https://orcid.org/0000-0001-6919-8383
SLE occurs in 22% of children with ANA-associated AIC.
Children of age >10 years and ANA titer >1/160 must be monitored long-term, for progression to SLE.
Abstract
Autoimmune cytopenia (AIC) in children may be associated with positive antinuclear antibodies (ANA) and may progress to systemic lupus erythematosus (SLE). We evaluated the risk of progression to SLE of childhood-onset ANA-associated AIC. In the French national prospective OBS’CEREVANCE cohort, the long-term outcome of children with ANA-associated AIC (ANA titer ≥1/160) and a subgroup of children who developed SLE were described. ANA were positive in 355 of 1803 (20%) children with AIC. With a median follow-up of 5.8 (range, 0.1-29.6) years, 79 of 355 (22%) patients developed SLE at a median age of 14.5 (1.1-21.4) years; 20% of chronic immune thrombocytopenic purpura, 19% of autoimmune hemolytic anemia, and 45% of Evans syndrome. None of the patients with ANA-negative test developed SLE. Severe manifestations of SLE were observed in 21 patients, and 2 patients died. In multivariate analysis including patients with positive ANA within the first 3 months after AIC diagnosis, age >10 years at AIC diagnosis (relative risk [RR], 3.67; 95% confidence interval [CI], 1.18-11.4; P = .024) and ANA titer >1/160 (RR, 5.28; 95% CI, 1.20-23.17; P = .027) were associated with the occurrence of SLE after AIC diagnosis. ANA-associated AIC is a risk factor for progression to SLE, especially in children with an initial ANA titer >1/160 and an age >10 years at AIC diagnosis. ANA screening should be recommended in children with AIC, and patients with ANA should be monitored long-term for SLE, with special attention to the transition period. This trial was registered at www.ClinicalTrials.gov as #NCT05937828.
References
1.
Kamphuis
S
, Silverman
ED
. Prevalence and burden of pediatric-onset systemic lupus erythematosus
. Nat Rev Rheumatol
. 2010
;6
(9
):538
-546
.2.
Groot
N
, Shaikhani
D
, Teng
YKO
, et al. Long-term clinical outcomes in a cohort of adults with childhood-onset systemic lupus erythematosus
. Arthritis Rheumatol
. 2019
;71
(2
):290
-301
.3.
Bader-Meunier
B
, Armengaud
JB
, Haddad
E
, et al. Initial presentation of childhood-onset systemic lupus erythematosus: a French multicenter study
. J Pediatr
. 2005
;146
(5
):648
-653
.4.
Ogbu
EA
, Chandrakasan
S
, Rouster-Stevens
K
, et al. Impact of autoimmune cytopenias on severity of childhood-onset systemic lupus erythematosus: a single-center retrospective cohort study
. Lupus
. 2021
;30
(1
):109
-117
.5.
Artım-Esen
B
, Çene
E
, Şahinkaya
Y
, et al. Autoimmune haemolytic anaemia and thrombocytopaenia in a single-centre cohort of patients with systemic lupus erythematosus from Turkey: clinical associations and effect on disease damage and survival
. Lupus
. 2019
;28
(12
):1480
-1487
.6.
Arbuckle
MR
, McClain
MT
, Rubertone
MV
, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus
. N Engl J Med
. 2003
;349
(16
):1526
-1533
.7.
Lambers
WM
, Westra
J
, Jonkman
MF
, Bootsma
H
, de Leeuw
K
. Incomplete systemic lupus erythematosus: what remains after application of American College of Rheumatology and Systemic Lupus International Collaborating Clinics criteria?
. Arthritis Care Res
. 2020
;72
(5
):607
-614
.8.
Olsen
NJ
, Karp
DR
. Hydroxychloroquine: an old drug with new tricks
. J Rheumatol
. 2021
;48
(6
):796
-798
.9.
Zimmerman
SA
, Ware
RE
. Clinical significance of the antinuclear antibody test in selected children with idiopathic thrombocytopenic purpura
. J Pediatr Hematol Oncol
. 1997
;19
(4
):297
-303
.10.
