Understanding Inflammatory Arthritis due to Immune Checkpoint Inhibitors

项目总结/摘要 该提案的主要目标是获得成为独立的临床和翻译所需的技能 风湿病学的研究员，以提高对一种新的风湿性疾病，炎性关节炎的认识 (IA)免疫检查点抑制剂（ICI）。ICIs正在彻底改变癌症治疗，但也导致 免疫相关不良事件。ICI诱导的IA是最有可能发生的免疫相关不良事件， 遇到的问题。ICI诱导的IA导致显著的发病率，在临床上是异质性的， 可以在ICI停止后持续存在。拟议的项目将利用一组特征良好的ICI患者- 诱导的IA和ICI治疗的对照患者谁不发展IA解决几个重要的问题。 首先，将评估ICI诱导的IA的临床异质性以及预测IA持续性的因素 将确定ICI治疗停止后的时间。其次，临床和免疫遗传风险因素， 将确定是否发生ICI诱导的IA。最后，血清细胞因子谱和自身抗体， 将在ICI诱导的IA患者和接受以下治疗的对照患者中比较ICI治疗后 ICIs和不发展IA。这些实验将解决这一新兴临床研究的关键知识缺口。 实体具体而言，定义相关的临床亚组将允许对以下疾病进行差异化监测和治疗： 患者了解IA发生的风险因素将允许在治疗前对患者进行风险分层。 疗法ICI诱导的IA患者血清中升高的细胞因子可作为未来的治疗靶点。 最后，了解自身抗体的存在以及它们在ICI治疗过程中何时产生， 深入了解发病机制并确定潜在的生物标志物。在开展研究的同时， 建议，候选人将参加各种职业发展活动，利用 约翰霍普金斯大学的丰富资源，在流变学部，彭博金梅尔癌症研究所 免疫疗法和彭博公共卫生学院。候选人将参加教学 课程作业，会议，并与来自风湿病学， 肿瘤学、实验室科学和数据科学。在这个奖项结束时，候选人将是一个独立的 在癌症免疫治疗和自身免疫性疾病领域的临床研究，并将建立一个多- 风湿性irAE和患者的标准化数据和生物样本采集中心联盟 已经存在自身免疫性疾病的患者接受ICI治疗。

Project Summary/Abstract The major goals of this proposal are to attain skills required to be an independent clinical and translational researcher in rheumatology and to enhance understanding of a new rheumatic disease, inflammatory arthritis (IA) due to immune checkpoint inhibitors (ICIs). ICIs are revolutionizing cancer treatment but also cause immune related adverse events. ICI-induced IA is the immune related adverse event most likely to be encountered by rheumatologists. ICI-induced IA causes significant morbidity, is clinically heterogeneous, and can persist after ICI cessation. The proposed project will utilize a group of well characterized patients with ICI- induced IA and ICI-treated control patients who do not develop IA to address several important questions. First, the clinical heterogeneity within ICI-induced IA will be evaluated and factors that predict persistence of IA beyond cessation of ICI therapy will be established. Next, clinical and immunogenetic risk factors for developing ICI-induced IA will be determined. Finally, serum cytokine profiles and autoantibodies before and after ICI treatment will be compared in patients with ICI-induced IA and control patients who are treated with ICIs and do not develop IA. These experiments will address key knowledge gaps for this emerging clinical entity. Specifically, defining relevant clinical subgroups will allow for differential monitoring and treatment of patients. Understanding risk factors for development of IA will allow for risk stratification of patients prior to therapy. Cytokines that are elevated in ICI-induced IA patient sera could serve as future therapeutic targets. Finally, understanding presence of autoantibodies and when they develop in the course of ICI treatment will give insight into pathogenesis and identify potential biomarkers. Concurrently with conducting research during the proposal, the candidate will participate in a variety of career development activities taking advantage of the rich resources of Johns Hopkins in the Division of Rheumatology, the Bloomberg Kimmel Institute for Cancer Immunotherapy, and the Bloomberg School of Public Health. The candidate will participate in didactic coursework, conferences, and mentoring meetings with a diverse group of mentors from rheumatology, oncology, laboratory science, and data science. At the end of this award, the candidate will be an independent clinical investigator in the area of cancer immunotherapy and autoimmune disease and will establish a multi- center consortium with standardized data and biospecimen collection for rheumatic irAEs and for patients with preexisting autoimmune disease who are treated with ICIs.