To this end, epidemiological evidence in favor of psoriasis being associated with cardiovascular comorbidity and potentially functioning as an independent cardiovascular risk factor has been summarized. As genetic overlap cannot satisfyingly explain the excess cardiovascular risk of patients with severe psoriasis, mechanistic studies are needed to further clarify the link.

Often, animal models are a good starting point to unravel pathogenetic mechanisms. With regard to psoriasis, older models often highlighted the role of the adaptive immune system (57), while novel approaches such as mannan-induced psoriasis shed more light on the crucial role of the innate immune system (58). Few studies have been performed to analyze the link between psoriasis and its cardiovascular comorbidity. One such approach takes advantage of the capacity of the TLR7 agonist imiquimod to induce a psoriasis-like inflammation in murine skin. Jin et al. succeeded in inducing a state of systemic inflammation through topical application of imiquimod onto interleukin-10-deficient mice, but noticed a decrease of body weight in these mice, while psoriasis patients show a trend toward obesity (59). Shibata et al. studied imiquimod-induced psoriasiform inflammation in mice deficient of adiponectin, an anti-inflammatory adipokine, and found a more severe phenotype in these knockout mice. Furthermore, intraperitoneal injections of adiponectin had a therapeutic effect in adiponectin knockout mice (60). While this study explored an indirect link between psoriasis and cardiovascular disease via metabolic factors, the only direct link the author is aware of comes from a study in the type-II collagen-specific antibody-induced psoriatic arthritis model. Using this model, Sherlock et al. demonstrated that IL-23 drives inflammation in the aortic root through activation of CD3⁺CD4⁻CD8⁻ T-lymphocytes (61).

Atherosclerosis as a key process in cardiovascular diseases has long been recognized as an inflammation-driven phenomenon (62, 63). This is also true for psoriasis (64, 65). The cardiologist Späh was among the first who discussed a potentially common inflammatory pathway and the idea of an integrated treatment approach (66). He stressed altered endothelial function and subsequent recruitment of leukocytes, primarily T-lymphocytes, to developing lesions as a shared early step in the process of plaque formation in atherosclerosis and psoriasis. Lymphocyte extravasation has indeed been studied in detail with the intention to develop targeted therapies for psoriasis, but to date, none of the potential candidates was found to be sufficiently effective to validate development into a marketed drug (67, 68). Meanwhile, many more shared mechanisms of atherosclerosis and psoriasis have been studied in detail.

Elaborating on the observations described above, a role namely for T-helper-1 lymphocytes (TH1 lymphocytes) has been established in atherosclerosis as well as psoriasis (Table 2). Although TH1 as well as TH2 lymphocyte responses can contribute to atherosclerosis, several lines of evidence suggest a predominant role of TH1 lymphocytes. These include the TH1 phenotype and function of most T-cell clones derived from atherosclerotic plaques as well as immunohistochemical studies on such plaques (69–71). Subsequently, high circulating levels of TH17 lymphocytes and IL-17 in patients with acute coronary syndrome, a positive correlation of IL-17 with levels of high-sensitivity C-reactive protein and IL-6 (predicting an increased risk of myocardial infarction) in those patients, and the observation that IL-17 inhibition in mice significantly reduces the size of atherosclerotic plaques, were all interpreted as indicators for a role of TH17 lymphocytes in atherosclerosis (72–74). Similarly, psoriasis was initially thought to be a prototypical TH1 lymphocyte-mediated disease, with these cells activating macrophages, neutrophils and CD8⁺ cytotoxic lymphocytes (75). Then, the role of TH17 lymphocytes was stressed in the light of clinical studies documenting the high clinical efficacy of therapies targeting the IL-17 pathway (76).

While the role of the adaptive immune system in the pathogenesis of psoriasis has been thoroughly investigated ever since the accidental observation of the therapeutic efficacy of cyclosporine A in 1979 (77), interest in the important role of the innate immune system has only recently experienced a renaissance (Table 2). Evidence for the contribution of neutrophils, which are predominant in pustular forms, but readily detectable also in chronic plaque type psoriasis, where they form the so-called Munro’s abscesses within the epidermis, comes from in vivo studies as well as organotypic 3D models and has recently been reviewed elsewhere (78). Further supporting the role of neutrophils is the clinical observation by Reich et al., who reported that psoriasis treatment with the anti-IL17A antibody secukinumab resulted in the near total elimination of intraepidermal IL-17-positive neutrophils as an early therapeutic effect (79). Neutrophils are equally important in atherosclerosis, as they interact with damaged endothelium, augment leukocyte recruitment via secretion of chemotactic mediators, and promote the development of foam cells, a macrophage subset driving atherosclerosis (80). Neutrophil localization to developing atherosclerotic plaques has been demonstrated in mouse models (81, 82) and human atherosclerotic lesions (83); their presence in occlusive thrombi and culprit lesions of acute coronary syndrome patients suggests a role in atherosclerotic progression (84).

