True vesicles: causes, symptoms, diagnosis, treatment

True pemphigus (pemphigus) (synonym: acantholytic pemphigus) is a severe chronically recurring autoimmune disease of the skin and mucous membranes, the morphological basis of which is the process of acantholysis - a violation of the connections between the cells of the epidermis. Blisters occur as a result of acantholysis. The mechanism of immune disorders has not been fully established.

Pemphigus affects people of all nationalities, but is more common among Jewish people. The disease is also often registered among Mediterranean peoples (Greeks, Arabs, Italians, etc.), in eastern India. Such frequent occurrence of pemphigus is possibly explained by consanguineous marriages, which are allowed in some nationalities. Most scientific literature devoted to the problem of pemphigus indicates the prevalence of this dermatosis among women.

Causes and pathogenesis of true pemphigus

Despite numerous studies, the etiology and pathogenesis of pemphigus remain unknown. There are many theories explaining the origin of the disease: the theory of chloride retention, the theory of toxic origin, the theory of cytological anomalies, the theory of neurogenic origin, the endocrine theory, the theory of enzymatic origin, the theory of autoimmune origin, etc. However, many existing theories are outdated and have only historical significance.

Based on currently available immunological data, pemphigus is an autoimmune disease, although the causes of immune system dysfunction in this pathology remain unclear. It is possible that the immune system changes under the influence of exogenous factors in the presence of genetic features of the immune system.

The data on cellular immunity studies are heterogeneous and they show an increase in IgG, autoantibodies in the blood serum, a decrease in T-cell immunity, a decrease in the proliferative response to T-cell mitogens such as concanavalin A and phytohemagglutinin. However, the data obtained are only present in patients with a severe and widespread process.

There is a difference in the production of various IgG in patients in the acute phase of the disease and in remission. IgG1 and IgG4 predominate in patients with exacerbations. It was found that IgG pemphigus antibodies fix both early (Clq, C3 C4) and late (C3-C9) complement components. Early complements can pre-accumulate in the keratinocyte membrane, which leads to the activation of late ones under the influence of pemphigus IgG. In this case, a complex is formed that disrupts the permeability of keratinocyte membranes.

Autoantibodies in the blood serum of patients with pemphigus are directed to antigens of the intercellular adhesive substance (desmosomes) of the stratified squamous epithelium, which correlates with disease activity.

Currently, three representatives of the desmoglein class (Dcr) are known. These are desmoglein-1 (Dcr1), desmoglein-2 (Dcr2), and desmoglein-3 (Dcr3). All of them are encoded by genes located on chromosome 18, which confirms their relationship. Electron microscopic studies have shown the localization of both Dcr1 and Dcr3 in desmosomes. Both desmogleins are well represented in stratified squamous epithelium and are associated with disulfide bonds with plakoglobulins, proteins of desmosomal plaques. Dcr2 is the most common desmosomal protein and is localized in desmosomes of nonepithelial cells.

Immunohistochemical studies have shown that Dcr1 is an antigen for pemphigus foliaceus, and Dcr3 for pemphigus vulgaris. This approach to the pathogenesis of pemphigus allows us to categorically state that there are only two forms: vulgaris and pemphigus foliaceus (superficial). All other forms are their variants.

Symptoms of true pemphigus

Clinically, acantholytic pemphigus is divided into common, vegetative, foliaceous and erythematous (seborrheic, or Senier-Usher syndrome).

Pemphigus vulgaris is characterized by a rash of flaccid blisters, usually located on unchanged skin and mucous membranes, with transparent contents. The blisters quickly open with the formation of painful erosions with a red, wet surface, increasing even with slight trauma. With friction, erosions can also occur on outwardly unchanged skin, especially near the blisters (Nikolsky's symptom). The rash can be located on any area of the skin, but most often the mucous membranes, skin folds, and areas subject to trauma are affected. In approximately 60% of patients, the process begins in the oral cavity and for a long time can be limited to this area, resembling stomatitis. Isolated lesions, sometimes with vegetations, hyperkeratosis, especially in children, often having significant similarities with impetigo, seborrheic dermatitis, pink lichen, bullous multiform exudative erythema and other dermatoses, can also be on the skin. For diagnostic purposes in such cases, smears-prints from erosive surfaces are examined to detect acantholytic cells and an immunomorphological study is performed to identify immune complexes in the epidermis.

