Transcript File

Vasculitis
• Vasculitis is a general term for vessel wall
inflammation.
• The clinical features of the various vasculitides
are protean and largely depend on the vascular
bed affected (e.g., CNS vs. heart vs. small bowel).
• Besides the findings referable to the specific
tissues involved, the clinical manifestations
typically include constitutional signs and
symptoms such as fever, myalgias, arthralgias,
and malaise.
• Vessels of any type in virtually any organ can be
affected, but most vasculitides affect small
vessels ranging in size from arterioles to
capillaries to venules.
• Some 20 primary forms of vasculitis are
recognized, and classification schemes attempt
(with variable success) to group them according
to vessel diameter, role of immune complexes,
presence of specific autoantibodies, granuloma
formation, organ specificity, and even population
demographics
Pathogenesis
• The two common pathogenic mechanisms of vasculitis
are immune-mediated inflammation and direct
invasion of vascular walls by infectious pathogens.
Infections can also indirectly induce a noninfectious
vasculitis, for example, by generating immune complexes
or triggering a crossreactive immune response.
Physical and chemical injury, such as from irradiation,
mechanical trauma, and toxins, can also cause
vasculitis
• In any given patient, it is critical to distinguish
between infectious and immunologic
mechanisms, because immunosuppressive
therapy is appropriate for immune-mediated
vasculitis but could very well be counterproductive for infectious vasculitides
Infectious Vasculitis
Arteritis can be caused by the direct invasion of infectious
agents, usually bacteria (Pseudomonas being the classic
example) or fungi, in particular Aspergillus and Mucor
species.
Vascular invasion can be part of a localized tissue infection (e.g.,
bacterial pneumonia or adjacent to abscesses), or—less commonly—
can arise from hematogenous spread of microorganisms during
septicemia or embolization from infective endocarditis.
Vascular infections can weaken arterial walls and culminate
in mycotic aneurysms, or can induce thrombosis and infarction.
Noninfectious Vasculitis
The major cause of noninfectious vasculitis is a
local or systemic immune response.
Immunologic injury in noninfectious vasculitis
may be caused by:
• Immune complex deposition
• Antineutrophil cytoplasmic antibodies
• Antiendothelial cell antibodies
• Autoreactive T cells
Immune Complex-Associated Vasculitis
This form of vasculitis can be seen in systemic immunologic disorders
such as systemic lupus erythematosus that are associated with
autoantibody production and formation of immune complexes that
deposit in vessels.
This type of vasculitis presents a number of diagnostic challenges. Only
rarely is the specific antigen responsible for immune complex
formation identified. Also, in most cases it is not clear whether the
pathogenic antigen-antibody complexes are deposited from the
circulation or form in situ.
In many suspected cases, even the antigen-antibody deposits are
scarce. In such instances, the immune complexes may have been
degraded by the time of biopsy; alternatively, other mechanisms may
underlie such “pauci-immune” vasculitides.
• Immune complex deposition is also implicated in the following
vasculitides:
Drug hypersensitivity vasculitis: In some cases (e.g.,penicillin), drugs act as
haptens by binding to serum proteins or vessel wall constituents; other
agents are themselves foreign proteins (e.g., streptokinase).
Regardless, antibodies directed against the drug modified proteins or foreign
molecules result in immune complex formation. The clinical manifestations
can be mild and self-limiting, or severe and even fatal; skin lesions are most
common. It is always important to consider drug hypersensitivity as a cause of
vasculitis since discontinuation of the offending agent usually leads to
resolution.
Vasculitis secondary to infections: Antibodies to microbial constituents can
form immune complexes that circulate and deposit in vascular lesions. In up
to 30% of patients with polyarteritis nodosa, the vasculitis is attributable to
immune complexes composed of hepatitis B surface antigens (HBsAg) and
anti-HBsAg antibody.
