Various inflammatory rheumatic diseases (RDs) are associated with an increased risk of developing cardiovascular (CV) disease. Increased cardiovascular morbidity and mortality has been reported in inflammatory arthritis (including rheumatoid arthritis, psoriatic arthritis, gout, and spondyloarthritis) and connective tissue disease (including vasculitis, systemic lupus erythematosus, and systemic sclerosis [SSc]). A better understanding of the vascular biology of the atherosclerotic process may also help explain why so many of our patients with a chronic inflammatory disease are subject to an increased risk of atherosclerotic vascular disease. A large population-based study from the United Kingdom recently showed there is a particularly high risk of CV disease in patients with SSc.1 This is in line with earlier studies that show SSc is independently associated with an increased risk of atherosclerotic vascular disease. New insights in the field of CV medicine may help explain this association as a novel mechanism of acute arterial occlusion (superficial plaque erosion), and this may pertain to SSc in particular.

Traditionally, acute arterial events were thought to be a result of the rupture of a vulnerable atherosclerotic plaque. A gradually growing atherosclerotic plaque characterized by accumulating cholesterol in the arterial wall is shielded from the systemic circulation by an overlying fibrous cap. Concomitant, ongoing inflammation can compromise the integrity of this protective cover, for instance, by the overexpression of collagenases by immune cells. Ultimately, this fibrous cap can rupture, thereby exposing the lipid and necrotic core of the plaque to the arterial circulation, directly followed by acute thrombus formation. It has recently become clear that a newly characterized mechanism of an acute occlusive arterial event is now becoming increasingly prevalent—the superficial plaque erosion. In atherosclerotic plaque erosion, local flow disturbances and immune cell activation result in superficial denudation of the endothelial cell layer from the basement membrane, their subsequent death by apoptosis directly followed by thrombus formation.2,3 The pathophysiological mechanisms leading up to vulnerable plaque rupture are distinctively different from those causing plaque erosion. Patients with SSc appear to be particularly prone to the latter, taking into account the considerable overlap of central pathophysiological mechanisms.

First, endothelial-to-mesenchymal transition (EndMT) is thought to play a prominent role in atherosclerotic plaque erosion. In response to signals such as transforming growth factor β (TGF-β), vascular endothelial growth factor, or loss of fibroblast growth factor signaling, endothelial cells can transition into mesenchymal-like cells. Ultimately, this can cause endothelial cells to lose their binding to the basement membrane, resulting in desquamation and plaque erosion.3 Interestingly, EndMT has been associated with different SSc disease manifestations, including interstitial lung disease, pulmonary arterial hypertension (PAH), and skin fibrosis. In line with this, EndMT is considered a crucial mechanism linking endothelial dysfunction to SSc pathophysiology. The same endogenous signals in SSc that drive EndMT in skin or lung inflammation and fibrosis could simultaneously drive EndMT in the arterial wall underlying atherosclerotic plaque erosion.

Second, endothelial cell apoptosis is a central feature of plaque erosion.3 Similarly, enhanced apoptosis of endothelial cells is a pivotal part of SSc pathophysiology as well. Recent analyses of affected skin tissue of patients with early diffuse cutaneous SSc suggest activated cytotoxic T cells orchestrate endothelial cell apoptosis. This study also showed that a circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with SSc4; these could cause apoptosis of endothelial cells, not just in organ tissue affected by SSc but also in the arterial wall, promoting atherosclerotic plaque erosion.

Third, neutrophil extracellular traps (NETs) released by activated neutrophils play an important role in plaque erosion. NETs, for instance, contain pro-oxidant molecules, cytokines, and tissue factor, and can capture circulating platelets. This subsequently results in the formation of a platelet-rich thrombus typically observed in plaque erosion.3 Again, this may be particularly relevant in SSc. Polymorphonuclear neutrophils (PMN) from patients with SSc have been shown to generate more NETs compared to PMN from age- and sex-matched controls. Interestingly, excessive NET generation was more pronounced in patients with SSc with vascular complications (ischemic digital ulcers and PAH), was already present during the early stages of disease and appeared to be sustained over time in patients with SSc with vascular complications.5 This aberrant NET production as part of SSc pathophysiology could concurrently render patients with SSc particularly prone to developing atherosclerotic plaque erosion.

Fourth, even the thrombi covering an eroded plaque show distinctive differences from those covering a ruptured atherosclerotic plaque. A thrombus formed over an eroded plaque tends to be rich in platelets (referred to as a white thrombus), whereas thrombi overlying ruptured plaques tend to be richer in fibrin (referred to as a red thrombus).3 In vascular biology, platelets play a unique role at the crossroads of inflammation, endothelial function, atherosclerosis, and thrombus formation. Platelets are not only considered to play an active role in SSc pathophysiology but can also be detected in a persistent activated state in SSc. This may enable prompt formation of a white thrombus in response to endothelial injury or erosion in SSc.

In conclusion, evolving insights in the biology of atherogenesis have led to a newly characterized mechanism of acute arterial thrombosis in response to atherosclerotic vascular disease or superficial plaque erosion. The mechanism of plaque erosion has thus far yet to be addressed in the field of rheumatology. Considering so many patients with inflammatory RDs are subject to an increased risk of CV disease, it is crucial that evolving insights of this magnitude in the field of CV medicine are extrapolated to our patients as well. Further research as to whether superficial plaque erosion does indeed occur more often in patients with inflammatory RDs is therefore warranted, particularly in patients with SSc, considering the convergence of implicated pathways.