Faubion, William A.

Abstract Background Darvadstrocel (DVS), a suspension of expanded allogeneic adipose-derived mesenchymal stem cells, is approved for the treatment of complex Crohn’s perianal fistulas (CPF). INSPIRE (EUPAS24267) is a European observational post-approval study evaluating real-world effectiveness and safety of DVS in patients with complex CPF for up to 36 months. Here we report preliminary clinical and safety outcomes from INSPIRE. Methods Patients with complex CPF who had received DVS according to local standard practice were eligible to enrol. Clinical response (closure of ≥50% of external openings [EOs]) and clinical remission (closure of all EOs) of DVS-treated fistulas that were draining at baseline, were evaluated in the all-treated (AT; received ≥1 dose of DVS with an evaluation for fistula response after 6 months) and per-protocol (PP; received DVS as per label-approved guidelines) cohorts. Treatment-emergent adverse events (TEAEs), serious TEAEs and AEs of special interest were reported for the safety cohort (all patients treated with DVS). Results As of April 2023, 652 patients had enrolled (Table 1). Complete data to evaluate 12-month clinical response and remission were available for 134 (AT cohort) and 124 (PP cohort) patients, of whom 79.9% (AT, n = 107) and 79.8% (PP, n = 99) had a clinical response and 76.1% (AT, n = 102) and 76.6% (PP, n = 95) had clinical remission (Figure 1). From baseline to Month 12, there was a decrease in the mean (standard deviation [SD]) Perianal Disease Activity Index score (–3.5 [3.3]; n/N = 96/302 and –3.7 [3.2]; n/N = 89/249) and a decrease in the mean (SD) Harvey–Bradshaw Index for Crohn’s disease activity (-0.3 [2.8]; n/N = 102/302 and -0.4 [2.9]; n/N = 95/249) in the AT and PP cohorts, respectively. Complete safety data were available for 619 patients (median [min–max] follow-up 480 [6–1595]) days. Overall, 26% (n = 162) had ≥1 TEAE and 10% (n = 63) ≥1 serious TEAE. The most frequent TEAEs were anal abscess (6.9%), COVID-19 (1.9%) and proctalgia (1.1%). No deaths were reported. One breast cancer lymph node metastasis and one ovarian epithelial cancer were reported; both events were confounded by immunosuppressant treatment and were not considered related to DVS treatment. Conclusion These preliminary data are consistent with the pivotal ADMIRE-CD study and demonstrate a single dose of DVS in patients with complex CPF is associated with positive clinical outcomes in up to 80% of patients, and a favourable safety profile, both of which are maintained after 12 months. The inherent limitations of registry-based studies mean these data should be interpreted with caution. However, the ongoing INSPIRE study will provide longer follow-up data to confirm these observations with respect to any study limitations.

