Small Vessel Vasculitides

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Small- Vessel Vasculitides
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Learning Objectives

• Review the 4 types of hypersensitivity reactions
• Understand the ANCA test
• Differentiate then consolidate the different ANCA
  diseases and Pulmonary-Renal syndromes
• Do some questions

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Vasculitis

• A clinicopathologic process characterized by
  inflammation of and damage to blood vessels,
  often resulting in complete or partial occlusion
  of the involved vessels, with resulting ischemic
  damage to the supplied organ/tissue.

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• Vasculitis may be a primary or secondary
  manifestation of a disease process
• May affect a single, or multiple organs

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Etiology

• Several have been proposed, however, there is no
  uniform consensus
• For now, lets focus on immune complex deposition
  a process similar to serum sickness

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Etiology

• Ag-Ab complexes deposit in blood vessel walls
  whose integrity have already been compromised by
  vasogenic amines (histamine, leukotrienes,
  bradykinin) released from activated platelets and
  mast cells
• Complement components (primarily the classical
  pathway) are activated and recruit PMNs

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Etiology

• Exactly why only certain immune complexes cause
  vasculitis and why only certain blood vessels are
  affected remains in large part a mystery

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Hypersensitivity Reactions

• Type I immediate HS
• classic allergy
• Prior sensitization
• IgE mediated
• Massive degranulation
• Early and late responses

• Type 2 cytotoxic HS
• IgG binds to target tissue
• C activation
• Direct cytotoxic action
• AIHA
• ITP
• Goodpastures
• Myasthenia Gravis

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Hypersensitivity Reactions

• Type 3 IC HS
• serum sickness
• Ab form complex with circulating Ag
• Deposition results in C activation
• Leukocytoclastic vasculitis is hallmark
  manifestation
• Arthus reaction

• Type 4 cell-mediated HS
• Delayed-type HS
• Previously sensitized T-cells are required
• Mantoux test
• Contact dermatitis
• Allograft rejection

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ANCA

• Anti-Neutrophil Cytoplasmic Antibodies
• Ab directed against proteins in the cytoplasmic
  granules of PMNs and monocytes
• Wegeners Granulomatosis
• Microscopic Polyangiitis
• Churg-Strauss
• Crescentic/necrotizing GN

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c-ANCA

• Serum from patients bind to cytoplasmic granules
  and show a granular appearance on
  immunofluorescence
• Proteinase-3 (PR-3) is the major antigen
• Serine protease
• Present in azurophilic granules
• Most labs reflexively send a confirmatory test
  for PR-3 when this pattern is seen, or have
  eliminated the immunofluorescence aspect entirely

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p-ANCA

• Localized, peri-nuclear staining pattern on PMNs
• Myeloperoxidase (MPO) is the major target Ag
• Elastase
• Cathepsin G
• Lactoferrin
• Lysozyme
• Permeability-increasing protein
• Only MPO has been convincingly associated with
  vasculitis, the others may be seen in other ANCA
  diseases (IBD, drugs, endocarditis)

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Proposed Mechanism of Disease

• PR-3 and MPO are mobilized to surface of PMNs
  and monocytes when activated by TNF-a or IL-1
• Now can react with circulating ANCA
• PMNs degranulate and induce inflammation locally
• How the ANCA are generated in the first place is
  less clear

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Wegeners

• Systemic disease
• Granulomatous vasculitis of upper and lower
  respiratory tract with associated GN, variable
  degrees of disseminated vasculitis
• Involves small arteries and veins
• Prevalence 3 per 100,000
• Extremely rare in blacks
• Equal MF ratio
• Mean age of onset is 40

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Wegeners

• Multiple b/l nodular cavitary infiltrates
• Lung biopsy classic granulomatous necrotizing
  vasculitis
• Nasal ulcers, sinus disease, septal perforation,
  saddle-bridge deformity, tracheal stenosis
• Nasal biopsy usually reveals the same, not as
  sensitive
• FSGS ? RPGN
• Kidney biopsy rarely shows granulomas or immune
  complex deposition (focal, segmental, necrotizing
  pauci-immune GN)

