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Background: There are a plethora of therapeutic options for the management of inflammatory bowel disease (IBD). Despite this, clinical outcomes with standard dosing often fall short of established targets. While efforts centre on developing novel therapies, there is an ongoing need to optimise the use of existing agents., Aims: To focus on strategies to optimise response to biologic (monoclonal antibody) therapies in IBD, including use of therapeutic drug monitoring (TDM)., Methods: An extensive review of the published literature., Results: TDM is a strategy aimed at enhancing the effectiveness of drugs with variable exposure-response relationships by measuring serum concentrations of biologic therapies and detecting neutralising antibodies. Reactive TDM is performed when therapeutic goals have not been achieved. Tumour necrosis factor alpha (TNF) inhibitors are the treatment class most frequently associated with immunogenicity and loss of response. Immunogenicity can be reduced through avoidance of low serum drug concentrations by dose optimisation or use of concomitant immunomodulator therapy. Subtherapeutic dosing in the absence of antidrug antibodies is best managed by dose escalation or dose interval reduction. Persistent neutralising drug antibodies necessitate switching to an alternative therapy. Proactively ensuring adequate serum trough levels might help sustain treatment durability and prevent loss of response. Newer non-TNF inhibitors demonstrate less robust exposure-response relationships, and TDM may not prove as beneficial., Conclusions: In the treat-to-target paradigm of IBD treatment, optimising treatment effect with dose optimisation, which may involve strategies including TDM, increases the likelihood of achieving clinical remission and may accomplish deeper levels of remission beyond symptom control., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: The operating properties of histologic indices for evaluating Crohn's disease (CD) activity are poorly characterized. We assessed the reliability and responsiveness of existing histologic indices/items used in CD and ulcerative colitis (UC), in addition to 3 novel items, and developed exploratory ileal, colonic, and colonic-ileal CD instruments., Methods: Blinded central readers independently reviewed paired baseline and week 12 image sets from the EXTEND trial. Disease activity was scored using 4 indices (the Global Histologic Activity Score, Geboes Score, Nancy Histological Index, and Robarts Histopathology Index) and 3 items identified by an expert panel (mucin depletion, basal plasmacytosis, and ileal pyloric gland metaplasia). Reliability and responsiveness were quantified using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an inter-rater ICC ≥0.40 and AUC ≥0.56. The dependent variable was histologic disease activity measured by a 100-mm visual analogue scale., Results: Paired image sets were available from 55 patients. Substantial to almost perfect inter-rater reliability (ICC, 0.63-0.87) and some responsiveness (AUC, 0.57-0.94) were observed for all existing indices regardless of whether individual colonic and ileal segments, combined colonic segments, or combined colonic and ileal segments were assessed and the calculation method used. Five items were tested as candidate items, and exploratory colonic, ileal, and colonic-ileal indices were developed., Conclusions: CD and UC indices were similarly reliable and responsive in measuring histologic CD activity. Exploratory index development did not offer benefit over current histologic instruments., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aims: Accurate determination of histological activity in ulcerative colitis (UC) is essential given its diagnostic and prognostic importance. Data on the relationship between histology and immune cell markers are limited. We aimed to evaluate the association between histological disease activity and immune cell marker concentration in colonic biopsies from patients with UC., Methods: Sigmoid colon biopsies from 20 patients with UC were retrospectively assessed using the Robarts Histopathology Index (RHI). Targeted mass spectrometry determined the concentration of 18 immune cell markers (cluster of differentiation (CD) 4, CD8, CD19, CD20, CD40, CD56, CD68, CD103, forkhead box p3 (FOXP3), human leucocyte antigen, DR alpha chain (HLA-DRA), interleukin 10 (IL-10), IL-23 subunit alpha (IL-23A), IL-23 receptor (IL-23R), IL-2 receptor alpha chain (IL-2RA), Ki67, lymphocyte-activation gene 3 (LAG-3), programmed cell death protein 1 (PD-1) and PD ligand 1 (PD-L1)). The association between RHI score and immune cell marker concentration was quantified using Spearman's rank correlation coefficient (ρ) and related 95% CIs., Results: Fourteen of the 18 immune cell marker proteins were detected, with tissue concentration ranging from 0.003 to 11.53 fmol/µg. The overall RHI score was positively correlated with CD19, CD20, CD40, FOXP3, LAG-3, PD-1 and PD-L1 concentration (ρ=0.596-0.799) and negatively correlated with CD56 concentration (ρ=-0.460). There was no significant association between RHI score and CD4, CD8, CD68, CD103, HLA-DRA or Ki67 concentration., Conclusions: This study provides insight into the correlation between immune cell marker expression and histological disease activity and the possible molecular and immunological determinants underlying microscopic disease activity in UC., Competing Interests: Competing interests: PLCL, ZW, WT, TVV and BL are employees of Alimentiv. GZ has received consulting fees from Alimentiv. VJ has received consulting/advisory board fees from AbbVie, Alimentiv, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, Second Genome, Sorriso pharmaceuticals, Takeda, Teva, Topivert, Ventyx, Vividion; and speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda. BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix, and Wyeth Pharmaceuticals; consulting fees from Millennium Pharmaceuticals, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging, Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma and Sigmoid Pharma; and speaker’s fees from UCB, AbbVie and J&J/Janssen. RKP has received consulting fees from Alimentiv, Verily and Allergan. NVC has received a research grant from R-Biopharm; and personal fees from AcelaBio, Alimentiv, Pfizer, ProciseDX and Ventyx. These activities were all outside of the submitted work. Alimentiv is an academic gastrointestinal contract research organisation (CRO), operating under the Alimentiv Health Trust. Alimentiv provides comprehensive clinical trial services, precision medicine offerings and centralised imaging solutions that include endoscopy, histopathology and MRI. The beneficiaries of theAlimentiv Health Trust are the employees of the enterprises it holds. GZ and VJ are consultants to Alimentiv and have a primary academic appointment; they do not hold equity positions or shares in Alimentiv., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis 1,2 , we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4 + T cells 3 and agonism of the pregnane X receptor 4 . Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems., (© 2023. The Author(s).)

