Transcript Wegener’s Granulomatosis - Vasculitis Patient Information

Wegener’s
Granulomatosis
Kelly Mitchell
July 5, 2006
Morning Report
History of Wegener’s
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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
The Controversy
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Wegener’s vs PR3-ANCA vasculitis
Lancet, 22 April 2006
 Suggestion that using Wegener’s name “needs
balanced discussion within the scientific community”
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Reiter's syndrome- reactive arthritis
The Problem with Changing
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Multiple ANCA+ diseases:
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microscopic polyangiitis (MPA)
"renal-limited" vasculitis (pauci-immune glomerulonephritis without
evidence of extrarenal disease)
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Churg-Strauss syndrome (CSS)
Drug-induced vasculitis
Goodpasture’s
Rheumatic disorders
Autoimmune GI disorders
CF
Diagnostic Criteria primarily clinical
Criteria for Classification
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Nasal or oral inflammation
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Abnormal chest radiograph
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Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities
Abnormal Urinary sediment
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Development of painful or painless oral ulcers or purulent or bloody nasal discharge
Microhematuria (>5 red blood cells per high power field) or red cell casts in urine
sediment
Granulomatous inflammation on biopsy
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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%
Classic Symptoms
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Upper respiratory tract
sinuses
 Nose
 ears
 trachea
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Lungs
Kidneys
Eye
 Scleritis
 Uveitis
 Orbital
pseudotumor
/proptosis
Upper Respiratory Tract
Ear
 Ear
infections that are slow to resolve.
 Recurrent otitis media.
 Decrease in hearing.
Upper Respiratory Tract
Nose
Nasal crusting
 Frequent
nosebleeds
 Erosion and
perforation of the
nasal septum. The bridge
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of the nose can collapse resulting in a
“saddle–nose deformity”.
Upper Respiratory Tract
Sinuses/Trachea
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Sinuses
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Chronic sinus
inflammation
Trachea
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subglottic stenosis
Lungs
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Nodules (which may
cavitate)
Alveolar opacities
 Pleural opacities
 Diffuse hazy
opacities (which may reflect
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alveolar hemorrhage)
Kidney
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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
RBC casts
Skin
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“palpable purpura” most
common
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Raynaud’s
phenomenon—due to
inadequate blood flow to
fingers and toes
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Ulcers
Miscellaneous
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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
Incidence of symptoms
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Symptom
At Onset
ENT
75%
Lung
50
Joints
30
Fever
25
Kidney
20
Cough
20
Eye
15
Skin
15
Weight Loss
10
Nervous System (Central/Peripheral) 0
Total
95%
85
70
50
75
50
50
45
35
10/15
One-third of patients may be without symptoms at onset of disease
Pathogenesis
Risk factors and inciting events
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Exact events obscure
Infectious—staph?
 Genetic
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single nucleotide polymorphism in a gene encoding a protein tyrosine
phosphatase (PTPN22)
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AAT deficiency
Environmental—inhalational?
Silica
 lead
 mercury
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Pathogenesis
ANCA
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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.
Pathogenesis
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“Priming” of Neutrophils
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Exposing PR3 and MPO epitopes
ANCA binding
Degranulation/ROS production/neutrophilendothelial cell interaction
Increased ANCA = Increased degranulation rate
Diagnosis
Criteria for Classification
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Nasal or oral inflammation
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Abnormal chest radiograph
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Chest radiograph showing the presence of nodules, fixed infiltrates, or
cavities
Abnormal urinary sediment
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Development of painful or painless oral ulcers or purulent or bloody nasal
discharge
Microhematuria (>5 red blood cells per high power field) or red cell casts
in urine sediment
Granulomatous inflammation on biopsy
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Histologic changes showing granulomatous inflammation within the wall
of an artery or in the perivascular or extravascular area (artery or arteriole)
Diagnosis
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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
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Kidney--segmental necrotizing glomerulonephritis that is usually pauciimmune on immunofluorescence / EM
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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)
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Seropositivity for C-ANCAs
Antineutrophil cytoplasmic
antibodies
ANCA
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~90% of Wegener's cases are ANCA+
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In limited dz, up to 40% may be ANCA neg
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80 - 90 % PR3-ANCA
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Remaining MPO-ANCA
Is ANCA sufficient?
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Concensus is that tissue dx is necessary
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Rarely may initiate tx w/o biopsy
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Should attempt to confirm w/ biopsy when able
Treatment
Traditional
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Prednisone (initiated at 1 mg/kg daily for 1 to
2 months. then tapered)
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Cyclophosphamide (2mg/kg daily for at least
12 months)
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>90% improve and 75% remit
Treatment
However, 50% in remission relapse
AND daily cyclophos is very toxic
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pancytopenia,
infection,
hemorrhagic cystitis
bladder cancer (increased 33-fold)
lymphoma (increased 11-fold)
Treatment
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Monthly IV cyclophosphamide -- less toxic but less
effective
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Weekly methotrexate -- maintains remission
Trimethoprim-sulfamethoxazole -- controversial
(?effective for disease limited to the respiratory tract), reduces the relapse rate
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Steroids —prednisone vs solumedrol
Plasmapheresis -unproven, awaiting MEPEX trial
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Recommended for anti-GBM+, pulm hemmorhage, renal failure
IVIG— recommended in the setting of infection during PLEX
Vasculidities
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Large vessel vasculitis
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Medium sized vessel vasculitis
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Takayasu arteritis
Giant cell arteritis
Polyarteritis nodosa
Isolated central nervous system vasculitis
Small vessel vasculitis
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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
What, then, is the role of ANCA?
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Is a positive test result a "true-positive"?
Does a negative ANCA assay exclude an "ANCAassociated" 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?