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Psoriasis and Vascular Risk: An Update

Niki Katsiki1, Panagiotis Anagnostis

1,2, Vasilios G. Athyros

1, Asterios Karagiannis

1 and

Dimitri P. Mikhailidis3,*

1Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital,

Thessaloniki, Greece; 2Division of Endocrinology, Police Medical Centre of Northern Greece, Thessaloniki, Greece;

3Department of

Clinical Biochemistry (Vascular Disease Prevention Clinic) and Department of Surgery, Royal Free Campus, University College

London Medical School, University College London (UCL), London, UK

Abstract: Psoriasis is a chronic systemic inflammatory disease characterized by topical skin lesions as well as an increased risk for car-

diovascular disease (CVD). There is also increasing evidence that patients with psoriasis are more prone to several CVD risk factors (hy-pertension, obesity, dyslipidemia and smoking), non-cardiac vascular diseases (carotid, peripheral artery and chronic kidney disease) and

metabolic co-morbidities (type 2 diabetes mellitus, metabolic syndrome, non-alcoholic fatty liver disease and obstructive sleep apnea) compared with the general population. The associations are even greater in patients with severe psoriasis and those with psoriatic arthri-

tis. Insulin resistance, endothelial dysfunction and obesity induced by several adipokines and inflammatory cytokines are proposed as the common mechanisms linking psoriasis with CVD, vascular risk factors and metabolic diseases.

The present narrative review considers the associations between psoriasis (and psoriatic arthritis) with CVD, vascular risk factors and metabolic diseases. Drugs that reduce CVD risk and improve metabolic parameters may also beneficially affect psoriasis severity and

prognosis. Furthermore, anti-psoriatic drugs can exert different effects on CVD risk and metabolic co-morbidities. Therefore, physicians should be aware of these associations in order to adequately monitor and treat psoriatic patients.

Keywords: Psoriasis, psoriatic arthritis, cardiovascular disease, vascular risk factors, metabolic syndrome, non-alcoholic fatty liver disease.

INTRODUCTION

Psoriasis, apart from topical skin lesions, is also characterized by chronic systemic inflammation that leads to an increased risk for atherosclerosis, cardiovascular disease (CVD) and vascular risk factors (including hypertension, obesity, dyslipidemia and smoking) [1,2]. Common mechanisms linking psoriasis with CVD include insulin resistance, endothelial dysfunction and obesity; several adi-pokines and inflammatory cytokines may be involved in this proc-ess [3]. Non-cardiac vascular disease such as carotid disease, pe-ripheral artery disease (PAD) and chronic kidney disease (CKD), and metabolic co-morbidities such as type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD) and obstructive sleep apnea syndrome (OSAS), are linked to increased CVD risk [4-10].

In this narrative review the significant associations between psoriasis (and psoriatic arthritis) with CVD events and risk factors as well as with the aforementioned non-cardiac and metabolic dis-eases are discussed. Furthermore, we consider the results of clinical studies and meta-analyses as well as the effects of different anti-psoriatic drugs on CVD risk and metabolic co-morbidities. Drugs used to reduce CVD risk and improve metabolic parameters that may influence psoriasis severity and prognosis are also discussed.

SEARCH STRATEGY

We searched MEDLINE up to November 30, 2013 for relevant publications using combinations of the following keywords: psoria-sis, psoriatic arthritis, vascular risk, hypertension, lipids, glucose, smoking, obesity, lipoprotein (a), coronary heart disease, myocar-dial infarction, stroke, carotid artery disease, peripheral artery dis-ease, chronic kidney disease, atherosclerotic renal artery stenosis,

*Address correspondence to this author at the Dept. of Clinical Biochemis-try (Vascular Disease Prevention Clinics), Royal Free Hospital campus,

University College London Medical School, University College London (UCL), Pond Street London NW3 2QG, UK; Tel: 0044 (0) 20 7830 2258;

Fax: 0044 (0) 20 7830 2235; E-mail: MIKHAILIDIS@aol.com

abdominal aortic aneurysms, metabolic syndrome, vitamin D, ob-structive sleep apnea, non-alcoholic fatty liver disease, uric acid, type diabetes mellitus, arterial stiffness, platelets, fibrinolysis, he-mostasis, endothelial dysfunction, inflammatory markers, cytoki-nes, adipokines, homocysteine and cancer.

We also examined the reference list of articles identified by this search strategy and selected those we judged relevant.

