3. Def: general term for vessel wall inflammation
clinical features : depend on the vascular bed affected
(e.g., central nervous system vs. heart vs. small bowel).
signs and symptoms : include fever, myalgias,
arthralgias, and malaise.
any organ can be affected; most vasculitides involve
small vessels, from arterioles to capillaries to venules.
4. There are vasculitic entities that primarily affect
the aorta and medium-sized arteries, while others
principally affect only smaller arterioles
some small- and large-vessel vasculitides may
involve medium-sized arteries, but large- and
medium-sized vessel vasculitides do not involve
vessels smaller than arteries
7. etiology
The two most common pathogenic mechanisms of
vasculitis are immune-mediated inflammation and direct
invasion of vascular walls by infectious pathogens.
infections can indirectly induce a noninfectious
vasculitis by generating immune complexes or triggering
cross-reactivity.
8. In it is critical to distinguish between infectious
and immunological mechanisms, because
immunosuppressive therapy is appropriate for
immunemediated vasculitis but could very well
worsen infectious vasculitis.
Physical and chemical injury, such as from
irradiation, mechanical trauma, and toxins, can
also cause vasculitis.
9. NONINFECTIOUS
VASCULITIS
The main immunological mechanisms that
initiate noninfectious vasculitis are
(1) immune complex deposition,
(2) antineutrophil cytoplasmic antibodies,
(3) anti–endothelial cell antibodies
10. Immune Complex–Associated
Vasculitis.
Many systemic immunological diseases, e.g:(SLE) and
polyarteritis nodosa, manifest as immune complex-mediated
vasculitis.
Antibody and complement are typically detected in vasculitic
lesions.
the nature of the antigens responsible for their deposition
cannot usually be determined.
Circulating antigen-antibody complexes may also be seen
(e.g., DNA–anti-DNA complexes in SLE–associated vasculitis
sensitivity and specificity of circulating immune complex
assays in such diseases are low.
11. immune complexes are implicated in the following vasculitides:
drug hypersensitivity. In some cases (e.g., penicillin) the drugs bind to
serum proteins antibodies directed against the drug-modified
proteins or foreign molecules
formation of immune complexes.
Manifestations vary widely but are most frequently seen in the skin
they can be mild and self-limiting, or severe and even fatal.
It is important to identify vasculitis due to drug hypersensitivities,
since discontinuation of the offending agent will typically lead to
resolution.
vasculitis secondary to viral infections, antibody to viral proteins
forms immune complexes that can be found in the serum and the
vascular lesions.
as many as 30% of patients with polyarteritis nodosa have an
underlying hepatitis B infection that produces a vasculitis attributable
to complexes of hepatitis B surface antigen (HBsAg) and anti-HbsAg
antibody.
12. In many cases of immune complex vasculitis, it is not
clear whether the antigen-antibody complexes form
elsewhere and then deposit in a particular vascular bed,
or form in situ.
in many cases, antigen-antibody deposits are scarce.
Either the immune complexes have been largely cleared
at the time of diagnosis, or other mechanisms may
apply in such “pauci-immune” cases.
13. Antineutrophil Cytoplasmic
Antibodies. ANCAs are a heterogeneous group of autoantibodies
directed against constituents (mainly enzymes) of
neutrophil primary granules, monocyte lysosomes, and
endothelial cells.
previously classified according to their intracellular
distribution, either cytoplasmic (c-ANCA) or perinuclear
(p-ANCA).
14. now, they are discriminated based on their target
antigens:
Anti-myeloperoxidase (MPO-ANCA): can be induced by
a variety of therapeutic agents, in particular
propylthiouracil. These have been called p-ANCA.
characteristic of microscopic polyangiitis and Churg-
Strauss syndrome
Anti-proteinase-3 (PR3-ANCA): These have been called
c-ANCA. are typical of Wegener granulomatosis
15. ANCAs serve as useful diagnostic markers for the
ANCA-associated vasculitides
ANCA titers rise with recurrent disease and are
therefore useful in clinical management.
Although the precise mechanisms are unknown, ANCA
can directly activate neutrophils stimulate
neutrophils to release reactive oxygen species and
proteolytic enzymes endothelial cell damage.
