RU2620552C1 - Method for treatment of heavy forms of psoriasis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: complex treatment is performed, including introduction of drugs to improve microcirculation, desensitizing and de-intoxication means, local therapy and introduction of stemokin immunomodulator. Stemokin is injected intramuscularly, 1 ml of solution for 7 days, a two-day break is made, the course of treatment is repeated. Next, stemokin is injected intramuscularly in the form of spray into each nasal passage 2 times a week for 2 months.

EFFECT: achievement of a pronounced clinical remission and lengthening of the inter-recessive period.

10 tbl, 1 ex

Description

The invention relates to medicine, namely to dermatovenerology, and can be used to treat severe forms of psoriasis.

The urgency of the problem of psoriasis is due to its wide prevalence from 0.1 to 10%, a tendency to relapse, an increase in incidence in recent years [Lima H.T., Minnillo R., Spencer J.M., Kimball A.B. Psoriasis prevalence among the 2009 AAD National Melanoma. Skin Cancer Screening Program participants. J Eur Acad Dermatol Venereol. 2012 Apr 4. doi: 10.1111 / j. 1468-3083.2012.04531.x. [Epub ahead of print; Korotkiy N.G., Ujuhu A.E., Abdulaeva A.E., The therapeutic possibilities of thymodepressin in patients with psoriasis and mechanisms of its therapeutic effect. // Clinic, 2013 -№1- S. 105-107], a tendency to increase the frequency of severe, disabling forms of the disease, such as psoriatic arthropathy, significantly worsening the quality of life [Kungurov N.V., Kokhan MM, Filimonkova N .N., Grishaeva E.V., Keniksfest Yu.V., Kashcheeva Y.V.// Herald of dermatology and venereology. - 2008. No. 2. S. 23-28; Stupin A.V. Polyunsaturated fatty acids in the complex therapy of various forms of psoriasis on the example of residents of the Primorsky Territory, (clinical and experimental study) abstract. 2009. S. 22.].

The treatment of psoriasis remains an urgent problem of dermatology, because, despite a wide range of therapeutic agents, there are currently no drugs leading to a complete cure of the disease. When choosing a therapy for patients with psoriasis, age, stage, clinical form and prevalence of the process, the presence of concomitant pathology are taken into account. / Complex immunomodulatory therapy of patients with psoriasis / Korotky N.G., Ujuhu V.Yu., Abdulaeva A.E. et al. // Ros. Journal of skin and sexually transmitted diseases. - 2001. - No. 1. - S. 14-16.]. A particular problem is the treatment of severe forms of psoriasis, since the necessary treatment often has complications, either expensive or does not lead to prolonged remission.

A known method of treatment using the biological drug infliximab, which excludes pro-inflammatory cytokines from the cascade of the immunopathological process [Piryatinskaya V.Α., Karyakina L.Α., Piryatinskaya AB, Lalaeva AM, Gribanova TV, Smirnova ON Psoriasis Differential diagnosis. The principles of treatment. Clinical Dermatology and Venereology. - 2011. - No. 1 - P. 87 -88.] Being a high-affinity target antibody, when it enters the body, it directly binds to its specific target cytokine molecule, thereby interrupting the development of inflammation in the skin, without being included in metabolic processes [Kurdina M.I. New in the systemic treatment of psoriasis. Clinical Dermatology and Venereology. 2011. - No. 5. - S. 54-59.].

However, this method of therapy is expensive and amounts to 1 million rubles. per year, while there is the possibility of patient immunity to treatment, as well as the occurrence of unwanted infections and complications from the cardiovascular system. [Chikin V.V., Znamenskaya L.F., Mineeva A.A. Pathogenetic aspects of the treatment of patients with psoriasis. Bulletin of Dermatology and Venereology. - 2014. - No. 5. - S. 86-89].

