WEGENER GRANULOMATOSIS

WEGENER GRANULOMATOSIS - Christopher M.Wise, MD
BASICS
DESCRIPTION
A disease characterized by granulomatous vasculitis involving multiple organs. The characteristic "triad" of involvement includes the upper airway (otitis, sinusitis, nasal mucosa), lungs, and kidneys. Other organ systems involved include the skin, joints, and nervous system (peripheral or central).
• As the condition progresses untreated, upper airway erosions, necrotic pulmonary nodules, and renal failure are common; without treatment, mortality rate is high.
• System(s) Affected: Upper Airways (sinusitis, otitis); Cardiovascular; Gastrointestinal; Nervous; Pulmonary; Renal/Urologic; Skin/Exocrine
ALERT
Pregnancy Considerations
• Rarely reported
• Should be considered only when patient is disease-free and off therapy
• Cyclophosphamide often causes sterility and is potentially teratogenic.
EPIDEMIOLOGY
• Predominant age: mean age of onset in mid-40s, but has been described in all age groups
• Predominant sex: Male > Female (3:2)
Incidence
Estimated at ~0.4/100,000
Prevalence
Three per 100,000
RISK FACTORS
None identified
Genetics
Increased presence in HLA-B8 and HLA-DR2
ETIOLOGY
The etiology is unknown; the autoimmune phenomena and immune complex deposition in arterial walls are implicated. Triggering infectious agents, yet unidentified, may be involved.
ASSOCIATED CONDITIONS
None


DIAGNOSIS
SIGNS AND SYMPTOMS
• Pulmonary infiltrates: 71%
• Sinusitis: 67%
• Arthralgia/arthritis: 44%
• Fever: 34%
• Cough: 34%
• Otitis: 25%
• Rhinitis: 22%
• Hemoptysis: 18%
• Ocular inflammation: 16%
• Weight loss: 16%
• Skin rash: 13%
• Epistaxis: 11%
• Renal failure: 11%
• Chest pain, anorexia, proptosis, dyspnea, oral ulcers, hearing loss, headache (all 10%)
TESTS
Lab
• Anemia, leukocytosis, and thrombocytosis common during active phases of disease
• Erythrocyte sedimentation rate usually markedly elevated (75%)
• Rheumatoid factor present in low to moderate titer in up to 50%
• Hematuria and/or cellular casts with moderate range proteinuria
• Renal insufficiency, mild to moderate at 1st, frequently progresses to end-stage renal disease.
• Antibodies to neutrophilic cytoplasmic antigens with a cytoplasmic pattern of staining (c-ANCA) are detected in 60-90% of patients. c-ANCA is highly specific (90+%); immunoblotting techniques or enzyme-linked immunoassay may detect antibodies to PR3 or MPO (anti-PR3 antibodies are more specific)
• Perinuclear staining (p-ANCA), is nonspecific and seen with other vasculitic syndromes or isolated necrotizing glomerulonephritis.
• Drugs that may alter lab results: Corticosteroids and cytotoxic drugs, used to treat the disease, may cause normalization of most abnormal laboratory findings.
• Disorders that may alter lab results: See disorders listed under "Differential Diagnosis."
Imaging
• Upper airways: Chronic otitis and sinusitis, often with evidence of erosion into bony structuresseen on plain radiographs
• CT scans of sinuses may show mucosal and bony involvement.
• Lungs: Radiographs show nodular pulmonary densities, often with central necrosis and cavitation. Local infiltrates or more diffuse interstitial involvement are also described, as are radiographic findings of pulmonary hemorrhage.
Diagnostic Procedures/Surgery
• Open lung biopsy is most likely to confirm granulomatous arteritis.
• Renal biopsy may give findings consistent with diagnosis, although findings are not always definitive.
• Sinus or upper airway mucosal biopsy is often helpful, although findings are often nonspecific.
• Diagnosis is best made by demonstration of granulomatous arteritis of involved organ, although compatible renal lesion in setting of chronic destructive sinusitis and/or pulmonary nodules may make a presumptive diagnosis.
• A positive serologic test for c-ANCA in the proper clinical setting is often diagnostic.
Pathological Findings
• Upper airways: Granulomatous inflammation frequently seen, although not specific unless showing actual vasculitis
• Lung: Granulomatous arteritis involving vessels; classically medium-sized arteries
• Kidney: Necrotizing and crescentic glomerulonephritis without immunofluorescent staining (pauci-immune) is common; granulomatous vasculitis rarely seen
• Skin: Vasculitic lesions, from leukocytoclastic vasculitis of small vessels; granulomatous arteritis seen occasionally
DIFFERENTIAL DIAGNOSIS
• Infectious otitis and sinusitis (bacterial or fungal)
• Midline granuloma or other upper airway malignancy
• Relapsing polychondritis
• Fungal or tuberculous pulmonary infections (Goodpasture syndrome)
• Other vasculitic syndromes (including polyarteritis nodosa, lymphomatoid granulomatosis, Churg-Strauss vasculitis, and overlap vasculitis syndromes)
• Any disease associated with necrotizing and crescentic glomerulonephritis, sarcoidosis
TREATMENT
STABILIZATION
• Patients are usually ill enough with fever, sinus or pulmonary involvement, or renal disease to require hospitalization for diagnostic tests (to rule out infectious causes) and appropriate biopsies.
