True pemphigus: causes, symptoms, diagnosis, treatment

True pemphigus (synonym: acantholytic pemphigus) is a severe chronic recurrent, autoimmune disease of the skin and mucous membranes, the morphological basis of which is the process of acantholysis, a violation of the connections between epidermal cells. Bubbles arise from acantholysis. The mechanism of immune disorders is not fully established.

People of all nationalities suffer from puzyrchatka, but people of Jewish nationality suffer more often. The disease is also often recorded among the Mediterranean peoples (Greeks, Arabs, Italians, etc.), in eastern India. Such a frequent occurrence of pemphigus, perhaps, is explained by the consanguineous marriages allowed in some nationalities. Most scientific literature on 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 onset 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 enzyme origin, the theory of autoimmune origin, etc. However, many existing theories are obsolete and have only historical significance.

Based on the currently available immunological data, pemphigus is an autoimmune disease, although the causes of the impaired functioning of the immune system in this pathology remain unclear. Perhaps the change in the immune system occurs under the influence of exogenous factors in the presence of genetic features of the immune system.

Data on studies of cellular immunity are heterogeneous and they show an increase in IgG, autoantibody in serum, a decrease in T-cell immunity, a decrease in the proliferative response to T-cell mitogens such as concanavalin A and phytohemagglutenin. However, the data obtained only occur 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 a state of remission. IgG1 and IgG4 predominate in patients with exacerbations. It was found that IgG pemphigus antibodies fix both early (Clq, C3 C4), and late (СЗ-С9) components of complement. Early complementations can pre-accumulate in the keratinocyte membrane, leading to late activation under the influence of pemphigus IgG. In this case, a complex that breaks the permeability of keratinocyte membranes occurs.

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

At present, three representatives of the desmoglyin class (Dcr) are known. This desmoglein-1 (Dсr1), desmoglein-2 (Dсr2) and desmoglein-3 (Dcr3). Weight, they are encoded by genes located on the 18th chromosome, which confirms their relationship. Electron microscope studies have shown the localization of both Dc1 and Dcr3 in desmosomes. Both desmoglyins are well represented in multilayer flat epithelium and are associated with disulfide bonds with placoglobulins - desmosomal plaque proteins. Dcr2 is the most common desmosome protein and is localized in the desmosomes of non-epithelial cells.

Immunohistochemical studies revealed that Dcr1 is an antigen for leaf-like, and Dcr3 is for vulgar pemphigus. This approach to the pathogenesis of pemphigus allows one to categorically assert the existence of only two of its forms: vulgar and leafy (superficial). All other forms are their variants.

Symptoms of true pemphigus

Clinically, acantholytic pemphigus is subdivided into ordinary, vegetative, leaf-like and erythematous (seborrheic, or Senira-Asher syndrome).

Ordinary pemphigus is characterized by eruptions of flaccid blisters located, as a rule, on unchanged skin and mucous membranes, with transparent contents. Bubbles are quickly opened with the formation of painful erosions, which have a red mopping surface, increasing even with mild trauma. When friction erosion can occur and externally unchanged, the skin, especially near the bubbles (a symptom of Nikolsky). Eruptions can be located in any area of the skin, but most often affect the mucous membranes, skin folds, as well as areas that are subject to trauma. Approximately in 60% of patients the process begins in the oral cavity and can be limited to this area for a long time, resembling stomatitis. Isolated lesions, sometimes with vegetations, hyperkeratosis, especially in children, often having a significant similarity with impetigo, seborrheic dermatitis, pink lichen, bullous multiforme exudate erythema and other dermatoses, can be on the skin. For the purpose of diagnosis, in such cases, fingerprints are examined from erosive surfaces to detect acantholytic cells and an immunomorphological study is performed to identify immune complexes in the spielermis.

Mixed forms with signs of pemphigus and pemphigoid are described, as well as variants that resemble Dhering's herpetiform dermatitis. The disease develops in middle and old age, although it can be observed in children.

