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What are some symptoms associated with vasculitis?



Does vasculitis mostly affect larger or smaller vessels?

Although several forms of vasculitis have a predilection
for relatively large vessels (e.g., large or medium-sized
muscular arteries), most affect small vessels (arterioles,
capillaries, and venules)


The two most common pathogenic mechanisms of
vasculitis are what?

-Immune-mediated inflammation
-Direct vascular invasion by infectious pathogens


The main immunologic mechanisms underlying noninfectious vasculitis are:

• Immune complex deposition
• Antineutrophil cytoplasmic antibodies
• Anti-endothelial cell antibodies
• Autoreactive T cells


What are some vasculitis conditions mediated by immune complex deposition?

Immunologic disorders such as SLE that are associated with autoantibody production.

Only rarely is the specific antigen responsible for immune complex formation known. While immune complexes are occasionally detected in the blood, in most instances it is not clear whether the pathogenic antigen-antibody complexes are deposited from the circulation or form in situ


Immune complex deposition is implicated in what vasculitides?

Drug hypersensitivity vasculitis. In some cases drugs (e.g.,
penicillin) act as haptens by binding to host proteins;
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. Antibody 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 antigen (HBsAg) and anti-HBsAg antibody


How do ANCAs cause vasculitis?

Many patients with vasculitis have circulating antibodies that react with neutrophil cytoplasmic antigens, so-called anti-neutrophil cytoplasmic antibodies (ANCAs).


What are ANCAs?

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.


What are some important ANCAs?

• Antiproteinase-3 (PR3-ANCA), previously called c-ANCA. PR3 is a neutrophil azurophilic granule constituent that shares homology with numerous microbial peptides, possibly explaining the generation of PR3- ANCAs. PR3-ANCAs are associated with Wegener granulomatosis.

• Anti-myeloperoxidase (MPO-ANCA), previously called p-
ANCA. MPO-ANCAs are induced by several therapeutic agents, particularly propylthiouracil. MPO-ANCAs are associated with microscopic polyangiitis and Churg-Strauss syndrome

The close association between ANCA titers and disease
activity suggests a pathogenic role for these antibodies.


What can ANCAs do?

ANCAs can directly activate neutrophils, stimulating the release of reactive oxygen species and proteolytic enzymes; in vascular beds, this may lead to endothelial cell injury.


Where else are ANCAs found?

ANCA antigens (especially PR3) either are constitutively expressed at low levels on the plasma membrane or are translocated to the cell surface in activated and apoptotic leukocytes


Describe the mechanism for ANCA vasculitis.

• 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 up regulate the surface expression of PR3 and MPO on
neutrophils and other cell types

• ANCAs bind these cytokine-activated cells, causing
further activation of neutrophils.

• ANCA-activated neutrophils cause endothelial cell
injury by releasing granule contents and reactive oxygen


T or F. The ANCA autoantibodies are directed against cellular constituents and do not form circulating immune complexes.



What is a condition that causes antibodies against endothelial cells?

Kawasaki disease


What is Giant cell (temporal) arteritis?

The most common form of vasculitis among the elderly in developed countries. It takes the form of chronic, typically granulomatous, inflammation of large to small size arteries


What arteries are most affected by Giant cell arteritis?

mainly those supplying the head—especially the temporal arteries. Vertebral and ophthalmic arteries, as well as the aorta (giant cell aortitis), also can be involved.

Because ophthalmic artery involvement can lead to sudden
and permanent blindness, affected persons must be diagnosed and treated promptly


What causes giant cell arteritis?

The bulk of evidence suggests the culprit is a T cell–mediated immune response to an as-yet uncharacterized vessel wall antigen.

Pro-inflammatory cytokines (especially TNF) and
anti-endothelial cell antibodies also contribute.


Why is an immune etiology suggested for giant cell arteritis?

- characteristic granulomatous inflammation,
- the association with certain MHC class II haplotypes, and - the excellent therapeutic response to steroids

all are in favor of an immune etiology.


How does temporal arteritis present clinically?

- rare before 50.
- Signs and symptoms may be vague and constitutional—fever, fatigue, weight loss—or take the form of facial pain or headache, most intense along the course of the superficial temporal artery, which is painful to palpation.
- elevated ESR


How common is ocular involvement in temporal arteritis patients?

Ocular symptoms

(associated with involvement of the ophthalmic artery)
abruptly appear in about 50% of patients; these range from diplopia to complete vision loss.

Diagnosis depends on biopsy and histology; however, because involvement in temporal arteritis is patchy a negative biopsy result does not exclude the diagnosis.


How is temporal arteritis treated?

Corticosteroid or anti-TNF therapies are effective treatments


What is Takayasu arteritis?

Takayasu arteritis is a granulomatous vasculitis of medium sized and larger arteries characterized principally by ocular
disturbances, upper body weakness, and marked weakening of the pulses in the upper extremities (hence the alternate name, pulseless disease).


