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Background and Aims: Crohn's perianal fistula healing rates remain low. We evaluated the efficacy of a protocolized multidisciplinary treatment strategy optimizing care in adults with Crohn's perianal fistulas., Methods: A new treatment strategy was established at a single tertiary center. The strategy comprised 3 dynamic stages of care directed toward achieving and maintaining fistula healing. Stage A, active disease, focused on early commencement and proactive escalation of biologic therapies and structured surgical reviews ensuring adequate fistula drainage and conditioning. Stage B, optimized disease with a seton in situ, focused on consideration for seton removal and appropriateness of definitive surgical closure and/or ablative techniques. Stage C, healed disease, focused on proactive care maintenance. Sixty patients were sequentially enrolled and prospectively followed for ≥12 months. Endpoints included clinical healing and radiologic remission in those with clinically active fistulas, and relapse in those with healed fistulas., Results: At baseline, 52% (n = 31) and 48% (n = 29) had clinically active and healed fistulas, respectively. For patients with clinically active fistulas, 71% achieved clinical healing after 22 months, with estimated healing rates of 39% and 84% at 1 and 2 years, respectively. Radiologic remission was achieved in 25%, significantly higher than baseline inclusion rates of 6%. For patients with healed fistulas, 7% experienced clinical relapse after 23 months, with no significant change in radiologic remission, 80% versus 86% at baseline., Conclusions: A protocolized treatment strategy proactively optimizing care resulted in high rates of clinical healing and improved radiologic remission of Crohn's perianal fistulas. Controlled-matched studies are needed., (© The Author(s) 2025. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background and Aims: Crohn's disease strictures are usually treated by a single endoscopic balloon dilation (EBD). We postulated repeat EBD and needle-knife stricturotomy (NKSt), together with inflammation controlled by intense drug therapy, may be more effective., Methods: Twenty-one patients with symptomatic strictures were randomized to a single EBD or intensive treatment with 3 balloon dilations 3 weeks apart and/or NKSt., Results: Of 21 patients, 2 of 5 (40%) undergoing a single EBD and 12 of 16 (72%) undergoing intensive treatment had symptom improvement (odds ratio, 4.49; 95% confidence interval, .54-37.4; P = .164). Eleven patients received >1 EBD without NKSt and 5 underwent ≥1 NKSt. NKSt-treated patients and those with concurrent intensified drug treatment had the best outcomes., Conclusions: Treatment for Crohn's disease strictures with repeat dilations or stricturotomy is feasible and safe and may improve stricture outcomes. Concurrent intensified drug treatment to eliminate inflammation is also associated with improved outcomes. (Clinical trial registration number: NCT03222011.)., Competing Interests: Disclosure The following author disclosed financial relationships: J. D. Schulberg: Speaker for Falk; advisory board for Abbvie. All other authors disclosed no financial relationships. Research support for this study was provided by the Australian National Health and Medical Research Council, Gastroenterological Society of Australia, Ferring IBD Clinician Establishment Award, Australasian Gastro Intestinal Research Foundation, and the Spotlight Foundation., (Copyright © 2025 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2025 AGA Institute. All rights reserved.)

