Cardiovascular disease risk in rheumatoid arthritis: Progress, debate, and opportunity

Introduction Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with a substantially increased risk of cardiovascular disease (CVD), leading to reduced lifespan, diminished quality of life, and increased health care costs. Much progress has been made in understanding the mechanisms and impact of this public health problem over the past decade, and strong evidence exists in key areas, including the estimation of the contribution of RA to cardiovascular mortality and identifying a link between methotrexate use and lower CVD mortality. However, there remain key areas of debate. Recently, there has been a veritable explosion of research into the link between RA and CVD. A Medline search of the combined terms “CVD” and “RA” returns 147 articles and 38 reviews published in just the past year, and a staggering 868 articles and 204 reviews over the past 5 years. However, only within the last 2 decades has the recognition of CVD as a major contributor to mortality in RA been appreciated, leading to a reduction in lifespan of a decade or more in some cases (1,2). Beyond mortality, the impact of CVD on quality of life (3), combined with the associated increase in health care costs (4), render CVD in RA a major public health problem. Addressing any public health problem involves several key steps, including measuring the problem’s magnitude, identifying susceptible subgroups, isolating mechanistic determinants, and testing the efficacy and effectiveness of interventions. The body of literature addressing these steps varies in size and quality, resulting in an incomplete assessment of the breadth of the problem. For example, while multiple studies across diverse populations have established a strong base of support for RA as a risk factor for higher rates of hospitalized myocardial infarction (MI) and CVD mortality, the volume and quality of evidence is lower for end points that are either difficult to define clinically or lack reliability when ascertained from administrative data sources (e.g., heart failure) and for estimates of risk among subgroups of patients with RA (i.e., those characterized by disease features, disease activity, or severity). There is even less evidence regarding the isolation of mechanistic determinants, and importantly, no trials have been published to demonstrate that any particular intervention can reduce CVD risk in RA. The latter is urgently needed, as clinicians caring for RA patients are currently required to guess at optimal management by applying untested results from observational studies or extrapolating from non-RA populations. While these deficiencies in progress are considerable, their recognition allows for the development of a focused research agenda. Well-written reviews (5,6) on the topic of CVD risk in RA have been published. Rather than reiterating the content of these, we sought to frame CVD in RA in the context of its public health impact. First, while it is not possible within the confines of this review to provide a systematic synthesis of all of the relevant literature, we have summarized several key studies for the aspects of CVD in RA in which relatively abundant or high-quality evidence is available. Second, we explore key areas of debate of CVD epidemiology, pathogenesis, and treatment/prevention for which evidence is lacking, with a special emphasis on the research agenda required to address these controversies.