Urticaria: Clinical Guidelines

List of Abbreviations

AE – angioedema;

anti-FcεRIα Ab – autoantibodies against the high-affinity IgE receptor α-chains;

anti-IgE Ab – autoantibodies against immunoglobulin E;

ATC – Anatomical Therapeutic Chemical Classification System

ACEI – ACE inhibitors;

ICD-10 – International Statistical Classification of Diseases and Related Health Problems, 10th Revision, adopted by the 43rd World Health Assembly;

nsH1-AH – non-sedating second-generation systemic antihistamines;

NSAIDs – medications from the groups "Other analgesics and antipyretics" (including acetylsalicylic acid**, paracetamol**), "Nonsteroidal anti-inflammatory and antirheumatic drugs" (including ibuprofen**) RAAKI – Russian Association of Allergologists and Clinical Immunologists;

TPO – thyroid peroxidase;

ESR — erythrocyte sedimentation rate;

CRP – C-reactive protein;

HR – heart rate

AAS – Angioedema Activity Score;

EAACI – European Academy of Allergy and Clinical Immunology

IgE – immunoglobulin E;

IgG – immunoglobulin G;

dsDNA – double-stranded DNA;

ssDNA – single-stranded DNA;

UAS 7 – Urticaria Activity Score 7;

UCT – Urticaria Control Test;

Terms and Definitions

Angioedema – diffuse swelling involving the entire dermis, subcutaneous adipose tissue, and/or mucous membrane and submucosal layer.

Autoinflammatory diseases/syndromes – a heterogeneous group of rare, genetically determined, hereditary conditions characterized by periodic attacks of fever and clinical symptoms mimicking rheumatic diseases, in the absence of autoimmune or infectious causes.

Urticaria – a group of diseases characterized by the development of wheals, angioedema, or both.

UAS 7 (Urticaria Activity Score 7), or Urticaria Activity Score 7, used to assess disease severity and treatment outcomes in spontaneous urticaria. UAS 7 involves a cumulative patient-reported score of the main disease symptoms (number of wheals and pruritus intensity) recorded every 24 hours for 7 consecutive days.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Urticaria (from Lat. Urtica – nettle) – a group of diseases characterized by the development of wheals, angioedema, or both [1, 2].

Conditions where wheals are a symptom [skin tests, autoinflammatory syndromes (diseases caused by mutations in protein-coding genes playing a key role in inflammatory response regulation, anaphylaxis, hereditary angioedema, etc.] are not classified as urticaria.

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

Proinflammatory mediators from activated mast cells, such as histamine, serotonin, platelet-activating factor, and cytokines, lead to vasodilation, increased capillary permeability, activation of sensory nerve fibers, extravasation of plasma, and recruitment of cells to the wheal formation site.

Mast cell degranulation can occur via various activation mechanisms, including the binding of immunoglobulins E (IgE) to high-affinity receptors (FcεRI) on the mast cell surface. An autoimmune mechanism of mast cell activation is currently considered in patients with urticaria. Nearly half of patients with chronic urticaria test positive for IgG autoantibodies against both IgE (5–10%) and FcεRI (35–40%). These IgG autoantibodies can bind FcεRI on mast cells and basophils, leading to their activation. In addition to autoreactive IgG, autoreactive IgE antibodies (IgE anti-TPO, IgE anti-dsDNA and ssDNA, IgE anti-IL-24, and others) may form, which trigger mast cell and basophil degranulation [3–5].

Another link in the pathogenesis of urticaria is impaired intracellular regulation of signaling mechanisms in mast cells and basophils [6–8].

Mast cell degranulation can be induced by complement components, neuropeptides, and unknown mechanisms. Certain non-immunological factors, such as heat or cold, a number of medications (NSAIDs, antivirals, contrast media, opioids, etc.), can lead to mast cell activation and degranulation [9].

Histologically, a wheal is characterized by edema of the upper and middle dermis, dilation of postcapillary venules and lymphatic vessels. Affected skin typically shows a mixed perivascular infiltrate composed of neutrophils or eosinophils, macrophages, and T cells, with no damage to the vessel wall [10]. In angioedema, which is a symptom of the disease, similar changes affect the deep layers of the skin and subcutaneous tissue [2].

1.3 Epidemiology of the Disease or Condition

The prevalence of acute urticaria is 20% [11], and 2.1–6.7% in the pediatric population [12], with acute urticaria being more common in children than in adults. Chronic spontaneous urticaria (CSU) affects up to 0.5–5% of the population, with women being affected more often than men [13]. According to a systematic review and meta-analysis, chronic urticaria in adults in the general population is 0.7% and 1.4%, respectively, and up to 1.1% in children under 15 years of age [14–18].

1.4 Features of Coding the Disease or Condition

L50 Urticaria:

L50.0 – Allergic urticaria;

L50.1 – Idiopathic urticaria;

L50.2 – Urticaria due to heat or cold;

L50.3 – Dermatographic urticaria;

L50.4 – Vibratory urticaria;

L50.5 – Cholinergic urticaria;

L50.6 – Contact urticaria;

L50.8 – Other urticaria;

L50.9 – Urticaria, unspecified;

T78.3 – Angioneurotic edema.

1.5 Classification of the disease or condition

Urticaria is classified by duration, types, and subtypes. A single patient may have two or more different forms of urticaria [1, 2, 19].

Acute urticaria is characterized by the development of wheals and/or angioedema lasting for less than 6 weeks. Inducible urticaria can take a chronic course; therefore, these forms are included in the classification of chronic urticaria. The clinical course of different forms of urticaria has specific features; for instance, delayed pressure urticaria presents as swelling at the pressure site developing several hours after exposure to the triggering factor. Sometimes, patients with chronic urticaria develop isolated edemas without wheals.

The classification of chronic urticaria is presented in Table 1. Urticaria can be a symptom of pathological conditions listed in Table 2, therefore differential diagnosis with these diseases is required [19].

Table 1. Classification of chronic urticaria [adapted from 19].

Note.

1 For example, autoreactive, due to the presence of mast cell-activating autoantibodies;

2 a form known as symptomatic dermographism;

3 known as cold contact urticaria;

4 known as delayed pressure urticaria;

5 known as heat contact urticaria.

Table 2. Conditions historically classified under urticaria, and syndromes involving urticaria/angioedema [2].

1.6 Clinical presentation of the disease or condition

According to its clinical course, conventional urticaria is subdivided into acute and chronic.

Acute urticaria is defined as the sudden appearance of wheals (each lasting no more than 24 hours) with a duration of less than 6 weeks, triggered by one or more inciting factors.

Chronic urticaria is a condition resulting from known and unknown causes, characterized by the daily or near-daily appearance of wheals lasting more than 6 weeks, with each individual wheal persisting for no more than 24 hours.

In the majority of cases, acute urticaria remains a single isolated episode in a patient's life.

Chronic urticaria is characterized by a fluctuating course without progressive worsening. According to the literature, the duration of chronic spontaneous urticaria in adults and children does not significantly differ. Remission occurs within one year in 10-30%, within 3 years in 30-50%, and after 5 years in 40-70% of patients [20]. Chronic urticaria persists for over a year in more than 70% of patients and lasts for more than 5 years in 14%. Concomitant angioedema is associated with disease duration [21].

Spontaneous (idiopathic) urticaria is the most common clinical variant of chronic urticaria. Clinically, it presents with wheals that lack a characteristic anatomical distribution and are accompanied by pruritus, or less commonly, a burning sensation. Wheals may tend to coalesce in areas subjected to the greatest friction from clothing or body parts rubbing against each other (buttocks, lumbar region, shoulders, thighs).

On the face, the lesions may be barely elevated above the skin surface.

In some cases, the rashes involve virtually the entire skin surface and may be accompanied by fever. Initially, wheals are pale pink due to the local dilation of the superficial dermal blood vessel network; subsequently, as edema increases in the connective tissue and compresses the microvascular network, they may acquire a porcelain-white appearance, frequently in children. As the edema subsides, the wheals gradually return to a pink color and then resolve without a trace.

Thus, the characteristic features of an urticarial wheal include:

• central edema of varying size, almost always surrounded by erythema;

• pruritus, occasionally accompanied by a burning sensation;

• reversibility (the wheal resolves without a trace within 1–24 hours).

A particular manifestation of urticaria is angioedema (earlier terms: angioneurotic edema, Quincke's edema, circumscribed angioedema, giant urticaria). The condition is characterized by rapidly developing, usually localized, deep edema of the skin or mucous membranes. The skin in the area of angioedema is paler, firm to the touch, tense, and does not pit on pressure. Angioedema most commonly develops in a single skin area, usually asymmetrically. An important clinical symptom distinguishing angioedema from urticaria is the absence of pruritus. Patients typically complain of a sensation of tightness or, less commonly, pain in the affected area. The process predominantly involves distensible tissues with loose subcutaneous fat—the eyelids, lips, cheeks, scrotum, prepuce, and less frequently the extremities, abdomen, as well as the mucous membranes of the oral cavity, tongue, and larynx.

The clinical presentation depends on the localization of the edema. Edema of the nasal mucosa may cause sneezing and nasal congestion. Involvement of the lips and tongue leads to marked asymmetrical enlargement and impaired speech. Laryngeal edema causes hoarseness, potentially progressing to aphonia due to vocal cord edema, followed by respiratory distress.

Angioedema may persist for several hours, in some cases up to 72 hours. Relapses frequently affect the same anatomical locations.

Thus, angioedema is characterized by the following features:

• rapidly developing edema of the deep dermal layers, subcutaneous tissue, and submucosa;

• a sensation of tightness and pain more frequently than pruritus;

• possible absence of erythema;

• resolution within up to 72 hours.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

The diagnosis of urticaria typically does not require laboratory confirmation (unlike the diagnosis of its underlying causes). Evaluation should begin with a detailed medical history and physical examination, along with basic laboratory tests to rule out severe systemic diseases. An extended diagnostic workup aimed at identifying the cause of urticaria is dictated by the clinical situation and the patient's history [2].

2.1 Complaints and Anamnesis

Main complaints include reversible wheals and/or angioedema, skin pruritus, and a sensation of tightness in cases of angioedema.

When taking the medical history, attention should be paid to the patient's description of the lesions (appearance, size, localization, duration of individual lesions, presence of pruritus, pain, etc.); the presence and/or absence of angioedema and its localization; onset of the disease and duration of the current urticaria episode; efficacy of systemic antihistamines; nature and efficacy of prior treatment; cyclic pattern of lesion appearance (time of day, relation to menstrual cycle, etc.); relationship of exacerbations to the intake of acetylsalicylic acid**, NSAIDs, ACE inhibitors, or other medications; stress; history of atopic diseases, personal and family history of urticaria; presence of physical triggers for urticaria exacerbation; identification of past or current chronic or acute diseases, surgical procedures, blood and blood component transfusions, travel to or residence in regions with a high risk of infectious or parasitic diseases, visits to public catering establishments; relationship of exacerbations to food intake; occupation and hobbies; results of previous examinations and treatments [2, 13].

When taking a history for urticaria, one should be guided by the questions presented in Appendix A3.2. A correctly and thoroughly taken history and assessment of clinical manifestations allow for the formulation of a further diagnostic plan and a clear differential diagnosis algorithm, minimizing the likelihood of overdiagnosis and misinterpretation of the obtained data.

2.2 Physical Examination

The diagnosis of urticaria is based on the detection of wheals and/or angioedema. Laboratory confirmation is only required to identify the underlying cause of the disease.

