Cardiometabolic comorbidities: the fingerprint of psoriasis

Intem Emerg M e d (2013) 8 (Suppl):SI55-S159
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Cardiometabolic comorbidities: the fingerprint of psoriasis
Paolo Gisondi • Giampiero Girolomoni
©SIMI2013
Abstract Psoriasis is a chronic inflammatory skin disease affecting 2-3% of the population worldwide. Plaque psoriasis
is characterized by red and scaly plaques generally located at
extensor sites such as the elbows and knees. The extent of skin
involvement is variable, ranging from a few localized plaques
to generalized involvement. Moderate to severe psoriasis
(> 10% of body surface area) is frequently associated with psoriatic arthritis and metabolic diseases (obesity, diabetes, nonalcoholic fatty liver disease, hypertension, dyslipidemia and
metabolic syndrome). Although the pathophysiological mechanisms underlying this association are unclear, a common genetic background as well as the systemic inflammatory state
related to psoriasis, with chronic elevation of cytokines such
as tumor necrosis factor-a and interleukin-6, -17, -20, -22, and
-23, may contribute to the overall morbidity. Moreover, patients with severe psoriasis are at increased risk of cardiovascular disease, highlighting the need for early cardiovascular
risk factor modifications. The recognition of comorbidities is
very important to ensure that the treatment of these patients is
tailoredto meet individuai needs, as some traditional systemic
anti-psoriatic agents can negatively affect cardio-metabolic
conditions and may have important interactions with the drugs
commonly used to treat them.
samento cutaneo è variabile, da poche placche al coinvolgimento generalizzato. La psoriasi moderata-grave (> 70% della superficie corporea) è frequentemente associata ad artrite psoriasica e a malattie metaboliche quali obesità, diabete, steatosi epatica, ipertensione, dislipidemia e sindrome metabolica. Nonostante i meccanismi fisiopatologici alla base
della associazione tra psoriasi e comorbilità non siano ancora ben definiti, si pensa che possa essere rilevante sia un
comune background genetico, che lo stato infiammatorio cronico correlato alla psoriasi con aumento di citochine quali
TNF-a, IL-6, IL-]7, lL-20, IL-22 e IL-23. Inoltre, i pazienti
con psoriasi mode rata-grave hanno un aumentato rischio di
malattie cardiovascolari, quali l'infarto del miocardio e l'ictus. E'molto importante che il trattamento della psoriasi sia
personalizzato, ovvero scelto tenendo in considerazione le
comorbilità del paziente. Infatti, alcuni farmaci sistemici per
il trattamento della psoriasi possono avere un impatto negativo sulle comorbilità od interagire con i farmaci concomitanti. La ciclosporina, ad esempio, può interagire negativamente con le statine causando rabdomiolisi e non è consigliabile nei pazienti con psoriasi e concomitante sindrome
metabolica.
Riassunto La psoriasi è una malattia infiammatoria cronica
della cute che colpisce il 2-3% della popolazione generale.
La psoriasi in placche è caratterizzata da placche eritemato-squamose classicamente localizzate a livello delle regioni estensorie quali gomiti e ginocchia. L'entità dell'interes-
Overview of psoriasis
P. Gisondi (;•:)
Department of Medicine, Section of Dermatology
University of Verona. Verona, Italy
Ph.:+39-045-8122547
Email: paolo.gisondi@univr.it
Psoriasis is an immune-mediated chronic inflammatory disease
affecting 2-3% of Caucasians. It is less common in Asians (about
0.1%) and rarely seen in Africans [1]. It can occur at any age,
although in the majority of individuals disease onset is before
the age of 40 years and is quite uncommon in children (0.7%)
[1]. Psoriasis affects genetically predisposed individuals and it
is commonly considered as a complex disease [2]. So far, 1020 chromosomal regions have been proposed to harbor psoriasis susceptibility genes. One locus consistently identified is the
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class I region of the major histocompatibility locus antigen cluster which encodes the human leukocyte antigen Cw6 [3].
However, its low penetrance (about 10%) indicates that other
genetic and environmental factors are also involved.
