[Cardiovascular comorbidity in rheumatic disease. Does sex play a role?]

The importance of sex- and gender-related features of various diseases regarding the impact of different risk factors on the natural course of disease, the response to therapy and outcome have only more recently been appreciated. Studies investigating sex- and gender-related aspects in rheumatoid arthritis (RA) are scarce. Unambiguous classification of factors of potential pathogenetic relevance or with the capacity to influence clinical course and disease management into sex- or gender- related aspects is difficult (Figure 1). The majority of RA patients is female. As illustrated by Figure 2, available evidence indicates a progressive decline in the incidence of this disease over the past 40 years in both men and women. There appears to be a cyclical pattern in the annual incidence rates with peaks and troughs occurring for both sexes, but at different times, which suggests the changing exposure to environmental factors which may promote or decrease RA. Current knowledge suggests that RA is characterized by chronic local and systemic inflammation which may trigger accelerated atherogenesis. Sex hormones may also play a pathogenetic role. Androgens and estrogens may stimulate the production of inflammatory cytokines in the synovial fluid. These cytokines then may influence sex hormone metabolism thus modifying sex hormone levels (Figure 3). Compared to the general population (Figures 4 and 5), the risk of cardiovascular morbidity and mortality is significantly increased in patients with rheumatic diseases and in particular in RA. This is evidenced by a higher incidence of congestive heart failure (Figure 6), coronary artery disease and (frequently silent) myocardial infarction, as well as sudden cardiac death. Several studies have demonstrated a significantly increased standardized mortality ratio in RA and identified cardiovascular events as the most frequent cause. Compared with expected mortality rates in the normal population, women with RA have a significantly more compromised life expectancy than men (Table 1). Amongst factors with uneven distribution between sexes are traditional cardiovascular risk factors (Table 2), but also more recently recognized potential risk indicators or risk modifiers such as inflammatory markers and sex hormones. Drugs directed against RA may influence the natural course of cardiovascular disease, as, e. g., indicated by the increased rates of cardiac events and stroke associated with cyclooxygenase-(COX-)2 inhibitor treatment. In contrast, the effect of pharmacotherapy for cardiovascular diseases on the course of RA is unexplored. Prospective cohort studies aiming at early detection of cardiovascular morbidity and precise and detailed characterization of disease manifestations will be required in order to more thoroughly understand the interplay of factors and conditions determining an individuals' risk for developing cardiovascular comorbidity in autoimmune diseases. This article summarizes the available evidence for sex- and gender-related differences in the disease manifestation of rheumatic disorders as well as in cardiovascular risk factors with an emphasis on the cardiovascular comorbidity observed in RA.