Measurement of blood pressure, heart rate, body temperature, evaluation of peripheral lymph nodes, liver, and spleen size, auscultation of the lungs and heart, and abdominal palpation may reveal symptoms of conditions potentially associated with the development and persistence of urticaria symptoms. When indicated to identify comorbid conditions, foci of chronic infection, or a severe and uncontrolled disease course, an appropriate workup should be performed [2, 13].

2.3 Laboratory Diagnostics

Comment: in cases of history indicating a triggering factor, further evaluation is indicated.

Comment: Aside from routine diagnostic methods, the diagnostic panel is dictated by the clinical situation and the patient's medical history.

Comments: CRP is a sensitive marker whose levels may be elevated in CSU due to mast cell activation accompanied by an inflammatory response. CRP levels correlate with disease activity, duration, and poor response to systemic antihistamines.

Comment: AIT is detected in more than 10% of CSU patients, diagnosed by anti-TPO IgG antibody levels. AIT in CSU patients is associated with other organ-specific and/or systemic autoimmune diseases and indicates a prolonged disease course, more frequently observed in adults. Further evaluation and treatment for AIT are carried out by an endocrinologist/pediatric endocrinologist in accordance with current clinical guidelines

Comment: usually, an assay of "liver" enzymes and bilirubin is performed: (Determination of aspartate aminotransferase activity in blood, Determination of alanine aminotransferase activity in blood, Determination of gamma-glutamyltransferase activity in blood, Determination of alkaline phosphatase activity in blood, Determination of total bilirubin level in blood, Determination of free and conjugated bilirubin level in blood) [24, 31].

Further evaluation is carried out in accordance with relevant clinical guidelines by a gastroenterologist and/or infectious disease specialist and/or other specialists.

Comments: Ordering examinations and selecting diagnostic tests are performed according to the clinical situation

For children: Grade of recommendation C (level of evidence – 3).

For adults: Grade of recommendation C (level of evidence – 5).

Comments: ordering examinations and selecting diagnostic tests are performed according to the clinical situation.

Comments: further evaluation is carried out in accordance with relevant clinical guidelines.

Comments: further evaluation is carried out in accordance with relevant clinical guidelines.

Comments: hypocomplementemic urticarial vasculitis is diagnosed based on two main criteria – urticaria and/or angioedema, or both for at least 6 months, and hypocomplementemia; minor symptoms may include arthralgia, mild glomerulonephritis, uveitis or episcleritis, and recurrent abdominal pain. In urticarial vasculitis, wheals are widespread across the entire skin surface without a predominant localization, persist for more than 24 hours, may be accompanied by pruritus, burning, or pain, and sometimes occur without these symptoms. Erythema is intense, and diascopy reveals punctate petechiae and ecchymoses in the center of the lesion [24, 47]

2.4 Instrumental Diagnostics

Comment:

• A positive test indicates the presence of functional IgG autoantibodies against the high-affinity IgE receptor (FcϵRIα) or IgE. The test has moderate specificity as a marker of these functional antibodies, and a negative test has a high negative predictive value to rule them out. In addition, a positive test is associated with urticaria severity and a poor response to systemic antihistamines (test description in Appendix A3.3).

• in children, the intradermal autologous serum skin test (autologous serum skin test) is not standardized, and its use in pediatric clinical practice is limited.

• performing the test is recommended by a specialist with experience in performing and skills in interpreting the results.

Comments: performed within the framework of relevant clinical guidelines

• In patients with suspected chronic inducible urticaria, it is recommended to consider performing appropriate provocation tests for diagnostic purposes [2].

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

Comments: performing provocation tests is not prohibited in children [2], however, the lack of standardization of provocation tests for pediatric patients significantly limits physicians in performing them due to the risk of ethical and legal negative situations.

Comment: The cold provocation test is performed by applying an ice cube to the forearm skin. The ice must be in a plastic bag or cup to avoid skin contact with water. The application time is 5 minutes. It can be increased or decreased (from 30 seconds to 20 minutes) in individual cases.

The test should be considered positive if palpable and clearly visible wheals and erythema are detected at the test site, in most cases accompanied by pruritus and/or burning

• performing provocation tests in children is not prohibited [2], however, the lack of standardization of provocation tests for pediatric patients significantly limits physicians in performing them due to the risk of ethical and legal negative situations.

• it is necessary to discontinue systemic antihistamines 48 hours before testing.

• determination of the trigger sensitivity threshold is not performed in the Russian Federation due to the lack of appropriate licensed medical devices.

Comments: The pressure test is performed by hanging a weight over the shoulder (7 kg on a shoulder strap 3 cm wide), or by vertical application of a weight using hollow cylinders on the back, thigh, or forearm for 15 minutes. The test should be considered positive if a delayed red palpable swelling appears at the test site. The test is evaluated 6 hours after the end of provocation testing. The reaction is usually not accompanied by pruritus, but may be accompanied by a burning sensation or pain. Pressure urticaria should be differentiated from symptomatic dermographism, which manifests immediately [2].

• performing provocation tests in children is not prohibited [2], however, the lack of standardization of provocation tests for pediatric patients significantly limits physicians in performing them due to the risk of ethical and legal negative situations.

• it is necessary to discontinue systemic antihistamines 48 hours before testing.

• determination of the trigger sensitivity threshold is not performed in the Russian Federation due to the lack of appropriate licensed medical devices.

Comments:

Heat urticaria must be differentiated from cholinergic urticaria and solar urticaria. Provocation testing should be performed by applying a hot stimulus to the skin of the volar forearm. Thermal provocation methods that can be used for skin testing include tests using metal/glass cylinders filled with hot water, hot water baths, or TempTest measurements (Fig. 1). Heat for 5 minutes at temperatures up to 44 °C. Some patients may require a shorter or longer provocation time and a higher temperature. Ten minutes after provocation testing, the test sites should be inspected and test results evaluated. The test is considered positive if palpable and clearly visible wheals and a wheal-and-flare skin reaction are visible in the test area. In most cases, this reaction is accompanied by pruritus and/or a burning sensation [2].

• Performing provocation tests in children is not prohibited [2]; however, the lack of standardization of provocation tests for pediatric patients significantly limits the physician in performing them due to the risk of ethical and legal adverse situations.

• it is necessary to discontinue systemic antihistamines 48 hours before testing.

• determination of the trigger sensitivity threshold is not performed in the Russian Federation due to the lack of appropriate licensed medical devices.

• It is recommended to consider performing a provocation test with ultraviolet radiation and visible light in patients with chronic urticaria with a corresponding medical history to diagnose solar urticaria (subtypes of inducible urticaria) [2].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Provocation testing should be performed by exposure to ultraviolet radiation and visible light. The use of sunscreens and photoactive drugs should be avoided before phototesting. Solar simulators with filters (UVA and UVB) or monochromators (UVA and UVB, visible light) should be used for provocation. Provocation testing should be performed on the buttocks separately in the UVA, broadband UVB, and visible light wavelength spectra. In patients with a negative reaction, photosensitivity to visible light can be tested using a projector (e.g., a slide projector) at a distance of 10 cm. In patients with solar urticaria, provocation leads to the development of urticaria at the site of exposure within 10 minutes. The test should be considered positive if a palpable wheal accompanied by pruritus and/or burning is visible in the test area [2].

The following devices are used: medical device type in accordance with the nomenclature classification of medical devices approved by the Russian Ministry of Health 132070 (Ultraviolet phototherapy irradiator for home use):

State Register of Medical Devices and Organizations (Individual Entrepreneurs Engaged in the Manufacture and Fabrication of Medical Devices)

https://roszdravnadzor.gov.ru/services/misearch

Comments:

• performing provocation tests in children is not prohibited [2], however, the lack of standardization of provocation tests for pediatric patients significantly limits physicians in performing them due to the risk of ethical and legal negative situations.

• it is necessary to discontinue systemic antihistamines 48 hours before testing.

• determination of the trigger sensitivity threshold is not performed in the Russian Federation due to the lack of appropriate licensed medical devices.

• It is recommended to consider performing a provocation test to diagnose dermographic urticaria (a subtype of inducible urticaria) in patients with chronic urticaria with a corresponding medical history [2].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: test for detecting dermographic urticaria: a smooth blunt object (a capped ballpoint pen or wooden tongue depressor) should be applied perpendicularly to the skin and drawn across the forearm or upper back with light pressure. The skin in the test area must not be damaged, infected, or inflamed. The test is considered positive if pruritus and a palpable wheal appear within 10 minutes after provocation. The appearance of erythema without pruritus indicates simple dermographism (a normal physiological response).

• performing provocation tests in children is not prohibited [2], however, the lack of standardization of provocation tests for pediatric patients significantly limits physicians in performing them due to the risk of ethical and legal negative situations.

• it is necessary to discontinue systemic antihistamines 48 hours before testing.

• determination of the trigger sensitivity threshold is not performed in the Russian Federation due to the lack of appropriate licensed medical devices.

Comments: To diagnose aquagenic urticaria, a cloth moistened with water or normal saline at a temperature of 35–37 °C is used. The cloth is placed on the patient's torso. The cloth can be removed after 40 minutes or earlier if the patient reports pruritus and the first wheals. The test is considered positive if urticarial rashes develop within the boundaries of the test area within 10 minutes after removing the wet cloth.

• performing provocation tests in children is not prohibited [2], however, the lack of standardization of provocation tests for pediatric patients significantly limits physicians in performing them due to the risk of ethical and legal negative situations.

• it is necessary to discontinue systemic antihistamines 48 hours before testing.

• It is recommended to consider performing a provocation test to diagnose cholinergic urticaria (a subtype of inducible urticaria) in patients with chronic urticaria with a corresponding medical history [2].

Level CLevel 3Level of recommendation evidence C (reliability level of evidence – 3).

Comments: The provocation test consists of performing moderate physical exercise appropriate for the patient's age and general condition (e.g., on a treadmill or stationary cycle ergometer). Cycle ergometry involves an impulse control mode of the cycle ergometer, i.e., accelerating or decelerating the pedaling speed to increase the heart rate by 15 beats per minute every 5 minutes up to a final maximum increase of 90 beats per minute above the baseline after 30 minutes. The time of appearance of wheals correlates with disease severity. The onset time of sweating and the appearance of the first symptoms are recorded. Observation is continued for another 10 minutes in the recovery period after 30 minutes of exercise.

• performing provocation tests in children is not prohibited [2], however, the lack of standardization of provocation tests for pediatric patients significantly limits physicians in performing them due to the risk of ethical and legal negative situations.

• it is necessary to discontinue systemic antihistamines 48 hours before testing.

• determination of the trigger sensitivity threshold is not performed in the Russian Federation due to the lack of appropriate licensed medical devices.

2.5 Other Procedures

2.5.1 Consultations and participation of specialist physicians in the diagnosis and therapy of patients with urticaria

Comment: Management of patients with acute urticaria and standard cases of chronic urticaria upon achieving disease control can be carried out by a pediatrician/general practitioner (in their absence, by a general practitioner / family physician).

The stage of diagnosis, prescription, and therapy monitoring is carried out with the participation of: an allergist-immunologist, dermatovenerologist, pediatrician/general practitioner, gastroenterologist, endocrinologist, pediatric endocrinologist, rheumatologist, oncologist, pediatric oncologists-hematologist, infectious disease specialist, neurologist, psychiatrist, hematologist, pulmonologist, and others, according to clinical necessity.

[2, 23, 25].

Comments: the examination—laryngoscopy / fiberolaryngoscopy / videolaryngoscopy / epipharyngolaryngoscopy—may be indicated in case of clinical necessity for differential diagnosis and for prescribing appropriate therapy / medical intervention by a specialist physician (otorhinolaryngologist or other specialist).

