PD-1^hiCXCR5^-CD4⁺T Peripheral Helper Cells Were Enriched and Potentially Predicted Clinical Response to Etanercept...

Rheumatoid arthritis (RA) remains a challenging autoimmune disease with variable treatment responses to tumor necrosis factor-α (TNF-α) inhibitors. This study investigates the clinical significance of PD-1^hiCXCR5^-CD4⁺T peripheral helper (Tph) cells in RA and their potential utility as biomarkers for predicting etanercept (ETN) therapy response. We enrolled 58 RA patients, 12 age- and sex-matched osteoarthritis patients, and 15 healthy controls, with Tph cells quantified by flow cytometry. Among 25 RA patients with inadequate response to conventional synthetic disease-modifying antirheumatic drugs receiving ETN therapy, treatment outcomes were stratified by ACR20 response criteria. Tph cell frequency was significantly elevated in RA patients and correlated positively with multiple disease activity indicators. At baseline, ETN nonresponders exhibited higher Tph proportions than responders (13.23 ± 2.60% vs. 10.82 ± 3.08%, p = 0.0467). Following ETN treatment, responders demonstrated significant Tph reduction (10.82% decreased to 7.97%, p = 0.0105), paralleling serum IL‑21 dynamics. In an exploratory analysis, baseline Tph levels showed an association with ETN response. These findings suggest that circulating Tph cells may serve as a candidate biomarker for RA disease activity and therapeutic response monitoring, warranting further validation in larger prospective cohorts.