Background: The optimal dosing strategy for infliximab in steroid-refractory acute severe ulcerative colitis (ASUC) is unknown. We compared intensified and standard dose infliximab rescue strategies and explored maintenance therapies following infliximab induction in ASUC., Methods: In this open-label, multicentre, randomised controlled trial, patients aged 18 years or older from 13 Australian tertiary hospitals with intravenous steroid-refractory ASUC were randomly assigned (1:2) to receive a first dose of 10 mg/kg infliximab or 5 mg/kg infliximab (randomisation 1). Block randomisation was used and stratified by history of thiopurine exposure and study site, with allocation concealment maintained via computer-generated randomisation. Patients in the 10 mg/kg group (intensified induction strategy [IIS]) received a second dose at day 7 or earlier at the time of non-response; all patients in the 5 mg/kg group were re-randomised between day 3 and day 7 (1:1; randomisation 2) to a standard induction strategy (SIS) or accelerated induction strategy (AIS), resulting in three induction groups. Patients in the SIS group received 5 mg/kg infliximab at weeks 0, 2, and 6, with an extra 5 mg/kg dose between day 3 and day 7 if no response. Patients in the AIS group received 5 mg/kg infliximab at weeks 0, 1, and 3, with the week 1 dose increased to 10 mg/kg and given between day 3 and day 7 if no response. The primary outcome was clinical response by day 7 (reduction in Lichtiger score to <10 with a decrease of ≥3 points from baseline, improvement in rectal bleeding, and decreased stool frequency to ≤4 per day). Secondary endpoints assessed outcomes to day 7 and exploratory outcomes compared induction regimens until month 3. From month 3, maintenance therapy was selected based on treatment experience, with use of thiopurine monotherapy, combination infliximab and thiopurine, or infliximab monotherapy, with follow-up as a cohort study up to month 12. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02770040, and is completed., Findings: Between July 20, 2016, and Sept 24, 2021, 138 patients were randomly assigned (63 [46%] female and 75 [54%] male); 46 received a first dose of 10 mg/kg infliximab and 92 received 5 mg/kg infliximab. After randomisation 1, we observed no significant difference in the proportion of patients who had a clinical response by day 7 between the 10 mg/kg and 5 mg/kg groups (30 [65%] of 46 vs 56 [61%] of 92, p=0·62; risk ratio adjusted for thiopurine treatment history, 1·06 [95% CI 0·94-1·20], p=0·32). We found no significant differences in secondary endpoints including time to clinical response or change in Lichtiger score from baseline to day 7. Two patients who received 10 mg/kg infliximab underwent colectomy in the first 7 days compared with no patients in the 5 mg/kg group (p=0·21). Three serious adverse events occurred in three patients in both the 10 mg/kg group and 5 mg/kg group. After randomisation 2, the proportions of patients with clinical response at day 14 (34 [74%] of 46 in the IIS group, 35 [73%] of 48 in the AIS group, and 30 [68%] of 44 in the SIS group, p=0·81), clinical remission at month 3 (23 [50%], 25 [52%], 21 [48%], p=0·92), steroid-free remission at month 3 (19 [41%], 20 [42%], 18 [41%], p=1·0), endoscopic remission at month 3 (21 [46%], 22 [46%], 21 [48%], p=0·98), and colectomy at month 3 (three [7%] of 45, nine [19%] of 47, five [12%] of 43, p=0·20) were not significantly different between groups. Between day 8 and month 3, the proportion of patients with at least one infectious adverse event possibly related to infliximab was two (4%) of 46 in the IIS group, eight (17%) of 48 in the AIS group, and eight (18%) of 44 in the SIS group (p=0·082). No deaths occurred in the study., Interpretation: Infliximab is a safe and effective rescue therapy in ASUC. In steroid-refractory ASUC, a first dose of 10 mg/kg infliximab was not superior to 5 mg/kg infliximab in achieving clinical response by day 7. Intensified, accelerated, and standard induction regimens did not result in a significant difference in clinical response by day 14 or in remission or colectomy rates by month 3., Funding: Australian National Health and Medical Research Council, Gastroenterology Society of Australia, Gandel Philanthropy, Australian Postgraduate Award, Janssen-Cilag., Competing Interests: Declaration of interests MCC is supported by a Gandel Major Philanthropy Grant and an Australian Postgraduate Award, and has received research funding from Janssen-Cilag. CFDLWS has served as a speaker for DiaSorin, has received educational support from Pfizer, Shire, and Ferring, has received research funding from the Robert C Bulley Charitable Foundation and St Vincent's Hospital Melbourne Research Endowment Fund, and is supported by an Australian National Health and Medical Research Council (NHMRC) Postgraduate Scholarship. DC has received educational support from Viatris and is supported by an NHMRC Postgraduate Scholarship. EKW has served as a consultant, advisory board member, or speaker for AbbVie, Bristol Myers Squibb, Ferring, Janssen, Celltrion, Falk, and Takeda, is supported by an NHMRC Emerging Leadership Level 1 Fellowship, and has received research support from Ferring and Janssen. AP has served as an advisory board member or received speaker fees from AbbVie, Ferring, Janssen, Pfizer, Takeda, and Dr Falk Pharma. BC has served as a consultant, advisory board member, or speaker for AbbVie, Celltrion, Chiesi, Ferring, Janssen, Eli Lilly, MSD, Pfizer, Takeda, and Shire, and has received research support from AbbVie, Celltrion, The Gastroenterological Society of Australia, the Helmsley Charitable Trust, the NHMRC, and Takeda. WN has received educational and research support from Pfizer, AbbVie, Janssen, Shire and Ferring. JB has served as a consultant, advisory board member, or speaker for AbbVie, Ferring, Janssen, Celltrion, Chiesi, Janssen, Pfizer, Amgen, GlaxoSmithKline, Bristol Myers Squibb, Microba, Anatara, and Takeda, and has received research support from the NHMRC, United States Department of Defense, AbbVie, Janssen, Ferring, Pfizer, and Takeda. MG has served on the advisory board of Pfizer and AbbVie and has received speaker fees and research grants from Abbvie, Celltrion, Janssen, Pfizer and travel grants from Pfizer. NM has received speaker fees from Takeda and Baxter, and educational support from Baxter. DRVL has received consulting fees from AbbVie and speaker fees for Takeda. NSD reports serving as an advisory board member or speaker for AbbVie, Celltrion, Chiesi, Ferring, Janssen, Eli Lilly, MSD, Pfizer, Takeda, and Shire, and has received research support from AbbVie, Celltrion, The Gastroenterological Society of Australia, and the NHMRC. RWL reports advisory board membership for AbbVie, Aspen, Bristol Myers Squibb, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, and Takeda, and research grants from the University of Sydney, the McCusker Charitable Foundation, Celltrion, Shire, Janssen, Takeda, Joanna Tiddy grant, the Gastroenterological Society of Australia, the NHMRC, The Gutsy Group, and Pfizer. MPS has received educational grants or research support from Gilead and Celltrion, speaker fees from Janssen, AbbVie, Ferring, Takeda, Pfizer, Shire, Celltrion, Eli Lilly, and Dr Falk Pharma, and has served on advisory boards or received consultancy fees for Janssen, Takeda, Pfizer, Celgene, AbbVie, MSD, Emerge Health, Gilead, Bristol Myers Squibb, Celltrion, and Eli Lilly, and has received travel grants from Pfizer and Dr Falk Pharma. PDC has served as a consultant, advisory board member, or speaker for AbbVie, Baxter, Ferring, Janssen, Celltrion and Emerge Health, and is supported by a NHMRC Emerging Leadership Level 2 Fellowship, and has received research support from AbbVie, Ferring, Janssen and Pfizer. All other authors declare no competing interests., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: To compare short-term patient-reported outcomes (PRO) of two contemporary matrix-associated autologous chondrocyte implantation (M-ACI) products for the treatment of large articular cartilage defects of the knee., Methods: A retrospective, registry-based, matched-pair analysis was performed, comparing PRO of patients undergoing isolated M-ACI with either Spherox™, a spheroid-based ACI (Sb-ACI), or NOVOCART™ Inject, a hydrogel-based ACI product (Hb-ACI), for a focal full-thickness cartilage defect of the knee ≥4 cm 2 . Matching parameters included age, sex, body mass index, defect size, defect localization, symptom duration and previous surgeries. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the International Knee Documentation Committee (IKDC) score were obtained up to the 24-month follow-up. The total KOOS response rate and percentage of patients attaining a substantial clinical benefit (SCB) in KOOS subscores were calculated., Results: A total of 45 patients per group were matched. The response rate after 24 months was not significantly different between the groups (Sb-ACI 64.4% vs. Hb-ACI 82.2%, p = 0.057). The number of patients with a SCB at 24 months was not significantly different in any KOOS subscore, despite significantly higher improvement of the total KOOS (14.8 ± 16.2 vs. 21.5 ± 15.4, p = 0.047) and KOOS pain in the Hb-ACI group (12.2 ± 18.6 vs. 20.6 ± 19.1, p = 0.037). The IKDC score in the Hb-ACI group was significantly higher at the 12- and 24-month follow-up (60.7 ± 20.2 vs. 70.9 ± 18.0, p = 0.013)., Conclusion: The response rate and number of patients achieving an SCB were not significantly different between patients treated with Sb-ACI or Hb-ACI. Both procedures can achieve favourable 2-year PRO. Hb-ACI was associated with better PRO between 1 and 2 years postoperatively; however, the clinical relevance of this benefit is yet to be proven., Level of Evidence: III, Retrospective comparative study., (© 2024 The Authors. Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background & Aims: Intestinal ultrasound (IUS) is increasingly used to assess Crohn's disease (CD) activity in clinical practice. However, application in clinical trials has been limited by heterogeneous scoring methods and concerns about reliability. We aimed to determine the inter- and intra-rater reliability of locally and centrally read IUS parameters for evaluating CD using prospectively performed scans., Methods: Twenty-four participants with CD and 6 gastroenterologists participated in a 2-day workshop where each participant underwent 6 IUS scans in total. Eight IUS parameters (bowel wall thickness [BWT], bowel wall stratification [BWS], color Doppler signal [CDS], inflammatory mesenteric fat [i-fat], submucosal prominence, submucosal layer thickness, haustra coli/peristalsis, and affected segment length) and an overall measure of sonographic disease activity were blindly assessed by the 6 local readers and 4 central gastroenterologist-sonographers. Reliability was quantified using intraclass correlation coefficients (ICCs). Institutional review board approval was granted for this study (12938)., Results: Five IUS parameters demonstrated at least moderate (ICC ≥0.41) inter- and intra-rater reliability when local and central reading was performed (BWT, CDS, i-fat, submucosal prominence, and affected segment length). Reliability was generally better with central, in distinction to local, reading. ICCs for BWS and i-fat were highest when evaluated as binary outcomes. Sensitivity analyses demonstrated that IUS parameters are most reliable when evaluated in the worst affected segment. Fair reliability was observed when local readers identified the worst affected segment., Conclusions: Local and central reading of IUS demonstrated at least moderate inter- and intra-rater reliability for several parameters. This study supports refining existing activity indices and incorporating IUS central reading into clinical trials., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: A substantial proportion of patients with inflammatory bowel disease (IBD) on intravenous infliximab require dose intensification. Accessing additional intravenous infliximab is labour-intensive and expensive, depending on insurance and pharmaceutical reimbursement. Observational data suggest that subcutaneous infliximab may offer a convenient and safe alternative to maintain disease remission in patients requiring dose-intensified infliximab. A prospective, controlled trial is required to confirm that subcutaneous infliximab is as effective as dose-intensified intravenous infliximab, to identify predictors of disease flare and to establish the role of subcutaneous infliximab therapeutic drug monitoring., Methods and Analysis: The DISCUS-IBD trial is an investigator-initiated, prospective, multicentre, randomised, open-label non-inferiority study comparing the rate of disease flares in participants randomised to continue dose-intensified intravenous infliximab to those switched to subcutaneous infliximab after 48 weeks. Participants are adult patients with IBD in sustained corticosteroid-free remission on any regimen of dose-intensified infliximab up to a maximum of 10 mg/kg 4-weekly intravenously. Participants allocated to intravenous infliximab will continue infliximab at the same dose-intensified regimen they were receiving at study enrolment. Subcutaneous infliximab dosing will be stratified by prior intravenous infliximab dosing. Clinical (Harvey-Bradshaw Index, partial Mayo score), biochemical (C reactive protein, faecal calprotectin), pharmacokinetic (drug-level±antidrug antibodies) and qualitative data are collected 12-weekly until study conclusion at week 48. 13 sites across Australia will participate in recruitment to reach a calculated sample size of 120 participants., Ethics and Dissemination: Multisite ethics approval was obtained from the Health District Human Research Ethics Committee (HREC) at The Alfred Hospital under a National Mutual Acceptance (NMA) agreement (HREC/90559/Alfred-2022; Local Reference: Project 618/22, version 1.6, 2 March 2023). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. DISCUS-IBD was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) prior to commencing recruitment., Trial Registration Number: ACTRN12622001458729., Competing Interests: Competing interests: RDL has received conference fees from Janssen and Celltrion Healthcare. AS has received speaker fees from Sandoz and received research support and advisory fees from AbbVie, Pfizer, and Arrow Pharmaceuticals. GJW has served as a speaker, a consultant or an advisory board member for Janssen, Galapagos, AbbVie, Ferring, Dr Falk Pharma, Nova Labs and Sandoz. GTM has received educational grants or research support from GESA, The Gutsy Group, NHMRC, MRFF, AbbVie, Janssen, Pfizer, Shire and Takeda; speaker fees from AbbVie, Ferring, Janssen, Orphan, Pfizer, Roche, Sandoz, Shire and Takeda and has serve on advisory boards for AbbVie, Emerge, Eli-Lilly, Gilead, Hospira, Janssen, Orphan, MSD, Pfizer, Shire and Takeda. KL declares speaker fees, advisory Board fees and/or conference travel/registration support from AbbVie, Bristol Myers Squibb, Chiesi, Dr Falk, Ferring, Gilead, Guidepoint, Intercept Pharmaceuticals, Janssen-Cilag, MSD, Norgine, Pfizer, Sandoz, Takeda and the RAH Research Fund. JA has served as a speaker, a consultant and an advisory board member for, and has received research funding from, Abbott, AbbVie, Allergan, Anatara, AstraZeneca, Bayer, Celgene, Falk, Ferring, Gilead, Hospira, Immunic, ImmunsanT, Janssen, MSD, Nestle, Progenity, Pfizer, Sandoz, Shire, Takeda, Vifor, RAH Research Fund, The Hospital Research Fund with all monies received by her department for research support. YKA reports grants from Janssen, during the conduct of the study; has received speaking and consulting fees from AbbVie, Bristol Myers Squibb, Celltrion, Chiesi, Dr Falk, Ferring, Janssen, Pfizer, Sandoz, Shire and Takeda; served on advisory boards for AbbVie, Bristol Myers Squibb, Chiesi, Janssen, NPS Medicine wise, Microba and received research and educational funding from Abbvie, Celltrion, Dr Falk, Janssen, Pfizer, Sandoz and Takeda. RVB has received grant/research support/speaker fees from AbbVie, Ferring, Janssen, Shire, Takeda, Bristol Myer Squibb and Emerge Health; and is a shareholder in Biomebank. SC declares advisory board participation, speaker fees, educational support and/or research support for Liverpool Hospital, South Western Sydney Local Health District (SWSLHD) Academic Unit or Crohn’s Colitis Cure from: AbbVie, Amgen, BMS, Celltrion, Chiesi, Eli-Lilly, Dr Falk, Ferring, Fresenius Kabi, Gilead, GSK, Janssen, MSD, Novartis, Organon, Pfizer, Sandoz, Takeda and non-pharmacological research support from Agency for Clinical Innovation, Gastroenterological Society of Australia, The Leona M and Harry B Helmsley Charitable Trust, Medical Research Future Fund, SWSLHD, Sydney Partnership for Health, Research and Enterprise (SPHERE). MG has served on the advisory board of Pfizer and has received speaker fees, research or travel grants from AbbVie, Celltrion, Dr Falk, Janssen, Pfizer, Pharmacosmos, Takeda. EKW declares speaker and consulting fees from AbbVie, BMS, Celltrion, Falk, Ferring, Janssen, Pfizer and research funding/support from AbbVie, Ferring, Janssen. JPS has received conference fees from Janssen, BMS, Takeda, educational grants from Pfizer, speaker fees from AbbVie, Takeda and Pfizer and an unrestricted grant from Tillots. PDC has served as a consultant, an advisory board member or a speaker for AbbVie, Baxter, Ferring, Janssen, Celltrion, Emerge Health, Shire and Takeda and received research support from Ferring, Shire, Janssen, AbbVie, and Takeda. MGW has received educational grants and speakers fees from AbbVie, Takeda and Ferring; travel grants from Pfizer; and has served on advisory boards for AbbVie. MPS has received educational grants or research support from Ferring, Orphan and Gilead; speakers fees from Janssen, AbbVie, Ferring, Takeda, Pfizer and Shire; and has served on advisory boards for Janssen, Takeda, Pfizer, Celgene, AbbVie, MSD, Emerge Health, Gilead and BMS. JM, PH, RBG, DC, MS, EC, LT, GH and AB declare no relevant competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There are wide-ranging probiotic choices in Australasia. We reviewed the efficacy of probiotics for the management of gastrointestinal (GI) conditions in adults and assessed relevance to clinical practice. The benefits of probiotics were inconsistent, with a strong consensus reached for only a few of the indications. As different species/strains and combinations differ in efficacy, results cannot be extrapolated from one to another. This review endorses specific probiotics for limited indications. Efficacy of most marketed probiotic formulations remains unstudied and unproven, warranting further research., (© 2024 Royal Australasian College of Physicians.)

