Although there are many examples of autoantibodies in disease-free individuals, they can be a preclinical phenomenon heralding future autoimmune rheumatic disease. They may be a marker for autoreactive B-cell activation and other inflammatory autoimmune processes. The increased prevalence of cardiovascular disease (CVD) in autoimmune rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus, and the increased risk of CVD in patients with rheumatic disease with autoantibodies, suggest that CVD may have autoimmune features. Autoantibodies might be risk markers for subclinical and clinical CVD development not only in patients with rheumatic diseases but in the general population as well.
Key points
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Preclinical rheumatic disease–related autoantibodies have been identified in stored samples before development of systemic lupus erythematosus and rheumatoid arthritis (RA).
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Autoreactive B cells can drive RA pathogenesis through generation of autoantibody-secreting plasma cells, presentation of autoantigens such as citrullinated peptides to T cells, production of proinflammatory cytokines, and formation of ectopic tertiary lymphoid structures, as are found in the RA synovium.
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It has been hypothesized that atherosclerosis might have autoimmune features because of the involvement of autoantigens and their autoantibodies in atherogenesis in both humans and animal models.
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Antiphospholipid antibodies, antinuclear antibodies, and RA–related autoantibodies have been associated with atherosclerosis in clinically active rheumatic diseases as well as in general population study samples.
Introduction
Preclinical autoimmunity, or the presence of autoantibodies before disease symptoms, has been well described for several autoimmune rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren syndrome, and antiphospholipid antibody syndrome (APS). In studies of preclinical autoantibodies before SLE development, Arbuckle and colleagues noted that autoantibodies less commonly associated with clinical sequelae of SLE such as antinuclear antibodies (ANA), anti-Ro, and antiphospholipid antibodies (APA) were present in the preclinical period more remote to clinical illness, whereas antibodies more specific for pathogenic features of SLE such as anti-Smith, antibodies against double-stranded DNA (dsDNA), and ribonucleoprotein (RNP) developed later, simultaneous to the onset of clinical features of SLE. Thus, benign autoimmunity was used to describe the earlier phase of autoantibody appearance during the preclinical period ( Fig. 1 ). Certainly, there are many examples of autoantibodies occurring in disease-free individuals: RA-related autoantibodies and ANA occur in increased number and titer with age-related loss of tolerance ; healthy relatives of individuals with autoimmune rheumatic diseases also have increased rates of autoantibody positivity. However, although ANA, rheumatoid factor, and APA may occur in the general population, individuals with such autoantibodies are also at increased risk for development of autoimmune rheumatic disease, with odds estimated as high as 10-fold to 30-fold.
Autoantibodies are markers for autoreactive B-cell activation, which can drive disease pathogenesis through a variety of mechanisms. Autoreactive B cells lead to the generation of autoantibody-secreting plasma cells, formation of immune complexes, presentation of autoantigens to T cells and costimulation, as well as the production of proinflammatory cytokines, chemokines, and lymphangiogenic growth factors. But when does benign become pathogenic autoimmunity during disease development? Early on, autoantigens activate self-reactive B cells, leading to the formation of short-lived plasma cells secreting autoantibodies. However, if self-reactive B cells enter germinal centers, they may undergo somatic hypermutation and affinity maturation of B-cell receptors, immunoglobulin class switching, generation of long-lived self-reactive B cells, and differentiation into long-lived plasma cells secreting high-affinity Fc receptor-binding autoantibodies. An example of such a transition is the formation of the ectopic tertiary lymphoid structures in the RA synovium, which clearly leads to the pathogenic autoimmune features of RA.
As described in detail elsewhere in this issue of Rheumatic Disease Clinics , the identification of preclinical autoimmunity before rheumatic disease development has led to substantial efforts to accurately describe autoimmune rheumatic disease pathogenesis such that individuals might be identified and targeted for primary prevention strategies, or secondary prevention strategies in the case of early disease features not yet meeting disease classification criteria. Recent data suggest that autoantibodies might be risk factors for development of cardiovascular disease (CVD) as well.