16. the antigenic targets of ANCAs was thought to be
intracellular unaccessible to circulating
antibodies, but now , believed that ANCA
antigens are present at low levels on the plasma
membrane or are translocated to the cell surface
in activated and apoptotic neutrophils
17. A plausible mechanism for ANCA vasculitis is the following:
• Drugs or cross-reactive microbial antigens induce release of
PR3 and MPO (e.g., in the setting of infections) incites ANCA
formation in a susceptible host.
• Subsequent infection, endotoxin exposure, or other
inflammatory stimuli elicit cytokines such as TNF that cause
surface expression of PR3 and MPO on neutrophils and other
cell types.
• ANCAs react with these cytokine-activated cells and either
cause direct injury (e.g., to endothelial cells) or induce further
activation (e.g., in neutrophils).
• ANCA-activated neutrophils degranulate and also cause
injury by releasing reactive oxygen species, engendering
endothelial cell toxicity and other indirect tissue injury.
19. Diagrammatic representation of the typical vascular sites involved with the
more common forms of vasculitis, as well as the presumptive etiologies. Note
that there is a substantial overlap in distributions.
ANCA, antineutrophil cytoplasmic antibody; SLE, systemic lupus
21. GIANT-CELL (TEMPORAL)
ARTERITIS the most common form of vasculitis among elderly
individuals in the United States and Europe.
It is a chronic, typically granulomatous inflammation
Vessels affected: large to small-sized arteries principally
the arteries in the head—especially the temporal
arteries—but also the aorta (giant-cell aortitis), the
vertebral and ophthalmic arteries
Ophthalmic arterial involvement can lead to permanent
blindness
22. Pathogenesis.
The cause of giant-cell arteritis remains elusive
most evidence supports an initial T cell–mediated
immune response against an unknown, possibly vessel
wall, antigen.
Pro-inflammatory cytokines (in particular TNF), and
anti–endothelial cell humoral immune responses also
probably contribute.
An immune etiology is supported by the characteristic
granulomatous reaction, a correlation with certain HLA
class II haplotypes, and a therapeutic response to
steroids.
The extraordinary predilection for a single vascular site
(temporal artery) remains unexplained
23. Morphology: involved AA segment show:
nodular intimal thickening reduces the lumenal
diameter.
Classic lesions : medial granulomatous inflammation
that leads to elastic lamina fragmentation
Multinucleated giant cells are found in 75% of
adequately biopsied specimens
Occasionally, granulomas and giant cells are rare or
absent, and lesions show only a nonspecific panarteritis
composed predominantly of lymphocytes and
macrophages.
24. there is an infiltrate of T cells (CD4+>
CD8+) and macrophages.
Inflammatory lesions are not continuous
along the vessel, and long segments of
relatively normal artery may be interposed.
The healed stage is marked by medial
scarring and intimal thickening, typically
with residual elastic tissue fragmentation.
25. B, Elastic tissue stain demonstrating focal destruction of internal elastic lamina
(arrow) and intimal thickening (IT) characteristic of long-standing or healed
arteritis.
C, Examination of the temporal artery of a patient with giant-cell arteritis shows a
26. Clinical Features.
rare before the age of 50.
Symptoms: may be vague and constitutional—fever,
fatigue, weight loss—or include facial pain or headache
that is most intense along the course of the superficial
temporal artery, which can be painful to palpation.
Ocular symptoms: range from diplopia to complete
vision loss.
27. Diagnosis:
depends on biopsy and histologic confirmation.
because giant-cell arteritis is extremely segmental,
adequate biopsy requires at least a 2- to 3-cm length of
artery
a negative biopsy result does not exclude the diagnosis.
Treatment
corticosteroids is generally effective
anti-TNF therapy showing promise in refractory cases
28. TAKAYASU ARTERITIS
Age: younger than 40 years
sex: female predominance
Affected vessels: the aorta and its major branches,with
frequent involvement of the subclavian and carotid arteries;
may also involve coronary, pulmonary, mesenteric, and renal
arteries
Symptoms and signs: fever, malaise, arthralgia, myalgia, and
weight loss, ischemic symptoms
(pulselessness,claudication, and blindness), loss or
asymmetry of pulses and blood pressure, bruits,
renovascular hypertension, and sometimes aortic
aneurysms
29. Takayasu arteritis.
A, Aortic arch
angiogram showing
narrowing of
brachiocephalic,
carotid, and
subclavian arteries
(arrows).