Hazzan
R
, Mukamel
M
, Yacobovich
J
, Yaniv
I
, Tamary
H
. Risk factors for future development of systemic lupus erythematosus in children with idiopathic thrombocytopenic purpura
. Pediatr Blood Cancer
. 2006
;47
(5 suppl
):657
-659
.11.
Altintas
A
, Ozel
A
, Okur
N
, et al. Prevalence and clinical significance of elevated antinuclear antibody test in children and adult patients with idiopathic thrombocytopenic purpura
. J Thromb Thrombolysis
. 2007
;24
(2
):163
-168
.12.
Saettini
F
, Cattoni
A
, Redaelli
M
, et al. Primary immunodeficiencies, autoimmune hyperthyroidism, coeliac disease and systemic lupus erythematosus in childhood immune thrombocytopenia
. Acta Paediatr
. 2021
;110
(2
):643
-651
.13.
Kittivisuit
S
, Vachvanichsanong
P
, McNeil
E
, Chotsampancharoen
T
. Childhood-onset systemic lupus erythematosus and immune thrombocytopenia: prevalence and risk factors
. Pediatr Blood Cancer
. 2021
;68
(8
):e29146
.14.
Khellaf
M
, Chabrol
A
, Mahevas
M
, et al. Hydroxychloroquine is a good second-line treatment for adults with immune thrombocytopenia and positive antinuclear antibodies
. Am J Hematol
. 2014
;89
(2
):194
-198
.15.
Roche
O
, Aladjidi
N
, Rakotonjanahary
J
, et al. Evaluation of the efficiency of hydroxychloroquine in treating children with immune thrombocytopenia (ITP)
. Am J Hematol
. 2017
;92
(5
):E79
-81
.16.
Ducassou
S
, Gourdonneau
A
, Fernandes
H
, et al; Centre de Référence National des Cytopénies Auto-immunes de l’Enfant CEREVANCE
. Second-line treatment trends and long-term outcomes of 392 children with chronic immune thrombocytopenic purpura: the French experience over the past 25 years
. Br J Haematol
. 2020
;189
(5
):931
-942
.17.
Pincez
T
, Aladjidi
N
, Heritier
S
, et al. Determinants of splenectomy long-term outcomes in pediatric autoimmune cytopenias
. Blood
. 2022
;140
(3
):253
-261
.18.
Rodeghiero
F
, Stasi
R
, Gernsheimer
T
, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group
. Blood
. 2009
;113
(11
):2386
-2393
.19.
Petri
M
, Orbai
A-M
, Alarcón
GS
, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus
. Arthritis Rheum
. 2012
;64
(8
):2677
-2686
.20.
Aringer
M
, Costenbader
K
, Daikh
D
, et al. European league against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus
. Arthritis Rheumatol
. 2019
;71
(9
):1400
-1412
.21.
Buchanan
GR
, Adix
L
. Grading of hemorrhage in children with idiopathic thrombocytopenic purpura
. J Pediatr
. 2002
;141
(5
):683
-688
.22.
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
.23.
Madison
JA
, Zuo
Y
, Knight
JS
. Pediatric antiphospholipid syndrome
. Eur J Rheumatol
. 2020
;7
(Suppl1
):S3
-S12
.24.
Pincez
T
, Fernandes
H
, Leblanc
T
, et al. Long term follow-up of pediatric-onset Evans syndrome: broad immunopathological manifestations and high treatment burden
. Haematologica
. 2022
;107
(2
):457
-466
.25.
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
.26.
Hadjadj
J
, Castro
CN
, Tusseau
M
, et al. Early-onset autoimmunity associated with SOCS1 haploinsufficiency
. Nat Commun
. 2020
;11
(1
):5341
.27.
