Endothelial dysfunction in psoriasis patients 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, resistance to traditional therapy, and a significant decrease in the quality of life of patients.

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

Psoriasis is currently considered 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 (TNF) a, production of interleukins (IL) 1, 2, 6, 8, 17, etc.

Patients with various immune-mediated diseases, including psoriasis, have a high risk of developing "systemic" comorbidities, such as cardiovascular diseases (CVD), obesity, diabetes, lymphoma, multiple sclerosis. Almost half of psoriasis patients over 65 years of age have 2-3 comorbid diseases. In psoriasis, concomitant cardiovascular diseases are more common than in the general population (almost 39% of patients) - arterial hypertension (1.5 times more often), ischemic heart disease, etc. In 14% of young patients with psoriasis, concomitant cardiovascular pathology is recorded in the form of various rhythm disorders, minor cardiac anomalies (mitral valve prolapse, abnormally located chords), arterial hypertension.

A large study on the prevalence of CVD included 130,000 case histories of patients with psoriasis. In severe psoriasis, arterial hypertension was found in 20% (in the control group - 11.9%), diabetes mellitus in 7.1% (in the control group - 3.3%), obesity in 20.7% (in the control - 13.2%), hyperlipidemia in 6% of patients (in the control - 3.3%). In psoriasis, a higher percentage of smokers is noted - 30.1 (in the control - 21.3%). In milder dermatosis, the differences compared to the control were less pronounced, but retained statistical significance. Similar data were obtained in the analysis of psoriasis patients in the EXPRESS-II study with infliximab]. The incidence of diabetes mellitus was 9.9%, arterial hypertension - 21.1%, hyperlipidemia - 18.4%, which significantly exceeds the indicators in the general population. Several mechanisms of increased arterial pressure in psoriasis have been identified. Firstly, higher production of endothelin-1, a powerful vasoconstrictor factor, by keratinocytes has been noted. Secondly, increased levels of free radical oxidation in psoriasis lead to impaired endothelial function and NO bioavailability.

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

Psoriasis is accompanied by an increase in heart rate both during the day and at night according to Holter monitoring, supraventricular arrhythmia. In severe cases of psoriasis, a hypercoagulation state develops.

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

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

According to clinical studies, psoriasis itself can be a risk factor for atherosclerosis, which is consistent with the well-known idea of the role of chronic systemic inflammation in the development of diseases. Clinical and experimental studies have shown that the key role in the development of atherosclerosis and psoriasis is mainly played by the same cytokines (IL-1, -6, TNF a, etc.). The reason for the association of psoriasis with atherosclerosis remains a subject of scientific debate, but in these pathological conditions, activation of generalized nonspecific inflammation and endothelial damage by reactive free radicals, oxidized low-density lipoproteins (LDL), high hydrostatic pressure, hyperglycemia, etc. may occur. Dysfunction of the endothelium is one of the universal mechanisms of pathogenesis of many diseases, leading to accelerated development of angiopathies, atherosclerosis, etc.

There is little information in the literature on the functional state of the vascular endothelium in psoriasis. In male patients with psoriasis, an increase in the activity of the von Willebrand factor, endothelin I was found, especially in the widespread process and in combination with metabolic syndrome. Dysfunction of the endothelium 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 NO and a high level of its inactivation, a state of oxidative stress and a violation of the antioxidant state. In patients with psoriasis, according to ultrasonography, endothelial function is impaired, the intima-media layer is thickened compared to healthy individuals, which allows us to consider psoriasis an independent factor of subclinical atherosclerosis.

Endothelial damage may result from various factors, including elevated homocysteine, LDL, insulin resistance, etc., their level correlates with endothelial dysfunction. Accumulated clinical and statistical data from studies confirm the facts of lipid metabolism disorders in psoriasis, characteristic of the atherosclerotic process. Type IIb dyslipidemia, which was combined with severe psoriasis, was detected in 72.3% of patients with psoriasis, and with CVD in 60% of patients. An atherogenic serum profile was observed in male patients with psoriasis with concomitant arterial hypertension. Repeated endothelial damage (mechanical pressure on vessel walls in arterial hypertension, etc.) and increased focal influx of plasma lipoproteins are the main mechanisms of atherogenesis.

