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BACKGROUND: Ustekinumab is increasingly used in pregnant women with inflammatory bowel disease (IBD). Existing safety data are reassuring, but the stability of ustekinumab levels in pregnancy, degree of transfer to the infant and time to infant clearance are unknown. METHODS: In this prospective observational study, ustekinumab-exposed women with IBD had trough levels measured in each trimester of pregnancy and at delivery. Infant ustekinumab levels were measured at delivery and ongoing until clearance was achieved. Trough ustekinumab level stability in individuals across pregnancy was compared by Skillings-Mack test. Spearman coefficients were used to correlate maternal and infant delivery levels, and median time to infant ustekinumab clearance was defined. RESULTS: 19 pregnant women receiving ustekinumab were included. There was no difference in ustekinumab levels across pregnancy in those with two or more representative trough levels (P = 0.83, n = 11). Infant delivery ustekinumab levels were higher than maternal levels, with a median infant:maternal ratio of 1.79 (IQR 1.26-3.1). There was a positive correlation between maternal and infant delivery ustekinumab levels (r = 0.75, P = 0.001) and an inverse correlation between the number of days from final antenatal dose and delivery infant ustekinumab level (r = -0.65, P = 0.006). Median time of infant ustekinumab clearance was 9 (range 6-19) weeks (n = 9). CONCLUSION: Ustekinumab drug levels appear stable in pregnancy, with a delivery infant:maternal ratio similar to that of anti-TNFs. Infant ustekinumab clearance was complete by 20 weeks post-partum, however, infants exposed in utero should avoid live vaccination before 12 months of age until further clearance data are obtained.

INTRODUCTION: Crohn's disease recurs after intestinal resection. This study evaluated accuracy of a new blood test, the Endoscopic Healing Index [EHI], in monitoring for disease recurrence. METHODS: Patients enrolled in the prospective POCER study [NCT00989560] underwent a postoperative colonoscopic assessment at 6 [2/3 of patients] and 18 months [all patients] following bowel resection, using the Rutgeerts score [recurrence ≥i2]. Serum was assessed at multiple time points for markers of endoscopic healing using the EHI, and paired with the Rutgeerts endoscopic score as the reference standard. RESULTS: A total of 131 patients provided 437 serum samples, which were paired with endoscopic assessments available in 94 patients [30 with recurrence] at 6 months and 107 patients [44 with recurrence] at 18 months. The median EHI at 6 months was significantly lower in patients in remission [Rutgeerts

The gut microbiota has a key role in the maintenance of good health, and in the pathogenesis of gastrointestinal diseases. These conditions include the inflammatory bowel diseases, colorectal cancer, coeliac disease and metabolic liver disease. Although the nature of the microbial disturbance in these conditions has not been fully characterised, this has not prevented the development of microbially based therapies. Microbial-changing therapies may address newly recognised pathophysiological contributors of disease and have the potential to replace or supplement standard therapies. Antibiotics play a role in initial Clostridiodes difficile disease and some specific inflammatory disorders. Probiotics have a more limited proven role. Faecal microbiota transplantation is of proven therapeutic benefit in recurrent C. difficile disease and ulcerative colitis. We review the current literature for microbiota-targeted therapies in gut disorders.

