AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
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• Workup
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• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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

Background

Wegener granulomatosis (WG) is a clinicopathologic entity that is very rare in children. Much of the information presented in this article is derived from adult literature. Strictly defined, the Wegener triad for generalized WG is necrotizing granulomatous lesions of the upper or lower respiratory tract, generalized necrotizing vasculitis involving both arteries and veins, and focal necrotizing glomerulonephritis (GN). Regional WG can occur when sinopulmonary disease occurs in the absence of renal disease. The largest historical series of WG patients included those with compatible clinical histories and histologic evidence of either vasculitis or granulomatous inflammation. This more inclusive definition of WG used in the 1970s and 1980s has been defined more strictly in the 1990s.

The Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis more strictly defined WG, distinguishing it from other forms of vasculitis with similar clinical features. Additionally, antineutrophil cytoplasmic autoantibodies (ANCA), which are associated with WG, can now be tested routinely and have provided clinicians an additional diagnostic tool. Newer reports adhere to stricter criteria, requiring one of the following to be classified as WG: histologic evidence of granulomatous inflammation, presence of pulmonary nodules, cavitary pulmonary lesions, or invasive bony disease in the upper respiratory tract. In this newer, more rigorous scheme, patients with clinical evidence of ANCA positive small vessel vasculitis, who lack granulomatous inflammation, are classified as having microscopic polyangiitis (MPA). These changing definitions of WG complicate the interpretation of earlier studies.

Because the various forms of ANCA-associated small vessel vasculitis (ie, WG, MPA, Churg-Strauss syndrome) respond to similar treatments, newer trials in patients with ANCA (+) small vessel vasculitis can be applied to patients who would previously have been classified as having WG. In this article, WG is used as a clinical diagnosis. ANCA-associated small vessel vasculitis and WG are used interchangeably unless otherwise indicated.

In 1939, Wegener initially described a group of patients with necrotizing granulomatous arteritis involving the upper and lower respiratory tracts, sinuses, middle ear, and nasopharynx. Before the institution of effective therapy, the mean survival of adults with untreated WG was only 5 months, with 82% of patients dying within the first year and 90% of patients dying within the second year. Despite improvement with the use of corticosteroids, the mean survival time was increased only to 12.5 months. With the advent of cytotoxic therapy for WG, patient survival has improved markedly. In 1983, Fauci et al reported a 93% complete remission rate in 85 patients (mean age 43.6 y, range 14-75 y) treated with prednisone and oral cyclophosphamide.

Pathophysiology

The hallmark lesion is necrotizing vasculitis of small arteries and veins together with granuloma formation that can be either intravascular or extravascular. Lung involvement is typically bilateral nodular cavitary infiltrates, which on biopsy demonstrate necrotizing granulomatous vasculitis. The renal biopsy lesion is that of a pauci-immune necrotizing and crescentic GN. The pathogenesis of WG is still unknown. Some researchers have speculated that ANCA may have a role in the development of small vessel vasculitis, but this has not been demonstrated in vivo. Others believe that respiratory infections may be part of the inciting event in either the onset of the disease or its relapses.

Frequency

United States

The incidence of WG is difficult to determine, but it is known to occur much more frequently in adults. One study analyzed the national mortality data from the National Center for Health Statistics, hospitalization data from the National Hospital Discharge Survey of nonfederal short stay hospitals, and data from the Statewide Planning and Research Cooperative System of New York State. Based on analysis of these data, the prevalence of WG was estimated to be at least 3 cases per 100,000 persons. A higher percentage (3.3%) of individuals younger than 20 years appeared in the New York data than in the national data (0.1%).

International

An approximate 5-year incidence rate of 1.3 cases per 100,000 persons exists in the United Kingdom.

Mortality/Morbidity

During the 10-year period from 1979-1988, WG was listed as the cause of death on 1784 death certificates. Twenty-two of these deaths were of children younger than 15 years.

• Pediatric end-stage renal disease (ESRD): According to the 1999 US Renal Data Systems (USRDS) Annual Data Report, from 1993-1997 WG was the underlying cause of ESRD in 40 pediatric patients older than 5 years and younger than 20 years.
• The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) 2005 Annual Report lists the causes of renal failure in their pediatric dialysis database encompassing 1992-2004. Of the more than 5600 children in the registry, Wegener granulomatosis was listed as the primary disease in 34 cases (0.6%). Permanent morbidity from disease or its treatment occurs in 87% of patients. Newer regimens should improve morbidity.

Race

• Adults: In 1992, Hoffman et al described 158 patients cared for at the National Institutes of Health (NIH). Ninety-seven percent of patients were white.
• Pediatric ESRD: Eighty-two percent of the pediatric patients with WG who developed ESRD in the United States were white.

Sex

• Adult: Essentially, the condition occurs equally in males and females. Of the 135 patients older than 19 years at the NIH, the male-to-female ratio was 70:65.
• Pediatric: Rottem et al (1993) studied 23 patients from the NIH who were younger than 19 years and had childhood-onset WG. Unlike adults, a female preponderance was found. The male-to-female ratio was 7:16.
• Pediatric ESRD: ESRD developed in roughly equal numbers of males and females with WG. In all, the male-to-female ratio was 19:21.

