AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Wegener granulomatosis (WG) is a systemic vasculitis of the medium and small arteries, venules, arterioles, and, occasionally, large arteries. Initially reported by Klinger in 1931, the condition was later described in more detail by Wegener. In 1954, Goodman and Churg provided the definitive description of WG with their identification of a triad of pathological features, including (1) systemic necrotizing angiitis, (2) necrotizing granulomatous inflammation of the respiratory tract, and (3) necrotizing glomerulonephritis. The largest reported experience with WG is that of Fauci and colleagues at the US National Institutes of Health.

In its classic presentation, WG is a form of systemic vasculitis that primarily involves the upper and lower respiratory tracts and the kidneys. A limited form of WG has clinical findings isolated to the upper respiratory tract and the lungs, although 80% of patients subsequently develop renal involvement.

Pathophysiology

In his publication, Wegener emphasized the vasculitic aspect over the granulomatous character of the disease. However, the earliest lesion of this disorder is injury and necrosis of the vessels that evolves into a necrotizing and palisading granuloma without inflammation. The continuum from granuloma to vasculitis may be an important step in understanding the possible etiology and pathogenesis of WG. Cellular immune processes are likely important in granulomatous inflammation. However, the recent discovery of antibodies to cytoplasmic antigens within neutrophils (antineutrophilic cytoplasmic antibody [ANCA], designated C-ANCA for diffuse cytoplasmic staining and P-ANCA for perinuclear staining by immunofluorescence) in most patients with WG raises the possibility of humoral autoimmunity. This is even more likely with the demonstration of the expression of serine proteinase 3, the predominant antigen for C-ANCA, on the surface of activated endothelial cells.

Tissue injury in WG is a result of interaction between the inflammatory cascade and the pathogenic immune response to the neutrophil granule proteins. Animal studies and indirect evidence from humans indicate that ANCAs are directly involved in the widespread tissue damage characteristic of WG. These antibodies likely induce necrotizing vasculitis and endothelial injury via activation of primed neutrophils, binding of activated neutrophils to the vascular endothelium, degranulation, and release of chemoattractants and other mediators. Further research will advance understanding of the pathogenesis of WG; ANCA involvement is only one piece of a larger puzzle.

Most patients with either classic or limited WG present with upper airway or pulmonary involvement. Renal involvement is also common, manifesting as acute renal failure or acute nephritis, sometimes with nephrotic-range proteinuria. Patients may also present with a clinical picture of rapidly progressive glomerulonephritis. Other organs and systems that may become involved are the joints, eyes, skin, nervous system, heart, and, less commonly, the gastrointestinal tract, subglottis or trachea, lower genital urinary tract, parotid glands, thyroid gland, and liver. WG-related CNS involvement can manifest as chronic hypertrophic pachymeningitis, pituitary involvement, and cerebral vasculitis. CNS involvement may be present at disease onset or could develop several years after WG diagnosis.

Pathologically, the pulmonary features of WG are necrotizing granulomatous pulmonary inflammation and, occasionally, alveolar capillaritis. The former results in nodular densities and lung infiltrates, and the latter results in diffuse pulmonary hemorrhage. The glomerulonephritis is characterized by focal necrosis and crescent formation without immunoglobulin or complement deposition, also called pauci-immune glomerulonephritis. Note that more accurate terminology would be pauci-immune complex because, as described above, immune processes may be involved in the pathogenesis of WG.

Frequency

International

A population-based study reported a prevalence of 8.5 cases per million population in Norfolk, England.

Mortality/Morbidity

WG is associated with a very high (>90%) mortality rate if it remains untreated. With aggressive therapy, mortality rates improve.

• A 1992 study by Hoffman et al noted a mortality rate of 13% at 8 years.
• In a 1996 study, Matteson et al noted mortality rates of 28% at 5 years and 36% at 10 years.
• A retrospective study by Booth et al from 2003 demonstrated a cumulative 5-year survival rate of 76% and a 1-year mortality rate of 18%.

Race

WG affects persons of all races.

