Endothelial dysfunction in patients with psoriasis and statins

Psoriasis is one of the most important medical and social problems of modern dermatology. The significance of this disease is due to its high population frequency (2-3%), systemic manifestations, torpidity of traditional therapy, a significant decrease in the quality of life of patients.

Psoriasis is a chronic recurrent dermatosis of a multifactorial nature characterized by hyperproliferation and violation of differentiation of epidermal cells, an inflammatory reaction in the dermis. For the disease is characterized by frequent damage to the joints and possible involvement in the pathological process of other organs (heart and blood vessels, eyes, intestines, kidneys). Close attention to this disease is due not only to the high specific gravity of dermatosis among other skin diseases, but also to the increase in morbidity, the increase in cases of severe course, the defeat of young people, and the early disability of patients.

Psoriasis today is considered as an immune-mediated inflammatory skin disease. Immunological mechanisms of development are of the Th-1 type, with the cellular response accompanied by the expression of interferon (IFN) y, tumor necrosis factor (FIO) a, the production of interleukins (IL) 1, 2, 6, 8, 17, etc.

Patients with various immuno-mediated diseases, including psoriasis, have a high risk of developing "systemic" comorbidity, for example, cardiovascular diseases (CVD), obesity, diabetes, lymphoma, multiple sclerosis. Almost half of psoriasis patients over the age of 65 have 2-3 comorbid diseases. In psoriasis, comorbid cardiovascular diseases (almost in 39% of patients) - arterial hypertension (1.5 times more often), coronary heart disease, etc. Occur in psoriasis more often than in the general population. 14% of patients with psoriasis of young age have cardiac involvement -Vascular pathology in the form of various rhythm disturbances, small heart abnormalities (mitral valve prolapse, abnormally located chords), arterial hypertension.

A major study on the prevalence of CVD has studied 130,000 case histories of patients with psoriasis. In severe psoriasis, hypertension was found in 20% (in the control group - in 11.9%), diabetes in 7.1% (in the control group - in 3.3%), obesity in 20.7% (in control - in 13.2%), hyperlipidemia - in 6% of patients (in control - in 3.3%). In psoriasis, a higher percentage of smokers - 30.1 (in control - 21.3%). With a lighter flow of dermatosis, the differences in comparison with the control are less pronounced, but they remained statistically significant. Similar data were obtained in the analysis of patients with psoriasis in the study EXPRESS-II with infliximab]. The incidence of diabetes mellitus was 9.9%, arterial hypertension 21.1%, hyperlipidemia 18.4%, significantly higher than the general population. Several mechanisms of increasing blood pressure in psoriasis have been revealed. First, higher production of keratinocytes of endothelin-1, a potent vasoconstrictor factor, was noted. Secondly, an increased level of free radical oxidation in psoriasis leads to disruption of endothelial function and bioavailability of NO.

European scientists, based on retrospective data, argue that psoriasis is an independent risk factor for myocardial infarction. And young patients with severe manifestations of psoriasis have the greatest risk of myocardial infarction. An increase in the risk of CVD death by 50% in young people suffering from psoriasis has been noted. The life expectancy of such patients is less than that of healthy individuals: men - 3.5 years, women - 4.4 years.

Psoriasis is accompanied by an increase in the heart rate, both during the day and at night, according to holter monitoring, supraventricular rhythm disorders. In severe psoriasis, a hypercoagulable state develops.

Platelets adhere to activated endothelial cells, secrete a number of pro-inflammatory cytokines, creating the basis for the early formation of an atherosclerotic plaque in psoriasis.

It is suggested that the development of comorbid conditions is most likely based on the common pathogenesis of the combining diseases and does not depend on economic factors, the availability of medical care, etc. Inflammation plays a key role in the pathogenesis of many chronic inflammatory systemic diseases, including psoriasis, rheumatoid arthritis, systemic lupus erythematosus , as well as in the development of atherosclerosis. In the modern doctrine of psoriasis, a significant pathogenetic role is assigned to chronic inflammation, which along with the immunopathological pathogenetic "component" (the immunopathological nature of inflammation) leads to metabolic and vascular disorders.

