Pemphigus: Clinical Guidelines

List of Abbreviations

ICD – International Classification of Diseases

HLA (Human Leukocyte Antigens)

Ig (Immunoglobulin)

Terms and Definitions

Adhesion (from Lat. adhaesio – sticking) – the formation of a bond between the surface layers of two dissimilar (solid or liquid) bodies brought into contact.

Acanthosis – an increase in the number of prickle cells in the stratum spinosum of the epidermis.

Acantholysis (from Greek *akantha* – thorn, *lysis* – dissolution) – destruction of intercellular bridges in the lower parts of the stratum spinosum.

Vulgar form (from Latin *vulgaris* – common) – common type.

Desmoglein (Greek *desmos* bond, connection) – a transmembrane glycoprotein belonging to cell adhesion molecules.

Desmosomes (Greek *desmos* bond, connection, + *sōma* body) – a type of intercellular junction providing strong adhesion between cells of the stratum spinosum.

Pemphigus – from Greek *pémphigos* – drop, blister.

Prednisolone equivalent – glucocorticoid potency of drugs compared to that of prednisolone** [1,2]

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Pemphigus (syn.: pemphigus) is a group of autoimmune bullous dermatoses in which the pathogenic role belongs to circulating autoantibodies directed against antigens of the desmosomal apparatus in stratified squamous epithelium (skin, mucous membranes of the oral cavity, esophagus, and other organs).

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

Pemphigus develops in genetically predisposed individuals. The most significant association is with specific alleles of the major histocompatibility complex (HLA) genes [3]. In different countries, correlation with various HLA-encoding alleles is observed [4-9]. The disease develops under the influence of various factors (thiol group-containing drugs, sun exposure, infectious agents, stress, certain foods, physical factors, etc.), although it is often impossible to identify a triggering factor [10]. A potential paraneoplastic origin of the disease should be noted [11]. The disease process initiates the recognition of self-molecules forming part of desmosomes by antigen-presenting cells, the abrogation of T- and B-cell tolerance to self-autoantigens, and the synthesis of autoantibodies [1]. Autoimmune processes lead to the disruption of cell-to-cell adhesion in the epidermis (acantholysis) due to the formation of IgG autoantibodies against so-called "pemphigus antigens" (the most important being desmogleins 1 and 3) and their binding to cell membrane glycoproteins. The resulting immune complexes subsequently cause the destruction of desmosomes and the appearance of intraepidermal blisters.

1.3 Epidemiology of the Disease or Condition

The incidence of pemphigus in European and North American countries ranges on average from 0.1 to 0.2 cases per 100,000 population per year [13].

In the Russian Federation, according to Federal State Statistics, the incidence of pemphigus in 2014 was 1.9 cases per 100,000 adult population (aged 18 years and older), and the prevalence was 4.8 cases per 100,000 adult population [14].

1.4 Features of Coding the Disease or Condition

Pemphigus [pemphigus] (L10):

L10.0 – Pemphigus vulgaris;

L10.1 – Vegetative pemphigus;

L10.2 – Pemphigus foliaceus;

L10.3 – Brazilian pemphigus;

L10.4 – Pemphigus erythematosus. Senear-Usher syndrome;

L10.5 – Drug-induced pemphigus;

L10.8 – Other forms of pemphigus;

L10.9 – Pemphigus, unspecified.

1.5 Classification of the disease or condition

Clinical classification of the disease:

1. Pemphigus vulgaris.

2. Vegetative pemphigus.

3. Herpetiform pemphigus.

4. Pemphigus foliaceus.

5. Brazilian pemphigus.

6. Pemphigus erythematosus. Senear-Usher syndrome.

7. Drug-induced pemphigus.

8. Other types of pemphigus: paraneoplastic pemphigus; IgA-pemphigus; subcorneal pustular dermatosis; intraepidermal neutrophilic dermatosis.

Classification of the disease by severity:

1. Mild severity.

2. Moderate severity.

3. Severe.

Severity is determined using the Mahajan criteria (Table 1) [15, 16].