Background: Clinical trials of novel therapies for the treatment of ulcerative colitis (UC) may benefit from immune cell profiling, however implementation of this methodology is limited in the multicenter trial setting by necessity of timely (within 6 to 8 h) isolation and processing of peripheral blood mononuclear cells (PBMC) from whole blood samples. Becton Dickinson Vacutainer CPT™ Cell Preparation Tubes (CPT™) limit required processing prior to shipping to a central lab to an initial centrifugation step within 24 h of sample collection. As shipping may delay final processing beyond 24 h, we analyzed cell viability and T cell composition in whole blood stored in CPT™ to determine if their use may accommodate processing delays typical for multicenter clinical trials., Methods: Whole blood samples from 3 patients with UC were collected in CPT™ (15 tubes/patient) and PBMC were processed at various timepoints (24-96 h). Cell viability and T cell composition (26 types) were evaluated by flow cytometry. Variability between technical and biological replicates was evaluated in the context of cell-type abundance, delayed processing time, and data normalization., Results: Total cell viability was <50% when processing was delayed to 48 h after collection and was further reduced at later processing timepoints. The effect of delayed processing on cell abundance varied widely across cell types, with CD4+, CD8+, naïve effector CD8+, and Tcm CD4 + T cells displaying the least variability in abundance with delayed processing. Normalization of cell counts to cell types other than total T cells corrected for the effect of delayed processing for several cell types, particularly Th17., Conclusions: Based on these data, processing of PBMC in CPT™ should ideally be performed within 48 h. Delayed processing of PBMC in CPT™ may be considered for cell types that are robust to these conditions. Normalization of cell abundance to different parental cell-types may reduce variability in quantitation and should be used in conjunction with the expected effect size to meet the experimental goals of a multicenter clinical trial., Competing Interests: Declaration of Competing Interest Bryan Linggi is an employee of Alimentiv Inc. Jonathan Cremer has nothing to declare. Zhongya Wang is an employee of Alimentiv Inc. Tanja Van Viegen is an employee of Alimentiv Inc. Séverine Vermeire reports grants from AbbVie, J&J, Pfizer, Takeda and Galapagos; consulting and/or speaking fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr. Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma. Pavine Lefevre is an employee of Alimentiv Inc. Lisa M. Shackelton reports consulting fees received from Alimentiv Inc. Vipul Jairath reports consulting/advisory board fees from AbbVie, Alimentiv Inc., Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, Second Genome, Sorriso Pharmaceuticals, Takeda, Teva, Topivert, Ventyx, and Vividion; and speaker's fees from, AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen, Pfizer, Shire, Takeda, and Fresenius Kabi. Wendy Teft is an employee of Alimentiv Inc. Niels Vande Casteele reports research grant from R-Biopharm; and personal fees from AcelaBio, Alimentiv, Pfizer, ProciseDX, and Ventyx. These activities were all outside of the submitted work. Bram Verstockt reports research support from Pfizer; speaker's fees from AbbVie, Biogen, Bristol Myers Squibb, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris; consultancy fees from AbbVie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Inotrem, Ipsos, Janssen, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma and Viatris. Alimentiv Inc. is an academic gastrointestinal contract research organization (CRO), operating under the Alimentiv Health Trust. Alimentiv Inc. provides comprehensive clinical trial services, precision medicine offerings, and centralized imaging solutions for endoscopy, histopathology, and other imaging modalities. The beneficiaries of the Alimentiv Health Trust are the employees of the enterprises it holds. VJ and NVC are consultants to Alimentiv Inc. and have primary academic appointments; they do not hold equity positions or shares in Alimentiv Inc., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Interleukin-12 (IL-12) and interleukin-23 (IL-23), which belong to the IL-12 family of cytokines, have a key role in intestinal homeostasis and inflammation and are implicated in the pathogenesis of inflammatory bowel disease. Upon their secretion by antigen-presenting cells, they exert both pro-inflammatory and anti-inflammatory receptor-mediated effects. An increased understanding of these biological effects, particularly the pro-inflammatory effects mediated by IL-12 and IL-23, has led to the development of monoclonal antibodies that target a subunit common to IL-12 and IL-23 (p40; targeted by ustekinumab and briakinumab), or the IL-23-specific subunit (p19; targeted by risankizumab, guselkumab, brazikumab and mirikizumab). This Review provides a summary of the biology of the IL-12 family cytokines IL-12 and IL-23, discusses the role of these cytokines in intestinal homeostasis and inflammation, and highlights IL-12- and IL-23-directed drug development for the treatment of Crohn's disease and ulcerative colitis., (© 2023. Springer Nature Limited.)

