Bridging clinical phenotypes with molecular mechanisms in autoimmune irAEs: An Etiopathogenic framework

Immune checkpoint inhibitors (ICI) have transformed the field of oncology and can induce a durable cancer treatment response in select cancer patients. ICI binding to these checkpoints allows the immune system to be activated in order to target tumor death, but this activation also brings multiple off-target side effects called immune related adverse events (irAE's) including rheumatic irAE's. Review aims will explore novel insights into rheumatic irAE's etiology and etiopathology including ICI-inflammatory arthritis, ICI-Polymyalgia Rheumatica, ICI-activated osteoarthritis, sicca-like syndrome, and ICI induced myositis. This chapter will review rheumatic irAE's and define their proposed mechanisms, which include generalized immune activation owing to checkpoint neutralization, direct off-target effects of checkpoint inhibitors and epitope spreading. Research using cellular profiling methods such as single cell transcriptomics and T cell profiling have helped explore the novel mechanism of these heterogenous rheumatic irAE's. Future goals of research include gaining a better understanding of pathogenesis of rheumatic irAE's to help target precision rheumatic irAE treatment.