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

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Presentation on theme: "Pediatric Vasculitis Philip Hashkes, MD, MSc Head, Pediatric Rheumatology Unit Shaare Zedek Medical Center Jerusalem."— 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 (1/10 6 /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 /10 6 /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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