Wegener’s Granulomatosis

1. Wegener’s Granulomatosis Kelly Mitchell July 5, 2006 Morning Report

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. 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

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. 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 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%

6. Classic Symptoms • Upper respiratory tract • sinuses • Nose • ears • trachea • Lungs • Kidneys

7. Eye • Scleritis • Uveitis • Orbital pseudotumor /proptosis

8. Upper Respiratory TractEar • Ear infections that are slow to resolve. • Recurrent otitis media. • Decrease in hearing.

9. Upper Respiratory TractNose • 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. Upper Respiratory TractSinuses/Trachea • Sinuses • Chronic sinus inflammation • Trachea • subglottic stenosis

11. Lungs • Nodules(which may cavitate) • Alveolar opacities • Pleural opacities • Diffuse hazy opacities(which may reflect alveolar hemorrhage)

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. RBC casts

14. Skin • “palpable purpura” most common • Raynaud’s phenomenon—due to inadequate blood flow to fingers and toes • Ulcers

15. Miscellaneous • JointsArthritis can occur, with joint swelling and pain • NervesPeripheral 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. 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 10/15 One-third of patients may be without symptoms at onset of disease

17. PathogenesisRisk 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. PathogenesisANCA • 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.

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. 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. 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

23. Antineutrophil cytoplasmic antibodies

24. 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

25. 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

26. TreatmentTraditional • 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

27. 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)

28. 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

31. 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 • 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

32. 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?