Sex

WG has a slight male predominance.

Age

WG has been described in persons of all ages, from young children to elderly adults.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Patients may present with a wide range of clinical manifestations, defined chiefly by the primary anatomic site of involvement.

Ears, nose, and throat or upper respiratory tract; lungs; and kidneys classification

The broad spectrum of organ involvement of WG has been described as ears, nose, and throat or upper respiratory tract (E); lungs (L); and kidneys (K); ie, the ELK, classification. This classification system suggests that within the spectrum of WG, patients may have involvement of any of the ELK sites singularly or in combination. Under the ELK system, any typical manifestation in E (ears, nose, and throat), L (lungs), or K (kidneys) associated with a typical histopathology or positive C-ANCA findings qualifies for the diagnosis of WG.

• Ears, nose, and throat
• • The most common symptom is nasal obstruction with serosanguineous discharge. Symptoms of chronic sinusitis may be present.
  • Patients often report deep central facial pain.
  • Middle ear involvement may lead to hearing loss, and patients also may present with hoarseness and stridor because of subglottic stenosis.
• Lungs
• • Patients may be asymptomatic or may present with cough and occasional hemoptysis.
  • Some patients develop progressive dyspnea and respiratory failure. Massive pulmonary hemorrhage is a rare feature.
• Kidneys: Patients with kidney involvement generally are asymptomatic, but some patients may notice mild hematuria. Edema secondary to nephrotic syndrome may be present.
• Nervous system
• • Neurologic involvement occurs in approximately one third of patients.
  • Some patients also develop symptoms of peripheral neuropathy with mononeuritis multiplex or cranial neuropathy involving the second, sixth, and seventh cranial nerves.
• Skin: Approximately 14% of patients manifest skin involvement, with a purpuric rash over the lower extremities.
• Eye and orbit: Eye and orbit complications occur in 29% of patients, who may present with red or swollen eyes.
• Joints: Joint symptoms occur frequently in persons with WG. Usually patients have only arthralgias, but up to 25% of patients may have inflammatory joint involvement. The arthritis may be monoarticular, oligoarticular, or polyarticular with swelling and pain of the joints. The arthritis is not erosive or deforming.

Physical

• Ear, nose, and throat
• • Destruction of the nasal cartilage may lead to saddle deformity of the nose and a central perforation of the nasal septum.
  • Middle ear involvement may lead to conductive hearing loss.
  • Nasal or oral ulceration and/or tenderness over the maxillary sinuses may be evident.
• Lung
• • Patients may show signs of atelectasis, including dullness on percussion, decreased breath sounds, and crackles upon auscultation.
  • Lower respiratory tract involvement also may produce signs of pulmonary consolidation, pleural effusion, or both.
• Nervous system: Examination of the nervous system confirms a pattern of mononeuritis multiplex and findings of cranial nerve paralysis.
• Skin
• • Dermatological findings are palpable purpura, necrotizing ulcerations, papules, nodules, petechiae, and superficial erosions.
  • Palpable purpura, the most common finding, is pathologically a leukocytoclastic vasculitis and is usually associated with concomitant renal involvement.
• Eye and orbit
• • Signs of conjunctivitis, episcleritis, and corneal ulceration may be present.
  • Proptosis may also be observed, which results from an inflammatory orbital mass (orbital pseudotumor).
• Joints: Patients may report joint pain and have signs of monoarticular, oligoarticular, or polyarticular arthritis, which may be symmetric or asymmetric and may be migratory. Usually, no joint erosions or deformities occur.

DIFFERENTIALS

Section 4 of 12  

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• Clinical
• Differentials
• Workup
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• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

WG localized to the upper respiratory tract should be distinguished from a lethal midline granuloma.

WG should also be distinguished from the systemic diseases listed above and, in particular, from Goodpasture syndrome.

Goodpasture syndrome (anti–glomerular basement membrane antibody disease)

Diagnostic criteria

The American College of Rheumatology has established the following criteria for the diagnosis of WG. These criteria were developed before ANCA testing was in widespread use as a diagnostic test for WG.