Background: Vedolizumab (VDZ) is an anti-α 4 β 7 integrin monoclonal antibody approved for inflammatory bowel disease treatment. VDZ serum and antidrug antibody (ADA) concentrations may be used for treatment optimization. In this article, the results of 5 commercial assays (Grifols, Immundiagnostik, Progenika, Sanquin, and Theradiag) measuring VDZ concentration and ADA were compared with those of the reference assays used in VDZ clinical studies. Our findings will assist clinicians in interpreting commercial assay results in the context of VDZ clinical trial data., Methods: VDZ-treated patient samples were used to evaluate the agreement between commercial assays and the reference VDZ serum concentration assay, based on linear regression, Bland-Altman, and qualitative agreement analyses. VDZ ADAs were detected using qualitative assays. Specificity, selectivity, accuracy, and precision were assessed using serum samples from healthy donors or patients with IBD (VDZ serum concentration <0.5 mcg/mL) spiked with VDZ, with/without other biologics (identical sample sets per assay)., Results: All assays were specific and selective for VDZ. Overall, the commercial assay results for VDZ-spiked samples correlated well with those of the reference serum concentration assay (R 2 ≥ 0.98). Compared with the Immundiagnostik and Theradiag assays, the Grifols, Sanquin, and Progenika assays had the best reference assay agreement (based on regression analysis, Bland-Altman plots, and qualitative agreement [Cohen's kappa ≥0.92]). All immunogenicity assays detected VDZ ADAs; only the reference assay detected VDZ ADAs in the presence of 15 mcg/mL VDZ, advising caution with commercial ADA assays if VDZ is present., Conclusions: All 5 commercial assays are suitable for VDZ therapeutic monitoring and ADA testing. However, the absolute values from the reference assays and the different commercial assays were not comparable, indicating that the same assay must be used for repeated monitoring of VDZ serum concentrations., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Introduction: Exposure-outcome relationship data show that higher infliximab concentrations are associated with better outcomes in patients with Crohn's disease (CD). However, most of these data were derived from adult patients on maintenance therapy. We aimed to investigate the association of infliximab concentrations during and early after induction therapy of infliximab with short-term and long-term clinical outcomes in a pediatric CD population., Methods: We conducted a post hoc analysis of the REACH trial which included pediatric patients with moderate-to-severe CD treated with infliximab (n = 103). The investigated outcomes were early clinical remission (CR) defined as a pediatric CD activity index score of ≤ 10, assessed at week 10, and long-term clinical response (LTCR) defined as a decrease from baseline in the pediatric CD activity index score of at least 15 points, with a total score of ≤ 30 and no need for drug discontinuation, assessed at weeks 30 and 54., Results: Based on multivariable logistic regression analysis, higher week 10 infliximab concentrations were independently associated with CR at week 10 (odds ratio: 1.54; 95% confidence interval: 1.06-2.22; P = 0.022) and LTCR at week 30 (odds ratio: 1.62; 95% confidence interval: 1.12-2.36; P = 0.010). Receiver operating characteristic analysis identified week 10 infliximab concentration thresholds of ≥7.1 μg/mL and ≥6.5 μg/mL to be associated with CR at week 10 and LTCR at week 30, respectively., Discussion: Higher postinduction infliximab concentrations are associated with both short-term and long-term favorable clinical outcomes in pediatric patients with CD. Tailoring dosing during induction to achieve higher infliximab exposure may lead to better outcomes in pediatric patients with CD., (Copyright © 2022 by The American College of Gastroenterology.)