Mixed forms with features of pemphigus and pemphigoid are described, as well as variants similar to Duhring's dermatitis herpetiformis. The disease develops in middle and old age, although it can also be observed in children.

Vulgar (common) pemphigus is usually acute and in most patients (more than 60% of cases) begins with lesions of the oral mucosa, being the only symptom of the disease for a long time. It is possible that the disease begins with lesions of the mucous membrane of the genitals, larynx, trachea. At first, single or few blisters appear, often located in the retromalar region, on the lateral surface of the tongue. Under the influence of food or teeth, the thin and flabby cover of the blisters quickly opens and bright red erosions are exposed, along the periphery of which you can sometimes see fragments of the covers of the blisters. Eroded areas of the oral mucosa are very painful: patients cannot chew and swallow food, there is pronounced salivation, deep cracks in the corners of the mouth, preventing it from opening. Patients with lesions of the oral mucosa sometimes consult a dentist and receive treatment for stomatitis for a long time. After 3-6 months, isolated blisters appear on the skin and, as the process progresses, generalization of the process begins. Pemphigus is characterized by the appearance of flaccid blisters (a monomorphic rash) on apparently unchanged, rarely erythromatous skin. The blisters can be small or large, with serous, and after some time - cloudy, sometimes hemorrhagic contents. Over time, the blisters tend to grow peripherally, merging with each other to form large scalloped foci. After some time, the contents of the blisters dry out, forming yellowish crusts, which fall off, leaving hyperpigmented secondary spots. If the blister cap is damaged, bright red painful erosions with a juicy red bottom are formed, separating thick exudate, along the periphery of which there are fragments of the blister cap. During this period, Nikolsky's symptom is almost always positive (not only in the immediate vicinity of the lesion, but also on areas of outwardly unchanged skin). The essence of this phenomenon is the detachment of clinically unchanged epidermis with sliding pressure on its surface. A modification of Nikolsky's symptom is the Asboe-Hansen phenomenon: when pressing with a finger on the cover of an unopened blister, its area increases due to acantholysis.

The "pear" phenomenon was described by N. D. Sheklakov (1961): under the weight of the fluid accumulated in the bladder with pronounced acantholysis, the area of its base increases and the bladder takes on a pear-shaped form. The movement of patients is limited due to the painfulness of the erosion.

Blisters may appear on an edematous and erythematous background and tend to cluster. It is believed that blisters in common pemphigus occur on unchanged skin and the clinical picture is similar to Duhring's dermatitis herpetiformis. In such cases, we are talking about herpetiform pemphigus. The literature provides the following clinical, histological and immunomorphological criteria for herpetiform pemphigus as a variant of common pemphigus:

• herpetiform nature of the rash, accompanied by burning and itching;
• suprabasal and subcorneal acantholysis with the formation of intraepidermal blisters;
• detection of IgG in the intercellular space of the epidermis.

Later, along with herpetiform rashes, patients increasingly develop large flaccid blisters on outwardly unchanged skin, and the clinical picture takes on the classic features characteristic of pemphigus vulgaris.

Erosions are slowly epithelialized and after healing of foci on mucous membranes and conjunctiva there are no scars. In case of secondary infection or involvement of the basement membrane in the pathological process, areas of cicatricial atrophy or scars are formed at the site of former lesions. Generalization of the process is often accompanied by deterioration of the general condition of patients, malaise, weakness, insomnia, increased body temperature, sometimes fever are observed. If treatment is not carried out, patients die from secondary infection or cachexia.

Histopathology. The lesions show loss of intercellular bridges, acanthosis and formation of intraepidermal cavities in the deep layers of the epidermis. The blisters contain round acantholytic Tzanck cells. IgG antibodies are detected in the intercellular spaces of the epidermis.

