Hereditary Epidermolysis Bullosa: Clinical Guidelines

List of Abbreviations

ICD – International Classification of Diseases

EBS – epidermolysis bullosa simplex

EBS – epidermolysis bullosa simplex

DEB – dystrophic epidermolysis bullosa

JEB – junctional epidermolysis bullosa

DDEB – dominant dystrophic epidermolysis bullosa

RDEB – recessive dystrophic epidermolysis bullosa

IIF – indirect immunofluorescence

Terms and Definitions

Congenital epidermolysis bullosa is a phenotypically and genetically heterogeneous group of genodermatoses characterized clinically by blisters arising on the skin and mucous membranes after minor mechanical trauma due to genetically determined defects in structural skin proteins that provide intraepidermal or dermoepidermal adhesion.

Lamina densa is an ultrastructural component of the basement membrane produced by basal keratinocytes, consisting predominantly of type IV collagen and type VII collagen.

Lamina lucida is an ultrastructural component of the basement membrane located between the lamina densa and the overlying basal keratinocytes.

Desmoplakin is a hemidesmosomal protein that provides a connection between the desmosomal plaque and keratin filaments.

Integrin α6β4 is a structural protein involved in the formation of hemidesmosomes.

Keratins 5 and 14 are type II keratin proteins that form intermediate filaments.

Kindlin is a structural protein expressed in focal adhesion sites, in the cytoplasm and nucleus of keratinocytes, and involved in keratinocyte migration, proliferation, and adhesion.

Type VII collagen is a structural protein of the skin that serves as the major component of anchoring fibrils and takes part in the adhesion of keratinocytes to the basement membrane.

Type XVII collagen (BP180, BPAG2, or bullous pemphigoid antigen 2) is a structural protein with a molecular weight of 180 kDa belonging to the non-fibrillar transmembrane collagen subfamily; it is a component of hemidesmosomes and participates in the adhesion of keratinocytes to the underlying basement membrane in stratified, pseudostratified, and transitional epithelium.

Laminin-332 is a structural protein connecting the basal keratinocytes of the epidermis and the dermis through specific interaction with integrin α6β4 in the hemidesmosome region and with type VII collagen on the dermal side.

Plakophilin-1 is a protein involved in maintaining the stability of the desmosomal plaque.

Plectin is a structural hemidesmosomal protein that links intermediate filaments.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Congenital epidermolysis bullosa is a phenotypically and genetically heterogeneous group of genodermatoses, the main clinical manifestation of which is blistering occurring after minor mechanical trauma to the skin and mucous membranes due to genetically determined defects in structural skin proteins that provide intraepidermal or dermoepidermal junctions.

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

The development of congenital epidermolysis bullosa (EB) is caused by mutations in genes encoding structural skin proteins that provide the connection between the epidermis and the dermis. To date, more than 1,000 mutations in 20 structural skin protein genes have been identified that can lead to the development of various clinical types of congenital epidermolysis bullosa [1, 2].

Mutations are associated with impaired protein synthesis: absence of the protein, synthesis of a functionally defective protein, or synthesis of a protein with structural abnormalities that facilitate access of proteases, leading to its rapid degradation.

Proteins associated with the development of the disease include keratins 5 and 14, desmoplakin, plakophilin-1, plectin, integrin α6β4, laminin-332, types VII and XVII collagens, and kindlin. These proteins have different localization in the skin: keratins 5 and 14 are localized in keratinocytes; integrin α6β4, laminin-332, and type XVII collagen are located within the lamina lucida of the basement membrane; type VII collagen is located beneath the lamina densa of the basement membrane; and kindlin is located at various levels of the epidermis.

1.3 Epidemiology of the Disease or Condition

According to estimates, the prevalence of congenital epidermolysis bullosa across 60 of the 85 constituent entities of the Russian Federation in 2016 was 3.9 per million population, and the incidence in 2016 was 0.33 per million population [3].

In most countries of the world, epidermolysis bullosa simplex predominates in the disease structure, while in a number of countries dystrophic epidermolysis bullosa predominates; the junctional type of the disease is diagnosed less frequently [4]. In the Russian Federation in 2016, a predominance of patients with simple and dystrophic congenital epidermolysis bullosa was noted (48% and 24%, respectively) [3]. Gender differences are not characteristic of congenital epidermolysis bullosa. Minors predominate among registered patients, which is due to the mortality of patients with severe EB before reaching adulthood and the lack of medical care-seeking by adult patients with a mild form of the disease.

1.4 Features of Coding the Disease or Condition

Q81 – Epidermolysis bullosa

Q81.0 – Epidermolysis bullosa simplex

Q81.1 – Epidermolysis bullosa letalis

Herlitz syndrome

Q81.2 – Epidermolysis bullosa dystrophica

Q81.8 – Other epidermolysis bullosa

Q81.9 – Epidermolysis bullosa, unspecified

1.5 Classification of the disease or condition

In 2020, the classification of congenital epidermolysis bullosa proposed in 2008 and revised in 2014 was updated [5, 6]. According to the 2020 classification revision, 4 main types of the disease are distinguished: epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), dystrophic epidermolysis bullosa (DEB), and Kindler syndrome (Table 1).

Table 1. Classification of congenital epidermolysis bullosa (2020 Revision) [5].

Epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), and dystrophic epidermolysis bullosa (DEB) are divided into clinical subtypes (Tables 2–4).

Table 2. Clinical subtypes of EBS [5]

Table 3. Clinical subtypes of junctional JEB [5]

Table 4. Clinical subtypes of dystrophic DEB [5]

Note: bold type indicates the most common subtypes

Within the main subtypes, about 30 clinical forms of the disease are distinguished. The classification of inherited epidermolysis bullosa also takes into account the levels of the skin at which blisters form.

1.6 Clinical presentation of the disease or condition

The main clinical sign of any type of inherited epidermolysis bullosa is the appearance of blisters upon minor mechanical trauma. All clinical forms of epidermolysis bullosa simplex are characterized by hemispherical, tense, fluid-filled blisters that occur more frequently in friction and trauma areas. In junctional and dystrophic epidermolysis bullosa, blisters are flaccid, with a folded blister roof hanging under the weight of the fluid, easily ruptured, and forming not only in trauma-prone areas but also in skin stretching areas (axillary and inguinal folds, neck). Multiple blisters and erosions with a large affected area can be observed in any subtype of the disease, whereas single ones occur predominantly in epidermolysis bullosa simplex subtypes. The formation of milia on the skin is intrinsic to any type of the disease, and pigmented nevi are characteristic of the recessive dystrophic subtype. Prolonged healing of erosions is observed in all junctional and dystrophic subtypes of the disease. Given the traumatic origin of erosive skin defects in patients with inherited epidermolysis bullosa, these defects can be considered as abrasions that may transform into slow-healing infected wounds, which morphologically represent ulcerated skin lesions. This is most characteristic of the junctional and dystrophic subtypes of the disease. Often, the surface of long-standing erosive and ulcerative skin defects is covered with pus due to secondary infection. In severe cases, widespread infected skin lesions are observed. The development of exuberant granulations within the ulcer base is possible, which is more characteristic of junctional inherited epidermolysis bullosa. Skin appendages—hair and nails—may be affected.

Inherited epidermolysis bullosa is characterized by the development of extracutaneous complications, the frequency, nature, and severity of which are determined by the disease subtype. The oral cavity and teeth, eyes, heart, respiratory system, gastrointestinal tract, genitourinary system, and musculoskeletal system may be affected.

Patients with inherited epidermolysis bullosa often develop nutritional deficiency associated with increased energy demand, gastrointestinal tract involvement, and malabsorption syndrome, accompanied by protein-energy malnutrition, hypovitaminosis A, B, C, D, E, micro- and macroelement deficiency, anemia, growth and developmental delay, including delayed puberty. The most frequent manifestations of the disease involving the gastrointestinal tract are esophageal strictures and stenoses, anal fissures, constipation accompanied by fecal impaction, and intestinal perforation. Infectious complications leading to sepsis and the development of malignant neoplasms are possible [7, 8]. Severe infectious complications (pneumonia and sepsis) are one of the frequent causes of death in infants and young children with junctional inherited epidermolysis bullosa. Aggressive cutaneous squamous cell carcinoma developing at the age of 15–30 years is the main cause of death in patients with recessive dystrophic inherited epidermolysis bullosa.

Patients suffering from any subtype of inherited epidermolysis bullosa complain of the formation of blisters and/or erosions on the skin and mucous membranes, which may be accompanied by pain and pruritus.

It has been shown that pruritus in inherited epidermolysis bullosa can be of allergic origin, representing an allergic reaction, usually to food products [9].

Epidermolysis bullosa simplex, generalized severe (Köbner)

The disease begins at birth or in the first months of life. This subtype is characterized by the formation of multiple generalized blisters. The first blisters usually occur on the feet, less often on other parts of the limbs, neck, back, and buttocks. The most pronounced clinical manifestations of the disease are recorded in the age period up to 1 year; subsequently, the skin condition stabilizes, with worsening observed in summer and significant improvement in winter. In early childhood, hyperkeratotic patches appear on the soles, along with palmoplantar hyperhidrosis, which persist into adulthood. During puberty and menopause, an improvement in the skin condition is observed.

Epidermolysis bullosa simplex, localized (Weber-Cockayne)

The initial appearance of blisters is usually observed on the feet and is associated with the onset of walking, but may occur earlier. Subsequently, blisters appear on the hands, and their formation is always associated with trauma. Epithelialization of blisters occurs with the formation of milia.