2.5.2 Assessment of disease activity and symptom control

Comments:

The Urticaria Activity Score 7 (UAS7) questionnaire is used to assess disease activity / disease severity and to evaluate treatment outcomes (Appendix G1);

The Angioedema Activity Score (AAS) questionnaire is used to assess angioedema activity (Appendix G2);

The Urticaria Control Test (UCT) questionnaire is used to assess disease control over the past 4 weeks in patients with chronic spontaneous and inducible urticaria (Appendix G3);

Dermatological Quality of Life Index (DLQI) questionnaire for patients with dermatological diseases aged 16 years and older (Appendix G4).

Currently, there are no validated instruments for assessing the severity of urticaria in children; however, the Urticaria Activity Score (UAS7) is most frequently used in clinical practice. Other tests may be used depending on the clinical situation [20].

2.5.3 Differential diagnosis of urticaria in diseases accompanied by urticarial rashes

Comments: The algorithm for the differential diagnosis of urticaria is presented in Appendix A3.5

Urticarial vasculitis (UV). Weals in UV persist for more than 24 hours and are accompanied by purpura and secondary hyperpigmentation caused by hemosiderin (Appendix A3.6).

Burning and pain are more common than pruritus. In addition to urticarial elements, UV may present with angioedema and livedo reticularis [61-63]. Alongside cutaneous symptoms, patients sometimes report fever, malaise, myalgia, and arthralgia. Confirmation of the diagnosis of UV requires a histological examination of a skin biopsy from the affected area. Typical histological features of UV include leukocytoclastic (predominantly neutrophilic) infiltration, fragmented leukocytes (leukocytoclasia), fibrin deposits within and around the vessel walls, damaged and swollen endothelial cells of postcapillary venules, and erythrocyte extravasation [61].

Bullous pemphigoid. It is more frequently diagnosed in patients over 60 years of age. At the onset of the disease, during the prodromal (non-bullous) period, clinical manifestations are variable and may include weals [61, 64, 65]. Such elements may be the sole manifestation of the disease for several months.

Erythema multiforme. Erythema multiforme is an acute disease of the skin and mucous membranes characterized by the sudden appearance of symmetrical, fixed red papules, some of which transform into typical and/or occasionally atypical targetoid papular lesions. There are two forms of erythema multiforme: major and minor. Both share a characteristic feature—the same type of primary lesions (targets)—but differ in the presence or absence of mucosal involvement and systemic symptoms. Typical primary skin lesions in erythema multiforme are targetoid elements (inflammatory macules or edematous papules) with sharp borders, round shape, 3–15 mm in diameter, pink-red or bright red in color, characterized by centrifugal growth with central depression, resulting in annular lesions. A raised border forms at the periphery of the rash, while the center of the element gradually becomes depressed and acquires a cyanotic hue. Mucosal lesions (of the lips and buccal mucosa, conjunctiva, and genitalia) are observed in 70% of patients. Mucosal involvement is typical of the major form.

When reviewing the history, it is necessary to ascertain any association with herpetic or mycoplasmal infection or the use of medications (sulfonamides, NSAIDs, tetracycline (tablets), benzylpenicillin**, etc.) [61, 66].

Cutaneous T-cell lymphoma. Cutaneous T-cell lymphoma frequently manifests with widespread pruritus. In the early stages of the disease, skin infiltrates that resolve within 24–48 hours and are accompanied by pruritus and sometimes angioedema may be interpreted as urticaria [61, 64, 67].

Mastocytosis (urticaria pigmentosa). Urticaria pigmentosa (also known as the maculopapular form of cutaneous mastocytosis) is the most common form of cutaneous mastocytosis. Urticaria pigmentosa is characterized by red-brown macules and papules that form a weal when rubbed (positive Darier's sign). In typical cases, the diagnosis is straightforward for experienced specialists; however, in a number of clinical cases, differential diagnosis is required [61, 68, 69]. Some patients also exhibit urticarial dermographism on outwardly normal skin.

Urticaria pigmentosa predominantly affects children. Manifestation before the age of one is observed in 80% of cases [68]. The prognosis of the disease is favorable. As a rule, symptoms resolve during adolescence [69]. Systemic symptoms are associated with the release of mast cell mediators and are not always present in urticaria pigmentosa. Systemic manifestations are typically characterized by pruritus, urticarial elements (edema and erythema of urticaria pigmentosa skin lesions), episodes of sudden flushing of the face and upper torso, tachycardia, vomiting, syncope, and shock. Such symptoms can be triggered by the administration of contrast agents, opioids, general anesthesia, and Hymenoptera stings [68].

Borreliosis (Lyme disease). The early localized form of tick-borne borreliosis (Lyme disease) can manifest as erythema migrans, which must be differentiated from urticaria. Anamnestic data in the diagnosis of Lyme disease may indicate a history of exposure to epidemiologically hazardous areas [61, 70].

Polymorphic eruption of pregnancy. Polymorphic eruption of pregnancy (also known as pruritic urticarial papules and plaques of pregnancy, or PUPPP) is characterized by the appearance of intensely pruritic, edematous, erythematous papules and plaques on the skin. The rash most frequently occurs in primigravidas during the third trimester of pregnancy and resolves within 7–10 days postpartum. The lesions are predominantly localized in the abdomen, thighs, and buttocks, often within striae [61, 71].

Fixed drug eruption. Fixed drug eruption is characterized by the appearance of rashes at the exact same site upon re-administration of the culprit drug. Causes of fixed eruptions may include NSAIDs, sulfonamides, and other medications. Skin lesions in fixed drug eruptions can resemble urticarial elements at various stages. The rashes are accompanied by pruritus and burning and can persist for up to three weeks. Taking a pharmacological history and conducting a thorough physical examination are of primary importance in differential diagnosis [61, 72].

Autoimmune progesterone dermatitis. Autoimmune progesterone dermatitis is rare and is characterized by polymorphic rashes that recur cyclically every month during the luteal phase of the menstrual cycle and spontaneously resolve during menstruation. The rashes are frequently represented by urticarial elements. Exacerbation of the disease may be observed with the use of progesterone-containing oral contraceptives [61, 73].

Reticular erythematous mucinosis. Reticular erythematous mucinosis is a rare disease occurring in middle-aged women, characterized by the appearance of erythematous macules, papules, and plaques arranged in a reticular pattern. Some patients present with urticaria-like macules and papules that require differential diagnosis with urticaria. Histological examination of a skin biopsy reveals perivascular and perifollicular lymphocytic infiltrates and mucin deposition between collagen fibers in the papillary dermis and the upper layers of the reticular dermis [61, 74].

Systemic lupus erythematosus (SLE). Urticarial and urticaria-like rashes are frequently encountered in systemic lupus erythematosus (SLE) and are considered cutaneous manifestations of SLE, especially during the active phase of the disease. Chronic spontaneous urticaria may be one of the initial symptoms of SLE, preceding its clinical manifestation by up to ten years. According to some authors, chronic spontaneous urticaria may indicate a severe course and unfavorable prognosis of SLE. The combination of skin lesions with arthralgia, general malaise, and moderate leukopenia is significant in diagnosing SLE in these patients. Prolonged continuous or remittent fever combined with joint syndrome and skin involvement should raise suspicion of SLE [61, 74, 75].

Autoinflammatory diseases (AIDs).

Cryopyrin-associated periodic syndromes (CAPS). CAPS represent a group of rare hereditary AIDs that include:

• familial cold autoinflammatory syndrome / familial cold urticaria (FCAS / FCU);

• Muckle-Wells syndrome (MWS);

• chronic infantile onset neurologic cutaneous articular syndrome / neonatal onset multisystem inflammatory disease – CINCA/NOMID.

The listed syndromes are characterized by an early onset, usually within the first year of life, recurrent or persistent fever, urticarial rash, a wide spectrum of joint involvement ranging from arthralgia to recurrent and persistent arthritis in severe variants, as well as (for MWS and CINCA/NOMID) involvement of the central and peripheral nervous system. The main complication is amyloidosis, which develops as a result of chronic inflammation and is frequently the cause of patient mortality.

All three syndromes are characterized by persistent skin rashes throughout life [61, 77-79].

Schnitzler syndrome (SS). Schnitzler syndrome (SS) is characterized by recurrent cutaneous urticarial rashes combined with monoclonal gammopathy, associated with clinical and biological signs of inflammation and the risk of developing AA amyloidosis and lymphoproliferative disorders. Cutaneous urticarial rashes are usually the first and main symptom of the disease, localized on the trunk, extremities, palms and soles, in the head and neck region, persisting for 12–24 hours, and may disappear or persist continuously (Fig. 5). Manifestations of systemic inflammation in this disease also include recurrent fever, bone pain, muscle pain, arthralgia/arthritis, lymphadenopathy, hepatosplenomegaly, and elevated acute-phase markers (ESR, CRP, SAA) [61, 80-81].

Acute febrile neutrophilic dermatosis (Sweet's syndrome). Acute febrile neutrophilic dermatosis (Sweet's syndrome) is characterized by fever, neutrophilic leukocytosis, and skin rashes in the form of painful edematous red-purple nodules or papules. When the elements coalesce, irregular-form plaques with clear borders are formed. Upon resolution, the skin in the center of the elements normalizes, and the rashes acquire an annular or arcuate shape. The appearance of rashes is preceded by a fever up to 39–40 °C and malaise. The dynamics of the rash are characterized by worsening over several weeks with gradual resolution of the elements. Peripheral blood shows leukocytosis greater than 10,000/mm3, an increased neutrophil count, and elevated ESR and CRP [61, 82].

Monoclonal mast cell activation syndrome. Monoclonal mast cell activation syndrome is characterized by symptoms caused by the release of mast cell mediators: urticarial rash, recurrent anaphylactic episodes with hypotension and syncope occurring without apparent causes (idiopathic anaphylaxis) or after hymenopteran stings. The diagnosis is confirmed by serial determination of blood tryptase levels, bone marrow biopsy with immunohistochemical and molecular genetic studies. Such patients do not meet the diagnostic criteria for systemic mastocytosis [61].

Carcinoid syndrome. Carcinoid syndrome is observed in approximately 10% of patients with carcinoid tumors localized in the gastrointestinal tract, less frequently in the lungs, and rarely in the reproductive system. Carcinoid syndrome is combined with symptoms of sudden flushing (especially of the face and upper body), severe hypotension, tachycardia, bronchospasm, abdominal pain, and diarrhea [83]. Carcinoid syndrome is diagnosed by examining the 24-hour urinary excretion of 5-hydroxyindoleacetic acid, the main metabolite of serotonin. The level of 5-hydroxyindoleacetic acid in the urine is elevated in patients with carcinoid syndrome, in contrast to normal levels in patients with mastocytosis [61, 83].

Differential diagnosis of urticaria in children can be difficult. Pain and burning are not typical symptoms of urticaria, but may be present in severe clinical presentations involving intense soft tissue edema and perivascular infiltration at the sites of urticarial elements. In such cases, the rashes, conversely, may not have a red or pink hue, but a paler color due to compression of dermal vessels. In some cases, acute urticaria involves soft tissue edema around joints, the appearance of which is due to pronounced confluent urticarial elements around the joint. In this case, tenderness of the soft tissues upon palpation may be noted without limitation of passive range of motion. At the same time, acute inflammatory joint changes in urticaria are rare, but do occur. However, this symptom strictly requires the exclusion of a systemic disease.