PSORIASIS AND ESTABLISHED VASCULAR RISK FAC-TORS

Hypertension

Both psoriasis and psoriatic arthritis have been linked to hyper-tension [11-13]. A recent meta-analysis also showed that the risk of developing hypertension was greater in patients with severe psoria-sis and those with psoriatic arthritis compared with those with mild psoriasis [odds ratio (OR) for hypertension: 1.49; 95% confidence interval (CI) 1.20-1.86 and 2.07; 95% CI 1.41-3.04 vs 1.30; 95% CI 1.15-1.47, respectively] [14]. Furthermore, masked hypertension [defined as elevated ambulatory blood pressure (ABPM) in the presence of normal office BP] has been reported in psoriatic pa-tients and thus 24-h ABPM should be considered in such patients [15]. Interestingly, psoriatic patients are more frequently non-dippers compared with controls even in normotensive states [16]; severity of the disease and obesity were independently correlated with increased nocturnal BP.

Increased heart rate has been previously associated with vascu-lar risk [17]. Patients with psoriasis were found to have higher heart rate compared with controls [18]. Heart rate recovery and variabil-ity may also be impaired in patients with psoriasis [19] or psoriatic arthritis [20], thus predisposing such patients to CVD. These meas-ures of autonomic reactivity may also predict clinical response to anti-tumor necrosis factor (TNF) treatment [21]. Cardiac valve abnormalities may also be more frequent in patients with psoriasis [22].

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Of note, apart from nonsteroidal anti-inflammatory drugs, tetra-cyclines, synthetic antimalarial drugs, lithium, and gold, certain antihypertensive agents have been implicated in psoriasis develop-ment including beta-blockers, angiotensin-converting enzyme in-hibitors and angiotensin II receptor antagonists [23-25].

Dyslipidemia

Dyslipidemia [defined as triglycerides (TG) 150 mg/dl, high-density lipoprotein cholesterol (HDL-C) levels < 40 mg/dl or hy-perlipoproteinemia] has been related to psoriasis presence and se-verity [26,27] as well as to psoriatic arthritis [28,29]; however, conflicting results also exist [30]. Higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were also asso-ciated with psoriasis as reported in a recent meta-analysis [31]. Furthermore, LDL size and HDL function may be impaired in pso-riasis; decreased LDL size and HDL efflux capacity were observed in psoriatic patients compared with controls [32,33]. In the same context, both total and small HDL particle concentrations have been related to aortic inflammation in psoriatic patients, even after ad-justment for CVD risk factors [34]. Elevated small dense LDL (sdLDL) levels have also been reported in patients with psoriatic arthritis [35]. Both small dense LDL particles and HDL dysfunction have been linked to increased vascular risk [36-39]. Interestingly, apart from short duration of psoriasis, high HDL-C levels were a significant predictor of clinical response to infliximab in psoriatic patients [40]. A population-based analysis found that during 5 years before and after psoriasis incidence, TC and LDL-C levels were significantly decreased in both the psoriasis and control cohorts, whereas HDL-C concentrations were increased in the psoriasis cohort; the use of cholesterol-reducing drugs was similar between cohorts [41]. Overall, mean TGs were higher and HDL-C was lower in psoriatic patients compared with non-psoriasis individuals [41]. Anti-psoriatic therapy was recently reported to improve HDL function [42]; in contrast, infliximab was shown to increase TG levels but in a very small study (n = 15) [43]. These data suggest a potential role of lipid metabolism in psoriasis with further studies being needed to establish any clinical implications in daily practice.

Statins play an important role in dyslipidemia treatment in sev-eral patient populations such as those with CHD [44], T2DM [45], MetS [46], NAFLD [47,48], CKD [49], AAA [50], ARAS [51], PAD [52] and carotid disease [53]. Apart from reducing CVD risk, statins have been studied with regard to potential anti-inflammatory and immunomodulatory properties; simvastatin and atorvastatin were reported to beneficially affect clinical outcomes and Psoriasis Area and Severity Index (PASI) score in psoriatic patients [54,55]. However, data are inconsistent [56,57] and thus the presence of any clinically meaningful statin-induced “anti-psoriatic” effects remains to be established in future studies. To our knowledge, there are no data on the effect of fibrates on psoriasis except of a case-report commenting on psoriasis exacerbation by gemfibrozil [58].

Patients with psoriasis have higher levels of apolipoprotein B (apoB) [59] and lipoprotein (a) [Lp(a)] compared with healthy indi-viduals [60]. Furthermore, Lp(a) has been associated with psoriasis severity [61]. With regard to psoriasis treatment, both psolaren plus UVA (PUVA) and narrow-band UVB radiation improved oxidative and inflammatory markers, but only PUVA reduced Lp(a) levels [62].