BACKGROUND: Loss of response to anti-TNF agents is a common clinical problem. Dose escalation may be effective for reestablishing clinical response in Crohn's disease (CD). AIMS: To perform a systematic review assessing the efficacy of escalated maintenance anti-TNF therapy in CD. METHODS: EMBASE, MEDLINE, Web of Science, and CENTRAL databases were searched for English language publications through to April 25, 2021. Full-text articles evaluating escalated maintenance treatment (infliximab or adalimumab) in adult CD patients were included. RESULTS: A total of 4733 records were identified, and 68 articles met eligibility criteria. Rates of clinical response (33%-100%) and remission (15%-83%) after empiric dose escalation for loss of response to standard anti-TNF therapy were high but varied across studies. Dose intensification strategies (doubling the dose versus shortening the therapeutic interval) were similarly efficacious. Dose-escalated patients tended to have higher serum drug levels compared to those on standard dosing. An exposure-response relationship following dose escalation was found in a number of observational studies. Randomised controlled trials comparing therapeutic drug monitoring (TDM) to empiric treatment intensification have failed to reach their primary end-points. Strategies including Bayesian dashboard-dosing and early treatment escalation targeting biomarker normalisation were found to be associated with improved long-term outcomes. CONCLUSIONS: Empiric escalation of maintenance anti-TNF therapy can recapture clinical response in a majority of patients with secondary loss of response to standard maintenance doses. Proactive optimisation of maintenance dosing might prolong time to loss of response in some patients.

BACKGROUND AND AIMS: Strictures are the commonest complication in Crohn's disease. Surgery and endoscopic dilation are the mainstays of treatment, while drug therapy has often been considered contraindicated. The benefit of nonsurgical treatments, particularly drug and endoscopic therapy, need to be defined. METHODS: Ovid MEDLINE, Embase, Emcare, PsycINFO, CINAHL and the Cochrane Library (inception until August 30, 2019) were searched. Studies with ≥ 10 patients with Crohn's disease strictures, reporting on outcomes following medication or endoscopic treatment, were included. RESULTS: Of 3480 records, 85 studies met inclusion criteria and formed the basis of this analysis. Twenty-five studies assessed drug therapy; none were randomized trials. Despite study heterogeneity anti-tumor necrosis factor (TNF) therapy appeared effective, with 50% of patients avoiding surgery after 4 years of follow up. No other drug therapy was of demonstrable benefit. Sixty studies assessed endoscopic therapy including 56 on endoscopic balloon dilation, two assessed needle knife stricturotomy, and two stent insertion. Dilation was equally effective for de novo and anastomotic strictures ≤ 5 cm in length, with most studies reporting a subsequent surgical rate of 30% to 50%. Repeat dilation was required in approximately half of all patients. CONCLUSIONS: Anti-TNF drug therapy and endoscopic balloon dilation are effective strategies for avoiding surgery in patients with stricturing Crohn's disease. Additional endoscopic therapies require further evaluation. Early data suggest that combining these therapies may provide greater benefit than individual therapies. Optimization of current drug and endoscopic therapy, and the incorporation of newer therapies, are needed for stricturing Crohn's disease.

BACKGROUND: Intestinal ultrasound (IUS) is a valuable tool for assessment of Crohn's disease (CD). However, there is no widely accepted luminal disease activity index. AIMS: To identify appropriate IUS protocols, indices, items, and scoring methods for measurement of luminal CD activity and integration of IUS in CD clinical trials. METHODS: An expert international panel of adult and paediatric gastroenterologists (n = 15) and radiologists (n = 3) rated the appropriateness of 120 statements derived from literature review and expert opinion (scale of 1-9) using modified RAND/UCLA methodology. Median panel scores of 1 to ≤3.5, >3.5 to <6.5 and ≥6.5 to 9 were considered inappropriate, uncertain and appropriate ratings respectively. The statement list and survey results were discussed prior to voting. RESULTS: A total of 91 statements were rated appropriate with agreement after two rounds of voting. Items considered appropriate measures of disease activity were bowel wall thickness (BWT), vascularity, stratification and mesenteric inflammatory fat. There was uncertainty if any of the existing IUS disease activity indices were appropriate for use in CD clinical trials. Appropriate trial applications for IUS included patient recruitment qualification when diseased segments cannot be adequately assessed by ileocolonoscopy and screening for exclusionary complications. At outcome assessment, remission endpoints including BWT and vascularity, with or without mesenteric inflammatory fat, were considered appropriate. Components of an ideal IUS disease activity index were identified based upon panel discussions. CONCLUSIONS: The panel identified appropriate component items and applications of IUS for CD clinical trials. Empiric evidence, and development and validation of an IUS disease activity index are needed.

