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8УДК 616-002.7: 616.5
ГРАНУЛЕМАТОЗ С ПОЛИАНГИИТОМ (ВЕГЕНЕРА) В ПРАКТИКЕ ВРАЧА-ДЕРМАТОВЕНЕРОЛОГА НА ПРИМЕРЕ КЛИНИЧЕСКОГО НАБЛЮДЕНИЯ
1Разнатовский К.И. (зав. кафедрой), 1Корнишева В.Г. (профессор кафедры)*, 1Раводин Р.А. (доцент), 2Чипан Л.Л. (зав. отделением), 2Красавцева Л.А. (врач-оридинатор)
Северо-Западный государственный медицинский университет им. И.И. Мечникова (кафедра дерматовенерологии); 2Городской кожно-венерологический диспансер, Санкт-Петербург, Россия
В статье рассмотрены современные аспекты этиологии, патогенеза и клиники гранулематоза с полиангиитом (гранулематоза Вегенера). На примере собственного клинического наблюдения представлен спектр возможных клинических проявлений заболевания со стороны кожи и слизистых оболочек, что особенно важно в практике врача-дерматовенеролога.
Ключевые слова: гранулематоз с полиангиитом, гранулематоз Вегенера, дерматовенерология
GRANULOMATOSIS WITH POLYANGIITIS (WEGENER) IN THE PRACTICE OF THE DERMATOVENEROLOGIST ON THE EXAMPLE OF CLINICAL OBSERVATION
1Raznatovsky K.I. (head of the department), 1Kornisheva V.G. (professor of the department), 1Ravodin R.A. (associate professor of the department), 2Chipan L.L. (head of the clinical department), 2Krasavtseva L.A. (physician) 1North-Western State Medical University named after I.I. Mechnikov (Department of Dermatovenerology); 2Municipal Dermatovenerologic Dispensary, St. Petersburg, Russia
The article deals with the modern aspects of etiology, pathogenesis and clinic of granulomatosis with polyangiitis (Wegener granulomatosis). On the example of own clinical observation, the range of possible clinical manifestations of the disease from the skin and mucous membranes is presented, which is especially important in the practice of a dermatovenerologist.
Key words: granulomatosis with polyangiitis, Wegener granulomatosis, dermatovenerology
Контактное лицо: Корнишева Вера Гавриловна, e-mail: v.g.kornisheva@gmail.com
Wegener's granulomatosis is a rare multisystem autoimmune disease of unknown etiology, which is characterized by necrotizing granulomatous inflammation of the vascular wall of small and medium-sized blood vessels, mainly affecting the upper respiratory tract, lungs, kidneys, organs of sight and hearing. The synonyms are: granulomatosis with polyangiitis (GPA), Wegener's disease, granulomatous-necrotizing vasculitis, necrotic granuloma of the upper respiratory tract with nephritis; granulomatous vasculitis associated with antibodies to the cytoplasm of neutrophils. In accordance with the decision of the 2nd International Consensus Conference (Chapel Hill, 2012), Wegener's granulomatosis began to be called granulomatosis with polyangiitis (GPA) [1, 2].
In 1897, Peter McBride was probably the first to give a description of a patient with granulomatous polyangiitis. In 1931, Klinger described a 70-year-old physician with constitutional symptoms, joint damage, proptosis, widespread inflammation of the upper respiratory tract, saddle-shaped deformity of the nose, glomerulonephritis and pulmonary lesions. In 1936, Dr. Frederich Wegener reported about three patients with similar clinical features and published their findings on their clinical and histopathological manifestations, which led to the designation of the disease of the same name. In 1954, Goodman and Churg were the first who described the triad of pathological signs of GPA, including 1) systemic necrotizing vasculitis, 2) necrotizing granulomatous inflammation of the airways and 3) necrotizing glomerulonephritis [3].
The epidemiology of the disease has rarely been studied, the prevalence is 25-60 cases per 1 million people, and the incidence is 3-12 cases per 1 million people per year. At the age of 40-65 years, there are more male patients (the male to female ratio is 1.5: 1), but in childhood there are more female patients [4]. In recent years, there has been an increase in the incidence in European countries, especially during the autumn-winter period [5, 6].
