Comparative Analysis of Circulating and Synovial Immune Cells in Early Untreated Rheumatoid Arthritis and Their...

To assess the relationship of circulating and synovial immune cells with synovial molecular pathology and disease outcomes in patients with early rheumatoid arthritis (RA).

Patients with early (<12 months) treatment-naive RA (n = 144) from the Pathobiology of Early Arthritis Cohort were included in this post hoc analysis. Following ultrasound (US)-guided synovial biopsy of the most active joint, patients received standard of care treatment and were observed for 12 months. Synovial biopsies were analyzed by immunohistochemistry and classified into synovial pathotypes. Peripheral blood (PB) samples (n = 70) underwent flow cytometry, whereas RNA sequencing from synovial tissue (n = 144) and matched PB (n = 55) were analyzed using signature-based deconvolution.

T peripheral helper cells (Tph) cells, identified by flow cytometry, were the only circulating immune cell subset positively correlated with both systemic markers of inflammation (erythrocyte sedimentation rate and C-reactive protein) and local inflammation (US synovial thickening and synovitis score). Circulating Tph cells were also significantly higher in patients who were seropositive and patients with lymphomyeloid synovitis. Conversely, circulating B cells showed a significant inverse correlation with markers of inflammation, US scores, and disease activity. Signature-based deconvolution of matched synovial and PB identified divergent immune cell signatures. Although PB signatures showed no associations with longitudinal outcomes, synovium signatures were linked to clinical outcomes. In particular, patients achieving remission at six months (Disease Activity Score in 28 joints < 2.6) had higher baseline synovial Tph signatures and a greater posttreatment reduction of the Tph signature.

Patients with early untreated RA showed divergent immune cell signatures between synovia and PB. Tph cells, in both compartments, emerged as key markers for inflammation, disease activity, and treatment response.