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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. No conflict of interest disclosures Off label medications in talk Rituximab for Wegener's granulomatosis

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Pediatric Vasculitis

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  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 Takayasuarteritis • IVIg for polyarteritisnodosa

  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-Schönleinpurpura • Isolated cutaneousleukocytoclastic vasculitis • Hypocomplementaemicurticarial 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;60:3413-24

  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 2010 69: 798-806

  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;363:221-32.

  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 1.2-2.6/106/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 2010 69: 798-806

  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

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