Pediatric Vasculitis
Philip Hashkes, MD, MSc
Head, Pediatric Rheumatology Unit
Shaare Zedek Medical Center
Jerusalem
Conflict of Interests Disclosures and
Off Label Medications
• No conflict of interest disclosures
• Off label medications in talk
– Rituximab for Wegener's granulomatosis
– Mycophenylate for Wegener's
granulomatosis
– Infliximab for Takayasu arteritis
– IVIg for polyarteritis nodosa
Objectives
• When to suspect and how to investigate
vasculitis in children
• To describe the new classification of
childhood vasculitis
• To expound on several specific
vasculitis entities in children highlighting
recent developments
Definition
• Inflammatory and destructive process
of blood vessels; inflammation must be
present in wall of blood vessel
When to Suspect Vasculitis
• Unexplained multisystem features
– Especially FUO, weight loss, rashes, hypertension,
edema, arthritis, neurologic symptoms
• Unexplained tests indicative of inflammation
– Elevated ESR, CRP
– Anemia, leukocytosis, eosinophilia, thrombocytosis
– Low or high complements, low albumin, elevated
globulin
• Hematuria, proteinuria
Systems Most Affected
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•
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•
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•
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Skin - purpuric rash, nodules, livedo reticularis
Gastrointestinal - pain, hemorrhage, infarct
Renal - glomerulonephritis, hypertension
Lung – pneumonitis, hemorrhage
Musculoskeletal - arthritis, myositis
Cardiovascular - ischemic heart disease
ENT – obstruction, chronic OM, sinusitis, nose
bleed
• Systemic features - fever, weight loss
Nervous system
• Central nervous system
– Headaches, stroke, TIA, seizures,
movement disorder
• Peripheral nervous system
– Palsy – especially drop foot/hand
– Sensory
• Polyneuropathy, mononeuritis multiplex
Vasculitis - Investigations
• Signs of inflammation
– ESR, CRP, CBC, immunoglobulins, complements,
albumin, Von Willebrand Antigen
• System involvement
– Liver, renal, urinalysis, muscle, pulmonary
functions, ENT, GI, eye, brain
• Autoimmunity - autoantibodies
– Antinuclear antibodies, rheumatoid factor, ANCA,
cryoglobulins
Red Blood Cell Cast,
Fresh first AM urine
Antineutrophil Cytoplasmic
Antibodies (ANCA)
• C-ANCA
(cytoplasmic)
• P- ANCA
(perinuclear)
• Possibly
pathogenic activation of
PMN
C-ANCA
• Antigen (by ELISA): neutral serine
proteinase 3 (PR3)
• Specific for Wegener’s granulomatosis
– Sensitivity and specificity > 90%
P-ANCA
• Antigen by (ELISA): myeloperoxidase
for microscopic polyarteritis
• Other antigens seen in ulcerative colitis,
other connective tissue diseases,
sclerosing cholangitis
Vasculitis - Investigations (cont.)
• Infectious tests: cultures, serology
– Streptococcus, hepatitis B,C, HIV, parvovirus
• ECG, echocardiography
• Electromyography, nerve conduction
• Imaging
– Chest, sinus radiographs/CT
– MRI (brain, neck, cardiac, abdominal)
• Angiography
– Formal, MRA, CT angio, PET scan
• Biopsies
– Skin, muscle, nerve, renal, lung, other
New Pediatric Classification by Size
of Vessel
• Large arteries (predominately)
– Takayasu arteritis
• Medium arteries (predominately)
– Kawasaki disease
– Classic polyarteritis nodosa
• Cutaneous polyarteritis
Ozen S, et al. Ann Rheum Dis 2006;65:936–41
Classification by Size (cont.)