B, Gross photograph
of two cross-sections
of the right carotid
artery taken at
autopsy of the patient
shown in A,
demonstrating marked
intimal thickening with
minimal residual
30. Histopathology:
Variable inflammatory response, including a necrotizing
acute inflammatory cell infiltrate, granulomatous
inflammation with giant cells, or a chronic lymphocytic
infiltrate
Acute phase shows inflammation and neovascularization in
the outer two thirds of media, adventitia, and adventitial fat
Healing lesions may show minimal inflammatory component;
often shows only medial scarring with focal loss of elastic
lamellae and marked intimal and adventitial thickening and
fibrosis
31. C, Histologic
view of active
Takayasu
aortitis,
illustrating
destruction of
the arterial
media by
mononuclear
inflammation
with giant cells
(arrows).
32. Clinical Features.
Initial symptoms : nonspecific (fatigue, weight loss, and fever).
With progression, vascular symptoms including reduced blood
pressure and weaker pulses in the upper extremities; ocular
disturbances, visual defects, retinal hemorrhages, and total
blindness; and neurologic deficits.
Involvement of the more distal aorta may lead to claudication of the
legs;
pulmonary artery involvement may cause pulmonary hypertension.
Narrowing of the coronary ostia may lead to myocardial infarction
involvement of the renal arteries leads to systemic hypertension in
roughly half of patients.
The course of the disease is variable. In some there is rapid
progression, while others enter a quiescent stage at 1 to 2 years,
permitting long-term survival
33. PAN
Idiopathic systemic disease
involving medium-sized and
small muscular arteries
age: fourth to sixth decades
Sex: maleto-female ratio is 2:1
S&S: nonspecific systemic
symptoms of weight loss and
fever with focal symptoms in
the specific organ involved
(peripheral neuropathy,
testicular pain, livedo reticularis,
myalgias, and gastrointestinal
infarction)
Associated with hepatitis B
infection
May become manifest in the
course of hairy cell leukemia,
rheumatoid arthritis, and
Sjِ gren syndrome
KWASAKI (mucocutaneous lymph
node syndrome, infantile PAN)
Acute self-limited disease
Mainly coronary arteries, but
any muscular artery may be
involved; subclavian, axillary,
iliac, femoral, renal, and
superior mesenteric artery
Age: infants and children
(range, 6 months to 15 years;
peaks at 13 to 24 months)
S&S: fever for at least 5 days
and at least four of the following
clinical features:
(conjunctival injection- cervical
lymphadenopathy- oral
mucosal changes-
polymorphous rash- swelling
or redness of the extremities)
34. Gross Pathology
❚ PAN
Tendency to occur at arterial
branching sites
Aneurysms or stenosis of the
arteries may be seen
Thrombosis is common
Kawasaki disease
Coronary ectasia or
aneurysm can be seen in the
acute stage
Regression of aneurysms is
seen in half of the cases
within 1 to 2 years
Progression of aneurysms to
stenotic lesions occurs in
about 10%
35. MICROSCOPIC picture
PAN Kawasaki disease
•various stages of development
● Acute injury : transmural
inflammation with focal
segmental (fibrinoid necrosis)
● Inflammation: initially
neutrophilic , later lymphocytes
and macrophages
● Healing lesions : granulation
tissue within the vessel wall and
luminal narrowing owing to
thrombosis or fibrointimal
proliferation
● Aneurysms and
pseudoaneurysms may develop
•Inflammation: lymphocytes and
macrophages first in the intima
and adventitia, then progresses
into the media
•Panarteritis with neutrophilic
infiltration, disruption of the
internal elastic lamina, smooth
muscle degeneration, and
edema in the media
● Healed lesions show
fibrointimal proliferation,
recanalization, thinning of the
media, destruction of the interna
elastic lamina, and fibrosis in the
adventitia
36. prognosis
PAN
Most patients have a chronic
relapsing course
highdose corticosteroids and
often cyclophosphamide are
typically beneficial
Factors associated with a
poor prognosis include age
greater than 50 years and
gastrointestinal, renal, or
cardiac involvement
Five-year survival rate
approaches 80% if treated
often fatal if untreated
Kwasaki
Coronary artery aneurysm
develops in 15% to 25% of
untreated cases
male patients, infants
younger than 6 months of
age, children older than 8
years, patients who did not
receive intravenous
immunoglobulin treatment or
who have persistent fever
despite treatment are at
highest risk for this
complication
Giant aneurysms (diameter
of coronary lumen ≥ 8 mm)
are at risk for rupture in the
acute phase
become stenotic with
progressive intimal
38. WEGENER
GRANULOMATOSIS
is a necrotizing vasculitis characterized by a triad of
Acute necrotizing granulomas of the upper
respiratory tract (ear, nose, sinuses, throat) or the
lower respiratory tract (lung) or both
Necrotizing or granulomatous vasculitis affecting
small to medium-sized vessels (e.g., capillaries,
venules, arterioles, and arteries), most prominent in
the lungs and upper airways but affecting other sites
as well
Renal disease in the form of focal necrotizing, often
crescentic, glomerulonephritis
39. “Limited” forms of Wegener granulomatosis may be
restricted to the respiratory tract.
