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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

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pediatric vasculitis

Pediatric Vasculitis

Philip Hashkes, MD, MSc

Head, Pediatric Rheumatology Unit

Shaare Zedek Medical Center

Jerusalem

conflict of interests disclosures and off label medications
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 Takayasuarteritis
    • IVIg for polyarteritisnodosa
objectives
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
Definition
  • Inflammatory and destructive process of blood vessels; inflammation must be present in wall of blood vessel
when to suspect vasculitis
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
Systems Most Affected
  • 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
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
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
slide9

Red Blood Cell Cast,

Fresh first AM urine

antineutrophil cytoplasmic antibodies anca
Antineutrophil Cytoplasmic Antibodies (ANCA)
  • C-ANCA (cytoplasmic)
  • P- ANCA (perinuclear)
  • Possibly pathogenic - activation of PMN
c anca
C-ANCA
  • Antigen (by ELISA): neutral serine proteinase 3 (PR3)
  • Specific for Wegener’s granulomatosis
    • Sensitivity and specificity > 90%
p anca
P-ANCA
  • Antigen by (ELISA): myeloperoxidase for microscopic polyarteritis
  • Other antigens seen in ulcerative colitis, other connective tissue diseases, sclerosing cholangitis
vasculitis investigations cont
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
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
Classification by Size (cont.)
  • Small vessels (predominately)
    • Granulomatous
      • Wegener’s granulomatosis
      • Churg - Strauss vasculitis
    • Non-granulomatous
      • Microscopic polyangiitis
      • Henoch-Schönleinpurpura
      • Isolated cutaneousleukocytoclastic vasculitis
      • Hypocomplementaemicurticarial vasculitis
other primary pediatric vasculitidies
Other Primary Pediatric Vasculitidies
  • Behçet’s disease
  • Isolated vasculitis of the CNS
  • Cogan’s syndrome
  • Unclassified
secondary vasculitis
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
Pseudovasculitis
  • 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
Other Methods of Classification
  • Pathology
    • Necrotizing/leukocytoclastic vasculitis
      • Polymorphonuclear cells
        • Polyarteritis nodosa, Henoch-Schonlein purpura
    • Granulomatous
      • Wegener’s granulomatosis, Takayasu’s arteritis, Churg -Strauss
  • Systemic vs. isolated (skin, CNS, organ)
case description
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
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
WG - Clinical Manifestations
  • Systemic features 90-95%
    • Fever, malaise, weight loss
  • Arthritis (55-65%) - large joints
  • Skin - nodules, ulceration, purpura (23-50%)

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 manifestations23
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 manifestations24
WG - Clinical Manifestations
  • Subglottic stenosis (14-41% in children)
  • More common with clinical significance than in adults
  • Stridor, hoarseness, respiratory distress
wg clinical manifestations25
WG - Clinical Manifestations
  • Lower respiratory tract (80-90%)
    • Pneumonia, pneumonitis (23%)
    • Hemoptysis (44%), nodules (42%), pleural effusion, pneumothorax
    • Abnormal pulmonary function (78%)
wg clinical manifestations26
WG - Clinical Manifestations
  • Renal (80-90%)
    • Abnormal urinalysis (75-88%)
    • Glomerulonephritis (focal, segmental, diffuse), 52-64%
    • Hypertension
    • Elevated creatinine, renal failure (42%)
wg clinical manifestations27
WG - Clinical Manifestations
  • Uveitis, scleritis, episcleritis, proptosis - psuedotumor (37-53%)
  • Nervous system (25%)
    • Peripheral neuropathy
wg investigations
WG - Investigations
  • 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 investigations29
WG - Investigations
  • Biopsies - skin, nasal, sinus, lung, renal
    • Upper respiratory frequently nondiagnostic
  • Vasculitis, capillaritis, granulomas
wg differential diagnosis
WG - Differential Diagnosis
  • Infectious - TB, fungal, syphilis, leprosy
  • Inflammatory – microscopic polyangitis, sarcoidosis, Goodpaster’s, Loeffler’s syndrome, other vasculitis
  • Lymphoma
wg pediatric classification criteria
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
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
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
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
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
Microscopic Polyangitis
  • Small vessel vasculitis
  • Glomerulonephritis
  • Pulmonary manifestations
  • P-ANCA positive in 80%
    • Myeloperoxidase
  • Treatment and prognosis similar to WG
churg strauss granulomatosis
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 description38
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
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
TA - Clinical Manifestations
  • 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
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
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
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
TA: Classification by Location, Type of Lesion
  • 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
TA – Other Clinical Associations
  • Autoimmune
    • Chron’s, immunodeficiency
  • Infectious – TB in developing countries
    • Many patients with positive TST
ta investigations
TA – Investigations
  • Signs of inflammation
    • ESR important in following course
  • Elevated factor VIII - related antigen
  • Rheumatoid factor (25%)
  • Hypergammaglobulinemia
imaging modalities used
Imaging Modalities Used
  • Ultrasound – Doppler
  • Echocardiography
  • Formal angiography
  • MRI/A
  • CT angio
  • PET scan
ta imaging
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
Imaging Findings
  • Stenosis (85-98%)
  • Occlusion
  • Dilatation, aneurysms (2-27%)
  • Mixed
    • Collateral formation
    • Wall thickening, edema
ta pathology rarely obtained
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
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
TA - Natural History Course
  • Triphasic
    • Preinflammatory, inflammatory, “burnt - out”
  • Remission and relapse (80%)
    • 20% only one course of disease
ta prognosis
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 description54
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
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
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
PAN - Rash
  • Palpable purpura
  • Nodules
pan rash58
PAN - Rash
  • Echymosis
  • Gangrene
  • Ulcers
pan rash59
PAN - Rash
  • Livedo reticularis
  • Splinter hemorrhage
systemic pan clinical cont
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
PAN - Pathology
  • Fibrinoid necrosis of medium sized muscular arteries
    • Acute and chronic
  • Partial thickness, segmental, skipped lesions
    • Mainly at bifurcation
pan evaluation
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
PAN - Evaluation (cont.)
  • ECG, echocardiogram
  • Nerve conduction, electromyography
  • EEG
  • Biopsy
    • Skin, muscle, sural nerve, renal
pan imaging
PAN - Imaging
  • MRI/A
  • CT angiography
  • Often difficult to image smaller vessels
pan angiography
PAN - Angiography
  • Renal, celiac, coronary, eyes
  • Segmental aneurysms, stenosis
    • “Beading”
pan pediatric classification
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
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
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 description69
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
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
Presentation of CNS vasculitis
  • Cognitive dysfunction
  • Severe headaches
    • Thunderclap
    • More frequented in non-progressive disease
  • Stroke
  • Seizures
  • Mental status changes
laboratory tests
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
Imaging
  • MRI/A, CT angiography
  • Formal angiography
    • Important for distal vasculitis
    • Stenosis, beading
pathology
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
Treatment
  • Relative short course of steroids in non-progressive vasculitis
  • Steroids and cyclophosphamide induction for progressive vasculitis
    • Azathioprine maintenance
  • Anticoagulation/antiplatelet
prognosis
Prognosis
  • Poor prognosis in untreated progressive disease
    • Multifocal, distal vessels, cognitive dysfunction
  • Good mortality prognosis in non-progressive disease but may be significant residual damage and functional disability
summary
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