Introduction
Preclinical autoimmunity, or the presence of autoantibodies before disease symptoms, has been well described for several autoimmune rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren syndrome, and antiphospholipid antibody syndrome (APS). In studies of preclinical autoantibodies before SLE development, Arbuckle and colleagues noted that autoantibodies less commonly associated with clinical sequelae of SLE such as antinuclear antibodies (ANA), anti-Ro, and antiphospholipid antibodies (APA) were present in the preclinical period more remote to clinical illness, whereas antibodies more specific for pathogenic features of SLE such as anti-Smith, antibodies against double-stranded DNA (dsDNA), and ribonucleoprotein (RNP) developed later, simultaneous to the onset of clinical features of SLE. Thus, benign autoimmunity was used to describe the earlier phase of autoantibody appearance during the preclinical period ( Fig. 1 ). Certainly, there are many examples of autoantibodies occurring in disease-free individuals: RA-related autoantibodies and ANA occur in increased number and titer with age-related loss of tolerance ; healthy relatives of individuals with autoimmune rheumatic diseases also have increased rates of autoantibody positivity. However, although ANA, rheumatoid factor, and APA may occur in the general population, individuals with such autoantibodies are also at increased risk for development of autoimmune rheumatic disease, with odds estimated as high as 10-fold to 30-fold.
Autoantibodies are markers for autoreactive B-cell activation, which can drive disease pathogenesis through a variety of mechanisms. Autoreactive B cells lead to the generation of autoantibody-secreting plasma cells, formation of immune complexes, presentation of autoantigens to T cells and costimulation, as well as the production of proinflammatory cytokines, chemokines, and lymphangiogenic growth factors. But when does benign become pathogenic autoimmunity during disease development? Early on, autoantigens activate self-reactive B cells, leading to the formation of short-lived plasma cells secreting autoantibodies. However, if self-reactive B cells enter germinal centers, they may undergo somatic hypermutation and affinity maturation of B-cell receptors, immunoglobulin class switching, generation of long-lived self-reactive B cells, and differentiation into long-lived plasma cells secreting high-affinity Fc receptor-binding autoantibodies. An example of such a transition is the formation of the ectopic tertiary lymphoid structures in the RA synovium, which clearly leads to the pathogenic autoimmune features of RA.
As described in detail elsewhere in this issue of Rheumatic Disease Clinics , the identification of preclinical autoimmunity before rheumatic disease development has led to substantial efforts to accurately describe autoimmune rheumatic disease pathogenesis such that individuals might be identified and targeted for primary prevention strategies, or secondary prevention strategies in the case of early disease features not yet meeting disease classification criteria. Recent data suggest that autoantibodies might be risk factors for development of cardiovascular disease (CVD) as well.
Antiphospholipid antibodies, rheumatoid arthritis-related autoantibodies, and cardiovascular disease, as well as subclinical atherosclerosis, in patients with autoimmune rheumatic disease
Patients with RA have an increased risk for CVD of 1.5-fold to 2-fold, comparable with the risk in type II diabetes mellitus. Moreover, the presence of traditional risk factors does not fully account for this degree of excess risk. Therefore, it has been proposed that autoimmune-mediated inflammation may contribute to increased CVD risk in RA. RA-related autoantibody positivity has been associated with increased risk of CVD events among patients with RA. There is an increased prevalence of subclinical measures of atherosclerosis in RA, and antibodies to modified citrullinated vimentin and anticyclic citrullinated peptide antibodies (anti-CCP) have been correlated with carotid intima media thickness (IMT) in early RA.
CVD is a leading cause for mortality in SLE, and given that APA are present in greater abundance in SLE compared with the general population, they have been evaluated as potential risk factors for CVD in SLE. In a large US prospective cohort of patients with SLE evaluated for myocardial infarction (MI) and subclinical atherosclerosis, patients with history of positivity for the lupus anticoagulant had a higher prevalence of history of MI (22% vs 9%, P = .04). In a unique prospective study for hard clinical cardiovascular end points in 182 Swedish patients with SLE free from CVD at baseline, Gustafsson and colleagues found that presence of any anticardiolipin autoantibodies (aCL) or anti-β2 glycoprotein (anti-β2GPI) autoantibodies were strongly associated with an increased risk of first CVD events over a mean of 8.3 years (hazard ratio [HR] 4.9, 95% confidence interval [CI] 1.76, 17.72). In contrast, anti-Smith, anti-dsDNA, and RNP had lower point estimates for this association, but these did not reach statistical significance. In a follow-up of 208 patients with SLE in the same inclusion cohort over 12 years, presence of any APA was predictive of cardiovascular mortality (HR 2.8, 95% CI 1.1–1.7) and again, whereas specific anti-dsDNA antibodies were associated with noncardiovascular mortality, they were not associated with cardiovascular mortality. Moreover, levels of aCL and anti-β2GPI autoantibodies were also associated with myocardial perfusion defects detected by single-photon emission computed tomography, but not in the distribution of major coronary arteries, suggesting that APA may also cause small, undetected thrombi in the coronary microcirculation.
