ReviewHow early is the atherosclerotic risk in rheumatoid arthritis?
Introduction
Rheumatoid arthritis (RA) is a prototypical chronic systemic inflammatory disease that can be reasonably considered an independent cardiovascular disease (CVD) risk factor, as well as diabetes mellitus (DM). Indeed, both cross-sectional and prospective studies demonstrated that incidence and prevalence of CVD in RA are increased to a degree comparable with that in type 2 DM and that this largely results from preclinical arterial wall atherosclerotic damage [1], [2], [3]. Of consequence, mortality rate for CVD, in particular for ischemic heart disease (IHD), is higher in RA patients than in the general population with an overall standardized mortality ratio ranging from 1.5 to 5.0 [4]. Both traditional risk factors than inflammatory and immune-mediated mechanisms are now recognized to act synergistically in determining the increased risk of subclinical atherosclerosis (ATS) and consequent CV events in RA [5]. In fact, an intriguing parallelism between immune-mediate mechanisms underlying RA synovial inflammation and ATS vascular damage has been well established [5].
The excess of CV mortality risk, however, has been widely recognized in patients with established long-lasting disease. Nevertheless, the relevance of prompt RA diagnosis and rapid suppression of inflammation in patients presenting with recent onset inflammatory polyarthritis has been emphasized in recent years [6]. Several reasons justify the importance of prompt disease diagnosis and treatment in an early phase from symptom onset, generally within 1 year. In fact, there is some evidence that the excess of CVD risk, mainly for IHD, seems to precede the ACR criteria-based diagnosis of RA and to begin early in the disease course, being apparent within the first 5 years after symptoms onset [7]. Moreover, it appears to be higher in young (< 55 years old) seropositive patients and independent of increased incidence of traditional risk factors [8], [9]. Male sex, higher age at diagnosis, disability, rheumatoid factor (RF) and comorbidity have been described as significant predictors of mortality at 10 years in a cohort of early RA [10]. The relevance of such findings is further strengthened by the observation that inflammatory and immune-mediated processes characterizing disease pathogenesis may predate clinical disease presentation or may be detected at the time of diagnosis [11]. Thus, considering the pivotal role played by inflammatory and disease-related immunologic factors in inducing subclinical ATS in RA [5], [12], [13], it is intriguing to postulate that exposure to these factors before disease clinical presentation may trigger and accelerate the atherosclerotic process in subjects at increased risk of RA development [14].
Purpose of the present review is to analyze the possible pathogenic links between traditional and disease-related CV risk factors characterizing disease before clinical manifestation onset and precocious atherosclerotic damage in patients with early RA.
Section snippets
Genetic factors
Genetic background has been recently recognized as an important factor in determining disease development and persistence, accounting for up to 50%–60% of disease susceptibility. The strongest genetic susceptibility effects are conferred by the HLA-DRB1 locus on chromosome 6 and by the protein tyrosine phosphatase 22 (PTPN22) gene on chromosome 1p13. Moreover, it is now recognized that particular genes, interacting with certain environmental factors such as smoking, play an important role in
Subclinical atherosclerosis
Endothelial dysfunction and high-resolution ultrasonographic measurement of carotid IMT are well established surrogate markers of subclinical ATS in RA able to identify two different stages of pathogenic mechanisms leading to atherosclerotic damage. Endothelial dysfunction, indeed, is considered the earliest, but reversible, stage of atherogenesis and multiple elements, including hemodynamic, traditional and inflammatory factors, have been associated with impaired endothelial function in RA [59]
Treatment
In RA, beneficial and cardioprotective effects of conventional disease-modifying anti-rheumatic drugs (DMARDs) and biologic agents have been reported for a number of CV risk conditions, including lipid profile, metabolic syndrome and surrogate measures of subclinical ATS, in particular in patients responding to anti-rheumatic therapy [69], [70], [71]. Treatment duration is an important factor which must be considered when the effect of anti-inflammatory therapy on vascular function is
Conclusion
In summary, recent evidence seems to suggest that in subjects with RA accelerated ATS may occur early in disease process and a pathogenic model could be hypothesized (Fig. 1). Genetic background has been demonstrated to be a relevant pathogenic factor not only in disease susceptibility but also in increasing preclinical atherosclerotic risk in this population. The demonstration that specific CV risk factors and inflammatory and immune-mediated mechanisms associated with atherosclerotic damage
Take-home messages
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Early RA patients are at increased risk of subclinical ATS just at disease onset.
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Multiple mechanisms contribute to determine precocious atherosclerotic damage in early RA.
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Traditional and disease-related ATS risk factors should be identified in the preclinical phase of the disease.
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Multidisciplinary algorithm for CVD risk management needs to be developed in patients with RA at disease onset.
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Appropriate CV risk management and rapid pharmacological therapy introduction should be considered,
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