Inflammatory arthritis immune related adverse events represent a unique autoimmune disease entity primarily driven by T cells, but likely not autoantibodies

Although the current paradigm posits that autoreactive T and B cells both contribute to inflammatory arthritis (IA), the existence of antibody-independent arthritis remains contentious. The immunological nature of IA immune related adverse events (irAE) following anti-PD-1/PD-L1 mediated immune checkpoint inhibition (ICI) therapy remains incompletely understood. Here, we analyzed the peripheral immunological phenotypes of a large cohort of IA irAE patients in comparison to serologically matched rheumatoid arthritis (RA) controls, ICI controls (patients treated with anti-PD-1/PD-L1 without developing irAE) and healthy controls, Our data revealed that IA irAE CD4⁺T cells are distinguished by reduced CXCR3 and CCR6 expression, and irAE CD8⁺T cells are distinguished by increased cytotoxic molecule expression, while both exhibit increased metabolic activity. We did not observe any significant alterations in humoral immunity in IA irAE patients compared to control groups. In contrast, seronegative RA controls exhibited significantly increased CD11c⁺CD21^-atypical B cell frequency and autoantibody levels. Furthermore, IA irAE patients are characterized by highly elevated levels of inflammatory cytokines and chemokines. We identified IL-6, IL-12 and IFNα as potential soluble factors contributing to some of the IA irAE immunological alterations. Altogether, our results suggest that IA irAE is an immunologically distinct disease entity with a potential segregation of T and B cell immunity, indicating that autoantibodies may not be necessary to break systemic immune tolerance in humans.