The closest is the method of using traditional therapy in combination with thymodepressin in various forms of psoriasis. [Short N.G., Ujuhu A.E., _ Abdulaeva A.E., Therapeutic possibilities of thymodepressin in patients with psoriasis and the mechanisms of its therapeutic effect. // Clinic, 2013 -№1- S. 105-107]. This synthetic peptide consisting of D-amino acids (glutamic acid and tryptophan) inhibits the reactions of humoral and cellular immunity, reversibly reduces the total number of lymphocytes (both helpers and suppressors), inhibits the spontaneous production of TNF-α, enhances the production of interleukin -7, not affects the production of interleukin 1, inhibits colony formation and the entry of stem cells - precursors of hematopoiesis in the S - phase. However, the treatment of severe forms of psoriasis consists in the administration of a 2 ml solution intramuscularly 1 time per day for 21 days.

This treatment method is financially quite expensive, in addition, the drug is a pure immunosuppressor, which can lead to side effects.

The objective of the invention is the development of combination therapy, which allows to achieve a stable and pronounced result through the use of an immunomodulator stemokine.

The objective is achieved by a method of treating severe forms of psoriasis, including traditional therapy using drugs to improve microcirculation, desensitizing and de-intoxication, external therapy in combination with the administration of an immunocorrector. As an immunocorrector, an immunomodulator Stomokin is used. Stemokine is injected intramuscularly with 1 ml of solution for 7 days, take a break for two days, and repeat the treatment. Next, stemokine is administered intranasally in the form of a spray in each nasal passage 2 times a week for 2 months.

The novelty of the method:

- As an immunocorrector, an immunomodulator Stemokin is used. L - isoleucyl - L - glutamyl - L - tryptophan sodium salt immunomodulator; increases the body's resistance to local and generalized infections; causes normalization of altered immunological parameters (relative and absolute number of lymphocytes, CD3 +, CD8, CD 19, CD 16+ lymphocytes, the absorption capacity of monocytes in relation to St. aureus); an increase in spontaneous chemiluminescence and affinity for the general antigenic determinant of antibodies; an increase in the number of HLA-DR + lymphocytes; possesses pronounced detoxification activity.

- Stemokine is injected intramuscularly with 1 ml of solution for 7 days, take a break for two days, and repeat the treatment.

- Next, stemokine is administered intranasally in the form of a spray in each nasal passage 2 times a week for 2 months.

The set of essential features of the invention allows to obtain a new technical result in patients with severe psoriasis consisting in obtaining clinical improvement confirmed by a decrease in the PASI index of 50% or more in 85% of patients, accompanied by a significant decrease in the concentration of individual cytokines in the blood (TNF-α, IL- 6) and an increase in the content of regulatory transport proteins (LF, a1-AT), the level of a2-MG is statistically significantly normalized. There are no relapses of psoriasis in 69% and 62% of patients after 3 and 6 months, respectively.

The drug stemokine is well tolerated, does not have mitogenic, polyclonal activity, antigenic properties, does not have allergenic, mutagenic, embryotoxic, teratogenic and carcinogenic effects.

Pharmacokinetics: With parenteral administration of the drug, the maximum concentration (Cmax) in the blood is reached after 5 minutes; in bone marrow, liver, kidneys, lymph nodes, Cmax is observed 30-40 minutes after administration.

The half-life of the drug is 24 hours, it is completely excreted from the body within 72 hours from the time of administration. The metabolites of the drug are excreted mainly in urine - up to 60%, up to 20% - with feces.

Indications for the use of this drug are boils, abscess, carbuncle. This drug has not been used to treat severe forms of psoriasis.

The mechanism of action of L - isoleucyl-L - glutamyl - L - tryptophan sodium salt is based on the effect of the drug on the proliferation and differentiation of early hematopoietic progenitor cells. [Encyclopedia of medicines]. The drug has a corrective effect on cellular and humoral immunity, normalizing the cytokine profile, however, the mechanism of action and the points of application of this drug have not been fully studied [Borisov I.V. Clinical and immunological rationale for the pathogenetic therapy of genital herpes. Abstract. dis. Cand. honey. sciences. M., 2007]. The maximum tropism of the drug was revealed to the bone marrow.

