Original article—alimentary tract
Increased Immune Reactivity Predicts Aggressive Complicating Crohn's Disease in Children

https://doi.org/10.1016/j.cgh.2008.04.032Get rights and content

Background & Aims

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.

Section snippets

Patient Population

Pediatric CD patients were enrolled from 21 participating sites of the Western Regional Pediatric IBD Research Alliance, the Pediatric IBD Collaborative Research Group, and the Wisconsin Pediatric IBD Alliance.6, 8, 9

To be eligible, all CD patients must have undergone complete colonoscopy with ileal intubation or complete colonoscopy and small-bowel follow-through. A diagnosis of CD for this study was based on standard diagnostic criteria.10 Blood was drawn at each of the participating sites

Patient Demographics

A total of 796 pediatric CD patients were eligible for analysis. The median age at diagnosis was 12 years (0.6–18 years), and the median disease duration as of last follow-up was 32 months (1–235 months). The cohort was composed of 56% male and 44% female patients, and 87% were white, and 28% were of Jewish background.

Clinical Phenotypes

A total of 236 (30.3%) patients presented with (96/796 [12%]) or developed (140/796 [18%]) at least 1 disease complication within the median follow-up time of 32 months (Table 1).

Discussion

Longitudinal analysis in our large pediatric multicenter cohort demonstrated that disease progression from uncomplicated to IP/S phenotypes and CD-related surgery is accelerated in the presence of antimicrobial immune reactivity. Both the number of immune responses and the magnitude of immune response to various microbial antigens were predictive of aggressive disease phenotypes on the basis of the results from the subgroup of patients who had serologies drawn before a complication occurred and

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Cited by (0)

Supported by National Institute of Health K23 DK066248 (M.D.), K23 RR016111 (S.K.), IBD Program Project Grant DK 46763 (S.R.T., J.I.R., K.D.T.), The Cedars-Sinai Board of Governors' Chair in Medical Genetics (J.I.R.), and General Clinical Research Center, Grant #MO1-RR00425 (K.D.T.).

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