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

Wegener's granulomatosis (syn.: gangrenous granuloma, centrofacial granuloma) is a severe, spontaneously occurring autoimmune granulomatous disease, which is based on necrotic vasculitis with damage to 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 quite rare, occurring equally in men and women (average age is 25-45 years). The incidence is 0.05-3 per 100,000 people.

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Causes of Wegener's granulomatosis

The cause of Wegener's granulomatosis disease remains unknown.

Wegener's granulomatosis is related to ANCA-associated vasculitis, therefore, the detection of ANCA in the blood serum, which serve as pathogenetic factors of the disease, can be considered a specific marker of this disease. The disease disrupts the processes of regulation of cytokine production (TNF-a, IL-1, IL-2, IL-6, IL-12).

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

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Pathomorphology of Wegener's granulomatosis

Two types of changes are found: necrotic granuloma and necrotic vasculitis. Granuloma is a necrotic focus of varying size surrounded by a polymorphonuclear infiltrate containing neutrophilic granulocytes, lymphocytes and plasma cells, occasionally eosinophilic granulocytes. Epithelioid cells are few or absent. Multinucleated giant cells of the foreign body type are encountered. Necrotic vasculitis affects small arteries and veins, in which alterative, exudative and proliferative changes develop successively. Fibrinoid necrosis of the vessel walls is characteristic, which are infiltrated mainly by neutrophilic granulocytes with nuclear disintegration ("nuclear dust"). Destruction of the walls may be accompanied by thrombosis of the vessel with the formation of acute, sometimes rupturing aneurysms, which leads to hemorrhages. Particularly common in Wegener's granulomatosis are microcirculatory vasculitis, mainly of a productive nature, localized in the kidneys, lungs, and subcutaneous fat layer. Necrotic vasculitis with thrombosis and central ulceration, including in foci of purpura, is determined in the skin. In the area of ulcerative lesions, skin and subcutaneous nodes, necrotic granulomas and necrotic vasculitis are usually found. Proliferation of the inner lining of blood vessels can lead to obliteration of their lumens.

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

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 proven by the detection of fixed immune complexes (IgG) and complement components (C3) in the lesions, particularly in the kidneys, using the immunofluorescence method. Granular deposits were found along the basement membranes, which are immune complexes. Antigen-antibody complexes were found subepidermally by electron microscopy. S.V. Gryaznov et al. (1987) believe that antibacterial defense is altered in this disease, possibly due to a neutrophil defect, which contributes to the development of infection. Cytophilic autoantibodies to the cytoplasmic structures of neutrophil granulocytes (ANCA) and, to a lesser extent, monocytes have been detected, which were previously considered specific to this disease; however, their specificity is currently being questioned, since these antibodies are detected in other vasculitides (Takayasu arteritis, Kawasaki arteritis, etc.).

Symptoms of Wegener's granulomatosis

It develops more often in adults, but can also be observed in children. A distinction is made between generalized, borderline and localized (malignant granuloma of the face) forms. Some authors consider the localized form to be an independent disease. In the generalized form, in addition to necrotic lesions of the mucous membranes of the nose, its sinuses, and the upper respiratory tract, leading to extensive destruction, there are changes in the internal organs (lungs, kidneys, intestines) caused by damage to small arteries and veins. Calcified foci are found in the lungs, and focal or diffuse glomerulonephritis in the kidneys. In the borderline form, severe pulmonary and extrapulmonary (including skin) changes are observed, but without pronounced kidney damage. In the localized form, skin changes with pronounced destruction of facial tissues predominate.

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, and damage to the lungs and kidneys.