In addition to the above-mentioned diseases, it should be borne in mind that children against the background of an acute infection may develop a specific disease-associated exanthem, as well as acute urticaria, the trigger for which may be drugs, homeopathic remedies, or herbal folk remedies. Differential diagnosis in children is carried out with: exanthem caused by enterovirus (ECHO viruses and Coxsackie viruses) and parvovirus infections. ECHO exanthem is characterized by an erythematous maculopapular or macular rash that disappears upon pressure and is not accompanied by pruritus. As a rule, it appears after 3 days of fever, spreading from the skin in the neck and around the ears gradually over the entire body. Apparently, the absence of prominent catarrhal symptoms and the appearance of the rash as the fever subsides lead some physicians to think of an allergic etiology of the rash. Parvovirus infection is characterized by a macular, maculopapular, "lacelike" erythematous rash that is not accompanied by pruritus, spreading to the face, extremities, and trunk. A distinguishing feature is the "slapped cheeks" sign. Many medicinal products contribute to the development of so-called drug-induced exanthem, which is sometimes mistaken for urticaria. In pediatric practice, a physician most frequently deals with the "outcome" of treating certain diseases, most often viral infections, with antibacterial drugs. Accurate recording of the time of rash onset during history taking is the basis for differential diagnosis of drug-induced exanthem: rashes appear, as a rule, on the 6th–10th day of therapy, and sometimes much later—on the 3rd–4th week (in the case of carbamazepine administration**) [84]. Drug-induced exanthem in children is most frequently observed in infectious mononucleosis, in the treatment of which systemic antimicrobial drugs (including beta-lactam antibacterial drugs: penicillins) are unjustifiably used [85-87].

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

The goal of urticaria therapy is to achieve complete symptom control [2].

Main principles and goals of urticaria treatment:

• Elimination and removal of triggering causes.

• Induction of tolerance.

• Symptomatic therapy aimed at reducing the release of mediators by mast cells and counteracting the effects of these mediators.

3.1. Elimination of triggering and causative factors

3.1.1. Medications

Comments: Medicinal products can be a cause and/or contributing factor (e.g., ACE inhibitors, NSAIDs) [88].

3.1.2 Treatment of infectious and inflammatory processes

Comments: Identified inflammatory processes in a patient with chronic urticaria require indicated treatment, just like in any other patient. The question of eradicating infectious agents, such as H. pylori in patients with chronic urticaria, remains open. A clear link between identified infectious agents and the development and maintenance of urticaria has not yet been confirmed. An identified parasitic infestation in a patient with chronic urticaria requires treatment. In each case, the decision is made individually.

Comments: in each case, the decision is made individually.

3.1.3 Diet

There is no special universal diet for patients with urticaria. Basic nutrition is selected individually, taking into account food tolerance. Patients with chronic urticaria are recommended to keep a diary with mandatory daily registration of urticaria symptoms (itch index, rashes, presence and localization of angioedema).

Comments: a diagnosis of food allergy cannot be based on a history that is inconsistent with food hypersensitivity. No diagnostic test (skin test, serum specific IgE, etc.) is clinically meaningful or should be interpreted in isolation from the clinical history. Elimination of identified allergens from the diet leads to improvement within 24–48 hours. Patients with daily or near-daily urticaria are advised to follow a hypoallergenic diet. A more accurate term for a diet restricting foods that are not true allergens is a low-histamine diet, or a pseudoallergen-free diet.

The term "hypoallergenic diet" functions as an umbrella term encompassing at least 3 groups of foods with specific properties:

1. foods with a high histamine content;

2. foods that release histamine in the body—histamine liberators;

3. certain others [96].

In cases of hypersensitivity to histamine and other biogenic amines in food causing a pseudoallergic reaction, improvement on a low-histamine diet occurs within 3 weeks. Approximately half of patients with chronic urticaria who followed a diet low in histamine liberators return to a normal diet after 6 months. Upon achieving remission or clinical improvement in chronic urticaria (CU), the diet may be expanded by introducing a new food every 3 days.

Making a decision to eliminate a specific food requires an accurate diagnosis as well as a risk-benefit assessment. Diets with severe restrictions can lead to nutritional deficiency [97].

Long-term restrictive diets are not recommended for chronic spontaneous urticaria due to the low level of evidence supporting their efficacy [93].

3.1.4 Physical factors

3.2. Tolerance Induction

3.3 Symptomatic therapy

Urticaria therapy aims to reduce mediator release from mast cells and counteract the effects of these mediators.

3.3.1 Management of Acute Urticaria and Angioedema

Systemic antihistamines (non-sedating, second-generation) at standard doses

Comment: systemic antihistamines (non-sedating, second-generation) for the complete or partial resolution of wheals and pruritus with the following preferred characteristics: selective H1-receptor antagonism, rapid onset of clinical effect, duration of action of 24 hours or more, absence of tachyphylaxis (tolerance), high safety profile, lack of sedative effects, absence of clinically significant interactions with food and drugs, and lack of cardiotoxicity; they should not be substrates for transport proteins or interact with the cytochrome P450 3A (CYP3A) system [1-5, 7, 63-81]. Individual systemic antihistamines (non-sedating, second-generation) differ in pharmacodynamics and pharmacokinetics, their ability to cross the blood-brain barrier and cause sedation (more pronounced with cetirizine**, in a dose-dependent manner), and potentially in their ability to suppress pro-inflammatory mediators involved in the allergic reaction [105, 106].

Parenteral administration of systemic antihistamines (sedating, first-generation) may be considered only for special indications (generalized urticaria with stable hemodynamic parameters) in accordance with the product information: clemastine (from 1 year of age – intramuscularly, from 18 years of age – intramuscularly or intravenously), chloropyramine** (from 1 month of age – intramuscularly or, in acute severe cases under medical supervision, intravenously).

For infants under 6 months of age, given the lack of approved systemic antihistamines (second-generation), a short course of dimetindene may be prescribed (dosing regimen for patients from 1 month to 12 years of age: 2 drops per 1 kg of body weight or 0.1 mg/kg divided into 3 doses).

In the event of laryngeal angioedema, emergency intubation or tracheostomy should be performed if necessary. When urticaria and/or angioedema are symptoms of anaphylaxis, appropriate therapy is indicated (see clinical guidelines for "Anaphylactic shock"). Patients with chronic induced urticaria who have experienced anaphylaxis must carry an emergency anti-shock kit, which must include 0.1% epinephrine** solution in 1.0 ml ampoules [107, 108].

Comments: to relieve an acute episode with a short course (up to 10 days in adults, 3-7 days in children), oral prednisolone** may be used at a dose of 20-50 mg/day in adults and 1-2 mg/kg/day in children. Tapering of glucocorticoids is not required for a short course of therapy. According to the product information, dexamethasone** may also be used [23, 85, 99, 109, 110].

#Methylprednisolone** may be used in adults with severe angioedema who require hospitalization for angioedema: 60 – 80 (125) mg intravenously at the start of therapy, followed by a transition to oral administration for 5-7 days [107, 112].

3.3.2 Management of Chronic Urticaria

The algorithm of physician actions for the symptomatic treatment of chronic urticaria [2] is provided in Appendix B (see Appendix B).

3.3.2.1 First-line therapy for chronic urticaria

Systemic antihistamines (non-sedating, second-generation) at standard doses

Comment: systemic antihistamines (non-sedating, second-generation) for the complete or partial elimination of wheals and pruritus with the following key characteristics: selective H1-receptor affinity, rapid onset of clinical effect, duration of action of 24 hours or more, absence of tachyphylaxis (tolerance), high safety profile, lack of sedative effect, absence of clinically significant interactions with food and other medicinal products, and lack of cardiotoxicity; they must not be substrates for transport proteins or interact with the cytochrome P450 3A (CYP3A) system [46, 54, 95, 113-115]. Individual systemic antihistamines (non-sedating, second-generation) differ in pharmacodynamics and pharmacokinetics, ability to cross the blood-brain barrier and cause sedation (more pronounced with cetirizine**, depending on the dose) and, potentially, in their ability to suppress pro-inflammatory mediators involved in the allergic reaction [105, 106].

Comment: The main objective of using systemic antihistamines (non-sedating, second-generation) is to prevent the effects of mast cell mediators in target organs. This group of drugs acts as an H1-receptor inverse agonist, stabilizing the receptors in an inactive state. This explains the need for long-term continuous administration of systemic antihistamines (non-sedating, second-generation). In patients with inducible forms of urticaria, systemic antihistamines (non-sedating, second-generation) may be prescribed on an as-needed basis in anticipation of a trigger (cold exposure, physical exertion, etc.). In cases of prolonged trigger exposure, the administration of systemic antihistamines (non-sedating, second-generation) may not differ from that in chronic spontaneous urticaria.

Desloratadine for children aged 6 to 12 months: 1 mg once daily; for children aged 1 to 5 years: 1.25 mg once daily; for children aged 6 to 11 years: 2.5 mg once daily; for adults and adolescents aged 12 years and older: 5 mg once daily.

Levocetirizine for children aged 2 to 6 years: 1.25 mg twice daily; for adults and children older than 6 years: 5 mg once daily.

Loratadine** for children aged 2 to 12 years with a body weight of 30 kg or less: 5 mg once daily; with a body weight of more than 30 kg: 10 mg once daily; for adults and adolescents older than 12 years: 10 mg once daily.

Fexofenadine; for chronic urticaria in adults and adolescents older than 12 years: 180 mg daily.

Cetirizine** for children aged 6 to 12 months: 2.5 mg once daily; for children aged 1 to 2 years: 2.5 mg twice daily; for children aged 2 to 6 years: 2.5 mg twice daily or 5 mg once daily; for adults and children older than 6 years: 5–10 mg once daily.

Ebastine for adults and adolescents older than 12 years: 10–20 mg once daily (a sublingual fast-dispersing formulation is available).

Rupatadine for adults and adolescents older than 12 years: 10 mg once daily.

Bilastine for adults and adolescents older than 12 years: 20 mg once daily.

Comments: Side effects of systemic antihistamines (sedating, first-generation) are caused by their penetration across the blood-brain barrier and binding to brain H1-receptors. This results in sedation, impaired coordination, and reduced attention span. In addition, systemic antihistamines (sedating, first-generation) block muscarinic receptors, leading to mucosal dryness, blurred vision, and urinary retention, as well as exerting quinidine-like effects on the myocardium that can cause arrhythmias. This group of drugs is characterized by tachyphylaxis and requires multiple daily doses to maintain efficacy.

Upregulation of systemic antihistamines (non-sedating, second-generation).

Comment: it should be borne in mind that dose escalation of systemic antihistamines (non-sedating, second-generation) is off-label (except for ebastine – up to a 2-fold increase starting from 15 years of age).

Nevertheless, based on clinical studies, adult patients may receive an increased dose of #fexofenadine – up to 1.5-fold (for adults) [126], up to 4-fold for #bilastine [128], #desloratadine, #ebastine, #fexofenadine, #levocetirizine, [122, 123, 126], 3-fold for #cetirizine** [129], 2-fold for #cetirizine** [130], and 2-fold for #rupatadine [131, 132].

If there is no response to a four-fold increased dose of systemic antihistamines (non-sedating, second-generation), further dose escalation should not be performed.

(Recommendation Grade C (Level of Evidence – 5)

Comments: If urticaria symptoms persist in children receiving an age-appropriate dose of systemic antihistamines (non-sedating, second-generation) for more than 2–4 weeks, or earlier if symptoms are intolerable to the patient, the dose of the systemic antihistamine (non-sedating, second-generation) may be doubled (second-line therapy) (a 2-fold dose increase for ebastine is permitted from 15 years of age).

