Inflammation plays a pivotal role in the pathogenesis of atherosclerotic vascular damage and the causal relationship between chronic inflammation an atherosclerotic cardiovascular (CV) disease has been widely explored in the last years. It is now accepted that atherosclerotic endothelial damage is the result of a complex and still unknown interplay between multiple pathogenic players, including traditional CV risk factors, immune-mediated mechanisms, and inflammatory triggers (1). Early in the course of atherosclerosis, activation of vascular smooth muscle cells and upregulation of pro-inflammatory mediators, including cytokines, vascular endothelial growth factors, and leukocyte adhesion molecules, represent the first step of atherosclerotic vascular damage. In this setting, it is intriguing to note that the same inflammatory markers involved in the pathogenesis of arterial wall atherosclerotic damage have been demonstrated to independently predict CV disease events (2). Interleukin (IL)-6 and high-sensitive C reactive protein (hsCRP) have been shown to be independent predictors of CV disease and ongoing research is directed to test the hypothesis that targeting chronic inflammation could prevent atherosclerosis progression and reduce CV events (3).

Of consequence, the evidence that the same pro-inflammatory molecules driving atherosclerosis play an essential role in the pathogenesis of systemic autoimmune rheumatic diseases (ARDs) discloses intriguing scenarios. Increased rate of CV events as well as enhanced prevalence of subclinical atherosclerosis, documented by imaging and vascular function instrumental methods are well-recognized in patients with ARDs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), and Sjögren's syndrome (SS) (4). In these patients, accelerated subclinical atherosclerosis has been associated not only to increased prevalence of classical CV risk factors, which induce atherosclerotic arterial wall damage enhancing the risk of CV disease (5, 6), but also to chronic inflammatory burden (7). Decisive evidence supports that, in particular in SLE and RA patients, long-standing systemic inflammation and oxidative stress contribute to endothelial dysfunction, organic damage of arterial wall, plaque formation and destabilization with subsequent higher risk of CV events (8, 9). Similarities of chronic inflammatory mechanisms and immune dysfunction processes between CV disease and ARDs further support this hypothesis and, although partially controlled by endogenous anti-inflammatory mechanisms, this chronic, low-grade activation and dysfunction of vascular endothelium is likely to induce and foster accelerated atherosclerosis and CV disease in these patients (8, 9). On the other hand, the contribution of chronic inflammation to precocious atherosclerosis in patients with SSc and SS is less clear, mostly due to the different pathogenesis and systemic features of these diseases. Microvascular disease is a pathognomonic hallmark of SSc and different factors, including dysregulation of vascular tone, defective angiogenesis, endothelial injury/activation elicited by the activation of innate and adaptive immune response and functional defects of progenitor endothelial cells, have been advocated as main pathogenic mechanisms underlying endothelial damage in the disease (10). Similarly, in SS, the pathogenesis of endothelial damage and accelerated atherosclerosis is still unclear (11). Indeed, SS is a chronic immune-mediated inflammatory disease characterized by glandular and systemic manifestations sharing many clinical and autoimmune similarities with RA and SLE (12). However, unlike RA and SLE, the disease is characterized by a low-grade systemic inflammation and by a slow and benign evolution, often not requiring immunosuppressive therapies or high dose corticosteroid treatment (13, 14). SS, therefore, represents an interesting model to analyze the direct effect of autoimmunity and chronic inflammation on atherosclerosis without therapy interference. In this setting, there is evidence that functional and organic subclinical atherosclerosis, characterized by higher prevalence of endothelial dysfunction, aortic stiffness, increased arterial wall intima-media thickness, left ventricular dysfunction and reduced coronary flow reserve, can been detected in young SS patients in comparison to healthy age-matched controls (11). Moreover, there is also evidence that some traditional CV risk factors are more prevalent in these patients in comparison to general population and, more importantly, some of these factors may exert a direct role in determining higher prevalence of subclinical atherosclerosis and higher risk of CV events, as recently observed (15–17). However, the contribution of autoimmune mechanisms and chronic inflammation to subclinical atherosclerosis in SS is still uncertain and studies are ongoing. Thus, this review aims to address the role of inflammation in contributing to increased risk of atherosclerosis in SS patients and the relevance of specific inflammatory biomarkers in the determination of CV risk in these patients.

