Wegener's granulomatosis

A granuloma cancerous, a granulomatosis not infectious necrotic

Giant cell it is granulomatous - a necrotic system vasculitis with selective in the beginning of disease a lesion of the top and inferior respiratory tracts and lungs, and in the subsequent and nephroses.

First description Wegener’s granulomatosis concerns 1931. H. Klinger and F. Wegener (1936, 1939) have secured disease as an independent syndrome with a characteristic triad of signs:

1. a necrotizing granulomatous vasculitis
2. a glomerulonephritis
3. a system necrotizing vasculitis with a lesion of arteries of fine calibre and a venous bed

Aetiology and pathogenesis

Idiopathic syndrome. The immune pathology Is supposed.

1. Direct influence of the hypothetical etiological factor without participation of immunopathological reactions.
2. The cellular or humoral immune answer to an autoantigen or foreign antigen.
3. Formation of the Central Electoral Committee with their bracing in a vascular wall. There is a complement activation which by a chemotaxis reacts on polymorphonuclear leucocytes. The last inpour into a pot lumen, break permeability of a vascular side, excrete lysosomal enzymes that leads to a necrosis of a vascular wall, a lumen occlusion.
4. The great value has a delayed skin reaction with formation of granulomas in sides of pots owing to interaction CD4 +-Т-cells and macrophages in reply to an unknown ANTIGEN (Ag). Age changes of sides of pots can promote "representation" any histic the ANTIGEN (Ag) behind which in norm immune supervision is not carried out.
5. As a result of interaction about the ANTIGEN (Ag) sensibilized lymphocytes excrete lymphokines which oppress migration of macrophages and concentrate them in places of a clump the ANTIGEN (Ag). The last liberate lysosomal enzymes, damage a vascular side, form granulomas and colossal cells.
6. The immune lesion of a vascular wall up to a necrosis is accompanied by microcirculation disturbance, rising of aggregation of thrombocytes, a hypercoagulation with development of clottages and a disseminated intravascular coagulation.

Pathoanatomical changes

At a biopsy of the inflamed tissues of a nose and a nasopharynx - granulomatous changes with presence of epithelial cells, Langhans cells, colossal cells of foreign bodys, appreciable damages of the pots, the variated erythrocytes, and also leucocytes of a different stage of a destruction. At a biopsy of lungs and skins - perivascular inflammatory exsudates and fibrin deposits in fine arteries, capillars and venules. A nephros biopsy - signs of a focal and segmentary glomerulonephritis of a different degree of manifestation, sometimes in a combination with necrotizing a vasculitis. At immunochemical research of biopsy samples of nephroses - extensive deposits of fibrin in veins and glomuluses; it specifies in particulate activation of the Hageman factor. Are found also, deposited by component C1q of a complement. The submicroscopy taps presence on a bacteriemic meningitis of the dense is subepithelial the located deposits, that too specifies in participation of the Ik-mechanism in a disease pathogenesis.

Clinic

Middle age of patients about 40 years, an interrelation of women to men 1:1.

1. The general implications: the fever, the general delicacy, a weight loss, arthralgias and (or) myalgias, is rarer arthritises.
2. Lesion a VMD: it is observed at 90 % of patients and it is characterised by a rhinitis with it is ulcerous-nekroticheskimi changes of a mucosa of adnexal sinuses, larynxes, tracheas (a persistent cold with is serous-sanious abjections, pains in the field of adnexal sinuses, nasal bleedings, it is possible punching of a nasal septum, deformation of a nose as saddle-like, an is serous-purulent average otitis).
3. The lesion of lungs is observed at more than 80 % of patients (tussis with an is purulent-sanious sputum, a pneumorrhagia, a pneumonia with predilection to disintegration and formation of lumens in lungs). At 1/3 patients radiological signs can not be accompanied by clinical implications of a pulmonary pathology.
4. Lesion of nephroses - quickly progressing glomerulonephritis at 2/3 patients with an appreciable proteinuria, a hematuria, disturbance of function of the nephroses accompanied by an uremia and a hypertensia.
5. Ulcerous-necrotic lesion of a skin (more than 40 % of patients), an osteoarticular atomy, a polymorphic dermal eruption.
6. Polyarthralgias, are rarer arthritises.
7. Lesion of other organs and systems. Eyes are amazed in 15 % of cases - an episcleritis, a periorbital granuloma with an exophthalmos and a loss of sight owing to an optic nerve ischemia. Peripheric excitatory system - in 15 % azygomorphous polyneuropathy. Heart - at 5 % of patients a pericarditis. The lesion of a myocardium or coronary arteries, and also GASTROINTESTINAL TRACT is not characteristic. Was rather rarely it is amazed a pulmonary artery, generative organs.