Obesity

Obesity has been associated with several dermatological condi-tions including skin cancer and psoriasis [63], especially in cases with late onset psoriasis [64]. A recent meta-analysis found that patients with psoriasis are more prone to obesity and the risk is even greater in those with severe compared with mild psoriasis [65]. Similarly, both in the general population and in psoriasis pa-tients, obese ones are more likely to develop psoriatic arthritis [66], especially when obesity is already prevalent at the age of 18 years

[67]. Furthermore, patients with psoriatic arthritis are more fre-quently obese than those with rheumatoid arthritis [68]. These asso-ciations may be at least partly explained by the secretion of proin-flammatory adipokines including leptin, adiponectin, interleukin-6 (IL-6), TNF-a and plasminogen activator inhibitor-1 (PAI-1) [69,70]; such markers have been implicated in the pathogenesis of several metabolic disorders such as obesity [71], MetS [4] and T2DM [72]. These inflammatory mediators can preserve the vicious cycle between obesity and psoriasis. Interestingly, obesity was also linked to worse clinical outcomes [73], sleep and life quality [74] as well as with a higher risk of anti-psoriatic drug discontinuation, inefficacy and adverse effects [75].

Diet-induced weight loss was shown to significantly improve PASI and Dermatology Life Quality Index (DLQI) in psoriatic patients [76,77]. Similarly, bariatric surgery was reported to exert beneficial effects in terms of clinical symptoms, need for drug ther-apy and quality of life in psoriatic patients [78]; apart from weight reduction, increases in glucagon-like peptide-1 (GLP-1) levels may be also responsible for these results [79]. In contrast, infliximab was shown to promote weight gain in patients with psoriasis and thus dietary consultation should be provided in such patients [80].

Smoking and Alcohol Consumption

Psoriatic patients are more prone to smoking [81]. Furthermore, smoking duration and intensity have been independently associated with psoriasis incidence [81,82] and severity [83]; possible mecha-nisms that are involved in this relationship include inflammatory, oxidative and genetic pathways [84]. In general, smoking damages the skin and can lead to several dermatological conditions apart from psoriasis, such as premature skin aging, acne, melanoma and hair loss [85]. Smoking has been also related to higher risk for de-veloping psoriatic arthritis [86,87] as well as with worse functional outcomes in patients with this arthritis [88]. Among psoriatic pa-tients, smokers are more likely to develop psoriatic arthritis than non-smokers [89]. On the other hand, smoking cessation may re-duce the risk of developing psoriasis [82] and lead to clinical im-provements in psoriatic patients [90].

Based on these data, the Recent National Psoriasis Foundation (NPF) guidelines [91] recommend the implementation of lifestyle changes including quitting smoking in daily practice when treating psoriatic patients. Of note, Staples et al [92] recently reported bene-ficial effects of nicotine replacement therapy on psoriasis symptoms in one patient; the authors commented on the known benefits of smoking in ulcerative colitis and on the possible common immu-nological processes between ulcerative colitis and psoriasis. In con-trast, bupropion, an “anti-smoking” drug, was found to aggravate psoriasis [93]. To our knowledge, there are no data on varenicline.

Similarly to smoking, alcohol consumption is more frequent in psoriatic patients [94]. Furthermore, alcohol users are at a higher risk of developing psoriasis compared with non-users [95]. Secre-tion of inflammatory cytokines, activation and proliferation of keratinocytes and lymphocytes are suggested as possible mecha-nisms leading to systemic inflammation and skin diseases in alco-holics [96]. These alcohol-induced effects may also explain the increased prevalence of CVD in heavy drinkers [97]. Of note, light-to-moderate alcohol consumption has been shown to exert cardio-protective and neuroprotective properties [98-100]; alcohol-induced beneficial effects on several receptors, protein kinase C, potassium channels and nitric oxide synthase as well as on lipids and hemo-static factors such as platelets and fibrinolytic activity may explain these findings [101-103]. In this context, a prospective analysis of the Nurses' Health Study II [104] reported that only non-light beer intake was associated with an increased risk of psoriasis in women and not light beer, red or white wine and liquors.

