Psoriasis as a systemic disease

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

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

To appear in: 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

This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.
 ACCEPTED MANUSCRIPT

Psoriasis as a systemic disease –

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

(igrozdev77@gmail.com)

P T
Psoriasis, a recalcitrant disease of chronic and systemic inflammation, affects approximately 2-
3% of the population, [1-3]. The cutaneous manifestations of this disease, often the most

RI
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

SC
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

NU
overview supporting the concept of understanding psoriasis as a systemic disease.

Epidemiological data MA
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,
ED

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
PT

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
CE

classification of comorbidities in psoriasis (Table 1):

Common Diseases
AC

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
 ACCEPTED MANUSCRIPT

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

Psoriasis and PsA

T
The prevalence of PsA in general population is estimated to 0.25% [8], while it is reported to be

P
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

RI
accepted rate of 7% [12].

SC
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

NU
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].
MA
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 IBD-
ED

3 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.
PT

Psoriasis and metabolic syndrome

Metabolic syndrome has been identified as a clustering of metabolic abnormalities in individuals
CE

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,
AC

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].

Impact of psoriasis onset and severity

T
Malbris et al conducted a cohort study among 8,991 hospitalized psoriasis patients and 19,757

P
ambulatory psoriasis patients [35]. The authors found a 50%-increased risk of CV mortality in

RI
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

SC
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

NU
psoriasis is associated with increased noncardiovascular mortality, but not with increased
cardiovascular risk [34]. MA
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
ED

[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
PT

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
CE

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
AC

higher [42]. Both alcohol and smoking may cause increased mortality in patients with moderate-
to-severe psoriasis [43].

Psoriasis and psychiatric/psychological diseases

The first reports on the impaired psychosomatic health of psoriasis patients date back to the 60-
ties 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
 ACCEPTED MANUSCRIPT

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].

P T
RI
Pathogenic mechanisms shared between psoriasis and co-morbidities

SC
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].

NU
MA
ED
PT
CE
AC
 ACCEPTED MANUSCRIPT

P T
RI
SC
NU
MA
ED
PT
CE
AC

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].
 ACCEPTED MANUSCRIPT

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.

T
Common inflammatory molecules and pathways between psoriasis and CVD

P
T-helper cells type 1 (Th1) and type 17 (Th17), and regulatory T cells (Treg) play integral roles

RI
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,

SC
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

NU
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
MA
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
ED

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].
PT

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
CE

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
AC

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, TNF-
alpha) 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
 ACCEPTED MANUSCRIPT

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,

T
and the presence of local and systemic inflammatory markers [49,79,80]. Activation of these

P
inflammatory cells (dendritic cells, macrophages and T cells) together with the release of pro-

RI
inflammatory 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].

SC
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

NU
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].
MA
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
ED

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
PT

[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
CE

in obesity and in psoriasis compared with healthy controls [88].

Common inflammatory molecules and pathways between psoriasis and diabetes

AC

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].
 ACCEPTED MANUSCRIPT

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].

P T
Common inflammatory molecules and pathways between psoriasis and hypertension

RI
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 tissue-

SC
homing receptors [96]. Moreover, blocking TNF-alpha by etanercept normalized the blood
pressure and vascular O2- production in angiotensin II-infused animals.

NU
Treatment data
As there is strong evidence that psoriasis is an independent risk factor for the development of
MA
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
ED

the adipokines, resistin and adiponectin [97]. The metabolic state of patients improved with
inflammatory control.
PT

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
CE

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
AC

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
 ACCEPTED MANUSCRIPT

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 anti-
rheumatic 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

T
adalimumab was well tolerated and significantly improved outcomes in patients with psoriasis

P
and co-morbidities when compared with patients in the placebo group [106]. When TNF

RI
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,

SC
stroke, and CV death compared with the nonbiological DMARDs [107].

Conclusion

NU
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
MA
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.
ED

References
PT

1. Gelfand, J.M., et al., Prevalence and treatment of psoriasis in the United Kingdom: a
population-based study. Arch Dermatol 2005. 141(12): p. 1537-41.
2. Griffiths, C.E. and J.N. Barker, Pathogenesis and clinical features of psoriasis. Lancet
CE

2007. 370(9583): p. 263-71.

