This study shows that RA, as a clinical disease, but not RA-related autoimmunity is associated with CV events. It is known that RA is associated with two-fold increased risk for CV disease compared to the general population (24–26). While the overall CV risk in RA patients is based on traditional risk factors as well as immune changes related to RA, the excess risk of RA is usually considered to be based on increased inflammation and/or autoimmunity (24). While elevated systemic markers of inflammation have shown to be associated with a higher CV risk (27), other studies have also reported that CV risk is higher in RA patients with positive ACPA (15–18), but such observation could be related to the severity of RA correlating with ACPA positivity (28), rather than to an independent association with ACPA. Hence, disentangling the effect of autoimmunity from the one of inflammation on CV risk in RA population is difficult, if not impossible.
The fact that ACPA and RF positivity precedes RA and that some individuals are positive for RF or ACPA without even developing the disease allows to separately assess the role of RA-related autoimmunity and RA, as an inflammatory joint disease, on CV risk (4–6). The analysis of GAZEL individuals that were positive for RF and/or ACPA permitted to directly evaluate the association between ACPA/RF and CV without the influence of arthritis. This analysis clearly showed that RA-related autoimmunity is not associated with an increased risk for CV disease, indicating that systemic inflammation is required for precipitating CV events. Hence, it is conceivable that effector function of autoantibodies, i.e. Fc- mediated cytokine release, which translates asymptomatic autoimmunity to inflammatory disease is critical for conveying CV risk (29).
In the GAZEL cohort, traditional risk factors such as male sex, age smoking, hypertension, hyperlipidemia and diabetes mellitus were independently associated with CV events. Notably, presence of RA was significantly associated with CV disease with a hazard ratio of 3.0. The strength of the association between CV events and RA is reflected by the fact that the number of ascertained RA cases was rather low in this cohort but nonetheless this association was robust. This observation also supports the robustness of the lack of association between autoantibodies and CV risk as the numbers of autoantibody positive subjects was much higher than the one with RA. The overall low number of ascertained RA cases can be explained by the fact that participants of the GAZEL cohort were mostly males (> 70%). Considering a prevalence of RA of 0.5% in the French population (2), that only up to 1/3 of RA patients being males and that not all subjects with self-reported RA could be validated, the numbers of observed and established RA cases fits the numbers of expected RA cases.
Strength of this study includes the fact that the increased risk of CV events in RA patients as compared to controls was confirmed in the same cohort and that also the associations between RA and CV events on one hand, and autoantibodies and CV events in the other were assessed in the same cohort. Another strength is that the ascertainment of RA cases did not rely merely on self-reporting but was confirmed by experienced rheumatologist, using a dedicated questionnaire that was developed and validated for this purpose. The only study which assessed the association between both ACPA and RF in non-RA patients is the one demonstrating that the presence of autoantibodies was associated with CV risk increased in African American women, and the diagnosis of RA was based on self-reporting information (19). Limitations are the fact that plasma was not available in the entire GAZEL cohort and hence autoantibody data were only obtained in a fraction of the cohort. On the other hand, subjects with plasma did not essentially differ from the others with respect to demographic characteristics, CV risk factors and CV events. Furthermore, the robustness of a lack of association between autoantibodies and CV events is supported by the fact that positive association could be observed for RA, despite the number of RA cases was substantially lower than the number of subjects positively tested for autoantibodies.