Inflammatory infiltration of exocrine glandular parenchyma around the ductal epithelium represents the hallmark of the disease and glandular epithelial cells are key regulators of local immune response. The chronic inflammation observed in SS is the result of a complex and still unexplored altered balance in local and systemic production of specific cytokines, which regulate the heterogeneity and cellular composition of inflammatory infiltrate (14). The glandular infiltrate is usually organized in focal aggregates and is mainly characterized by T and B lymphocytes and, to a lesser extent, by macrophages, plasmacytoid dendritic cells and natural-killer cells (18). Phenotype and severity of inflammatory cell infiltration change according to disease stage and correlate to systemic extra-glandular manifestations suggesting that local inflammatory and immune response is linked to systemic features of the disease (18). Several pathways mediate inflammatory damage in SS pathogenesis.

Several ex-vivo and in vitro studies in the last years explored and analyzed cellular and molecular mechanisms by which chronic inflammation and inflammatory molecules drive atherosclerosis, especially in systemic ARDs (1, 28). In this setting, endothelial cells represent the key players in the initiation of atherosclerotic damage and endothelial activation triggers upregulation of numerous cell adhesion molecules such as ICAM-1, VCAM-1, and selectin, which in turn, mediate interaction and recruitment of inflammatory cells within vessel wall. Pro-inflammatory cytokines, such as monocyte chemoattractant protein-1 (MCP-1) and IL-8, enhance this process by increasing monocyte and macrophage migration under endothelial layer. Subsequently, infiltration of damaged arterial wall by monocyte/macrophage cells promotes the uptake, by macrophage TLRs, of oxidized low-density lipoprotein (ox-LDL), thus leading to lipid accumulation and foam cell formation (1, 28). In this setting, it is has been observed that type I IFNs also contribute to atherosclerotic inflammatory damage, thus highlighting an interesting shared inflammatory mechanism SS and atherosclerosis pathogenesis. Indeed, in mouse models of atherosclerosis, IFNβ enhances endothelial cell-macrophage interaction favoring both leukocyte migration in atherosclerotic site through the induction of CCL5-CCR5 axis and plaque destabilization (29). Moreover, as observed in SS, pDCs, which may be detected in atherosclerotic lesions, represent major source of type I IFNs. Self-apoptotic debris released by necrotic cells or neutrophil-derived proteins, known as neutrophil extracellular traps (NETs), have been demonstrated to stimulate pDCs in the vessel wall inducing type I IFN response and atherogenesis (30, 31). In particular, NETs and material release by apoptotic and necrotic cells, by TLR7/TLR9 binding, induce a strong IFNα response which may prime neutrophils to stimulate NET formation, triggering a positive feedback amplification (31) (Figure 1). Of interest, increased expression of TLRs, which have been implicated in the pathogenesis of ARDs, has been detected on the surface of endothelial cells, thus suggesting an intriguingly link between atherosclerotic endothelial damage and autoimmune disease pathogenesis (9).

Moreover, macrophage activation is associated with release of other inflammatory mediators and reactive oxygen species to amplify inflammatory reaction. It has been demonstrated that oxidative stress has an important role in the atherosclerotic process by promoting the oxidation of LDL and, in this context, there is evidence that ox-LDL proteins are involved in all atherosclerosis steps, starting from recruitment of monocytes within arterial wall to foam cell and plaque formation and, possibly, plaque rupture (32). Finally, immune dysregulation, through the involvement of T lymphocytes, further enhances this process. Th1 cells, in particular, secrete several cytokines, such as IFNγ, IL-2, IL-12, and IL-18 and TNFα, which are known to promote and accelerate atherosclerosis, thus contributing to vascular endothelial damage and plaque progression (1, 28).

In this setting, cytokines are directly involved in the differentiation from monocytes to macrophages in the arterial wall and in driving Th cell polarization toward Th1 and Th2 phenotypes (28). Interestingly, pro-inflammatory cytokines, in particular TNFα, IL-6, and IL-18, and adhesion molecules involved in the atherosclerotic process have been associated with endothelial dysfunction, carotid atherosclerosis, CV morbidity and risk of CV events and mortality in patients with systemic ARDs (9). Recently, the role of Th17 cells in driving atherosclerosis deserved considerable attention. In fact, IL-17 has been demonstrated to exert a pro-atherogenic effect by promoting chemokine-dependent infiltration of monocytes and inflammatory cells within the arterial wall, by upregulating the expression of adhesion molecules, including ICAM-1 and E-selectin, and by induction of pro-inflammatory cytokine, such as TNFα and IL-6, involved in atherosclerotic damage (33). In combination with IFNγ, IL-17 reduces the number of smooth muscle cells, increases collagen production and, therefore, favors fibrosis development, thus leading to plaque instability (33). Finally, Th17 cells can also induce the production of IL-21 and IL-22, pro-inflammatory cytokines involved in macrophage accumulation in the arterial wall as well as T lymphocyte activation.

