Abstract: Objectives: Female sex and anticitrullinated protein antibodies (ACPA) are associated with higher disease activity in rheumatoid arthritis (RA). Since disease-related inflammation is linked to cardiovascular risk, we explored whether sex and ACPA influenced the association between disease activity at study entry and cardiovascular risk in established RA. Methods: We evaluated 4008 patients with prevalent RA from an international observational cohort enrolled between 1985 and 2012. Outcomes included major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction and stroke) and ischaemic cardiovascular events (iCVE: MACE, angina, revascularisation, transient ischaemic attack and peripheral arterial disease). Follow-up accrued from enrolment until the first event or censoring. Multivariable Cox models stratified by centre risk evaluated disease activity, sex, ACPA and their interactions. Results: We documented 193 MACE and 299 iCVE. Disease activity and sex were associated with MACE (all p 0.017) and iCVE (p?0.005) but ACPA was only associated with MACE (p=0.043). A three-way interaction on MACE (p=0.034) but not iCVE was noted. Among ACPA-negative patients, disease activity was associated with MACE in males (HR 1.57 (95% CI 1.14 to 2.16)) but not females (p-for-interaction=0.022). Among ACPA-positive patients, neither the disease activity x sex interaction (p=0.929), nor main effect of disease activity on MACE (p=0.124) was significant, but male sex was (HR 1.61 (95% CI 1.15 to 2.27)). Among females, neither disease activity x ACPA interaction (p=0.523) nor disease activity (p=0.319) was significant for MACE, but ACPA was (HR 1.57 (95% CI 1.02 to 2.42)). Conclusions: The effect of disease activity at enrolment on cardiovascular risk in prevalent RA varies across patient groups with different sex and ACPA characteristics.

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