Age

Most patients with WG are adults. Eighty-five percent of patients with WG studied at the NIH were older than 19 years.

• Pediatrics: Rottem et al (1993) studied 23 patients from the NIH who were younger than 19 years and had childhood-onset WG. The mean age of onset of clinical disease in the pediatric group was 15.4 years (range 9.3-19.4 y), and a median of 8 months passed from onset of symptoms until a definitive diagnosis was secured.
• Pediatric ESRD: The median age of patients with WG who developed ESRD in the United States was 16 years.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
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History

Patients with Wegener granulomatosis (WG) can have a multitude of symptoms, depending on the organ systems involved. These symptoms are listed by organ systems.

• Ear, nose, and throat findings
• • The symptoms causing pediatric patients to seek medical care usually are attributable to the upper and lower respiratory tract.
  • Rottem et al (1993) reported that 87% of their pediatric patients presented with ear, nose, and throat (ENT) pathology that included sinusitis (61%), nasal disease (48%), otitis media (39%), hearing loss (26%), and ear pain (22%). Ultimately, 91% of pediatric patients developed upper respiratory problems, with sinus involvement occurring in 83% of pediatric patients.
  • When patients with WG present with nasal and sinus disease, constitutional symptoms may seem severe relative to the physical findings.
• Central airway findings
• • WG may involve the larynx, subglottic space, trachea, and mainstem bronchi.
  • Subglottic stenosis was reported in 4% of pediatric patients at presentation and ultimately developed in 48% of pediatric patients. This was significantly greater than the 10% occurrence of subglottic stenosis in adults reported by Hoffmann et al (Ann Intern Med, 1992).
  • In a series of 51 adults with WG, all patients presenting with symptoms such as persistent cough, stridor, or dyspnea on exertion were found to have tracheobronchial lesions. Interestingly, unsuspected tracheobronchial lesions were found in 37% of patients undergoing bronchoscopy for evaluation of parenchymal disease.
  • Ulcerative tracheobronchitis was the most frequently observed lesion and was found in 35% of patients.
  • An additional 9.8% of patients had subglottic stenosis.
  • Four patients had cicatricial tracheal or bronchial narrowing at the site of previous inflammation.
• Pulmonary manifestations
• • Pulmonary involvement can be asymptomatic, insidious in onset, or severe and fulminant.
  • In Rottem's (1993) series, lung disease occurred in 22% of patients at presentation and eventually developed in 74% of patients.
  • Pulmonary infiltrates (61%), pulmonary nodules (43%), and hemoptysis (26%) were the most common abnormalities.
  • Radiographic abnormalities may occur in the absence of symptoms. Patients with WG may present with life-threatening diffuse alveolar hemorrhage, which is often accompanied by progressive GN. Radiographically, patients with alveolar hemorrhage present with infiltrates, usually bilateral as shown in Image 1. These infiltrates clear rapidly, as shown in Image 2.
• Renal manifestations
• • GN was present in only 9% of patients at presentation but ultimately developed in 61% (14 of 23) of patients at some point during the course of the disease. GN manifests as hematuria, proteinuria (in most cases), and renal insufficiency. Hypertension and gross hematuria are typically uncommon.
  • Of note, 8 of Rottem's (1993) 23 patients (35%) developed chronic renal insufficiency, with 2 patients requiring dialysis. Alternatively, 57% of the 14 patients with renal involvement developed chronic renal insufficiency, and 14% of patients required dialysis.
  • When one observes children with ANCA (+) vasculitis and GN who often present with more indolent disease, the incidence of ESRD can be significantly higher. Ellis et al (1995) reported a 60% incidence of ESRD in 5 children treated at 2 centers. A more recent single center series by Valentini et al (1998) found an incidence of 14% in 7 pediatric patients. These various reports support the need to maintain a high index of suspicion for renal disease in children with vasculitis in an effort to reduce long-term morbidity from late disease recognition.
• Ocular manifestations
• • Eye disease occurred in 13% of Rottem's (1993) patients at the outset of disease and 48% of patients overall.
  • Dacryocystitis, proptosis, eye pain, and episcleritis were the most common abnormalities.
  • Retroorbital pseudotumor causes proptosis and eye pain.
  • In a series of 13 adult and pediatric patients presenting with ocular involvement, 11 patients had nasal, sinus, or ear symptoms in the months preceding presentation. Ocular symptoms typically developed subacutely and then rapidly progressed. Only 5 of these patients had constitutional symptoms, and, during the period of follow-up, only 1 patient developed renal disease. All patients developed an orbital mass, and all but 2 patients eventually developed bilateral eye disease.
  • Disease remission generally occurred in response to corticosteroids and immunosuppression, but treatment was not standardized. Some patients were left with visual impairment.
  • Because of both the risk of ocular disease and the potential ophthalmologic adverse effects of corticosteroids, pediatric patients should have an ophthalmologic examination at diagnosis and yearly thereafter, should symptoms develop.
• General manifestations
• • Rottem's (1993) study revealed that systemic symptoms, including arthralgia/arthritis (30%), fever (22%), weight loss (13%), and rash (9%), were present at disease onset in a number of instances.
  • During follow-up, musculoskeletal symptoms occurred in 78% of patients, fever in 43% of patients, weight loss in 26% of patients, and rash in 52% of patients.
• Other organ involvement
• • Neurologic and cardiovascular systems can be involved as well.
  • Literature on adults states that 4% of patients present with nervous system involvement, but nervous system involvement eventually develops in 10-34% of patients.
  • A peripheral neuropathy, such as mononeuritis multiplex, has been the most frequent neurologic manifestation described in adult patients.
  • Cardiac involvement is rarely detected antemortem but includes pericarditis and coronary arteritis in 10-20% of cases. Necrotizing vasculitis of the coronary vessels can result in a myocardial infarction or sudden death.

