Biologics for Reducing Cardiovascular Risk in Psoriasis Patients

Psoriasis is a chronic inflammatory skin disease with a high prevalence of cardiovascular disease (CVD), obesity, dyslipidemia, hypertension, diabetes mellitus, and metabolic syndrome. Among them, CVD is the most common cause of morbidity and mortality in psoriasis patients. Since CVD is associated with considerable morbidity and mortality, primary care clinicians are increasingly committed to reducing the risk of CVD in patients with psoriasis. Biologics targeting TNF-α, IL-12/23, and IL-17 are systemic therapies that can dramatically improve the condition of psoriasis. Recent studies have reported that these inflammatory cytokine signals may promote atherosclerosis, suggesting that biologics might be effective for improving psoriasis as well as reducing the risk of CVD. Here, we reviewed cardiovascular risk in psoriasis patients, the association between psoriatic inflammation and atherosclerosis, and the efficacy of biologics for reducing the risk of cardiovascular diseases.


Introduction
Psoriasis is a chronic inflammatory skin disease characterized by erythema with scaling. It affects 2-3% of the world's population and about 0.5% of Asians [1][2][3][4]. Innate and acquired immunity is involved in the pathogenesis of psoriasis. Moreover, psoriasis is an independent risk factor for cardiovascular events, and the cardiovascular risk is particularly high in patients with severe psoriasis [5]. The increased prevalence of cardiovascular risk factors such as obesity, dyslipidemia, hypertension, diabetes mellitus, and metabolic syndrome in patients with psoriasis is also associated with an increased risk of developing cardiovascular diseases such as myocardial infarction, angina pectoris, and stroke [6][7][8][9]. Chronic inflammation is considered a strong link between psoriasis and associated cardiovascular events [10]. Various cytokines and inflammatory cells play a central role in developing psoriatic lesions, resulting in endothelial dysfunction [11,12]. Recently, the concept of the "psoriasis march" has been proposed, in which systemic inflammation caused by psoriasis and obesity leads to insulin resistance and vascular endothelial dysfunction, which in turn promotes atherosclerosis and the development of cardiovascular disease (CVD) [13]. It is essential to note the high incidence of CVD in patients with psoriasis, since CVD is directly related to morbidity and mortality. This means that cardiovascular risk should be assessed in patients with psoriasis, and lifestyle modifications should be made to manage blood pressure, blood glucose, and lipids. In addition, strict therapeutic control is also important to control the systemic inflammation of psoriasis. The advent of biologics has dramatically changed the treatment of psoriasis. TNF-α inhibitors, IL-23 inhibitors, and IL-17 inhibitors are highly effective against psoriatic skin lesions [14][15][16][17][18][19][20][21]. Recently, clinical studies and basic research have suggested that these biologics, which target inflammatory cytokines, effectively reduce cardiovascular risk [11,[22][23][24][25][26][27][28][29]. This article discusses cardiovascular risk in psoriasis, the association between psoriatic inflammation and atherosclerosis, and the cardiovascular-risk-reducing effects of biologics.
However, it seems almost evident that managing both diseases and controlling symptoms would decrease the incidence of CVD.
Psoriasis relates to dyslipidemia, which is also a factor of risk for CVD. In a systemic review, 20 out of 25 studies, including 265,512 psoriasis patients, reported that psoriasis was significantly associated with dyslipidemia. The OR for dyslipidemia ranged from 1.04 to 5.55 in 238,385 psoriasis patients [15]. The serum levels of triglyceride, cholesterol, and LDL were significantly higher in psoriasis patients, but not HDL levels [16]. Furthermore, TNF-α and other proinflammatory cytokines promote dyslipidemia by increasing the levels of LDL-C and oxLDL-C, decreasing the quality of lipoprotein, and reducing the level of HDL-C [17,18]. Using nuclear magnetic resonance spectroscopy, the lipid profile in psoriasis patients is similar to that observed in diabetes patients [19]. These lipid abnormalities in psoriasis patients drive systemic inflammation and promote insulin resistance, finally leading to the development of CVD.