3. Foundation, N.P. National Psoriasis Foundation. [cited 2009 July 10]; Psoriasis
Statistics]. Available from: http://www.psoriasis.org/about/stats.
AC

4. Mrowietz U, Reich K. Psoriasis – new insights into pathogenesis and treatment. Dtsch
Arztebl Int 2009; 106(1-2): 11-8.
5. Henseler T, Christophers E. Disease concomitance in psoriasis. J Am Acad Dermatol 199;
32: 982–6.
6. Christophers E. Comorbidities in psoriasis. J Eur Acad Dermatol Venereol 2006; 20:52-5.
7. Puig-Sanz L. Psoriasis, a systemic disease? Actas Dermosifiliogr 2007; 98(6): 396-402.
8. Haglund E, Bremander AB, Petersson IF, et al. Prevalence of spondyloarthritis and its
subtypes in southern Sweden. Ann Rheum Dis 2011; 7: 943-8.
9. Wilson FC, Icen M, Crowson CS, McEvoy MT, Gabriel SE, Kremers HM. Incidence and
clinical predictors of psoriatic arthritis in patients with psoriasis: a population-based stud.
Arthritis Rheum 2009; 61: 233-9.
10. Alenius GM, Stenberg B, Stenlund H, et al. Inflammatory joint manifestations are
prevalent in psoriasis: prevalence study of joint and axial involvement in psoriatic patient,
and evaluation of a psoriatic and arthritic questionnaire. J Rheumtol 2002; 29: 2577-82.
11. National Psoriasis Foundation 2009 Survey Panel Snapshot. National Psoriasis
Foundation website. www.psoriasis.org/research/survey-panels/current-survey-panel.
 ACCEPTED MANUSCRIPT

12. Zachariae H, Zachariae R, Blomquist K, et al. Quality of life and prevalence of arthritis
reported by 5, 795 members of the Nordic Psoriasis Associations. Data from Nordic
Quality of Life Study. Acta Derm Venereol 2002; 82: 108-13.
13. Nair R, Henseler T, Jenish S, Stuart P, Bichakjian C, Lenk W. Evidence for two psoriasis
susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by geno
me-wide scan. Hum Mol Genet 1997; 6: 1349-56.

T
14. Lee F, Bellary S, Francis C. Increased occurrence of psoriasis in patients with Crohn‟s

P
disease and their relatives. Am J Gastroenterol 1990: 85: 962-3.

RI
15. Nair RP, Stuart P, Henseler T, Jenisch S, Chia NV, Westphal E, et al. Localization of
psoriasis-susceptibility locus PSORS1 to 60-kb interval telomeric to HLA-C. Am J Hum
Genet 2000; 66: 1833-44.

SC
16. Hampe J, Schreiber S, Shaw SH, Lau KF, Bridger S, Macpherson AJ, et al. A genome-
wide analysis provides evidence for novel linkages in inflammatory bowel disease in a
large European cohort. Am J Hum Genet 1999; 64: 808-16.

NU
17. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech.
2009 May-Jun;2(5-6):231-7.
18. Zimmet P, Magliano D, Matsuzawa Y, Alberti G, Shaw J. The metabolic syndrome: a
MA
global public health problem and a new definition. J Atheroscler Thromb. 2005;12(6):
295 - 300.
19. Sommer DM, Jenisch S, Suchan M, Christophers E, Weichenthal M. Increased
prevalence of the metabolic syndrome in patients with moderate to severe psoriasis. Arch
ED

Dermatol Res. 2006 Dec;298(7):321-8.

20. Gisondi P, Tessari G, Conti A, Piaserico S, Schianchi S, Peserico A, et al. Prevalence
of metabolic syndrome in patients with psoriasis: a hospital-based case-control study. Br J
PT

Dermatol. 2007 Jul;157(1):68-73.

21. Cohen AD, Sherf M, Vidavsky L, Vardy DA, Shapiro J, Meyerovitch J. Association
between psoriasis and the metabolic syndrome. A cross-sectional study. Dermatology.
CE

2008;216(2):152-5.
22. Shapiro J, Cohen AD, David M, Hodak E, Chodik G, Viner A, et al. The association
between psoriasis, diabetes mellitus, and atherosclerosis in Israel: a case-control study. J
AC

Am Acad Dermatol. 2007 Apr;56(4):629-34.

