Wegener's granulomatosis is characterized by necrotizing granulomatous inflammation, small and medium-sized vessel vasculitis, and focal necrotizing glomerulonephritis, often with crescent formation. Typically, the upper and lower respiratory tract and the kidneys are affected, but any organ may be. Symptoms vary depending on the organs and systems affected. Patients may present with upper and lower respiratory tract symptoms (eg, recurrent nasal discharge or epistaxis, cough), followed by hypertension and edema, or with symptoms reflecting multiorgan involvement. Diagnosis usually requires biopsy. Treatment is with corticosteroids plus an immunosuppressant. Remission is usually possible, although relapses are common.

Wegener's granulomatosis occurs in about 1/25,000 people; it is most common among whites but can occur in all ethnic groups and at any age. Mean age at onset is 40.

The cause is unknown, although immunologic mechanisms play a role. Most patients with active generalized disease have antineutrophil cytoplasmic antibodies (ANCA).

Pathophysiology

Characteristically, granulomas form with histiocytic epithelioid cells and often with giant cells. Plasma cells, lymphocytes, neutrophils, and eosinophils are present. Inflammation affects tissues as well as vessels; vasculitis may be a small or large component of the disease. Micronecrosis, usually with neutrophils (microabscesses), occurs early. Micronecrosis progresses to macronecrosis. A central area of necrosis (called geographic necrosis) is rimmed by lymphocytes, plasma cells, macrophages, and giant cells. A zone of fibroblastic proliferation with palisading histiocytes may surround the area.

Nonspecific chronic inflammation and tissue necrosis occurs in the nose. The lungs are most likely to display the full spectrum of histopathologic abnormalities. In the kidneys, the most common finding is a proliferative crescentic focal glomerulonephritis with necrosis and thrombosis of individual loops or larger segments of the glomerulus. Vasculitic lesions and disseminated granulomas occur only occasionally.

Symptoms and Signs

Onset may be insidious or acute; the full spectrum of the disease may take years to evolve. Some patients present initially with upper and lower respiratory tract symptoms; at some point later, the kidneys are affected. In other patients, onset of systemic manifestations is relatively acute; several organs and systems, such as the upper respiratory tract, peripheral nervous system (causing mononeuritis multiplex), kidneys (causing glomerulonephritis), and lower respiratory tract (causing hemorrhage, lung nodules, cavities, or a combination), are simultaneously affected.

• Upper respiratory tract: Sinus pain, serosanguineous or purulent discharge, and epistaxis may occur. The mucosa appears granular (like cobblestones) and is friable; ulcers, thick dark crusts, and septal perforation are common. Nasal chondritis can occur with swelling, pain, and collapse of the nasal bridge (saddle nose). Patients may report recurrent sinusitis that has responded inadequately to multiple antibiotic regimens and has required one or more sinus operations before diagnosis. Secondary infections (eg, due to Staphylococcus aureus) may develop. Subglottic stenosis may develop, causing symptoms such as pain in the larynx, hoarseness, dyspnea, wheezing, and stridor.
• Ears: Otitis, sensorineural hearing loss, vertigo, and chondritis may occur. The middle ear, inner ear, and mastoids are often affected.
• Eyes: Eyes may appear red and swollen. Nasolacrimal duct inflammation and obstruction may affect the eye; conjunctivitis, scleritis, uveitis, or retinal vasculitis may also occur. Inflammatory infiltrates in the retro-orbital space (orbital pseudotumor) can cause proptosis, compression of the optic nerve, and blindness. Extension into the extraocular muscles leads to diplopia. If serious eye symptoms develop, evaluation and treatment are required immediately to prevent permanent vision loss.
• Lower respiratory tract: Respiratory manifestations are common. Inflammation of the major bronchi and branches can cause localized wheezing, postobstructive pneumonia, and atelectasis. Single or multiple pulmonary nodules, with or without cavitation, and parenchymal infiltrates, sometimes cause symptoms, such as chest pain, shortness of breath, and productive cough. Dyspnea with bilateral infiltrates, with or without hemoptysis, may indicate alveolar hemorrhage, and must be evaluated immediately.
• Heart: Coronary artery disease may occur, but rarely.
• Musculoskeletal system: Patients may present with myalgias, arthralgias, or nonerosive inflammatory arthritis.
• Skin: Leukocytoclastic vasculitis, tender subcutaneous nodules, papules, livedo reticularis, or pyoderma gangrenosum may develop.
• Nervous system: Vasculitis may cause ischemic peripheral neuropathy, brain lesions, or extension of lesions from contiguous sites. Lesions that originate in the sinuses or middle ear may extend directly to the retropharyngeal area and base of the skull, leading to cranial neuropathy, proptosis, diabetes insipidus, or meningitis.
• Kidneys: Symptoms and signs of glomerulonephritis develop. Urinary sediment may be abnormal, and serum creatinine may increase rapidly. Edema and hypertension may result. Rapidly progressive glomerulonephritis, which is life threatening, can develop.
• Other organs: Occasionally, an inflammatory mass occurs in the breasts, kidneys, prostate, or other organs.

