Vedolizumab and Ustekinumab Levels in Pregnant Women With Inflammatory Bowel Disease and Infants Exposed In Utero.

BACKGROUND & AIMS: Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of ustekinumab and vedolizumab levels and the time at which infant drug levels become undetectable. METHODS: This multicenter prospective observational cohort study recruited pregnant or preconception women with inflammatory bowel disease receiving vedolizumab or ustekinumab. Trough drug levels, clinical data, and biochemical data were documented preconception, during each trimester of pregnancy, and postpartum. Maternal and cord blood drug levels were measured at delivery and in infants until undetectable. Infant outcomes were assessed until 2 years of age. RESULTS: A total of 102 participants (vedolizumab, n = 58) were included. The majority of mothers were, and remained, in clinical and biochemical remission. Maternal vedolizumab levels decreased over the course of pregnancy in association with increasing weight, rather than increasing gestation. Maternal ustekinumab levels remained stable. The median time to drug becoming undetectable in the infant was shorter for vedolizumab (11 wk; range, 5-19 wk; n = 32) than ustekinumab (14 wk; range, 9-36 wk; n = 17) and correlated positively with infant delivery level. Thirty-two of 41 (88%) and 17 of 30 (67%) vedolizumab- and ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age, respectively. Pregnancy and infant outcomes were favorable. Twenty infants with undetectable drug levels received the rotavirus vaccine, with no adverse reactions reported. CONCLUSIONS: Maternal vedolizumab levels decreased, whereas ustekinumab levels remained stable over the course of pregnancy. Most vedolizumab- and approximately half of ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age. No concerning maternal or infant safety signals were identified.

Characterisation of biomarkers of intestinal barrier function in response to a high fat/high carbohydrate meal and corticotropin releasing hormone.

BACKGROUND: Variation of circulating concentrations of putative biomarkers of intestinal barrier function over the day and after acute physiological interventions are poorly documented on humans. This study aimed to examine the stability and pharmacokinetics of changes in plasma concentrations of intestinal Fatty-acid -binding -protein (IFABP), Lipopolysaccharide-binging-protein (LBP), soluble CD14, and Syndecan-1 after acute stress and high fat-high-carbohydrate meal. METHODS: In a single-blinded, cross-over, randomised study, healthy volunteers received on separate days corticotropin-releasing hormone (CRH, 100 µg) or normal saline (as placebo) intravenously in random order, then a HFHC meal. Participants were allowed low caloric food. Markers of intestinal barrier function were measured at set timed intervals from 30 minutes before to 24 hours after interventions. RESULTS: 10 participants (50% female) completed all three arms of the study. IFABP decreased by median 3.6 (IQR 1.4-10)% from -30 minutes to zero time (p = 0.001) and further reduced by 25 (20-52)% at 24 hours (p = 0.01) on the low caloric diet, but did not change in response to the meal. Syndecan-1, LBP and sCD14 were stable over a 24-hour period and not affected acutely by food intake. LBP levels 2 hours after CRH reduced by 0.61 (-0.95 to 0.05) µg/ml compared with 0.16 (-0.3 to 0.5) µg/ml post placebo injection (p = 0.05), but other markers did not change. CONCLUSION: Concentrations of IFABP, but not other markers, are unstable over 24 hours and should be measured fasting. A HFHC meal does not change intestinal permeability. Transient reduction of LPB after CRH confirms acute barrier dysfunction during stress.

Intestinal barrier biomarkers in clinical evaluation of patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with chronic intestinal barrier dysfunction, though its non-invasive assessment remains challenging. This study aimed to determine how four putative circulating markers vary across differing states of intestinal inflammation and with therapy in patients with IBD. METHODS: Plasma samples from one prospective cross-sectional and four longitudinal studies, including healthy controls, were analysed for markers of lipopolysaccharide translocation, lipopolysaccharide-binding protein (LBP) and soluble-CD14 (sCD14), and markers of epithelial injury, syndecan-1 and intestinal-type fatty acid-binding protein (IFABP). Inflammatory activity was determined using objective measures. RESULTS: Compared with healthy subjects, concentrations of LBP and sCD14 were higher in patients with active (P < 0.001) and severe ulcerative colitis (UC) (P < 0.0001) and active Crohn's disease (CD) (P < 0.001). In UC in remission, LBP was less than in active disease (P = 0.011) LBP levels decreased longitudinally before and after induction of medical therapy in patients with IBD (P = 0.030) and as severe UC was brought into remission at weeks 2 and 12 (P ≤ 0.022). Response to treatment was associated with higher baseline levels of LBP (P = 0.019) and soluble-CD14 (P = 0.014). Concentrations of syndecan-1 and IFABP were or tended to be lower in UC and CD in active disease and did not change with successful therapy. CONCLUSION: While markers of epithelial injury were subnormal with active disease and did not change with therapy, markers of lipopolysaccharide translocation directly reflected intestinal inflammation, reduced with successful therapy and predicted treatment response.

Readmission rate and complications following biopsy of the ampulla of Vater-A retrospective data analysis.