• Small vessels (predominately)
– Granulomatous
• Wegener’s granulomatosis
• Churg - Strauss vasculitis
– Non-granulomatous
• Microscopic polyangiitis
• Henoch-Schönlein purpura
• Isolated cutaneous leukocytoclastic vasculitis
• Hypocomplementaemic urticarial vasculitis
Other Primary Pediatric Vasculitidies
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•
•
•
Behçet’s disease
Isolated vasculitis of the CNS
Cogan’s syndrome
Unclassified
Secondary Vasculitis
• Connective tissue disease - SLE, RA,
sarcoidosis
• Infection - SBE, hepatitis B, C,
rickettsia, HIV, sepsis, TB, syphilis,
gonorrhea, meningococcal, parvovirus
• Drugs - penicillin, cefaclor, sulfa
• Malignancy - lymphoma
• Genetic autoinflammatory syndromes
Pseudovasculitis
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Myxoma, cholesterol emboli
Blood vessel, thrombotic disease
Antiphospholipid antibody syndrome
Congenital conditions
– Mid-Aortic syndrome
– Ehlers-Danlos syndrome
– Other rare syndromes
Other Methods of Classification
• Pathology
– Necrotizing/leukocytoclastic vasculitis
• Polymorphonuclear cells
–Polyarteritis nodosa, HenochSchonlein purpura
– Granulomatous
• Wegener’s granulomatosis, Takayasu’s
arteritis, Churg -Strauss
• Systemic vs. isolated (skin, CNS, organ)
Case Description
• 16 year old female with recurrent otitis
with effusion for 1.5 yrs – tubes placed
• 1 month of arthritis, low grade fever,
tingling in leg
• Chest x-ray, nodule in LLL
• ESR of 98
• C-ANCA positive
Wegener’s Granulomatosis (WG)
• Necrotizing granulomata of upper and
lower respiratory tracts, kidneys
– Small to medium size vessels
• Rare in childhood (1/106/yr); mode in
young adults
• Male 2: female 1
• Systemic disease vs. limited to upper
respiratory tract
WG - Clinical Manifestations
• Systemic features 90-95%
– Fever, malaise, weight loss
• Arthritis (55-65%) - large joints
• Skin - nodules, ulceration, purpura (2350%)
From 4 series of 130 patients
Largest from the ARChiVe registry (n=65)
Cabral D, et al, Arthritis Rheum 2010;60:3413-24
WG - Clinical Manifestations
• Upper respiratory tract
(80-90%; 20%
presenting symptom)
– Chronic rhinorrhea,
epistaxis, nasal
crusting, sinusitis,
otitis (40-65%)
– Nasal septal necrosis
(“saddle nose”)
– Biopsy frequently non
diagnostic
WG - Clinical Manifestations
• Subglottic stenosis
(14-41% in children)
• More common with
clinical significance
than in adults
• Stridor, hoarseness,
respiratory distress
WG - Clinical Manifestations
• Lower respiratory tract
(80-90%)
– Pneumonia,
pneumonitis (23%)
– Hemoptysis (44%),
nodules (42%),
pleural effusion,
pneumothorax
– Abnormal pulmonary
function (78%)
WG - Clinical Manifestations
• Renal (80-90%)
– Abnormal urinalysis (75-88%)
– Glomerulonephritis (focal, segmental,
diffuse), 52-64%
– Hypertension
– Elevated creatinine, renal failure
(42%)
WG - Clinical Manifestations
• Uveitis, scleritis,
episcleritis, proptosis psuedotumor (3753%)
• Nervous system
(25%)
– Peripheral
neuropathy
WG - Investigations
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•
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•
•
Signs of inflammation
Urinalysis, renal function, collection
Radiographs/CT
Pulmonary function tests
C-ANCA (positive >90%)
– Debate if can use ANCA to
monitor disease activity
WG - Investigations
• Biopsies - skin,
nasal, sinus, lung,
renal
– Upper respiratory
frequently
nondiagnostic
• Vasculitis,
capillaritis,
granulomas
WG - Differential Diagnosis
• Infectious - TB, fungal, syphilis, leprosy
• Inflammatory – microscopic polyangitis,
sarcoidosis, Goodpaster’s, Loeffler’s
syndrome, other vasculitis
• Lymphoma
WG: Pediatric Classification Criteria
• Histopathology – granulomatous
vasculitis/perivasculitis
• Upper airway involvement
• Laryngo-tracheo-bronchial stenoses
• Pulmonary involvement by chest x-ray/CT
• ANCA positivity
• Renal involvement – proteinuria/hematuria/biopsy
Need 3 of 6: 93.3% sensitivity, 99% specificity
Ozen S, et al. Ann Rheum Dis 2010 69: 798-806
WG - Treatment
• 100% mortality within months without
treatment
• Induction: Corticosteroids, oral
cyclophosphamide vs. rituximab
– Cyclophophamide many side effects infections, neutropenia, hemorrhagic cystitis,
bladder carcinoma
– Corticosteroids alone doesn’t prevent death
• Methotrexate induction in milder cases
WG - Rituximab
• Anti mature B-cell (CD20) antibody
• Recent trial (RAVE) of 197 patients
including adolescents from age 15 years
• Equal efficacy in inducing remission,
less relapse rate than
cyclophosphamide. Equal adverse
effects (followed only for 6 months).
