Immune signatures precede and accompany subclinical joint inflammation in ACPA-positive individuals at high risk for RA

This observational study performed single-cell transcriptomic and plasma proteomic profiling on blood samples from anti-citrullinated protein antibody (ACPA)-positive individuals at high risk for developing rheumatoid arthritis (RA). The population included ACPA-positive imminent progressors, stratified by the presence or absence of ultrasound-detectable subclinical synovitis, who were compared with ACPA-positive non-progressors. The primary aim was to identify immune signatures associated with the transition to subclinical joint inflammation.

The main findings describe distinct immune signatures at different stages. In ultrasound-negative (USneg) future progressors, type-1 interferon (IFN-I) activation was observed in circulating CD14+ classical monocytes and GZMK+ CD8+ T cells, preceding the detection of subclinical joint inflammation. In ultrasound-positive (USpos) future progressors, a phenotypic shift in CD14+ monocytes towards IL1β+ expression and clonal expansion of GZMB+ cytotoxic CD8+ T cells was identified at the onset of subclinical synovitis. Plasma proteomics suggested a shift from innate immune pathways in USneg progressors toward effector and tissue-remodeling signatures in USpos progressors. No quantitative effect sizes, p-values, or confidence intervals were reported for these associations.

Safety and tolerability data were not reported. Key limitations include the observational design, which cannot establish causation, and the lack of reported quantitative effect measures, sample size, and follow-up duration. The study population was highly selected (ACPA-positive individuals at high risk for RA), and the findings are descriptive associations. The clinical relevance and applicability of these immune signatures for predicting progression or guiding interventions in clinical practice are not established.