Lupus néonatal

LUPUS AU
COURS DE LA
GROSSESSE ET
CHEZ L’ENFANT
Rolando Cimaz
GROSSESSE ET LUPUS
Rapport F/M: 9/1 (total)
1. Effet de la grossesse sur les
poussées lupiques
2. Effet du lupus sur l’évolution de la
grossesse (foetale/matérnelle)
EFFET DE LA GROSSESSE SUR LES POUSSEES LUPIQUES
Fréquence des poussées durant la
grossesse : 13-60%
Augmentation de la fréquence :
Petri, 1991; Mintz, 1986; Ruiz-Irastorza, 1996
Fréquence inchangée :
Lockshin, 1989; Derksen, 1994; Carmona, 1999
EFFET DE LA GROSSESSE SUR LES POUSSEES LUPIQUES
Différences entre les études
Différences en termes de
- critères d’inclusion
- méthodes d’étude
- nombre de patients
- administration de corticoides
- critères diagnostiques
Difficultés en termes de
- diagnostique différentiel entre une
poussée et certains signes de
grossesse
- diagnostique différentiel entre une
poussée renale et la pré-eclampsie
LUPUS ET GROSSESSE
Questions medicales
Est ce que le lupus est en phase de remission ?
Les medicaments sont-ils inoffensifs ?
Quel sera le meilleur traitement en cas de poussée de
lupus ?
Adresser le patient à un centre de niveau 3 : suivi
multidisciplinaire
Questions sociales
Est ce que la patiente pourra s’occuper du nouveauné?
Possibilité d’hospitalisation
Effet du lupus sur l’évolution de
la grossesse
• Avortements
• Prématurité
• Retard de croissance intra-utérin (RCIU)
• Pre-éclampsie
Difficulté de conception et lupus
Une maladie multi-systemique autoimmunitaire
Auto-anticorps multiples
Differents degrés d’intérference reproductive
Autoanticorps associés avec la
difficulté de conception
* Anti-Laminin
* Anti-Thyroglobulin
* Lymphocytotoxic
* Anti-Poly (ADP-ribose)
* Anti-Corpus Luteum
* Anti-Prolactin
* Anti-CD36
* Anti-Prothrombin
* Anti-Thromboplastin
* Anti-Mitochondrial M5 type
* Anti-Annexins
Anti-CL
Anti-PS
Anti-PI
Anti-PT
Anti-β
β2GPI
LAC
Pathologie placentaire
•Hypoperfusion des villositées : faible poids de
naissance
•Thromboses placentaires multiples
•Vasculopathie des artères spiralées
•Accélération de l’athérosclérose.
Gharavi AE, et al. Clin Obstet Gynecol 2001.
Magid MS, et al. Am J Obstet Gynecol 1998.
Placental pathology associated with APS
Levy RA et al, Lupus 1998
aPL: Thrombogenic action
Platelets
Endothelial cells
Anticoagulant mechanisms
Fibrinolytic pathways
Local effect on trophoblasts and
villous cells: annexin V
Gharavi AE; Pierangeli SS; Levy RA; Harris EN.
Clin Obstet Gynecol 2001.
ANTI
ANTIRo/SS
Ro/SSandANTI
ANTILA/SS
LA/SSRo/SS--AAand
LA/SS--BB
in
inRHEUMATIC
RHEUMATICDISEASE
DISEASE
Anti Ro/SS-A
Anti La/SS-B
SLE
35-40%
10-15%
SS
40-95%
40-87%
RA
UCTD
4%
12%
0%
3%
SSc
9-11%
2%
Normals
0.44%
0.04%
PREGNANCY
PREGNANCYOUTCOME
OUTCOME IN
IN
WOMEN
WOMENWITH
WITHAUTOIMMUNE
AUTOIMMUNE
DISEASES
-RO/SSA
DISEASESAND
ANDANTI
ANTI-RO/SSA
ANTIBODIES
ANTIBODIES
AAPROSPECTIVE
PROSPECTIVECONTROLLED
CONTROLLEDSTUDY
STUDY
OF
OF100
100WOMEN
WOMEN
Brucato A., et al. Lupus 2002;11:716-721
MATERNAL
MATERNAL DIAGNOSES
DIAGNOSES
Anti Ro pos
Anti Ro neg
SLE
53
58
SS
RA
25
0
1
9
UCTD
19
21
OTHERS
3
100
18
107
Total
Pregnancy
Pregnancy Outcome
Outcome in
in SLE
SLE
Ro+
N. women
(pregnancies)
Ro -
53 (61)
(61) 58 (86
(86)
86)
Pregnancy losses
10%
19%
Prematurity (<34 wk)
Mean gest. age
(3%)
(3%)
38 wk
(1%)
38 wk
Matern. mean age
30 yrs
30 yrs
Cesarean sections
49%
53%
Médicaments
The use of hydroxychloroquine in lupus
pregnancy – the British experience.