Due to insufficient evidence, such treatment strategy should be followed with caution in children: for pediatric patients, the decision to increase the dose of systemic antihistamines (non-sedating, second-generation) must be made on an individual basis [19, 134, 135]. Studies have been described demonstrating the safety of up to a four-fold dose increase in children under 12 years of age for #cetirizine, and over 12 years of age for #rupatadine [134], as well as two-, three-, and four-fold increases for various systemic antihistamines (non-sedating, second-generation) [135].

The prescription of drugs for off-label indications, doses, or age restrictions is carried out by decision of the medical commission, with the approval of the Local Independent Ethics Committee of the medical organization (if available) and subject to obtaining the informed consent of the patient/legal representative and the patient aged 15 years or older.

3.3.2.2 Second-line therapy for chronic urticaria

Comments: The drug is recommended for patients aged 12 years and older who do not respond to systemic antihistamines (second-generation). The recommended dose of omalizumab** for the treatment of spontaneous urticaria is 300 mg subcutaneously every 4 weeks for at least 6 months of treatment.

In the absence of an adequate response to the licensed dose, the dose of #omalizumab** may be increased up to 600 mg and/or the dosing interval reduced to 2 weeks (carried out by decision of the medical committee, with the approval of the Local Independent Ethics Committee of the medical organization (if any), and subject to obtaining informed consent from the patient/parents (legal representatives) and a child over 15 years of age) [147-151]. The expected time to onset of the effect of omalizumab** ranges from several days to several weeks. Early discontinuation of therapy may lead to the loss of late-responder patients. Initiating omalizumab** therapy does not preclude the simultaneous discontinuation of systemic antihistamines (non-sedating, second-generation). Unlike in patients with bronchial asthma, prescribing omalizumab** in patients with chronic idiopathic (spontaneous) urticaria does not require considering total IgE levels or body weight.

3.3.2.3 Third-line therapy for chronic urticaria

#Cyclosporine**

Comments: Treatment with #cyclosporine** must be carried out by physicians experienced in immunosuppressive therapy and capable of ensuring adequate patient monitoring: regular physical examinations, peripheral blood pressure measurements (24-hour ambulatory blood pressure monitoring if necessary), and monitoring of laboratory parameters. The drug administration requires constant monitoring of renal function, liver function, and blood pressure. Before initiating cyclosporine therapy, it is necessary to rule out infectious diseases (tuberculosis, hepatitis B and C), hypertension, kidney disease, liver disease, and malignancies, and to review concomitant medication therapy data, which must be checked during each subsequent visit. Blood pressure is monitored before treatment, at weeks 2, 4, 6, and 8, and monthly thereafter (measured twice; values should not exceed 140/90 mmHg for adult patients).

Laboratory parameters requiring monitoring: a complete blood count is necessary because #cyclosporine** can cause adverse events such as leukopenia, anemia, and thrombocytopenia (baseline, then monthly) [162]; blood creatinine test (baseline — the mean of 2 separate fasting measurements; if the discrepancy is 10%, the test must be repeated; then at weeks 2, 4, 6, and 8, and monthly thereafter); blood potassium test (baseline, then monthly); serum total magnesium test (baseline, then monthly); biochemical blood test to assess lipid metabolism disorders, aspartate aminotransferase, alanine aminotransferase, bilirubin, and blood urea nitrogen (baseline, then monthly); uric acid (baseline, then monthly); #cyclosporine** blood level test (if available) to monitor the safety of ongoing systemic cyclosporine** therapy (plasma creatinine and urea, hyperlipidemia, hyperuricemia, hyperkalemia, hypomagnesemia, hyperglycemia; #cyclosporine** may also cause a dose-dependent, reversible increase in plasma bilirubin concentration and liver enzyme activity); baseline tuberculin skin test; screening tests for malignancy if necessary [162]

#Cyclosporine** may cause adverse events such as increased 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 [162]

An increase in blood creatinine levels may indicate nephrotoxicity and require a dose reduction: by 25% if the blood creatinine level increases by more than 30% from baseline, and by 50% if it doubles. If dose reduction over 4 weeks does not lead to a decrease in blood creatinine levels, #cyclosporine** should be discontinued.

The recommended dose range of #cyclosporine** is 2-5 mg/kg, averaging 3.5 mg/kg, divided into 2 doses. If the initial dose of 2.5 mg/kg per day does not achieve a satisfactory response within 2 weeks, the daily dose is increased to the maximum of 5 mg/kg. After a satisfactory response is achieved, the dose is gradually reduced and, if possible, the drug is discontinued. If relapse occurs, a repeat course is given.

Upon achieving a satisfactory clinical result, #cyclosporine** is discontinued, and in the event of a subsequent exacerbation, it is resumed at the previous effective dose. The drug should be tapered gradually, reducing the dose by 1 mg/kg per week for 4 weeks or by 0.5–1 mg/kg every 2 weeks.

The use of live attenuated vaccines during #cyclosporine** treatment is not recommended. Vaccination against pneumococcus and influenza is recommended for patients receiving this therapy [162]. Long-term therapy with #cyclosporine** (more than 3 months) should be avoided.

3.3.3 Management of Urticaria and/or Angioedema Exacerbation

Comments: to relieve an exacerbation with a short course (up to 10 days in adults, 3-7 days in children), oral prednisolone** may be used at a dose of 20-50 mg/day in adults and 1-2 mg/kg/day in children. Tapering of glucocorticoids is not required for a short course of therapy. According to the instructions, dexamethasone** may also be used [23, 99, 109, 110].

Methylprednisolone** may be used in adults with severe angioedema requiring hospitalization for angioedema: 60 – 80 (125) mg intravenously at the start of therapy, followed by a switch to oral administration for 5-7 days [107, 112].

Comments: The indication for surgery in patients with laryngeal angioedema is determined based on clinical examination findings. In cases where the exacerbation of urticaria and/or angioedema is a symptom of anaphylaxis, appropriate therapy is indicated (see the clinical guidelines for "Anaphylactic shock"). Patients with a history of anaphylaxis must carry an emergency anti-shock kit, which must include epinephrine** 0.1%–1.0 ml solution in ampoules.

Comments: only patients with delayed pressure urticaria may receive dermatological glucocorticoids (topical corticosteroid therapy) [163, 165].

3.4. Alternative Therapy for Urticaria

#Dapsone** (ATC code J04BA) starting from 25 mg/day with a gradual increase up to 100 mg/day [166] or at a dose of 100 mg/day for 3 or 6 weeks [167].

Level of Evidence BGrade of Recommendation 3Level of Recommendation B (level of evidence – 3

or

#Sulfasalazine** (ATC code A07EC01) 500 mg, 2000 mg, 3000 mg, or 4000 mg/day [166].

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

or

#Methotrexate** (ATC code L01BA) — tablets (2.5 mg every 12 hours, 2-3 days a week for 1-2 weeks, or 10-15-20 mg/day once weekly) [166].

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

or

#human normal immunoglobulin** (ATC code J06BA02) – intravenously 0.2-0.5-1 g/kg/day – single dose or for 3 days, or 0.4 g/kg/day, or 2 g/kg/day for 5 days, or 2 g/kg every 4-6 weeks, or 0.15 g/kg (as a course of 6 to 51 administrations depending on the clinical situation) [166],

or

#montelukast (ATC code R03DC03) – tablets (10 mg daily) [168, 169].

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

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

or

plasmapheresis (medical service code A18.05.001.001) – 3 times over 5 days, total removed plasma volume 4.2-9.01 L (average 6.9 L) [170], or 6 procedures every other day, removed plasma volume 200-300 ml (total removed plasma volume during the course 2000 ml) [114].

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

Comments: The prescription of drugs for off-label indications, doses, or age restrictions is carried out by decision of the medical commission, with the approval of the Local Independent Ethics Committee of the medical organization (if any), and subject to obtaining informed consent from the patient/legal representative.

3.5. Management of Urticaria During Pregnancy and Lactation

Comments: all pregnant patients with urticaria, taking intoacedcount the safety principle of drug use during pregnancy and breastfeeding, should take systemic antihistamines (non-sedating, second-generation) for treatment to eliminate pruritus and wheals: Loratadine** (ATC code: R06AX13) with possible extrapolation to Cetirizine** (ATC code: R06AE07) and extrapolation to Levocetirizine (ATC code: R06AE09) [2, 171, 172].

Modern systemic antihistamines (non-sedating, second-generation) are used as first-line therapy for urticaria in pregnant women. The use of these drugs is associated with an acceptable risk. These agents belong to category B (animal reproduction studies have not shown a risk of adverse effects to the fetus, but there are no adequate and well-controlled studies in pregnant women). Currently, there are no data on birth defects in children born to women who took systemic antihistamines (non-sedating, second-generation) during pregnancy [171, 173-176].

All systemic antihistamines are excreted into breast milk in low concentrations. Safety studies on increased doses of systemic antihistamines (non-sedating, second-generation) taken by pregnant and lactating women have not been conducted.

The use of systemic antihistamines (sedating, first-generation) immediately before delivery may cause respiratory depression and other adverse events in newborns. Drugs of the subsequent stages are used taking into account individual indications, the risk-benefit assessment for the pregnant woman and the fetus, teratogenicity, and embryotoxicity [2].

Given the expanded indications for the prescription of omalizumab** in chronic urticaria, its potential use during pregnancy is being discussed, and cases of safe and effective use of omalizumab** in pregnant patients with chronic idiopathic (spontaneous) urticaria have been described [177-180].

According to FDA classification, cyclosporine** belongs to category C: the benefit of use may outweigh the risks. The potential use of #cyclosporine** during pregnancy in patients with chronic urticaria is being discussed; there is currently experience with the drug in pregnant patients with autoimmune and other pathologies [181-183].

3.6. Surgical treatment

Not used for the treatment of urticaria.

Surgical intervention for urticaria is performed if the patient has a comorbid pathology.

3.7. Other Treatments

Pain management is not used.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: The education program for patients (legal representatives of patients) with urticaria should include the provision of information about the disease, the formulation of an individual treatment plan for the patient, and training in completing disease severity and control assessment diaries. The goal of education is to provide the patient with urticaria and their family members with the information necessary for the most effective treatment. Education provides for educational work among all participants in the treatment process: the patient with urticaria, their family members, and medical workers.

5. Prevention and Dispensary Observation

Prevention is aimed at maintaining long-term remission and preventing relapses, and includes elimination measures: elimination or limitation of exposure to physical or other triggers of urticaria (cold, heat, physical exertion, ACE inhibitors, NSAIDs, etc.), monitoring disease activity using questionnaires (UAS7, UCT, AAS), and taking baseline therapy.

Comments: an individualized approach to vaccination must be ensured.

Vaccination is not performed during the period of disease exacerbation. Considering that the benefit of vaccination outweighs the potential risks, it is necessary to ensure the possibility of carrying out required preventive vaccinations under conditions of a stable course of the disease.

Dispensary follow-up (Active surveillance)

The management of patients with acute urticaria and in standard cases of chronic urticaria upon achieving disease control can be carried out by a pediatrician/general practitioner (in their absence, by a family physician).

The stage of diagnosis, prescription, and monitoring of therapy is carried out with the participation of: an allergist-immunologist, dermatovenerologist, pediatrician/general practitioner. If indicated, consultations are scheduled with a gastroenterologist, endocrinologist, pediatric endocrinologist, rheumatologist, oncologist, pediatric hematologist-oncologist, infectious disease specialist, neurologist, psychiatrist, hematologist, otorhinolaryngologist, pulmonologist, and/or other specialists according to clinical necessity.

