RU2348423C2 - Method of treatment of atopic dermatitis in children - Google Patents

Abstract

FIELD: medicine; dermatology.

SUBSTANCE: treatment of children suffering from atopic dermatitis is ensured with introduction of Licopide dosed 1 mg daily within 10 days in combination with baseline conventional therapy. Then Licopide based therapy is continued until course dose 20 tablets is obtained, in combination with allergen-specific immunotherapy of causally dependent allergens (ASIT).

EFFECT: higher efficiency of AD treatment due to corrected immune and cytokine imbalance, more persistent remission provided in patients without by-effects and significantly reduced volume of baseline pharmacotherapy.

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Description

The invention relates to medicine, namely to allergology - clinical immunology, pediatrics, dermatology, and can be used in a clinic for the treatment of patients with atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory allergic skin disease accompanied by debilitating itching, which occurs, as a rule, in early childhood in people with a hereditary predisposition to atopic diseases, which has a wave-like recurrent course associated with a change in the function of the cellular and humoral parts of the immune system and leading physical and emotional maladaptation of the patient and his family. The prevalence of blood pressure has increased over the past three decades and, according to various authors, is 10-15% in children under 5 years old and 15-20% in schoolchildren. In AD, a high degree of colonization was noted. aureus, high triggering and frequent combination with viral infection caused by H. Simplex, as well as fungal infection. Recently, the existence of common pathogenetic mechanisms and a pathophysiological relationship between severe blood pressure, asthma and allergic rhinitis has been proven.

Historically, the treatment of allergic diseases over a long period of time was mainly aimed at eliminating the action of provoking factors and correcting the development of pathophysiological mechanisms. In most cases, the developed schemes for the use of various groups of drugs allow you to monitor the condition of patients with blood pressure and relieve the main symptoms of the disease. However, they do not eliminate the pathogenetic mechanisms of the inflammatory allergic process, are clinically ineffective, high cost, often difficult to practice in practice and can lead to the development of adverse reactions [E.S. Fedenko, N.I. Ilyina. Allergic skin diseases in clinical practice // Russian Allergological Journal.- 2005.- No. 3.- P.55-61]. There is an urgent need for effective and safe methods of treating blood pressure, which would enable early intervention and long-term control over the course of the disease [Ellis C., Abeck D., Alien R. Et al. New clinical data and modern strategies for the treatment of blood pressure. // Allergology. - 2003. - No. 4. - S.50-58].

The effectiveness of therapy can be increased when combined immunotherapy is used in the treatment of blood pressure [Macharadze D.Sh., Zolotareva T.A., Bosenko Yu.A. Treatment of infectious complications of atonic dermatitis in children. // Russian Allergological Journal. - 2004. - No. 4. - S.65-71]. The basis of AD are immunological mechanisms that determine the imbalance of Th1 and Th2 cells and hyperproduction of IgE, which justifies the need for various types of immunocorrection aimed at the implementation of the immune system. The methods of immunocorrection include plasmapheresis, allergen-specific immunotherapy (ASIT), the use of immunocorrective drugs proper, as well as immunosuppressants. According to E.S. Fedenko, a positive effect in patients with blood pressure, especially with frequently recurring pyoderma, was exerted by polyoxidonium, diutsifon, which are included in the combination therapy regimen [E.S. Fedenko. Atopic dermatitis: rationale for a phased approach to therapy. // Consilium medicum. - 2001. - T.3. - No. 4. - S.176-183].

A known method of treating blood pressure during an exacerbation of the drug roncoleukin (recombinant interleukin-2) in the form of intravenous drip monotherapy, the course dose was 2-5 injections with an interval of 2-3 days [RU 2195314 C1, 12/27/2002].

There is a method of treating blood pressure with the drug affinoleukin (a set of transfer factor proteins), which is added subcutaneously from the 5th day of treatment of complex therapy [RU 2248804 C2, 03/27/2005].

As a result of treatment with roncoleukin and affinoleukin, there was a tendency to a decrease in the severity of clinical symptoms of exacerbation of blood pressure, and the duration of remission of the disease was extended.

The disadvantages of the known methods is the exacerbation of inflammatory symptoms after the 2-3rd injection (affinoleukin), the development of influenza-like syndrome for administration (roncoleukin).

