Pemphigus is a more severe chronic recurrent maculopapular skin disease that manifests as batches of large blisters with histopathological evidence of spicule cell loosening.
There are 4 types of pemphigus in the past: common pemphigus and its reactive phase proliferative pemphigus, deciduous pemphigus and its light or heterogeneous erythematous pemphigus; with the development of diagnostic techniques, there are now 4 additional types, namely herpes-like pemphigus, IgA pemphigus, paraneoplastic pemphigus and drug-induced pemphigus; this section only describes the first 4 types, and the other 4 types are described in a special section later.
Etiology and pathogenesis
Indirect immunofluorescence (IIF) found that there are autoantibodies against squamous epithelial intercellular material (pemphigus antibodies) in the serum of patients, mainly of IgG type, and the antibody titer is consistent with the severity of the disease. Direct immunofluorescence (DIF) staining revealed intercellular deposits of IgG and complement in the epidermal keratin-forming cells of the skin surrounding the pemphigus damage.
The antigen of pemphigus is desmoglein (Dsg), a glycoprotein located in the pontine granules, and is divided into three types, Dsg1, 2, and 3; the antigen of common pemphigus is Dsg3 with a molecular weight of 130 kD, and the antigen of deciduous pemphigus is Dsg1 with a molecular weight of 160 kD, both of which are combined with the 85 kD pontine zymoglobin in the pontine granules ( plakoglobin;
When the antibody to Dsg1 or Dsg3 binds, it causes the epidermal cells to produce and release fibrinolytic activator, which converts fibrinolytic enzyme into fibrinolytic enzyme, leading to the destruction of intercellular adhesive material and the loosening of the spinal cells, resulting in clinical blistering.
[Clinical manifestations
Mostly occurs in middle-aged and old people aged 30 to 60 years old, with a similar incidence in men and women.
More than half of the patients have blisters and vesicles in the oral mucosa before the appearance of lesions, which do not heal for a long time. The blisters appear on normal-looking skin, with clear or slightly mixed fluid, thin and flaccid walls, and a positive Ney’s sign. The blisters rupture to reveal a flushed vesicular surface, with a little exudate or crust, the wound heals slowly, with self-conscious burning pain, leaving pigmented spots after healing.
The blisters are small at the beginning, commonly on the chest, back or head and face, and then gradually increase and can spread all over the body. There are often fever, anorexia and other systemic symptoms. The course of the disease is chronic, with blisters rising and falling, and it can be prolonged for many years. Due to the large number of traumatic lesions, large losses of water, electrolytes and proteins, and difficulties in eating due to oral damage, the patient gradually fails and often dies due to secondary infections.
2. Proliferative aspergillosis Less common, with a younger age of onset, and divided into 2 types.
(1) Neumann’s type: It occurs in skin folds, such as the axillae, groin, vulva, perianal area, umbilicus and under the female breast. The early damage is similar to that of the common type, but after the blisters are broken, papillary proliferation occurs on the vesicular surface with fishy pus, which gradually expands to the surrounding area. The course of the disease is very slow.
(2) Hallopeau type: A milder benign type with small pustules and papillary proliferation in the axillae and groin, similar to proliferative dermatitis, with a better prognosis.
3, deciduous pemphigus is also more common, mostly in the head, face and upper back of the chest, a few loose blisters, positive Ney’s sign, blister wall is thin, very easy to rupture, soon dry and thin yellow-brown crust, gradually developed to the whole body, the skin dark red, with a large number of blade-like scabs, there is a bad smell. Sometimes there is no obvious blistering and resembles exfoliative dermatitis. Oral cavity damage is rare, and the prognosis is better than that of the common type.
4. Erythrodermic aspergillosis, also known as Senear-Usher syndrome, is considered to be a limited or early lesion of deciduous aspergillosis. The lesions occur on the head, face, and upper median seborrheic area of the chest and back. The facial lesions are often erythematous and resemble lupus erythematosus, with thin crusts. On the chest and back, there are scattered small erythematous patches and loose thin-walled blisters with positive Ney’s sign, which quickly rupture and form thin crusts, and the scalp, chest and back lesions resemble seborrheic dermatitis.
