Atopic Dermatitis: Clinical Guidelines

List of Abbreviations

IL – interleukin

IFN – interferon

ICD – International Classification of Diseases

UVA-1 – ultra-long-wave ultraviolet therapy

NB-UVB – narrow-band ultraviolet B therapy

EASI – Eczema Area and Severity Index

IgE – immunoglobulin E

IGA – Investigator's Global Assessment

SCORAD – Scoring of Atopic Dermatitis

# - The use of a medicinal product for indications (characteristics) not specified in its instructions for use (off-label) is carried out by the decision of a medical commission, with the permission of the Local Ethics Committee of the medical organization (if any), subject to the signed informed voluntary consent of one of the parents or another legal representative in accordance with Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation" (as amended by Federal Law No. 482-FZ dated December 30, 2021).

** - The drug is included in the list of vital and essential drugs (Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On approval of the list of vital and essential drugs for medical use for 2020, the list of drugs for medical use, including drugs for medical use prescribed by decisions of medical commissions of medical organizations, the list of drugs intended to provide for persons with hemophilia, cystic fibrosis, pituitary nanism, Gaucher disease, malignant neoplasms of lymphoid, hematopoietic and related tissues, multiple sclerosis, hemolytic-uremic syndrome, systemic-onset juvenile arthritis, mucopolysaccharidosis types I, II and VI, persons after organ and/or tissue transplantation, and the minimum assortment of drugs required for the provision of medical care" (as amended on June 9, 2023).

Terms and Definitions

Atopic dermatitis is a multifactorial genetically determined inflammatory skin disease characterized by pruritus, a chronic relapsing course, and age-related features in the localization and morphology of lesions.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Atopic dermatitis is a multifactorial genetically determined inflammatory skin disease characterized by pruritus, a chronic relapsing course, and age-related features in the localization and morphology of lesions.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Genetic factors in the development of atopic dermatitis include filaggrin gene mutations leading to impaired epidermal barrier function in atopic dermatitis, as well as a family history of allergic diseases [1].

The development of skin inflammation involving T-lymphocytes is associated with immune system defects. In the acute phase of the disease, a Th2 response predominates, characterized by the stimulation of Th2 cells followed by IgE hyperproduction; in the chronic phase, there is a switch from a Th2 to a Th1 immune response [2]. Key cytokines involved in the pathophysiological mechanisms of atopic dermatitis include IL-4, IL-5, IL-13, IL-31, and IFN-γ, which require the JAK/STAT signaling pathway, including Janus kinase 1 (JAK-1), for signal transduction [3]. Many studies have described the pathogenetic role of IL-4 in the development of allergen-specific IgE-mediated reactions in atopic dermatitis, which consists in switching antibody synthesis to IgE. IL-4 binds not only to the IL-4 receptor but also to the IL-13 receptor; these cytokines share similar biological functions. IL-13 also plays an important role in the development of the Th2 type of immune response in atopic dermatitis [4].

The role of allergies to food allergens, house dust mites, plant pollen, Staphylococcus aureus enterotoxins, molds, and IgE autoreactivity in the mechanisms of disease development has been proven [5, 305, 306].

1.3 Epidemiology of the Disease or Condition

Atopic dermatitis is one of the most common diseases (accounting for 20% to 40% of skin diseases), occurring in all countries, in both sexes, and across various age groups. The prevalence of atopic dermatitis among the pediatric population is up to 20%, and among the adult population, it is 2–8% [6]. According to Federal Statistical Observation data, in 2022, the prevalence of atopic dermatitis was 384.7 cases per 100,000 of the total population (0.38%), and the incidence (newly diagnosed) was 157.1 cases per 100,000 of the total population. At the same time, the prevalence of atopic dermatitis among children aged 0 to 14 years in 2022 was 1,436.3 cases per 100,000 child population (1.4%), the incidence was 654.3 cases per 100,000 child population, and in the 15 to 17 age group, the prevalence of atopic dermatitis was 1,052.1 cases per 100,000 of the corresponding population (1.05%), and the incidence was 347.8 cases per 100,000 of the corresponding population [307]. The incidence of atopic dermatitis among children aged 15 to 17 in the Russian Federation was 1,047 cases per 100,000 of the corresponding population, and the prevalence was 329 cases per 100,000 of the corresponding population [7].

Atopic dermatitis may be associated with respiratory allergies, specifically allergic rhinitis and bronchial asthma. According to various sources, the risk of developing respiratory allergies in patients with atopic dermatitis is 30–80%; 60% of patients with atopic dermatitis have a latent tendency to develop bronchial asthma, and 30–40% of patients develop bronchial asthma [8, 9]. According to a systematic review, bronchial asthma was diagnosed in 29.5% of children with atopic dermatitis aged 6 years or older [10]. Pollinosis was detected in 48.4% of patients with atopic dermatitis compared to 24.4% of individuals without atopic dermatitis, and bronchial asthma was diagnosed in 24.1% of patients with atopic dermatitis compared to 8.9% of individuals without atopic dermatitis [11].

The risk of developing an allergic reaction and bronchial asthma is significantly higher in children with food allergies and atopic dermatitis [12].

According to the "atopic march" concept, patients with atopic dermatitis and food allergies may sequentially develop other atopic diseases—allergic rhinitis and bronchial asthma—over the course of their lives [13, 14]. The relationship between these diseases then depends on the severity of atopic dermatitis: symptoms of bronchial asthma and allergic rhinitis may develop in 20% of children with moderate disease and 60% with severe disease [15]. It is hypothesized that there is a subset of patients with atopic dermatitis in whom bronchial obstruction develops as early as skin lesions, or even precedes them, and therefore bronchial asthma in this case cannot be considered the outcome of the "atopic march" [16, 17].

1.4 Features of Coding the Disease or Condition

L20 Atopic dermatitis

L20.0 Besnier's prurigo

L20.8 Other atopic dermatitis: eczema: flexural, infantile (acute) (chronic), endogenous (allergic); neurodermatitis: atopic (localized), (diffuse)

L20.9 Atopic dermatitis, unspecified

1.5 Classification of the disease or condition

There is no universally accepted clinical classification.

1.6 Clinical presentation of the disease or condition

In most cases, atopic dermatitis begins in early childhood (under 2 years of age). The disease is characterized by age-specific clinical manifestations and a chronic relapsing course with periodic exacerbations and remissions that may last for several years. The patient may have a history of other atopic diseases (allergic rhinitis, bronchial asthma). A family history of allergic diseases (bronchial asthma, allergic rhinitis, atopic dermatitis) is typical. The disease is characterized by seasonality of exacerbations, with worsening in the cold season and improvement in the summer. Exacerbation of the process can also develop under the influence of a number of triggering factors (allergens, irritants, food products, emotional stress, etc.). Increased sweating can increase the intensity of pruritus.

Clinical manifestations of atopic dermatitis differ across different age periods. The main differences lie in the localization of lesions and the ratio of exudative and lichenoid components of the rashes.

The infantile stage of atopic dermatitis usually begins at 2–3 months of life. This period is dominated by the exudative form of the disease, in which inflammation is acute or subacute. Symmetrical erythematous, papulo-vesicular rashes are noted on the skin of the face and scalp, with exudation leading to crusting and scaling. Subsequently, the rashes spread to the skin of the outer legs, forearms, torso, and buttocks, and may also appear in natural skin folds. Dermographism is usually red or mixed. Subjectively, skin itching of varying intensity is observed. By the end of this period, lesions persist mainly in the antecubital and popliteal fossae, as well as the wrists and neck. Exacerbations of the disease are largely associated with dietary factors. The infantile period of atopic dermatitis typically ends by the second year of life with clinical recovery (in 60% of patients) or transitions into the next period (childhood).

The childhood stage of atopic dermatitis is characterized by rashes that are less exudative than in the infantile period, presenting as inflammatory miliary and/or lenticular papules, papulo-vesicles, and erythematous-squamous elements localized on the skin of the upper and lower extremities, wrists, forearms, antecubital and popliteal fossae, ankles, and feet. It is characterized by the presence of pruritic nodules, erosions, and excoriations, as well as minor erythema and infiltration in the areas of rashes on the torso, upper and lower extremities, and less frequently on the face. Dermographism becomes pink, white, or mixed. Eyelid pigmentation, dyschromia, and frequently angular cheilitis appear.

The adolescent and adult stage of atopic dermatitis is characterized by rashes predominantly on the flexural surfaces of the extremities (in the antecubital and popliteal fossae, flexural surfaces of the ankle and wrist joints), on the back of the neck, and in the retroauricular areas. The rashes present as erythema, papules, desquamation, infiltration, lichenification, multiple excoriations, and fissures. Areas of hypo- or hyperpigmentation remain in the lesion foci as rashes resolve. Over time, the skin clears of rashes in most patients, with only the popliteal and antecubital fossae remaining affected.

Palmar and plantar hyperlinearity, follicular hyperkeratosis ("horny" papules on the lateral surfaces of the shoulders, forearms, and elbows), cheilitis, nipple eczema, and folds on the anterior surface of the neck may occur. Periorbital skin hyperpigmentation and the appearance of a fold beneath the lower eyelid (Dennie-Morgan lines) are observed. Increased skin dryness is noted. Dermographism is persistent white or mixed. Itching is pronounced, constant, and less frequently paroxysmal. In adolescents and adults, the lichenoid form of the disease frequently predominates, characterized by dryness, pronounced skin markings, edema and infiltration of the skin, large confluent foci of skin lichenification, and persistent, stubborn itching. The pruriginous form of the disease is relatively rare, characterized by rashes in the form of multiple isolated dense edematous papules, upon the apex of which small vesicles may appear. Lesions may be widespread, with a preferential localization on the skin of the extremities.