• An occasional patient can be managed as an outpatient.
GENERAL MEASURES
• Careful attention to upper airway drainage
• Supportive measures for pulmonary, renal, or neurologic involvement
Diet
• Vigorous nutritional support may be needed early in the illness.
• Reduce calories salt in patients on prednisone.
• High fluid intake prevents hemorrhagic cystitis from cyclophosphamide.
Activity
There are no specific restrictions; fatigue, fever, and weight loss usually limit activity.
MEDICATION (DRUGS)
First Line
• Prednisone (1)[C]
- Given initially in high doses (60-100 mg/d)
- After the initial 2-4 weeks, may be tapered to alternate-day regimen then gradually discontinued over 2-6 months in most patients, depending on clinical course
• Cyclophosphamide (2,3)[A]
- In critically ill patient, may be given initially at a dose of 4 mg/kg/d IV for 2-3 days then at 2 mg/kg/d PO
- In stable patient, start at 2 mg/kg/d PO
- Dosage may need to be adjusted based on patient response and toxicity (usually bone marrow suppression)
- Usually continued for 1-2 years after patient is felt to be in remission, then tapered slowly, with careful monitoring for reactivation of disease
- Give dose in morning to decrease amount of drug present overnight in bladder
• Methotrexate 15-25 g/wk PO has been shown in a recent trial to be successful in maintaining remission in patients treated with cyclophosphamide. Methotrexate may be used in place of cyclophosphamide in some patients without pulmonary or renal involvement. (1,3)[B]
• There are no absolute contraindications, although diabetes, hypertension, and metabolic bone disease are relative contraindications to prednisone.
• Precautions
- Carefully monitor a patient taking corticosteroids.
- Consider reducing dose of cyclophosphamide with baseline leukopenia or renal insufficiency.
• Significant possible interactions
- Prednisone may interfere with hypoglycemics and antihypertensives.
- Cyclophosphamide may increase risk of other drugs with potential for bone marrow toxicity.
Second Line
• Azathioprine: For patients with history of severe bone marrow toxicity or hemorrhagic cystitis from cyclophosphamide
• Trimethoprim-sulfamethoxazole (TMP-SMX) has been used alone with success in some patients with limited (usually upper airway) disease, and has some potential as an adjunctive therapy with prednisone and cyclophosphamide.
• Methotrexate: For some patients without renal involvement; may be useful in maintaining remission in patients with stable disease, as an alternative to chronic cyclophosphamide therapy
• Rituximab has been reported to be useful in isolated cases or small series of patients.
• Etanercept does not appear to be of benefit, based on information from a recent clinical trial.
FOLLOW-UP
PROGNOSIS
• Without treatment, almost uniformly fatal, with a 10% 2-year survival; mean survival of 5 months
• With aggressive treatment, survival improved to 75-90% at 5 years.
• Treatment-related toxicity is significant, especially from long-term cyclophosphamide. After 1 year of diseasefree interval, cyclophosphamide is usually changed to methotrexate or tapered, although some patients may demonstrate disease reactivation. (4)[A]
COMPLICATIONS
• Disease related
- Destructive nasal lesions with "saddle nose" deformity
- Deafness from refractory otitis
- Necrotic pulmonary nodules with hemoptysis
- Interstitial lung disease
- Renal failure
- Foot drop from peripheral nerve disease
- Skin ulcers, digital and limb gangrene from peripheral vascular involvement
• Drug related
- Prednisone: Weight gain, hyperglycemia, hypertension, hypokalemia, skin thinning and bruising, infection, osteoporosis
- Cyclophosphamide: Bone marrow suppression (especially leukopenia, neutropenia), alopecia, hemorrhagic cystitis, mucosal membrane irritation, sterility and premature gonadal failure, secondary malignancies (especially leukemias) with long-term therapy. Risk of bladder cancer is 5% (10 years) and 16% (15 years) after first treatment, and is related to previous cystitis.
PATIENT MONITORING
• Early, careful monitoring of upper airway, pulmonary, and renal manifestations
• Blood pressure, glucose, potassium for steroid effects
• Frequent (every 2-4 weeks) complete blood count with differential to monitor for bone marrow toxicity from cyclophosphamide. Leukopenia is most common. Dose needs to be reduced if peripheral white blood cell count 3000/mm3.
• Urinalysis for potential of hemorrhagic cystitis from cyclophosphamide. Consider cystoscopy for persistent or recurrent hematuria.
• Acute phase reactants (ESR, CRP) and serum c-ANCA levels may be useful in monitoring disease activity during follow-up. (5)[A]
REFERENCES
1. Specks U. Methotrexate for Wegener's granulomatosis: What is the evidence? Arthritis Rheum. 2005;52:2237-2242.
2. Goek ON, Stone ON. Randomized controlled trials in vasculitis associated with anti-neutrophil cytoplasmic antibodies. Curr Opin Rheumatol. 2005;17:257-264.
3. DeGroot K, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005;52:2461-2469.
4. Seo P, et al. Damage caused by Wegeneris granulomatosis and its treatment: Prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET). Arthritis Rheum. 2005;52:2168-2178.
5. Hogan SL, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med. 2005;143:621-631.
MISCELLANEOUS
See also: Polyarteritis Nodosa