Progression of the disease is observed up to 4–5 years of age, followed by a gradual improvement of the skin condition. Plantar hyperkeratosis develops up to 10 years of age; during puberty, hyperhidrosis and thickening of the toenails appear or intensify.

Epidermolysis bullosa simplex herpetiformis (Dowling-Meara)

Multiple generalized blisters on the skin and oral mucosa appear from birth or during the first week of life and have no clear association with trauma. A tendency to grouping (herpetiform arrangement) and secondary pigmentation are observed from 3–6 months of age. Progression of the disease is observed up to 1 year of age, followed by stabilization of the process and gradual improvement up to the complete cessation of blister formation or their rare appearance due to mechanical trauma. Plantar hyperkeratosis and nail changes develop from the first years of life. From 2 years of age, the seasonality of exacerbations becomes distinct—worsening in summer and improvement in winter; in some patients, the resolution of rashes is recorded during fever.

Patients also experience extracutaneous manifestations of the disease: constipation, anal fissures, respiratory distress, pallor, weakness, dizziness, esophageal reflux, anemia. Basal cell carcinoma of the skin may occur in adults.

Generalized severe junctional epidermolysis bullosa (Herlitz lethal)

The disease is characterized by the appearance and spread from birth or the first days of life of flaccid, multiple, rapidly rupturing blisters and/or erosions on the skin and mucous membranes, the formation of granulations on the distal phalanges of the fingers and toes with complete loss of nail plates, in the perioral and periumbilical areas, and in the occipital and sacral regions. Quite often at birth, aplasia cutis, involvement of the glottis and subglottic space accompanied by hoarseness, premature dentition, nail deformities, or anonychia are observed.

Extracutaneous manifestations of the disease include growth and developmental delay, respiratory disorders, anemia, and less commonly, gastroenteritis, pneumonia, and sepsis. Laryngotracheal lesions are the most severe. Death in early childhood is associated with the development of sepsis, respiratory failure, and multiple organ failure.

Generalized intermediate junctional epidermolysis bullosa (non-Herlitz)

The first blisters appear from birth or the first days of life, predominantly on the hands and feet, as well as on mucous membranes, spreading to other parts of the body. Blisters are flaccid, multiple, rapidly rupturing with the formation of erosions. After the replacement of primary teeth with permanent ones, enamel hypoplasia and "pitted" depressions in it are discovered.

Subsequently, the condition of the skin and mucous membranes improves, and skin erosions epithelialize with the formation of superficial atrophy. Sometimes only the hands and feet remain affected. The development of onychodystrophy and nail loss, as well as alopecia, is possible. The disease may be accompanied by protein-energy malnutrition, aggravated by gastrointestinal involvement in the form of oral erosions and constipation. Cases of localized involvement of the hands and feet with nail dystrophy and enamel hypoplasia without serious health impairments have been described. A distinguishing feature of the disease from mild recessive subtypes of dystrophic epidermolysis bullosa is dental enamel hypoplasia and pits in it.

Junctional epidermolysis bullosa with late onset

Blisters and erosions appear not from birth, but in childhood or young adulthood.

In addition to typical blisters and erosions, predominantly located on the hands and feet, and less frequently on the elbows, knees, and in the oral cavity, onychodystrophy or anonychia is noted, along with hyperhidrosis, amelogenesis imperfecta (improper or defective development of tooth enamel), loss of dermatoglyphics, and slowly progressive skin atrophy.

Erosions heal with scarring atrophy, which, when localized on the oral mucosa, leads to microstomia and ankyloglossia. Corneal erosions and opacification, as well as symblepharon, are also frequently observed. Over time, diffuse alopecia develops, and in adults, squamous cell carcinoma of the skin.

Extracutaneous manifestations of the disease include growth and developmental retardation, respiratory disorders, anemia, and less commonly, gastroenteritis, pneumonia, and sepsis. Laryngotracheal involvement has the most severe course. Fatal outcomes in the first months and years of life are associated with respiratory failure, pneumonia, sepsis, and malnutrition. Patients who survive the early years of life subsequently suffer from dysphagia, esophageal strictures, genitourinary system anomalies, urethral strictures, laryngeal stenosis, breathing difficulties, and anemia.

Dominant dystrophic epidermolysis bullosa congenita

Only in a small number of patients do blisters on the skin and oral mucosa appear from birth, while in the majority they appear from the first month of life. Blisters are typically located in areas of pressure and friction, but may also appear spontaneously on any skin areas, most frequently in acral zones. From the second year of life, spontaneous blister formation ceases, and by 4–5 years of age, blisters appear only after significant trauma. Milia and pigmented nevi form on healed skin areas. The appearance of rashes on the oral mucosa becomes rare or completely ceases by 9–10 years of age. Skin condition stabilizes during puberty and remains unchanged in subsequent years. In rare cases, blister formation ceases by 12–13 years. Whitish areas of shagreen skin in the form of papules and plaques on the back along the spine, on the neck, chest, and lower back are noticeable in some patients after 10–16 years. Nail involvement progresses with age.

Nail plates lost during the first years of life due to blister formation beneath them do not regenerate, although the contours of the nail beds are not smoothed out; the remaining nail plates become small in size (micronychia), grayish-yellow, and thickened. In some patients, whitish areas of "shagreen skin" in the form of papules and plaques may be observed on the back along the spine, on the neck, chest, and lower back.

Extracutaneous manifestations of the disease include dysphagia, esophageal strictures, constipation, and anal fissures.

Recessive dystrophic epidermolysis bullosa, severe generalized (Hallopeau-Siemens)

The disease begins at birth (many patients are born with an absence of the epidermis on the hands and/or feet), less commonly from the first days of life. Mucosal involvement is also observed from the first days of life.

It is characterized by the appearance of multiple flaccid blisters and erosions that rapidly increase in size. Nikolsky's sign is sharply positive. Healing of erosions is slow—ranging from 3–4 days (for small erosions) to several months; the epithelialization process worsens with age. After healing, scarring atrophy of the skin is noted, with scar formation in skin folds restricting movement. Pseudosyndactyly and finger contractures develop from the first months and years of life; their progression hinders the growth and development of the hands and feet, impairing self-care and mobility. During puberty, stabilization of skin manifestations is noted.

Children lag behind in psychomotor, physical, and sexual development. By adolescence, intellectual development evens out, but extreme emaciation, low height and weight, reduced mobility persist, and body hair growth is absent after puberty.

When erosions are present on the ocular mucosa, the frequency of erosive episodes decreases with age; erosions heal with cloud-like corneal opacification and symblepharon. Healing of oral erosions results in scarring with the development of microstomia, obliteration of the vestibular folds, ankyloglossia, flattening of the lingual papillae, and a peculiar speech defect; healing of erosions in the pharynx and esophagus leads to dysphagia, esophageal strictures and stenosis, and esophageal reflux; healing of erosions in the rectum results in anal stenosis with difficult defecation. Patients experience dental caries and dental malposition, as well as partial or complete tooth loss. The genitourinary system is frequently affected, with the formation of urethral and vaginal strictures, and renal failure is observed. The musculoskeletal system is affected, presenting with myalgia, arthralgia, osteoporosis, and flexion contractures of the fingers leading to deformities of the hands and feet. Progressive hypochromic anemia and an elevated ESR are observed in all patients.

In the third to fourth decades of life, rapidly metastasizing squamous cell carcinoma of the skin develops in the area of chronic skin ulcers and/or on scars.

Recessive dystrophic epidermolysis bullosa inversa

Blisters on the skin and mucosa appear from the first week of life; from 2–6 years of age, rashes localize to the typical sites for this subtype—predominantly in the folds, proximal extremities, neck, and trunk. Involvement of the hands and feet is minimal, although some nails are lost in childhood. Healing of erosions in the oral cavity and esophagus with scarring is characteristic, leading to microstomia, ankyloglossia, and esophageal strictures. The same processes on other mucous membranes cause diarrhea or constipation, micturition disorders, corneal opacity, symblepharon, and vaginal strictures.

Disease progression is accompanied by the appearance of multiple flaccid blisters and erosions that rapidly increase in size. Nikolsky's sign is sharply positive. Healing of erosions is slow—ranging from 3–4 days (for small erosions) to several months; the epithelialization process worsens with age. After healing, scarring atrophy of the skin is noted, where scar formation in physiological folds may be accompanied by the development of contractures that restrict movement. Pseudosyndactyly and finger contractures develop from the first years of life; their progression hinders the growth and development of the hands and feet, and impairs self-care and mobility.

Children lag in physical and sexual development due to nutritional deficiency, chronic inflammatory processes, and elevated energy metabolism.

The disease is characterized by the frequent development of complications affecting many organs and systems: ocular involvement, oral mucosal involvement with the development of microstomia and ankyloglossia, dental-jaw system involvement with impaired tooth eruption, upper and lower gastrointestinal tract involvement with the development of esophageal strictures and stenosis, constipation, and rectal fissures. Genitourinary system involvement is common, characterized by urethral strictures and secondary renal damage accompanied by renal failure. Musculoskeletal complications are characterized by the development of pseudosyndactyly and large joint contractures, which impair patient self-care. A frequent complication of this disease type is the development of severe resistant hypochromic anemia and secondary hematologic complications.

At the age of 15–25 years, rapidly metastasizing squamous cell carcinoma of the skin develops in the area of chronic skin ulcers and/or on scars.