Stone JH, et al, NEJM 2010;363:221-32.
WG - Treatment (cont.)
• Maintenance – methotrexate, azathioprine,
mycophenalate
– For at least 2 years
• Trimethoprim-sulfamethasone in limited disease
– May prevent flares in nasal staphylococcus carriers
– Prophylaxis for PCP
• Other therapies
– Anti–TNF: etanercept not effective, less safe –
malignancies, vascular thrombosis
– Topical steroid injection, dilations for subglottic
disease
WG - Prognosis
• Remission obtained in > 90%
• >50% will relapse
• >80% 5 year survival
– Disease related deaths
• Respiratory, renal failure
– Treatment related
• Infections, malignancies
– Children more severe upper respiratory then
adults; less renal disease
Microscopic Polyangitis
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•
•
•
Small vessel vasculitis
Glomerulonephritis
Pulmonary manifestations
P-ANCA positive in 80%
– Myeloperoxidase
• Treatment and prognosis
similar to WG
Churg Strauss Granulomatosis
• Medium size arteritis with granulomas
• Eosinophilia, P-ANCA (40%)
• “Asthma - like” attacks
– Pulmonary infiltrates - non fixed
– Frequent allergic history
• Mononeuritis multiplex common
• Less renal involvement than WG
• Very rare in childhood
Case Description
• 15 year-old female (Asian ancestry) with 2 month
history of low-grade fever, weight loss, malaise,
headaches, exertion right leg pain, 2 episodes of
syncope
• Examination – severe hypertension, decreased pulses
in neck, left hand, right leg pulses
• ESR – 90, Hb – 9.9, ANA and ANCA negative
• Abdominal Doppler US – renal artery stenosis
Takayasu’s Arteritis (TA)
• Also “pulseless” disease
• Young < 40 years
• 1/3 < 20 years
• Asian, African-American females
• Incidence 1.2-2.6/106/yr
• Large artery vasculitis - aorta, aortic
arch, carotid, subclavian, renal, iliac
TA - Clinical Manifestations
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Systemic (65%) - fever, weight loss
Hypertension (85%)
Palpitations, dyspnea, syncope
Headache (50%), visual disturbances
(30%), dizziness, syncope
• Arthritis, arthralgia, myalgia (65%)
• Gastrointestinal symptoms (50%)
• Claudication - walking, upper extremities
TA - Physical Examination
• Hypertension
• Decrease in pulses
• Differential blood pressure in limbs
– Measure 4 limbs
• Bruits - carotid, subclavian, aorta, renal,
femoral arteries (70-80%)
• Signs of aortic insufficiency
• Growth abnormalities, atrophy of affected
extremities
TA: Children vs. Adults
• Children usually have the “triad”
– Systemic features, hypertension,
elevated ESR
– More systemic features, renal artery
involvement, less claudication than
adults
TA: Pediatric Classification Criteria
• Angiographic abnormalities of the aorta or its main branches
and pulmonary arteries showing aneurysm/dilatation, narrowing
or occlusion not related to fibromuscular dysplasia (mandatory
criterion)
Plus one of the five following criteria:
• Pulse deficit or claudication
• Four limbs BP discrepancy
• Bruits
• Hypertension
• Acute phase reactant
