ReviewUnfavorable cardiovascular risk profiles in untreated and treated psoriasis patients
Introduction
Psoriasis is a chronic inflammatory skin disorder affecting approximately 2% of the general population. It is characterized by epidermal hyperproliferation, abnormal differentiation of epidermal keratinocytes and a lymphocyte infiltration consisting mostly of T-lymphocytes. In the pathogenesis of psoriasis many different inflammatory cells are involved with major roles for the T-lymphocyte and the cytokine network and chemokines [1]. At the site of inflammation activated T-lymphocytes predominantly release type 1 cytokines like interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2). IFN-γ may contribute to hyperproliferation of keratinocytes in the skin by inhibiting their apoptosis [2]. IL-2 stimulates the T-lymphocyte proliferation and TNF-α activates and increases keratinocyte proliferation. Other effects of TNF-α are stimulation of production of cytokines from T-lymphocytes and macrophages, chemokine release from macrophages, and the expression of adhesion molecules on vascular endothelial cells. In case of such an extended inflammation, it is conceivable also to assume systemic consequences. Most health care providers, including dermatologists, do not associate psoriasis with an unfavorable cardiovascular risk profile, but more and more evidence is emerging that this might be the case. The higher prevalence of classic cardiovascular risk factors, like smoking, hypertension and obesity contribute to atherogenesis in psoriasis patients, but psoriasis itself and its systemic treatment may also stimulate premature atherogenesis, increasing the cardiovascular risk. In rheumatoid arthritis (RA), which is also a chronic inflammatory disease with a comparable pathogenesis, it has already been demonstrated that these patients have an increased prevalence of atherosclerosis compared to the general population [3]. The atherosclerosis in RA is not only associated with classic cardiovascular risk factors, but with the inflammatory process as well [4]. Additional support for this notion has come from research with laboratory mice. A mouse was created with a deficiency in the interleukin (IL)-1 receptor antagonist gene that normally functions as a naturally occurring inhibitor of IL-1 [5]. These mice developed three apparently spontaneous inflammatory diseases arthritis, psoriasis-like dermatitis and arteritis [6]. This suggests that the inflammatory process in psoriasis may also affect the arterial wall, promoting the atherosclerotic process. In the present review, we describe all available evidence for the association between psoriasis and cardiovascular disease to assess the indication for risk evaluation and preventive measures in these patients.
Section snippets
Methods
A literature search was performed using the PubMed database. We identified 926 articles that were published in the English language from January 1970 to January 2006. The following MeSH terms were used: psoriasis, cardiovascular diseases, inflammation, atherogenesis, hydroxymethylglutaryl-coa reductase inhibitors, obesity, smoking, hypertension, homocysteine, insulin resistance, blood platelets, oxidative stress and endothelial cells. The following text words were also searched for:
Psoriasis and cardiovascular disease risk
Mallbris et al. performed a historical cohort study to assess the risk for cardiovascular mortality among psoriasis patients [7]. Remarkably, patients who were treated at least once as inpatient had a 50% increased overall risk for cardiovascular death compared to the general population. The excess risk was clearly associated with the severity of psoriasis expressed as the number of hospital admissions. Especially patients admitted at young age had an unexpectedly high excess cardiovascular
Psoriasis genetics and cardiovascular disease risk
Twin studies support a genetic basis of psoriasis [14], [15]. Although the way gene variants influence the disease is complex, a clear association was found with the PSORS1 gene locus on chromosome 6, accounting for approximately 35–50% of the genetic contribution to psoriasis [16], [17]. Carriers of this HLA-Cw*0602 allele exhibit an earlier disease onset, more extensive skin lesions and a more severe disease [18]. Psoriasis patients who are predisposed to have such an extended inflammation
Psoriasis treatment and cardiovascular disease risk
Depending on the severity of the psoriasis various treatments are available. Anti-psoriatic therapies are mainly targeted at reducing the inflammatory process in the skin. Topical treatments, corticosteroids, Vitamin D analogues, dithranol and tar are preferred in mild forms of psoriasis (<10% of the body area affected). The next option will be phototherapy, which can be divided into UVB-light therapy and photochemotherapy (PUVA). In more severe forms of psoriasis (>10% of the body area
Lipid profile
In moderate to severe psoriasis, a significantly deteriorated lipid profile was observed compared to healthy controls with higher values of cholesterol, triglycerides, LDL and low HDL [36]. In less severe cases, only values of HDL were significantly lower compared to controls [37]. Moreover, the lipid profile may be affected during systemic treatment with anti-psoriatic medication like acitretin or cyclosporin, potentially increasing the overall risk for cardiovascular diseases.
Hypertension
In a
Oxidative stress
Patients with psoriasis exhibit several markers of oxidative stress and show impaired antioxidant status. The oxidative stress develops when the antioxidant capacity is overwhelmed leading to oxidative damage of lipids and proteins. Oxidative stress and increased free radical generation, reactive oxygen species and superoxide anion liberation occur in inflamed skin in psoriasis [59]. Malondialdehyde (MDA), a marker of lipid peroxidation, is increased in plasma and red blood cells of patients
Possible role of statins in psoriasis
HMG-CoA reductase inhibitors (statins) have pleiotropic effects and may be beneficial to patients with psoriasis: in addition to cholesterol lowering, statins have other anti-atherosclerotic, cardiovascular risk reducing effects [72]. Statins directly upregulate endothelial nitric oxide synthase in vitro, which reduces the monocyte adhesion to the endothelial surface and the oxidation of LDL. Moreover, statins also have immunomodulatory activities that may improve the psoriasis skin [73]. By
Discussion
It is clear that psoriasis is associated with a higher risk of cardiovascular disease. The excess risk is influenced by the psoriasis severity, indicating an inflammation dependent effect. This association is corroborated by genetic studies confirming overlapping pathogenic features, like overexpression of pro-inflammatory cytokines in both psoriasis and cardiovascular disease. It would be interesting to be able to confirm the association of PSORS1 with cardiovascular disease in future research.
Conclusion
Psoriasis is associated with an unfavorable cardiovascular risk profile: many clinical studies confirm this association. The cardiovascular risk factors are accumulating in psoriasis patients. Three elements contribute to the cardiovascular risk profile in psoriasis patients (Fig. 1). The most important one is the systemic inflammation in psoriasis; this deteriorates the complete cardiovascular risk profile. Secondly, systemic therapies of which its effect depends on the sum of
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