In adults, skin involvement is less extensive, observed predominantly in the folds and ending in scarring that restricts movement. Diffuse alopecia develops with age, up to complete baldness. Mucosal involvement progresses with age: persistent dysphagia is observed. In the third to fourth decades of life, rapidly metastasizing squamous cell carcinoma of the skin develops in the area of chronic skin ulcers and/or on scars.

Hearing impairment occurs due to narrowing of the external auditory canal. Delayed puberty and absence of body hair growth after puberty are noted.

Pruriginous dystrophic epidermolysis bullosa

The disease begins at birth or in early childhood, in isolated cases from the onset of puberty.

The disease is characterized by mild blister formation, predominantly on the extremities; after erosion healing, cicatricial skin atrophy and milia remain. The predominantly acral distribution of rashes in children is replaced with age by an almost exclusive involvement of the lower legs and rare blistering, as scratching the skin immediately causes erosions (positive Nikolsky sign). In adults, lichenoid papules and plaques, prurigo-like nodular eruptions, and onychodystrophy develop on the lower legs. Exceptionally severe pruritus triggers blistering, excoriations, and milia.

Kindler syndrome

Typical clinical manifestations of Kindler syndrome develop from birth and include blistering of the skin and mucous membranes, subsequent scarring leading to cicatricial deformities, contractures, pseudosyndactyly, microstomia and ankyloglossia, progressive poikiloderma, photosensitivity, stenosing processes of the gastrointestinal and urogenital tracts in the form of esophageal, ureteral, and vaginal strictures, dental and jaw pathology (impaired tooth eruption, caries, periodontitis, bleeding and structural weakness of the gums and/or their swelling, progressive loosening and painless loss of permanent teeth up to complete adentia). Nail dystrophies (thinning, curvature, dorsal pterygium), lower eyelid ectropion, palmoplantar keratoderma, pseudoainhum (circular fibrous bands of the digits leading to spontaneous amputation), lip leukokeratosis, sweating disorders (anhidrosis or hypohidrosis), and skeletal anomalies are frequently observed. In adulthood, patients with Kindler syndrome have an increased risk of developing squamous cell carcinoma of the skin and mucous membranes.

Other subtypes of inherited epidermolysis bullosa are extremely rare.

Clinical manifestations of inherited epidermolysis bullosa may vary even within the same mutation and resemble each other across different mutations in various genes.

With any type of inherited epidermolysis bullosa, the development of anemia, protein, and electrolyte metabolism disorders is possible. The development of these disorders is more likely with widespread skin involvement and in cases of oral cavity and gastrointestinal tract lesions, which contribute to nutritional deficiency in patients with decreased serum levels of total protein, albumin, iron, ferritin, transferrin, and altered serum urea and creatinine levels.

Skin and mucosal integrity breaches present in any type of inherited epidermolysis bullosa contribute to the development of infectious complications affecting the skin, oral mucosa, gastrointestinal tract, urogenital system, and in severe cases, sepsis.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnosis of inherited epidermolysis bullosa is based on the correlation of anamnestic data, clinical presentation, and the results of pathomorphological examinations of skin biopsy material.

Criteria for establishing the diagnosis/condition:

1) anamnestic data: onset of the disease from birth or in the first months or years of life, the relationship between skin trauma and the appearance of blistering eruptions, possible presence of a similar disease in relatives (taking into account the inheritance type—autosomal recessive or autosomal dominant—and varying gene penetrance, due to which two relatives may have different disease severity, from mild to severe).

2) Physical examination demonstrates the characteristics of the rashes, whose primary morphological element is a blister, the specific localization of the rashes, involvement of skin appendages, teeth, and internal organs in various clinical forms of inherited epidermolysis bullosa.

3) Pathomorphological examination of skin biopsy (surgical) material is performed for the differential diagnosis of inherited epidermolysis bullosa with other bullous skin diseases, as well as for diagnosing disease complications, such as squamous cell carcinoma of the skin. To diagnose disease subtypes, it is necessary to perform a pathomorphological examination of skin biopsy (surgical) material using immunofluorescence methods, which evaluates the binding of antibodies to structural skin proteins in the basement membrane zone. A decrease in intensity or absence of antibody binding to a specific protein indicates impaired its production. The disease subtype can also be determined by examining the skin biopsy specimen using transmission electron microscopy.

4) Molecular genetic testing methods are necessary to identify the mutant gene.

Considering that the clinical manifestations of inherited epidermolysis bullosa can vary even in the case of a single mutation and be similar in mutations of different genes, determining the disease subtype requires pathomorphological examination of skin biopsy material using immunofluorescence methods.

2.1 Complaints and Anamnesis

Complaints and medical history are described in the section "Clinical Presentation".

2.2 Physical Examination

Physical examination findings are described in the section "Clinical Presentation".

2.3 Laboratory Diagnostics

Laboratory diagnostic methods are necessary to detect complications of inherited epidermolysis bullosa and monitor their therapy.

Comments: patients with inherited epidermolysis bullosa may develop anemia.

Comments: the frequency of monitoring is determined individually, but at least once a year, and more frequently if clinically indicated. The recommended list for annual screening is formed based on expert consensus and the pathogenesis of EB, considering the high risk of specific systemic complications.

Assessment of nutritional status and metabolism to diagnose protein-energy malnutrition and identify micronutrient deficiencies caused by impaired nutrition due to GI tract involvement, malabsorption, and chronic inflammation:

- determination of total protein level in blood,

- determination of albumin level in blood,

- determination of serum transferrin level in blood,

- determination of urea level in blood,

- determination of creatinine level in blood,

- determination of serum iron level in blood,

- determination of ferritin level in blood,

- determination of total calcium level in blood,

- determination of 25-OH vitamin D level in blood.

Assessment of liver function and hepatotoxicity risk to monitor potential drug-induced liver injury during ongoing pharmacotherapy:

- determination of aspartate aminotransferase level in blood,

- determination of alanine aminotransferase level in blood,

- determination of gamma-glutamyl transferase level in blood,

- determination of alkaline phosphatase level in blood,

- determination of total bilirubin level in blood,

- determination of conjugated (direct) bilirubin level in blood.

Assessment of electrolyte balance and risk of metabolic disorders to correct abnormalities arising from chronic fluid and electrolyte loss through extensive wound surfaces:

- determination of sodium level in blood,

- determination of potassium level in blood,

- determination of chlorides level in blood.

Assessment of metabolic disorders to monitor lipid metabolism, which may be impaired due to chronic inflammation and specific nutritional support:

- determination of cholesterol level in blood,

- determination of triglycerides level in blood.

Assessment of systemic inflammation activity:

- determination of C-reactive protein level in blood serum as a non-specific marker of inflammatory activity.

Direct high-grade evidence for this specific list is lacking due to the rarity of the disease; however, its clinical expediency is supported by EB management guidelines [85] and generally accepted principles of managing chronic systemic diseases.

Comments: patients with inherited epidermolysis bullosa may develop bacterial urinary tract infections due to scarring and urethral strictures, which necessitate a complete blood count (urinalysis) for detection. Inherited epidermolysis bullosa can also be complicated by renal amyloidosis, glomerulonephritis, and chronic kidney disease, requiring laboratory monitoring [7, 18, 19].

Comments: if clinically indicated (e.g., lack of response to antibacterial therapy, characteristic features), an additional microbiological (culture) examination of wound discharge for fungi (yeasts, molds) is recommended. Inoculation on additional nutrient media is necessary to identify glucose-non-fermenting Gram-negative microorganisms.

When issuing a report on a microbiological test, it is advisable to indicate the group of isolated microorganisms in accordance with the ranking of bacteria by their clinical significance in EB.

The frequency and multiplicity of tests performed are determined by the clinical situation.

If necessary, susceptibility testing methods are used: disc diffusion method for systemic antimicrobials, gradient diffusion method for systemic antimicrobials, dilution method for systemic antimicrobials, automated analyzers for systemic antimicrobials, and breakpoint concentration method for systemic antimicrobials.

2.4 Instrumental Diagnostics

Comments: due to impaired swallowing, there is a risk of contrast aspiration into the respiratory tract in patients with epidermolysis bullosa. Therefore, using a water-soluble contrast agent rather than barium suspension is the most rational approach [42, 69].

2.5 Other Procedures

Comments: skin biopsy specimens for pathomorphological examination are obtained from a lesion with a fresh blister. The examination reveals a subepidermal cleft in inherited epidermolysis bullosa. Pathomorphological examination of skin biopsy material does not allow for diagnosing the specific subtype of inherited epidermolysis bullosa.

Comments: performing immunofluorescence studies requires obtaining a skin biopsy specimen with a fresh blister present for no more than 24 hours. The biopsy is taken at the border of visibly healthy skin and a fresh blister or in a friction zone (30 minutes after cessation of friction). The expression of structural skin proteins whose gene mutations lead to the disease is determined—such as keratins type 5 and 14, plectin, plakophilin-1, desmoplakin, type VII and XVII collagens, laminin α3, β3, γ3 chains, integrin α6 and β4 subunits, kindlin-1, and others at the dermo-epidermal junction. To evaluate the results of immunofluorescence studies on skin biopsies from patients with inherited epidermolysis bullosa, a skin biopsy from a healthy individual is required to compare the expression of corresponding proteins in the biopsies of a healthy person and the patient. Skin protein expression in a patient with inherited epidermolysis bullosa may be normal, reduced, or absent.

Comments: patients with inherited epidermolysis bullosa may develop cardiac, gastrointestinal, and systemic inflammatory complications. A severe complication is sepsis, which can affect any internal organ.