LINKED CONTENT This article is linked to Biemans et al papers. To view these articles, visit https://doi.org/10.1111/apt.15689 and https://doi.org/10.1111/apt.16505

BACKGROUND: The gastrointestinal microbiota is the key antigenic drive in the inflammatory bowel diseases. Randomized controlled trials (RCTs) in ulcerative colitis have established fecal microbiota transplantation (FMT) as an effective therapy. We have conducted a systematic review to evaluate the efficacy of FMT in Crohn's disease. METHODS: A systematic literature search was performed through to August 2020 (MEDLINE; Embase). Studies were included if they reported FMT administration in patients with Crohn's disease, and reported on clinical outcomes. RESULTS: Fifteen studies published between 2014 and 2020, comprising 13 cohort studies and two RCTs, were included in the analysis. The majority of trials evaluated FMT for induction of remission, with follow-up duration varying from 4 to 52 weeks. One RCT in 21 patients, of single-dose FMT versus placebo, following steroid-induced remission, showed a higher rate of steroid-free clinical remission in the FMT group compared to the control group: 87.5% vs 44.4% at week 10 (P = 0.23). Another RCT, two-dose FMT in 31 patients, showed an overall clinical remission rate of 36% at week 8, however, with no difference in clinical or endoscopic endpoints between FMT administered by gastroscopy and colonoscopy. Considering all studies, the clinical response rates in early follow up were higher following multiple FMT than with single FMT. FMT dose did not appear to influence clinical outcomes, nor did whether FMT was fresh or frozen. FMT delivered via upper gastrointestinal route demonstrated higher early efficacy rates of 75 to 100% compared with lower delivery route rates of 30% to 58%, but on follow up beyond 8 weeks, this difference was not maintained. Whether pre-FMT antibiotic administration was beneficial was not able to be determined due to the limited number of patients receiving antibiotics and varying antibiotic regimens. No serious adverse events were reported. CONCLUSIONS: Preliminary studies suggest that FMT may be

BACKGROUND: Azathioprine and mercaptopurine are considered safe during pregnancy. However, the pharmacokinetic effects of pregnancy on thiopurine metabolism are undefined. AIMS: To characterise thiopurine metabolism in pregnancy and measure infant metabolite levels and outcomes. METHODS: Women with IBD who were taking a thiopurine and pregnant or trying to conceive were recruited. Maternal thiopurine metabolites were measured pre-conception, in each trimester, at delivery and post-partum. Infant metabolite levels, full blood examination and liver function testing were performed at birth, and repeated until levels undetectable and haematological and biochemical abnormalities resolved. RESULTS: Forty patients were included with measurements on at least two occasions, and two with only mother-baby levels at delivery. The median maternal 6-TGN level dropped in the second trimester compared with post-partum (179.0 vs 323.5 pmol/8 × 108 RBCs, P < 0.001) and the median 6-MMP level increased in the second trimester compared with post-partum (1103.0 vs 329.5 pmol/8 × 108 RBCs, P < 0.01). At delivery, the median 6-TGN level was lower in infants (n = 20) than mothers (78.5 vs 217 pmol/8 × 108 RBCs) (P < 0.001). Metabolites were not detected at 6 weeks in any infants. Anaemia was not seen, but thrombocytosis and abnormal liver biochemistry were detected in 80% of infants from 6 weeks, which gradually improved. CONCLUSIONS: 6-TGN levels decrease and 6-MMP levels increase in the second trimester of pregnancy. Infants are exposed to thiopurine metabolites at low levels with clearance by 6 weeks and no anaemia. The cause of infant thrombocytosis and abnormal liver biochemistry in the absence of metabolites is unclear.

