Clin Rheumatol. 2025 Nov 26. doi: 10.1007/s10067-025-07824-y. Online ahead of print.
ABSTRACT
BACKGROUND: Patients with rheumatoid arthritis (RA) face significantly elevated cardiovascular risks, yet the underlying immunological mechanisms remain incompletely understood, particularly in refractory RA subgroups.
OBJECTIVE: To investigate the association between Th17/Treg immune imbalance and cardiovascular complications in RA patients, with a focus on delineating the unique pathological mechanisms in refractory subgroups.
METHODS: This single-center retrospective cohort study (2015-2024) included 3,464 RA patients (1,872 common RA; 1,592 refractory RA) diagnosed per 2010 ACR/EULAR criteria. Flow cytometry quantified Th17 and Treg absolute counts and ratios. Patients were stratified into four immunophenotypic subgroups: Group A (Treg-deficient/Th17-normal-or-low), Group B (Treg-normal-or-high/Th17-normal-or-low), Group C (Treg-normal-or-high/Th17-high), and Group D (Treg-deficient/Th17-high). Cardiovascular outcomes included coronary artery disease, myocardial infarction, and related events.
RESULTS: In all RA, elevated Th17/Treg ratios correlated with increased cardiovascular risk (χ2 = 8.222, P = 0.016), while individual cell counts lacked predictive value. In refractory RA, Treg counts independently predicted events (χ2 = 6.050, P = 0.049), with Group A (Treg-deficient/Th17-normal-low) showing the highest event rate (9.4% vs. 4.9%, P = 0.048). Treg-deficient patients exhibited altered lipid profiles; Treg-normal-or-high refractory RA had higher smoking rates (20.0% vs. 12.6%, P = 0.008).
CONCLUSION: Th17/Treg imbalance serves as a central predictor of cardiovascular risk in general RA, whereas Treg deficiency dominates in refractory RA. The interplay between immune dysregulation (Treg exhaustion), pro-inflammatory HDL remodeling, and behavioral factors constructs an "immune-metabolic-environmental" axis driving cardiovascular pathogenesis. These findings provide novel biomarkers and precision intervention targets for stratified RA management. Key Points • Treg absolute count, not Th17/Treg ratio, independently predicts cardiovascular events in refractory RA. • A novel immunophenotypic stratification (Groups A-D) identifies high-risk Group A with the highest CAD incidence. • Treg deficiency drives pro-inflammatory HDL remodeling, revealing an immune-metabolic crosstalk in RA. • Distinct mechanisms exist between common and refractory RA, defining an integrated immune-metabolic-environmental axis.
PMID:41299138 | DOI:10.1007/s10067-025-07824-y