Vulgar (ordinary) pemphigus is usually acute and in most patients (more than 60% of cases) begins with a lesion of the oral mucosa, being for a long time the only symptom of the disease. Perhaps the onset of the disease with the defeat of the mucous membrane of the genital organs, larynx, trachea. At the beginning there are single or a few bubbles, often located in the retro-molar area, on the lateral surface of the tongue. Under the influence of the tooth or teeth, the thin and flabby bubble cover quickly opens and bright red erosions are exposed, sometimes on the periphery of which one can observe scraps of bubble covers. Eroded areas of the oral mucosa are very painful: patients can not chew and swallow food, marked salivation, deep cracks in the corners of the mouth, do not allow it to open. Patients with a lesion of the oral mucosa sometimes turn to the dentist and receive treatment for a long time about stomatitis. After 3-6 months, single blisters appear on the skin and progression begins the generalization of the process. For pemphigus, the appearance of flaccid blisters (the monomorphic nature of the rash) is apparently unchanged, rarely on erythromatous skin. Bubbles can be small or large, with serous, and after a certain time - unclear, sometimes hemorrhagic contents. Over time, the blisters tend to peripherally grow, merge with each other to form large scalloped foci. After a while, the contents of the blisters dry up, forming yellowish crusts, with the loss of which remain hyperpigmented secondary spots. When the blisters of the bladder are damaged, bright red erosions are formed with a juicy red bottom separating the dense exudate, at the periphery of which there are scraps of the bladder cover. In this period, the symptom of Nikolsky is almost always positive (not only in the immediate vicinity of the lesion, but also in areas of externally unchanged skin). The essence of this phenomenon lies in the detachment of the clinically unchanged epidermis with sliding pressure on its surface. Modification of the symptom of Nikolsky is the phenomenon of Asbo-Hansen: when you press your finger on the cover of an unexplained bladder, its area increases due to acantholysis.

The phenomenon of "pear" was described by ND Sheklakov (1961): under the weight of accumulated liquid in the bubble with pronounced phenomena of acantholysis, the area of its base increases and the bubble acquires a pear-shaped form. Movement of patients due to painful erosion is limited.

Bubbles can appear on the edematic and erythematous background and tend to group. It is believed that blisters with ordinary pemphigus occur on unchanged skin and the clinical picture resembles the herpetiform dermatitis of Dühring. In such cases, it is a herpetiform pemphigus. In the literature, the following clinical, histological and immunomorphological criteria for herpetiform pemphigus as a variant of ordinary pemphigus are given:

• herpetiformity of the rashes accompanied by burning and itching;
• suprabasal and subcorneal acantholysis by the formation of intraepidermal blisters;
• detection of IgG in the intercellular space of the epidermis.

In the future, along with herpetiform eruptions, large flaccid blisters appear on patients with apparently unchanged skin, and the clinical picture takes on the classic features peculiar to vulgar pemphigus.

Erosions slowly epithelized and after healing of the foci on the mucous membranes and conjunctiva scarring does not remain. In case of secondary infection or when the basal membrane is involved in the pathological process, areas of cicatricial atrophy or scars form at the site of the former lesions. The generalization of the process is often accompanied by worsening of the general condition of patients, malaise, weakness, insomnia, fever, sometimes fever. If treatment is not performed, patients die from joining a secondary infection or cachexia.

Histopathology. In lesion lesions, loss of intercellular bridges is noted, in the deep layers of the epidermis - acanthosis, the formation of intra-epidermal cavities. Bubbles contain round acantholytic cells of Tzanka. In the intercellular spaces of the epidermis, antibodies of the IgG class are detected.

Histogenesis. At the base of acantholysis there are changes in the cementing substance that is in direct contact with the outer layer of the plasma membrane of epithelial cells and in a larger number in desmosomes. It is established that in the primary damage of the cementing substance, the immune disorders play an important role. By the method of direct immunofluorescence, antibodies of the IgG type were detected in the skin. Localized in the intercellular spaces of the epidermis. The method of indirect immunofluorescence revealed antibodies against the components of the intercellular cementing substance of the epidermis when treated with luminescent anti-IgG serum. C3-complement components were also found, which allows attributing this disease to immunocomplex.