Background The impact of pregnancy on levels of biologic agents in patients with IBD is undefined and time to elimination in vedolizumab‐exposed infants is unknown. Aims To determine the effect of pregnancy on infliximab, adalimumab and vedolizumab levels and to study infant vedolizumab clearance Methods In a prospective observational study, maternal drug levels were measured pre‐conception, in each trimester, at delivery and postpartum. The association between drug levels and gestation in weeks was assessed using generalised estimating equation modelling. Infant vedolizumab levels were performed at birth (cord blood), 6 weeks and 3 months or until undetectable. Results We included 50 IBD patients (23 on infliximab, 15 on adalimumab and 12 on vedolizumab) with at least two intrapartum observations, plus 5 patients on vedolizumab with only mother and baby samples at delivery. Modelling showed no change in adalimumab levels, an increase in infliximab levels of 0.16 (95% CI 0.08‐0.24) µg/L/week (P < 0.001) and a decrease of 0.18 (95% CI: −0.33 to −0.02) µg/L/week (P = 0.03) for vedolizumab. In 17 mother‐baby pairs, median infant vedolizumab levels at birth were lower than maternal levels (P < 0.05) with an infant:maternal ratio of 0.7 (IQR 0.5‐0.9). Vedolizumab was undetectable between 15 and 16 weeks of age in all 12 infants completing follow‐up testing. Conclusions During pregnancy, adalimumab levels remain stable, while infliximab levels increase and vedolizumab levels decrease. However, the increments were small suggesting that intrapartum therapeutic drug monitoring and dose adjustment are not indicated. Unlike infliximab and adalimumab, infant vedolizumab levels are lower in cord blood than in mothers and appear to clear rapidly.

BACKGROUND: Microbial factors are likely to be involved in the recurrence of Crohn's disease (CD) after bowel resection. We investigated the luminal microbiota before and longitudinally after surgery, in relation to disease recurrence, using 16S metagenomic techniques. METHODS: In the prospective Post-Operative Crohn's Endoscopic Recurrence (POCER) study, fecal samples were obtained before surgery and 6, 12, and 18 months after surgery from 130 CD patients. Endoscopy was undertaken to detect disease recurrence, defined as Rutgeerts score ≥i2, at 6 months in two-thirds of patients and all patients at 18 months after surgery. The V2 region of the 16S rRNA gene was sequenced using Illumina MiSeq. Cluster analysis was performed at family level, assessing microbiome community differences between patients with and without recurrence. RESULTS: Six microbial cluster groups were identified. The cluster associated with maintenance of remission was enriched for the Lachnospiraceae family [adjusted OR 0.47 (0.27-0.82), P = .007]. The OTU diversity of Lachnospiraceae within this cluster was significantly greater than in all other clusters. The cluster enriched for Enterobacteriaceae was associated with an increased risk of disease recurrence [adjusted OR 6.35 (1.24-32.44), P = .026]. OTU diversity of Enterobacteriaceae within this cluster was significantly greater than in other clusters. CONCLUSIONS: Luminal bacterial communities are associated with protection from, and the occurrence of, Crohn's disease recurrence after surgery. Recurrence may relate to a higher abundance of facultatively anaerobic pathobionts from the Enterobacteriaceae family. The ecologic change of depleted Lachnospiraceae, a genus of butyrate-producing bacteria, may permit expansion of Enterobacteriaceae through luminal environmental perturbation.