Dynamic (dispensary) follow-up of a patient with chronic urticaria is carried out every 3-6 months by an allergist-immunologist or dermatovenerologist. If the patient is taking immunosuppressive drugs, the follow-up must include diagnostic measures to monitor the patient's condition (indicated in the relevant sections).

6. Organization of Medical Care

Patients with urticaria and angioedema, depending on necessity, may receive any type, conditions, and form of medical care provided for by the legislation of the Russian Federation.

The management of patients with urticaria and angioedema is usually handled by an allergist-immunologist/dermatovenerologist, as well as a pediatrician/general practitioner and other specialists if necessary.

Hospitalization is most often carried out in an allergology/dermatovenerology/pediatric/therapeutic department.

Primary health care includes measures for the prevention, diagnosis, treatment of urticaria and associated diseases, medical rehabilitation, and the formation of a healthy lifestyle.

Primary pre-medical health care is provided by medical personnel with secondary medical education.

Primary physician-delivered health care is provided by general practitioners, district general practitioners, pediatricians, district pediatricians, and family physicians; in pediatric practice, a family physician should only at the primary stage carry out the routing (referral) of a pediatric patient to a pediatrician, including, for example, if the need arises, providing medical care in urgent and emergency forms in the absence of a pediatrician at the primary care level (at the stage of primary health care).

If there are medical indications for medical care that does not require inpatient conditions, the district general practitioner, district pediatrician, general practitioner (family doctor), medical worker with secondary medical education, general practitioner, or pediatrician shall refer the patient to the office of an allergist-immunologist and/or dermatovenerologist of a medical organization to provide primary specialized health care.

Primary specialized health care is provided by a dermatovenerologist or an allergist-immunologist, and in their absence, by a general practitioner or pediatrician.

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

If there are medical indications, the patient may be provided with emergency medical care, including specialized emergency medical care.

Indications for hospitalization:

1. Severe forms of acute urticaria and laryngeal angioedema with a risk of asphyxia.

2. Urticaria accompanying anaphylaxis.

3. Severe forms of chronic urticaria exacerbation and angioedema refractory to outpatient treatment.

Specialized, including high-tech, medical care is provided by allergists-immunologists and/or dermatovenerologists, and pediatricians in inpatient settings and includes the prevention, diagnosis, treatment of diseases and conditions requiring the use of special biological drugs, methods, and complex medical technologies, as well as medical rehabilitation.

The duration of the inpatient stage of medical care for all patients with urticaria (including day-care settings) depends on the severity of the patient's condition, the nosological form of urticaria, and the speed and degree of achieving the clinical effect of therapy.

If a patient has medical indications for high-tech medical care, the referral of the patient to a medical organization providing high-tech medical care is carried out in accordance with the Procedure for referring citizens of the Russian Federation for the provision of high-tech medical care.

An episode of acute urticaria and/or angioedema without further recurrence usually does not require an in-depth examination; adult patients are monitored in out-patient clinics by an allergist-immunologist, dermatovenerologist, or general practitioner; children are monitored in out-patient clinics by a pediatrician, with a frequency, on average, of 1 time in 3–6 months, and specialist consultations are conducted as indicated. Comprehensive examination with dynamic condition control, and consultations with other specialists as indicated are carried out for children 1 time in 6–12 months, depending on the severity and nature of the course of the process, as indicated, on an outpatient basis / in a day hospital / in an inpatient setting.

7. Additional Information

Avoid conditions that cause overheating: overly warm clothing, excessive physical activity, consumption of hot meals and drinks, etc.

In case of delayed pressure urticaria and symptomatic dermographism, avoid tight clothing, carrying heavy loads, widen backpack straps to reduce pressure on the skin surface, avoid long hikes in case of foot edema, etc.

Avoid conditions that cause cooling: too light clothing, consumption of cold drinks and food, prolonged stay in the cold.

In solar urticaria, avoid direct sun exposure, wearing open clothing, refrain from vacations in regions with high insolation, use topical sunscreens with SPF 50+, wear covered clothing and wide-brimmed hats.

Acute spontaneous urticaria in most cases remains the only episode in a patient's life.

In acute urticaria accompanying an anaphylactic reaction, the absence of medical care and delay in its provision can be fatal;

In cold urticaria, after bathing in cold water, a patient may die due to systemic manifestations (drop in blood pressure, suffocation);

Laryngeal edema without medical care can be fatal;

The average duration of chronic spontaneous urticaria ranges from 2 to 5 years [190, 191].

Spontaneous remission is observed in 30–50% of patients with CSU within 1 year [192, 193]. The incidence of spontaneous remission is higher in children [194, 195]. Symptoms persist within 5 years in 30% of patients. More than 20% of patients suffer for longer than 5 years [192, 196].

Chronic urticaria is characterized by a wave-like course without progressive deterioration.

Systemic antihistamines are effective in 40–60% of patients with chronic spontaneous urticaria.

Criteria for Evaluating the Quality of Medical Care

Table 1. Criteria for assessing the quality of medical care provided to patients with urticaria and/or angioedema

References

Appendix A1. Working Group Composition

1. Kubanov Alexey Alekseevich - President of the All-Russian Public Organization "Russian Society of Dermatovenerologists and Cosmetologists", Director of the State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, Academician of the RAS, Moscow.

2. Baranov Alexander Alexandrovich - Advisor to the Head of the Research Institute of Pediatrics and Children's Health of the Central Clinical Hospital of the RAS, Honorary President of the Union of Pediatricians of Russia, Academician of the RAS, Professor;

3. Namazova-Baranova Leila Seymurovna - Head of the Department of Faculty Pediatrics at the Pirogov Russian National Research Medical University, Head of the Research Institute of Pediatrics and Children's Health of the Central Clinical Hospital of the RAS, Chief freelance pediatric specialist in preventive medicine of the Russian Ministry of Health, President of the Union of Pediatricians of Russia, Academician of the RAS, Professor.

4. Araviyskaya Elena Roaldovna – Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation, Department of Dermatovenerology with Clinic, Doctor of Medical Sciences, Professor, Saint Petersburg.

5. Astafieva Natalia Grigorievna – Head of the Department of Clinical Immunology and Allergology at the V.I. Razumovsky Saratov State Medical University of the Russian Ministry of Health, Doctor of Medical Sciences, Professor, Saratov.

6. Bazaev Vitaly Tadiozovich — North Ossetian State Medical Academy of the Russian Ministry of Health, Head of the Department of Dermatovenereology, Doctor of Medical Sciences, Associate Professor, Vladikavkaz.

7. Borzova Elena Yuryevna — Professor at the V.A. Rakhmanov Department of Skin and Venereal Diseases, I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health, Chief Researcher at the Department of Clinical Genetics, Research Institute of Pediatrics, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Allergist-Immunologist, Doctor of Medical Sciences, PhD (UK), Moscow.

8. Vishneva Elena Aleksandrovna — Deputy Director for Science, Research Institute of Pediatrics and Child Health, Central Clinical Hospital of the Russian Academy of Sciences; Associate Professor, Department of Faculty Pediatrics, Pirogov Russian National Research Medical University, Doctor of Medical Sciences, Moscow.

9. Gallyamova Yulia Albertovna — Russian Medical Academy of Continuous Professional Education (RMACPE), Professor at the Department of Dermatovenereology and Cosmetology, Doctor of Medical Sciences, Associate Professor, Moscow.

10. Danilycheva Inna Vladimirovna — Leading Researcher, Department of Allergology and Immunotherapy, National Research Center - Institute of Immunology, Federal Medical-Biological Agency of Russia; Head of the Ucare Center, Candidate of Medical Sciences, Moscow.

11. Elisyutina Olga Guryevna — Senior Researcher, Department of Allergology and Skin Immunopathology, National Research Center - Institute of Immunology, Federal Medical-Biological Agency of Russia; Allergist-Immunologist, Doctor of Medical Sciences, Moscow.

12. Znamenskaya Lyudmila Fedorovna — Senior Researcher, Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, Doctor of Medical Sciences.

13. Ilyina Natalia Ivanovna — Vice President of the Russian Association of Allergologists and Clinical Immunologists (RAACI), Deputy Director for Clinical Work and Chief Physician, National Research Center - Institute of Immunology, Federal Medical-Biological Agency of Russia; Doctor of Medical Sciences, Professor, Moscow.

14. Kalugina Vera Gennadyevna — Researcher, Research Institute of Pediatrics and Child Health, Central Clinical Hospital of the Russian Academy of Sciences, Allergist-Immunologist.

15. Karamova Arfenya Eduardovna — Head of the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, Candidate of Medical Sciences.

16. Levina Yulia Grigoryevna — Head of the Department of Clinical Immunology and Allergology, Associate Professor at the Department of Faculty Pediatrics, Pirogov Russian National Research Medical University; Allergist-Immunologist, Candidate of Medical Sciences;

17. Meshkova Raisa Yakovlevna — Honored Doctor of the Russian Federation, Chief Freelance Allergist-Immunologist of the Smolensk Region Department of Health, Head of the Department of Clinical Immunology and Allergology at Smolensk State University, Head of the Ucare Center, Doctor of Medical Sciences, Professor, Smolensk.

18. Olisova Olga Yuryevna — Head of the Department, Director of the V.A. Rakhmanov Clinic of Skin Diseases, Honored Doctor of the Russian Federation, Professor, Doctor of Medical Sciences, Highest Qualification Category Physician, Corresponding Member of the Russian Academy of Sciences.

19. Novik Gennady Aizikovich — Head of the Professor I.M. Vorontsov Department of Pediatrics, Faculty of Postgraduate and Additional Professional Education, Saint Petersburg State Pediatric Medical University; Professor, Doctor of Medical Sciences;

20. Samtsov Alexey Viktorovich — Head of the Department of Skin and Venereal Diseases, S.M. Kirov Military Medical Academy, Honored Doctor of the Russian Federation, Doctor of Medical Sciences, Professor.

21. Selimzyanova Liliya Robertovna — Head of the Department of Standardization and Foundations of Evidence-Based Medicine, Research Institute of Pediatrics and Child Health, Central Clinical Hospital of the Russian Academy of Sciences; Associate Professor at the Department of Faculty Pediatrics, Pirogov Russian National Research Medical University; Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University (Sechenov University); Candidate of Medical Sciences;

22. Sokolovsky Evgeny Vladislavovich — Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, Head of the Department of Dermatovenereology with Clinic, Doctor of Medical Sciences, Professor, Saint Petersburg.

23. Fedenko Elena Sergeevna — Head of the Department of Allergology and Skin Immunopathology, National Research Center - Institute of Immunology, Federal Medical-Biological Agency of Russia, Moscow, Doctor of Medical Sciences, Professor.

24. Fedorova Olga Sergeevna — Vice-Rector for Research and Postgraduate Training, Siberian State Medical University of the Russian Ministry of Health, Head of the Department of Faculty Pediatrics with a Course of Childhood Diseases at the Faculty of General Medicine, Doctor of Medical Sciences, Associate Professor.

25. Fomina Daria Sergeevna — Chief Freelance Specialist Allergist-Immunologist of the Moscow Healthcare Department, Head of the Moscow City Scientific and Practical Center of Allergology and Immunology at City Clinical Hospital No. 52, Associate Professor at the Department of Clinical Immunology and Allergology, I.M. Sechenov First Moscow State Medical University, Candidate of Medical Sciences, Associate Professor.

26. Khayrutdinov Vladislav Rinatovich — Professor at the Department of Skin and Venereal Diseases, S.M. Kirov Military Medical Academy, Doctor of Medical Sciences.

27. Chikin Vadim Viktorovich — Senior Researcher, Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, Doctor of Medical Sciences.