23. Naldi L, Chatenoud L, Linder D, Belloni Fortina A, Peserico A, Virgili AR, et al.
Cigarette Smoking, Body Mass Index, and Stressful Life Events as Risk Factors for Psoria
sis: Results from an Italian Case-Control Study. Journal of Investigative Dermatology.
2005;125(1):61-7.
24. Dreiher J, Weitzman D, Davidovici B, Shapiro J, Cohen AD. Psoriasis and dyslipidaemia:
a population-based study. Acta Derm Venereol. 2008;88(6):561-5.
25. Cohen AD, Gilutz H, Henkin Y, Zahger D, Shapiro J, Bonneh DY, et al. Psoriasis and
the metabolic syndrome. Acta Derm Venereol. 2007;87(6):506-9.
26. McDonald CJ, Calabresi P. Psoriasis and occlusive vascular disease. Br J Dermatol. 1978
Nov;99(5):469-75.
27. Ena P, Madeddu P, Glorioso N, Cerimele D, Rappelli A. High prevalence of
cardiovascular diseases and enhanced activity of the renin-angiotensin system in psoriatic
patients. Acta Cardiol. 1985;40(2):199-205.
28. Stern RS, Lange R. Cardiovascular disease, cancer, and cause of death in patients with
psoriasis: 10 years prospective experience in a cohort of 1,380 patients. J Invest Dermatol.
1988 Sep;91(3):197-201.
 ACCEPTED MANUSCRIPT

29. Pearce DJ, Morrison AE, Higgins KB, Crane MM, Balkrishnan R, Fleischer Jr AB, et
al. The comorbid state of psoriasis patients in a university dermatology practice. J
Dermatolog Treat. 2005;16(5/6):319-23.
30. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of
myocardial infarction in patients with psoriasis. JAMA 2006 Oct 11;296(14):1735-41.
31. Gelfand JM, Dommasch ED, Shin DB, Azfar RS, Kurd SK, Wang X, Troxel AB. The risk

T
of stroke in patients with psoriasis. J Invest Dermatol 2009; 129(10): 2411-8.

P
32. Prodanovich S, Kirsner RS, Kravetz JD, Ma F, Martinez L, Federman DG. Association

RI
of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and m
ortality. Arch Dermatol. 2009 Jun;145(6):700-3.
33. Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Patients with

SC
severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the
General Practice Research Database. Eur Heart J 2010; 31(8): 1000-6.
34. Stern RS, Huibregtse A. Very severe psoriasis is associated with increased

NU
noncardiovascular mortality but not with increased cardiovascular risk. J Invest Dermatol
2011; 131(5): 1159-66.
35. Mallbris L, Akre O, Granath F, Yin L, Lindelof B, Ekbom A, et al. Increased risk for card
MA
iovascular mortality in psoriasis inpatients but not in outpatients. Eur J Epidemiol 2004;
19(3): 225-30.
36. Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. Prevalence of
cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol. 2006 Nov;55
ED

(5):829-35.
37. Bessis D. [Severe psoriasis: beyond the skin, what are the risks of not treating the
disease?]. Ann Dermatol Venereol. 2008 Jul;135 Suppl 5:S285-9.
PT

38. Wolf R, Wolf D, Ruocco V. Alcohol intake and psoriasis. Clin Dermatol. 1999 Jul-
Aug;17(4):423-30.
39. Lindegard B. Diseases associated with psoriasis in a general population of 159,200
CE

middle-aged, urban, native Swedes. Dermatologica. 1986;172(6):298-304.

40. Poikolainen K, Reunala T, Karvonen J, Lauharanta J, Karkkainen P. Alcohol intake: a
risk factor for psoriasis in young and middle aged men? Bmj. 1990 Mar 24;300(6727):780
AC

-3.
41. Morse RM, Perry HO, Hurt RD. Alcoholism and psoriasis. Alcohol Clin Exp Res.
1985 Sep-Oct;9(5):396-9.
42. Herron MD, Hinckley M, Hoffman MS, Papenfuss J, Hansen CB, Callis KP, et al. Impact
of obesity and smoking on psoriasis presentation and management. Arch Dermatol. 2005;
141: 1527-34.
43. Poikolainen K, Karvonen J, Pukkala E. Excess mortality related to alcohol and smoking
among hospital - treated patients with psoriasis. Arch Dermatol 1999; 135(12): 1490-3.
44. Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of depression,
anxiety, and suicidality in patients with psoriasis: a population-based cohort study. Arch
Dermatol. 2010 Aug;146(8):891-5.
45. Gupta MA, Gupta AK. Psychiatric and psychological co-morbidity in patients with
dermatologic disorders: epidemiology and management. Am J Clin Dermatol. 2003; 4:
833-42.
46. Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with
acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol. 1998;139:846-50.
 ACCEPTED MANUSCRIPT

