Transcript VASCULITIDIS

VASCULITIS
PROF. DR. FERDA ÖZKAN
VASCULITIS
This is a heterogenous group of
disorders characterized by
inflammation & damage of
blood vessels followed by
thrombosis & ischemic
manifestations in the tissues
supplied by the blood vessels.
Classification
the size and type of blood vessel
involved
vascular beds and organs affected
associated clinical features
etiology
 pathogenic mechanisms
 hypersensitivity – drugs, serum sickness
 infections
 immune-mediated injury.
Classification of vasculitis
based on Pathogenesis
Direct infection
Immunologic
Unknown
1-Direct infection
Bacterial- Neissera
Rickettsial-Rocky mountain spotted
fever
Spirochetal-Syphilis
Fungal-aspergillosis, mucormycosis
Viral-herpes zoster-varicella
Infectious arteritis
Rickettsial disease, syphilis, septic
emboli, walls of abscesses.
A mycotic aneurysm is a spot at a
branch-point of an artery where a
septic embolus (usually) has lodged and
set up an infection, weakening the wall.
2-Immunologic
Immune complex-mediated
Antineutrophil cytoplasmic antibody
(ANCA)-mediated
Direct antibody mediated
Cell-mediated
Inflammatory bowel disease
Paraneoplastic vasculitis
3-Unknown
Giant cell (temporal) arteritis
Takayasu arteritis
Polyarteritis nodosa
Immunologic-Immune complex-mediated
Infection induced-hepatitis B,C
 Henoch-Schönlein purpura
 SLE and RA
 Drug induced
 Cryoglobulinemia
 Serum sickness
Immunologic-ANCA-mediated
Wegener granulomatosis
Microscopic polyangiitis
(microscopic polyarteritis)
Churg-Strauss syndrome
Immunologic-Direct antibody mediated
Goodpasture syndrome
(anti-GBM antibodies)
Kawasaki disease
(anti-endothelial antibodies)
Immunologic -Cell mediated
Organ allograft rejection
Pathogenesis of Noninfectious
Vasculitis
Immune complex deposition
ANCA’s
Anti-endothelial cell antibodies
Autoreactive T cells
Immune mediated vasculitis
Vasculitis related to deposition of immune
complexes
 Consequence of immune complex formation
and localization
 Ability of the immune complex to activate
complement
 Release of local vasoactive factors which
can increase vascular permeability
Immune complex deposition
 The vascular lesions resemble those found in
experimental immune complex-mediated
conditions, such as the local Arthus
phenomenon and serum sickness .
 Immune reactants and complement can be
detected in the serum or vessels of patients
with vasculitis (e.g., DNA-anti-DNA
complexes are present in the vascular lesions
of systemic lupus erythematosus-associated
vasculitis and IgG, IgM, and complement in
cryoglobulinemic vasculitis).
 Hypersensitivity to drugs causes
approximately 10% of vasculitic skin lesions,
largely through vascular deposits of immune
complexes. Some, such as penicillin, conjugate
serum proteins; others, like streptokinase ,
are themselves foreign proteins.
 The manifestations vary and range from
small-vessel hypersensitivity and
leukocytoclastic vasculitis to polyarteritis
nodosa, Wegener granulomatosis, and ChurgStrauss syndrome and from mild and selflimiting to severe and even fatal.
In vasculitis associated with viral
infections, immune complexes can be
found in the serum and in the vascular
lesions of some patients, particularly in
cases of polyarteritis nodosa (for
example, HBsAg-anti-HbsAg in
hepatitis-induced vasculitis).
ANCA’S
ANCAs are a heterogeneous group of
autoantibodies directed against
enzymes mainly found within the
azurophil or primary granules in
neutrophils, in the lysosomes of
monocytes, and in ECs.
The description of these autoantibodies
is based on the immunofluorescent
patterns of staining of ethanol-fixed
neutrophils.
Two main patterns are recognized:
one shows cytoplasmic localization of
the staining (c-ANCA), and the most
common target antigen is proteinase-3
(PR3), a neutrophil granule constituent.
The second shows perinuclear staining
(p-ANCA) and is usually specific for
myeloperoxidase (MPO).
Antineutrophil cytoplasmic antibody
(ANCA)
 ANCA has been found in patients with: Wegener’s
granulomatosis, microscopic polyangitis;
polyarteritis nodosa; Churg-Strauss syndrome.
 c-ANCA: classical, diffuse cytoplasmic ANCA;
stains the entire cytoplasm of alcohol fixed white
cells in a granular pattern;
associated with Wegener’s (found in 95%)
 p-ANCA: anti-neutrophil antibodies to myelooperoxidase;
stain the peri-nuclear region
associated with microscopic polyangitis, ChurgStrauss syndrome, and crescentic
glomerulonephritis.
