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 rare multisystem disease characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tracts and kidneys and by necrotizing vasculitis affecting small- and medium-sized vessels. In 1931, Klinger first classified WG as a variant of polyarteritis nodosa (see Polyarteritis Nodosa). In 1936, Wegener described the disease as a distinct entity with specific clinical and histopathologic criteria.

Pathophysiology

The etiology of WG remains unknown. Current research has focused on the relevant mechanisms of inflammation, particularly the effect of inflammatory mediators and immune effector cells on the endothelium. Evidence suggests that WG is an autoimmune inflammatory process, with antineutrophil cytoplasmic antibodies (c-ANCA) directed at neutrophil proteinase 3 (PR3) involved in the pathophysiology of the disease. Neutrophils and endothelial cells are involved in early lesions as both targets and promotors of inflammation. c-ANCA may be responsible for events that lead to the activation of neutrophils, which, in turn, selectively target the endothelium.¹ Endothelial cell damage and activation of neutrophils produce inflammatory mediators, leading to recruitment of monocytes and T cells and increased endothelial damage.

Frequency

United States

WG is a rare disease with an as yet undetermined incidence. The prevalence of WG in the United States of America is estimated to be 3 cases per 100,000 people.²

International

The incidence in the United Kingdom is estimated at 8.5 cases per million persons per year.

Mortality/Morbidity

• The most common causes of death for persons with WG include renal and respiratory failure, infection, malignancy, and, less often, heart failure and myocardial infarction.³ The 1-year survival rate in persons with untreated disease is estimated at 18%.
• Most morbidity is currently treatment related.

Race

WG is mostly reported in whites; it rarely occurs in blacks. Black race may be a predictor of treatment resistance in ANCA-positive vasculitides.

Sex

The male-to-female ratio is reportedly 1:1-2:1. A study of 244 patients found a higher male-to-female ratio (2.12:1) for disease affecting the kidneys and at least one other organ system. Females may be more treatment resistant.

Age

Onset may occur at any age; patients typically present at age 35-55 years. Less than 15% of cases occur in children.³

CLINICAL

Section 3 of 12  

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

History

Necrotizing granulomas may be found in any organ system. The upper respiratory tract (especially the nose and sinuses) is the most commonly affected site. The typical presentation includes upper airway symptoms, such as sinusitis or nasal discharge. The lungs are affected in 85% of patients. Disease severity is usually related to renal involvement, which occurs in 75% of patients.

Cutaneous manifestations occur in 35-50% of patients, and they may be the presenting sign of disease in 13% of patients. Patients exhibiting cutaneous manifestations more commonly have renal and articular disease. Ulcers and vesicles are associated with more severe and extensive disease.

• Patients may report the following chronic, nonspecific constitutional symptoms: 
• • Fever
  • General malaise
  • Fatigue
  • Arthralgias
  • Weight loss
• The classic upper respiratory tract manifestations are chronic sinus symptoms that fail to respond to treatment for sinusitis.
• Chronic otitis, hearing loss, nonhealing ulcerations in the nasal and oral mucosa, and nonspecific ocular disturbances are other symptoms.
• Various cutaneous eruptions or ulcerations may be the only presenting symptoms.
• Cough hemoptysis, dyspnea, and chest pain may accompany pulmonary disease.
• Renal disease may manifest as oliguria and hematuria.

Physical

Physical findings are described below.

• General: Patients may be febrile and appear ill.
• Neurologic: Patients may have mononeuritis multiplex, neuropathy, stroke, seizure, cerebritis, or meningitis.²
• Head, ears, eyes, nose, and throat  
• • Ocular findings include conjunctivitis, keratitis, and scleritis.
  • Proptosis may signal retrobulbar granuloma.
  • Xanthelasma has been reported.
  • Nearly 75% of patients present with ear, nose, and throat findings.
  • Subglottic stenosis and tracheal stenosis may prove fatal if not treated.²
  • Sinusitis and disease in the nasal mucosa are the most common findings.
  • Purulent or sanguinous nasal discharge may be seen.
  • Otitis media may be present; deformation or destruction of the pinnae or nose (saddle nose) is rare.
  • Oral involvement is rare; however, a classic presentation includes "strawberry gingival hyperplasia."²
• Integument  
• • Cutaneous findings are variable and usually nonspecific.
  • Palpable purpura, papules, subcutaneous nodules, and ulcerations are the most common findings.
  • Ulcerations may resemble pyoderma gangrenosum (see Pyoderma Gangrenosum).
  • Petechiae, vesicles, pustules, hemorrhagic bullae, livedo reticularis, digital necrosis, subungual splinter hemorrhages, and genital ulcers resembling squamous cell carcinoma have been reported.
  • The lower extremities are most commonly affected.