The etiology of the disease is unknown. It is assumed that there is a provocative role of infectious agents (Staphylococcus aureus) with the presence of genetic susceptibility [7-16]. GPA is characterized by vasculitis of small and medium vessels, "geographical" necrosis and granulomatous inflammation, especially of the upper respiratory tract. Cellular immune processes underlie the formation of the primary vascular lesion - granulomas. At the same time, tissue damage is associated with the activation of cellular immune responses and the development of concomitant inflammation. The determination of anti-cytoplasmic IgA antibodies (cANCA) in most patients with GPA also confirms the significance of the humoral autoimmune response. One of the antigens is serine protease 3 (PR3-cANCA). The pathogenetic role of PR3-cANCA in GPA is confirmed by their identification in the active phase of the disease in 80-90% of patients with GPA [17-19]. Experiments in vitro have shown that neutrophil activation is one of the effects of PR3-cANCA, leading to the formation of active oxygen and elastase and secretion of PR3, which in turn contributes to tissue damage [8, 20]. Data from in vitro studies confirmed the role of complement in ANCA-associated systemic vasculitis and suggested the involvement of cANCA in neutrophil activation and endothelial damage. In general, these processes lead to the development of necrotic vasculitis [21-22].
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GPA has a wide range of clinical manifestations, which includes common manifestations in the form of fever, sweating, lethargy, loss of appetite, and weight loss. The most characteristic lesions of the upper respiratory tract (mouth ulcers, hyperplastic gingivitis, sinusitis, rhinitis, nasal bleeding, saddle-shaped deformity of the nose, otitis media, hearing loss) occur in the debut of the disease in 80% of patients, and 80% of patients have pulmonary manifestations (in the form of pulmonary infiltrates, cough, hemoptysis, shortness of breath, pulmonary hemorrhages), in 75% of patients the kidneys (glomerulonephritis) can be affected. Ophthalmic manifestations (conjunctivitis, episcleritis, uveitis, vasculitis, optic nerve, occlusion of retinal proptosis) are less commonly observed, there may be arthritis, arthralgia, neuropathy, paralysis of the cranial nerves, pericarditis, myocarditis, arrhythmias, abdominal pain, gastrointestinal bleeding. Skin lesions are quite rare; they are not specific and include: palpable purpura, skin ulcers (the latter may resemble gangrenous pyoderma), vesicles, pustules, hemorrhagic blisters, livedo reticularis, and subungual hemorrhages. They are more characteristic developments in the later stages of the disease [23-34]. Routine laboratory tests for GPA are not specific. Results may include the followings:
•rheumatoid factor is positive with low titer in two thirds of patients, whereas antinuclear antibodies can be present in only 10-20% of patients;
•complete blood count: mild normochromic normocytic anemia is present in 50% of patients; possible leukocytosis with a predominance of neutrophilia;
•increased markers of inflammation - the sedimentation rate of Westergren erythrocytes (ESR) and C-reactive protein (CRP) in 90% of patients with active and generalized pathology.
The diagnosis is made on the basis of the criteria of the European League against Rheumatism (EULAR), the International Pediatric Rheumatological Clinical Research Organization (PRINTO) and the European Society of Pediatric Rheumatology (PreS) (Table) [34].
Table
GPA diagnostic criteria (EULAR I PRINTO I PReS, 2010)
Criteria Definition
1. Pathomorphology Granulomatous inflammation in the artery wall, perivascular or extravascular zone
2. Disease of the upper respiratory tract Chronic purulent or hemorrhagic inflammation of the nasal cavity, nasal bleeding, crusts, granulomas. Perforation of the nasal septum, saddle-shaped deformity ofthe nose. Chronic or recurrent sinusitis
3. Disease of larynx, trachea and bronchi Retropharyngeal, tracheal or bronchial stenosis
4. Damage to the lunqs Nodes, cavities or fixed infiltrates according to x-ray or CT examination
5. ANCA The presence of ANCA according to immunofluorescence studies or ELISA (MPO/p, PR3 / cANCA)
6. Kidney damage Proteinuria> 0.3 g / day or albumin / creatinine> 30mmol/ mg in the morning urine. Hematuria or red blood cell count is> 5 cells in sight. Reduction ofglomerular filtration according to the Schwarz formula <50% of normal. Necrotizing pauci-immuneqlomerulonephritis
The diagnosis of GPA is established inthe presence of at least 3of6 criteria
The diagnosis of granulomatosis with polyangiitis remains a challenge for a practicing dermatologist, taking into consideration the lack of specific dermatological manifestations of the disease. We share our own experience - under our supervision there was a 64-year-old patient who was admitted for in-patient treatment in the dermatological department of St. Petersburg
State Budgetary Healthcare Institution "Municipal Dermatovenerologic Dispensary" with a diagnosis of the "Distributed chronic pyoderma, ulcerative-necrotic form". Comorbidities: Psoriasis vulgaris. Progressive stage. Winter period. Coronary heart disease. Hypertension stage 2, risk 3. Chronic obstructive pulmonary disease. Hemorrhoids, in the period of exacerbation. During hospitalization, the patient complained of papular lesions on the skin, painful ulcers on the head, groin and mammary glands. He had been considered a patient with psoriasis since 2007, when psoriatic lesions appeared in the form of papules and plaques on the body. He was treated on an outpatient basis with improvement; it was possible to achieve remission of the disease which was lasting up to 3 years. Periodic exacerbations - autumn-winter. In early June, 2018, the nature of the rash changed: weeping ulcers appeared on the mammary glands, behind the left auricle. In August, ulcers appeared on the scalp, which became covered with purulent crusts; the patient did not receive treatment, and did not seek for medical help. At the same time period, patient noted an exacerbation of psoriasis - she turned to the Dermatovenerologic Dispensary at place of residence, from where the patient was sent for inpatient treatment (late September 2018). At admission the general condition is satisfactory, hemodynamics is stable. As for organs and systems, there are no specific features. On examination, the process of skin lesion is widespread and presented on the scalp of the head with dense crusts of gray, 1-2 cm in diameter, when squeezed, there is no discharge. On the right temporal region there is an ulcerative defect up to 1.5 cm in diameter with clear boundaries and an inflammatory runs along the periphery; there is a purulent discharge from the ulcer surface. Behind the left auricle - an ulcer 1.5 cm in diameter, deep, with a valiform edge and serous-purulent discharge (Fig.1).
