Understanding Inflammatory Arthritis due to Immune Checkpoint Inhibitors

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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.