Antineutrophil Cytoplasmic Antibodies
• ANCAs are a heterogeneous group of autoantibodies
directed against constituents (mainly enzymes) of
neutrophil primary granules, monocyte lysosomes, and
endothelial cells.
• ANCAs are very useful diagnostic markers; their titers
generally mirror clinical severity, and a rise in titers after
periods of quiescence is predictive of disease recurrence.
• Although a number of ANCAs have been described, two are
most important. These were previously grouped according
to the intracellular distribution of the target antigens
(cytoplasmic [c-ANCA] or perinuclear [p-ANCA]), but are
now classified according to their antigen specificity:
• Anti-proteinase-3 (PR3-ANCA, previously c-ANCA):
PR3 is a neutrophil azurophilic granule constituent that shares homology with numerous microbial
peptides, raising the possibility that the generation of PR3- ANCAs is triggered by certain infections.
PR3-ANCAs are associated with polyangiitis.
•
Anti-myeloperoxidase (MPO-ANCA, previously p-ANCA): MPO is a lysosomal granule constituent
involved in oxygen free radical generation (Chapter 3). MPO ANCAs are induced by several
therapeutic agents, particularly propylthiouracil. MPO-ANCAs are associated with microscopic
polyangiitis and Churg-Strauss syndrome.
•
ANCAs can directly activate neutrophils, stimulating the release of reactive oxygen species and
proteolytic enzymes; in vascular beds, such activation also leads to destructive interactions
between inflammatory cells and endothelial cells.
While the antigenic targets of ANCA are primarily intracellular (and therefore not usually
accessible to circulating antibodies), it is now clear that ANCA antigens (especially PR3) are either
constitutively expressed at low levels on the plasma membrane or are translocated to the cell
surface in activated and apoptotic leukocytes.
•
• A plausible mechanism for ANCA vasculitis is the following:
- Drugs or cross-reactive microbial antigens induce ANCA formation;
alternatively, leukocyte surface expression or release of PR3 and MPO (in the
setting of infections) incites ANCA development in a susceptible host.
- Subsequent infection, endotoxin exposure, or inflammatory stimulus elicits
cytokines such as TNF that upregulate the surface expression of PR3 and MPO
on neutrophils and other cell types.
- ANCAs react with these cytokine-activated cells, causing either direct injury
(e.g., to endothelial cells) or further activation (e.g., of neutrophils).
- ANCA-activated neutrophils cause tissue injury by releasing granule
contents and reactive oxygen species.
Since ANCA autoantibodies are directed against cellular constituents and do
not form circulating immune complexes, the vascular lesions do not typically
contain demonstrable antibody and complement. Thus, ANCA-associated
vasculitides are often described as “pauci-immune.”
Antiendothelial Cell Antibodies
• Antibodies to endothelial cells, perhaps
induced by defects in immune regulation, may
predispose to certain vasculitides, for
example, Kawasaki disease
Giant Cell (Temporal) Arteritis
• Giant cell (temporal) arteritis is the most common form of
vasculitis among older individuals in the United States and
Europe
• It is a chronic inflammatory disorder of large to small-sized
arteries that principally affects arteries in the head—
especially the temporal arteries—but also the vertebral
and ophthalmic arteries.
• Ophthalmic arterial involvement can lead abruptly to
permanent blindness; consequently, giant cell arteritis is a
medical emergency requiring prompt recognition and
treatment.
• Lesions also occur in other arteries, including the aorta
(giant cell aortitis)
• Pathogenesis:
Most evidence suggests that giant cell arteritis
stems from a T-cell–mediated immune response
against one of handful of vessel wall antigens that
drives subsequent proinflammatory cytokine
production (particularly TNF). A cellular immune
etiology is supported by the characteristic
granulomatous response, a correlation with certain
MHC class II haplotypes, and a prompt therapeutic
response to steroids.
• MORPHOLOGY:
- Involved arterial segments develop intimal thickening
that reduces the luminal diameter.
