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Background: Myeloid cells are critical determinants of the sustained inflammation in Crohn's Disease (CD). Targeting such cells may be an effective therapeutic approach for refractory CD patients. Bromodomain and extra-terminal domain protein inhibitors (iBET) are potent anti-inflammatory agents; however, they also possess wide-ranging toxicities. In the current study, we make use of a BET inhibitor containing an esterase sensitive motif (ESM-iBET), which is cleaved by carboxylesterase-1 (CES1), a highly expressed esterase in mononuclear myeloid cells., Methods: We profiled CES1 protein expression in the intestinal biopsies, peripheral blood, and CD fistula tract (fCD) cells of CD patients using mass cytometry. The anti-inflammatory effect of ESM-iBET or its control (iBET) were evaluated in healthy donor CD14 + monocytes and fCD cells, using cytometric beads assay or RNA-sequencing., Results: CES1 was specifically expressed in monocyte, macrophage, and dendritic cell populations in the intestinal tissue, peripheral blood, and fCD cells of CD patients. ESM-iBET inhibited IL1β, IL6, and TNFα secretion from healthy donor CD14 + monocytes and fCD immune cells, with 10- to 26-fold more potency over iBET in isolated CD14 + monocytes. Transcriptomic analysis revealed that ESM-iBET inhibited multiple inflammatory pathways, including TNF, JAK-STAT, NF-kB, NOD2, and AKT signaling, with superior potency over iBET., Conclusions: We demonstrate specific CES1 expression in mononuclear myeloid cell subsets in peripheral blood and inflamed tissues of CD patients. We report that low dose ESM-iBET accumulates in CES1-expressing cells and exerts robust anti-inflammatory effects, which could be beneficial in refractory CD patients.

Prediction of endoscopic post-operative recurrence (POR) in Crohn's disease (CD) patients following ileocolonic resection (ICR) using clinical risk factors alone has thus far been inadequate. While peripheral blood leukocyte (PBL) DNA methylation has shown promise as a tool for predicting recurrence in cancer, no data in CD patients exists. Therefore, this study explored the association and predictive value of PBL DNA methylation in CD patients following ICR. From a cohort of 117 CD patients undergoing ICR, epigenome-wide PBL methylation profiles from 25 carefully selected patients presenting either clear endoscopic remission ( n = 12) or severe recurrence ( n = 13) were assessed using the Illumina MethylationEPIC (850K) array. No statistically significant differentially methylated positions (DMPs) or regions (DMRs) associated with endoscopic POR were identified (FDR p ≤ 0.05), further evidenced by the low accuracy (0.625) following elastic net classification analysis. Nonetheless, interrogating the most significant differences in methylation suggested POR-associated hypermethylation in the MBNL1 , RAB29 and LEPR genes, respectively, which are involved in intestinal fibrosis, inflammation and wound healing. Notably, we observed a higher estimated proportion of monocytes in endoscopic POR compared to remission. Altogether, we observed limited differences in the genome-wide DNA methylome among CD patients with and without endoscopic POR. We therefore conclude that PBL DNA methylation is not a feasible predictive tool in post-operative CD.

Background & Aims: We investigated the effects of inducing deep remission in patients with early Crohn's disease (CD)., Methods: We collected follow-up data from 122 patients (mean age, 31.2 ± 11.3 y) with early, moderate to severe CD (median duration, 0.2 years; interquartile range, 0.1-0.5) who participated in the Effect of Tight Control Management on CD (CALM) study, at 31 sites, representing 50% of the original CALM patient population. Fifty percent of patients (n = 61) were randomly assigned to a tight control strategy (increased therapy based on fecal level of calprotectin, serum level of C-reactive protein, and symptoms), and 50% were assigned to conventional management. We categorized patients as those who were vs were not in deep remission (CD endoscopic index of severity scores below 4, with no deep ulcerations or steroid treatment, for 8 or more weeks) at the end of the follow-up period (median, 3.02 years; range, 0.05-6.26 years). The primary outcome was a composite of major adverse outcomes that indicate CD progression during the follow-up period: new internal fistulas or abscesses, strictures, perianal fistulas or abscesses, or hospitalization or surgery for CD. Kaplan-Meier and penalized Cox regression with bootstrapping were used to compare composite rates between patients who achieved or did not achieve remission at the end of the follow-up period., Results: Major adverse outcomes were reported for 34 patients (27.9%) during the follow-up period. Significantly fewer patients in deep remission at the end of the CALM study had major adverse outcomes during the follow-up period (P = .01). When we adjusted for potential confounders, deep remission (adjusted hazard ratio, 0.19; 95% confidence interval, 0.07-0.31) was significantly associated with a lower risk of major adverse outcome., Conclusions: In an analysis of follow-up data from the CALM study, we associated induction of deep remission in early, moderate to severe CD with decreased risk of disease progression over a median time of 3 years, regardless of tight control or conventional management strategy., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)