Wegener Granulomatosis

BASICS

DESCRIPTION

A disease characterized by granulomatous vasculitis involving multiple organs
The characteristic triad of involvement includes the upper airway (e.g., otitis, sinusitis, nasal mucosa), lungs, and kidneys.
Other organ systems involved include the skin, joints, and nervous system (peripheral/central).
As the condition progresses untreated, upper airway erosions, necrotic pulmonary nodules, and renal failure are common.
Without treatment, mortality rate is high. With treatment, survival rate is ~75% at 5 years.
System(s) affected: upper airways (sinusitis, otitis); cardiovascular; gastrointestinal; nervous; pulmonary; renal/urologic; skin/exocrine
Synonym(s): antibodies to neutrophilic cytoplasmic antigens (ANCA)-associated vasculitis (to include patients with Wegener and microscopic polyangiitis); granulomatosis with polyangiitis (recommended to replace Wegener as diagnostic term) (1)

EPIDEMIOLOGY

Incidence

~0.4 to 1.2/100,000 persons per year and possibly increasing over the past decade
Mean age of onset is the mid-40s, but the disease has been described in all age groups.
Predominant sex: male > female (3:2)

Prevalence
3/100,000 persons

ETIOLOGY AND PATHOPHYSIOLOGY

Unknown etiology
Autoimmune phenomena and immune-complex deposition in arterial walls are implicated, and the activation of neutrophils by bacteria or other infectious agents may be important as well.
- Role of antibodies directed against neutrophils is currently being investigated.
A specific triggering infectious agent has not been identified.

Genetics
Increased presence in HLA-B8 and HLA-DR2, more recently increase in HLA-DP and genetic variants involved in alpha-1-antitrypsin and protease-3 (2)

DIAGNOSIS

HISTORY

Fever: 34%
Weight loss: 16%
Cough: 34%
Arthralgia/arthritis: 44%
Epistaxis: 11%
Hemoptysis: 18%
Rash: 13%
Chest pain, anorexia, proptosis, dyspnea, oral ulcers, hearing loss, headache: all <10%

PHYSICAL EXAM

Ocular inflammation: 16%
Otitis: 25%
Sinusitis: 67%
Rhinitis: 22%
Rash: 13%

DIFFERENTIAL DIAGNOSIS

Otitis media and sinusitis (bacterial or fungal)
Midline granuloma/upper airway malignancy
Relapsing polychondritis
Fungal/tuberculous pulmonary infections
Goodpasture syndrome
Other vasculitic syndromes (including polyarteritis nodosa, microscopic polyangiitis, lymphomatoid granulomatosis, Churg-Strauss vasculitis, and overlap vasculitis syndromes)
Any disease associated with necrotizing and crescentic glomerulonephritis, sarcoidosis

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

CBC: anemia, leukocytosis, and thrombocytosis common during active phases of disease
ESR usually markedly elevated (75%)
Rheumatoid factor present in low to moderate titers in up to 50%
Hematuria and/or cellular casts with moderate-range proteinuria
Renal failure (11%): renal insufficiency, mild to moderate at first; frequently progresses to end-stage renal disease
Upper airways: chronic otitis and sinusitis, often with evidence of erosion into bony structures " seen on radiographs or tomography
Pulmonary infiltrates (71%): Lung radiographs show nodular pulmonary densities, often with central necrosis and cavitation. Local infiltrates or more diffuse interstitial involvement is also described, as are radiographic findings of pulmonary hemorrhage.

Follow-Up Tests & Special Considerations

Antibodies to neutrophilic cytoplasmic antigens with a cytoplasmic pattern of staining (cANCAs) are detected in 60 " 90% of patients. cANCAs are highly specific (90% positive); immunoblotting techniques or ELISA may detect antibodies to PR3/MPO (anti-PR3 antibodies are more specific).
Perinuclear staining (pANCAs) is nonspecific and is seen with other vasculitic syndromes/isolated necrotizing glomerulonephritis.
CT may show mucosal and bony involvement in sinuses and better define pulmonary lesions.

Diagnostic Procedures/Other

Sinus/upper airway mucosal biopsy is often helpful, although findings are often nonspecific.
Open lung biopsy most likely to confirm granulomatous arteritis
Renal biopsy may give findings consistent with diagnosis, although it is not always definitive.
Diagnosis is best made by demonstration of granulomatous arteritis of involved organ, although a compatible renal lesion in the setting of chronic destructive sinusitis and/or pulmonary nodules may make a presumptive diagnosis.
A positive test for cANCA (or anti-PR3 antibodies) in proper clinical setting is often diagnostic.

