This issue of eMedRef provides information to clinicians on the pathophysiology, diagnosis, and therapeutics of Wegener's granulomatosis

Grine, Kristen

Jansen, Matthew

University of Missouri: MOspace

Wegener’s Granulomatosis Page 1 of 5    4.27.09 Wegener's Granulomatosis Background  1. Form of systemic vasculitis with "classic" and "limited" forms  2. Classic Wegener's involves a triad of upper respiratory disease, lower respiratory disease and glomerulonephritis1-6  o Upper respiratory disease:   Sinusitis, nasal obstruction, otitis media, mastoiditis o Lower respiratory disease:   Cough, dyspnea, hemoptysis o Glomerulonephritis (GN):   Asymptomatic, acute renal failure 3. Limited form - isolated upper or lower respiratory disease  o Occurs in approx 25% of cases o Up to 80% will eventually develop GN  Pathophysiology  1. Type III immune complex mediated hypersensitivity  o Results in necrotizing vasculitis of small and medium arteries 2. Prevalence - 3 per 100,0002  3. Risk factors: males, >50% Caucasian, age 50-60 years6  4. Morbidity:1-7  o Musculoskeletal:   Myalgias  Arthralgias  Arthritis o Venous thromboembolism common (7 per 100 person-years) o Respiratory:   Alveolar hemorrhage o Dermatologic:   Vesicular and hemorrhagic lesions  Palpable purpura o Renal:   Renal failure  Rapidly progressive glomerulonephritis o Cardiac:   Dilated cardiomyopathy  Pericarditis  Conduction abnormalities o Neurologic:   Mononeuritis multiplex  CNS lesions  Ocular abnormalities (scleritis, corneal ulcer, uveitis, optic neuropathy) o GI, GU and reproductive manifestations less common 5. Mortality:  o If untreated:   90% mortality rate at 2 years o Treated with cyclophosphamide:   Mortality rate 20-28% at 5 years and 35% at 10 years Wegener’s Granulomatosis Page 2 of 5    4.27.09 o Other therapies may have better prognosis o Chronic renal failure most common cause of death8   Diagnostics  1. History2,6  o Nonspecific complaints:   Night sweats, anorexia, arthralgias, wt loss common, fever (90%) o Pulmonary involvement (100%)   May be asymptomatic in 1/3 in limited form o Upper or lower airway dz   Hemoptysis, sinusitis, chronic nasal discharge, dyspnea o Acute or chronic renal failure 2. Physical exam2,6,7  o Skin:   Vasculitic lesions, rash, palpable purpura, subcutaneous nodules o HEENT:   Mucosal ulcerations, exophthalmos, saddle nose deformity, hearing loss, otitis, neuritis, hyperplastic gingivitis o Lung:   Pneumonitis and pleural effusion o Tumor-like masses in lung, breast and kidney 3. Diagnostic testing2,3,6  o Laboratory evaluation o Anti-neutrophil cytoplasmic antibodies (ANCA): (SOR:B)   Indirect immunofluorescence: c-ANCA or p-ANCA patterns  Enzyme-linked immunosorbent assay (ELISA) of PR3-ANCA and MPO-ANCA antibodies  Up to 90% ANCA positive with active generalized disease   Only 60-70% sensitive with limited form o Microscopic hematuria o Tissue biopsy at site of active disease used to confirm diagnosis2  o Skin lesions preferred due to less invasive procedure 4. Diagnostic imaging  o Chest x-ray   May show cavitary nodules, alveolar or pleural opacities o Chest CT   May show wedge shaped densities, narrowing of bronchial lumen, enlarged peripheral pulmonary arteries, hemorrhage or infiltrates o Angiography   May show aneurysmal dilation o Echocardiography   May show systolic dysfunction or pericardial effusion 5. Diagnostic "Criteria"9  o Nasal or oral inflammation   Painful or painless ulcers or purulent or bloody nasal discharge o Abnormal CXR showing nodules, fixed infiltrate or cavities o Urinary sediment   Microscopic hematuria >5 RBCs/hpf with or without RBC casts o Granulomatous inflammation on biopsy of artery or perivascular area Wegener’s Granulomatosis Page 3 of 5    4.27.09 o 88.2% sensitivity and 92% specificity 6. Other testing:  o CBC   Leukocytosis, thrombocytosis, normochromic normocytic anemia o ESR (marked elevation) o Serum creatinine (marked elevation) o UA (red cells, red cell casts, proteinuria) o RF (negative) o ANA (negative) o Hepatitis serology (negative)2 7. Treatment may be predicated on positive ANCA results  o Seek histopathologic confirmation before beginning long term treatment  Differential Diagnosis  1. Key DDx  o Polyarteritis Nodosa (PAN)   Auto-antibodies rarely present  Non-granulomatous o Anti-GBM antibody (Goodpasture's) dz   Positive anti-GBM antibody  Negative ANCA serology  Limited to pulmonary and renal involvement o Churg-Strauss Syndrome   Typically c-ANCA negative o Systemic lupus erythematosus   Negative ANCA serology 2. Extensive DDx  o Sjögren's syndrome   ANCA negative  Lacrimal and salivary