Histogenesis. Acantholysis is based on changes in the cementing substance, which is in direct contact with the outer layer of the plasma membrane of epithelial cells and in greater quantities in desmosomes. It has been established that immune disorders play a major role in the primary damage to the cementing substance. Direct immunofluorescence revealed IgG antibodies in the skin, localized in the intercellular spaces of the epidermis. Indirect immunofluorescence revealed antibodies against components of the intercellular cementing substance of the epidermis when treated with luminescent human anti-IgG serum. The C3 component of complement was also detected, which allows us to classify this disease as an immune complex disease.

The mechanisms of immune disorders in pemphigus have not yet been established. It is believed that the main pathogenetic role belongs to the antigen to desmoglein III circulating in the blood, which is a glycoprotein in a complex with plakoglobin and is a mediator of cellular adhesion in the desmosome area. It is assumed that the onset of the antigen-antibody reaction, promoting acantholysis, is preceded by the activation of proteases and plasminogen activator. By means of immunochemical analysis of epidermal antigens, E.P. Matushevskaya (1996) identified a previously unstudied antigen - water-soluble globulin of the skin a2-BGK. In addition, two specific proteins a2-GPVP-130 and a2-GPLP-160 associated with the common and foliaceous forms of pemphigus, respectively, were found in the blister fluid. Damage to the immune system at various levels, including the thymus and skin, a possible role of genetic factors suggested by familial cases of the disease, and data on increased detection of some tissue compatibility antigens are indicated. In particular, an association of the disease with HLA-A10, HLA-A26, HLA-DRW6, HLA-DRW4, and BW38 has been established. It is believed that carriers of the DRw6 serotype have a 2.5-fold increased risk of developing the disease, and predisposition to pemphigus is associated with linkage disequilibrium with the DQw3 and DQwl alleles of the DQ locus. A new allele (PV6beta) of the same locus has been discovered, and a test with PV6beta - allele-specific oligonucleotide has been proposed for diagnosing the disease at early stages or in atypical cases. The role of viral infection has not been proven. Mainly B-cell immunity changes, but with a long course, a T-cell defect also develops. Insufficiency of interleukin-2 synthesis has been revealed. Vegetating pemphigus is characterized by the presence of papillomatous-verrucous growths in the area of erosions, localized mainly in the folds of the skin and periorificially. In some patients, the lesions may be similar to those in vegetating pyoderma due to the appearance of vegetation with pustular elements (vegetating pemphigus of Hallopeau). The differential diagnostic sign in such cases is the detection by direct immunofluorescence of IgG, which form immune complexes with the antigen in the epidermis. Vegetating pemphigus of this type proceeds more favorably than the classic Neumann variant.

Pathomorphology. Acanthosis with elongation of epidermal outgrowths and dermal papillae and proliferation of epithelial cord cells. In the area of warty vegetations - acanthosis, papillomatosis, intraepidermal abscesses containing eosinophilic granulocytes. The presence of these abscesses is characteristic of vegetative pemphigus. In the Hallopeau type, in foci representing blisters-pustules, acantholysis is observed with the formation of small suprabasal slits around the pustules. The cavities are filled with eosinophilic granulocytes and acantholytic cells.

To ensure correct diagnosis, it is necessary to biopsy the skin from the lesion with fresh, preferably small blisters. Early signs of pemphigus are intercellular edema of the epidermis and destruction of intercellular bridges (desmosomes) in the lower parts of the Malpighian layer. As a result of the loss of communication between the epithelial cells (acantholysis), first cracks are formed, and then blisters, localized mainly suprabasally. Nasal cells, although they lose communication with each other, remain attached to the basal membrane. The cavity of the bubble, as a rule, contains rounded acantholytic cells with large hyperchromatic nuclei and palely stained cytoplasm. Acantholysis can also be observed in the epithelial sheaths of hair follicles, where, as in the epidermis, cracks are formed, mainly above the basal layer. In old blisters, the following occurs: regeneration of the epidermis, their bottom is covered with several layers of epithelial cells. In places of rejection of the bladder cover, its bottom is lined with cells of the basal layer. During the healing process, proliferation of dermal papillae and elongation, sometimes significant, of epidermal outgrowths are noted. In these cases, the histological picture resembles vegetative pemphigus. Inflammatory changes in the dermis can be pronounced. The infiltrate consists of eosinophilic granulocytes, plasma cells and lymphocytes.