There is usually no mucosal damage. In addition to antibodies to aspergillosis, there may also be antinuclear antibodies in the serum of this type, and IgG and complement deposits may be found in the interspinous cells and epidermal dermal junction on DIF examination.
Diagnosis and differential diagnosis
1. Clinically, the recurrent occurrence of relaxing blisters on normal skin with a positive Ney’s sign is seen, and the common type and deciduous type damage is more generalized throughout the body, often with oral damage. The proliferative type occurs in the skin folds. The erythematous type of damage occurs in the head, face, chest and back seborrheic areas.
2, cytological examination from the bottom of fresh blisters scraped tissue smear, stained with Richter or Kimsa, can be seen single or clusters of spiny layer loose cells (pemphigoid cells).
3, histopathological examination for intra-epidermal echinoderm relaxation blisters, common type blisters located above the basal layer, proliferative type with echinoderm hypertrophy and papilloma-like hyperplasia. The deciduous and erythematous blisters are located in the subepidermal stratum corneum or granular layer.
The immunopathology DIF shows IgG and complement deposits between the epidermal cells at the damage site. iiF examination, the patient’s serum can be found with antibodies to aspergillosis, and its titer is consistent with the disease activity.
Treatment
1. Supportive therapy is extremely important. Those with extensive damage should be given a high-protein diet and multivitamin supplements. Pay attention to the water and electrolyte balance, fasting people should be supplemented by intravenous. Systemic failure can be transfused with small amounts of blood or plasma several times, and anabolic hormones such as nandrolone phenylpropionate or connilone should be given. Strengthen care, pay attention to skin cleanliness and hygiene to reduce secondary infection of trauma and prevent decubitus ulcers.
2.Systemic treatment
(1) Glucocorticoid: The drug of choice for the treatment of this disease. These drugs can inhibit the production of aspergillus antibodies and inhibit the activity of fibrinogen activator (PA) and induce the secretion of PA inhibitory factor. High doses are needed at the beginning so that the disease can be controlled as soon as possible and new blister formation can be inhibited.
The first dose can be determined according to the extent and severity of the damage. 30-40 mg of prednisone can be given daily to mild patients with lesions accounting for less than 10% of the body surface area; 60 mg can be given daily to moderately ill patients with lesions accounting for about 30% of the body surface area; 80 mg can be given daily to severely ill patients with lesions accounting for more than 50% of the body surface area. If there is still new blistering after 3-5 d, immediately increase the original dose by 50% until the disease is controlled, the original damage is healed and there is no new blistering.
When the dose is reduced to 30mg/d, the dose can be gradually reduced to every other day to reduce the inhibition of HPA (hypothalamus-pituitary-adrenal) axis. In severe cases, shock therapy can also be used, such as methylprednisolone 0.5-1g, intravenous drip, and after 5 d, change to prednisone 60mg/d, if there are still new blisters, 1 month later, shock therapy can be used again.
If new blisters occur during the reduction process, immediately increase the current dosage by 50%, observe for 1 to 3 weeks, and then slowly reduce the dosage. If available, the dose can be adjusted every 2 to 3 weeks by testing the antibody titer of pemphigus with IIF and referring to the change of titer. Most patients need to use maintenance doses for several years, and a few can be withdrawn completely. For milder proliferative and erythematous aspergillosis, the dose of prednisone should be smaller, such as starting with 30-50 mg/d, and gradually reducing the dose after the disease is controlled.
Savin pointed out that before the application of hormones, the main causes of death in aspergillosis were skin infections and electrolyte disorders caused by the disease, while after the application of hormones, the main causes of death were complications of hormones, such as respiratory infections, pulmonary embolism, diabetes mellitus and peptic ulcers, so it is necessary to always Therefore, we must be alert to the occurrence of side effects and take corresponding measures to deal with them in time.