Table 1. Severity grades of pemphigus vulgaris

Classification of the disease by phase of course:

1. Progressive phase (disease onset) in the absence of systemic corticosteroid therapy.

2. Progressive phase during ongoing systemic corticosteroid therapy.

3. Phase of drug-induced remission during high-dose glucocorticosteroid therapy.

4. Phase of drug-induced remission during maintenance-dose glucocorticosteroid therapy.

Classification of the disease in relation to ongoing treatment:

1. Glucocorticosteroid-responsive (do not specify in the diagnosis).

2. Glucocorticosteroid-resistant.

1.6 Clinical presentation of the disease or condition

Pemphigus vulgaris (L10.0) is the most frequent form of the disease, characterized by the presence of blisters of various sizes with a thin, flaccid roof and serous contents, arising on seemingly unchanged skin and/or mucous membranes of the oral cavity, nose, pharynx, and genitals. Characteristic signs include hypersalivation and specific halitosis. Blisters persist for a short time (from several hours to a day). On mucous membranes, their appearance sometimes goes unnoticed because the thin blister roofs rupture rapidly, forming long-lasting, painful erosions. Some skin blisters may dry into crusts. Erosions in pemphigus vulgaris are usually bright pink with a shiny, moist surface. They tend to peripheral growth; generalization of the skin process is possible, leading to extensive lesions, worsening of the general condition, secondary infection, development of intoxication, and a fatal outcome in the absence of therapy. One of the most characteristic signs of acantholytic pemphigus is the Nikolsky sign, which is a clinical manifestation of acantholysis and represents the detachment of the epidermis upon mechanical impact on the skin within the lesions, adjacent to them, and possibly on distant areas of the skin.

Seborrheic or erythematous pemphigus (Senear-Usher syndrome) (L10.4) is a minor form of pemphigus foliaceus and is characterized by the appearance of rashes on the skin of the face, back, chest, and scalp; mucous membranes are not affected. Rashes present as bright pink plaques, on the surface of which easily removable, thin, or loose crusts soaked in serous exudate, or yellowish scales, are identified. In the place of removed scales and crusts, an erosive surface with a shiny, bright red surface is revealed. Over time, blisters characteristic of pemphigus appear at the periphery of the plaques and on seemingly unchanged skin of the upper half of the trunk and upper extremities. They are typically ephemeral, with a flaccid, thin roof, rapidly rupturing to form erosions. The Nikolsky sign is weakly positive predominantly within the lesions.

Pemphigus foliaceus (L10.2) is characterized by erythematous-squamous rashes and thin-walled blisters that repeatedly appear in the same places, upon the rupture of which pink-red erosions are exposed, followed by the formation of lamellar crusts, sometimes quite massive due to the constant drying of the discharging exudate. Involvement of mucous membranes is uncharacteristic. Rapid spread of rashes in the form of flat blisters, erosions merging with one another, layered crusts, and scales is possible, with the development of exfoliative erythroderma, worsening of the general condition, and the addition of a secondary infection. The Nikolsky sign is positive both in the lesions and on seemingly healthy skin.

Vegetating pemphigus (L10.1) is a minor benign form of pemphigus vulgaris. Depending on the primary elements, two types of vegetating pemphigus are distinguished. Type I (Neumann type) of vegetating pemphigus is the classical form, in which the primary morphological element is a flaccid blister. Type II (Hallopeau type) of vegetating pemphigus is regarded as "vegetating pyoderma": the primary morphological element is a pustule resulting from acantholysis, histologically with a predominant content of eosinophilic leukocytes. Type I (Neumann type) is characterized by the appearance of blisters, most often on the mucous membranes of the oral cavity, around natural orifices (mouth, nose, genitals), and in the area of skin folds (axillary, inguinal, retroauricular, inframammary). Blisters rupture easily. Soft, juicy, malodorous vegetations covered with a serous and/or purulent coating, with the presence of pustules at the periphery, form at the base of the resulting erosions. The Nikolsky sign is positive only near the lesions. In the terminal stage, the skin process resembles pemphigus vulgaris.