• Nasal or oral inflammation - Development of painful or painless oral ulcers or purulent or bloody nasal discharge
• Abnormal chest radiograph findings - Nodules, fixed infiltrates, or cavities
• Urinary sediment - Microhematuria (>5 red blood cells per high-power field) or red blood cell casts in urine sediment
• Granulomatous inflammation noted at biopsy - Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole)

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Findings from routine laboratory tests are nonspecific in persons with WG. Abnormalities include leukocytosis, thrombocytosis (>400,000/µL), marked elevation of the erythrocyte sedimentation rate and C-reactive protein level, and normocytic normochromic anemia.
• Anemia is present in up to 50% of patients. A peripheral blood smear may show schistocytes and burr cells. Leukocytosis is observed with a neutrophilic predominance in the differential cell count. Eosinophilia is not a feature of WG.
• ANCAs can be detected by performing assays. The 2 types of assays in common use are immunofluorescence and enzyme immunoassay.
• • Three types of immunofluorescence patterns are recognized. C-ANCAs stain the cytoplasm diffusely and are directed against antigen serine proteinase 3. See Image 4. P-ANCAs are usually directed against myeloperoxidase (MPO). See Image 5. The atypical pattern is found in a wide variety of systemic disorders, including inflammatory bowel disease, systemic immune-mediated diseases, and infections.
  • The positive predictive value of C-ANCAs in the diagnosis is only 45-50%. In a characteristic clinical setting, a positive ANCA finding greatly increases the possibility of an accurate diagnosis of WG. However, in 10-20% of patients with active WG, ANCA findings have been reported to be negative.
  • Measurement of ANCA by immunoblotting techniques or enzyme-linked immunoassay is more accurate than by immunofluorescence. The combination of a C-ANCA pattern with immunofluorescence testing and serine proteinase 3–ANCA by immunoassay is associated with WG. Anti-MPO antibodies associated with a P-ANCA pattern occurs in approximately 10% of patients with WG. The P-ANCA directed against non-MPO molecules (eg, elastase, lactoferrin, others) may occur in association with a variety of nonvasculitic disorders.
  • Almost all patients with active systemic WG have positive ANCA findings, commonly directed against serine proteinase 3. Approximately 80-95% of all ANCA found in patients with WG is C-ANCA/anti–serine proteinase 3. Most of the remaining 5-20% is P-ANCA–positive with antibodies directed against MPO. The diagnostic accuracy of ANCA testing becomes greater in patients with the classic presentation, in whom C-ANCA has a 98% posttest probability of predicting the diagnosis WG.
  • In a large study of patients from the Mayo Clinic, the specificity of C-ANCA testing for classic WG was found to exceed 90%. When the disease was confined to the upper and/or lower respiratory tracts without systemic vasculitis, the sensitivity was 67% in active disease and 32% during remission. In patients with evidence of systemic vasculitis, the sensitivity was 96%, which dropped to 41% during remission.
• In patients with renal involvement, urinalysis can reveal proteinuria, microscopic hematuria, and the presence of red blood cell casts. Nephrotic-range proteinuria can be observed.

Imaging Studies

• Chest radiograph findings may include one or more of the following (see Images 8-10):
• • Nodules, which may cavitate
  • Alveolar opacities
  • Pleural opacities
  • Diffuse hazy opacities, which may reflect alveolar hemorrhage
• CT scans may show sharper definition of the pulmonary lesions and orbital or paranasal sinus involvement where appropriate (see Images 11-13).
• Sinus radiographs may also be helpful in the evaluation of WG. The findings are opacification, erosion, and mucosal thickening; these signs are certainly not specific to WG (see Image 14).