Background & Aims: End points to determine the efficacy and safety of medical therapies for Crohn's disease (CD) and ulcerative colitis (UC) are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in inflammatory bowel disease., Methods: Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists., Results: A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for UC. In CD, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In UC, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities., Conclusions: This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of CD and UC., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: ERELATE was a phase 4, multinational, retrospective, observational study., Aim: To evaluate the relationship between intravenous vedolizumab exposure and treatment outcomes over 52 weeks in adults with ulcerative colitis (UC) or Crohn's disease (CD)., Methods: Real-world data from patients with UC or CD treated with intravenous vedolizumab in nine centres in six countries were collected retrospectively. Treatment outcomes were collected at Weeks 14, 26 and 52. An established population pharmacokinetic model (incorporating observed vedolizumab concentrations based on a Bayesian approach) was used to predict individual vedolizumab exposure. Vedolizumab exposure-response relationship was evaluated overall, by indication and based on baseline characteristics., Results: The study population (n = 695; UC, n = 304; CD, n = 391) had a median age of 39 years; 47.9% were male and 86.9% had prior tumour necrosis factor antagonist exposure. By Week 14, clinical, endoscopic, deep (clinical plus endoscopic) and biologic remission was achieved by 47.3%, 59.6%, 30.7% and 19.0% of patients respectively. Higher vedolizumab trough concentration early in treatment was consistently associated with clinical remission at later time points. Clinical remission at Week 14 and Week 52 was associated with Week 6 trough concentrations of ≥31.0 and ≥32.0 μg/ml respectively. Importantly, multivariable analysis identified baseline clearance as the only exposure measure predictive of clinical and deep remission at Week 52., Conclusions: In this real-world study, a positive exposure-response relationship was observed for vedolizumab. Vedolizumab concentration during induction may be an important predictor of short- and long-term outcomes, and similarly, vedolizumab baseline clearance may be an important predictor of remission., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Immune cell trafficking is a critical element of the intestinal immune response, both in homeostasis and in pathological conditions associated with inflammatory bowel disease (IBD). This process involves adhesion molecules, chemoattractants and receptors expressed on immune cell surfaces, blood vessels and stromal intestinal tissue as well as signalling pathways, including those modulated by sphingosine 1-phosphate (S1P). The complex biological processes of leukocyte recruitment, activation, adhesion and migration have been targeted by various monoclonal antibodies (vedolizumab, etrolizumab, ontamalimab). Promising preclinical and clinical data with several oral S1P modulators suggest that inhibition of lymphocyte egress from the lymph nodes to the bloodstream might be a safe and efficacious alternative mechanism for reducing inflammation in immune-mediated disorders, including Crohn's disease and ulcerative colitis. Although various questions remain, including the potential positioning of S1P modulators in treatment algorithms and their long-term safety, this novel class of compounds holds great promise. This Review summarizes the critical mediators and mechanisms involved in immune cell trafficking in IBD and the available evidence for efficacy, safety and pharmacokinetics of S1P receptor modulators in IBD and other immune-mediated disorders. Further, it discusses potential future approaches to incorporate S1P modulators into the treatment of IBD., (© 2022. Springer Nature Limited.)

In patients with Crohn's disease and ulcerative colitis, poor correlation between symptoms and active luminal inflammation has been well established. As a result, the field has moved towards the use of endoscopic assessment to evaluate inflammatory activity. Numerous endoscopic indices have been used for this purpose although none are completely validated. The Simple Endoscopic Score for Crohn's Disease and the Crohn's Disease Endoscopic Index of Severity have been used most frequently; however in addition to incomplete validation, they have important limitations for clinical use, including complexity of scoring and poor reliability of items such as stenosis. The Rutgeerts' score for postoperative Crohn's disease was developed primarily as a prognostic rather than evaluative tool and also requires additional validation. In ulcerative colitis, the Mayo endoscopic subscore has been used as the regulatory standard, although the Ulcerative Colitis Endoscopic Index of Severity may provide a more granular assessment of individual components of disease activity. The use of combined outcomes with patient reported outcomes (PROs) and endoscopic indices has received favor by regulatory bodies but require further validation. This review describes the indications for endoscopic assessment in trials, the indices most frequently utilized for these purposes, and potential future approaches to assessment of disease activity., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Preliminary data indicates that proactive therapeutic drug monitoring (TDM) is associated with better outcomes compared with empiric dose escalation and/or reactive TDM, and that pharmacokinetic (PK) modelling can improve the precision of individual dosing schedules in Crohn's disease (CD). However, there are no data regarding the utility of a proactive TDM combined PK-dashboard starting early during the induction phase, when disease activity and drug clearance are greatest. The aim of this randomised, controlled, multicentre, open-label trial is to evaluate the efficacy and safety of a proactive TDM combined PK dashboard-driven infliximab dosing compared with