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Pediatric Vasculitis Philip Hashkes, MD, MSc

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Presentation on theme: "Pediatric Vasculitis Philip Hashkes, MD, MSc"— Presentation transcript:

1 Pediatric Vasculitis Philip Hashkes, MD, MSc
Head, Pediatric Rheumatology Unit Shaare Zedek Medical Center Jerusalem

2 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

3 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

4 Definition Inflammatory and destructive process of blood vessels; inflammation must be present in wall of blood vessel

5 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

6 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

7 Nervous system Central nervous system
Headaches, stroke, TIA, seizures, movement disorder Peripheral nervous system Palsy – especially drop foot/hand Sensory Polyneuropathy, mononeuritis multiplex

8 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

9 Red Blood Cell Cast, Fresh first AM urine

10 Antineutrophil Cytoplasmic Antibodies (ANCA)
C-ANCA (cytoplasmic) P- ANCA (perinuclear) Possibly pathogenic - activation of PMN

11 C-ANCA Antigen (by ELISA): neutral serine proteinase 3 (PR3)
Specific for Wegener’s granulomatosis Sensitivity and specificity > 90%

12 P-ANCA Antigen by (ELISA): myeloperoxidase for microscopic polyarteritis Other antigens seen in ulcerative colitis, other connective tissue diseases, sclerosing cholangitis

13 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

14 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

15 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

16 Other Primary Pediatric Vasculitidies
Behçet’s disease Isolated vasculitis of the CNS Cogan’s syndrome Unclassified

17 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

18 Pseudovasculitis Myxoma, cholesterol emboli
Blood vessel, thrombotic disease Antiphospholipid antibody syndrome Congenital conditions Mid-Aortic syndrome Ehlers-Danlos syndrome Other rare syndromes

19 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)

20 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

21 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

22 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:

23 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

24 WG - Clinical Manifestations
Subglottic stenosis (14-41% in children) More common with clinical significance than in adults Stridor, hoarseness, respiratory distress

25 WG - Clinical Manifestations
Lower respiratory tract (80-90%) Pneumonia, pneumonitis (23%) Hemoptysis (44%), nodules (42%), pleural effusion, pneumothorax Abnormal pulmonary function (78%)

26 WG - Clinical Manifestations
Renal (80-90%) Abnormal urinalysis (75-88%) Glomerulonephritis (focal, segmental, diffuse), 52-64% Hypertension Elevated creatinine, renal failure (42%)

27 WG - Clinical Manifestations
Uveitis, scleritis, episcleritis, proptosis - psuedotumor (37-53%) Nervous system (25%) Peripheral neuropathy

28 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

29 WG - Investigations Biopsies - skin, nasal, sinus, lung, renal
Upper respiratory frequently nondiagnostic Vasculitis, capillaritis, granulomas

30 WG - Differential Diagnosis
Infectious - TB, fungal, syphilis, leprosy Inflammatory – microscopic polyangitis, sarcoidosis, Goodpaster’s, Loeffler’s syndrome, other vasculitis Lymphoma

31 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 :

32 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

33 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:

34 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

35 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

36 Microscopic Polyangitis
Small vessel vasculitis Glomerulonephritis Pulmonary manifestations P-ANCA positive in 80% Myeloperoxidase Treatment and prognosis similar to WG

37 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

38 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

39 Takayasu’s Arteritis (TA)
Also “pulseless” disease Young < 40 years 1/3 < 20 years Asian, African-American females Incidence /106/yr Large artery vasculitis - aorta, aortic arch, carotid, subclavian, renal, iliac

40 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

41 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

42 TA: Children vs. Adults Children usually have the “triad”
Systemic features, hypertension, elevated ESR More systemic features, renal artery involvement, less claudication than adults

43 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 :

44 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)

45 TA – Other Clinical Associations
Autoimmune Chron’s, immunodeficiency Infectious – TB in developing countries Many patients with positive TST

46 TA – Investigations Signs of inflammation
ESR important in following course Elevated factor VIII - related antigen Rheumatoid factor (25%) Hypergammaglobulinemia

47 Imaging Modalities Used
Ultrasound – Doppler Echocardiography Formal angiography MRI/A CT angio PET scan

48 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

49 Imaging Findings Stenosis (85-98%) Occlusion
Dilatation, aneurysms (2-27%) Mixed Collateral formation Wall thickening, edema

50 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

51 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

52 TA - Natural History Course
Triphasic Preinflammatory, inflammatory, “burnt - out” Remission and relapse (80%) 20% only one course of disease

53 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

54 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

55 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

56 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%)

57 PAN - Rash Palpable purpura Nodules

58 PAN - Rash Echymosis Gangrene Ulcers

59 PAN - Rash Livedo reticularis Splinter hemorrhage

60 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

61 PAN - Pathology Fibrinoid necrosis of medium sized muscular arteries
Acute and chronic Partial thickness, segmental, skipped lesions Mainly at bifurcation

62 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

63 PAN - Evaluation (cont.)
ECG, echocardiogram Nerve conduction, electromyography EEG Biopsy Skin, muscle, sural nerve, renal

64 PAN - Imaging MRI/A CT angiography
Often difficult to image smaller vessels

65 PAN - Angiography Renal, celiac, coronary, eyes
Segmental aneurysms, stenosis “Beading”

66 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 :

67 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

68 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

69 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

70 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”)

71 Presentation of CNS vasculitis
Cognitive dysfunction Severe headaches Thunderclap More frequented in non-progressive disease Stroke Seizures Mental status changes

72 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

73 Imaging MRI/A, CT angiography Formal angiography
Important for distal vasculitis Stenosis, beading

74 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

75 Treatment Relative short course of steroids in non-progressive vasculitis Steroids and cyclophosphamide induction for progressive vasculitis Azathioprine maintenance Anticoagulation/antiplatelet

76 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

77 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


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