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%
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”.
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
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
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
29.
30.
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?