Herpetiform pemphigus (L10.8) is a rare atypical bullous dermatosis in which rashes may present as plaques with papules and vesicles located at their periphery, or as grouped papules, vesicles, or tense blisters, as in dermatitis herpetiformis of Duhring.

Paraneoplastic pemphigus (L10.8) typically resembles the clinical picture of pemphigus vulgaris in its clinical manifestations, with simultaneous involvement of the skin and mucous membranes, but sometimes atypical skin lesions are observed, accompanied by itching and resembling erythema multiforme, bullous pemphigoid, or toxic epidermal necrolysis. Erosive and ulcerative lesions of the lips, oral cavity, nose, and pharynx with sharp pain are frequent, and scarring keratitis is frequently observed [17, 18].

Drug-induced (medication) pemphigus (L10.5) may resemble the clinical picture of pemphigus vulgaris, seborrheic, or foliaceus pemphigus.

IgA-dependent pemphigus (L10.8) is a rare group of autoimmune intraepidermal bullous dermatoses characterized by vesiculopustular rashes, neutrophilic infiltration, acantholysis, and the presence of both fixed and circulating IgA autoantibodies directed against antigens of the intercellular binding substance of stratified squamous epithelium. The clinical picture of IgA-dependent pemphigus, regardless of the type of its manifestation, is represented by flaccid vesicles or pustules located on both hyperemic and seemingly "healthy" skin. Pustules tend to merge to form annular lesions with crusts in the central part. Rashes are most often localized on the skin in the axillary regions, scrotum, trunk, and upper and lower extremities. Less commonly, the skin of the scalp and retroauricular region, as well as the mucous membranes, are involved in the pathological process. Patients frequently complain of intense itching. As a rule, IgA-dependent pemphigus has a more benign course compared to IgG-dependent pemphigus.

Example of clinical diagnosis formulation: acantholytic pemphigus, vulgaris form, severe grade, glucocorticosteroid-resistant, exacerbation.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

The diagnosis of pemphigus is established on the basis of:

1) anamestic data;

2) physical examination, including visual inspection of the skin and mucous membranes;

3) cytological examination for acantholytic cells from the base of erosions of the mucous membranes and/or skin;

4) pathomorphological examination of skin biopsy material from lesion sites.

5) Pathomorphological examination of skin biopsy (surgical) material using immunofluorescence methods and/or blood serum examination by indirect immunofluorescence to detect IgG and IgA autoantibodies

2.1 Complaints and Anamnesis

In patients with pemphigus vulgaris (L10.0), the first rashes most often appear on the mucous membranes of the oral cavity, nose, pharynx, and/or the red border of the lips. After 3–12 months, the process becomes more widespread with involvement of the skin. Patients are troubled by pain when eating, talking, and swallowing saliva.

Seborrheic or erythematous pemphigus (Senear-Usher syndrome) (L10.4), unlike pemphigus vulgaris, in which mucous membranes are usually affected first, begins on seborrheic areas of the skin (face, back, chest, scalp). The disease may remain localized for many months and years. However, the spread of lesions to new areas of the skin and mucous membranes (most often the oral cavity) is possible. In some patients, transformation of the seborrheic form into the vulgaris form with generalization of the pathological process may occur.

Patients with pemphigus foliaceus (L10.2) complain of skin lesions.

Patients with vegetating pemphigus (L10.1) are troubled by rashes on the mucous membranes of the oral cavity, around natural orifices (mouth, nose, genitals), and in the area of skin folds (axillary, inguinal, retroauricular, inframammary). Involvement of mucous membranes may be accompanied by pain. The disease may have a benign course for many years in the form of localized lesions with a satisfactory general condition of the patient.

In herpetiform pemphigus (L10.8) patients complain of rashes, usually accompanied by severe itching. In the absence of adequate therapy, the disease may progress and acquire features of pemphigus vulgaris or pemphigus foliaceus.