Physical

Physical examination findings are listed in a head-to-toe manner. Because patients may have involvement of only a few organ systems, many of the physical findings listed may not be present.

• Head, ears, eyes, nose, and throat findings
• • Eyes - Conjunctivitis, scleritis, or proptosis
  • Ears - Chronic otitis media
  • Nose - Persistent rhinorrhea, epistaxis, nasal crusting, mucosal ulceration, or septal perforation; occasionally, saddle nose deformity
  • Throat - Pharyngitis with possible ulcerations
• Neck findings
• • Stridor can be present with tracheal involvement.
  • Distended neck veins can be observed in cardiac involvement and manifest in congestive heart failure (CHF).
• Chest findings
• • Tachypnea may be noted in patients with significant anemia, airway disease, or lung parenchymal involvement.
  • Wheezing may be noted.
• Cardiovascular manifestations: Heart sounds may be distant if pericardial effusion is present.
• Abdominal findings
• • Abdominal pain can be observed.
  • Rarely, GI bleeding can occur.
• Manifestations in the extremities
• • Findings of arthritis can be observed.
  • Edema from fluid retention can be noted in patients with significant GN leading to renal failure.
• Neurologic manifestations
• • A sensory, motor, or mixed sensory/motor peripheral neuropathy can be present. These are manifestations of mononeuritis multiplex, which is the most common form of neurologic involvement in WG.
  • Cranial nerve involvement can occur but is rare.
• Skin findings
• • Rashes are present in approximately 50% of patients (adult or children).
  • Rashes vary from palpable purpura, ulcers, vesicles, papules, and subcutaneous nodules.
• Clinical assessment: Various scoring systems have been used in an attempt to objectively assess the vasculitis disease activity. The Birmingham Vasculitis Activity Scoring system, which was first reported in 1994, has been favorably adopted by the rheumatology and nephrology community. This scoring system evaluates signs and symptoms in 9 organ systems and has been used in a number of treatment studies in an attempt to objectively measure differences in disease activity after the addition of an investigational agent (eg, etanercept).

Causes

The pathogenesis is still unknown.

• Some researchers have speculated that the ANCAs may have a role in the development of small vessel vasculitis.
• • One hypothesis is that an infection results in the production of proinflammatory cytokines, such as tumor necrosis factor–alpha (TNF-alpha) or interleukin-1.
  • These cytokines induce resting neutrophils (ie, polymorphonuclear neutrophils [PMNs]) to express ANCA antigens (ie, myeloperoxidase, proteinase 3) that are normally contained within cytoplasmic granules, on their cell surfaces.
  • These local cytokines also increase expression of adhesion molecules, allowing activated PMNs to attach to vascular endothelial cells.
  • Circulating ANCA bind to these primed PMNs, leading to activation and degranulation with production of oxygen radicals that induce endothelial injury.
  • This hypothesis is derived from in vitro data and has not been documented in vivo. Nonetheless, it is an attractive hypothesis, because relapses of WG are usually triggered by a respiratory infection. Furthermore, prophylactic antibiotics that reduce respiratory relapses may reduce systemic relapses, as well.
• From a genetic predisposition standpoint, an increased association of WG and the human leukocyte antigen (HLA)-B8 and HLA-DR2 gene loci exists. Recent data have revealed that a functional polymorphism, 620W, in the gene encoding for an intracellular tyrosine phosphatase (PTPN22) is a risk factor for the development of Wegener granulomatosis. Patients with ANCA (+) WG were found to have a significantly higher frequency of the PTPN22 620W allele when compared with healthy controls (p< 0.001).