BACKGROUND: Point-of-care ultrasound (POCUS), performed by a gastroenterologist, provides safe and convenient imaging allowing for immediate clinical decision in Crohn's disease. The minimum training required to gain competency, its accuracy and clinical utility requires evaluation. METHODS: In this pilot study, Crohn's disease activity and extent were assessed using POCUS (performed by a single gastroenterologist following the completion of 200 supervised scans), magnetic resonance enterography (MRE) and ileo-colonoscopy. The presence of complications was assessed by POCUS and MRE. Accuracy of POCUS was analysed with respect to MRE and ileo-colonoscopy. Agreement between modalities was assessed using kappa coefficient. RESULTS: Forty-two patients had a POCUS paired with MRE. Thirty-eight patients had a POCUS paired with ileo-colonoscopy. When compared to MRE, POCUS was accurate in the assessment of disease activity (sensitivity 87.5%, specificity 61.1%, ROC 0.74), extent (sensitivity 77.8%, specificity 83.3%, ROC 0.81) and complications (sensitivity 85.7%, specificity 94.3%, ROC 0.90). Agreement between POCUS and MRE was moderate (kappa estimates 0.50, P < 0.001, 0.61, P < 0.001 and 0.76, P < 0.001) for disease activity, extent and complications, respectively. When compared to ileo-colonoscopy, POCUS was accurate in the assessment of disease activity (sensitivity 72%, specificity 86%, ROC 0.79) and extent (sensitivity 85.7%, specificity 86%, ROC 0.86). For POCUS and ileo-colonoscopy, kappa estimates were 0.55, P < 0.001 for disease activity and 0.62, P < 0.001 for disease extent. CONCLUSION: POCUS performed by a gastroenterologist after completion of limited training is accurate for assessing Crohn's disease activity, extent and the presence of complications.

BACKGROUND AND AIMS: Strictures are the most common Crohn's disease complication, but their natural history is unknown. This study aimed to characterize inflammation, predict prognosis, and understand the impact of drug therapy using magnetic resonance enterography (MRE). METHODS: Patients with a stricture diagnosed on MRE over a 5-year period were reviewed for MRE disease extent and inflammation, clinical course, C-reactive protein, response to anti-TNF therapy, endoscopic dilatation, hospitalization, and surgery. RESULTS: 136 patients had 235 strictures (77, one and 59, ≥ 2 strictures). TREATMENT: 46% of patients underwent surgery after a median 6 months; median follow-up for those not requiring surgery was 41 months. Predictors of surgery: Hospitalization because of obstruction predicted subsequent surgery (OR 2.50; 95% CI 1.06-5.90) while anti-TNF therapy commenced at stricture diagnosis was associated with a reduced risk (OR 0.23; 95% CI 0.05-0.99). MRE characteristics associated with surgery were proximal bowel dilatation ≥ 30-mm diameter (OR 2.98; 95% CI 1.36-6.55), stricture bowel wall thickness ≥ 10-mm (OR 2.42; 95% CI 1.11-5.27), and stricture length > 5-cm (OR 2.56; 95% CI 1.21-5.43). 81% of patients with these three adverse MRE features required surgery versus 17% if none were present (P < 0.001). Accuracy for these three MRE variables predicting surgery was high (AUC 0.76). CONCLUSION: Magnetic resonance enterography findings in Crohn's disease strictures are highly predictive of the disease course and the need for future surgery. MRE may also identify who would benefit from treatment intensification. Anti-TNF therapy is associated with reduced risk of surgery and appears to alter the natural history of this complication.

BACKGROUND AND AIM: Disease recurs frequently after Crohn's disease resection. The role of serological antimicrobial antibodies in predicting recurrence or as a marker of recurrence has not been well defined. METHODS: A total of 169 patients (523 samples) were prospectively studied, with testing peri-operatively, and 6, 12 and 18 months postoperatively. Colonoscopy was performed at 18 months postoperatively. Serologic antibody presence (perinuclear anti-neutrophil cytoplasmic antibody [pANCA], anti-Saccharomyces cerevisiae antibodies [ASCA] IgA/IgG, anti-OmpC, anti-CBir1, anti-A4-Fla2, anti-Fla-X) and titer were tested. Quartile sum score (range 6-24), logistic regression analysis, and correlation with phenotype, smoking status, and endoscopic outcome were assessed. RESULTS: Patients with ≥ 2 previous resections were more likely to be anti-OmpC positive (94% vs 55%, ≥ 2 vs < 2, P = 0.001). Recurrence at 18 months was associated with anti-Fla-X positivity at baseline (49% vs 29%; positive vs negative, P = 0.033) and 12 months (52% vs 31%, P = 0.04). Patients positive (n = 28) for all four antibacterial antibodies (anti-CBir1, anti-OmpC, anti-A4-Fla2, and anti-Fla-X) at baseline were more likely to experience recurrence at 18 months than patients negative (n = 32) for all four antibodies (82% vs 18%, P = 0.034; odds ratio 6.4, 95% confidence interval 1.16-34.9). The baseline quartile sum score for all six antimicrobial antibodies was higher in patients with severe recurrence (Rutgeert's i3-i4) at 18 months, adjusted for clinical risk factors (odds ratio 1.16, 95% confidence interval 1.01-1.34, P = 0.039). Smoking affected antibody status. CONCLUSIONS: Anti-Fla-X and presence of all anti-bacterial antibodies identifies patients at higher risk of early postoperative Crohn's disease recurrence. Serologic screening pre-operatively may help identify patients at increased risk of recurrence.