(2) Immunosuppressants: They can inhibit the formation of autoantibodies and are the main adjuvant therapy for this disease. The commonly used ones are azathioprine and cyclophosphamide, with the initial dosage of 2mg/kg/d, which can be reduced to lmg/kg/d when the disease is controlled and no new herpes occur, and should be continued for at least 4 months.
Or use methotrexate (MTX) 10-20mg intravenously or intramuscularly, once a week for 6-8 weeks. Several immunosuppressive drugs can also be used alternately to reduce side effects. The glucocorticoid dose can be reduced slightly faster when adding such drugs. For milder cases of aspergillosis, immunosuppressants can also be applied alone. In severe cases, cyclophosphamide shock therapy can be used, with cyclophosphamide 600 mg IV, 1 time/d for 2 d; repeat treatment after half a month if necessary. It can also be combined with glucocorticoid shock therapy.
Cyclosporin A (Cyclosprin A) is a new generation immunosuppressant, the dose is 5-8mg/kg/d, divided into 2 doses. 4-6 weeks, after the disease is controlled, reduce to 2-3mg/kg/d, can be used continuously for 1~2 years. This drug can be used in combination with prednisone or in patients who are resistant to glucocorticoid therapy. Note that this drug should not be used in combination with imidazole or triazole drugs such as ketoconazole, fluconazole or itraconazole to avoid the risk of significantly increased blood levels.
(3) Mycophenolate (Mycophenolate mofetil, MMF): A new type of immunosuppressant that inhibits the synthesis of nucleic acids and blocks the proliferation of T and B lymphocytes.
Enk et al. combined MMF and prednisone to treat 12 patients with common aspergillosis who relapsed after treatment with azathioprine and prednisone, the dose of MMF was 1g, 2 times/d, and prednisone was 2mg/kg/d, and achieved good The efficacy of MMF and prednisone is 2 mg/kg/d, and good results were achieved. 11 cases were followed up for 1 year without recurrence.
(4) Radix et Rhizoma: It has anti-inflammatory and immunosuppressive effects. Weng Mengwu et al. treated aspergillosis with Leigongteng syrup and found that about 39% of patients could effectively control the disease and have long-term remission with little side effects. It is believed that the therapeutic effect of the drug on aspergillosis may be caused by inhibiting the proliferation of T and B lymphocytes and suppressing the production of autoantibodies by B cells. It is proposed that in patients with new-onset mild to moderate aspergillosis, treatment with raphe is preferred, and if the disease is not effective for 2 weeks or is not completely controlled, prednisone 30 mg/d is used instead or added.
(5) Aminophenone (DDS): It can be used to treat some mild and moderate cases of common aspergillosis and deciduous aspergillosis at a dose of 100-300 mg/d. It has the advantage of fewer and safer side effects. It has been reported to be ineffective for those with high titers of aspergillosis antibodies, and effective for those with negative or low titers of aspergillosis antibodies, with some patients relapsing half a month after stopping the drug and then still effective.
(6) Heparin: The mechanism of action is to inhibit the formation of rosettes of T and B lymphocytes, reduce the toxicity of antibodies to target cells, and inhibit the collaboration between T-B lymphocytes. It has been reported that in 34 patients with aspergillosis, 13 cases were treated with heparin alone, 9 cases were mostly healed and 3 cases had no new rash; 21 cases were healed by combined application of heparin and glucocorticoids all with reduced or unchanged hormone dosage.
(7) Plasma exchange therapy: It can clear the antibodies of aspergillosis in the blood plasma and achieve the effect of reducing the loosening of the spinous layer and relieving the disease. It is suitable for those who have severe disease, high titer of pemphigus antibodies in blood and ineffective glucocorticoid treatment at doses greater than 2mg/kg/d. It is given once or twice a week, with each exchange of 0.5 to 2L, and can be performed 4 to 10 times in a row depending on the condition. This therapy can be applied with other therapies to reduce the dosage of other drugs and improve the efficacy.