Plant pollen is rich in protein, sterols and lipids, providing crucial nutrition for many pollinators. However, we know very little about the quantity, quality and timing of pollen availability in real landscapes, limiting our ability to improve food supply for pollinators. We quantify the floral longevity and pollen production of a whole plant community for the first time, enabling us to calculate daily pollen availability. We combine these data with floral abundance and nectar measures from UK farmland to quantify pollen and nectar production at the landscape scale throughout the year. Pollen and nectar production were significantly correlated at the floral unit, and landscape level. The species providing the highest quantity of pollen on farmland were Salix spp. (38%), Filipendula ulmaria (14%), Rubus fruticosus (10%) and Taraxacum officinale (9%). Hedgerows were the most pollen-rich habitats, but permanent pasture provided the majority of pollen at the landscape scale, because of its large area. Pollen and nectar were closely associated in their phenology, with both peaking in late April, before declining steeply in June and remaining low throughout the year. Our data provide a starting point for including pollen in floral resource assessments and ensuring the nutritional requirements of pollinators are met in farmland landscapes., (© 2024 The Authors New Phytologist © 2024 New Phytologist Foundation.)

The role of antibiotics in the treatment of ulcerative colitis is limited. We present a case of a 25-year-old woman who presented with a flare of ulcerative colitis after an episode of infectious gastroenteritis on a background of known primary sclerosing cholangitis. After the flare, she experienced persistent abdominal pain and diarrhea associated with elevated fecal calprotectin and deep rectosigmoid ulcerations on endoscopy. After unsuccessful trials of vedolizumab, infliximab, and tofacitinib, the patient was commenced on ustekinumab, tacrolimus, and oral vancomycin. Tacrolimus was ceased successfully, but while on maintenance ustekinumab therapy, 2 attempts to cease vancomycin resulted in symptom recurrence and rising fecal calprotectin that improved with vancomycin recommencement. To date, the patient has been on vancomycin continuously for 18 months and remains clinically well with colonoscopy demonstrating inactive colitis. This case highlights how vancomycin may be beneficial in the management of treatment-refractory ulcerative colitis as an adjunct to biologic therapy., (© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Purpose: Cross-sectional imaging facilitates the assessment of transmural healing in patients with Crohn's disease. This systematic review addresses the utility of MRI and intestinal ultrasound (IUS) in the assessment of disease activity in response to drug therapy compared with endoscopy in patients with luminal Crohn's disease., Methods: Database searches were undertaken using predefined terms. Studies with ≥10 patients with luminal Crohn's disease with paired endoscopy and imaging (MRI or IUS) after treatment initiation were included. Publications were identified through searches of six bibliographic databases, all run on June 24, 2022. Records were screened on title and abstract, then full text, by two independent reviewers., Results: In total, 5,760 records were identified, with 24 studies meeting the inclusion criteria. Ten studies examined IUS and found good correlation between IUS and endoscopic remission (κ = 0.63-0.73). Early reduction in bowel wall thickness at 4 to 8 weeks predicted endoscopic response at 12 to 38 weeks (area under the receiver operating characteristic curve [AUROC], 0.77; odds ratio, 10.8; P = .01). Twelve studies examined MRI, with the Magnetic Resonance Index of Activity score having high accuracy for predicting endoscopic remission (AUROC, 0.97; sensitivity, 93%; specificity, 77%). A Simplified Magnetic Resonance Index of Activity score cutoff of ≥1 identifies active endoscopic disease (AUROC, 0.92; 95% confidence interval, 0.88-0.95; P < .0001)., Conclusions: IUS and MRI are both reliable, noninvasive modalities for assessing transmural healing in patients with Crohn's disease and are accurate in monitoring the response to drug therapy. These modalities can be used to monitor response to biologic induction therapy, with early changes predictive of response to treatment., (Copyright © 2023 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Objective: We postulated that adalimumab [ADA] drug clearance [CL] may be a more critical determinant of therapeutic outcome than ADA concentration. This was tested in Crohn's disease [CD] patients undergoing ADA maintenance treatment., Methods: CD patients from four cohorts received ADA induction and started maintenance therapy. Therapeutic outcomes consisted of endoscopic remission [ER], sustained C-reactive protein [CRP] based clinical remission [defined as CRP levels below 3 mg/L in the absence of symptoms], and faecal calprotectin [FC] level below 100 µg/g. Serum albumin, ADA concentration, and anti-drug antibody status were determined using immunochemistry and homogeneous mobility shift assay, respectively. CL was determined using a nonlinear mixed effect model with Bayesian priors. Statistical analysis consisted of Mann-Whitney test and logistic regression with calculation of odds ratio. Repeated event analysis was conducted using a nonlinear mixed effect model., Results: In 237 enrolled patients [median age 40 years, 45% females], median CL was lower in patients achieving ER as compared with those with persistent active endoscopic disease [median 0.247 L/day vs 0.326 L/day, respectively] [p <0.01]. There was no significant difference in ADA concentration between patients in endoscopic remission compared with those with recurrence [median 9.3 µg/mL vs 11.7 µg/mL, respectively]. Sustained CRP-based clinical remission and FC levels below 100 µg/g were generally associated with lower CL and higher ADA concentration. Repeated event analysis confirmed those findings with better performances of CL than concentration in associating with ER and other outcomes., Conclusion: Lower ADA clearance is associated with an improved clinical outcome for patients with Crohn's disease and may be a superior pharmacokinetic measure than concentration., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab., Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models., Results and Discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p<0.11) [corrected] higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD., Competing Interests: JG has served as speaker, consultant, and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos, Lilly, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine and Vifor Pharma. MD is a consultant for Prometheus Laboratories, Janssen, Abbvie, Takeda, Celgene, Gilead, U.C.B., Pfizer, Arena, and Eli Lilly as well as co-Founder of Mi Test Health and Trellus Health. TD is employee of Prometheus Laboratories; MK, AH, and EW: research grants from Prometheus Laboratories; DM: consultant Prometheus Laboratories, Merck; Palatin Bio; Takeda; Prometheus Biosciences; Palisade Bio.s. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Spencer, Dubinsky, Kamm, Chaparro, Gionchetti, Rizzello, Gisbert, Wright, Schulberg, Hamilton, McGovern and Dervieux.)