Anti-psoriatic therapy may be less effective and with a higher risk of toxicity and poor compliance in alcohol users [96,105]. In this context, physicians should establish the drinking status in pa-

Psoriasis and Vascular Risk Current Pharmaceutical Design, 2014, Vol. 20, No. 00 3

tients with psoriasis, possibly with the implementation of both vali-dated questionnaires [e.g. Alcohol Use Disorders Identification Test (AUDIT)] and laboratory markers, as some patients conceal their alcohol consumption [106,107].

T2DM and MetS

This topic is covered in detail below.

Overall, psoriasis and psoriatic arthritis have been associated with increased prevalence of hypertension, dyslipidemia, obesity, smoking and alcohol consumption; this association increases with the severity of psoriasis. Treatment of these CVD risk factors may improve psoriasis symptoms, severity and outcomes.

PSORIASIS AND EMERGING VASCULAR RISK FACTORS

Inflammation plays a key role in the pathogenesis of psoriasis; several inflammatory biomarkers have been implicated in the proc-ess including adipokines, C-reactive protein (CRP), IL-6 and PAI-1 [108] as mentioned above [69,70]. A recent meta-analysis focusing on inflammatory markers found that CRP, IL-6, TNF-a, E-selectin and intracellular adhesion molecule (ICAM)-1 were significantly higher in patients with psoriasis [109]. Interestingly, as inflamma-tory state is higher in psoriatic arthritis compared with psoriasis, certain biomarkers such as CRP, IL-6 and matrix metalloprotease-3 (MMP-3) may be used to differentiate the 2 diseases [110,111]. Elevated CRP levels have been linked to both the presence and severity of psoriasis; improvements have been reported following psoriasis treatment [112-114]; similar data have been reported for psoriatic arthritis [115,116]. CRP also correlated with the length of psoriasis remission [117].

A recent study reported impaired rheological profile (in terms of blood viscosity, erythrocyte aggregation and fibrinogen) in pso-riatic patients compared with healthy individuals; these markers were improved following anti-TNFa treatment [118]. Similarly, in a previous study [119], elevated PAI-1 levels were decreased (con-currently with PASI) after treatment with ranitidine in patients with psoriasis.

Platelet aggregation and activity are increased in patients with psoriasis [120,121] and psoriatic arthritis [122]. Furthermore, plate-let reactivity correlated with psoriasis severity (as assessed by PASI) [120]. Similarly, mean platelet volume has been associated with the presence and severity of both psoriasis and psoriatic arthri-tis [123]. Elevated platelet-monocyte complexes have been ob-served in patients with psoriatic arthritis [124].

In psoriasis patients, platelet P-selectin expression was signifi-cantly reduced to the level of the controls following successful treatment [125]; platelet P-selectin expression also correlated with PASI. These findings suggest its use as a marker of treatment effi-cacy in psoriatic patients. Interestingly, platelet P-selectin was as-sociated with plasma P-selectin, thus supporting a possible role of the latter in clinical practice [125]. Of note, thrombocytopenia has been described as a rare adverse effect of TNF-inhibitor therapy [126,127]. In contrast, other anti-psoriatic therapies may cause thrombocytosis [128].

Arterial stiffness, a novel vascular marker [129], has been asso-ciated with several CVD risk factors including hypertension [130], T2DM [131], obesity [132] and smoking [133,134]. Psoriasis was previously shown to correlate with increased arterial stiffness [135-137]; there is evidence linking psoriasis duration and severity with increased arterial stiffness [138], although conflicting results also exist [139-141]. Patients with psoriatic arthritis have also higher arterial stiffness compared with controls [142,143]. Interestingly, anti-TNFa therapy can improve arterial stiffness in patients with psoriatic arthritis [144].

Psoriasis has also been related to endothelial dysfunction; circu-lating endothelial cells (CECs), microparticles (MPs) and von Willebrand factor (vWF) levels were significantly higher and flow-

mediated dilation (FMD) was lower in psoriatic patients compared with controls [145,146]. Patients with psoriatic arthritis also exhibit endothelial function impairment [147]. Furthermore, vascular endo-thelial growth factor (VEGF) levels were increased in psoriatic patients compared with controls and they were significantly corre-lated with psoriasis severity (as assessed by PASI) [148]. Similar results were observed in patients with psoriatic arthritis [149] and certain polymorphisms of VEGF and other growth factors [epider-mal growth factor (EGF) and fibroblast growth factors 1 and 2 (FGF1 and FGF2)] have been reported to protect from the devel-opment of psoriatic arthritis [150]. Such findings highlight the role of angiogenesis and inflammation in the pathogenesis of psoriasis [151]. In this context, circulating levels of endocan (endothelial cell-specific molecule-1 that is regarded as a surrogate endothelial dysfunction marker) correlated with psoriasis severity (as assessed by PASI) and other CVD risk markers [i.e. carotid artery intima-media thickness (cIMT) and hsCRP] [152]. However, conflicting results on the link between psoriasis and endothelial impairment also exist [153]. TNF inhibitors were shown to improve endothelial function in patients with psoriasis or psoriatic arthritis [154]. On the other hand, VEGF inhibitors may beneficially affect clinical out-comes in psoriasis but data are still scarce and the risk of serious adverse effects limits their clinical use [155,156].