Among the triggers for the development of psoriasis, emotional stress and the psychoemotional status of the patient are of primary importance, however, the presence of infectious diseases, foci of chronic infection (tonsillitis, sinusitis, infections of the upper respiratory tract) can also trigger the appearance of the first signs of psoriasis. [O.Yu. Olisova. Psoriasis: epidemiology, pathogenesis, clinic, treatment Dermatology. Con. med. - 2010 / - No. 4. - S. 3-8]. Thus, increasing the body's resistance to local and generalized infections of L-isoleucyl-L-glutamyl-L-tryptophan sodium salt acts on one of the main trigger factors, reducing the risk of exacerbations.

L - isoleucyl - L - glutamyl - L - tryptophan sodium salt affects the processes of differentiation of lymphoid cells, inducing the expression of differentiation antigens on leukocytes.

After exposure to radiation, taking cytostatic drugs L - isoleucyl - L - glutamyl - L - tryptophan, the sodium salt accelerates the restoration of the population of committed and pluripotent cells - the precursors of hematopoiesis.

The method is as follows. A patient is examined to determine the severity of the lesion, erythema, desquamation and infiltration by determining the PASI index, which is greater than 50, or when psoriatic plaques have an exudative component, based on which the severe form of psoriasis is determined. Traditional treatment is prescribed, including drugs to improve microcirculation, desensitizing and detoxification drugs, and external therapy is performed. Assign an immunocorrector.

The generally accepted treatment of patients is carried out in accordance with the clinical recommendations for patients with psoriasis prepared by the Expert Council of the Russian Society of Dermatovenerologists and includes:

- antihistamines

- drugs to improve microcirculation: pentoxifylline 2% -5 ml per 200 ml of 0.9% saline solution intravenously drip No. 5-10, nicotinic acid 1% -1 ml intramuscularly No. 5-10,

- hyposensitizing and efferent therapy (calcium chloride 1% -100 ml, reamberin 400 ml intravenously)

- vitamin therapy (vitamins B5, B6, B12),

- Essential 10.0 IV No. 10 with its subsequent administration per os up to 3 months.

- in patients with severe psoriasis, metat-rexate was used in the treatment at a dose of 15 mg / week for 2-3 weeks.

In external therapy, 2% salicylic and papaverine ointments, solidol ointments (cartalin, picladol), local glucocorticosteroid preparations (hydrocortisone, mometasone furoate) were used, depending on the clinical manifestations of the process. Physiotherapeutic methods were also used in the treatment: sessions of common quartz, oxygen baths.

To enhance treatment, an immunomodulator Stemokine 1 ml (0.1 mg) of the solution is prescribed for 7 days - 2 courses with a two-day break. Next, intranasal administration of stemokine in each nasal passage is prescribed 2 times a week for 2 months to prevent recurrence of the skin process.

66 patients with an established diagnosis of Psoriasis, progressive stage, without preliminary specific treatment for 2-6 months, PASI index was more than 50, or an exudative component was examined.

Exclusion Criteria: Age under 18 or over 45; the presence of acute infectious diseases and exacerbations of concomitant chronic diseases, parasitic invasion at the time of the study, allergic, autoimmune and oncological diseases, diabetes mellitus, epilepsy, mental illness; the presence of manifestations of the disease in the form of psoriatic arthritis; taking immunotropic drugs; pregnancy, lactation; lack of voluntary informed consent.

In addition, 30 practically healthy donors aged 20-40 years (men and women) of comparable age were selected, selected according to the results of a routine medical examination (control group). At the time of the examination, the donors were clinically healthy, without chronic diseases, they did not receive preventive vaccinations and were not prescribed immunotropic drugs over the past 2 months. They did not have a burdened family, allergological and immunological history.

Verification of the diagnosis of psoriasis was based on:

1. The presence of papular elements of pink-red color with clear boundaries, dense texture, rising above the skin level, prone to fusion and plaque formation of various shapes and sizes, covered with small, loose scales of silver-white color, easily falling off when scraping; typical localization of rashes (extensor surfaces of the upper and lower extremities, lumbar region, scalp); damage to the nail plates in the form of symptoms of thimble, oil stain, onycholysis, onychodystrophy and onychogryphosis.