100% sensitivity, 99.9% specificity
Ozen S, et al. Ann Rheum Dis 2010 69: 798-806
TA: Classification by Location, Type
of Lesion
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Type I - aortic arch
Type II - thoracic and abdominal aorta
Type III - diffuse aortic involvement
Type IV - Aortic and other arteries
Obstructive lesions (US, Japan)
Aneurysms (India, Africa)
TA – Other Clinical Associations
• Autoimmune
– Chron’s, immunodeficiency
• Infectious – TB in developing
countries
– Many patients with positive TST
TA – Investigations
• Signs of inflammation
– ESR important in following course
• Elevated factor VIII - related antigen
• Rheumatoid factor (25%)
• Hypergammaglobulinemia
Imaging Modalities Used
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Ultrasound – Doppler
Echocardiography
Formal angiography
MRI/A
CT angio
PET scan
TA - Imaging
• Angiography
– Also important for
central blood pressure
measurement
• MRI/MRA
– Wall thickness and
edema in addition to
detecting
stenosis/aneursyms
– Less invasive for
follow-up
Imaging Findings
• Stenosis (85-98%)
• Occlusion
• Dilatation, aneurysms
(2-27%)
• Mixed
• Collateral formation
• Wall thickening,
edema
TA – Pathology – Rarely obtained
• Panarteritis, focal, segmental lesions
– Including vasa vasorum
• Loss of muscular, elastic tissue, giant
cells, granulomata, intima and media
hyperplasia and fibrosis
TA - Treatment
• Corticosteroids
– Follow ESR, imaging regularly
• Methotrexate
• Cyclophosphamide
• Anti-TNF - infliximab
• Bypass surgery
– Only when inflammation subsided
– Balloon angioplasty less effective,
stent not effective
TA - Natural History Course
• Triphasic
– Preinflammatory, inflammatory,
“burnt - out”
• Remission and relapse (80%)
– 20% only one course of disease
TA - Prognosis
• Hard to determine and correlate disease
activity and vasculitis progression
• Bad prognostic signs: hypertension,
congestive heart failure, syncope
• >90% 5 year survival
• Death: aneurysm rupture, myocardial
infarction, stroke, cardiac failure
• Morbidity: from hypertension, ischemic
damage
Case Description
• 10 year old male, developed fever,
muscle pain, rash one week post strep
• Physical exam nodular and livedo
reticularis rash, tenderness over
muscles
• ESR, CRP increased, anemia
• Deep skin/muscle biopsy diagnostic
Polyarteritis Nodosa (PAN)
• 2 types: classic and cutaneous
• Rare in childhood
• Unlike adults, rarely associated with
hepatitis B
• May be associated with streptococcal
infection - especially cutaneous PAN
• Associated with familial Mediterranean fever
• Peak age 9-11 years; sex - equal
distribution
PAN - Clinical Manifestations
• Systemic features (94%)
– Fever, weight loss, splenomegaly,
insidious
• Rash - (50-60%)
• Arthritis, myalgia (50-60%)
• Gastrointestinal (67%)
– Pain, malabsorption, diarrhea, infarct
• Cardiovascular (44%)
PAN - Rash
• Palpable purpura
• Nodules
PAN - Rash
• Echymosis
• Gangrene
• Ulcers
PAN - Rash
• Livedo reticularis
• Splinter hemorrhage
Systemic PAN - Clinical (cont.)