Similar changes are found on the mucous membranes. When the mucous membrane of the oral cavity is affected, it is very difficult to excise the entire blister, so smears-prints are used for diagnosis. In which, after staining using the Romanovsky-Giemsa method, acantholytic cells are found (Tzanck test). However, this test only supplements, but in no way replaces, the histological examination. Electron microscopic examination of the skin in the blister area and in clinically unchanged areas of it revealed major changes in the area of intercellular contacts. In the initial stages of acantholysis, changes in the intercellular substance were detected almost throughout the entire length of the Malpighian layer, which leads to the loss of the ability to form desmosomal connections. Cells that have lost their connection with each other become rounded, the number of tonofilaments in them decreases. They are concentrated around the nucleus, then undergo lysis and disappear.

The histogenesis of this type of pemphigus is the same as that of common pemphigus.

Pemphigus foliaceus is characterized by the superficial location of the blisters, as a result of which they are clinically barely noticeable, quickly covered with scaly crusts, often layered due to the repeated formation of blisters under them. The process is usually generalized, unlike ordinary pemphigus, it occurs with an inflammatory reaction, which gives the lesions a similarity to exfoliative erythroderma, psoriasis, seborrheic dermatitis and other dermatoses. Mucous membranes are rarely affected. Nikolsky's symptom is sharply positive, with trauma, extensive erosive surfaces occur. The prognosis for this form is less favorable than for ordinary pemphigus.

Pathomorphology. In fresh lesions, acantholysis usually occurs in the granular layer or directly under it with the formation of subcorneal blisters. Acantholysis may occur both at the base and in the roof of the blister. Sometimes, as a result of acantholysis, the horny and partially granular layers may separate without the formation of a blister. In the periphery of the cleft, the epidermocytes do not have desmosomes and tend to separate, as a result of which clefts may also form in the middle parts of the epidermis. Separation of the entire epidermis above the basal layer is possible. In old lesions, with a more benign course of the disease, acanthosis, papillomatosis and hyperkeratosis are usually observed, sometimes with hyperkeratotic plugs in the mouths of the hair follicles. In areas of hyperkeratosis, pyknosis with heterochromia of individual cells may be observed, resembling the “grains” in appearance in Darier’s disease; in the dermis, there is a moderately pronounced infiltrate, sometimes with the presence of eosinophilic granulocytes.

Histogenesis. The formation of a blister in pemphigus foliaceus is also based on acantholysis, which occurs as a result of a pathological antigen-antibody reaction, but the autoantibodies are directed against a different antigen than in the above-mentioned types of pemphigus, namely desmoglein I, another important protein component of desmosomes in a complex with plakoglobin I. In addition, the so-called eosinophilic spongiosis, which is detected in the epidermis in the earliest stages of the pathological process, sometimes before the development of acantholysis, morphologically resembling Duhring's herpetiform dermatitis, can play a role in the development of blisters. Electron microscopy at this period of the disease reveals dissolved intercellular cement and a reduced number of desmosomes. Tonofilaments are located perinuclearly, as in dyskeratosis. In this type of pemphigus, autoantibodies identical to those in common pemphigus are detected in the intercellular spaces of the epidermis.

We consider erythematous pemphigus as a limited variant of foliaceous pemphigus, but there is an opinion that it is an independent form of pemphigus or a combination of pemphigus with lupus erythematosus. This is indicated by clinical and morphological signs characteristic of both diseases. The lesions are located mainly on the back, chest and in the interscapular region. They have clinical signs of pemphigus (blisters), lupus erythematosus (erythema, sometimes atrophy) and seborrheic dermatitis (layering of scaly crusts) and can also resemble impetigo, exudative psoriasis. Nikolsky's symptom is positive, changes in the mucous membranes are often observed.