Procedures

• Tissue biopsy
• • Diagnosis of WG is generally confirmed by findings from a tissue biopsy sample from a site of active disease.
  • Biopsy of a nasopharyngeal lesion demonstrating culture-negative granulomatous inflammation is suggestive of the diagnosis.
  • If no lesion is present in the upper respiratory tract, the next step is to perform a biopsy of an affected organ, such as a kidney or lung.
  • Although findings from a transbronchial lung biopsy may occasionally support the diagnosis, thoracoscopic or open lung biopsy may be required. For that reason, kidney biopsy is often preferred.
• Renal biopsy
• • Renal biopsy may be easier to perform and has a greater diagnostic yield.
  • This reveals segmental crescentic necrotizing glomerulonephritis with little or no immunoglobulin or complement deposition with immunofluorescence (pauci-immune). Generally, vasculitis is not observed, but this histology helps in establishing the diagnosis. Renal biopsy findings cannot be used to distinguish between WG and microscopic polyarteritis (see Image 3).
• Lung biopsy
• • Lung biopsy is performed in the absence of renal involvement. Either open or thoracoscopic lung biopsy may be performed.
  • Biopsy may reveal typical findings of vasculitis and granulomatous inflammation, although chronic infections should be excluded (see Images 1-2).

Histologic Findings

Necrotizing granuloma dominates the pathologic findings from lung biopsy, and vasculitis is not a prerequisite for the diagnosis. Basophilic necrosis surrounded by palisaded histocytes is the characteristic histologic feature. Vasculitis involves small arteries, veins, and capillaries and has granulomatous features with giant cells. Alveolar hemorrhage is associated with inflammation of the alveolar capillaries, so-called capillaritis. Renal histology is described above.

TREATMENT

Section 6 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

The prognosis associated with untreated systemic WG is poor, with up to 90% of patients dying within 2 years, usually from respiratory or renal failure. Long-lasting remissions can be induced in most patients with cytotoxic agents, particularly cyclophosphamide, administered in combination with corticosteroids. Approximately 90% of patients respond to cyclophosphamide, and approximately 75% experience complete remission. Subsequently, 30-50% of those who respond have at least one relapse, requiring another course of therapy.

Current treatment of WG is based on patient classification of either severe or limited disease. Severe WG threatens a vital organ or life and requires urgent treatment, whereas limited WG does not pose this threat.

Results from several randomized controlled trials in patients with WG and other antineutrophil cytoplasm antibody–associated vasculitides have recently been reported. These reports guide evidence-based therapy in these patients. The considerable toxicity of cyclophosphamide had been a concern. Replacing cyclophosphamide with azathioprine after the successful induction of remission has proven effective in preventing relapses. Even low-dose methotrexate can replace cyclophosphamide in patients without critical organ manifestations as induction treatment. However, a prolonged maintenance treatment that lasts 6-12 months is mandatory.

