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?