A. Characteristics

1. Necrotizing (caseating) granulomatous vasculitic disease
2. Uncommon disease with prevalence <1:10,000 persons
3. Male to Female Ratio is ~1.3 to 1
4. >95% patients are Caucasian
5. Typical onset is age 20-40 years
6. Treatment with glucocorticoids + cyclophosphamide greatly improves survival
7. Life expectancy of patients is reduced compared to general population

B. Pathophysiology

1. Immune Dysfunction
   1. Anti-neutrophil cytoplasmic autoantibodies grouped as C-ANCA and P-ANCA
   2. May be targetted at proteinase III (C-ANCA, PR3) found in macrophages and neutrophils
   3. C-(Cytoplasmic)-ANCA is present in 50-70% of Wegener's cases and targets PR3
   4. PR3 is elastinolytic neutral serine protease
   5. C-ANCA is positive in >90% of patients with active disease
   6. About ~60% with inactive Wegener's
   7. P-(Perinuclear)-ANCA found in PAN, some p-ANCA specific for myeloperoxidase
   8. P-ANCA positivity in patients with lung lesions is most likely PAN
   9. ANCA may have direct cytotoxic effects on endothelial cells and on neutrophils
2. T Cell and B Cell Dysfunction Likely
   1. Activated T cells present
   2. T cells may be required to help B lymphocytes make ANCA
   3. T cell likely required for macrophage activation and granuloma formation
   4. Unclear if gamma interferon or Th2 cytokines (not IL10) predominate
   5. T cell/endothelial activation likely through adhesion and costimulatory molecules
3. Mechanism [15]
   1. The ANCA may be directly involved in endothelial cell damage in some types of vasculitis
   2. Inciting antigen, possibly PR3, activates dendritic cells in lungs
   3. Activated dendritic cells travel from lungs to lymph nodes, activate CD4+ T helper cells
   4. IL12 produced by activated dendritic cells stimulates Th1 phenotype
   5. Proliferating activated Th1 cells return to lung where antigen persists
   6. These Th1 cells secrete IFNg and TNFa, induce macrophage igration and maturation
   7. Chronic T cell activation leads to B cell stimulation, production of ANCA
   8. ANCA bind to targets on neutrophil surfaces, and Fc region of ANCA stimulate neutrophil
   9. ANCAs induce firm adhesion (not rolling) of neutrophils to endothelial surface
   10. ANCA induce release of reactive oxygen species and proteolytic enzymes from neutrophils
   11. ANCA-activated neutrophils also secrete proinflammatory cytokines
   12. Together, these effects cause neutrophil mediated endothelial damage

C. Pathology

1. Acute necrotizing vasculitis
   1. Granulomas (with giant cells) of the upper and lower respiratory tracts
   2. Pneumonitis with bilateral nodular and cavitary infiltrates (95%)
   3. Larynx usually subglottic involvement
2. Focal necrotizing vasculitis, most prominent in the lungs and upper airways [3]
   1. Can get acute focal necrosis in oral cavities
   2. Paranasal sinuses with chronic sinusitis (90%)
   3. Larynx or trachea: subglottic stenosis
   4. Mucosal ulcerations of the nasopharynx (75%)
   5. Pulmonary hemorrhage may occur
3. Renal Disease
   1. Focal or diffuse necrotizing glomerulitis (80%)
   2. Initial stages of renal disease: proteinuria ± microscopic hematuria
   3. Focal necrotizing glomerulonephritis (GMN), may resolve or progress to crescentic GMN
4. Anti-Basement Membrane (Anti-BM) Antibodies
   1. ~10% of patients with pulmonary-renal syndrome have both ANCA and anti-BM Abs
   2. Most patients (>50%) with pulmonary-renal syndrome have only ANCA
   3. However, true Wegener's Granulomatosis in these patients is uncommon (~10%)