2. On diagnostic phenomena (psoriatic triad): a) stearin stain phenomenon: when scraping papules and plaques, peeling is intensified, giving the surface of the papules some similarity with a drop of stearin; b) the phenomenon of the terminal film: the appearance after the complete removal of the scales of the wet, thin, shiny, translucent surface of the elements; c) the phenomenon of blood dew (Auspitz phenomenon): with further scraping after rejection of the terminal film on the exposed wet surface, point (drop) bleeding occurs.

3. The presence of the Koebner phenomenon (the emergence of new elements in place of mechanical or chemical stimuli).

4. Patient complaints: itching of varying degrees of intensity.

Patients were divided into groups: group 2A consisted of patients with severe psoriasis, which was used only by conventional treatment, group 2B included patients with severe psoriasis, who, along with conventional therapy (with the exception of metatrexate), used modern domestic immunomodulator, which is a sodium salt of synthetic a peptide consisting of the L-amino acid residues of isoleucine, glutamic acid and tryptophan (stemokine). Registration number: No. LSR-003014/09 of 04.16.2009. Patients were injected intramuscularly with 1 ml (0.1 mg) of the solution for 7 days, after a two-day break, the course was repeated, and then intranasal administration of stemokine in each nasal passage was prescribed 2 times a week for 2 months.

The examination of the main group included the taking of an anamnesis, instrumental methods of investigation (duodenal sounding), a standard laboratory examination, which included: a general blood test with the formula, a general urinalysis; blood test for syphilis, the level of total protein, sugar, bilirubin, cholesterol, ALT, ACT; ELISA of blood for the determination of AT to hypertension opisthorchia and lamblia, feces for protozoa, feces for dysbiosis.

On admission, the average value of the PASI index in patients with severe psoriasis group 2A was 48.4 ± 2.03, in group 2B - 51.8 ± 2.4, with almost the same values in men and women.

A comparative study of the effect of traditional therapy and therapy using the immunomodulator stemokine in patients with PST (groups 2A and 2B, respectively) found that in the group of patients taking combined treatment with an immunomodulator, initially comparable with traditional therapy and significantly reduced the level of a2-MG to treatment (p1 = 0.0004), after treatment, this indicator normalizes.

Statistically significant differences were found between groups 2A and 2B after treatment (p = 0.049), which confirms the more pronounced effectiveness of combination therapy with stemokine compared with the generally accepted treatment regimen (Table 1).

In the study of the concentration of a1-AT after therapy in severe patients in group 2A, there was a slight downward trend in this indicator and the absence of differences from the level characteristic of healthy donors. Against the background of conventional therapy in combination with an immunomodulator (group 2B), on the contrary, an increase in serum a1-AT level was observed with a statistically significant difference compared with the control p = 0.0006, while pathologically high a1-AT level was detected in 30% of patients ( table 2).

When studying the content of lactoferrin, even more pronounced changes were noted: before treatment, the serum concentration of LF was statistically significantly increased, in comparison with the control group, in groups 2A and 2B (Table 3).

After conventional treatment, group 2A showed a trend towards a decrease in the average concentration of lactoferrin in 56%, but its level remained statistically significantly higher compared to the control (p = 0.0001). After combined treatment with stemokine, the LF level increased and also statistically significantly differed from the control group (p = 0.0001) (Table 3).

In this case, individual variability in patients before and after treatment was approximately doubled compared with the control group (Table 3). A pathologically high level (3.62 μg / ml) was found in 36.6% of patients with severe psoriasis.

In addition, to clarify the effect of therapy on immunological parameters, we studied the serum level of some cytokines that are actively involved in the development of the clinical picture and the maintenance of the inflammatory response, contributing to the chronicity and relapse of the skin process.

