Systemic Vasculitis

 The primary systemic vasculitides are

inflammatory disorders of blood vessels that are
characterized by immune-mediated injury leading
to vessel necrosis, thrombosis, stenosis, or some
combination of these.
 Vessels in any organ may be affected, but each
vasculitis is characterized by different preferential
vessel size or territory and tissue targeting.
 They may be organ- or life-threatening, so prompt
diagnosis and treatment are necessary.
 The vasculitides are defined based on generally
affected vessel size (small, medium, or large).
 Antineutrophil cytoplasmic antibody (ANCA)–
associated vasculitides (AAVs) have known
associations with characteristic autoantibodies.
 Small Vessel Vasculitis:
ANCA-Associated Vasculitides (AAVs):
 Granulomatosis with polyangiitis (GPA; previously
known as Wegener’s granulomatosis).
 Microscopic polyangiitis (MPA).
 Eosinophilic granulomatosis with polyangiitis
(EGPA; previously known as Churg-Strauss
syndrome).
 Renal-limited vasculitis (RLV).
 Affect small and medium-sized blood vessels and
may be associated with ANCA.
 AAVs to have an incidence of approximately 10 to
20 per million.
 The peak age at onset is 65 to 74 years, with a
female-to-male ratio of 1.5:1.
 EGPA is the least common of the AAVs, with an
incidence of approximately 1.0 to 3.0 per million,
and it also has a weaker association with ANCA
than GPA and MPA.
Henoch-Schönlein Purpura:
 Henoch-Schönlein purpura (HSP) is a small vessel
vasculitis that occurs most frequently in young
children, with a peak age at onset of 4 to 6 years,
but can also occur in adults.
 HSP accounts for almost half of all cases of
childhood vasculitis.
 In children younger than 17 years of age, the
annual incidence of HSP is approximately 20 per
100,000.
 Males are more commonly affected than females
(approximately 2:1), and HSP occurs more
frequently during the winter and spring months.
 Medium Vessel Vasculitis

 Polyarteritis nodosa (PAN) is a medium vessel

vasculitis that is characterized by arterial
aneurysmal and stenotic lesions of muscular
arteries, often located at segmental and branch
points.
 In contrast to small vessel vasculitis, renal
involvement in PAN is not characterized by
glomerulonephritis but rather by aneurysms and
stenoses of renal arteries
that may result in hypertension or renal dysfunction
or both.
 ANCAs are usually negative in PAN.
 PAN may occur either as a primary vasculitis or
secondary to viral infections, mainly hepatitis
B or C, or human immunodeficiency virus (HIV).
 Kawasaki disease is a medium vessel vasculitis
most often seen in boys younger than 5 years of
age.
 It is the second most common vasculitis in
childhood after HSP, accounting for about 23% of
all childhood
 Large Vessel Vasculitis

 Giant cell arteritis (GCA), also known as

temporal arteritis, is the most common form of
vasculitis in adults.
 It is a large vessel vasculitis that typically affects
patients of Eastern European descent, with a
mean age at onset of 70 to 75 years.
 It affects women more commonly than men (3:1).
 About 40% of patients with GCA have the related
condition, polymyalgia rheumatica (PMR), which
is characterized by subacute onset of aching and
stiffness in the muscles of the neck, shoulder
girdle,
and hip girdle.
 Only 10% to 25% of patients with PMR have or
will develop GCA.
 Takayasu’s arteritis (TAK), or “pulseless
disease,” is a rare large vessel vasculitis that
was initially identified in young women from East
Asia but is now described worldwide. In adults,
the female-to-male ratio is about 8:1, with an
average age at diagnosis in the mid-20s.
 PATHOLOGY
 Proposed triggers of disease include infection and
environmental exposures (e.g., chemicals,
 Among the AAVs, the pathology of GPA is typically
pollutants).
characterized by necrotizing granulomatous
 Humoral and cellular immune responses, cytokine
inflammation of small blood vessels supplying the
release, chemokine activation, and immune complex
upper and lower respiratory tract.
deposition are important in disease pathogenesis.
 In both GPA and MPA, renal pathology shows a
 Normal protective and repair processes in the vessel
pauci-immune necrotizing crescentic
can also contribute to injury and ischemia.
glomerulonephritis.
 For example, after injury, cellular migration and
 In EGPA, there is a strong association with allergic
proliferation occurring as part of vessel repair can
and atopic disorders, including allergic rhinitis,
result in intimal hyperplasia, and the procoagulant
nasal polyposis, and asthma.
milieu that is protective against hemorrhage may
 Approximately 70% of patients with EGPA have
lead
elevated levels of immunoglobulin E (IgE) and
to thrombosis and vessel occlusion.
eosinophilia of peripheral blood and tissue.
 Impairment of blood flow in injured vessels results in
 Small vessel histopathology typically reveals
tissue ischemia and damage.
transmural
 The degree of blood flow impairment varies along a
eosinophilic infiltrates with scattered plasma cells
broad spectrum of severity and may depend on the
and lymphocytes and extravascular granulomas.
type of vasculitis as well as the size and location of
the vessels involved.
 The pathology of HSP is characterized by a
leukocytoclastic vasculitis of small vessels with IgA
deposition seen on immunofluorescence.
 Various infectious agents, including bacteria and
viruses, have been reported as triggers for HSP.
 The pathology of GCA and TAK are very similar
histologically.
 In both, large vessels demonstrate a
lymphoplasmacytic inflammatory infiltrate.
 Giant cells and granulomas may be seen in the
media, and lumen-occlusive arteritis may occur
from exuberant intimal hyperplasia.
 Additional pathologic features include proliferation
of vascular smooth muscle cells and fragmentation
of the internal elastic lamina.
 CLINICAL PRESENTATION AND DIAGNOSIS