Where does Takayasu arteritis typically affect?

Takayasu arteritis classically affects the aortic arch and arch vessels; a third of cases also involve the remainder of the aorta and its branches

Pulmonary arteries are involved in 50% of patients,
and renal and coronary arteries also can be affected


How is Takayasu arteritis differentiated from Temporal arteritis?

Made largely on the basis of a patient’s age; those older than 50 years are designated giant cell aortitis, and those younger than 50 years, Takayasu aortitis.


How does Takayasu arteritis present clinically?

- Constitutional symptoms

- With progression, vascular signs and symptoms appear and dominate the clinical picture.

- Distal aorta disease can manifest as leg claudication, and pulmonary artery involvement can cause pulmonary hypertension.

- Narrowing of the coronary ostia can lead to MI, and

- involvement of the renal arteries causes systemic hypertension in roughly half of the patients.


What vascular signs are common with Takayasu?

-reduced upper extremity blood pressure and pulse strength;
-neurologic deficits; and
-ocular disturbances, including visual field defects, retinal hemorrhages, and total blindness.


Prognosis of Takayasu?

Some cases rapidly progress, while others become quiescent after 1 to 2 years. In the latter scenario, long-term survival, albeit with visual or neurologic deficits, is possible


What is Polyarteritis nodosa (PAN)?

segmental transmural (involve only part of the vessel circumference) necrotizing inflammation of small or medium-sized muscular arteries that typically involves the
renal and visceral vessels and spares the pulmonary circulation.


What is PAN associated with?

There is no association with ANCAs, but a third of
the patients have chronic hepatitis B infection, which leads to the formation of immune complexes containing hepatitis
B antigens that deposit in affected vessels.


What organs are most affected by PAN?

-liver, and
-GI tract


How does PAN present clinically?

primarily a disease of young adults but can occur in all age groups. The clinical course may range from acute to chronic but typically is episodic, with long symptom-free intervals.

The systemic findings are constitutional and vascular involvement in widely scattered


"Classic' presentation of PAN.

- rapidly accelerating hypertension due to renal artery involvement;
- abdominal pain and bloody stools caused by vascular gastrointestinal lesions;
- diffuse muscular aches and pains; and peripheral
neuritis, predominantly affecting motor nerves.

Renal involvement often is prominent and constitutes a major cause of death in these patients.


Treatment of PAN.

Untreated, PAN typically is fatal; however, immuno-suppression can yield remission or cure in 90% of the cases.


What is Kawasaki disease?

Kawasaki disease is an acute, febrile, usually self-limited illness of infancy and childhood (80% of the patients are younger than 4 years of age) associated with an arteritis of
mainly large to medium-sized vessels. Its clinical significance stems from the involvement of coronary arteries.

Coronary arteritis can cause aneurysms that rupture or thrombose, resulting in myocardial infarction.


What causes Kawasaki disease?

In genetically susceptible persons, a variety of infectious agents (mostly viral) have been posited to trigger the disease. The vasculitis may result from a delayed-type hypersensitivity response directed against cross-reactive or newly uncovered vascular antigen(s).

Subsequent cytokine production and polyclonal B cell activation result in autoantibodies to endothelial cells and smooth muscle cells that precipitate the vasculitis.


Clinical presentation of Kawasaki disease.

- conjunctival and oral erythema and blistering,
- edema of the hands and feet,
- erythema of the palms and soles, a desquamative rash,
- cervical lymph node enlargement (hence its other name, mucocutaneous lymph node syndrome).

CRASH and burn


What can Kawasaki disease lead to?

Approximately 20% of untreated patients develop CV sequelae, ranging from asymptomatic coronary arteritis, to coronary artery ectasia, to large coronary artery aneurysms with rupture or thrombosis, MI, and sudden death.


How is Kawasaki disease treated?

With intravenous immunoglobulin therapy and aspirin, the rate of symptomatic coronary artery disease is reduced to about 4%.


What is Microscopic polyangiitis?

a necrotizing vasculitis that generally affects capillaries, as well as small arterioles and venules. It also is called hypersensitivity vasculitis or leukocytoclastic vasculitis


Where does microscopic polyangitis manifest?

The skin, mucous membranes, lungs, brain, heart, gastrointestinal tract, kidneys, and muscle all can be involved;

necrotizing glomerulonephritis (seen in 90% of patients) and pulmonary capillaritis are particularly common


Microscopic polyangitis is associated with what conditions?

a number of immune disorders, such as Henoch-Schönlein purpura, essential mixed cryoglobulinemia, or the vasculitis associated with connective tissue disorders.


How does microscopic polyangitis present?

Depending on the vascular bed involved, major features
include hemoptysis, hematuria, proteinuria, abdominal pain or bleeding, muscle pain or weakness, and palpable cutaneous purpura.


How is microscopic polyangitis treated?

With the exception of patients with widespread renal or CNS involvement, immunosuppression and removal of the offending agent induce durable remissions.