DIFFERENTIALS

Section 4 of 11  

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

Other Problems to be Considered

Pediatrics, Henoch-Schönlein-Purpura
Other ANCA-associated small vessel vasculitides (ie, Microscopic Polyangiitis, Churg-Strauss Syndrome)
Rheumatoid arthritis with systemic vasculitis
Mixed cryoglobulinemia
Renal vein thrombosis with pulmonary embolism

WORKUP

Section 5 of 11  

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

Lab Studies

• Laboratory features - General
• • Nonspecific laboratory abnormalities include anemia, thrombocytosis, and leukocytosis in 30-60% of adults.
  • Marked eosinophilia is rare.
  • Rheumatoid factor is positive in a low titer in two thirds of patients, whereas antinuclear antibody is present in 10-20% of patients.
  • Serum complement levels are within the reference range or increased.
  • Westergren erythrocyte sedimentation rate and C-reactive protein are elevated in 90% of patients with active and generalized disease.
• ANCA
• • The most specific serologic tests are autoantibodies directed against cytoplasmic constituents of neutrophils and monocytes. A cytoplasmic staining pattern on indirect immunofluorescence (cANCA) is characteristic.
  • More specific antibody assays, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA), have been used to determine the antigen at which these ANCAs are directed.
  • The antigen toward which the cANCA is directed most often is proteinase 3, which is contained in the azurophilic granules of the neutrophil. The cANCA test is not specific for proteinase 3 because other neutrophil proteins, such as bacteriocidal/permeability increasing (BPI) protein and, more rarely, myeloperoxidase, can stain similarly. Moreover, antiproteinase 3 antibodies are not specific for WG because they are found in other forms of vasculitis.
  • Generally, performance of both indirect immunofluorescent ANCA testing and more specific ANCA testing is recommended in the clinical setting of vasculitis.
  • Despite some limitations, when used appropriately, the ANCA test provides a tool that can aid greatly in the diagnosis of small vessel vasculitis. Circulating cANCAs are detected in 90% of patients with active generalized (sinopulmonary, renal) WG and also in 40-70% of patients with active regional (sinopulmonary) disease. By contrast, approximately 30-40% of patients in remission have a positive cANCA. This emphasizes the need to treat the patient with a clinical relapse, not a positive ANCA test result.
  • Clinical entities classified as small vessel vasculitis include WG, microscopic polyangiitis (MPA), and Churg-Strauss syndrome. All are forms of small vessel vasculitis with multiorgan involvement, and all are associated with ANCA. In contrast to WG, the indirect immunofluorescence staining pattern in MPA and Churg-Strauss syndrome is often perinuclear (pANCA). This is an artifactual phenomenon that occurs during the ethanol fixation process of neutrophils, resulting in the displacement of the basic positively charged proteins (eg, myeloperoxidase, lactoferrin, lysozyme, elastase, cathepsin G) from the cytoplasm to the nuclear region. Myeloperoxidase is the antigen at which these autoantibodies are most often directed in the setting of small vessel vasculitis. This antibody can be observed in MPA, Churg-Strauss syndrome, idiopathic crescentic GN, and, occasionally, in WG.
  • A positive finding on a pANCA test alone can be observed in a number of other diseases that would not qualify as small vessel vasculitis. These include inflammatory bowel disease, Kawasaki disease, polyarteritis nodosa, Felty syndrome, and infections, such as HIV and endocarditis. Because of the variability of the pANCA target antigen, more specific antibody testing is recommended strongly. A positive pANCA test result should only be used to diagnose small vessel vasculitis when used in conjunction with a positive antimyeloperoxidase titer in the setting of high clinical suspicion.
  • In summary, be cautious not to equate a positive ANCA test result with disease. When used appropriately, the ANCA test is a very powerful test with high degrees of sensitivity and specificity; however, when used in the wrong setting, it can lead to misdiagnosis with resultant inappropriate treatment using potentially toxic therapy. Indeed, a positive cANCA test result in patients with only sinusitis has a posttest probability of 7-16% of correctly diagnosing WG. In patients with sinusitis, pulmonary infiltrates or nodules, and active urinary sediment with red blood cell casts, a positive cANCA test finding has a posttest probability of WG of 98%. Moreover, ANCA tests should not be used to correlate with clinical disease in those with established diagnoses of vasculitis.

Imaging Studies

• Chest radiography
• • Chest radiography should be performed in all patients with respiratory symptoms. Chest radiography should be performed likewise in patients with GN and the clinical suspicion for a systemic vasculitis.
  • Asymptomatic pulmonary infiltrates or nodules can be observed on chest radiography.
  • Findings on chest radiography are abnormal in two thirds of adults with WG.
  • The most characteristic finding is single or multiple pulmonary nodules with or without cavitation.
• Chest CT imaging: As expected, this test is more sensitive than chest radiography when evaluating involvement of the lung parenchyma.
• Sinus CT imaging
• • This is the radiographic test of choice to evaluate sinus disease.
  • Findings on thin section sinus CT imaging are abnormal in more than 90% of adults with WG. A similar number would be expected in the pediatric population, based on an 83% incidence of sinusitis reported by Rottem et al (1993).