Furthermore, many studies have found psoriasis to be an independent risk factor for atherosclerosis, myocardial infarction, stroke, and diabetes [5,. In particular, CVDs such as atherosclerosis, myocardial infarction (MI), and stroke are among the most critical complications because they are fatal. To investigate the causes of death in psoriasis, a large cohort study was conducted in the United Kingdom from 1987 to 2002. Comparing 3603 severe psoriasis patients with 14,330 healthy controls, the study found that life expectancy was approximately six years shorter in patients with severe psoriasis. Cardiovascular events were the most common cause of death [52]. Table 1 lists epidemiological studies published between 2006 and 2021 that examined the association between psoriasis and CVD [5,9,49,.
CVD included MI, coronary artery disease, angina, atherosclerosis, peripheral vascular disease, stroke, ischemic heart disease, cerebrovascular disease, CVD mortality, and coronary heart disease. Most studies found that the presence of psoriasis increased the risk of CVD, although some studies found no association between psoriasis and CVD risk. The risk of MI and stroke in mild psoriasis and severe psoriasis requiring systemic therapy was generally increased in severe psoriasis. As described above, many epidemiologic studies have been conducted. A systematic review including these epidemiological studies revealed that psoriasis increases the risk of CVDs such as MI and stroke [77][78][79], and statin administration is recommended to reduce CVD risk in patients at risk for CVD [80,81]. However, in practice, only a small percentage of physicians prescribe statin administration to those who need statin treatment [81]. Therefore, Barbieri et al. investigated measures to improve CVD prevention through specialist-led care from the perspective of healthcare professionals and patients. Results of the study showed that dermatologists and psoriasis patients had a positive view of participating in a specialist-led model of care to improve CVD prevention [82]. This suggests that dermatologists need to be more proactive in communicating with psoriasis patients and engaging in statins and other treatments to reduce CVD risk in psoriasis patients. The American Academy of Dermatology and National Psoriasis Foundation recommend assessing the risk of CVD in psoriasis patients. The screening of hypertension and diabetes and the assessment of CV risk every 3-6 years are encouraged for psoriasis patients [83]. In an effort to reduce CVD risk in patients with psoriasis, Garchick and Berger et al. proposed an algorithm to be used in patients with psoriasis who have a BSA >10% or who require biologic agents or phototherapy ( Figure 1) [84]. If the patient is at high risk, an appropriate CVD risk assessment should be performed, and the initiation of statin therapy should be considered. Even if the patient is not at high risk, performing a standard cardiovascular risk assessment is essential. Since dermatologists are the primary point of contact for psoriasis care, it is important for us to keep in mind that patients with severe psoriasis should be screened for a thorough CVD risk assessment. patients with psoriasis who have a BSA >10% or who require biologic agents or photo-therapy ( Figure 1) [84]. If the patient is at high risk, an appropriate CVD risk assessment should be performed, and the initiation of statin therapy should be considered. Even if the patient is not at high risk, performing a standard cardiovascular risk assessment is essential. Since dermatologists are the primary point of contact for psoriasis care, it is important for us to keep in mind that patients with severe psoriasis should be screened for a thorough CVD risk assessment.

Atherosclerosis in Psoriasis Patients
It is known that coronary artery plaques are more common in patients with psoriasis than in healthy individuals [50]. In the pathogenesis of psoriasis, inflammatory cytokines such as TNF-α, IL-23, and IL-17 form the primary pathogenesis and cause systemic inflammation. These inflammatory cytokines may cause vascular damage not only in the skin, but also in other parts of the body, and increase the risk of developing CVD via atherosclerosis. In fact, psoriasis and atherosclerosis have much in common [3,4,85,86]. It has been reported that treatment targeting IL-1β reduces atherosclerosis [24]. Therefore, it has been suggested that treatment targeting TNF-α, IL-23, and IL-17, which play a major role in shaping psoriasis pathology, may also contribute to the reduction in atherosclerosis.