Diagnosis

• Routine laboratory tests, including urinalysis
• Tests for ANCA
• Biopsy for definitive diagnosis

Wegener's granulomatosis should be suspected in patients with chronic, unexplained respiratory symptoms and signs (including otitis media in adults), particularly if manifestations in other organ systems, especially the kidneys, also suggest the disorder. Routine laboratory tests are done, but ANCA testing and biopsy yield the most specific findings.

Routine laboratory tests include ESR or C-reactive protein, CBC with differential, serum albumin and total protein, serum creatinine, urinalysis, 24-h urine protein, and chest x-ray. In most patients with active disease, ESR and C-reactive protein are elevated, and serum albumin and total protein are decreased; anemia, thrombocytosis, and mild to moderate eosinophilia are detected. Dysmorphic RBCs and RBC casts, detected during urinalysis, indicate glomerular involvement. Proteinuria may be detected. Serum creatinine may be increased.

Serologic testing to detect ANCA is followed by enzyme-linked immunosorbent assay (ELISA) to check for specific antibodies. Most patients with active disease have cytoplasmic ANCA (cANCA), with antibodies against proteinase-3 (PR3); these findings plus characteristic clinical findings suggest Wegener's granulomatosis.

Some patients with other disorders (eg, bacterial endocarditis, TB) test positive for ANCA. If characteristic clinical findings are absent, a positive ANCA result does not confirm Wegener's granulomatosis. ANCA testing should not be used to guide treatment. During apparent remission, ANCA may increase or ANCA test results may change from negative to positive. In some of these patients, symptoms do not recur; in others, symptoms recur or worsen soon after the test is done or during the next few weeks, months, or sometimes years.

Biopsy should be done if possible to confirm the diagnosis. Clinically abnormal sites may be biopsied first, but lung biopsy is most likely to detect characteristic findings. Open thoracotomy provides the best access to affected tissue. Biopsies of lung or sinus tissue are cultured to exclude infection. Renal biopsy may be necessary to confirm the diagnosis and to exclude other causes, especially if serum creatinine is elevated. Biopsy results may also provide histologic information that can help guide treatment (eg, renal fibrosis, which is irreversible with immunosuppressive treatment).

Differential diagnosis includes other vasculitic disorders that affect small and medium-sized vessels. Polyarteritis nodosa is unlikely if lung involvement is prominent and glomerulonephritis is present. Infections, especially due to slow-growing fungi or acid-fast organisms should be ruled out by staining and by culture of the sampled tissues. RA should not be diagnosed based only on the presence of rheumatoid factor, which is present in one half of patients with Wegener's granulomatosis.

Prognosis

Prognosis depends on the extent of the disorder—whether it is limited to nasal and pulmonary lesions, with little or no systemic involvement, or it affects many organs, causing severe systemic vasculitis.

Use of immunosuppressants for severe disease has dramatically improved prognosis. With treatment, complete remission is possible for about 70% of patients, but about one half of them eventually relapse; relapse may occur when treatment is stopped or many years after it is stopped. Resuming or increasing treatment can usually control the disorder. However, the disease or treatment causes significant morbidity in 90% of patients.

Treatment

• Emergency treatment with corticosteroids and cyclophosphamideSome Trade Names
  CYTOXAN
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  for severe disease
• Corticosteroids and methotrexateSome Trade Names
  RHEUMATREX
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  for less severe disease
• Kidney transplantation if necessary

Treatment depends on the severity of disease. A multidisciplinary approach is required for multiorgan disease; a rheumatologist, an otorhinolaryngologist, a pulmonologist, and sometimes a nephrologist may be included.

Patients who have severe life- or organ- threatening manifestations (eg, alveolar hemorrhage, rapidly progressive glomerulonephritis, mononeuritis multiplex with motor involvement) require immediate treatment and hospital admission. These patients require high-dose corticosteroids and cyclophosphamideSome Trade Names
CYTOXAN
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(see Vasculitis: Treatment). The role of rituximabSome Trade Names
RITUXAN
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in severe or refractory disease is under study.

For less severe disease, corticosteroids and methotrexateSome Trade Names
RHEUMATREX
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are used. MethotrexateSome Trade Names
RHEUMATREX
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or azathioprineSome Trade Names
IMURAN
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is used to maintain remission.

Irrigation of sinuses with saline, with or without mupirocinSome Trade Names
BACTROBAN
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2% nasal ointment, helps minimize crusting and secondary staphylococcal infections.

Treatment of subglottic stenosis is difficult. Systemic immunosuppressants may not be effective. Intralesional injection of long-acting corticosteroids, with gentle progressive dilation, markedly improves outcomes and helps prevent unnecessary tracheostomies.

Patients should be taught about the disorder so that relapses can be detected early. Patients should learn how to test their urine for blood and protein and be instructed to notify their physician at the first sign of hematuria.

Kidney transplantation has been successful; the risk of relapse after transplantation is reduced compared with maintenance dialysis treatment (possibly in part due to use of immunosuppressants to prevent rejection).

Last full review/revision May 2008 by Carmen E. Gota, MD

Content last modified February 2012