Pediatric Vasculitis

Philip Hashkes, MD, MScHead, Pediatric Rheumatology

UnitShaare 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

• 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

• 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

• 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, Henoch-Schonlein 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

(23-50%)

From 4 series of 130 patientsLargest 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 (37-53%)

• Nervous system (25%) – Peripheral

neuropathy

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 - 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% specificityOzen 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

• 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• 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 reactant100% sensitivity, 99.9% specificity

Ozen S, et al. Ann Rheum Dis 2010 69: 798-806

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

• 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

• 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.)

• 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 involvement89.6% 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 non-progressive 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 non-

progressive 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