Chapter 11- Vasculitis Flashcards
What is vasculitis?
Vasculitis is a general term for vessel wall inflammation.
What are the clinical features of various vasculitis?
The clinical features of the various
vasculitides are diverse and largely depend on the vascular bed affected (e.g., central nervous
system vs. heart vs. small bowel).
Besides the findings referable to the specific tissue(s)
involved, the clinical manifestations typically include constitutional signs and symptoms such as
fever, myalgias, arthralgias, and malaise.
What vessels are affected by vasculitis?
- Vessels of any type
- in virtually any organ can be affected
What vessel is mostly affected by vasculitis?
most vasculitides involve small
vessels, from arterioles to capillaries to venules. [63] ]
Several of the vasculitides tend to affect only vessels of a particular size or particular vessel beds.
There are vasculitic entities that
primarily affect the aorta and medium-sized arteries, while others principally affect only smaller
arterioles.
Some 20 primary forms of vasculitis are recognized, and classification schemes attempt (with variable success) to group them according to vessel size, role of immune complexes, presence of specific autoantibodies, granuloma formation, organ specificity, and even population demographics! Though a subject of ongoing evolution, [64] the so-called Chapel Hill nomenclature remains the most widely accepted approach to organizing this diverse group of entities [65] ( Table 11-4 and Fig. 11-22 ). As we will see, there is considerable clinical
and pathologic overlap among many of them.
TABLE 11-4 – Classification and Characteristics of Selected Immune-Mediated
Vasculitides
Vasculitis
Type
- LARGE-VESSEL VASCULITIS
- Aorta and large branches to extremities, head, and neck
- MEDIUMVESSEL
- Main visceral arteries and their branches
- VASCULITIS
- SMALL-VESSEL
VASCULITIS - Arterioles, venules, capillaries, and occasionally small arteries
TABLE 11-4 – Classification and Characteristics of Selected Immune-Mediated
Vasculitides
LARGE-VESSEL
VASCULITIS
- EXAMPLE: Giant-cell (temporal) arteritis
Granulomatous inflammation; frequently involves the temporal artery.
Usually occurs in patients older than age 50 and is
associated with polymyalgia rheumatica
2M: Malaki at Matanda
TABLE 11-4 – Classification and Characteristics of Selected Immune-Mediated
Vasculitides
Aorta and large branches to extremities, head,
and neck
Takayasu arteritis
Granulomatous inflammation usually occurring in patients
younger than age 50
TABLE 11-4 – Classification and Characteristics of Selected Immune-Mediated
Vasculitides
MEDIUMVESSEL
VASCULITIS
Polyarteritis
nodosa
Necrotizing inflammation typically involving renal arteries but sparing pulmonary vessels
Walang Pulmo
TABLE 11-4 – Classification and Characteristics of Selected Immune-Mediated
Vasculitides
Main visceral arteries and their branches
Kawasaki disease
Arteritis with mucocutaneous lymph node syndrome; usually occurs in children.
Coronary arteries can be involved with
aneurysm formation and/or thrombosis
TABLE 11-4 – Classification and Characteristics of Selected Immune-Mediated
Vasculitides
SMALL-VESSEL
VASCULITIS
Wegener granulomatosis
Granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small vessels, including
glomerular vessels. Associated with PR3-ANCAs
TABLE 11-4 – Classification and Characteristics of Selected Immune-Mediated
Vasculitides
Arterioles,
venules,
capillaries, and
occasionally small
arteries
- Churg-Strauss syndrome
- Microscopic polyangiitis
TABLE 11-4 – Classification and Characteristics of Selected Immune-Mediated
Vasculitides
Arterioles, venules, capillaries, and occasionally small arteries
Churg-Strauss
syndrome
Churg-Strauss
syndrome
Eosinophil-rich granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small vessels.
- *Associated with asthma and blood eosinophilia.**
- *Associated with MPO-ANCAs**
TABLE 11-4 – Classification and Characteristics of Selected Immune-Mediated
Vasculitides
Arterioles, venules, capillaries, and occasionally small arteries
Microscopic
polyangiitis
Necrotizing small-vessel vasculitis with few or no immune
deposits; necrotizing arteritis of small and medium-sized
arteries can occur.
Necrotizing glomerulonephritis and
pulmonary capillaritis are common.
Associated with MPOANCAs.
large- and medium-sized vessel vasculitides involve vessels smaller than arteries.
T or F
FALSE
Note that 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.
FIGURE 11-22 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 erythematosus.