The most severe manifestation of atopic dermatitis is erythroderma, which is characterized by universal skin involvement in the form of erythema, infiltration, lichenification, and desquamation, accompanied by symptoms of intoxication and thermoregulation disorders (hyperthermia, chills, lymphadenopathy).

Clinical and morphological forms of atopic dermatitis:

• Exudative

• Erythematous-squamous

• Erythematous-squamous form with lichenification

• Lichenoid

• Pruriginous

Laboratory examination of patients with atopic dermatitis may reveal peripheral blood eosinophilia, as well as elevated levels of total and allergen-specific serum IgE.

Stages of the disease

The stage of exacerbation or pronounced clinical manifestations is characterized by the presence of erythema, papules, microvesicles, weeping, multiple excoriations, crusts, desquamation, and pruritus of varying intensity.

Stages of remission:

- incomplete remission is characterized by a significant decrease in disease symptoms with persistence of skin infiltration, lichenification, dryness and flaking, as well as hyper- or hypopigmentation in the lesions;

- complete remission is characterized by the absence of all clinical symptoms of the disease [18].

Extent of the Skin Process

In limited-localized process, the lesion area does not exceed 10% of the skin surface.

In widespread process, the lesion area ranges from 10% to 50% of the skin surface.

In diffuse process, the lesion area exceeds 50% of the skin surface.

Severity of Atopic Dermatitis

Mild course of the disease is characterized predominantly by limited-localized skin manifestations, mild pruritus, rare exacerbations (less than 1–2 times a year), with relapse duration of up to 1 month, predominantly in the cold season. The duration of remission is 8–10 months or more. A good response to ongoing therapy is noted.

In moderate course, a widespread character of the lesions is observed. The frequency of exacerbations is 3–4 times a year with an increase in their duration. The duration of remissions is 2–3 months. The process becomes persistent with a poor response to ongoing therapy.

In severe course of the disease, the skin process is widespread or diffuse in character with prolonged exacerbations, rare and short-lived remissions (frequency of exacerbations 5 times a year or more, duration of remission 1–1.5 months). Treatment yields short-term and insignificant improvement. Severe pruritus is noted, leading to sleep disturbance [18].

Complicated Forms of Atopic Dermatitis

The course of atopic dermatitis is often complicated by secondary infection (bacterial, mycotic, or viral). This feature, characteristic of patients with atopic dermatitis, reflects impaired anti-infective defense due to disturbed synthesis of antimicrobial peptides and epidermal barrier dysfunction.

1. The most frequent infectious complication of atopic dermatitis is the addition of a secondary bacterial infection. It presents as streptoderma and/or staphyloderma with characteristic skin manifestations against the background of atopic dermatitis exacerbation. Pyococcal complications manifest as various forms of pyoderma: ostiofolliculitis, folliculitis, vulgaris, less commonly streptococcal impetigo, and sometimes furuncles.

2. Various mycotic infections (dermatophytes, yeast-like, mold, and other types of fungi) also frequently complicate the course of atopic dermatitis, leading to more prolonged exacerbations, lack of improvement, or worsening of the condition. The disease acquires a persistent character. The presence of mycotic infection can alter the clinical picture of atopic dermatitis: lesions with clear scalloped, slightly elevated edges appear, angular cheilitis frequently relapses, and lesions of the retroauricular, inguinal folds, nail bed, and genitalia are noted.

3. Patients with atopic dermatitis, regardless of the acuity of the process, are prone to viral infections (most commonly herpes simplex virus, human papillomavirus, molluscum contagiosum virus). Herpetic superinfection can lead to a rare but severe complication — Kaposi's varicelliform eruption. The disease is characterized by widespread vesicular eruptions, severe pruritus, fever, and rapid addition of pyococcal infection. Involvement of the central nervous system, eyes, and development of sepsis are possible.

4. Benign lymphadenopathy is usually associated with exacerbations of atopic dermatitis and manifests as enlargement of lymph nodes in the cervical, axillary, inguinal, and femoral regions. The size of the nodes may vary; they are mobile, elastic in consistency, and painless. Benign lymphadenopathy resolves spontaneously with improvement of the condition or during ongoing treatment. A persistent, pronounced enlargement of lymph nodes despite a decrease in disease activity requires a diagnostic biopsy to rule out lymphoproliferative disease.

5. Complications of atopic dermatitis involving the eyes manifest as recurrent keratoconjunctivitis accompanied by itching. In severe cases, chronic conjunctivitis can progress to ectropion and cause persistent tearing. Keratoconus may develop. Early cataracts can also develop, usually associated with the frequent use of glucocorticoids used in dermatology in the periorbital area.

The development of neurological and psychiatric abnormalities – sleep disorders due to intense pruritus, social maladjustment caused by external defects, contribute to increased anxiety, the development of depression, and other psychiatric and neurological disorders, including suicidal ideation, is possible.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Comments: To establish a diagnosis of atopic dermatitis, a combination of three major and at least three minor criteria is required.

The major and minor diagnostic criteria of J.M. Hanifin and G. Rajka are distinguished:

Major diagnostic criteria (3 or more):

Minor diagnostic criteria (3 or more):

• pruritus;

• typical morphology and localization of skin lesions: in infants and young children – redness and rashes on the face and extensor surfaces of the extremities; in older children and adults – lichenification and excoriations in the flexural folds of the extremities;

• chronic relapsing course;

• history of atopic diseases in the patient or their relatives.

• dry skin (xerosis);

• palmar («lined») and plantar hyperlinearity or follicular hyperkeratosis;

• elevated serum levels of total and specific IgE;

• early onset of the disease (under 2 years of age);

• tendency toward cutaneous infections (S. aureus, H. simplex);

• localization of the skin process on the hands and feet;

• nipple eczema;

• cheilitis;

• recurrent conjunctivitis;

• Denny-Morgan fold (an extra infraorbital fold);

• keratoconus;

• anterior subcapsular cataract;

• periorbital skin hyperpigmentation;

• facial pallor/erythema;

• seborrheic eczema;

• anterior neck folds;

• itching associated with increased sweating;

• exacerbation of the process and increased itching under the influence of triggering factors (wool clothing, soap, allergens, irritants, food products, emotional stress, etc.);

• perifollicular accentuation;

• food intolerance;

• seasonality of exacerbations (worsening in the cold season and improvement in summer);

• white dermographism.

Differential diagnosis of atopic dermatitis is carried out with cutaneous T-cell lymphoma, chronic eczema, allergic and irritant contact dermatitis, seborrheic dermatitis, nummular eczema, scabies, psoriasis, ichthyosis, pityriasis rubra pilaris, dermatophytosis, immunodeficiency states (X-linked Wiskott-Aldrich syndrome, hyper-IgE syndrome), etc.

In children, atopic dermatitis should be differentiated from all the above-mentioned diseases, as well as from diaper dermatitis.

2.1 Complaints and Anamnesis

Pruritus is a constant symptom of the disease across all age groups [20]. Pruritus is classified as a major diagnostic criterion for atopic dermatitis according to J.M. Hanifin and G. Rajka.

Comments: The concordance of anamnestic data with the major and minor diagnostic criteria for atopic dermatitis according to J.M. Hanifin and G. Rajka is assessed.

2.2 Physical Examination

To establish a diagnosis, the primary step is a visual inspection of the patient's skin. The clinical manifestations of the disease are described in detail in the «Clinical Presentation» section.

2.3 Laboratory Diagnostics

Comments: Monitoring complete blood count parameters is necessary during therapy with cyclosporine**, as cyclosporine** can cause adverse events such as leukopenia, anemia, thrombocytopenia [21] and other immunosuppressants or selective immunosuppressants [308, 309]. During treatment with abrocitinib, baricitinib**, upadacitinib**, the development of anemia, lymphopenia, and thrombocytopenia is possible [22].

Comments: Monitoring blood chemistry parameters is necessary during therapy with cyclosporine**, since cyclosporine** may cause adverse events, including an increase in plasma creatinine and urea concentrations, hyperlipidemia, hyperuricemia, hyperkalemia, hypomagnesemia, and hyperglycemia. Cyclosporine** may also cause a dose-dependent, reversible increase in plasma bilirubin concentration and liver enzyme activity. Hepatotoxic effects of cyclosporine** with the development of cholestasis, jaundice, hepatitis, and liver failure are possible [21]. During treatment with abrocitinib, baricitinib**, upadacitinib**, an increase in blood cholesterol levels and elevated blood levels of alanine aminotransferase and aspartate aminotransferase may occur [22].

Comments: Monitoring urinalysis parameters is necessary during therapy with cyclosporine**, since cyclosporine** can cause toxic kidney damage and, furthermore, possessing immunosuppressive activity, it may contribute to the development of infectious lesions of the kidneys and urinary tract [21].

Comments: Elevated serum levels of total and specific IgE serve as a minor diagnostic criterion for atopic dermatitis [44, 45]. It is recommended to determine the blood levels of specific immunoglobulins E (testing the level of antibodies to plant, animal, and chemical antigens in the blood) during initial diagnosis and in the course of dynamic monitoring in order to identify sensitization and potential trigger factors (testing the level of antibodies to plant, animal, and chemical antigens in the blood), including when performing skin tests is not feasible.

2.4 Instrumental Diagnostics

Not applicable.

2.5 Other Procedures

Comments: When diagnosing atopic dermatitis in adult patients, differential diagnosis with cutaneous T-cell lymphomas or other dermatoses is carried out. In atopic dermatitis, acanthosis of varying severity is observed, with elongation of epidermal rete ridges and their branching. Areas of parakeratosis and exocytosis may be detected. Perivascular or confluent lymphohistiocytic infiltrates are found in the dermis; in chronic courses, infiltration is minimal, and fibrosis predominates.

