Pediatric Vasculitis Lessons from...
Transcript of Pediatric Vasculitis Lessons from...
Pediatric Vasculitis Lessons from ARChiVe
David CabralBritish Columbia Children’s Hospital
Vancouver, CANADA
A Registry of Childhood Vasculitis
Learning objectives
• Focus on pediatric AAV & PAN: differences between children & adults in -
➢Classification➢Disease presentation➢Outcome ➢Treatment
• Opportunities for biological study in kids
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Patient presents to ED
• 5 year-old first nations girl - chronic mild asthma; father had JIA
• Swollen feet; ankle pain (arthritis) & rash
• Microscopic hematuria/proteinuria; normal creatinine
➢followed 2-weekly in resident O/P clinic
IgA Vasculitis (HSP)!
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Two-weekly HSP follow-up
• Initial improvements, then slow worsening
• 6w acute worsening “unwell”
– spreading rash, facial puffiness, hypertension
– urine output; > 100 rbc; casts+
• Admitted to ICU oliguric renal failure – (K+ 6.5, creatinine >700; PCR 700)
➢Hemodialysis,
➢BP control
➢Kidney biopsy➢ help treatment decisions
➢ differential diagnosis
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Differential diagnosis of IgAV / HSP?
• Infection• TTP• PSGN• SLE• FMF• Other vasculitis• DADA2 in the young?
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Histopathology Dominant IgA immunofluorescenceIncreased mesangiumMesangial electron dense deposits
Purpura / petechiae*- LL predominance PLUS one of
• Arthritis* /arthralgia• Abdominal pain• Renal involvement*• Characteristic histopathology
Criteria (EULAR/PRINTO /PRES )
For IgA Vasculitis (HSP)
Actual Histopathology
REPORT: Focal segmental pauci-immune Glomerulonephritis with 50% crescents and associated tubular injury
PLUS p- / MPO ANCA
DIAGNOSIS: Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV)
• Is it common, do other kids get it?
• What type of vasculitis? Does it matter?
• How do we treat & is it dangerous?
• How long do we need to treat?
• What is the outcome?
• Is it the same as adults?
…. from family &/or doctors
➢Classification➢Disease presentation➢Outcome ➢Treatment
• Do they differ?
– Intrinsically!
– Effects of disease and treatment differ in a growing child with immature immune system!
• Kids provide opportunity for biological discovery
– Preponderent genetic influence
– Less co-morbidity
Adult vs pediatric vasculitis….should they be studied independently?
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• Case reports / case series
• No pediatric RCT
• ‘Adapted’ adult data
• Expert pediatric consensus
Wilkinson et al. J Rheumatol 2007
Chronic Childhood Vasculitis is rare! Where do we get answers to these questions?
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A Registry for Childhood Vasculitis
Pediatric Vasculitis InitiativeA CIHR Emerging Team Grant in Rare Disease (2012)
2006
2013
ARChiVe /Pedvas: Cumulative data & samples
48 sites, 10 countries_______________________________________________________________
( )
2012 PedVas
biosamples &Follow-up data
Follow up: n=107
With Biosamples: n=165(RNA, DNA, serum, plasma, urine - 21 sites, 7 countries)
Primary systemic vasculitisHeterogeneous group of syndromes
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Single organ vasculitis
PACNS
Cutaneous Vascultiis
*
*
Multifactorial / polygenic
Autoimmune / Inflammatory
Differing histopathology
Few to multiple organs
Mild to rapidly fatal
Acute / chronic
Small / medium / large vessels
- Several disease syndromes
- overlapping presentations *
Figure adapted from: Watts & Dharmapalaiah (2012). Arthritis Research UK Topical Reviews.
…. Classification - why?
To define clinically homogeneous groups:
• to define disease course & outcome
• to prognosticate
• to participate in clinical studies (RCTs)
• May define biological uniqueness !
➢ Biomarker discovery
➢ etiological discovery
➢ Mechanisms
How do we classify childhood vasculitis?
