Background/Purpose: Disease activity associated with cardiovascular (CV) risk in rheumatoid arthritis (RA). Females with RA exhibit higher disease activity than males. Yet, males with RA incur greater CV risk compared to females. We theorized that the impact of disease activity on CV risk may differ between males and females. Also, RA patients with anticitrullinated protein antibodies (ACPA) experience greater CV morbidity and mortality compared to those without. ACPA associated with higher disease activity and lower remission rates. Hence, we posited that the effect of inflammation on CV risk may vary across ACPA positive and negative patients. Lastly, male sex associated with better clinical outcomes in ACPA negative but not ACPA positive RA. Therefore, we here explored whether the relationship between disease activity and CV risk in RA varied across sex and ACPA status. 

Methods: We evaluated 4008 RA patients free of CV disease upon enrollment to an international consortium. The outcome was major adverse cardiovascular events (MACE) defined as nonfatal myocardial infarction, nonfatal stroke, or CV death. Missing data were imputed using multiple imputation with 10 repetitions. Multivariable Cox models stratified by center risk assessed the impact of disease activity score on 28-joint counts with C-reactive protein (DAS28CRP), sex, ACPA positivity, as well as the two- and three-way interactions of DAS28CRP with ACPA and/or sex on risk of MACE after adjusting for age, diabetes, hypertension, family history of CV disease, smoking, total cholesterol to high-density lipoprotein ratio, and RA duration.

Results: Over 23,279 patient years, 193 MACE were recorded. Upon multivariable adjustment, there were main effects of DAS28CRP (HR 1.17, 95% CI 1.03-1.32, p=0.017), male sex (HR 1.83, 95% CI 1.37-2.43, p< 0.001), and ACPA positivity (HR 1.38, 95% CI 1.01-1.90, p=0.043) on MACE risk in the entire cohort. The three-way interaction between DAS28CRP, sex, and ACPA was significant (p=0.034), indicating that the impact of RA activity on MACE risk differed according to sex and ACPA status. Among ACPA negative patients, the sex X DAS28CRP interaction was significant (p=0.022) such that disease activity associated with MACE risk in males (HR 1.57, 95% CI 1.14-2.16, p=0.006) but not females (HR 0.96, 95% CI 0.72-1.29, p=0.790, Figures 1 and 2). Among ACPA positive patients, the sex X DAS28CRP interaction (p=0.929) and main effect of DAS28CRP (HR 1.13, 95% CI 0.97-1.31, p=0.124) were not significant, while that of sex was (HR 1.61, 95% CI 1.15-2.27, p=0.006). Considering the ACPA X DAS28CRP interaction stratified by sex, ACPA modified the effect of DAS28CRP on MACE risk in males (p=0.004), with DAS28CRP associating with MACE in ACPA negative (as above) but not positive patients (HR 1.14, 95% CI 0.94-1.37, p=0.189). Among females the ACPA X DAS28CRP interaction (p=0.523) and DAS28CRP main effect (HR 1.10, 95% CI 0.91-1.34, p=0.319) were not significant but that of ACPA was (HR 1.57, 95% CI 1.02-2.42, p=0.039).

Conclusion: Among ACPA negative patients, higher RA activity associated with greater risk of MACE only in males, whereas in ACPA positive DAS28CRP was not associated with MACE risk.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-effect-of-inflammation-on-cardiovascular-risk-in-rheumatoid-arthritis-varies-according-to-sex-and-anticitrullinated-protein-antibody-status/