a widespread form of the disease can affect eyes,
skin, and other organs, notably the heart;
clinically, this resembles polyarteritis nodosa except
that there is also respiratory involvement.
40. Pathogenesis.
an inhaled infectious or other environmental agent
T cell–mediated hypersensitivity reaction
such a pathogenesis is supported by the presence of
granulomas and a dramatic response to
immunosuppressive therapy.
PR3-ANCAs are present in up to 95% of cases
(diagnostic)
After immunosuppressive treatment, a rising PR3-
ANCA titer suggests a relapse; most patients in
remission have a negative test or falling titers
(prognostic)
41. Morphology.
Upper respiratory tract : range from inflammatory sinusitis
with mucosal granulomas to ulcerative lesions of the nose,
palate, or pharynx, rimmed by granulomas with geographic
patterns of central necrosis and accompanying vasculitis .
The necrotizing granulomas are surrounded by a zone of
fibroblastic proliferation with giant cells and leukocyte
infiltrate, reminiscent of mycobacterial or fungal infections.
Multiple granulomas can coalesce to produce
radiographically visible nodules that can also cavitate
42. late-stage disease may be marked by extensive
necrotizing granulomatous involvement of the
parenchyma.
alveolar hemorrhage may be prominent.
Lesions may ultimately undergo progressive fibrosis
and organization.
A spectrum of renal lesions may be seen : In early
stages, (focal and segmental necrotizing
glomerulonephritis; More advanced glomerular
lesions (crescentic glomerulonephritis).
43. Clinical and Prognosis
Sex: Males > females
age : about 40 years.
classic features :persistent pneumonitis with bilateral
nodular and cavitary infiltrates (95%), chronic sinusitis
(90%), mucosal ulcerations of the nasopharynx (75%),
and evidence of renal disease (80%).
Other features : rashes, muscle pains, articular
involvement, mononeuritis or polyneuritis, and fever.
44. Left untreated, the disease is usually rapidly
fatal; 80% of patients die within 1 year.
Treatment with steroids, cyclophosphamide, and
more recently TNF-antagonists, have turned
Wegener granulomatosis into a chronic remitting
and relapsing disease
45. CHURG-STRAUSS SYNDROME
(allergic granulomatosis and angiitis)
relatively rare
small-vessel necrotizing vasculitis
classically associated with asthma, allergic rhinitis, lung
infiltrates, peripheral hypereosinophilia, and
extravascular necrotizing granulomas.
Morphology: histologically similar to polyarteritis
nodosa or microscopic polyangiitis but are also
characteristically accompanied by granulomas and
eosinophils.
46. Pathogensis:
The etiology remains obscure
but has been suggested to result from hyper-
responsiveness to an allergic stimulus; in asthmatics,
leukotriene receptor antagonists are reported as a
trigger
ANCAs (mostly MPO-ANCAs) are present in less than
half the cases and raise the possibility that there are
distinct subsets of patients with the syndrome.
Nevertheless, when present, the ANCAs are probably
responsible for the vascular manifestations of the
disease.
47. Clinical :
Cutaneous involvement (palpable purpura),
gastrointestinal tract bleeding, and renal disease
(primarily as focal and segmental
glomerulosclerosis) are the major associations.
Myocardial infiltrates of eosinophils and cytotoxicity
caused by them are implicated in the
cardiomyopathy seen in Churg-Strauss syndrome;
the heart is involved in 60% of patients, and
accounts for almost half of the deaths in the
syndrome.
