Psoriasis as a systemic disease Ivan Grozdev MD PhD, Neil Korman MD, Nikolai Tsankov MD PhD PII: DOI: Reference:

S0738-081X(13)00292-7 doi: 10.1016/j.clindermatol.2013.11.001 CID 6801

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Clinics in Dermatology

Please cite this article as: Grozdev Ivan, Korman Neil, Tsankov Nikolai, Psoriasis as a systemic disease, Clinics in Dermatology (2013), doi: 10.1016/j.clindermatol.2013.11.001

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Ivan Grozdev MD, Niel Korman MD, Nikolai Tsankov MD PhD

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Psoriasis, a recalcitrant disease of chronic and systemic inflammation, affects approximately 23% of the population, [1-3]. The cutaneous manifestations of this disease, often the most renowned, typically wax and wane throughout the progression of this life-long disease. However, similarities in the inflammatory process and the spectrum of associated diseases, as well as in the response to certain types of treatment, have enabled psoriasis to be classified as one of the "immune-mediated inflammatory diseases" (IMID), a group that also includes rheumatoid arthritis, Crohn's disease, and other conditions [4]. The goal of this article is to provide an overview supporting the concept of understanding psoriasis as a systemic disease.

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Epidemiological data

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It has been epidemiologically observed that the frequency of some noncutaneous diseases and conditions is significantly increased in psoriasis [5]. Christophers divides comorbidities into two groups [6]. The first group includes diseases that are pathogenetically associated with psoriasis, such as psoriatic arthritis (PsA), Crohn‟s disease (CD), pustular dermatoses. The second group includes diseases such as metabolic syndrome and cardiovascular diseases (CVD) that are associated with psoriasis through its severe chronic course. Puig-Sanz suggests that comorbidities are secondary manifestations of a disease that can occur at different times and in one or more organs [7]. Although they are secondary conditions, comorbidities can sometimes have an even greater social health impact than primary conditions. Puig-Sanz suggested the following classification of comorbidities in psoriasis (Table 1):

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Common Diseases Psoriatic arthritis Crohn disease Persistent Activation of Cutaneous T Cells Cutaneous T-cell lymphoma Chronic/Systemic Skin Inflammation Metabolic syndrome Atherogenic dyslipidemia Hypertension Abdominal obesity Diabetes and insulin resistance Predisposition to thrombosis Nonalcoholic hepatic steatosis Comorbidities Related to Impaired Quality of Life Anxiety, depression Smoking, alcoholism Comorbidities Related to Treatment Nephrotoxicity, hepatotoxicity, dyslipidemia, skin cancer

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Table 1. Classification of psoriasis co-morbidities (Adapted from: Puig-Sanz 2007)7

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Psoriasis and PsA The prevalence of PsA in general population is estimated to 0.25% [8], while it is reported to be between 5% and 48% among patients with psoriasis [9-11]. These results demonstrate that the prevalence of arthritis in patients with psoriasis may actually be higher than the previously accepted rate of 7% [12].

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Psoriasis and CD Prevalence of psoriasis among patients with CD is higher than in general population. Results from 5 independent case-control studies reveal that 9% of patients with CD have psoriasis versus 1.4% of the controls [13]. Additionally, families with psoriasis or CD have an increased risk of developing the other disease, respectively. Another study shows that 10% of CD patients have a first-degree relative with psoriasis compared to 3% of the controls [14]. Psoriasis and CD have also genetic link through the HLA-system. The most important susceptibility locus for psoriasis is on chromosome 6p21, also known as PSORS-1 [15]. A chromosome locus 6p23, also known as IBD-3, is partially responsible for the genetic susceptibility for CD [16]. The gene, encoding TNF-alpha, is situated close to PSOR-1 and IBD3 supporting the genetic importance of TNF-alpha for both diseases. Furthuer studies are needed in order to elucidate if different TNF-alpha gene mutations could lead to an increased risk of psoriasis and CD.

