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Background and Aims: Standardising health outcome measurements supports delivery of care and enables data-driven learning systems and secondary data use for research. As part of the Health Outcomes Observatory [H2O] initiative, and building on existing knowledge, a core outcome set [COS] for inflammatory bowel diseases [IBD] was defined through an international modified Delphi method., Methods: Stakeholders rated 90 variables on a 9-point importance scale twice, allowing score modification based on feedback displayed per stakeholder group. Two consecutive consensus meetings were held to discuss results and formulate recommendations for measurement in clinical practice. Variables scoring 7 or higher by ≥80% of the participants, or based on consensus meeting agreement, were included in the final set., Results: In total, 136 stakeholders (45 IBD patients [advocates], 74 health care professionals/researchers, 13 industry representatives, and four regulators) from 20 different countries participated. The final set includes 18 case-mix variables, three biomarkers [haemoglobin to detect anaemia, C-reactive protein and faecal calprotectin to detect inflammation] for completeness, and 28 outcomes (including 16 patient-reported outcomes [PROs] and one patient-reported experience). The PRO-2 and IBD-Control questionnaires were recommended to collect disease-specific PROs at every contact with an IBD practitioner, and the Subjective Health Experience model questionnaire, PROMIS Global Health and Self-Efficacy short form, to collect generic PROs annually., Conclusions: A COS for IBD, including a recommendation for use in clinical practice, was defined. Implementation of this set will start in Vienna, Berlin, Barcelona, Leuven, and Rotterdam, empowering patients to better manage their care. Additional centres will follow worldwide., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Objective: Uniform and standardised quality measurement allows care assessment and improvement. Following a pragmatic consensus method we aimed to agree on a selection of measurable quality indicators that can be used to assess, benchmark and gradually improve inflammatory bowel disease (IBD) care in Flanders., Methods: Of 49 structures, 135 processes and 37 outcome indicators identified through literature, 58 were preselected and reformulated into measurable outcome indicators by four IBD physicians. A larger expert group scored the 58 indicators on a 10-point importance scale twice, endorsed by patient and expert perspectives in between rounds. Additional items could be suggested. A final selection and subset of indicators with room for improvement were agreed upon during a consensus meeting., Results: Fifty indicators received an importance score of 7 or higher by ≥80% of the participants (seven IBD nurses, one abdominal surgeon, one chief medical officer and 31 IBD physicians including two paediatricians). Eight indicators scored highly important by 60-80%, two indicators reintroduced by patients and one newly suggested, were discussed during the consensus meeting. Among 26 participants, eight indicators were agreed to be added to the final selection. Of the 58 selected items, 19 were retained in the improvement subset, related to patient-reported outcomes, use of hospital services and survival, patient characteristics, monitoring of disease activity and remission, endoscopy guidelines, infection prevention, steroid and other medication use., Conclusion: Fifty-eight indicators were selected to assess IBD care in Flanders and a subset of 19 for use in clinical practice to steer quality improvement initiatives., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Disability, an important aspect of disease burden in patients with inflammatory bowel disease [IBD], has been suggested as a valuable clinical endpoint. We aimed to investigate how disease acceptance and perceived control, two psychological predictors of subjective health, are associated with IBD-related disability., Methods: In this cross-sectional study, adult IBD patients from the University Hospitals Leuven received a survey with questions about clinical and demographic characteristics, disease acceptance and perceived control [Subjective Health Experience model questionnaire], and IBD-related disability [IBD Disk]. Multiple linear regressions assessed predictors of IBD-related disability in the total sample and in the subgroups of patients in clinical remission or with active disease., Results: In the total sample (N = 1250, 54.2% female, median [interquartile range: IQR] age 51 [39-61] years, 61.3% Crohn's disease, 34.9% active disease), adding the psychological predictors to the model resulted in an increased explained variance in IBD-related disability of 19% compared with a model with only demographic and clinical characteristics [R2adj 38% vs 19%, p <0.001]. The increase in explained variance was higher for patients in clinical remission [ΔR2adj 20%, p <0.001] compared with patients with active disease [ΔR2adj 10%, p <0.001]. Of these predictors, disease acceptance was most strongly associated with disability in the total sample [β = -0.44, p <0.001], as well as in both subgroups [β = -0.47, p <0.001 and β = -0.31, p <0.001 respectively]. Perceived control was not significantly associated with disability when accounting for all other predictors., Conclusions: Disease acceptance is strongly associated with IBD-related disability, supporting further research into disease acceptance as a treatment target., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. 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.)