Paraneoplastic pemphigus (L10.8) occurs against the background of neoplasia and may also occur during or shortly after chemotherapy for malignant neoplasms. In most cases, paraneoplastic pemphigus is associated with lymphoproliferative neoplasms, thymoma, sarcoma, carcinoma, and solid tumors of various localizations. After tumor removal, rapid regression of the rash and complete recovery are possible.

The development of drug-induced pemphigus (L10.5) is most often associated with the intake of medications containing sulfhydryl radicals, penicillamine**, captopril**, and beta-lactam antibacterial drugs: penicillins, and is caused by biochemical rather than autoimmune reactions. In cases of drug-induced pemphigus, complete recovery is possible after drug withdrawal.

Patients with IgA-dependent pemphigus complain of skin lesions and, less commonly, mucosal lesions. Patients often complain of intense pruritus.

All clinical forms of pemphigus are characterized by a prolonged chronic relapsing course, leading in the absence of treatment to impairment of the patient's general condition, and in some cases to a fatal outcome.

2.2 Physical Examination

Objective clinical manifestations of pemphigus detected during physical examination are described in section 1.6 "Clinical Presentation".

Comments: Nikolsky's sign is not a pathognomonic feature of pemphigus, but it is usually positive in pemphigus. It may be positive in other skin diseases.

2.3 Laboratory Diagnostics

Comments: The presence of acantholytic cells is not a pathognomonic but a very important diagnostic sign; at the onset of the disease, especially in pemphigus erythematosus (seborrheic pemphigus), acantholytic cells may be absent.

Comments: The test allows the detection of circulating IgG autoantibodies (in the case of pemphigus vulgaris, foliaceus, erythematosus, vegetans, and herpetiformis) or circulating IgA autoantibodies (in the case of IgA-dependent pemphigus) against surface antigens of keratinocytes/epitheliocytes, in patterns similar to those observed in immunofluorescence studies of a biopsy of clinically uninvolved patient skin [19, 24].

This research method does not replace the direct immunofluorescence assay, but complements it.

Comments: Complete blood count (CBC) is performed before initiating systemic corticosteroid therapy as monotherapy or in combination with immunosuppressants or antineoplastic drugs (rituximab**, #methotrexate**) and during its course to assess the patient's condition, identify potential complications of previous therapy, and prescribe supportive therapy [18].

Comments: A general clinical blood chemistry test is performed before initiating systemic corticosteroid therapy as monotherapy or in combination with immunosuppressants or antineoplastic drugs (rituximab**, #methotrexate**) and during its course to assess the patient's condition, identify potential complications of previous therapy, and prescribe supportive therapy [18]. The test helps detect adverse effects of glucocorticosteroid and other ongoing therapies, such as hyperglycemia, hypokalemia, Na⁺ retention, manifestations of a negative nitrogen balance resulting from protein catabolism, etc.

Comments: Urinalysis (routine) is performed before initiating systemic corticosteroid therapy as monotherapy or in combination with immunosuppressants or antineoplastic drugs (rituximab**, #methotrexate**) and during its course to assess the patient's condition, identify potential complications of previous therapy, and prescribe supportive therapy. The test allows for the detection of adverse effects of glucocorticosteroid and other ongoing therapies, such as glucosuria.

2.4 Instrumental Diagnostics

Comment: Performed before initiation, three months after starting treatment, and every six months during systemic corticosteroid therapy to detect possible development of osteoporosis as a complication.

Comments: Targeted chest X-ray is performed to detect complications of ongoing immunosuppressive therapy and to diagnose paraneoplastic pemphigus.

Comments: Comprehensive ultrasound examination of the abdominal organs is performed to detect complications of ongoing immunosuppressive therapy and to diagnose paraneoplastic pemphigus.

2.5 Other Procedures

Comments: It is preferable to perform a skin or mucous membrane biopsy from a freshly formed blister (present for no more than 24 hours). The examination reveals intraepidermal suprabasal acantholysis in pemphigus vulgaris or acantholysis at the granular cell layer level in pemphigus foliaceus/seborrheic pemphigus [19, 20].

