Vasculitis
Ameen Kabaha,MD
wolfson medical center
Definition
The vasculitides are defined by the
presence of leukocytes in the vessel
wall with reactive damage to mural
structures
Loss of integrity leads to bleeding
Compromise of the lumen leads to
tissue ischemia and necrosis
Definition
Affected vessels vary in size,
type, and location in association
with the specific vasculitic
disorder
Vasculitis may be primary or
secondary
The vasculitides are often serious
They require prompt recognition and
therapy
The distribution of affected organs
may suggest a particular vasculitic
disorder, but significant overlap is
observed
CLASSIFICATION
Large vessel vasculitis
Takayasu arteritis affects the aorta
and its primary branches
Giant cell arteritis or temporal
arteritis, a chronic vasculitis of large and
medium vessels, most prominently
involves the cranial branches of the
arteries originating from the aortic arch
Medium sized vessel vasculitis
Polyarteritis nodosa a systemic
necrotizing vasculitis that typically affects
the small and medium-sized muscular
arteries
In some cases, however, only the smaller
vessels are affected, a condition that has
been called microscopic polyarteritis or
polyangiitis (closer to Wegeners
granulomatosis than PAN)
Medium sized vessel vasculitis
Kawasaki disease is an arteritis of
large, medium, and small arteries,
particularly the coronary arteries.
The disease usually occurs in
children, and is often associated with
a mucocutaneous lymph node
syndrome
Small vessel vasculitis
Churg-Strauss arteritis (also called
allergic granulomatosis and angitis)
Vasculitis of the medium and small sized
muscular arteries
often found with vascular and extravascular
granulomatosis
classically involves the arteries of the lung
and skin, but may be generalized
Small vessel vasculitis
Wegener's granulomatosis
A systemic vasculitis of the medium and small
arteries, as well as the venules and arterioles
Typically produces granulomatous
inflammation of the upper and lower
respiratory tracts and necrotizing, pauciimmune glomerulonephritis in the kidneys
WG usually associated with ANCA
(antineutrophi cytoplasmic antibody)
Small vessel vasculitis
Microscopic polyarteritis is a vasculitis
which primarily affects capillaries, venules,
or arterioles. Involvement of small and
medium-sized arteries may also be
present. ANCA is present
Henoch-Schnlein purpura is a
systemic vasculitis that is characterized by
the tissue deposition of IgA-containing
immune complexes.
Small vessel vasculitis
Essential cryoglobulinemic vasculitis characterized by
the presence of cryoglobulins, which are serum proteins
that precipitate in the cold and dissolve upon rewarming.
Cryoglobulins typically are composed of a mixture of
immunoglobulins and complement components.This
disorder is most often due to HCV infection
Hypersensitivity vasculitis hypersensitivity reaction to
a known or suspected substance such as a vasculitic
drug reaction. In hypersensitivity vasculitis, the presence
of skin vasculitis with palpable petechiae or purpura is
typically a major finding.
Small vessel vasculitis
Vasculitis secondary to connective tissue
disorders in association with SLE, rheumatoid
arthritis, relapsing polychondritis, Behcet's
disease, and other CTD.
Vasculitis secondary to viral infection most
commonly observed with HB and HC viruses,
but may also be seen with HIV, CMV, EB virus,
and Parvovirus B19
Demographic characteristics of
807 patients with vasculitis
Disease category
Percent with
disorder
Mean age
at onset
Percent
female
Polyarteritis nodosa
15
48
38
Churg-strauss syndrome
50
37
Wegeners granulamatosis
10
45
37
Hypersensivity vasculitis
12
47
54
Henoch-schonlein purpura
10
17
46
Giant cell arteritis
26
69
75
Takayasus arteritis
26
86
Other vasculitis, type unspecified
16
44
55
Hunder, GG, Arend, WP, Bloch, DA, et al. Arthritis Rheum 1990; 33:1065.
