Bullous pemphigoid is a chronic autoimmune skin disease affecting mainly older people. Its symptoms are similar to those of pemphigus and are reduced to the formation of tense blisters on the skin of the arms, legs, and abdomen; the distribution of pathological foci is usually symmetrical. Diagnosis of bullous pemphigoid is performed by examining the patient, histological examination of skin tissues in the affected areas, immunological studies. Treatment of the disease includes immunosuppressive and cytotoxic therapy using glucocorticosteroid and cytostatic agents.
L12.0 Bullous pemphigoid
Bullous pemphigoid (parapemphigus, senile herpetiform dermatitis) is a chronic recurrent autoimmune disease characterized by damage to the subepidermal layers of the skin with the development of tense blisters and other pathological changes. Unlike ordinary pemphigus, acantholysis does not occur with this disease, and the formation of blisters in the epidermis is a secondary process. For the first time, Lever drew attention to this in 1953, who isolated the bullous pemphigoid into a separate nosological unit – before that, the term “pemphigus” united all types of vesicular rash. Pathology is mainly affected by people over 60 years old, but about 100 cases have been described in dermatology when bullous pemphigoid developed in childhood or adolescence. Such forms of the disease are called infantile and adolescent bullous pemphigoid, respectively.
There are also indications of the relationship between this bullous dermatosis and some oncological diseases, which allows us to consider it as a paraneoplastic process. Patients with this pathology, developing against the background of cancer of the stomach, lungs, bladder, are described. In some cases, bullous pemphigoid can be provoked by taking medications (furosemide, potassium iodide, amoxicillin), skin trauma. The incidence of the disease is about 1-13 cases per 1 million population, elderly men predominate among the patients. The risk of developing bullous pemphigoid increases very much with age – it is estimated that the probability of contracting this pathology at the age of 90 is more than 300 times higher than at 60.
The etiology of this disease currently remains the subject of scientific discussion, research in this area has helped to form several basic hypotheses explaining the causes of this condition. It is most widely believed that this autoimmune disease develops due to the presence of certain mutations that alter the main histocompatibility complex. This is partly confirmed by the fact that among patients with bullous pemphigoid, the number of persons with DQB1 0301 as a second-class allele of GCs is increased. However, to date, no mutations or other genetic disorders have been identified that could be unambiguously associated with this skin disease.
The pathogenesis of bullous pemphigoid has been studied somewhat better than the etiology, which allows us to reliably assert the autoimmune nature of this condition. The main target for attack by the immune system are two proteins of the epidermis – one of them, BP180, is a transmembrane protein and is currently associated with type 17 collagen. The second antigen involved in the development of bullous pemphigoid, BP230, is located inside the cytoplasm of epidermal cells and presumably belongs to the group of plaquins. These two proteins are related in their function – they participate in the formation of semidesmosomes and maintain the ordered structure of the multilayer epithelium.
In all patients with bullous pemphigoid, class G antibodies are detected in the blood plasma, which have the ability to bind with autoantigens BP180 and BP230. Their appearance is associated with the development of autoreactive T-lymphocytes in the body against the above-mentioned proteins of epithelial cells. T-lymphocytes are responsible for the cellular immune response, simultaneously activating B-lymphocytes that produce antibodies. The binding of T-lymphocytes and antibodies to their own proteins of the skin and mucous membranes activates the complement system, which attracts other immunocompetent cells, mainly neutrophils and eosinophils, to the pathological focus. In some patients with bullous pemphigoid, a significant involvement of labrocytes (mast cells) in the pathogenesis of the disease was revealed.
Initially, the semidesmosomes in the basal layer of the epidermis are affected, numerous vacuoles arise between the processes of cells. Their fusion with each other leads to the formation of a subepidermal bubble filled with exudate, from above it is covered with an unchanged epidermis, which retains intercellular connections. However, then it undergoes necrosis, and the regeneration of the basal layer leads to the covering of the bottom of the bladder with a layer of newly formed cells, and the focus becomes intraepidermal. Thus, at this stage of development of the bullous pemphigoid, it most strongly resembles an ordinary pemphigoid, with the exception that the development of bubbles did not occur due to acantholysis, but the destruction of intercellular bridges only in the basal layer with its subsequent regeneration.
Inflammatory processes in bullous pemphigoid are not equally pronounced in different patients, however, signs of at least minimal infiltration of the skin by lymphocytes, neutrophils and eosinophils are always present. Foci can be located perivascularly in the case of minor inflammation and fill the entire thickness of the skin with pronounced inflammatory processes, sometimes accompanying bullous pemphigoid.