Comments: An allergological evaluation is necessary to confirm the allergic nature of atopic dermatitis, identify causative allergens in order to develop lifestyle and dietary recommendations, and determine the feasibility of allergen-specific immunotherapy. Allergological testing can be performed via skin testing with non-bacterial allergens (cutaneous allergen testing), determination of serum allergen-specific IgE antibody levels, and provocation tests. The choice of allergological testing method is determined by the availability and equipment of the allergy clinic and the presence/absence of contraindications to skin testing (acute exacerbation of the disease, need for systemic antihistamines).

Comments: The scope of the evaluation is determined by an allergist-immunologist. Skin tests are performed in an allergy clinic setting by a specially trained nurse and an allergist-immunologist. Prick tests or scarification tests are most commonly used. The results of allergen skin testing are correlated with the results of negative and positive control tests.

Comments: Determining serum allergen-specific IgE antibody levels is particularly important when skin test results are inconclusive or when they cannot be performed (e.g., during an exacerbation of an allergic disease or in the presence of other contraindications). The reliability of the result is affected by the test system used, which may have low sensitivity and specificity, resulting in both false-positive and false-negative outcomes. Component-resolved (molecular) diagnostics is used to map a patient's allergen sensitization at the molecular level using purified natural or recombinant allergenic molecules instead of allergen extracts. This method can be used in cases of discrepancies between anamnestic data, cutaneous allergen test results, and specific IgE antibody levels to allergen extracts, as well as in the presence of indications for food anaphylaxis, cross-reactive food allergy, and the inefficacy of AIT.

Comments: SCORAD is an integral score that includes the evaluation of six objective symptoms: erythema, edema/papules, crusts/oozing, excoriations, lichenification/scaling, skin dryness, and two subjective symptoms (intensity of pruritus and sleep disturbance). Mild atopic dermatitis corresponds to a SCORAD value <25; moderate severity corresponds to a SCORAD value between 25 and 50; severe atopic dermatitis corresponds to a SCORAD value >50.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

Patients with atopic dermatitis may receive topical or systemic therapy, as well as phototherapy (ultraviolet radiation). Moisturizing and emollient agents (emollients) are indicated for all patients with atopic dermatitis. Topical pharmacotherapy is administered for any severity—mild, moderate, or severe—of skin lesions in atopic dermatitis. Topical medications used in atopic dermatitis include glucocorticoids, other dermatitis drugs excluding glucocorticoids (pimecrolimus**, indicated for mild and moderate atopic dermatitis, and tacrolimus**, indicated for moderate and severe atopic dermatitis), and other dermatological agents (zinc pyrithione). For topical treatment in children, cream formulations and single-component topical agents are preferred: glucocorticoids, other dermatitis drugs excluding glucocorticoids (tacrolimus** and pimecrolimus**). Multi-component topical drugs—corticosteroids combined with antibiotics or corticosteroids combined with other agents—are indicated only when bacterial and/or fungal infection is clinically and/or laboratory confirmed. Inappropriate use of multi-component topical drugs may contribute to the development of additional sensitization to the components of the topical medicinal product in children.

Systemic therapy and phototherapy (ultraviolet radiation) are prescribed for moderate and severe atopic dermatitis. For systemic therapy in patients with atopic dermatitis, dermatitis drugs excluding glucocorticoids (abrocitinib and dupilumab**) and selective immunosuppressants (baricitinib** and upadacitinib**) may be used. Phototherapy (ultraviolet radiation) involves ultraviolet irradiation of the skin using various methods.

To reduce pruritus intensity, systemic antihistamines are prescribed to patients with atopic dermatitis. Oral formulations are preferred in children, in the absence of contraindications, to minimize painful medical procedures. Routine use of systemic antihistamines in children with atopic dermatitis should be avoided. There is insufficient evidence to support the efficacy of this drug class for relieving pruritus in atopic dermatitis. However, they may be used if the antipruritic effect of topical glucocorticoids and/or other non-glucocorticoid dermatitis drugs is insufficient. If systemic antihistamines are necessary in pediatric patients, second-generation drugs should be preferred due to their superior safety profile compared to first-generation drugs.

3.1.1. Moisturizing and emollient agents

Comments: Emollients can be used in the form of lotions, creams, ointments, cleansers, and bath products. The choice of product and its formulation is made individually, taking into account patient preferences, individual skin characteristics, season, and climatic conditions.

Patients with atopic dermatitis must constantly, frequently, and in large quantities use moisturizing and emollient agents (at least 3–4 times a day) both independently and immediately after water procedures [48–50]. An effective method for restoring the skin barrier in patients with atopic dermatitis is the use of emollients that compensate for filaggrin deficiency [310, 311].

The most pronounced effect of moisturizing and emollient products is observed with their regular use in the form of creams, ointments, bath oils, and soap substitutes. The choice of product and its formulation is made individually, taking into account patient preferences, individual skin characteristics, season, time of year, and climate. Ointment-based products (greasier) can be used in cold weather, while creams and gels with a high water content should be used in summer. Lotions have a higher water content that can evaporate, and therefore they should not be used in patients with pronounced xerosis.

To achieve a clinical effect, it is necessary to use a sufficient volume of emollient products (an adult with widespread skin lesions consumes up to 600 grams per week, a child consumes up to 250 grams per week) [38].

3.1.2 Topical therapy

• For patients with mild, moderate, and severe atopic dermatitis, it is recommended to use topical therapy: corticosteroids used in dermatology, and/or other non-steroidal dermatological agents [6, 24].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comments: In mild atopic dermatitis, low-potency (Group I) and moderate-potency (Group II) corticosteroids used in dermatology are preferred. In moderate and severe atopic dermatitis, high-potency (Group III) and very high-potency (Group IV) corticosteroids are advisable, in the minimum effective doses (Appendix G3). To rapidly treat a flare-up of atopic dermatitis, topical agents and emollients under wet wrap dressings can be used. First, topical agents (corticosteroids and/or emollients) are applied to the affected skin areas, then a damp cotton or gauze cloth is applied, followed by a dry outer bandage [51–54]. Caution should be exercised when using moderate-potency (Group II) and high-potency (Group III) corticosteroids with wet wrap dressings due to the risk of adrenal suppression [54, 55]. The efficacy of topical therapy is assessed 2 weeks after initiating a new topical agent.

Corticosteroids used in dermatology

clobetasol 0.05% topical cream, 0.05% topical ointment applied in a thin layer to affected skin areas 1–2 times a day for 3–4 weeks [56–59].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: A contraindication to prescribing clobetasol is age under 1 year. Very high-potency corticosteroids (Group IV) should not be used in children with atopic dermatitis. Clobetasol is recommended for short-term use; it should not be applied under occlusive dressings. Short repeated courses may be administered if necessary. Atrophic skin changes resulting from prolonged corticosteroid use may occur on the face more frequently than on other body parts [312]. When prescribing clobetasol cream and ointment to children, the drug should not be used for more than 5 days or applied under an occlusive dressing.

or

betamethasone** 0.05% topical ointment applied twice daily to the affected skin area in a thin layer with light rubbing for 2–4 weeks [60].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: A contraindication to prescribing betamethasone** 0.05% topical ointment is age under 1 year.

or

betamethasone** 0.05% topical cream applied once daily to patients with atopic dermatitis on the affected skin area in a thin layer twice daily with light rubbing for 2–4 weeks [61–63].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: A contraindication to prescribing betamethasone** 0.05% topical cream is age under 1 year.

or

triamcinolone 0.1% topical ointment is applied in a thin layer to affected skin areas 2–3 times a day for 2–4 weeks. An occlusive dressing may be used [64–66].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: A contraindication to prescribing #triamcinolone 0.1% topical ointment is age under 2 years.

or

fluticasone 0.05% topical cream, 0.005% topical ointment applied 1 or 2 times a day in a thin layer in an amount no greater than necessary to cover the entire affected area, and gently rubbed in for 2–4 weeks [67–69].

Level of Evidence CGrade of Recommendation 5Level of Clinical Effectiveness C (level of evidence – 5)

Comments: A contraindication to prescribing fluticasone ointment and cream is age under 10 years.

or

mometasone** cream 0.1%, ointment 0.1% applied in a thin layer to affected skin areas once daily for 2–4 weeks [70–78].

Level of Evidence CGrade of Recommendation 5Level of Clinical Effectiveness C (level of evidence – 5)

Comments: A contraindication to prescribing mometasone** cream 0.1%, ointment 0.1% is age under 2 years.

or

methylprednisolone aceponate 0.1% cream, ointment, emulsion for topical use applied once daily in a thin layer to affected skin areas for 2–4 weeks [79–83].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: A contraindication to prescribing methylprednisolone aceponate 0.1% cream, ointment, emulsion for topical use is age under 4 months.

or

alclometasone cream 0.05%, ointment 0.05% applied to pediatric patients with atopic dermatitis on affected skin areas in an even layer 2–3 times a day for 2–4 weeks. In children and during the follow-up treatment period, the drug may be used once a day [84–88].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: A contraindication to prescribing alclometasone 0.05% cream and 0.05% topical ointment is age under 6 months.

or

#hydrocortisone** 0.1% topical cream, 0.1% topical ointment applied to affected skin areas in a thin layer no more than 1–3 times a day for 2–4 weeks [89–97].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Use of 0.1% #hydrocortisone** cream, ointment, and emulsion is possible from 6 months of age.

or

prednisolone** 0.5% topical ointment applied in a thin layer to affected skin areas 1–3 times a day [99].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: A contraindication to prescribing prednisolone** 0.5% topical ointment is age under 1 year. The duration of use should not exceed 14 days.

or

fluocinolone acetonide 0.025% ointment, 0.025% liniment for topical use in adults 2–4 times a day, up to 25 days; for children, use once a day for no more than 5 days. Course: no more than 2 weeks; when applied to the skin of the face — no more than 5 days [97].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Topical calcineurin inhibitor preparations

pimecrolimus** 1% topical cream applied twice daily to adults and children over 3 months of age with mild and moderate atopic dermatitis on the affected surface in a thin layer [100–109].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: Pimecrolimus** topical cream is indicated for both short-term and long-term treatment of mild and moderate atopic dermatitis in adults, adolescents, and children (from 3 months of age). Long-term intermittent use is possible (once a week or less frequently). Long-term use for up to 12 months with breaks is possible. A contraindication to prescribing pimecrolimus** is age under 3 months.

