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Wegener’s Granulomatosis Kelly Mitchell July 5, 2006 Morning Report History of Wegener’s In 1931, two patients died from prolonged sepsis with inflammation of blood vessels scattered throughout the body. In 1936, Wegener first described a distinct syndrome in three patients found to have necrotizing granulomas involving the upper and lower respiratory tract. In 1954, seven more patients described, resulting in definate criteria The Controversy Wegener’s vs PR3-ANCA vasculitis Lancet, 22 April 2006 Suggestion that using Wegener’s name “needs balanced discussion within the scientific community” Reiter's syndrome- reactive arthritis The Problem with Changing Multiple ANCA+ diseases: microscopic polyangiitis (MPA) "renal-limited" vasculitis (pauci-immune glomerulonephritis without evidence of extrarenal disease) Churg-Strauss syndrome (CSS) Drug-induced vasculitis Goodpasture’s Rheumatic disorders Autoimmune GI disorders CF Diagnostic Criteria primarily clinical Criteria for Classification Nasal or oral inflammation Abnormal chest radiograph Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities Abnormal Urinary sediment Development of painful or painless oral ulcers or purulent or bloody nasal discharge Microhematuria (>5 red blood cells per high power field) or red cell casts in urine sediment Granulomatous inflammation on biopsy Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole) * For purposes of classification, a patient shall be said to have Wegener's granulomatosis if at least 2 of these 4 criteria are present. The presence of any 2 or more criteria yields a sensitivity of 88.2% and a specificity of 92.0% Classic Symptoms Upper respiratory tract sinuses Nose ears trachea Lungs Kidneys Eye Scleritis Uveitis Orbital pseudotumor /proptosis Upper Respiratory Tract Ear Ear infections that are slow to resolve. Recurrent otitis media. Decrease in hearing. Upper Respiratory Tract Nose Nasal crusting Frequent nosebleeds Erosion and perforation of the nasal septum. The bridge of the nose can collapse resulting in a “saddle–nose deformity”. Upper Respiratory Tract Sinuses/Trachea Sinuses Chronic sinus inflammation Trachea subglottic stenosis Lungs Nodules (which may cavitate) Alveolar opacities Pleural opacities Diffuse hazy opacities (which may reflect alveolar hemorrhage) Kidney Glomerulonephritis w/ associated hematuria and proteinuria Can lead to renal failure if not treated aggressively Renal masses (rare) Active urine sediment: red blood cell casts RBC casts Skin “palpable purpura” most common Raynaud’s phenomenon—due to inadequate blood flow to fingers and toes Ulcers Miscellaneous Joints Arthritis can occur, with joint swelling and pain Nerves Peripheral nerve involvement leads to numbness, tingling, shooting pains in the extremities, and sometimes to weakness in a foot, hand, arm, or leg Meninges Prostate gland Genito–urinary tract Constitutional symptoms of fatigue, low–grade fever, and weight loss Incidence of symptoms Symptom At Onset ENT 75% Lung 50 Joints 30 Fever 25 Kidney 20 Cough 20 Eye 15 Skin 15 Weight Loss 10 Nervous System (Central/Peripheral) 0 Total 95% 85 70 50 75 50 50 45 35 10/15 One-third of patients may be without symptoms at onset of disease Pathogenesis Risk factors and inciting events Exact events obscure Infectious—staph? Genetic single nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) AAT deficiency Environmental—inhalational? Silica lead mercury Pathogenesis ANCA ANCAs may be not only markers for Wegener's granulomatosis and related disorders, but they may also be actors in pathogenesis Neutrophils exposed to cytokines such as TNF, express PR3 & MPO (the targets for ANCAs) Adding ANCAs to these cytokine-primed neutrophils causes them to generate oxygen radicals and release enzymes capable of damaging blood vessels. Pathogenesis “Priming” of Neutrophils Exposing PR3 and MPO epitopes ANCA binding Degranulation/ROS production/neutrophilendothelial cell interaction Increased ANCA = Increased degranulation rate Diagnosis Criteria for Classification Nasal or oral inflammation Abnormal chest radiograph Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities Abnormal urinary sediment Development of painful or painless oral ulcers or purulent or bloody nasal discharge Microhematuria (>5 red blood cells per high power field) or red cell casts in urine sediment Granulomatous inflammation on biopsy Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole) Diagnosis Biopsy specimens showing the triad of vasculitis, granulomata, and large areas of necrosis Sinuses Nose Skin--leukocytoclastic vasculitis with little or no complement and immunoglobulin on immunofluorescence Kidney--segmental necrotizing glomerulonephritis that is usually pauciimmune on immunofluorescence / EM Lung--vasculitis and granulomatous inflammation (Only large sections of lung tissue obtained via thoracoscopic or open lung biopsy are likely to show all of the histologic features) Seropositivity for C-ANCAs Antineutrophil cytoplasmic antibodies ANCA ~90% of Wegener's cases are ANCA+ In limited dz, up to 40% may be ANCA neg 80 - 90 % PR3-ANCA Remaining MPO-ANCA Is ANCA sufficient? Concensus is that tissue dx is necessary Rarely may initiate tx w/o biopsy Should attempt to confirm w/ biopsy when able Treatment Traditional Prednisone (initiated at 1 mg/kg daily for 1 to 2 months. then tapered) Cyclophosphamide (2mg/kg daily for at least 12 months) >90% improve and 75% remit Treatment However, 50% in remission relapse AND daily cyclophos is very toxic pancytopenia, infection, hemorrhagic cystitis bladder cancer (increased 33-fold) lymphoma (increased 11-fold) Treatment Monthly IV cyclophosphamide -- less toxic but less effective Weekly methotrexate -- maintains remission Trimethoprim-sulfamethoxazole -- controversial (?effective for disease limited to the respiratory tract), reduces the relapse rate Steroids —prednisone vs solumedrol Plasmapheresis -unproven, awaiting MEPEX trial Recommended for anti-GBM+, pulm hemmorhage, renal failure IVIG— recommended in the setting of infection during PLEX Vasculidities Large vessel vasculitis Medium sized vessel vasculitis Takayasu arteritis Giant cell arteritis Polyarteritis nodosa Isolated central nervous system vasculitis Small vessel vasculitis Churg-Strauss arteritis Wegener's granulomatosis Microscopic polyarteritis Henoch-Schönlein purpura Essential cryoglobulinemic vasculitis Hypersensitivity vasculitis Vasculitis secondary to connective tissue disorders -- SLE, rheumatoid arthritis, relapsing polychondritis, Behcet's disease Vasculitis secondary to viral infection —hepatitis B and C, HIV, CMV, EBV, Parvo B19 What, then, is the role of ANCA? Is a positive test result a "true-positive"? Does a negative ANCA assay exclude an "ANCAassociated" vasculitis? Is the presence of a positive ANCA assay in and of itself sufficient to establish the diagnosis (ie, does it preclude the need for biopsy?) Does an increase in ANCA titer predict a disease flare? Does a persistently negative ANCA ensure disease quiescence?