• The 3 phases of treatment of WG are (1) induction of remission, (2) maintenance of remission, and (3) treatment of relapse.
• The treatment of choice for induction therapy of WG is cyclophosphamide and prednisone, especially in patients with renal involvement or severe lung disease. Oral prednisone is started at 1-1.5 mg/kg/d, and oral cyclophosphamide is added at a dose of 2 mg/kg/d. Once control has been established, the dosage of prednisone is gradually tapered over a 2-month period, and cyclophosphamide is maintained for an additional 6-12 months after the last evidence of stability.
• The role of monthly intravenous cyclophosphamide (pulse therapy) is controversial. Several studies, including that by Guillevin et al from 1997, have shown comparable rates of remission; however, other studies, such as that by Gross from 1994, showed decreased efficacy. These conclusions may not be valid because nonresponders had more severe disease compared with responders. Therefore, perhaps intravenous cyclophosphamide should not be used, at least initially, in patients with severe or life-threatening disease.
• In patients who present with rapidly progressive glomerulonephritis, alveolar hemorrhage, or both, intravenous glucocorticoids should be administered at a much higher dose.
• Pulse therapy with methylprednisolone at 0.5-1 g/d for 3 consecutive days is followed by oral prednisone.
• A higher dose of oral cyclophosphamide (4 mg/kg/d) or intravenous cyclophosphamide (0.75 g/m² of body surface area at intervals of 3-4 wk) is administered.
• In severely ill patients, intravenous gamma globulin has been used at some centers with some success, but this is not a proven therapy. In patients who do not tolerate cyclophosphamide, other cytotoxic agents such as azathioprine, chlorambucil, or methotrexate have been used.
• Methotrexate may be an alternative agent in mild–to–moderately severe disease when patients do not have pulmonary hemorrhage or fulminant renal failure.
• Plasmapheresis generally produces no added benefit, although it may be beneficial in patients who are dependent on dialysis, who have severe pulmonary hemorrhage, or who have concurrent anti–glomerular basement membrane antibody disease.
• Other therapies such as intravenous immunoglobulin, mycophenolate mofetil, leflunomide, and etanercept have been administered to a small number of patients. Data for these and other therapies, including tumor necrosis factor inhibitors, are insufficient to endorse their widespread use.
• Based on recent clinical trials, a new approach to immunosuppression has emerged for patients with WG.
• • According to studies by Jayne from 2003 and Langford et al from 1999, a shorter course of induction treatment with cyclophosphamide, usually for a duration of 3-6 months, is recommended. A longer maintenance therapy with less toxic agents (eg, azathioprine, methotrexate) is continued for at least 1 year after remission is achieved. For patients who develop frequent exacerbations, long-term use of low-dose prednisone, methotrexate, or azathioprine may be appropriate.
  • Most patients with limited WG may be treated with glucocorticoids and methotrexate alone. Remission could occur in up to 75% of these patients with treatment regimens not including cyclophosphamide.
  • The relapse rate following remission ranges from 20-46%, with most relapses occurring within the first year after cessation of immunosuppressive therapy.
  • Infections may play a role in relapse by inducing expression of cytoplasmic antigens on the surface of circulating neutrophils, releasing oxygen radicals, and causing vascular injury.
  • Relapses generally respond to re-treatment with cyclophosphamide and prednisone. Daily treatment with the antibiotic sulfamethoxazole-trimethoprim has reduced relapse rates in published series. A placebo-controlled study by Stegeman et al published in 1996 demonstrated that 82% of subjects receiving cotrimoxazole remained in remission, compared with 60% of those in the placebo group. The mechanism of its efficacy is unknown. Speculations have been made that the efficacy may be due to either the anti-infective or anti-inflammatory effects of this drug.
  • ANCA titers usually parallel the course of vasculitis, especially C-ANCA. Acute phase reactants (eg, erythrocyte sedimentation rate, C-reactive protein level) also parallel the course of WG, although they can rise with concurrent infection without active disease.
  • Although decreasing titers of ANCA predict a lower risk for clinical relapse, the relationship between ANCA titers and disease activity is not absolute and may be discordant in one third of patients.
  • Studies have shown that a rise in ANCA titers in asymptomatic patients may be used to predict a relapse, but therapy should not be initiated unless early clinical findings of relapse also appear.
  • Rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be effective in the treatment of immune disorders due to autoantibodies. A recent prospective study of long-term effects of rituximab in 10 patients with ANCA-positive vasculitis refractory to conventional therapy or subsequent relapse was published. Treatment consisted of intravenous infusions of rituximab 375 mg/m² weekly for 4 consecutive weeks. All patients experienced a rapid clinical improvement following the administration of rituximab. This therapy could be considered in patients with severe WG who fail to respond to standard therapy (Stasi, 2006).
  • Etanercept, which blocks tumor necrosis factor-alpha, has been shown to be ineffective in maintenance of remission in patients with WG. Durable remissions were achieved in only a minority of the patients in one prospective study, and the rate of treatment-related complications was high.

Surgical Care

Inflammatory insult leads to tissue necrosis and fibrotic damage to the nose, subglottic areas, trachea, and bronchi. Consider surgical intervention in such situations.

