Cardiovascular and Metabolic Diseases Comorbid with Psoriasis: Beyond the Skin.

A close association of systemic inflammation with cardiovascular diseases and metabolic syndrome is recently a popular topic in medicine. Psoriasis is a chronic inflammatory skin disease with a prevalence of approximately 0.1-0.5% in Asians. It is characterized by widespread scaly erythematous macules that cause significant physical and psychological burdens for the affected individuals. The accelerated inflammation driven by the TNF-α/IL-23/IL-17A axis is now known to be the major mechanism in the development of psoriasis. Psoriasis is not a mere skin disease; it is significantly associated with cardiovascular diseases and metabolic syndrome, which suggests that the chronic skin inflammation extends the systemic inflammation beyond the skin. In this article, we review the epidemiological and pathological aspects of psoriasis and its comorbidities.

Introduction

The close association of systemic inflammation with cardiovascular diseases (CVD) and metabolic syndrome is a recent topic in medicine (1-3). Inflammatory skin diseases such as psoriasis are an integral part of diseases causing systemic inflammation (4). Psoriasis is a common immune-mediated chronic inflammatory skin disease that is characterized by the altered proliferation and differentiation of keratinocytes, vascular remodeling and inflammation in the skin (Figure). Psoriasis shows a diverse prevalence across populations worldwide: 2.5% in Europeans, 0.05-3% in Africans and 0.1-0.5% in Asians (5-8). Psoriasis patients comprise 4.43% of all Japanese dermatological patients (8). Men are likely to experience a higher severity of the disease than women are. Phenotypic heterogeneity of psoriasis has also been reported among ethnic populations. Small plaque psoriasis is specific to Asian populations, while severe psoriasis is more predominant in Western populations (5-8). Recent genome-wide association studies have identified numerous risk-associated variants within 44 susceptibility loci for psoriasis, including HLA-C*06:02, LCE3D, IL23R and CARD14. HLA-C*12:02 may be a susceptibility locus for late-onset psoriasis in the Japanese population (5, 9-11). These susceptibility genes are predominantly related to the innate and adaptive immune systems and skin barrier functions (5, 9).

Figure.

Pathophysiology of psoriasis and its comorbidities (simplified model modified from references 5, 8 and 67). The initial trigger of psoriasis is thought to be the activation of plasmacytoid dendritic cells (DCs) by complexes of host DNA and the antimicrobial peptide LL-37 (cathelicidin) produced by keratinocytes after minor injuries. Plasmacytoids and recruited inflammatory DCs (pDCs and iDCs) produce TNF-α, IL-12 and IL-23. IL-23 is critically involved in the generation and activation of IL-17-producing effector cells. In humans and experimental psoriasis models, γδT cells (Vγ9Vδ2 T cells in human), innate lymphoid cells type 3 (ILC3) and Th17 cells are detected in the lesional skin and blood, and these cells readily produce IL-17A. IL-17A binds to the IL-17 receptor (IL-17R), which is composed of IL-17RA and IL-17RC. IL-17A upregulates the proliferation and downregulates the differentiation of keratinocytes and also enhances the recruitment of neutrophils and aids in the crosstalk between neutrophils and keratinocytes. Chronically released proinflammatory cytokines (e.g., TNF-α, IL-1) from poorly controlled psoriatic skin to the circulatory system potentiates and perpetuates the systemic inflammation and induces insulin resistance, endothelial dysfunction and cardiovascular diseases. This systemic inflammation also causes obesity, hypertension, dyslipidemia and type 2 diabetes mellitus. These systemic involvements interact with each other to increase the mortality for psoriatic patients from cardiovascular diseases.

