Clinical, Imaging, and Endoscopic Outcomes of Children Newly Diagnosed with Crohn's Disease - PROJECT SUMMARY/ABSTRACT
Therapeutic goals in pediatric Crohn's Disease (CD) have shifted from clinical improvement or remission to
endoscopic healing (EH) by ileocolonoscopy and transmural healing (TH) by magnetic resonance enterography
(MRE). Patients achieving complete healing (CH, EH and TH) experience fewer hospitalizations or surgery. We
hypothesize that specific pre-treatment clinical, radiologic, transcriptomic, genomic, and microbial factors along
with attainment of targeted anti-TNF biologic exposure will be associated with the primary endpoint, CH, and the
major secondary endpoints, EH and TH, 52 weeks after anti-TNF start. We will test this hypothesis in a
prospective cohort study of 550 newly diagnosed pediatric-onset CD subjects treated with anti-TNF medication
within 6 months of diagnosis guided by therapeutic drug monitoring (TDM).
Aim 1. Evaluate putative associations and explore novel associations between CH and baseline
measures of clinical and radiologic severity. We hypothesize that pre-treatment nutritional status,
antimicrobial serologies, and MRE findings will be associated with year 1 CH. Formal hypothesis tests will be
carried out with appropriately controlled Type I error probabilities to confirm the predictive power of a set of pre-
specified baseline measures using a logistic regression model based on the year 1 CH outcome.
Aim 2. Evaluate putative associations and explore novel associations between anti-TNF drug levels, CH,
and host and microbial genomic and transcriptomic factors. We hypothesize that pre-treatment gene
expression signatures and microbial factors will be associated with early anti-TNF drug levels and year 1 CH.
We will characterize the host genotype, baseline mucosal and longitudinal fecal microbial taxonomic profile, and
baseline ileal and colon host transcriptome. Those variables identified as significantly associated will be
candidates for the final prediction model determined in Aim 3.
Aim 3. Use a k-fold cross-validation procedure to determine the optimal predictive model of year 1 CH.
We hypothesize that a model which includes host gene signatures and microbes will improve prediction of CH
beyond one based on clinical and imaging factors alone. The model will include clinical and imaging predictors
from Aim 1 and host and microbial characteristics found to be potentially explanatory in Aim 2.
Impact. The proposed inception cohort study, CAMEO, will provide a robust platform to study factors that
contribute to healing in pediatric CD that can then be translated into practice, as well as guiding future therapies
targeting the host immune response and microbiota in patients unlikely to achieve healing.
.