The material is fixed in buffered 10% formalin. When taking a biopsy, it is advisable to capture a small intact blister if possible. If it is not possible to obtain an intact bullous lesion – 1/3 of the obtained biopsy specimen should consist of the blister fragment and 2/3 of the adjacent skin/mucous membrane [19].

Comments: To perform pathomorphological examination of a skin biopsy specimen using immunofluorescence methods for diagnosing pemphigus, it is necessary to take a biopsy of clinically normal skin adjacent to the lesion (preferably in the upper trunk and at a distance of about 1 cm from it).

The examination allows detecting [19, 21, 22]:

- IgG and/or complement component C3 deposits on the surface of epidermal keratinocytes, forming a "fine-mesh" pattern – in pemphigus vulgaris, pemphigus foliaceus, seborrheic pemphigus, pemphigus vegetans, and herpetiform pemphigus;

- IgA deposits on the surface of epidermal keratinocytes, forming a "fine-mesh" pattern – in IgA-pemphigus, while IgG deposits are either not detected or detected in insignificant amounts;

- IgG and/or complement component C3 deposits both on the surface of epidermal keratinocytes and along the dermo-epidermal junction in the form of a linear pattern or granules in paraneoplastic pemphigus, or in rare cases of coexistent pemphigus and bullous pemphigoid.

After biopsy, the material should be wrapped in a sterile gauze sponge moistened abundantly with 0.9% sodium chloride solution**, and delivered to the laboratory within 2 hours for freezing and cryostat sectioning. Immunofluorescence examination of the patient's skin biopsy specimen can be performed using either direct or indirect methods [23].

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

3.1 Conservative Treatment

prednisolone** or other systemic corticosteroids orally for adults and children according to the prednisolone equivalent at a dose of 80–100 mg per day, but not less than 1 mg per kg of the patient's body weight.

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comments: Oral therapy with prednisolone** at a dose of 80–100 mg per day, but not less than 1 mg per kg of the patient's body weight, or other systemic corticosteroids according to the prednisolone equivalent represents the first stage of treatment for patients with pemphigus, lasting for 3 weeks, less frequently 4 or more weeks [26–30, 69, 76, 77, 82].

In severe patient conditions, higher doses are prescribed – up to 200 mg per day and higher. The daily dose of the drug is taken strictly in the morning hours (before 11:00 AM). In addition, high doses of systemic corticosteroids can be administered in two stages at 7:00–8:00 AM and 10:00–11:00 AM, but mandatory after each meal [26–30, 69, 76, 77, 82].

In refractory cases, one systemic corticosteroid may be replaced with another.

In intensive care settings under appropriate indications for patients with pemphigus whose general condition is assessed as severe, in the absence of a positive response to standard therapy, pulse therapy with methylprednisolone lyophilizate for solution for intravenous and intramuscular administration ** (intravenously 1 g/day for 4 days; not used in neonates) [82] or an equivalent dose of dexamethasone solution for injection ** intravenously [11, 14, 82].

Systemic corticosteroids form the basis of therapy for patients with pemphigus and are prescribed orally to every patient with a confirmed diagnosis. A contraindication to prescribing prednisolone** is age under 3 years, but they can be prescribed for vital indications, so there are no absolute contraindications to their use. In addition to systemic corticosteroids, adjuvant therapy (azathioprine**, #methotrexate**, etc.) can be prescribed, which allows reducing their dose or overcoming resistance to systemic corticosteroids. Symptomatic therapy is prescribed when indicated.

Comments: The initial reduction of the systemic corticosteroid dose is possible by 1/4–1/3 of the maximum dose after achieving a distinct therapeutic effect. The duration of this stage depends on the patient's clinical condition.

Comments: Thus, over the course of 8 weeks, ¼ of a prednisolone** tablet is withdrawn, and over 128 weeks, a maintenance dose of 6.25–3.75 mg per day is reached. This regimen helps avoid disease relapse during the dose-reduction period. The maximum permissible minimum maintenance dose can vary from 2.5 to 30 mg per day. Sometimes, in severe pemphigus, the maintenance dose cannot be reduced below 40–50 mg per day. The duration of treatment is determined individually; as a rule, therapy is lifelong, and only in rare cases is it possible to discontinue systemic corticosteroids.