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Psoriasis and metabolic syndrome Metabolic syndrome has been identified as a clustering of metabolic abnormalities in individuals and is associated with an increased risk of type 2 diabetes and cardiovascular disease [17]. The most recent definition of metabolic syndrome requires central obesity (BMI > 30 kg/m2) and any two of the following abnormalities: elevated plasma triglycerides, reduced HDL cholesterol, elevated blood pressure and raised fasting plasma glucose [18]. In a study comparing 625 hospitalized psoriasis patients and 1044 surgically treated patients, it was shown that hyperlipidemia, hypertension, coronary artery disease, type 2 diabetes, and increased BMI are increased in psoriasis than in controls [19]. Moreover, the presence of these conditions in a single patient, defined as metabolic syndrome, was two times more frequent if the patients suffered from psoriasis. A case-control study revealed elevated triglycerides and abdominal obesity are more frequent in 338 adult patients with plaque psoriasis than in 334 controls with other skin diseases [20]. The association of psoriasis with metabolic syndrome and its components has been confirmed in other large epidemiological studies [21-24]. Cohen et al found that this association is more significant in elderly patients over 50 years of age [25]. Psoriasis and CVD It has been more than 35 years since McDonald et al reported that rates of occlusive vascular diseases such as thrombophlebitis, myocardial infarction, pulmonary embolism, and cerebrovascular incidents, were significantly higher in psoriasis patients than those without psoriasis [26]. Since then substantial data has been accumulating on the association between psoriasis and CVD [27-29]. Moreover, psoriasis has been found to be an independent risk factor

ACCEPTED MANUSCRIPT for myocardial infarction, stroke, coronary artery, cerebrovascular, and peripheral vascular diseases, and CV mortality [30-33]. However, the data of a 10-year prospective study of a cohort of 1376 patients enrolled in a photochemotherapy follow-up study did not support the hypothesis that severe psoriasis is an independent risk factor for CVD [34].

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Impact of psoriasis onset and severity Malbris et al conducted a cohort study among 8,991 hospitalized psoriasis patients and 19,757 ambulatory psoriasis patients [35]. The authors found a 50%-increased risk of CV mortality in hospitalized patients. The risk was positively associated with the number of hospitalizations and the earlier age of first hospitalization. In their large population-based study among patients of the General Practice Research Database in United Kingdom, Gelfand et al also demonstrated that young and severe psoriasis patients were more likely to have myocardial infarction [30]. Diabetes, obesity, and other CV risk factors are also more prevalent in severe than in mild psoriasis [36]. However, in their prospective study Stern et al concluded that very severe psoriasis is associated with increased noncardiovascular mortality, but not with increased cardiovascular risk [34].

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Psoriasis, alcohol, and smoking Alcoholism and liver cirrhosis are reportedly more common in psoriasis with a reported prevalence of alcoholism of 18% among psoriatic patients compared with 2% in other dermatologic controls [37]. Alcohol consumption is positively correlated with psoriasis severity [38,39]. It is higher before psoriasis onset than it is before other skin disease onset and psoriasis sustain drinking [40]. Among hospitalized dermatological patients, alcoholism is more prevalent in psoriasis than in other skin diseases [41]. A case-control study revealed that the risk of psoriasis was higher in ex-smokers and current smokers than in those who never smoked, and smoking was strongly associated with the occurrence of pustular lesions [23]. Within the General Practice Research Database in United Kingdom, smoking is more prevalent in psoriasis patients than in controls [30]. In a cross-sectional study, patients with psoriasis, enrolled in the prospective Utah Psoriasis Initiative, had a significantly higher prevalence of obesity and smoking than the general population of Utah. The prevalence of obese smokers was significantly higher [42]. Both alcohol and smoking may cause increased mortality in patients with moderateto-severe psoriasis [43]. Psoriasis and psychiatric/psychological diseases The first reports on the impaired psychosomatic health of psoriasis patients date back to the 60ties of last century [44]. The association between psoriasis and high depression scores, anxiety, obsessiveness, and difficulty in verbalizing emotions (especially anger) is well known [45]. Furthermore, an association has been reported between severe psoriasis and clinical depression and suicide ideation in 7.2% of hospitalized patients [46]. This association was found in only 2.5% of outpatients, which is comparable to that found in general medical patients (2.4% to 3.3%). Psychological comorbidity in psoriasis probably contributes to a sedentary lifestyle, alcoholism, and smoking, and all these increase the risk of other comorbidities in these patients. In the study of Gelfand et al among patients enrolled in the General Practice Research Database in the United Kingdom, it was demonstrated that annually 10,400 cases of depression, 7,100 cases of anxiety, and 350 case of suicide could be related to concomitant psoriasis [47]. Depression is more prevalent in psoriasis patients who are young, males, and suffer from a severe disease [48]. The severity of depression correlates with pruritus. Alleviation of the itch may

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improve the course of the depression as well as the treatment of depression may reduce the pruritus [49]. An association between psoriasis and stressful life events in the year preceding diagnosis has been reported, suggesting that psychological stress may have a role in the pathogenesis of psoriasis [23]. Furthermore, psoriasis-related stress can play a role in the exacerbation of psoriasis, and greater stress reactivity has been associated with onset of psoriasis at an earlier age [45].