• Renal (83%)
– Hypertension
• Renal artery stenosis
– Glomerulonephritis to renal failure
• Nervous system (40%)
– Central : Seizures, psychosis, stroke, coma
– Peripheral: mononeuritis multiplex
• Other - testicular swelling, claudication
PAN - Pathology
• Fibrinoid necrosis of
medium sized
muscular arteries
– Acute and chronic
• Partial thickness,
segmental, skipped
lesions
– Mainly at
bifurcation
PAN - Evaluation
• Signs of inflammation
– ESR, CRP, WBC, anemia,
immunoglobulins
• Urinalysis
• Hepatitis B rare, strep. serology
• Factor VIII related antigen, neopterin
– Endothelial activation
• Negative ANCA
PAN - Evaluation (cont.)
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•
•
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ECG, echocardiogram
Nerve conduction, electromyography
EEG
Biopsy
– Skin, muscle, sural nerve, renal
PAN - Imaging
• MRI/A
• CT angiography
• Often difficult to
image smaller vessels
PAN - Angiography
• Renal, celiac,
coronary, eyes
• Segmental
aneurysms,
stenosis
– “Beading”
PAN: Pediatric Classification
• Histopathology or angiographic abnormalities
(mandatory)
Plus one of the five following criteria:
• Skin involvement
• Myalgia/muscle tenderness
• Hypertension
• Peripheral neuropathy
• Renal involvement
89.6% sensitivity, 99.6% specificity
Ozen S, et al. Ann Rheum Dis 2010 69: 798-806
PAN - Treatment
• Mortality of systemic PAN 100% when only
corticosteroids used
• Cyclophosphamide induction
– Azathioprine, methotrexate maintenance
– IVIg in some resistant cases
– Newer therapies not studied
• Consider penicillin prophylaxis when
streptococcus involved
– Especially cutaneous disease
PAN - Prognosis
• Better with aggressive therapy
– 5 year survival 60-85%
• Deaths from GI, renal involvement
– Treatment side-effects
• Minimal mortality in Streptococcus
associated cutaneous disease
Case Description
• 8 year old male presented with severe headaches
and seizure (focal)
• Family reported decrease in school ability in last 2
months
• Inflammatory markers and autoantibodies normal
• Lumbar puncture increased protein levels
• MRI infarcts/inflammatory lesions in brain
• Narrowing of multiple arteries confirmed by
angiography
Isolated CNS vasculitis
• Rare
• All ages groups
• Four major types
– Viral induced – varicella
– Non-progressive – one blood vessel
– Progressive
• Larger vessels (angiography “positive”)
• Smaller vessels (angiography “negative”)
Presentation of CNS vasculitis
• Cognitive dysfunction
• Severe headaches
– Thunderclap
– More frequented in non-progressive
disease
• Stroke
• Seizures
• Mental status changes
Laboratory tests
• Unrevealing in large vessel disease
• Increased inflammatory markers in small
vessel disease
• Lumbar puncture
– Most common increased protein
• Increased local IgG production
– Pleocytosis
Imaging
• MRI/A, CT angiography
• Formal angiography
– Important for distal vasculitis
– Stenosis, beading
Pathology
• In order to diagnosis small vessel
vasculitis, biopsy is necessary if
vascular imaging is normal
– Perform in area of MRI abnormality
– Leptomeningeal
• Often granulomatous
Treatment
• Relative short course of steroids in nonprogressive vasculitis
• Steroids and cyclophosphamide
induction for progressive vasculitis
– Azathioprine maintenance
• Anticoagulation/antiplatelet
Prognosis
• Poor prognosis in untreated progressive
disease
– Multifocal, distal vessels, cognitive
dysfunction
• Good mortality prognosis in nonprogressive disease but may be
significant residual damage and
functional disability
Summary
• Primary vasculitis is rare in childhood
• Some differences exist between childhood
and adult vasculitis
• Usually present with multisystem disease
• High degree of suspicion
• Necessary work up is often invasive –
imaging, biopsies
• High morbidity and mortality if not treated
adequately