Pathogenesis of Psoriasis

Like other forms of systemic inflammation, tumor necrosis factor (TNF)-α is a key pro-inflammatory cytokine in psoriasis because its inhibitor significantly improves coronary microvascular dysfunction and levels of highly sensitive C-reactive protein, as well as ameliorates psoriatic symptoms (12). In addition, recent therapeutic success with other biologics seems to have revealed the pivotal role of the TNF-α/interleukin (IL)-23/IL-17 axis in the pathogenesis of psoriasis (Figure). The initial trigger of psoriasis is thought to be the activation of plasmacytoid dendritic cells (DCs) being stimulated by complexes of host DNA and the antimicrobial peptide LL-37 (cathelicidin), which are produced by keratinocytes after minor injuries (8, 13-15). Activated plasmacytoid DCs and damaged keratinocytes produce interferon (IFN)-α and TNF-α, which results in the further production of TNF-α, IL-12 and IL-23 by plasmacytoids and recruited inflammatory DCs (8, 14, 15) (Figure). IL-12 promotes the differentiation of naïve CD4+ T cells into IFN-γ-producing T helper (Th) 1 cells. IL-23 is critically involved in the generation and activation of IL-17-producing effector cells (13, 15, 16) (Figure). In humans and experimental models of psoriasis, γδT cells (Vγ9Vδ2 T cells in human), innate lymphoid cells type 3 (ILC3) and Th17 cells are detected in blood and lesional skin. These cells readily produce IL-17A and IL-22 (8, 17, 18). IL-17A binds to the IL-17 receptor (IL-17R), which is composed of IL-17RA and IL-17RC (19) (Figure). IL-17A upregulates the proliferation of keratinocytes and downregulates its differentiation (20) and also enhances the recruitment of neutrophils and aids in the crosstalk between neutrophils and keratinocytes by upregulating the neutrophil-attractive chemokines CXCL8 and CXCL1 (21). IL-17A promotes the expression of TNF-α by keratinocytes (19), which indicates that the above-mentioned TNF-α/IL-23/IL-17 axis likely forms a vicious loop in the development of psoriasis lesions (Figure). The mechanistic hypothesis coincides with the fact that antibodies against TNF-α, IL-23(p19), IL-23(p40), IL-23R, IL-17A or IL-17RA exert remarkable clinical effects on psoriasis both in Caucasian and Asian ethnicities (8, 22-31). In contrast, the decisive pathogenic roles of IL-12, IFN-γ and IL-22 in psoriasis remain elusive, as clinical trials of the anti-IL-12 p35-p40 antibody (SMART), anti-IFN-γ antibody (HuZAF) and anti-IL-22 antibody (fezakinumab) have been discontinued (8).

High Clinical Burden in Psoriasis

Both the physical and psychological quality of life are significantly impaired in all populations of psoriasis sufferers (32-35), and patients' adherence to medication regimens and satisfaction with their results are very poor (36). The disease burden of psoriasis is further increased by its association with psoriatic arthritis, which is characterized by seronegative spondyloarthropathies, enthesitis and elevated C-reactive protein levels (5, 37-39). Approximately 15-30% of Caucasians with psoriasis eventually develop psoriatic arthritis (37). Although the prevalence is lower in Asian populations (Chinese 5.3-7.3%, Japanese 10.5% and Korean 11.2%), psoriatic arthritis significantly hampers patients' daily lives (37, 40). Additionally, psoriasis has significant comorbidity with CVD and metabolic syndrome.