The closest analogue of the proposed method is a method for the treatment of atopic dermatitis (AD) in children, including basic pharmacotherapy and the use of lycopide inside of 1 tablet (1 mg) for 10 days [Methodical manual for doctors "Immunotherapeutic possibilities of using lycopid in pediatrics". - M., 2000]. A known method of treatment relates to the treatment of atopic dermatitis in children, complicated by furunculosis or streptostaphyloderma with recurrent or continuous course. Therefore, basic therapy was supplemented with antibacterial.

Despite the positive results obtained in the treatment of blood pressure in a known manner, the following disadvantages are inherent in it:

1. Short term therapeutic effect, which requires repeated courses of treatment after 2-4 months.

2. Limitation of indications for the use of lycopid in children with blood pressure only to a group of children with complicated secondary infection (furunculosis, streptoderma) forms of the disease. The main focus of the immunomodulating effect on strengthening anti-infectious immunity, the prevention of infectious complications, the phenomenon of secondary immunodeficiency.

3. Correction of the mechanisms of secondary immune deficiency by lycopid does not provide modulation of the immune mechanisms of allergic inflammation, which determines the need for long-term maintenance of basic therapy and significant costs for treatment and the disease as a whole.

The objective of the invention is the development of a method for the treatment of atopic dermatitis in children, devoid of the disadvantages inherent in the known method.

The problem is solved in that in the method of treating atopic dermatitis in children, including basic traditional pharmacotherapy and the use of lycopide, according to the invention, lycopide is taken 1 mg for 30 days, first daily to a dose of 10 mg, and then every other day to a course dose of 20 mg s simultaneous conduct of accelerated parenteral allergen-specific immunotherapy (ASIT) with non-infectious causative allergens.

We examined 90 children aged 3 to 18 years with AD, with a disease duration of 1 to 15 years (in 22.2% of children, a mild course was verified, in 66.6% it was mild, in 11.1% it was severe diseases). The complex of therapeutic measures during the exacerbation period included antihistamines and membrane stabilizing agents, enterosorbents and drugs, corrective disorders in the gastrointestinal system, and external therapy. In the process of the study, standard general clinical and immuno-allergic examinations were carried out. Determination of indicators of immune status (CD 3, CD 4, CD 8, CD 16, CD 22, CD 25, CD 95 - immunofluorescence method; Ig M, G, A, E - ELISA; CEC - precipitation method with PEG 6000); determination of the level of cytokines (IL-4, IL-13, IFNγ) in biological fluids (blood serum, saliva) by enzyme-linked immunosorbent assay using a sandwich variant with reagents from R&D diagnostics Inc. (USA).

In the group of examined patients, laboratory signs of immune imbalance were revealed, characterized by a decrease in the level of T-lymphocytes (CD3 + - 42.6 ± 3.12%), a change in the regulatory index of CD4 + / CD8 + due to the predominance of subpopulations of T2-lymphocytes, an increase in the number of CD22 + cells, and an increase in the content IgE In half the cases, a decrease in IgG and a decrease in the content of serum and secretory IgA in the overwhelming majority of children with blood pressure compared with the control group, a decrease in the phagocytic activity of neutrophils (phagocytic index (Hamburger index) - 44.2 ± 2.4%, and phagocytic number ( Wright index) -3.1 ± 0.2 micro-bodies) during the period of exacerbation and the presence of more than half of the examined clinical signs of insufficiency of the immune system functions. In the group of children with a mild course of blood pressure and a focal form, changes in the immune status were minimal, and during the period of subsidence of clinical manifestations, the indices in the overwhelming majority were similar to those in the control group. With moderate and severe blood pressure in children, the indicators of the cellular and humoral immunity during the exacerbation period significantly differed from the data of the control group. These changes in the immune and cytokine status persisted during the period of remission of the disease (figure 1).

In children with AD, a change in the system spectrum of the studied cytokines relative to the control group was less significant than the local one. So, in the blood serum, the content of IL-4 was 55.2 ± 4.2 pg / ml, IL-13 - 39.4 ± 4.9 pg / ml, IFNγ - 21.2 ± 2.0 pg / ml (Fig. one). The results of monitoring the content of these cytokines allow us to recommend them as markers of allergic inflammation and as immunological criteria for evaluating the effectiveness, adequacy and timeliness of immunocorrective therapy.