In addition, pro-inflammatory cytokines may induce atherosclerosis by acting on some traditional CV risk factors. Dyslipidemia is directly linked to systemic inflammation and some cytokines as TNFα and IL-6 have been shown to induce a pro-atherogenic profile and insulin resistance in patients with ARDs (9). Chronic inflammation leads to oxidative changes that alter HDL structure, thus impairing the anti-inflammatory and anti-oxidant effect of HDL proteins (9).

Taken together, these data suggest that pro-inflammatory cytokines and systemic inflammation contribute to all stages of atherosclerosis starting from activation of endothelial layer and recruitment of inflammatory cells within arterial layer to monocyte differentiation and foam cell formation. At later stages of atherosclerosis, these molecules promote apoptosis of arterial smooth muscle cells, matrix degradation and fibrosis with subsequent destabilization and rupture of atherosclerotic plaques. In this intriguing scenario, the evidence that circulating biomarkers of inflammation predict future CV events in patients with ARDs as well as in healthy subjects further reinforce the strict interplay between chronic inflammation and atherosclerosis. Among measurable inflammatory molecules, CRP represents the gold standard biomarker of chronic inflammation with both systemic and local effects and is employed as useful tool in the prediction of CV risk. Several lines of evidence support that CRP, measured by hsCRP, is a strong predictor of future CV events, including stroke, myocardial infarction and sudden death from cardiac causes, in the general population independently of classic CV risk factors (2). Experimental studies demonstrated that CRP is detectable in the vascular intima of atherosclerotic lesions where drives all stages of atherosclerosis (34). In particular, CRP enhances LDL uptake by macrophages and induces foam cell formation. Moreover, CRP contributes directly to thrombosis by inducing the production of pro-coagulant tissue factors with activation of thrombosis at site of inflammation, increases IL-12 production by macrophages, with subsequent induction of IFNγ and ThCD4+ cell differentiation, and triggers the expression and activity of plasminogen activator inhibitor-1, thus leading to atherogenesis through the decrease of fibrinolysis activity. Finally, CRP contribute to plaque neovascularization and instability through increased production of metalloproteinases (34). In this setting, IL-6 represents an adjunctive candidate biomarker for predicting CV morbidity and mortality through its direct induction of CRP hepatic synthesis. Indeed, IL-6 has been linked to atherosclerosis and CV disease in the setting of ARDs as well as in the general population. In particular, IL-6 induces endothelial dysfunction, stimulates the formation of foam cells, reduces the production of HDL-cholesterol and has been associated with cerebrovascular events and peripheral atherosclerotic disease (1). In recent years, interesting studies explored the role of IL-1 signal pathway in the progression of atherosclerosis due to its direct effect on the synthesis of different inflammatory cytokines, including IL-6 and CRP. A direct demonstration of IL-1β, the circulating form of IL-1, as biomarker of atherosclerotic risk is currently lacking due to technical problems in plasma cytokine measurement. However, recent studies demonstrated that IL-1β and IL-18 are activated by caspase-1 in the setting of Nod-like receptor family protein 3 (NLRP3) inflammasome (1, 9). Enhanced expression of NLRP3 inflammasome has been depicted in carotid atherosclerotic plaques and is associated with plaque vulnerability. Moreover, cholesterol stored in macrophages induces IL-1β production by an inflammasome-mediated pathway, thereby suggesting a potential link between cholesterol deposition within arterial wall and macrophage/monocyte promotion of local atherosclerotic progression (Figure 2) (35).

In conclusion, the contribution of inflammation to the pathophysiology of atherosclerosis is complex and not still completely investigated. Undoubtedly, the evidence that inflammatory systemic ARDs, usually characterized by chronically elevated levels of pro-inflammatory cytokines, are associated with an increased risk of CV disease strongly links inflammation to the complex pathogenic pathways contributing to atherosclerotic arterial damage. Moreover, the demonstration that modulation of inflammatory response in patients with systemic ARDs may reduce CV risk and incidence of CV events further supports the inflammatory hypothesis as relevant player, in association with other factors, in the induction and perpetuation of atherosclerotic damage (1). In this setting, multiple pathways have been identified as potential therapeutic targets for the prevention and treatment of CV disease. Recently, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) trial demonstrated that administration of canakinumab, an inhibitor of IL-1β activity, is associated with a significant reduction of recurrent CV events in patients with previous myocardial infarction and persistently elevated levels of hsCRP further supporting the hypothesis that controlling chronic inflammation is important for the prevention of recurrent CV events in the general population (1).