 Clinical manifestations of the systemic

vasculitides are diverse and differ not only
among disorders but also among patients.
 Typical clinical manifestations associated with
the size of the affected vessel.
 Fever, weight loss, malaise, anorexia,
arthralgias,
and myalgias may occur with all vasculitides.
Small Vessel Vasculitis
ANCA-Associated Vasculitides
 GPA most commonly affects the sinuses and upper
airway, the lungs, and the kidneys, although almost
any organ system may be affected.
 Chronic refractory sinusitis, nasal crusting and
ulcers, epistaxis, septal perforations, and otitis
media are common presenting manifestations.
 Chronic nasal cartilaginous inflammation and
destruction may lead to the characteristic “saddle
nose” deformity.
 Lung involvement in GPA or MPA can include
pulmonary nodules (often cavitary in GPA),
infiltrates, or diffuse alveolar hemorrhage due to
capillaritis.
 Life-threatening pulmonary hemorrhage may
manifest simply as progressive acute dyspnea with
hypoxia or respiratory failure, and not necessarily
hemoptysis.
 Laryngotracheal disease may manifest as
hoarseness or subglottic stenosis; orbital
pseudotumors can also occur
 The renal manifestations in GPA, MPA, or RLV
are those of nephritic syndrome, including acute
renal failure, hematuria, hypertension, and
subnephrotic proteinuria. Urine microscopy may
reveal dysmorphic red blood cells.
 Renal biopsy reveals pauci-immune necrotizing
crescentic glomerulonephritis.
 Additional organ manifestations that may occur in
either GPA or MPA include neurologic, cutaneous,
musculoskeletal, cardiovascular, and
constitutional signs and symptoms.
 Patients may have subacute symptoms (weeks to
months of sinusitis, arthralgias, and fatigue) or
may exhibit acute “pulmonary-renal syndrome”
with rapidly progressive glomerulonephritis and
life-threatening alveolar hemorrhage with
respiratory
failure.
 In EGPA, the clinical features comprise severe  The differential diagnosis for positive ANCA
asthma, eosinophilia (>1500 cells/mL), and testing includes drug-induced effects, infections,
vasculitis involving two or more organs. and other autoimmune conditions.
 Additional organ involvement in EGPA may  EGPA can be distinguished from other AAVs on
include the nervous system, kidneys, skin, heart, the basis of a prior history of adult-onset asthma
and gastrointestinal tract. or allergic rhinitis and blood or tissue
 Sinus involvement in EGPA is typically not eosinophilia.
destructive as in GPA, and pulmonary infiltrates  The differential diagnosis for any small vessel
may be fleeting. vasculitis includes infection, disorders of
 The diagnosis of any of the AAVs is most coagulation, drug toxicity, atherosclerotic and
frequently established by tissue biopsy (e.g., embolic disease, malignancy, and secondary
kidney, lung, skin, sinus, nerve). vasculitides associated with other autoimmune
 ANCA testing plays an important diagnostic role diseases.
in suspected small vessel vasculitis and is
helpful in differentiating between GPA and MPA.
 Almost 90% of patients with renal disease have
positive ANCA on testing. Most GPA patients
have the cytoplasmic (cANCA) antiproteinase 3
(anti-PR3)
type, whereas most MPA patients have the
perinuclear (pANCA) antimyeloperoxidase (anti-
MPO) type.
Henoch-Schönlein Purpura  The differential for HSP includes other causes of
abdominal pain, other causes of purpura in
 Patients with HSP have lower extremity purpura, childhood, and hypersensitivity vasculitis.
arthritis (typically of the large joints), abdominal  Hypersensitivity vasculitis is also a small vessel
pain, and renal disease at presentation. vasculitis that may occur in both children and
 In children, arthritis and abdominal pain affect adults and may be idiopathic or triggered by
about infections or drug exposures.
75% of patients; the gastrointestinal  It typically manifests as an isolated cutaneous
manifestations may precede the purpura by up to leukocytoclastic (neutrophils and neutrophil
2 weeks and include hematochezia. debris in small vessels) vasculitis that is self-
 The most common renal manifestation is limited with treatment of the underlying cause
microscopic hematuria with or without proteinuria. (e.g., treatment of infection, discontinuation of
 The diagnosis of HSP is most often based on drug culprit).
clinical and laboratory evidence, although skin or
renal biopsy revealing IgA deposition may be
helpful in solidifying the diagnosis.
 By classification criteria from the EULAR, patients
with HSP must have purpura or petechiae with
lower limb predominance and at least one of the
following: arthritis or arthralgias; abdominal pain;