Our current understanding of the molecular pathogenesis
of psoriasis assigns centrai importance to an interaction between acquired and innate immunity [4] The disease is characterized by a series of linked cellular changes in the skin, including hyperplasia of epidermal keratinocytes, elongated and
dilated capillary loops, and infiltration of T lymphocytes, neutrophils, and other types of leukocytes in the affected skin [5].
At disease onset, plasmocytoid dendritic cells are activated in
the epidermis and dermis and produce tumor necrosis factor
(TNF)-a and interleukin (IL)-23, which promote the development of T helper (Th)l and T h l 7 cells [6]. Both sets of T
cells scerete several mediators, including interferon-y, TNFa, IL-6, lL-22 and IL-17, which are responsible for the inflammatory changes and epidermal hyperplasia 171. Epidermal
keratinocytes are the primary target of the immune responses, but they also strongly contribute to disease chronicity by
releasing chemokines and cytokines that attract and activate
inflammatory cells.
Plaque psoriasis is by far the most common clinical form
of the condition (90% of patients with psoriasis) and is characterized by well delineated red and scaly plaques |4|. The extent of involvement is variable, ranging from a few localized
plaques at extensor sites to generalized involvement (Fig. 1 ).
Rarely, psoriasis may involve the whole body, a condition referred to as erythroderma. Flexural (also known as inverse or
intertriginous) psoriasis refers to plaque psoriasis at submammary, groin, axillary, genital and natal cleft sites, and is typically less scaly. Seborrhoeic psoriasis is localized to seborrhoeic areas of the face, scalp and trunk. In guttate psoriasis,
there is an acute eruption of small (< 1 cm) papules of psoriasis that usually appear after a streptococcal infection. Distinctive
nail changes occur in about 50% of ali psoriasis patients and
are more common in those with psoriatic arthritis [8].
Psoriasis can decrease the quality of life, reducing employment and income levels [9] in addition to the negative
functional, psychological, and social impacts of the disease
110]. Several factors contribute to this burden, such as symptoms specifically related to the skin (for example, chronic itch,
pain and scaling), problems related to treatments (mess, odor,
inconvenience), psoriatic arthritis (functional impairment), and
the effect of living with a highly visible, disfiguring skin disease (diftìculties in relationships and poor self-esteem) [11].
Treatments available for psoriasis are various and they are
chosen according to its severity. Topical therapies include corticosteroids and vitamin D analogues, which are used in patients with mild disease. Phototherapy, narrow-band ultraviolet B light (UVB), photochemotherapy, psoralen plus U V A
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Fig. 1 Limited (a) and severe (b) chronic plaque psoriasis
light (PUVA), and conventional systemic agents such as cyclosporine, methotrexate and acitretin are reserved for moderate to severe cases (Table 1 ). In patients who do not tolerate
these treatments or in case of their inefficacy or contraindications, second-line systemic therapies, consisting of biological
drugs, i.e. the T N F - a antagonists adalimumab, etanercept and
infliximab, and ustekinumab, an anti-lL 12/23 monoclonal antibody, are administered. The retention rate is higher for of
T N F - a antagonists than for conventional treatments because
the former are better tolerated in case of continuous and longterm therapy [12, 13].
Comorbidities: the fingerprint of psoriasis
Several epidemiological studies have confirmed the association of chronic plaque psoriasis with comorbidities, which
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Table 1 Systemic treatments currently approved for moderate to severe
chronic plaque psoriasis
Conventional treatments
Biological drugs
Narrow-band ultraviolet ( U V ) B light
Adalimumab
Photochemotherapy. psoralen plus U V A light ( P U V A )
Etanercept
Cyclosporine
Infliximab
Methotrexate
Ustekinumab
Acitretin
can be classified in two major groups: (I) psoriatic arthritis
(PsA) and inflammatory bowel diseases such as Crohn's disease and ulcerative colitis and (2) cardio-metabolic disorders
such as myocardial infarction, stroke and hypertension, obesity, diabetes, dyslipidaemia, fatty liver disease and metabolic
syndrome. These comorbidities are a distinctive, specific and
identifying hallmark of psoriasis. They provide the equivalent of a fingerprint since they have not been associated with
other skin diseases (Fig. 2). The association between psoriasis and comorbidities can be explained by considering a common genetic background, the systemic effects of chronic inflammation, insulin resistance and an unhealthy life style.
