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Background: Inflammatory bowel disease (IBD) follows a heterogenous disease course and predicting a patient's prognosis is challenging. There is a wide burden of illness in IBD and existing tools measure disease activity at a snapshot in time. Comprehensive assessment of IBD severity should incorporate disease activity, prognosis, and the impacts of disease on a patient. This review investigates the concept of disease severity in adults with IBD to highlight key components contributing to this., Methods: To perform this narrative review, a Medline search was conducted for full-text articles available at 1st March 2024 using search terms which encompassed disease activity assessment, disease severity, prognosis, natural history of Crohn's disease (CD) and ulcerative colitis (UC), and the burden of IBD., Results: Current methods of disease assessment in IBD have evolved from a focus on the burden of symptoms to one that includes inflammatory targets, genetic, serological, and proteomic profiles, and assessments of quality-of-life (QoL), disability, and psychosocial health. Longitudinal studies of IBD suggest that the burden of illness is driven by disease phenotype, clinical markers of complicated disease course (previous intestinal resection, corticosteroid use, perianal disease in CD, recent hospitalisations in UC), gut inflammation, and the impact of IBD on the patient., Conclusions: Disease severity in IBD can be difficult to conceptualise due to the multitude of factors that contribute to IBD outcomes. Measurement of IBD severity may better encapsulate the full burden of illness rather than gut inflammation alone at a single timepoint and may be associated with longitudinal outcomes., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

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.)

Background: Given the introduction of new advanced therapies for inflammatory bowel diseases (IBDs), expanded risk mitigation strategies are essential., Aims: To create a comprehensive set of statements on assessment procedures and vaccinations before starting monoclonal antibodies, Janus kinase (JAK) inhibitors or sphingosine-1-phosphate (S1P) modulators for IBD., Methods: We examined literature, guidelines and drug product information regarding vaccination and assessment recommendations for initiating advanced IBD therapies. Using a modified Delphi approach, delegates voted anonymously on the acceptability of these statements prior to and following consensus discussion., Results: We developed eight statements on the domains of infectious diseases screening, vaccinations and assessments prior to commencing JAK inhibitors and S1P modulators. Six statements received agreement. Pre-advanced therapy screening for infectious diseases was established, and the vaccination protocol was revised. Malignancy, cardiovascular and thromboembolic risk assessments are necessary before initiating JAK inhibitors. Those starting S1P modulators need cardiac and ophthalmic assessments., Conclusions: These consensus statements combine vaccination and assessments on the currently available advanced therapies for IBD as a single comprehensive document that may reduce IBD complications associated with use of advanced therapies. Knowledge gaps identified during the consensus process will provide further research opportunities., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: The exposure-response relationship is less established for adalimumab (ADA) compared with infliximab in inflammatory bowel disease (IBD). Evidence supporting therapeutic drug monitoring post dose-intensification of ADA is limited. We aimed to explore the association between ADA drug levels and Crohn's disease (CD) activity at loss of response, and at 6 and 12 months post dose-intensification., Methods: We performed a retrospective study of adult patients with CD receiving dose-intensified weekly ADA following secondary loss of response at 3 tertiary centers across 5 years. ADA trough levels were analyzed using a drug-sensitive enzyme-linked immunosorbent assay at loss of response, and 6 and 12 months after dose-intensification. Rates of clinical remission, objective remission (C-reactive protein <5 mg/L, fecal calprotectin <150 µg/g, or absence of inflammation at endoscopy or imaging), and ADA failure were investigated., Results: A total of 131 CD patients were included, with a median disease duration of 9 (interquartile range, 4-17) years. 51% were biologic exposed prior to ADA and 50% received concomitant immunomodulators. Baseline drug levels measured at secondary loss of response did not discriminate between subsequent responders and non-responders at either 6 or 12 months post dose-intensification. However, both higher drug levels at 6 and 12 months and a higher increment from baseline were associated with improved outcomes. On receiver-operating characteristic analyses, post-escalation ADA drug levels >10.7 µg/mL (area under the receiver-operating characteristic curve [AUROC], 0.66; P = .013) and >10.9 µg/mL (AUROC, 0.67; P = .032) were associated with objective remission at 6 and 12 months, respectively., Conclusions: Drug levels following dose-intensification rather than at the time of secondary loss of response were associated with subsequent CD remission., (© 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.)