Vasculitic
syndrome
Pathology
Vessel
size
Vessels involved
Takayasu's arteritis
Granulomatou
s angiitis
Large
Aorta and major branches
Temporal (giant
cell) arteritis
Granulomatou
s angiitis
Large
Aorta and major branches, large and
medium-sized arteries (predilection for
extracranial branches of carotid artery)
Polyarteritis
nodosa
Necrotizing
vasculitis
Medium Large, medium, and small arteries
Churg-Strauss
syndrome
Granulomatou
s angiitis
Medium
Large, medium, and small arteries
Small
Wegener's
granulomatosis
Granulomatou
s angiitis
Medium Medium and small arteries, venules, and
Small
arterioles
Kawasaki disease
(syndrome)
Necrotizing
vasculitis
Medium
Medium and small arteries, venules, and
arterioles
Microscopic
polyangiitis
Necrotizing
vasculitis
Small
Medium and small arteries, venules, and
arterioles
Hypersensitivity
vasculitis
Leukocytoclas
tic vasculitis
Small
Small vessels (capillaries, venules, arterioles)
Henoch-Schnlein
purpura
Leukocytoclas
tic vasculitis
Small
Small vessels (capillaries, venules, arterioles)
Vasculitic syndrome
Age
History
Takayasu's arteritis
15-25
Females and Asians at much higher risk; arm or
leg claudication
Temporal (giant cell)
arteritis
60-75
Headache, tongue or jaw claudication, scalp
tenderness, hip or shoulder girdle stiffness
Polyarteritis nodosa
40-60
Muscle and joint pain, abdominal pain
Churg-Strauss
syndrome
40-60
History of asthma or allergy, shortness of
breath, abdominal pain
Wegener's
granulomatosis
30-50
Arthralgias, myalgias, sinusitis, bloody nasal
discharge, shortness of breath
Microscopic
polyangiitis
40-60
Myalgias, abdominal pain or bleeding,
hemoptysis, dyspnea
Kawasaki disease
(syndrome)
1-5
Fever, skin rash
Hypersensitivity
vasculitis
30-50
Exposure history (usually medication), infection
Henoch-Schnlein
purpura
5-20
Preceding URI, abdominal pain, bloody diarrhea
Vasculitic syndrome
Physical examination
Takayasu's arteritis
Decreased pulses, subclavian/aortic bruits
Temporal (giant cell)
arteritis
Tenderness, decreased temporal artery pulse
Polyarteritis nodosa
Hypertension, livedo reticularis, mononeuritis
multiplex
Churg-Strauss syndrome
Pulmonary infiltrates, neuropathies,
petechiae, purpura, ulcerations
Wegener's granulomatosis
Pain over sinus areas, nasal or oral ulcers,
chest pain, proptosis, cranial nerve deficits
Microscopic polyangiitis
Mononeuritis multiplex, rales, purpura,
synovitis
Kawasaki disease
(syndrome)
Conjunctivitis, cervical lymphadenopathy,
polymorphous exanthem
Hypersensitivity vasculitis
Palpable purpura
Henoch-Schnlein purpura
Palpable purpura
Vasculitic
syndrome
Evaluation
Treatment
Takayasu's arteritis
Arteriogram, vascular ultrasound,
computed tomography, magnetic
resonance imaging
Corticosteroids
Temporal (giant cell)
arteritis
Erythrocyte sedimentation rate,
temporal artery biopsy
Corticosteroids
Polyarteritis nodosa
Biopsy of involved tissue,
mesenteric angiography, fecal occult
blood
Corticosteroids,
cyclophosphamide
Churg-Strauss
syndrome
Eosinophilia on differential, biopsy of
involved tissue
Corticosteroids
Wegener's
granulomatosis
Sinus x-rays, chest x-ray, ANCA,
Corticosteroids,
biopsy of affected tissue, fecal occult
cyclophosphamide
blood, urinalysis
Microscopic
polyangiitis
ANCA, biopsy of affected tissue,
fecal occult blood
Corticosteroids,
cyclophosphamide
Kawasaki disease
(syndrome)
Tests to rule out other diseases
Gamma globulin,
aspirin
Hypersensitivity
vasculitis
Tests to rule out other diseases
Avoidance of inciting
agent
Henoch-Schnlein
purpura
Fecal occult blood, urinalysis
Supportive; if severe,
glucocorticoids
Clinical manifestations
The presence of vasculitis should be considered in
patients who present with systemic symptoms in
combination with evidence of single and/or multiorgan
dysfunction
Common complaints and signs of vasculitis include
Fatigue, weakness
Fever, arthralgias, abdominal pain
Hypertension, renal insufficiency (with an active urine sediment)
Neurologic dysfunction.