The drug is prescribed twice daily to affected skin areas on any parts of the body, including the head, face, neck, and intertriginous areas. It is particularly indicated for sensitive skin areas [109]. At the first signs of atopic dermatitis relapse, therapy should be resumed. If symptoms persist for 6 weeks, the patient's condition should be reassessed. It should not be prescribed to pregnant women (efficacy and safety studies have not been conducted).

Women during lactation should use with caution and should not apply to the mammary gland area. During the use of pimecrolimus**, exposure to sunlight, visits to solariums, PUVA therapy, and ultraviolet skin irradiation with UV-B or UV-A rays should be avoided.

or

tacrolimus** for patients with moderate and severe atopic dermatitis: adults — 0.03% topical ointment or 0.1% topical ointment; children over 2 years of age — 0.03% topical ointment applied twice daily in a thin layer to affected skin areas [94, 100, 110–127].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: The duration of treatment according to this regimen should not exceed three weeks. Thereafter, the frequency of application is reduced to once daily, and treatment is continued until complete regression of the lesions. If there is no positive dynamics within 14 days, a repeated medical consultation is required to clarify further therapeutic tactics. After 12 months of maintenance therapy (using tacrolimus** twice a week), the drug should be temporarily discontinued, and the need to continue maintenance therapy should then be considered.

The use of 0.1% tacrolimus** ointment is contraindicated in children under 16 years of age. A contraindication to prescribing 0.03% tacrolimus** ointment is age under 2 years.

During the use of tacrolimus**, exposure to sunlight, visits to solariums, ultraviolet skin irradiation with UV-B or UV-A rays, and PUVA therapy should be avoided. For 2 hours after application, emollients should not be used on skin areas where tacrolimus** ointment was applied.

zinc pyrithione 0.2% topical cream is applied in a thin layer to affected skin areas 2 times daily in children from 1 year of age; application under an occlusive dressing is possible;

zinc pyrithione 0.2% aerosol is sprayed from a distance of 15 cm 2–3 times daily in children from 1 year of age in cases of pronounced weeping [128–130].

Comments: The treatment course following this regimen for atopic dermatitis is 3–4 weeks.

GCR CLeE 4Grade of Recommendations C (Level of Evidence – 4)

naphthalane oil liniment 10% is applied in a thin layer, without rubbing, to affected skin areas 2 times a day [131].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: The drug has anti-inflammatory, antipruritic, disinfectant, and healing effects.

3.1.3 Systemic therapy to reduce pruritus intensity

clemastine 1 mg, orally for adults and children over 12 years of age – 1 tablet (1 mg) in the morning and evening for 7–10 days. In difficult-to-treat cases, the daily dose may be up to 6 tablets (6 mg); for children aged 6–12 years – ½–1 tablet before breakfast and at bedtime [99, 132, 133].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Clemastine in tablet form is contraindicated under the age of 6 years.

or

chloropyramine** 25 mg orally for children aged 1 month to 12 months – 6.25 mg (¼ tablet) 2–3 times a day crushed into a powder form together with baby food; for children aged 1 year to 6 years – 8.3 mg (1/3 tablet) 2–3 times a day; for children aged 7 to 14 years – 12.5 mg (½ tablet) 2–3 times a day; for children over 14 years of age and adults – 1 tablet 3–4 times a day (75–100 mg per day) [134–138].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Chloropyramine** in tablet form is contraindicated under the age of 6 months or up to 14 years, depending on the drug manufacturer.

or

quifenadine 10 mg, 25 mg, 50 mg tablets for adults at 25–50 mg 2–4 times a day; for children aged 3 to 7 years – 10 mg orally 2 times a day, for children aged 7 to 12 years – 10–15 mg orally 2–3 times a day, for children over 12 years of age and adults – 1 tablet of 25 mg orally 2–3 times a day for 10–15 days [99, 139, 140].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Contraindications to prescribing quifenadine tablets include age under 3 years (for the 10 mg dosage) and age under 18 years (for the 50 mg dosage).

or

loratadine** syrup 1 mg/ml, tablets 10 mg, for children aged 2 to 12 years weighing less than 30 kg – 5 mg (5 ml) once daily orally; for body weight over 30 kg – 10 mg (10 ml) once daily; for children over 12 years of age and adults – 10 mg (10 ml) once daily orally for 14–28 days [141–143].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

or

cetirizine** #oral drops 10 mg/ml, tablets 10 mg – for children aged 6 to 12 months (strictly by prescription and under close medical supervision) – 2.5 mg (5 drops) orally once daily, for children aged 1 to 2 years – 2.5 mg (5 drops) orally 1–2 times daily, for children aged 2 to 6 years – 2.5 mg (5 drops) orally 2 times daily or 5 mg (10 drops) orally once daily, for children over 6 years of age and adults – 10 mg orally once daily for 14–28 days [144–148, 321, 326, 327].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: Cetirizine** tablets are contraindicated under 6 years of age; cetirizine** oral drops are contraindicated under 6 months or 1 year of age depending on the manufacturer.

or

levocetirizine 5 mg – for children over 6 years of age and adults – 5 mg orally once daily for 14–28 days [149–153].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: A contraindication to prescribing levocetirizine is age under 6 years.

or

levocetirizine 5 mg tablets, oral drops 5 mg/ml – for children aged 2 to 6 years – 1.25 mg (5 drops) 2 times daily; total daily dose is 2.5 mg (10 drops), for children over 6 years of age and adults – 5 mg orally once daily for 14–28 days [296-301].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Contraindications to prescribing levocetirizine in tablet form include age under 6 years, and contraindications to prescribing levocetirizine in drop form include age under 2 years.

clemastine solution for injection 1 mg/ml intramuscularly or intravenously for adults 2 mg (2 ml) 2 times daily (morning and evening); for children – 0.025 mg per kg of body weight per day intramuscularly, divided into 2 injections; for 5–7 days [131].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Clemastine injection solution is contraindicated in children under 1 year of age. Oral dosage forms are preferred for children in the absence of contraindications to minimize painful medical procedures.

or

chloropyramine** solution for injection 20 mg/ml for children aged 1 month to 1 year at 5 mg (0.25 ml of solution) intramuscularly once daily; for children aged 1 year to 6 years – 10 mg (0.5 ml of solution) intramuscularly once daily; for children aged 6 to 14 years – 10–20 mg (0.5–1 ml of solution) intramuscularly once daily; for children over 14 years of age and adults – 20–40 mg (1–2 ml of solution) intramuscularly once daily for 5–7 days [131].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Chloropyramine** solution for injection is contraindicated in newborns. Oral dosage forms are preferred for children in the absence of contraindications to minimize painful medical procedures. If systemic antihistamines are needed in pediatric practice, second-generation drugs should be favored due to their better safety profile compared to first-generation drugs [301-302]. When using first-generation systemic antihistamines, the treatment course should be short (no more than 10 days) due to the high probability of adverse events [303].

3.1.4 Physiotherapy

Patients with moderate-to-severe atopic dermatitis may be prescribed ultraviolet skin irradiation [154–165]. Before prescribing phototherapy to patients with atopic dermatitis, a complex of laboratory tests should be performed to identify contraindications, including a general (clinical) blood count, urinalysis, general biochemical blood test, consultation with a general practitioner or pediatrician, endocrinologist, and obstetrician-gynecologist (for women). Examination by other specialists is recommended according to indications [166–171].

narrowband ultraviolet B (NB-UVB) phototherapy with a wavelength of 311 nm for adult patients with atopic dermatitis [154–156].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

or

narrowband ultraviolet B (NB-UVB) phototherapy with a wavelength of 311 nm for children with atopic dermatitis [157, 158].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: Data on the use of phototherapy in childhood are limited; therefore, caution should be exercised. Narrowband UVB phototherapy is prescribed to children 5 years of age and older. When prescribing narrowband UVB phototherapy, the child's psycho-emotional characteristics, general condition, ability to stay in the cabin independently, and compliance with medical staff instructions must be taken into account.

or

long-wave ultraviolet A1 (UVA1) phototherapy (wavelength 340–400 nm) for adults [159–163].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: Long-wave ultraviolet A1 phototherapy is contraindicated in children under 18 years of age.

or

selective phototherapy (broadband ultraviolet B phototherapy with a wavelength of 280–320 nm) for adult patients with atopic dermatitis [164].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: Data on the use of phototherapy in childhood are limited.