standard of care (SOC) dosing in patients with moderately to severely active CD., Methods and Analysis: Eligible adolescent and adult (aged ≥16-80 years) patients with moderately to severely active CD will be randomised 1:1 to receive either infliximab monotherapy with proactive TDM using a PK dashboard (iDose, Projections Research) or SOC infliximab therapy, with or without a concomitant immunomodulator (IMM) (thiopurine or methotrexate) at the discretion of the investigator. The primary outcome of the study is the proportion of subjects with sustained corticosteroid-free clinical remission and no need for rescue therapy from week 14 throughout week 52. Rescue therapy is defined as any IFX dose escalation other than what is forecasted by iDose either done empirically or based on reactive TDM; addition of an IMM after week 2; reintroduction of corticosteroids after initial tapering; switch to another biologic or need for CD-related surgery. The secondary outcomes will include both efficacy and safety end points, such as endoscopic and biological remission, durability of response and CD-related surgery and hospitalisation., Ethics and Dissemination: The protocol has been approved by the Institutional Review Board Committee of the Beth Israel Deaconess Medical Center (IRB#:2021P000391). Results will be disseminated in peer-reviewed journals and presented at scientific meetings., Trial Registration Number: NCT04835506., Competing Interests: Competing interests: ASC: reports consultancy fees from Janssen, AbbVie, Artugen, Procise, Prometheus, Arena, Grifols, Bacainn, Bristol Myers Squibb. VJ has received consulting/advisory board fees from AbbVie, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Asieris, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genetech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Reistone Biopharma, Roche, Sandoz, Takeda, Teva, Topivert; speaker’s fees from, AbbVie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda. CS: reports consultancy fees from AbbVie, BMS, Lilly, Janssen, Pfizer, Prometheus, Takeda, Trellus Health; speaker's fees for CME activities for AbbVie, Janssen, Pfizer, Takeda; grant support from the Crohn’s and Colitis Foundation, Leona M. and Harry B. Helmsley Charitable Trust, AbbVie, Janssen, Pfizer, Takeda; intellectual property owned by MiTest Health (Software Company) and ColonaryConcepts; equity interest and co-founder of MiTest Health and ColonaryConcepts. KP reports lecture fees from Mitsubishi Tanabe Pharma and Physicians Education Resource; consultancy fee from Prometheus Laboratories and scientific advisory board fees from ProciseDx and Scipher Medicine Corporation. JFV: reports research support from Roche/Genentech, Takeda, Applied Molecular Transport, Celgene/Bristol Myers Squibb, AbbVie, Arena Pharmaceuticals. GZ: reports consulting fees from Alimentiv. BC: reports financial support for advisory boards and consultancy from AbbVie, Celgene-Bristol Myers Squibb, Pfizer, Sublimity Therapeutics, Takeda, TARGET RWE; CME Companies: Cornerstones, Vindico; speaker's fees from AbbVie; educational grant from Pfizer. MD: reports consultancy fees from AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim International, Bristol Myers Squibb, Cengene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead, Janssen Global Services, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals USA, UCB SA; research grants from AbbVie, Janssen Global Services, Pfizer, Prometheus Biosciences; ownership interest (stocks) Trellus Health and holds licensing fee with Takeda Pharmaceuticals USA. TR: reports speaker's fees from Takeda Pharmaceuticals, Janssen, Pfizer, Bristol Myers Squibb; data adjudication committee fees from Ferring/Rebiotix; advisory boards fees from AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Coral Genomics (and shareholder), Ferring, Genentech/Roche, Gilead, Gossamer, Intercept, Janssen, Lilly, Pfizer, Prometheus, Sanofi, Takeda. BES: discloses research grants from Takeda, Pfizer, Theravance Biopharma R&D, Janssen; consulting fees from 4D Pharma, Abivax, AbbVie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Bacainn Therapeutics, Boehringer-Ingelheim, Boston Pharmaceuticals, Bristol yers Squibb, Calibr, Capella Bioscience, Celgene, Celltrion Healthcare, ClostraBio, Enthera, F. Hoffmann-La Roche, Ferring, Galapagos, Gilead, GlaxoSmithKline, GossamerBio, Immunic, Index Pharmaceuticals, Innovation Pharmaceuticals, Ironwood Pharmaceuticals, Janssen, Kaleido, Kallyope, Lilly, MiroBio, Morphic Therapeutic, Oppilan Pharma, OSE Immunotherapeutics, Otsuka, Palatin Technologies, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Redhill Biopharma, Rheos Medicines, Salix Pharmaceuticals, Seres Therapeutics, Shire, Sienna Biopharmaceuticals, Sun Pharma, Surrozen, Takeda, Target PharmaSolutions, Teva Branded Pharmaceutical Products R&D, Thelium, Theravance Biopharma R&D, TLL Pharma, USWM Enterprises, Ventyx Biosciences, Viela Bio, Vivante Health, Vivelix Pharmaceuticals; and stock for Vivante Health and Ventyx Biosciences. NVC: received research grants from R-Biopharm, Takeda and UCB; and personal fees from AcelaBio, Alimentiv, Celltrion, ProciseDX, Prometheus, R-Biopharm, Takeda, UCB, Ventyx and Vividion. The remaining authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients treated with immune checkpoint inhibitors (ICIs) may develop ICI-associated enterocolitis, for which there is no approved treatment., Aims: We aimed to systematically review the efficacy and safety of medical interventions for the prevention and treatment of ICI-associated enterocolitis., Methods: MEDLINE, EMBASE, and the Cochrane Library were searched to identify randomized controlled trials (RCTs), cohort and case-control studies, and case series/reports, evaluating interventions (including corticosteroids, biologics, aminosalicylates, immunosuppressants, and fecal transplantation) for ICI-associated enterocolitis. Clinical, endoscopic, and histologic efficacy endpoints were evaluated. The Grading of Recommendations, Assessment, Development, and Evaluation criteria were used to assess overall quality of evidence., Results: A