Background & Aims: Dysbiosis of the gut microbiota is considered a key contributor to inflammatory bowel disease (IBD) etiology. Here, we investigated potential associations between microbiota composition and the outcomes to biological therapies., Methods: The study prospectively recruited 296 patients with active IBD (203 with Crohn's disease, 93 with ulcerative colitis) initiating biological therapy. Quantitative microbiome profiles of pretreatment and posttreatment fecal samples were obtained combining flow cytometry with 16S amplicon sequencing. Therapeutic response was assessed by endoscopy, patient-reported outcomes, and changes in fecal calprotectin. The effect of therapy on microbiome variation was evaluated using constrained ordination methods. Prediction of therapy outcome was performed using logistic regression with 5-fold cross-validation., Results: At baseline, 65.9% of patients carried the dysbiotic Bacteroides2 (Bact2) enterotype, with a significantly higher prevalence among patients with ileal involvement (76.8%). Microbiome variation was associated with the choice of biological therapy rather than with therapeutic outcome. Only anti-tumor necrosis factor-α treatment resulted in a microbiome shift away from Bact2, concomitant with an increase in microbial load and butyrogen abundances and a decrease in potentially opportunistic Veillonella. Remission rates for patients hosting Bact2 at baseline were significantly higher with anti-tumor necrosis factor-α than with vedolizumab (65.1% vs 35.2%). A prediction model, based on anthropometrics and clinical data, stool features (microbial load, moisture, and calprotectin), and Bact2 detection predicted treatment outcome with 73.9% accuracy for specific biological therapies., Conclusion: Fecal characterization based on microbial load, moisture content, calprotectin concentration, and enterotyping may aid in the therapeutic choice of biological therapy in IBD., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Patients with inflammatory bowel diseases (IBD) sometimes require investigational medicinal therapy in a clinical trial. Before enrollment, patients must meet strict eligibility criteria, hampering recruitment rates. We investigated the rates, causes, and outcomes of screening failure (SF) in a tertiary IBD center., Methods: We reviewed all IBD patients screened for sponsored multicenter phase 1-3 induction studies with available global SF rates between January 2008 and March 2021. We compared our SF rates with the global SF rates. Causes of SF were categorized into disease activity, hematology, chemistry, microbiology, protocol violation, and withdrawal of consent. Patient outcomes were categorized into rescreening for the same trial, screening for another trial, (re)introduction of commercially available therapy, surgery, or watchful waiting., Results: During the study period, 642 local screenings were performed as part of 53 studies. We identified an overall SF rate of 17.1%, compared with 39.2% in the global study population (P < .00001). Causes of SF at our center included ineligible disease activity (36.4%), microbiology (25.5%), protocol violation (16.4%), withdrawal of consent (9.1%), chemistry (6.4%) and hematology (6.4%). Thirty SFs could have been avoided by prescreening that was more thorough. After SF, 34 patients were rescreened for the same trial, 17 screened for another trial, 38 initiated approved therapy, 9 were referred for surgery, and 12 did not receive further therapy., Conclusions: A significant proportion of IBD patients consenting to clinical trials fail their screening. Main causes of SF are ineligible disease activity and abnormal finding on microbiology. Approximately one-fourth of SFs could have been avoided by prescreening that was more thorough., (© The Author(s) 2022. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Adequate infliximab concentrations during induction treatment are predictive for deep remission [corticosteroid-free clinical and endoscopic remission] at 6 months in children with inflammatory bowel diseases [IBD]. Under standard infliximab induction dosing, children often have low infliximab trough concentrations. Model-informed precision dosing [MIPD; i.e. model-based therapeutic drug monitoring] is advocated as a promising infliximab dosing strategy. We aimed to develop and validate an MIPD framework for guiding paediatric infliximab induction treatment., Methods: Data from 31 children with IBD [4-18 years] receiving standard infliximab induction dosing (5 mg/kg at week [w]0, w2 and w6) were repurposed. Eight paediatric population pharmacokinetic models were evaluated. Modelling and simulation were used to identify exposure targets, identify an optimal sampling strategy, and develop a multi-model prediction algorithm for implementation into an MIPD software tool. A role for infliximab clearance monitoring was evaluated., Results: A 7.5 mg/L infliximab concentration target at w12 was associated with 64% probability of deep remission at 6 months. With standard dosing, less than 80% of simulated children <40 kg attained this target. The w12 target was most accurately and precisely achieved by implementing MIPD at w6 using the w6 infliximab concentration [rapid assay required]. The multi-model algorithm outperformed single models when optimizing the w6 dose based on both w2 and w4 concentrations. MIPD using only the w2 concentration resulted in biased and imprecise predictions. Infliximab clearances at w6 and w12 were predictive for deep remission., Conclusions: A freely available, multi-model MIPD tool facilitates infliximab induction dosing and improves deep remission rates in children with IBD., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aim: Pneumocystis jirovecii pneumonia [PJP] is a very rare, potentially life-threatening pulmonary fungal infection that occurs in immunocompromised individuals including patients with inflammatory bowel disease [IBD]. Our aim was to describe immunosuppressive treatment exposure as well as the outcome in IBD patients with PJP., Methods: PJP cases were retrospectively collected through the COllaborative Network For Exceptionally Rare case reports of the European Crohn's and Colitis Organisation. Clinical data were provided through a case report form., Results: In all, 18 PJP episodes were reported in 17 IBD patients [10 ulcerative colitis and seven Crohn's disease]. The median age at PJP diagnosis was 55 years (interquartile range [IQR], 40-68 years]. Two PJP [11.1%] occurred in patients on triple immunosuppression, 10 patients [55.6%] had double immunosuppressive treatment, four patients [22.2%] had monotherapy and two PJP occurred in absence of immunosuppressive treatment [one in a human immunodeficiency virus patient and one in a patient with a history of autologous stem cell transplantation]. Immunosuppressive therapies included steroids [n = 12], thiopurines [n = 10], infliximab [n = 4], ciclosporin [n = 2], methotrexate [n = 1], and tacrolimus [n = 1]. None of the patients diagnosed with PJP had received prophylaxis. All patients were treated by trimethoprim/sulphamethoxazole or atovaquone and an intensive care unit [ICU] stay was required in seven cases. Two patients [aged 71 and 32 years] died, and one patient had a recurrent episode 16 months after initial treatment. Evolution was favourable for the others., Conclusion: This case series reporting potentially fatal PJP highlights the need for adjusted prophylactic therapy in patients with IBD on immunosuppressive therapy., (© The Author(s) 2022. 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: As more therapeutic options with their own characteristics become available for inflammatory bowel disease [IBD], drug development and individual treatment decision-making needs to be tailored towards patients' preferences and needs. This study aimed to understand patient preferences among IBD patients, and their most important treatment outcomes and unmet needs., Methods: This qualitative study consisted of [1] a scoping literature review, [2] two focus group discussions [FGDs] with IBD patients [n = 11] using the nominal group technique, and [3] two expert panel discussions., Results: IBD patients discussed a multitude of unmet needs regarding their symptoms, side-effects, and psychological and social issues for which they would welcome improved outcomes. In particular, IBD patients elaborated on the uncertainties and fears they experienced regarding the possible need for surgery or an ostomy, the effectiveness and onset of action of their medication, and the medication's long-term effects. Furthermore, participants extensively discussed the mental impact of IBD and their need for more psychological guidance, support, and improved information and communication with healthcare workers regarding their disease and emotional wellbeing. The following five characteristics were identified during the attribute grading as most important: prevent surgery, long-term clinical remission, improved quality of life [QoL], occurrence of urgency and improved labour rate., Conclusions: This study suggests that IBD drug development and treatment decision-making are needed to improve IBD symptoms and adverse events that significantly impact IBD patients' QoL. Furthermore, this study underlines patients' need for a shared decision-making process in which their desired treatment outcomes and uncertainties are explicitly discussed and considered., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Objective: To infer potential mechanisms driving disease subtypes among patients with inflammatory bowel disease (IBD), we profiled the transcriptome of purified circulating monocytes and CD4 T-cells., Design: RNA extracted from purified monocytes and CD4 T-cells derived from the peripheral blood of 125 endoscopically active patients with IBD was sequenced using Illumina HiSeq 4000NGS. We used complementary supervised and unsupervised analytical methods to infer gene expression signatures associated with demographic/clinical features. Expression differences and specificity were validated by comparison with publicly available single cell datasets, tissue-specific expression and meta-analyses. Drug target information, druggability and adverse reaction records were used to prioritise disease subtype-specific therapeutic targets., Results: Unsupervised/supervised methods identified significant differences in the expression profiles of CD4 T-cells between patients with ileal Crohn's disease (CD) and ulcerative colitis (UC). Following a pathway-based classification (Area Under Receiver Operating Characteristic - AUROC=86%) between ileal-CD and UC patients, we identified MAPK and FOXO pathways to be downregulated in UC. Coexpression module/regulatory network analysis using systems-biology approaches revealed mediatory core transcription factors. We independently confirmed that a subset of the disease location-associated signature is characterised by T-cell-specific and location-specific expression. Integration of drug-target information resulted in the discovery of several new ( BCL6 , GPR183 , TNFAIP3 ) and repurposable drug targets ( TUBB2A , PRKCQ ) for ileal CD as well as novel targets ( NAPEPLD , SLC35A1 ) for UC., Conclusions: Transcriptomic profiling of circulating CD4 T-cells in patients with IBD demonstrated marked molecular differences between the IBD-spectrum extremities (UC and predominantly ileal CD, sandwiching colonic CD), which could help in prioritising particular drug targets for IBD subtypes., Competing Interests: Competing interests: B Verstockt reports research support for research from Pfizer, speaker’s fees from Abbvie, Biogen, Bristol Myers Squibb, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris and consultancy fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, Bristol Myers Squibb, Galapagos, Guidepont, Ipsos, Janssen, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma and Viatris. SV has received research support from AbbVie, Johnson & Johnson, Pfizer, and Takeda; lecture fees from AbbVie, Centocor, Ferring, Genentech/Roche, Hospira, Johnson & Johnson, Merck Sharp & Dohme, Pfizer, Takeda, and Tillotts; and consulting fees from AbbVie, Abivax, Celgene, Celltrion, Centocor, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Hospira, Johnson & Johnson, Merck Sharp & Dohme, Mundipharma, Pfizer, ProDigest, Prometheus, Second Genome, Takeda, and Tillotts. JS reports lecture fees from Abbvie, Takeda, Janssen, and Nestle Health Sciences. MF reports financial support for: research from AbbVie, Amgen, Biogen, Janssen, Pfizer, Takeda; consultancy from Abbvie, Boehringer-Ingelheim, Lilly, MSD, Pfizer, Sandoz, Takeda, and Thermo Fisher; speaking from Abbvie, Amgen, Biogen, Boehringer-Ingelheim, Falk, Ferring, Janssen, Lamepro, MSD, Mylan, Pfizer, Sandoz, Takeda, and Truvion Healthcare. JC, SaV and PS do not have any conflicts to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Patients with ulcerative colitis (UC) regard rapid onset of action among the most important aspects of their treatment. We used the partial Mayo Clinic Score (pMCS) and component patient-reported subscores to assess the rapidity and sustainability of response to filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, in adults with moderately to severely active UC in the phase 2b/3 SELECTION trial. The association between early symptomatic improvements and health-related quality of life (HRQoL) outcomes was also assessed., Methods: In these post hoc analyses of the double-blinded, randomized, placebo-controlled 58-week SELECTION trial (NCT02914522), rectal bleeding and stool frequency diary data on days 1-15 and pMCS remission and response at multiple time points including weeks 10 and 58 were evaluated. HRQoL was assessed using the Inflammatory Bowel Disease Questionnaire at weeks 10 and 58., Results: Filgotinib 200 mg relative to placebo improved rectal bleeding and stool frequency within 7 days ( P < 0.05). By week 2, greater proportions of filgotinib 200 mg-treated patients than placebo-treated patients achieved pMCS remission (biologic-naive, 15.1% vs 8.0%, P = 0.0410; biologic-experienced, 10.3% vs 4.2%, P = 0.0274). A similar treatment effect was observed at week 58 ( P < 0.0001). Day 7 rectal bleeding and stool frequency subscores were associated with the Mayo Clinic Score response at weeks 10 and 58. Patients in pMCS remission at weeks 10 and 58 had greater improvements in the Inflammatory Bowel Disease Questionnaire score than those not in pMCS remission., Discussion: Filgotinib 200 mg daily resulted in rapid and sustained improvements in both UC symptoms and HRQoL., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Inflammatory bowel disease (IBD) is an emerging global disease characterised by chronic inflammation of the gastrointestinal tract. However, IBD is also manifested by several extraintestinal symptoms which, along with the intestinal symptoms, impact on the mental and emotional well-being of patients. Despite therapeutic advancements, only one-third of the diagnosed patients receiving approved medical treatments achieve short-term to medium-term remission. Consequently, patients who do not get successfully treated might resort to using complementary and alternative approaches to manage their symptoms, with or without consulting their treating clinician. Despite their possible potential, such approaches have various risks stemming from unknown adverse reactions and possible interference with medically approved therapies. In this study, we present the results of a well-performed literature review where we included randomised clinical trials which have assessed the efficacy of complementary approaches and dietary therapy on at least one of the following four outcomes: clinical remission, endoscopic remission, modulation of molecular biomarkers or quality of life metrics. By pointing out intraoutcome and interoutcome concordance, we identified possible candidates for clinical adoption and further study in larger randomised clinical trials covering the broad spectrum of IBD heterogeneity. We finally proposed a patient-centric clinical care model and a series of recommendations for stakeholders, with special attention to complementary approaches and dietary strategies, aimed at achieving holistic remission., Competing Interests: Competing interests: BV reports research support for research from Pfizer, speaker’s fees from Abbvie, Biogen, Bristol Myers Squibb, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris and consultancy fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, Bristol Myers Squibb, Galapagos, Guidepont, Ipsos, Janssen, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma and Viatris. SV has received research support from AbbVie, Johnson & Johnson, Pfizer, and Takeda; lecture fees from AbbVie, Centocor, Ferring, Genentech/Roche, Hospira, Johnson & Johnson, Merck Sharp & Dohme, Pfizer, Takeda, and Tillotts; and consulting fees from AbbVie, Abivax, Celgene, Celltrion, Centocor, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Hospira, Johnson & Johnson, Merck Sharp & Dohme, Mundipharma, Pfizer, ProDigest, Prometheus, Second Genome, Takeda, and Tillotts. JS reports lecture fees from Abbvie, Takeda, Janssen, and Nestle Health Sciences. MF reports financial support for: research from AbbVie, Amgen, Biogen, Janssen, Pfizer, Takeda; consultancy from Abbvie, Boehringer-Ingelheim, Lilly, MSD, Pfizer, Sandoz, Takeda, and Thermo Fisher; speaking from Abbvie, Amgen, Biogen, Boehringer-Ingelheim, Falk, Ferring, Janssen, Lamepro, MSD, Mylan, Pfizer, Sandoz, Takeda, and Truvion Healthcare. JC, SV and PS do not have any conflicts to disclose., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Fatigue is highly prevalent among patients with inflammatory bowel disease (IBD), and only limited treatment options are available. Based on the hypothetical link between low serum tryptophan concentrations and fatigue, we determined the effect of 5-hydroxytryptophan supplementation on fatigue in patients with inactive IBD., Methods: A multicenter randomized controlled trial was performed at 13 Belgian hospitals, including 166 patients with IBD in remission but experiencing fatigue, defined by a fatigue visual analog scale (fVAS) score of ≥5. Patients were treated in a crossover manner with 100 mg oral 5-hydroxytryptophan or placebo twice daily for 2 consecutive periods of 8 weeks. The primary end point was the proportion of patients reaching a ≥20% reduction in fVAS after 8 weeks of intervention. Secondary outcomes included changes in serum tryptophan metabolites, Functional Assessment of Chronic Illness Therapy Fatigue scale, and scores for depression, anxiety, and stress. The effect of the intervention on the outcomes was evaluated by linear mixed modeling., Results: During 5-hydroxytryptophan treatment, a significant increase in serum 5-hydroxytryptophan (estimated mean difference, 52.66 ng/mL; 95% confidence interval [CI], 39.34-65.98 ng/mL; P < .001) and serotonin (3.0 ng/mL; 95 CI, 1.97-4.03 ng/mL; P < .001) levels was observed compared with placebo. The proportion of patients reaching ≥20% reduction in fVAS was similar in placebo- (37.6%) and 5-hydroxytryptophan (35.6%)-treated patients (P = .830). The fVAS reduction (-0.18; 95% CI, -0.81 to 0.46; P = .581) and Functional Assessment of Chronic Illness Therapy Fatigue scale increase (0.68; 95% CI, -2.37 to 3.73; P = .660) were both comparable between 5-hydroxytryptophan and placebo treatment as well as changes in depression, anxiety, and stress scores., Conclusions: Despite a significant increase in serum 5-hydroxytryptophan and serotonin levels, oral 5-hydroxytryptophan did not modulate IBD-related fatigue better than placebo. (Trial Registration: Belgian Federal Agency for Medication and Health Products, EudraCT number: 2017-005059-10 and ClinicalTrials.gov: NCT03574948, https://clinicaltrials.gov/ct2/show/NCT03574948.)., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Although subcutaneous formulations of infliximab CT-P13 and vedolizumab are registered for treating moderate-to-severe inflammatory bowel disease [IBD], many questions on their use remain unanswered. We set up a multi-stakeholder initiative resulting in a position statement., Methods: Based on publicly available data, statements on subcutaneous infliximab and vedolizumab were developed and reviewed by 45 Belgian IBD physicians in a three-round modified Delphi process. During a consensus meeting, input from 16 IBD patients, nine IBD nurses and two clinical pharmacologists was provided and statements were further discussed, modified and scored. Statements achieving agreement by at least 70% of the IBD physicians were accepted., Results: The Delphi process resulted in 79 agreed statements. In patients initiating intravenous therapy, IBD physicians would only consider switching to subcutaneous formulations in patients achieving both clinical and biological response [for Crohn's disease] or both clinical and endoscopic response [for ulcerative colitis]. For patients under maintenance therapy, switching to subcutaneous formulations was only considered in those achieving both clinical and endoscopic response while receiving standard dosing of infliximab or vedolizumab. While awaiting more scientific data, IBD physicians should consider weekly subcutaneous injections or switching back to an intravenous formulation in case of loss of response. Finally, switching to a subcutaneous formulation should always be a shared decision., Conclusions: All stakeholders welcomed subcutaneous infliximab and vedolizumab. However, more scientific data are needed to select the right patients and timing for switching to these newer formulations, and to explore the optimal strategy in case of loss of response., (© The Author(s) 2022. 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.)