What are the two most common pathogenic mechanisms of vasculitis
- immune-mediated inflammation and
- direct invasion of vascular walls by infectious pathogens.
Predictably, infections can also indirectly induce a noninfectious vasculitis how?
generating immune complexes or
triggering cross-reactivity.
In any given patient, it is critical to distinguish between infectious and immunological mechanisms,
Why?
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.
T or F
True
The main immunological mechanisms that initiate noninfectious vasculitis are
(1) immune complex deposition
, (2) antineutrophil cytoplasmic antibodies, and
(3) anti–endothelial cell antibodies.
What is Immune Complex–Associated Vasculitis?
The lesions resemble those found in experimental immune complex–mediated conditions such
as the Arthus reactionandserum sickness ( Chapter 6 ).
Many systemic immunological diseases, such as systemic lupus erythematosus (SLE) and polyarteritis nodosa, manifest as immune complex-mediated vasculitis.
Antibody and complement are typically detected in
vasculitic lesions, although 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 [Chapter 6]), but the sensitivity and
specificity of circulating immune complex assays in such diseases are low.
In addition, immune
complexes are implicated in the following vasculitides:
- Immune complex deposition underlies the vasculitis associated with drug hypersensitivity.
- secondary to viral infections
Immune complex deposition underlies the vasculitis associated with drug
hypersensitivits, what is the mechanism?
. In some cases (e.g., penicillin) the drugs bind to serum proteins; other agents, like streptokinase, are themselves foreign proteins.
In either case, antibodies
directed against the drug-modified proteins or foreign molecules lead to the formation of immune complexes.
Manifestations vary widely but are most frequently seen in the skin
(see below); 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.
How does vasculitis occur secondary to viral infections?
In vasculitis secondary to viral infections, antibody to viral proteins forms immune complexes that can be found in the serum and the vascular lesions.
Thus, as many as
30% of patients with polyarteritis nodosa (see below) have an underlying hepatitis B infection that produces a vasculitis attributable to complexes of hepatitis B surface antigen (HBsAg) and anti-HbsAg antibody.
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 if they form in situ from the seeding of antigen in a vessel wall followed by antibody binding ( Chapter 6 ).
Moreover, in many cases of presumed immune complex vasculitis, antigen-antibody deposits
are scarce
. Either the immune complexes have been largely cleared at the time that the tissue
diagnosis is made, or else other mechanisms may apply in such “pauci-immune” cases
What are antineutrophil cytoplasmic antibodies (ANCAs)?
Many patients with vasculitis have circulating antibodies that react with neutrophil cytoplasmic
antigens, so-called antineutrophil cytoplasmic antibodies (ANCAs) .
ANCAs are a
heterogeneous group of autoantibodies directed against constituents (mainly enzymes) of neutrophil primary granules, monocyte lysosomes, and endothelial cells.
ANCA were
classified according to their:
intracellular distribution,
- either cytoplasmic (c-ANCA) or
- perinuclear (p-ANCA)
.
More commonly now, ANCAs are discriminated based on their target antigens:
- Anti-myeloperoxidase (MPO-ANCA):
- Anti-proteinase-3 (PR3-ANCA)
What is MPO?
MPO is a lysosomal granule constituent normally
involved in generating oxygen free radicals ( Chapter 2 ). MPO-ANCAs can be induced
by a variety of therapeutic agents, in particular propylthiouracil. These have been called
p-ANCA.
How can MPO-ANCAs can be induced?
MPO-ANCAs can be induced
by a variety of therapeutic agents, in particular propylthiouracil.
These have been called
p-ANCA.
What is Anti-proteinase-3 (PR3-ANCA)?
Anti-proteinase-3 (PR3-ANCA):
PR3 is also a neutrophil azurophilic granule constituent.
That it shares homology with numerous microbial peptides may explain how PR3-ANCAs
develop. [66] These have been called c-ANCA.
Although not entirely specific, PR3-ANCAs are typical of what?
Wegener granulomatosis
Although not entirely specific,MPOANCAs are typical of what?
- microscopic polyangiitis and Churg-Strauss syndrome (see below);
racial and geographic variables also influence the association of particular ANCAs and disease
entities
T or F
True
Why do ANCAs serve as useful diagnostic markers for the ANCA-associated vasculitides?
ANCAs serve as useful diagnostic markers for the ANCA-associated vasculitides, and their titers
may reflect the degree of inflammatory activity.
ANCA titers also rise with recurrent disease and
are therefore useful in clinical management.
The close association between ANCA titers and
disease activity suggests a pathogenic role.