total of 160 studies (n = 1514) were included (one RCT, 3 retrospective cohort studies, 156 case reports/case series). Very low quality evidence from one RCT suggests budesonide is not effective for prevention of ICI-associated enterocolitis in ipilimumab-treated patients (relative risk 0.93 [95% confidence interval 0.56, 1.56]). Very low quality evidence suggests that corticosteroids, infliximab, and vedolizumab may be effective for treatment of ICI-associated enterocolitis by inducing clinical response and remission. No validated indices for measuring disease activity were used. Biologic treatment was used in 42% (641/1528) of patients, as reported in 97 studies. ICIs were discontinued in 65% (457/702) of patients, as reported in 63 studies., Conclusions: Current treatment recommendations for ICI-associated enterocolitis are based on very low quality evidence, primarily from case reports and case series. Large-scale prospective cohort studies and RCTs are needed to develop prophylactic and therapeutic treatments to minimize interruption or discontinuation of oncological therapies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Eosinophils have been implicated in the pathogenesis of ulcerative colitis and have been associated with disease course and therapeutic response. However, associations between eosinophil density, histologic activity, and clinical features have not been rigorously studied., Methods: A deep learning algorithm was trained to identify eosinophils in colonic biopsies and validated against pathologists' interpretations. The algorithm was applied to sigmoid colon biopsies from a cross-sectional cohort of 88 ulcerative colitis patients with histologically active disease as measured by the Geboes score and Robarts histopathology index (RHI). Associations between eosinophil density, histologic activity, and clinical features were determined., Results: The eosinophil deep learning algorithm demonstrated almost perfect agreement with manual eosinophil counts determined by 4 pathologists (interclass correlation coefficients: 0.805-0.917). Eosinophil density varied widely across patients (median 113.5 cells per mm2, interquartile range 108.9). There was no association between eosinophil density and RHI (P = 0.5). Significant differences in eosinophil density were seen between patients with Montreal E3 vs E2 disease (146.2 cells per mm2 vs 88.2 cells per mm2, P = 0.005). Patients on corticosteroids had significantly lower eosinophil density (62.9 cells per mm2 vs 124.1 cells per mm2, P = 0.006). No association between eosinophil density and biologic use was observed (P = 0.5)., Conclusions: We developed a deep learning algorithm to quantify eosinophils in colonic biopsies. Eosinophil density did not correlate with histologic activity but did correlate with disease extent and corticosteroid use. Future studies applying this algorithm in larger cohorts with longitudinal follow-up are needed to further elucidate the role of eosinophils in ulcerative colitis., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Artificial intelligence [AI] techniques are quickly spreading across medicine as an analytical method to tackle challenging clinical questions. What were previously thought of as highly complex data sources, such as images or free text, are now becoming manageable. Novel analytical methods merge the latest developments in information technology infrastructure with advances in computer science. Once primarily associated with Silicon Valley, AI techniques are now making their way into medicine, including in the field of inflammatory bowel diseases [IBD]. Understanding potential applications and limitations of these techniques can be difficult, in particular for busy clinicians. In this article, we explain the basic terminologies and provide a particular focus on the foundations behind state-of-the-art AI methodologies in both imaging and text. We explore the growing applications of AI in medicine, with a specific focus on IBD to inform the practising gastroenterologist and IBD specialist. Finally, we outline possible future uses of these technologies in daily clinical practice., (© The Author(s) 2021. 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 and Aims: Quantifying placebo rates and the factors influencing them are essential to inform trial design. We provide a contemporary summary of clinical, endoscopic, histological and safety placebo rates in induction and maintenance clinical trials of ulcerative colitis, and identify factors influencing them., Methods: MEDLINE, EMBASE and the Cochrane library were searched from April 2014 to April 2020, updating a prior meta-analysis that searched from inception to April 2014. We included placebo-controlled trials of aminosalicylates, corticosteroids, immunosuppressives, small-molecules and biologics in adults with ulcerative colitis. Placebo rates were pooled using random-effects and mixed-effects meta-regression models to assess the associated study-level., Results: In 119 trials [92 induction, 27 maintenance] clinical, endoscopic and histological remission placebo rates for induction trials were 11% (95% confidence interval [CI] 9-13%), 19% [95% CI 15-23%] and 15% [95% CI 11-19%], respectively; for maintenance trials, clinical and endoscopic placebo remission rates were 18% [95% CI 12-25%] and 20% [95% CI 15-25%], respectively. Higher endoscopic subscore and a higher rate of exposure to prior biologic therapy at enrolment were associated with lower clinical and endoscopic placebo remission rates. Absence of central reading was associated with an increase in placebo endoscopic response and remission rates. More follow-up visits and increasing trial duration were associated with higher clinical placebo rates., Conclusions: Placebo rates in ulcerative colitis trials vary according to the endpoint assessed, whether it is for assessment of response or remission, and whether the trial is designed for induction or maintenance. These contemporary rates across different endpoints and drug classes will help to inform trial design., (© The Author(s) 2021. 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.)

