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Behçet’s disease
Isabelle Koné-PautPediatric Rheumatology
Paris, Le Kremlin-Bicêtre, France
Pediatric aspects
Pediatric Behçet’disease
Clinical challenges
What is Behçet’s disease?
• Recurrent oral ulceration (at least 3/year)
plus at least 2 of• Genital ulceration• Erythema nodosum, pustular lesion or necrotic folliculitis• Uveitis (total, posterior) or retinal vasculitis• Skin hypersensitivity (Positive pathergy test)
Mehdi, 27/08/88
Sept 2003 Headaches, intermittent diplopia, VIth nerve palsis CSF 49 cells, sterile
MRI high-density T2-weight signals in the right caudate nucleus
Mehdi, 27/08/88Jan. 2004: Fever, headachesCSF: 3100 cells, proteins: 1,4g/l
Feb. 2004: right hemiparesis + buccal aphtosis
CSF: 21 cells, proteins: 0,58g /l
Pathologic findings: perivascular lymphocytic infiltratePathologic findings: perivascular lymphocytic infiltrate
cerebral pedunculicerebral pedunculi
caudate nuclei + posteriorcaudate nuclei + posteriorarm of intern capsulaarm of intern capsula
August 2004 Fever, headaches, meningitis
CSF: 860 cells, proteins: 1,14g/l
Mehdi, 27/08/88
Behçet’s disease
buccal aphtosis, pseudo-folliculitis, pustula
Sam, 23/10/00
Mai 2005 Recurrent fever, 3- days every 3 weeks, chills Buccal aphtosis No lymphadenopathy, knee arthralgia Ibuprofen effective No mutation in MEFV gene
PFAPA?
Sam, 23/10/00
March 2007 Weight loss, severe headaches, lethargy,
photophobia Optic neuritis , papilledema Increased ESR Right intern jugular vein thrombosis
Absence of other procoagulant risk factor1 episod of perianal ulceration in 2006
Is it Behçet’s disease?
Florence, 1987
Fevers monthly since infancy, chillsBipolar aphtosis, severe acne, erythema nodosum since one yearHeadaches, conjunctivitisAbdominal pain, diarrhea, arthralgiaSkin reactions after vaccination
MVK Genotype V377I, S135L
16 year-old
Final diagnosis in 2006! MKD
Behçet’s disease and overlapping conditions
BEHCETCROHN
FMF
pFAPA
SPAB27
COMPLEXAPHTHOSIS
TAKAYASU
MAGIC
POLYCHONDRITIS
VKH
MKD
Pediatric Behçet’disease
Information from the literature
PED-BD prevalence
• Overall in high-risk Eastern countriesMean : 20/100 000
• Overall in low-risk Western countriesMean : 2.5/100 000
• In children: 2 nationwide surveysFrance & Italy: 1/150 000
Two categories of reported patients
• Pediatric-Behçet’s diseaseDefinite (completed) BD <16y
• Juvenile-onset Behçet’s diseaseFirst symptom before 16y but completed in
adulthood
Literature review (PBD)
Authors
Country
Patients
Benam
Maroc
26
Picco
Italie
23
Fujik
Japon
31
Hamza
Tunisie
14
Koné-
France
55
M/F
Cas F
AB
AG
Skin
Pathergy
Uveitis
Neurol
G Intest
Arthritis
Thromb.
Fever
4.2
8E/3F
80.7
92.3
>30.8
NP
57.7
31
19
NP
11.53
15.4
1.87
NP
100
65
45
15
25
25
73
NP
8
NP
0.82
NP
100
58
55
NP
29
12
30
NP
6
NP
1.8
1E/1F
100
64
71
NP
14
42
NP
17
16
NP
0.9
8E/4F
100
79
82
NP
36
42
40
60
20
NP
Literature review (JBD)
Author
Country
Patients
Bahrabri
S.Arabia
12
Kim
Korea
40
Benam
Maroc
22
M/F
Cas F
AB
AG
Skin
Pathergy
Uveitis
Neurol
G Intest
Arthritis
Thromb.