47. Gelfand JM, Weinstein R, Porter SB, Neimann AL, Berlin JA, Margolis DJ. Prevalence
and treatment of psoriasis in the United Kingdom: a population-based study. Arch
Dermatol 2005; 141(12): 1537-41.
48. Gupta MA, Gupta AK, Kirkby S, Weiner HK, Mace TM, Schork NJ, et al. Pruritus
in psoriasis. A prospective study of some psychiatric and dermatologic
correlates. Arch Dermatol. 1988 Jul;124(7):1052-7.

T
49. Boehncke WH, Boehncke S, Tobin AM, Kirby B. The „psoriatic march‟: a concept of

P
how severe psoriasis may drive cardiovascular comorbidity. Exp Dermatol 2011; 20:

RI
303–307.
50. Mehta NN, Yu Y, Saboury B, Foroughi N, Krishnamoorthy P, Raper A, et al. Systemic
and Vascular Inflammation in Patients With Moderate to Severe Psoriasis as Measured by

SC
[18F] - Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography
(FDG-PET/CT): A Pilot Study. Arch Dermatol 2011; 147(9): 1031-9.
51. Dowlatshahi EA, Kavousi M, Nijsten T, Ikram MA, Hofman A, Franco OH, Wakkee M.

NU
Psoriasis is not associated with atherosclerosis and incident cardiovascular events: the
Rotterdam study. J Invest Dermatol 2013, Apr 4 [Epub ahead of print].
52. Armstrong AW, Voyles SV, Armstrong EJ, Fuller EN, Rutledge JC. A tale of two
MA
plaques: convergent mechanisms of T-cell-mediated inflammation in psoriasis and
atherosclerosis. Exp Dermatol. 2011;20(7): 544–549.
53. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009; 361(5):496–509.
54. Robert C, Kupper TS. Inflammatory skin diseases, T cells, and immune surveillance. N
ED

Engl J Med. 1999;341(24):1817–1828.

55. Rizova H, Nicolas JF, Morel P, et al. The effect of anti-CD4 monoclonal antibody
treatment on immunopathological changes in psoriatic skin. J Dermatol Sci. 1994;7(1):1–
PT

13.
56. Kourosh AS, Miner A, Menter A. Psoriasis as the marker of underlying systemic disease.
Skin Therapy Lett 2008; 13(1): 1-5.
CE

57. Libby P. The molecular mechanisms of the thrombotic complications of atherosclerosis. J

Intern Med. 2008;263(5):517–527.
58. Uyemura K, Demer LL, Castle SC, et al. Cross-regulatory roles of interleukin (IL)-12 and
AC

IL-10 in atherosclerosis. J Clin Invest. 1996;97(9): 2130–2138.

59. Methe H, Brunner S, Wiegand D, Nabauer M, Koglin J, Edelman ER. Enhanced T-
helper-1 lymphocyte activation patterns in acute coronary syndromes. J Am Coll Cardiol.
2005;45(12): 1939–1945.
60. Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest 2006;
116(5): 1218-22.
61. Takahashi H, Tsuji H, Hashimoto Y, Ishida-Yamamoto A, Iizuka H. Serum cytokines and
growth factor levels in Japanese patients with psoriasis. Clin Exp Dermatol.
2010;35(6):645–649.
62. Zaba LC, Cardinale I, Gilleaudeau P, et al. Amelioration of epidermal hyperplasia by
TNF inhibition is associated with reduced Th17 responses. J Exp Med.
2007;204(13):3183–3194.
63. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and Th1
cells are increased in psoriasis. J Invest Dermatol 2010; 130(5): 1373-83.
64. Biasucci LM, Liuzzo G, Grillo RL, et al. Elevated levels of C-reactive protein at
discharge in patients with unstable angina predict recurrent instability. Circulation.
1999;99(7):855–860.
 ACCEPTED MANUSCRIPT

65. Hashmi S, Zeng QT. Role of interleukin-17 and interleukin-17-induced cytokines

interleukin-6 and interleukin-8 in unstable coronary artery disease. Coron Artery Dis.
2006;17(8):699–706.
66. Chabaud M, Miossec P. The combination of tumor necrosis factor alpha blockade with
interleukin-1 and interleukin-17 blockade is more effective for controlling synovial
inflammation and bone resorption in an ex vivo model. Arthritis Rheum.

