Wegener's granulomatosis: causes, symptoms, diagnosis, treatment

Wegener's granulomatosis (syn: gangrenous granuloma, centrofacial granuloma) is a serious, spontaneously occurring autoimmune granulomatous disease, which is based on necrotic vasculitis with lesions of small vessels of the upper respiratory tract, especially the mucous membrane of the nasal cavity and kidneys.

Epidemiology of Wegener's granulomatosis

Wegener's granulomatosis is rare enough, to the same extent in men and women (mean age is 25-45 years). The incidence is 0.05-3 per 100 000 people.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]

Causes of Wegener's granulomatosis

The cause of the development of Wegener's granulomatosis disease remains unknown.

Wegener's granulomatosis refers to ANCA-associated vasculitis, so a detection in the serum of ANCA, which serves as pathogenetic factors of the disease, can be considered a specific marker of this disease. When the disease is disrupted, the regulation of production of cytokines (TNF-a, IL-1, IL-2, IL-6, IL-12).

Pathomorphological changes are represented by fibrinoid necrosis of the vascular wall with development around the necrotic foci of peri-vascular leukocyte infiltration and the subsequent formation of granulomas containing macrophages, lymphocytes and giant multinucleate cells.

[12], [13], [14], [15], [16]

Pathomorphology of Wegener's granulomatosis

There are two types of changes: necrotic granuloma and necrotic vasculitis. Granuloma is a focus of necrosis of various sizes, surrounded by a polymorphonuclear infiltrate containing neutrophilic granulocytes, lymphocytes and plasma cells, occasionally eosinophilic granulocytes. Epithelioid cells are few or absent. There are multi-nuclear giant cells such as foreign bodies. Necrotizing vasculitis affects small arteries and veins, in which successive development of alterative, exudative and proliferative changes. Characterized by fibrinoid necrosis of the walls of the vessels, which are infiltrated mainly by neutrophilic granulocytes with the decay of nuclei ("nuclear dust"). The destruction of the walls can be accompanied by a thrombosis of the vessel with the formation of sharp, sometimes rupturing aneurysms, which leads to hemorrhages. Especially common in Wegener's granulomatosis are the vasculitis of the microcirculatory bed, mostly productive in nature, localized in the kidneys, lungs and subcutaneous fat layer. The skin determines necrotizing vasculitis with thrombosis and central ulceration, including in the foci of purpura. In the field of ulcerative lesions, skin and subcutaneous nodes, as a rule, necrotic granulomas and necrotic vasculitis are found. Proliferation of the inner membrane of the vessels can lead to obliteration of their lumens.

Differentiate the disease from nodular periarteritis, which also affects arteries and veins, mainly of medium caliber, and necrotic granulomatous changes are observed. However, with Wegener's granulomatosis, small arteries and veins are involved in more than periarteritis, and granulomas are always necrotic. In the early stages, it is very difficult to differentiate these two diseases; later, granulomas with eosinophilic granulocytes, as well as epithelioid and giant cells located radially around the necrosis zone, are usually found in Wegener's granulomatosis.

Histogenesis of Wegener's granulomatosis

Most authors associate the pathogenesis of Wegener's granulomatosis with immune disorders leading to a hyperergic vascular reaction, which is proved by the detection by immunofluorescence of fixed immune complexes (IgG) and complement components (C3) in lesions, in particular in the kidneys. Deposits of a granular character along the basal membranes, which are immune complexes, have been identified. Antigen-antibody complexes were found by electron microscopy subepidermally. S.V. Gryaznov et al. (1987) believe that with this disease, antibacterial protection has been altered, possibly due to a neutrophil defect, which contributes to the development of infection. Cytophilic autoantibodies to the cytoplasmic structures of neutrophilic granulocytes (ANCA) and to a lesser extent monocytes, previously considered as specific for this disease, have been found, but their specificity is currently being questioned, as these antibodies are detected in other vasculitis (Takayasu arteritis, Kawasaki arteritis and other).

Symptoms of Wegener's granulomatosis

It often develops in adults, but it can also occur in children. There are generalized, borderline and localized (malignant granuloma of the face) forms. Some authors consider the localized form an independent disease. In generalized form, in addition to necrotic lesions of the nasal mucous membranes, sinuses, upper airways, leading to extensive destruction, changes in internal organs (lungs, kidneys, intestines) due to lesions of small arteries and veins are observed. In the lungs there are calcified foci, in the kidneys - focal or diffuse glomerulonephritis. With the borderline form, severe pulmonary and extrapulmonary (including skin) changes occur, but without marked renal involvement. With a localized form, skin changes predominate with a pronounced destruction of the facial tissues.

The main clinical symptoms of Wegener's granulomatosis include ulcerative necrotic changes in the upper respiratory tract (ulcerative necrotic rhinitis, laryngitis, sinusitis), trachea and bronchi, lung and kidney damage.

