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 Lungs Kidneys sinuses Nose
ears
trachea
Lungs
Kidneys

7. Eye
Scleritis
Uveitis
Orbital pseudotumor /proptosis

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

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. Upper Respiratory Tract Sinuses/Trachea
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 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. Incidence of symptoms Symptom At Onset Total ENT 75% 95% Lung 50 85
Joints
Fever
Kidney
Cough
Eye
Skin
Weight Loss
Nervous System (Central/Peripheral) 0 10/15
One-third of patients may be without symptoms at onset of disease

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. 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.

19. Pathogenesis “Priming” of Neutrophils ANCA binding
Exposing PR3 and MPO epitopes
ANCA binding
Degranulation/ROS production/neutrophil-endothelial cell interaction
Increased ANCA = Increased degranulation rate

20. Criteria for Classification
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+ 80 - 90 % PR3-ANCA
In limited dz, up to 40% may be ANCA neg
% 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. 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

27. Treatment pancytopenia, infection, hemorrhagic cystitis
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 Medium sized 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?