Comorbidity with Cardiovascular Diseases

A recent meta-analysis and systematic review of 14 cohorts identified a CVD risk in individuals with severe psoriasis (defined as requiring systemic therapy or hospital admission): the risk ratio relative to the general population was 1.37 [95% confidence interval (CI): 1.17-1.60] for CVD mortality, 3.04 (95% CI: 0.65-14.35) for myocardial infarction and 1.59 (95% CI: 1.34-1.89) for stroke (41) (Table 1). The relative risks of CVD were highest in younger, more severe psoriasis patients [3.10 (95% CI: 1.98-4.86) for myocardial infarction at 30 years of age], and the absolute risks were greatest in older individuals with severe psoriasis (23.2 excess myocardial infarctions per 10,000 person-years at 60 years of age) (41). A German cross-sectional study that included 4,185 patients with psoriasis and a prospective cohort of German Health Insurance beneficiaries (n=1,811,098) showed that psoriasis was significantly associated with myocardial infarction (odds ratio: 2.26; 95% CI: 1.03-4.96) (42). In a longitudinal study, psoriasis slightly increased the incident risk for myocardial infarction (relative risk: 1.14; 95% CI: 1.06-1.22), with the highest risk increments found in systemically treated psoriasis, which accounted for 17 excess cases of myocardial infarction per 10,000 person-years (42). A significantly higher risk of myocardial infarction has been observed in psoriasis patients in the United Kingdom (43). For example, for a 30-year-old patient with mild or severe psoriasis, the adjusted relative risk of having a myocardial infarction is 1.29 (95% CI: 1.14-1.46) or 3.10 (95% CI: 1.98-4.86), respectively, compared with the control population (43). Furthermore, patients with severe psoriasis have an increased risk of CVD mortality that is independent of traditional CVD risk factors (44, 45). In a prospective cohort study that included 48,523 patients with psoriasis and 208,187 controls in the United Kingdom, 1,257 patients with psoriasis (2.59%) had a major CVD, compared with 4,784 controls (2.30%), during a median follow-up of 5.2 years (46). A multivariable analysis showed that the patients with psoriasis had significantly higher incidence of CVD than did the controls, with a hazard ratio (HR) 1.37 (95% CI: 1.29-1.45) for hypertension, HR 2.74 (95% CI: 2.41-3.12) for transient ischemic attack, HR 1.54 (95% CI: 1.36-1.73) for atrial fibrillation, HR 1.23 (95% CI: 1.05-1.44) for valvular heart disease, HR 1.32 (95% CI: 1.17-1.49) for thromboembolism and HR 1.57 (95% CI: 1.39-1.78) for congestive heart failure. The age- and gender-adjusted HRs of a major CVD for psoriasis were 1.10 (95% CI: 1.04-1.17) and 1.40 (95% CI: 1.07-1.84) for severe psoriasis (46).

Table 1.

Comorbidity of Cardiovascular Diseases in Psoriasis.

References	Subjects	Brief description
Ref.41	Meta-analysis of 14 cohorts	Risk ratio relative to general population
		Cardiovascular disease mortality; 1.37 (95% CI 1.17-1.60)
		Myocardial infarction; 3.04 (95% CI 0.65-14.35)
		Stroke; 1.59 (95% CI 1.34-1.89)
Ref.42	German cross-sectional study (n=4,185)	Adjusted odds ratio
	German Health Insurance beneficiaries (n=1,811,098)	Myocardial infarction; 2.26 (95% CI 1.03-4.96)
Ref.43	Control patients (n=556,995)	Adjusted relative risk in a 30-year old patient
	Mild psoriasis (n=127,139)	Myocardial infarction in mild psoriasis; 1.29 (95% CI 1.14-1.46)
	Severe psoriasis (n=3,837)	Myocardial infarction in severe psoriasis; 3.10 (95% CI 1.98-4.86)
Ref.44	Control patients (n=14,330)	Adjusted relative risk in a 40-year old patient
	Severe psoriasis (n=3,603)	Cardiovascular mortality in severe psoriasis; 2.69 (95% CI 1.45-4.99)
Ref.46	Prospective study for 5.2 years follow-up	Fully adjusted hazard ratio
	Control patients (n=208,187)	Cardiovascular events; 1.02 (95% CI 0.95-1.08)
	Psoriasis (n=48,523)
Ref.47	Hospital and clinic patients (n=113,065)	Adjusted odds ratio
		Coronary heart disease; 1.27 (95% CI 1.01-1.58)
		Hypertension; 7.78 (95% CI 7.25-8.36)
Ref.61	Control patients (n=24,285)	Adjusted odds ratio
	Psoriasis (n=12,502)	Hypertension; 1.37 (95% CI 1.29-1.46)