1990: ACR criteria• 33-66% children with WG (GPA) unclassifiable (1996)*
2004: The pediatric classification initiative
2010: Pediatric-specific vasculitis classification criteria EULAR/PRINTO/PRES criteria
2012: Revised International Chapel Hill Consensus Conference: Nomenclature of Vasculitides (CHCC 2)
2017: DCVAS provisional criteria new for GPA. An collaborative transatlantic endeavor
*J Rheumatol 1996 23(11):1981-7; J Rheumatol 1996 23(11):1968-74; J Rheumatol 2007 34(1):224-6
Ankara 2008______________________________
Pediatric Classification criteria for GPA EULAR/PRINTO/PRES Criteria
1. Nasal / sinus inflammation
2. Abnormal radiograph or CT of chest
3. Abnormal urinalysis (hematuria +/or proteinuria)
4. Granulomatous inflammation on biopsy/ (necrotizing pauci-immune GN
5. Subglottic, tracheal, endobronchial stenosis
6. PR3-ANCA or C-ANCA staining
Classification as GPA requires 3 of above criteria
Ozen et al, ARD 2010
1990 ACR
Criteria (n=87)
EULAR/PRINTO/ PRES
criteria (n=98)
843
14
101 of 155 classified as GPA
one way or another
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MD Diagnosis Sens Spec
1990 ACR 69% 67%
2008 EULAR/PRINTO/PRES 77% 61%
Uribe, A. J Rheumatol 2012
ACR or EULAR/PRINTO/PRES classification criteria for GPAapplied to 155 patients with chronic Sm-Med ves vasc.
33 also
MPA
1990 ACR
Criteria (n=87)
EULAR/PRINTO/ PRES
criteria (n=98)
843
14
5 also
MPA
2 also
MPA
40 of 101 are also MPA
by CHCC definition
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MD Diagnosis Sens Spec
1990 ACR 69% 67%
2008 EULAR/PRINTO/PRES 77% 61%
Uribe, A. J Rheumatol 2012
ACR or EULAR/PRINTO/PRES classification criteria for GPAapplied to 155 patients with chronic Sm-Med ves vasc.
CHCC definition of MPA
applied to patient groups
Differences between pediatric GPA and MPA?
GPA
n=183
MPA
n=48
Med age at diagnosis yrs 14 12
Female % 62 73
Kidney disease % 83 55
More severe
Pulmonary disease % 74
More severe
44
GI symptoms % 36 58
MPO / p –ANCA % 26 55
PR3 / c – ANCA % 67 17
Cabral et al. A&R, 2016
21% childhood AAV unclassifiable as GPA, MPA or EGPA
• GWAS: N = 2687 patients, 7650 controls Lyons et al., NEJM, 2012
Key conclusions: genetic markers of AAV
➢ 4 loci associated with AAV➢ 6 loci specific to either GPA or MPA➢ Association with ANCA -type stronger than ‘phenotype’
Biological basis for vasculitis types?Genetically distinct subsets within adult AAV
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Biological basis for vasculitis types?Transcriptomic biomarker discovery in kids!__________________________________________________
30 patients provided clinical data & samples for RNA sequencing
ANCA associated vasculitis (AAV) 20
GPA 16
MPA 4
Unclassified Vasculitis 8
Polyarteritis nodosa (PAN) 2
Erin E. Gill, Robert Hancock Lab. UBC
GPA-like cluster (n=13; 8 F)
• 9 GPA; 4 UCV
• Anti- PR3: MPO = 70:30
• genes involved innate immunity; & predominantly neutrophil degranulation
MPA-like cluster (n=14; 9F)
• 4 MPA; 5 GPA; 2 PAN; 3 UCV
• Anti- PR3: MPO = 45:55
• genes involved adaptive immunity; & T-Cell activation
Outlier cluster: No pattern 2GPA; one UCV 22
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Erin E. Gill, Robert Hancock Lab. UBC
Different gene expression patterns hierarchical clustering to 3 groups
RNA-Seq Data unbiased analysis:3809 differentially expressed genes
Different gene expression patterns in GPA /MPA ~like groups
As few as 20 differentially expressed genes may accurately classify individuals to GPA -/ MPA- like groups
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Evidence of neutrophil activation in GPA
178 (8%) of 2,217 highly expressed genes in GPA-like cluster involved in neutrophil degranulation; genes depicted here with NetworkAnalyst.