Mechanisms of immune disorders in pemphigus have not yet been established. It is believed that the main pathogenetic role belongs to the circulating antigen to desmoglyin III, which is a glycoprotein in combination with placoglobin and is a mediator of cell adhesion in the region of desmosomes. It is assumed that the onset of the antigen-antibody reaction promoting acantholysis is preceded by the activation of proteases and the plasminogen activator. By immunochemical analysis of epidermal antigens. Matushevskaya (1996) revealed previously unknown antigen - water-soluble skin globulin a2-BGC. In addition, two specific proteins of a2-GPVP-130 and a2-GPLP-160, associated, were found in the vesicle fluid. Respectively, with ordinary and leaf-like forms of pemphigus. It indicates damage to the immune system at various levels, including thymus and skin, the possible role of genetic factors, presupposed from family cases, data on the increased detection of certain antigens of tissue compatibility. In particular, the association of the disease with HLA-A10, HLA-A26, HLA-DRW6, HLA-DRW4, BW38 has been established. DRw6 serotype carriers are believed to have a 2.5-fold increased risk of developing the disease, and a predisposition to pemphigus disease is associated with a nonequilibrium adherence to the DQw3 and DQwl alleles of the DQ locus. A new allele (PV6beta) of the same locus was discovered and a sample with a PV6beta allele with a specific oligonucleotide for the diagnosis of the disease in the early stages or in atypical cases was suggested. The role of viral infection has not been proven. Basically, B-cell immunity changes, but with a prolonged course, a T-cell defect also develops. The insufficiency of interleukin-2 synthesis has been revealed. The vesicating pemphigus is distinguished by the presence in the erosion area of papillomatous-verrux sprouts localized mainly in the folds of the skin and periorually. In some patients, lesions can be similar to those in vegetative pyoderma due to the appearance of vegetation in pustular elements (Allogo vegging pemphigus). A differential diagnostic feature in such cases is the detection by the method of direct immunofluorescence of IgG forming immune complexes with the antigen in the epidermis. The vegetative pemphigus of this type proceeds more favorably than the classical version of Neumann.

Pathomorphology. Acanthosis with elongation of epidermal outgrowths and dermal papillae and proliferation of epithelial cords. In the field of verrukoses vegetation - acanthosis, papillomatosis, intra-epidermal abscesses, containing eosinophilic granulocytes. The presence of these abscesses is characteristic of the vesicating pemphigus. With the type Allopo in the foci, which are bubble pustules, there is acantholysis with the formation around the pustules of small supramarginal necks. The cavities are filled with eosinophilic granulocytes and acantholytic cells.

To ensure proper diagnosis, it is necessary to biopsy the skin from the lesion with fresh, predominantly 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 the connection between the epithelial cells (acantholysis), gaps are first formed, followed by bubbles localized predominantly above the base. Nasal cells, although they lose touch with each other, remain attached to the basal membrane. The cavity of the bladder, as a rule, contains rounded acantholytic cells with large hyperchromatic nuclei and pale stained cytoplasm. Acantholysis can be observed in the epithelial vagina of the hair follicles, where, like in the epidermis, crevices are formed, mainly above the basal layer. In old bladders, the epidermis regenerates; the bottom is covered with several layers of epithelial cells. In the places of rejection of the bubble cover, its bottom is lined with cells of the basal layer. In the process of healing, proliferation of papillae of the dermis and elongation, sometimes significant, of epidermal processes are noted. In these cases, the histological picture resembles a vesicating pemphigus. In the dermis, inflammatory changes can be pronounced. The infiltrate consists of eosinophilic granulocytes, plasmocytes and lymphocytes.

Similar changes are found on the mucous membranes. When the mucous membranes of the oral cavity are affected, it is very difficult to excise a whole bubble, so they use smears-prints for diagnosis. In which after coloring according to the method of Romanovsky-Giemsa find acantholytic cells (Ttsanka test). However, this test only supplements, but in no case replaces the histological study. Electron microscopic examination of the skin in the region of the bladder and in clinically unchanged areas reveals the main changes in the field of intercellular contacts. In the initial stages of the formation of acantholysis, changes in the intercellular substance were observed almost throughout the Malpighian layer, which leads to a loss of the ability to form desmosomal bonds. Cells that have lost communication with each other are rounded, the number of tonofilamentes in them decreases. They concentrate around the nucleus, then undergo lysis and disappear.

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

The leaf pemphigus is characterized by a superficial arrangement of the blisters, as a result of which they are clinically insignificant, quickly covered with scaly crusts, often layered due to the repeated formation of bubbles under them. The process is usually generalized, unlike usual pemphigus, it proceeds with an inflammatory reaction, which gives the lesions a similarity to exfoliative erythroderma, psoriasis, seborrheic dermatitis and other dermatoses. Mucous membranes are rarely affected. The symptom of Nikolsky is dramatically positive, when traumatizing there are vast erosive surfaces. The prognosis with this form is less favorable than with ordinary pemphigus.