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Pathogenic mechanisms shared between psoriasis and co-morbidities

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Although epidemiological studies have demonstrated an elevated risk of adverse cardiac events among psoriasis patients, they do not provide insight to the etiology of this elevated risk. The term “march of psoriasis” was first introduced by Boehncke et al as to describe the causal link that may exist between psoriasis and CVD (Figure 1) [49].

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Figure 1. Common pathways of psoriasis and atherosclerosis (Boehncke WH et al, Exp Dermatol 2011)49 The concept is that systemic inflammation associated with psoriasis enhances insulin resistance, causing endothelial dysfunction, subsequent atherosclerosis and ultimately coronary events. Psoriasis patients have significant inflammation not only in the skin, but also subclinical inflammation in the liver, joints, tendons and vascular tree even after adjusting for traditional cardiovascular risk factors, suggesting that psoriasis itself predisposes to pro-inflammation pathways independent of traditional risk factors [50].

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However, the concept of “psoriatis march” was not supported by the results of a detailed population-based study with a follow-up of more than 10 years [51]. By using standardized measures of atherosclerosis, it was demonstrated that psoriasis patients of a cohort with predominantly mild disease are as likely to develop atherosclerosis and cardiovascular events as subjects without psoriasis.

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Common inflammatory molecules and pathways between psoriasis and CVD T-helper cells type 1 (Th1) and type 17 (Th17), and regulatory T cells (Treg) play integral roles in psoriasis and atherosclerosis pathogenesis. In psoriasis, the disease cycle is perpetuated through Th1 cytokines (interferon [IFN]-gamma, interleukin [IL]-2, and tumor necrosis factor [TNF]-alpha), stimulated keratinocytes, as well as the production of more cytokines (TNF-alpha, IL-1, and IL-6) and chemokines [52,53]. The recruitment and localization of T cells to the dermis and epidermis are mediated through various adhesion molecules and integrins. Psoriasis involves upregulation of adhesion molecules such as E-selectin, ICAM-1 (IntraCellular Adhesion Molecule) [54,55]. In atherosclerotic plaques, there is the same cytokine milieu of TNF-alpha, IL-6, IL-8, and IL-17, as that found in the gut of a patient with Crohn‟s disease, in a psoriatic plaque, or in an arthritic joint. The rupture of the plaque is triggered by the same factors of infection and emotional stress that cause flares in these diseases [56]. Endothelial dysfunction in atherosclerosis is associated with an increased level of TNF-alpha and other cytokines [57]. Dendritic cells within the plaques are activated to express IL-12 in higher quantities, initiating transcription of IFN-gamma [58]. Increased IFN-gamma transcription factors exist in T cells of patients with acute coronary syndrome [59]. The initiation and perpetuation of these Th1 responses known in psoriasis and atherosclerotic plaques demonstrates a link between these two conditions [52]. Th17 cells, stimulated by IL-23, produce IL-17 and IL-22, which activate keratinocyte proliferation and release of other inflammatory proteins [53,60]. IL-17 is the mechanistic link between T-cell activation and inflammation. It is known to induce the key psoriatic cytokines of TNF-alpha, and IL-1, IL-6, and IL-8, among a cascade of inflammatory mediators. Its key role in driving epidermal activation in psoriatic plaques is evidenced by the mechanism of certain therapies. IL-17 is increased in patients with psoriasis. Its levels correlate positively with lesion area and decrease with therapy [61,62], while the correlation with disease severity is controversial [63]. IL-17 is also seen at higher levels, along with IL6, IL-8, and C-reactive protein, in the plasma of patients who have suffered unstable angina and acute MI [64,65]. Endothelial cell injury leads to cytokine release and Th17 differentiation. Similar to psoriasis, TNF-alpha and IL-17 synergistically upregulate further cytokine transcription [66]. IL-17 and IFN-gamma levels are undetectable in healthy volunteers but are elevated in patients with coronary artery disease (CAD). The utility of measuring IL-17 levels in psoriasis patients to identify those at a higher risk for MI is under investigation [52]. Angiogenesis is a recognized feature common to psoriasis and atherosclerosis and vascular endothelial growth factor (VEGF) is a potent pro-angiogenic factor which has been reported to be upregulated in both conditions, thus may be a link between the two diseases [67,68]. VEGF is produced by human keratinocytes in response to stimulation with cytokines (IL-17, IL-8, TNFalpha) involved in psoriasis pathogenesis. Treg inhibit T-cell activation and proliferation through IL-10, transforming growth factor (TGF), and cell–cell interaction [69-71]. The inhibitory function of Treg may be reduced in psoriasis patients [72]. Increased levels of TGF exist in the serum and epidermis of psoriasis patients, correlating with psoriasis disease severity [73,74]. A decrease in TGF receptors in psoriatic

