Search

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.)

Acute severe ulcerative colitis (ASUC) is a medical emergency that affects approximately 25% of patients with ulcerative colitis at some point in time in their lives. Outcomes of ASUC are highly variable. Approximately 30% of patients do not respond to corticosteroids and up to 50% of patients do not respond to rescue therapy (infliximab or cyclosporin) and require emergency colectomy. Data are emerging on infliximab dosing strategies, use of cyclosporin as a bridge to slower acting biologic agents and Janus kinase inhibition as primary and sequential therapy. In this review, we outline contemporary approaches to clinical management of ASUC in the setting of failure to respond to traditional rescue therapies.

Background: Acute severe ulcerative colitis (ASUC) is a medical emergency for which colectomy is required in patients who do not respond to rescue therapy. While previous studies have predominantly focused on predicting outcome to first-line corticosteroid therapy, there is a need to understand the factors associated with response to rescue therapies in order to improve clinical outcomes. We reviewed the evidence regarding factors associated with response to rescue therapy in adults with ASUC and identified future directions for research., Methods: A systematic search of the literature was conducted, and 2 reviewers independently assessed studies for inclusion., Results: Of 3509 records screened, 101 completed studies were eligible for inclusion. We identified 42 clinical, hematological, biochemical, endoscopic, or pharmacological factors associated with response to rescue therapy. Older age (≥50 years), thiopurine experience, and cytomegalovirus or Clostridioides difficile infection were associated with a higher risk of nonresponse to rescue therapy. Biochemical factors associated with poorer response included an elevated C-reactive protein (CRP) ≥30mg/L on admission, hypoalbuminemia and an elevated ratio of CRP to albumin. Severe endoscopic findings, including a Mayo endoscopic score of 3 or Ulcerative Colitis Endoscopic Index of Severity ≥5, portended poorer outcomes. The role of fecal calprotectin and therapeutic value of measuring infliximab drug levels in ASUC remain to be defined., Conclusions: Response to rescue therapy can be predicted by several specific factors, which would aid clinical decision-making. Existing and emerging factors should be integrated within predictive and prognostic models to help improve clinical outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Recent data, indicating that inflammatory bowel disease (IBD) may be a risk factor for future chronic kidney disease, highlight the need to study the safety and clinical effectiveness of advanced IBD therapies in patients with end stage renal disease (ESRD), defined as an eGFR <15 mL/min/1.73m 2 . Upadacitinib, a selective oral Janus kinase (JAK) 1 inhibitor, has demonstrated efficacy in the management of moderate to severe ulcerative colitis. There is also emerging data indicating that JAK inhibition may be clinically effective in the setting of steroid-refractory acute severe ulcerative colitis (ASUC). There is, however, a lack of "real-world" data documenting the use of JAK inhibitors in patients with ESRD. Here, we report the use of upadacitinib in a patient with ESRD for the management of steroid-refractory ASUC, demonstrating, for the first time, the safe and clinically effective use of upadacitinib in this population., (© 2023 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: Inflammatory bowel disease colitis-associated dysplasia is managed with either enhanced surveillance and endoscopic resection or prophylactic surgery. The rate of progression to cancer after a dysplasia diagnosis remains uncertain in many cases and patients have high thresholds for accepting proctocolectomy. Individualised discussion of management options is encouraged to take place between patients and their multidisciplinary teams for best outcomes. We aimed to develop a toolkit to support a structured, multidisciplinary and shared decision-making approach to discussions about dysplasia management options between clinicians and their patients., Methods: Evidence from systematic literature reviews, mixed-methods studies conducted with key stakeholders, and decision-making expert recommendations were consolidated to draft consensus statements by the DECIDE steering group. These were then subjected to an international, multidisciplinary modified electronic Delphi process until an a priori threshold of 80% agreement was achieved to establish consensus for each statement., Results: In all, 31 members [15 gastroenterologists, 14 colorectal surgeons and two nurse specialists] from nine countries formed the Delphi panel. We present the 18 consensus statements generated after two iterative rounds of anonymous voting., Conclusions: By consolidating evidence for best practice using literature review and key stakeholder and decision-making expert consultation, we have developed international consensus recommendations to support health care professionals counselling patients on the management of high cancer risk colitis-associated dysplasia. The final toolkit includes clinician and patient decision aids to facilitate shared decision-making., (© 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.)