Two forms - localised and generalised excrete. At the localised form are amazed mainly a VMD (or eyes): the complicated nasal breath, a persistent cold with an unpleasant odour, a clump of bloody crusts in a nose, nasal bleedings, a voice hoarseness; the listed symptoms that fade, become aggravated. At the generalised form the fever of various expression, cold fits and sweats, polymorphic eruptions and hemorrhages, hoarse paroxysmal tussis with purulent-krovjanistoj sputum take place, a picture of a pneumonia with bent to abscessing and exudate appearance, pulmonary heart increase, symptoms of a lesion of nephroses (the proteinuria, a hematuria, renal insufficiency), are possible arthritises, arthralgias and myalgias, an anaemia, neutrophilic a leukocytosis, an ESR acceleration. There can be a chondritis of auricles, to IT owing to a vasculitis, an aseptic meningitis and signs of a granulomatous lesion a CNS

At a number of patients a lesion a VMD, lungs, the Peripheric excitatory system, nephroses educes for lack of a glomerulonephritis. Such cases carry to circumscribed variant Wegener’s granulomatosis. It is necessary to underline, that abjection of clinical variants Wegener’s granulomatosis is conditional, as mainly the lesion of this or that organ can be only a stage of advance of disease.

During disease excrete 4 stages:

1. Rhinogenous granulomatosis (it is purulent-necrotic, is ulcerous-necrotic rhinosinusitis, a nasopharyngitis and a laryngitis with a destruction of an osteal and cartilaginous septum, an orbit).
2. Pulmonary stage - process diffusions on a pulmonary tissue
3. Generalised lesion - change of lungs, nephroses, cardiovascular system, GASTROINTESTINAL TRACT (an aphthous stomatitis, a glossitis, dyspeptic disorders)
4. End-stage - the renal and cardiopulmonary insufficiency which is leading to death within year from the beginning of disease

Diagnostics

Approximately 25 % of patients in an initial stage have no signs of a lesion of nephroses or lungs and only for 50 % of patients Wegener’s granulomatosis is diagnosed in the first 3-6 months from the disease beginning, and at 7 % this disease is not diagnosed even within 5-16 years from appearance of the first clinical symptoms.

• Normochromic anaemia, thrombocytosis, neutrophilic a leukocytosis
• The ESR acceleration, diseases correlating with activity. The nonspecific marker of activity Wegener’s granulomatosis can be found in 50 % of cases.
• Level serumal Ig within norm, rising of the maintenance of the Central Electoral Committee, a hypocomplementemia; appearance antibody to a membrane of glomuluses is not characteristic
• Antineutrophilic cytoplasmatic antibodies - at 40-99 % of patients. Specificity of antibodies to a proteinase for diagnostics Wegener’s granulomatosis reaches 98 %, however sensitivity fluctuates 33-99 %. antineutrophil cytoplasmic antibody are found in 30-40 % of patients with circumscribed or generalised forms Wegener’s granulomatosis in remission, at 70-80 % of patients in activity and at 80-99 % with active generalised Wegener’s granulomatosis. There are data, that rising of a caption antineutrophil cytoplasmic antibody can precede appearance of clinical signs of an exacerbation
• Biopsy of lungs (the biopsy of adnexal sinuses is a little informative) - an open biopsy of infiltrative or cavitary formations
• The biopsy of nephroses allows to define degree of their lesion that is the extremely important for early revealing of a renal pathology

Classification criteria of diagnosis Wegener’s granulomatosis

2 criterias and more possess specificity of 92 % and sensitivity of 88 %. The biopsy has Crucial importance. In the absence of last or in the presence of complexity of performance, not informativeness of the received data - is introduced additional criterion - a pneumorrhagia (sensitivity of 87 %, specificity of 93 %).