D. Symptoms [2,3,4]

1. Presentation
   1. Nasal, sinus, tracheal or ear abnormalities ~90%
   2. Pulmonary infiltrates or nodules ~45%
   3. Renal Abnormalities ~15%
   4. Ocular Anomalies ~10%
   5. Subglotic Stenosis - more common in persons <20 years of age
2. Overall Prevalence of Symptoms
   1. Sinusitis or mucosal ulcerations >90%
   2. Pulmonary >80%
   3. Renal >70%
   4. Ocular ~50%
3. Airway
   1. Rhinorrhea and/or Epistaxis
   2. Purulent Nasal Discharge
   3. Sinusitis
   4. Hemoptysis
   5. Septal perforation or nasal bridge collapse ("saddle nose deformity") may occur
   6. Subglottic stenosis
   7. Computerized tomographic (CT) scan may show ground glass opacities
4. Kidney
   1. Hematuria
   2. Oliguria
   3. Segmental necrotizing glomerulonephritis
5. Ear
   1. Hearing deficiency due to serous otitis media
   2. Both conductive and sensorineural hearing loss can occur
6. Bony Abnormalities: destruction of nasal septum leading to saddle nose deformity
7. Skin lesions
   1. ~25% of patients with WG have skin involvement
   2. Palpable purpura is most common, usually lower extremities
   3. Papules with necrotic center can develop (? malignant pyoderma)
   4. Malignant Pyoderma [5]
   5. Usually found on face, ears, upper
      1. Composed of abscess with granuloma
      2. May predate other findings in WG (but must have positive c-ANCA)
8. Meningitis with hydrocephalus may occur
9. Ocular Involvement (~50%)
   1. Conjunctivitis
   2. Retrobulbar orbital masses, nasolacrimal duct obstruction
   3. Episcleritis
   4. Scleritis
   5. Keratitis
   6. Iritis
   7. Retinitis
   8. Uveitis
10. Systemic Symptoms
    1. Arthralgias (may progress to frank arthritis)
    2. Fevers
    3. Malaise
    4. Weight Loss
    5. Fatigue due to anemia (of chronic disease)
11. Increased incidence of venous thromboembolism (>10% per year) [6]

E. Diagnosis

1. Laboratory Evaluation
   1. Leukocytosis common (may have >15K/µL neutrophils)
   2. Eosinophil levels may be elevated
   3. ESR elevated, often >80mm/hr in active patients
   4. Complement levels low; IgE levels normal
   5. Urinalysis: hematuria and proteinuria ± red cell casts
   6. Elevated BUN and Creatinine - may be rapidly progressive
   7. Hypercalcemia may occur (vitamin D metabolites) [7]
2. ANCA
   1. C-ANCA+ in ~90% of patients with active disease (~98% specificity)
   2. Overall C-ANCA+ in ~66% of patients (that is, positive in only 50% of inactive patients)
   3. P-ANCA+ in ~ 5% of patients with active disease
   4. Pro-PR3-ANCA is no better than mature-PR3-ANCA as a measure of Wegener's activity [8]
   5. ANCA levels cannot be used to guide immunosuppression [8]
3. Pathology of Biopsy Specimen (see above)
   1. Lung granulomas: central necrosis, with giant cells
   2. Vascular: artery wall markedly thickened, fibrotic, and infiltrated with white cells
   3. Giant cells are present throughout
   4. Must rule out mycobacterial and fungal disease with special stains and cultures
   5. Skin lesion biopsies may be most useful
4. Differential of Granulomatous Lung Lesions
   1. Mycobacterial Infection
   2. Fungal Infection
   3. Sarcoidosis
   4. Polyarteritis Nodosa (PAN) is very uncommon in the lung and usually not granulomatous
   5. Foreign Body Reaction
   6. Toxin Response - including berryliosis, silicosis, others
   7. Parasitic Infection (unusual)
5. Differential Diagnosis of Tracheal Stenosis [9]
   1. Acute / chronic tracheobronchitis - croup in children
   2. Tuberculous tracheitis
   3. Sarcoidosis
   4. Wegener's Granulomatosis
   5. Amyloidosis (primary pulmonary type)
   6. Relapsing Polychondritis - also causes saddle-nose deformity
   7. Tracheopathica osteoplastica - rare benign disease of abnormal cartilage deposisition