The choice of allergens for ASIT is based on specific allergological diagnostics, which includes the following mandatory components: collection of an allergological history, staging of skin tests with allergens, provocative or elimination tests (if indicated), laboratory diagnosis, determination of allergen-specific IgE to allergens that are responsible for the clinical manifestations of the disease in this patient.

When children with AD of lycopide were included in the complex treatment regimen, correction of the systemic and local contents of IL-4, 13 and INFU was observed for 3 months, but did not persist for more than 6 months. from the start of treatment (figure 2, 3).

During ASIT monotherapy, registration of the immunomodulating effect was noted no earlier than 2 months from the start of treatment. A significant correction of the cytokine profile in children with blood pressure was observed after at least 3 months of ASIT. The levels of IL-4, IL-13 locally and systemically decreased gradually, during the first year of therapy, the content of IFNγ significantly differed from the values before treatment by 6 months. therapy (Fig.4, 5), which is clinically illustrated by the achievement of control over the disease.

Against the background of combined treatment (lycopid + accelerated ASIT with non-infectious allergens), 1 month after the start of therapy, a tendency to a decrease in IL-4, IL-13 and an increase in INFγ was observed, which persisted after 3 and 6 months from the start of therapy both in blood serum and locally in saliva. Clinically, patients experienced a rapid onset of remission of the disease and achieved a long, complete control of the disease (6, 7).

This is due to the fact that lycopid in combination with accelerated ASIT non-infectious allergens behaves as a means of therapeutic correction of immune cytokine mechanisms of allergic inflammation in atopic dermatitis in children, while lycopid is known from available sources of information as a drug for the treatment and prevention of infectious diseases and infectious complications allergic diseases, infectious syndrome with secondary immunodeficiencies. In pediatric practice, lycopid is used to prevent acute respiratory viral infections and influenza, in the treatment of chronic diseases of the upper and lower respiratory tract, purulent skin infections, herpetic infections, acute and chronic hepatitis A, B and C, dysbiotic conditions, protracted infections in newborns (pneumonia, enterocolitis, bronchitis, sepsis). (http://peptek.ru/PRODUCT/LICOPID/Instruct.html).

It has been established that due to the synergistic combination of immunomodulating effects of lycopide and accelerated ASIT by non-infectious allergens on various subpopulations of immunocompetent cells, including T-lymphocytes, macrophages, etc., the imbalance in the production and functional activity of the cytokine system and the production of immune cells to the predominance of Th1 subpopulations is ensured lymphocytes, the number and functional activity of the cells of the humoral unit are modulated, the activity of allergic inflammation and Ig synthesis is stopped E.

During the first three weeks of therapy, a significant improvement in the condition of patients was noted: itchy skin decreased, skin rashes did not recur, and sleep was normal. The severity of clinical manifestations on the SCORAD scale decreased by 81%. Moreover, with combined immunotherapy with lycopid + accelerated ASIT by non-infectious allergens, a noticeable correction of cytokine disorders was noted at the 1st month of treatment, immunocorrecting therapeutic effect was observed at 6 months and lasted for a long time during the ASIT maintenance regimen. Clinically, patients experienced a rapid onset of remission and achieved a long, complete control of the disease.

Thus, the technical result provided by the claimed method is to achieve correction of the immune and cytokine imbalance, to stop the allergic process, to achieve a longer, complete control of the disease, because the duration of the therapeutic effect is increased (in the treatment of blood pressure according to the program of the prototype method, a repeated course of treatment with lycopid is carried out after 2-4 months, and during treatment according to the program of the proposed method, repeated administration of lycopide is not necessary).

Figure 1 presents the cytokine status of children with blood pressure.

Figure 2 presents the dynamics of cytokines in serum in children with blood pressure when included in the treatment of lycopid.

Figure 3 presents the dynamics of cytokines in saliva in children with blood pressure when included in the treatment of lycopid.

Figure 4 presents the dynamics of cytokines in serum in children with blood pressure when included in the treatment of ASIT.

Figure 5 presents the dynamics of cytokines in saliva in children with blood pressure when included in ASIT therapy.

Figure 6 presents the dynamics of cytokines in serum in children with blood pressure when you turn on combination immunotherapy lycopid + ASIT.