Infliximab dosage de-escalation without prior knowledge of drug concentrations may put patients at risk for underexposure and trigger the loss of response. A single-model approach for model-informed precision dosing during infliximab maintenance therapy has proven its clinical benefit in patients with inflammatory bowel diseases. We evaluated the predictive performances of two multi-model approaches, a model selection algorithm and a model averaging algorithm, using 18 published population pharmacokinetic models of infliximab for guiding dosage de-escalation. Data of 54 patients with Crohn's disease and ulcerative colitis who underwent infliximab dosage de-escalation after an earlier escalation were used. A priori prediction (based solely on covariate data) and maximum a posteriori prediction (based on covariate data and trough concentrations) were compared using accuracy and precision metrics and the classification accuracy at the trough concentration target of 5.0 mg/L. A priori prediction was inaccurate and imprecise, with the lowest classification accuracies irrespective of the approach (median 59%, interquartile range 59%-63%). Using the maximum a posteriori prediction, the model averaging algorithm had systematically better predictive performance than the model selection algorithm or the single-model approach with any model, regardless of the number of concentration data. Only a single trough concentration (preferably at the point of care) sufficed for accurate and precise prediction. Predictive performance of both single- and multi-model approaches was robust to the lack of covariate data. Model averaging using four models demonstrated similar predictive performance with a five-fold shorter computation time. This model averaging algorithm was implemented in the TDMx software tool to guide infliximab dosage de-escalation in the forthcoming prospective MODIFI study (NCT04982172)., (© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Biologicals represent the cornerstone of treatment for moderate-to-severe inflammatory bowel diseases (IBD). Many patients cycle between biologicals when encountering loss of response or adverse events., Aim: To assess the occurrence of serious infections and malignancies with exposure to several (classes of) biologicals., Methods: We performed a retrospective cohort study in a tertiary referral centre including consecutive IBD patients exposed to adalimumab, infliximab, ustekinumab or vedolizumab between 1996 and 2019. All serious infections and malignancies, as well as potential confounders, were accounted for., Results: In total, 1575 patients were included with a median (interquartile range) follow-up of 10 (6-16) years and a duration of biological therapy of 71 (39-112) months. Incidence rates of serious infections were 3.4 per 100 patients' years (PY) in the post-biological setting. Serious infections after biological exposure were associated with systemic steroids in monotherapy (hazard ratio 2.96 [95% confidence interval 1.78-4.93], p < 0.0001), combination therapy of systemic steroids and a biological (2.44 [1.37-4.34], p = 0.002), female gender (1.25 [1.04-1.51], p = 0.02), and prior serious infections in the pre-biological setting (1.42 [1.03-1.96], p = 0.03). Malignancy rates were 1.06 per 100PY in the post-biological setting and increased with older age at biological initiation (1.04 [1.02-1.05], p < 0.0001). The risk for serious infections or malignancies was independent of type and number of biologicals to which the patient was exposed., Conclusion: This study shows that the sequential use of biological therapy in IBD does not seem to convey an overall higher risk of serious infections or malignancies, but that underlying more refractory disease seems to increase this risk., (© 2022 John Wiley & Sons Ltd.)