ANCA staining
c-ANCA
p-ANCA
 One plausible hypothesis for a causative role
of ANCAs in vasculitis is summarized briefly as
follows:
 (1) An underlying disorder (e.g., an infection)
elicits pro-inflammatory cytokines such as
TNF, and granulocyte-macrophage colonystimulating factor, and microbial products such
as endotoxin, which together cause neutrophils
and other inflammatory cells to express PR3
and MPO on their surfaces.
 (2) These stimulate the formation of ANCAs.
 (3) ANCAs react with circulating cytokineprimed neutrophils and cause them to
degranulate
 (4) PMNs activated by ANCA cause
endothelial cell toxicity and other direct tissue
injury.
 ANCAs directed against neutrophil
constituents other than PR3 and MPO are
also found in some patients with a wide
range of inflammatory but nonvasculitic
disorders such as inflammatory bowel
disease, autoimmune liver disease,
primary sclerosing cholangitis, and
rheumatoid arthritis, and in some
patients with malignancies and infections
Anti-endothelial Cell Antibodies
Antibodies to ECs, perhaps induced by
defects in immune regulation, may
predispose to certain vasculitides, such
as those associated with SLE and
Kawasaki disease.
Diagrammatic representation of the sites of the vasculature involved by
the major forms of vasculitis. The widths of the trapezoids indicate the
frequencies of involvement of various portions. LCA, leukocytoclastic
angiitis. Small-vessel vasculitis
Vasculitis
Immune mediated vaculitides
Wegener’s Granulomatosis
Bürger’s Disease (thromboangitis
obliterans)
Takayasu Arteritis
Kawasaki’s disease
Infectious arteritis
Raynaud’s disease
Pathology: Small vessels
Hypersensitivity vasculitis
 Examples include serum sickness, drug-
induced vasculitis- many of the lesions
show immune complexes in lesions.
 Skin is most commonly affected, but a
wide range of organs can be.
 Pathology:(in skin)
 fibrinoid necrosis – vessels break
down; brisk inflammatory reaction
with PMN infiltrate
 leukocytoclastic vasculitis karyorrhexis (nuclear
fragmentation) of WBCs in vasculitic
lesion
 palpable purpura – extravasation
of RBCs from necrotic vessel +
inflammation.
Causes
 Connective tissue
diseases - SLE, RA
 Infections - Hepatitis B
 Drugs (all 'P's) Penicillins,
Phenothiazines,
Phenylbutazones,
Propylthiouracil
 Hematologic disease Cryoglobulinemia,
Paraproteinemia - e.g.
multiple myeloma
 Idiopathic
Antigens
 microorganisms,
 drugs,
 tumor,
 autoantigens.
Pathology: Small vessels
Henoch-Schönlein Purpura
 form of hypersensitivity vasculitis in kids, young adults
 clinical:
purpura on buttocks, arms, legs
necrotizing vasculitis involving small dermal vessels
arthritis
abdominal pain – often with bloody diarrhea/other evidence of
intestinal bleeding, due to mucosal/submucosal vasculitis
 kidney involvement in 1/3 – proteinuria, nephrotic syndrome,
gross/microscopic hematuria.
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 Pathology:
 glomerulonephritis is often focal, mesangial proliferative
in type; often self-limiting
 IgA is predominant Ab in glomerular and skin lesions.
Pathology: Small vessels
Mixed Cryoglobulinemia syndrome
 Clinical:
widespread small vessel vasculitis, often
associated with severe glomerulonephritis
purpura
arthralgia or arthritis
cryoglobulins
reversibly precipitatie in the cold
consist of IgM rheumatoid factors
most seen in patients with HCV
Pathology:
vessels show deposits containing
cryoglobulins and complement
leukocytoclastic vasculitis.
Leukocytoclastic vasculitis
Pathology: Small to Medium-sized vessels
Wegener’s Granulomatosis
 can occur from teens to old age; peak at age 40,
slight male proponderance. 82% die in a year
without treatment.
 serious systemic disorder characterized by:
 acute necrotizing granulomas in upper and/or lower
respiratory tract
 focal necrotizing or granulomatous vasculitis, affecting
small to medium sized vessels in lungs mostly
 also skin, joints, nerves, ears
 glomerulonephritis, often crescenteric proliferative 
renal failure
symptoms:
upper respiratory tract (sinusitis,
epistaxis, nasal obstruction, otitis
media, deafness),
lower respiratory tract
(productive cough, hemoptysis,
dyspnea),
renal failure.