The Crohn's Disease Exclusion Diet (CDED) with partial enteral nutrition (PEN) is an emerging treatment option for Crohn's disease (CD). A 35-year-old pregnant woman presented with newly diagnosed ileal CD. At 14/40 gestation, CDED + PEN was prescribed without drug therapy. Outcomes included Harvey-Bradshaw Index, weight, and bowel wall thickness/Limberg score measured on intestinal ultrasound (IUS). In this patient, CDED + PEN achieved clinical and biochemical remission, improvements on IUS, gestational weight gain, and healthy birth weight without drug therapy. Sustained remission was achieved postpartum. Our case highlights the potential effectiveness of CDED + PEN to induce remission for active CD during pregnancy., (© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Proficient colonoscopy technique that optimises patient comfort while simultaneously enhancing the timely detection of pathology and subsequent therapy is an aspirational and achievable goal for every endoscopist. This article aims to provide strategies to improve colonoscopy quality for both endoscopists and patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Infliximab is an effective salvage therapy in acute severe ulcerative colitis; however, the optimal dosing strategy is unknown. We performed a systematic review and meta-analysis to examine the impact of infliximab dosage and intensification on colectomy-free survival in acute severe ulcerative colitis., Methods: Studies reporting outcomes of hospitalized steroid-refractory acute severe ulcerative colitis treated with infliximab salvage were identified. Infliximab use was categorized by dose, dose number, and schedule. The primary outcome was colectomy-free survival at 3 months. Pooled proportions and odds ratios with 95% confidence intervals were reported., Results: Forty-one cohorts (n = 2158 cases) were included. Overall colectomy-free survival with infliximab salvage was 79.7% (95% confidence interval [CI], 75.48% to 83.6%) at 3 months and 69.8% (95% CI, 65.7% to 73.7%) at 12 months. Colectomy-free survival at 3 months was superior with 5-mg/kg multiple (≥2) doses compared with single-dose induction (odds ratio [OR], 4.24; 95% CI, 2.44 to 7.36; P < 0.001). However, dose intensification with either high-dose or accelerated strategies was not significantly different to 5-mg/kg standard induction at 3 months (OR, 0.70; 95% CI, 0.39 to 1.27; P = 0.24) despite being utilized in patients with a significantly higher mean C-reactive protein and lower albumin levels., Conclusions: In acute severe ulcerative colitis, multiple 5-mg/kg infliximab doses are superior to single-dose salvage. Dose-intensified induction outcomes were not significantly different compared to standard induction and were more often used in patients with increased disease severity, which may have confounded the results. This meta-analysis highlights the marked variability in the management of infliximab salvage therapy and the need for further studies to determine the optimal dose strategy., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aim: Acute severe ulcerative colitis (ASUC) is a medical emergency requiring prompt therapeutic intervention. Although infliximab has been used as salvage therapy for over 15 years, clinical predictors of treatment success are lacking. We performed a retrospective analysis to identify factors that predict colectomy and may guide dose intensification., Methods: Fifty-four hospitalized patients received infliximab for ASUC at seven Australian centers (April 2014-May 2015). Follow-up was over 12 months. The data were primarily analyzed for predictors of colectomy. Accelerated (AI) versus standard (SI) infliximab induction strategies were also compared., Results: Of 54 patients identified, the overall colectomy rate was 15.38% (8/52) at 3 months and 26.92% (14/52) at 12 months. Two patients were lost to follow-up. There was a numerically higher colectomy rate in those treated with AI compared with SI (P = 0.3); however, those treated with AI had more severe biochemical disease. A C-reactive protein (CRP)/albumin ratio cut-off of 0.37 post-commencement of infliximab and before discharge was a significant predictor of colectomy with an area under receiver operating curve of 0.73. Pretreatment CRP and albumin levels were not predictive of colectomy. A Mayo Endoscopic Score of 2 had a 94% PPV for avoidance of colectomy following infliximab salvage., Conclusions: The baseline Mayo Endoscopic Score and the CRP/albumin ratio following infliximab salvage are significant predictors of treatment response for ASUC and identify patients at high risk of colectomy. Whether this risk can be mitigated using infliximab dose intensification requires prospective evaluation before the CRP/albumin ratio can be integrated into ASUC management algorithms., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with an age of onset that affects young people during the peak of their reproductive years. Management of flares of disease during pregnancy can be complex and there are few case reports of pregnant women with acute severe ulcerative colitis (ASUC). We present the case of a 31-year-old pregnant woman who at 16 weeks gestation developed ASUC in the context of primary non-response to infliximab therapy. She subsequently underwent an emergency laparoscopic colectomy after failing to respond to hydrocortisone and cyclosporine salvage therapy. Her pregnancy was further complicated by HELLP (Haemolysis, Elevated liver enzymes and Low Platelets) syndrome resulting in premature delivery at 27 weeks gestation. This case highlights the management issues involved in ASUC during pregnancy and the assessment of disease activity, use of salvage therapies, and provides a framework to approach this complex medical emergency., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (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: Data supporting the optimal maintenance drug therapy and strategy to monitor ongoing response following successful infliximab (IFX) induction, for acute severe ulcerative colitis (ASUC), are limited. We aimed to evaluate maintenance and monitoring strategies employed in patients post-IFX induction therapy., Methods: Patients in six Australian tertiary centers treated with IFX for steroid-refractory ASUC between April 2014 and May 2015 were identified via hospital IBD and pharmacy databases. Patients were followed up for 1 year with clinical data over 12 months recorded. Analysis was limited to patient outcomes beyond 3 months., Results: Forty one patients were identified. Five of the 41 (12%) patients underwent colectomy within 3 months, and one patient was lost to follow-up. Six of 35 (17%) of the remaining patients progressed to colectomy by 12 months. Maintenance therapy: Patients maintained on thiopurine monotherapy (14/35) versus IFX/thiopurine therapy (15/35) were followed up. Two of 15 (13%) patients who received combination maintenance therapy underwent a colectomy at 12 months, compared with 1/14 (7%) patients receiving thiopurine monotherapy (P = 0.610). Monitoring during maintenance: Post-discharge, thiopurine metabolites were monitored in 15/27 (56%); fecal calprotectin in 11/32 (34%); and serum IFX levels in 4/20 (20%). Twenty of 32 (63%) patients had an endoscopic evaluation after IFX salvage with median time to first endoscopy of 109 days (interquartile range 113-230)., Conclusion: Following IFX induction therapy for ASUC, the uptake of maintenance therapy in this cohort and strategies to monitor ongoing response were variable. These data suggest that the optimal maintenance and monitoring strategy post-IFX salvage therapy remains to be defined., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Competing Interests: Competing interests: None declared.