The most highly connected genes among these included MAPK1 and MAPK14, the heatshock protein HSPA1B, PSEN1, and polyubiquitin-C (UBC)
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Evidence of T cell activation in MPA
CD4 and genes in MHCII pathway (ie towards CD4 T cell activation) highly expressed in MPA-like samples
Normalized read counts of T cell subtype-specific transcription factors were used to determine relative ratios of different T cell populations in MPA vs GPA
Individuals in the MPA-like cluster had a slightly lower ratio of Th1:Th2 cells (P = 0.038) than individuals in the GPA-like cluster, and a much higher ratio of Th2:all T cells (p= 3.0E-06).
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Classifying vasculitis!The Indian fable of the elephant & 6 blind men
“…it’s a pillar”
“…a rope”
“..a tree branch”
“.. a hand fan”
“…a huge wall”
“ .. a solid pipe”
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Is pediatric & adult GPA the same at onset?
Children**n=183
Adults*n=55-80
Peak incidence yrs 13.5 55
Female % 62 30-50
Constitutional features % 88 60
Kidney disease % 83 55
Pulmonary disease % 74 60
ENT disease %- subglottic stenosis %
7010
6512
*Koldingsnes A&R, 2000; Mahr A&R, 2008; Stone NEJM, 2010; **Cabral et al; A&R 2016
Pediatric GPA more severe, more organs affected
….treatment
• preventing relapses
• limit accumulating disease/treatment damage
- Use evidence-based adult strategies & guidelines!
- What do we actually do in pediatrics?
Are the treatments dangerous?Children no longer die soon after diagnosis.
• Mortality reduced with cyclophosphamide & steroids
• Treatment risks (short & long term)
- Life-threatening infection*
- Malignancy
- Cardiovascular disease
- Fragile bones
- Infertility*
- Interrupted growth and development*
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Reducing the treatment risks.Evidence based treatment strategies in adults
• Limit cyclophosphamide to remission induction - Never >6 m
• Less toxic drugs for remission maintenance - MTX, AZA, MMF
• Milder less toxic drugs from outset - MTX, AZA, MMF
• Alternatives to CYC - Rituximab, infliximab, tociluzimab, etc
• Limit corticosteroid duration - Minimum to none after 6-12m
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Treatment of severe GPA/MPA
INDUCTION MAINTENANCE
Cyclophosphamide
• IV: 15mg/kg (d1,14,28 ->q3wk)
• Oral: 2mg/kg/d
3-6 months (max 6m)
DMARD alternatives -
• AZATHIOPRINE 2 mg/kg/d
• METHOTREXATE 0.3 mg/kg/wk
• MYCOPHENOLATE MOFETIL 2g/d
• LEFLUNOMIDE 20 mg/d
? Plasmapheresis ??
+ Cotrimoxazole (prophylaxis against P. Jiroveci & ENT relapse)
Or Rituximab Or Rituximab
> 24 months …??
R+ Corticosteroids
J Rheumatol 2016;43:97-120
How do we treat severe pediatric GPA/MPA?
Treatment Stage
Survey PHYSICIANS
N=142
Archive PATIENTS
N=231
Remission Induction
Cyclophosphamide % 66 76
Rituximab % 31 12
MTX / AZA / MMF % 10
Remission Maintenance
Azathioprine 45 45Methotrexate 23 24Mycophenolate 18 14Rituximab 11 10Cyclophosphamide 10
Cabral et al. A&R, 2016; Westwell-Roper et al. PROJ 2017
For how long will she need medicines?Duration of Maintenance (physician survey)
Duration (m) %
Corticosteroids
24 4
18 6
12 40
6 39
Immunosuppressant
36 14
24 46
18 19
12 13
PVAS & PGA = 0
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Westwell-Roper et al. PROJ 2017
For how long will she need medicines?Duration of Maintenance (physician survey)
Duration (m) %
Corticosteroids
24 4
18 6
12 40
6 39
Immunosuppressant
36 14
24 46
18 19
12 13
PVAS & PGA = 0
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Westwell-Roper et al. PROJ 2017
Preliminary Data: Biological
Measures of Disease Activity
Dirk Foell Lab, MunsterKelly Brown Lab, Vancouver
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Preliminary data: vasculitis remains active following treatment and when clinical measures suggest no activity
Erin E. Gill, Robert Hancock Lab, Vancouver
…outcomes• What do we know in pediatrics?
• What do we need to know?