3.1.5 Systemic therapy for patients with atopic dermatitis

abrocitinib film-coated tablets, 100 mg or 200 mg once daily orally for adults and children aged 12 years and older [172–177].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: Abrocitinib should be taken at approximately the same time each day, regardless of meals. The drug can be used in combination with dermatitis medications, excluding topical glucocorticoids, or as monotherapy. In adults and adolescents (12–18 years of age) with moderate-to-severe atopic dermatitis, abrocitinib at a dose of 100 mg and 200 mg once daily as monotherapy or in combination with background topical drug therapy demonstrated a rapid reduction in the severity of objective signs of atopic dermatitis and pruritus. The proportion of patients achieving an IgA response at week 12 and/or week 16 of therapy among patients receiving abrocitinib at doses of 100 mg or 200 mg once daily was significantly higher than in the placebo group. A reduction in pruritus intensity of 4 points or more on a visual analogue scale ranging from 0 to 10 points was observed significantly more often in patients receiving abrocitinib 100 mg and 200 mg once daily compared to the placebo group, with differences becoming significant as early as 2 weeks of therapy and persisting at week 12 of treatment. If adequate therapeutic efficacy of abrocitinib treatment is not achieved after 24 weeks, discontinuation should be considered. During treatment with abrocitinib, therapy safety monitoring is required due to the potential development of lymphopenia, thrombocytopenia, and increased blood cholesterol levels. Abrocitinib treatment may be interrupted if a complete blood count shows a decrease in lymphocyte or platelet counts [172–178]. Abrocitinib is contraindicated in children under 12 years of age.

or

baricitinib** film-coated tablets, 2 mg or 4 mg orally once daily for adult patients [179, 180]

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: Baricitinib** can be taken at any time regardless of meals. Baricitinib** may be prescribed as monotherapy or in combination with topical corticosteroids. Concomitant use with topical corticosteroids may increase the efficacy of baricitinib. A dose of 2 mg once daily is suitable for patients aged 75 years and older, and may also be used in patients with a history of chronic or recurrent infection. Prescribing baricitinib** at a dose of 2 mg once daily should be considered in patients who have achieved sustained control of disease activity after using the drug at a dose of 4 mg once daily and in whom dose reduction can be recommended.

The efficacy of baricitinib** in the treatment of patients with atopic dermatitis is supported by clinical trial results [179, 180]. The severity of atopic dermatitis, assessed by the EASI score, decreased by 55–59% at week 16 of treatment with baricitinib** 4 mg orally once daily in patients not receiving topical therapy. If baricitinib** therapy at a dose of 4 mg orally was accompanied by topical glucocorticoid therapy used in dermatology, the severity of atopic dermatitis according to the EASI score decreased by an average of 67%. At week 16, the severity of atopic dermatitis according to EASI decreased by 75% or more (EASI75) in 48% of patients with atopic dermatitis treated with baricitinib** and dermatological glucocorticoids. A reduction in pruritus in patients was observed as early as the 2nd day of therapy, and by week 16 of therapy, pruritus decreased by an average of 51.2% [179]. Long-term study results indicate that if an initial treatment response is present, the effect is maintained during maintenance therapy.

During treatment with baricitinib**, adverse events may occur [181]. Therefore, safety monitoring of baricitinib** therapy is required. Patients receiving baricitinib** therapy may experience lymphopenia, thrombocytopenia, increased blood cholesterol levels, and elevated blood alanine aminotransferase and aspartate aminotransferase activities, which necessitates a complete blood count and general biochemical blood test. It is contraindicated to initiate therapy or baricitinib** should be temporarily discontinued if the blood neutrophil count drops below 1×10⁹/L, the absolute lymphocyte count in the blood drops below 0.5×10⁹/L, or the total blood hemoglobin level drops below 8 g/dL. Contraindications for prescribing baricitinib** include childhood under 18 years of age. If an elevation in alanine aminotransferase and aspartate aminotransferase activity is detected that raises suspicion of drug-induced liver injury, the use of baricitinib** should be temporarily discontinued until this diagnosis is ruled out.

or

dupilumab** 200 or 300 mg solution for subcutaneous injection – for pediatric patients aged 6 years and older. For patients with a body weight of 15 to < 30 kg: starting dose – 600 mg (two 300 mg injections), followed by 300 mg every 4 weeks; for patients with a body weight of 30 to < 60 kg: starting dose – 400 mg (two 200 mg injections), followed by 200 mg every 2 weeks; for patients with a body weight of 60 kg and more, the starting dose is 600 mg (two 300 mg injections), followed by 300 mg every 2 weeks [182–185].

GOR ALEL 2Level of recommendation validity A (level of evidence reliability – 2)

Comments: A contraindication to prescribing dupilumab** to patients with atopic dermatitis is childhood under 6 years of age.

or

dupilumab** 300 mg solution for subcutaneous injection at a starting dose for adult patients with atopic dermatitis of 600 mg (two 300 mg injections at different injection sites), followed by 300 mg every 2 weeks. Depending on the individual therapeutic response, the dose may be increased to 300 mg weekly [186–192]:

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: Dupilumab** may be used as monotherapy or concomitantly with dermatological drugs. The injection can be administered either by the patient themselves or by their caregiver. Prior to initiating dupilumab**, patients and/or their caregivers must be instructed on how to prepare and administer the drug injection in accordance with the instructions for medical use. Dupilumab** may also be used in patients with moderate-to-severe atopic dermatitis combined with severe bronchial asthma.

The efficacy of dupilumab** in the treatment of patients with atopic dermatitis is confirmed by clinical trial results [189–191]. The severity of atopic dermatitis, assessed by the EASI (Eczema Area and Severity Index) score, decreased by 75% or more (EASI75) at week 16 with dupilumab** therapy administered as 1 injection every 2 weeks in 44–51% of patients not receiving topical therapy. If dupilumab** therapy administered as 1 injection every 2 weeks was accompanied by topical glucocorticoid therapy used in dermatology, the treatment efficacy was 10–20% higher than dupilumab** monotherapy, and at week 16 of treatment, the severity of atopic dermatitis according to EASI decreased by 75% or more (EASI75) in 69% of patients with atopic dermatitis treated with dupilumab** and dermatological glucocorticoids. A reduction in pruritus in patients was observed as early as the 2nd week of therapy, and by week 16 of therapy, pruritus decreased by an average of 53.9%. By week 52 of therapy, the effect was maintained, and a reduction in atopic dermatitis severity by 75% or more compared to baseline (EASI75) was observed in 65% of patients with atopic dermatitis treated with dupilumab** 1 injection every 2 weeks and topical glucocorticoid therapy used in dermatology [186–188].

or

upadacitinib** prolonged-release film-coated tablets, 15 mg once daily orally for children aged 12 years and older [193–195].]

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: Upadacitinib** is contraindicated in children under 12 years of age.

or

upadacitinib** prolonged-release film-coated tablets, 15 mg or 30 mg once daily for adult patients as a single dose [193–200].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: The drug can be taken regardless of meals. The tablet should be swallowed whole without chewing, breaking, or crushing. Upadacitinib** can be used in combination with glucocorticoids used in dermatology, or as monotherapy. On sensitive skin areas (face, neck, genital skin, and intertriginous areas), dermatitis medications other than glucocorticoids (pimecrolimus**, tacrolimus**) may be applied during upadacitinib** therapy. In atopic dermatitis, upadacitinib** is contraindicated in children under 12 years of age.

cyclosporine** at an initial dose of 2.5–3 mg/kg of body weight per day in 2 divided doses at 12-hour intervals. If necessary, the dose of the drug can be increased to a maximum of 5 mg/kg of body weight per day, depending on the individual condition of the patient. Once a positive result is achieved, the dose should be gradually reduced until complete withdrawal [201–206].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: Contraindications for prescribing cyclosporine** include age under 18 years for all non-transplant indications, except for nephrotic syndrome.

The severity of atopic dermatitis decreases by 50% after 6–8 weeks of continuous treatment with cyclosporine**. Patients receiving a higher initial dose of the drug (4–5 mg/kg/day) achieve faster improvement—within 2 weeks (a 40% reduction in severity)—than patients receiving a lower initial dose (2.5–3 mg/kg/day; a 22% reduction in severity). However, after 6–8 weeks of cyclosporine** therapy, there was no difference in response between patients receiving higher and lower doses of the drug, while patients receiving the higher dose reported more side effects associated with cyclosporine** [206, 207]. The duration of continuous cyclosporine** therapy should ideally be limited to 2 years [208].

• For patients with severe atopic dermatitis, systemic corticosteroids are recommended orally for the treatment of flares according to the following schedule—for the first 2–3 days [6, 209]:

methylprednisolone** 16–20 mg once daily after breakfast

or

prednisolone** 20–25 mg after breakfast and 5 mg after lunch.

Next, once daily after breakfast for the following 2–3 days:

methylprednisolone** 12 mg

or

prednisolone** 15 mg.

Next, once daily after breakfast for the following 2–3 days:

methylprednisolone** 8 mg

or

prednisolone** 10 mg once daily.

Next, once daily after breakfast with subsequent discontinuation of the drug:

methylprednisolone** 4 mg

or

prednisolone** 5 mg [99].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: If necessary, systemic corticosteroid therapy can be continued for another 2–3 days once daily after breakfast: methylprednisolone** 2 mg or prednisolone** 2.5 mg. Systemic corticosteroids in children with atopic dermatitis are not recommended for routine use, but may be used to relieve severe atopic dermatitis flares in short courses at a dose not exceeding 0.5 mg/kg/day #prednisolone** [313] or #methylprednisolone** 0.5 mg/kg/day for 1–2 weeks, for a maximum of 1 month [314, 315, 316, 317]. The risk of side effects limits the use of this group of drugs in children. Randomized controlled trials confirming the efficacy of this treatment method are currently lacking or have not been conducted, despite its long-term use in clinical practice [318]. There are currently no clear guidelines on monitoring the status of patients receiving systemic corticosteroids; necessary examinations and/or tests and corrective measures are prescribed on an individual basis depending on the duration of the course and clinical manifestations (e.g., skin atrophy, weight gain, sleep disturbances, mood changes, hyperglycemia, peptic ulcers/gastritis, osteoporosis, increased susceptibility to infections, etc.). Blood glucose monitoring and assessment of adrenal suppression (as determined by an endocrinologist/pediatric endocrinologist) may be considered during high-dose and/or long-term therapy [319].

