BASICS

DESCRIPTION

• Wegener’s granulomatosis is a necrotizing vasculitic syndrome of small-sized blood vessels that affects multiple organs.

• Most commonly affected organs include kidney, lung, upper respiratory tract, eyes, ears, and skin.

• Dr. Friedrich Wegener first described the disease in 1936.

EPIDEMIOLOGY

Incidence

The reported annual incidence of Wegener’s granulomatosis is 10 per million population.

Prevalence

The prevalence of Wegener’s granulomatosis in the US is approximately 3 per 100,000 persons.

RISK FACTORS

• Wegener’s granulomatosis is primarily a disease of Caucasian patients and rarely affects African Americans.

• A slight male preponderance is also reported.

Genetics

Some alleles have been identified as protective factors against Wegener’s granulomatosis, although further research is being performed to identify any genetic association.

GENERAL PREVENTION

Early diagnosis is crucial to prevent end-organ damage and life-threatening complications.

PATHOPHYSIOLOGY

• The hallmark of this disease is necrotizing granulomas of small vessels.

• Evidence suggests that Wegener’s granulomatosis is an autoimmune inflammatory process, in which the cytoplasmic variants of antineutrophilic cytoplasmic antibodies (cANCAs) are directed at neutrophil proteinase 3 (PR3). Neutrophils and endothelial cells are thought to be both targets and promoters of inflammation.

ETIOLOGY

The etiology of Wegener’s granulomatosis remains unknown, although several chromosomes are being investigated for possible loci predisposing to this disease.

COMMONLY ASSOCIATED CONDITIONS

• Wegener’s granulomatosis is a multisystem disease.

• Classic features are vasculitis, glomerulonephritis, and granulomas of the upper and lower respiratory tract.

DIAGNOSIS

HISTORY

• The onset of Wegener’s granulomatosis is variable; it may be indolent or may have a rapid and severe onset.

• Approximately 80–90% of patients have symptoms of a cold, runny nose, or sinusitis that fail to respond to therapy or last longer than usual.

• Patients may report nasal membrane ulcerations and crusting, hearing problems, decline in vision, cough (with or without hemoptysis), rash and/or skin sores, fever, malaise, loss of appetite, weight loss, arthralgias, night sweats, and hematuria.

PHYSICAL EXAM

• Ophthalmic findings:

– Ocular symptoms are the first manifestation in 20% of patients. Approximately half of the patients with Wegener’s granulomatosis develop ocular involvement over the course of the disease.

– Orbital involvement has been reported in 45–70% of patients. Orbital inflammation can cause pain, diplopia, proptosis, and loss of vision.

– Common ocular findings include tearing due to nasolacrimal duct obstruction, peripheral ulcerative keratitis, scleritis, and episcleritis.

– Uveitis, retinal vasculitis, retinal artery occlusion, optic nerve vasculitis, optic neuropathy, restricted movement of extraocular muscles, yellow eyelid lesions, and conjunctival scarring may also be found.

– Proptosis in the setting of upper and lower respiratory disease is highly suggestive of Wegener’s granulomatosis.

• Systemic findings:

– Patients may be febrile and appear ill.

– Neurologic: Patients may have mononeuritis multiplex, neuropathy, stroke, seizure, cerebritis, or meningitis.

– Ears, nose, and throat: Sinusitis and nasal mucosal disease are the most common findings. Other findings include purulent or sanguinous nasal discharge, otitis media, hearing loss from auditory tube dysfunction, deformation or destruction of the nose (saddle nose), subglottic stenosis.

– Oral involvement is rare; however, “strawberry gingival hyperplasia” is classic of this disease.

– Skin: palpable purpura, papules, subcutaneous nodules, ulcerations resembling pyoderma gangrenosum, petechiae, vesicles, pustules, hemorrhagic bullae, digital necrosis, subungual splinter hemorrhages, and genital ulcers resembling squamous cell carcinoma have been reported.

– The lower extremities are most commonly affected.

– Renal: rapidly progressive glomerulonephritis owing to chronic renal failure

– Pulmonary: pulmonary nodules or infiltrates, pulmonary hemorrhage leading to hemoptysis

– Arthritis

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• cANCA blood test in the presence of signs and symptoms of Wegener’s granulomatosis is highly suggestive of this disease. ANCA is reported to be positive in only 67% of patients with Wegener’s granulomatosis.

• Anemia, mild leukocytosis, and elevated ESR are nonspecific findings.

• Urinalysis may also show hematuria, erythrocyte casts, and proteinuria in patients with glomerulonephritis.

Imaging

Initial approach

Chest radiographs may show infiltrates, nodules, masses, or cavities. The presence of hilar adenopathy alone is not compatible with the diagnosis of Wegener’s granulomatosis.

Follow-up & special considerations

• CT of the chest is more sensitive than chest radiography and can often show abnormalities in the presence of a normal radiograph.

• Sinonasal CT studies should include both soft tissue and bone algorithms. Findings include mucosal thickening, opacification, air–fluid level, bony destruction (mainly of the nasal septum), and sclerosing osteitis.

• Orbital MRI may demonstrate granulomatous infiltration of the orbit.

