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…?