Figure 7 presents the dynamics of cytokines in saliva in children with blood pressure when you turn on combination immunotherapy lycopid + ASIT.

Below are the results that explain this method of treatment of atopic dermatitis.

Example 1 (basic therapy + lycopid)

Patient T., 16 l. Diagnosis: atopic dermatitis, adolescent form, moderate course, acute stage. Upon admission, she complained of skin itching, burning and soreness of the skin, erythematous skin rashes, dryness, peeling and thickening of the skin, crusts, disturbance of night sleep. Suffers from atopic dermatitis from the 1st year of life. The course of the disease is year-round with exacerbations in the autumn-winter period. Itchy skin is amplified against the background of psychoemotional disorders, eating sharp, smoked foods. The severity of clinical manifestations on the SCORAD scale was 38 points. The initial serum cytokine status data: IL-4 - 54.1 pg / ml, IL-13 - 38.2 pg / ml, INFγ - 22.0 pg / ml; in saliva: IL-4 - 89.2 pg / ml, IL-13 - 124.4 pg / ml, INFγ - 11.6 pg / ml.

The patient was treated with standard therapy with an antihistamine (cetrin 10 mg, 1 tablet 2 times a day), an adsorbent drug (polysorb at an age dosage 3 times a day) and an external agent (Elidel cream) with the inclusion of the drug lycopide 1 mg in tablet form daily in the morning on an empty stomach under the tongue for 10 days. Then the patient continued taking lycopid every other day until a course dose of 20 tablets.

After a course of therapy with lycopid, a significant improvement in the patient's condition was noted: skin itching decreased, skin rashes significantly decreased and did not recur, sleep was normalized. The severity of clinical manifestations on the SCORAD scale was 11 points (a decrease in severity by 71%). Table 1 presents a study of the cytokine status of the patient in the dynamics of treatment.

Table 1 Cytokine Status Indicators Control group Before treatment 1 month 3 month 6 months Blood serum IL-4 8.5 54.1 26.2 12.5 54.7 IL-13 10.9 38,2 39,4 29.1 38.3 INFγ 50.6 22.0 36.1 42.3 20.9 Saliva IL-4 0.3 89.2 65.7 42.5 85.7 IL-13 2.7 124,4 96.1 54.7 120,4 INFγ 65 11.6 20,2 28.0 13.9 Note: the control group is healthy children of the appropriate age.

Moderate correction of cytokine imbalance was noted in the third month after treatment with lycopid and was short-lived. The patient was discharged from the department in satisfactory condition with an improvement in clinical status with recommendations for a repeated course of taking lycopide after 3-6 months.

Example 2 (basic therapy + ASIT).

Patient L., 11 years old. Diagnosis: atopic dermatitis, adolescent form, moderate course, acute stage. Upon admission, she complained of skin rashes, itching, burning and soreness of the skin, excoriation and cracks that disturb sleep and daily activity. Suffers from atopic dermatitis from the 1st year of life. The course of the disease is year-round with exacerbations in the autumn-winter period. He does not use standard protocols for treating the disease, he does not comply with the diet, and is only treated externally using hormonal drugs. The severity of clinical manifestations on the SCORAD scale was 58 points. The initial serum cytokine status data: IL-4 - 55.1 pg / ml, IL-13 - 39.4 pg / ml, INFγ - 21.1 pg / ml; in saliva: IL-4 - 87.2 pg / ml, IL-13 - 122.5 pg / ml, INFγ - 12.4pg / ml.

The patient was treated with basic therapy with an antihistamine (cetrin 10 mg, 1 tablet 2 times a day), an absorbent drug (polysorb at an age dosage 3 times a day) and an external agent (Elidel cream).

When stopping the process of exacerbation, ASIT was initiated by causative allergens by injection subcutaneously in the forearm in increasing dosages during the period of subsidence of clinical manifestations. At the 3rd month of therapy, a significant improvement in the patient's condition was observed: skin itching decreased, did not bother at all at night, skin rashes significantly decreased and did not recur, sleep was normalized. The severity of clinical manifestations on the SCORAD scale was 19 points (a decrease in severity by 67%).