Other Tests

• Pulmonary function tests
• • In patients old enough to cooperate, spirometry, plethysmography, and diffusion capacity should be performed as soon as possible to identify abnormalities and provide a baseline.
  • Good inspiratory and expiratory loops should be obtained. If these are flattened, subglottic stenosis or other causes for central airway obstruction should be suspected.
  • Because most pediatric subglottic stenosis is not found initially, spirometry, particularly with a good baseline flow volume loop, can be used to screen noninvasively for this development.
  • In adults, limitation to flow and decrease of the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) are the most common pulmonary function test abnormalities.
  • Focal and interstitial infiltrates and peripheral mass lesions produce decreased lung volumes.
  • A decreased diffusion capacity is a common finding in WG, but the diffusion capacity may still fall within the reference range.
  • In alveolar hemorrhage, the single breath diffusion capacity is increased.

Procedures

• Renal biopsy
• • While findings on a renal biopsy are often negative for the presence of granulomas in WG, renal biopsy is nonetheless a very useful diagnostic tool, especially in the setting of pulmonary-renal syndrome.
  • A kidney biopsy can usually be performed without incident, even in a relatively unstable patient. This test can help confirm a suspected ANCA-associated small vessel vasculitis in the kidney, such as WG, by detecting a pauci-immune necrotizing and crescentic GN.
  • More importantly, a renal biopsy allows exclusion of anti–glomerular basement membrane (GBM) antibody disease in the setting of a pulmonary renal syndrome. Because of the importance of treating anti-GBM with plasma exchange, this therapy is often started empirically and continued until this disease can be ruled out.
  • A renal biopsy documenting the focal, necrotizing, and crescentic GN of WG is shown in Image 3.
• Bronchoscopy
• • Bronchoscopy can demonstrate lesions of the larynx, subglottic space, trachea, and mainstem bronchi. As mentioned, spiral CT imaging has also been used to examine these lesions and is viewed as a complementary modality.
  • Bronchoscopy allows clear views of the mucosa and allows appreciation of dynamic lesions, such as tracheomalacia and bronchomalacia, that are observed in WG.
  • Transbronchial biopsy in diffuse lung disease has a low yield of diagnostic findings, presumably because of the geographic nature of the granulomatous inflammation.
• Biopsies of other sites
• • When patients with WG present with a limited form with upper airway disease, orbital disease, or pulmonary disease, the differential diagnosis may include infectious and neoplastic diseases and other forms of vasculitis. Biopsies of the nasal mucosa, even when ulcerated, often are not diagnostic.
  • Often, necrosis and granuloma formation are observed but are without the true vasculitis required for definitive diagnosis.
  • Bronchoscopic biopsy of ulcerative or exophytic lesions of the tracheal or bronchial mucosa is more likely to show necrotizing or nonnecrotizing granulomas but often does not demonstrate vasculitis.
  • In the presence of nodules or infiltrates on chest radiography or CT imaging, lung biopsy findings often are diagnostic, and patchy necrosis, granulomatous inflammation, and vasculitis are observed.
  • In the setting of pulmonary hemorrhage, pulmonary biopsy is much more risky. If doubt exists as to the cause of a new infiltrate, bronchoscopy can be used to confirm the presence of blood. Lavage fluid is bloody and contains hemosiderin-laden macrophages. Stains and cultures should be obtained to rule out infection.

Histologic Findings

Renal biopsy findings reveal few, if any, immune deposits (pauci-immune) on immunofluorescence. Light microscopy reveals a necrotizing and crescentic GN.

TREATMENT

Section 6 of 11  

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Medical Care

The mainstay of treatment for Wegener granulomatosis (WG) is a combination of corticosteroids and cytotoxic agents. Because the dosages and the manner of administration can vary according to the stage of treatment, the treatment section is separated into 3 parts: acute supportive treatment, induction therapy, and maintenance therapy.