Pathomorphology. Changes are similar to pemphigus foliaceus. In old elements, follicular hyperkeratosis with acantholysis and dyskeratosis in the granular layer are noted. With clinical similarity, lupus erythematosus is differentiated from erythematosus pemphigus only histologically. Acantholysis and localization of the blister in the granular layer of the epidermis, minor inflammatory infiltrates in the dermis in erythematosus pemphigus distinguish it from lupus erythematosus.

Histogenesis. Changes in the epidermis revealed by electron microscopy are similar to those in pemphigus foliaceus, as well as the autoimmune status. However, in this disease, the direct immunofluorescence method reveals luminescence of the basement membrane as a result of the deposition of immunoglobulin G in it, as well as antinuclear antibodies, which is typical of autoimmune diseases in general. Th. Van Joost et al. (1984), conducting an immunomorphological study in seborrheic pemphigus, found that the pathogenesis of this disease is due to a primary defect in the function of T-suppressors, expressed in hyperproduction of autoantibodies.

Differential diagnosis. Pemphigus vulgaris must be distinguished from other forms of true pemphigus, pemphigoid, Duhring's disease and other blistering diseases.

In the clinical course of vegetative pemphigus, a distinction is made between classical (Neumann type) and benign (Gallopeau type) forms.

Symptoms. In Neumann's type, flaccid blisters appear suddenly, as in the vulgar form, the cover of which quickly opens, revealing bright red erosions of oval, round or irregular shape, which tend to grow peripherally. Eruptions often appear around natural openings and in folds (inguino-femoral, intergluteal, axillary, under the mammary glands, in the umbilical area). Over time (on the 5th-6th day), juicy, small, bright red vegetations with a foul-smelling discharge form on the surface of the erosions. The number and size of vegetative erosions increases. Pustules may appear along the periphery of the erosion. Nikolsky's symptom is positive in most patients.

In benign vegetative pemphigus (Gallopeau type), lesions are predominantly located on intertriginous areas of the skin and less frequently on the mucous membranes of the mouth. The course of the disease is more favorable. This form is always accompanied by pustular and follicular elements merging into infiltrated plaques with vegetations.

Histopathology. In the early stages of the disease, the histological picture in the area of blisters and erosions is similar to that observed in common pemphigus. Papillomatous and warty growths are characterized by papillomatosis and acanthosis with intraepidermal abscesses consisting of eosinophilic granulocytes. Immunomorphological studies in the intercellular spaces of the epidermis of patients reveal IgG deposits.

Differential diagnosis. Neumann's pemphigus vegetans must be differentiated from common pemphigus, secondary recurrent syphilis, drug-induced toxicoderma (iododerma, bromoderma), vegetative form of follicular dyskeratosis Darier, chronic familial benign pemphigus Hailey-Hailey.

Pemphigus foliaceus is much less common than the common type.

Symptoms. Pemphigus foliaceus has characteristic specific features: the appearance of superficial flabby blisters with a thin cover on unchanged or slightly hypersensitized skin. Their cover quickly ruptures even with a light touch or under the pressure of the blister fluid. In this case, juicy, bright red erosions with exudate are exposed, which soon dry up into layered scaly crusts. Extensive eroded areas covered with layered crusts resemble exfoliative erythroderma. An important clinical sign of pemphigus foliaceus is the repeated, sometimes continuous, formation of superficial blisters under the crusts at the site of previous erosions.

Nikolsky's symptom (this symptom was first described in the leaf-shaped form) is well expressed both near the lesions and in distant areas of the skin. As in other forms, the general condition of patients is disturbed (body temperature rises, secondary infection occurs, cachexia develops).

Histopathology. Histologically, pemphigus foliaceus shows acantholysis, usually in the granular layer or under it (subcorneal fissures), and acantholysis is pronounced. There is a pronounced inflammatory infiltrate in the dermis. IgG antibodies are detected in the intercellular spaces of the epidermis.

Differential diagnosis. Pemphigus foliaceus must be differentiated from erythroderma of various origins (secondary erythroderma, toxicoderma), common pemphigus, Duhring's dermatitis herpetiformis (blistering form), toxic epidermal necrolysis of erythematous (seborrheic) pemphigus, etc.

