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Unit 3 B&L > BL 3-11-14 8-9AM VASCULITIS-Janson_Hirsh > Flashcards

BL 3-11-14 8-9AM VASCULITIS-Janson_Hirsh Flashcards

1
Q

Vasculitis

A

= a heterogeneous group of clinical disorders characterized by inflammation of blood vessels

  • inflammation may involve arteries of any size
  • -> spectrum of clinical & pathologic features
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2
Q

Terminology/Classification of Vasculitis

A

Can be based on:

  • size of vessel involved (Chapel Hill Classification)
  • type of pathologic change in vessel wall
  • clinical presentation

May be…

  • Primary
  • Secondary
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3
Q

Vasculitis may be secondary to…

A
  • infectious disorders like Hep B/C & endocarditis
  • drug hypersensitivity
  • CT diseases (RA, SLE, Sjögren’s)
  • Cryoglobulins
  • Malignancies
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4
Q

Large-vessel vasculitis - Types

A

Giant cell arteritis

Takayasu’s arteritis

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5
Q

Giant cell arteritis - Location

A

Inflammation usually in …

  • temporal arteries
  • vessels originating from aortic arch
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6
Q

Giant cell arteritis - symptoms/manifestations

A
  • temporal headache
  • jaw claudication
  • scalp tenderness
  • visual loss
  • giant cell arteritis w/ disruption of internal elastic lamina
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7
Q

Takayasu’s arteritis - Location

A

Inflammation usually in:

  • aortic arch & its branches
  • any part of the aorta
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8
Q

Takayasu’s arteritis - Symptoms / Manifestations

A
  • claudication of upper > lower extremities
  • CNS events
  • granulomatous panarteritis
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9
Q

Medium-vessel vasculitis - Types

A

Polyarteritis nodosa

Kawasaki’s disease

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10
Q

Polyarteritis nodosa - location (vessels & organs)

A
  • small & medium-sized arteries

- may affect any organ, but skin, joints, peripheral nerves, gut, & kidney are most commonly involved

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11
Q

Polyarteritis nodosa - manifestation

A
  • focal but panmural necrotizing arteritis

- predilection for involvement at vessel bifurcation

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12
Q

Kawasaki’s disease - location (vessels) & usual age group & cause

A
  • small and medium-sized arteries
  • acute febrile illness primarily affecting infants & young children
  • probable infectious vector resulting in cytokine-mediated endothelial damage
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13
Q

Kawasaki’s disease

A 
Fever
Prominent mucocutaneous changes
Cervical lymphadenopathy
Polymorphous rash
Erythema & Edema of hands & feet
Desquamation
Myocarditis
Coronary vasculitis
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14
Q

Small-vessel vasculitis - two big groups

A
  1. Antineutrophil cytoplasmic antibody (ANCA) positive vasculitides:
  2. Antineutrophil cytoplasmic antibody (ANCA) negative vasculitides
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15
Q

Antineutrophil cytoplasmic antibody (ANCA) positive vasculitides:

A
  • small cell vasculitis

Types:

  • Granulomatosis with polyangiitis (Wegener’s) (GPA)
  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
  • Microscopic polyangiitis (MPA)
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16
Q

Antineutrophil cytoplasmic antibody (ANCA) negative vasculitides

A
  • small cell vasculitis

Types:

  • Henoch-Schönlein Purpura (HSP)
  • Essential cryoglobulinemic vasculitis
  • Cutaneous leukocytoclastic angiitis
17
Q

Granulomatosis with polyangiitis (Wegener’s)

A

= pauci-immune, necrotizing, granulomatous arteritis usually associated w/ serum cytoplasmic-ANCA (c-ANCA +)

  • small & medium-sized arteries
  • URI (sinuses), lungs, & kidneys (+other organs)
18
Q

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

A
  • necrotizing extravascular granulomas & vasculitis of small arteries/venules
  • associated with +ANCA
  • asthma
  • eosinophilia (present at early stage)
  • multiorgan involvement (lungs, skin, peripheral nerves, gut, heart, renal (rare))
19
Q

Microscopic polyangiitis (MPA)