• Saddle nose deformity can be surgically repaired.
• For subglottic stenosis, laser treatment, balloon dilatation, or resection of the stenotic area with reanastomosis (performed as the definitive procedure) may be performed.
• Obstruction of the nasal lacrimal ducts can be corrected by surgical means.
• Recurrent middle ear infections due to dysfunction of the eustachian tube can be treated by introducing ventilating tubes through the tympanic membranes.
• For patients who develop stenosis of the major bronchi, dilatation, placement of silastic stents, or both may be beneficial. Intralesional injections of corticosteroids may also be beneficial in these patients.
• Patients with renal failure should be considered for transplantation. Recurrence of WG in the transplanted kidney has not been reported.

Consultations

This multisystem disease may require a multidisciplinary approach to management, involving rheumatologists, pulmonologists, nephrologists, and otolaryngology surgeons.

MEDICATION

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• References

For induction therapy, prednisone and cyclophosphamide are started; prednisone is tapered over 2-3 months, and cyclophosphamide is continued for 6-12 months following disease remission. Azathioprine or methotrexate has been used with some success in patients who do not tolerate cyclophosphamide therapy.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Modify body's immune response to diverse stimuli.

Drug Category: Alkylating agents

Have improved prognosis of patients with WG. Medication is initiated with corticosteroids but is continued for at least 12 mo following disease remission.

Drug Category: Immunosuppressive agents

Useful in patients who experience adverse effects with cyclophosphamide. Generally started at lower dose and gradually increased over time. Onset of effect generally takes several weeks; therefore, use in severe disease not advised. Patients also may be placed on maintenance therapy with azathioprine following induction therapy with cyclophosphamide.

Methotrexate and azathioprine are immunosuppressive medications that may be used in patients with WG. Can be used in patients unable to tolerate cyclophosphamide because of adverse effects. Work gradually over several weeks and, therefore, are recommended in patients with mild-to-moderate disease. Patients also may be placed on maintenance therapy with either of these agents following induction therapy with cyclophosphamide.

Drug Category: Antibiotics

Cotrimoxazole is recommended for prophylaxis against Pneumocystis carinii pneumonia. Continued as long as patient is on immunosuppressive therapy. Recent data show cotrimoxazole may be beneficial in decreasing relapses during maintenance therapy of WG.

FOLLOW-UP

Section 8 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Regular long-term follow-up evaluations are required to detect morbidities related to cytotoxic therapy. These morbidities include, leukemia, lymphoma, and bladder cancers.
• Patients taking oral cyclophosphamide should undergo complete blood cell counts every 2 weeks, and the drug should be withheld temporarily if the white blood cell count falls below 4000/µL.

Complications

• Massive hemoptysis
• Acute respiratory failure
• Acute or chronic renal failure
• Deafness
• Blindness
• Neuropathy
• Saddle nose and perforation of nasal septum

Prognosis

• The overall mortality rate was 13% at 8 years in the Hoffman et al series from 1992. Permanent disease-related morbidity occurred in 86%, and effects included chronic renal insufficiency (42%), end-stage renal failure requiring dialysis (10%), hearing loss (35%), nasal deformity (28%), tracheal stenosis (13%), and visual loss (8%).
• In the series by Matteson et al from 1996, the mortality rate was 28% at 5 years and 36% at 10 years. The causes of death were either complications from underlying disease (eg, myocardial infarction, heart failure, kidney failure) or complications from treatment (eg, infection, malignancy).
• A 2003 series by Booth et al demonstrated a mortality rate of 18% and a 5-year cumulative patient survival rate of 76%. Mortality was associated with age older than 60 years, the development of end-stage renal failure, and an initial creatinine value of greater than 2.26 mg/dL.

Patient Education

• Patients and families must understand the seriousness of WG, the necessity for potentially very toxic therapy, the importance of continuous monitoring and follow-up, and the risk of relapse even after disease remission.

MISCELLANEOUS

Section 9 of 12  

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• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• WG must be differentiated from other vasculitides because treatment and prognosis are different for the different diseases.
• Limited WG should be differentiated from chronic infection.
• Hemorrhagic cystitis and transitional carcinoma of the bladder are complications of cyclophosphamide therapy; therefore, monitoring the urinary segment is important. Azathioprine or methotrexate may be substituted for patients who develop bladder complications.
• Whether tissue diagnosis is always required for WG remains controversial at present. However, most clinicians do not pursue tissue diagnosis in patients with a characteristic clinical picture and elevated C-ANCA levels.