Risk factors associated with atherosclerosis, such as hypertension and diabetes mellitus, increase vascular endothelial damage. High levels of LDL cholesterol in the blood gradually lead to excessive accumulation of LDL cholesterol in the intima of blood vessels. The accumulated LDL cholesterol is oxidized by reactive oxygen species and converted to oxidized LDL. Macrophages take up the oxidized LDL via scavenger receptors and become foam cells. Over time, the foam cells promote atherosclerosis by promoting atheroma plaque formation [87]. Macrophages in the plaque release inflammatory cytokines

Atherosclerosis in Psoriasis Patients
It is known that coronary artery plaques are more common in patients with psoriasis than in healthy individuals [50]. In the pathogenesis of psoriasis, inflammatory cytokines such as TNF-α, IL-23, and IL-17 form the primary pathogenesis and cause systemic inflammation. These inflammatory cytokines may cause vascular damage not only in the skin, but also in other parts of the body, and increase the risk of developing CVD via atherosclerosis. In fact, psoriasis and atherosclerosis have much in common [3,4,85,86]. It has been reported that treatment targeting IL-1β reduces atherosclerosis [24]. Therefore, it has been suggested that treatment targeting TNF-α, IL-23, and IL-17, which play a major role in shaping psoriasis pathology, may also contribute to the reduction in atherosclerosis.
Risk factors associated with atherosclerosis, such as hypertension and diabetes mellitus, increase vascular endothelial damage. High levels of LDL cholesterol in the blood gradually lead to excessive accumulation of LDL cholesterol in the intima of blood vessels. The accumulated LDL cholesterol is oxidized by reactive oxygen species and converted to oxidized LDL. Macrophages take up the oxidized LDL via scavenger receptors and become foam cells. Over time, the foam cells promote atherosclerosis by promoting atheroma plaque formation [87]. Macrophages in the plaque release inflammatory cytokines such as IL-1 and TNF-α. These inflammatory cytokines are thought to promote further atherosclerosis [88,89] (Figure 2).
Various studies have shown that acquired immunity also plays a vital role in atherosclerosis. It has been found that CD4+ T cells are present in atheroma plaques [90]. CD4+ T cells also play a significant role in the pathogenesis of psoriasis, especially Th1 cells and Th17 cells. Th1 cells differentiate and produce IFN-γ under the action of IL-12. IFN-γ is also involved in the production of proinflammatory cytokines, the upregulation of gene expression of adhesion molecules, the production of psoriasis-related cytokines, and the activation of macrophages and vascular endothelial cells, leading to the development of atherosclerotic lesions [91,92]. such as IL-1 and TNF-α. These inflammatory cytokines are thought to promote further atherosclerosis [88,89] (Figure 2). Various studies have shown that acquired immunity also plays a vital role in atherosclerosis. It has been found that CD4+ T cells are present in atheroma plaques [90]. CD4+ T cells also play a significant role in the pathogenesis of psoriasis, especially Th1 cells and Th17 cells. Th1 cells differentiate and produce IFN-γ under the action of IL-12. IFN-γ is also involved in the production of proinflammatory cytokines, the upregulation of gene expression of adhesion molecules, the production of psoriasis-related cytokines, and the activation of macrophages and vascular endothelial cells, leading to the development of atherosclerotic lesions [91,92].