- Classic lesions exhibit medial granulomatous
inflammation centered on the internal elastic lamina
that produce elastic lamina fragmentation
- An infiltrate of T cells (CD4+ > CD8+) and macrophages.
Inflammatory lesions are only focally distributed along
the vessel (segmental)
Clinical Features:
- Giant cell arteritis is rare before age 50.
- Symptoms may be only vague and constitutional—fever, fatigue,
weight loss—or there may be facial pain or headache, most intense
along the course of the superficial temporal artery, which can be
painful to palpation. Ocular symptoms (associated with
involvement of the ophthalmic artery) appear abruptly in about
50% of patients; these range from diplopia to complete vision loss.
- Diagnosis depends on biopsy and histologic confirmation. However,
because giant cell arteritis can be extremely focal within an artery,
adequate biopsy requires at least a 1-cm segment; even then, a
negative biopsy result does not exclude the diagnosis.
- Corticosteroids or anti-TNF therapies are typically effective.
Takayasu Arteritis
• This is a granulomatous vasculitis of medium and larger
arteries characterized principally by ocular disturbances
and marked weakening of the pulses in the upper
extremities (hence the name pulseless disease).
• manifests with transmural fibrous thickening of the aorta—
particularly the aortic arch and great vessels—with severe
luminal narrowing of the major branch vessels
• shares many attributes with giant cell aortitis, including
clinical features and histology. Indeed, the distinction is
typically made based on the age of the patient; younger
than 50
Polyarteritis Nodosa
• Polyarteritis nodosa (PAN) is a systemic vasculitis of
small- or medium-sized muscular arteries, typically
involving renal and visceral vessels but sparing the
pulmonary circulation.
• about 30% of patients with PAN have chronic hepatitis
B and deposits containing HBsAg-HBsAb complexes in
affected vessels, indicating an immune complex–
mediated etiology in that subset.
• The cause remains unknown in the remaining cases;
there may be etiologic and clinical distinctions between
classic idiopathic PAN, the cutaneous forms of PAN,
and the PAN associated with chronic hepatitis.
• MORPHOLOGY:
• Classic polyarteritis nodosa is characterized by segmental transmural
necrotizing inflammation of small- to medium sized arteries.
• Vessels of the kidneys, heart, liver, and gastrointestinal tract are involved
in descending order of frequency. The inflammatory process weakens the
arterial wall and can lead to aneurysms or even rupture. Impaired
perfusion with ulcerations, infarcts, ischemic atrophy, or hemorrhages
may be the first sign of disease.
• During the acute phase, there is mixed infiltrate of neutrophils,
eosinophils, and mononuclear cells, frequently accompanied by fibrinoid
necrosis . Later, the acute inflammatory infiltrate is replaced by fibrous
(occasionally nodular) thickening of the vessel wall that can extend into
the adventitia.
• Characteristically, all stages of activity (from early to late) may coexist in
different vessels or even within the same vessel, suggesting ongoing and
recurrent insults.
• Clinical Features.:
- Although typically a disease of young adults, PAN can also occur in
pediatric and geriatric populations.
- Clinical manifestations result from ischemia and infarction of
affected tissues and organs.
- The course is frequently remitting and episodic, with long
symptom-free intervals.
- A “classic” presentation can involve some combination of rapidly
accelerating hypertension due to renal artery involvement;
abdominal pain and bloody stools caused by vascular
gastrointestinal lesions; diffuse myalgias; and peripheral neuritis,
predominantly affecting motor nerves. Renal involvement is often
prominent and a major cause of mortality.
- Untreated, PAN is typically fatal; however, immunosuppression can
yield remissions or cures in 90% of cases.
Kawasaki Disease
• Kawasaki disease is an acute febrile, usually self-limited
illness of infancy and childhood (80% of patients are 4
years old or younger);
• it is associated with an arteritis affecting large to
medium-sized, and even small vessels.