Introduction: Therapeutic Drug Monitoring (TDM) has an important role in the management of inflammatory bowel disease (IBD) patients on infliximab (IFX) or adalimumab and is recommended in IBD patients presenting a loss of response under anti TNF agent. But, TDM was not recommended for others biotherapies., Areas Covered: Analyzing all publications about TDM and biologics in IBD patients, we reported the major results for each biotherapy., Expert Opinion: Emerging data suggest that TDM will probably be similarly useful forIFX SC. In contrast, there is no demonstrated clinical benefit to the use of TDM with golimumab. For vedolizumab results for the use of both reactive and proactive TDM are discordant. For ustekinumab, data supports the existence of an exposure response relationship, albeit of a lesser magnitude than with anti-TNF agents. Finally, recent data from small case series suggests that TDM could be valuable in optimizing anti-IL23 agents, particularly risankizumab, but this requires further clarification. Consistent with the new concept of 'proactive' strategy, recent data support the utility of dashboard-driven model informed precision dosing (MIDP) of anti-TNF agents, in particular infliximab. Dashboards are software systems using Bayesian population pharmacokinetic modelling to individualize recommendations for target drug levels.

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.)

Background: A treat-to-target strategy for inflammatory bowel disease (IBD) recommends iterative treatment adjustments to achieve clinical and endoscopic remission. In asymptomatic patients with ongoing endoscopic activity, the risk/benefit balance of this approach is unclear, particularly with prior exposure to advanced therapies., Methods: Using the RAND/University of California Los Angeles Appropriateness Method, 9 IBD specialists rated appropriateness of changing therapy in 126 scenarios of asymptomatic patients with ulcerative colitis and Crohn's disease and active endoscopic disease. Disease extent and behavior, prior treatment, prior complications, and recent disease progression were considered, as were factors that might influence decision-making, including age and pregnancy. Ratings were collected through anonymous survey, discussed at an in-person meeting, and finalized in a second anonymous survey., Results: Panelists rated change in therapy as appropriate (i.e., expected benefit sufficiently outweighs potential harms from continuing therapy) in 96/126 scenarios, generally in patients with progressive, complicated, and/or extensive disease, while changing therapy was rated uncertain in 27 scenarios of mild and/or stable disease. Changing therapy was rated inappropriate in ulcerative colitis patients with mild and stable disease previously exposed to ≥3 therapies or with improved endoscopic activity, and in Crohn's disease patients with only scattered aphthous ulcers. The validated threshold for disagreement was not crossed for any scenario. Patient age older than 65 years and a plan for pregnancy in the next year might influence decision-making in some settings., Discussion: Appropriateness ratings can help guide clinical decision-making about changing therapy to achieve endoscopic remission in asymptomatic patients with IBD until data from ongoing randomized studies are available., (Copyright © 2024 by The American College of Gastroenterology.)

Competing Interests: Conflicts of interest: Varan Perananthan was the Clinical Pharmacology Trainee participant on the Australian Prescriber Editorial Executive Committee at the time of writing. He was excluded from editorial decision-making related to the acceptance and publication of this case study. Miles Sparrow has received research support from Gilead and Celltrion, and speaker fees from Janssen, AbbVie, Ferring Pharmaceuticals, Takeda Pharmaceuticals, Pfizer, Celltrion Healthcare, Eli Lilly and Dr. Falk Pharma. He has been on advisory boards for Janssen, Takeda Pharmaceuticals, Pfizer, Celgene, AbbVie, MSD, Emerge Health, Gilead, Bristol Myers Squibb, Celltrion Healthcare and Eli Lilly. Anna Foley has no conflicts of interest to declare.