Table 1. Tapering schedule for systemic corticosteroids (prednisolone**), starting from 4 tablets by days of the week

azathioprine** for adults and children from 3 years of age at 1.5–2 mg/kg/day in 3–4 divided doses orally [31–40, 78].

For the pediatric population – Grade of Recommendation C (Level of Evidence 3)

For the adult population – Grade of Recommendation C (Level of Evidence 4)

Comments: Treatment with azathioprine** should be carried out strictly under the control of a complete blood count. A contraindication to prescribing azathioprine** is age under 3 years.

or:

#methotrexate** subcutaneously, intramuscularly, or orally for adult and pediatric patients with pemphigus at 10–15–20 mg, if necessary – up to 25–30 mg, once a week. The duration of therapy is determined individually [29, 30, 41–48, 77].

GCR CLEL 3Grade of Recommendations C (Level of Evidence 3)

Comments: During treatment with #methotrexate**, monitoring of complete blood count, general biochemical blood tests, and urinalysis is required at least 1–2 times a week.

Comments: Contraindication: children under 3 years of age. #Folic acid** deficiency may enhance the toxic effect of #methotrexate**. Concomitant administration of #фолиевой кислоты** may reduce the toxic effect of #метотрексата** (gastrointestinal symptoms, stomatitis, alopecia, and increased liver enzyme activity).

#Cyclosporine** at an initial dose of 2.5–5 mg/kg of body weight per day in 2 divided doses (morning and evening). If no improvement is observed after 4 weeks of #cyclosporine** treatment at a daily dose of 2.5 mg/kg body weight per day, the dose may be increased up to 5 mg/kg body weight per day in the absence of clinically significant laboratory abnormalities [44–49, 78, 82–84].

Level of Recommendations CLevel of Evidence 5Level of Recommendations C (Level of Evidence 5)

Comments: Treatment with #cyclosporine** should be carried out strictly under the control of blood pressure and blood and urine creatinine levels.

Switching from one drug to another in case of insufficient therapeutic efficacy should be performed no earlier than 3 weeks later.

plasmapheresis 3 procedures per week for 1–3 months [57, 58].

GCP CLE 4Grade of Recommendation C (Level of Evidence 4)

Comments: Plasmapheresis should not be used in routine practice. It may be used in severe resistant cases in combination with systemic corticosteroids and immunosuppressants. Complete remission was achieved in 57% of patients, and partial regression of rashes in 28% [58]. One randomized study revealed no positive effect of plasmapheresis [59]

or

extracorporeal photochemotherapy [60, 61].

GCP CLE 4Grade of Recommendation C (Level of Evidence 4)

Comments: May be used for resistant pemphigus unresponsive to systemic corticosteroid therapy. Improvement of patients' condition and a steroid-sparing effect have been described in small case series [52, 53].

or

rituximab** in adult patients: 1000 mg as an intravenous infusion, followed 2 weeks later by a second intravenous infusion of 1000 mg in combination with glucocorticoid therapy with a gradual tapering of the latter [11, 73, 79, 80].

GCR BLOCE 2Grade of Recommendation B (Level of Evidence 2)

Comments: Prior to initiating rituximab** therapy, all patients should be screened for hepatitis B. The minimum test set should include determination of hepatitis B virus surface antigen (HBsAg) in the blood and antibodies to hepatitis B virus core antigen (anti-HBc) in the blood. Patients with positive hepatitis B serological markers should consult a gastroenterologist before using rituximab**; such patients should be appropriately monitored and managed for hepatitis B reactivation in accordance with standard guidelines.

