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