A
  • pauci-immune, necrotizing vasculitis, serum perinuclear-ANCA (p-ANCA) + common
  • arterioles, capillaries, & venules
  • –> pulmonary hemorrhage
  • –> glomerulonephritis
  • –> palpable purpura
  • –> peripheral neuropathy
  • –> joint & abdominal pain
20
Q

Henoch-Schönlein Purpura (HSP)

A

Leukocytoclastic (neutrophilic perivascular / transmural infiltrate)
OR
Necrotizing vasculitis

  • often w/ IgA deposition
  • ANCA NEGATIVE vasculitides of small vessels
  • -> palpable purpuric skin lesions lower extremities
  • -> arthritis
  • -> abdominal pain
  • -> hematuria
21
Q

Essential cryoglobulinemic vasculitis

A
  • a small-vessel vasculitis
    Cryoglobulins = Igs reversibly precipitated by reduced temperatures
    —> deposited in small vessels including glomerulocapillaries
    —> stimulate complement activation & cellular inflammatory response
  • -> purpura
  • -> arthralgias
  • -> weakness
  • -> peripheral neuropathy
  • -> Raynaud’s phenomenon
  • -> glomerulonephritis
  • -> pulmonary hemorrhage possible
  • Often rheumatoid factor & HepC Ab +
  • ANCA negative
22
Q

Cutaneous leukocytoclastic angiitis

A
  • ANCA negative vasculitides (small-vessel)
  • arterioles & venules
  • -> palpable purpuric skin lesions
  • -> arthralgias
  • -> systemic symptoms may be present, usually secondary to immune response [drugs, bugs, CT disease, malignancy
  • -> leukocytoclastic vasculitis
23
Q

Signs/Symptoms of Vasculitis

A

Found, to some extent, in all systemic vasculitides

  • skin lesions
  • constitutional symptoms (fever, anorexia, weight loss, weakness, fatigue)
  • MSK symptoms (arthralgias, arthritis, myalgias, peripheral neuropathy)
24
Q

Laboratory features of Vasculitis

A

Reflect systemic inflammation.

  • Anemia of inflammatory disease
  • Thrombocytosis
  • Low albumin
  • Elevated ESR & CRP
  • Polyclonal gammopathy
  • Possibly elevated liver enzyme tests, low complement levels, cryoglobulins
25
Q

Diagnosis of Vasculitis

A

Hx & PE to determine extent of organ involvement

Serum autoAbs (RF, ANA, ANCA)

Biopsy of affected organ

If biopsy inaccessible, angiogram to show:

  • segments of smooth arterial stenosis alternating w/ areas of normal or dilated artery
  • tapered occlusions
  • thrombosis
26
Q

Vasculitis - Incidence

A

Rare group of disorders

Mean age of onset in 5th decade
- but, can occur at extremes of age

About equal in sex distribution
- except for female predominance in Takayasu’s & giant cell arteritis

27
Q

Vasculitis - Ethnic associations

A

Can occur in any population

Higher incidence of Takayasu’s arteritis in Japanese & Asian populations

Higher incidence of giant cell arteritis in populations of N. European background & in northern latitudes

28
Q

Amount of vessel involvement in vasculitis

A

Considerable overlap exists in patterns of pathologic involvement in vasculitic syndromes.

  • Tend to be both focal & segmental lesions
  • Entire circumference of vessel may not be involved
29
Q

Pathology of Large & Medium vessel vasculitis (cell infiltrate, effects on vessels etc.)

A

Typically panarteritis

Infiltration through vessel wall, to varying degrees, of:

  • lymphocytes
  • monocytes
  • histiocytes
  • eosinophils
  • -> Can be associated w/ granuloma or giant cell formation in some disorders
  • -> Disruption of elastic lamina: intimal thickening results in narrowing/obliteration of vessel lumen
30
Q

Pathology of Small vessel vasculitis

A

“Leukocytoclastic” vasculitis
= necrotizing vasculitis w/ PMN-derived nuclear debris that often accompanies neutrophilic perivascular infiltration of vessel wall

–> typically fibrinoid necrosis of vessel wall w/ transmural inflammatory rxn

Often find Immunoglobulin (IgM, IgA in HSP) & Complement (C3) vascular deposition in vasculitic lesions

