RU2367429C2 - Psoriasis therapy - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine and can be used for treatment of psoriasis patients. Simvastatin monotherapy is offered therefor. Said therapy is administered during 2 months. Simvastatin is introduced in a dose 40 mg/days.

EFFECT: therapy ensures effective disease treatment with using one medicine.

2 ex, 1 tbl

Description

The present invention relates to medicine, and more specifically relates to a method for the treatment of psoriasis.

Psoriasis is a common (1-3% of the population) autoimmune dermatosis with a genetic predisposition, clinically manifested by scaly papules, a chronically relapsing course with frequent damage to the joints and possible involvement of other organs and systems. Pathomorphologically, psoriasis is characterized by skin T-cell infiltration and excessive keratinocyte proliferation. In psoriasis, as a result of T-cell activation resulting from exposure to unidentified triggers, the concentration of proinflammatory cytokines (name, alpha, IL-6, IL-8, IL-1) and type 1 T-helper profile cytokines (IFN-gamma) are locally increased [one]. This, in turn, leads to the activation of dendritic cells, keratinocytes, Langerhans cells and the development of chronic skin inflammation.

With psoriasis, not only the skin is affected. It has been established that the presence of psoriasis in people younger than 40 years old increases the risk of myocardial infarction 3-4 times [2], which can be explained both by lipid metabolism disorders, the frequency of which increases with psoriasis [3], and subclinical chronic inflammation of the walls of large and medium vessels.

There are three main types of psoriasis therapy - topical (local), systemic and light therapy. Psoriasis, affecting more than 10% of the skin, is an indication for the appointment of systemic therapy.

Currently, several drugs are used for the standard systemic treatment of psoriasis, but their use is limited by a number of disadvantages (see table).

Effect disadvantages Methotrexate [4] Reduced skin manifestations 1. At the moment, the effectiveness cannot be considered strictly proven, despite the widespread use of the drug 2. Does not reduce the risk of cardiovascular complications of psoriasis 3. A large number of side effects requiring regular monitoring of toxicity. Retinoids [5-7] Reduced skin manifestations 1. Probably increases the risk of cardiovascular complications of psoriasis 2. Side effects - cheilitis, increased cholesterol, triglycerides, pancreatitis. 3. High cost Cyclosporin A [8] Reduced skin manifestations 1. Probably increases the risk of cardiovascular complications of psoriasis 2. Many side effects, including those affecting the cardiovascular system - arterial hypertension, nephrotoxicity, hypomagnesemia, hyperkalemia, hyperuricemia, hyperlipidemia, hypertrichosis. High probability of side effects requires regular monitoring of toxicity. 3. High cost The so-called biological agents-alefasept, efalizumab, etanercept [9-11] Reduced skin manifestations 1. Does not reduce the risk of cardiovascular complications of psoriasis 2. Not registered in the Russian Federation 3. High cost (from 350 thousand to 550 thousand rubles per year of treatment) 4. Side effects - suppression of the immune system, which can lead to the development of disseminated tuberculosis, lymphomas; thrombocytopenia, lymphopenia

As follows from the table, the drugs currently used to treat psoriasis primarily affect its skin manifestations, do not reduce the risk of cardiovascular disease and have a large number of side effects.

The most studied and most commonly used drug for psoriasis is the folic acid analog methotrexate. Methotrexate has been used to treat psoriasis for more than forty years [4]. The mechanism of action of methotrexate is based on the inhibition of the activity of a number of enzymes involved in folic acid metabolism. The non-specific action of methotrexate causes a significant number of side effects when it is used: diseases of the gastrointestinal tract, disorders in the hematopoietic system, diseases of the liver, lungs, kidneys, cardiovascular system, central nervous system, etc., which greatly limits the use of methotrexate.

Thus, modern therapy for psoriasis is imperfect, which is associated primarily with insufficient clinical efficacy in relation to skin lesions, the absence of a positive effect on the increased risk of cardiovascular disease in psoriasis, and a large number of side effects.

The problem that the invention solves is a simultaneous decrease in the severity of skin manifestations of psoriasis, an improvement in the lipid profile and a decrease in the risk of cardiovascular complications with a decrease in the frequency of side effects, optimization of the cost-effectiveness parameter of treatment.

The method consists in the use of statins inhibitors of HMG-CoA reductase for the treatment of psoriasis. As a therapeutic agent, a specific statin is used - simvastatin, taken at a dose of 40 mg / day for 2 months.

The HMG-CoA reductase enzyme catalyzes the synthesis of mevalonic acid from HMG-CoA and is a key factor in cholesterol synthesis. Statins effectively reduce the cholesterol biosynthesis in humans, in particular, reduce the synthesis of cholesterol in the liver, which leads to an increase in the expression of low-density lipoprotein cholesterol receptors [12]. A number of mevalonic acid derivatives, for example, farnesyl pyrophosphate and geranyl pyrophosphate, have the ability to interact with intracellular signaling molecules, such as RAS and Rho, whose change in activity affects the synthesis of many molecules, including those involved in the functioning of the immune system.