Inflammation (vasculitis) of a small artery along
with adjacent granulomatous inflammation, in
which epithelioid cells and giant cells
Clinical Findings
 Respiratory System – upper respiratory
tract infections, saddle nose deformity,
pneumonitis, pleural effusion
 Renal - hematuria, hypertension, renal
failure
 Ocular - conjunctivitis, uveitis
 Skin - urticaria, palpable purpura, livedo
reticularis.
 Diagnosis: c-ANCA found in
majority but not specific
 Pathology: lung lesions are most
diagnostic
 lesions usually multiple, well
circumscribed, variable size
 coagulative necrosis
surrounded by granulation
tissue; ghost outlines of
vessels in necrotic zone,
multinucleate giant cells may
be present
 extrapulmonary lesions – same
combo of granulomatous
inflammation and vasculitis in
upper respiratory tract, skin.
 Elsewhere vasculitis
The lung of a patient with fatal Wegener
granulomatosis, demonstrating large
nodular lesions
Pathology: Medium-sized vessels
Buerger’s Disease (thromboangitis obliterans)
 predominates in young adult male (20-45)
tobacco smokers; female smokers as well.
Sligtly more common in Asians, Ashkenazi
Jews.
 clinical:
ischemia, usually of lower limbs, progressing
to gangrene
absence of atherosclerotic stigmata or risk
factors
associated with migratory thrombophlebitis
The lumen is occluded by a thrombus
containing two abscesses
Pathology: Medium-sized vessels
Polyarteritis Nodosa
 40-50s, M:F 2:1. May be life threatenting; 5 year
survival <15%, 80% with therapy
 fever, myalgia, weight loss, foot drop, weakness,
abdominal pain, hypertension from renal arteriole
involvement
 mononeuritis complex - asymmetric peripheral
neuropathy with sudden or subacute onset due to
nerve infarction; many modalities lost in one nerve
 local ischemia, inflammation of affected organs
 kidney, GI tract, joints/muscles, heart, nervous
system, skin, lungs may be affected.
Pathogenesis (no single mechanism, some
cases are idiopathic) :
Immune Complex deposition:
Hepatitis B Ag, tumor Ag, certain
drugs
Pathology
 All stages of activity may coexist
in different vessels, even in one
vessel.
 Early: focal, fibrinoid
necrosis of
artery/arteriole wall;
transmural inflammation –
PMN, eosinophilic poly
infiltrate
 Intermediate:
mural/occlusive thrombi
 Late: aneurysms if
segmental involvement
 with healing, wall infiltrated
by fibroblasts -> fibrous
thickening of wall -> nodular
appearance.
Pathology: Large vessels
Giant cell arteritis and temporal arteritis
Mean age of onset 70 years;
Commonly associated with clinical syndrome
polymyalgia rheumatica:
pain, stiffness in shoulder & pelvic girdles
in absence of evidence of weakness or
atrophy
 ESR
response to low-moderate steroid doses.
Temporal (giant cell) arteritis
 Granulomatous inflammatory process can
affect any elastic and muscular artery:
most often seen in superficial temporal
artery, other cranial arteries
chief clinical risk is blindness
clinical presentation: headache, scalp
tenderness, claudication of the jaw (tired
jaw on chewing), transient visual
disturbances, musculoskeletal symptoms
(polymyalgia rheumatica) , fever, malaise,
weight loss, anemia.
 Extracranial disease in 10-15%:
intermittent claudication is common
arterial bruits, blood pressure abnormalities.
 Treatment: responds well to steroids.
 Complications
coronary artery involvement  myocardial
ischemia
aortic valve incompetence
aortic dissection
aortic aneurysm, may rupture.
Pathology
Inflammation
confined to media;
mixed cell infiltrate
– lymphocytes,
macrophages
Giant cells may be
present at junction
of intima and media
(eating internal
elastic lamina)
Intimal
proliferation.
Elastic tissue stain demonstrating focal destruction of
internal elastic membrane (arrow) and intimal thickening
(IT) characteristic of long-standing or healed arteritis
Pathology: Large vessels
Takayasu Arteritis or Aortitis
 Common in Far east; women 15-45 affected
 Chronic inflammatory disease involving both
systemic and pulmonary circulations
 Aorta & major branches most commonly
affected – coronaries
 Clinical: stenosis is characteristic
 Pathology: artery wall inflammation 
fibromuscular intimal proliferation, mural
thrombi
 granulomatous panarteritis
 vessel converted into rigid tube, associated with
stenosis.