31
Q

Suspected Pathophysiologic Mechanisms for Vasculitis

A
  1. Immune Complexes (IC)
  2. Antineutrophil Cytoplasmic Antibodies (ANCA)
  3. Antiendothelial Antibodies
  4. T cell-dependent Mediated Endothelial Cell Injury
  5. Infection of Endothelial Cells
32
Q

Immune Complexes in Vasculitis

A

Several pieces of evidence suggest IC’s as able to instigate vasculitis:

Human serum sickness from horse Ig (anti-venoms)

Hepatitis B surface antigen & IgM in arterial wall of pt w/ polyarteritis nodosa

Animal models of serum sickness

  • PAF & other vasoactive mediators released in inflammatory/cytokine response probably induce vascular permeability
  • -> deposition of circulating IC at vascular endothelium, activation of complement, attraction of PMNs

May be involved in hypersensitivity vasculitis, HSP, cryoglobulinemia, & Hep B–associated vasculitis

33
Q

Antineutrophil Cytoplasmic Antibodies (ANCA) in Vasculitis - Staining

A

= Abs to Ags found in cytoplasm of neutrophils

Cytoplasmic staining (c-ANCA)

  • in granulomatosis w/ polyangiitis
  • binds to proteinase 3 (PR3) found in primary granules of PMN

Perinuclear staining (p-ANCA)

  • in microscopic polyangiitis
  • binds to myeloperoxidase (MPO), another primary granule constituent which migrates to perinuclear area w/ alcohol fixation of PMNs
34
Q

Antineutrophil Cytoplasmic Antibodies (ANCA) in Vasculitis - Mechanism

A

Inflammatory cytokines
activate PMNs to release & express PR3 & MPO on cell surface

Binding of ANCA to neutrophil cell surface leads to further neutrophil activation & possibly enhanced binding to vascular endothelial cells
—> resultant vascular damage

PR3 & MPO also found on surface of activated endothelial cells.

ANCA may not be essential for initiating vasculitis, but may amplify inflammatory vascular response

35
Q

Antiendothelial antibodies in Vasculitis

A

= demonstrated in several autoimmune & vasculitic diseases
- In vitro, can damage endothelial cells by both antibody-dependent cellular cytotoxicity (ADCC) & complement activation mechanisms.

These Abs directed toward structures on surface of endothelial cells not found in all vasculitic syndromes :(

36
Q

T Cell Dependent Mediated Endothelial Cell Injury in Vasculitis

A

-T-cell responses in initiation & perpetuation of vascular injury have been suggested in Takayasu’s, granulomatosis w/ polyangiitis, & giant cell arteritis.

Giant cell arteritis:
- over-representation of HLA-DR4 haplotype
= sequence polymorphism w/in hypervariable region 2 of HLA-DRB1 gene (probable Ag-binding element of HLA-DR molecule)
—> suggests Ag-driven vascular inflammation

This polymorphism is not shared by patients w/ rheumatoid arthritis.

37
Q

Infection of Endothelial Cells in Vasculitis

A
  • Many infectious agents can infect endothelial cells

Infected endothelial cells:

  • promote binding of IC & PMNs to endothelium
  • express MHC class II genes
  • enhance local lymphocyte proliferation
  • release stimulatory & proliferative cytokines

These changes may promote vascular inflammatory response & initiate T cell proliferative response

38
Q

Treatment as Relates to Pathophysiology of Vasculitis

A

Treat / remove inciting agent or Ag :

  • drugs
  • infections – endocarditis, hepatitis B & C

Treatment determined by pathogenic process, extent of inflammation & vascular involvement, and rate of progression of disease

Glucocorticoids –> control inflammatory features

High dose glucocorticoids + cytotoxic drug (cyclophosphamide)
–> for rapidly progressive disease w/ significant major organ involvement (lung, kidney, gut)

Plasmapheresis
- in hepatitis C-induced cryoglobulinemia & ANCA-positive vasculitides

Rituximab

  • anti-CD20 B cell mAb
  • efficacious for severe ANCA-associated vasculitis
39
Q

Vasculitis - Primary vs. Secondary inciting agents

A

Primary: inciting agent unknown

Secondary: inciting agent may be…

  • IC deposition
  • autoantibodies (anti-endothelial, ANCAs)
  • antigen-driven inflammation
  • infection of endothelial cells

Unit 3 B&L (18 decks)

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