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

Immune checkpoint inhibitor (ICI)-induced inflammatory arthritis (IA) is an increasingly recognized immune-related adverse event (irAE), yet its underlying immunopathogenesis remains poorly understood. Unlike rheumatoid arthritis (RA), where autoantibodies and B cell dysfunction are central features, the contribution of humoral immunity to IA irAE is unclear. Here, we performed in-depth immunophenotyping of peripheral blood from patients with IA irAE, and compared them with seronegative RA patients, ICI-treated patients without irAE, and healthy controls. IA irAE was marked by a distinct T cell-dominated profile, with CD4 T cells exhibiting reduced CXCR3 and CCR6 expression, and both CD4 and CD8 T cells showing increased cytotoxic molecule expression and metabolic activation. In contrast to seronegative RA, IA irAE patients displayed no significant elevation in autoantibody levels or atypical CD11cCD21- B cells. IA irAE was further characterized by a proinflammatory cytokine milieu, with elevated levels of IL-6, IL-12, and type I IFN, which correlated with the observed T cell activation phenotypes. Altogether, our findings define IA irAE as an immunologically distinct entity from RA, representing a naturally occurring model of antibody-independent systemic autoimmunity in humans. These results suggest that pathogenic T cell responses, potentiated by specific inflammatory cytokines, may be sufficient to drive arthritis in the absence of humoral autoimmunity, offering new insights into immune tolerance breakdown and therapeutic targeting in irAEs. One Sentence Summaryinflammatory arthritis irAE is a T cell driven, autoantibody independent autoimmunity