Table 2 presents the study of cytokine status in the dynamics of treatment.

table 2 Cytokine Status Indicators Control group Before treatment 1 month 3 month 6 months Blood serum IL-4 8.5 55.1 50.3 43.3 19.6 IL-13 10.9 39,4 36.1 31.6 23.3 INFγ 50.6 21.1 25,2 33.6 41.3 Saliva IL-4 0.3 87.2 77.3 54.7 31,2 IL-13 2.7 122.5 106.1 78,4 42.6 INFγ 65 12,4 15.1 28.0 41,4 Note: the control group is healthy children of the appropriate age.

Against the background of ASIT, a gradual normalization of the cytokine content was noted, which was more pronounced by 6 months from the start of therapy. The patient was discharged from the department in satisfactory condition with an improvement in clinical status for further ASIT on an outpatient basis.

Example 3 (basic therapy + lycopid + accelerated ASIT non-infectious causative allergens)

Patient P., 13 years old. Diagnosis: atopic dermatitis, adolescent form, moderate course, acute stage. On admission, she complained of skin rashes, itching, dry skin, which disturb social activity and determine sleep disorders. Suffers from atopic dermatitis from the 1st year of life. The course of the disease is year-round with exacerbations in the autumn-winter period. The severity of clinical manifestations on the SCORAD scale was 41 points. The initial serum cytokine status data: IL-4 - 52.6 pg / ml, IL-13 - 41.2 pg / ml, INFγ - 21.1 pg / ml; in saliva: IL-4 - 87.2 pg / ml, IL-13 - 122.5 ± 5.7 pg / ml, INF-12.4 ± 1.6 pg / ml.

The patient underwent basic therapy with an antihistamine (cetrin 10 mg, 1 tablet 2 times a day), an absorbent drug (polysorb at an age dosage 3 times a day) and an external agent (Elidel cream).

Then, the drug was administered the drug lycopid once sublingually on an empty stomach daily, 1 tablet (1 mg). The drug was taken for 10 days, then the patient continued to take lycopide every other day until a course dose of 20 tablets with simultaneous allergen-specific immunotherapy with causative allergens by subcutaneous injection in the forearm in increasing doses.

After a full course of therapy on day 21, a significant improvement in the patient's condition was noted: itchy skin decreased, skin rashes did not recur, and sleep was normal. The severity of clinical manifestations on the SCORAD scale was 8 points (a decrease in severity by 81%).

Table 3 presents the study of cytokine status in the dynamics of treatment.

Table 3 Cytokine Status Indicators Control group Before treatment 1 month 3 month 6 months Blood serum IL-4 8.5 52.6 27.4 15,5 12.1 IL-13 10.9 41.2 29.6 24.0 19.1 INFγ 50.6 21.1 31.1 42.0 47.8 Saliva IL-4 0.3 87.2 68.9 48,2 44.0 IL-13 2.7 122.5 98.5 87.4 81.3 INFγ 65 12,4 17.5 24.0 27,2 Note: the control group is healthy children of the appropriate age.

With combined immunotherapy, lycopid + accelerated ASIT with non-infectious allergens, correction of cytokine disorders was noted at the 2nd month of treatment, becoming more pronounced by the 6th month, remaining for a long time. The patient was discharged from the department in satisfactory condition with an improvement in clinical status for further ASIT on an outpatient basis.

Thus, the inclusion of combination therapy with lycopid + accelerated ASIT by non-infectious antigens in the course of treatment of patients with atopic dermatitis leads to a lasting positive therapeutic effect, and the severity of the clinical manifestations of the disease decreases by an average of 81 ± 3%, the immune and cytokine imbalance normalizes. After 3 and 6 months from the start of therapy, when applying the lycopid + accelerated ASIT regimen with non-infectious causally relevant allergens, the clinical effectiveness increases on the SCORAD scale to 93% and the cytokine imbalance normalizes, i.e. there is a decrease in the severity of allergic inflammation.

All these advantages will make it possible to widely apply the proposed method in clinical practice for the treatment of atonic dermatitis in children.

Claims (1)

A method of treating atopic dermatitis in children, including basic traditional pharmacotherapy and taking lycopide 1 mg daily for 10 days, characterized in that the lycopide is continued treatment every other day until a course dose of 20 tablets with simultaneous allergen-specific immunotherapy with causative allergens (ASIT).

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