Background and Aim: C-reactive protein (CRP)-to-albumin ratio (CAR) is a novel score with prognostic value in inflammatory conditions. This study assessed the performance of CAR as an objective marker of disease activity and prediction of subtherapeutic infliximab trough levels in patients with inflammatory bowel disease (IBD)., Methods: A retrospective study was conducted on three different patient cohorts with IBD: patients who had (i) fecal calprotectin (FC) measurements; (ii) Mayo Endoscopic Scores; and (iii) infliximab trough levels available. The relative performances of CAR, albumin, and CRP were compared in predicting disease activity (based on FC or Mayo Endoscopic Score) and infliximab trough levels., Results: In both the FC ( n  = 289) and endoscopy ( n  = 65) cohorts, albumin and CAR correlated with objective disease activity. CAR (area under the curve [AUC] 0.70) was only marginally better at detecting active disease, measured by FC, compared to CRP (AUC 0.68). A CAR >0.15 was able to detect Mayo 3 disease (AUC 0.83, sensitivity 81%, specificity 89%). Albumin ( r  = 0.38) and CAR ( r  = -0.42) correlated with infliximab trough levels ( n  = 204). The optimal CAR for detecting subtherapeutic infliximab trough levels was >0.08 (AUC 0.70, sensitivity 66%, specificity 64%). Both albumin and CAR were independent predictors of subtherapeutic infliximab trough levels but correlated poorly with infliximab trough levels longitudinally in the same patient., Conclusion: CAR was only a modest discriminator of subtherapeutic infliximab levels and offers little more than CRP in detecting active disease. CAR has potential to detect severe Mayo 3 disease and could be calculated in patients admitted with suspected acute severe ulcerative colitis., (© 2024 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Precision-dosing models forecast infliximab doses to achieve targeted trough concentrations in patients with inflammatory bowel disease (IBD). These models have shown to reduce nonresponse and improve patient outcomes. We compared infliximab doses determined by iDOSE precision dosing with standard dosing, and the associated drug costs, in patients with IBD. In this retrospective study, patients with IBD treated with infliximab every 8 weeks at 5 mg/kg were included. An infliximab dose was named dose X if 3 previous infliximab doses, laboratory values including trough infliximab concentrations, and the patient's weight were recorded. The actual dose X was compared to an iDOSE-predicted dose X. Net drug use and costs were evaluated. A total of 174 patients-56% men; median age, 36 (interquartile range, 29-47) years; 135 with Crohn disease; and 31 with ulcerative colitis-were included, with 417 dose X recordings. Median prior infliximab therapy was 2 (0-4) years. Comparing actual dose X with predicted dose X, 52% and 32% of doses were subtherapeutic when aiming for trough concentrations of 5-10 and 3-7 μg/mL, respectively. Treatment costs increased by 102% and 29% for the 2 trough ranges, respectively. On multivariate regression analysis, subtherapeutic infliximab concentrations were associated with ulcerative colitis compared with Crohn disease (odds ratio, 9.81; 95% confidence interval, 1.28-75.40; P = .028) and predose X infliximab trough concentration [odds ratio, 0.07; 95% confidence interval, 0.03-0.15; P < .001]. Over half of maintenance infliximab drug doses were too low to achieve infliximab blood concentrations of 5 μg/mL or greater. While applying precision dosing may improve patient outcomes, drug costs could be considerably greater., (© 2023 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Inflammatory bowel disease (IBD) is associated with chronic intestinal barrier dysfunction, though its non-invasive assessment remains challenging. This study aimed to determine how four putative circulating markers vary across differing states of intestinal inflammation and with therapy in patients with IBD., Methods: Plasma samples from one prospective cross-sectional and four longitudinal studies, including healthy controls, were analysed for markers of lipopolysaccharide translocation, lipopolysaccharide-binding protein (LBP) and soluble-CD14 (sCD14), and markers of epithelial injury, syndecan-1 and intestinal-type fatty acid-binding protein (IFABP). Inflammatory activity was determined using objective measures., Results: Compared with healthy subjects, concentrations of LBP and sCD14 were higher in patients with active (P < 0.001) and severe