Background and Aim: Obtaining endoscopic biopsies from the ampulla of Vater is important for the diagnosis of lesions that are suspicious for neoplasia. The clinical safety profile is not well defined in the literature. Our aim was to evaluate the procedure-related readmission rate and complications from ampullary biopsy in patients undergoing duodenoscopy and endoscopic retrograde cholangiopancreatography (ERCP). Methods: A retrospective data analysis was performed on adult patients at Austin Hospital who underwent ampullary biopsies between 1 January 2010 and 1 March 12022. Medical records were identified using pathology databases. The electronic health record was reviewed for baseline characteristics including demographics, date, indication for ampullary biopsy, procedure type (duodenoscopy or ERCP), and procedural associated interventions during ERCP. Readmissions to the Austin Emergency Department within 30 days following the biopsy were identified, and complications were noted. Results: A total of 506 records were reviewed and 246 episodes of ampullary biopsy met the inclusion criteria. The procedure-related readmission rate for all episodes was 6.1%, which included pain (3.3%), pancreatitis (2.0%), cholangitis (1.6%), and bleeding (0.8%). Ampullary biopsies with ERCP had a procedure-related readmission rate of 8.4%, whereas ampullary biopsies without ERCP had a rate of 2.2%. Increased readmissions and complications were associated with male sex (P = 0.01 and P = 0.05, respectively). There was no association between the number of biopsies taken and complications. Conclusion: Performing an ampullary biopsy without an associated ERCP carries a low rate of clinical complications and procedure-related readmissions. The combination of ERCP and ampullary biopsy increases the risk four-fold.

A novel Monash Pouch diet in patients with an ileoanal pouch is tolerable and has favorable metabolic luminal effects.

Aims: To evaluate a whole-food diet strategy (the Monash Pouch diet [MPD]) designed based on the interacting roles dietary factors play with pouch health. Specifically, its tolerability and acceptability, whether it achieved its dietary and metabolic goals, and the effects on symptoms and inflammation were examined. Methods: In a 6-week open-label trial, patients with ileoanal pouches educated on the MPD were assessed regarding diet tolerability and acceptance, food intake (7-day food diaries), pouch-related symptoms (clinical pouchitis disease activity index), and, in 24-h fecal samples, calprotectin, fermentative biomarkers, and volatile organic compounds (VOC). Results: Of 12 patients, 6 male, mean (SD) age 55 (5) and pouch age 13 (2) years, one withdrew with partial small bowel obstruction. Tolerability was excellent in 9 (75%) and acceptance was high (81%). Targeted changes in dietary intake were achieved. Fecal branched- to short-chain fatty acid ratio increased by median 60 [IQR: 11-80]% (P = 0.02). Fecal VOCs for 3 compounds were also increased, 2-methyl-5-propan-2-ylcyclohexa-1,3-diene (Fold-change [FC] 2.08), 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane (FC 3.86), propan-2-ol (FC 2.10). All six symptomatic patients achieved symptomatic remission (P = 0.03). Fecal calprotectin at baseline was 292 [176-527] µg/g and at week 5 was 205 [148-310] µg/g (P = 0.72). Conclusion: Well tolerated and accepted, the MPD achieved targeted changes in intakes and fermentation of carbohydrates relative to that of protein. There were signals of improvement in symptoms. These results indicate the need for a randomized-controlled trial. (Trial registration: ACTRN12621000374864; https://www.anzctr.org.au/ACTRN12621000374864.aspx).

Transcutaneous vagal nerve stimulation protects against stress-induced intestinal barrier dysfunction in healthy adults.

BACKGROUND: Intestinal barrier dysfunction is the likely initiating event in multiple human diseases. Currently, there are limited therapeutic strategies to address its dysfunction. Animal studies suggest that vagal nerve stimulation may improve intestinal barrier function, but this has not been evaluated in humans. This study aimed to determine the effect of vagal nerve stimulation on intestinal permeability in adults administered a bolus dose of intravenous corticotropin releasing hormone (CRH) which has been shown to increase small intestinal permeability in healthy human subjects. METHODS: In a cross-over study, 16 volunteers (median age 34 years, 11 female) were randomized to receive auricular transcutaneous vagal nerve or sham stimulation (10 minutes each side) after intravenous administration of 100 µg of CRH. Intestinal barrier function was measured before and 2 h after each intervention with dual-sugar urine testing (lactulose:mannitol ratio) and intestinal fatty-acid binding protein (I-FABP). KEY RESULTS: Exposure to CRH increased I-FABP concentrations by a median of 49 (IQR 4-71)% (p = 0.009). Lactulose:mannitol ratios were 0.029 (0.025-0.050) following vagal stimulation compared with 0.062 (0.032-0.170) following sham stimulation (p = 0.0092), representing a fall of 53 (22-71)%. I-FABP concentrations did not change (p = 0.90). CONCLUSIONS: Brief non-invasive vagal nerve stimulation consistently reduces paracellular permeability of the small intestine after CRH administration, but does not entirely mitigate I-FABP release from the epithelium. Studies of vagal nerve stimulation in disease states are warranted.