Wegener’s Granulomatosis Kristine Scruggs AM Report 14 September 2009

Presentation Upper Airway (95%) Persistent rhinorhea Purulent/bloody nasal discharge Oral and/or nasal ulcers Sinus pain Other: Hoarseness, stridor, earache, conductive and/or sensorineural hearing loss, otorrhea Lower Airway (85-90%) Cough Dyspnea Hemoptysis Pleuritic pain Pulmonary consolidation and/or Pleural effusion Renal (77%) Glomerulonephritis Proteinuria Hematuria, RBC casts Eyes (52%) Conjunctivitis Dacryocystitis Episcleritis/scleritis Granulomatous sclerouveitis Ciliary vessel vasculitis Retroorbital mass lesions -> Proptosis Skin (46%) Papules, vesicles, palpable purpura, ulcers, or subcutaneous nodules CNS (23%) Cranial neuritis, mononeuritis multiplex, cerebral vasculitis and/or granuloma Cardiac (8%) Pericarditis, coronary vasculitis, cardiomyopathy Other (common) Malaise, weakness, arthralgias, anorexia, weight loss, fever.

Epidemiology 3/100,000 patients Much more common in Caucasians M:F = 1:1 Mean age of onset ~40 yrs Occurs at any age 15% at <19 yrs, but rare before adolescence

Diagnosis Clinical Criteria: Nasal or oral inflammation Abnormal CXR showing nodules, fixed infiltrates, or cavities Abnormal urinary sediment (microscopic hematuria +/- RBC casts) Granulomatous inflammation on biopsy of an artery or perivascular area 2+ yields sens. of 88%, spec. of 92% Laboratory Evaluation: Leukocytosis Thrombocytosis (>400,000/mm3) Elevated ESR, CRP Normochromic, normocytic anemia

Diagnosis, cont. Biopsy Taken from site of active disease Leukocytoclastic, necrotizing vasculitis with little or no complement and IgG on immunoflorescence Granulomatous inflammation differentiates from MPA Kidney: segmental necrotizing GN, pauci- immune on immunofluorescence or EM ANCA Indirect immunofluorescence assay: c-ANCA or p-ANCA 90-95% sensitive ELISA: PR3 or MPO

Differential Diagnosis Medium Vessel Polyarteritis nodosa Renal infarcts, renal vasculitis, visceral microaneurysms ANCA - Kawasaki’s disease Coronary artery involvement Mucocutaneous lesions, LAD Large Vessel Giant cell (temporal) arteritis Takayasu’s arteritis Small Vessel Churg-Strauss syndrome Asthma, eosinophilia ANCA + Microscopic polyangiitis ANCA + Pulm-Renal syndrome No granulomatous disease Henoch-Schonlein purpura Dermal-Renal syndrome Cryoglobulinemic vasculitis Cutaneous leukocytoclastic angiitis Behcet’s disease Goodpasture’s syndrome Pulm-Renal syndrome Anti-GBM

Jennette, et al. NEJM. November 1997.

+ + +

80 90

Pulmonary Hemorrhagic Alveolar Capillaritis Neutrophils in the alveolar septa and hemorrhage into the alveolar spaces Jennette, et al. NEJM. November

Treatment Recommendations Induction of Remission Daily oral cyclophosphamide + glucocorticoids (most aggressive Rx) Monthly cyclophosphamide + glucocorticoids Low-dose weekly oral MTX + glucocorticoids (mild disease) No role for PLEX unless DAH present Maintenance of Remission (12-18 mos) Weekly oral MTX Daily oral Azathioprine Cyclophosphamide not advised 2/2 toxicity Glucocorticoids should be quickly tapered off Treatment of Relapse - Reinduction

Prognosis Morbidities of disease: Renal insufficiency Hearing loss Tracheal stenosis Saddle nose deformity Chronic sinus dysfunction Morbidities of treatment: Glucocorticoids – DM, infection, cataracts, osteoporosis, cushingoid features Cyclophosphamide – Cystitis (30%), bladder cancer (6%), myelodysplasia (2%), permanent infertility Disease was universally fatal prior to established treatment regimens With above therapies, improvement seen in >90%, CR in 75% Relapse seen in 50% of CR Reinduction almost always successful

References Jennette JC, Falk RJ. Small-Vessel Vasculitis. N Engl J Med Nov 20; 337 (21): Kasper, et al. Harrison’s Principles of Internal Medicine, 16 th Ed. King, et al. Up To Date. Clinical manifestations and diagnosis of Wegener's granulomatosis and microscopic polyangiitis Apr 21. Stone JH, et al. Initial and maintenance therapy of Wegener's granulomatosis and microscopic polyangiitis. Up To Date Jun 19.