gland involvement o Microscopic polyangiitis   Typically c-ANCA negative o Renal limited vasculitis   Negative ANCA serology  No systemic manifestations  o Drug-induced ANCA associated vasculitis   Propylthiouracil, hydralazine, minocycline o Inflammatory myopathies   Primarily muscle and skin involvement  No renal and pulmonary Sx o Rhinitis   Limited to nose  No renal and pulmonary Sx  Therapeutics10  1. Initial therapy  o High-dose steroids (PO or pulse IV) and cyclophosphamide (PO or pulse IV) until remission induced   Remission may take 3-6 months  Wegener’s Granulomatosis Page 4 of 5    4.27.09 o Methylprednisolone or prednisone: (SOR:B)   Pulse therapy - all patients with necrotizing/crescentic GN or severe respiratory dz   7-15 mg/kg (max 500-1000 mg/day) for 3 days  PO therapy - on day one or after pulse therapy (if pulse therapy indicated)   1 mg/kg per day for 2-4 weeks (max 80 mg/d)  Tapered to 20 mg per day by the end of 8-10 weeks  Maintain 20 mg/d x2 weeks  Then reduce dose by 2.5 mg/week until taking 10 mg/d  Then reduce dose by 1 mg/week until off o Cyclophosphamide (CYC) for 3-6 months to induce remission: (SOR:B)   PO therapy (1.5-2 mg/kg per day)  Pulse IV (0.5-1 g/sq.meter body surface area every few weeks)   PO therapy has led to fewer relapses   Drink eight 8 oz glasses of water per day – avoids cystitis  CBC every 2 weeks and UA monthly  Pneumocystis carinii prophylaxis - always o Methotrexate may be substituted for cyclophosphamide in mild disease if serum creatinine <2 mg/dL (SOR:B)  PO therapy weekly:   Start with 0.3 mg/kg, max 15 mg  Increase by 2.5 mg each week, to max 20-25 mg/week  Combine with steroids as with CYC  2. Once proteinuria or hematuria develop - rapid progression to renal failure 3. Maintenance therapy (SOR:B)  o Cytotoxic therapy with methotrexate OR azathioprine preferred over cyclophosphamide   Usually continued 1-2 years after remission  Methotrexate:   PO weekly 0.3 mg/kg, max 15 mg  Increase by 2.5 mg each week to max 20-25 mg/week   Azathioprine:   2 mg/kg/day  Decrease to 1.5 mg/kg per day at 1 year o Glucocorticoids   May be slowly tapered after 1 month or maintained on low dose/alternate day dosing for duration of therapy o Trimethoprim/Sulfamethoxazole (SOR:C)  Mechanism of action unclear  Proven as maintenance therapy in RCTs up to 2 years out  Use only in mild cases; weigh benefits and risk   Follow-Up  1. Serial ANCA titers may predict relapse - measured every 2 months  o Predictive value of increased ANCA titer for relapse   57% for cytoplasmic/classic ANCA  71% for PR3-ANCA  100% for MPO-ANCA Wegener’s Granulomatosis Page 5 of 5    4.27.09 2. Referral to rheumatologist, pulmonologist or nephrologist – based on clinical/objective evaluation 3. Continue monitoring CBC and UA after CYC discontinued  References 1. Hoffman, GS, Kerr, GS, Leavitt, RY, et al. Wegener's granulomatosis: An analysis of 158 patients. Ann Intern Med 1992; 116:488. 2. Kasper, Dennis, Eugene Braunwald, Anthony Fauci, Stephen Hauser, and Dan Longo. Harrison's Principles of Internal Medicine. 16th Ed. New York: McGraw Hill, 2005. pp. 2001-7 3. Finkielman, JD. ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis. Am J Med 01-JUL-2007; 120(7): 643.e9-14 4. Harper, SL, Letko, E, Samson, CM, et al. Wegener's granulomatosis: The relationship between ocular and systemic disease. J Rheumatol 2001; 28:1025. 5. Fechner, FP, Faquin, WC, Pilch, BZ. Wegener's granulomatosis of the orbit: a clinicopathological study of 15 patients. Laryngoscope 2002; 112:1945. 6. Stone, JH. Limited versus severe Wegener's granulomatosis: baseline data on patients in the Wegener's granulomatosis etanercept trial. Arthritis Rheum 2003; 48:2299. 7. Daoud, MS, Gibson, LE, DeRemee, RA, et al. Cutaneous Wegener's granulomatosis: Clinical, histopathologic, and immunopathologic features of thirty patients. J Am Acad Dermatol 1994; 31:605. 8. Matteson, EL, Gold, KN, Bloch, DA, Hunder, GG. Long-term survival of patients with Wegener's granulomatosis from the American College of Rheumatology Wegener's Granulomatosis Classification Criteria Cohort. Am J Med 1996; 101:129.  9. Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum 1990;33:1101---7. 10. Regan MJ, Hellmann, DB, Stone, JH. Treatment of Wegener's granulomatosis. Rheum Dis Clin North Am 01-NOV-2001; 27(4): 863-86, viii    Authors:  Kristen Grine, MD, & Matthew Jansen, MD, Penn State Hershey Medical Center, PA  Editor:  Robert Marshall, MD, MPH, Capt MC USN, Puget Sound Family Medicine Residence, Naval Hospital, Bremerton, WA  

Wegener's granulomatosis

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