(I) Pathogenesis
The presence of anti-keratin intercellular material antibodies in the blood circulation of patients with all types of pemphigus, and the titer of antibodies parallel to the severity of the disease, the addition of the serum of patients with pemphigus in the culture of epidermal organs, 48 to 72 hours later can appear in the upper part of the basal cells spine loosening phenomenon, the occurrence of spine loosening may be related to the protease produced by the combination of antigen antibody, it has been confirmed that pemphigus It has been confirmed that the antibody combined with keratinocytes can cause epidermal cells to release fibrinolytic enzyme activator, which activates the fibrinase system and leads to spine disintegration, and the antigen of pemphigus exists in the connecting egg of keratinocytes from the bridging grain, which is a glycoprotein, and the antigen of common type pemphigus has a molecular weight of 210,000u (Dalton); the antigen of erythematous type pemphigus is a bridging grain core glycoprotein with a molecular weight of 160,000u.
(II) Pathogenesis
Immunofluorescence revealed that IgG autoantibodies against the surface of keratin-forming cells (pemphigus antibodies) are an important hallmark of pemphigus. Direct immunofluorescence revealed that patients have anti-cell surface antibodies in their epidermis, and indirect immunofluorescence revealed that serum has anti-epidermal cell surface IgG antibodies.
The two diseases are difficult to distinguish on immunofluorescence, and indirect immunofluorescence substrates have a great impact on the results. There is a correlation between circulating aspergillus antibody titers and disease severity, i.e., the higher the titer, the more severe the disease, and there is a statistically significant difference in this correlation, although some patients do not fully conform to this rule, and therefore disease severity is more important than aspergillus antibody titers in the treatment of such patients.
The pemphigus antigen is a complex of bridging granule molecules, and immunoelectron microscopic studies have demonstrated that the pemphigus antigen is located on the surface of keratin-forming cells at the site of bridging granule attachment, and immunoprecipitation and immunoagglutination experiments at the molecular level have shown that the deciduous pemphigus antigen is a 100 kDa glycoprotein and the common pemphigus antigen is a 130 kDa glycoprotein, which are the causes of common pemphigus and deciduous pemphigus, respectively. causative agents.
Passive transfer of patient serum to experimental animals can produce echinoderm loosening, and the addition of IgG to human skin cultured in vitro has been shown to cause echinoderm loosening, and this antibody-mediated echinoderm loosening does not require the involvement of complement or inflammatory cells. However, it is not completely clear how antibody binding to the surface of keratin-forming cells causes epidermal cell junctions to break down, resulting in spine disintegration and blister formation.
Pemphigus vulgaris can be triggered by an underlying autoimmune response to certain drugs, such as captopril, isoniazid, indomethacin (anti-inflammatory pain), ethambutol, pautazone, penicillin, propranolol, pyrithione hydrochloride, rifampin, and has been reported after burns, sunburn, ultraviolet light, and x-ray exposure. Myasthenia gravis, lupus erythematosus, autoimmune thyroiditis, thymoma, Sjogren’s syndrome, pemphigoid aspergillosis, pernicious anemia, and Hodgkin’s disease.
The basic pathological changes are spine disintegration of epidermal spine cells, formation of intraepidermal fissures and large blisters, and spine disintegration cells in the herpes fluid, which have large, spherical cytosomes with large, dark-stained nuclei and uniformly basophilic cytoplasm.
The site of echinococcosis differs between the different types of pemphigus. In common pemphigus, echinococcosis occurs above the basal layer, so the blisters are on the basal layer; in proliferative pemphigus, the site of echinococcosis is the same as in common pemphigus, but there is marked hypertrophy and papillomatous hyperplasia of the spinous layer with intraepidermal abscesses composed of eosinophils; in deciduous and erythematous pemphigus, the site of echinocococcosis is in the granular layer or the upper part of the spinous layer, and the blisters formed are the most In tuberculosis-like pemphigoid, the echinocytosis occurs in the middle of the sphenoid layer and the blisters are filled with eosinophils or neutrophils.
The main criteria are clinical manifestations, histopathology of the lesions and immunofluorescence examination.
The basic damage of all types of pemphigus is flaccid thin-walled blisters and vesicles, which do not heal easily.