3.1.6 Treatment of complicated atopic dermatitis

Atopic dermatitis is frequently complicated by bacterial skin infections that require antibacterial therapy [210, 211]. For localized forms of secondary infection, topical therapy with antibiotics and antimicrobial agents used in dermatology, and/or corticosteroids combined with antibiotics, or corticosteroids combined with other agents, and/or antiseptics and disinfectants, or other therapeutic agents is often sufficient.

In cases of widespread bacterial skin lesions developing in patients with atopic dermatitis, systemic antibacterial drugs must be used. Before prescribing systemic antibacterial drugs, a microbiological (culture) examination of purulent discharge for aerobic and facultatively anaerobic microorganisms should be performed to identify the pathogen, along with a microbiological (culture) examination of rash elements for susceptibility to antibacterial and antifungal drugs. Pending the results of microbiological testing, treatment with systemic antibacterial drugs active against the most common pathogens, primarily S. aureus, is initiated in most cases. Combinations of penicillins, including beta-lactamase inhibitor combinations, first- or second-generation cephalosporins, macrolides, and fluoroquinolones (in adults), are highly effective. The duration of systemic antibacterial therapy is typically 7–10 days.

3.1.7 Topical therapy for complicated atopic dermatitis

fusidic acid, 2% topical cream or 2% topical ointment applied to infected lesions 3 times daily for 7–14 days [212–215].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: There are no age restrictions for the use of 2% fusidic acid cream and 2% ointment.

or

#bacitracin + neomycin topical powder 2–4 times daily, topical ointment 250 IU/g + 5000 IU/mg applied topically to infected lesions 2–3 times daily for 7 days [216, 217].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: There are no age restrictions for the use of bacitracin + neomycin powder and ointment.

or

mupirocin 2% topical ointment applied to infected lesions 2–3 times daily for no more than 10 days [218, 219].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: There are no age restrictions for the use of mupirocin ointment, except in elderly patients with conditions where absorption of large amounts of polyethylene glycol is possible, or in the presence of moderate to severe renal impairment.

or

erythromycin topical ointment (10,000 IU/g) applied topically to infected lesions 2–3 times daily for 7–14 days [220].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: There are no age restrictions for the use of erythromycin ointment.

or

silver sulfadiazine 2% topical cream applied to infected lesions 2–3 times daily for 7–14 days [220, 221].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: A contraindication for prescribing silver sulfadiazine cream is infancy under 2 months of age.

hydrocortisone + oxytetracycline topical ointment, topical spray applied topically to infected lesions 2–4 times daily for 7–14 days [99].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: A contraindication for prescribing hydrocortisone + oxytetracycline spray is age under 18 years. A contraindication for prescribing hydrocortisone + oxytetracycline ointment is age under 2 years.

or

tetracycline + triamcinolone topical spray—irrigate infected lesions with a spray stream 2–4 times daily, holding the container upright at a distance of 15–20 cm from the skin, for 5–10 days [222, 223].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comments: A contraindication for prescribing tetracycline + triamcinolone spray is age under 3 years.

or

hydrocortisone + fusidic acid topical cream applied topically to infected lesions 3 times daily in adults and children aged 2 years and older for 14 days [224].

GCR BLeE 2Grade of Recommendations B (Level of Evidence – 2)

Comments: A contraindication for prescribing hydrocortisone + fusidic acid cream is age under 2 years.

or

Gentamicin + Dexpanthenol + Mometasone + Econazole topical cream applied to affected skin areas in a thin layer with gentle rubbing 2 times daily; treatment duration is usually 1–2 weeks, and use of the drug for more than 4 weeks is not recommended [225–227].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: Treatment duration with Gentamicin + Dexpanthenol + Mometasone + Econazole cream is usually 1–2 weeks. The drug should not be used for more than 4 weeks. A contraindication for prescribing Gentamicin + Dexpanthenol + Mometasone + Econazole cream is age under 18 years.

or

betamethasone + fusidic acid cream for topical use for adult patients with atopic dermatitis topically on infected lesions 2 times a day for 7 days [228].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: A contraindication for prescribing betamethasone + fusidic acid cream is age under 1 year.

or

betamethasone + gentamicin + clotrimazole cream for topical use, ointment for topical use topically on infected lesions 2 times a day for adults and children aged 2 years and older for 7–14 days [99, 229–233].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

or

hydrocortisone + natamycin + neomycin ointment for topical use apply to infected lesions 2–4 times a day [234, 235].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: In children under 1 year of age, hydrocortisone + natamycin + neomycin ointment should be used with caution.

boric acid + resorcinol + phenol + fuchsin topical solution is applied using a swab or glass rod to affected skin areas 2–4 times a day. After the liquid dries, ointments and pastes can be applied to the treated area [131, 220].

Comments: Boric acid + resorcinol + phenol + fuchsin preparation should not be used by women during pregnancy and breastfeeding

or

methylthioninium chloride 1% solution for local and topical use, [aqueous] for adults and children from birth; the solution is applied using a swab or glass rod to affected areas 2–3 times a day [131, 220].

Comments: The use of aqueous methylthioninium chloride solution is possible during pregnancy and breastfeeding.

3.1.8 Systemic antibacterial therapy

amoxicillin + clavulanic acid** for adults and children over 12 years (weighing 40 kg or more) film-coated tablets, 250 mg + 125 mg, 1 tablet 3 times a day or 875 mg + 125 mg, 1 tablet 2 times a day for 5–14 days or dispersible tablets for adults and children over 12 years (weighing 40 kg or more), 500/125 mg 3 times a day for 5–14 days, for children from 2 to 12 years or with body weight less than 40 kg, at doses of 125/31.25 mg or 250/62.5 mg [236].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: A contraindication for prescribing amoxicillin + clavulanic acid** film-coated tablets is age under 12 years. A contraindication for prescribing amoxicillin + clavulanic acid** dispersible tablets is age under 1 year.

or

cefuroxime** 250 mg orally 2 times a day for adults and children aged 3 years and older for 5–10 days [237–239].

Strong recommendation grade CLOE 2Level of Evidence C (Level of Evidence — 2)

Comments: A contraindication for prescribing cefuroxime** film-coated tablets is age under 3 years.

or

ceftriaxone** 1–2 g per day intramuscularly or intravenously for children over 12 years 1 time a day, for newborns up to 2 weeks – 20–50 mg/kg/day, for children from 3 weeks to 12 years – 20–80 mg/kg/day in 2 doses [238].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: Ceftriaxone** is contraindicated in premature infants up to 41 weeks of postmenstrual age inclusive. Ceftriaxone** should be prescribed with caution during breastfeeding.

acyclovir** 200 mg tablets for adults and children from 3 years old orally 5 times a day. The course of treatment is 5 days, but can be extended for severe infections.

Acyclovir** tablets 200-400 mg for adults and adolescents orally 5 times a day, IV: 5-10 mg/kg every 8 hours. The course of treatment is, on average, 7-14 days; for children IV: children aged 12 to 18 years and adults #5-10 mg/kg every 8 hours, from 3 months to 12 years: 20 mg/kg every 8 hours for 14 days, orally 20 mg/kg x 4 times a day (maximum dose 800 mg), up to 3 months 20 mg/kg [304].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

or

#Valacyclovir tablets 500 mg, orally for a course of 5-7 days. For adults: 2 tablets (1 g) 2 times a day or 1 tablet 500 mg 3 times a day, for children older than 3 months, oral tablets 20 mg/kg 2 times a day (maximum dose 1000 mg) [304].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: In case of a disseminated process accompanied by fever and severe intoxication symptoms, hospitalization in a hospital with a box ward is necessary. In a hospital setting, intravenous administration of acyclovir** should be carried out. Topical therapy consists of using antiseptics and disinfectants (boric acid + resorcinol + phenol + fuchsin, #methylthioninium chloride 1% solution for local and topical use, [aqueous] on lesions and surrounding skin 2–3 times a day, for 3–5 days, etc.) [325]

In case of eye involvement, 3% acyclovir** eye ointment should be used, placed into the lower conjunctival sac 5 times a day. Treatment is continued for at least 3 days after symptoms resolve.

A contraindication to prescribing oral acyclovir** tablets is age under 3 years.

For acyclovir** (for short and prolonged courses): monitoring of renal function is necessary (blood urea test, blood creatinine test, nephron function test by creatinine clearance (Rehberg's test) (creatinine clearance calculated using the Schwartz formula), electrolytes (blood sodium test, blood potassium test, total blood calcium test), complete blood count.

calcium gluconate** [99].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Calcium gluconate** is available as a solution for intravenous and intramuscular administration and as tablets. Calcium gluconate** 100 mg/ml solution for intravenous and intramuscular administration is administered intramuscularly or intravenously to adults at 5–10 ml of the 100 mg/ml solution daily, every other day, or every 2 days depending on the patient's condition. Intramuscular administration of calcium gluconate** 100 mg/ml solution for intravenous and intramuscular administration is contraindicated in children. The drug is administered to children only intravenously: in children under 6 months – 0.1–1 ml, 7–12 months – 1–1.5 ml every 2–3 days; over 1 year, depending on age, 2 to 5 ml of the 100 mg/ml solution is administered every 2–3 days.

#sodium thiosulfate** solution for intravenous administration 300 mg/ml [99, 242, 328, 329].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: #Sodium thiosulfate** is administered intravenously slowly. Adults are administered a single dose of 5-10 ml of the solution, children at a rate of 1-2 ml per 10 kg of body weight for 5 days. In childhood, the drug should be used with caution. The use of the drug is possible in combination therapy for exacerbation of the disease combined with topical therapy. When administered into the body, it exerts a detoxifying effect; #sodium thiosulfate** possesses antioxidant and anti-inflammatory properties.

