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.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry nameend="c2" namest="c1"> 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. </entry> </row> </tbody> </tgroup> </Table>

Association of Th17/Treg immune imbalance and cardiovascular complications in RA patients: retrospective cohort study in refractory subgroups

期刊论文
发表日期：

2025年11月26日

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Qin-Yi Su,
Meng-Yuan Wang,
Liu Yang,
Chen-Qi Xue,
Jing-Wen Cheng,
Zi-Qian Liang,
Xin-Yao Liu,
Zhi-Yuan Ren,
Yuan-Chi Li,
Han Niu,
Hui-Shan Sun,
Sheng-Xiao Zhang

摘要

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.