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epidermis may indicate a reduced activity of TGF [69-71,75]. In atherosclerosis, TGF and IL-10 may inhibit plaque formation [76,77]. Several lines of evidence suggest that psoriasis and CAD have reductions in the inhibitory function of Treg [52]. Chronic inflammation and pro-inflammatory cytokines play significant roles in the pathogenesis of both psoriasis and vascular disease. Evidence suggests that psoriasis and CVD share common pathogenic features [79,80] including immunological processes, inflammatory cytokine profiles, and the presence of local and systemic inflammatory markers [49,79,80]. Activation of these inflammatory cells (dendritic cells, macrophages and T cells) together with the release of proinflammatory cytokines (e.g., TNF-alpha, IFN-gamma, IL-12) contribute to the development of psoriatic lesions and play a major role in the development and vulnerability of atherosclerotic plaque [57,81,82]. The question of whether psoriasis has the capacity to directly cause vascular inflammation and thrombosis remains unknown. An attempt to elucidate this question is the employment of a murine model of psoriasis that recapitulates many aspects of the disease but without having the standard CVD risk factors [78]. Using this model Wang et al have identified that sustained skin inflammation is sufficient to promote vascular inflammation and thrombosis [83].

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Common inflammatory molecules and pathways between psoriasis and obesity Adipose tissue is an active endocrine organ with many secretory products. Leptin, an adipokine secreted by adipocytes, has been shown to participate in the pathogenesis of immune-mediated inflammatory diseases (IMIDs) such as type 1 diabetes, rheumatoid arthritis (RA), inflammatory bowel disease, and psoriasis [84]. High levels of leptin in obese patients are associated with increased proinflammatory mediators which may lead to development of psoriasis [85]. Adiponectin, another adipocyte-specific protein, was shown to inhibit TNF-alpha production [86]. It also inhibits the biological activity of TNF-alpha [87]. In endothelial cells, adiponectin downregulates the expression of adhesion molecules, ICAM-1 and vascular cell adhesion molecule 1, thus contrasting the effect of TNF-alpha. Plasma levels of adiponectin are decreased in obesity and in psoriasis compared with healthy controls [88].

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Common inflammatory molecules and pathways between psoriasis and diabetes Chronic inflammation in psoriasis leads to increased insulin-like growth factor-II (IGF-II) in the skin and blood of psoriasis patients [89]. IGF-II promotes epidermal proliferation and is also implicated in promoting atherosclerosis, in modulating body fat mass and lipid metabolism in mice, and is linked to diabetes and hyperlipidemia in animal and human models [90]. Immunocytes and KCs in psoriatic skin produce angiogenic factors, such as VEGF, which promote angiogenesis and endothelial cell activation. VEGF is also increased in hyperinsulinemic states such as the metabolic syndrome, in which adipocytes are its primary source [91]. Therefore, hyperinsulinemic states such as obesity and the metabolic syndrome might promote susceptibility to psoriasis or exacerbate existing psoriasis not only through their role in promoting and facilitating inflammation, but also through increased and sustained levels of circulating VEGF. Common inflammatory molecules and pathways between psoriasis and hypercoagulation In psoriasis, thrombotic events could be triggered through established platelet activation [92]. Activated platelets may exert a role in psoriasis pathogenesis by favoring leukocyte rolling in the skin microvasculature [93]. In psoriasis patients, there is a homeostatic misbalance toward a prothrombotic state, which might be sustained by platelet hyperactivity [94].