Clinical manifestations
The diagnosis of vasculitis is often delayed
because the clinical manifestations can be
mimicked by a number of other disorders
Certain signs are strongly suggestive:
Mononeuritis multiplex
Palpable purpura (hypersensitivity vasculitis,
HSP, microscopic polyarteritis)
Pulmonary-renal involvement (Wegeners
granulotamosis, microscopic polyangitis, r/o
anti GBM
Diagnostic approach
History
Drugs
Hepatitis
Systemic disease
Age and gender
Physical examination
extent of vascular lesions
distribution of affected organs
presence of additional disease processes
Mononeuritis multiplex and palpable purpura
Diagnostic approach
Laboratory tests
RFT, muscle enzymes, LFT, ESR, hepatitis
serologies, urinalysis, chest x-ray, and
electrocardiogram
Other tests that may be warranted include CSF
analysis, CNS imaging, PFT, and cultures
Additional testing
ANA
Complement (low in Mixed cryo and SLE)
HB, HCV serology
ANCA (anti PR3 in Wegeners, anti MPO in
microscopic polyangitis)
Electromyography
Tissue biopsy
Arteriography
American College of Rheumatology 1990 criteria for the classification of
Takayasu arteritis
Criterion
Definition
Age at disease
onset 40 years
Development of symptoms or findings related to Takayasu
arteritis at age 40 years
Claudication of
extremities
Development and worsening of fatigue and discomfort in
muscles of one or more extremities while in use, especially
the upper extremities
Decreased
brachial artery
pressure
Decreased pulsation of one or both brachial arteries
Blood pressure
difference >10
mmHg
Difference of >10 mmHg in systolic blood pressure between
arms
Bruit over
subclavian
arteries or aorta
Bruit audible on auscultation over one or both subclavian
arteries or abdominal aorta
Arteriogram
abnormality
Arteriographic narrowing or occlusion of the entire aorta, its
primary branches, or large arteries in the proximal upper or
lower extremities, not due to arteriosclerosis, fibromuscular
dysplasia, or similar causes; changes usually foci or segmental
For purposes of classification, a patient shall be said to have Takayasu arteritis if at least three of these six
criteria are present. The presence of any three or more criteria yields a sensitivity of 90.5 percent and
a specificity of 97.8 percent
ACR criteria for the classification of
Giant cell arteritis
In a patient with vasculitis, the finding of three of
the following five criteria was associated with a
94 percent sensitivity and a 91 percent
specificity for the diagnosis of GCA
Age 50 years at time of disease onset
Localized headache of new onset
Tenderness or decreased pulse of the temporal artery
ESR greater than 50 mm/h
Biopsy which includes an artery, and reveals a
necrotizing arteritis with a predominance of
mononuclear cells or a granulomatous process with
multinucleated giant cells
Visibly enlarged temporal artery in a patient with Giant cell arteritis
V
i
Giant cell arteritis
Temporal artery biopsy in giant cell (temporal) arteritis.
Left panel: Granulomatous and lymphocytic inflammation of the adventitia and medial
wall of the temporal artery. Right panel: Elastic tissue stain showing disruption of the
elastica (arrows) due to immunologically mediated destruction of the elastica.
The ACR criteria for the
classification of polyarteritis nodosa
Ten criteria for the classification of polyarteritis nodosa in a patient with a
vasculitis
Unexplained weight loss > 4 kg
Livedo reticularis
Testicular pain or tenderness
Myalgias
Mononeuropathy or polyneuropathy
New onset DBP > 90 mmHg
Elevated levels of serum BUN (>40 mg/dL) or creatinine (>1.5 mg/dL)
Evidence of HB virus infection via serum antibody or antigen serology
Characteristic arteriographic abnormalities
A biopsy of small- or medium-sized artery containing polymorphonuclear cells
A sensitivity and specificity for the diagnosis of polyarteritis of 82 and 87
percent, respectively, has been found in the patient with a documented
vasculitis in whom at least three of the criteria are present
Livedo reticularis
Polyarteritis nodosa
Renal arteriogram in large vessel polyarteritis nodosa showing characteristic
microaneurysms (small arrows) and abrupt cutoffs of small arteries (large arrows
Polyarteritis nodosa
Light micrograph of a small muscular renal artery in polyarteritis nodosa.
