To assess the relationship of circulating and synovial immune cells with synovial molecular pathology and disease outcomes in early Rheumatoid Arthritis (RA).
Early (<12 months) treatment-naïve RA patients (n=144) from the Pathobiology of Early Arthritis Cohort (PEAC) were included in this posthoc analysis. Following ultrasound-guided synovial biopsy of the most active joint, patients received standard-of-care treatment and were followed up for 12 months. Synovial biopsies were analysed by immunohistochemistry and classified into synovial pathotypes. Peripheral blood samples (n=70) underwent flow cytometry, while RNA-sequencing from synovial tissue (n=144) and matched peripheral blood (n=55) were analysed using signature-based deconvolution.
T-peripheral-helper cells (Tph), identified by flow cytometry, were the only circulating immune cell subset positively correlated with both systemic (ESR and CRP) and local inflammation (ultrasound synovial thickening and synovitis score). Circulating Tph cells were also significantly higher in seropositive patients and patients with lympho-myeloid synovitis. Conversely, circulating B-cells showed a significant inverse correlation with inflammatory markers, ultrasound scores, and disease activity. Signature-based deconvolution of matched synovial and peripheral blood identified divergent immune cell signatures. While peripheral blood signatures showed no associations with longitudinal outcomes, synovium signatures were linked to clinical outcomes. In particular, patients achieving remission at 6 months (DAS28<2.6) had higher baseline synovial Tph signatures and a greater post-treatment reduction of the Tph signature.
Early untreated RA patients showed divergent immune cell signatures between synovia and peripheral blood. Tph cells, in both compartments, emerged as key markers for inflammation, disease activity, and treatment response.
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