According to clinical studies, psoriasis in itself as a whole can be a risk factor for the development of atherosclerosis, which is consistent with the well-known concept of the involvement of chronic systemic inflammation in the development of diseases. Clinical and experimental studies have shown that the key cytokines (IL-1, -6, TNF, and so on) play a key role in the development of atherosclerosis and psoriasis. The reason for the association of psoriasis with atherosclerosis remains a subject of scientific discussion, however, in these pathological states, activation of generalized nonspecific inflammation and damage to the endothelium by reactive free radicals, oxidized low-density lipoproteins (LDL), high hydrostatic pressure, hyperglycemia, etc., may occur. Endothelium is one of the universal mechanisms of the pathogenesis of many diseases, leads to an accelerated development of angiopathies, atherosclerosis t. D.

In the literature there are few information about the functional state of the vascular endothelium in psoriasis. In patients with psoriasis of men, an increase in the activity of von Willebrand factor, endothelin I, was established, especially in the prevalent process and combination with metabolic syndrome. Endothelial dysfunction in patients with psoriasis and arterial hypertension is probably due to a violation of the activity of oxidative metabolism of L-arginine and is manifested by a decrease in the bioavailability of N0 and its high level of inactivation, oxidative stress and an antioxidant state. In patients with psoriasis, according to ultrasonography, the endothelial function is impaired, the intima-media layer is thickened in comparison with healthy individuals, which allows to consider psoriasis as an independent factor of subclinical atherosclerosis.

Damage to the endothelium can be the result of the action of various factors, including increased levels of homocysteine, LDL, insulin resistance, etc., their level correlates with endothelial dysfunction. The accumulated clinical and statistical data of the studies confirm the facts of lipid metabolism disorders in psoriasis, characteristic of the atherosclerotic process. In 72.3% of patients with psoriasis, IIb type of dyslipidemia was detected, which was associated with severe psoriasis, in 60% of patients with CVD. With concomitant arterial hypertension, patients with psoriasis of men had an atherogenic serum profile. Repeated damage to the endothelium (mechanical pressure on the walls of blood vessels with arterial hypertension, etc.) and increased focal flow of plasma lipoproteins are the main mechanisms of atherogenesis.

We have shown the presence of endothelial dysfunction in patients with ordinary psoriasis on the basis of the study of the content of certain endothelial damaging factors in the serum and the substances by which the endothelium regulates vessel growth. One of the many biochemical markers aimed at detecting endothelial dysfunction is the C-reactive protein (CRP). In patients with psoriasis, a significant increase in the content of vascular endothelial growth factor (VEGF) in the blood has been established. In 83.9% of patients, the VEGF level exceeded 200 pg / ml (more than 3 times the control group). The degree of change in this indicator depended on the stage and prevalence of dermatosis, the presence of concomitant (cardiovascular) pathology, lipid metabolism disorders. A significant increase in CRP was observed in patients with advanced psoriasis. A direct correlation between the level of CRP and the PASI index was revealed. The study of lipid profile of blood serum allowed to establish violations of lipid metabolism in 68% of patients, significant differences in CH, LDL, cholesterol and TG in patients before and after 45 years compared with those in healthy subjects (p <0.05) . Hypercholesterolemia was detected in 30.8% of patients under 45 years of age and 75.0% in patients older than 45 years. In 68% of patients the level of LDL cholesterol was higher than normal, most patients had hypertriglyceridemia. The content of HDL cholesterol was lower in healthy subjects in 56% of cases, more often in patients older than 45 years.

