Rheumatoid arthritis and heart disease: the chicken and the egg?

Abstract

In this issue of the Journal, Holmqvist et al. [1] reported an increased risk of myocardial infarction (MI) soon after the diagnosis of rheumatoid arthritis (RA). This increased risk was apparent in both rheumatoid factor (RF)-positive and negative patients, as well as patients diagnosed in recent years when treatment regimes have been more aggressive. Furthermore, the relative risks for MI and ischaemic heart disease remained stable throughout the follow-up period with no evidence of an increasing cardiovascular disease (CVD) risk later in the RA disease course. This evidence challenges conventional wisdom that the increased risk of CVD may occur later in the RA disease course and is highest amongst RF-positive patients [2]. This finding of early increased risk of CVD following RA disease onset raises the issue of when the increased risk of CVD begins for patients with RA. Maradit-Kremers et al. [3] reported an increased risk of hospitalized MI in the 2 years prior to diagnosis of RA. In contrast, in another recent article by Holmqvist et al. [4], no statistically significant increases in CVD risk were found prior to onset of RA symptoms. However, these results were inconclusive because of lack of statistical power. Indeed, an elevated relative risk for ischemic heart disease amongst patients with RA of 1.5 was found, but it was not significant because of the small number of ischemic heart disease events (i.e. only 20 events amongst the patients with RA). Determining which comes first, the onset of RA or the increased risk of CVD, could provide mechanistic insights to help unravel the relative contributions of genetic susceptibilities, shared aetiologies, inflammation and other RA disease–related factors in the manifestation of CVD in patients with RA. For instance, if the increased risk of CVD coincides with the onset of RA, this suggests RA disease–related factors may play a major role in the increased risk of CVD. However, if the increased risk of CVD begins prior to the onset of RA, genetic factors and shared aetiologies are implicated. If this is the case, treating the RA disease may have limited impact on the increased risk of CVD in RA. It is difficult to determine which comes first, the onset of RA or the increased risk of CVD, because both diseases exist subclinically for some period of time before they manifest clinically. Systemic inflammation, as well as RF positivity, occurs in patients for some time prior to the development of symptoms of RA [5, 6]. Atherosclerosis is also an inflammatory process that begins with endothelial activation and culminates in a MI [7]. Subclinical measures of atherosclerosis such as intima-media thickness are increased early in the disease course of patients with RA, indicating acceleration of atherosclerosis occurs at or before the onset or RA [8]. The latencies of RA and CVD are unknown, so it may not be possible to determine which process begins or accelerates first. Furthermore, it is unclear to what extent the control of RA disease activity and inflammation will reduce the risk of CVD in patients with RA. Whilst evidence shows that controlling disease activity reduces RA disease–related joint damage, further study is needed to determine the impact of tight control on the risk of CVD in patients with RA [9, 10]. Indeed, Holmqvist et al. [1] found no change in the relative risk of MI in patients diagnosed recently and treated more intensely. However, there are other possible explanations for this lack of improvement, such as lack of adequate control of inflammation and possible detrimental effects of RA therapies on the risk of CVD. In that regard, further research is needed to determine the long-term effect of biologic therapies on cardiovascular outcomes as initial studies of subclinical cardiovascular measures show mixed and possibly transient effects [11]. However, several studies have reported improved cardiovascular outcomes following methotrexate therapy [12, 13] In addition, long-term or high-dose corticosteroid use adversely affects cardiovascular outcomes, but low doses use may not [14]. The diversity of the treatment regimes amongst patients with RA complicates the ability to unravel the effects of each treatment from the effects of a strategy to tightly control RA disease activity and inflammation on the risk of CVD. Figure 1 displays factors that may influence the risk of CVD amongst patients with RA and when they may occur. There is likely some increased risk of CVD amongst patients with RA because of genetic factors and shared aetiologies. An additional increase in risk because of RA disease and/or treatment–related factors and inflammation is also likely. However, the timing of start of this additional risk relative to the onset of RA symptoms is unknown, as indicated on the figure by the arrow along the x-axis indicating the onset of RA symptoms may occur at or after this additional risk begins. The shaded region on the figure depicts the portion of the increased risk of CVD which is potentially modifiable by controlling RA disease–related factors and inflammation. The proportion of the increased risk of CVD because of RA disease/treatment–related factors and inflammation (i.e. the size of the shaded region) is unknown. Which comes first: the onset of rheumatoid arthritis (RA) or the increased risk of cardiovascular disease (CVD)? The risk of CVD may increase before the onset of RA symptoms because of genetic susceptibilities and shared aetiologies. *The risk of CVD associated with RA disease related factors and inflammation may begin prior to the onset of RA symptoms. **The portion of CVD risk caused by RA disease/treatment–related factors (indicated by the shaded region) is unknown. In addition, Holmqvist et al. noted increased risk for MI of similar magnitude in both RF-positive and RF-negative patients. This finding contradicts several previous reports of lower CVD risk amongst patients with RF-negative RA [15–17]. Perhaps patients with RF-negative RA and mild disease activity were somehow not included in the Holmqvist study. Alternatively, because RF positivity is often associated with RA disease severity, the lack of association between RF positivity and the risk of CVD may indicate controlling disease activity in RA would have minimal impact on controlling the risk of CVD. In conclusion, the report by Holmqvist et al. shows increased risk of CVD early in the disease course of RA, in both RF-negative and RF-positive patients, and this increased risk is evident in patients diagnosed with RA in recent years when more aggressive treatment strategies were employed. This evidence underscores the need for vigilance concerning assessment of CVD risk amongst all patients with RA. At the time of RA diagnosis, traditional cardiovascular risk factors should be assessed and preventive measures should be initiated as indicated. This assessment should be performed in all patients with RA, not just those with positive RF or long-standing disease. Finally, additional research is needed to determine the effect of tight control of inflammation and RA disease activity on the risk of CVD amongst patients with RA. No conflict of interest was declared.