶-将是 与患有RA-ILD的退伍军人的ILD进展独立相关。在目标2中，我们将连接国家VHA 数据来源，并使用先进的因果推理方法来确定相关的RA疗法 在患有RA-ILD的退伍军人中，ILD进展较慢，存活率提高。我们假设，相比于 肿瘤坏死因子抑制物(TNFi)、非TNFi生物疗法(利妥昔单抗、abatacept和tocilizumab)将 在患有RA-ILD的退伍军人中，ILD进展较少，死亡风险较低。影响： 拟议研究的结果将有助于临床医生对患有退伍军人疾病的患者进行个性化治疗选择 RA-ILD是一种高危人群，目前几乎没有数据来指导治疗选择。私家侦探将完成这项工作 在临床和医学领域多学科专家团队的指导下的研究计划 在VHA内从事药物流行病学研究，建立在他早期研究生产力的基础上。这个 药物流行病学和因果推断方法学的伴随辅导培训计划 通过高级、身临其境的课程和专业会议获得的信息将使PI能够进行 在VHA内对RA和RA-ILD进行高影响力研究。在完成这个奖项后，PI将做好准备 独立的研究生涯，目标是改善患有RA的退伍军人的长期结果。

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 1.3 million individuals in the U.S., causing physical disability, reduced quality of life, premature mortality, and enormous health care costs. Veterans with RA die from respiratory diseases at a rate three times higher than the general population. Much of this excess respiratory mortality affecting Veterans with RA is attributable to interstitial lung disease (ILD), which has a prognosis as poor as many cancers. Despite advances in RA treatment over the past two decades with the adoption of novel therapies and more aggressive treatment strategies, the optimal management of RA-ILD is unknown. Two critical limitations for effectively managing Veterans with RA-ILD are 1) the inability to identify Veterans with progressive RA-ILD—those most likely to benefit from anti-fibrotic or aggressive immunomodulatory therapies and 2) a lack of data on the comparative effectiveness and safety of disease- modifying RA therapies in this population. Therefore, the overall objectives of this project are to leverage unique prospective Veteran RA-ILD cohorts and data linkages within the Veterans Health Administration (VHA) to 1) identify prognostic serum and genetic biomarkers for RA-ILD and 2) compare the effectiveness and safety of RA therapies in Veterans with RA-ILD. Our central hypotheses are that serum and genetic biomarkers will be independently associated with, and accurately predict, RA-ILD progression, and select RA therapies will differentially slow ILD progression and improve related survival. In Aim 1, we will utilize prospective RA-ILD cohorts to identify prognostic serum and genetic biomarkers and derive progressive RA-ILD predictive models. We hypothesize that biomarkers from RA-ILD pathophysiologic domains—novel disease-related autoantibodies, genetic markers, pro-inflammatory cytokines, and matrix metalloproteinases—will be independently associated with ILD progression in Veterans with RA-ILD. In Aim 2, we will link national VHA data sources and use advanced causal inference methodology to identify RA therapies that are associated with less ILD progression and improved survival in Veterans with RA-ILD. We hypothesize that compared to tumor necrosis factor inhibitors (TNFi), non-TNFi biologic therapies (rituximab, abatacept, and tocilizumab) will be associated with less ILD progression and have a lower mortality risk in Veterans with RA-ILD. Impact: The results from the proposed research will assist clinicians with personalized treatment selection in Veterans with RA-ILD, a high-risk population with little data to currently guide treatment selection. The PI will complete this research plan under the mentorship of a multidisciplinary team of experts in clinical and pharmacoepidemiologic research within the VHA, building upon his early research productivity. The accompanying mentored training program in pharmacoepidemiology and causal inference methodology obtained through advanced, immersive coursework and professional meetings will position the PI to conduct high-impact research in RA and RA-ILD within the VHA. Upon completion of this award, the PI will be poised for an independent research career targeting improvements in the long-term outcomes for Veterans with RA.