2. Histopathological examination of the newly emerged blisters showed intraepidermal blisters due to spine disintegration.
Immunofluorescence examination of the skin around the blisters for direct immunofluorescence showed inter-epidermal spine cell fluorescence, which was caused by IgG and/or C3 deposition, and indirect immunofluorescence examination of sera from patients with active disease could detect antibodies to aspergillosis.
Pemphigus is mainly divided into common pemphigus, proliferative pemphigus, deciduous pemphigus, and erythematous pemphigus.
1. Herpes vulgaris (remphigus vulgaris)
(1) Skin damage: The symptoms of the disease are often painful and rarely itchy, and the primary damage is flaccid blisters, which can occur on the surface of the skin in any part of the body, usually on the surface of normal-looking skin, or on erythematous skin, and the new blisters are usually flaccid or become flaccid within a short period of time. or scratching the skin with normal appearance, the epidermal cells may be loosened and the epidermis may fall off or the blisters may occur in the epidermis at the rubbing place soon after rubbing, this phenomenon is called epidermolysis bullosa or Nikolsky’s sign.
The blisters are more common on the head and face, neck, chest and back, axillae, groin, etc. The lesions can be limited to one to several places for several months; they can also spread all over the body within a few weeks, often leaving brown pigmentation and milia after the lesions fade, and occasionally pigment loss.
(2) Mucosal damage: In most patients, painful mucosal erosions are the typical clinical manifestation of pemphigus vulgaris, and may be the only symptom for about 5 months before the lesions appear. Other sites of involvement include conjunctiva, anus, ear canal, labia, vagina, cervix, glans, and other mucous membranes.
2. Pemphigus vegetans is a rare form of pemphigus vulgaris.
(1) It is characterized by myxoid and papilloma-like proliferation on the vesicular surface, surrounded by an inflammatory redness, with a thick crust on the surface and a foul odor, surrounded by fresh blisters.
(2) It occurs in the axillae, groin, anus, vulva, under the breast, umbilicus and other folds.
(3) The disease is divided into two types, the heavy type (neumann type) and the light type (Hallopeau) with a benign course. Although the latter has many similarities with proliferative dermatitis, immunofluorescence shows that both types of proliferative aspergillosis have cell surface IgG deposition.
(4) The course of the disease is chronic, with mild self-conscious symptoms that may remit over the course of the disease.
3. deciduous aspergillosis (pemphigus foliaceas)
(1) The characteristic clinical lesion is a scaly, crusty vesicular surface on an erythematous base.
(2) The primary damage is erythematous basal surface, which may appear as blisters with thin walls that rupture easily to form a shallow in vesicular surface; later blisters occur less frequently.
(3) In early or limited damage, the lesions are mostly distributed on the face, scalp and upper back and other seborrheic areas, and the damage gradually expands, with self-conscious burning, pain and pruritus.
(4) The oral mucosa is rarely involved, and the Ney’s sign is positive.
4. pemphigus erythematosus, also known as Senear-ushel syndrome, can be transformed into pemphigus erythematosus.
The lesions are mainly located on the scalp, face, back and other seborrheic areas of the skin, and there is usually no mucosal damage. IgG and C3 deposits may also be seen in the basement membrane zone.
Disease laboratory tests
(1) Smear of fresh blister basal fluid scraped and stained with Kimsa stain shows single or clusters of loose spiny cells with large and uniformly stained nuclei, a clear band around the nucleus, dense staining of peripheral cells and disappearance of spines, which are spiny loose cells and are diagnostic for aspergillosis.
(2) Direct immunofluorescence examination: take a frozen section of the blister or its surrounding skin, and immunoglobulin and complement deposition can be seen among the spinal cells.
(3) Indirect immunofluorescence test: the patient’s serum is taken to detect antibodies to aspergillosis, and its titer is positively correlated with the disease.
(4) There is a decrease in total plasma protein and varying degrees of anemia. Initial routine blood tests may show an increase in total leukocytes, neutrophilic and eosinophilic leukocytes, and often varying degrees of accelerated sedimentation.
Lack of specificity, patients mostly have mild anemia, the degree of anemia is proportional to the severity of the disease, total leukocyte count increases, half of the patients have elevated eosinophils, increased sedimentation, liver and kidney function tests are basically normal.