For a long time it was believed that with Wegener's granulomatosis pathological changes from the heart are rare enough and they do not affect the prognosis. This is due to the low or asymptomatic course of heart disease. Thus, Wegener's granulomatosis is characterized by the asymptomatic course of the coronary artery; described cases of the development of painless myocardial infarction. However, it is shown that the lesion of the coronary arteries occurs in 50% of patients (submitted series of autopsies). A more typical result of coronary artery disease may be dilated cardiomyopathy (DCM). Occasionally, granulomatous myocarditis, valvular defects and pericarditis are noted, which can be explained by the involvement of small artery valves and pericardium. AH is noted in patients with a generalized variant of the disease when involved in the pathological process of the kidneys.

The skin is involved in the process again approximately in 50% of patients. There are extensive ulcerative necrotic lesions of the central part of the face as a consequence of the spread of the process from the nasal cavity; ulcerous lesions of the oral mucosa; mainly in the late stages of the process may be polymorphic eruptions: petechiae, ecchymosis, erythematoma-papular, nodular necrotic elements, ulcerative necrotic lesions such as gangrenous pyoderma on the trunk and distal limbs. The outlook is unfavorable. The development against the background of immunosuppressive therapy of the disease of generalized tumor in the form of malignant histiocytosis is described.

A similar skin lesion, but usually without a hemorrhagic component, can be observed with a so-called granulomatous lymphoma that differs from Wegener's granulomatosis with a predominant lung injury without changes in the upper respiratory tract and, possibly, the kidneys, an increased risk of developing lymphomas. Presence of atypical lymphocytes in polymorphic infiltrates.

Classification of Wegener's granulomatosis

Depending on the clinical picture, localized (isolated lesions of ENT organs, eyes), limited (system manifestations without glomerulonephritis) and generalized forms are isolated. In 1976, the ELK classification was proposed (De Remeier R. Et al.), According to which the "incomplete" (isolated lesions of the ENT organs or lungs) and "complete" (defeat of two or three organs: E-ENT organs , L - lungs, K - kidneys) variants.

[17], [18], [19], [20], [21]

Diagnosis of Wegener's granulomatosis

The laboratory data do not have any Wegener-specific granulomatosis.

• Clinical blood test (normochromic anemia of mild degree, neutrophilic leukocytosis, thrombocytosis, increased ESR).
• Biochemical blood test (increase in the level of C-reactive protein, which correlates with the degree of disease activity).
• Immunological study (detection of ANCA in serum).

For morphological confirmation of the diagnosis of Wegener's granulomatosis, patients are shown a biopsy of the mucous membrane of the upper respiratory tract, lung tissue (open or transbronchial), periorbital tissue, in rare cases - kidney biopsy.

For the diagnosis of Wegener's granulomatosis, the following classification criteria proposed by R. Leavitt et al. (1990):

• inflammation of the nose and mouth (ulcers in the mouth, purulent or spotting from the nose);
• detection on the roentgenogram of light nodules, infiltrates or cavities;
• microhematuria (> 5 erythrocytes in the field of vision) or accumulation of erythrocytes in urine sediment;
• biopsy - granulomatous inflammation in the wall of the arteries or in the perivascular and extravascular space.

The presence of two or more criteria allows us to diagnose "Wegener's granulomatosis" (sensitivity - 88%, specificity - 92%).

[22], [23], [24]

Treatment of Wegener's granulomatosis

Monotherapy with glucocorticoids with granulomatosis Wegener is not used. Combined use of glucocorticoids and cyclophosphamide inside is recommended. Treatment with cyclophosphamide should be performed for at least 1 year after remission, which is associated with the need to monitor side effects (pulmonary infectious complications and bladder cancer). Methotrexate, mycophenolate mofetil can be used in patients without rapidly progressive nephritis and severe lung damage [with cyclophosphamide (cyclophosphamide) intolerance, to maintain remission]. In severe cases, pulse therapy is prescribed with cyclophosphamide and glucocorticoids, plasmapheresis.

To maintain remission of Wegener's granulomatosis in limited forms and in the early phase of the disease, as well as the length of prevention of infectious complications, co-trimoxazole (sulfamethoceazole + trimethoprim) is prescribed.

Prognosis of Wegener's granulomatosis

In the absence of therapy, the average survival rate of patients is 5 months. Treatment with only glucocorticoids increases life expectancy to 12 months. When appointing combinations of glucocorticoids and cyclophosphamide, as well as in the conduct of plasmapheresis, the frequency of exacerbations does not exceed 39%, lethality - 21%, and the five-year survival rate - 70%.

Background

The disease was isolated in a separate nosological form F Wegener in the early 30's. XX in 1954. G. Godman and W. Churg proposed a diagnostic triad of the disease (pulmonary and systemic vasculitis, nephritis, necrotizing granulomatosis of the respiratory system).

[25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]