28. Shulzhenko Andrey Evgenyevich — Professor at the Department of Clinical Allergology and Immunology, Faculty of General Medicine, A.I. Evdokimov Moscow State University of Medicine and Dentistry; Head of the Department of Allergology and Immunotherapy, National Research Center - Institute of Immunology, Federal Medical-Biological Agency of Russia; Doctor of Medical Sciences, Moscow.

The authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Allergists-immunologists

2. Dermatovenerologists

3. Internists

4. Pediatricians

5. General practitioners (family physicians)

6. Otolaryngologists

7. Anesthesiologists-intensivists

8. Endocrinologists;

9. Pediatric endocrinologists;

10. Rheumatologists

11. Infectious disease specialists

12. Medical students, residents, PhD students, attendees of continuing professional development courses in the specified specialties, etc.

Methods used for evidence collection/selection:

• electronic database searching.

Description of methods used for evidence collection/selection:

• the evidence base for the recommendations includes publications included in the Cochrane Library, EMBASE, and MEDLINE databases. The search depth was at least 5 years.

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

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation:

• External peer review;

• Internal expert review.

Description of the guideline validation method:

The preliminary version of these guidelines was reviewed by independent experts, who were asked to comment primarily on how accessible the interpretation of the evidence underlying the recommendations is for understanding.

Feedback was obtained from primary care physicians and district therapists regarding the clarity of the recommendations and their assessment of the recommendations as a practical tool for daily practice.

The preliminary version was also sent to a non-medical reviewer for comments from the patients' perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and the resulting changes made to the recommendations were logged. If no changes were made, the reasons for refusing to make changes were logged.

Consultation and peer review:

The draft version was posted for broad discussion on the website of the Russian Association of Allergologists and Clinical Immunologists so that all interested parties could participate in discussing and improving the recommendations.

The draft recommendations were also reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

Working Group:

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

Appendix A3.1 Regulatory and legal documents

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

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

• Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017 "On approval of criteria for assessing the quality of medical care"

• Order of the Ministry of Health of the Russian Federation No. 606n dated November 7, 2012 «On Approval of the Procedure for the Provision of Medical Care to the Population in the Profile «Allergology and Immunology»»

• Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012 «On Approval of the Procedure for the Provision of Pediatric Care»

• https://grls.rosminzdrav.ru

• Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724);

• International Statistical Classification of Diseases and Related Health Problems (ICD-10);

• Order of the Ministry of Health of the Russian Federation No. 1183n dated December 20, 2012 "On approval of the nomenclature of positions of medical and pharmaceutical workers".

• Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. "Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section: Qualification Characteristics of Positions of Healthcare Workers."

• Federal Law No. 489-FZ dated December 25, 2018 «On Amendments to Article 40 of the Federal Law «On Compulsory Medical Insurance in the Russian Federation» and the Federal Law «On the Fundamentals of Protecting Citizens' Health in the Russian Federation» Regarding Clinical Guidelines».

• Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines."

• Order of the Russian Ministry of Health No. 804n dated October 13, 2017 «On Approval of the Nomenclature of Medical Services».

• Order of the Russian Ministry of Health No. 1094n dated November 24, 2021 «On Approval of the Procedure for Prescribing Medicinal Products, Prescription Form Templates for Medicinal Products, the Procedure for Issuing Said Prescription Forms Containing Prescriptions for Narcotic Drugs or Psychotropic Substances, the Procedure for Their Manufacture, Distribution, Registration, Accounting, and Storage, as well as the Rules for Issuing Prescription Forms, Including in the Form of Electronic Documents»

• «On Approval of the Procedure for Prescribing Medicinal Products, Prescription Form Templates for Medicinal Products, the Procedure for Issuing Said Forms, Their Accounting and Storage»

• Order of the Ministry of Health and Social Development of the Russian Federation "On the procedure for the use of medicinal products in patients for vital indications" No. 494 dated August 9, 2005

• Information letter of the Russian Ministry of Health on the possibility of purchasing a medicinal product by trade name (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu).

Appendix A3.2 Key History-Taking Questions in Urticaria

1 In this case, urticaria is not a disease per se and should be regarded as a symptom of the underlying condition

Appendix A3.3 Intradermal Autologous Serum Skin Test

In patients with autoreactive (autoimmune) urticaria (in the presence of anti-FcεRI or anti-IgE autoantibodies), the intradermal autologous serum skin test (autologous serum skin test) demonstrates high sensitivity and specificity (65–81% and 71–78%, respectively), confirming its autoimmune origin. The interpretation of a positive intradermal autologous serum skin test (autologous serum skin test) involves recording wheals formed by the release of mast cell mediators and/or their direct effect on skin vessels.

This test is performed by an allergist-immunologist in an allergology department/office in an outpatient setting or in a hospital.

The procedure for the intradermal autologous serum test is as follows. Blood is drawn under sterile conditions from the cubital vein into a test tube, left at room temperature for 30 minutes, and then centrifuged for 10 minutes at 400–500 g. The prepared serum is used immediately for the test. The test is performed on the flexor surface of the forearm, excluding the wrists and areas where wheals were present in the preceding 48 hours (skin areas refractory to further mast cell activation). The distance between each injection is at least 3–5 cm. After treating the skin with an antiseptic and disinfectant preparation, the patient is injected intradermally with 50 μl (0.05 ml) of undiluted autologous serum, along with equivalent volumes of sterile normal saline (negative control) and histamine at a concentration of 10 μg/ml (positive control); the distance between each injection is 3–5 cm. Results are evaluated after 30 minutes. In addition to intradermal injection, the test methodology may include prick testing. The test is considered positive if the diameter of the hyperemic wheal is equal to or exceeds the negative control by 1.5 mm or more, provided that the histamine test is positive.

Performing the test regularly and simultaneously on both arms helps reduce the risk of error and increases the clinical value of this diagnostic tool.

However, it should be noted that diagnostic tests (both for confirming the induced and autoimmune forms) are limited in children due to the lack of standardized approaches for evaluating results in pediatric practice.

Appendix A3.4 Algorithm for the differential diagnosis of conditions accompanied by wheals and/or angioedema [adapted from 2]

1 – Along with ACE inhibitors, angiotensin II receptor blockers can also cause angioedema, albeit less frequently than ACE inhibitors

2 – A thorough family history should be taken, and the age of disease onset should be clarified

11. – Determine the level of inflammatory markers (CRP, ESR), neutrophilic infiltrates on skin biopsy, and screen for gene mutations associated with hereditary periodic fever syndromes (CAPS) if there is strong suspicion

11. – It should be clarified how long an individual urticarial lesion persists

5 – Determine the level of C4, C1 inhibitors and their function, additionally – tests for antibodies to C1q and C1 inhibitor if acquired angioedema (AAE) is suspected; search for mutations if the above tests are within normal limits but the patient's clinical picture corresponds to hereditary angioedema (HAE).

6 – If remission does not occur 6 months after ACE inhibitor discontinuation, test the C1 inhibitor

7 – Is there damage to small vessels of the papillary and reticular dermis and/or fibrinoid deposits in perivascular and interstitial locations in the biopsy specimen of the affected skin area, suggesting urticarial vasculitis?

8 – It should be clarified whether urticaria appears upon physical stimuli (heat, cold, vibration, pressure, sunlight, etc.)

9 – Consider provocation testing in a patient with suspected induced urticaria (Table 3, Appendix A3.4).

10 – Acquired autoinflammatory syndromes, incl. Schnitzler syndrome, systemic juvenile idiopathic arthritis, hereditary cryopyrin-associated periodic syndromes (CAPS): familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, neonatal-onset multisystem inflammatory disease (NOMID), much less frequently – hyper-IgD syndrome, tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

11 – Occasionally, the occurrence of recurrent angioedema is associated with neither mast cells nor bradykinin, and the pathogenetic mechanisms remain unknown, which is classified as "idiopathic angioedema".

Appendix A3.6 Key Questions to Confirm/Exclude Vasculitis in Patients

Appendix A3.7 Alternative Measures and Medications for Urticaria Treatment

Alternative interventions and medications for the treatment of urticaria*

*-These recommendations have a low level of evidence, but clinical experience shows that they may be considered in certain situations based on individual indications [2].

# - Off-label drug prescribing (outside the indications approved in the drug instructions) is carried out by decision of the medical commission, with the permission of the Local Ethics Committee of the medical organization (if any), subject to the signed informed consent of the patient who has reached the age of 15 and a legal representative (in the case of a pediatric patient)

Appendix A3.8 Explanation of notes.

…** – 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 2020, as well as lists of drugs for medical use and the minimum assortment of drugs required for medical care" (as amended by Orders of the Government of the Russian Federation No. 3073-r dated November 23, 2020 and No. 3781-r dated December 23, 2021 "On amendments to Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019).

...# - off-label use (outside the indications approved in the drug instructions) is carried out by decision of the medical commission, with the permission of the Local Ethics Committee of the medical organization (if any), subject to the signed informed consent of the patient who has reached the age of 15 and a legal representative (in the case of a pediatric patient).

Appendix B. Physician Action Algorithms

Appendix B1. Management algorithm for a patient with chronic urticaria [adapted from 2].

Appendix C. Patient Information

1. To prevent recurrences of urticaria, patients should avoid exposure to triggering factors: heat, cold, physical exertion, skin friction.

2. Patients with chronic recurrent and physical urticaria are advised to practice gentle skin care using specialized cleansers adapted for sensitive skin.

3. Patients with cholinergic urticaria should avoid intense physical exertion.

4. Patients with delayed pressure urticaria should avoid pressure on the skin.

5. In case of contact urticaria, contact with triggering factors should be avoided.

DIETARY FEATURES FOR PATIENTS WITH CHRONIC SPONTANEOUS URTICARIA

1. Basic nutrition is selected individually, taking into account food tolerance.

2. It is recommended to keep a diary with mandatory daily recording of urticaria symptoms (pruritus index, rashes, presence and localization of angioedema).

3. In case of food allergy, an elimination diet is prescribed with the exclusion of identified food allergens.

4. Food allergens as a cause of CSU are rarely identified, more commonly in children. These include common foods – milk, nuts, eggs, fish, peanuts, shellfish, wheat, and soy ("big eight"). In recent years, sesame, celery, and lupine (whose beans replace soy) have been added to this list.

5. In the absence of food allergy, products with special properties are restricted (foods with a high histamine content; histamine liberators that release histamine in the body; certain others). Diets restricting these groups of food products that are not allergens are called low-histamine diets or "pseudoallergen-free" diets.

1. Foods with a high histamine content –

   1. Native — tomatoes, spinach; meat (beef, veal, pork); pork liver; chicken; fresh and frozen fish (tuna, salmon, mackerel, saury, mackerel pike); fresh seafood;

   2. canned — pork ham, beef sausages; fermented cheeses; fermented drinks; sauerkraut; canned tuna; canned anchovies (sprats); canned and smoked herring and caviar;

   3. soybean paste, red pepper paste, mayonnaise, yogurt, cheese, ketchup, wine and beer, which contain a high amount of histamine.

2. Food products — histamine liberators

   1. strawberries, chocolate, egg white; pork; cinnamon; papaya; legumes (peas, soy, lentils, beans, peanuts) due to the lecithin present;

   2. instant foods release histamine;

   3. grapes, bananas, strawberries and citrus fruits (lemons, oranges, mandarins), pineapples, tomatoes, nuts, alcoholic beverages including wine, green tea, and chocolate.