There is diffuse inflammation of the adventitia and marked thickening of the inner
layers by loose connective tissue (arrows). The lumen (L) is significantly narrowed.
Involvement of a vessel this large would be unusual in microscopic polyarteritis or
Wegener's granulomatosis
Kawasaki disease
Diagnosis requires the presence of fever
lasting five days or more without any other
explanation, combined with at least four of
the five following physical findings
Bilateral conjunctival injection
Oral mucous membrane changes (fissured
lips, injected pharynx, strawberry tongue)
Peripheral extremity changes (erythema of
pams and soles, edema of hands or feet)
Polymorphous rash
Cervical lymphadenopathy
Nonexudative conjunctivitis in a child with Kawasaki disease
Palmar erythema and cracked, red lips in a young girl with Kawasaki
disease
The ACR criteria for the classification of
hypersensitivity vasculitis ( 3 or more)
Age >16
Use of a possible offending drug
Palpable purpura
Maculopapular rash
Biopsy of a skin lesion showing
neutrophils around an arteriole or venule
Leucocytoclastic vasculitis
Leukocytoclastic vasculitis appearing as raised purpura.
This lesion can occur with any vasculitic syndrome and in the collagen vascular
diseases
Criteria for classification of HSP (3 or more)
Palpable purpura
Bowel angina
Gastrointestinal bleeding
Hematuria
Age at onset 20 years
No new medications
The Antineutrophil Cytoplasmic
AntibodyAssociated Vasculitides
ANCA were reported in association with
segmental necrotizing glomerulonephritis
in the early 1980s
Later, it was reported in patients with
Wegeners granulomatosis, microscopic
polyangiitis, Churg-Strauss syndrome and
renal-limited vasculitis
These are commonly referred to as the
ANCA-associated vasculitides.
C-ANCA pattern
Demonstration of cytoplasmic antineutrophil cytoplasmic antibodies (C-ANCA) by
indirect immunofluorescence with normal neutrophils. There is heavy staining in
the cytoplasm while the multilobulated nuclei (clear zones) are nonreactive.
These antibodies are usually directed against proteinase 3 and most patients
have Wegener's granulomatosis
P-ANCA pattern
Demonstration of perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) by
indirect immunofluorescence with normal neutrophils. Staining is limited to the
perinuclear region and the cytoplasm is nonreactive. Among patients with vasculitis,
the antibodies are usually directed against myeloperoxidase. However, a P-ANCA
pattern can also be seen with autoantibodies against a number of other antigens
including lactoferrin and elastase. Non-MPO P-ANCA can be seen in a variety of
nonvasculitic disorders
The 1990 ACR Classification Criteria for
Wegeners Granulomatosis (2 or more)
Nasal or oral inflammation
Painful or painless oral ulcers or purulent or
bloody nasal discharge
Abnormal CXR
Nodules, fixed infiltrates, or cavities
Urinary sediment
Microhematuria or RBC casts
Granulomatous inflammation
on biopsy specimen
within the wall of an artery or in the
perivascular area
The 1990 ACR Classification Criteria for ChurgStrauss syndrome( 4 or more)
Asthma
Wheezing or high-pitched rales
Eosinophilia
>10% of white blood cell differential
Mononeuropathy or polyneuropathy
Mononeuropathy, multiple mononeuropathies, or polyneuropathy
Pulmonary infiltrates, nonfixed
Paranasal sinus abnormality
Acute or chronic PNS pain, tenderness, or radiographic opacification
Extravascular eosinophils
Biopsy of artery, arteriole, or venule showing accumulations
of eosinophils in extravascular areas
Vasculitis and eosinophilic infiltration in Churg Strauss syndrome
Small artery in a patient with Churg Strauss syndrome showing intimal fibrinoid
necrosis and mural infiltration by histiocytes consistent with a necrotizing
granulomatous vasculitis. There is marked extravascular eosinophilia
Clinical Features of the Primary ANCA
Associated Vasculitides
Feature
Wegner,s
Microscopic
granulamatosis polyangitis
Churg-Strauss
Syndrome
ANCA
positivity
80%90%
70%
50%
ANCA antigen PR3 >> MPO
specificity
MPO > PR3
MPO > PR3
Fundamental
histology
Leukocytoclastic
vasculitis; no
granulomatous
inflammation
Eosinophilic
tissue infiltrates
and vasculitis;
Granulomas
have eosinophilic
necrosis
Leukocytoclastic
vasculitis;necroti
ing,
Granulomatous
inflammation
ANCA antineutrophil cytoplasmic antibody; MPO myeloperoxidase; PR3 proteinase 3.