BACKGROUND: The intestinal microbiota is involved in the pathogenesis of inflammatory bowel disease. A reduction in the diversity of the intestinal microbiota as well as specific taxonomic and functional shifts have been reported in Crohn's disease and may play a central role in the inflammatory process. The aim was to systematically review recent developments in the structural and functional changes observed in the gastrointestinal microbiome in patients with Crohn's Disease. RESULTS: Seventy-two abstracts were included in this review. The effects of host genetics, disease phenotype, and inflammatory bowel disease treatment on the gastrointestinal microbiome in Crohn's disease were reviewed, and taxonomic shifts in patients with early and established disease were described. The relative abundance of Bacteroidetes is increased and Firmicutes decreased in Crohn's disease compared with healthy controls. Enterobacteriaceae, specifically Eschericia coli, is enriched in Crohn's disease. Faecalibacterium prausnitzii is found at lower abundance in Crohn's disease and in those with postoperative recurrence. Observed functional changes include major shifts in oxidative stress pathways, a decrease in butanoate and propanoate metabolism gene expression, lower levels of butyrate, and other short-chain fatty acids, decreased carbohydrate metabolism, and decreased amino acid biosynthesis. CONCLUSIONS: Changes in microbial composition and function have been described, although a causative role remains to be established. Larger, prospective, and longitudinal studies are required with deep interrogation of the microbiome if causality is to be determined, and refined microbial manipulation is to emerge as a focused therapy.

BACKGROUND: Programmes specific to inflammatory bowel disease (IBD) that facilitate transition from paediatric to adult care are currently lacking. AIM: We aimed to explore the perceived needs of adolescents with IBD among paediatric and adult gastroenterologists and to identify barriers to effective transition. METHODS: A web-based survey of paediatric and adult gastroenterologists in Australia and New Zealand employed both ranked items (Likert scale; from 1 not important to 5 very important) and forced choice items regarding the importance of various factors in facilitating effective transition of adolescents from paediatric to adult care. RESULTS: Response rate among 178 clinicians was 41%. Only 23% of respondents felt that adolescents with IBD were adequately prepared for transition to adult care. Psychological maturity (Mean = 4.3, standard deviation (SD) = 0.70) and readiness as assessed by adult caregiver (Mean = 4, SD = 0.72) were prioritised as the most important factors in determining timing of transfer. Self-efficacy and readiness as assessed by adult caregiver were considered the two most important factors to determine timing of transition by both groups of gastroenterologists. Poor medical and surgical handover (Mean = 4.10, SD = 0.8) and patients' lack of responsibility for their own care (Mean= 4.10, SD = 0.82) were perceived as major barriers to successful transition by both paediatric and adult gastroenterologists. CONCLUSIONS: Deficiencies exist in current transition care of adolescents with IBD in Australia and New Zealand. Standardising transition care practices with strategies aimed at optimising communication, patient education, self-efficacy and adherence may improve outcomes.