Inflammatory bowel diseases (IBDs) are thought to develop as a result of complex interactions between host genetics, the immune system and the environment including the gut microbiome. Although an improved knowledge of the immunopathogenesis of IBDs has led to great advances in therapy such as the highly effective anti-tumor necrosis factor class of medications, a significant proportion of patients with Crohn's disease and ulcerative colitis do not respond to anti-tumor necrosis factor antibodies. Further understanding of the different immune pathways involved in the genesis of chronic intestinal inflammation is required to help find effective treatments for IBDs. In this review, the role of the mucosal innate and adaptive immune system in IBD is summarized, highlighting new areas of discovery which may hold the key to identifying novel predictive or prognostic biomarkers and new avenues of therapeutic discovery.

A 43-year-old ASA PS II male patient developed a pneumothorax while breathing pontaneously through a supraglottic airway device during a general anaesthetic. Unexplained hypoxaemia occurred after an episode of coughing. Clinical examination appeared to be normal apart from the persistent oxygen desaturation. A pneumothorax was diagnosed in the post anaesthesia care unit by chest X-ray. The pneumothorax responded to conventional management and the patient made an uneventful recovery. We recommend a high index of suspicion in any patient who coughs and later has unexplained hypoxaemia during general anaesthesia, even if a supraglottic airway device has been inserted.

This paper proposes a new hybrid neural network (NN) model that employs a multistage online learning process to solve the distributed control problem with an infinite horizon. Various techniques such as reinforcement learning and evolutionary algorithm are used to design the multistage online learning process. For this paper, the infinite horizon distributed control problem is implemented in the form of real-time distributed traffic signal control for intersections in a large-scale traffic network. The hybrid neural network model is used to design each of the local traffic signal controllers at the respective intersections. As the state of the traffic network changes due to random fluctuation of traffic volumes, the NN-based local controllers will need to adapt to the changing dynamics in order to provide effective traffic signal control and to prevent the traffic network from becoming overcongested. Such a problem is especially challenging if the local controllers are used for an infinite horizon problem where online learning has to take place continuously once the controllers are implemented into the traffic network. A comprehensive simulation model of a section of the Central Business District (CBD) of Singapore has been developed using PARAMICS microscopic simulation program. As the complexity of the simulation increases, results show that the hybrid NN model provides significant improvement in traffic conditions when evaluated against an existing traffic signal control algorithm as well as a new, continuously updated simultaneous perturbation stochastic approximation-based neural network (SPSA-NN). Using the hybrid NN model, the total mean delay of each vehicle has been reduced by 78% and the total mean stoppage time of each vehicle has been reduced by 84% compared to the existing traffic signal control algorithm. This shows the efficacy of the hybrid NN model in solving large-scale traffic signal control problem in a distributed manner. Also, it indicates the possibility of using the hybrid NN model for other applications that are similar in nature as the infinite horizon distributed control problem.