Background and Aims: Disease-related behaviours that may maintain or worsen symptom burden remain largely unexplored in inflammatory bowel disease [IBD]. In this study, we developed and validated an instrument assessing IBD-related, modifiable behaviours and explored which behaviours prospectively correlate with fatigue, a debilitating and common symptom in IBD., Methods: Initially, 72 items reflecting IBD-related behaviours were generated based on literature review and input from clinicians and people diagnosed with IBD. During wave 1, 495 IBD patients rated to what extent each behaviour was applicable to them. Additionally, disease activity, fatigue, IBD-related concerns and psychological variables were assessed. During a follow-up visit 4-12 weeks later [wave 2], a random selection of 92 patients from wave 1 completed the measures assessing the IBD-related behaviours, disease activity and fatigue once more., Results: A principal component analysis with oblique rotation revealed seven components in the 72 IBD behaviours, which could be interpreted as: [1] Avoiding food and activities, [2] Access to toilets, [3] Avoidance of sex, [4] Cognitive avoidance, [5] Not sharing with others, [6] Alternative treatments and [7] Disease management. Each component was reduced to three to five representative items, resulting in a final, 25-item IBD-Bx questionnaire showing good concurrent validity [alphas > 0.63] and reliability. Almost all components were cross-sectionally related to levels of fatigue. Avoiding food and activities and Access to toilets significantly predicted fatigue at wave 2 when controlling for baseline fatigue., Conclusions: The IBD-Bx is a valid and reliable questionnaire of IBD-related behaviours, some of which predict future fatigue burden., (© 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) 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.)

Microbial dysbiosis is an established finding in patients with inflammatory bowel disease (IBD), but host-microbial interactions are poorly understood. We aimed to unravel the effect of microbiota exposure on intestinal epithelial cells. Confluent Transwell® organoid monolayers of eight UC patients and eight non-IBD controls were co-cultured for six hours with microbiota (3x10 8 cells) of UC patients or a healthy volunteer (HV), in the presence or absence of an inflammatory cytokine mix. Transepithelial electrical resistance (TEER), fluorescein isothiocyanate (FITC) dextran measurements, and RNA sequencing were performed on epithelial cells, and 16S rRNA sequencing on microbiota samples before and after co-culture. Transcriptomic response following microbiota exposure was not different between epithelial cells from UC patients or non-IBD controls. Following UC microbiota exposure, but not HV microbiota, a strong decrease in epithelial barrier integrity was observed in both UC and HV epithelial cells by TEER and FITC dextran measurements. Exposure of inflamed epithelium to UC microbiota induced transcriptomic stress pathways including activation of EGR1, MAPK and JAK/STAT signaling, as well as AP-1 family and FOSL transcripts. Stress responses after HV microbiota stimulation were milder. We conclude that not the epithelial cell origin (UC versus non-IBD) but the microbial donor drives transcriptomic responses, as exposure to UC microbiota was sufficient to induce stress responses in all epithelial cells. Further research on therapies to restore the microbial balance, to remove the constant trigger of dysbiosis, is required.

