Wegener's granulomatosis is a necrotizing vasculitis characterized by inflammation of blood vessels. It commonly involves the respiratory tract and kidneys. Diagnosis is based on clinical criteria including nasal or oral inflammation, lung abnormalities on chest imaging, hematuria or red blood cell casts on urinary sediment, and granulomatous inflammation on biopsy. The disease is associated with positive testing for PR3-ANCA. Treatment involves corticosteroids and cyclophosphamide or methotrexate to induce remission, though relapses are common due to toxicity of cyclophosphamide. The role of ANCA testing in diagnosis and monitoring disease activity requires further clarification.

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 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
 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
 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 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. 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
 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. 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
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?