The right carotid artery taken at autopsy of
the patient demonstrating marked intimal
thickening with minimal residual lumen
Aortitis is literally inflammation of
the aorta, and it is representative of a
cluster of large-vessel diseases that
have various or unknown etiologies.
While inflammation can occur in
response to any injury, including
trauma, the most common known
causes are infections or connective
tissue disorders.
Infections can trigger a noninfectious
vasculitis by generating immune
complexes or by cross-reactivity.
The etiology is important because
immunosuppressive therapy, the main
treatment for vasculitis, could
aggravate an active infectious process.
Inflammation of the aorta can cause
aortic dilation, resulting in aortic
insufficiency.
Also, it can cause fibrous thickening and
ostial stenosis of major branches,
resulting in reduced or absent pulses,
low blood pressure in the arms, possibly
with central hypertension due to renal
artery stenosis.
Depending on what other vessels are
involved, ocular disturbances,
neurological deficits, claudication, and
other manifestations of vascular
impairment may accompany this
The disease has 3 phases:
Phase I is (prepulseless
inflammatory period)
Phase II (vascular inflammation)
Phase III (fibrosis stage)
 Pathologic changes involved in Takayasu
arteritis are the same as for giant cell
arteritis.
Involved vessel walls develop irregular
thickening and intimal wrinkling.
Early in the disease, mononuclear
infiltration with perivascular cuffing is
seen.
That extends to the media, followed by
granulomatous changes and patches of
necrosis and scarring (fibrosis) of all
layers, especially the intima.
Late stages have lymphocytic infiltration.
 When the abdominal aorta and its branches, eg,
the renal arteries, are involved, central
hypertension may develop.
 Accurate blood pressure measurement may be
difficult because of arterial lesions affecting supply
to the extremities.
 Takayasu arteritis primarily involves the aorta,
its main branches, and, in 50% of cases, the
pulmonary artery.
 The initial vascular lesions frequently occur in or at
the origin of the left subclavian artery, which can
cause weakened radial pulse and easy fatigability in
the left arm.
 As the disease progresses, the left common carotid,
vertebral, brachiocephalic, right-middle or proximal
subclavian, right carotid, and vertebral arteries, as
well as the aorta, also are affected, as well as retinal
vessels.
Destruction of the arterial media by
mononuclear inflammation with giant cells
Complications:
Aortic insufficiency,
angina pectoris,
myocardial infarction,
stroke,
limb ischemia,
renal artery hypertension,
all consequences of vascular diseases.
Cogan's disease
 Cogan's disease is another rare disease
usually affecting young adults.
 It features abrupt onset of
nerve deafness,
interstitial keratitis, and/or
a systemic vasculitis often with
aortic aneurysm formation.
 It's apparently caused by an autoantibody
against inner ear and endothelium
Kawasaki's disease
 A febrile disease which resembles adult
polyarteritis nodosa histologically but occurs in
babies.
 Need to see five of these six signs:
 fever (will last more than five days)
 non-purulent conjunctivitis in both eyes
 rash
 red cracked lips and/or strawberry tongue and/or red
oral mucosa
 red palms and soles (later they desquamate)
 a big (1.5 cm or more) lymph node in the neck.
Most patients are of Japanese of
Korean ancestry, regardless of where
they live, but no HLA links are found.
The most serious concern is coronary
vasculitis, which causes myocardial
infarcts. Healing can produce coronary
aneurysms,
The cause remains obscure.
Raynaud's disease &
phenomenon
 Spasm and occlusion of the arteries supplying
the fingers, which turn white, then red, then
blue.
 Triggered by cold weather, it's most often
idiopathic; known causes range from vasculitis
syndromes to operating jack-hammers.
 Scleroderma patients and some others have
this process greatly exacerbated by
hyperplastic arteriolar sclerosis in the digital
arteries.
Type of
vasculitis
Aorta and its
branches
Large and
medium-sized
arteries
Medium-sized
muscular
arteries
Takayasus
arteritis
+++
+
Giant cell
arteritis
+
+++
+++
Polyarteritis
+++
+++
Wegeners
granulomatosis
++
Kawasaki
disease
++
Small
muscular
arteries
Venules,
arterioles
+
+++
+++
Vasculitis
associated with
connective
tissue disease
++
+++
Leukocytoclastic
vasculitis:
HenochSchönlein
purpura,
hypersensitivity
vasculitis,
+
+++
+
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