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9a1c wg mitchell-7-5-06

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9a1c wg mitchell-7-5-06

  1. 1. Wegener’sGranulomatosis Kelly Mitchell July 5, 2006 Morning Report
  2. 2. 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
  3. 3. 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”  Reiters syndrome- reactive arthritis
  4. 4. 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
  5. 5. Criteria for Classification Nasal or oral inflammation  Development of painful or painless oral ulcers or purulent or bloody nasal discharge Abnormal chest radiograph  Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities Abnormal Urinary sediment  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 Wegeners 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%
  6. 6. Classic Symptoms Upper respiratory tract  sinuses  Nose  ears  trachea Lungs Kidneys
  7. 7. Eye Scleritis Uveitis Orbital pseudotumor /proptosis
  8. 8. Upper Respiratory Tract Ear Ear infections that are slow to resolve. Recurrent otitis media. Decrease in hearing.
  9. 9. 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”.
  10. 10. Upper Respiratory Tract Sinuses/Trachea Sinuses  Chronic sinus inflammation Trachea  subglottic stenosis
  11. 11. Lungs Nodules (which may cavitate) Alveolar opacities Pleural opacities Diffuse hazy opacities (which may reflect alveolar hemorrhage)
  12. 12. 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
  13. 13. RBC casts
  14. 14. Skin “palpable purpura” most common Raynaud’s phenomenon —due to inadequate blood flow to fingers and toes Ulcers
  15. 15. 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
  16. 16. Incidence of symptoms Symptom At Onset Total ENT 75% 95% Lung 50 85 Joints 30 70 Fever 25 50 Kidney 20 75 Cough 20 50 Eye 15 50 Skin 15 45 Weight Loss 10 35 Nervous System (Central/Peripheral) 0 10/15One-third of patients may be without symptoms at onset of disease
  17. 17. 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
  18. 18. Pathogenesis ANCA ANCAs may be not only markers for Wegeners 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.
  19. 19. Pathogenesis “Priming” of Neutrophils  Exposing PR3 and MPO epitopes ANCA binding Degranulation/ROS production/neutrophil- endothelial cell interaction Increased ANCA = Increased degranulation rate
  20. 20. Diagnosis Criteria for Classification Nasal or oral inflammation  Development of painful or painless oral ulcers or purulent or bloody nasal discharge Abnormal chest radiograph  Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities Abnormal urinary sediment  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)
  21. 21. 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 pauci- immune 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
  22. 22. Antineutrophil cytoplasmic antibodies
  23. 23. ANCA ~90% of Wegeners cases are ANCA+  In limited dz, up to 40% may be ANCA neg 80 - 90 % PR3-ANCA Remaining MPO-ANCA
  24. 24. 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
  25. 25. 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
  26. 26. 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)
  27. 27. 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
  28. 28. Vasculidities Large vessel vasculitis  Takayasu arteritis  Giant cell arteritis Medium sized vessel vasculitis  Polyarteritis nodosa  Isolated central nervous system vasculitis Small vessel vasculitis  Churg-Strauss arteritis  Wegeners granulomatosis  Microscopic polyarteritis  Henoch-Schönlein purpura  Essential cryoglobulinemic vasculitis  Hypersensitivity vasculitis  Vasculitis secondary to connective tissue disorders -- SLE, rheumatoid arthritis, relapsing polychondritis, Behcets disease  Vasculitis secondary to viral infection —hepatitis B and C, HIV, CMV, EBV, Parvo B19
  29. 29. What, then, is the role of ANCA? Is a positive test result a "true-positive"? Does a negative ANCA assay exclude an "ANCA- associated" 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?

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