Therapeutic drug monitoring (TDM) with measurement of serum drug and antidrug antibodies (ADAb) is used widely to confirm therapeutic exposure, rule out immunogenicity, and optimize treatment of biologics in patients with inflammatory bowel diseases. 1 A recent genome-wide association study found the variant HLA-DQA1∗05 to increase the risk of development of antibodies against infliximab (IFX) and adalimumab (ADM) 2-fold, regardless of concomitant immunomodulator use. 2 , 3 However, there is currently limited evidence showing whether patients who develop antibodies to 1 anti-tumor necrosis factor (TNF) are prone to develop antibodies to the subsequent anti-TNF. Our aim was to investigate the risk of subsequent antibody development in cases (with ADAb to prior anti-TNF) versus control subjects (without ADAb to prior anti-TNF) using a large cohort of patients with inflammatory bowel diseases who underwent TDM with a drug-tolerant assay., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Therapeutic drug monitoring (TDM) has emerged as a useful tool for optimising the use of biologics, and in particular anti-tumour necrosis factor (anti-TNF) therapy, in inflammatory bowel disease (IBD). However, challenges remain and are hindering the widespread implementation of TDM in clinical practice. These barriers include identification of the optimal drug concentration to target, the lag time between sampling and results, and the proper interpretation of anti-drug antibody titres among different assays. Solutions to overcome these barriers include the harmonisation of TDM assays and the use of point-of-care testing. Other unmet needs include well designed prospective studies and randomised controlled trials focusing on proactive TDM, particularly during induction therapy. Future studies should also investigate the utility of TDM for biologics other than anti-TNF therapies in both IBD and other immune-mediated inflammatory diseases such as rheumatoid arthritis and psoriasis, and the use of pharmacokinetic modelling dashboards and pharmacogenetics towards individual personalised medicine., Competing Interests: Declaration of interests KP has received a lecture fee from Mitsubishi Tanabe Pharma and Physicians Education Resource; a consultancy fee from Prometheus Laboratories; and scientific advisory board fees from ProciseDx and Scipher Medicine Corporation. NVC has received research grants and personal fees from R-Biopharm, Takeda, and UCB; and personal fees from Alimentiv (formerly Robarts Clinical Trials), Celltrion, and Prometheus Laboratories. ASC has received consultancy fees from AbbVie, Janssen, Takeda, Bacainn, Arena Pharmaceuticals, Grifols, Prometheus Laboratories, Samsung, Bristol Myers Squibb, and Pfizer; and research support from Inform Diagnostics. SV has received grants from AbbVie, Johnson and Johnson, Pfizer, and Takeda; consultancy fees from AbbVie, Arena Pharmaceuticals, Avaxia, Boehringer Ingelheim, Celgene, Dr Falk Pharma, Ferring, Galapagos, Genentech (Roche), Gilead, Hospira, Janssen, Mundipharma, Merck Sharp & Dohme, Pfizer, Prodigest, Progenity, Prometheus Biosciences, Alimentiv, Second Genome, Shire, Takeda, Theravance, and Tillots Pharma; and speaker fees from AbbVie, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Janssen, Pfizer, Shire, Takeda, and Tillots Pharma. NA has received a grant from Pfizer and lecture fees from Janssen, Pfizer, and Takeda. TK reports personal fees from Alfresa Pharma, Covidien, Eli Lilly, Ferring Pharmaceuticals, Janssen, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kyaku, Pfizer, Takeda Pharmaceutical, Thermo Fisher Scientific, AbbVie, Astellas, Celltrion, EA Pharma, Nippon Kyaku, Mochida Pharmaceutical, Mitsubishi Tanabe Pharma, Zeria Pharmaceutical, Gilead Sciences, Janssen, and JIMRO; and grants from AbbVie, EA Pharma, Otsuka Holdings, Zeria Pharmaceutical, Kyorin Pharmaceutical, Mochida Pharmaceutical, Thermo Fisher Scientific, Alfresa Pharma, and Nippon Kyaku. WJS reports research grants from AbbVie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, and Theravance Biopharma; consultancy fees from AbbVie, Abivax, Admirx, Alfasigma, Alimentiv, Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Salix (Bausch Health), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech (Roche), Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic, Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, and Zealand Pharma; and stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences, Prometheus Laboratories, Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, and Vivreon Biosciences. PMI reports lecture fees from AbbVie, Bristol Myers Squibb, Celgene, Falk Pharma, Ferring, Gilead, Merck Sharp & Dohme, Janssen, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire, and Warner Chilcott; financial support for research from Merck Sharp & Dohme, Pfizer, and Takeda; and advisory fees from AbbVie, Arena Pharmaceuticals, Genentech, Gilead, Hospira, Janssen, Lilly, Merck Sharp & Dohme, Pfizer, Pharmacosmos, Procise, Prometheus Biosciences, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VHsquared, Vifor Pharma, and Warner Chilcott. MF reports financial support for research from AbbVie, Amgen, Biogen, Janssen, Pfizer, and Takeda; consultancy fees from AbbVie, Boehringer-Ingelheim, Celltrion, Janssen, Lilly, Medtronic, Merck Sharp & Dohme, Pfizer, Sandoz, Takeda, and Thermo Fisher Scientific; and speaker fees from AbbVie, Amgen, Biogen, Boehringer-Ingelheim, Falk, Ferring, Janssen, Lamepro, Merck Sharp & Dohme, Mylan, Pfizer, Sandoz, Takeda, and Truvion Healthcare. PGK has received consultancy and speaker fees from AbbVie, Janssen, Pfizer, Takeda, Ferring, and Novartis; and scientific grants from Takeda and