Lower levels of folic acid and higher concentrations of homo-cysteine (Hcy) have been reported in psoriatic patients [157,158] as well as in psoriatic arthritis [159]. Furthermore, Hcy levels corre-lated with psoriasis severity (as assessed by PASI) [160]. Of note, exposure to UV radiation may slightly decrease folic acid and in-crease Hcy concentrations in psoriasis patients [161]. Methotrexate has also been linked to elevations in Hcy levels and thus co-administration with folate is recommended [162]. In contrast, TNF-inhibitors may reduce Hcy levels in patients with psoriatic arthritis [163].

Vitamin D (vit D) deficiency has been linked to atherosclerosis [164], MetS [165] and statin intolerance [166]. Patients with psoria-sis and psoriatic arthritis have also lower vit D levels compared with healthy controls [167,168], especially in the winter [168]. With regard to psoriasis treatment, vit D analogs are both effective and safe topical agents, although there is a tendency towards the use of topical corticosteroids [169,170]; combination therapies are even more efficient as reported in a recent meta-analysis [171]. In this context, a previous study supported the efficacy and cost-effectiveness of adding calcipotriol cream in patients with psoriatic arthritis that were partial responders to etanercept [172]. Oral ad-ministration of vit D represents another therapeutic option for pso-riasis [173,174] and, based on its anti-inflammatory properties, it has also been proposed for psoriatic patients with MetS [175]. Of note, UV radiation exerts its beneficial effects mainly via enhanced vit D production in the skin [176].

Obstructive sleep apnea syndrome (OSAS), frequently seen in MetS patients, is linked to increased CVD risk [177]. Patients with psoriasis are more prone to OSAS prevalence than the general population [178]. Especially, patients with long disease duration and severe psoriasis should be assessed for the presence of OSAS [178]. Vice versa, patients with OSAS are at an increased risk of developing psoriasis or psoriatic arthritis [179]. Certain cytokines and neuropeptides may explain at least partly these associations [180]. With regard to psoriasis treatment, data are scarce; in one study, adalimumab did not affect OSAS [181].

Overall, psoriasis and psoriatic arthritis are characterized by inflammation, endothelial dysfunction, prothrombotic changes in coagulation and fibrinolysis, increased arterial stiffness and hyper-homocysteinemia. Anti-TNFa therapy may improve several of these disorders. Furthermore, vit D deficiency and OSAS are frequently seen in such patients. Therefore, physicians, and especially derma-tologists and rheumatologists, should be aware of these associations when treating psoriatic patients.

4 Current Pharmaceutical Design, 2014, Vol. 20, No. 00 Katsiki et al.

PSORIASIS AND CVD

Coronary Heart Disease (CHD)/Myocardial Infarction (MI)

Patients with psoriasis and psoriatic arthritis are at a high risk for MI compared with controls [182,183]; the risk increases with the severity of the disease [184]. Similarly, increased prevalence and severity of coronary artery calcification was reported in psori-atic patients [185]. Furthermore, a link between severe psoriasis and CVD mortality has been recently reported [186]. Excess death rate in such patients has been attributed mainly to CHD [187]. Coronary flow reserve (CFR) was lower in patients with psoriasis compared with healthy individuals [188]; CFR was negatively correlated to psoriasis duration and severity (as assessed by PASI). Interestingly, psoriasis was related to angiographically proven CHD independ-ently of traditional CVD risk factors in patients referred for coro-nary angiography [189]; among psoriatic patients, those with longer duration of the disease were more likely to develop CHD. Patients with severe psoriasis undergoing percutaneous coronary revascu-larization (PCI) had an increased risk of CVD morbidity and all-cause mortality compared with controls and those with mild disease [190]. Common pathways behind psoriasis and atherosclerosis as well as psychological effects may explain these relationships [91]. In this context, statins may be “dually” protective in terms of both CVD risk and psoriasis activity due to their lipid-lowering and anti-inflammatory properties [191].