Special Concerns

• P carinii pneumonia
• • P carinii pneumonia has an annual incidence of 1% but is a potentially deadly complication of immunosuppressive therapy in patients with WG. A rate of 6% was reported in a retrospective study, in which 11 of 180 patients taking corticosteroids and a second immunosuppressive agent developed P carinii pneumonia.
  • Prophylaxis with trimethoprim-sulfamethoxazole (160/800 mg, 3 times weekly) increases life expectancy and reduces medical costs for these patients.

ACKNOWLEDGMENTS

Section 10 of 12  

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• Acknowledgments
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The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor Glen Thomson, MD, to the development and writing of this article.

MULTIMEDIA

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• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  The biopsy specimen of a lung from a patient with Wegener granulomatosis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.
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Media file 2:  The biopsy specimen of a lung from a patient with Wegener granulomatosis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.
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Media file 3:  Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of Wegener granulomatosis.
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Media file 4:  Wegener granulomatosis. Staining for antineutrophil cytoplasmic antibody by indirect immunofluorescence shows heavy cytoplasmic staining, whereas nuclei are nonreactive (see Images 5-6). Image courtesy of K. Orr, MD.
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Media file 5:  Wegener granulomatosis. Perinuclear antineutrophil cytoplasmic antibody staining pattern by indirect immunofluorescence shows perinuclear staining, whereas cytoplasm is nonreactive (see Image 4 and Image 6). Image courtesy of K. Orr, MD.
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Media file 6:  Wegener granulomatosis. This pattern is that of homogenous antinuclear antibodies (see Images 4-5). Image courtesy of K. Orr, MD.
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Media file 7:  Wegener granulomatosis. Linear deposition of immunoglobulin G and C3 are observed on renal biopsy specimen from a patient with Goodpasture syndrome. Immunofluorescence staining. Image courtesy of K. Orr, MD.
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Media file 8:  Wegener granulomatosis. Bilateral nodules observed on plain chest radiograph from a patient with hemoptysis and hematuria. Image courtesy of G. Eschun, MD.
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Media file 9:  This 42-year-old man presented with hemoptysis, weight loss, and night sweats. He was diagnosed with the limited form of Wegener granulomatosis.
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Media file 10:  Wegener granulomatosis. This patient presented with massive hemoptysis. No nodules are identified on the chest radiograph, although a subsequent CT scan showed several noncavitating nodules.
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Media file 11:  Wegener granulomatosis. A 58-year-old woman developed hemoptysis and renal failure. This CT scan shows lung nodules and ground-glass opacity secondary to pulmonary hemorrhage.
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Media file 12:  Bilateral noncavitating pulmonary nodules in a patient positive for antineutrophil cytoplasmic antibodies. Probable diagnosis is Wegener granulomatosis.
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Media file 13:  Bilateral cavitating nodules in a patient with Wegener granulomatosis.
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Media file 14:  Extensive thickening of the maxillary sinuses in a patient with Wegener granulomatosis. The patient also had intermittent epistaxis.
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REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
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• References

• Aasarod K, Iversen BM, Hammerstrom J, et al. Wegener''s granulomatosis: clinical course in 108 patients with renal involvement. Nephrol Dial Transplant. May 2000;15(5):611-8. [Medline].
• Afeltra A, Sebastiani GD, Galeazzi M, et al. Antineutrophil cytoplasmic antibodies in synovial fluid and in serum of patients with rheumatoid arthritis and other types of synovitis. J Rheumatol. Jan 1996;23(1):10-5. [Medline].
• Allen A, Pusey C, Gaskin G. Outcome of renal replacement therapy in antineutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol. Jul 1998;9(7):1258-63. [Medline].
• Baranger TA, Audrain MA, Castagne A, et al. Absence of antineutrophil cytoplasmic antibodies in giant cell arteritis. J Rheumatol. May 1994;21(5):871-3. [Medline].
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