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Wegeners

• Peripheral WBC tests indicate an unbalanced TH1
  cytokine pattern
• 90 are PR-3 positive (c-ANCA) during active
  disease
• A few pts will be MPO positive rather than PR-3
• BUT
• You must establish tissue diagnosis!! Aim for
  lungs.
• Must differentiate from other rare diseases such
  as angiocentric immunoproliferative diseases and
  lymphomatoid granulomatosis

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Wegeners Rx

• Previously, uniformly fatal in matter of weeks to
  months
• Cyclophosphamide (2mg/kg/day)
• Maintain WBC gt3000 PMN gt1500
• 6-12 months!!
• Glucocorticoids
• 1mg/kg/day, taper at 1 month and off at 6 months
• Remission rate 75
• 90 have marked improvement
• Plasmapheresis in refractory/progressive cases

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Microscopic Polyangiitis

• Disease entity characterized by a necrotizing
  vasculitis with few or no immune complexes,
  affecting small vessels (arterioles, capillaries,
  venules)
• First coined in ???

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Microscopic Polyangiitis

• Disease entity characterized by a necrotizing
  vasculitis with few or no immune complexes,
  affecting small vessels (arterioles, capillaries,
  venules)
• First coined in 1992, by the Chapel Hill
  Consensus Conference on the Nomenclature of
  Systemic Vasculitides
• Incidence is uncertain due to previous lumping
  together with PAN. Etiology unknown.

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Microscopic Polyangiitis

• Pauci-immune GN is very common (79)
• renal biopsy is identical to that in Wegeners
• Pulmonary infiltrates and hemorrhage may occur as
  a result of capillaritis, but biopsies lack
  granulomas
• Upper airway disease and pulm nodules/cavities
  absent
• Immunohistochemical staining lacks IC deposition,
  suggesting that IC complex formation is not part
  of the pathogenesis

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Microscopic Polyangiitis

• 75 of patients are c-ANCA
• Treatment is identical to Wegeners, and
  distinguishing between the two is somewhat
  academic
• 5-yr survival is 74

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Churg-Strauss Syndrome

• Incidence 1 per 1,000,000
• Occurs at any age, but mean is 48yrs
• Clinical Tetrad
• Asthma
• Eosinophilia (blood and peripheral)
• Extravascular granuloma
• Vasculitis affecting mutiple organs
• Involves small and medium-sized arteries,
  capillaries, and veins

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Churg-Strauss Syndrome

• Granulomatous inflammation with eosinophilic
  infiltration of involved organs
• Lung
• Kidney
• Skin
• Heart
• Presents as systemic syndrome (fever, malaise,
  anorexia, weight loss) with severe asthma attacks
  (may be precipitated by initiation of leukotriene
  inhibitors)

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Churg-Strauss Syndrome

• p-ANCA sensitivity 48
• Treatment
• Glucocorticoids titrated to control asthma
• Add cyclophosphamide as second line as in
  Wegeners

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Goodpastures Syndrome

• A specific subset of anti-GBM disease in which
  pulmonary hemorrhage occurs
• Target noncollagenous domain of a3 chain of Type
  IV collagen
• Typically seen in young males (5-40y/o)
• Type II HS reaction - inflammation and tissue
  destruction mediated by direct Ab binding and
  secondary activation of classical C pathway or
  direct activation of cytotoxic T-cells or
  phagocytes

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Goodpastures Syndrome

• Kidney
• RPGN and crescentic GN are most common
• Pulmonary hemorrhage (50-60 of all pts), quite
  rare in patients gt50y/o
• NOT associated with ANCA positivity

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Goodpastures Syndrome

• Gold standard diagnostic test?
• Renal biopsy with immunohistochemical staining
• Circulating anti-GBM antibodies (IgG) is 90-95
  sensitive
• Levels directly correlate with severity, organ
  survival, and relapse
• Treatment
• Plasmapheresis daily until titers undetectable
  (1-2 weeks!)
• Prednisone 1mg/kg/day
• Cyclophosphamide or azathioprine