such as smoking, over-eating and lack of exercise, ali of which
are common in patients with psoriasis [ 141. Psoriasis and obesity-related inflammatory states can reciprocally enhancing
conditions. Indeed, it is likely that cytokines released from
psoriatic keratinocytes or inflammatory cells infiltrating psoriatic skin mediate metabolic effects such as insulin resistance, favoring the development of type II diabetes mellitus
[15,16]. However, it is also possible that metabolic comorbidities actively contribute to increasing the psoriasis-related inflammatory state through the release of pathogenetic mediators from the liver and/or visceral adipose tissues, such as
reactive oxygen species, C reactive protein (CRP), IL-6 and
adipokines [17].
Fig. 2 The" fingerprint" of psoriasis, i.e. the most common comorbidities
associated with psoriasis
lotype. Although PsA was formerly considered a mild disease,
recent studies showed that it is erosive and deforming in
40-60% of patients, with bone damage arising in the first years
after disease onset [ 19].'^ Patients with PsA suffer from a decreased quality of life, pain and functional impairment, and
have a significant higher mortality than the age-matched general population [20]. Nowadays, the early diagnosis of PsA
has become a key concern, as early treatment with T N F - a
blockers can prevent irreversible joint damage and deformities [21]. PsA usually either coincides with or follows the development of psoriasis, whereas it precedes psoriasis only in
a minority of cases. Therefore, in case of suspicion, dermatologists are in a strategie position to diagnose PsA or refer
the pafient to a rheumatologist [22]. Validated questionnaires
may be helpful in identifying patients with articular symptoms, who should be carefully screened for PsA [23]. Moreover,
our group found that subclinical enthesopathy may be a useful marker for identifying those patients who are at higher risk
of eventually developing PsA [24].
Psoriatic arthritis
Psoriasis can involve the skin, nails and musculoskeletal structures. The proportion of psoriatic patients developing PsA
ranges from 6% to 42% according to different studies [18].
PsA can develop at any time, including during childhood, but
it typically appears in adults between the age of 30 and 50
years. PsA can affect the peripheral joints, entheses, the synovial sheaths of tendons and the axial skeleton. It is classified
in the spondyloarthritis (SpA) group together with ankylosing spondylitis, reactive arthritis. arthritis associated with inflammatory bowel disease and undifferentiated SpA. PsA
shares with these diseases the axial involvement, extra-articular manifestations and association with the H L A - B 2 7 hap-
Metabolic comorbidities
Epidemiological studies indicate a strong association between psoriasis and obesity. Patients with psoriasis are more
frequently overweight or obese than the general population,
and the severity of psoriasis correlates with the body mass
index (BMl) [25]. The association between obesity and psoriasis was recently confirmed also in pediatrie patients [26].
Obesity generally precedes the development of psoriasis.
Indeed, multiple measures of adiposity, such as B M I , waist
and hip circumference and waist-hip ratio are independent
risk factors for the development of psoriasis and PsA [27,28].
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The relationships between psoriasis and obesity are explained
by the complexes properties of adipose tissue, which is an
active endocrine organ that secretes adipocyte-derived hormones and pro-inflammatory adipokines, including chemerin,
resistin, visfatin, l L - 6 and T N F - a which are released by
macrophages and lymphocytes and accumulate in the visceral fat. Visceral obesitx is strongly associated with metabolic syndrome, characterized by a set of metabolic changes,
in particular insulin resistance, that confer a higher pro-inflammatory and pro-thrombotic risk. Metabolic syndrome
includes at least three of the following conditions: abdominal obesity [waist circumference > 102cm (40 in) men; > 88
cm (35 in) women], elevated serum triglycerides: [> 150 mg/dl
( 1.7 mmol/1) or under treatment], low H D L cholesterol [men
<40 mg/dl (1 mmol/1); women <50 mg/dl (1.3 mmol/1) or
under treatment], elevated blood pressure (> 130/85 mmHg
or under treatment), and elevated fasting glucose (> 110
mg/dL or under treatment) [29]. In a cross-sectional study,
we found that patients with psoriasis had a higher prevalence
of metabolic syndrome than patients with other inflammatory skin diseases, after controlling for sex and age [30.1 %
vs. 20.6%, odds ratio (OR): 1.65, 95%C.I. 1.16-2.35] [30].
