Wegener’s Granulomatosis Kelly Mitchell July 5, 2006  Morning Report
History of Wegener’s <ul><li>In 1931, two patients died from prolonged sepsis with inflammation of blood vessels scattered...
The Controversy <ul><li>Wegener’s vs PR3-ANCA vasculitis </li></ul><ul><ul><li>Lancet, 22 April 2006 </li></ul></ul><ul><u...
The Problem with Changing <ul><li>Multiple ANCA+ diseases: </li></ul><ul><ul><li>microscopic polyangiitis (MPA) </li></ul>...
Criteria for Classification <ul><li>Nasal or oral inflammation   </li></ul><ul><ul><li>Development of painful or painless ...
Classic Symptoms <ul><li>Upper respiratory tract  </li></ul><ul><ul><li>sinuses  </li></ul></ul><ul><ul><li>Nose </li></ul...
Eye <ul><li>Scleritis </li></ul><ul><li>Uveitis </li></ul><ul><li>Orbital pseudotumor /proptosis </li></ul>
Upper Respiratory Tract Ear <ul><li>Ear infections that are slow to resolve. </li></ul><ul><li>Recurrent otitis media.  </...
Upper Respiratory Tract   Nose <ul><li>Nasal crusting  </li></ul><ul><li>Frequent nosebleeds  </li></ul><ul><li>Erosion an...
Upper Respiratory Tract   Sinuses/Trachea <ul><li>Sinuses </li></ul><ul><ul><li>Chronic sinus inflammation </li></ul></ul>...
Lungs <ul><li>Nodules   (which may cavitate)  </li></ul><ul><li>Alveolar opacities  </li></ul><ul><li>Pleural opacities  <...
Kidney <ul><li>Glomerulonephritis w/ associated hematuria and proteinuria </li></ul><ul><li>Can lead to renal failure if n...
RBC casts
Skin <ul><li>“ palpable purpura” most common </li></ul><ul><li>Raynaud’s phenomenon—due to inadequate blood flow to finger...
Miscellaneous <ul><li>Joints Arthritis can occur, with joint swelling and pain </li></ul><ul><li>Nerves Peripheral nerve i...
Incidence of symptoms <ul><li>Symptom At Onset Total </li></ul><ul><li>ENT  75% 95% </li></ul><ul><li>Lung  50  85 </li></...
Pathogenesis Risk factors and inciting events <ul><li>Exact events obscure </li></ul><ul><ul><li>Infectious—staph? </li></...
Pathogenesis ANCA <ul><li>ANCAs may be not only markers for Wegener's granulomatosis and related disorders, but they may a...
Pathogenesis <ul><li>“ Priming” of Neutrophils </li></ul><ul><ul><li>Exposing PR3 and MPO epitopes </li></ul></ul><ul><li>...
<ul><li>Nasal or oral inflammation   </li></ul><ul><ul><li>Development of painful or painless oral ulcers or purulent or b...
Diagnosis <ul><li>Biopsy specimens showing the triad of vasculitis, granulomata, and large areas of necrosis  </li></ul><u...
 
Antineutrophil cytoplasmic antibodies
ANCA <ul><li>~90% of Wegener's cases are ANCA+ </li></ul><ul><ul><li>In limited dz, up to 40% may be ANCA neg </li></ul></...
Is ANCA sufficient? <ul><li>Concensus is that tissue dx is necessary </li></ul><ul><li>Rarely may initiate tx w/o biopsy <...
Treatment Traditional <ul><li>Prednisone  (initiated at 1 mg/kg daily for 1 to 2 months. then tapered)  </li></ul><ul><li>...
Treatment <ul><li>However, 50% in remission relapse  </li></ul><ul><li>AND daily cyclophos is very toxic </li></ul><ul><li...
Treatment <ul><li>Monthly IV cyclophosphamide  --  less toxic but less effective </li></ul><ul><li>Weekly methotrexate  --...
 
 
Vasculidities <ul><li>Large vessel vasculitis  </li></ul><ul><ul><li>Takayasu arteritis  </li></ul></ul><ul><ul><li>Giant ...
What, then, is the role of ANCA? <ul><li>Is a positive test result a &quot;true-positive&quot;?  </li></ul><ul><li>Does a ...
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Endoscopic Laser surgery For Subglottic Stenosis in Wegerners Granulomatosis Endoscopic Laser surgery For Subglottic Stenosis in Wegerners Granulomatosis

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Endoscopic Laser surgery For Subglottic Stenosis in Wegerners Granulomatosis Endoscopic Laser surgery For Subglottic Stenosis in Wegerners Granulomatosis

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

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