Differential diagnostics

• Generalised variant
  • Diseases with an is pulmonary-renal syndrome: (it is excluded according to a biopsy of dermal rashes, localisation of lesions of pots, the eosinophilia is not typical for Wegener’s granulomatosis, and for a polyarthritis the granulomatous inflammation of tissues of a nose and lungs), a microscopical polyarteritis, syndrome Churg-Straus, a Goodpasture's syndrome, a hemorrhagic vasculitis, HARD CURRENCY (Le-kl, depression of level of a complement), a streptococcal pneumonia with a glomerulonephritis, subacute in a phase of a vascular lesion of nephroses (positive sowings of blood, changeable cardial hums) is not characteristic
  • angiocentric Immunoproliferative disorders: lymphomatoid a granulomatosis, angiocentric a cancerous lymphoma
  • Diseases with a granulomatosis: a granuloma of midline of a head, a sarcoidosis, a berylliosis, a tuberculosis, system mycoses, a syphilis, a leprosy
  • AIDS
  • Subacute extracapillary glomerulonephritis (at a primary lesion of nephroses)
• The local and circumscribed variant
  • Infection contaminations a VMD (mycobacterioses, mycoses, helminthiases, an actinomycosis, a syphilis), tumours (a squamous carcinoma, an extranodal lymphoma), inhalation influence VOC.
  • Granulomatous infection contaminations of lungs (mycobacterioses, mycoses) can be combined with a vasculitis and a necrosis, the biopsy of lungs should be spent only after reception of negative takes of cultural research.

Treatment

Cyclophosphamide application.

Intravenously in a dose of 5-10 mg/kg within 2-3 days, and in need of 7 days with the subsequent transition to intake on 1-2 mg/kg within 2-3 weeks, then in a maintenance dose of 50-25 mg a day during till 1 year and more. It is recommended fast intravenous infusions of unitary doses every 2-3 week. The general analysis of urine, the control is necessary for preventive maintenance of a hemorrhagic cystitis - abundant drink of fluid of 2,5-3 l a day.

Contraindications: an agranulocytosis, intolerance of a preparation, a sepsis.

Associated application of cyclophosphamide and Prednisolonum is recommended. The mean of introduction of cyclophosphamide depends on acuteness of disease, in an acute phase the preparation is introduced century/venno At achievement of clinical effect - temperature normalisation, reduction or disappearance of infiltrates of lungs, normalisation of function of nephroses and depression of a proteinuria, a hematuria, haemoglobin normalisation, ESR retardation - patients are translated on intermittent reception of a preparation (on 200 mg each 1-3 days) with a gradual dose decline of Prednisolonum to bolstering.

According to G. Hoffman, in connection with possibility of relapse treatment by cyclophosphamide should be continued not less than 2-3 years, and glucocorticoids can be cancelled in 12-24 months. At quickly progressing forms it is shown sphygmus-therapy by cyclophosphamide.

In independent researches it has been shown, that sphygmus-therapy should not be applied at patients with serious quickly progressing variant Wegener’s granulomatosis.

At intolerance of cyclophosphamide, and also in the absence of a serious lesion of nephroses and lungs it is possible to spend associated therapy by Methotrexatum (20 mg a week) and Prednisolonum.

Efficacyy of treatment is shown by cyclosporine.

There are reports on a treatment positive effect a human donor polyvalent immunoglobulin.

For preventive maintenance of infectious complications from the party a VMD - Trimethoprimum (160-480 mg/days)/sulfometaksozon (800-2400 mg/days)

Plasmapheresis and hemosorption

Are recommended at the acute forms of a Wegener's granulomatosis which are badly giving in to treatment by immunodepressants, especially at quickly progressing flow with a lesion of nephroses and intolerance of cytostatics.

The forecast

In the absence of treatment - average lifetime 5 months of the Cause of death: respiratory insufficiency, renal insufficiency, intercurrent infection contaminations. Associated therapy by Cyclophosphanum and gamma-linolenic acid leads to remission in 4 years at 93 % sick, and some till 10 years.