BL 3-11-14 8-9AM VASCULITIS-Janson_Hirsh Flashcards
Vasculitis
= a heterogeneous group of clinical disorders characterized by inflammation of blood vessels
- inflammation may involve arteries of any size
- -> spectrum of clinical & pathologic features
Terminology/Classification of Vasculitis
Can be based on:
- size of vessel involved (Chapel Hill Classification)
- type of pathologic change in vessel wall
- clinical presentation
May be…
- Primary
- Secondary
Vasculitis may be secondary to…
- infectious disorders like Hep B/C & endocarditis
- drug hypersensitivity
- CT diseases (RA, SLE, Sjögren’s)
- Cryoglobulins
- Malignancies
Large-vessel vasculitis - Types
Giant cell arteritis
Takayasu’s arteritis
Giant cell arteritis - Location
Inflammation usually in …
- temporal arteries
- vessels originating from aortic arch
Giant cell arteritis - symptoms/manifestations
- temporal headache
- jaw claudication
- scalp tenderness
- visual loss
- giant cell arteritis w/ disruption of internal elastic lamina
Takayasu’s arteritis - Location
Inflammation usually in:
- aortic arch & its branches
- any part of the aorta
Takayasu’s arteritis - Symptoms / Manifestations
- claudication of upper > lower extremities
- CNS events
- granulomatous panarteritis
Medium-vessel vasculitis - Types
Polyarteritis nodosa
Kawasaki’s disease
Polyarteritis nodosa - location (vessels & organs)
- small & medium-sized arteries
- may affect any organ, but skin, joints, peripheral nerves, gut, & kidney are most commonly involved
Polyarteritis nodosa - manifestation
- focal but panmural necrotizing arteritis
- predilection for involvement at vessel bifurcation
Kawasaki’s disease - location (vessels) & usual age group & cause
- small and medium-sized arteries
- acute febrile illness primarily affecting infants & young children
- probable infectious vector resulting in cytokine-mediated endothelial damage
Kawasaki’s disease
Fever Prominent mucocutaneous changes Cervical lymphadenopathy Polymorphous rash Erythema & Edema of hands & feet Desquamation Myocarditis Coronary vasculitis
Small-vessel vasculitis - two big groups
- Antineutrophil cytoplasmic antibody (ANCA) positive vasculitides:
- Antineutrophil cytoplasmic antibody (ANCA) negative vasculitides
Antineutrophil cytoplasmic antibody (ANCA) positive vasculitides:
- small cell vasculitis
Types:
- Granulomatosis with polyangiitis (Wegener’s) (GPA)
- Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
- Microscopic polyangiitis (MPA)
Antineutrophil cytoplasmic antibody (ANCA) negative vasculitides
- small cell vasculitis
Types:
- Henoch-Schönlein Purpura (HSP)
- Essential cryoglobulinemic vasculitis
- Cutaneous leukocytoclastic angiitis
Granulomatosis with polyangiitis (Wegener’s)
= pauci-immune, necrotizing, granulomatous arteritis usually associated w/ serum cytoplasmic-ANCA (c-ANCA +)
- small & medium-sized arteries
- URI (sinuses), lungs, & kidneys (+other organs)
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
- 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))
Microscopic polyangiitis (MPA)
- pauci-immune, necrotizing vasculitis, serum perinuclear-ANCA (p-ANCA) + common
- arterioles, capillaries, & venules
- –> pulmonary hemorrhage
- –> glomerulonephritis
- –> palpable purpura
- –> peripheral neuropathy
- –> joint & abdominal pain
Henoch-Schönlein Purpura (HSP)
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
Essential cryoglobulinemic vasculitis
- 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
Cutaneous leukocytoclastic angiitis
- 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
Signs/Symptoms of Vasculitis
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)
Laboratory features of Vasculitis
Reflect systemic inflammation.
- Anemia of inflammatory disease
- Thrombocytosis
- Low albumin
- Elevated ESR & CRP
- Polyclonal gammopathy
- Possibly elevated liver enzyme tests, low complement levels, cryoglobulins
Diagnosis of Vasculitis
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
Vasculitis - Incidence
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
Vasculitis - Ethnic associations
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
Amount of vessel involvement in vasculitis
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
Pathology of Large & Medium vessel vasculitis (cell infiltrate, effects on vessels etc.)
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
Pathology of Small vessel vasculitis
“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
Suspected Pathophysiologic Mechanisms for Vasculitis
- Immune Complexes (IC)
- Antineutrophil Cytoplasmic Antibodies (ANCA)
- Antiendothelial Antibodies
- T cell-dependent Mediated Endothelial Cell Injury
- Infection of Endothelial Cells
Immune Complexes in Vasculitis
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
Antineutrophil Cytoplasmic Antibodies (ANCA) in Vasculitis - Staining
= 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
Antineutrophil Cytoplasmic Antibodies (ANCA) in Vasculitis - Mechanism
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
Antiendothelial antibodies in Vasculitis
= 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 :(
T Cell Dependent Mediated Endothelial Cell Injury in Vasculitis
-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.
Infection of Endothelial Cells in Vasculitis
- 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
Treatment as Relates to Pathophysiology of Vasculitis
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
Vasculitis - Primary vs. Secondary inciting agents
Primary: inciting agent unknown
Secondary: inciting agent may be…
- IC deposition
- autoantibodies (anti-endothelial, ANCAs)
- antigen-driven inflammation
- infection of endothelial cells