Comments: anemia frequently develops in patients with inherited epidermolysis bullosa, especially in severe cases.

Comments: frequent complications of severe inherited epidermolysis bullosa include esophageal strictures and stenosis. Gastroesophageal reflux, constipation, coprostasis, colitis, diarrhea, and malabsorption syndrome may develop. Some patients may develop pyloric atresia.

Comments: patients with inherited epidermolysis bullosa may develop dilated cardiomyopathy [25].

Comments: starting from 1 year of age, children with EB require an annual examination by a pediatric cardiologist due to the risk of developing dilated cardiomyopathy.

Comments: patients with inherited epidermolysis bullosa may develop corneal erosions and scars, blepharitis, symblepharon, ectropion, keratitis, decreased visual acuity, and in severe cases, blindness.

Comments: patients with inherited epidermolysis bullosa may develop narrowing of the external auditory canal, hearing loss, and nasal passage stenosis due to granulation tissue formation.

Comments: patients with inherited epidermolysis bullosa may develop periodontitis, enamel hypoplasia, multiple caries, microstomia, and ankyloglossia.

Comments: patients with inherited epidermolysis bullosa may develop periodontitis, enamel hypoplasia, multiple caries, microstomia, and ankyloglossia.

Comments: patients with inherited epidermolysis bullosa may develop syndactyly, esophageal strictures, etc., requiring surgical correction.

Comments: patients with inherited epidermolysis bullosa may experience genitourinary tract involvement, urethral strictures and stenosis, and recurrent cystitis [33].

Comments: patients with inherited epidermolysis bullosa may experience genitourinary tract involvement, urethral strictures and stenosis, and recurrent cystitis [33], as well as complaints of dysuria and urinary retention, and skin and mucosal lesions of the genitourinary system, in order to prescribe treatment for the developed urinary system pathology if necessary.

Comments: a geneticist consultation (examination) should be performed in the following situations: for patients with inherited epidermolysis bullosa; for couples planning a pregnancy who have a previously born child with inherited epidermolysis bullosa, a family history of the disease in one of the parents, confirmed or suspected cases of the disease in the family, as well as to determine the probability of having an affected child and the possibility of identifying the mutant gene and specific mutation. The results of genetic risk assessment influence the parents' decision to continue or terminate the pregnancy.

Comments: patients suffering from dystrophic, junctional inherited epidermolysis bullosa, and Kindler syndrome have a significantly increased risk of developing cutaneous squamous cell carcinoma. In patients with recessive dystrophic inherited epidermolysis bullosa, cutaneous squamous cell carcinoma is characterized by an early age of onset, aggressive clinical course, and is the leading cause of death.

Comments: patients suffering from dystrophic, junctional inherited epidermolysis bullosa, and Kindler syndrome have a significantly increased risk of developing cutaneous squamous cell carcinoma.

Comments: patients with easily traumatized oral, esophageal, and gastric mucosa, for whom eating is painful, may require a specialized diet dominated by minced and liquid foods.

Comments: patients with inherited epidermolysis bullosa, especially those with a severe clinical course, may develop anxiety and depression requiring pharmacotherapy.

Comments: patients with inherited epidermolysis bullosa, especially those with a severe clinical course, may develop depression requiring pharmacotherapy.

Comments: patients with inherited epidermolysis bullosa, especially those with a severe clinical course, may experience delayed puberty and amenorrhea.

Comments: patients with inherited epidermolysis bullosa, especially those with a severe clinical course, may experience delayed puberty and amenorrhea.

Comments: the term "life-limiting conditions" in pediatric practice denotes conditions for which there is no reasonable hope of cure and from which children will die. Children with incurable diseases or life-limiting conditions receive palliative medical care. Compiled in 2012 based on the practical experience of five UK children's hospices, the "Directory of Life-Limiting Conditions in Childhood" is classified according to the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10). Specifically, within the ICD-10 chapter "Congenital malformations, deformations and chromosomal abnormalities", this directory classifies code Q81 Epidermolysis bullosa as a life-limiting condition. Since epidermolysis bullosa in children is classified as a life-limiting disease, such children may receive comprehensive palliative medical care based on medical indications. In Herlitz lethal junctional epidermolysis bullosa, it is recommended to initiate palliative care for the child immediately upon confirmation of the diagnosis. In severe generalized forms of dystrophic epidermolysis bullosa, practical experience has also been accumulated in providing palliative medical care to children from the time of diagnosis.

Comments: the choice of pain assessment scale should correspond to the patient's age and communicative abilities:

- for newborns and infants under 1 year of age – Neonatal Infant Pain Scale (NIPS) (Appendix G1);

- for children from 1 to 3 years of age – Face, Legs, Activity, Cry, Consolability (FLACC) Behavioral Scale (Appendix G2);

- for children from 3 years of age – Wong-Baker FACES Pain Rating Scale (Appendix G3);

- for non-verbal patients of any age – Critical-Care Pain Observation Tool (CPOT) (Appendix G4).

Initial pain assessment is performed during the primary examination, and reassessment is carried out if pain persists or appears thereafter. The frequency of assessment is determined by the patient's condition, and evaluation of analgesic therapy effectiveness is mandatory. In cases of severe pain syndrome inadequately controlled by non-opioid analgesics, the administration of opioid analgesics should be considered.

Comment: monitoring of body weight, height, and BMI in infants under 1 year of age should be performed monthly, and in children over 1 year of age and adults, every 3 months. Every 6–12 months, a blood laboratory screening is recommended, which includes a complete blood count (CBC) with differential + erythrocyte sedimentation rate (ESR), total blood protein, blood urea, blood creatinine, blood alkaline phosphatase activity, blood glucose, blood cholesterol, serum iron, serum ferritin, serum transferrin, electrolytes (blood sodium, blood potassium, blood chlorides), blood zinc, and blood selenium; annually – vitamin B1, blood L-carnitine (free and total), blood vitamin B12 (cyanocobalamin), and serum folic acid.

Due to the high incidence of vitamin D deficiency, osteopenia, and osteoporosis, all patients with the dystrophic form of inherited epidermolysis bullosa must undergo assessment of mineral and bone metabolism: blood 25-OH vitamin D testing (at least once every 6 months); total blood calcium, blood albumin with calculation of albumin-corrected calcium, serum total magnesium, inorganic blood phosphorus, blood creatinine, and blood alkaline phosphatase activity (at least once every 6 months); and, according to indications, blood osteocalcin, blood C-terminal telopeptide, and blood N-terminal propeptide of type 1 procollagen (P1NP) testing.

Dietary counseling: children – every three months, adults – every 6 months, or more frequently if necessary.

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

To date, there is no causal (etiological) therapy for inherited epidermolysis bullosa. Management includes care for affected and unaffected skin, topical treatment of skin and mucous membrane lesions, treatment of extra-cutaneous complications of the disease, relief of pain and pruritus, use of multivitamins with minerals, and specialized medical nutrition prescribed by specialists in relevant fields (dermatovenerologist, pediatrician, general practitioner/internist, hematologist/pediatric hematologist-oncologist, gastroenterologist, clinical nutritionist/dietitian, surgeon/pediatric surgeon, dentist/pediatric dentist, ophthalmologist, otolaryngologist, nephrologist, urologist/pediatric urologist-andrologist, endocrinologist/pediatric endocrinologist, palliative care physician) and others as clinically indicated [22, 24, 36].

Treatment goals:

- ensure the highest possible quality of life for the patient;

- prevent and treat cutaneous exacerbations and complications;

- ensure the patient's physical development corresponds to age norms (achieving physical development indicators within the 25th–75th percentile range after correction of nutritional status, with the recommended target being the 50th percentile);

- ensure the prevention of complications and correction of extracutaneous manifestations of RDEB.

Mandatory components of treatment:

- symptomatic therapy with atraumatic dressing materials;

- dietary therapy using specialized nutrition;

- prevent and treat exacerbations of the infectious and inflammatory skin process to reduce the degree of contamination;

- therapy of extracutaneous complications.

As indicated:

- antibacterial therapy (local and systemic).

3.1 Conservative Treatment

Pharmacotherapy is aimed at eliminating pruritus and pain, combating infectious complications of the disease, correcting pathology of the gastrointestinal tract, teeth, musculoskeletal system, and other complications (anemia, pseudosyndactyly, esophageal strictures, osteoporosis, etc.).

Before opening blisters, as well as before dressing changes, erosions and ulcers are treated with an antiseptic and disinfectant solution, exclusively aqueous. Blisters are opened using a hypodermic needle, surgical needle, scissors, or scalpel treated with an antiseptic and disinfectant preparation. The blister is punctured parallel to its roof without damaging the base, creating two openings, an entrance and an exit. The contents are gently removed using a gauze wipe with light blotting motions to avoid increasing the blister area. In case of severe pain in the blister area, its contents can be aspirated with a syringe. Removal of the blister roof is undesirable due to additional pain, although it may be removed to prevent refilling of the blister with exudate. Punctured blisters are then re-treated with an antiseptic and disinfectant solution.

Wound healing therapy:

zinc oxide 10% topical ointment is applied in a thin layer, with a dressing applied if necessary [37].

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

Comments: apply only to superficial and uninfected lesions. There are no age restrictions for the use of 10% zinc oxide ointment.

zinc oxide suspension for topical application. Using a swab moistened with the preparation, apply the suspension to the affected skin areas 2–3 times a day [37].