Background: In medically refractory Ulcerative Colitis (UC), proctocolectomy with ileoanal pouch procedure (IAPP) is the preferred continence-preserving surgical option. Functional outcomes post-surgery and long-term complication rates in the biologic era remain ambiguous. This review primarily aims to provide an update on these outcomes. Secondarily, risk factors associated with chronic pouchitis and pouch failure are explored., Methods: Two online databases (MEDLINE and EMBASE) were searched on 4 October 2022 for English studies from 2011-present relating to long-term outcomes of IAPP in inflammatory bowel disease (IBD) patients. Adult patients with 12 month follow-up were included. Studies focused on 30-day post-operative outcomes, non-IBD patients or studies including less than 30 patients were excluded., Results: Following screening and full-text review of 1094 studies, 49 were included. Median sample size was n = 282 (IQR: 116-519). Median incidences for chronic pouchitis and pouch failure were 17.1% (IQR: 12-23.6%) and 6.9% (IQR: 4.8-10.8%), respectively. Upon multivariate analysis, chronic pouchitis development was most significantly associated with pre-operative steroid use, pancolitis and extra-intestinal IBD manifestations, whilst pouch failure was most significantly associated with pre-operative diagnosis of Crohn's disease (compared to UC), peri-operative pelvic sepsis and anastomotic leak. Overall patient satisfaction was very high with four included studies reporting greater than 90% satisfaction rates., Conclusion: Long-term complications for IAPP were common. However, despite this, patient satisfaction post-IAPP was high. Up-to-date knowledge of complication rates and their risk factors improves pre-operative counselling, management planning and patient outcomes., (© 2023 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Background and Objectives: The role of therapeutic drug monitoring for ustekinumab in the treatment of Crohn's disease has not been defined. This study aimed to explore the relationship of serum ustekinumab trough concentration (UTC) with clinical and biochemical disease outcomes in a real-world setting., Methods: We performed a retrospective analysis of Crohn's disease patients treated at a single tertiary centre. Ustekinumab was given as a single intravenous induction dose, followed by maintenance subcutaneous injections every 4 to 8 weeks. Rates of clinical remission (Harvey-Bradshaw Index ≤ 4), biochemical remission (C-reactive protein < 5 mg/l and faecal calprotectin < 150 μg/g) and complete remission were assessed at baseline and at the time of UTC testing during maintenance therapy. The association between baseline variables and UTC was tested using linear regression. We also performed an external validation analysis of UTC cut-offs established in four previously published studies., Results: This study included 43 patients. Compared to 8-weekly dosing, a 2.49- and 2.65-fold increase in UTC was associated with 6-weekly and 4-weekly dosing respectively. However, there was no significant difference in clinical, biochemical or complete remission among the dosing groups. An external validation of previously published optimal UTC cut-offs found low predictive value for our patient population., Conclusions: In this study, dosing interval was the only determinant significantly associated with a higher UTC for patients on maintenance ustekinumab therapy. While a higher UTC may be achieved with dose escalation, it was not associated with improved rates of clinical or biochemical response in our cohort., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) remains the preferred surgical option for medically refractory ulcerative colitis. Management of individuals with an IPAA prior to and during pregnancy presents challenges that can have serious consequences. Infertility, mechanical obstructive and inflammatory pouch complications are frequently encountered in pregnant women with an IPAA. Mechanical obstructions occur due to a variety of underlying aetiologies, including stricturing disease, adhesions and pouch twists. Conservative management of such obstructions often results in resolution of symptoms without a need for endoscopic or surgical intervention, although endoscopic decompression may be attempted in isolation or as a bridge to definitive surgical intervention. Parenteral nutrition, and early delivery, may also be necessary. Faecal calprotectin and intestinal ultrasound, both of which are accurate in pregnancy, are useful in the setting of suspected inflammatory pouch complications, in some circumstances allowing for avoidance of pouchoscopy. Penicillin-based antimicrobials can be considered first line in pregnancy for the management of pouchitis and pre-pouch ileitis, and biologics can be safely instituted in the setting of refractory disease or suspected Crohn's disease-like inflammation of the pouch or pre-pouch ileum. Pragmatism, clear patient communication and multidisciplinary discussion are essential in approaching pregnant women with complications of an IPAA, particularly given the lack of definitive evidence to guide therapeutic decisions., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis of small to medium vessels. Gastrointestinal involvement is uncommon and is associated with higher mortality. Treatment is based on empiric evidence. In this article, we report a case of EGPA-related pancolitis and stricturing small bowel disease managed with a combination of mepolizumab and surgical resection., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Autoimmune and inflammatory disorders, including inflammatory bowel disease (IBD), commonly affect women of childbearing age, warranting the use of immunomodulatory agents at a time where pregnancy may be desired. In utero exposure to pro-inflammatory mediators from maternal IBD, IBD-associated intestinal dysbiosis, and immunomodulatory drug use may impact neonatal immune system development during what is considered to be a critical period, with potential long-lasting impacts on susceptibility to disease. Both the innate and adaptative immune systems of the neonatal differ to that of the adult in terms of both cellular composition and sensitivity to antigenic and innate stimulation. The infant immune system gradually develops to more closely resemble that of the adult. Exposure to maternal inflammation in utero may aberrantly impact this period of infant immune system development, with maternal autoimmune and inflammatory disorders shown to affect the physiologic changes in serum cytokine abundance observed during pregnancy. The maternal and neonatal intestinal microbiome greatly influence infant mucosal and peripheral immune system development, and thereby impact the susceptibility to short-term inflammatory diseases, the adequacy of vaccine response, and later life risk of atopic and inflammatory disorders. Maternal disease, mode of delivery, method of feeding, time of weaning to include solid foods in the diet, and neonatal antibiotic exposure all influence the composition of the infant microbiome, and thereby infant immune system maturation. How exposure to specific immunosuppressive medications in utero alters infant immune cell phenotype and response to stimulation has been explored, but with existing studies limited by the time at which samples are performed, heterogenicity in methods, and small sample size. Furthermore, the impact of more recently introduced biologic agents have not been explored. Evolving knowledge in this field may influence therapeutic preferences for individuals with IBD planning to conceive, particularly if substantive differences in the risk of infant infection and childhood immune disease are identified., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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 