Test Interpretation

Upper airways: Granulomatous inflammation is seen frequently, although it is 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 is seen rarely.
Skin: vasculitic lesions from leukocytoclastic vasculitis of small vessels; granulomatous arteritis is seen occasionally.

TREATMENT

Patients with significant renal involvement or serious pulmonary disease require cyclophosphamide or rituximab for optimal initial control in most cases but may be converted to methotrexate, azathioprine, mycophenolate, or other agent after several months of inactive disease.
Rituximab is an effective therapy for patients with serious active disease refractory to cyclophosphamide and may be used as initial therapy as an alternative to cyclophosphamide.
Some patients without serious renal/pulmonary involvement may respond to methotrexate as initial immunosuppressive therapy without requiring cyclophosphamide therapy.

MEDICATION

First Line

Prednisone
- Given initially in high doses (60 to 100 mg/day)
- After initial 2 to 4 weeks, may be tapered and discontinued over 2 to 6 months in most patients, depending on clinical course
- Maintaining chronic low dose (5 to 10 mg/day) may reduce the risk of relapse.
- Used in combination with induction therapy
Cyclophosphamide
- May be dosed orally or IV: IV 15 mg/kg IV every 2 to 3 weeks for 3 to 6 months, or 1.5 to 2 mg/kg PO daily (3)[A]
- Dosage may need to be adjusted based on patient response and toxicity (usually bone marrow suppression).
- Usually continued for 6 to 24 months after patient appears 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.
Rituximab 1,000 mg IV, 2 doses 2 weeks apart, or 375 mg/m2 IV, weekly for 4 weeks has been shown in prospective studies to be very useful in patients as an alternative to cyclophosphamide or in those with relapsing disease (4,5,6 and 7)[A].
Methotrexate 15 to 25 mg/week PO has been shown to be successful in maintaining remission in patients following induction with cyclophosphamide. Methotrexate may be used in place of cyclophosphamide in some patients without pulmonary/renal involvement.
Azathioprine 2 mg/kg/day may be useful in maintaining remission in patients treated with cyclophosphamide and is comparable in efficacy with methotrexate for this purpose.
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/renal insufficiency.
- Methotrexate contraindicated in patients with renal insufficiency
Significant possible interactions
- Prednisone may interfere with hypoglycemics and antihypertensives.
- Cyclophosphamide may increase risk of bone marrow toxicity.

Second Line

Azathioprine or mycophenolate: for patients with history of severe bone marrow toxicity/hemorrhagic cystitis from cyclophosphamide; may be useful in maintaining remission in patients with stable disease after remission is obtained
Rituximab 1,000 mg IV (1 to 2 doses) every 6 months may be useful in maintaining remission as alternative to above (8)[B].
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
IVIG has been reported to be useful in case reports of patients with disease relapses.
Continuation of low-dose prednisone may help reduce the rate of relapse (9)[B].

ISSUES FOR REFERRAL

Rheumatology, otolaryngology (ENT), ophthalmology, pulmonology, nephrology, and dermatology consultants are often needed initially to evaluate and/or manage ongoing organ-specific problems.

SURGERY/OTHER PROCEDURES

Surgery is indicated for diagnostic purposes only.

INPATIENT CONSIDERATIONS

Admission Criteria/Initial Stabilization

Adequate fluid balance and exclusion of alternative pathology for renal disease
Intensive pulmonary monitoring may be needed for patients with severe pulmonary involvement with hemoptysis and/or pulmonary hemorrhage.
Pulmonary hemorrhage/hemoptysis; respiratory failure; unstable renal function

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

Early, careful monitoring of upper airway, pulmonary, and renal manifestations
BP, glucose, and potassium for steroid effects
CBC with differential every 1 to 2 weeks to monitor for bone marrow toxicity from cyclophosphamide. Leukopenia is most common. Dose must be reduced if peripheral WBC count <3,000/mm3.
Urinalysis for potential of hemorrhagic cystitis from cyclophosphamide; consider cystoscopy for persistent/recurrent hematuria.
Rituximab may be associated with transient neutropenia in the first 2 to 4 months of therapy and may be associated with hypoglobulinemia and immunosuppression with long-term use.
Acute-phase reactants (erythrocyte sedimentation rate, C-reactive protein) and serum cANCA levels may be useful in monitoring disease activity during follow-up.