• MRI of the brain may show diffuse linear dural thickening, and local dural thickening contiguous with orbital, nasal, and paranasal disease. In few cases, granulomatous lesions in brain parenchyma are observed. Pituitary gland and infundibulum involvement are also reported.

Diagnostic Procedures/Other

The definitive diagnosis of Wegener’s granulomatosis is established by performing a tissue biopsy.

Pathological Findings

A classic triad of vasculitis, granuloma, and large areas of necrosis (geographic necrosis) admixed with acute and chronic inflammatory cells is diagnostic of Wegener’s granulomatosis.

DIFFERENTIAL DIAGNOSIS

• Wegener’s granulomatosis may often be confused with chronic sinusitis, atypical bacterial pneumonia, thoracic aspergillosis, and primary or metastatic lung cancer.

• Other conditions to be considered include the following:

– Microscopic polyangiitis

– Churg–Strauss syndrome

– Goodpasture’s syndrome

– Systemic lupus erythematosus

– Sarcoidosis

TREATMENT

MEDICATION

First Line

• Untreated Wegener’s granulomatosis is fatal.

• Often, the initial therapy for patients is prednisone (initiated at 1 mg/kg daily). This dose is maintained for 1–2 months and then tapered.

• Cyclophosphamide is initiated at 2 mg/kg daily and continued for at least 6–12 months. Patients can then be switched to azathioprine (2 mg/kg/day). Approximately 90% of patients improve with this treatment and 75% remit.

• 50% of the patients who remit may relapse.

• Oral daily cyclophosphamide causes serious toxicity including cytopenia, infection, and hemorrhagic cystitis. Long-term use of cyclophosphamide in patients with Wegener’s granulomatosis significantly increases the risk of cancers, especially bladder cancer and lymphoma.

• Monthly intravenous cyclophosphamide is less toxic but is also reported to be less effective.

Second Line

• Weekly methotrexate is an effective alternative for patients with non–life-threatening Wegener’s granulomatosis. This regimen is reported to be beneficial in maintaining remission.

• Trimethoprim–sulfamethoxazole is considered by some to cause reduction in the relapse rate, especially when the disease is limited to the upper respiratory tract. Furthermore, it is considered beneficial in preventing pneumonia secondary to Pneumocystis carinii.

• Azathioprine has also been used as an alternative immunosuppressant.

• Plasmapheresis has been reported to be beneficial in cases of pulmonary hemorrhage.

• Calcium supplements should be given to any patient on steroids to prevent bone loss.

• Gastrointestinal prophylaxis should also be considered in patients on steroids.

ADDITIONAL TREATMENT

General Measures

Early diagnosis and treatment are crucial to decreasing morbidity and mortality in patients with Wegener’s granulomatosis.

Issues for Referral

Patients with this disease should be referred to otolaryngologists, pulmonologists, nephrologists, and dermatologists.

IN-PATIENT CONSIDERATIONS

Initial Stabilization

• Patients with Wegener’s granulomatosis may present with acute respiratory failure, pericarditis, myocardial infarction, or acute renal failure.

• A patient with subglottic stenosis should receive a tracheotomy.

• For a patient presenting with proptosis or declining vision, orbital and sinus imaging should be done immediately.

Admission Criteria

• Patient with any life-threatening complication should be admitted for further management.

– For a patient presenting with proptosis and declining vision, an oculoplastics consult along with ENT consult should be obtained immediately for admission. Urgent surgical decompression may be necessary in case of progressive proptosis causing optic nerve damage.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Patients have to be monitored very closely in the initial stages of Wegener’s granulomatosis until the patient is in remission.

– Close monitoring of blood work and urinalysis is necessary to detect complications of immunosuppressive therapy.

Patient Monitoring

• CBC count should be performed weekly for the first 1–2 months in patients on oral cyclophosphamide.

• Urinalysis, serum creatinine, urine protein and creatinine ratios, and erythrocyte sedimentation rates should be monitored monthly for the first several months.

• cANCA titers are screened every 3–6 months. In case of clinical relapse, cANCA is checked more frequently.

DIET

Patients should be advised of salt and water retention when on glucocorticoids.

PATIENT EDUCATION

• Patients on oral cyclophosphamide should drink ample fluids and attempt to void every 4 hours to maintain high urine output and reduce the risk of hemorrhagic cystitis.

• Patients should be advised to take oral cyclophosphamide in the morning to avoid high bladder concentrations in the middle of the night when fluid intake is minimal.

• Patients should be advised to report to their doctors for any signs of cold, sinusitis, fever, or hematuria.

• Women of child-bearing age should be advised to not start a pregnancy in the presence of active disease.

PROGNOSIS

With advanced treatments and earlier diagnosis, Wegener’s granulomatosis patients have improved prognosis.

COMPLICATIONS

• Chronic renal insufficiency is reported in approximately 35% patients.

• Renal failure can lead to dialysis or kidney transplant.

• Permanent morbidity from disease or its treatment is reported in more than 80% of patients.

• Nasal deformity occurs in approximately half the patients with Wegener’s granulomatosis.

• Subglottic stenosis occurs in 35% of patients.

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