Wegener’s Granulomatosis - PowerPoint PPT Presentation

Wegener’s Granulomatosis

Kelly Mitchell

July 5, 2006

Morning Report

• 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

• 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

• 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

• 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%

• Upper respiratory tract
• sinuses
• Nose
• ears
• trachea
• Lungs
• Kidneys

• Scleritis
• Uveitis
• Orbital pseudotumor /proptosis

• Ear infections that are slow to resolve.
• Recurrent otitis media.
• Decrease in hearing.

• Nasal crusting
• Frequent nosebleeds
• Erosion and perforation of the nasal septum.The bridge of the nose can collapse resulting in a “saddle–nose deformity”.

• Sinuses
• Chronic sinus inflammation
• Trachea
• subglottic stenosis

• Nodules(which may cavitate)
• Alveolar opacities
• Pleural opacities
• Diffuse hazy opacities(which may reflect alveolar hemorrhage)

• 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

• “palpable purpura” most common
• Raynaud’s phenomenon—due to inadequate blood flow to fingers and toes
• Ulcers

• 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

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

• 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

• 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.

• “Priming” of Neutrophils
• Exposing PR3 and MPO epitopes
• ANCA binding
• Degranulation/ROS production/neutrophil-endothelial cell interaction
• Increased ANCA = Increased degranulation rate

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)

• 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

• ~90% of Wegener's cases are ANCA+
• In limited dz, up to 40% may be ANCA neg
• 80 - 90 % PR3-ANCA
• Remaining MPO-ANCA

• Concensus is that tissue dx is necessary
• Rarely may initiate tx w/o biopsy
• Should attempt to confirm w/ biopsy when able

• 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

However, 50% in remission relapse

AND daily cyclophos is very toxic

• pancytopenia,
• infection,
• hemorrhagic cystitis
• bladder cancer (increased 33-fold)
• lymphoma (increased 11-fold)

• 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

• 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

• 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?