A hospital-based study conducted by Shiba et al. in Japan analyzed the prevalence of coronary heart disease (n=5,167, 4.5%), hypertension (n=16,476, 14.5%), dyslipidemia (n=9,236, 8.1%), diabetes mellitus (n=11,555, 10.2%) and psoriasis (n=1,197, 1.1%) in 113,065 patients (47). Their multivariate analysis showed that psoriasis was an independent variable associated with coronary heart disease (adjusted odds ratio: 1.27; 95% CI: 1.01-1.58; p=0.0404), hypertension (7.78; 95% CI: 7.25-8.36; p<0.0001), dyslipidemia (2.35; 95% CI: 2.19-2.52; p<0.0001) and diabetes (2.86; 95% CI: 2.67-3.06; p<0.0001) (47).

Comorbidity with Metabolic Syndrome

The association of psoriasis with metabolic syndrome (obesity, glucose intolerance, hypertension and dyslipidemia) has also been well documented (48, 49). As Henseler and Christophers reported in an earlier study (50), obesity and type 2 diabetes mellitus are significantly associated with psoriasis in the United Kingdom (51), Israel (52, 53), Italy (54), Germany (55) and Denmark (56) (Table 2). These results have been consistent with those for psoriasis patients in Japan (57), Korea (58) and Thailand (59). Psoriasis is also comorbid with other components of metabolic syndrome, such as dyslipidemia (51, 52, 60) and hypertension (51, 52, 55, 61). Furthermore, a significant association of psoriasis with dyslipidemia (58) and hypertension (59) has been reported in Asian populations. Moreover, patients with severe psoriasis had a higher prevalence of diabetes (51) and obesity (51) than did those with mild psoriasis. In this context, it is intriguing that dipeptidyl peptidase-4 inhibitors, a new class of antidiabetic agents, have been shown to improve skin symptoms in some psoriasis patients (62). Because topical vitamin D3 application is effective in treating psoriasis (63), the vitamin D3 level and bone mineral density have been assessed (64, 65). In those studies, the serum level of vitamin 25(OH)D3 was inversely correlated with the severity of psoriasis (64). Patients with a low bone mineral density showed a statistically significant longer average duration of psoriasis than those with better bone density (65).

Table 2.

Comorbidity of Metabolic Syndrome in Psoriasis.

References	Subjects	Brief description
Ref.42	German cross-sectional study (n=4,185)	Adjusted odds ratio
	German Health Insurance beneficiaries (n=1,811,098)	Diabetes mellitus; 2.36 (95% CI 1.26-4.41)
Ref.45	Control patients (n=14,330)	Adjusted hazard ratio
	Psoriasis (n=3,603)	Mortality from diabetes mellitus; 2.86 (95% CI 1.08-7.59)
Ref.46	Prospective study for 5.2 years follow-up	Adjusted hazard ratio
	Control patients (n=208,187)	Diabetes mellitus; 1.18 (95% CI 1.06-1.31)
	Psoriasis (n=48,523)
Ref.47	Hospital and clinic patients (n=113,065)	Adjusted odds ratio
		Diabetes mellitus; 2.86 (95% CI 2.67-3.06)
		Dyslipidemia; 2.35 (95% CI 2.19-2.52)
Ref.51	Control patients (n=14,065)	Adjusted odds ratio in severe psoriasis
	Severe psoriasis (n=3,854)	Diabetes mellitus; 1.62 (95% CI 1.3-2.01)
		Obesity; 1.79 (95% CI 1.55-2.05)
Ref.52	Control patients (n=6,643)	Adjusted odds ratio
	Psoriasis (n=340)	Diabetes mellitus; 1.5 (95% CI 1.2-2.0)
		Dyslipidemia; 1.2 (95% CI 1.0-1.6)
		Obesity; 1.3 (95% CI 1.0-1.7)
Ref.53	Control patients (n=74,987)	Adjusted odds ratio
	Psoriasis (n=16,851)	Diabetes mellitus; 1.58 (95% CI 1.49-1.68)
Ref.56	Danish population based twin study (n=34,781 twins)	Odds ratio
		Diabetes mellitus; 1.53 (95% CI 1.03-2.27)
		Obesity; 1.81 (95% CI 1.28-2.55)
Ref.57	Control patients (n=16,028)	Odds ratio
	Psoriasis (n=429)	Obesity; 2.25 (95% CI 1.57-3.22)
Ref.60	Control patients (n=22,996)	Adjusted odds ratio
	Psoriasis (n=10,669)	Dyslipidemia; 1.19 (95% CI 1.12-1.26)