Objectives: To study infliximab (IFX) pharmacokinetics in children with inflammatory bowel disease (IBD) during induction therapy to predict outcome and explore if other covariates influenced outcome., Study Design: All children with IBD starting IFX therapy (5 mg/kg at weeks 0, 2, 6, and 12) for active luminal disease from May 2017 to May 2019 were included and followed prospectively. Patients were sampled at multiple timepoints during induction (trough concentrations and peak concentration at weeks 0, 2, 6, and 12, and intermediate concentration at weeks 1-4). IFX concentrations and cumulative drug exposure were correlated with outcome at 6 months. Endoscopic remission was defined as Simple Endoscopic Score for Crohn's Disease of <3 or Mayo endoscopic subscore of 0, and deep remission as endoscopic with clinical remission (Pediatric Ulcerative Colitis Activity Index/Pediatric Crohn's Disease Activity Index of <10)., Results: There were 252 serum induction concentrations obtained from 32 patients (81% on concomitant thiopurines). Children in endoscopic remission (all in deep remission) at 6 months had significantly higher drug concentrations from week 4 onward. A receiver operating characteristics curve analysis identified IFX trough concentrations at week 12 of ≥5.0 μg/mL and area under the curve at weeks 0-12 of ≥4056.0 μg∗day/mL as the minimal target to achieve endoscopic remission at 6 months (area under the receiver operating characteristics curve, 0.796 [95% CI, 0.62-0.97] and area under the receiver operating characteristics curve, 0.778 [95% CI, 0.61-0.94], respectively). In addition, our findings suggest that proteomic analysis may help to understand IFX response., Conclusions: Higher IFX exposure during induction therapy in pediatric patients with IBD is associated with significantly better endoscopic and deep remission rates at 6 months. Drug concentrations differentiate remitters from nonremitters from week 4 after induction onward., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Less than 50% of patients with inflammatory bowel diseases (IBD) receiving monoclonal antibody (mAb) therapy achieve endoscopic remission. Poor outcomes may indicate a need for dose optimization. During therapeutic drug monitoring (TDM), drug concentrations are measured, and when found too low, dosage regimen escalations are performed. To date, benefits of TDM of mAbs in patients with IBD are uncertain., Areas Covered: This review presents an overview of what clearance monitoring is, how it can be performed, and why and when it may be valuable in treating patients with IBD. Virtual patients were used for illustration. A literature search was performed to summarize current evidence for clearance monitoring in IBD and other disease settings., Expert Opinion: During clearance monitoring, mAb clearance is calculated and monitored over time. Higher mAb clearance in patients with IBD has been associated with higher target load (target-mediated drug disposition), protein-losing enteropathy (fecal drug loss), and immunogenicity. Although not prospectively confirmed, clearance monitoring might facilitate identification of (yet) asymptomatic disease flares or presence of (yet) undetectable anti-drug antibodies. Furthermore, clearance monitoring may be used to predict treatment outcomes. Whether dosage regimen adjustments can modify the clearance time course and the treatment outcome is to be determined.

Background: Multiple investigations are available to aid the diagnosis and monitoring of disease activity in inflammatory bowel disease (IBD). Fecal calprotectin (FC) is an established surrogate for intestinal inflammatory activity. Therapeutic drug monitoring (TDM) including thiopurine metabolites, anti-tumor necrosis factor (TNF) levels and antidrug antibody measurements are a step toward personalized medicine in IBD, but face access barriers. We aimed to assess test availability and barriers for these investigations in European practice., Methods: Five-hundred questionnaires were distributed to workshop participants at the 11th Congress of the European Crohn's and Colitis Organisation (ECCO). Access to FC, TDM for thiopurines and anti-tumor necrosis factor agents, as well as factors associated with usage and barriers to access were recorded., Results: Responses were obtained from 195 attendees from 38 countries across a range of practices, healthcare settings and levels of experience. FC was available to 92.3% while access to anti-TNF (78.9%, P = 0.02 vs.  thiopurine TDM, P = 0.0002 vs.  FC) and thiopurine TDM (67.7%, P = 0.0001) were less widespread. Cost was a frequently cited barrier to test access or usage, with access having a significant West-East and North-South divide across all three investigations. The strongest independent predictor of access to all tests was healthcare spending per capita (P = 0.005 for FC; P < 0.0001 for both TDM)., Conclusion: FC, anti-TNF and thiopurine TDM are increasingly incorporated as part of routine practice in IBD care across Europe and have the potential to impact positively on patient care. However, access barriers remain of which we found test cost the most significant with the investment required to reduce these barriers., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Few data are available regarding the combination of biologics or small molecules in inflammatory bowel disease (IBD) patients. We report safety and efficacy of such combinations through a retrospective multicentre series., Methods: Combination therapy was defined as the concomitant use of two biologics or one biologic with a small molecule. Patient demographics, disease characteristics and types of combinations were recorded. Safety was evaluated according to the occurrence of serious infection, opportunistic infection, hospitalisation, life-threatening event, worsening of IBD or immune-mediated inflammatory diseases (IMID), cancer and death. Efficacy was evaluated as the physician global assessment of the combination and comparison of clinical/endoscopic scores of IBD/IMID activity prior and during combination., Results: A total of 104 combinations were collected in 98 patients. Concomitant IMID were present in 41 patients. Reasons for starting combination therapy were active IBD (67%), active IMID or extra-intestinal manifestations (EIM) (22%), both (10%) and unclassified in 1. Median duration of combination was 8 months (interquartile range 5-16). During 122 patient-years of follow-up, 42 significant adverse events were observed, mostly related to uncontrolled IBD. There were 10 significant infections, 1 skin cancer and no death. IBD disease activity was clinically improved in 70% and IMID/EIM activity in 81% of the patients. Overall, combination was continued in 55% of the patients., Conclusions: Combination of biologics and small molecules in patients with IBD and IMID/EIM seems to be a promising therapeutic strategy but is also associated with a risk of opportunistic infections or infections leading to hospitalisation in 10%., (© 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Introduction and Aim: Thiopurines - although used frequently in inflammatory bowel diseases (IBD) - carry a significant safety risk, particularly with prolonged use and/or in elderly patients. Stopping therapy, however, may trigger relapses. We assessed the long-term outcome of elderly IBD patients after discontinuation of thiopurine while in clinical remission., Methods: Electronic medical records from IBD patients >60 years whoever received thiopurine treatment were reviewed. Patients who stopped thiopurine after 60 years of age while in clinical and/or endoscopic remission were included. Long-term outcomes included duration of clinical remission, time to clinical relapse, and development of malignancy., Results: In total, 142 patients receiving thiopurines while they were >60 years were identified. Ninety-one patients stopped thiopurines at >60years while in clinical and/or endoscopic remission. After a median follow-up of 66 months, 28 (30.8%) developed a clinical relapse. The median duration of TP therapy in relapses was significantly shorter than in patients who remained in remission (median 45 vs. 103 months, respectively; p  = .005). After relapse, 10 patients started a biological (36%) and seven received steroids (25%). Surgery was needed in 36% of patients (10/28). Overall, 26 malignancies developed., Conclusion: Discontinuation of TP in elderly IBD patients in clinical and/or endoscopic remission results in sustained clinical remission in two-thirds of patients. Patients who flare can mostly be rescued with biologicals although one-third necessitate surgery. A significant proportion of patients developed malignancies under but also after thiopurines discontinuation, indicating that these patients necessitate a continued close follow-up. Decision-making in this vulnerable subgroup of patients remains difficult.

Background: Oncostatin M (OSM) has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and as a marker for nonresponsiveness to anti-tumor necrosis factor (TNF) therapy. We further unraveled the potential of OSM and related receptors as markers of diagnosis, prognosis, and therapy response in IBD., Methods: We collected inflamed mucosal biopsies and serum from patients with Crohn disease (CD) and with ulcerative colitis: (1) newly diagnosed patients who were treatment-naïve, (2) patients initiating anti-TNF or (3) vedolizumab therapy, (4) postoperative patients with CD, and (5) multiple-affected families with IBD including unaffected first-degree relatives (FDRs). We measured the gene expression of mucosal OSM and its receptors OSMR/LIFR and co-receptor IL6ST, and the protein expression of serum OSM. Statistical significance was defined as P < 0.05., Results: Newly diagnosed patients showed significantly increased mucosal OSM/OSMR compared with control patients, with the highest enrichment for OSM (fold change [FC] >17.9). Likewise, ileal OSM/OSMR were significantly upregulated in postoperative recurrent CD. Serum OSM was increased in newly diagnosed patients and postoperative patients with recurrent CD (FC ≥ 2.6). In families with IBD, higher serum levels were observed in FDRs than in control families (FC = 2.2). Furthermore, elevated colonic OSM/OSMR (but not serum OSM) were associated with the early need for biologic therapy (FC ≥ 1.9), and higher OSM was also predictive of primary nonresponse to both anti-TNF and vedolizumab therapy (FC ≥ 2.4). Immunohistochemistry highlighted mucosal OSM expression in macrophages., Conclusions: We found that OSM is a diagnostic biomarker in the tissue and serum not only of newly diagnosed patients with IBD and postoperative patients with recurrent CD but also of their FDRs. Higher colonic OSM levels are furthermore associated with poor prognosis and with primary nonresponse to biologic therapies. Therefore, OSM could guide clinical decision-making., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Aims: Controversies regarding infliximab treatment in elderly patients with inflammatory bowel diseases remain. We evaluated the effect of patient's age on infliximab exposure, efficacy and safety., Methods: Retrospective case-control data of patients receiving infliximab induction treatment were analysed. A population pharmacokinetic model was developed to estimate individual pharmacokinetic parameters. A logistic regression model was used to investigate the effect of exposure on endoscopic remission. Repeated time-to-event models were developed to describe the hazard of safety events over time., Results: A total of 104 patients (46 elderly, ≥65 years) were included. A two-compartment population pharmacokinetic model with linear elimination adequately described the data. Infliximab clearance decreased with older age, higher serum albumin, lower fat-free mass, lower C-reactive protein and absence of immunogenicity. Yet, infliximab exposure was not significantly different between elderly and nonelderly. Regardless of age, an infliximab trough concentration at week (w)14 of 15.6 mg/L was associated with a 50% probability of attaining endoscopic remission between w6 and w22. Infliximab exposure during induction treatment was not a risk factor of (severe) adverse events. The hazard of severe adverse events and malignancy increased by 2% and 7%, respectively, with increasing year of age. Concomitant immunomodulator use increased the hazard of infection by 958%, regardless of age., Conclusions: Elderly patients attained infliximab exposure and endoscopic remission similarly to nonelderly patients. Therefore, the same infliximab trough concentration target can be used in therapeutic drug monitoring. The hazards of severe adverse events and malignancy increased with age, but not with infliximab exposure., (© 2021 British Pharmacological Society.)