(8) High-dose static injection of γ-immunoglobulin (IVIG): The mechanism of action may be related to the following factors: anti-unique antibodies in immunoglobulin can effectively neutralize disease-causing antibodies; binding to specific B-cell receptors to make the receptor function down-regulated; accelerating the catabolism of autoantibodies, speeding up their clearance process and reducing antibody synthesis, thus rapidly reducing the antibody titer of aspergillosis in blood.
It is suitable for those whose condition cannot be controlled by high-dose glucocorticoids and immunosuppressants or who have serious contraindications. Usage: Administered at 0.4-2g/kg/d, at a rate of no more than 2mg/kg/min, for 3-5d, repeated once a month. Domestic Liu Xiangnong et al. reported 9 cases of severe aspergillosis using moderate doses of hormone plus cyclophosphamide and IVIG to achieve better results.
(9) Gold preparation: It is also an adjuvant treatment method. The drug has anti-inflammatory effect and reduce the role of aspergillosis antibody titer, can reduce the amount of glucocorticoids, reduce its side effects. Its preparation has gold sodium thiomalate (Gold sodium thiomalate), intramuscular injection once a week, the first week for 10mg, the second week 25mg, and then 50mg per week until the lesion control and then reduce the amount; or every 2 to 4 weeks intramuscular injection 50mg.
Some authors believe that this drug, in combination with moderate amounts of prednisone, is an effective early treatment for common aspergillosis, and is more likely to provide relief in most patients than combined treatment with prednisone and immunosuppressants, and sometimes effective in lighter patients treated with gold salts alone. (10) Levamisole and prednisone combination: levamisole 100-200mg daily, after 2-8 weeks of treatment to achieve significant effect, you can reduce the amount of hormone, later levamisole also reduced to 50mg / d, weekly for 3 d.
(11) Enzyme inhibitors: They are still in the experimental stage. Since the onset of pemphigus is caused by the combination of antibodies to pemphigus and antigens on the epidermal cell membrane, certain proteases are produced to cause the spine layer to loosen. Organ culture and animal tests have shown that certain protease inhibitors can inhibit spine layer relaxation, indicating that these drugs have some potential in the treatment of aspergillosis.
In China, Nie Zhuxiang and others treated five cases of common pemphigus with the fibrinolytic enzyme inhibitor haemophilic acid at a dose of 0.125g, taken four times a day, along with a small dose of prednisone, and observed for half to six months, which could better control the disease.
(12) Chinese medicine treatment: those with critical damage pancytopenia are first treated with glucocorticoids, and after the symptoms are relieved, herbal formulas for clearing heat, detoxification and dampness are added, which can help stabilize the disease and reduce the amount of hormones. If the disease is chronic, the body is weak, or the defense function of the body is reduced by long-term use of glucocorticosteroids, the stomach can be nourished, the spleen can be strengthened and the blood can be supported, or the qi can be nourished in the formula for clearing heat and detoxifying the blood can be added.
(13) antibiotics: used when the damage is extensive and there is secondary infection.
3.Departmental treatment When the lesions are small, 2% mupirocin or 1% erythromycin ointment can be applied externally or Reynolds paste dressing, in which 1% hydrocortisone or other glucocorticoids can also be added. Chen Ming used 0.1% dexamethasone cream for erythematous aspergillosis, and 2% chloramphenicol can be added to the cream for infected traumas.
Those with extensive damage can take a medicinal bath, such as 1:10,000 potassium permanganate solution or herbal decoction (Yinhua, Diyu, Qin Pi, etc.) for medicinal bath. If there are conditions, it is best to take exposure therapy, baking with a lamp stand, so that the wound surface dries and crusts, which can reduce the chance of secondary infection. For oral cavity erosion, use Dobei liquid or 1% hydrogen peroxide to rinse the mouth, and then apply 1% iodine glycerin. In severe pain, 2% lidocaine or 1% dacronin solution can be applied before eating.