• Acute supportive treatment
  • From an immunosuppressive standpoint, most centers treat patients with either oral prednisone or intravenous methylprednisolone. Pulse methylprednisolone at a dose of 7-15 mg/kg/dose typically is administered in 3 successive doses followed by prednisone at 1-2 mg/kg/d.
  • Cyclophosphamide (CYP) is administered in one of two ways. Many centers prefer oral CYP to induce a remission and optimally reduce the incidence of relapses. Others prefer intravenous CYP, which is as efficacious at inducing a remission as the oral preparation. Intravenous CYP can be administered safely with aggressive hydration and 2-mercaptoethane sulfonate sodium (mesna) to minimize the risk of hemorrhagic cystitis. Additionally, the cumulative dose tends to be much lower with the IV preparation, which should result in a reduction in dose-related long-term malignancy risks.
  • Other treatments that have been used empirically but have not been well studied include plasma exchange and the use of intravenous immunoglobulin (IVIG). The former treatment brings the theoretical advantage of removing a circulating agent that may be causative, whereas the latter may be immunomodulating.
  • Additional supportive treatments, such as oxygen, assisted ventilation, transfusion, extracorporeal membrane oxygenation (ECMO), and dialysis, have been used as life-saving measures.
• Induction immunosuppressive therapy
  • This phase of treatment is defined arbitrarily as the period occurring between 2 weeks and 6 months after diagnosis. Oral corticosteroid therapy is administered typically as prednisone (1-2 mg/kg/d), which is continued for 1-3 months before being tapered down. Some centers taper to alternate day prednisone at a dose of 1-2 mg/kg qod 2 months into treatment. Others slowly reduce the dose of steroids that are continued on a daily basis.
  • With regard to the CYP dose, centers administering monthly CYP IV administer an initial dose of 500 mg/m²/dose and a white blood cell (WBC) count performed 10-14 days later is used to determine the next dose. Dose increase in increments of 250 mg/m²/dose occurs to a maximum dose of 1000 mg/m²/dose. Oral CYP is administered at a starting dose of 2 mg/kg/d (not to exceed 150 mg). Dosage reductions occur based on the presence of leukopenia/neutropenia on WBC counts monitored weekly during the first 1-2 months.
  • Approximately 10% of adult cases are unresponsive to conventional therapy of corticosteroids plus CYP. Rescue therapies may consist of IVIG and plasma exchange.
  • Treatment of refractory disease (resistant to corticosteroids and CYP) has also been studied in small single center reports. Infliximab, a chimeric, monoclonal anti-TNF-a antibody, was added to the standard therapy of CYP and steroids, and successfully induced a remission in 5 of 6 adult patients with disease previously unresponsive to therapy.
  • More recently, rituximab successfully induced a remission in 10 of 10 adult patients with previously refractory disease.
• Maintenance immunosuppressive therapy
• • This period is defined arbitrarily as the period that follows the first 6 months of treatment. The duration of treatment is quite debatable. Many adult centers now stop corticosteroids 3-4 months into therapy and discontinue all treatment as early as 6 months. Other centers use the 6-month cut off as a time to transition the patient to a less toxic regimen, substituting azathioprine (AZA) for CYP at this point. Rottem et al (1993) chose to treat children with oral CYP for 1 year after remission was achieved before reducing the dosage by 25 mg every 2 months as tolerated. Median treatment time with oral CYP was 28 months.
  • This author's experience in children with ANCA-associated vasculitis and GN was to transition patients to AZA after a typical 6-month treatment period with CYP IV. A select group of patients who had either a poor response to CYP IV or life-threatening disease at presentation were treated with oral CYP, which was continued for 1 year. Those treated with oral CYP were changed at 1 year to either AZA or methotrexate (MTX) in an effort to provide sufficient immunosuppressive therapy while avoiding long-term use of CYP.
  • Newer therapeutic regimens include the use of methotrexate (MTX) as a substitute for CYP during the induction stage of treatment. This has been tried in both children and adults. This agent appears to be reasonably effective (71% remission rate) if selectively used in patients with non–life-threatening forms of WG and when used in conjunction with corticosteroids. Its use may prove to be beneficial to patients with life-threatening WG if used in the maintenance phase of treatment; however, better studies are needed.
  • AZA has been proven inferior to CYP during the induction phase of treatment but may have its greatest role in maintaining a remission state, as discussed above. It is far less toxic than CYP and usually is well tolerated.
  • Mycophenolate mofetil (MMF), an immunosuppressive medication initially used successfully in renal transplantation, has relatively low toxicity and a lymphocyte selective mode of action. More recent indications include immunologic diseases, such as systemic lupus erythematosus (SLE) and nephrotic syndrome. Nowack et al (1999) suggested the use of MMF during the maintenance phase of treatment in 11 adult patients with ANCA-associated systemic vasculitis (9 WG patients, 2 MPA patients). Patients were started on a regimen of MMF and low-dose oral corticosteroids after a 14-week induction period with steroids and oral CYP. Outcome was assessed only to 15 months but was very good. Only 1 patient relapsed 14 months into the maintenance treatment phase. MMF was well tolerated at a dose of 2 g/d, with minimal side effects. A more recent study by Joy et al evaluated MMF in patients with non–life-threatening recurrent or cyclophosphamide resistant ANCA (+) small-vessel vasculitis. A 24-weektreatmentperiodinconjunction with corticosteroids resulted in a marked reduction in disease activity as assessed by BVAS. It was concluded that MMF may be useful in this setting to avoid recurrent treatment with alkylating agents.
  • Trimethoprim-sulfamethoxazole (TMP-SMZ) has become a mainstay of WG treatment. Prior to its use, Pneumocystis carinii pneumonia occurred in 6% of the population with WG studied at the NIH. P carinii pneumonia occurred in patients being treated with both corticosteroids and cytotoxic drugs for either initial therapy or treatment of a relapse. More than one quarter of the patients had not had WG involvement of the lungs.
  • Reports exist of TMP-SMZ being used in isolation without other immunosuppressive medications in the induction phase of treatment in patients with very limited disease, but prospective trials of TMP-SMZ as monotherapy have been disappointing. In adults, TMP-SMZ has been shown to prevent relapses of WG in remission. This action of TMP-SMZ may be due to anti-inflammatory action or decrease in infections, particularly respiratory tract infections. Because of the need for P carinii prophylaxis early in therapy and the ability of TMP-SMZ to prevent relapse, institute this therapy early and continue it during corticosteroid and cytotoxic therapy.
  • Newer treatment strategies include blockade of tumor necrosis factor- a (TNF- a). Etanercept is a soluble TNF-a receptor blocker, which has been well studied in patients with WG. Results of the Wegener's Granulomatosis Etanercept Trial (WGET) Research Group were recently published. In a study of 180 patients with WG, etanercept or placebo was added to standard maintenance therapy (steroids plus CYP or MTX). Etanercept had no significant reduction in sustained remission rates or percentage of patients experiencing a severe/life-threatening disease flare relative to controls. In addition, solid cancers developed in 6 patients in the etanercept group compared with none in the control group (p=0.01). It would appear that this agent is not only ineffective but also potentially puts patients with WG at an increased risk for complications and is therefore not recommended.
• Treatment summary
• • At present time, a typical approach to a patient with ANCA (+) vasculitis and GN is to treat with prednisone (1-2 mg/kg/d, not to exceed 80 mg) for 1-2 months before tapering to an alternate day dosing schedule. As for cytotoxic agents, CYP is administered for 6-12 months before changing to AZA. The decision on the duration of CYP is related to the severity of disease at its outset. Patients with non–life-threatening disease typically receive monthly CYP IV for 6 months in conjunction with corticosteroids. If in remission, the patient is changed to AZA at 2 mg/kg/d while steroids continue to be tapered slowly. Those with pulmonary hemorrhage (life-threatening disease) are treated with oral CYP for 1 year in conjunction with corticosteroids. Once again, AZA is substituted for CYP at 1 year if the patient is in remission. Remission is defined as lack of symptoms, stable renal function, benign findings on urinalysis (except for some proteinuria), and a stable erythrocyte sedimentation rate.
  • Newer adult data raise the question of whether the induction treatment phase can be shortened to 3 months with transition from CYP to AZA. The European Vasculitis Study Group analyzed a group of 144 patients with ANCA-associated vasculitis (WG and microscopic polyangiitis) who achieved remission with induction therapy of prednisolone and CYP (2 mg/kg/d) for 3 months. After a 3-month induction phase, patients were randomized to CYP (1.5 mg/kg/d) or AZA (2 mg/kg/d). Remission rates and side effects were similar in both groups. The authors concluded that once remission is achieved with a 3-month course of prednisolone and CYP, patients can be safely switched from CYP to AZA to reduce the exposure to CYP.
  • It has been the author's approach to perform a repeat renal biopsy to confirm a histologic remission before transitioning off of CYP. As mentioned above, patients are started on TMP-SMZ at the outset of induction treatment for P carinii prophylaxis and are continued during the maintenance phase of treatment in an effort to reduce disease relapses.

