AGE, SEROPOSITIVITY AND INFLAMMATION DETERMINE RISK VERSUS BENEFIT OF ENDOGENOUS ESTROGENS ON CORONARY ATHEROSCLEROSIS IN RHEUMATOID ARTHRITIS

Background: Endogenous estrogens appear cardioprotective in females in general population studies. Yet, proinflammatory effects of estrogens have been described in chronic autoimmune diseases depending on stage, cell-type involved, target organ microenvironment and their metabolism. The impact of estrogens on coronary atherosclerosis and cardiovascular risk in rheumatoid arthritis (RA) is unknown. Objectives: We here explored the influence of serum estrone and estradiol on coronary atherosclerosis, its progression and their link with cardiovascular events in patients with RA. Methods: Coronary atherosclerosis (noncalcified, mixed or fully calcified, and low-attenuation plaque) was evaluated with computed tomography angiography in 140 patients without cardiovascular disease and reassessed in 100 after 6.9±0.4 years. Lesions yielding >50% luminal stenosis were considered obstructive. Serum bioactive estrone (E1) and 17β-estradiol (E2) were measured during baseline and follow-up plaque evaluations with commercial ELISA. Multivariable robust negative binomial regression evaluated interactions of estrogens with age and ACPA positivity predicting plaque numbers at baseline and interactions of estrogens with time-averaged C-reactive protein (TA-CRP) predicting numbers of new plaques at follow-up. Multivariable Cox regression models evaluated the association of estrogens with cardiovascular event risk. All models minimally adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score and plaque progression and cardiovascular event models further adjusted for baseline plaque. Results: Higher baseline E1 associated with greater total plaque burden, including noncalcified and low-attenuation plaques, in patients older but not younger than 55 years (p-interaction = 0.006, 0.006 and 0.004 respectively, Figure 1A). Higher E1 associated with lower total, mixed and fully calcified plaque burden in ACPA negative patients (p-interaction = 0.017, 0.012 and 0.008 respectively) and greater mixed plaque burden in ACPA positive ones (Figure 1A). The interactions of E2 with age over 55 years and ACPA status were not significant (results not shown). In patients showing increasing−but not decreasing−E1 levels at follow-up, higher TA-CRP(ln) associated with more new total and noncalcified plaques (p-interaction = 0.002 and 0.022 respectively, Figure 1B). Likewise, higher TA-CRP(ln) associated with more new noncalcified lesions only in patients with increasing E2 (p-interaction = 0.050); in contrast, in those with decreasing E2, higher TA-CRP associated with more new fully calcified (low-risk) lesions (p-interaction = 0.037, Figure 1B). E1 inversely associated with cardiovascular risk (hazard ratio [HR] 0.39 [95% confidence interval 0.19-0.81] per standard deviation increase in E1], after adjustments for cardiac risk score and plaque burden (Figure 2A), while E2(ln) did not (HR 0.87 [0.50-1.51] per standard deviation increase in log transformed E2). Addition of E1 to a model of cardiac risk score and baseline plaque burden enhanced cardiovascular risk prediction; area under the curve (AUC) increased from 0.81 (95% CI 0.66-0.95) to 0.85 (95% CI 0.73-0.96) and integrated discrimination improvement (IDI) = 0.06 (standard error 0.023), p = 0.008 (Figure 2B). Notably, the inverse association of E1 with event risk was stronger in patients <55 years (HR 0.17 [0.06-0.48]) and those without obstructive plaque at baseline (HR 0.21 [0.09-0.48], p-interaction = 0.008 and 0.002 respectively). Conclusion: The effects of endogenous estrogens on baseline plaque vary according to age and ACPA status, and their increase over time was linked to a stronger association between cumulative inflammation and plaque progression. E1 inversely associated with event risk after accounting for cardiovascular risk score and atherosclerosis burden, suggesting additional potential benefits of estrogens on plaque biology and stability. REFERENCES: NIL. Figure 1. Influence of endogenous estrogens on coronary atherosclerosis burden (A ) and their change from baseline on plaque progression (B ) Acknowledgements: NIL. Disclosure of Interests: George Karpouzas Janssen, Scipher, Pfizer, Bianca Papotti: None declared, Sarah Ormseth: None declared, Marcella Palumbo: None declared, Elizabeth Hernandez: None declared, Matthew Budoff: None declared, Nicoletta Ronda: None declared. DOI: 10.1136/annrheumdis-2024-eular.3719 Keywords: Biomarkers, Imaging, Cardiovascular diseases, Atherosclerosis Citation: , volume 83, supplement 1, year 2024, page 819Session: Rheumatoid arthritis (Poster View)

Biomarkers, Imaging, Cardiovascular diseases, Atherosclerosis