As for neutrophils, involvement of monocytes and macrophages has readily been demonstrated in both diseases (Table 2). These are regularly detectable in psoriatic lesions (85). Using a mouse model where the psoriatic phenotype is induced by topical application of the immunomodulator imiquimod, Costa et al. demonstrated that induction of the phenotype depends exclusively on hematopoietic cells. Using conditional knockout mouse strains, the active contribution of monocytes and macrophages on disease propagation and exacerbation was shown (86). With regard to atherosclerosis, Tabas and Lichtman recently reviewed how macrophages can be programmed for functions on a spectrum from inflammatory and host defense to resolution and repair in atherosclerotic plaques (87). In general, inflammatory macrophages carry out processes that promote atherosclerosis progression, including plaque necrosis and thinning of a protective fibrous cap. By contrast, resolving macrophages carry out functions that can suppress plaque progression and promote plaque regression, including clearing dead cells and secreting collagen that can form a protective scar over the lesion (88).

Besides these vigorously studied cells of the adaptive immune system, platelets seem to also actively contribute to atherosclerosis and psoriasis (Table 2). Platelets are widely known to have prominent functions in hemostasis and thrombosis, but their involvement in immune and inflammatory processes is now more and more recognized (89). Their potential to influence such process is not surprising, given their capacity to release a plethora of mediators and to interact with numerous cells and tissues through a variety of adhesion molecules. In psoriasis, platelet activation can be used to monitor disease activity through quantification of platelet activation markers in the patients’ blood (90). Mechanistically, it is thought that activated platelets facilitate leukocyte extravasation (91). Similar effects link platelets to atherosclerosis (92, 93). The clinically relevant role of platelets in this context is underlined by the success of platelet inhibitory drugs in treating and preventing acute arterial thromboembolic events (94).

In recent years, a factor attracting particular attention in the context of psoriatic as well as atherosclerotic inflammation is IL-17A. Its role as a major driver of psoriatic inflammation is now well accepted and underlined by the numerous lines of evidence, including the development of a psoriatic phenotype in mice overexpressing IL-17A in the epidermis (95), or the high efficacy of IL-17A-blocking biologics in the treatment of psoriasis (96). By contrast, deciphering the exact role of IL-17A in atherosclerosis remains a challenging task (Table 2). Numerous studies documented pro-atherogenic effects. For example, in a hypercholesterolemic animal model, IL-17A inhibition reduced atheroma area and stenosis. At the molecular level, expression of the chemokine CCL5 (CC chemokine ligand 5), the cytokines IL-6 and TNF-α, several adhesion molecules including vascular cell adhesion molecule 1, and the pro-thrombotic molecule TF was reduced (74). Complementary experiments were conducted in murine models, where addition of exogenous IL-17A-stimulated pathological changes associated with increased plaque instability, while IL-17A inhibition resulted in regression of atherosclerosis (97–99). Ex vivo studies on human plaque fragments showed that exposure to IL-17A induced pro-inflammatory, pro-thrombotic, plaque destabilizing, and cell-attracting effects (100). On the other hand, there is also some evidence suggesting that IL-17A may have anti-atherosclerotic effects, as another mouse model characterized by increased IL-17A expression showed significantly smaller atherosclerotic lesions. In the same publication, an association between IL-17A expression and plaque stability in human carotid artery plaques was reported (101). Moreover, a study from Simon et al. on almost 1,000 patients with acute myocardial infarction demonstrated that low serum levels of IL-17A are associated with a higher risk for major cardiovascular events (102). Overall, many experts lean toward the concept of IL-17A being primarily pro-atherogenic, although some uncertainty persists.

Thus, over the last decade, multiple shared pathogenetic mechanisms have been identified in psoriatic and atherosclerotic plaque formation. These similarities do not, however, explain why psoriasis might actually represent an independent cardiovascular risk factor, as suggested by the majority of epidemiologic studies. Of major importance in this regard was the notion that psoriasis cannot be regarded as isolated cutaneous inflammation, but rather represents a chronic systemic inflammatory disease. To this end, several groups have identified biomarkers of inflammation in the blood of psoriasis patients which correlate with psoriasis severity, such as C-reactive protein (103), erythrocyte sedimentation rate (104), and the platelet activation marker P-selectin (90). Documentation of vascular inflammation through (18)F-fluorodeoxyglucose positron emission tomography computed tomography (PET-CT) in psoriasis patients, pioneered by Mehta and co-workers, points into the same direction (4). More recently, the group demonstrated that psoriasis severity associates with aortic vascular inflammation detected by that method (93), suggesting that psoriatic inflammation affects blood vessels and induces inflammation in the vessel walls. Studies in mouse models confirm that chronic skin-specific inflammation can indeed induce vascular inflammation (94).