It was revealed that the concentration of IL-1β before and after therapy in groups 2A and 2B was statistically unchanged and did not significantly differ from the levels typical for healthy donors (Table 4), thus, we were not able to identify the effect of the treatment on IL level -1β.

A more pronounced difference was demonstrated by the concentration of TNF-α: before treatment, a statistically significant increase in cytokine was detected in all groups of patients with psoriasis (Table 5). Against the background of conventional therapy (group 2A), the TNF-α indicator did not normalize compared to the control, while after treatment with the use of an immunomodulator (group 2B), a decrease in the concentration of TNF-α in the blood serum was more than 2 times almost to the indicators control (table. 5), and if before treatment we see the statistical significance of the differences in comparison with the control group, then after the combined treatment there is no significance.

Individual variability in groups before treatment was comparable, and after treatment increased (Table 5).

A study of the concentration of IL-8 in serum showed that a statistically significant increase was observed in group 2A, in group 2B there was an increase in the content of IL-8 without significant differences in comparison with the control (Table 6).

When determining the effect of the course of therapy on the concentration of IL-8, it was noted that in group 2A there was a tendency to a decrease in the cytokine content during treatment in 71% of patients, but despite this, its level was statistically significantly increased relative to the control group. After the use of complex treatment in combination with stemokine, an increase in IL -8 concentration was noted, however, there were no statistically significant differences, which is probably due to the large individual variability of the indicator both before and after treatment (Table 6).

Analysis of the concentration of IFN-γ before the course of therapy in group 2A and 2B showed (Table 7) that its level in the blood serum was significantly higher than in the control group. Determination of the content of IFN-γ after a conventional course of therapy revealed a decrease in IFN-γ in 54% of cases, but it remained statistically significantly higher when compared with control values.

In the group with TFP, against the background of the use of conventional therapy and an immunomodulator, the concentration of IFN-γ in the blood serum remained almost unchanged while maintaining the statistical significance of the differences with the control. Individual variability of IFN-γ levels before and after treatment was comparable to control.

The concentration of IL-6 showed marked differences: the serum content of IL-6 in all groups was statistically significantly increased, compared with the control indicators with high variability of the indicator (table. 8).

A study of the content of IL - 6 after conventional treatment showed that it had a tendency to increase, while against the background of treatment with stemokine, a tendency to a decrease in the concentration of IL - 6 was revealed, however, the statistical significance of the differences in comparison with the control remained (Table 8) .

A study of the effect of therapy on regulatory transport proteins and cytokines in patients with severe psoriasis showed that their average concentrations did not change after conventional treatment, which may indicate insufficient effectiveness of therapy aimed not only at curing the disease, but at stopping its manifestations. When stemokine was added to the treatment regimen, we noted normalization of the concentration of a2-MG, a tendency to increase a1-AT and LF, a twofold decrease in the content of TNF-α, which plays an important role in the pathogenesis of psoriatic disease, and a decrease in the concentration of IL-6, while while with conventional therapy for PST it rises even more.

The criterion for the clinical effectiveness of the prescribed treatment was the reduction of complaints, regression of foci, or stabilization of the process. An objective criterion was the decline in the PASI index.

As a result of the traditional treatment, a decrease in the ΡASI index by 75% or more was recorded, which corresponds to a marked improvement in the clinical picture in 30.8% of patients with PST in group 2B compared to 12.5% in group 2A. In 14 patients in group 2B and 22 patients in group 2A, the PASI index decreased by 50-74%, which corresponded to a satisfactory improvement. Slight dynamics of the skin process was observed only in 4 people in the group with combined treatment, while after conventional therapy 12 people had this improvement.

Only 1 patient (2.5%) with PST did not have a visible improvement in the process. When describing clinical and morphological changes in patients with complex therapy, including the immunomodulator Stemokin, it is important to note that by 3-4 days of treatment in 5 patients (19.2%) there was an increase in hyperemia of plaques against the background of a decrease in the remaining manifestations: peeling infiltration.