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Inflammatory markers in psoriasis, such as TNF-alpha, IL-1, IL-6, can induce synthesis and release of acute-phase proteins, i.e. CRP and serum amyloid A by the liver. They also can increase the expression of cellular adhesion molecule on endothelial cells (e.g., ICAM-1, vascular cell adhesion molecule), which is required for the migration of leukocytes out of the circulation into the inflamed tissue, and potentially modulate prothrombic factors, thus increasing plasminogen activator inhibitor-1 and decreasing tissue plasminogen activator [95].

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Common inflammatory molecules and pathways between psoriasis and hypertension Angiotensinogen is the precursor of angiotensin-I, which, after conversion to angiotensin-II, has a major role in blood pressure regulation. It was shown that upon angiotensin II stimulation peripheral blood T cells are activated to produce TNF-alpha, IFN-gamma, and to express tissuehoming receptors [96]. Moreover, blocking TNF-alpha by etanercept normalized the blood pressure and vascular O2- production in angiotensin II-infused animals.

Treatment data

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As there is strong evidence that psoriasis is an independent risk factor for the development of metabolic and CV co-morbiditites, the most important question is whether long-term control of psoriasis could prevent, reverse, or attenuate its co-morbidities. An investigation into the effect of continuous systemic therapy found that patients who responded to therapy had significant correlations between PASI and high-sensitivity CRP, vascular endothelial growth factor, and the adipokines, resistin and adiponectin [97]. The metabolic state of patients improved with inflammatory control.

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Cholesterol lowering agents A pilot study evaluated the effectiveness of simvastatin which is a cholesterol lowering statin on serum lipoprotein levels and dermatitis in patients with severe psoriasis [98]. The authors found elevated high-density lipoprotein cholesterol levels and diminished PASI during the therapy concluding that statins can correct lipid metabolism and reduce cutaneous lesions in psoriasis. Wolkenstein P et al reported a decreased risk of psoriasis associated with statin intake [99]. Oral statins also enhance the therapeutic effect of topical steroids against psoriasis [100]. Thiazolidindiones Shafiq et al studied the effect of pioglitazone in psoriasis. In 70 patients with moderate to severe disease, the PASI scores improved significantly in treated vs. placebo patients with greater benefit being noted in those receiving higher doses of pioglitazone [101]. Traditional systemic therapies for psoriasis Traditional systemic therapies for psoriasis using methotrexate and cyclosporine may reduce the risk of cardiovascular disease by decreasing inflammation [102]. Treatment with methotrexate has been shown to be associated with decreased risk of CVD [103]. However, the traditional treatments are limited by the potential for adverse effects such as hypertension, dyslipidemia, hyperhomocysteinemia, and renal and hepatic toxicity. Biologic agents Novel investigations have focused on how biologics, used in psoriasis or rheumatoid arthritis (RA) may affect patients‟ CV risk factors and adverse cardiac outcomes. In a retrospective

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cohort, it was shown that the risk of diabetes was lower in psoriasis patients starting a TNF-alpha blocker or hydroxychloroquine compared with those initiated on other disease-modifying antirheumatic drugs (DMARD) [104]. Methotrexate initiation was not associated with any significant diabetes risk reduction. When compared with placebo, there was no significant difference in the rate of major adverse cardiovascular events (MACE) in patients receiving either anti-IL-12 ⁄ 23 or anti-TNF-alpha agents [105]. The Phase 3, REVEAL, trial indicated that adalimumab was well tolerated and significantly improved outcomes in patients with psoriasis and co-morbidities when compared with patients in the placebo group [106]. When TNF inhibitors were compared with nonbiological DMARDs on the effect of adverse cardiac outcomes in RA patients, the patients using TNF-alpha blockers experienced a reduced hazard of adverse cardiac outcomes including nonfatal myocardial infarction, transient ischemic attack, stroke, and CV death compared with the nonbiological DMARDs [107].

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Conclusion

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Psoriasis is now considered a chronic, immune-mediated inflammatory disease presenting with skin lesions and development of co-morbidities. Further investigation of the epidemiologic link between psoriasis and co-morbidities should take into account various confounding factors. The proposed common pathways between psoriasis and co-morbidities highlight the importance of treating psoriasis as a multifaceted disease and the need of regular screening of psoriasis patients for CV risk factors.

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Psoriasis as a systemic disease.

Psoriasis is an inflammatory immune-mediated disease that affects the skin and has pathogenic effects with systemic impact. The relationship between p...
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