• Its clinical significance stems primarily from a
predilection for coronary artery involvement that can
cause aneurysms that rupture or thrombose, resulting
in acute myocardial infarctions.
• Originally described in Japan, the disease has a
worldwide distribution and is the leading cause of
acquired heart disease in children.
• The pathogenesis of Kawasaki disease is
unknown. A variety of infectious agents
(mostly viral) have been implicated in
triggering the disease in genetically
susceptible individuals. The vascular damage
is primarily mediated by activated T cells and
monocytes/macrophages.
• MORPHOLOGY:
The vasculitis resembles that seen in
polyarteritis nodosa, although the fibrinoid
necrosis is usually less prominent than in PAN.
• Clinical Features:
• Kawasaki disease typically presents with conjunctival and oral
erythema and blistering, edema of the hands and feet, erythema of
the palms and soles, a desquamative rash, and cervical lymph node
enlargement (hence its other name, mucocutaneous lymph node
syndrome).
• Approximately 20% of untreated patients develop cardiovascular
sequelae, ranging from asymptomatic coronary arteritis, to
coronary artery ectasia, to giant coronary artery aneurysms (7 to 8
mm) leading to rupture or thrombosis, myocardial infarction, and
sudden death.
• If the disease is recognized early in its course, treatment with
intravenous immunoglobulin and aspirin sharply reduce the risk of
symptomatic coronary artery disease.
Microscopic Polyangiitis
• Microscopic polyangiitis is a necrotizing vasculitis that
generally affects capillaries, as well as small arterioles
and venules.
• It is also called hypersensitivity vasculitis or
leukocytoclastic vasculitis.
• Necrotizing glomerulonephritis (90% of patients) and
pulmonary capillaritis are particularly common.
• Can be a feature of a number of immune disorders,
such as Henoch-Schönlein purpura, essential mixed
cryoglobulinemia, and vasculitis associated with
connective tissue disorders.
• Pathogenesis: In some cases, antibody responses to
antigens such as drugs (e.g., penicillin), microorganisms
(e.g., streptococci), heterologous proteins, or tumor
proteins have been implicated. These can either lead to
immune complex deposition or trigger secondary
immune responses (e.g., the development of ANCAs)
that are pathogenic. Indeed, most cases are associated
with MPO-ANCA.
• Recruitment and activation of neutrophils within
affected vascular beds is likely responsible for the
disease manifestations.
• MORPHOLOGY:
These lesions morphologically resemble PAN but
typically spare medium-sized and larger arteries;
consequently, infarcts are uncommon.
In some areas (typically postcapillary venules), only
infiltrating neutrophils, many undergoing apoptosis,
are seen, giving rise to the term leukocytoclastic
vasculitis (Fig. 11-27A). little or no immunoglobulin
are found in most lesions (so-called “pauci-immune
injury”).
• Clinical Features:
Depending on the vascular bed involved,
major clinical features include hemoptysis,
hematuria and proteinuria, bowel pain or bleeding,
muscle pain or weakness, and palpable cutaneous
purpura.
Except in those in whom widespread renal or brain
involvement develop, immunosuppression induces
remission and markedly improves long-term
survival
Churg-Strauss Syndrome
• Churg-Strauss syndrome is a small-vessel necrotizing
vasculitis classically associated with asthma, allergic
rhinitis, lung infiltrates, peripheral hypereosinophilia, and
extravascular necrotizing granulomata.
• Also called allergic granulomatosis and angiitis, it is a
relatively rare disease.
• Vascular lesions can be histologically similar to
polyarteritis nodosa or microscopic polyangiitis, but are
also characteristically accompanied by granulomas and
eosinophils.
• ANCAs (mostly MPO-ANCAs) are present in less than half
the cases, when present, the ANCAs are likely involved in
the pathogenesis of the vascular lesions.