Bullous pemphigoid symptoms
In most cases, the first manifestations of the disease occur in people over 60 years of age. Initially, before the formation of bubbles (pre–bubble stage), the symptoms of bullous pemphigoid are weak and rather nonspecific – patients complain of itching of varying intensity, localized on the skin of the arms and legs or the lower abdomen. Sometimes there may be redness of the skin, minor erythematous rashes. Over time, tense bubbles form on the affected areas, having a hemispherical shape and a diameter of 1-3 centimeters. In about a third of cases of bullous pemphigoid, erosions form on the mucous membranes of the oral cavity and vagina. The “cover” of the bubbles, consisting of the epidermis, is strong enough, so these formations have a certain injury resistance. The contents of the blisters with bullous pemphigoid have a serous character, but in some cases may change to hemorrhagic or even purulent.
When the bubbles are opened, red erosions with a delicate and moist surface remain on the surface of the skin. The restoration of the epidermis above them occurs quite quickly, the traces after healing are insignificant. In addition to blisters with bullous pemphigoid, urticary rashes of different sizes and intensity often develop. Of the other symptoms, in addition to skin itching and rashes, patients may experience fever, loss of appetite, weight loss. Especially often such manifestations occur in weakened and emaciated individuals, while bullous pemphigoid can even cause death. The disease has a long and chronic course, symptoms and skin manifestations may weaken and become active again over time. Prior to the development of effective methods for the treatment of bullous pemphigoid, it was found out that spontaneous recovery can occur in 15-30% of cases.
The definition of such a disease as bullous pemphigoid is made on the basis of examination data by a dermatologist, immunological studies and histological examination of tissues of pathological foci. Upon examination, depending on the stage of pathology development, erythematous rash, formed blisters arranged symmetrically, urticary rashes of varying intensity, healing erosions, sometimes covered with a crust may be observed. A general blood test in about half of cases of bullous pemphigoid shows moderate eosinophilia, sometimes leukocytosis. Also, in peripheral blood, using the immunoprecipitation reaction, IgG can be detected that have the ability to bind to the BP180 and BP230 antigens.
Histological studies of bullous pemphigoid include simple light microscopy and immunofluorescence microscopy. When examined under a microscope at various stages of bubble formation, an epidermal gap can be detected, then a subepidermal bubble, which turns into an intraepidermal one. The dermis under the pathological focus is sharply edematous, leukocyte infiltration, consisting mainly of lymphocytes, eosinophils and neutrophils, can be expressed in different ways. Immunofluorescence microscopy reveals the accumulation of class G immunoglobulins and complement fractions (most often C3) along the basement membrane of the epidermis. In bullous pemphigoid, these molecules are predominantly concentrated on the outside of the basement membrane. Differential diagnosis should be carried out with ordinary pemphigus, multiform exudative erythema and epidermolysis bullosa.
Bullous pemphigoid treatment
The first–line drugs used for the treatment of bullous pemphigoid are glucocorticosteroids – prednisolone, methylprednisolone and others. Treatment is long-term, therapy begins with high dosages of steroids, gradually lowering the dose for 6-9 months. Considering that many patients with bullous pemphigoid are elderly people, it is not possible to carry out full-fledged therapy with glucocorticosteroids due to significant side effects. Often in such a situation, treatment is performed by a combination of a reduced dose of steroids inside and local application of ointments based on them.
Therapy of bullous pemphigoid with immunosuppressive agents, for example, cyclosporine, has good results. Cytostatic agents are used similarly – methotrexate, cyclophosphamide. Plasmapheresis with double filtration can significantly accelerate recovery and increase the effectiveness of therapy for bullous pemphigoid. Externally, in addition to ointments with glucocorticosteroids, antiseptics (for example, aniline dyes) are used to prevent complications such as secondary infection. However, in any case, the treatment of this disease is very long and takes at least one and a half years, and even at the same time, 15-20% of patients then have relapses.
Prognosis and prevention
The prognosis of the classical bullous pemphigoid is uncertain in most cases. This is due to the fact that the disease is chronic and difficult to predict, and most patients are elderly, often with other concomitant pathologies. Early high estimates of mortality from bullous pemphigoid (from 10 to 40%%) are now considered somewhat incorrect, since age, the presence of other diseases and other factors were not taken into account when calculating. Childhood and adolescent forms of this pathology in most cases are successfully cured. Persons suffering from bullous pemphigoid or who have successfully undergone treatment should avoid exposure to traumatic factors on the skin – UVI, high or low temperatures, mechanical injuries. This can provoke the development of a relapse of the disease.