ulcerative colitis (UC) (P < 0.0001) and active Crohn's disease (CD) (P < 0.001). In UC in remission, LBP was less than in active disease (P = 0.011) LBP levels decreased longitudinally before and after induction of medical therapy in patients with IBD (P = 0.030) and as severe UC was brought into remission at weeks 2 and 12 (P ≤ 0.022). Response to treatment was associated with higher baseline levels of LBP (P = 0.019) and soluble-CD14 (P = 0.014). Concentrations of syndecan-1 and IFABP were or tended to be lower in UC and CD in active disease and did not change with successful therapy., Conclusion: While markers of epithelial injury were subnormal with active disease and did not change with therapy, markers of lipopolysaccharide translocation directly reflected intestinal inflammation, reduced with successful therapy and predicted treatment response., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Thiopurines are established treatments for inflammatory bowel disease (IBD), yet concerns remain regarding their safety., Aim: To evaluate the use of thiopurine-allopurinol combination therapy compared to standard thiopurine therapy in IBD., Methods: We performed a multicentre, randomised, placebo-controlled trial to compare the efficacy and safety of thiopurine-allopurinol versus thiopurine with placebo for adults commencing a thiopurine for IBD. Patients had active disease at baseline; dosing of therapy was based on a pre-specified regimen and subsequent metabolites. The primary outcome was the proportion of patients achieving a composite of symptomatic disease activity remission (Harvey Bradshaw Index <5 for Crohn's disease, Simple Clinical Colitis Activity Index <4 for ulcerative colitis) and a faecal calprotectin <150 μg/g after 26 weeks of treatment., Results: The trial was terminated early due to slow recruitment. We randomised 102 participants (54 thiopurine-allopurinol, 48 thiopurine with placebo) with similar age (median 42 vs 48 years) and sex distribution (46% women per group). A higher proportion achieved the primary outcome in the thiopurine-allopurinol group (50% vs 35%, p = 0.14) and fewer participants stopped their allocated therapy due to adverse events (11% vs 29%, p = 0.02). Also, within the thiopurine-allopurinol group, thiopurine dose adjustments were less frequent (69% vs 92%, p = 0.03), a higher proportion achieved an early therapeutic 6-TGN level at week 6 (71% vs 53%, p = 0.19), and adverse events attributed to therapy were less frequent (15% vs 44%, p = 0.002)., Conclusion: Thiopurine-allopurinol therapy is safe and mitigates thiopurine adverse effects, thus enhancing tolerability without compromising efficacy (ACTRN12613001347752)., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Inflammatory bowel disease (IBD) therapies now utilise higher doses of immunomodulatory and biologic therapies, predisposing patients to an increased risk of infections., Aims: We aimed to determine whether infections were associated with high anti-tumour necrosis factor (TNF) drug levels in IBD and to quantify the risk and consequences of infections., Methods: Two retrospective studies were performed, a descriptive cohort study and a matched case-control study. For the matched case-control study, cases of infection occurring on anti-TNF agents were matched in a 1:2 ratio to controls of anti-TNF treated patients without infections., Results: In the descriptive study, 76 infections occurred in 60 patients, including 49 bacterial, 24 viral, four fungal and four parasitic. Of these, 61 (80.3%) were on biologics, 49 (64.5%) on immunomodulators and 11 (14.5%) on corticosteroids. Thirty-four (44.7%) were on combination therapy, 27 (35.5%) on biologic monotherapy and 15 (19.7%) on immunomodulator monotherapy. Median anti-TNF drug levels in infection cases were 3.9 μg/mL for infliximab and 6.0 μg/mL for adalimumab. In the case-control study, 32 cases of infection in 27 anti-TNF treated patients were matched with 64 anti-TNF treated controls without infections. Among infection cases, 59.5% were on combination therapy versus 40.6% on biologic monotherapy (P = 0.59). Median drug levels for cases and controls respectively were 3.9 μg/mL versus 5.5 μg/mL for infliximab (P = 0.72) and 6.0 μg/mL versus 9.9 μg/mL for adalimumab (P = 0.34)., Conclusion: Infections in patients with IBD were common, and the risk was highest with combination therapy. Infections were not associated with high serum anti-TNF levels., (© 2023 Royal Australasian College of Physicians.)