Background: Inflammatory bowel disease (IBD), comprising ulcerative colitis and Crohn's disease, commonly affects individuals of childbearing age. Pregnancy in women with IBD presents an anxiety-provoking prospect for practitioners and patients alike, with disease flares occurring in between 20% and 55% of patients antenatally., Objective: The aim of this review is to provide an overview of antenatal IBD management principles and therapeutic goals, with a specific focus on the role of general practitioners., Discussion: A collaborative approach is favoured in managing pregnancy and IBD. Preconception counselling should be prioritised, with emphasis on the importance of achieving three months of preconception corticosteroid-free remission. Close monitoring of disease activity in pregnancy is crucial, warranting the careful interpretation of both clinical and biochemical parameters. Reassurance regarding the safety of IBD medications in pregnancy and vaginal delivery can be provided in the majority of cases. Specialist support should be sought expeditiously in the setting of disease flare, particularly where symptoms and biochemical parameters are refractory to escalation of 5-aminosalicylates or topical therapies, corticosteroids or biologic agents are required, or an emergent IBD complication is suspected.

Antibiotic resistance is becoming increasingly prevalent amongst bacterial pathogens and there is an urgent need to develop new types of antibiotics with novel modes of action. One promising strategy is to develop resistance-breaker compounds, which inhibit resistance mechanisms and thus resensitize bacteria to existing antibiotics. In the current study, we identify bacterial DNA double-strand break repair as a promising target for the development of resistance-breaking co-therapies. We examined genetic variants of Escherichia coli that combined antibiotic-resistance determinants with DNA repair defects. We observed that defects in the double-strand break repair pathway led to significant resensitization toward five bactericidal antibiotics representing different functional classes. Effects ranged from partial to full resensitization. For ciprofloxacin and nitrofurantoin, sensitization manifested as a reduction in the minimum inhibitory concentration. For kanamycin and trimethoprim, sensitivity manifested through increased rates of killing at high antibiotic concentrations. For ampicillin, repair defects dramatically reduced antibiotic tolerance. Ciprofloxacin, nitrofurantoin, and trimethoprim induce the promutagenic SOS response. Disruption of double-strand break repair strongly dampened the induction of SOS by these antibiotics. Our findings suggest that if break-repair inhibitors can be developed they could resensitize antibiotic-resistant bacteria to multiple classes of existing antibiotics and may suppress the development of de novo antibiotic-resistance mutations., (© 2022 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Background: Strictures are the most common structural complication of Crohn's disease. Surgery and endoscopic balloon dilation are the main treatments; drug therapy has been considered contraindicated. Given that most strictures have an inflammatory component, we aimed to find out whether strictures are responsive to drug treatment and whether intensive drug therapy is more effective than standard drug therapy., Methods: This open-label, single-centre, randomised controlled trial was performed in one specialist inflammatory bowel disease centre in Australia. Patients aged 18 years or older with Crohn's disease were included. Eligible patients had a de novo or postoperative anastomotic intestinal stricture on MRI or ileocolonoscopy, symptoms consistent with chronic or subacute intestinal obstruction (postprandial abdominal pain in the presence of a confirmed stricture), and evidence of active intestinal inflammation. Patients were randomly assigned (2:1) to receive intensive high-dose adalimumab (160 mg adalimumab once per week for 4 weeks followed by 40 mg every 2 weeks, with escalation of dose at 4 months and 8 months if assessment of disease activity indicated active inflammation) plus thiopurine (initial dose of azathioprine 2·5 mg/kg or mercaptopurine 1·5 mg/kg, with dose adjustment based on thiopurine metabolite testing) or standard adalimumab monotherapy (160 mg at week 0, 80 mg at week 2, then 40 mg every 2 weeks) using stratified fixed block randomisation. Stratification factors were stricture dilation at study baseline colonoscopy and current biologic drug use. The primary endpoint was improvement (decrease) in the 14-day obstructive symptom score at 12 months by one or more points compared with baseline. This trial is registered with ClinicalTrials.gov, NCT03220841, and is completed., Findings: Between Sept 10, 2017, and Sept 6, 2019, 123 patients were screened and 77 randomly assigned to intensive adalimumab plus thiopurine treatment (n=52) or standard adalimumab treatment (n=25). At 12 months, improvement in obstructive symptom score was noted in 41 (79%) of 52 patients in the intensive treatment group and 16 (64%) of 25 in the standard treatment group (odds ratio [OR] 2·10 [95% CI 0·73-6·01]; p=0·17). Treatment failure occurred in five (10%) patients in the intensive treatment group versus seven (28%) in the standard treatment group (OR 0·27 [95% CI 0·08-0·97]; p=0·045); four patients in each group required stricture surgery (0·44 [0·10-1·92]; p=0·27). Crohn's Disease Activity Index was less than 150 in 36 (69%) patients in the intensive treatment group versus 15 (60%) in the standard treatment group (1·50 [0·56-4·05]; p=0·42). MRI at 12 months showed improvement using the stricture MaRIA score (≥25%) in 31 (61%) of 51 versus seven (28%) of 25 patients (3·99 [1·41-11·26]; p=0·0091). MRI complete stricture resolution was seen in ten (20%) versus four (16%) patients (1·28 [0·36 to 4·57]; p=0·70). Intestinal ultrasound at 12 months showed improvement (>25%) in bowel wall thickness in 22 (51%) of 43 versus seven (33%) of 21 patients (2·10 [0·71 to 6·21]; p=0·18). Faecal calprotectin normalised in 32 (62%) versus 11 (44%) patients (2·04 [0·77-5·36]; p=0·15). Normalisation of CRP was seen in 32 (62%) versus 11 (44%) patients (2·04 [0·77-5·36]; p=0·15). Eight (15%) patients in the intensive treatment group and four (16%) in the standard treatment group reported serious adverse events. No deaths occurred during the study., Interpretation: Crohn's disease strictures are responsive to drug treatment. Most patients had improved symptoms and stricture morphology. Treat-to-target therapy intensification resulted in less treatment failure, a reduction in stricture-associated inflammation, and greater improvement in stricture morphology, although these differences were not significantly different from standard therapy., Funding: Australian National Health and Medical Research Council, Gastroenterological Society of Australia Ferring IBD Clinician Establishment Award, Australasian Gastro Intestinal Research Foundation, AbbVie, and the Spotlight Foundation., Competing Interests: Declaration of interests BC reports personal fees from AbbVie, Emerge, Gilead, Pfizer, Takeda, Janssen, Ferring, Fresenius Kabi, and Roche; and grants from Pfizer. GTM reports personal fees from AbbVie, Emerge, Gilead, Hospira, MSD, Pfizer, Takeda, Janssen, Fresenius Kabi, Roche, and Ferring. MAK reports grants and personal fees from AbbVie and Janssen; and personal fees from Takeda, Pfizer, and Ferring. NSD reports personal fees from AbbVie, Pfizer, Chiesi, Sandoz, and Eli Lilly; and grants and personal fees from Janssen. PDC reports and has served as a speaker, consultant, and advisory board member for Ferring, Shire, Janssen, AbbVie, Takeda, and Baxter. TRS reports personal fees from Siemens and Bayer. The remaining authors declared no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (© 2021 John Wiley & Sons Ltd.)