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

Comments: there are no age restrictions for the use of zinc oxide suspension.

chlorhexidine** 0.05% aqueous solution for topical and local application [24, 37–39].

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

Comments: use with caution in pediatric practice.

chlorhexidine** 0.5% aqueous solution for topical and local application [24, 37–39];

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

Comments: use with caution in pediatric practice.

or

#methylthioninium chloride 1% solution for local and external application, [aqueous] to affected areas 2–3 times a day [37];

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

Comments: in adults and children from birth, the solution is applied using a swab or glass rod. The aqueous solution of #methylthioninium chloride may be used during pregnancy and breastfeeding.

or

hydroxymethylquinoxalindioxide 0.5% and 1% solution for intracavity administration, local and external use for patients over 18 years of age [37];

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

Comments: contraindicated in children (under 18 years of age).

or

benzyldimethyl-myristoylamino-propylammonium solution for topical application 0.01% [24, 37, 38];

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

Comments: contraindicated in children under 3 years of age.

or

octenidine dihydrochloride + phenoxyethanol solution for local and external application [24, 37].

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

Comments: used in pediatric practice without age restrictions.

dioxomethyltetrahydropyrimidine 3%, 10% ointment for local and external application is applied daily to affected areas in a thin layer in an amount of 5–10 g for 15–30 days [37];

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

Comments: prior to application, the wound should be treated with an antiseptic and disinfectant preparation, and necrotic tissue residues should be removed. Use in children under 3 years of age, during pregnancy and lactation should be carried out under medical supervision.

or

dexpanthenol 5% cream for external use, 5% ointment for external use, 4.63% spray for external use [24, 37, 39–41].

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

Comments: dexpanthenol cream, ointment, and spray can be prescribed to adults and children of any age. The use of the spray in children should be supervised by adults.

soft silicone-coated dressing [24, 43]

or

sterile absorbent dressing with a soft silicone coating that absorbs exudate, maintains an optimal moist wound environment, and minimizes the risk of maceration [24, 43].

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

Comments: a primary (contact) dressing material is first applied to the surface of erosive and ulcerative skin defects. Non-adhesive materials without an adhesive backing are preferred, preventing the dressing from sticking to the patient's skin. The dressing is pre-cut to the contours of the wound defect to a size 1–2 cm larger than the skin defect. Dressings are changed according to the manufacturer's instructions. Silicone-based foam dressings may be used.

Comments: a primary (contact) dressing material is first applied to the surface of erosive and ulcerative skin defects. Non-adhesive dressings without an adhesive backing are preferred, preventing the dressing from sticking to the patient's skin. The dressing is pre-cut to the contours of the wound defect to a size 1–2 cm larger than the skin defect. Hydrogel dressings are changed daily or as they dry out; other types of non-adhesive dressings are changed every 3–4 days, or daily in the presence of excessive discharge from the surface of erosions and ulcers.

Comments: in case of excessive exudation on the wound surface, dressings capable of effectively absorbing excess discharge while maintaining a moist environment and ensuring atraumatic removal are required. These include alginate, hydrocolloid, foam, superabsorbent, and modern high-absorption lipid-colloid dressings. The choice of a specific dressing type depends on the intensity of exudation and the clinical presentation.

Comments: dressings containing silver ions, povidone-iodine, and/or other antibacterial agents should be used for no more than 3 days. The choice of a specific type of antimicrobial dressing depends on the nature of the wound infection and the patient's individual characteristics.

Comments: secondary dressings must securely fix the primary dressing material, ensuring its stable position without excessive pressure on the skin. It is recommended to use modern elastic self-fixing and net materials that ensure minimal skin trauma during dressing changes.

Comments: gauze-structure wipes must not be applied directly to the wound surface due to the risk of adhesion. Absorbent non-woven dressings do not adhere to the wound because of the underlying primary dressings. Dressings should be applied without forming creases on the surface. When saturated with exudate, they must be replaced.

Comments: fixation materials should be used with caution due to their adhesive surface. Hypoallergenic adhesive tapes and retention dressings with a soft silicone coating can be removed from the skin of patients with epidermolysis bullosa with minimal epidermal stripping.

cholecalciferol** oral drops for children [11, 26, 48];

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

Comments: a contraindication for prescribing cholecalciferol** oral drops is an age under 4 weeks of life.

or

cholecalciferol capsules for adults [11, 26, 48].

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

Comments: a contraindication for prescribing cholecalciferol in capsule form is an age under 18 years.

3.2 Surgical Treatment

Indications for surgical treatment (complications associated with inadequate food intake for more than 3 days, presence of contractures and pseudosyndactyly, esophageal stenosis, strictures and narrowing of the urogenital tract, etc.) in patients with inherited epidermolysis bullosa are determined by a surgeon, urologist, or obstetrician-gynecologist [11, 24, 28].

Esophageal strictures are the most common extracutaneous complications of epidermolysis bullosa (predominantly RDEB), which cause dysphagia and odynophagia that prevent oral feeding and the intake of adequate nutrients, leading to impaired nutritional status, wasting, and delayed physical development. Impaired swallowing can also lead to food refusal or a significant decrease in food volume, progressive weight loss, aspiration pneumonia, and airway obstruction. To eliminate dysphagia and reduce the risk of complications, restoration of esophageal patency is required [3, 4, 9, 10, 11].

Comments: contraindications to this surgical intervention include decompensated esophageal stenosis (absence of lumen in the narrowed segment). Within a week after balloon dilation, the following are recommended: a liberal drinking regimen and the use of liquid formulas for enteral nutrition on the first day with a gradual diet expansion, and antacids. To minimize traumatic impact during anesthetic management and endoscopic manipulations, it is recommended to use various non-adhesive silicone-coated materials (dressings) to cover the facial skin where the anesthesia mask fits and to tape the mouthguard to prevent gum trauma. In addition, the dressing is used as a fixation material when establishing peripheral access, and for securing the pulse oximeter and electrocardiography electrodes [9, 10, 11].

Comments: indications for surgical treatment are determined by a pediatrician/general practitioner, gastroenterologist, and dietitian in cooperation with a surgeon/pediatric surgeon. Retrograde esophageal balloon dilation and nutritional support using enteral nutrition formulas are performed through the gastrostomy. It is important to note that esophageal dilation, single or sequential, can alleviate dysphagia but cannot guarantee a sufficient increase in oral food intake to correct nutritional deficiencies, and therefore dilation does not replace gastrostomy. Gastrostomy and balloon dilation are complementary procedures that optimize the management of patients with EB. As needed, the gastrostomy can be replaced or closed.

Other indications for surgical treatment include complications associated with contractures and pseudosyndactyly, and narrowing of the urogenital tract in patients with inherited epidermolysis bullosa, which are determined by a surgeon, urologist / pediatric urologist-andrologist, or obstetrician-gynecologist.

3.3 Other Treatment

erythromycin 10,000 IU/g ointment for topical use, apply to affected skin areas 2–3 times a day [38, 90];

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

or

mupirocin 2% ointment for topical use – a small amount of ointment is applied to the affected skin surface 2–3 times a day using a cotton or gauze swab to infected skin lesions for 7 days [22, 28, 36–39];

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

Comments: a sterile bandage or gauze dressing may be applied over the ointment application area. There are no restrictions on use in children.

or

fusidic acid 2% cream, 2% ointment for topical use, applied to affected skin areas in a thin layer 3–4 times a day [37, 38];

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

Comments: fusidic acid cream and ointment are used in adults and children from birth up to 18 years of age.

or

gentamicin 0.1% ointment for topical use, applied in a thin layer to the affected area 3–4 times a day. Course of treatment is 7–14 days [37, 38];

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

Comments: gentamicin ointment should be used with caution during the neonatal period and in premature infants.

or

lincomycin 2% ointment for topical use, applied in a thin layer to the skin at the lesion site in adults and children over 1 month of age 2–3 times a day [37, 38];

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

Comments: 2% lincomycin ointment is contraindicated in newborns (under 1 month).

or

bacitracin + neomycin ointment for external use is applied in a thin layer to the affected areas 2–3 times a day, if appropriate – under a dressing [27, 37–39];

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

Comments: the drug should not be used for extensive skin lesions, since absorption of the drug can cause an ototoxigenic effect accompanied by hearing loss.

or

silver sulfadiazine 2% cream for external use is applied to the wound 2–3 times a day [37, 38];

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

Comments: a contraindication to the use of the drug is infancy under 2 months of age (risk of developing kernicterus).

or

sulfadiazine 1% cream, 1% ointment for external use, after surgical debridement of the wound surface, is applied to it in a layer 2–4 mm thick 1–2 times a day [37, 38].

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

Comments: the use of sulfadiazine 1% cream is contraindicated in premature newborns, as well as in children during the first 2 months after birth. A contraindication to the use of sulfadiazine 1% ointment is children under 1 year of age. Sulfadiazine 1% ointment should not be used to treat deep purulent wounds with abundant exudation.

dioxomethyltetrahydropyrimidine + chloramphenicol 40 mg/g + 7.5 mg/g ointment for external use. Sterile gauze pads are impregnated with the drug and loosely pack the wound. Dressings are performed daily, once a day, until the wound is completely cleansed of purulent-necrotic masses [37];

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

Comments: a contraindication to prescribing the drug is children under 1 year of age.

or

dioxomethyltetrahydropyrimidine + sulfadimethoxine + trimecaine + chloramphenicol** ointment for external use. Sterile gauze pads are impregnated with the drug and loosely pack the wound. Dressings are performed daily, once a day, until the wound is completely cleansed of purulent-necrotic masses [37].