TNF-a inhibitors significantly decreased MI risk and incident rate in psoriatic patients compared with topical treatment [192] independently of therapy duration [193]; a non-significant reduction was also observed when TNF-a inhibitors were compared with oral agents/phototherapy. Methotrexate was previously shown to reduce CVD incidence (including CHD and MI) in psoriatic patients [194].

Stroke

Both mild and moderate-severe psoriasis have been linked to increased stroke incidence, whereas only severe cases were related to CVD mortality as reported in recent meta-analyses [186,195,196]. Systemic inflammation, insulin resistance and endo-thelial dysfunction are implicated in the development of atheroscle-rosis and CVD in such patients [197]. Longer disease duration and presence of psoriatic arthritis may further increase CVD risk [198]. Patients with psoriasis are also more likely to develop atrial fibrilla-tion (AF) [199], although conflicting results also exist [200]. Hospi-tal stay and in-hospital mortality were lower in patients with derma-toses (including psoriasis) presenting with acute ischemic stroke [201]. However, psoriatic patients had an increased risk of suba-rachnoid hemorrhage when admitted to hospital [202]. Similarly, a nationwide study from Sweden found a more than doubled risk of hemorrhagic stroke during the first year after hospitalization for psoriasis, whereas the risk for ischemic stroke was not affected [203].

Treatment with biological agents or methotrexate was recently shown to significantly decrease stroke events in patients with severe psoriasis [204], although a previous meta-analysis reported no ef-fects on CVD events rate (including stroke) following biological therapies (i.e. anti-IL-12/IL-23 antibodies or anti-TNF-a) in patients with chronic plaque psoriasis [205]. A more recent study also found that CVD events were similar between psoriatic patients on usteki-numab and the general population [206]. In contrast, cyclosporine has been previously associated with increased BP and higher risk for MI, stroke and CVD death compared with placebo [207]. Nev-ertheless, further research is needed to establish treatment strate-gies, with regard to CVD risk, in patients with psoriasis.

Overall, patients with psoriasis and psoriatic arthritis are more prone to CHD and stroke; a link between severe psoriasis and CVD mortality has also been reported. There is evidence supporting a cardioprotective role for TNF-a inhibitors, although further studies are required to confirm these associations.

PSORIASIS AND NON-CARDIAC VASCULAR DISEASE

Carotid Disease

Carotid disease has been associated with the presence and se-verity of psoriasis [208], even after adjusting for traditional CVD risk factors [209]. Similar results have been reported in patients with psoriatic arthritis [143]. Furthermore, patients with psoriatic arthritis had higher carotid total plaque area (TPA) and cIMT than those with psoriasis alone [210,211]. Of note, ultrasound assess-ment of the carotid arteries was shown to improve risk stratification compared with the use of Framingham Risk Score alone in patients with psoriasis and psoriatic arthritis [212], thus supporting its im-plementation in clinical practice. With regard to anti-psoriatic ther-apy, carotid plaques were less frequent and cIMT was significantly lower in patients with psoriatic arthritis on TNF-a inhibitors than in those on disease-modifying antirheumatic drugs (DMARDs) [213]; TNF-a therapy duration was inversely correlated to cIMT. How-ever, the presence of carotid plaques has been linked to worse treatment outcomes in terms of achieving and maintaining minimal disease activity (MDA) in patients with psoriatic arthritis on TNF-a inhibitors [214].

PAD

Previous studies reported a higher prevalence of PAD in pa-tients with psoriasis and psoriatic arthritis [215,216]. Biologic ther-apy may reduce CVD risk in such patient populations [217]. How-ever, data are scarce and further studies are needed to establish the role of PAD in the presence, severity and treatment of psoriasis. Of note, PAD has been related to other vascular diseases such as CHD [218], carotid disease [219], CKD [220] and systemic atherosclero-sis [8], thus highlighting the importance of screening for polyvascu-lar disease in such patients [221].

CKD

Psoriasis has been related to an increased risk of developing CKD, especially in moderate and severe cases [222]. Renal im-pairment not only raises CVD risk but also can lead to death in psoriatic patients [223]. Furthermore, glomerular diseases [224] as well as nephrotoxicity with cyclosporine [225] and methotrexate [226] should be taken into consideration when treating patients with psoriasis. In contrast, infliximab treatment was proven safe and effective in patients with psoriatic arthritis undergoing hemodialysis due to CKD [227].

Atherosclerotic renal artery stenosis (ARAS) and abdominal aortic aneurysms (AAA)

We found no data on AAA and ARAS in psoriatic patients.

