Wegener’s granulomatosis is an uncommon disease that begins as a limited granulomatous inflammation of the upper and/or lower respiratory mucosa and progresses to a generalized necrotizing granulomatous vasculitis with glomerulonephritis. The etiology of the disease is unknown, and although it resembles an infectious process, the causative agent has not been isolated. It has been suggested that the basis of the disease is allergy based on histological changes. The incidence is 2:1 in men and women and can occur in all age groups. Pathology Inflammatory granular tissue biopsies of the nose and nasopharynx show granulomatous tissue containing epithelioid cells, Langham cells, and foreign body giant cells, with much vascular destruction, extravasation of red blood cells, and numerous leukocytes in varying degrees of fragmentation. Lung and skin biopsies showed perivascular inflammatory exudate and fibrin deposition in small arteries, capillaries and veins. Renal biopsy showed varying degrees of focal and segmental glomerulonephritis with occasional necrotizing vasculitis. Immunohistochemistry showed extensive fibrin deposition in the blood vessels and glomeruli. Fibrin deposition in the glomerulus suggests partial activation of a coagulation factor (Hageman factor). Immune complexes precipitated by C1q were found and disappeared after treatment with cyclophosphamide and prednisone. Dense subepithelial deposits suggestive of an immune complex reaction were detected by electron microscopy on the epithelial side of the basement membrane, and immunofluorescence showed scattered complement and IgG deposits. Symptoms, signs and laboratory tests The onset of the disease is insidious or acute, and the onset of typical clinical manifestations sometimes takes several years. The presenting history is usually one of upper respiratory tract symptoms and severe hemorrhagic rhinorrhea, paranasal sinusitis, nasal mucosal ulceration (secondary to bacterial infection), plagioid or purulent otitis media with hearing loss, cough, hemoptysis, and pleurisy. Patients with nasal granuloma are often mistaken for chronic paranasal sinusitis. The nasal mucosa is red and granular in appearance, brittle, bleeds easily, and the septum may be perforated. Other early symptoms include fever, general malaise, loss of appetite, weight loss, wandering polyarthropathy, skin damage, blockage of the nasolacrimal ducts and protrusion of the eyeballs, and ocular manifestations such as outer scleral inflammation. Otocarditis, myocardial infarction (due to vasculitis), aseptic meningitis and non-healing granulomas of the central nervous system can also occur. The disease eventually progresses to diffuse vascular damage, manifested by necrotizing inflammatory skin lesions, pulmonary damage with cavity formation, diffuse leukocytoclastic vasculitis, and focal glomerulonephritis, which may progress to diffuse crescentic glomerulonephritis with hypertension and uremia. Occasionally, the disease is limited to pulmonary involvement. Renal involvement is a hallmark of systemic disease, with proteinuria, hematuria, and erythrocyte tubular pattern on urinalysis. Without immediate and appropriate treatment, renal impairment is bound to occur. Serum complement is normal or elevated, sedimentation is accelerated, and leukocytosis is increased. In addition, there may be significant anemia. Anti-nuclear antibodies and lupus cells are negative. Anti-neutrophil cytoplasmic antibodies (ANCA) are often positive at high levels and are a relatively sensitive and specific marker for diagnosis and follow-up of the patient’s condition. Further differentiation reveals that Wegener-associated ANCA (C-ANCA), which is clearly reactive with proteinase E, is 97% specific for the disease, and that intra-alveolar hemorrhage is more likely in patients with significant IgA-C-ANCA. Diagnosis The diagnosis can be made with characteristic clinical manifestations, serological features and pathological findings. Renal biopsy can assess the extent of renal involvement and is important for early determination of the spread of the lesion in the kidney. Sometimes an open chest biopsy of pulmonary nodules and cavitary lesions is required to make the diagnosis. Closely packed clusters of atypical cells can be found in the sputum of patients with lung involvement. The differential diagnosis includes: 1) polyarteritis nodosa, 2) vascular nephropathy in the vascular phase of infectious bacterial endocarditis, 3) systemic lupus erythematosus, 4) lethal midline granulomas (e.g., lymphoma), and 5) rapidly or slowly progressing glomerulonephritis. Biopsy of skin lesions and pathologic limitations of vascular damage may exclude polyarteritis nodosa. Eosinophilia is common in ChurgStrauss syndrome, but not in Wegener’s granulomatosis; and there is no granulomatous inflammation of the nose or lungs in Churg-Strauss syndrome. Infectious bacterial endocarditis is associated with positive blood cultures and a variable heart murmur. Systemic lupus erythematosus with antinuclear antibodies and lupus cells in the serum and reduced serum complement levels. Lethal midline granuloma without angiogenic granulomatous inflammation. Anti-neutrophil myeloperoxidase antibodies (P-ANCA) are associated with other types of necrotizing vasculitis, particularly microscopic nodular polyarteritis causing intra-alveolar hemorrhage and crescentic glomerulonephritis, and must be distinguished from Wegener’s granulomatosis (C-ANCA and protease E specific) and Goodpasture syndrome (with anti-glomerular basement membrane antibodies). Prognosis and treatment Once the diffuse vasculopathy begins, all symptoms progress rapidly to renal failure. Patients with limited lesions have only nasal and pulmonary damage, with little or no systemic involvement. The pulmonary lesions may improve or worsen spontaneously. Treatment with immunosuppressive and cytotoxic drugs has greatly improved the prognosis of what was once a lethal disease. Early diagnosis and treatment are critical because the remission rate is now high and severe renal complications can be avoided and reduced. Cyclophosphamide (1-2 mg/kg daily orally or as a single rapid intravenous infusion every 2-3 weeks) is the drug of choice. Corticosteroids may reduce vasogenic edema and are given concomitantly with the above drugs (prednisone 1 mg/kg orally daily). Prednisone is tapered after 2-3 months and is eventually maintained by oral cyclophosphamide alone (long-term intravenous administration seems to be less effective). After clinical remission, cyclophosphamide should be used for at least one year and then tapered at a rate of 25 mg every 2-3 months. Azathioprine is also effective, but less so, and may be used as an alternative or adjunct to cyclophosphamide in patients who cannot tolerate cyclophosphamide therapy. However, “pulsed” treatment with methotrexate, i.e., methotrexate ≤20-30 mg/week orally, may be a better alternative. Long-term prophylactic oral methotrexate/sulfamethoxazole (160/800 mg to 480/2400 mg daily) is very effective for upper respiratory tract lesions and can be used alone for long-term treatment when the disease is controlled by cyclophosphamide and corticosteroids. Occasionally, anemia is so pronounced that blood transfusions are required. With treatment, even progressive lesions may achieve complete long-term remission. Renal transplantation in renal failure has been successful, although renal damage typical of Wegener’s granulomatosis has been reported in one patient who underwent transplantation of a cadaveric kidney. High-dose cyclophosphamide administration may lead to an increased incidence of solid tumors years later. A history of hemorrhagic cystitis is associated with an increased chance of subsequent bladder cancer.