Fever
1.4
-
100
91
83
57
50
50
-
11.8
5.8
30
0.67
22%
100
82.5
72.5
17.3
27
2.5
5
27
-
NP
1.44
-
NP
90.9
77
-
72.7
-
NP
NP
13.7
NP
Prevalence of eye involvement in Pediatric BD series
BD patients (n)
• Kim DK (40)• Fujikawa (51)• Bahabri (12)• Picco (30)• Kone Paut (65)• Eldem (20)
0 20 40 60 80 100
Eldem (1998) 80%
Kone Paut (1998) 61
Picco de Marco 56%
Bahabri 90%
FujiKawa (1999) 29%
Kim DK (1994) 27%
PED-BD characteristics
• Strong genetic component– Sibling recurrence rate of 10 for pediatric
patients Koné-Paut et al. J Pediatrics 1999; 135: 89-93
– Genetic anticipation Fresko et al. Ann Rheum Dis 1998;57: 45-8
– Segregation analysis in paediatric subgroupsuggests AR inheritance Molinari et al. Am J Med Genet2003; 122A: 115-8
Familial aggregation in BDInfluence of age of onset
Figure 1: Distribution of familial and sporadic cases as a function of age of criteria
0,00
0,05
0,10
0,15
0,20
0,25
0,30
0,35
0,40
0,45
0-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70
Age of criteria
Per
cent
of
case
s
SPORADIC
FAMILIAL
N=4
N=1
N=12
N=3
N=77
N=9
N=46
N=0
N=72
N=4 N=91
N=2
N=83
N=3
N=44
N=0
N=25
N=0
N=16
N=0
N=8
N=0N=4
N=0 N=0 N=0 N=1 N=0
PED-BD characteristics
• Completed < 16 y, very rare• No suitable definition, resembles adult
disease– Long lasting and insidious onset– Less frequency of uveitis– Treatment, from adult experience– Prognosis and outcome unknown
PED-BD Cohort study
Aim of the study
To build –up a prospective cohort of pediatric patients,evaluation of the natural history, survival analyses,prognosis factors (multivariate analysis, Cox model)
To collect at least 200 trios for whole genome screening in order to identify the genes responsible for the Mendelian component of BD (that we evidenced in the pediatric group, Molinari et al Am J Med Genet 2003
Methods
• Homogenous collection of retrospective and prospective data• A list of calling symptoms (minimal requirement) to enter the study• Settlement of an evolving online data base containing the patient
chart (selected items)• Analysis of patients charts each year by the scientific committee,
decision for BD or not BD• At the end of the study
– Statistical analysis comparing BD patients and controls– Controls being patients qualified as not BD
• Establishment of diagnostic criteria or decision tree
In parallel, if possible, collection of DNAs (trios & multiplexes)
Inclusion criteria
• First symptom before the age of 16 years• Informed consent obtained
– For anonymous data collection– For DNAs collection (if appropriate)
• New or already known patient (max 3 years), andfollow-up at least 4 years
• No significant concomitant disease (that mayinterfere with BD evaluation)
• Fulfillment of criteria established according to a list,built by the scientific commitee)
Updates
Data Inclusion Year 1 Year 2 Year 3 Year 4
Demographics andfamilial data
X X
Genetics X X
Clinics andtherapeutics
X X X X X
Paraclinics X X X X X
Summary X X X X X
In real time upon eventAutomatically recalled, each year
Total number of Inclusion: n=27
0
2
4
6
8
10
12
14
Janury
08
February
08
March 08
Month
Nu
mb
er
of
Inc
lus
ion
Number of Inclusion
Inclusions March 2008
Ages at inclusion
0
1
2
3
4
5
6
1 3 5 7 9 11 13 15 17 19
n patients
0
2
4
6
8
10
12
14
16
18
Signs
Inclusion criteria (associated signs with oral aphtosis )
Inclusion criteria in 27 patients
Financial support
Source APHP, PHRC call 2007Total 4-y grant 255 000 €
COSTSStaff expenses
– Computer scientist : 35000 €– Clinical research officer: 192800€– Statistics: 6000€
Missions– Meetings: 20000€
Total 253 000€
Agenda
• 2007– Constitution of expert committee, first meeting, data base
settlement, ethical procedures– Collection of DNAs (trios and multiplexes)
• 2008– Pilot study, chart review by experts, extension of contributors,
presentation– Collection of DNAs
• 2008/10– Chart review each year, communication at PReS meeting each
year, statistical analyses– Collection of DNAs
• 2010– Genetic studies– Publication
ACTORS
CoordinationClinical
I Koné-PautTA TranS Ozen
H Ozdogan
Technical supportClean-WebStatistics
A Letierce INSERM 569Y Mikaeloff
LogisticsL Becquemont URC Bicêtre
Scientific committee(preliminary list)S Al MayoufB BodaghiC BodemerF DavatchiM Gattorno
A GulM HoferI Touitou
B Wechsler
Other from Israel (R Brick), Germany(C Zouboulis), Japan…?