For a long time, it was believed that pathological changes in the heart are quite rare in Wegener's granulomatosis and they do not affect the prognosis. This is due to the low- or asymptomatic course of heart damage. Thus, asymptomatic course of coronary arteryitis is characteristic of Wegener's granulomatosis; cases of development of painless myocardial infarction have been described. However, it has been shown that coronary artery damage occurs in 50% of patients (according to series of autopsies). A more typical result of coronary arteryitis may be dilated cardiomyopathy (DCM). Granulomatous myocarditis, valvular defects and pericarditis are occasionally noted, which can be explained by the involvement of small areoles of the valvular apparatus and pericardium. Arterial hypertension is noted in patients with a generalized variant of the disease with involvement of the kidneys in the pathological process.

The skin is involved in the process secondarily in approximately 50% of patients. There are extensive ulcerative-necrotic lesions of the central part of the face as a result of the spread of the process from the nasal cavity; ulcerative lesions of the oral mucosa; mainly, at the late stages of the process there may be polymorphic rashes: petechiae, ecchymoses, erythemato-papular, nodular-necrotic elements, ulcerative-necrotic lesions such as gangrenous pyoderma on the trunk and distal parts of the extremities. The prognosis is unfavorable. The development of a generalized tumor process in the form of malignant histiocytosis against the background of immunosuppressive therapy of the disease has been described.

Similar skin lesions, but usually without a hemorrhagic component, can be observed in the so-called granulomatous lymphomatoid, which differs from Wegener's granulomatosis by its predominant lesion of the lungs without changes in the upper respiratory tract and, possibly, the kidneys, an increased risk of developing lymphomas, and the presence of atypical lymphocytes in polymorphic infiltrates.

Wegener's granulomatosis classification

Depending on the clinical picture, localized (isolated damage to the ENT organs, eyes), limited (systemic manifestations without glomerulonephritis) and generalized forms are distinguished. In 1976, the ELK classification (De Remee R. et al.) was proposed, according to which "incomplete" (isolated damage to the ENT organs or lungs) and "complete" (damage to two or three organs: E - ENT organs, L - lungs, K - kidneys) variants are distinguished.

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Diagnosis of Wegener's granulomatosis

Laboratory data do not show any abnormalities specific to Wegener's granulomatosis.

• Clinical blood test (mild normochromic anemia, neutrophilic leukocytosis, thrombocytosis, increased ESR).
• Blood biochemistry (increased levels of C-reactive protein, which correlates with the degree of disease activity).
• Immunological study (detection of ANCA in blood 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, and, in rarer cases, a kidney biopsy.

To diagnose Wegener's granulomatosis, the following classification criteria proposed by R. Leavitt et al. (1990) are used:

• inflammation of the nose and mouth (oral ulcers, purulent or bloody discharge from the nose);
• detection of nodules, infiltrates or cavities on a chest radiograph;
• microhematuria (>5 red blood cells in the field of view) or accumulation of red blood cells in the urine sediment;
• biopsy - granulomatous inflammation in the arterial wall or in the perivascular and extravascular space.

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

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Treatment of Wegener's granulomatosis

Monotherapy with glucocorticoids is not used in Wegener's granulomatosis. Combined administration of glucocorticoids and oral cyclophosphamide is recommended. Cyclophosphamide treatment should be continued for at least 1 year after achieving remission, due to 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 intolerance to cyclophosphamide (cyclophosphamide), to maintain remission]. In severe cases, pulse therapy with cyclophosphamide and glucocorticoids, plasmapheresis are prescribed.

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

Prognosis of Wegener's granulomatosis

In the absence of therapy, the average survival of patients is 5 months. Treatment with glucocorticoids alone increases life expectancy to 12 months. When prescribing combinations of glucocorticoids and cyclophosphamide, as well as when performing plasmapheresis, the frequency of exacerbations does not exceed 39%, mortality is 21%, and five-year survival is 70%.

History of the issue

The disease was identified as an independent nosological form by F. Wegener in the early 1930s. In 1954, G. Godman and W. Churg proposed a diagnostic triad for this disease (pulmonary and systemic vasculitis, nephritis, necrotizing granulomatosis of the respiratory system).

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