Patients with pemphigus vulgaris should receive premedication with methylprednisolone** at a dose of 100 mg intravenously 30 minutes before the start of each infusion to reduce the frequency and severity of infusion reactions [73]. Rituximab** must be administered only as an intravenous infusion via a separate catheter. The recommended initial infusion rate for the first infusion is 50 mg/h; after the first 30 minutes, the rate can be increased by 50 mg/h every 30 minutes, up to a maximum rate of 400 mg/h. Subsequent infusions of rituximab** can be initiated at a rate of 100 mg/h and increased by 100 mg/h every 30 minutes, up to a maximum rate of 400 mg/h. During the infusion, patients should be closely monitored for early signs of cytokine release syndrome. The infusion must be stopped immediately in patients who develop symptoms of severe reactions, particularly severe dyspnea, bronchospasm, or hypoxia. Subsequent infusions of rituximab** should be administered no earlier than 16 weeks after the previous administration.

Maintenance therapy with rituximab** at a dose of 500 mg intravenously should be administered at months 12 and 18 of therapy, and every 6 months thereafter, based on clinical evaluation. In case of relapse, patients may receive 1000 mg of rituximab** intravenously.

In the event of a relapse in a pemphigus patient receiving rituximab** therapy, the attending physician should consider resuming systemic corticosteroid therapy or increasing their dose based on clinical evaluation. A contraindication to prescribing rituximab** in pemphigus is age under 18 years. Nevertheless, a case of rituximab** administration in combination with systemic corticosteroids has been described in a 16-year-old patient with severe pemphigus, resulting in complete regression of rashes within 1.5 months and discontinuation of systemic corticosteroids within 8 months [81].

3.2 Surgical Treatment

Not applicable.

3.3 Other Treatment

Comments: Garlic, onions, mustard, horseradish, broccoli, cauliflower, cassava, mango, guarana, kola nut, black walnut, raspberries, cherries, cranberries, rosemary, vanillin, coffee, ginger roots, ginseng, tea, mate, and various spices (coriander, cumin, black pepper) should be excluded from the diet [14, 54]. In case of oral cavity involvement, pureed soups and mucous porridges should be included in the patient's diet to prevent complete refusal of food. The diet should restrict table salt and carbohydrates while providing adequate protein and vitamins. Foods containing thiol groups and phenolic compounds—tannins—may provoke exacerbation of pemphigus.

Pain management is not used.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Patients may be cleared for work that does not require excessive physical and mental strain, and is not associated with hypothermia or sun exposure. Insolation is contraindicated for patients with all forms of pemphigus; sunscreens with the maximum protection factor must be used consistently. It is important for patients to observe a proper regimen of work, rest, and sleep. Mineral water and mud therapy at resorts, as well as therapeutic and cosmetic massages, are not permitted.

5. Prevention and Dispensary Observation

Prophylaxis is not applied.

To prevent exacerbations of the disease, the dose of systemic corticosteroids is reduced very slowly to a maintenance dose strictly under the supervision of a dermatovenereologist. In summer and during viral infection epidemics, it is inadvisable to reduce the dose of systemic corticosteroids. Prior to surgical interventions or dental prosthetics, it is inadvisable to reduce the dose of systemic corticosteroids, or betamethasone injections (contraindicated in children under 3 years) at a dose of 1 ml intramuscularly may be administered 5 days prior to the planned surgical intervention, immediately before surgery, and one week after [77]. Corrective therapy is mandatory.

After discharge from the hospital, such patients must remain under the continuous supervision of a dermatovenereologist and related specialists [62, 63]. Dispensary monitoring is mandatory for all patients suffering from pemphigus. The frequency of visits to the dermatovenereologist should depend on the severity of pemphigus and the daily dose of systemic corticosteroids.

During the tapering phase of the daily dose of systemic corticosteroids, follow-up by a dermatovenereologist should occur every 10–14 days to monitor the tapering rate and assess the patient's condition. With a further slowed tapering rate of the daily dose of systemic corticosteroids (prednisolone** daily dose of 20 mg), the follow-up frequency is once every 3 months [71, 72].

Once the maintenance dose is reached, patients need to visit the dermatovenereologist twice a year.

