Type I interferon activation in classical monocytes and GZMK+ CD8+ T cells characterises the ultrasound-negative phase of imminent rheumatoid arthritis

OBJECTIVES: Rheumatoid arthritis (RA) is a prototypical autoimmune disease, characterised by prolonged systemic autoimmunity before organ-specific tissue inflammation. Understanding immune mechanisms that drive the transition from systemic autoimmunity to joint-specific pathology is key to arthritis prevention. In this study, we define immune signatures in anticitrullinated protein antibodies-positive (ACPA+) at-risk individuals who imminently progress to RA, comparing those with and without ultrasound (US)-detectable subclinical synovitis. METHODS: We performed single‑cell RNA sequencing and proteomic profiling on prospectively collected blood samples from high-risk ACPA+ imminent progressors (n = 22), who were further stratified by the presence or absence of US-detectable subclinical synovitis and compared them with ACPA+ nonprogressors (n=18). RESULTS: We found type I interferon (IFN-I) upregulation in peripheral CD14+ classical monocyte and Granzyme K protein (GZMK)+ CD8+ T cells in US-negative (USneg, n = 11) imminent progressors. In contrast, US-positive (USpos, n = 11) progressors exhibited a phenotypic shift in CD14+ classical monocytes towards interleukin 1 beta (IL1ß)+ expression and clonal expansion of GZMB+ cytotoxic CD8+ T cells. GZMB+ and GZMK+ CD8+ T cells were largely clonotypically distinct. Plasma proteomics also revealed a shift from Toll-like receptor-associated innate pathways in USneg progressors towards effector and tissue-remodelling signatures in USpos progressors. CONCLUSIONS: In ACPA+ high-risk individuals, IFN-I-driven activation of peripheral innate CD14+ classical monocytes and GZMK+ CD8+ T cell subsets occur before the onset of subclinical synovitis when RA is imminent. Distinct inflammatory and effector programmes, including GZMB+ CD8+ T cells clonal expansion, are associated with the onset of subclinical synovitis.