Early (12m) Outcome of 105 children with AAVRemissions, relapses & tracking disease activity
• Majority renal (78%) +/or pulmonary disease (80%)
• 49% inactive disease post-induction (PVAS=0)
• 64% had inactive disease at 12m (PVAS=0)
• 42% achieved remission at 12m (PVAS=0, 0+Pred)
• A large proportion (63%) have damage by 12m
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Morishita et al; A & R 2017
Early (12m) Outcome of 105 children with AAVHospitalizations, morbidity & mortality
Damage as reported by pediatric-adapted VDI.
- 66 (63%) > 1 item at 12m (Med VDI = 1; range 0-6)
43 (41%) patients had 80 hospitalizations- 46% disease flares
- 15% other disease related (investigation, rehab)
- 16% infections
- 5% treatment / medication related adverse events
- 18% unrelated
12 (11%) patients ESRD; 2 renal transplants
No deaths
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Morishita et al; A & R 2017
Renal prognosis at one year
58% moderately impaired renal function at TOD
• 37% have persisting impairment.
Patients with renal failure at TOD unlikely to recover normal renal function
• 50% dialysis dependent or transplanted by 12m
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What do we need to know
Pediatric specific evidence-base data on:
• Long term outcome of Ped – AAV
• Predictors of outcome
• Efficacy CYC versus RTX
• Short, med, long term drug specific toxicities
• Better measures of disease activity / inactivity
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Shifting gears
Polyarteritis Nodosa (PAN)
Necrotising vasculitis
• Medium-Small arteries (c.f. MPA)
• fibrinoid necrosis
• Micro-aneurysms
• ANCA negative
• Idiopathic, or
- infection associated
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Classification Criteria (EULAR/PRINTO /PRES) for Childhood Polyarteritis Nodosa
Involvement of small-medium arteries on
Histopathology (necrotising vasculitis)OR
Angiogram (aneurysm/stenosis/occlusion)
PLUS one of
1. Skin involvement (livedo /nodules /infarcts)
2. Myalgia or muscle tenderness
3. Hypertension
4. Peripheral Neuropathy (sensory / mononeuritismultiplex)
5. Renal involvement
Loss of function variants in ADA2 found to be associated with Polyarteritis Nodosa
NEJM, 2014
What is Deficiency of adenosine deaminase 2
• Monogenic (AR) vasculitis syndrome
– Loss of function mutation CECR1 gene
• Clinical overlap with PAN (MVV)
• Clinical manifestations:
– Early-onset inflammatory manifestations
– Livedo reticularis
– Recurrent strokes
– Hematological manifestations• Hypo-g globulinemia• red cells, neutrophils, platelets down
Navon et al. N Engl J Med 370(10): 921-931 (2014).
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• PAN (Extent / severity dependent)
– Corticosteroids (i.e. Prednisone)
– Cyclophosphamide /azathioprine /methotrexate
• DADA2
– limited response to traditional PAN therapy– Better response to anti-TNF therapies– anti-TNF prevents strokes
How to ensure timely diagnosis of DADA2 to ensure targeted therapy & improved outcome?
PAN versus DADA2 therapy_______________________________________
AIM: Screen patients in the PedVasregistry for variants in ADA2
Screening criteria (must meet one criterion):
Diagnosis
• Diagnosed as PAN
• Unclassifiable phenotype
Early onset disease
• < 5 years of age
Central nervous system involvement
• Stroke
60 patients met this criteria for screening by– targeted Sanger sequencing
– adenosine deaminase activity testing
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PedVas patients with rare ADA2 mutations
ID Ethnicity SexAge at
Onset
Age at
Diag
Initial
DiagnosisADA2 Mutation (CDS)
P1 South Asian F 11y 12y PAN c.[139G>C];[139G>C]
P2 South Asian F 11y 12y PAN c.[139G>A];[139G>A]
P3 East Asian M 16y 16y UCV c.[25C>T];[140G>C]
P4 South Asian M 11y 12y PAN c.[1069G>A];[1069G>A]
P5 Caucasian F 1 wk NA Undiagnosed c.[1052T>A];[1052T>A]