The effectiveness of statins in the treatment of atherosclerosis has been proven in numerous studies. Attempts to use statins for the treatment of autoimmune diseases are limited by a small number of studies in rheumatoid arthritis and multiple sclerosis [13; fourteen]. So, in the TARA study (Trial of Atorvastatin in Rheumatoid Arthritis - a study of atorvastatin in rheumatoid arthritis), the insignificant clinical effect of atorvastatin in moderately active rheumatoid arthritis was demonstrated [13]. The authors of the study emphasize that statins can be used in RA and some other autoimmune diseases only as an additional method. On the other hand, in one experimental work, simvastatin had no effect on the severity of collagen-induced arthritis in mice [15], which allowed the authors to suggest that statins have too weak immunomodulatory effects in order to modify the course of autoimmune diseases.

In this regard, according to the applicants, the technical solution for the use of statins in the treatment of psoriasis, which has shown marked clinical improvement in patients receiving simvastatin monotherapy, has an inventive step. Positive results of the study confirm the authors' hypothesis that statins block the activation of T-lymphocytes, which plays a large role in the pathogenesis of psoriasis, and their ability to improve the lipid profile and anti-inflammatory activity significantly reduces the risk of cardiovascular complications characteristic of this disease.

Thus, the pharmacological properties of statins suggest an effect on several targets at once with psoriasis - inflammation of the skin, inflammation of the vascular wall, impaired lipid metabolism.

Currently, the following drugs of the statins group are registered in Russia - simvastatin, atorvastatin, fluvastatin, rosuvastatin and lovastatin.

The proposed method for the treatment of psoriasis was tested in a clinical setting using simvastatin as an example. An open study was conducted of the efficacy and safety of taking simvastatin at a dose of 40 mg / day for 8 weeks. The dose of simvastatin was selected on the basis of evidence that taking simvastatin 40 mg / day for cardiovascular pathology leads to a reliable clinical effect, which consists in reducing mortality, regardless of cholesterol level [16].

The criteria for inclusion in the study were age from 18 to 80 years, the diagnosis of psoriasis made more than 3 months before inclusion in the study, psoriasis in more than 10% of the skin, voluntary informed consent of the patient to participate in the study.

The exclusion criteria were:

1. Serious liver or kidney disease.

2. Increased activity of transaminases more than 1.5 times higher than the upper limit of normal.

3. History of malignant neoplasms (except for basal cell carcinoma of the skin).

4. Pregnancy and lactation.

5. Reception of gemfibrozil and other fibrates.

6. Reception of nicotinic acid.

7. Receiving antifungal drugs introconazole and ketoconazole.

8. Taking antibiotics of the macrolide group - erythromycin, azithromycin and clarithromycin.

9. Reception of verapamil.

10. Reception of large quantities (more than 1 liter per day) of grapefruit juice.

11. Any conditions that, in the opinion of the researcher, could impede the participation of the patient in the study.

While participating in the study, patients were not allowed other types of systemic therapy for psoriasis and phototherapy.

The primary objectives of the study were to determine the effect of simvastatin on the prevalence and severity index of psoriasis (psoriasis area-and-severity index, PASI), a 50% reduction in PASI. The secondary goals of the study were to study the effect of simvastatin on a general assessment of the prevalence of psoriatic skin lesions by a doctor and on the quality of life of patients with psoriasis. The statistical significance of the “before-after” differences was evaluated using the Wilcoxon test.

The study included 6 patients with psoriasis (average age 51 years, average disease duration 12.8 years). Over the 8 weeks of treatment, a statistically significant decrease in PASI, an overall assessment of skin lesion by a physician, was recorded. All patients participating in the study achieved a more than 50% reduction in PASI. A significant change in the quality of life index in the dynamics of treatment was not detected.

Clinical examples

Patient V., 76 years old, took part in the study from 10/04/2006 to 12/13/2006. Diagnosis: "exudative psoriasis, progressive stage." The diagnosis was made in 1994. The onset of the disease is associated with psychoemotional stress. Exacerbations develop in autumn and winter. Of concomitant diseases - Hypertension II. Chronic non-obstructive bronchitis. Glaucoma. Cataract. From research: OAK - without pathology. OAM - without features. Biochemical blood test - all indicators are within normal limits. The PASI index on the first visit was 21 points. The pathological skin process is localized on the scalp, in the axillary regions, in the intergluteal fold, in the abdomen, on the upper and lower extremities, it is represented by bright red papules and plaques with scales on the surface and a corolla of hyperemia on the periphery. Simvastatin therapy 40 mg per day was prescribed. PASI on the second visit fell to 8 points, this improvement continued on the third visit (8 week). There were single elements of pale pink color with a slight peeling in the area of the intergluteal folds. In place of the former rashes - hypo- and hyperpigmented spots.

Patient K., 24 years old, took part in the study from 04.10.2006 to 29.29.2006. Diagnosis: "Exudative psoriasis. Progressive Stage ”Has been sick since 2002. Exacerbations develop, usually in the fall and winter. No somatic pathology was detected. PASI at the first visit was 45 points. The pathological skin process was localized on the scalp, on the skin of the trunk, on the upper and lower extremities, in the crease region, represented by bright red papules with scales on the surface and a corolla of hyperemia on the periphery. Simvastatin therapy 40 mg per day was prescribed. PASI on the second visit (4 weeks of treatment) was 7 points and on the third (8 week) - 2 points. In the place of the former rashes, hypopigmented spots remained. On the scalp - thickening and peeling have become less intense.

Thus, the use of statins in psoriasis can be an effective, safe and cost-effective treatment method, aimed at simultaneously reducing the severity of skin inflammation and reducing the risk of cardiovascular disease.

Claims (1)

A method of treating psoriasis by administering simvastatin at a dose of 40 mg per day for two months.