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

Comments: in children aged from 4 weeks to 1 year, the drug should be used with caution.

fluoroquinolones [48, 49];

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

or

macrolides [49, 52];

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

or

other beta-lactam antibacterial drugs [48, 49];

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

lactulose** syrup [24, 53];

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

Comments: the daily dose of lactulose** can be taken once or divided into two using a measuring cup.

or

macrogol** powder for oral solution [24].

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

Comments: a contraindication to prescribing macrogol** powder for oral solution in 10 g sachets is children under 8 years of age, or up to 12 years, or up to 18 years (depending on the manufacturer).

Benzocaine + Boric acid + Sea buckthorn (Hippophae rhamnoides) fruit oil + Chloramphenicol aerosol for topical use is applied to the wound surface, cleaned of pus and necrotic tissues as much as possible, covering it evenly with a thin layer of foam daily or every other day, and in open wound treatment – 1–4 times a day depending on the nature of the inflammation and the stage of regeneration of damaged tissues [37, 38].

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

• If there is a sensation of pain in the lesion sites for systemic therapy, recommended for patients with congenital epidermolysis bullosa are analgesics or nonsteroidal anti-inflammatory and antirheumatic drugs [11, 22, 24, 38, 47, 53, 110].

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

diphenhydramine** 50 mg tablets [54, 58];

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

Comments: a contraindication to prescribing diphenhydramine** in tablet form is children under 14 years of age.

or

clemastine 1 mg orally [56];

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

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

or

clemastine solution for intravenous and intramuscular administration 1 mg/ml intramuscularly for the prevention or treatment of allergic and pseudo-allergic reactions in adults: 2 mg (2 ml) 2 times a day (morning and evening); in children: 0.025 mg per kg of body weight per day, divided into 2 injections [56];

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

Comments: parenteral administration of systemic antihistamines is preferable in cases of intense pruritus. A contraindication to prescribing clemastine in the form of a solution for intravenous and intramuscular administration is children under 1 year of age.

or

loratadine** syrup or tablets [55, 58].

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

Comments: the drug is prescribed for complications in the form of pruritic dermatoses in accordance with the instructions for use. A contraindication to prescribing loratadine** syrup is children under 2 years of age, in tablet form – children under 3 years of age (some manufacturers indicate other age restrictions for prescribing loratadine**).

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

diphenhydramine 1% gel for external use is applied topically to affected skin areas in adults and children over 2 years of age (a 3–5 cm strip of gel for a palm-sized lesion area) 3–4 times a day and distributed with light massaging movements [58];

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

Comments: a contraindication to prescribing diphenhydramine 1% gel is children under 2 years of age.

or

#pimecrolimus** 1% cream for external use is applied 2 times a day in a thin layer to the affected skin areas and gently rubbed in until completely absorbed [37, 58].

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

Comments: the cream can be applied to the skin of any part of the body, including the head, face, neck, and diaper rash areas. Treatment is continued until symptoms completely disappear. Moisturizers for daily skin care can be used during treatment with the cream. The cream should not be used under an occlusive dressing, since safety with use under an occlusive dressing (possible increase in systemic exposure) has not been evaluated.

or

#tacrolimus** 0.03% ointment for external use is applied in a thin layer to affected skin areas in adults and children over 2 years of age [37, 59].

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

Comments: the drug can be applied to any part of the body, including the face and neck, and in skin folds. The drug should not be applied to mucous membranes and under occlusive dressings.

Comments: nutrition is especially important for patients with a large skin lesion area, since they lose nutrients and moisture with tissue fluid, which is necessary for wound healing and fighting infection. Patient nutrition should be rich in proteins, carbohydrates, fats, and also contain vitamins, minerals, dietary fiber, and a large amount of fluid. If there are a large number of blisters and erosions, the patient needs replacement of lost fluid.

The main options for nutritional support are oral intake (sipping) or tube feeding (via gastrostomy), as well as fortifying regular foods with nutritional formulas. The calculation of the planned nutritional intake is carried out individually based on energy and protein requirements. Polymeric isocaloric and hypercaloric enteral nutrition formulas containing dietary fiber are recommended for use. In the presence of malabsorption signs, enteropathy, protein-energy malnutrition, or poor tolerance of polymeric formulas, oligomeric isocaloric and hypercaloric enteral nutrition formulas are prescribed. In children with inherited epidermolysis bullosa (IEB) presenting with cow's milk protein allergy, extensively hydrolyzed protein formulas with normal or increased calorie content or amino acid-based formulas are used. An additional indication for selecting an amino acid-based formula is severe malnutrition, as amino acid formulas ensure maximum nutrient absorption under conditions of significant depression of the digestive and absorptive capacity of the digestive tract.

The energy value of the product should provide the child with 660–700 kcal/day. The recommended substrate intake for adult patients with IEB can correspond to an energy requirement of 30–40 kcal/kg/day, with a protein requirement of up to 2 g/kg/day.

Comments: in severe cases of inherited epidermolysis bullosa, as well as in mild skin lesions accompanied by oral cavity involvement, special attention to nutrition is required. The diet of patients with inherited epidermolysis bullosa and oral mucosal lesions and/or adentia must be mechanically, thermally, and chemically sparing (pureed and semi-liquid, not hot).

The main indicator of diet therapy adequacy is weight gain, which is considered optimal if it exceeds 10 g/kg/day, moderate at 5–10 g/kg/day, and low if less than 5 g/kg/day.

Comments: for mixed or artificial feeding, low-lactose or lactose-free formula should be used. In cases of cow's milk protein allergy, breastfed infants should continue nursing, while the mother is prescribed a balanced dairy-free diet. For mixed or artificial feeding, the infant requires a specialized medical nutrition product based on extensively hydrolyzed protein or amino acids. Children over one year of age with persistent symptoms of cow's milk protein allergy are also indicated specialized pediatric medical nutrition products based on extensively hydrolyzed protein or amino acids to establish an adequate dairy-free diet.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Patients with inherited epidermolysis bullosa are contraindicated from working with industrial chemical and physical irritants, as well as under psycho-emotional or physical stress [60].

If patients with inherited epidermolysis bullosa show signs of depression, psychological rehabilitation treatment must be carried out in cooperation with psychiatrists, child psychiatrists, and psychotherapists [61, 62].

In the presence of pseudosyndactyly and joint contractures, physical therapy sessions, orthoses, and compression gloves are indicated to preserve the mobility of finger and toe joints [63].

Comments: supportive psychotherapy is also indicated for the patients' families [61, 62].

5. Prevention and Dispensary Observation

Accounting and follow-up of patients with skin anomalies (malformations) are provided in accordance with the Procedure for the Provision of Medical Care to the Population in the Profile "Dermatovenereology", approved by Order of the Russian Ministry of Health No. 582n dated September 24, 2025, and the implementation of clinical dispensary observation of patients with congenital and/or hereditary diseases in accordance with the Procedure for the Provision of Medical Care to Patients with Congenital and/or Hereditary Diseases, approved by Order of the Russian Ministry of Health No. 274n dated April 21, 2022.

For the purpose of objective assessment of condition severity, the validated BEBS (Birmingham Epidermolysis Bullosa Severity score) scale may be used (Appendix G5).

The BEBS scale is a standardized tool for assessing the severity of IEB. Three degrees of severity are distinguished according to this scale:

o Mild (0–20 points): characterized by the absence of complications and a need for hospitalization less than 2 times per year.

o Moderate (20–45 points): presence of complications that do not interfere with self-care and study/work; frequency of hospitalizations less than 3 times per year.

o Severe (> 45 points): presence of complications that interfere with self-care and study/work, with the need for regular hospitalization (3 or more times per year). This grading allows standardizing the approach to assessing the patient's condition and planning the scope of medical care.

Comments: the preventive complex includes the selection of soft, seamless clothing and orthopedic footwear; dietary correction excluding hard, coarse, and hot foods; systematic use of non-adhesive dressings; application of specialized topical skin care products; regular special oral care using soft toothbrushes and antiseptic solutions.

Comments: this category of patients, especially in the presence of long-standing non-healing erosions, has an increased risk of developing aggressive, early-onset (20–30 years) squamous cell carcinoma. The screening program includes:

– complete examination of the skin and visible mucous membranes every 6 months;

– close attention to areas of chronic hyperkeratosis and lesions with a verrucous surface;

– timely performance of multiple skin biopsies from areas of hyperkeratosis and verrucous growths, especially those resistant to therapy;

– upon histological confirmation of squamous cell carcinoma, early radical excision of the skin lesion with adequate margins of healthy tissue is indicated.

6. Organization of Medical Care

Indications for planned hospitalization in a medical organization:

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

– insufficient effectiveness of treatment performed in an outpatient setting in patients with limited rashes;

2) Indications for providing inpatient medical care:

– insufficient effectiveness of treatment performed in an outpatient setting;

– development of a secondary infection not controllable in an outpatient setting.

Indications for patient discharge from a medical organization:

– Partial regression of rashes (partial or complete epithelialization of erosions, or a decrease in the depth or size of ulcers, or a decrease in purulent discharge on the surface of erosions and ulcers).

Medical care for patients with inherited epidermolysis bullosa is provided in the form of:

– primary health care;

– emergency, including specialized emergency medical care;

– specialized medical care.