What is Wegner Granulomatosis?

A necrotizing vasculitis characterized
by a specific triad of findings:

• Granulomas of the lung and/or the upper respiratory
tract (ear, nose, sinuses, throat)
• Vasculitis of small to medium-sized vessels (capillaries,
venules, arterioles, and arteries), most prominently inthe lungs and upper respiratory tract
• Glomerulonephritis


What does Wegener's resemble clinically?

clinically, this resembles polyarteritis nodosa with the additional feature of respiratory involvement

common in 40-45 y/o men


What causes Wegener's?

Wegener granulomatosis is likely to be initiated as a
cell-mediated hypersensitivity response directed against
inhaled infectious or environmental antigens. PR3-ANCAs are present in almost 95% of cases and probably drive the
subsequent tissue injury; they also are useful markers of disease activity.

After immunosuppressive therapy, ANCA levels fall dramatically, while rising titers are predictive of


How does Wegener's present clinically?

-bilateral pneumonitis with nodules and cavitary
lesions (95%),
-chronic sinusitis (90%),
-mucosal ulcerations of the nasopharynx (75%), and -renal disease (80%);

patients with low-grade renal involvement may
demonstrate only hematuria and proteinuria responsive to therapy, whereas more severe disease can portend rapidly progressive renal failure.

Rash, myalgias, articular involvement, neuritis, and fever can also occur.


Prognosis of Wegener's?

If untreated, the mortality rate at 1 year is 80%.


What is the treatment for Wegener's?

Treatment with steroids, cyclophosphamide, TNF inhibitors and anti–B cell antibodies (Rituximab) has improved this picture considerably.

Most patients with Wegener granulomatosis now survive,
but remain at high risk for relapses that can ultimately lead to renal failure.


What is Churg Strauss Syndrome?

(also called allergic granulomatosis and angiitis) is a small vessel necrotizing vasculitis classically associated with asthma, allergic rhinitis, lung infiltrates, peripheral
eosinophilia, extravascular necrotizing granulomas, and a striking infiltration of vessels and perivascular tissues by eosinophils


What are the major associations of Churg Stauss?

Cutaneous involvement (with palpable purpura), GI bleeding, and renal disease (primarily as focal and segmental glomerulosclerosis)


What does the the myocardial eosinophilic infiltrates seen in CS cause?

cytotoxicity often leads to cardiomyopathy; cardiac involvement is seen in 60% of patients and is a major cause of morbidity and death.


What causes CS?

may stem from “hyper responsiveness” to some normally innocuous allergic stimulus.

MPO-ANCAs are present in a minority of cases, suggesting that the disorder is pathogenically heterogeneous.


What differentiates CS from polyarteritis nodosa or microscopic polyangiitis?

The vascular lesions differ from those by virtue of the presence of granulomas and eosinophils


What is Thromboangiitis Obliterates (Buerger Disease)?

a distinctive disorder that frequently results in severe vascular insufficiency and gangrene of the extremities.

Characterized by focal acute and chronic inflammation of medium-sized and small arteries, especially the tibial and radial arteries, associated with thrombosis; occasionally, secondary extension into adjacent veins and nerves may be seen.


Patient population with Buerger?

almost exclusively in heavy tobacco smokers and usually develops before age 35


Etiology of Buerger?

unknown. Direct endothelial cell toxicity caused by some component of tobacco is suspected; alternatively,
a reactive compound in tobacco may modify vessel wall components and induce an immune response.

Indeed, most patients with Buerger disease are hypersensitive to tobacco extracts. A genetic predilection is suggested by an increased prevalence in certain ethnic groups (Israeli, Indian subcontinent, Japanese) and an association with certain HLA haplotypes.


How does Buerger Disease present?

Early manifestations include cold-induced Raynaud phenomenon, instep foot pain induced by exercise (instep claudication), and a superficial nodular phlebitis (venous

The vascular insufficiency of Buerger disease tends to be accompanied by severe pain—even at rest—undoubtedly from the neural involvement.

Chronic extremity ulcerations can develop, progressing over time (occasionally precipitously) to frank gangrene.


How can Buerger disease attacks be avoided?

Smoking abstinence in the early stages of the disease often can ameliorate further attacks; however, once established, the vascular lesions do not respond to smoking abstinence.


What else is vasculitis associated with?

- malignancies and immunologic disorders such as rheumatoid arthritis, SLE, antiphospholipid antibody syndrome, and Henoch-Schönlein purpura.

- infections


Infectious vasculitis is common to which pathogens?

Localized arteritis may be caused by the direct invasion of arteries by infectious agents, usually bacteria or fungi, and
in particular Aspergillus and Mucor spp.

Vascular invasion can be part of a more general tissue infection (e.g., bacterial pneumonia or adjacent to abscesses), or—less commonly— arise from hematogenous spread of bacteria during septicemia or embolization from infective endocarditis.