Cytological examination (Tzanck smear): scrape the vesicular surface with a blunt knife and apply thinly on a slide, or use a slide to press lightly on the vesicular surface, then fix, Ritter or Giemsa staining, visible cells are round, oval, intercellular bridges disappear, the nucleus is round with lighter staining, visible nucleoli, cytoplasmic basophilic, which is called aspergillus cells or Tzanck cells.
Indirect immunofluorescence examination: More than 90% of patients with this disease have anti-epidermal cell surface antibodies in their sera. The titer of herpes major antibodies roughly parallels the severity and activity of the disease, and the titer may decrease or turn negative after clinical symptoms improve, but it is not the only indication to judge the severity of the disease. Herpes aspergillus antibodies are seen in burns, Lyell’s toxic epidermal necrolysis loosening disease, and penicillin rash, but this antibody The titer is weak and does not bind to epidermal cells in vivo and does not cause tissue damage.
Histopathology: The histopathological changes of each type of aspergillosis are characterized as follows.
1. common type of pemphigus: the lower layer of spiny cells, the basal cell layer occurs on the spine loosening, generating fissures and blisters, only a layer of basal cells remains at the base, located on the dermal papillae, similar to intestinal villi called villi, there are spiny loosening cells in the blister fluid, this cell is larger than normal cells, round, nuclear concentration in the center, uniform cytoplasm, a circle of lightly stained clear area around the nucleus, this cell is also called Tzanck cells. The upper part of the dermis is mildly edematous, with a few eosinophils and neutrophils infiltrating.
2. Proliferative pemphigoid: early damage with spine loosening fissures or cavity formation below the spine layer, visible villi, small eosinophilic abscesses in the epidermis, late hyperkeratosis, spine layer hypertrophy in the form of papilloma-like hyperplasia, pathological changes similar to common pemphigoid, but the formation of villi and subepidermal extension is particularly obvious, old lesions have no diagnostic value.
3. Deciduous aspergillosis: spines are loosened, fissures or blisters occur in the granular layer and below it, and granular layer cells are loosened by spines to form gluten cells similar to dyskeratosis (nuclear crinkling and deep staining, redder cytoplasm), which has diagnostic value, with inflammatory cell infiltration in the dermis and more eosinophils.
4. Erythrodermic aspergillosis: pathological changes are similar to deciduous aspergillosis, but the old damage follicles are hyperkeratotic, granular layer spines are loosened, and dyskeratotic cells are often significant.
Direct immunofluorescence examination: It is of great value for diagnostic typing and differential diagnosis of pemphigus. When lesions and normal looking skin are taken for examination, IgG and C3 deposits are found on the surface of epidermal cells in almost all patients; in common pemphigus and proliferative pemphigus, the fluorescence reaction is mainly in the subepidermal layer, in deciduous pemphigus and erythematous pemphigus the fluorescence reaction is mainly in the upper epidermal layer, and in erythematous pemphigus lesions DIF is seen Characteristic IgC and C3 deposition in the basement membrane zone.
Electron microscopic observation: early studies suggested local or total lysis of the intercellular matrix of the epidermis and widening of the cell gap, followed by the disappearance of bridge granule destruction leading to spine loosening formation. recent studies have shown that destruction of bridge granules or impaired formation is the main cause of blister formation. electron microscopic observation of the skin in non-lesioned areas shows destruction of bridge granules and reduction in their number.
(I) Treatment
1. Supportive treatment
A high protein, high vitamin, high calcium diet should be given, pay attention to the water-electrolyte balance, those who have difficulty in eating should be supplemented intravenously, and those who are anemic and have significant malnutrition should be given blood transfusion. Long-term use of corticosteroids should be supplemented with potassium to prevent hypokalemia. If there is bacterial or fungal infection, adequate amount of sensitive antibiotics or antifungal drugs should be given.