Fig. 1. Behind the left auricle - an ulcer 1.5 cm in diameter, deep, with a valiform edge and serous-purulent discharge.
On the skin of the lower medial quadrants of both mammary glands there are two symmetrically located round ulcers up to 3.5 cm in diameter, with clear boundaries and elevated edges, with a moderately pronounced sero-purulent discharge from the surface (Fig. 2).
Fig. 2. On the skin of the lower medial quadrant of mammary gland there is round ulcer up to 3.5 cm in diameter, with clear boundaries and elevated edges, with a moderately pronounced sero-purulent discharge from the surface.
In the area of the right inguinal-femoral fold, an ulcerated ulcer is up to 3 cm in length and up to 1 cm in width, with a roller-like edge and serous-purulent discharge. In the area of the chest, abdomen, mammary glands and hips there are rashes of flat red lenticular papules covered with whitish scales. When scraping papules, the positive symptoms of the psoriatic triad are determined. On the rear of the right hand there is a palpable purpura up to 1 cm in diameter.
The results of the blood test are: leukocytosis - 12.6-109/l, neutrophilia - 76%, lymphopenia - 18%, other indicators
- within the normal range, an increase in ESR - 47 mm/h. CRP - 135 mg/l. Markers of viral hepatitis B and C are not detected, F-50 is negative. Ketone bodies are present in the urine - 1 mmol/l, in the urine sediment, altered erythrocytes of 8-10 are found in the field of view, other indicators are within the normal range. In the biochemical analysis of blood, the level of glucose is increased - 12 mmo/l, the GGTP (Gamma-glutamyltranspeptidase) is increased - 89.9 U/l, the level of creatinine is increased
- 101 mmol/l, the other indicators are within reference values. ECG is a variant of the norm.
Received antibacterial, desensitizing therapy, glucocorticosteroids parenterally (30 mg of prednisolone). On the background of the therapy, a moderately pronounced positive dynamics was observed: the ulcers began to clear, there was no tendency for their growth, however, hemorrhagic spots appeared on the skin. After 12 days from the start of therapy, the patient's body temperature rose to 37.5, which was regarded as a manifestation of ARVI or exacerbation of chronic bronchitis. The patient began to complain of heart failure and shortness of breath. An x-ray of the chest organs was performed: in the lingular segment of the left lung infiltration was determined, in other parts of the lung there were no pathological changes. Antibiotics (cefazolin) were prescribed for the diagnosed pneumonia -on the fifth day of antibiotic therapy, the patient began to develop mouth ulcers (on the mucous tongue, soft palate), ranging in size from 0.2 to 0.5 cm in diameter. Against the background of the therapy, the fever disappeared, but the patient began to notice the appearance of hemorrhages on the legs (inner surface of the thighs, anterior surface of the legs), mucous membranes of the nasal cavity and pharynx. Screening for systemic ANCA-associated vasculitis was performed - cANCA was detected in a titer of 1: 640 (with a cytoplasmic luminescence type). A CT scan of the breast was performed, a subpleural region of lung tissue consolidation in S6 of the right lung, a focal peribronchial region of S4 consolidation of the left lung, and a solid lung node in S5 of the left lung were found.
Based on the available clinical and laboratory data, GPA was diagnosed and the patient was transferred to a specialized multidisciplinary clinic. On the example of the presented patient, we observed the debut of GPA, which began with a skin lesion resembling gangrenous pyoderma. The presence of concomitant psoriasis created additional difficulties in the formulation of a correct diagnosis. The process progressed rather quickly, but only the appearance of of mouth ulcers, as well as the appearance hemorrhagic lesions on the skin, allowed us to suspect GPA.
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Постуупила в редакцию журнала 03.06.2019
Рецензент: Л.П. Котрехова
