Pediatric Vasculitis Philip Hashkes, MD, MSc Head, Pediatric Rheumatology Unit Shaare Zedek Medical...
-
Upload
eustace-simpson -
Category
Documents
-
view
236 -
download
1
Transcript of Pediatric Vasculitis Philip Hashkes, MD, MSc Head, Pediatric Rheumatology Unit Shaare Zedek Medical...
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