The gut microbiota appears to play a central role in health, and alterations in the gut microbiota are observed in both forms of inflammatory bowel disease [IBD], namely Crohn's disease and ulcerative colitis. Yet, the mechanisms behind host-microbiota interactions in IBD, especially at the intestinal epithelial cell level, are not yet fully understood. Dissecting the role of host-microbiota interactions in disease onset and progression is pivotal, and requires representative models mimicking the gastrointestinal ecosystem, including the intestinal epithelium, the gut microbiota, and immune cells. New advancements in organoid microfluidics technology are facilitating the study of IBD-related microbial-epithelial cross-talk, and the discovery of novel microbial therapies. Here, we review different organoid-based ex vivo models that are currently available, and benchmark their suitability and limitations for specific research questions. Organoid applications, such as patient-derived organoid biobanks for microbial screening and 'omics technologies, are discussed, highlighting their potential to gain better mechanistic insights into disease mechanisms and eventually allow personalised medicine., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

The expression of Triggering Receptor Expressed on Myeloid cells ( TREM)-1 has been described as a predictive marker for anti-Tumor Necrosis Factor (TNF)-α monoclonal antibody (mAb) therapy responsiveness in patients with inflammatory bowel disease (IBD). Here we investigated expression of TREM-1 specifically in CD14+ monocytes in relation to anti-TNF response. The pretreatment TREM-1 expression levels of CD14+ monocytes of Crohn's disease (CD) patients were predictive of outcome to anti-TNF mAb therapy, with low TREM-1 expression associated with response to anti-TNF. FACSorting of CD14+ monocytes with different TREM-1 levels showed that differentiation towards regulatory CD206+ M2 type macrophages by anti-TNF was suppressed in CD14+ monocytes with high TREM-1 expression. Activity of the Fcγ-Receptor and autophagy pathway, both necessary for M2 type differentiation and the response to anti-TNF, were decreased in CD14+ monocytes with high expression of TREM-1. We confirmed that the activity of the Fcγ-Receptor pathway was decreased in the CD patients that did not respond to anti-TNF therapy and that it was negatively correlated with TREM-1 expression levels in the CD patient cohort. In conclusion, our results indicate that TREM-1 expression levels in CD14+ monocytes associate with decreased autophagy and FcγR activity resulting in decreased differentiation to M2 type regulatory macrophages upon anti-TNF mAb treatment, which may explain anti-TNF non-response in IBD patients with high expression levels of TREM-1 ., Competing Interests: MF received research grants from Amgen, Biogen, Janssen, Pfizer, Takeda, consultancy fees from Abbvie, Boehringer-Ingelheim, Janssen, MSD, Pfizer, Sandoz, Takeda, and speakers fees from Abbvie, Amgen, Biogen, Boehringer-Ingelheim, Falk, Ferring, Janssen, Lamepro, MSD, Mylan, Pfizer, Takeda. SV received research grants from MSD, AbbVie, Takeda, Pfizer, Janssen, consultancy fees from AbbVie, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer Inc, Galapagos, Mundipharma, Hospira, Celgene, Second Genome, Progenity, Lilly, Arena, GSK, Amgen, Ferring, Gilead and Janssen, and speakers fees from AbbVie, MSD, Takeda, Ferring, Hospira, Pfizer, Janssen, and Tillots. BV reports financial support for research from Pfizer; lecture fees from Abbvie, Biogen, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda and Truvion; consultancy fees from Janssen, Guidepont and Sandoz; all outside of the submitted work. MW received research grants from GlaxoSmithKline, Boehringer Ingelheim and Stryker and speakers fees from Takeda and Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Prins, Verstockt, Ferrante, Vermeire, Wildenberg and Koelink.)

Objectives: Worry is the most common psychological complaint among patients with Inflammatory Bowel Disease (IBD). This study aimed to translate and test the psychometric properties the Rating Form of IBD Patient Concerns (RFIPC) among Dutch-speaking patients with IBD in Belgium. It also aimed to describe worries and concerns, and to examine possible differences in worry patterns between patients with different disease types and disease activities., Methods: The RFIPC was translated into Dutch following the guidelines of the Rome Foundation and was completed by patients with Crohn's disease (CD, n  = 336) and ulcerative colitis (UC, n  = 160). To test concurrent validity, the Depression Anxiety Stress Scales (DASS-21) were used. Factor structure was examined with confirmatory factor analysis., Results: The four-factor structure including subscales 'impact of the disease', 'sexual intimacy', 'complications of the disease' and 'body stigma' was confirmed in the Dutch sample. All factors had high internal consistency (>.70). Correlations with DASS-21 suggest good concurrent validity, all r s>.30, p s<.001. No differences in the RFIPC scores were observed between patients with CD and UC. Patients with active disease (53%) had higher scores than patients in remission (47%). Across all groups, the order of top concerns was consistent and included worries about energy level, side effects of medication, having an ostomy bag/surgery, and uncertain nature of the disease., Conclusions: The Dutch version of the RFIPC is a valid and reliable measure of IBD-specific worries and concerns which can be used in both research and clinical settings.

Background and Goals: Active inflammatory bowel diseases (IBD) represent an independent risk factor for venous thromboembolism. The authors investigated the hemostatic profile of IBD patients before and after induction treatment with infliximab, vedolizumab, and methylprednisolone., Study: This prospective study included 62 patients with active IBD starting infliximab, vedolizumab, and/or methylprednisolone, and 22 healthy controls (HC). Plasma was collected before (w0) and after induction therapy (w14). Using a clot lysis assay, amplitude (marker for clot intensity), time to peak (Tmax; marker for clot formation rate), area under the curve (AUC; global marker for coagulation/fibrinolysis), and 50% clot lysis time (50%CLT; marker for fibrinolytic capacity) were determined. Plasminogen activator inhibitor-1 (PAI-1) and fibronectin were measured by ELISA. Clinical remission was evaluated at w14., Results: At baseline, AUC, amplitude, and 50%CLT were significantly higher in IBD patients as compared with HC. In 34 remitters, AUC [165 (103-229)% vs. 97 (78-147)%, P=0.001], amplitude [119 (99-163)% vs. 95 (82-117)%, P=0.002], and 50%CLT [122 (94-146)% vs. 100 (87-129)%, P=0.001] decreased significantly and even normalized to the HC level. Vedolizumab trough concentration correlated inversely to fibronectin concentration (r, -0.732; P=0.002). The increase in Tmax for infliximab-treated remitters was significantly different from the decrease in Tmax for vedolizumab-treated remitters (P=0.028). The 50%CLT increased (P=0.038) when remitters were concomitantly treated with methylprednisolone., Conclusions: Control of inflammation using infliximab most strongly reduced those parameters that are associated with a higher risk of venous thromboembolism.