Background: There is considerable interest in improving the education and care of women with inflammatory bowel disease (IBD) to improve pregnancy outcomes. Despite increased awareness, not all women with IBD have access to pregnancy-related education and the quality of counseling is variable. We aimed to assess the effectiveness of a simple educational intervention for improving pregnancy-related knowledge and to evaluate the effect of education on patient outcomes including anxiety, depression, and quality of life in women with IBD., Methods: This prospective study of women with IBD who were pregnant or planning a pregnancy evaluated the effectiveness of a single gastroenterologist-led educational intervention in improving pregnancy-related knowledge, measured using the Crohn's and Colitis Pregnancy Knowledge score 1 month postintervention. Secondary outcomes included the effect on anxiety and depression, quality of life, medication adherence, and patient satisfaction., Results: One hundred women with IBD were recruited. Fifty percent were pregnant at the time of the intervention. Baseline knowledge scores were similar independent of the patients' pregnancy status or whether they had previously received counseling from their gastroenterologist. Median Crohn's and Colitis Pregnancy Knowledge scores postintervention (n = 82) were higher than preintervention scores (14/17 vs 10/17; P < 0.001). In addition, 32% of patients had poor knowledge at baseline (score ≤7/17), compared to only 5% after the intervention (P < 0.001). There was a significant improvement in total anxiety and depression and quality of life scores postintervention. Medication adherence and patient satisfaction were excellent., Conclusions: Uptake of this gastroenterologist-led educational intervention has the potential to improve pregnancy knowledge, promote medication adherence, and enhance quality of life for women with IBD globally., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 an effective therapy in Crohn's disease. However large controlled trials are needed. No serious safety concerns have been identified., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

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., (© 2021 Royal Australasian College of Physicians.)

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., (© 2021 John Wiley & Sons Ltd.)

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 × 10 8 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 × 10 8 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 × 10 8 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., (© 2021 John Wiley & Sons Ltd.)

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., (© 2021 John Wiley & Sons Ltd.)

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., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

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: 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., (© 2020 John Wiley & Sons Ltd.)

Background and Aims: Inflammatory bowel disease [IBD] affects women during their childbearing years. Gastrointestinal ultrasonography [GIUS] accurately identifies disease activity in non-pregnant patients with IBD. The utility of GIUS in pregnancy has not been established. We aimed to determine the feasibility and accuracy of GIUS in the assessment of IBD during pregnancy progression., Methods: A multicentre observational study of women with IBD undergoing GIUS during pregnancy. Clinicians assessed the adequacy of bowel views and disease activity in four colonic segments and the terminal ileum. Location[s] in which views were impeded by the uterus were documented. GIUS disease activity [bowel wall thickness >3 mm] was compared with biochemical disease activity [faecal calprotectin >100 μg/g]., Results: Ninety patients and 127 GIUS examinations were included [median gestation 19 weeks, range 4-33]. Adequate colonic views were obtained in 116/127 [91%] scans. Adequate ileal views were obtained in 62/67 [93%] scans <20 weeks and 30/51 [59%] scans at 20-26 weeks. There was a positive correlation between bowel wall thickness and calprotectin [r = 0.26, p = 0.03]. GIUS delivered a specificity of 83%, sensitivity of 74%, and negative predictive value of 90% compared with calprotectin., Conclusions: GIUS is a feasible and accurate modality for monitoring IBD in pregnancy. Adequate GIUS views of the colon and terminal ileum can be obtained in the majority of patients up to 20 weeks of gestation. Beyond 20 weeks, GIUS provides good views of the colon but the terminal ileum becomes difficult to assess., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., Competing Interests: The authors have no conflicts of interest to declare.EK Wright has received research support from AbbVie and Ferring and has acted as a speaker at symposiums sponsored by AbbVie, Janssen and Pfizer; I Wang, D Wong, WR Connell and AJ Thompson have no disclosures; SJ Bell has received speakers fees from AbbVie, Janssen and Shire; KL Novak has received research support from AbbVie, acted as speaker for AbbVie, Janssen and Pfizer; MA Kamm has acted as an advisor to Abbott and Janssen, has received research support from AbbVie, and has acted as a speaker at symposiums sponsored by AbbVie and Janssen., (© 2020 Australasian Society for Ultrasound in Medicine.)