The pathogenetic link between psoriasis and cardiovascular comorbidity is likely provided through insulin resistance and endothelial dysfunction, as these are known drivers for atherosclerosis (105). Insulin resistance is typically defined as decreased sensitivity to metabolic actions of insulin that promote glucose disposal. This is not only an important feature of diabetes mellitus but also a prominent component of cardiovascular disorders, which are characterized by endothelial dysfunction (106). Conversely, endothelial dysfunction is also present in diabetes mellitus (107). In addition to its essential metabolic actions, insulin has important vascular actions that involve stimulation of the production of nitric oxide from endothelium, leading to vasodilation (Figure 1A). This effect has metabolic consequences, too, as increased blood flow ultimately leads to augmented glucose disposal in skeletal muscle (108). On the other hand, insulin signaling in endothelial cells regulates secretion of the vasoconstricting factor endothelin-1. Inflammation shifts this equilibrium as it induces insulin resistance via cytokines, which alter insulin signaling in endothelial cells, ultimately reducing the production of vasodilating nitric oxide and inducing endothelial dysfunction (109) (Figure 1B). Noteworthy, TNF-α, a central cytokine in the pathogenesis of many chronic inflammatory diseases including psoriasis, is a major insulin antagonist (110).

The concept of the “psoriatic march” provides a framework to explain how psoriatic inflammation drives cardiovascular comorbidity via atherosclerosis independently from the presence of additional cardiovascular risk factors (111, 112) (Figure 2). According to this concept, psoriasis is a chronic systemic inflammatory disorder, as evidenced by elevated biomarkers of systemic inflammation. Noteworthy, not only classical markers for systemic inflammation have been shown to be elevated but also resistin and leptin (113, 114). These belong to a family of mediators secreted by adipocytes called adipokines. Resistin and leptin are insulin antagonizing adipokines. Collectively, the adipokine milieu in the blood of psoriasis patients is strikingly similar to that of prediabetic individuals and is a hint toward a state of insulin resistance. The diagnosis of insulin resistance is based on the so-called homeostasis model assessment of insulin resistance (HOMA-IR) index, calculated on the basis of a blood test, or an oral glucose tolerance test (115, 116). Using these approaches, two cross-sectional studies demonstrated that psoriasis patients exhibit insulin resistance at clinical levels (113, 117). Besides the insulin-antagonizing effects, numerous adipokines in general and leptin in particular may drive atherosclerosis through immunomodulation, including the upregulation of adhesion molecules on endothelial cells (118). At the level of endothelial cells, insulin resistance is thought to induce endothelial dysfunction via the pathway described above, resulting in vascular stiffness at the functional level. Indeed, several groups found evidence for endothelial dysfunction, using ultrasound methods. In particular, flow-mediated vascular dilation was impaired (119–122). In one of these studies, insulin resistance was assessed as well via the HOMA-IR and found to be significantly higher when compared to non-psoriatic controls, again stressing the link between insulin resistance and endothelial dysfunction in psoriasis (122). This cascade drives atherosclerosis, which ultimately causes cardiovascular diseases such as myocardial infarction and stroke.

Although not in the focus of this review, it is interesting to note that inflammation-induced insulin resistance may well help to explain the altered epidermal homeostasis observed in the epidermis of psoriatic plaques (123, 124), a phenomenon that might have implications beyond psoriasis (125).

