Understanding Inflammatory Arthritis due to Immune Checkpoint Inhibitors

项目摘要/摘要 这项建议的主要目标是获得成为独立的临床和翻译医生所需的技能 研究风湿病并增进对一种新的风湿病-炎性关节炎的认识 (IA)由于免疫检查点抑制剂(ICIS)。ICIS正在给癌症治疗带来革命性的变化，但也导致了 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 风湿病专家所遇到的。ICI诱发的IA导致显著的发病率，在临床上是不同的，并且 ICI停止后仍可持续。拟议的项目将利用一组具有良好特征的ICI患者- 诱导IA和ICI治疗的对照患者谁没有发生IA来解决几个重要问题。 首先，我们将评估ICI所致IA的临床异质性以及预测IA持续性的因素。 超过停止ICI的治疗将被确立。接下来，临床和免疫遗传风险因素 发展ICI诱导的IA将是确定的。最后，检测前、后血清细胞因子谱和自身抗体 ICI后的治疗将对ICI诱发的IA患者和对照组患者进行比较 ICIS，不发展IA。这些实验将填补这一新兴临床领域的关键知识空白 实体。具体地说，界定相关的临床亚组将允许区别监测和治疗 病人。了解发生IA的风险因素将使患者能够在 心理治疗。ICI诱导的IA患者血清中升高的细胞因子可能成为未来的治疗靶点。 最后，了解自身抗体的存在以及它们在ICI治疗过程中何时发展将 洞察发病机制并确定潜在的生物标志物。在进行研究的同时 该提案中，应聘者将参加各种职业发展活动，利用 约翰霍普金斯大学在彭博基梅尔癌症研究所风湿病学部的丰富资源 免疫疗法和彭博公共卫生学院。候选人将参加说教 课程作业、会议和与风湿病不同导师的辅导会议， 肿瘤学、实验室科学和数据科学。在这个奖项结束时，候选人将是一名独立的 在癌症免疫治疗和自身免疫性疾病领域的临床研究员，并将建立一个多 为风湿性虹膜脑脊髓炎和 接受ICIS治疗的先前存在的自身免疫性疾病。

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.