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Wegener’s Granulomatosis. Kelly Mitchell July 5, 2006 Morning Report. History of Wegener’s. In 1931, two patients died from prolonged sepsis with inflammation of blood vessels scattered throughout the body.

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wegener s granulomatosis

Wegener’s Granulomatosis

Kelly Mitchell

July 5, 2006

Morning Report

history of wegener s
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
the controversy
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
the problem with changing
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
criteria for classification
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%

classic symptoms
Classic Symptoms
  • Upper respiratory tract
    • sinuses
    • Nose
    • ears
    • trachea
  • Lungs
  • Kidneys
slide7
Eye
  • Scleritis
  • Uveitis
  • Orbital pseudotumor /proptosis
upper respiratory tract ear
Upper Respiratory TractEar
  • Ear infections that are slow to resolve.
  • Recurrent otitis media.
  • Decrease in hearing.
upper respiratory tract nose
Upper Respiratory TractNose
  • Nasal crusting
  • Frequent nosebleeds
  • Erosion and perforation of the nasal septum.The bridge of the nose can collapse resulting in a “saddle–nose deformity”.
upper respiratory tract sinuses trachea
Upper Respiratory TractSinuses/Trachea
  • Sinuses
    • Chronic sinus inflammation
  • Trachea
    • subglottic stenosis
lungs
Lungs
  • Nodules(which may cavitate)
  • Alveolar opacities
  • Pleural opacities
  • Diffuse hazy opacities(which may reflect alveolar hemorrhage)
kidney
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
slide14
Skin
  • “palpable purpura” most common
  • Raynaud’s phenomenon—due to inadequate blood flow to fingers and toes
  • Ulcers
miscellaneous
Miscellaneous
  • JointsArthritis can occur, with joint swelling and pain
  • NervesPeripheral 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
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

pathogenesis risk factors and inciting events
PathogenesisRisk 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
pathogenesis anca
PathogenesisANCA
  • 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
Pathogenesis
  • “Priming” of Neutrophils
    • Exposing PR3 and MPO epitopes
  • ANCA binding
  • Degranulation/ROS production/neutrophil-endothelial cell interaction
  • Increased ANCA = Increased degranulation rate
diagnosis
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)
diagnosis21
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
slide24
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
is anca sufficient
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
treatment traditional
TreatmentTraditional
  • 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
treatment
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)
treatment28
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
vasculidities
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
what then is the role of anca
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?