The Medscape CME course Examining the Ears, Nose, and Oral Cavity in the Older Patient may be of interest.

Causes

The etiology is unknown. Studies suggest that c-ANCA may be directly related to the pathogenesis. Other studies favor a delayed-type hypersensitivity reaction to unknown antigens.

• Despite little evidence of an infectious etiology, WG has been successfully treated with trimethoprim and sulfamethoxazole.
• In some studies, relapse rates have been associated with chronic nasal carriage of Staphylococcus aureus.⁴
• Large studies have failed to show a genetic predisposition for the disease.

DIFFERENTIALS

Section 4 of 12  

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

Other Problems to be Considered

Polyarteritis nodosa
Microscopic polyarteritis
Cryoglobulinemic vasculitis
Lethal midline granuloma
Lymphomatoid granulomatosis

WORKUP

Section 5 of 12  

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

Lab Studies

• Antineutrophil cytoplasmic autoantibodies: c-ANCA with PR3 specificity is most specific for WG. c-ANCA is found in 80-95% of active cases. Titers may be used to monitor disease activity. As many as 25% of active cases of WG express perinuclear antibodies (p-ANCA) specific to myeloperoxidase.⁵
• Immunofluorescence and enzyme-linked immunosorbent assay: The sensitivity and specificity exceed 90% and 98%, respectively, when immunofluorescence and enzyme-linked immunosorbent assay testing are combined.²
• CBC count with differential: Mild anemia and leukocytosis are common. Eosinophilia is more common in persons with Churg-Strauss syndrome than in those with WG (see Churg-Strauss Syndrome (Allergic Granulomatosis).
• Erythrocyte sedimentation rate:  It is elevated but may decrease with response to treatment.
• Urinalysis: RBCs, casts, and albumin may be found with renal involvement.
• Rheumatoid factor: levels may be slightly elevated.
• Electrolytes: Elevated BUN and creatinine levels may signify renal involvement. Calculated creatinine clearance  may be elevated.

Imaging Studies

• Radiography findings are often varied and nonspecific
• • Chest radiography: Pulmonary infiltrates and granulomas are seen with lower respiratory tract involvement.
  • Sinus radiography: Bony destruction, thickening, and sclerosing osteitis of the nasal cavity, mastoid air cells, and maxillary sinuses is reported.²

Procedures

• Skin biopsy: The histopathologic findings are usually nonspecific; however, findings highly suggestive of WG may be present. Deep punch or incisional biopsy specimens may better demonstrate granulomas and affected vessels.
• Biopsy: Lung and renal biopsy findings have more diagnostic significance than findings from cutaneous biopsy.

Histologic Findings

Histopathologic findings may be as variable as cutaneous manifestations. Necrotizing vasculitis, granulomatous vasculitis, extravascular palisading granulomas, and leukocytoclastic vasculitis are reported most commonly, although more than half of all skin biopsy specimens return nonspecific findings. Necrotizing vasculitis is usually correlated with petechiae, purpura, and ecchymoses (especially on the lower extremities). Palisading granulomas are most commonly observed with indurated nodules on the upper extremities. Granulomatous vasculitis is associated with erythematous papules, nodules, and ulcerations.

TREATMENT

Section 6 of 12  

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

Medical Care

• Aggressive medical therapy is usually necessary to control pulmonary and renal involvement.
• Immunosuppressive therapy with cyclophosphamide (CYC) at 2 mg/kg/d up to 200 mg/d and corticosteroids at 0.5-1 mg/kg/d up to 80 mg/d is the treatment of choice for remission induction.
• Glucocorticoids are tapered after 1 month of therapy and discontinued within 6-9 months. CYC is discontinued one full year after remission.³
• After 3-6 months beyond induction of remission, azathioprine, methotrexate (MTX), and leflunomide may be useful as adjuncts for transition to remission-maintenance therapy.⁶
• Local disease may be controlled with glucocorticoids.
• Trimethoprim and sulfamethoxazole (Bactrim) and potassium iodide (SSKI) have been reported to be useful in a small number of patients.
• Infliximab may be used at dosages of 3-5 mg/kg for adjunctive treatment of WG, with infusions every 4 weeks following induction. Anecdotal evidence indicates a dose-response phenomenon, with higher doses leading to more remissions.
• Remission with rituximab therapy has been shown in a small number of patients with disease refractory to other medications.⁷
• Predictors of treatment resistance include female sex, black race, and presentation with severe renal disease.
• Predictors of relapse following remission include anti-PR3 seropositivity, upper respiratory tract involvement, and lung involvement.
• In the results of a small study, minimally invasive procedures such as intralesional steroid injections had a more favorable outcome than invasive surgery when treating tracheobronchial WG in specific cases.⁸