The choice of a method of treatment of a patient with psoriasis, as a rule, is determined by the severity of the disease. According to some estimates, 60-75% of patients have effective external treatment, but with advanced psoriasis, additional use of phototherapy, systemic treatment or a combination thereof is necessary. All systemic methods of treatment of psoriasis are designed for short courses due to a significant spectrum of clinically significant side effects of medications used. Systemic therapy does not allow monitoring the course of the disease for a long time, patients with severe forms of psoriasis are often disappointed by the low effectiveness of treatment. It should be noted the effect of systemic therapy (cytostatics) of psoriasis on the state of the vascular endothelium and, accordingly, an increased risk of developing cardiovascular complications. Thus, treatment with methotrexate, along with a hepatotoxic effect, is accompanied by a significant increase in the level of homocysteine, one of the markers of the risk of developing cardiovascular diseases. Adverse changes in lipid metabolism are characterized by therapy with acitretin. Cyclosporine has a nephrotoxic effect, causes metabolic disorders in the form of hypertriglyceridemia and hypercholesterolemia. In recent years, more attention is paid to the use of inhibitors of HMG-CoA reductase - statins for various chronic inflammatory diseases. In patients with rheumatoid arthritis, a favorable association was found between taking statins (simvastatin, atorvastatin), disease activity, and inflammation marker levels - CRP, IL-6, etc. There is an opinion that statins related to lipid-lowering drugs have a number of additional non-lipid, pleiotropic effects and can be used in patients with chronic inflammatory skin diseases (limited scleroderma, chronic lupus erythematosus). Organoprotective effects of statins - improvement of endothelial function, lowering levels of markers of inflammation, destruction of tissues - develop much faster than the content of blood OKHS decreases. In patients with chronic inflammatory skin diseases, one of the most important in realizing the mechanisms of action of statins is their immunomodulatory properties. Statins have the ability to reduce the expression and action of various molecules on the surface of leukocytes, are able to block transendothelial migration and chemotaxis of neutrophils, the secretion of some pro-inflammatory cytokines such as TNF a, INF-γ.

In 2007, the results of the first study of simvastatin in patients with psoriasis are presented. Therapy with simvastatin 7 patients for 8 weeks resulted in a significant decrease in the PASI index by 47.3%, as well as an improvement in the quality of life on the DLQJ scale. Treatment with atorvastatin 48 patients with advanced psoriasis and arterial hypertension in combination with standard therapy significantly reduced the content of OXC, TG and LDL, the PASI index by the end of the 1st month of treatment. By the 6th month of therapy, a further increase in the clinical effect was noted.

Rosuvastatin is a statin of the last generation, a fully synthetic inhibitor of HMG-CoA reductase. The drug has the longest half-life among all statins and is the only statin that is minimally metabolized by the cytochrome P450 system, and therefore the likelihood of its interaction with many drugs is low. This property of rosuvastatin facilitates its appointment as part of complex therapy of patients. Rosewastatin molecules are more hydrophilic than molecules of most other statins, highly selective for hepatocyte membranes and have a more pronounced inhibitory effect on the synthesis of LDL cholesterol than other statins. One of the main features of rosuvastatin is its lipid-lowering efficacy in the initial dose (10 mg per day), which increases with increasing dose to the maximum. It is also established that the drug is able to reliably increase the level of HDL cholesterol, which is an independent marker of cardiovascular risk, and by this effect is superior to atorvastatin. The powerful anti-inflammatory potential of rosuvastatin can be explained by its ability to enter the systemic circulation at very high concentrations, while other statins "work" only in the liver.

The experience of using in the complex therapy of 24 patients with ordinary psoriasis at the age of 47-65 years rosuvastatin (in a dose of 10 mg) indicates not only the hypolipidemic but also the anti-inflammatory effect of the drug at the end of the 4th week. During the treatment with rosuvastatin, a significant reduction in VEGF levels (by 36.2%) and CRP (by 54.4%), OCS (by 25.3%), TG (by 32.6%), LDL cholesterol (by 36, 4%) relative to pre-treatment indicators. There was a significant decrease in the PASI index (from 19.3 ± 2.3 to 11.4 ± 1.1 points).

It should be noted that no side effects, as well as changes in the level of hepatic transaminases, bilirubin and blood glucose on the background of rosuvastatin was not detected.

Thus, therapy with rosuvastatin has led not only to a decrease in atherogenic lipid fractions and inflammatory factors, but also to a decrease in the level of the vascular endothelial growth factor. The lack of correlation between CRP and VEGF suggests that a decrease in VEGF is direct, and not mediated through the effect on blood lipids and inflammation factors by the effect of the drug. It has now been proven that the effects of statins are multifaceted - they have a positive effect on the lipid spectrum, the growth of neoplasms, inhibiting the development of this process, has a favorable pleiotropic effect (including improved endothelial function, increased bioactivity of nitric oxide, possibly stabilization of psoriatic and atherosclerotic plaques account of the inhibition of angiogenesis in them). Given the above described effects of statins, as well as the safety of their use, the possibility of oral administration and a relatively low cost, it seems appropriate to use them in psoriasis.

EI Sarian. Endothelial dysfunction in patients with psoriasis and statins // International Medical Journal - №3 - 2012

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