Pathomorphology. In fresh foci, acantholysis occurs usually in a granular layer or directly below it with the formation of bubbles of subcorneal localization. The phenomena of acantholysis can be both in the base and in the bladder cover. Sometimes, due to acantholysis, the horny and partially granular layer can separate without forming a bubble. In the circumference of the cleft epidermocytes do not have desmosomes and there is a tendency to separate them, as a result of which the gaps may form in the middle parts of the epidermis. It is possible to separate the entire epidermis from the basal layer. In older foci in 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, pycnosis with heterochromy of individual cells may be observed, reminiscent of the appearance of "grain" in Darya's disease, in the dermis a moderately pronounced infiltrate, sometimes with the presence of eosinophilic granulocytes.

Histogenesis. The formation of the bladder in leaf-shaped pemphigus is also based on acantholysis resulting from the pathological reaction of the antigen-antibody, but the autoantibodies are directed against the antigen other than the above-mentioned types of pemphigus, namely desmoglyin I, another important protein component, desmosomes in combination with placoglobin I In addition, the so-called eosinophil spongiosis can play a role in the development of blisters, which appears in the epidermis in the earliest stages of the pathological process, sometimes before the development of acantholysis, I recall morphologically herpetiform dermatitis of Dühring. In electron microscopy, during this period, the disease exhibits dissolved intercellular cement and a reduced number of desmosomes. Tonofilaments are arranged perinuclear, as in dyskeratosis. In this type of pemphigus, the autoantibodies detected in the intercellular spaces of the epidermis are identical with those of the ordinary pemphigus.

Erythematous pemphigus is considered by us as a limited variant of foliar pemphigus, but there is an opinion that it is an independent form of pemphigus or a combination of pemphigus with red lupus. This is indicated by the clinical and morphological features characteristic of both diseases. Foci of lesion are located mainly on the back, chest and in the interscapular area. They have clinical signs of pemphigus (blisters), lupus erythematosus (erythema, sometimes atrophy) and seborrheic dermatitis (layering of scaly crusts) may also resemble impetigo, exudative psoriasis. The symptom of Nikolsky is positive, changes in the mucous membranes are often observed.

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

Histogenesis. Changes in the epidermis. Revealed by electron microscopy, are similar to those of leaf-like pemphigus, as well as autoimmune status. However, with this method of direct immunofluorescence, the luminescence of the basal membrane is revealed 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), carrying out immunomorfologic research in seborrheic pemphigus, found that the pathogenesis of this disease is the primary defect of the function of T-suppressors, expressed in hyperproduction of autoantibodies.

Differential diagnosis. Ordinary pemphigus should be distinguished from other forms of true pemphigus, pemphigoid, Dühring's disease and other vesicular diseases.

In the clinical course of vegetative pemphigus, classical (Neumann type) and benign (Gallopo type) forms are distinguished.

Symptoms. With the type of Neumann, suddenly, as with a vulgar form, flabby bubbles appear, the cover of which is quickly opened, exposing bright red erosions of oval, round or irregular shape, which tend to peripheral growth. Eruptions often appear around natural openings and in folds (inguinal-femoral, interannual, axillary, under the mammary glands, in the navel region). With time (5-6 days) on the surface of erosions are formed juicy, small, bright red vegetation with fetid detachable. The number and size of vegetative erosions increases. Pustules can appear on the periphery of erosion. The symptom of Nikolsky in most patients is positive.

With benign vegetative pemphigus (type Gallopo), lesions are predominantly located on the intertriginous areas of the skin and, less often, 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 that merge into infiltrated plaques with vegetation.

Histopathology. In the early stages of the disease, the histological pattern in the region of blisters and erosions is similar to that observed with ordinary pemphigus. Papillomatous and verrux sprouting are characterized by the phenomena of papillomatosis and acanthosis with intra-epidermal abscesses, consisting of eosinophilic granulocytes. Immunomorphological studies in the intercellular spaces of the epidermis in patients exhibit IgG deposits.

Differential diagnosis. The vesicating pemphigus of Neumann must be differentiated from ordinary pemphigus, secondary recurrent syphilis, drug toxicodermia (iododerm, bromoderm), vegetative form of follicular daratosis Darya, chronic family benign pemphigus Haley-Haley.

The leaf pemphigus is much less common than the common.