The Medscape CME course Risks of Immunosuppressive Therapies Including Biologic Agents in Patients With Rheumatic Diseases and Co-Existing Chronic Viral Infections may be of interest.

Surgical Care

• Some patients may require myringotomy for chronic otitis media.
• Airway obstruction due to severe subglottic stenosis may necessitate tracheostomy.
• Renal transplantation may be considered in patients with controlled disease. Glomerulonephritis usually does not affect the transplanted kidney.

Consultations

• Internal medicine specialists best coordinate patient care.
• Consult a pulmonologist and a nephrologist to help manage and evaluate the extent of respiratory and renal disease, respectively.
• Consult with an ear, nose, and throat (ENT) specialist to help diagnose and manage upper respiratory tract disease.
• Other consultations may be necessary, depending on the affected systems and extent of disease.

MEDICATION

Section 7 of 12  

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

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Antineoplastics

CYC is the treatment of choice. Therapy is usually continued for 6-12 months following remission. Many authorities continue immunosuppressive therapy past 12 months because of the high rate of relapse. Corticosteroids (eg, prednisone, prednisolone) are usually combined with CYC at the beginning of treatment, but they are tapered over 3-6 months. MTX may be used as an alternative to CYC in the initial treatment of early disease; however, CYC is superior for remission induction in cases of pulmonary or extensive involvement. Trimethoprim and sulfamethoxazole and potassium iodide have been less frequently reported to be effective in treating WG.

Drug Category: Corticosteroids

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

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in this clinical setting.

Drug Category: Antithyroids

Most commonly used therapy for this condition is oral potassium iodide.

Drug Category: Biologics/TNF-alpha inhibitors

TNF-alpha may play a role in ANCA-associated activation of neutrophils and monocytes and/or in neutrophil adherence to endothelial cells. Of note, results of the Wegener's Granulomatosis Etanercept Trial (WGET)⁹ have shown no effectiveness of etanercept (Enbrel) in the maintenance of disease remission. A high rate of complications was noted in the etanercept group, including a higher rate of solid cancer development.

FOLLOW-UP

Section 8 of 12  

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

Further Outpatient Care

• Patients should have regularly scheduled follow-up visits with the physician primarily responsible for managing the patient's disease. Visits should focus on disease involvement of pertinent organ systems and untoward effects of therapeutic agents.

In/Out Patient Meds

• See Medication.

Deterrence/Prevention

• No known deterrent measures exist to prevent development of this disease.

Complications

• The extent of renal disease is related to most of the complications.
• Respiratory problems may arise because of upper airway obstruction or pulmonary involvement.
• Vision and hearing loss have been reported.
• Other complications may be encountered secondary to immunosuppressive therapy.

Prognosis

• Untreated disease is associated with a high mortality rate.
• With aggressive medical therapy, 90% of patients improve and 75% of patients achieve remission.
• Relapses occur in 50% of patients.

Patient Education

• Patients must be educated with regard to the serious nature of their disease. Potential risks and adverse effects of immunosuppressive medications should be detailed.
• Caregivers must instruct patients to watch for worsening respiratory status, fever or chills, epistaxis, nasal congestion, mucosal or cutaneous ulcerations, and unexplained or nonresolving cutaneous eruptions.

MISCELLANEOUS

Section 9 of 12  

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

Medical/Legal Pitfalls

• Failure to properly diagnose WG, which is especially difficult at disease onset or with an incomplete constellation of classic features, is a pitfall.

ACKNOWLEDGMENTS

Section 10 of 12  

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

The authors and editors of eMedicine gratefully acknowledge the contributions of previous Chief Editor, William James, MD, to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

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

Media file 1:  Large ulceration of the pharynx covered with a dense necrotic membrane.
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Media file 2:  Necrotic, purpuric, and blistering plaque on the wrist.
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Media file 3:  Several necrotic, purpuric, and blistering papules and plaques on the hands.
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REFERENCES

Section 12 of 12

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

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Article Last Updated: Jun 5, 2008