histopathology demonstrating IgA deposition; and
renal involvement.
Medium Vessel Vasculitis
Polyarteritis Nodosa
 The most common organ systems affected in
PAN are the gastrointestinal, renal, and nervous
systems. Mesenteric aneurysms or stenoses
resulting in gut ischemia lead to symptoms of
abdominal pain
or “intestinal angina” (pain after eating).
 Renal artery aneurysms or stenoses result in
hypertension or renal dysfunction, rather than
glomerulonephritis as in MPA.
 Neurologic involvement may manifest as
mononeuritis multiplex (painful asymmetrical
sensory and motor peripheral neuropathy
involving at least two separate nerve areas).
 Orchitis may be seen, manifesting as acute
testicular pain.
 Anemia, elevated erythrocyte sedimentation rate
or C-reactive protein or both, and hypertension (if
renal artery involvement is present) are common.
 As in all vasculitides, constitutional symptoms
may also be present.
 The diagnosis of PAN is made based on
angiographic or biopsy findings in the
appropriate clinical setting.
 ANCAs typically are absent in PAN.
 A work-up for infection, including tests for
hepatitis B and C and HIV, is warranted, given
their known associations with PAN.
 The differential diagnosis includes MPA and
mixed cryoglobulinemic vasculitis (defined by
the presence of cryoglobulins in the blood).
 The latter vasculitis shares many clinical
features with PAN, including peripheral
neuropathy, arthralgias, myalgias, purpura, and
association with hepatitis C.
Kawasaki Disease
 The clinical presentation of Kawasaki disease
includes fever lasting longer than 5 days,
conjunctival injection, oropharyngeal changes
(strawberry tongue, mucous membrane
desquamation), peripheral extremity changes
(cutaneous desquamation), polymorphous rash,
and cervical
lymphadenopathy.
 Arthralgias, abdominal pain, hepatitis, aseptic
meningitis, and uveitis have also been reported.
 Coronary artery aneurysms, one of the most
serious complications of this vasculitis, appear
within the
first 4 weeks after onset of disease and are often
detectable with echocardiography.
 Although areas of ectasia and small aneurysms
may regress, larger aneurysms often persist and
can result in coronary ischemia at any time after
development, even into adulthood.
 Kawasaki disease is a triphasic disease,
consisting of an acute febrile period lasting up
to 14 days, a subacute phase of 2 to 4 weeks,
and a convalescent phase that can last months
to years.
 In the acute phase, the fever is persistent and
high (>38.5° C) and is minimally responsive to
antipyretics.
 The differential diagnosis is wide and includes
viral infections, toxin-mediated illnesses (e.g.,
toxic shock syndrome, scarlet fever), systemic
juvenile idiopathic arthritis, hypersensitivity
reactions, and drug reactions (e.g., Stevens-
Johnson syndrome).
Large Vessel Vasculitis
Giant Cell Arteritis or Temporal Arteritis
 At presentation, patients with GCA most
commonly have new continuous headache, jaw
claudication, visual disturbances (e.g., amaurosis
fugax, diplopia), fatigue, and arthralgias.
 They are usually older than 50 years of age, have
tender or thickened temporal arteries, and have an
elevated erythrocyte sedimentation rate (>50
mm/hr by the Westergren method).
 Disease onset may be insidious or acute.
 Blindness due to anterior ischemic optic
neuropathy occurs in 10% to 15% of patients with
GCA and can occur at disease onset.
 Given the association between GCA and PMR,
patients with PMR should be educated regarding
signs and symptoms of GCA, and patients with
GCA should be monitored for symptoms of PMR.
 The diagnosis of GCA is often made by a biopsy
of the superficial temporal artery. It is important to
obtain a sufficient length of tissue (2 to 3 cm)
because the vasculitis can have “skip lesions.”
Takayasu’s Arteritis
 The typical clinical manifestations of TAK include a
systolic blood pressure difference of greater than
10 mm Hg between the arms, decreased brachial
or radial artery pulses, bruits auscultated over the
subclavian arteries or aorta, claudication of
extremities, neck or jaw pain, headache,
dizziness, hypertension, constitutional symptoms,
arthralgias, and myalgias.
 The diagnosis of TAK is often based on vascular
imaging studies that demonstrate long, tapering
stenotic lesions or aneurysmal lesions in the aorta
and primary branches.
 The differential diagnosis includes syphilis,
spondyloarthropathies, rheumatoid arthritis,
inflammatory bowel disease, and connective
tissue disorders. Vascular imaging studies
including computed tomographic angiography and
magnetic resonance angiography are typically
performed for both diagnosis and disease
surveillance.