Abstract Background DEVELOP is a multi-center, global, prospective, observational, longitudinal registry of long-term safety of infliximab (and other treatments) in paediatric patients (pts) with inflammatory bowel disease (IBD) <18 years (yrs) at diagnosis. Over the course of follow-up, many pts required changes in therapy. Ustekinumab (UST) is approved for treatment of Crohn’s disease (CD) in adults and is currently being evaluated for safety/efficacy in paediatric pts. This report focuses on assessment of safety of UST in paediatric pts with CD from DEVELOP. Methods Data included paediatric pts treated with UST from 31 May 2007 through 30 June 2022; data are collected every 6 months. The analyzed population included: all paediatric pts (all pts), pts weighing <40kg (<40kg group), and pts weighing ≥40kg (≥40kg group). Assessments included medical and treatment history, UST exposure, adverse events (AEs), serious AEs (SAEs), CD-related SAEs leading to hospitalization, IBD surgeries, serious and opportunistic infections, malignancies, and deaths. Results A total of 150 pts received UST (49.3% females); 31 in the <40kg group and 119 in the ≥40kg group (Table 1). Most treated pts (92.0%) were 12-17yrs. The majority (91%) of pts were initially dosed with UST every 8 weeks (q8w); at the last known dose, 64% received UST q8w and 22% q4w. Mean (SD) age of initial UST exposure was 15yrs (2.19). Prior IBD surgery was reported in 65.3% pts. The majority of pts (98%) had prior biologic therapy and 72% received ≥2 biologics prior to UST. Overall, 37/150 (24.7%) of pts discontinued UST during follow-up, with a mean (SD) time to discontinuation of 16.7 (17.00) months; 84/150 (56.0%) were exposed to UST for ≥24 months. Rates (events/100 pt-yrs) of AEs were higher in the ≥40kg group (177.62) than in the <40kg group (101.27). Rates of SAEs were slightly lower among the ≥40kg group (25.42) vs <40kg (32.67). There were no SAEs related to infusion or injection site reactions. Rates of serious infections and CD-related hospitalizations were low and similar between groups, and rates of IBD-related surgeries were similar between groups (Figure 1). One malignancy (malignant carcinoid tumor) was reported in a female (18yrs) in the ≥40kg group with a history of prior therapy with vedolizumab, methotrexate, and 6-MP. No deaths or opportunistic infections were reported. Conclusion The safety profile observed for this off-label use of UST in paediatric CD pts in DEVELOP was similar to that of the treated adult population, despite most paediatric pts having prior biologic exposure. No new safety signals are identified in this paediatric population.

ABSTRACTBackgroundInflammatory bowel disease (IBD) in adults with primary sclerosing cholangitis (PSC) is characterized by pancolonic involvement, a high frequency of rectal sparing, and an increased risk of pouchitis and colorectal neoplasia. The clinical features of IBD in pediatric patients with PSC have not been well described. The aim of this study was to characterize the frequency, clinical features, and natural history of IBD in pediatric patients diagnosed with PSC.MethodsA retrospective chart review was performed for all patients 18 years of age or younger diagnosed with PSC seen at the Mayo Clinic between 1975 and 1999. Endoscopic and histologic features and surgical and postsurgical outcomes were recorded.ResultsFifty‐two children with PSC were identified. Forty‐three patients (84%) were also diagnosed with IBD. In 36 of 43 cases, there was a sufficient diagnostic evaluation to allow a detailed review. Thirty‐two of 36 patients (89%) had ulcerative colitis and 4 of 36 patients (11%) had Crohn’s disease. In 4 of 36 patients (11%), IBD was asymptomatic. Although the most frequent endoscopic presentation of IBD was universal colitis, endoscopic rectal sparing was frequently noted (27% of colonoscopic studies). Of the four patients diagnosed with Crohn disease, in none did perianal, fistulizing, or stricturing disease develop. Proctocolectomy was performed in six patients (17%); three operations were performed for dysplasia. Pouchitis complicated four of the five ileal pouch–anal anastomoses procedures.ConclusionsAmong pediatric patients (1) PSC without IBD is uncommon; (2) asymptomatic IBD may be associated with PSC; (3) because the time to dysplasia may be accelerated, once the diagnosis of IBD is made in the setting of PSC, heightened endoscopic surveillance may be indicated; (4) pouchitis occurs frequently in these patients.