Medical care may be provided in the following settings:

– outside a medical organization (at the location of the emergency, including specialized emergency medical team dispatch, as well as in a vehicle during medical evacuation);

– outpatiently (in settings not requiring round-the-clock medical observation and treatment);

– in a day hospital (in settings providing medical observation and treatment during daytime hours, not requiring round-the-clock medical observation and treatment);

– inpatiently (in settings providing round-the-clock medical observation and treatment).

Primary health care provides measures for the diagnosis and treatment of inherited epidermolysis bullosa, prevention of its complications, medical rehabilitation of patients, and the promotion of a healthy lifestyle.

Primary health care includes:

– primary pre-medical health care;

– primary general medical care;

– primary specialized health care.

Primary health care is provided in outpatient settings and day care settings.

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

Primary general medical care is provided by general practitioners, district general practitioners, pediatricians, district pediatricians, and general family physicians.

If there are medical indications for medical care that does not require inpatient conditions, the district general practitioner, district pediatrician, general family physician, medical worker with secondary medical education, general practitioner, or pediatrician shall refer the patient to a dermatologist's office at a medical organization to receive primary specialized health care.

Primary specialized health care is provided by a dermatovenereologist, pediatrician, or general practitioner.

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

Emergency, including specialized emergency, medical care is provided to patients requiring urgent medical intervention by paramedic mobile emergency teams, medical mobile emergency teams, and specialized mobile emergency teams, including pediatric ones.

Specialized medical care is provided by dermatovenereologists and/or pediatricians on an outpatient basis or in inpatient settings and includes prevention, diagnosis, treatment, and medical rehabilitation.

In the presence of medical indications, treatment is carried out with the involvement of medical specialists in accordance with the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers (Order of the Russian Ministry of Health No. 205n dated May 2, 2023 (as amended on December 4, 2023) "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers" (Registered with the Russian Ministry of Justice on June 1, 2023, No. 73664)).

Routine medical care is provided during preventive measures, for conditions not accompanied by a life threat and not requiring emergency or urgent care, where delaying care for a certain time will not lead to a worsening of the patient's condition, life, or health.

Medical care in a medical organization providing specialized medical care is provided based on medical indications upon a patient's independent visit or together with their legal representative, by referral from a medical worker with secondary medical education, district general practitioner, district pediatrician, general family physician, general practitioner, or pediatrician of a medical organization providing primary health care, as well as when the patient is delivered by an emergency medical team.

7. Additional Information

Dental treatment and prosthetics are significantly hindered due to poor access in the presence of microstomia, as well as the extreme fragility of the mucous membrane with the formation of blisters and erosions. The installation and wearing of removable dentures are practically impossible; there are isolated reports on other effective types of prosthetics, in particular, dental implantation [66].

If articulation disorders develop, their correction is necessary to ensure clear speech. The older the child gets, the harder it is to correct speech defects. Speech disorders in a child with inherited epidermolysis bullosa also depend on frequent complications, such as ankyloglossia (short lingual frenulum), microstomia (acquired narrowing of the oral aperture), or shallow oral vestibule. In this case, surgical correction methods are impossible. The most effective methods for preventing such complications are regular physical exercises aimed at working the muscles of the mouth and tongue: articulation exercises, classes with a medical speech therapist, and vocal training.

Vaccinations should be carried out according to the vaccination schedule or an individual plan. Great attention is paid to the chickenpox vaccine**. Vaccination should be carried out outside the manifestations of acute infectious diseases against the background of well-controlled measures of symptomatic and supportive treatment. Indications and scope of vaccination are determined by the pediatrician. Vaccination with the tuberculosis vaccine** is contraindicated in children with recessive dystrophic inherited epidermolysis bullosa and patients with generalized manifestations of junctional and simplex inherited epidermolysis bullosa.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Kubanov Alexey Alekseevich – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, President of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

2. Potekaev Nikolay Nikolaevich – Doctor of Medical Sciences, Professor, Chief freelance specialist in dermatovenereology and cosmetology of the Russian Ministry of Health, President of the National Alliance of Dermatovenereologists and Cosmetologists. No conflict of interest.

3. Baranov A.A. – Academician of the Russian Academy of Sciences, Professor, MD; Honorary President of the Union of Pediatrists of Russia, Advisor to the Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Center for Children's Health No. 2 of the Petrovsky National Research Centre of Surgery, Professor of the Department of Pediatrics and Pediatric Rheumatology of the N.F. Filatova Children's Infectious Diseases Hospital, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health, Chief freelance pediatrician of the Russian Ministry of Health.

4. Namazova-Baranova L.S. – Academician of the Russian Academy of Sciences, Professor, MD, President of the Union of Pediatrists of Russia; Past-President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health of the National Medical Research Center for Children's Health No. 2 of the Petrovsky National Research Centre of Surgery, Head of the Department of Faculty Pediatrics of the Institute of Motherhood and Childhood of the Pirogov Russian National Research Medical University (Pirogov University) of the Russian Ministry of Health, Chief freelance pediatric specialist in preventive medicine of the Russian Ministry of Health, Chairman of the Executive Committee of the Union of Pediatrists of Russia.

5. Zhukova Olga Valentinovna – Doctor of Medical Sciences, Professor, Chief freelance specialist in dermatovenereology and cosmetology of the Central Administrative District of the Russian Federation. No conflict of interest.

6. Dolya Olga Valentinovna – Doctor of Medical Sciences, Professor, Member of the National Alliance of Dermatovenereologists and Cosmetologists. No conflict of interest.

7. Porshina Oksana Vladimirovna – Candidate of Medical Sciences, Member of the National Alliance of Dermatovenereologists and Cosmetologists. No conflict of interest.

8. Dvornikov Anton Sergeevich – Doctor of Medical Sciences, Professor, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

9. Martynov Andrey Alexandrovich – Doctor of Medical Sciences, Professor, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

10. Olisova Olga Yuryevna – Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

11. Karamova Arfenya Eduardovna – Candidate of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

12. Chikin Vadim Viktorovich – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

13. Albanova Vera Igorevna – Doctor of Medical Sciences, Professor, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

14. Murashkin Nikolay Nikolaevich – Doctor of Medical Sciences, Professor, Member of the Union of Pediatrists of Russia, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

15. Makarova Svetlana Gennadievna – Doctor of Medical Sciences, Deputy Director for Research at the National Medical Research Center for Children's Health of the Russian Ministry of Health, Allergist-Immunologist, Member of отмечается Союза педиатров России. No conflict of interest.

16. Roman V. Epishev – Candidate of Medical Sciences, Dermatologist at the Department of Dermatology and Allergology, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

17. Alexander I. Materikin – Candidate of Medical Sciences, Head of the Department of Dermatology with Day Care Hospital, Research Institute of Pediatrics and Children's Health, Academician B.V. Petrovsky National Research Centre of Surgery, Member of the Union of Pediatricians of Russia, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

18. Olga S. Orlova – Candidate of Medical Sciences, Dermatovenereologist at the National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

19. Elena V. Polevichenko – Doctor of Medical Sciences, Professor at the Department of Oncology, Hematology and Radiology, Pediatric Faculty, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Chief freelance pediatric specialist in palliative care of the Ministry of Health of the Russian Federation, Board Member of the Association of Professional Participants in Hospice Care. No conflict of interest.

20. Ekaterina S. Monchakovskaya – Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

21. Lyudmila F. Znamenskaya – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

22. Olga G. Artamonova – Candidate of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

23. Ksenia I. Plakhova – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

24. Denis V. Zaslavsky – Doctor of Medical Sciences, Professor, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

25. Marat N. Gadzhimuradov – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists. No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Dermatovenereologists.

2. Pediatricians.

3. Residents and trainees of continuing professional education programs in «dermatovenereology» and «pediatrics».

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

Table 2. Levels of Evidence (LE) rating scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

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

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.

Target audience for these clinical guidelines:

1. Dermatovenereologists.

2. Pediatricians.

3. Residents and trainees of continuing professional education programs in «dermatovenereology» and «pediatrics».

Table 3. Levels of Evidence (LE) rating scale for diagnostic methods (diagnostic interventions)

Table 4. Levels of Evidence (LE) rating scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

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

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

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

1. Procedure for the provision of medical care in the field of «dermatovenereology», approved by Order No. 582n of the Ministry of Health of the Russian Federation dated September 24, 2025.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Oral hygiene in a child with congenital epidermolysis bullosa should be initiated as early as possible. Dental plaque formed as a result of food intake leads to rapid growth of oral pathogenic microflora. In congenital epidermolysis bullosa, oral hygiene is complicated by the presence of blisters and erosions. Wounds formed in the oral cavity in congenital epidermolysis bullosa heal very poorly due to the abundance of microorganisms. Delayed oral hygiene and tooth brushing lead to gingivitis, periodontitis, and dental caries, resulting in tooth loss. Caries prevention can be achieved through good oral hygiene, frequent professional care, tooth fluorination, and regular intake of fluoride-containing supplements. For tooth brushing (which is possible even in severe forms), a single-tufted toothbrush with a small curved head and very soft, dense, and short tufted bristles is chosen. Before use, the brush is soaked in hot water and then treated with alcohol-free antiseptic and disinfectant preparations. Prior to brushing, dental plaque is softened with special foams, and ointments are applied to the lips to reduce the risk of trauma. An oral irrigator is used to clean the interdental spaces. If lesions appear on the oral mucosa, they are treated with special oral gels, pastes, and oils containing antiseptics, anesthetics, and regenerative agents. Rinsing the mouth with mouthwashes or herbal decoctions after every meal is mandatory.