Clinical examination and laboratory monitoring (blood sodium and potassium testing, blood chloride testing, coagulation study (screening hemostasis test), complete blood count, general general-practice blood chemistry test) should be performed at least twice a year, or more frequently if necessary. Annual monitoring includes blood electrolyte levels (blood sodium, potassium, and chloride testing), chest X-ray, densitometry, comprehensive ultrasound of the abdominopelvic organs, kidneys, thyroid and parathyroid glands, comprehensive pelvic organs (transvaginal and transabdominal), mammography (in women), prostate ultrasound (in men), esophagogastroduodenoscopy, tumor marker blood tests, and consultations with related specialists (general practitioner, endocrinologist, otorhinolaryngologist, dentist, etc.).

6. Organization of Medical Care

Indications for hospital admission to a medical organization:

1) rashes corresponding to the clinical presentation of autoimmune pemphigus;

2) exacerbation of pemphigus.

Indications for patient discharge from a medical organization

1) stabilization of the process;

2) epithelialization of 70% of erosions.

7. Additional Information

It is necessary to prevent secondary infection in the lesions, especially in widespread skin involvement with multiple weeping erosions.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Kubanov Alexey Alekseevich – Academician of the RAS, Doctor of Medical Sciences, Professor, Director of the State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, President of the Russian Society of Dermatovenereologists and Cosmetologists.

2. Vitaly T. Bazaev – MD, Associate Professor, Head of the Department of Dermatovenereology, North Ossetian State Medical Academy, member of the Russian Society of Dermatovenereologists and Cosmetologists.

3. Yulia A. Gallyamova – MD, Professor, Head of the Course of Dermatovenereology and Cosmetology at the Department of Allergology and Immunology with the Course of Dermatovenereology and Cosmetology, Penza Institute for Advanced Medical Training – branch of the Russian Medical Academy of Continuing Professional Education of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.

4. Igor Yu. Golousenko – MD, Professor at the Russian University of Medicine of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.

5. Lyudmila F. Znamenskaya – MD, Leading Researcher at the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.

6. Arfenya E. Karamova – PhD, Associate Professor, Head of the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.

7. Nataliya V. Makhneva – MD, Head of the Scientific and Organizational Department, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.

8. Mariya A. Nefedova – Junior Researcher at the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.

9. Yury N. Perlamutrov – MD, Professor, Head of the Department of Skin and Venereal Diseases, Russian University of Medicine of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetology.

10. Olga A. Pritulo – MD, Professor, Head of the Department of Dermatovenereology and Cosmetology, S.I. Georgievsky Medical Institute, V.I. Vernadsky Crimean Federal University, member of the Russian Society of Dermatovenereologists and Cosmetologists.

11. Nataliya P. Teplyuk – MD, Professor at the Department of Skin and Venereal Diseases, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), member of the Russian Society of Dermatovenereologists and Cosmetologists.

12. Vadim V. Chikin – MD, Senior Researcher at the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.

Conflict of interest:

The authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Medical specialists: dermatovenereologists, dentists.

2. Faculty members of medical educational institutions in the specialty «Dermatovenereology».

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

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

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

• Procedure for the provision of medical care in the profile «dermatovenereology», approved by Order of the Ministry of Health of the Russian Federation No. 924n dated November 15, 2012.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

1. When taking systemic corticosteroids, regular monitoring is required for blood pressure, complete blood count (CBC), and general clinical blood chemistry parameters

2. blood test (blood glucose levels, water-electrolyte balance). It should be taken into account that systemic corticosteroids can reduce resistance to infection; therefore, hypothermia should be avoided.

3. The dose of systemic corticosteroids should be tapered to a maintenance dose very slowly, strictly under the supervision of a dermatovenereologist.

4. During the summer season and periods of viral infection outbreaks, or prior to surgical interventions and dental prosthetics, the dose of systemic corticosteroids should not be reduced.

5. The diet should limit table salt and carbohydrates while providing adequate protein and vitamins. In case of oral cavity lesions, frequent and small meals are recommended; pureed soups and mucous gruels should be included in the patient's diet to prevent complete refusal of food.

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

Rating scales, questionnaires, and other assessment tools are not used.