TO THE EDITOR:

Autoimmune diseases can reveal underlying primary immune deficiencies (PIDs), among which are cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathway variants. From 2015, this pathway has become a classical clinical entity combining autoimmune cytopenia (AIC) and various immunopathologic manifestations (IMs).1,2 The role of CTLA-4 in controlling lymphocyte activation can be disrupted in case of dominant heterozygous CTLA-4 variants,3,4 recessive homozygous mutations, or deletions of lipopolysaccharide-responsive beige-like anchor (LRBA)5,6 or DEF6 variants.7 Abatacept, a CTLA-4 fusion protein labeled in rheumatoid arthritis,8 is a logical targeted option for those patients.

In 2019, a preliminary study of the French OBS’CEREVANCE cohort of children with AIC identified CTLA-4 pathway pathogenic variants in 10 of 80 cases of pediatric-onset Evans syndrome (pES).9 pES is now recognized as a severe long-lasting disease: numerous IMs appearing with increasing age in...

1.
Lo
B
,
Fritz
JM
,
Su
HC
,
Uzel
G
,
Jordan
MB
,
Lenardo
MJ.
CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency
.
Blood.
2016
;
128
(
8
):
1037
-
1042
.
2.
Gámez-Díaz
L
,
Seidel
MG.
Different apples, same tree: visualizing current biological and clinical insights into CTLA-4 insufficiency and LRBA and DEF6 deficiencies
.
Front Pediatr.
2021
;
9
:
662645
.
3.
Kuehn
HS
,
Ouyang
W
,
Lo
B
, et al
.
Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4
.
Science.
2014
;
345
(
6204
):
1623
-
1627
.
4.
Schubert
D
,
Bode
C
,
Kenefeck
R
, et al
.
Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations
.
Nat Med.
2014
;
20
(
12
):
1410
-
1416
.
5.
Moser von Filseck
J
,
Čopič
A
,
Delfosse
V
, et al
.
Intracellular transport. Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4-phosphate
.
Science.
2015
;
349
(
6246
):
432
-
436
.
6.
Gámez-Díaz
L
,
August
D
,
Stepensky
P
, et al
.
The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency
.
J Allergy Clin Immunol.
2016
;
137
(
1
):
223
-
230
.
7.
Serwas
NK
,
Hoeger
B
,
Ardy
RC
, et al
.
Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis [published correction appears in Nat Commun. 2019;10:4555]
.
Nat Commun.
2019
;
10
(
1
):
3106
.
8.
Kremer
JM
,
Westhovens
R
,
Leon
M
, et al
.
Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig
.
N Engl J Med.
2003
;
349
(
20
):
1907
-
1915
.
9.
Hadjadj
J
,
Aladjidi
N
,
Fernandes
H
, et al;
Members of the French Reference Center for Pediatric Autoimmune Cytopenia (CEREVANCE)
.
Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes
.
Blood.
2019
;
134
(
1
):
9
-
21
.
10.
Aladjidi
N
,
Fernandes
H
,
Leblanc
T
, et al
.
Evans syndrome in children: long-term outcome in a prospective French national observational cohort
.
Front Pediatr.
2015
;
3
:
79
.
11.
Pincez
T
,
Fernandes
H
,
Leblanc
T
, et al
.
Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden [published online ahead of print 14 January 2021]
.
Haematologica.
doi:10.3324/haematol.2020.271106.
12.
Aladjidi
N
,
Leverger
G
,
Leblanc
T
, et al;
Centre de Référence National des Cytopénies Auto-immunes de l’Enfant (CEREVANCE)
.
New insights into childhood autoimmune hemolytic anemia: a French national observational study of 265 children
.
Haematologica.
2011
;
96
(
5
):
655
-
663
.
13.
Schwab
C
,
Gabrysch
A
,
Olbrich
P
, et al
.
Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects
.
J Allergy Clin Immunol.
2018
;
142
(
6
):
1932
-
1946
.
14.
Kiykim
A
,
Ogulur
I
,
Dursun
E
, et al
.
Abatacept as a long-term targeted therapy for LRBA deficiency
.
J Allergy Clin Immunol Pract.
2019
;
7
(
8
):
2790
-
2800
.
15.
Hara
R
,
Umebayashi
H
,
Takei
S
, et al
.
Intravenous abatacept in Japanese patients with polyarticular-course juvenile idiopathic arthritis: results from a phase III open-label study
.
Pediatr Rheumatol Online J.
2019
;
17
(
1
):
17
.
16.
Harigai
M
,
Ishiguro
N
,
Inokuma
S
, et al
.
Safety and effectiveness of abatacept in Japanese non-elderly and elderly patients with rheumatoid arthritis in an all-cases post-marketing surveillance
.
Mod Rheumatol.
2019
;
29
(
5
):
747
-
755
.
17.
Genovese
MC
,
Pacheco-Tena
C
,
Covarrubias
A
, et al
.
Long-term safety and efficacy of subcutaneous abatacept in patients with rheumatoid arthritis: 5-year results from a phase IIIb trial
.
J Rheumatol.
2018
;
45
(
8
):
1085
-
1092
.
18.
Ozen
G
,
Pedro
S
,
Schumacher
R
,
Simon
TA
,
Michaud
K.
Safety of abatacept compared with other biologic and conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: data from an observational study
.
Arthritis Res Ther.
2019
;
21
(
1
):
141
.
19.
Randell
RL
,
Becker
ML.
Safety updates in novel therapeutics for pediatric rheumatic disease
.
Curr Opin Rheumatol.
2021
;
33
(
5
):
403
-
408
.
20.
Slatter
MA
,
Engelhardt
KR
,
Burroughs
LM
, et al
.
Hematopoietic stem cell transplantation for CTLA4 deficiency
.
J Allergy Clin Immunol.
2016
;
138
(
2
):
615
-
619
.
21.
Seidel
MG
,
Böhm
K
,
Dogu
F
, et al;
Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation
.
Treatment of severe forms of LPS-responsive beige-like anchor protein deficiency with allogeneic hematopoietic stem cell transplantation
.
J Allergy Clin Immunol.
2018
;
141
(
2
):
770
-
775
.
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