P6 Caucasian F 10 mo 3y Undiagnosed c.[1052T>A];[1052T>A]
P7 East Asian F 4y 4y PAN c.[139G>A];[139G>A]
P8 South Asian F 3y 5y GPANo identified variants in
coding / splice-site regions
P9 Caucasian F 6 mo 8 mo UCV c.[139G>C]; deletion
P10 South Asian M 11y 11y cPAN c.927G>A
P11 Caucasian F 2y NA Undiagnosed c.1252G>T
• Arg9Trp (c.25C>T) and Ala357Thr (c.1069G>A) novel assoc. with DADA2• Leu351Gln (c.1052>A) novel variant
Patients screened by ADA2 enzyme levels____________________________________________________________
Clinical manifestations of DADA2 patientsID Fever Cutaneous Nervous System Other Organ Systems Vascular Imaging
Hypo-g-glob-ulinemia
P1 NoNodules;
Livedo reticularisNone
Blurred vision;Anemia
Microaneurysms in hepatic & splenic artery
Notdone
P2 YesNodules;
Diffuse digital swellingMotor mononeuritis
multiplexOral ulcers;
Abdominal painMicroaneurysms in splanchnic vessels
Not done
P3 YesPainful subcutaneous
nodulesMeningitis/encephalitis
Brainstem infarctNone No abnormal findings
Not done
P4 YesUlcers
Livedo reticularis;Superficial infarctions
Midbrain infarcts Blurred visionAneurysms in renal,
splanchnic & vertebral arteries
Low IgM
P5 YesLivedo racemosa vs cutis
marmorataDiffuse cerebral
atrophy
Oral ulcers;Bloody diarrhea;
Perforated bowel;Anemia; Neutropenia
No abnormal findings Low IgM
P6 Yes NoneStroke;
Cranial nerve involvement
Blurred vision; Neutropenia
Chronic liver disease;Perforated bowel;
No abnormal findings Low IgM
P7 YesSubcutaneous edema;
Nodules
Stroke;Cranial nerve involvement
Blurred visionRestricted diffusion on left
thalamusLow IgM
P8 YesSubcutaneous edema;
Polymorphous rashDecreased tendon
reflexes
Oral ulcers; Anal fissures;
Saddle nose deformity;Glomerulonephritis
No vascular imaging performed
Normal
P9 YesLivedo reticularis;
Raynaud’s phenomenon
Oculomotor nerve involvement;
Lacunar cerebral infarctions
Oculomotor palsy; Ileitis;
Splenic infarction;Hypertension
Decreased diameter of thoracic aorta and right
radial artery; Irregularities of the abdominal aorta
Notdone
Summary of ped- DADA2 screening
• 9 of 60 (15%) screened had DADA2
• 8 with bi-allelic variants in ADA2 » 3 novel variants
• Early onset with fever, livedo, stroke/neuro findings » but also 4/9 were over 10» 3 patients south asian; one east Asian
• PAN phenotype predominantly but » GPA» Early onset unexplained inflammatory brain
disease
• 4 of 9 treated with anti-TNF responded well
________________________________________________________
Gibson et al. Arthritis and Rheum, 2019).
Screening adult PAN for DADA2Presented ACR 2018 for VCRC (Merkel)
• 117 patients with idiopathic PAN from Vasculitis Clinical Research Consortium PAN cohort (Hep B neg)
• 4 /117 with bi-allelic ADA2 ‘damaging’ variants – 4 others had mono-allele variant (1/4 predicted damaging)
• 5 with low ADA2 enzyme activity
DADA2 with no identified ADA2 variants (peds/adults)
Extended sequencing intronic and non coding regions, modifying alleles, epigenetic modifications, or environmental exposures.
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Overview: about pediatric vasculitis
• Heterogeneity evident between, & within, different syndromes– phenotype, outcome, biology, etc.
• Childhood AAV different to adults and the extent of the differences still to be determined
• Pediatric vasculitis patients provide a unique opportunity for bench research
• Ongoing international, multicenter collaboration is essential.
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Acknowledgements
PedVas / ARChiVe Network
BCCH Clinical Team
Lori Tucker
Ross Petty
Kristin Houghton
Jaime Guzman
Andrea Human
Kelly Brown Lab
Kristen Gibson
Iwona Niemietz
Jordan Chiu
Sara Marrello
Children with vasculitis and their families
PedVas GroupSusanne BenselerDirk FoellColin RossBob HancockRaashid LuqmaniJinko Graham
Kelly BrownKim MorishitaChristoph KesselErin GillMarinka TwiltGuilia AmaroliKristen GibsonAngelyne Rivera