3.2. Other treatment

Comments: Allergen-specific immunotherapy can be performed with indoor allergens/indoor allergoids and/or tree pollen allergens and/or grass pollen allergens/grass pollen allergoids in children older than 5 years and adults. There are subcutaneous and sublingual methods of AIT. Indications, choice of drug, method, and contraindications for allergen-specific immunotherapy are determined by an allergist-immunologist. Allergen-specific immunotherapy is prescribed only after relief of atopic dermatitis exacerbation with adequate therapy, as well as sanation of foci of chronic infection and treatment of concomitant diseases. It is performed by an allergist-immunologist in an allergology office or hospital setting. The duration and schedule of allergen-specific immunotherapy are determined individually.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Patients with atopic dermatitis in remission may undergo comprehensive spa and resort treatment, the effectiveness of which is due to the combination of therapeutic effects of climatotherapy, balneotherapy, and pelotherapy. Referral of patients to balneological, mud-cure, or climatic resorts is possible [254–256]. Contraindications to balneotherapy and mud therapy include: all diseases in the acute stage or during an exacerbation of a chronic process, infectious diseases (tuberculosis, syphilis, etc.), pregnancy, bleeding and predisposition to it, malignant neoplasms, uterine fibroids, mastopathy, circulatory insufficiency above stage IIA, progressive angina pectoris and angina decubitus, cardiac asthma, and prognostically unfavorable heart rate and myocardial conduction disorders.

Comments: Carried out using the application method at a temperature of 38–40 °C or 42–44 °C with an exposure time of 15–20 minutes.

Comments: Climate therapy helps improve skin condition and enhances the quality of life in patients with atopic dermatitis. Referral of patients to resorts with a moderately humid or highly humid marine climate, as well as a middle-mountain climate, is indicated.

Comments: For patients with atopic dermatitis, in order to reduce the impact of stress on the frequency of exacerbations of the skin process, it is useful to conduct group psychotherapy, training in relaxation techniques and behavioral modification. Psychological interventions, including autogenic training or behavioral therapy, relaxation techniques, and meditation, can have a positive effect on the course of atopic dermatitis.

Comments: Patients with atopic dermatitis are recommended climatotherapy and thalassotherapy (complex treatment with marine climate and swimming) to reduce the impact of aeroallergens and pollutants on the body, as well as to stimulate natural climatic factors leading to the normalization and improvement of skin barrier properties, blood supply, perspiration, sleep, reduction of itching, and improvement of the course of other atopic diseases. Traditionally, hydrocarbonate-calcium-magnesium waters (including thermal waters) are used in the form of therapeutic baths (therapeutic mineral baths), along with climate therapy [45, 211, 340].

5. Prevention and Dispensary Observation

Primary prevention of atopic dermatitis is aimed at preventing the occurrence and impact of risk factors for the development of the disease and includes a set of hypoallergenic measures:

Comment: this age period is considered optimal and represents the so-called "window of tolerance".

Comments: Currently, there is no convincing data on the efficacy of hypoallergenic or elimination diets during pregnancy regarding the development of atopic dermatitis in the general population [271].

Comments: Smoking is unacceptable during pregnancy and lactation; passive smoking should be avoided from the first days of a child's life.

Secondary prevention of atopic dermatitis is a set of measures aimed at eliminating pronounced risk factors that under certain conditions (stress, weakened immunity, excessive loads on any other functional systems of the body) can lead to the onset, exacerbation, and relapse of the disease.

Comments: Any preventive elimination measures prescribed for a long period can have a negative impact on family members, impairing their quality of life.

Tertiary prevention is a set of measures aimed at preventing exacerbations or the development of complications of atopic dermatitis.

Comments: Research data have shown no association between vaccination and the subsequent development of AD or its exacerbations; AD is not a contraindication to routine vaccinations. Vaccination is indicated for patients with AD to prevent or reduce the likelihood of a severe (complicated) course of vaccine-preventable infections, including those affecting the skin (e.g., chickenpox). Vaccination is carried out in accordance with Order of the Russian Ministry of Health No. 1122n dated December 6, 2021, "On Approval of the National Schedule of Preventive Vaccinations, the Schedule of Preventive Vaccinations by Epidemiological Indications, and the Procedure for Conducting Preventive Vaccinations," and Methodological Guidelines MU 3.3.1.1095-02 "Medical Contraindications to Preventive Vaccinations with National Immunization Schedule Preparations."

Patients receiving immunosuppressive therapy must consult a physician prior to vaccination with live vaccines; immunization with attenuated live vaccines should ideally be performed 4 weeks before initiating immunosuppressive therapy. In cases of confirmed chicken egg protein allergy, a consultation with an allergist-immunologist may be conducted prior to vaccination. Vaccination is not performed during the acute phase of the disease.

6. Organization of Medical Care

• As part of primary health care provision, general practitioners, district pediatricians, and general family physicians, upon detecting skin rashes, pruritus, or symptoms or signs of atopic dermatitis in patients, shall refer the patient to a dermatovenerological medical organization or an allergist-immunologist office for primary specialized health care, and shall also provide medical care in accordance with the recommendations of the dermatovenerological medical organization and/or the allergist-immunologist if there are no medical indications for referral.

• If it is impossible to provide medical care within the framework of primary specialized medical care and if there are medical indications, the patient is referred to a medical organization providing specialized medical care.

• Specialized, including high-tech, medical care is provided by dermatovenerologists and/or allergist-immunologists in inpatient settings.

Indications for scheduled hospitalization in a medical organization:

1) Indications for providing medical care in a day hospital setting:

• insufficient efficacy of outpatient treatment in patients with localized rashes;

2) Indications for inpatient medical care:

• lack of response to ongoing outpatient treatment;

• severe atopic dermatitis requiring systemic therapy or phototherapy;

• onset of a secondary infection not controllable in an outpatient setting;

• development of a viral infection (Kaposi's varicelliform eruption).

3) Indications for discharging a patient from a medical organization:

• partial or complete regression of rashes.

7. Additional Information

None.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Kubanov Alexey Alekseevich – Academician of the RAS, Doctor of Medical Sciences, Professor, Director of the State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, President of the Russian Society of Dermatovenereologists and Cosmetologists, Moscow. No conflict of interest.

2. Namazova-Baranova Leyla Seymurovna – Academician of the RAS, Doctor of Medical Sciences, Professor, Head of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Head of the Research Institute of Pediatrics and Child Health of the Central Clinical Hospital of the RAS of the Ministry of Science and Higher Education of Russia, President of the Union of Pediatricians of Russia, Moscow. No conflict of interest.

3. Volnukhin Vladimir Anatolyevich - Doctor of Medical Sciences, Professor, Chief Researcher at the Department of Dermatovenereology and Cosmetology, Specialized Medical Care Department, Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology, Member of the National Alliance of Dermatovenereologists and Cosmetologists, Moscow. No conflict of interest.

4. Dvornikov Anton Sergeevich - Doctor of Medical Sciences, Professor, Head of the Department of Dermatovenereology and Cosmetology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Member of the Russian Society of Dermatovenereologists and Cosmetologists, Moscow. No conflict of interest.

5. Ilyina Nataliya Ivanovna – Doctor of Medical Sciences, Professor, Deputy Director for Clinical Work, Chief Physician of the National Research Center Institute of Immunology of the Federal Medical-Biological Agency of Russia, Vice-President of the Russian Association of Allergologists and Clinical Immunologists, Moscow. No conflict of interest.

6. Zaslavsky Denis Vladimirovich – Doctor of Medical Sciences, Professor, Professor at the Department of Dermatovenereology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Member of the Russian Society of Dermatovenereologists and Cosmetologists, Saint Petersburg. No conflict of interest.

7. Karamova Arfenya Eduardovna – Candidate of Medical Sciences, Associate Professor, Head of the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, Member of the Russian Society of Dermatovenereologists and Cosmetologists, Moscow. No conflict of interest.

8. Martynov Andrey Aleksandrovich - Doctor of Medical Sciences, Professor, Head of the Department of Dermatovenereology and Cosmetology, Russian Academy of Medical Education of the Russian Ministry of Health, Leading Researcher at the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, Member of the Russian Society of Dermatovenereologists and Cosmetologists, Moscow. No conflict of interest.

9. Olisova Olga Yurievna - Corresponding Member of the RAS, Doctor of Medical Sciences, Professor, Head of the Rakhmanov Department of Skin and Venereal Diseases, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health, Member of the Russian Society of Dermatovenereologists and Cosmetologists, Moscow. No conflict of interest.

10. Potekaev Nikolay Nikolaevich – Doctor of Medical Sciences, Professor, Director of the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology of the Moscow Healthcare Department, President of the National Alliance of Dermatovenereologists and Cosmetologists, Moscow.

11. Selimzyanova Liliya Robertovna – Candidate of Medical Sciences, Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia, Moscow. No conflict of interest.

12. Khaitov Musa Rakhimovich - Corresponding Member of the RAS, Doctor of Medical Sciences, Professor, Director of the National Research Center Institute of Immunology of the Federal Medical-Biological Agency of Russia, President of the Russian Association of Allergologists and Clinical Immunologists, Moscow. No conflict of interest.

13. Chikin Vadim Viktorovich – Doctor of Medical Sciences, Senior Researcher at the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, Member of the Russian Society of Dermatovenereologists and Cosmetologists, Moscow. No conflict of interest.

Conflict of Interest: The authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Medical specialists: dermatovenereologists, allergists-immunologists, pediatricians, general practitioners (family physicians), general internists.

2. Residents and trainees of continuing professional education cycles in the specified specialties.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The clinical guidelines update mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Procedure for the Provision of Medical Care in the Profile of "Dermatovenereology", approved by Order of the Ministry of Health of the Russian Federation No. 924n dated November 15, 2012.