In the groups, the long-term results of the treatment after 3 and 6 months after the questionnaire survey were evaluated (Table 10): after 3 months, psoriasis recurrence was noted by 31% of patients in group 2, while stressful situations in 7 patients caused exacerbation, while in In group 1, after canceling treatment, including metatrexate, 56% of patients indicated exacerbation of the skin process. After 6 months, an exacerbation of the process was noted by 38.4% in group 2B and 71% in group 2A. Statistical analysis revealed a significant improvement in the process when comparing groups 1 and 2: after 3 months, X ² = 6.73, p = 0.035; after 6 months, X ² = 4.67, p = 0.031. After 6 months, 2 patients indicated progression of the disease with the use of alcoholic beverages.

I would like to note that all patients of group 2B noted an improvement in overall well-being, as well as tolerance to infections during treatment and 3 and 6 months after.

Thus, it can be stated that as a result of treatment, there was a good positive dynamics in the clinical picture of psoriasis: a decrease not only in objective complaints, but also in the severity of skin manifestations. Moreover, a mild form of dermatosis responded better to conventional treatment, while a significant improvement in the process and more stable remission in patients with PST were observed in 30.8% with the use of the immunomodulator stemokine compared to 12.5% with conventional therapy.

Clinical example:

Patient Ch, 42 years old, was hospitalized in the dermatovenereological department with a diagnosis of plaque psoriasis, partial erythroderma, progressive stage. On examination, the PASI index is 62, which corresponded to severe psoriasis. Given that when examining TNF-α = 7.2 pcg / ml, IL-6 = 8.45 pcg / ml, and A2-MG = 0.8 g / l, the patient received conventional therapy: reamberin 400 ml intravenous drip No. 10 , sodium thiosulfate 30% - 10 ml intravenously No. 5, in combination with an immunomodulator stemokine. Stemokine was injected intramuscularly with 1 ml of solution for 7 days, a break was made for two days, the course of treatment was repeated, then stemokine was administered intranasally in the form of a spray in a single dose in each nasal passage 2 times a week for 2 months. Outwardly, the patient used 2% salicylic ointment in combination with methylprednisolone aceponate. Regression or defragmentation of individual foci was noted after the first course of therapy, i.e. on day 8. By day 18, the PASI index regressed by 80%. and was 15. Control after 3 and 6 months showed the absence of exacerbation of the skin process.

Patient P, 34 years old, was hospitalized in the dermatovenereological department with a diagnosis of plaque psoriasis with an exudative component, a progressive stage. On examination, the PASI index is 34. Given this indicator and the presence of exudation, the process corresponded to a severe form of psoriasis. When examining TNF-α more than 6 pkg / ml, IL-6 more than 6.5 pkg / ml, a2-MG≤1.5 g / l, in connection with which the patient received conventional therapy: reamberin 400 ml intravenous drip No. 10, sodium thiosulfate 30% -10 ml intravenously No. 5, in combination with the Stemokin immunomodulator, which was administered intramuscularly with 1 ml of the solution for 7 days, took a break for two days, the treatment was repeated, then stemokine was administered intranasally in the form of a spray in a single dose in each nasal 2 times a week for 2 months. Outwardly, the patient used 2% salicylic ointment in combination with methylprednisolone aceponate. Regression or defragmentation of individual foci was noted after the first course of therapy, those on day 8. By day 18, the PASI index regressed by 80%. and was 15. Control after 3 and 6 months showed the absence of exacerbation of the skin process.

Thus, we were able to develop a fairly effective method of treating severe forms of psoriasis with pronounced clinical remission and prolongation of the inter-relapse period.

Claims (1)

A method of treating severe forms of psoriasis, including traditional therapy using drugs to improve microcirculation, desensitizing and detoxifying, external therapy in combination with the use of an immunocorrector, characterized in that an immunomodulator Stemokin is used as an immunocorrector, which is administered intramuscularly with 1 ml of solution for 7 days , take a break for two days, repeat the treatment, then administer stemokine intranasally in the form of a spray into each nasal passage 2 times a week for 2 months .