Bullous pemphigoid.

Pemphigoid bullosa (synonyms: pemphigoid, parapemphigus, senile pemphigus, senile herpetiform dermatitis) is an autoimmune disease that usually develops in people over 60 years of age, including as paraneoplasia. It can occur in children. Pemphigoid is a benign chronic disease, the clinical picture of which is very similar to pemphigus vulgaris, and the histological picture is similar to dermatitis herpetiformis.

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Causes and pathogenesis of bullous pemphigoid

In recent years, studies have shown that autoimmune processes play an important role in the pathogenesis of dermatosis. In patients with bullous pemphigoid, IgG antibodies, IgA antibodies to the basement membrane, deposition of IgG, less often IgA and the C3 component of complement in the basement membrane of both the skin and the mucous membrane were found in the blood serum and blister fluid. It was found that the titer of antibodies and circulating immune complexes in pemphigoid correlates with the activity of the disease.

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Pathomorphology of bullous pemphigoid

At the beginning of the process, numerous vacuoles are formed between the cytoplasmic processes of the basal cells, which then merge and form larger subepidermal blisters against the background of a sharp edema of the dermis. The blister cover is unchanged epidermis, the cells of which are stretched, but the intercellular bridges are not damaged. Subsequently, necrosis of the epidermal cells occurs. The regenerating epidermis, advancing from the edges of the blister, gradually captures its bottom, as a result of which the blister becomes intraepidermal, sometimes subkeratinous. Inflammatory phenomena in the dermis are expressed in different ways. If the blisters developed on unchanged skin, then the infiltrates are located perivascularly. If the blisters are formed against the background of an inflammatory process, the infiltrates in the dermis are very massive. The composition of the infiltrate is polymorphic, but mainly lymphocytes with an admixture of neutrophils and especially eosinophils, which can also be found in the contents of the blister among the fibrin threads, predominate. During an immunomorphological study of the infiltrates, M. S. Nester et al. (1987) found a large number of T-lymphocytes in the lesions, including T-helpers and T-suppressors, macrophages and intraepidermal macrophi. Such a composition of the infiltrate indicates the role of cellular immune reactions in the formation of blisters with the involvement of macrophages in the process. Electron microscopic study of the lesions at various stages of the process showed that in the earliest stages, edema of the upper dermis is observed, and small vacuoles are formed between the basal cells inside the basement membrane zone. Later, the space between the plasma membrane of the basal cells and the basal plate, which is the base of the blister, expands. Then it partially thickens and collapses. The processes of the basal cells contact with the cells of the filtrate of the dermis, eosinophilic granulocytes penetrate the epidermis and defunct in it. In 40% of cases, eosinophilic spongiosis is observed with the presence of a chemotactic factor in the vesicular fluid. In 50% of cases, globular bodies are detected in the zone of the basal membrane, which histologically, ultrastructurally and immunologically do not differ from those in lichen planus, lupus erythematosus, dermatomyositis and other dermatoses. Using the method of direct immunofluorescence, J. Horiguchi et al. (1985) found immunoglobulins G and M, C3 components of complement and fibrin in them. Destructively altered epithelial cells of the bladder cap participate in the origin of these bodies.

Differentiation of this disease from common pemphigus is not difficult even with intraepidermal localization of blisters. Pemphigus is characterized by primary changes in the epidermis, where acantholytic blisters are formed, while in pemphigoid, acantholysis is absent, and the changes in the epidermis are secondary. It is very difficult, often impossible, to distinguish bullous pemphigoid from diseases with subepidermal localization of blisters. Blisters that have developed on a non-inflammatory basis may not contain eosinophilic granulocytes, and then they are difficult to differentiate from blisters in bullous epidermolysis or late cutaneous porphyria. Blisters that have developed on an inflammatory basis are very difficult to differentiate from blisters in benign pemphigoid of the mucous membranes and herpetiform dermatitis. In benign pemphigoid of the mucous membranes, a more intense rash of blisters is observed on them than in pemphigoid. Unlike herpetiform dermatitis, bullous pemphigoid does not have papillary microabscesses that subsequently form multilocular blisters. Bullous pemphigoid differs from multiform exudative erythema by the absence of perivascularly located eosinophilic granulonites located near the dermal papillae, the mononuclear nature of the infiltrate near the dermoepidermal junction, and early epidermal changes in the form of spongiosis, exocytosis, and necrobiosis. In all difficult cases, immunofluorescence diagnostics are necessary.

Histogenesis of bullous pemphigoid

Pemphigoid, like pemphigus, is an autoimmune dermatose. Antibodies in this disease are directed against two antigens - BPAg1 and BPAg2. The BPAg1 antigen is located in the attachment sites of hemidesmosomes in the keratinocytes of the basal layer, the BPAg2 antigen is also located in the hemidesmosome region and is presumably formed by type XII collagen.