Surgical Care

The role of surgery in WG is adjunctive and only rarely indicated.

• If a sinus biopsy is desired, an otolaryngologist should be consulted. An additional indication for ears, nose, and throat (ENT) surgery would be airway reconstructive surgery for subglottic stenosis failing intratracheal dilatation.
• Urgent surgical decompression of the orbit may be necessary when visual impairment is due to stretching or compression of the optic nerve.

Consultations

• Pediatricians seeing patients with suspected WG, ANCA-associated vasculitis, or pulmonary renal syndrome should involve a pediatric medical subspecialist with additional expertise in this area, such as a pediatric nephrologist, pulmonologist, or rheumatologist.
• In addition, a baseline ophthalmologic examination should be considered.
• If a sinus biopsy is desired, an otolaryngologist should be consulted.

Diet

Because of the risks of salt and water retention when on corticosteroids, pediatric patients are usually restricted to 2 mEq/kg/d of sodium (molecular weight 23 mg/mEq). The sodium intake should not exceed 2000 mg/d.

• Fluid intake
• • Patients on oral CYP are asked to drink approximately 2000 cc/m²/d and attempt to void every 4 hours to maintain high urine output and reduce the risk of hemorrhagic cystitis.
  • Similarly, oral CYP should be taken as a one-time dose upon awakening in the morning to avoid high bladder concentrations in the middle of the night when fluid intake diminishes.

Activity

• Contact sports are to be avoided for 1 month following a kidney biopsy. Otherwise, activities are as tolerated.
• Because patients are immunosuppressed, patients should attempt to minimize exposure to ill contacts.

MEDICATION

Section 7 of 11  

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

Medications include immunosuppressive medications (ie, corticosteroids, cytotoxic agents) and TMP-SMZ (ie, methylprednisolone or prednisone, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, and TMP-SMZ).

Drug Category: Systemic corticosteroids

Immunosuppressant and anti-inflammatory action used to reduce activity of systemic vasculitis. High-dose methylprednisolone is used to halt pulmonary hemorrhage and reverse crescentic GN. Decreases inflammation by suppression of migration of PMNs and reversal of increased capillary permeability.

Drug Category: Alkylating agents (cytotoxic agents)

Interfere with inflammatory response by decreasing bone marrow response through the interference of DNA cross-linking.

Drug Category: Immunosuppressive agents

Patients with immune dysregulation and autoimmunity often benefit from immunosuppression. Adjunctive immunosuppressants may be used in place of cyclophosphamide. Administered in addition to corticosteroids.