Erythematous (seborrheic) pemphigus (Senier-Usher syndrome) is one of the variants of true pemphigus, as evidenced by frequent cases of its transition to common or foliaceous pemphigus.

Symptoms: Erythematous pemphigus has symptoms of such dermatoses as erythematous lupus, pemphigus and seborrheic dermatitis.

As a rule, early rashes appear on the scalp, facial skin (in the cheek area or on the bridge of the nose with transition to adjacent areas of the cheeks, forehead), later lesions appear on the trunk. Erythematous lesions with clear boundaries are observed, on the surface of which there are thin or loose grayish scaly crusts. In case of weeping, the lesions are covered with grayish-yellow or brownish crusts. Crusts appear as a result of drying of the exudate of blisters, which are formed on the lesions or adjacent areas of the skin. The blisters that appear are often not noticeable to either the patient or the doctor, since they are thin and flabby. They quickly open and become covered with dense or loose crusts, can merge with each other or remain isolated for a long time. Nikolsky's symptom is positive in most patients.

On the scalp, the rash may resemble seborrheic dermatitis.

The mucous membranes are affected in approximately one third of patients. The course of the disease is long, with remissions.

Histopathology. Histopathology reveals fissures or bullae beneath the stratum corneum or granulosum of the epidermis as in pemphigus foliaceus. Follicular hyperkeratosis is often pathognomonic of pemphigus erythematosus.

Using the direct immunofluorescence method, fixed IgG is detected in the intercellular space of the epidermis in patients with erythematous pemphigus.

Differential diagnosis. Erythematous (seborrheic) pemphigus must be distinguished from lupus erythematosus, seborrheic eczema, common, foliaceous, Brazilian pemphigus, subcorneal pustular dermatosis of Sneddon-Wilkinson.

Treatment of pemphigus

Since pemphigus is an autoimmune disease, its treatment should be exclusively pathogenetic. In this regard, modern treatment of patients with pemphigus is carried out with corticosteroid hormonal drugs and consists of two stages:

1. achieving optimal results (complete cessation of new rashes, resolution of morphological elements) in a hospital setting;
2. long-term outpatient treatment with maintenance doses under close dispensary supervision.

Corticosteroids are prescribed in large shock doses depending on the severity and prevalence of the process, the patient's weight. According to various authors, the dose is 1-2 mg/kg of the patient's weight. To reduce the dose and side effects of corticosteroids, as well as to increase the effectiveness of treatment, glucocorticosteroids are combined with methotrexate.

Combination according to different schemes. Some authors recommend prescribing immunosuppressants after achieving a therapeutic effect from corticosteroids. Other authors prescribe methotrexate at the beginning of treatment once a week at 10-15 mg.

Immunosuppressants, in particular methotrexate, suppress antibody synthesis, slow down allergic processes and have a non-specific anti-inflammatory effect. Methotrexate (EBEWE) has the most favorable ratio of effectiveness and tolerability compared to other cytostatics.

Cyclosporine A (Sandimmune-Neoral) is effective in treating pemphigus. The initial dose of cyclosporine is 2.5 mg per 1 kg of weight. Its effectiveness is increased by combining cyclosporine with corticosteroids.

To enhance the therapeutic effect of corticosteroids, systemic enzymes (phlogenzym, wobenzym) are added to the treatment. The dose depends on the severity of the disease and is on average 2-3 tablets 3 times a day.

To restore the disrupted protein, carbohydrate and fat metabolism, increase the activity of immunobiological processes and reduce decalcification, anabolic hormones - retabolil - should be added to corticosteroid therapy. Retabolil also stimulates protein synthesis in the body.

Aniline dyes, creams, ointments containing glucocorticosteroids and antibiotics, and agents that enhance epithelialization are used externally.

To improve metabolic processes, microcirculation and epithelialization in the affected areas, some authors add laser therapy to basic therapy.

Since the blood serum of patients with active pemphigus contains antibodies to the intercellular substance of the epidermis and circulating immune complexes, plasmapheresis, plasmasorption and hemosorption methods are used to remove these substances from the vascular bed.