Background: Rheumatoid arthritis (RA) increases cardiovascular risk (CVR) in 50-100% of patients due to chronic inflammatory processes that accelerate atherosclerosis. This phenomenon is associated with premature vascular aging equivalent to 10-20 years. Previous studies have identified key CVR biomarkers such as GDF-15, CHI3L1/YKL-40, and PCSK9. However, these studies do not consider sex dimorphism and its influence on accelerated CVR in RA patients.

Objectives: 1. To characterize sex-differentiated clinical and proteomic profiles associated with cardiovascular risk in RA patients. 2. To identify the impact of menopause in the clinical and molecular CV phenotype in RA women

Methods: Multicenter cross-sectional study with 86 RA patients and 229 healthy donors (HD) from the HARMONi cohort matched by sex and age. Demographic, analytical, and clinical profiles of participants were evaluated, including autoimmune and disease activity scores, as well as CVR indicators (BMI, hypertension, menopause status, lipid profile, and atheroma plaque presence). Additionally, proteomic analyses were performed using Olink technology, including 184 proteins linked to inflammation and CVR (Inflammation & CVDIII panels). Groups were compared using t-tests/Mann-Whitney U and chi-square/Fisher exact tests; correlations employed Spearman rho; proteomic analysis used multivariate regression adjusted for confounders.

Results: Compared with HD, RA patients showed a significantly higher number of altered proteins (n=160), which were associated with higher disease activity, autoantibodies positivity and the presence of several CV risk factors. Both male (n=144) and female (n=154) RA patients showed broad systemic immune activation compared with HD, which support a common core RA signature, involving chemokine-driven leukocyte recruitment, synovial fibroblast activation, matrix degradation, and angiogenesis, which collectively sustain chronic synovitis and structural damage.

Among RA patients, men further displayed a more adverse clinical and vascular profile than women, characterized by higher rheumatoid factor titres, elevated cardiovascular SCORE2 values and greater prevalence of carotid plaque. This clinical profile was accompanied by a proteomic signature dominated by Th1/Th17 inflammation (IL 17C, CXCL9/10/11, TNF), endothelial activation and angiogenesis (CDCP1, VEGFA, vWF, EGFR), oxidative stress and lipid dysfunction (PCSK9, PON3, FGF 21), along with chronic tissue damage markers (GDF 15 and CHI3L1), indicating a predominantly inflammatory, endothelial and metabolic imbalance in RA men that aligns with their higher CV burden.

RA women showing atheromatous plaque were older, more frequently hypertensive, dyslipidaemic and smokers compared to those without. In this subgroup, proteins involved in chronic inflammation, metabolism and vascular remodelling were consistently overexpressed, including, GDF-15 (tissue stress and vascular damage), CHI3L1 (inflammation and matrix remodeling), TFPI (coagulation regulation), PCSK9 and FABP4 (lipid-adipocyte axis), as well as chemokines and vascular wall damage mediators (MCP-1, CXCL9/CXCL16, OPN, U-PAR, TIMP4, CTSD).

This pattern was intensified in postmenopausal women and in those with moderate-high SCORE2, where the same proteins reappeared along with metabolic stress and TNF signaling markers, configuring a clearly proatherogenic endotype. In contrast, young premenopausal women with low SCORE2 presented a less inflammatory proteome and lower subclinical vascular burden, suggesting an initially protected phenotype that is lost with aging and menopause.

Across sexes, men and women shared a “core” of key proteins associated with the presence of ateroma plaques or high SCORE2: GDF 15 and CHI3L1 as axes of tissue damage and vascular inflammation, PCSK9 and FGF 21 as metabolic lipid regulators, and chemokines/remodelers (CXCL9, OPN, uPAR, TIMP4, and CTSD) associated with plaque presence.

Conclusions: This study identified distinct, sex-differentiated clinical–proteomic CVR signatures in RA. Women show a stepwise transition from a relatively protected premenopausal profile to a pro-atherogenic postmenopausal endotype tightly linked to age, plaque and traditional CV risk factors. Men display an earlier and more intense inflammatory, endothelial and metabolic imbalance that parallels a higher burden of carotid plaques.

The distinct clinical and proteomic profiles observed in male and female RA patients emphasize the need for sex-differentiated strategies in both risk assessment and therapeutic interventions.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.