Patients with Crohn disease (CD) and ulcerative colitis (UC) suffer from chronic relapsing intestinal inflammation. While many studies focused on adaptive immunity, less is known about the role of innate immune cells in these diseases. Innate lymphoid cells (ILCs) are recently identified cells with a high cytokine-producing capacity at mucosal barriers. The aim was to study the impact of biological treatment on ILC in CD and UC. Patients initiating anti-tumor necrosis factor (TNF), ustekinumab, or vedolizumab treatment were prospectively followed up and peripheral and intestinal ILCs were determined. In the inflamed gut tissue of patients with inflammatory bowel disease, we found an increase of ILC1 and in immature NKp44 - ILC3, whereas there was a decrease of mature NKp44 + ILC3 when compared to healthy controls (HCs). Similar but less pronounced changes in ILC1 were observed in blood, whereas circulating NKp44 - ILC3 were decreased. Fifteen percent of CD patients had NKp44 + ILC3 in blood and these cells were not detected in blood of HCs or UC patients. Therapy with three different biologicals (ustekinumab targeting the IL-12/23 cytokines, anti-TNF and vedolizumab) partly restored intestinal ILC subset equilibrium with a decrease of ILC1 (except for ustekinumab) and an increase of NKp44 + ILC3. Anti-TNF also mobilized more NKp44 + ILC3 in circulation. As ILC1 are proinflammatory cells and as NKp44 + ILC3 contribute to homeostasis of intestinal mucosa, the observed effects of biologicals on ILCs might contribute to their clinical efficacy., (Copyright © 2020 Creyns, Jacobs, Verstockt, Cremer, Ballet, Vandecasteele, Vanuytsel, Ferrante, Vermeire, Van Assche, Ceuppens and Breynaert.)

The emergence of biosimilars is generally considered as an opportunity to guarantee accessibility to affordable treatments and to enhance financial sustainability of national health systems. Since 2017, five biosimilars of adalimumab were approved by the European Medicines Agency [EMA] for use in inflammatory bowel disease: ABP 510, SB5, GP2017, FKB327, and MSB11022. In this position statement, the available efficacy and safety data of the different adalimumab biosimilars in immune-mediated inflammatory diseases are summarised. Furthermore, the Belgian IBD research group [BIRD] formulates statements concerning the use of adalimumab biosimilars in inflammatory bowel disease., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: We aimed to identify biomarkers that might be used to predict responses of patients with inflammatory bowel diseases (IBD) to vedolizumab therapy., Methods: We obtained biopsies from inflamed colon of patients with IBD who began treatment with vedolizumab (n = 31) or tumor necrosis factor (TNF) antagonists (n = 20) and performed RNA-sequencing analyses. We compared gene expression patterns between patients who did and did not enter endoscopic remission (absence of ulcerations at month 6 for patients with Crohn's disease or Mayo endoscopic subscore ≤1 at week 14 for patients with ulcerative colitis) and performed pathway analysis and cell deconvolution for training (n = 20) and validation (n = 11) datasets. Colon biopsies were also analyzed by immunohistochemistry. We validated a baseline gene expression pattern associated with endoscopic remission after vedolizumab therapy using 3 independent datasets (n = 66)., Results: We identified significant differences in expression levels of 44 genes between patients who entered remission after vedolizumab and those who did not; we found significant increases in leukocyte migration in colon tissues from patients who did not enter remission (P < .006). Deconvolution methods identified a significant enrichment of monocytes (P = .005), M1-macrophages (P = .05), and CD4+ T cells (P = .008) in colon tissues from patients who did not enter remission, whereas colon tissues from patients in remission had higher numbers of naïve B cells before treatment (P = .05). Baseline expression levels of PIWIL1, MAATS1, RGS13, and DCHS2 identified patients who did vs did not enter remission with 80% accuracy in the training set and 100% accuracy in validation dataset 1. We validated these findings in the 3 independent datasets by microarray, RNA sequencing and quantitative PCR analysis (P = .003). Expression levels of these 4 genes did not associate with response to anti-TNF agents. We confirmed the presence of proteins encoded by mRNAs using immunohistochemistry., Conclusions: We identified 4 genes whose baseline expression levels in colon tissues of patients with IBD associate with endoscopic remission after vedolizumab, but not anti-TNF, treatment. We validated this signature in 4 independent datasets and also at the protein level. Studies of these genes might provide insights into the mechanisms of action of vedolizumab., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Telemonitoring can be implemented to enhance disease monitoring and ultimately reduce the number of outpatient visits and associated costs. We developed an in house IBD mobile app and established a proof of concept study to demonstrate the effectiveness and accuracy of the telemonitoring tool for monitoring of disease activity. Methods: An IBD mobile app was designed through close collaboration between the Information Technology and Gastroenterology department of University Hospitals of Leuven. The study was proposed to all patients in remission under stable biological therapy visiting the outpatient clinic. During one-year follow-up, patients completed weekly and monthly questionnaires on their mobile device or on a website. Entered data were directly sent to the electronic medical record. Predefined red flags or alerts, generated by the answers to the questionnaires, were monitored daily. Results: The pilot study in 45 patients demonstrated accurate monitoring of disease activity with fast intervention during flares. During the 12-months follow-up period, an alert for disease activity was generated for 9 different patients out of 1296 completions of the questionnaire. Symptoms resolved spontaneously in 8 patients. One patient reported consecutive PRO-2 increase, endoscopy confirmed an IBD flare and therapy was switched. For the remaining 36 included patients, no alerts indicating disease activity increase were reported. Median compliance to all weekly and monthly questionnaires during 1 year was 52% (IQR: 24-91). Conclusions: We developed the mynexuzhealth IBD app with full integration in the electronic medical record. The app enabled continuous remote monitoring and showed accurate detection of flares.

Inflammatory bowel disease (IBD) affects patients during their peak reproductive years. This raises important questions, in both patients and healthcare providers, regarding conception, pregnancy, and breastfeeding. Lack of information and insufficient communication among healthcare providers can leave patients with limited information and even contradictory advice. Given the fact that pregnant and/or breastfeeding IBD patients are excluded from clinical studies the evidence on many questions related to pregnancy and postpartum period is limited. However, there exists increasing data from case series and cohort studies that allows to provide clinical guidance. The overarching concept is that optimizing the mother's health is critical for optimizing the health of the unborn child and benefit of continuing medical therapy in IBD during pregnancy outweighs possible risks in most instances. This paper provides an up-to-date systematic review of the literature on IBD in pregnancy and proposes guidance to questions frequently encountered by healthcare professionals., (© 2020 S. Karger AG, Basel.)