Khamashta MA, Buchanan NMM, Hughes GRV
Lupus 1996;5:S16-S22
Ocular toxicity and antenatal
exposure to chloroquine or
hydroxychloroquine for
rheumatic diseases.
Klinger G, et al.
Lancet 2001;358:813-4
Renal function of children exposed
to cyclosporine in utero.
Lo Giudice P, Dubourg L, HadjAissa A, Said ME, Claris O, Audra
P, Martin X, Cochat P.
Nephrol Dial Transplant
2000;15:1575-1579
Alterations in the immune system of
children from mothers treated with
immunosuppressive agents during
pregnancy
R. Cimaz, et al., Toxicology Letters 2003 (in press)
We have evaluated the immune function of
children born from mothers treated with
immune suppressants for connective tissue
diseases in 9 babies whose 6 mothers had
been taking cyclosporine A (2),
azathioprine (1) and dexamethasone (3)
during pregnancy, and in 14 babies from
mothers with similar diseases but who had
not been treated (controls).
leukocytes (x 103/mm3)
22
20
18
16
14
12
10
8
6
4
patients
controls
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
age (months)
3
platelets (x 10 /mm3)
1050
900
750
patients
600
controls
450
300
150
0
0 1 2 3 4 5 6 7 8 9 1011 1213 1415 1617 1819 20
age (months)
Hb (g/100 ml)
16
14
12
10
8
6
4
2
0
patients
controls
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
age (months)
90
80
%
70
60
50
40
30
20
10
0
CD3
CD4
CD8
CD19
90
80
%
70
60
50
40
30
20
10
0
CD3
CD4
CD8
CD19
CD4
CD8
CD19
80
70
%
60
50
40
30
20
10
0
CD3
patients
control s
IgA(m
g/dl)
100
90
80
70
60
50
40
30
20
10
0
IgA p
IgA c
1-3 m
4-6 m
7-11 m
12-24 m
age (months)
300
Ig
M
(m
g
/d
l)
250
200
150
IgM p
IgM c
100
50
0
1-3 m
4-6 m
7-12 m
13-24 m
IgG(m
g/dl)
age (months)
1000
900
800
700
600
500
400
300
200
100
0
IgG p
IgG c
1-3 m
4-6 m
7-12 m
age (months)
13-24 m
mg/dl
1200
1100
1000
900
800
700
600
500
400
300
200
100
0
6-12 mo.
patients
controls
mg/dl
IgG1
1000
900
800
700
600
500
400
300
200
100
0
IgG2
IgG3
IgG4
12-24 mo.
patients
controls
IgG1
IgG2
IgG3
IgG4
Réponse a la vaccination contre Hep B (titre
d’anticorps, mIU/ml; protectif >10 mIU/ml).
DOSES
0
PATIENTS
0
10
CONTROLS
0
20
319
1
22
14
2
3
337
52
261
289
253
699
45
1000
82
>1000
1000
36
116
414
>1000
IL-2 (left panel) and IFN-γ production (right panel)
(pg/ml,medians) by stimulated PBMC
20000
30000
25000
P = NS
20000
16000
Cya
Dex
Ctr
15000
10000
P = NS
12000
Cya
Dex
Ctr
8000
4000
5000
0
0
PMA+Iono
PMA+Iono
LUPUS ET GROSSESSE
“Pregnancy in patients with SLE
should not be regarded as an
unacceptable high risk condition
provided that conception is accurately
planned and patients are managed
according to a careful multidisciplinary
treatment schedule”.
Carmona F, Font J, Cervera R, et al.
Eur J Obst Gynecol 1999; 83: 137-142
LUPUS NEONATAL
+
BLOC CARDIAQUE
CONGENITAL
COMPLET (BAV)
RASH
Reichlin M, Brucato A, Prak MB, et al.
Autoantibodies to native 60 kD Ro/SSA
and denaturated 52 kD Ro/SSA are
concentrated in eluates from the heart
of a child who died with complete
congenital heart block.
Arthritis Rheum 1994; 37: 1698-1703.