Overall, psoriasis and psoriatic arthritis are linked to carotid disease, PAD and CKD. There are limited data reporting improve-ments in cIMT following anti-TNF-a therapy. Further research is needed to evaluate treatment strategies, with regard to non-cardiac vascular diseases, in patients with psoriasis.

PSORIASIS AND T2DM

A link between T2DM and psoriasis presence and severity has been previously reported [184,228] and confirmed in recent meta-analyses [229,230]. Patients with psoriatic arthritis are also more likely to develop T2DM [228,229], especially women [231]. Possi-ble mechanisms involve the presence of systemic inflammation, insulin resistance, obesity and, consequently, MetS in psoriatic patients [195]. In a Spanish population, patients with late-onset and non-familial psoriasis as well as those with psoriatic arthritis had a highest risk of T2DM [232]. In contrast, in a US population-based cohort study, women and those with early-onset psoriasis were most likely to develop T2DM [198].

Apart from improvements in insulin sensitivity, metformin may exert beneficial cutaneous effects is several dermatological condi-tions, including psoriasis [233]. In this context, co-administration of

Psoriasis and Vascular Risk Current Pharmaceutical Design, 2014, Vol. 20, No. 00 5

metformin and methotrexate in psoriatic patients needs to be evalu-ated in future studies as it can reduce CVD risk, psoriasis severity and methotrexate dose, although there may be concerns regarding vitamin B12, folate and Hcy metabolism that possibly will require monitoring and treatment [234]. Pioglitazone therapy was associ-ated with reductions in psoriasis severity (as assessed by PASI) in a recent meta-analysis [235]; data on sulfonylureas are scarce. Sita-gliptin, a dipeptidyl peptidase-IV (DPP-IV) inhibitor, was shown to improve psoriatic skin lesions [236]; similar beneficial effects have also been reported for GLP-1 agonists [237,238]. In contrast, insu-lin therapy was related to psoriasis exacerbation [239,240].

Retinoid therapy reduced insulin sensitivity [241], whereas methotrexate was shown to improve insulin sensitivity and glucose control in diabetic mice [242]. Furthermore, treatment with TNF-a inhibitors or hydroxychloroquine has been linked to a lower risk for T2DM compared with other nonbiologic DMARDs [243]. How-ever, hyperglycemia induced by adalimumab (a TNF-a inhibitor) has been reported in a psoriatic patient [244].

PSORIASIS AND METS

Mets is a cluster of central obesity, dyslipidemia, hypertension and insulin resistance. These features are more frequently seen in psoriatic patients than in the general population [245]; of note the most common MetS component among patients with psoriasis was central obesity, followed by hypertriglyceridemia and low HDL-C levels in the National Health and Nutrition Examination Survey (2003-2006) [246]. Several adipokines and cytokines can contribute to the presence of such co-morbidities in psoriasis [3]. It follows that MetS prevalence (and severity) is significantly higher in pa-tients with psoriasis compared with controls as reported in several studies [247,248]; a recent meta-analysis confirmed the association between MetS and psoriasis presence as well as severity [249]. Patients with psoriatic arthritis are also more likely to develop MetS compared with controls [250] with an even higher risk for MetS compared with psoriatic individuals [210,211]. Interestingly, pa-tients with psoriatic arthritis and MetS have a greater cIMT than patients with psoriatic arthritis without MetS and psoriatic patients with or without MetS [210].

A recent study found that multifactorial treatment of MetS (in-cluding diet, atorvastatin, antihypertensive drugs and metformin and/or glibenclamide) improved psoriasis severity, although no systemic or topical psoriatic drug was administered, in patients with mild plaque-type psoriasis [251]. Multifactorial treatment has also been previously shown to exert beneficial effects on CVD risk, liver and renal function as well as SUA levels in MetS patients [46,252,253]. Therefore, patients with psoriasis and psoriatic arthri-tis should be evaluated in terms of metabolic risk factors and they should be adequately treated [254]. With regard to anti-psoriatic treatment, etanercept and adalimumab therapy improved several MetS features (mainly waist circumference, TGs, HDL-C and glu-cose) compared with methotrexate in patients with psoriatic arthritis [255]; similar results have been reported for these TNF-a inhibitors in patients with psoriasis [256,257].