Clinical Features of the Primary ANCA
Associated Vasculitides, continued
Feature Wegner,s
granulamatosis
Microscopic Churg-Strauss
polyangitis
Syndrome
ENT
Nasal septal
perforation,
saddle-nose deformity,
conductive or
Sensorineural hearing
loss, subglottic stenosis
Absent or mild
Nasal polyps,
Allergic rhinitis,
conductive
hearing loss
Eye
Orbital pseudotumor,
scleritis (risk of
Scleromalacia
perforans),episcleritis,
uveitis
Occasional
eye disease:
scleritis,
episcleritis,
uveitis
Occasional eye
disease:scleritis,
episcleritis, uveitis
Clinical Features of the Primary ANCA
Associated Vasculitides, continued
Feature Wegner,s
granulamatosis
Microscopic Churg-Strauss
polyangitis
Syndrome
Lung
Nodules, infiltrates,
Alveolar
cavitary lesions, alveolar hemorrhage
hemorrhage
Asthma, fleeting
infiltrate, alveolar
hemorrhage
Kidney
Segmental necrotizing
gn, rare granulmatous
Segmental
Necrotizing gn
Segmental
Necrotizing gn
Clinical Features of the Primary ANCA
Associated Vasculitides, continued
Feature
Wegner,s
granulamatosis
Microscopic Churg-Strauss
polyangitis Syndrome
Heart
Occasional valvular
lesions
Rare
Heart failure
Peripheral
nerve
Vasculitic neuropathy
(10%)
(58%)
(78%)
Eosinophilia
Mild, occasional
None
All
Clinical features
WG
There is substantial overlap
Upper Respiratory Tract and Ears
Most characteristic of Wegeners granulomatosis
More than 90% of patients with WG eventually develop
upper airway or ear abnormalities
The nasal symptoms of WG include nasal pain and
stuffiness, rhinitis, epistaxis, and brown or bloody crusts
May lead to septal erosions, septal perforation, or, in
many cases, the saddle-nose deformity
Two principal categories of ear disease conductive
and sensorineural hearing lossare typical of WG
Saddle-nose deformity in Wegeners granulomatosis.
Clinical features
CS
In 60% to 70% of patients with the ChurgStrauss syndrome, allergic rhinitis is the earliest
disease manifestation
Rhinitis may be severe and may require serial
polypectomies to relieve obstruction and
sinusitis
Nasal crusting and conductive hearing loss (due
to serous otitis or granulomatous middle ear
inflammation) may also occur in the CS
syndrome.
Trachea
Subglottic stenosis are serious and
potentially fatal complications of WG
Subglottic involvement is often
asymptomatic initially, but becomes
apparent as hoarseness, pain, cough,
wheezing, or stridor
The most accurate means of assessing
tracheal stenosis is by direct laryngoscopy
Eyes
Orbital masses termed pseudotumors, which are
characteristic WG in a retrobulbar location,
causing proptosis, diplopia, or visual loss
Scleritis may lead to necrotizing anterior scleritis
and blindness
Peripheral ulcerative keratitis
Other ocular manifestations include
conjunctivitis, episcleritis, keratitis, and uveitis
Nasolacrimal duct obstruction is most typical of
WG
Lungs
In WG :
Asymptomatic lung nodules
Fleeting (or fixed) pulmonary infiltrates
Fulminant alveolar hemorrhage
The nodules are usually multiple and
bilateral, are often cavitary
May lead to lung hemorrhage, and
hemoptysis
Lungs
A subset of patients with ANCA-associated
vasculitis (MPA) may have pulmonary interstitial
fibrosis
Obstructive airway disease and fleeting
pulmonary in-filtrates are the hallmarks of the
CS syndrome.