Aims: To evaluate a whole-food diet strategy (the Monash Pouch diet [MPD]) designed based on the interacting roles dietary factors play with pouch health. Specifically, its tolerability and acceptability, whether it achieved its dietary and metabolic goals, and the effects on symptoms and inflammation were examined., Methods: In a 6-week open-label trial, patients with ileoanal pouches educated on the MPD were assessed regarding diet tolerability and acceptance, food intake (7-day food diaries), pouch-related symptoms (clinical pouchitis disease activity index), and, in 24-h fecal samples, calprotectin, fermentative biomarkers, and volatile organic compounds (VOC)., Results: Of 12 patients, 6 male, mean (SD) age 55 (5) and pouch age 13 (2) years, one withdrew with partial small bowel obstruction. Tolerability was excellent in 9 (75%) and acceptance was high (81%). Targeted changes in dietary intake were achieved. Fecal branched- to short-chain fatty acid ratio increased by median 60 [IQR: 11-80]% ( P  = 0.02). Fecal VOCs for 3 compounds were also increased, 2-methyl-5-propan-2-ylcyclohexa-1,3-diene (Fold-change [FC] 2.08), 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane (FC 3.86), propan-2-ol (FC 2.10). All six symptomatic patients achieved symptomatic remission ( P  = 0.03). Fecal calprotectin at baseline was 292 [176-527] μg/g and at week 5 was 205 [148-310] μg/g ( P  = 0.72)., Conclusion: Well tolerated and accepted, the MPD achieved targeted changes in intakes and fermentation of carbohydrates relative to that of protein. There were signals of improvement in symptoms. These results indicate the need for a randomized-controlled trial. (Trial registration: ACTRN12621000374864; https://www.anzctr.org.au/ACTRN12621000374864.aspx)., (© 2023 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: Ileoanal pouch patients frequently attribute pouch-related symptoms and pouchitis with diet. We aimed to assess perceived food intolerance and habitual dietary intake and their relationship with pouch indication, symptoms and current or history of pouchitis., Methods: In this cross-sectional study, patients with an ileoanal pouch completed a dietary intolerance and a food frequency questionnaire, that specifically quantifies habitual intake of FODMAPs. Perceived dietary intolerance rates, nutrient intake and diet quality, and their differences based on pouch indication, symptom, and current or history of pouchitis were assessed. Associations between intolerances and intake, and between dietary intake with pouchitis risk were analysed using univariable and multivariable regression analysis., Results: Of the 58 (10 FAP and 48 UC) patients with complete data, 81% of UC and 80% of FAP patients reported dietary intolerances. Overall diet quality was good. Differences in dietary intake were limited to a few food groups. Patients with a history of pouchitis had a lower intake of fruits (p = 0.03) and nuts (p = 0.004). Patients with current pouchitis had a lower intake of nuts (p = 0.02). On multivariable logistic regression, intake of dietary fibre was associated negatively [OR 0.68(95%CI:0.51-0.92)] and of non-digestible oligosaccharides positively with pouchitis history [OR 5.5(95% CI:1.04-29.1)]., Conclusions: In patients with an ileoanal pouch, perceived dietary intolerances are common but had minimal impact on nutritional adequacy and diet quality. Negative associations of the intakes of fruits, nuts and dietary fibre and positive association with non-digestible oligosaccharides with a history of pouchitis require further study to inform dietary recommendations., Competing Interests: Conflicts of interest Zaid S Ardalan has no disclosures to declare. CKY has received research support for investigator-driven studies for Atmo Biosciences, Ferring Pharmaceuticals, Danone and Yakult Australia. KML: has no disclosures to declare. LP: has no disclosures to declare. JA: has no disclosures to declare. FR: has no disclosures to declare. MPS: Has (i) received educational grants or research support – Ferring, Orphan, Gilead; and (ii) received speaker’s fees – Janssen, Abbvie, Ferring, Takeda, Pfizer, Shire, and (iii) Serves as a consultant and advisory board member for Janssen, Takeda, Pfizer, Celgene, Abbvie, MSD, and Emerge Health. PRG has served as consultant or advisory board member for Anatara, Atmo Biosciences, Immunic Therapeutics, Janssen, Novozymes, Falk Pharma and Takeda. He has received research grants for investigator-driven studies from Atmo Biosciences. He holds shares in Atmo Biosciences. He has published two educational/recipe books on the low FODMAP diet. ZSA, PRG and CKY also work in a department that financially benefits from the sales of a digital application and booklets on the low FODMAP diet. Funds raised contribute to research of the Department of Gastroenterology and to the University. No author receives personal remuneration., (Copyright © 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)