E. Treatment [10,15]

1. Untreated disease has very poor prognosis with >80% death within 6-12 months
2. Induction Therapy with Immunosuppressive Regimen [10]
   1. Best appears to be cyclophosphamide, 2mg/kg po initially for 1 year
   2. Cyclophosphamide should be held for white blood cell counts <2K/µL
   3. Prednisone, 1mg/kg x 6-12 months, with tapering to alternate day therapy
   4. Induces remission in ~75% of patients in 1 month
   5. Symptoms usually decrease in 1 week
   6. Overall, ~90% of patients undergo remission
   7. If improvement occurs after 1 month, taper prednisone slowly by 5mg/d on alternate days
   8. Cyclophosphamide can be discontinued when remission is achieved
   9. Initiate methotrexate as maintenance therapy at 0.3mg/kg qweek up to 15mg weekly
   10. Methotrexate should be continued for at least 2 years and then tapered if in remission
3. WG flares may be anticipated by rising or persistent c-ANCA levels [4]
4. Severe Renal Disease
   1. Cyclophosphamide 1gm IV may be given initially, then convert to oral 2mg/kg/day
   2. Methylprednisolone 0.5-1gm IV often given for 1-3 days with taper
   3. Plasma exchange leads to a higher rate of renal recovery than intravenous methylprednisolone in severe vasculitis patients [16]
   4. Plasma exchange should be added to cyclophosphamide with renal decline
   5. Pulse intravenous cyclophosphamide is not as effective as po in long term
5. Long Term Therapy [10,11]
   1. Cyclophosphamide maintained at 2mg/kg/d po until complete remission
   2. Taper cyclophosphamide by 25mg each q2-3 months until stopped or disease remits
   3. Glucocorticoids tapered as symptoms improved
   4. Consider other agents including methotrexate (preferred) or azathioprine
   5. Azathioprine is clearly effective as maintenance therapy 2mg/kg for or patients in clinical remission after 3 months of cyclophosphamide [12]
   6. Methotrexate may be preferred for long term maintenance but relapses are common and careful monitoring is required
6. Alternative Agents [11]
   1. Azathioprine - use as steroid sparing agent, if cyclophosphamide is not tolerated, and for maintenance therapy to prevent relapse [12]
   2. Mycophenolate mofetil, a B cell selective immunosuppressive, of some benefit [13]
   3. Dose of mycophenolate (CellCept®) is 1gm po bid and reduced ANCA levels [13]
   4. Etanercept, a TNFa blocker, of no benefit for maintenance therapy in WG when added to standard glucocorticoids and methotrexate [14]
   5. Major new trials in ANCA vasculitis underway in USA and Europe
7. Recurrenct WG - ANCA positivity or increase also predicted recurrence [4]
8. Outcomes [10]
   1. Excellent response to immunosuppressive therapy
   2. Complete remission ~75%, partial ~90% within one year
   3. Death ~10% of patets due to disease and/or to therapy
   4. Suggests cell mediated immune mechanism
   5. ANCA titers do not predict disease response or recurrence [8]
   6. However, in patients on low dose therapy, increased ANCA titers may herrald a flare
9. Strongly consider pneumocystis prophylaxis in all immunosuppressed patients

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14. Wegener's Granulomatosis Etanercept Trial Research Group. 2005. NEJM. 352(4):351
15. Bosch X, Guilabert A, Espinosa G, Mirapeix E. 2007. JAMA. 298(6):655
16. Jayne DR, Gaskin G, Rasmussen N, et al. 2007. J Am Soc Nephrol. 18(7):2180