Although the precise mechanisms are unknown,
ANCA can directly activate neutrophils and may thereby stimulate neutrophils to release
reactive oxygen speciesandproteolytic enzymes; within the vasculature, this also leads to
endothelial cell-neutrophil interactions and subsequent endothelial cell damage. [67]
Why do ANCAs might not be expected to be accessible to circulating antibodies?
antigenic targets of ANCAs are primarily intracellular
but there is now abundant evidence that ANCA antigens
(in particular PR3) are either constitutively present at low levels on the plasma membrane or
are translocated to the cell surface in activated and apoptotic neutrophils
A plausible mechanism for ANCA vasculitis is the following:
- Drugs or cross-reactive microbial antigens induce ANCAs; alternatively, neutrophil surface expression or 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.
Interestingly, ANCAs directed against constituents other than PR3 and MPO are also found in
some patients with inflammatory disorders that do not involve vasculitis (e.g., inflammatory
bowel disease, primary sclerosing cholangitis, rheumatoid arthritis).
T or F
True
Antibodies to endothelial cells may predispose to certain vasculitides, for example is what?
Kawasaki
disease
We will now briefly present several of the best-characterized vasculitides, again emphasizing
that there is substantial overlap among the different entities. Moreover, it should be kept in mind
that some patients with vasculitis do not have a classic constellation of findings that allows them
to be neatly pigeonholed into one specific diagnosis.
What is Giant-cell (temporal) arteritis?
- most common form of vasculitis among elderly individuals in the United States and Europe.
- It is a chronic, typically granulomatous inflammation of large to small-sized arteries that
- affects principally the arteries in the head—especially the temporal arteries—but also the vertebral and ophthalmic arteries. [71]
Giant cell arteritis principally affects the artery of the head particularly what?
temporal arteries—but also the vertebral and ophthalmic arteries. [71]
In Ophthalmic arterial involvement of Gian arteritis can lead and result to what?
can lead to permanent blindness; consequently, giant-cell arteritis is a medical emergency
requiring prompt recognition and treatment
consequently, giant-cell arteritis is a medical emergency
requiring prompt recognition and treatment
T or F
True
Giant cell Arteritis can also occur where aside from the head and vertebra?
. Lesions also occur in other arteries, including the
aorta (giant-cell aortitis)
What is the pathogenesis of Giant cell arteritis?
remains elusive, although most evidence supports an initial T cell–mediated immune response against an unknown, possibly vessel wall, antigen.
Proinflammatory cytokines (in **particular TNF)**, and **anti–endothelial cell humoral immune responses also probably contribute.**[72]
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.
What is the morphology of Giant Arteritis?
Involved arterial segments develop nodular intimal thickening (withoccasional thromboses) that reduces the lumenal diameter.
Classic lesions exhibit medial granulomatous inflammation that leads to elastic lamina fragmentation; there is an infiltrate of T cells (CD4+> CD8+) and macrophages.
Multinucleated giant cells are found in
upwards of 75% of adequately biopsied specimens ( Fig. 11-23 ).
Occasionally, granulomas
and giant cells are rare or absent, and lesions show only a nonspecific panarteritis composed predominantly of lymphocytes 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.
FIGURE 11-23 Giant-cell (temporal) arteritis.
- A, H&E stain of section of temporal artery showing giant cells at the degenerated internal elastic lamina in active arteritis (arrow).
- 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 thickened, nodular, and tender segment of a vessel on the surface of head (arrow).
FIGURE 11-24 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 lumen.
C, Histologic view of
active Takayasu aortitis, illustrating destruction of the arterial media by mononuclear
inflammation with giant cells (arrows).
FIGURE 11-25 Polyarteritis nodosa.
There is segmental fibrinoid necrosis and thrombotic
occlusion of the lumen of this small artery. Note that part of the vessel wall at the upper
right (arrow) is uninvolved.
FIGURE 11-26 Representative forms of ANCA-associated small-vessel vasculitis.
A, Leukocytoclastic vasculitis (microscopic polyangiitis) with fragmentation of neutrophils in
and around blood vessel walls. B and C, Wegener granulomatosis.
B, Vasculitis of a small
artery with adjacent granulomatous inflammation including epithelioid cells and giant cells
(arrows). C, Gross photo from the lung of a patient with fatal Wegener granulomatosis,
demonstrating large nodular centrally cavitating lesions
FIGURE 11-27 Thromboangiitis obliterans (Buerger disease). The lumen is occluded by a
thrombus containing abscesses (arrow), and the vessel wall is infiltrated with leukocytes