PSORIASIS AND NAFLD

NAFLD incidence is higher in patients with psoriasis compared with controls [258]; the increased presence of obesity and MetS in such patients contributes to NAFLD development [259]. Several mechanisms have been proposed to account for these associations including inflammatory adipokines, cytokines and insulin resistance [259]. Furthermore, NAFLD may negatively affect the course of psoriasis as it has been related to the development of psoriatic ar-thritis in psoriatic patients [145]; NAFLD also correlated with PASI [260]. Vice versa, patients with psoriasis and NAFLD are more prone to severe liver fibrosis compared with NAFLD patients with-out psoriasis [261]. Methotrexate therapy may exert hepatotoxic adverse effects and thus liver tests should be monitored in patients

with psoriasis on methotrexate [262]. A recent study reported that etanercept was more effective in preventing hepatic fibrosis than psoralen and UVA (PUVA) therapy in psoriatic patients [263].

Epicardial fat has been recently proposed as a novel CVD risk factor [264]. Up-to-date, only 3 studies have been published (in 2013) that reported increased epicardial fat tissue in patients with psoriasis independently of age and MetS [265-267]. Epicardial fat mass was also associated with waist circumference, coronary artery calcification and cIMT in these patients [265,266].

PSORIASIS AND SERUM URIC ACID (SUA)

Hyperuricemia is more frequent in patients with psoriasis than controls, even after adjusting for age, gender and MetS features [268]. Furthermore, SUA levels have been associated with PASI in such patients [269]. Interestingly, elevated SUA levels correlated with MetS prevalence in patients with psoriasis [270] as well as with subclinical carotid disease in patients with psoriatic arthritis [271]. With regard to psoriasis therapy, cyclosporine may lead to increased SUA levels and subsequent renal function impairment; co-administration with allopurinol was shown to reduce the severity of these adverse effects in animal studies [272].

Overall, patients with psoriasis and psoriatic arthritis are char-acterized by a greater incidence of T2DM, MetS, NAFLD and hy-peruricemia. These co-morbidities can negatively affect both pso-riasis severity and CVD risk. Therefore, they should be diagnosed early, frequently monitored and adequately treated in psoriatic pa-tients.

Table 1 summarizes the risk of CVD events, vascular risk fac-tors, non-cardiac vascular diseases and metabolic co-morbidities associated with psoriasis.

PSORIASIS AND CANCER

Although this review focuses on the links between psoriasis and vascular disease, it is important to briefly mention that these pa-tients also have an increased risk of another serious disease (i.e. cancer). Furthermore, some of the anti-psoriatic drugs mentioned above may influence that risk. A recent meta-analysis found that patients with psoriasis are more prone to certain solid cancers, mainly those linked to smoking and alcohol consumption, including respiratory, upper aerodigestive and urinary tract cancers as well as liver cancer [273]. Furthermore, due to treatment with PUVA, cy-closporine and methotrexate, non-melanoma skin cancers (and es-pecially squamous cell carcinoma) are more frequent in these pa-tients [274]; similar results have been found for biologic therapies [275]. In contrast, TNF-a inhibitors were not associated with in-creased cancer risk in patients with psoriasis or psoriatic arthritis in a previous meta-analysis [276]. Only a few studies evaluated the possible carcinogenic risk of narrow-band UVB radiation in psori-atic patients, reporting no such effect [277].

CONCLUSIONS

Psoriasis, apart from topical skin lesions, is also characterized by chronic systemic inflammation that, via several adipokines and cytokines, leads to an increased risk for atherosclerosis, CVD events and other co-morbidities (including T2DM, MetS, NAFLD, CKD, PAD and carotid disease). Several studies and meta-analyses have reported a higher prevalence of CVD events, vascular risk factors, non-cardiac vascular and metabolic diseases in patients with psoriasis compared with the general population; the risk is even higher in patients with severe psoriasis and those with psori-atic arthritis. Drugs that reduce CVD risk and improve metabolic parameters may also beneficially affect psoriasis severity and prog-nosis. Anti-psoriatic drugs may exert different effects on CVD risk and metabolic co-morbidities. Therefore, physicians should be aware of these associations in order to adequately monitor and treat psoriatic patients in terms of CVD and metabolic risk factors.

6 Current Pharmaceutical Design, 2014, Vol. 20, No. 00 Katsiki et al.

DECLARATION OF INTEREST

This review was written independently. The authors did not receive financial or professional help with the preparation of the manuscript. Some of the authors have given talks, attended confer-ences and participated in advisory boards and trials sponsored by various pharmaceutical companies.

ACKNOWLEDGEMENTS

Declared none.

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Received: January 30, 2014 Accepted: April 15, 2014