48. MICROSCOPIC
POLYANGIITIS
necrotizing small-vessel vasculitis with few or no immune
deposits
Affecting: arterioles, venules, and capillaries in the skin,
kidneys, and lungs (glomeruli and pulmonary capillaries)
Mean age: of onset is 50 years
Sex: slight male predominance
Symptoms are nonspecific and include hemoptysis,
hematuria, proteinuria, palpable purpura, neuropathy,
myalgias, and arthralgias
Serum-positive p-ANCA is characteristic (70% of cases)
49. Pathogensis:
In some cases, an antibody response to antigens such as
drugs (e.g., penicillin), microorganisms (e.g., streptococci),
heterologous proteins, or tumor proteins has been implicated
this can either result in immune complex deposition or may
trigger secondary immune responses (e.g., the development
of p-ANCAs) that are pathogenic.
most lesions are pauci-immune and MPO-ANCAs are
causally im-plicated.
activation of neutrophils within a particular vascular bed may
be responsible for the disease manifestations.
50. Morphology:
Destruction of the vessel wall by polymorphonuclear and
mononuclear infiltrates, often with leukocytoclasia and segmental
fibrinoid necrosis
Associated hemorrhage is common
Cutaneous lesions often involve upper and middle dermal venules
Pulmonary lesions : inflammation and necrosis of interalveolar
septa and capillaries with neutrophils, nuclear dusts, and intra-
alveolar hemorrhage
Renal lesions: necrotizing and crescentic glomerulonephritis
May affect small and medium-sized arteries
Occasional thrombosis present in arteritis results in tissue
infarction and ulceration
Granulomatous inflammation is not seen
51. Prognosis:
With the exception of those who develop
widespread renal or brain involvement,
cyclophosphamide and steroid
immunosuppression induces remission and
markedly improves long-term survival.
52. OBLITERANS (BUERGER
DISEASE)
Inflammatory and occlusive vascular disorder
affecting : small and medium-sized arteries and veins
Sites: the vessels of the distal upper and lower extremities;
rare involvement of mesenteric arteries and veins
sex: young men who are heavy smokers; occasionally
reported in women smokers
age :before 40 years
Symptoms: advanced disease may present with
claudication, ischemic ulcers, or gangrene
53. Pathogenesis.
The strong relationship to cigarette smoking is
thought to be due to
direct endothelial cell toxicity by some component of
tobacco
or an idiosyncratic immune response to the same
agents.
Most patients have hypersensitivity to intradermally
injected tobacco extracts, and impaired endothelium-
dependent vasodilation when challenged with
acetylcholine.
Genetic influences are suggested by an increased
prevalence in certain ethnic groups (Israeli, Indian
subcontinent, Japanese) and an association with
certain HLA haplotypes.
54. Gross Pathology
Segmental involvement of arteries or veins with acute
or organized thrombosis and luminal narrowing
55. Histopathology
Involves both small and medium-sized arteries and veins
Acute lesions are diagnostic and consist of cellular inflammatory
thrombus and mild acute transmural inflammation without fibrinoid
necrosis
Microabscesses within the thrombus, often with multinucleated
giant cells
Older lesions show organizing thrombosis with chronic
inflammation resulting in luminal occlusion; recanalization is often
seen
Internal elastic lamina remains intact in acute and chronic lesions
Superficial migratory thrombophlebitis with or without inflammatory
thrombus is seen in fewer than half of the patients
56. Prognosis:
No laboratory or serologic tests are useful in
establishing diagnosis
Tobacco use appears to be a universal factor
associated with this condition
Cessation of smoking with or without steroid therapy
usually renders a good prognosis
57. VASCULITIS ASSOCIATED
WITH OTHER DISORDERS Vasculitis resembling hypersensitivity angiitis or classic
polyarteritis nodosa may sometimes be associated with other
disorders, such as rheumatoid arthritis, SLE, cancer, or
systemic illnesses such as Henoch-Schönlein purpura.
Identifying the underlying pathology may be therapeutically
important.
For example, although classic immune complex lupus
vasculitis and antiphospholipid antibody syndrome are
morphologically similar, anti-inflammatory therapy is
required in the former while anticoagulant therapy is
indicated in the latter.
58. INFECTIOUS VASCULITIS
Localized arteritis caused by the direct invasion of infectious
agents
usually bacteria or fungi, and in particular Aspergillus and
Mucor species.
can be part of a localized tissue infection (e.g., bacterial
pneumonia or adjacent to abscesses), or—less commonly—it
can arise from hematogenous seeding of bacteria during
septicemia or embolization from infective endocarditis.
Vascular infections can weaken arterial walls mycotic
aneurysms
or can induce thrombosis and infarction.