DIET

Vigorous nutritional support may be needed early in the illness.
Calorie and salt reduction in patients on prednisone
High fluid intake to prevent hemorrhagic cystitis from cyclophosphamide; MESNA may be considered for IV infusion.

PATIENT EDUCATION

Nutritional and drug counseling when patient is able to return home
Vasculitis Foundation (formerly the Wegener Granulomatosis Association), PO Box 28660, Kansas City, MO 64188: www.vasculitisfoundation.org and www.wegenersgranulomatosis.net

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 to 10 years.
Severe renal and pulmonary disease are the most prominent risk factors for death.
Survival has improved significantly over the past 30 to 40 years, and limitation of cyclophosphamide therapy has resulted in a decrease in treatment-related morbidity.
Relapses may occur in 40 " 50% of patients over 2 to 5 years of follow-up.
Treatment-related toxicity is significant, especially from long-term cyclophosphamide. After a 6-month to 1-year disease-free interval, cyclophosphamide is usually changed to methotrexate, azathioprine, or mycophenolate, although some patients may demonstrate disease reactivation.

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
- Deep vein thrombosis, pulmonary embolism, and other thromboembolic events are more common in patients with long-standing disease.
Drug-related
- Prednisone: weight gain, hyperglycemia, hypertension, hypokalemia, skin thinning and bruising, infection, osteoporosis
- Cyclophosphamide: bone marrow suppression (especially leukopenia, neutropenia), alopecia, hemorrhagic cystitis, mucositis, premature gonadal failure, malignancies (especially leukemias) with long-term therapy; risk of bladder cancer is 5% (10 years) and 16% (15 years)
- Rituximab: immunosuppression, hypoglobulinemia (30 " 40%) after repeated doses.

REFERENCES

11 Falk RJ, Gross WL, Guillevin L, et al. Granulomatosis with polyangiitis (Wegener 's): an alternative name for Wegener 's granulomatosis. Arthritis Rheum. 2011;63(4):863 " 864.22 Lyons PA, Rayner TF, Trivedi S, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367(3):214 " 223.33 Harper L, Morgan MD, Walsh M, et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis. 2012;71(6):955 " 960.44 Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221 " 232.55 Smith RM, Jones RB, Guerry MJ, et al. Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012;64(11):3760 " 3769.66 Specks U, Merkel PA, Seo P, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013;369(5):417 " 427.77 Miloslavsky EM, Specks U, Merkel PA, et al. Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vascultis. Arthritis Rheum. 2013;65(9):2441 " 2449.88 Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014;371(19):1771 " 1780.99 Walsh M, Merkel PA, Mahr A, et al. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis. Arthritis Care Res (Hoboken). 2010;62(8):1166 " 1173.

ADDITIONAL READING

Holle JU, Gross WL, Latza U, et al. Improved outcome in 445 patients with Wegener 's granulomatosis in a German vasculitis center over four decades. Arthritis Rheum. 2011;63(1):257 " 266.
Watts RA, Mooney J, Skinner J, et al. The contrasting epidemiology of granulomatosis with polyangiitis (Wegener 's) and microscopic polyangiitis. Rheumatology (Oxford). 2012;51(5):926 " 931.

CODES

ICD10

M31.30 Wegener 's granulomatosis without renal involvement
M31.31 Wegener 's granulomatosis with renal involvement

ICD9

446.4 Wegener 's granulomatosis

SNOMED

Wegener 's granulomatosis (disorder)
Wegener 's granulomatosis of larynx
Wegener 's granulomatosis of nose
Wegener 's granulomatosis with multisystem involvement

CLINICAL PEARLS

Biopsies of mucosal lesions, skin lesions, lung, or kidney typically are needed to confirm a diagnosis of Wegner granulomatosis, but tissue diagnosis is often difficult unless an open lung biopsy is done.
A positive cANCA (or anti-PR3 antibody) test in the setting of a patient with two of three classic areas of involvement (i.e., nephritis, pulmonary lesions, sinusitis/otitis) may be sufficient for a clinical diagnosis.
Aggressive therapy with potent immunosuppressive therapy is needed for most patients with Wegener granulomatosis. Patients with severe renal/pulmonary manifestations usually require cyclophosphamide for initial disease control.
After initial remission, most patients should be continued on methotrexate, azathioprine, or mycophenolate or intermittent rituximab as maintenance therapy to reduce the risk of relapse.
Rituximab appears to be useful for patients with relapsing disease and is often an appropriate initial therapy for many patients.
Mortality rates are falling as a result of more effective intervention but remain elevated substantially in severe disease.

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