Most patients report the new onset of asthma
months to years before the appearance of overt
vasculitis
Chest radiographs are abnormal in only one
third of patients
Multifocal cavitary nodules in Wegeners granulomatosis.
Alveolar hemorrhage in microscopic polyangiitis.
Kidneys
The most serious renal disease among the
ANCA-associated vasculitides is RPGN
More than 75% of patients with WG will
eventually develop renal involvement
The progression of the disease often appears to
accelerate once kidney involvement is obvious
Appearance of an active urine sediment or a rise
in serum creatinine level in WG need immediate
full evaluation and prompt treatment
Kidneys
Renal disease associated with MPA is usually detected
well after onset of the disease
There is also a form of pauci-immune vasculitis in which
the inflammation is confined to the kidneys, with no overt
disease in other organ systems
Such cases are referred to as renal-limited vasculitis
The kidney is typically the organ that is slowest to
respond to therapy in ANCA-associated vasculitis
GN may lead to fibrotic crescents and other scarring
within the kidney, leading to progression to end-stage
renal disease
Normal glomerulus
Light micrograph of a normal glomerulus.
There are only 1 or 2 cells per capillary tuft, the capillary lumens are open,
the thickness of the glomerular capillary wall (long arrow) is similar to that of
the tubular basement membranes (short arrow), and the mesangial cells and
mesangial matrix are located in the central or stalk regions of the tuft (arrows).
Fibrinoid necrosis occurring in the renal biopsy specimen
of a patient with Churg-Strauss syndrome. Note the segmental
localization of the necrosis to a single quadrant of the glomerulus
Arthritis/Arthralgias
Musculoskeletal symptoms occur in at least 60%
of patients with ANCA-associated vasculitis
The combination of joint complaints, cutaneous
nodules, and the high frequency of rheumatoid
factor positivity among patients with ANCA
associated vasculitis lead to the misdiagnosis of
rheumatoid arthritis
Arthralgias are more common than frank arthritis
The recurrence of musculoskeletal complaints in
a patient in remission often marks the start of a
disease flare
Skin
In both the CS syndrome and WG, cutaneous
nodules may occur at sites that are also
common locations for rheumatoid nodules
Skin findings in the ANCA-associated
vasculitides also include all of the potential
manifestations of cutaneous vasculitis
Palpable purpura
vesiculobullous lesions, papules, ulcers
digital infarctions
splinter hemorrhages.
Purpura in microscopic polyangiitis.
Nervous System
Sensory neuropathy is commonly associated
with the ANCA-associated vasculitides
Mononeuritis multiplex occurs more commonly
in the CS syndrome (up to 78% of patients ) and
MPA (up to 58% ) than in WG
CNS abnormalities occur in approximately 8% of
patients with WG , usually in the form of cranial
neuropathies, mass lesions, or pachymeningitis
Heart
The CS syndrome is the form of ANCAassociated vasculitis that is most likely to
involve the heart
Usually in the form of rapid-onset heart
failure
Cardiac complications in WG and MPA are
less common
Blood
Eosinophilia is characteristic of the CS
syndrome
Mild eosinophilia (up to 15%) may also
occur in WG
Most patients with CS syndrome also have
elevated serum Ig E levels
Treatment
Severe WG requires urgent treatment with
cyclophosphamide and high doses of glucocorticoids
More than 90% of patients improved substantially on this
regimen, and 75% achieved disease remissions
Because of its tendency to involve such major organs as
the kidneys, lungs, and peripheral nerves in a severe
fashion, microscopic polyangiitis usually requires both
glucocorticoids and a cytotoxic agent from the outset of
therapy for disease control.
In WG, daily cyclophosphamide may be more likely to
result in durable remissions
Meticulous monitoring, particularly of the WBC is
essential
Measuring CBC every 2 weeks is appropriate for
patients treated daily with cyclophosphamide
Shorter courses of induction treatment with
cyclophosphamide (e.g., 3 to 6 months),
followed by longer periods of treatment with
either azathioprine or methotrexate to maintain
disease remission
Among patients with limited WG, remission is
induced in approximately three fourths of
patients with the use of methotrexate (up to 25
mg/wk) and glucocorticoids alone
Many patients with CS syndrome may be treated
effectively with glucocorticoids alone, although
cyclophosphamide or other cytotoxic agents
should be considered for severe cases