Pathophysiology of Comorbidity

As mentioned above, psoriasis is a chronic inflammatory skin disease driven by the TNF-α/IL-23/IL-17 axis (1, 4, 10). This notion is well supported by the high clinical efficacy of biologics against the TNF-α/IL-23/IL-17 pathway (5, 8, 15, 66). The release of excessive amounts of proinflammatory cytokines such as TNF-α and IL-1 may cause chronic low-grade systemic inflammation (67, 68) (Figure). The chronic state of inflammation appears to be a central mechanism underlying the pathophysiology of insulin resistance, visceral adiposity, hypertension and dyslipidemia. All of these conditions increase the risk for the development of type 2 diabetes and cardiovascular disease (67-69) (Figure). Consistent with this hypothesis, subclinical systemic and vascular inflammation have been detected by 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with psoriasis (70). In a six-month prospective study, carotid arterial stiffness in patients with psoriasis was significantly improved by anti-TNF-α therapy (71). In addition, other markers for systemic inflammation such as asymmetric dimethylarginine, red blood cell distribution width, the neutrophil-to-lymphocyte ratio, and the platelet-to-lymphocyte ratio, have proven to be upregulated in psoriatic patients (72-74).

In parallel with the above notions, the blockade of TNF-α by etanercept (anti-TNF-α treatment) improves the glucose tolerance in obese diabetic Zucker rats (75). Anti-TNF-α treatment with etanercept also suppresses cerebral damage caused by middle cerebral artery occlusion/reperfusion in both normal and diabetic rats (76). Furthermore, the inhibition of TNF-α production by a thalidomide analog decreases triglyceride levels and increases high-density lipoprotein levels in rats fed hypercholesterolemic diets (77).

Conclusion

Although the pathomechanisms of psoriasis are not fully understood, increasing research attention is being paid to the cutaneous-to-systemic expansion of the inflammatory process, which is now identified as the “psoriatic march” or “inflammatory skin march” (67, 68). This systemic inflammatory expansion is also seen in patients with severe eczema who have an increased risk for CVD (78). Another important fact related to “inflammatory skin march” is the significant association of psoriasis with other immune-mediated or autoimmune diseases such as inflammatory bowel disease (79, 80), multiple sclerosis (81) and autoimmune hepatitis (82). In addition, frequent comorbidity is noted in psoriasis and autoimmune bullous diseases (83-88). Further immunological studies into the genuine master switch underlying the comorbidity are warranted.

Finally, a disfigured appearance because of psoriasis may affect the psychological stability of patients (89). The cosmetic disfigurement associated with psoriasis increases the risk of depression, anxiety, feeling stigmatized and self-harm ideation, which profoundly impairs their satisfaction and adherence to medical care (36, 89, 90). In addition, internal physicians may hesitate to perform electrocardiogram, echocardiogram and even blood examinations, especially in severe cases with extensive skin eruption. These undesirable factors may delay the correct diagnosis and treatment of comorbid CVD and metabolic syndromes. As anti-TNF-α treatment is feasible for managing both skin lesions and comorbidities in psoriasis (12, 66), the early diagnosis and appropriate intervention by internal physicians in cooperation with dermatologists is required in order to increase the physical and mental quality of life in psoriatic patients.

The authors state that they have no Conflict of Interest (COI).