Most observations discussed so far support the notion that cardiovascular comorbidity is a clinically relevant problem for patients suffering from severe psoriasis. In spite of this, several studies document that these patients are not adequately monitored and treated for cardiovascular risk factors. A survey conducted between October 2010 and April 2011 among primary care physicians and cardiologists showed that most of the responding physicians (251 of 1,200 questionnaires sent out were returned) did not routinely screen psoriasis patients for cardiovascular risk factors (126). A cross-sectional study based on National Ambulatory Medical Care Survey data from 2005 to 2009 demonstrated that less than half of the psoriasis patients were screened for at least one cardiovascular risk factor (127). Finally, in a cross-sectional study of patients with hypertension in Great Britain, psoriasis patients were more likely to have uncontrolled hypertension compared with non-psoriatic individuals (128). This is in contrast to recommendations from numerous organizations and societies, who unanimously suggest such a screening (129–131). Takeshita et al. recently summarized what most experts currently agree upon, much of it being identical to what is comprised in current recommendations for the general adult population (132, 133): traditional cardiovascular risk factors should be evaluated. These include total and high-density lipoprotein cholesterol, systolic blood pressure, use of antihypertensive therapy, diabetes, and current smoking. In addition, lifestyle interventions, such as weight loss and smoking cessation, should be encouraged among patients who are obese and who are current smokers, respectively. A controlled clinical trial published a decade ago already showed the potential advantages of a more comprehensive approach to psoriasis treatment, as obese patients with moderate-to-severe psoriasis had a better response to low-dose cyclosporine A if a calorie-reduced diet was included in their treatment regimen (134).

The state of chronic systemic inflammation in psoriasis may at least contribute to atherosclerosis via insulin resistance and endothelial dysfunction and therefore be partially responsible for the increased cardiovascular risk of patients with severe psoriasis. This raises the question whether continuous systemic anti-inflammatory treatments may help to reduce this excess risk. Recently, data from the CANTOS trial suggest that this is principally feasible. That trial evaluated the efficacy of the interleukin-1β-blocking antibody canakinumab in more than 10,000 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter on nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. At a median follow-up of 3.7 years, the incidence rate was 4.50 events per 100 patient-years in the placebo-group, and between 3.86 and 4.11 events per 100 patient-years in the different canakinumab dosing groups. Thus, the trial documented a small, but statistically significant reduction of recurrent cardiovascular events in a high-risk population (135).

An early hint that continuous systemic anti-inflammatory treatment might reduce the cardiovascular risk of psoriasis came from a retrospective study by Prodanovich et al. who analyzed the files of more than 7,000 American veterans who had been treated over extended periods of time with methotrexate for their psoriasis. They found a significantly reduced incidence of cardiovascular diseases in those patients (136). Since then, several observational studies analyzing the effects of methotrexate or TNF-α inhibitors came to similar conclusions (137, 138), while others failed to document such protective effects (139, 140). Complementary to these studies, small controlled trials were performed, evaluating changes of biomarkers for cardiovascular risk under systemic anti-psoriatic treatment. Indeed, several groups reported amelioration of such markers under successful therapy. These include cytokines, adipokines, endothelial dysfunction, and carotid intima-media thickness (141–145).

Based on some of these observations, more ambitious projects were launched, sponsored by pharmaceutical companies. A pilot study on 30 psoriasis patients looked at vascular inflammation in the ascending aorta and carotid arteries by means of PET-CTs. In this study, decreases in vascular inflammation were observed in patients treated with adalimumab compared with placebo when data for the ascending aorta and carotid arteries were analyzed separately at 15 weeks (146). A larger study including 107 patients showed no difference over 16 weeks in the adalimumab-treated group compared to placebo and a modest increase in vascular inflammation in the carotid arteries after 52 weeks of treatment with adalimumab (147). A commentary on that publication suggested that the study might have been too small or of insufficient duration to show an effect, and that it was the carotid arteries and ascending aorta that were studied, not the coronary arteries, which might explain the negative result (20). Another study using the IL-17A-blocking antibody secukinumab was performed in a multi-center setting in Germany. A recently presented abstract on the occasion of the congress of the European Academy for Dermatology and Venereology in Geneva in 2017 documented a trend toward improvement in vascular elasticity, but no date from that trial have so far been published in a peer-reviewed manner.

Taken together, there is some evidence in favor of the idea to reduce the excess cardiovascular risk of psoriasis patients through systemic anti-inflammatory therapy. TNF-α and IL-17A are interesting targets in this regard, as the former is an important insulin antagonist, and the latter seems to exhibit primarily pro-atherogenic effects, although some anti-atherogenic effects have also been reported (148). The CANTOS study can serve as proof of concept for the principal capacity of anti-inflammatory therapy to reduce the cardiovascular risk, but it also points out that even in a high-risk population the effect size might be relatively small. This may explain why much smaller and shorter studies can easily fail to show efficacy in this regard, even more so, if relatively health patients are enrolled, as has been the case in the German trial using secukinumab. Although this approach remains intellectually appealing, it may be more effective and efficient in a real-world scenario to address other major cardiovascular risk factors associated with psoriasis in order to reduce the patients’ excess cardiovascular risk, e.g., through appropriate treatment of the metabolic syndrome or components thereof, or through lifestyle interventions (smoking!).