We have shown the presence of endothelial dysfunction in patients with common psoriasis based on the study of the content in the blood serum of some factors damaging the endothelium and substances with which the endothelium regulates vascular growth. One of the many biochemical markers aimed at identifying endothelial dysfunction is C-reactive protein (CRP). In patients with psoriasis, a significant increase in the content of vascular endothelial growth factor (VEGF) in the blood was found. In 83.9% of patients, the VEGF level exceeded 200 pg / ml (more than 3 times compared to 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 the CRP content was noted in patients with common psoriasis. A direct correlation was found between the CRP level and the PASI index. The study of the lipid spectrum parameters of blood serum allowed us to establish lipid metabolism disorders in 68% of patients, reliable differences in TC, LDL-C, VLDL-C and TG in patients under and over 45 years of age compared to those in healthy individuals (p < 0.05). Hypercholesterolemia was detected in 30.8% of patients under 45 years of age and 75.0% of patients over 45 years of age. In 68% of patients, the LDL-C level was higher than normal, and hypertriglyceridemia was detected in most of the subjects. The content of HDL-C was lower than in healthy individuals in 56% of cases, more often in patients over 45 years of age.

The choice of treatment for a patient with psoriasis is usually determined by the severity of the disease. According to some estimates, topical treatment is effective in 60-75% of patients, but in the case of widespread psoriasis, additional use of phototherapy, systemic treatment, or a combination of both is necessary. All systemic methods of treating psoriasis are designed for short courses due to a significant range of clinically significant side effects of the drugs used. Systemic therapy does not allow controlling the course of the disease for a long time; patients with severe forms of psoriasis are often disappointed with the low effectiveness of treatment. It is necessary to note 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 hepatotoxic action, 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 also characteristic of acitretin therapy. Cyclosporine has a nephrotoxic effect, causes metabolic disorders in the form of hypertriglyceridemia and hypercholesterolemia. In recent years, more and more attention has been paid to the use of HMG-CoA reductase inhibitors - statins in various chronic inflammatory diseases. In patients with rheumatoid arthritis, a favorable association was found between the use of statins (simvastatin, atorvastatin), disease activity, and levels of inflammation markers - CRP, IL-6, etc. There is an opinion that statins, which are lipid-lowering agents, also 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 - improved endothelial function, decreased levels of inflammation markers, tissue destruction - develop much faster than the decrease in the blood TC content. In patients with chronic inflammatory skin diseases, one of the most important in the implementation of 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 proinflammatory cytokines, such as TNF a, INF y.

In 2007, the results of the first study of simvastatin in patients with psoriasis were presented. Simvastatin therapy of 7 patients for 8 weeks resulted in a reliable decrease in the PASI index by 47.3%, as well as an improvement in the quality of life according to the DLQJ scale. Treatment of 48 patients with widespread psoriasis and arterial hypertension with atorvastatin in combination with standard therapy significantly reduced the content of TC, TG and LDL, and 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 latest-generation statin, 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 administration as part of complex therapy for patients. Rosuvastatin 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-C than other statins. One of the main features of rosuvastatin is its lipid-lowering efficacy already at the initial dose (10 mg per day), which increases with an increase in the dose to the maximum. It has also been established that the drug is able to reliably increase the level of HDL-C, which is an independent marker of cardiovascular risk, and in this effect is superior to atorvastatin. The powerful anti-inflammatory potential of rosuvastatin can be explained by its ability to enter the systemic circulation in very high concentrations, whereas other statins “work” only in the liver.

The experience of using rosuvastatin (at a dose of 10 mg) in combination therapy of 24 patients with common psoriasis aged 47-65 years indicates not only a hypolipidemic, but also an anti-inflammatory effect of the drug by the end of the 4th week. During rosuvastatin therapy, a reliable decrease in the levels of VEGF (by 36.2%) and CRP (by 54.4%), TC (by 25.3%), TG (by 32.6%), LDL-C (by 36.4%) was obtained relative to the values before treatment. A reliable decrease in the PASI index value was noted (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 liver transaminases, bilirubin and blood glucose were detected while taking rosuvastatin.

Thus, rosuvastatin therapy resulted not only in a decrease in atherogenic lipid fractions and inflammation factors, but also in a decrease in the level of vascular endothelial growth factor. The absence of a correlation between CRP and VEGF suggests that the decrease in VEGF is a direct effect of the drug, not an effect mediated through the effect on blood lipids and inflammation factors. It has now been proven that the effects of statins are multifaceted - they have a positive effect on the lipid spectrum, tumor growth, inhibiting the development of this process, and have a favorable pleiotropic effect (including improved endothelial function, increased nitric oxide bioactivity, and possibly stabilization of psoriatic and atherosclerotic plaque due to 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 relatively low cost, it seems appropriate to use them in psoriasis.

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

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