Previously, there was no known association in patients with SLE between APA and coronary artery calcification (CAC), a marker of overall atherosclerotic burden. However, in a small group of patients with SLE (N = 60), Plazak and colleagues recently reported an increased risk of CAC in patients with both increased aCL and anti-β2GPI IgG levels, and among 139 patients with SLE, Romero-Diaz and colleagues reported increased levels of aCL in those with CAC.
Antiphospholipid antibodies, antinuclear antibodies, and rheumatoid arthritis-related autoantibodies and cardiovascular disease, as well as subclinical atherosclerosis, in patients without autoimmune rheumatic disease
The increased prevalence of CVD in autoimmune rheumatic diseases such as RA and lupus, and the increased risk of CVD in patients with rheumatic disease with autoantibodies suggest that CVD may have autoimmune features. Studies identifying relationships between autoantibodies and cardiovascular outcomes in individuals without clinically active autoimmune diseases certainly support the role of autoimmunity in the pathogenesis of CVD. In 3 general population samples, RF positivity has been associated with ischemic heart disease. Tomasson and colleagues reported an increased risk of cardiovascular mortality in RF-positive patients followed prospectively over 23 years in their Icelandic Reykjavik population-based cohort, even after excluding participants with any joint symptoms (HR 1.60, 95% CI 1.08–2.37). Also, in a recent nested case-control study within a cohort of middle-aged healthy UK men followed for CVD, participants with anti-CCP2 positivity had more ischemic heart disease (odds ratio [OR] 4.23, 95% CI 1.22–14.61). We measured the association of RA-related autoantibodies with CAC, using data from a community-based sample of 6814 men and women enrolled in the MESA (Multi-Ethnic Study of Atherosclerosis) trial. Although we found that RA-related autoantibodies were associated with CAC in African American and white women, these data need to be verified in other general population cohorts without clinically active RA, and associations between RA-related autoantibodies and IMT need to be investigated.
Although there is a paucity of studies identifying clear-cut associations between specific ANA and cardiovascular outcomes in patients with SLE, one study evaluating patients without SLE presenting with chest pain found that patients with triple vessel coronary artery disease had higher odds of positive ANA (OR 11.67, 95% CI 3.91–17.82) compared with controls with negative angiograms. In addition, in a population-based cohort study of 7852 patients who had ANA testing, Liang and colleagues found that a positive ANA was associated with risk of MI, independent of the presence of SLE diagnosis (HR 1.29, 95% CI 1.03–1.61). Furthermore, there are numerous studies reporting associations between APA and cardiovascular outcomes in individuals without autoimmune rheumatic diseases. In particular, in several studies, APA have been found in the sera and plaques of individuals with clinical cardiovascular events. A few studies have reported positive correlations between APA and IMT, and in a case-control study of 50 male patients with acute MI, Dropinski and colleagues found APA level to be higher in MI cases, and APA level correlated with IMT as well. Although previous studies in individuals without SLE did not identify associations between APA and CAC, we did find associations when we tested the hypothesis that circulating APA are associated with subsequent subclinical atherosclerosis, measured as CAC in a cohort of community-based African American and white young adults followed prospectively for subclinical and clinical cardiovascular outcomes in the CARDIA (Coronary Artery Risk Development in Young Adults) study. After adjustment for traditional cardiovascular risk factors, APA were associated with subclinical atherosclerosis measured as CAC greater than 0 after 15 years of follow-up. IgG and IgA anti-β2GPI antibodies were associated with CAC greater than 0 measured after 15 years of follow-up (anti-β2GPI IgG: OR 6.4, 95% CI 2.4–16.8; IgA: OR 5.6, 95% CI 2.3–13.2). Anti-β2GPI IgM was marginally associated with CAC greater than 0 (IgM: OR 1.7, 95% CI 1.0–3.1), and aCL IgG were also associated with CAC greater than 0 (OR 5.1, 95% CI 1.4–18.6). Associations between rheumatic disease autoantibodies and subclinical and clinical atherosclerosis in individuals without rheumatic disease have led us to propose a possible model in which preclinical autoantibodies are not only risk factors for connective tissue disease development but also for subclinical and clinical CVD ( Fig. 2 ), and their association with CVD development might occur in parallel with, or even independent of the presence of autoimmune rheumatic diseases.
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