Behçet Disease
• Behçet disease is a small- to medium-vessel
neutrophilic vasculitis that classically presents
as a clinical triad of recurrent oral aphthous
ulcers, genital ulcers, and uveitis.
• There is an association with certain HLA
haplotypes (HLA-B51, in particular) and a
cross-reactive immune response to certain
microorganisms is implicated.
Granulomatosis with Polyangiitis
• Previously called Wegener granulomatosis
• It is a necrotizing vasculitis characterized by a triad of:
1- Necrotizing granulomas of the upper respiratory tract (ear, nose, sinuses,
throat) or the lower respiratory tract (lung) or both.
2- 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 involving other sites as well.
3- Focal necrotizing, often crescentic, glomerulonephritis.
• “Limited” forms of this disease may be restricted to the respiratory tract.
Conversely, a widespread form of the disease can affect eyes, skin, and
other organs, notably the heart; clinically, this resembles PAN except that
there is also respiratory involvement.
• Pathogenesis:
Granulomatosis with polyangiitis likely represents a
form of T-cell–mediated hypersensitivity response
to normally “innocuous” inhaled microbial or other
environmental agents; such a pathogenesis is
supported by the presence of granulomas and a
dramatic response to immunosuppressive therapy.
PR3-ANCAs are also present in up to 95% of cases;
they are a useful marker of disease activity and may
participate in disease pathogenesis. Most patients
in remission have a negative test or falling titers
• MORPHOLOGY:
Upper respiratory tract lesions 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 proliferating
fibroblasts associated with giant cells and leukocytic infiltrate, reminiscent of
mycobacterial or fungal infections.
Multiple granulomas can coalesce to produce radiographically visible nodules
that can also cavitate; late stage disease may be marked by extensive
necrotizing granulomatous involvement of the parenchyma , and alveolar
hemorrhage may be prominent.
A spectrum of renal lesions can be seen . In early stages, glomeruli exhibit
only focal necrosis(focal and segmental necrotizing glomerulonephritis). More
advanced glomerular lesions are characterized by crescentic
glomerulonephritis.
• Clinical Features:
- Males are affected more often than females, at an average age of
about 40 years.
- Classic features include 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 include rashes, myalgias, articular involvement,
neural inflammation, and fever.
- Left untreated, the disease is usually rapidly fatal, with 80%
mortality within 1 year.
- Treatment with steroids, cyclophosphamide, and more recently
TNF antagonists have turned this formerly fatal condition into a
chronic relapsing and remitting disease.
Thromboangiitis Obliterans
(Buerger Disease)
• Thromboangiitis obliterans (Buerger disease) is
characterized by segmental, thrombosing, acute
and chronic inflammation of medium-sized and
small arteries,principally the tibial and radial
arteries, with occasional secondary extension
into the veins and nerves of the extremities.
• It is a distinctive disease that often leads to
vascular insufficiency, typically of the
extremities.
• It occurs almost exclusively in heavy cigarette
smokers, usually before age 35.
• Pathogenesis:
The strong relationship with cigarette smoking
may stem from either a direct idiosyncratic
endothelial cell toxicity caused by some component
of tobacco, or an immune response to components
of tobacco smoke that modify host vascular wall
proteins.
There is an increased prevalence in certain ethnic
groups (Israeli, Indian subcontinent, Japanese) and
an association with particular HLA haplotypes.
• Clinical Features:
• Early manifestations include cold induced Raynaud phenomenon ,
leg pain induced by exercise that is relieved on rest (intermittent
claudication), instep foot pain induced by exercise (instep
claudication), and a superficial nodular phlebitis (venous
inflammation).
• severe pain—even at rest—undoubtedly due to the neural
involvement.
• Chronic extremity ulcerations develop, progressing over time to
frank gangrene.
• Smoking abstinence in the early stages of the disease can often
ameliorate further attacks; however, once established, the vascular
lesions typically do not respond to smoking abstinence.