2. Procedure for the Provision of Medical Care to the Population in the Profile of "Allergology and Immunology", approved by Order of the Ministry of Health of the Russian Federation No. 606n dated November 7, 2012

Classification of glucocorticoids used in dermatology

Baseline screening before initiating cyclosporine** therapy

Before initiating cyclosporine** therapy, baseline screening must be performed, and a number of parameters must be monitored during treatment to timely detect potential adverse events [45].

Regular blood pressure monitoring is required during cyclosporine** treatment. If blood pressure rises, appropriate antihypertensive therapy should be administered.

Before initiating cyclosporine** treatment, the results of the following studies should be obtained:

− Complete blood count (CBC) with differential to monitor for potential blood and lymphatic system disorders (leukopenia, anemia, thrombocytopenia);

− General general-practice blood biochemistry test to monitor renal function, liver status, and metabolism (blood urea test, blood creatinine test, blood aspartate aminotransferase activity assay, blood alanine aminotransferase activity assay, blood gamma-glutamyl transferase activity assay, blood potassium test, blood triglycerides test, blood cholesterol test, blood uric acid test).

− Determination of hepatitis B surface antigen (HBsAg) in the blood;

− Determination of total IgM and IgG antibodies (anti-HCV IgG and anti-HCV IgM) to hepatitis C virus in the blood;

− Determination of IgM and IgG antibodies (IgM, IgG) to human immunodeficiency virus HIV-1 in the blood;

− Determination of IgM and IgG antibodies (IgM, IgG) to human immunodeficiency virus HIV-2 in the blood.

− Complete (clinical) urinalysis to monitor renal function.

To monitor therapy safety after 4 months of treatment with cyclosporine** and every 3 months thereafter, the following should be performed:

− Complete (clinical) blood count, differential;

− General general-practice blood biochemistry test to monitor renal function, liver status, and metabolism (blood urea test, blood creatinine test, blood aspartate aminotransferase activity assay, blood alanine aminotransferase activity assay, blood gamma-glutamyl transferase activity assay, blood potassium test, blood triglycerides test, blood cholesterol test, blood uric acid test).

− Complete (clinical) urinalysis to monitor renal function.

Baseline screening prior to initiating therapy with abrocitinib, baricitinib**, or upadacitinib**

Prior to initiating therapy with abrocitinib, baricitinib**, or upadacitinib**, patients with atopic dermatitis should undergo baseline screening followed by monitoring of a number of parameters to timely detect potential adverse events of therapy [45, 261].

Caution should be exercised when using abrocitinib, upadacitinib**, and baricitinib** in patients aged 65 years and older, current or past long-term smokers, patients with atherosclerotic cardiovascular diseases or other cardiovascular disease risk factors, patients with risk factors for malignancies, as well as patients with known risk factors for venous thromboembolism in addition to those listed above [261, 262]. Patients must be monitored for signs or symptoms of infection, and regular skin examinations should be performed in patients at elevated risk for skin cancer [261–263].

Prior to initiating therapy with abrocitinib, baricitinib**, or upadacitinib**, the results of the following tests should be obtained:

− Complete (clinical) blood count, differential, to monitor for potential hematologic and lymphatic system disorders (neutropenia, lymphopenia, thrombocytopenia). Therapy with abrocitinib, upadacitinib**, or baricitinib** should not be initiated in patients with an absolute lymphocyte count of less than 500 cells/mm³ and/or an absolute neutrophil count of less than 1000 cells/mm³ [263]. Therapy with upadacitinib** or baricitinib** should also not be initiated if the total blood hemoglobin level is below 8 g/dL.

− General general-practice blood biochemistry test to assess liver status and lipid metabolism (blood aspartate aminotransferase activity assay, blood alanine aminotransferase activity assay, blood triglycerides test, blood cholesterol test, low-density lipoprotein cholesterol test, blood phospholipids test, high-density lipoprotein cholesterol test).

− Complete (clinical) urinalysis to monitor renal function.

− Determination of hepatitis B surface antigen (HBsAg) in the blood;

− Determination of total IgM and IgG antibodies (anti-HCV IgG and anti-HCV IgM) to hepatitis C virus in the blood;

− Consultation with an infectious disease specialist if a patient is diagnosed with hepatitis B or C to determine the feasibility of therapy with abrocitinib, baricitinib**, or upadacitinib**;

− Consultation with a phthisiatrician.

During therapy with abrocitinib, baricitinib**, or upadacitinib**, 4 weeks after initiating therapy and every 3 months thereafter, the following tests should be performed to monitor potential adverse events of therapy:

− Complete (clinical) blood count, differential. Therapy with abrocitinib, upadacitinib**, or baricitinib** should be discontinued if the neutrophil count is less than 1x10⁹ cells/L and/or the lymphocyte count is less than 0.5x10⁹ cells/L. Therapy with upadacitinib** or baricitinib** should be discontinued if the total blood hemoglobin level drops below 8 g/dL. Treatment may be resumed when the neutrophil count, lymphocyte count, and/or total blood hemoglobin level exceed these values.

− General general-practice blood biochemistry test to assess liver status and lipid metabolism (blood aspartate aminotransferase activity assay, blood alanine aminotransferase activity assay, blood triglycerides test, blood cholesterol test, low-density lipoprotein cholesterol test, blood phospholipids test, high-density lipoprotein cholesterol test). If drug-induced liver injury is suspected based on the results of blood aspartate aminotransferase activity and blood alanine aminotransferase activity assays, treatment with baricitinib** or upadacitinib** should be discontinued.

During therapy with abrocitinib, baricitinib**, or upadacitinib**, patients must be closely monitored for signs and symptoms of tuberculosis, including patients with a negative test result for latent tuberculosis prior to initiating therapy.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

1. Given that atopic dermatitis is a chronic disease, regular baseline therapy with moisturizing and emollient topical agents is necessary to prevent relapses.

2. To avoid side effects, self-administration and uncontrolled use of topical corticosteroids should be avoided.

3. Given that atopic dermatitis is a chronic disease, regular skin care is required to prevent relapses:

4. Daily water procedures using soap-free medical cosmetics — shower gels and oils;

5. Daily application of emollient to damp skin immediately after bathing at least twice a day;

6. Keep fingernails trimmed regularly;

7. Follow the physician's recommendations regarding topical therapy medications;

8. Regularly wash clothing, towels, and bed linens in water with detergent before reuse;

9. If sensitization to house dust mites is confirmed, use acaricidal agents when washing;

10. Do not keep carpets in the room;

11. Store books in closed cabinets;

12. Soft toys should be washed regularly;

13. Treat mold-covered surfaces with specialized products;

14. Clean air conditioner filters at least once every 2 weeks;

15. Avoid keeping indoor potted plants;

16. Vacuum regularly and perform daily wet cleaning of the room;

17. If sensitization to furry animal allergens is confirmed, cease contact with them;

18. Do not use feather- or down-filled pillows and blankets. Pillows should be made of synthetic fibers that are easy to wash;

19. To avoid adverse effects, self-administration and uncontrolled use of topical treatments (corticosteroids, topical calcineurin inhibitors, antibacterial, antifungal, and antiviral drugs) should be avoided.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Investigator's Global Assessment (IGA) of Disease Severity

Original name: Investigator’s global assessment (IGA).

Source (official developer website, validation publication): https://www.eczemacouncil.org/research/investigator-global-assessment-scale/

Type (underline):

- rating scale

- index

- questionnaire

- other (specify): -

Purpose: assessment of the overall severity of atopic dermatitis

Content (template):

The IGA score is used to assess the severity of atopic dermatitis. It evaluates the severity of atopic dermatitis at the time of assessment.

Key: Skin lesions are assessed visually and by palpation. IGA is a 5-point scale ranging from 0 to 4 that reflects the severity of erythema, skin thickening (induration), and scaling. A score of 0 corresponds to clear skin, while the maximum score of 4 corresponds to severe atopic dermatitis.

Appendix G2. SCORAD Index

The SCORAD index is designed to assess the severity of atopic dermatitis.

Original title: Scoring of Atopic Dermatitis (SCORAD).

Source (official developer website, validation publication): Consensus report of the European Task Force on Atopic Dermatitis. Severity of scoring of atopic dermatitis: the SCORAD index. Dermatology.1993; 186: 23–31.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify): -

Purpose: assessment of the severity of atopic dermatitis.

Content (template):

SCORAD provides a scoring system for six objective symptoms: erythema, edema/papular elements, crusts/oozing, excoriations, lichenification/scaling, and skin dryness. The intensity of each sign is evaluated on a 4-level scale: 0 – none, 1 – mild, 2 – moderate, 3 – severe. When assessing the body surface area affected, the 'rule of nines' should be used, where the unit of measurement is the patient's palm surface area, equivalent to one percent of the total skin surface. The numbers indicate the surface area values for patients older than 2 years, and those in parentheses are for children under 2 years of age (Fig. 1). Subjective symptoms (itching sensation, sleep disturbance) are assessed in children older than 7 years and adults; in younger children, subjective symptoms are assessed with the help of parents, to whom the assessment principle is explained beforehand.

The SCORAD index is calculated using the formula: SCORAD = A/5 + 7B/2 + C,

where: A is the extent of skin lesions,

B is the sum of the intensity levels of clinical symptoms of atopic dermatitis,

C is the sum of subjective symptom scores on a visual analogue scale.

On the ruler at the bottom of the figure, a point is marked corresponding to the severity of the assessed subjective sign, averaged over the last 3 days.

Index values can range from 0 (no disease) to 103 (maximum severity of atopic dermatitis).

Mild atopic dermatitis corresponds to a SCORAD value < 25.

Moderate atopic dermatitis corresponds to a SCORAD value from 25 to 50.

Severe atopic dermatitis corresponds to a SCORAD value > 50.