Increased immune reactivity predicts aggressive complicating Crohn's disease in children.
OBJECTIVE
The ability to identify children with CD who are at highest risk for rapid progression from uncomplicated to complicated phenotypes would be invaluable in guiding initial therapy. The aims of this study were to determine whether immune responses and/or CARD15 variants are associated with complicated disease phenotypes and predict disease progression.


METHODS
Sera were collected from 796 pediatric CD cases and tested for anti-Cbir1 (flagellin), anti-outer membrane protein C, anti-Saccharomyces cerevisiae, and perinuclear antineutrophil cytoplasmic antibody by using enzyme-linked immunosorbent assay. Genotyping (Taqman MGB) was performed for 3 CARD15 variants (single nucleotide polymorphisms 8, 12, and 13). Associations between immune responses (antibody sum and quartile sum score, CARD15, and clinical phenotype were evaluated.


RESULTS
Thirty-two percent of patients developed at least 1 disease complication within a median of 32 months, and 18% underwent surgery. The frequency of internal penetrating, stricturing, and surgery significantly increased (P trend < .0001 for all 3 outcomes) with increasing antibody sum and quartile sum score. Nine percent of seropositive groups had internal penetrating/stricturing versus 2.9% in the seronegative group (P = .01). Twelve percent of seropositive groups underwent surgery versus 2% in the seronegative group (P = .0001). The highest antibody sum group (3) and quartile sum score group (4) demonstrated the most rapid disease progression (P < .0001). Increased hazard ratio was observed for antibody sum group 3 (7.8; confidence interval, 2.2-28.7), P < .002 and quartile sum score group 4 (11.0; confidence interval, 1.5-83.0, P < .02).


CONCLUSIONS
The rate of complicated CD increases in children as the number and magnitude of immune reactivity increase. Disease progression is significantly faster in children expressing immune reactivity.
Dubinsky
Marla C
MC
Department of Pediatrics, IBD Center, Cedars Sinai Medical Center, Los Angeles, California, USA. dubinskym@csmc.edu
Kugathasan
Subra
S
Mei
Ling
L
Picornell
Yoana
Y
Nebel
Justin
J
Wrobel
Iwona
I
Quiros
Antonio
A
Silber
Gary
G
Wahbeh
Ghassan
G
Katzir
Lirona
L
Vasiliauskas
Eric
E
Bahar
Ron
R
Otley
Anthony
A
Mack
David
D
Evans
Jonathan
J
Rosh
Joel
J
Hemker
Maria Oliva
MO
Leleiko
Neal
N
Crandall
Wallace
W
Langton
Christine
C
Landers
Carol
C
Taylor
Kent D
KD
Targan
Stephan R
SR
Rotter
Jerome I
JI
Markowitz
James
J
Hyams
Jeffrey
J
D000293:Adolescent; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood; D000907:Antibodies, Bacterial / Q000097:blood; D000908:Antibodies, Fungal / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease / Q000175:diagnosis* / Q000276:immunology* / Q000601:surgery; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005408:Flagellin / Q000276:immunology; D005838:Genotype; D006801:Humans; D007107:Immune System / Q000502:physiology*; D007223:Infant; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D011110:Polymorphism, Genetic; D011379:Prognosis; D012441:Saccharomyces cerevisiae / Q000276:immunology; D013223:Statistics as Topic
D019268:Antibodies, Antineutrophil Cytoplasmic; D000907:Antibodies, Bacterial; D000908:Antibodies, Fungal; C502160:CBir1 flagellin; D053473:Nod2 Signaling Adaptor Protein; D005408:Flagellin