Background and Aims Over 80 monogenic causes of very early onset inflammatory bowel disease (VEOIBD) have been identified. Prior reports of the natural history of VEOIBD have not considered monogenic disease status. The objective of this study is to describe clinical phenotypes and outcomes in a large single-center cohort of patients with VEOIBD and universal access to whole exome sequencing (WES). Methods Patients receiving IBD care at a single center were prospectively enrolled in a longitudinal data repository starting in 2012. WES was offered with enrollment. Enrolled patients were filtered by age of diagnosis <6 years to comprise VEOIBD cohort. Monogenic disease was identified by filtering proband variants for rare, loss-of-function or missense variants in known VEOIBD genes inherited according to standard Mendelian inheritance patterns. Results This analysis included 216 VEOIBD patients, followed for a median of 5.8 years. Seventeen patients (7.9%) had monogenic disease. Patients with monogenic IBD were younger at diagnosis and were more likely to have Crohn’s disease phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations. Patients with monogenic disease were also more likely to experience outcomes of ICU hospitalization, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, hematopoietic stem cell transplant, and death. Forty-one patients (19.0%) had infantile-onset disease. After controlling for monogenic disease, patients with infantile-onset IBD did not have increased risk for most severity outcomes. Conclusions Monogenic disease is an important driver of disease severity in VEOIBD. WES is a valuable tool in prognostication and management of VEOIBD.

No abstract

Crohn's disease is an inflammatory bowel disease (IBD) which most often presents with patchy lesions in the terminal ileum and colon and requires complex clinical care. Recent advances in the targeting of cytokines and leukocyte migration have greatly advanced treatment options, but most patients still relapse and inevitably progress. Although single-cell approaches are transforming our ability to understand the barrier tissue biology of inflammatory disease, comprehensive single-cell RNA-sequencing (scRNA-seq) atlases of IBD to date have largely sampled pre-treated patients with established disease. This has limited our understanding of which cell types, subsets, and states at diagnosis are predictive of disease severity and response to treatment. Here, through a combined clinical, flow cytometric, and scRNA-seq study, we profile diagnostic human biopsies from the terminal ileum of treatment-naive pediatric patients with Crohn's disease (pediCD; n=14) and from non-inflamed pediatric controls with functional gastrointestinal disorders (FGID; n=13). To fully resolve and annotate epithelial, stromal, and immune cell states among the 201,883 single-cell transcriptomes, we develop and deploy a principled and unbiased tiered clustering approach, ARBOL, yielding 138 FGID and 305 pediCD end cell clusters. Notably, through both flow cytometry and scRNA-seq, we observe that at the level of broad cell types, treatment-naive pediCD is not readily distinguishable from FGID in cellular composition. However, by integrating high-resolution scRNA-seq analysis, we identify significant differences in cell states that arise during pediCD relative to FGID. Furthermore, by closely linking our scRNA-seq analysis with clinical meta-data, we resolve a vector of lymphoid, myeloid, and epithelial cell states in treatment-naive samples which can distinguish patients with less severe disease (those not on anti-TNF therapies (NOA)), from those with more severe disease at presentation who require anti-TNF therapies. Moreover, this vector was also able to distinguish those patients that achieve a full response (FR) to anti-TNF blockade from those more treatment-resistant patients who only achieve a partial response (PR). Our study jointly leverages a treatment-naive cohort, high-resolution principled scRNA-seq data analysis, and clinical outcomes to understand which baseline cell states may predict inflammatory disease trajectory.

Lay Summary A pediatric patient with Crohn’s disease refractory to anti-tumor necrosis factor therapy, vedolizumab, ustekinumab, and 6-mercaptopurine achieved rapid clinical remission with upadacitinib. This is the first report of successful use of upadacitinib in pediatric inflammatory bowel disease.