Comprehensive Risk Factor Control Attenuates Excess Cardiovascular Risk in Rheumatoid Arthritis: A Prospective Cohort Study

OBJECTIVE: Rheumatoid arthritis (RA) confers substantially elevated cardiovascular disease (CVD) risk. We quantified the association between joint risk factor control and incident CVD among RA patients and examined modification by genetic susceptibility. METHODS: In this prospective UK Biobank cohort, 4,426 RA patients and 17,704 matched non-RA controls were followed for CVD, coronary heart disease (CHD), stroke, and heart failure. A nine-component risk factor control score (0-9) was constructed, incorporating healthy diet, smoking, physical activity, blood pressure, glycated hemoglobin, low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, body mass index, and estimated glomerular filtration rate. Cox models, sensitivity analyses, and restricted mean survival time (RMST) were applied. Least absolute shrinkage and selection operator (LASSO) regression identified CVD-predictive metabolomic features; mediation analysis quantified the metabolomic risk score (MRS) contribution. Polygenic risk score (PRS) joint analyses assessed genetic effect modification. RESULTS: Better control was associated with graded CVD risk reduction (moderate: HR 0.77, 95% CI 0.64-0.93; high: HR 0.46, 95% CI 0.33-0.64 vs. low). High control yielded CVD and CHD risks comparable to non-RA controls and lower stroke risk (HR 0.34, 95% CI 0.13-0.91). RMST showed +3.58 CVD-free years (95% CI 2.49-4.68; P < 0.001). Mediation indicated partial MRS mediation (indirect proportion 34.1%; 20.8% adjusted). No significant interaction with MRS; high control attenuated risk even in high genetic risk. CONCLUSION: Comprehensive control attenuates and may offset RA-excess CVD risk, even with high genetic susceptibility. The effect is partially metabolically mediated yet independent of metabolic status, supporting dual-pathway prevention.