Drug Category: Antibiotics

Indicated to prevent infections and possibly disease relapses.

FOLLOW-UP

Section 8 of 11  

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

Further Inpatient Care

• Consider follow-up renal biopsy at time of transition off of CYP.

Further Outpatient Care

• Perform weekly CBCs for the first 1-2 months in patients on oral CYP.
• Measure CBC 10-14 days after IV CYP to assess nadir WBC and decide on next CYP IV dosage.
• Urinalysis, serum creatinine, CBC, urine protein and creatinine ratios, and erythrocyte sedimentation rates are checked monthly for the first several months.
• More time is gradually allowed between follow-up visits if the patient is stable.
• ANCA titers are screened every 3-6 months or more often if clinical relapse is apparent.

In/Out Patient Meds

• See Treatment and Medication.

Complications

• Subglottic stenosis
• Nasal deformity
• Permanent hearing loss
• Visual loss
• Chronic renal insufficiency
• Steroid adverse effects (eg, weight gain, hypertension, cataracts, avascular necrosis of the hip)
• Serious infections
• Increased risk of infertility
• Increased risk of malignancy (especially bladder cancer and lymphoma)
• Death

Prognosis

• Remission rates of 87% are reported by Rottem et al (1993). Relapses occurred in 53% of patients.
• Earlier disease recognition and more aggressive treatment regimens will hopefully improve both remission and relapse rates.
• Permanent morbidity from disease or its treatment occurs in 87% of patients. Newer regimens should improve outcome.
• Chronic renal insufficiency occurs in 35% of patients.
• Nasal deformity occurs in 48% of patients, and fixed subglottic stenosis occurs in 35% of patients.
• Of children with WG, 2 of 23 died 2.2 and 15 years after disease onset.

Patient Education

• Educate patients to contact their physicians for symptoms of sinusitis, cough, fever, swelling, or gross hematuria. These could be symptoms of either a disease relapse or an infection in an immunocompromised host.
• For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.

MISCELLANEOUS

Section 9 of 11  

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

Medical/Legal Pitfalls

• Failure to make a diagnosis

Special Concerns

• Females of childbearing age are discouraged from engaging in sexual activity. Many are placed on oral contraceptives with close monitoring of their blood pressure.

MULTIMEDIA

Section 10 of 11  

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

Media file 1:  Wegener granulomatosis. Shown is a chest radiograph of an 11-year-old girl who presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with pallor, hemoptysis, and hypertension. Her bilateral fluffy infiltrates are suggestive of a pulmonary hemorrhage. Indeed, she had an antineutrophil cytoplasmic autoantibodies (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis (GN) associated with her pulmonary hemorrhage. Supportive therapy consisted of mechanical ventilation and hemodialysis along with immunosuppressive therapy. Her anti–glomerular basement membrane antibody test result was negative. She is now nearly 2 years from this episode, and she has a serum creatinine of 0.7 mg/dL and no residual pulmonary disease.
	View Full Size Image
Media type:  X-RAY

Media file 2:  Wegener granulomatosis. An 11-year-old girl presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with pallor, hemoptysis, and hypertension. She had an antineutrophil cytoplasmic autoantibodies (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis (GN) associated with her pulmonary hemorrhage (see Image 1). A follow-up chest radiograph obtained several days later shows a complete resolution of her pulmonary infiltrates. This rapid resolution is more consistent with hemorrhage than with pneumonia.
	View Full Size Image
Media type:  X-RAY

Media file 3:  Wegener granulomatosis. A renal biopsy specimen from a 13-year-old girl with antineutrophil cytoplasmic antibody (cANCA)–positive pulmonary renal syndrome. Seven weeks after presenting with sinusitis, she presented with an acute abdomen, pulmonary hemorrhage, and acute renal failure (creatinine 4.9 mg/dL). This biopsy specimen shows a necrotizing and crescentic glomerulonephritis (Silver stain).
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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

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• Kist-van Holthe JE, Ho PL, Stablein D, et al. Outcome of renal transplantation for Wilms' tumor and Denys-Drash syndrome: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant. Jun 2005;9(3):305-10. [Medline].
• Lamprecht P, Voswinkel J, Lilienthal T, et al. Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener''s granulomatosis. Rheumatology (Oxford). Nov 2002;41(11):1303-7. [Medline].
• Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. Nov 1994;87(11):671-8. [Medline].
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• Rottem M, Fauci AS, Hallahan CW. Wegener granulomatosis in children and adolescents: clinical presentation and outcome. J Pediatr. Jan 1993;122(1):26-31. [Medline].
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• Stegeman CA, Cohen Tervaert JW, de Jong PE. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener''s granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med. Jul 4 1996;335(1):16-20. [Medline].
• Taketomo CK, Hodding JH, Kraus DM. Pediatric Dosage Handbook, 4th ed. Hudson, Ohio:. Lexi-comp Inc;1997.
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Article Last Updated: May 16, 2006