The association between psoriasis and metabolic syndrome
was confirmed in a recent meta-analysis showing that psoriasis carries a pooled OR for metabolic syndrome of 2.26
(95%C.I. 1.70-3.01 ) [31 ]. Indeed, psoriasis was strongly associated with diabetes in several cross-sectional studies and
was identified as a risk factor for diabetes development in
controlied prospective studies [32,33]. Fatty liver disease,
the hepatic manifestation of metabolic syndrome, ranges from
pure steatosis to steatohepatitis and cirrhosis [34]. We found
that the prevalence of fatty liver, diagnosed on the basis of
patient history, blood sampling and ultrasonography, in patients with chronic plaque psoriasis was remarkably greater
than in non-psoriasis control subjects (47% vs. 28%; p <
0.0001) matched by age, sex and B M l [35].
Psoriasis and the cardiovascular risk
Although, the relationship between psoriasis and an increased
risk of cardiovascular disease (C VD) is stili controversi al, several studies have shown that individuals with severe psoriasis
are at greater risk of CVD-related mortality as well as stroke
and myocardial infarction. The increased C V D risk appears
to be limited to young patients with severe psoriasis [36].
However, uncertainty remains about whether the C V D risk is
directly attributable to psoriasis, as the majority of studies have
failed to adequately adjust for key traditional risk factors [37].
Moreover, patients with psoriasis have a higher prevalence of
these risk factors [38].
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The global approach to patients with psoriasis
and comorbidities
The association between psoriasis with C V D and metabolic
disorders has important clinical and therapeutic implications.
A comprehensive screening of patients with psoriasis should
include careful assessment of the global cardiovascular risk,
such as measurement of pulse and blood pressure, determination of B M l and measurement of fasting blood lipids and glucose. The choice of systemic treatment for psoriasis is influenced by the concomitance of metabolic comorbidities, because methotrexate, cyclosporine, acitretin and biologics may
negatively impact these associated disorders. Methotrexate
should be prescribed with caution in overweight/obese patients
or in patients with high alcohol consumption, diabetes mellitus or virai hepatitis, because of their increased risk of developing liver toxicity [39]. Cyclosporine can induce or worsen
arterial hypertension, alter glucose tolerance and/or interfere
with fatty acid metabolism, thereby favoring dyslipidemia [40].
In addition, pharmacological treatment of dyslipidemia requires
caution because statins can induce myotoxicity in patients on
cyclosporine or acitretin [41]. Hypertriglyceridemia, hypercholesterolemia and an increase in body weight can occur in patients treated with anti T N F - a agents [42]. Yet there are also
data showing that treatment with methotrexate and/or T N F - a
blockers can reduce the C V D risk. In a large Danish cohort
study, the rate of cardiovascular events was lower in the group
of patients treated with biologics (n=693) and M T X (n=799)
than in those treated with cyclosporine, acitretin or phototherapy (n=908) [43]. Finally, patients with moderate-to-severe
psoriasis are candidates for cardiovascular risk reduction. Nonpharmacological intervention, such as a low-calorie diet, should
be recommended to obese patients. Indeed, we found that moderate weight loss (5-10% of body weight) increases the responsiveness of obese patients with moderate to severe chronic plaque psoriasis to sub-optimally dosed cyclosporine [44].
A n understanding of patients with psoriasis in the context of
comorbidities is of paramount importance to ensure that treatment is tailored to meet their individuai needs.
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