Physical exertion associated with increased sweating, trauma-prone situations, and abrupt movements should be avoided. Bandages, clothing, and closed footwear help minimize skin trauma. Swimming is acceptable in good general condition and in the absence of skin rashes.

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

Appendix G1.

PAIN ASSESSMENT

(for newborns and infants under one year of age)

Russian title: Neonatal Infant Pain Scale.

Original title: Neonatal Infant Pain Scale (NIPS).

Source (official developer website, publication with validation):

Sarkaria E, Gruszfeld D. Assessing Neonatal Pain with NIPS and COMFORT-B: Evaluation of NICU's Staff Competences. Pain Res Manag. 2022 Mar 16;2022:8545372. doi: 10.1155/2022/8545372.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: the scale is designed to assess acute procedural pain responses in preterm and term newborns.

Content (template): The NIPS scale assesses pain based on six behavioral indicators: facial expression, cry, breathing pattern, arm movements, leg movements, and state of arousal. Assessment is performed by observing the infant during 1-minute intervals before, during, and after the procedure. The total NIPS score is the sum of points for all descriptor items. The minimum score is 0, and the maximum is 7. A score above 3 indicates pain. In critically ill infants or those receiving paralytic medications, pain may be underestimated (low scoring).

Note:

1. Pain is assessed for the first time when signs of pain appear (see questions below).

2. Record repeated pain assessments (if pain persists) here.

The frequency of pain assessment depends on the condition, and the analgesic effect is evaluated over time.

Key (interpretation):

0 – no pain;

3–5 points – moderate pain;

> 5 points – severe pain.

Notes: any child scoring above 3 on the NIPS scale is experiencing pain. Limitations in the use of the scale are possible: falsely low values may be observed in neonates whose condition is assessed as severe or critical, when the response to pain may be altered, or in children receiving sedative or relaxant medications.

Appendix G2.

PAIN ASSESSMENT

(for children aged 1 to 3 years)

Russian title: FLACC Behavioral Scale.

Original title: Clinical validation of FLACC (face, legs, activity, cry, consolability).

Source (official developer website, publication with validation):

Voepel-Lewis T, Zanotti J, Dammeyer JA, Merkel S. Reliability and validity of the face, legs, activity, cry, consolability behavioral tool in assessing acute pain in critically ill patients. Am J Crit Care. 2010;19(1):55-62. doi:10.4037/ajcc2010624

Pain assessment in pediatric non-verbal patients. — Moscow: Prospekt Publishing House, 2019. — 40 p. https://www.rcpcf.ru/wp-content/uploads/2019/09/Ocenka_boli_all.pdf

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: used in children from 2 months to 3 years of age and in patients unable to report pain.

Content (template): the scale takes into account facial expression, leg movements, type of cry, how easily the child is consoled, and behavioral characteristics. The total FLACC score is the sum of points across all description items.

Scoring key (interpretation): the minimum score is 0, the maximum is 10 points.

Total sum across five categories: 0 points - relaxed, 1-3 - mild discomfort, 4-6 - mild pain, 7-10 - severe pain.

Notes: the higher the score, the more severe the pain and the worse the child feels.

4. Pain is assessed for the first time when signs of pain appear (see questions below).

5. Record the reassessment of pain (if pain persists) here.

6. The frequency of pain assessment depends on the condition, and the analgesic effect is evaluated over time.

Appendix G3.

PAIN ASSESSMENT

(children aged 3 years and older and adults)

Wong-Baker FACES Pain Rating Scale

Russian title: Pain assessment using the Wong-Baker FACES Pain Rating Scale.

Original title: Wong–Baker Faces Pain Rating Scale.

Source (official developer website, publication with validation):

https://ru.qaz.wiki/wiki/Wong-Baker_Faces_Pain_Rating_Scale

https://wongbakerfaces.org/

Garra G. et al. The Wong-Baker pain FACES scale measures pain, not fear // Pediatric emergency care. – 2013. – Vol. 29. – No. 1. – P. 17-20.

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: designed for pain assessment in adult patients and children older than 3 years.

Content (template): the faces scale consists of 6 faces, ranging from smiling (no pain) to crying (worst pain).

Key (interpretation):

No hurt – 0

Hurts little bit – 2

Hurts little more – 4

Hurts even more – 6

Hurts whole lot – 8

Hurts worst – 10

Notes: the specialist assessing pain must explain to the patient in an accessible form the need to choose which of the presented faces describes their pain level: "Show how much you hurt right now." Sometimes, using this

scale, the patient may define their emotions more than their pain.

1. Pain is assessed for the first time during the initial nursing examination.

2. Record the reassessment of pain (if pain persists or occurs later) here.

3. The frequency of pain assessment depends on the patient's condition, and the analgesic effect is evaluated.

Appendix G4.

Pain assessment in non-verbal patients

(CPOT-- Critical-Care Patient Observation Tool) 

Russian title: "CPOT Scale" or "Critical-Care Pain Observation Tool".

Original title: Critical-Care Pain Observation Tool (CPOT).

Source (official developer website, publication with validation):

Gélinas C, Fillion L, Puntillo KA, Viens C, Fortier M. Validation of the critical-care pain observation tool in adult patients. Am J Crit Care. 2006;15(4):420-427.

Shahid A, Sept BG, Longmore S, Owen VS, Moss SJ, Soo A, Fiest KM, Gélinas C, Stelfox HT. Development and preclinical testing of the critical care pain observation tool for family caregiver use (CPOT-Fam). Health Sci Rep. 2022;6(1):e986. doi: 10.1002/hsr2.986

Hoshino H, Ikeda M, Matsuishi Y, Enomoto Y, Shimojo N, Kotani M, Kobayashi S, Kido T, Hayashi S, Furuya Y, Inoue Y. Validity and reliability of the Critical-Care Pain Observation Tool (CPOT) for critically ill pediatric patients. PLoS One. 2025 Apr 18;20(4):e0320373. doi: 10.1371/journal.pone.0320373

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: designed for objective pain assessment in adult patients in intensive care units (ICUs) who cannot verbally describe their sensations (e.g., due to intubation and mechanical ventilation, impaired consciousness, sedation, or dementia). It allows pain to be assessed based on behavioral indicators.

Content (template):

Scoring key: the total score is the sum of four criteria, each scored from 0 to 2 points. Thus, the total score ranges from 0 to 8.

Notes: assessed across four behavioral domains: facial expression, body movements, muscle tension, and compliance with the ventilator / vocalization. Score interpretation:

0–1 – no pain, rest / watchful waiting;

2–5 – pain present, but pharmacological intervention not strictly required (at physician's discretion);

6–8 – pain present, consider pharmacological therapy (at physician's discretion).

Instructions for using the Critical-Care Pain Observation Tool (CPOT):

1. Assess pain at rest (R), observing the patient for 1 minute twice a day (morning and evening).

• in the "score" box: indicate the number and letter. For example, "1R" – score of 1 at rest.

• in the "intervention provided" box: indicate zero "0" if rest / watchful waiting.

  2. Reassess pain during painful procedures (P): endotracheal tube change, nasogastric tube insertion/change, urinary catheter insertion/change, to detect changes in patient pain behavior.

• in the "score" box: indicate the number and letter. For example, "6P" – score of 6 during procedure.

• in the "intervention provided" box: indicate the intervention performed per physician's order.

3. Assess pain again to check the patient's response (Re) to the intervention provided:

• in the "time" box: if IV medication is prescribed, evaluate pain 30 minutes after administration; if per os medication, 1 hour after intake; if non-pharmacological therapy or rest, evaluate 15 minutes after the previous pain assessment.

• in the "score" box: indicate the number and letter. For example, "3Re" – patient response score of 3.

• in the "intervention provided" box: indicate zero "0" if pain is reduced to the resting level and stop assessment until the next painful procedure. If pain does not decrease to the resting level, provide intervention per physician's order.

Source: Table 1 (p.421) in Gélinas, C., Fillion, L., Puntillo, K., Viens, C., & Fortier, M. (2006). Validation of a Critical-Care Pain Observation Tool in adult patients. American Journal of Critical Care, 15(4), 420-427.

Appendix G5.

Birmingham Epidermolysis Bullosa Severity score (child/adult) – BEBS

Russian title: Birmingham Epidermolysis Bullosa Severity score, "BEBS scale".

Original title: Birmingham Epidermolysis Bullosa Severity score (BEBS).

Source (official developer website, publication with validation):

Moss C, Wong A, Davies P. The Birmingham Epidermolysis Bullosa Severity score: development and validation. Br J Dermatol. 2009;160(5):1057-1065. doi:10.1111/j.1365-2133.2009.09041.x

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Purpose: the scale is designed for objective assessment of disease severity in patients of all ages (0 to 64 years) with any subtype of inherited epidermolysis bullosa (IEB). It aims to standardize patient status assessment, facilitate clinical care and research.

Content (template): the BEBS scale includes 11 items covering key manifestations of EB.

Full name (child/adult):

Form (diagnosis):

Key (interpretation): the total score is calculated by summing the scores across all criteria. The total score is interpreted as follows: 0–20 points – mild severity; 21–45 points – moderate severity; > 46 points – severe severity.

Explanatory notes: skin damage area carries the highest weight and is scored up to 50 points. The remaining 10 items are scored up to 5 points each, giving a maximum possible total score of 100. In addition to skin lesion area, the scale takes into account the involvement of nails, oral cavity, eyes, larynx, and esophagus; hand scarring; presence of skin cancer; chronic wounds; scarring alopecia; and nutritional status (nutritional deficiency).