Background A multitude of studies have suggested that there is a link between obesity and inflammation. Various in vitro and animal studies have shown that saturated fatty acids are largely responsible for the induction of various pro‐inflammatory pathways. As vegetarians consume about half the amount of saturated fat as omnivores, we hypothesized that they would have less inflammation for any given amount of obesity. Objective To quantitate the inflammatory status of adipose tissue from obese vegetarians and omnivores. Methods The study included 8 obese vegetarians (1 male) and 8 obese omnivores matched for age, sex, and BMI. Body composition was measured by DXA. A blood sample to measure plasma free fatty acids (FFA) and abdominal and femoral subcutaneous adipose tissue biopsies to measure macrophage content, and the fatty acid composition were collected. Each participant also completed a Food Frequency Questionnaire (FFQ) to determine their average dietary intake. Results By design there were no differences in age, weight, BMI, percentage body fat, fat free mass or adipocyte size between the omnivore and vegetarian group. The plasma FFA of vegetarians revealed that they had greater proportions of the polyunsaturated fatty acids linoleic, linolenic and DHA ( p = 0.04, 0.05, 0.05 respectively ). Surprisingly, there was no difference in the fatty acid composition of the adipose tissue samples (abdominal or femoral) between the two groups. The FFQ data showed no significant difference in total fat, protein, or carbohydrate intake between the groups. However, the omnivore group had significantly greater intake of saturated fat and cholesterol than the vegetarian group ( p = 0.05, 0.04, respectively). The inflammatory status of adipose tissue was quantified by measuring macrophage content (total, pro‐inflammatory M1, and anti‐inflammatory M2 macrophages). There was no difference in total, M1 or M2 macrophage content between the vegetarian and omnivore groups. We also quantified the senescent cell population within the adipose tissue and again found no difference between the groups. Conclusions While vegetarians have significantly greater proportions of polyunsaturated fatty acids in plasma FFA than omnivores, this was not true for adipose tissue fatty acid composition. As expected, omnivores consume significantly greater amounts of saturated fatty acids, but there was no difference in adipose tissue inflammatory status between the two groups when measured using flow cytometry and senescent cell population. It is possible that the burden of obesity is more important than the consumption of saturated fatty acids in terms of human adipose tissue inflammation.

Background Forty distinct primary sclerosing cholangitis (PSC) genomic loci have been identified through multiancestry meta-analyses. The polygenic risk score (PRS) could serve as a promising tool to discover unique disease behaviour, like PSC, underlying inflammatory bowel disease (IBD). Aim To test whether PRS indicates PSC risk in patients with IBD. Materials and methods Mayo Clinic and Washington University at St Louis IBD cohorts were used to test our hypothesis. PRS was modelled through the published PSC loci and weighted with their corresponding effect size. Logistic regression was applied to predict the PSC risk. Results In total, 63 (5.6%) among 1130 patients with IBD of European ancestry had PSC. Among 381 ulcerative colitis (UC), 12% had PSC; in contrast to 1.4% in 761 Crohn disease (CD). Compared with IBD alone, IBD-PSC had significantly higher PRS (PSC risk: 3.0% at the lowest PRS quartile vs 7.2% at the highest PRS quartile, Ptrend =.03). In IBD subphenotypes subgroup analysis, multivariate analysis shows that UC-PSC is associated with more extensive UC disease (OR, 5.60; p=0.002) and younger age at diagnosis (p=0.02). In CD, multivariate analysis suggests that CD-PSC is associated with colorectal cancer (OR, 50; p=0.005). Conclusions We found evidence that patients with IBD with PSC presented with a clinical course difference from that of patients with IBD alone. PRS can influence PSC risk in patients with IBD. Once validated in an independent cohort, this may help identify patients with the highest likelihood of developing PSC.

INTRODUCTION: Patients with ulcerative colitis (UC) who are likely to have primary sclerosing cholangitis (PSC) should be identified because PSC can influence UC clinical behavior and outcomes.The aim of this study was to establish a model incorporating clinical and genetic risk predictors that identifies patients with UC at risk of developing PSC. METHODS: We conducted a retrospective case-control study. Inflammatory bowel disease cohorts from multiple institutions were used as discovery and replicate datasets. Quality control criteria, including minor allele frequency, call rates, Hardy-Weinberg equilibrium, cryptic relatedness, and population stratification (through principal components), were used. Discriminative accuracy was evaluated with area under the receiver operating characteristic curve. RESULTS: Fifty-seven of 581 patients (9.8%) with UC had PSC. Multivariate analysis showed that patients with UC-PSC had more extensive disease (odds ratio [OR], 5.42; P = 1.57E-04), younger diagnosis age (younger than 20 years; OR, 2.22; P = 0.02), and less smoking (OR, 0.42; P = 0.02) than those with UC. After linkage disequilibrium pruning and multivariate analyses, 3 SNPs (rs3131621 at 6p21.33; rs9275596 and rs11244 at 6p21.32) at the HLA region were found associated with a 2- to 3-fold increased risk of PSC. Our model demonstrated good discriminatory power (area under the receiver operating characteristic curve, 88%). DISCUSSION: Three variants in HLA (6p21.3) region significantly distinguished patients with UC-PSC from patients with UC alone. Once further validated in an independent large cohort, our model could be used to identify patients with UC at risk of PSC, and it could also help guide disease management.