T
2001;44(6):1293–1303.

P
67. Canavese M, Altruda F, Ruzicka T, et al. Vascular endothelial growth factor (VEGF) in

RI
the pathogenesis of psoriasis--a possible
target for novel therapies? J Dermatol Sci. 2010; 58: 171-6.
68. Numasaki M, Lotze MT, Sasaki H. Interleukin-17 augments tumor necrosis factor-alpha-

SC
induced elaboration of proangiogenic factors from fibroblasts. Immunol Lett.
2004;93(1):39–43.
69. George J. Mechanisms of disease: the evolving role of regulatory T cells in

NU
atherosclerosis. Nat Clin Pract Cardiovasc Med. 2008;5(9): 531–540.
70. Gotsman I, Gupta R, Lichtman AH. The influence of the regulatory T lymphocytes on
atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27(12):2493–2495.
MA
71. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune
tolerance. Cell. 2008;133(5):775–787.
72. Kagen MH, McCormick TS, Cooper KD. Regulatory T cells in psoriasis. Ernst Schering
Res Found Workshop. 2006;56:193–209.
ED

73. Flisiak I, Chodynicka B, Porebski P, Flisiak R. Association between psoriasis severity and
transforming growth factor beta(1) and beta(2) in plasma and scales from psoriatic
lesions. Cytokine. 2002;19(3): 121–125.
PT

74. Flisiak I, Zaniewski P, Chodynicka B. Plasma TGF-beta1, TIMP-1, MMP-1 and IL-18 as
a combined biomarker of psoriasis activity. Biomarkers. 2008;13(5):549–556.
75. Leivo T, Leivo I, Kariniemi AL, Keski-Oja J, Virtanen I. Down- regulation of
CE

transforming growth factor-beta receptors I and II is seen in lesional but not non-lesional
psoriatic epidermis. Br J Dermatol. 1998; 138(1):57–62.
76. Mallat Z, Besnard S, Duriez M, et al. Protective role of interleukin-10 in atherosclerosis.
AC

Circ Res. 1999;85(8):e17–e24.

77. Mallat Z, Gojova A, Marchiol-Fournigault C, et al. Inhibition of transforming growth
factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype
in mice. Circ Res. 2001; 89(10):930–934.
78. Ward NL, Loyd CM, Wolfram JA, Diaconu D, Michaels CM, McCormick TS. Depletion
of antigenpresenting cells by clodronate liposomes reverses the psoriatic skin phenotype
in KC-Tie2 mice. Br J Dermatol. 2011; 164:750–758.
79. Alexandroff AB, Pauriah M, Camp RD, Lang CC, Struthers AD, Armstrong DJ. More
than skin deep: atherosclerosis as a systemic manifestation of psoriasis. Br J Dermatol.
2009; 161:1–7.
80. Spah F. Inflammation in atherosclerosis and psoriasis: common pathogenic mechanisms
and the
potential for an integrated treatment approach. British Journal of Dermatology. 2008;
159:10–17.
81. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature.
2007; 445:866–873.
 ACCEPTED MANUSCRIPT

82. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med.
2005; 352:1685–1695.
83. Wang Y, Gao H, Loyd CM, Fu W, Diaconu D, Liu S, Cooper KD, McCormick TS,
Simon DI, Ward NL. Chronic skin-specific inflammation promotes vascular inflammation
and thrombosis. J Invest Dermatol 2012; 132(8): 2067-75.
84. Trayhurn P. The biology of obesity. Proc Nutr Soc 2005; 64:31–8

T
85. Hamminga EA, van der Lely AJ, Neumann HA et al. Chronic inflammation in psoriasis

P
and obesity: implications for therapy. Med Hypotheses 2006; 67:768–73

RI
86. Campfield LA, Smith FJ, Guisez Y et al. Recombinant mouse OB protein: evidence for a
peripheral signal linking adiposity and central neural networks. Science 1995; 269:546–9
87. Wulster-Radcliffe MC, Ajuwon KM, Wang J et al. (2004) Adiponectin differentially

SC
regulates cytokines in porcine macrophages. Biochem Biophys Res Commun 316:924–9
88. Davidovici BB, Sattar N, Prinz J, Puig L, Emery P, Barker JN, van de Kerkhof P, Stahle
M, Nestle FO, Girolomoni G, Krueger JG. Psoriasis and systemic inflammatory diseases:

NU
potential mechanistic links between skin disease and co-morbid conditions. J Invest
Dermatol 2010; 137(7): 1785-96.
89. Yoo H, Kim SJ, Kim Y et al. Insulin-like growth factor-II regulates the 12-lipoxygenase
MA
gene expression and promotes cell proliferation in human keratinocytes via the
extracellular regulatory kinase and phosphatidylinositol 3-kinase pathways. Int J Biochem
Cell Biol 2007; 39:1248–59
90. Zaina S, Nilsson J. Insulin-like growth factor II and its receptors in atherosclerosis and in
ED

conditions predisposing to atherosclerosis. Curr Opin Lipidol 2003; 14:483–9

91. Cao Y. Angiogenesis modulates adipogenesis and obesity. J Clin Invest 2007; 117:2362–
8.
PT

92. Kasperska-Zajac A, Brzoza Z, Rogala B .Platelet function in cutaneous diseases. Platelets

2008; 19:317–21
93. Ludwig RJ, Schultz JE, Boehncke WH et al. Activated, not resting, platelets increase
CE

leukocyte rolling in murine skin utilizing a distinct set of adhesion molecules. J Invest
Dermatol 2004; 122:830–6
94. Gisondi P, Girolomoni G. Psoriasis and atherothrombotic diseases: disease-specific and
AC

non-disease-specific risk factors. Semin Thromb Hemost 2009; 35:313–24

95. Barton BE. The biological effects of interleukin 6. Med Res Rev 1996; 16:87–109
96. Guzik TJ, Hoch NE, Brown KA et al. Role of the T cell in the genesis of angiotensin II
induced hypertension and vascular dysfunction. J Exp Med 2007; 204:2449–60
97. Boehncke S, Salgo R, Garbaraviciene J et al. Effective continuous systemic therapy of
severe plaque-type psoriasis is accompanied by amelioration of biomarkers of
cardiovascular risk: results of a prospective longitudinal observational study. J Eur Acad
Dermatol Venereol 2011; 25: 1187–1193.
98. Shirinsky IV, Shirinsky VS. Efficacy of simvastatin in plaque psoriasis: A pilot study. J
Am Acad Dermatol. 2007; 57: 529-31.
99. Wolkenstein P, Revuz J, Roujeau JC, et al. Psoriasis in France and associated risk factors:
results of a case-control study based on a large community survey. Dermatology 2009;
218: 103-9.
100. Naseri M, Hadipour A, Sepaskhah M, Namazi MR. The remarkable beneficial
effect of adding oral simvastatin to topical betamethasone for treatment of psoriasis: a
double-blind, randomized, placebo-controlled study. Niger J Med. 2010;19(1):58–61.
 ACCEPTED MANUSCRIPT

101. Shafiq N, Malhotra S, Pahndhi P, et al. Pilot trial: pioglitazone versus placebo in
patients with plaque psoriasis (the P6). Int J Dermatol. 2005; 44: 328-33.
102. Ghazizadeh R, Shimizu H, Tosa M, Ghazizadeh M. Pathogenetic mechanisms
shared between psoriasis and cardiovascular disease. Int J Med Sci 2010; 7(5): 284-9.
103. Prodanovich S, Ma F, Taylor JR et al. Methotrexate reduces incidence of vascular
diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol 2005;

T
52:262–7

P
104. Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S.

RI
Association between disease-modifying antirheumatic drugs and diabetes risk in patients
with rheumatoid arthritis and psoriasis. JAMA 2011;305(24):2525–2531.
105. Ryan C, Leonardi CL, Krueger JG et al. Association between biologic therapies

SC
for chronic plaque psoriasis and cardiovascular events: a
meta-analysis of randomized controlled trials. JAMA 2011; 306: 864–871.
106. Kimball AB, Bensimon AG, Guerin A et al. Efficacy and safety of adalimumab

NU
among patients with moderate to severe psoriasis with co-morbidities: subanalysis of
results from a randomized, double-blind, placebo-controlled, phase III trial. Am J Clin
Dermatol 2011; 12: 51–62.
MA
107. Greenberg JD, Kremer JM, Curtis JR, et al. Tumour necrosis factor antagonist use
and associated risk reduction of cardiovascular events among patients with rheumatoid
arthritis. Annals of the RheumaticDiseases. 2011;70(4):576–582.
ED
PT
CE
AC