Song
Y
, Zhang
Y
, Li
Z
, Liu
J
, Xiao
J
, Song
H
. Potential risk factors for the development from immune thrombocytopenia to systemic lupus erythematosus: a case-control study in Chinese children
. Ann Hematol
. 2022
;101
(7
):1447
-1456
.28.
Provan
D
, Arnold
DM
, Bussel
JB
, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia
. Blood Adv
. 2019
;3
(22
):3780
-3817
.29.
Pediatric Hematology and Immunology Society in collaboration with the General Pediatrics Group
. Idiopathic thrombocytopenic purpura
. Arch de Pediatr
. 2007
;14
:1394
-1398
.30.
Tahiat
A
, Yagoubi
A
, Ladj
MS
, et al. Diagnostic and predictive contribution of autoantibodies screening in a large series of patients with primary immunodeficiencies
. Front Immunol
. 2021
;12
:665322
.31.
Gormezano
NWS
, Kern
D
, Pereira
OL
, et al. Autoimmune hemolytic anemia in systemic lupus erythematosus at diagnosis: differences between pediatric and adult patients
. Lupus
. 2017
;26
(4
):426
-430
.32.
Esteves
GCX
, Gormezano
NWS
, Pereira
OL
, et al. Distinct clinical correlates of immune thrombocytopenic purpura at diagnosis of childhood-onset and adult SLE
. Mod Rheumatol
. 2018
;28
(4
):649
-653
.33.
Ramírez Gómez
L
, Uribe Uribe
O
, Osio Uribe
O
. Childhood systemic lupus erythematosus in Latin America. The GLADEL experience in 230 children
. Lupus
. 2008
;17
(6
):596
-604
.34.
Lube
GE
, Ferriani
MPL
, Campos
LMA
, et al. Evans syndrome at childhood-onset systemic lupus erythematosus diagnosis: a large multicenter study
. Pediatr Blood Cancer
. 2016
;63
(7
):1238
-1243
.35.
Oni
L
, Wright
RD
, Marks
S
, Beresford
MW
, Tullus
K
. Kidney outcomes for children with lupus nephritis
. Pediatr Nephrol
. 2021
;36
(6
):1377
-1385
.36.
Santos
FPST
, Nascimento
BR
, Calderaro
DC
, Ferreira
GA
, Correa
H
. Neuropsychiatric syndromes in childhood-onset systemic lupus erythematosus: a systematic review and meta-analysis
. J Clin Rheumatol
. 2021
;27
(5
):206
-214
.37.
Moulis
G
, Comont
T
, Germain
J
, et al; CARMEN investigators group
. Significance of antinuclear antibodies in primary immune thrombocytopenia: results of the CARMEN registry
. Blood Adv
. 2020
;4
(9
):1974
-1977
.38.
Liu
Y
, Chen
S
, Yang
G
, et al. ANA-positive primary immune thrombocytopaenia: a different clinical entity with increased risk of connective tissue diseases
. Lupus Sci Med
. 2021
;8
(1
):e000523
.39.
McGhee
JL
, Kickingbird
LM
, Jarvis
JN
. Clinical utility of antinuclear antibody tests in children
. BMC Pediatr
. 2004
;4
:13
.40.
Trindade
VC
, Carneiro-Sampaio
M
, Bonfa
E
, Silva
CA
. An update on the management of childhood-onset systemic lupus erythematosus
. Paediatr Drugs
. 2021
;23
(4
):331
-347
.41.
James
JA
, Kim-Howard
XR
, Bruner
BF
, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus
. Lupus
. 2007
;16
(6
):401
-409
.42.
Sternhagen
E
, Bettendorf
B
, Lenert
A
, Lenert
PS
. The role of clinical features and serum biomarkers in identifying patients with incomplete lupus erythematosus at higher risk of transitioning to systemic lupus erythematosus: current perspectives
. J Inflamm Res
. 2022
;15
:1133
-1145
.43.
Munroe
ME
, Lu
R
, Zhao
YD
, et al. Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification
. Ann Rheum Dis
. 2016
;75
(11
):2014
-2021
.© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
2024
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