2. Systemic treatment
(1) Corticosteroid: It is the drug of choice for the treatment of this disease. Should try to achieve early treatment, adequate control, correct reduction, followed by the maintenance amount. The general dosage is 80-120mg prednisone per day. After 1 week of treatment, if there is no obvious efficacy, the dosage should be increased, mainly based on the number of new blisters, the speed of blister healing and the antibody titer of aspergillosis to judge the efficacy. The possibility of secondary infection should be excluded before increasing the dose. After the skin lesions are controlled, the drug should be continued for 2 to 3 weeks and then the dose should be reduced. Oral lesions often do not subside easily in the short term and are not necessarily used as a standard for dose reduction. The maintenance dose is usually 10-15mg per day, which can be changed to every other day in case of small doses. If blisters occur during the dose reduction process, the dose reduction can be suspended and stabilized for a period of time. Most patients need to maintain corticosteroids for several years, and a few patients can be completely withdrawn. In the process of applying hormones, attention should be paid to the possible side effects such as diabetes, gastric ulcer, osteoporosis, recurrence of tuberculosis and Candida albicans infection.
(2) Immunosuppression: For patients with stable disease, remission can be achieved in some cases with immunosuppression alone. For most cases, immunosuppression combined with corticosteroids can reduce hormone dosage and avoid or reduce the side effects of high-dose hormones. Cyclophosphamide 1~2mg/(kg-d) orally or thiopurine 1~2.5mg/(kg・d) (50~100mg per day) is appropriate. Methotrexate 25mg per week, intramuscularly. Immunosuppressants are generally effective after 1 month of use. After the efficacy, the hormone dosage is generally reduced first, and then the immunosuppressant dosage is reduced to the maintenance amount. In the process of using immunosuppressants, the side effects such as anemia, liver and kidney function damage, infection and renal failure should be closely observed.
(3) Gold preparation: gold sodium thiomalate (gold sodium thiomalate)
For those who cannot tolerate corticosteroids or immunosuppressants, it can be injected intramuscularly once a week, the first 10mg, the second 25mg, and then 50mg each time until the lesions are controlled, and then maintained with gold, 50mg every 2-4 weeks.
(4) Plasma replacement therapy: When the patient’s disease progresses rapidly or has a high serum aspergillus antibody titer and is not sensitive to high-dose corticosteroid therapy, plasma replacement therapy can be considered. It is replaced once a week with 1000-2000 ml each time.
(5) Cyclozapine: the dosage is 5-6mg/(kg・d), and it has certain efficacy when taken orally.
3. Topical treatment
The purpose of local treatment is to protect the wound surface and prevent infection.
(1) for small areas can be used 0.1% Ethacridine (Levanox), compound copper sulfate solution or Phellodendron decoction wet compresses. To gentian violet zinc oxygen shan, pine iodine oil, etc. made of oil gauze external dressing.
(2) For larger areas, crust and exudate more available potassium permanganate solution or 0.1% benzalkonium bromide (Neosporin) to clean the trauma. Use sterilized petroleum jelly gauze, Vickers oil gauze external dressing trauma, if possible, exposure therapy.
(3) For mucosal damage, use 2% to 3% boric acid solution, 1% hydrogen peroxide (hydrogen peroxide), 1% alum solution to gargle every 3 to 4 hours, with disinfection and astringent effect. After gargling, use 2.5% aureomycin glycerin coating externally, or gargle with Chinese herbal medicine honeysuckle, white chrysanthemum decoction or use gold lotus tablets 2 tablets orally each time.
(II) Prognosis
1. Before the use of corticosteroids, the prognosis of aspergillosis is extremely poor and the mortality rate is extremely high. The prognosis is related to the following factors.
(1) The mortality rate is higher in elderly and juvenile patients than in middle-aged patients.
(2) Death occurs within 3 years and its prognosis is very good if survival exceeds 5 years.
(3) Those who do not receive timely and effective treatment have a poor prognosis.
(4) Erythrodermic aspergillosis has a better prognosis than all other types of aspergillosis.
2. Causes of death in aspergillosis
(1) Infection: Respiratory infection caused by bacteria or viruses is an important cause of death.
(2) Side effects from treatment with corticosteroids and immunosuppressants play a role in causing patient death. Such as infection, gastrointestinal bleeding, gastric perforation, embolism, and cardiac failure.
(3) Secondly, aspergillosis itself and complications such as cancer also play a role in causing death.
Complications of aspergillosis
It is often accompanied by varying degrees of fever, anorexia, fatigue, etc. Due to extensive skin erosion, massive extravasation of body fluids, excessive loss of protein, electrolytes and body fluids, and weakness, it is easy to combine sepsis, pneumonia and other secondary infections.