•Accessibility of SSA/Ro and anti-SSB/La antigens to
maternal autoantibodies in apoptotic human fetal cardiac
myocytes. Miranda-Carus ME et al. J Immunol
1998;161:5061-5069.
•Anti-SSA/Ro and anti-SSB/La autoantibodies bind the
surface of apoptotic fetal cardiocytes and promote
secretion of tumor necrosis factor α by macrophages.
Miranda-Carus ME et al. J Immunol 2000;165:5345-5351.
•Subcellular redistribution of La/SSB autoantigen during
physiologic apoptosis in the fetal mouse heart and
conduction system. Tran HB et al. Arthritis Rheum
2002;46:202-208.
Microchimerism
Cells that have trafficked from fetus to mother
Cells that have trafficked from mother to fetus
Cells from a blood transfusion
Cells from a twin
Autoimmune diseases in which
microchimerism has been investigated
Systemic sclerosis
Myositis
Primary biliary cirrhosis
Sjögren’s syndrome
Thyroiditis
Systemic lupus
Neonatal lupus
Maternal Microchimerism in NLS Myocardium
A. Stevens, MD, PhD
MICROCHIMERISM: 1222 DR11 “CELLS” PER MILLION !!
…passe moi des
cellules
DR11 CHIMERISM
NLE 6B BGLOB
Spectrum and progression of conduction abnormalities in
infants born to mothers with anti-SSA/Ro-SSB/La
antibodies. Askanase AD et al. Lupus 2002;11:145-151.
187 CHB.
•Wide spectrum of conduction abnormalities (8.5%).
•Progression from 1st
2nd
3rd degree block.
•CHB irreversible (possible regression of lesser degree
blocks).
BRADYCARDIA
•Mazel JA, et al. Electrocardiographic abnormalities in a
murine model injected with IgG from mothers of children
with congenital heart block. Circulation 1999;99:19141918.
•Cimaz R, et al. Transient neonatal bradycardia without
heart block associated with anti-Ro antibodies. Lupus
1997;6:487-488.
•Brucato, et al. Anti-Ro-associated sinus bradycardia in
newborns. Circulation 2000;102:e88-89.
QT interval prolongation in asymptomatic
anti-SSA/Ro positive infants without
congenital heart block
R Cimaz, M Stramba-Badiale, A Brucato, L Catelli,
P Panzeri, PL Meroni
Arthritis Rheum 2000; 43: 1049-1053
Notre étude a inclu 21 infants sans BAV –
nés de mères avec SLE= 8, Sjogren’s
syndrome = 3, UCTD = 10 - et avec
anticorps anti-SSA/Ro.
580
560
540
P=0.001
520
500
480
QTc 460
(msec)
440
420
400
380
360
340
anti SSA/Ro n=7
anti SSA/Ro +
n=21
Cimaz R et al., Arthritis Rheum, 2003;48:266
QTc (msec)
550
p = 0.001
500
450
400
350
1st ECG
1 year follow-up ECG
n = 21
anti-Ro 60
anti-Ro 52
90
90
80
80
70
70
60
50
U/ml
U /m l
60
40
50
40
30
30
20
20
10
10
0
0
1
2
3
4
5
6
7
age (months)
8
9
10 11 12
0
0
1
2
3
4
5
6
7
age (months)
8
9
10
11
12
CASE REPORT
Ultraviolet light exposure is not a requirement for the
development of cutaneous neonatal lupus
Cimaz et al., Lupus
2002;11:257-260
Hepatobiliary disease in neonatal lupus: prevalence and
clinical characteristics in cases enrolled in a national
registry.
•Choléstase
•Elévation des
aminotransférases
•Insuffisance hépatique
Lee et al, 2002
J Rheumatol 2002;29:187-91
Mother
Baby
Neutrophil binding by IgG
Inhibition studies
Defining the incidence and
spectrum of neonatal lupus. A
prospective study.
70%
60%
n=128
50%
40%
n=124
30%
n=120
n=107
20%
10%
n=128
n=120
n=124
n=124
n=45
n=120
n=105
al
ity
ab
no
rm
ra
sh
B
CH
C
he
pa
tic
gt
an
y
m
a-
ga
m
as
t
al
t
an
y
th
ro
m
an
em
ia
bo
cy
to
pe
ni
ne
a
ut
ro
an
pe
y
ni
he
a
m
at
ol
og
ic
0%
Cimaz et al., J Pediatr 2003; 142: 678-683
CONCLUSION
…merci de votre
attention…