Abstract Background The development of Crohn’s disease [CD] involves immune cell signalling pathways regulated by epigenetic modifications. Aberrant DNA methylation has been identified in peripheral blood and bulk intestinal tissue from CD patients. However, the DNA methylome of disease-associated intestinal CD4+ lymphocytes has not been evaluated. Materials and Methods Genome-wide DNA methylation sequencing was performed from terminal ileum CD4+ cells from 21 CD patients and 12 age- and sex-matched controls. Data were analysed for differentially methylated CpGs [DMCs] and methylated regions [DMRs]. Integration was performed with RNA-sequencing data to evaluate the functional impact of DNA methylation changes on gene expression. DMRs were overlapped with regions of differentially open chromatin [by ATAC-seq] and CCCTC-binding factor [CTCF] binding sites [by ChIP-seq] between peripherally derived Th17 and Treg cells. Results CD4+ cells in CD patients had significantly increased DNA methylation compared to those from the controls. A total of 119 051 DMCs and 8113 DMRs were detected. While hypermethylated genes were mostly related to cell metabolism and homeostasis, hypomethylated genes were significantly enriched within the Th17 signalling pathway. The differentially enriched ATAC regions in Th17 cells [compared to Tregs] were hypomethylated in CD patients, suggesting heightened Th17 activity. There was significant overlap between hypomethylated DNA regions and CTCF-associated binding sites. Conclusions The methylome of CD patients shows an overall dominant hypermethylation yet hypomethylation is more concentrated in proinflammatory pathways, including Th17 differentiation. Hypomethylation of Th17-related genes associated with areas of open chromatin and CTCF binding sites constitutes a hallmark of CD-associated intestinal CD4+ cells.

Abstract Intestinal permeability may correlate with adverse outcomes during hematopoietic stem cell transplantation (HSCT), but longitudinal quantification with traditional oral mannitol and lactulose is not feasible in HSCT recipients because of mucositis and diarrhea. A modified lactulose:rhamnose (LR) assay is validated in children with environmental enteritis. Our study objective was to quantify peri-HSCT intestinal permeability changes using the modified LR assay. The LR assay was administered before transplant, at day +7 and +30 to 80 pediatric and young adult patients who received allogeneic HSCT. Lactulose and rhamnose were detected using urine mass spectrometry and expressed as an L:R ratio. Metagenomic shotgun sequencing of stool for microbiome analyses and enzyme-linked immunosorbent assay analyses of plasma lipopolysaccharide binding protein (LBP), ST2, REG3α, claudin1, occludin, and intestinal alkaline phosphatase were performed at the same timepoints. L:R ratios were increased at day +7 but returned to baseline at day +30 in most patients (P = .014). Conditioning regimen intensity did not affect the trajectory of L:R (P = .39). Baseline L:R ratios did not vary with diagnosis. L:R correlated with LBP levels (r2 = 0.208; P = .0014). High L:R ratios were associated with lower microbiome diversity (P = .035), loss of anaerobic organisms (P = .020), and higher plasma LBP (P = .0014). No adverse gastrointestinal effects occurred because of LR. Intestinal permeability as measured through L:R ratios after allogeneic HSCT correlates with intestinal dysbiosis and elevated plasma LBP. The LR assay is well-tolerated and may identify transplant recipients who are more likely to experience adverse outcomes.