Immunoelectron microscopic study using the peroxidase-antiperoxidase method showed localization of IgG, C3 and C4 components of the complement in the lamina lucida of the basement membrane and the lower surface of the basal epithelial cells. In addition, the C3 component of the complement is found on the other side of the basement membrane - in the upper parts of the dermis. In some cases, IgM deposits are found. Circulating antibodies against the basement membrane zone are noted in 70-80% of cases, which is pathognomonic for pemphigoid. There are a number of works showing the dynamics of immunomorphological changes in the skin at the sites of blisters formation. Thus, I. Carlo et al. (1979). studying the skin near the lesion, they discovered beta1-lobulin, a plasma protein that regulates the biological activity of the C3 component of complement; in the area of the basement membrane, along with the C3 component of complement, they identified immunoglobulin G. T. Nishikawa et al. (1980) found antibodies against basal cells in the intercellular spaces.

Enzymes secreted by infiltrate cells also play a role in the histogenesis of the bladder. It has been found that eosinophils and macrophages accumulate near the basement membrane, then migrate through it, accumulate in the lamina lucida and the spaces between the basal cells and the basement membrane zone. In addition, in response to complement activation, pronounced degranulation of mast cells occurs. Enzymes secreted by these cells cause tissue degradation and thus participate in bladder formation.

Histopathology

Histologically, the epidermis separates from the dermis, forming a subepidermal blister. Acantholysis is not observed. As a result of early regeneration of the bottom of the blister and its peripheral part, the subepidermal blister becomes intraepidermal. The blister contents consist of histiocytes, lymphocytes with an admixture of eosinophils.

The bottom of the blister is covered with a thick layer of leukocytes and fibrin. The dermis is edematous, diffusely infiltrated and consists of histiocytic elements, lymphocytes, the number of eosinophils varies.

The vessels are dilated, their endothelium is edematous. Due to the lack of acantholysis, Tzanck cells are absent in the smears-imprints. The location of IgG and the C3 component of complement along the basement membrane is noted.

Symptoms of bullous pemphigoid

The disease usually occurs in individuals of both sexes over 60 years of age, but can be observed at any age. The main clinical sign is the presence of tense blisters that arise on an erythemato-edematous background, less often on unchanged skin and are predominantly localized on the abdomen, extremities, in skin folds, in 1/3 of cases on the mucous membrane of the oral cavity. Local foci are observed. Nikolsky's symptom is negative, Tzanck cells are not detected. In some cases, polymorphism of the rash, scarring can be observed, mainly in benign pemphigoid of the mucous membranes and in local cicatricial pemphigoid. There are observations of a combination of cicatricial changes and widespread bullous eruptions in children with IgA deposition in the dermoepilemal zone against the background of low titers of IgA antibodies against the basement membrane, which is interpreted as childhood cicatricial pemphigoid with linear IgA deposits, if combinations of this process with another pathology are excluded. The disease begins with the appearance of blisters on erythematous or erythematous-urticarial spots, rarely - on outwardly unchanged skin. The blisters are usually located symmetrically, herpetiform rashes are rarely noted. Blisters from 1 to 3 cm in size have a round or hemispherical shape, filled with transparent serous contents, which can then turn into purulent or hemorrhagic. Due to the dense cover, they are very resistant to trauma and are clinically similar to herpetiform dermatitis. Large blisters are sometimes not so tense and outwardly very much resemble those in common pemphigus. Simultaneously with the blisters, small and large urticarial rashes of pink-red or stagnant-red color appear. This is especially noticeable at the moment of spreading of the process, when erythematous phenomena around the blisters regress or can completely disappear. After opening of the blisters, slightly moist pink-red erosions are formed, which quickly epithelize, sometimes even on their surface crusts do not have time to form. An increase in the size of erosions, as a rule, is not observed, but sometimes their peripheral growth is noted. Favorite places of localization of blisters are skin folds, forearms, inner surface of the shoulders, trunk, inner surface of the thighs. Damage to the mucous membranes is uncharacteristic, but the erosions that form on the mucous membrane of the oral cavity or vagina are clinically similar to erosions in common pemphigus.

Subjectively, the rash is accompanied by slight itching, rarely - itching, pain and fever. In severe widespread cases, as well as in elderly and emaciated patients, loss of appetite, general weakness, weight loss, and sometimes death are observed. The disease lasts a long time, periods of remission alternate with periods of relapse.

The course of the disease is chronic, the prognosis is much more favorable than with pemphigus.

Differential diagnosis

Bullous pemphigoid should be distinguished from true pemphigus, Duhring's dermatitis herpetiformis, erythema multiforme exudative, etc.

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Treatment of bullous pemphigoid

The therapy depends on the severity and prevalence of the process. Therapy should be comprehensive and individual. The main therapeutic agent is glucocorticosteroids, which are prescribed at a rate of 40-80 mg of prednisolone per day with a gradual decrease. Higher doses of the drug may be prescribed. Encouraging results are observed with the use of immunosuppressants (cyclosporine A) and cytostatics (methotrexate, azathioprine, cyclophosphamide). There are reports of high therapeutic efficacy in combining glucocorticosteroids with methotrexate, azathioprine or plasmapheresis. To increase the effectiveness of therapy, corticosteroids are prescribed simultaneously with systemic enzymes (phlogenzym, wobenzym). The dose depends on the severity of the disease and averages 2 tablets 2-3 times a day. Aniline dyes, creams, ointments containing glucocorticosteroids are used externally.