Symptoms. The leaf pemphigus has the characteristic specific features: appearance on the unchanged or slightly hypersmated skin of superficial flabby bubbles with a race tire. Their tires quickly burst, even with a light touch or under the pressure of the bubble liquid. At the same time juicy, bright red erosions with exudate are exposed, which soon shrinks into layered scaly crusts. Extensive eroded areas, covered with layered crusts, resemble exfoliative erythroderma. An important clinical feature of leaf-like pemphigus is repeated, sometimes continuous, formation of superficial blisters under the crusts in place of the former erosions.

The symptom of Nikolsky (this symptom is first described in leaf form) is well expressed both in the vicinity of the lesion and in the remote areas of the skin. As with other forms, the general condition of patients is disturbed (body temperature rises, secondary infection joins, cachexia develops).

Histopathology. Histologically, with leaf-shaped pemphigus, acantholysis is usually observed in the granular layer or under it (subcorneal fissures), acantholysis is expressed. In the dermis there is a pronounced inflammatory infiltrate. In the intercellular spaces of the epidermis, antibodies of the IgG class are detected.

Differential diagnosis. The leaf pemphigus must be differentiated from erythroderma of various origins (secondary erythroderms, toxicoderma), pemphigus vulgaris, During's herpetiform dermatitis (bubble form), toxic epidermal necrolysis of erythematous (seborrheic) pemphigus, etc.

Erythematous (seborrhoeal) pemphigus (Senir-Asher syndrome) is one of the variants of true pemphigus, as evidenced by the frequent cases of its transition into an ordinary or leaf-like pemphigus.

Symptoms. When erythematous pemphigus there are symptoms of such dermatoses, as erythematous lupus, pemphigus and seborrheic dermatitis.

As a rule, early eruptions occur on the scalp, the skin of the face (in the cheeks or on the back of the nose with a transition to the adjacent areas of the cheeks, forehead), later lesions appear on the trunk. There are erythematous foci with clear boundaries, on the surface of which there are thin or loose grayish scaly crusts. In case of wetting, lesions are covered with grayish-yellow or brownish crusts. Cortex occurs as a result of drying of bubble exudate, which are formed on the lesions or adjacent areas of the skin. Emerging blisters are often not noticeable for both the patient and the doctor, as they are thin and flabby. They are quickly opened and covered with dense or loose crusts, can merge with each other or remain isolated for a long time. The symptom of Nikolsky is positive in most patients.

On the scalp, the eruptions can be similar to seborrheic dermatitis.

Mucous membranes are affected in about a third of patients. The course of the disease is long, with remissions.

Histopathology. When histopathological examination, crevices or blisters are identified under the horny or granular layer of the epidermis, as in leaf-shaped pemphigus. For erythematous pemphigus, follicular hyperkeratosis is often pathognomonic.

The method of direct immunofluorescence in the intercellular space of the epidermis in patients with erythematous pemphigus shows fixed IgG.

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

Treatment of pemphigus

Since pemphigus is an autoimmune disease, its treatment should be exclusively pathogenetic. In connection with this, modern treatment of patients with pemphigus is performed by corticosteroid hormones and consists of two stages:

1. achievement of optimal results (complete cessation of new rashes, resolution of morphological elements) in a hospital environment;
2. long-term outpatient treatment with maintenance doses under careful follow-up.

Corticosteroids are prescribed in large shock doses, depending on the severity and prevalence of the process, the weight of the patient. According to different 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 improve the effectiveness of treatment, glucocorticosteroids are combined with methotrexate.

A combination of different schemes. Some authors recommend prescribing immunosuppressants after achieving a therapeutic effect on corticosteroids. Other authors prescribe methotrexate at the beginning of treatment once a week for 10-15 mg.

Immunosuppressants, in particular methotrexate, suppress the synthesis of antibodies, slow down allergic processes and have a nonspecific anti-inflammatory effect. Methotrexate (EBEWE) distinguishes the most favorable ratio of efficacy and tolerability compared to other cytostatics.

In the treatment of pemphigus, cyclosporin A (sandimmun-neoral) has a good effect. The initial dose of cyclosporine is 2.5 mg per kg of body weight. Efficacy is enhanced by the combination of cyclosporine with corticosteroids.

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

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

Outwardly, aniline dyes, creams, ointments containing glucocorticosteroids and antibiotics, agents that enhance epithelialization are used.

To improve metabolic processes, microcirculation and epithelialization in lesions to basic therapy, some authors attach laser therapy.

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