IL-17 is a cytokine produced by CD4+ T cells. Th17 cells are activated mainly through cytokine signaling from dendritic cells [3]. The IL-17 receptor is expressed on epidermal cells in the skin, and IL-17 activates epidermal cells to cooperate with inflammatory cells to form the psoriasis pathology. The IL-17 receptor is known to be expressed on vascular endothelial cells, and its action on vascular endothelial cells is believed to promote the production of inflammatory cytokines such as granulocyte colony stimulating factor (G-CSF) and IL-6, promoting atherosclerosis [93]. On the other hand, other reports indicate that IL-17 does not promote atherosclerosis. In addition, IL-17 stabilizes plaque and may have an anti-atherogenic effect. IL-17 is a cytokine produced by CD4+ T cells. Th17 cells are activated mainly through cytokine signaling from dendritic cells [3]. The IL-17 receptor is expressed on epidermal cells in the skin, and IL-17 activates epidermal cells to cooperate with inflammatory cells to form the psoriasis pathology. The IL-17 receptor is known to be expressed on vascular endothelial cells, and its action on vascular endothelial cells is believed to promote the production of inflammatory cytokines such as granulocyte colony stimulating factor (G-CSF) and IL-6, promoting atherosclerosis [93]. On the other hand, other reports indicate that IL-17 does not promote atherosclerosis. In addition, IL-17 stabilizes plaque and may have an anti-atherogenic effect.

The Effect of Psoriasis Treatments on Cardiovascular Risk
The main strategy to reduce the risk of CVD has been the prevention of atherosclerosis through strict lipid control. In fact, the risk of CVD can be reduced by statin administration [80,94]. More recently, it has been found that statin administration reduces vascular endothelial inflammatory markers [95]. Thus, it is clear that lipid control is important in reducing CVD risk. In addition, the recent success of the CANTOS (Canakinumab Antiinflammatory Thrombosis Outcomes Study) trial has established evidence that the suppression of inflammatory cytokines reduces CVD risk. In this study, the anti-inflammatory effects of IL-1β inhibitor canakinumab administration were compared between three different doses and placebo in 10,061 patients with a history of myocardial infarction and high-sensitivity C-reactive protein levels. The results validated that anti-inflammatory therapy with canakinumab reduced the recurrence of CVD events [24]. Moreover, a recent study showed that biologics could reduce coronary inflammation assessed as perivascular fat attenuation index [96]. Furthermore, biologics can decrease intima-media thickness (IMT), an indicator of subclinical atherosclerotic plaque development, by reducing inflam-mation [80,[86][87][88][89][90][91][92][93][94][95][96][97][98][99][100]. In fact, cardiovascular events were reduced in psoriasis patients with biological treatment (HR 0.58 (0.30-1.10)) in a Danish nationwide cohort study [101]. Therefore, anti-inflammatory therapy targeting TNF-α, IL-23, and IL-17, the main pathological factors in psoriasis, can potentially contribute to the reduction in CVD risk and psoriatic skin rash.
Weight gain and higher BMI have been reported with TNF-α inhibitors; weight loss should be requested at the same time when using TNF-α inhibitors [102,103]. TNF-α inhibitors have been reported to be effective in treating insulin resistance in psoriasis patients [104], but no such reports have been reported for other biologic agents. Metaanalysis suggests that TNF-α inhibitor treatment reduces CVD risk [105,106]. The risk of myocardial infarction was also reduced with TNF-α inhibitors [107]. While these clinical studies suggest that TNF-α inhibitors may contribute to CVD risk reduction, some studies have shown the opposite. In summary, there is currently disagreement as to whether TNF-α inhibitors can reduce the risk of CVD, and further accumulation of evidence is needed.
IL-23 is a cytokine composed of two subunits, IL-12p40 and IL-23p19. IL-23 induces Th17 cell differentiation. The IL-23/IL-17 axis is central to psoriasis pathogenesis, and blocking IL-23 is highly effective for psoriasis lesions. Some studies showed the proatherogenic role in IL-23. IL-23 is highly expressed in atherosclerotic lesions [108], serum levels of IL-23 are elevated in patients with carotid atherosclerosis compared to healthy controls, and IL-23 and IL-23R mRNA levels are significantly elevated in carotid plaques. It has also been found that patients with elevated serum IL-23 levels have higher mortality [25]. Granulocyte macrophage colony-stimulating factor (GM-CSF) promotes plaque progression, which is mediated by IL-23, and increases apoptosis susceptibility in macrophages by promoting proteasomal degradation of the IL-23-mediated apoptosis susceptibility in macrophages by promoting proteasomal degradation of the cell survival protein B-cell lymphoma 2 (Bcl-2) and by increasing oxidative stress [26]. Information on IL-23 inhibitors' CVD risk reduction remains at the research level, with some studies suggesting that IL-23 is protective against atherosclerosis by acting to maintain the intestinal barrier and homeostasis of the intestinal microbiota [109]. On the other hand, some studies using LDL receptor-deficient mice have shown that IL-23 does not affect atherosclerosis [110].
IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F are known as IL-17 family members [111]. Secukinumab, ixekizumab, bimekizumab, and brodalumab as IL-17 inhibitors have been used to treat psoriasis [14,16,18,19]. IL-17A and IL-17F are mainly associated with psoriasis, forming homodimers of each or heterodimers of both subunits [111]. Secukinumab and ixekizumab target IL-17A, and bimekizumab targets both IL-17A and IL-17F. On the other hand, brodalumab targets the IL-17 receptor, IL-17RA. These IL-17 inhibitors have also shown efficacy against psoriatic skin lesions in direct comparative studies with etanercept and ustekinumab [18,112,113]. The effect of IL-17A on vascular dysfunction has been examined in a mouse model; administration of angiotensin II increases IL-17 protein from T cells and aortic media. Mice showed improvement in blood pressure elevation and vascular dysfunction associated with administering angiotensin II [29]. Another laboratory has shown that blocking IL-17A reduces peripheral oxidative stress levels, proinflammatory cytokines, and vascular inflammation [23]. Furthermore, there is a report that IL-17A expression is high in atherosclerotic plaques from patients with ischemic symptoms [108]. These results show that IL-17A increases plaque instability and causes atherosclerosis. On the other hand, the results from other researchers demonstrated that IL-17A has a protective role in atherosclerosis. IL-17A levels are not involved in atherosclerotic plaque formation because there is no correlation between serum IL-17A levels and carotid intima-media thickness [27]. Thus, reports on IL-17A and atherosclerotic plaque formation have yielded different views. In 2019, the benefit of secukinumab, an IL-17A antagonist, for cardiovascular markers was investigated in the CARIMA (Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated with Secukinumab) study. In this study, patients with moderate to severe plaque psoriasis without clinical CV disease were treated with secukinumab, and endothelial function was measured by flow-mediated dilation (FMD) as the primary endpoint. Baseline FMD was predominantly lower in psoriatic patients compared to healthy volunteers; secukinumab did not make a difference at 12 weeks, but there was an increase in FMD in psoriatic patients receiving secukinumab at 52 weeks [11]. Furthermore, another recent study, a prospective observational study for coronary artery plaque characteristics in psoriasis patients with biologics, showed IL-17 inhibitors reduced non-calcified plaque burden in psoriasis patients, suggesting the crucial role of IL-17 in atherosclerotic pathways [22]. Although future extensive clinical studies are needed, this is an important study that suggests a reduction in CVD risk by suppressing IL-17A.

Conclusions
Psoriasis is not only a cutaneous but also a systemic inflammatory disease, a group of diseases that carries a very high cardiovascular risk. Therefore, it is necessary to break away from treating psoriasis as a skin-only target and treat it as a systemic disease to avoid highly lethal cardiovascular disorders. We need to focus on obesity, dyslipidemia, diabetes, hypertension, and metabolic syndrome, which are frequently associated with psoriasis, and provide integrated treatment in close collaboration with other medical departments. Inflammatory cytokines, mainly TNF-α, IL-17, and IL-23, which occur in the pathogenesis of psoriasis, are thought to increase the risk of CVD, leading not only to psoriasis but also to vascular dysfunction. Therefore, it is suggested that biologics targeting these molecules may have a positive impact not only on the pathogenesis of psoriasis but also on CVD risk.

Conflicts of Interest:
The authors have declared no conflict of interest.