As widely demonstrated in RA and SLE patients, recent evidence now supports that SS patients are characterized, in comparison to general population, by nearly one and a half-fold increased risk of both CVD and cerebrovascular events early during the course of the disease (16, 17). This encouraged to perform a number of investigations aimed to understand mechanisms underpinning this enhanced risk.

First of all, the disease itself emerged as predictor of subclinical atherosclerosis independently by other CV risk factors (36). In addition, increasing evidence suggests that some traditional CV risk factors, namely hypertension, dyslipidaemia and metabolic syndrome, are more prevalent in SS in comparison to age and sex-matched general population and that these factors may exert a role in determining both higher prevalence of subclinical atherosclerotic damage and increased risk of CV events (5, 6, 15). However, how and at what extent these classic CV risk factors interact with disease-specific immune and inflammatory features is still unclear.

The markers of endothelial activation and damage and of chronic inflammation investigated until now failed to result predictors of subclinical atherosclerosis or to be associated with increased risk of CV events in SS patients. This may suggest that other mechanisms are implicated with increased prevalence of subclinical atherosclerosis in SS or that these biomarkers exert a different mechanism in the pathogenesis of endothelial damage and in the induction of atherosclerosis. Surely, the relationship between the disease itself and inflammatory and immune dysfunction factors is quite complex and still to be clarified. Disease activity measured by EULAR SS disease activity index did not correlate with subclinical atherosclerotic damage, probably due to the low disease activity index frequently detected in these patients (39, 48). However, patients with systemic extra-glandular involvement, including central nervous system, appear to be characterized by higher risk of CV events and, on the other hand, patients with more concomitant traditional CV risk factors present higher prevalence of extra-glandular manifestations, in particular liver and central nervous system involvement, in comparison to those without traditional risk factors (16, 44). Actually, chronic damage more than disease activity seems to be associated with higher prevalence of aortic stiffness in SS patients independently by Framingham score (48). As already stated, SS is usually characterized by a benign course with long periods of quiescence. Of consequence, a single measurement of disease activity could not reflect cumulative damage of inflammation. On the other hand, chronic damage may characterize patients with more severe disease over time, often requiring immunosuppressive therapies and higher corticosteroid doses. In this context, it is interesting to note that corticosteroid treatment has been associated with higher risk of CV events in an Italian SS cohort (16).

Taken together, these data suggest that classic CV traditional risk factors and immune system dysregulation exert a central role in the pathogenesis of atherosclerosis in SS patients even though the mechanisms by which they interplay and act need to be further clarified. Indeed, a peculiar poorer immunologic profile, with lower frequency of anti-SSA/SSB antibodies, leukopenia and hypergammaglobulinaemia, seems to identify patients with higher number of traditional CV risk factors, such as hypercholesterolemia (16, 37, 59, 60). On the other hand, a disease phenotype characterized by systemic extra-glandular involvement, presence of organic damage related to chronic active disease and disease- specific immunologic profile should be considered at higher risk to develop CV disease and, of consequence, more aggressively treated to prevent this risk. In this context, research should be addressed to better clarify the contribution of inflammation to atherosclerosis development in SS. As mentioned above, CRP serum concentrations in SS are usually similar to healthy controls and, of more importance, do not appear to be correlated to an increased prevalence of subclinical organic atherosclerotic artery wall damage, except for aortic stiffness. Among other markers of inflammation detected at higher levels in SS patients, only calprotectin has been associated with increased risk of early atherosclerosis, suggesting that future research should be specifically addressed to better investigate the contribution of these molecules to atherosclerotic damage in SS. According to actual knowledge, a possible model of arterial wall atherosclerotic damage in SS may involve the combined action of endothelial layer chronic damage and sub-endothelial infiltration of some inflammatory molecules possibly driving specific pathways within vessel intima (Figure 3).

In conclusion, we believe that addressing interaction between chronic inflammation, immune system dysregulation, CV disease, and other comorbidities in patients with SS has to be acknowledged and directly targeted to improve CV prevention. In the future, better understanding of these specific pathways contributing to atherosclerotic damage in SS patients may lead to the identification and optimization of personalized targeted therapies to be employed in these patients.

EB designed and wrote the whole manuscript and prepared the Table. EB, GC, and RG designed the Figure. All Authors revised and approved the manuscript. RG revised and approved the final manuscript draft.