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., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Australia has one of the highest incidence rates of inflammatory bowel disease (IBD) in the world. Early diagnosis and treatment for IBD is critical. For Crohn disease, in particular, this may change the natural history of disease and reduce disability. Faecal calprotectin is a sensitive test that can be used by primary care physicians to assist in determining which patients with gastrointestinal symptoms may have IBD. This allows for prompt identification of patients who may benefit from endoscopy. Regular re-evaluation of disease status with strategies that can safely, readily and reliably detect the presence of inflammation with faecal biomarkers and imaging is important. To avoid the risks of cumulative radiation exposure, magnetic resonance imaging and/or intestinal ultrasound, rather than computed tomography scanning, should be performed when possible. Drug treatments for IBD now include five biological drugs listed by the Pharmaceutical Benefits Scheme: adalimumab, infliximab, golimumab, vedolizumab and ustekinumab. Such developments offer the possibility for improved disease control in selected patients.

Background: Anti-TNF prevents postoperative Crohn's disease recurrence in most patients but not all. This study aimed to define the relationship between adalimumab pharmacokinetics, maintenance of remission and recurrence., Methods: As part of a study of postoperative Crohn's disease management, some patients undergoing resection received prophylactic postoperative adalimumab. In these patients, serum and fecal adalimumab concentration and serum anti-adalimumab antibodies [AAAs] were measured at 6, 12 and 18 months postoperatively. Levels of Crohn's disease activity index [CDAI], C-reactive protein [CRP] and fecal calprotectin [FC] were assessed at 6 and 18 months postoperatively. Body mass index and smoking status were recorded. A colonoscopy was performed at 6 and/or 18 months., Results: Fifty-two patients [32 on monotherapy and 20 on combination therapy with thiopurine] were studied. Adalimumab concentration did not differ significantly between patients in endoscopic remission vs recurrence [Rutgeerts ≥ i2] [9.98µg/mL vs 8.43 µg/mL, p = 0.387]. Patients on adalimumab monotherapy had a significantly lower adalimumab concentration [7.89 µg/mL] than patients on combination therapy [11.725 µg/mL] [p = 0.001], and were significantly more likely to have measurable AAA [31% vs 17%, p = 0.001]. Adalimumab concentrations were lower in patients with detectable AAA compared with those without [3.59 µg/mL vs 12.0 µg/mL, p < 0.001]. Adalimumab was not detected in fecal samples. Adalimumab serum concentrations were lower in obese patients compared with in non-obese patients [p = 0.046]., Conclusion: Adalimumab concentration in patients treated with adalimumab to prevent symptomatic endoscopic recurrence postoperatively is, for most patients, well within the therapeutic window, and is not significantly lower in patients who develop recurrence compared with in those who remain in remission. Mechanisms of anti-TNF failure to prevent postoperative recurrence remain to be determined in these patients.

Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD; however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: The intestinal microbiota is a key antigenic driver in Crohn's disease [CD]. We aimed to identify changes in the gut microbiome associated with, and predictive of, disease recurrence and remission., Methods: A total of 141 mucosal biopsy samples from 34 CD patients were obtained at surgical resection and at colonoscopy 6 and/or 18 months postoperatively; 28 control samples were obtained: 12 from healthy patients [healthy controls] and 16 from hemicolectomy patients [surgical controls]. Bacterial 16S ribosomal profiling was performed using the Illumina MiSeq platform., Results: CD was associated with reduced alpha diversity when compared with healthy controls but not surgical controls [p < 0.001 and p = 0.666, respectively]. Beta diversity [composition] differed significantly between CD and both healthy [p < 0.001] and surgical [p = 0.022] controls, but did not differ significantly between those with and without endoscopic recurrence. There were significant taxonomic differences between recurrence and remission. Patients experiencing recurrence demonstrated elevated Proteus genera [p = 0.008] and reduced Faecalibacterium [p< 0.001]. Active smoking was associated with elevated levels of Proteus [p = 0.013] postoperatively. Low abundance of Faecalibacterium [< 0.1%] and detectable Proteus in the postoperative ileal mucosa was associated with a higher risk of recurrence (odds ratio [OR] 14 [1.7-110], p = 0.013 and 13 [1.1-150], p = 0.039, respectively) when corrected for smoking. A model of recurrence comprising the presence of Proteus, abundance of Faecalibacterium, and smoking status showed moderate accuracy (area under the curve [AUC] 0.740, 95% confidence interval [CI] [0.69-0.79])., Conclusions: CD is associated with a microbial signature distinct from health. Microbial factors and smoking independently influence postoperative CD recurrence. The genus Proteus may play a role in the development of CD., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Fecal biomarkers are used increasingly to monitor Crohn's disease (CD). However, the relative accuracy of different markers in identifying inflammation has been poorly evaluated. We evaluated fecal calprotectin (FC), lactoferrin (FL), and S100A12 (FS) using endoscopic validation in a prospective study of the progression of CD after intestinal resection., Methods: Data were collected from 135 participants in a prospective, randomized, controlled trial aimed at preventing postoperative CD recurrence. Three hundred nineteen stool samples were tested for FC, FL, and FS preoperatively and 6, 12, and 18 months after resection. Colonoscopy was performed at 6 and/or 18 months. Endoscopic recurrence was assessed blindly using the Rutgeerts score. C-reactive protein (CRP) and Crohn's Disease Activity Index (CDAI) were assessed., Results: FC, FL, and FS concentrations were elevated preoperatively (median: 1347, 40.9, and 8.4 μg/g, respectively). At 6 months postoperatively, marker concentrations decreased (166, 3.0, 0.9 μg/g) and were higher in recurrent disease than remission (275 versus 72 μg/g, P < 0.001; 5.7 versus 1.6 μg/g, P = 0.007; 2.0 versus 0.8 μg/g, P = 0.188). FC > 135 μg/g, FL > 3.4 μg/g, and FS > 10.5 μg/g indicated endoscopic recurrence (score ≥ i2) with a sensitivity, specificity, and negative predictive value (NPV) of 0.87, 0.66, and 91%; 0.70, 0.68, and 81%; 0.91, 0.12, and 71%, respectively. FC and FL correlated significantly with the presence and severity of endoscopic recurrence, whereas FS, CRP and CDAI did not., Conclusions: FC was the optimal fecal marker for monitoring disease activity in postoperative CD and was superior to CRP and CDAI. FL offered modest sensitivity for detecting recurrent disease, whereas S100A12 was sensitive but had low specificity and NPV.