Pfizer. DD has served as a speaker, a consultant, and an advisory board member for Merck Sharp & Dohme, AbbVie, Takeda, Pfizer, Janssen, Amgen, Biogen, and Krka. JL has received unrestricted grants from AbbVie, Almirall, Celgene, Eli Lilly, Janssen-Cilag, LEO Pharma, Novartis, and UCB; speaker fees for AbbVie, Almirall, BMS, Janssen-Cilag, Pfizer, and UCB; and consultancy fees for AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen-Cilag, LEO Pharma, Novartis, and UCB. NK has received speaker fees from Janssen. WA has received consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Dynacare, Janssen, Merck, Novartis, Pfizer, Sandoz, and Takeda. AJY has received consultant or advisory board fees from Prometheus Laboratories, Takeda, Arena Pharmaceuticals, and Bristol Myers Squibb. SD has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Merck Sharp & Dohme, UCB, Ferring, Cellerix, Takeda, Nycomed, Pharmacosmos, Actelion, Alphawasserman, Genentech, Grunenthal, Pfizer, AstraZeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor Pharma, Johnson and Johnson, Nikkiso Europe, and Theravance. MCD has received consultancy fees from Janssen, AbbVie, Pfizer, Takeda, UCB, Celgene, Bristol Myers Squibb, Prometheus Biosciences, Arena Pharmaceuticals, and Lilly; and grant support from AbbVie, Pfizer, and Janssen. LPB has received grant support from AbbVie, Merck Sharp & Dohme, and Takeda; consulting fees from AbbVie, Janssen, Genentech, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Boerhinger-Ingelheim, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestle, Enterome, Allergan, Merck Sharp & Dohme, Roche, Arena Pharmaceuticals, Gilead, Hikma, Amgen, Bristol Myers Squibb, Vifor, Norgine, Mylan, Lilly, Fresenius, Oppilan Pharma, Sublimity Therapeutics, Applied Molecular Transport, OSE Immunotherapeutics, and Enthera; and stock or stock options from Clinical Trials Mobile Application. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Certolizumab pegol (CZP) is effective for moderately to severely active Crohn's disease (CD). Higher plasma concentrations are associated with better outcomes and increased drug clearance is the driver of subtherapeutic CZP concentrations., Objective: We aimed to develop a prediction model incorporating predicted CZP clearance and patient variables to allow estimation of the probability for remission prior to initiating therapy., Methods: A population pharmacokinetic model estimated baseline CZP clearance in patients with CD from nine phase II and III trials. Multivariable prediction models were developed and validated using the PRECiSE 1 and PRECiSE 2 datasets to identify candidate predictors for a composite remission outcome (Crohn's Disease Activity Index ≤ 150 and fecal calprotectin concentration ≤ 250 μg/g) at Weeks 6 or 26. An online clinical decision support tool (CDST) was developed., Results: Baseline predicted CZP clearance ≥ 0.5 L/day was associated with subtherapeutic Week 6 CZP plasma concentrations. Baseline weight (odds ratio [OR] 1.04; 95% confidence interval [CI] 1.02-1.07), calculated CZP clearance (OR 0.92; 95% CI 0.87-0.96), hematocrit (OR 2.55; 95% CI 1.43-4.54), and fecal calprotectin (OR 0.66; 95% CI 0.54-0.80) were associated with Week 6 remission (p ≤ 0.0015 for all predictors). Baseline weight (OR 1.04; 95% CI 1.02-1.07), calculated CZP clearance (OR 0.93; 95% CI 0.88-0.97), and Patient-Reported Outcome-2 (PRO2) (OR 0.93; 95% CI 0.87-0.99) were associated with Week 26 remission (p ≤ 0.033 for all predictors)., Conclusions: Patients who are predicted to have accelerated baseline CZP clearance are at risk of subtherapeutic CZP concentrations. Patient-level probabilities for a composite remission outcome can be predicted for patients with CD by entering commonly available patient- and disease-related factors into an online CDST ( https://premedibd.com ) incorporating predicted CZP clearance., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Although there is interest in developing pharmacotherapies for the treatment of immune checkpoint inhibitor-associated enterocolitis (ICIC), there is currently no consensus on how to optimally measure disease activity in this condition., Aims: To identify all scoring indices used for the measurement of disease activity in ICIC, assess their operating properties, and explore their potential utility as outcome measures., Methods: We searched MEDLINE, EMBASE and the Cochrane Library from inception to November 2020 to identify studies that evaluated disease activity and severity in patients with ICI-associated enterocolitis. These scoring tools could be designed specifically for ICIC or adapted from other diseases, and assessed clinical, endoscopic, or histologic disease activity., Results: Sixty-four studies were included. The Common Terminology Criteria for Adverse Events is commonly used to describe symptoms, although has only been partially validated and was not designed as a disease activity index. Endoscopic and histologic indices used in inflammatory bowel disease have been adopted for ICIC including the Mayo Endoscopic Subscore, Ulcerative Colitis Endoscopic Index of Severity, Simple Endoscopic Score for Crohn's Disease, Nancy Histological Index, Robarts Histopathological Index, and Geboes Score, among others. None of these indices has been validated for use in ICIC, and all lacked content validity and responsiveness., Conclusions: There are no validated clinical, endoscopic, or histologic outcomes to assess disease activity in ICIC. Development and validation of reliable and responsive outcome measures that can be used to measure disease activity will be paramount for both clinical practice and for the development of treatments., (© 2021 John Wiley & Sons Ltd.)