3. Others.

   1. Food additives (E-100-E-518): azo dyes (E102-124), benzoate preservatives (E210-219), gelling agents, leavening agents, humectants, emulsifiers, flavor enhancers, antioxidants, anti-caking agents, sweeteners, baking ingredients, flavor enhancers, modified starches, antifoaming agents, stabilizers, flavorings. Some of these are part of chewing gum, lozenges, and similar products.

   2. Natural salicylates, tartrazine;

   3. Unidentified aromatic substances in tomatoes, white wine, herbs.

List of preferred foods:

Lean beef, boiled; cereal and vegetable soups (vegetarian, on secondary beef broth); olive oil, sunflower oil; boiled potatoes; porridges (buckwheat, oatmeal, rice); natural plain yogurts, cottage cheese, fermented baked milk, kefir; white rennet cheeses; fresh cucumbers, parsley, dill; baked apples; tea, sugar, decaffeinated coffee; dried fruit compote, except raisins; whole grain bread, crispbreads.

Only fresh, unpreserved or freshly frozen foods are used.

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

Assessment of disease activity

Assessment of spontaneous urticaria activity is a unified scoring system [58, 197]. UAS 7 (Urticaria Activity Score 7) is the Urticaria Activity Index used to assess disease severity and treatment outcomes for spontaneous urticaria. UAS 7 involves a cumulative scoring of the main symptoms of the disease (number of wheals and itch intensity) by the patient every 24 hours for 7 consecutive days (Appendix G1). This assessment is convenient for both the patient and the physician and allows for an objective evaluation of the patient's condition and individual response to therapy [19].

This activity scoring cannot be used to assess the activity of physical urticaria and isolated angioedema.

An important tool for assessing the course of the disease and treatment efficacy is the Urticaria Control Test. It can be used to assess disease control over the past 4 weeks in patients with chronic spontaneous and inducible urticaria. It requires answering 4 questions concerning the control of disease symptoms, impact on quality of life, treatment efficacy, and overall disease control. Each answer is scored from 0 to 4. The maximum total score for answering the questions is 16, which demonstrates complete disease control. The cutoff value is 12 points. A score of UCT ≤ 11 indicates uncontrolled chronic urticaria (Appendix G2) [19, 198, 199].

For patients with angioedema, the AAS test (Angioedema Activity Score) has been developed (Appendix G 3) [200]. The quality of life of a patient with chronic urticaria is assessed using the Dermatologic Life Quality Index (DLQI) questionnaire (Appendix G4).

Appendix G1. 7-Day Urticaria Activity Score (UAS 7)

Russian title: Urticaria Activity Score 7 (UAS 7) for 7 days

Original title: Urticaria Activity Score 7 (UAS 7)

Source (official developer website, validation publication): Hawro T, Ohanyan T, Schoepke N, Metz M, Peveling-Oberhag A, Staubach P, Maurer M, Weller K. The Urticaria Activity Score-Validity, Reliability, and Responsiveness. J Allergy Clin Immunol Pract. 2018 Jul-Aug;6(4):1185-1190.e1

Zuberbier T., et.al. Pseudoallergen-free diet in the treatment of chronic urticaria. A prospective study. Acta Derm Venrol.1995 Nov;75(6):484-7. Zuberbier T, Abdul Latiff AH, Abuzakouk M, Aquilina S, Asero R, Baker D, Ballmer-Weber B, Bangert C, Ben-Shoshan M, Bernstein JA, Bindslev-Jensen C, Brockow K, Brzoza Z, Chong Neto HJ, Church MK, Criado PR, Danilycheva IV, Dressler C, Ensina LF, Fonacier L, Gaskins M, Gáspár K, Gelincik A, Giménez-Arnau A, Godse K, Gonçalo M, Grattan C, Grosber M, Hamelmann E, Hébert J, Hide M, Kaplan A, Kapp A, Kessel A, Kocatürk E, Kulthanan K, Larenas-Linnemann D, Lauerma A, Leslie TA, Magerl M, Makris M, Meshkova RY, Metz M, Micallef D, Mortz CG, Nast A, Oude-Elberink H, Pawankar R, Pigatto PD, Ratti Sisa H, Rojo Gutiérrez MI, Saini SS, Schmid-Grendelmeier P, Sekerel BE, Siebenhaar F, Siiskonen H, Soria A, Staubach-Renz P, Stingeni L, Sussman G, Szegedi A, Thomsen SF, Vadasz Z, Vestergaard C, Wedi B, Zhao Z, Maurer M. The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. 2022 Mar;77(3):734-766.

Type: index

Purpose: retrospective assessment of spontaneous urticaria activity in patients older than 18 years.

Content (template):

Patient Urticaria Diary

Full Name ____________________________ Sex _________ Age _____________ Date of initiation ____________

This calendar will help you assess the course of your urticaria and identify factors/triggers that cause or worsen your symptoms.

Please record daily, once a day (for the past 24 hours):

1) approximately how many wheals appeared;

2) how severe the skin itching was;

3) symptoms — indicate the cumulative severity of manifestations;

4) whether you took medications for urticaria (and when);

5) indicate the triggers of manifestations

Assessment of urticaria activity

Values can range from 0 to 21 points per week for itching and from 0 to 21 per week for the number of wheals. The total UAS7 score per week can range from 0 to 42 points. Severe chronic urticaria corresponds to 28–42 points; moderate to 16–27 points; mild to 7–15 points; 0 — absence of symptoms.

Notes: This assessment is convenient for both the patient and the physician and allows for an objective evaluation of the patient's condition and individual response to therapy.

This assessment is convenient for both the patient and the physician and allows for an objective evaluation of the patient's condition and individual response to therapy. Not applicable for assessing angioedema or inducible urticaria.

Appendix G2. Angioedema Activity Score (AAS)

Russian title: Angioedema Activity Score (AAS)

Original title: AAS (Angioedema Activity Score)

Source (official developer website, validation publication): copyright: Moxie GmbH (www.moxie-gmbh.de). Weller K, Groffik A, Magerl M, Tohme N, Martus P, Krause K, Metz M, Staubach P, Maurer M. Development, validation, and initial results of the Angioedema Activity Score. Allergy 2013; DOI: 10.1111/all.12209.

Type: rating scale

Purpose: assessment of angioedema activity in adult patients, retrospective (over 4 weeks).

Content (template):

The AAS scale consists of 5 questions.

The AAS scoring system is very simple.

The answer to the first question carries no points and is not included in the calculation of AAS values.

Appropriate time intervals (first question) are marked with the number "1", followed by ratings corresponding to scores from 0 to 3.

Angioedema Activity Score.

Patient's Full Name_________________________________________________________________

Date of completion (DD.MM.YYYY)______________________________________________________

Please record complaints for the past 24 hours once a day in the tables below. Please provide complete answers to all questions.

Key (interpretation):

The AAS scale consists of 5 questions.

The AAS scoring system is very simple.

Values between 0 and 3 are calculated for each item that can be marked by the patient. All items marked by the patient are summed.

Accordingly, the minimum and maximum AAS scores are 0 and 15.

The answer to the first question carries no points and is not included in the AAS calculation. Please find the values for each item in the form below.

This form should only be used by medical personnel to calculate AAS scores.

Patients must not view this form.

Notes: designed for retrospective assessment of angioedema activity in patients over 18 years of age over a 4-week period.

Angioedema Activity Score over 4 weeks (AAS 28). An AAS 28 score of less than 25 corresponds to mild disease, 25–75 to moderate, and greater than 75 to severe disease.

Appendix G3. Urticaria Control Test (UCT)

Russian title: Urticaria Control Test (UCT)

Original title (if applicable): Urticaria Control Test

Source (official developer website, validation publication): Weller K, Groffik A, Church MK, Hawro T, Krause K, Metz M, Martus P, Casale TB, Staubach P, Maurer M. Development and validation of the Urticaria Control Test: a patient-reported outcome instrument for assessing urticaria control. J Allergy Clin Immunol. 2014 May;133(5):1365-72, 1372.e1-6.

Type: other (test)

Purpose: Assessment of symptom control in spontaneous and inducible urticaria in adult patients.

Content (template):

Base your answers on how you have felt over the past 4 weeks

Key (interpretation):

Each answer is scored from 0 to 4. The maximum total score of 16 indicates complete disease control. The threshold value is 12 points. A UCT score ≤ 11 indicates uncontrolled chronic urticaria.

Notes:

Used for retrospective assessment of symptom control in spontaneous and inducible urticaria.

Appendix G4. Dermatology Life Quality Index (DLQI) questionnaire for patients aged 16 years and older

Russian title: Dermatology Life Quality Index Questionnaire (DLQI)

Original title (if applicable): Dermatology Life Quality Index (DLQI)

Source (official developer website, validation publication): Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)–a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210–216. doi: 10.1111/j.1365-2230.1994.tb01167.x. [PubMed], Finlay AY, Khan GK. Dermatology Life Quality Index. http://www.bad.org.uk. Accessed Apr 1992. https://en.wikipedia.org/wiki/Dermatology_Life_Quality_Index, Lennox RD, Leahy MJ. Validation of the Dermatology Life Quality Index as an outcome measure for urticaria-related quality of life. Ann Allergy Asthma Immunol. 2004 Aug;93(2):142-6. doi: 10.1016/S1081-1206(10)61466-4. PMID: 15328673. Copyright belongs to Finlay AY and Khan GK. Partial or full use of this material is permitted only with the author's permission

Type: other: questionnaire

Purpose: Assessment of quality of life in patients with dermatological diseases

Content (template):

Center ID: _____________________________________________________

Patient ID: ___________________________________________________

Doctor's Full Name: _____________________________________________________

Date of completion (DD.MM.YYYY): ________________________________________

Visit No.

The aim of this questionnaire is to measure how much your skin problem has affected your life OVER THE LAST WEEK. Please tick 􀀵􀀵 one box for each question.

1. Over the last week, how much itchy, sore, painful or stinging was your skin?

Very severely

Severely

Not at all a little

2. Over the last week, how embarrassed or self-conscious have you been because of your skin?

Very severely

Severely

Slightly

Not at all

3. Over the last week, how much did your skin interfere with you going shopping or looking after your home or garden?

Very severely

Severely

Slightly

Not at all

Not applicable

4. Over the last week, how much did your skin influence the clothes you wore?

Very severely

Severely

Slightly

Not at all

Not applicable

5. Over the last week, how much did your skin affect any social or leisure activities?

Severely

Slightly

Not at all

Not applicable

6. Over the last week, how much did your skin make it difficult to do any sport?

Severely

Slightly

Not at all

Not applicable

7. Over the last week, has your skin condition completely prevented you from working or studying?

Yes

No

Not applicable

8. Over the last week, how much did your skin condition cause problems with your partner, close friends, or relatives?

Very severely

Severely

Slightly

Not at all

Not applicable

9. Over the last week, how much was your skin condition the cause of any sexual problems?

Very severely

Severely

Slightly

Not at all

Not applicable

10. Over the last week, how much did the treatment for your skin condition cause you difficulties, such as creating a mess at home or taking up your time?

Very severely

Severely

Slightly

Not at all

Not applicable

Please check if you have answered EVERY question. Thank you.

Signature _________________________

Key (Interpretation) and Explanations

Scoring the impact on quality of life: 3 points – very much, 2 points – quite a lot, 1 – a little, 0 points – no effect on quality of life. The maximum possible total score is 30. Interpretation of question 7: yes – 3 points, no – 0 points.

Total score: 0–1 points – no effect on the patient's quality of life, disease under control; 2–5 points – small effect; 6–10 points – moderate impairment of quality of life; 11–20 points – very large effect on quality of life; 21–30 points indicates an extremely large effect on the patient's life.