Background: Women with inflammatory bowel diseases (IBD) often receive biologicals during pregnancy to maintain disease remission. Data on outcome of vedolizumab-exposed pregnancies (VDZE) are sparse., Aims: To assess pregnancy and child outcomes of VDZE pregnancies and to compare these results to anti-TNF exposed (TNFE) or both immunomodulatory and biologic unexposed (CON IBD) pregnancies., Methods: A retrospective multicentre case-control observational study was performed., Results: VDZE group included 79 pregnancies in 73 IBD women. The TNFE and CON IBD group included 186 pregnancies (162 live births) in 164 IBD women and 184 pregnancies (163 live births) in 155 IBD women, respectively. At conception, cases more often had active disease ([VDZE: 36% vs TNFE: 17%, P = .002] and [VDZE: 36% vs CON IBD: 24%, P = .063]). No significant difference in miscarriage rates were found between groups (VDZE and TNFE: 16% vs 13%, P = .567; VDZE and CON IBD: 16% vs 10%, P = .216). In live-born infants, median gestational age and birthweight were similar between groups. Median Apgar score at birth was numerically equal. Prematurity was similar in the VDZE group compared to the control groups, even when correcting for disease activity during pregnancy. The frequency of congenital anomalies was comparable between groups as were the percentages of breastfed babies. During the first year of life, no malignancies were reported and infants' infection risk did not significantly differ between groups., Conclusion: No new safety signal was detected in VDZE pregnancies although larger, prospective studies are required for confirmation., (© 2019 John Wiley & Sons Ltd.)

Background and Study Aims: Quality of care is a very timely topic in medicine. We designed a questionnaire to measure perceived quality of care and to explore areas of improvement., Patients and Methods: In this prospective study a questionnaire was developed and administered to all patients with inflammatory bowel disease participating in a randomized clinical trial. The questionnaire was based on validated surveys and supplemented with novel, relevant questions. Factors associated with (poor) quality of care were identified., Results: Between October 2016 and January 2017, all 107 patients participating in a randomized controlled trial completed the questionnaire (63% male, 76% ulcerative colitis, median age of 47 years). The median satisfaction score was 9 out of 10. Areas of improvement were that too little attention was paid to the disease impact on family and work, dietary and exercise pattern, daily activities and quality of life. Multivariate analysis showed that clinical remission [5.77 (2.03-16.39), p=0.001] was a predictor of good quality of care., Conclusions: In this large IBD trial bureau, inflammatory bowel disease patients were very satisfied with the quality of care. Domains for quality improvement, such as attention to the impact of IBD on family and work, were identified., (© Acta Gastro-Enterologica Belgica.)

Background: The incidence of Clostridium difficile infection (CDI) has been rising in the overall population as well as in patients with inflammatory bowel disease (IBD). However, the incidence of CDI in IBD may be changing owing to alterations in medical therapies., Objective: The aim of this study was to establish the incidence of CDI in IBD over the past two decades and compare risk factors, disease characteristics and outcomes between IBD and non-IBD patients., Patients and Methods: In this retrospective case-control study, the incidence of CDI in IBD was followed for 18 years. The electronic database of our centre was reviewed for all stool samples received from patients admitted to gastroenterology wards or visiting the outpatient clinic. Diagnosis of CDI was based on diagnostic criteria that evolved throughout the years., Results: IBD patients (n=44) with CDI were found to be younger (P=0.0001), have less cardiovascular comorbidity (P=0.023), fewer prior hospitalizations (P=0.009) and fewer prior antibiotic use (P=0.005). More IBD patients were on biologic therapy (P=0.0001) or steroids (P=0.001) but less likely taking proton pump inhibitors (P=0.001). The number of stool testing per year increased as well as the median number of positive stool samples for CDI (2% in 2000-2008 to 3% in 2009-2017, P=0.032). Pseudomembranes were only seen in non-IBD patients (28%, P=0.048). There was no difference in the choice of antibiotics between IBD and non-IBD patients [metronidazole (36 vs. 51%) and vancomycin (36 vs. 26%), P=0.090 and 0.190]. The 1-year mortality rate was lower in IBD patients compared with non-IBD patients (0 vs. 32%, P=0.0001)., Conclusion: In the past two decades, the incidence of CDI in IBD and non-IBD patients has increased. However, the overall outcome of CDI in IBD patients was favourable compared with non-IBD patients.

Background: Rising evidence demonstrates that there are no differences in efficacy and safety between infliximab (IFX) originator and IFX biosimilar CT-P13 in the treatment of inflammatory bowel diseases (IBDs). However, most data are derived from adult patients, and data on pharmacokinetics are limited. The authors evaluated long-term IFX trough levels, immunogenicity, and remission rates in children with IBD who switched from IFX originator to biosimilar CT-P13., Methods: In this single-center study, all children with Crohn disease and ulcerative colitis receiving maintenance IFX therapy were switched from originator to biosimilar CT-P13. Demographics, disease activity indices, and IFX drug levels were collected from 6 months before (baseline) till 6 months after switching to CT-P13. All data are presented as median (interquartile range)., Results: A total of 42 children (26 Crohn disease and 16 ulcerative colitis), with a median duration on IFX originator of 13.5 (6.8-35.5) months before switching to CT-P13, were included. No significant changes in IFX trough levels occurred after switching. The median baseline IFX trough level was 5.7 mcg/mL (3.8-9.3) versus 6.5 mcg/mL (3.9-8.6) at month 6 after switching (P = 0.900). Antibodies to IFX appeared in one patient after switching. The proportion of patients in clinical and/or biological remission did not significantly change after switching (all P > 0.05). No significant changes were observed in C-reactive protein, erythrocyte sedimentation rate, albumin, weight, and body mass index after the switch. Safety profile was also comparable., Conclusions: Pediatric patients with IBD on IFX originator can be successfully switched during maintenance to biosimilar CT-P13 without affecting efficacy, pharmacokinetics, immunogenicity, or safety.

Background: With the changed therapeutic armamentarium for Crohn's disease (CD) and ulcerative colitis (UC), biomarkers predicting treatment response are urgently needed. We studied whole blood and mucosal expression of genes previously reported to predict outcome to anti-TNF therapy, and investigated if the signature was specific for anti-TNF agents., Methods: We prospectively included 54 active IBD patients (24CD, 30UC) initiating anti-TNF therapy, as well as 22 CD patients initiating ustekinumab and 51 patients initiating vedolizumab (25CD, 26UC). Whole blood expression of OSM, TREM1, TNF and TNFR2 was measured prior to start of therapy using qPCR, and mucosal gene expression in inflamed biopsies using RNA-sequencing. Response was defined as endoscopic remission (SES-CD ≤ 2 at week 24 for CD and Mayo endoscopic sub-score ≤ 1 at week 10 for UC)., Findings: Baseline whole blood TREM1 was downregulated in future anti-TNF responders, both in UC (FC = 0.53, p = .001) and CD (FC = 0.66, p = .007), as well as in the complete cohort (FC = 0.67, p < .001). Receiver operator characteristic statistics showed an area under the curve (AUC) of 0.78 (p = .001). A similar accuracy could be achieved with mucosal TREM1 (AUC 0.77, p = .003), which outperformed the accuracy of serum TREM1 (AUC 0.58, p = .31). Although differentially expressed in tissue, OSM, TNF and TNFR2 were not differentially expressed in whole blood. The TREM1 predictive signal was anti-TNF specific, as no changes were seen in ustekinumab and vedolizumab treated patients., Interpretation: We identified low TREM-1 as a specific biomarker for anti-TNF induced endoscopic remission. These results can aid in the selection of therapy in biologic-naïve patients., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Vedolizumab is an IgG1 anti-α4β7 integrin antibody approved for the treatment of inflammatory bowel diseases [IBD], but without clear safety data during conception, pregnancy and nursing. Animal studies showed that mucosal vascular addressin cell adhesion molecule 1 [MAdCAM-1] is expressed by maternal vessels in the placenta and recruits α4β7-expressing cells that are considered important for maternal/fetal tolerance. Blocking this interaction by vedolizumab might affect this process. We aimed to evaluate pregnancy outcomes in vedolizumab-treated female IBD patients., Methods: We conducted a retrospective, multicentre Belgian observational study. Details on disease activity, prenatal complications, delivery and neonatal outcome were collected through a case report form., Results: Twenty-four pregnancies were reported. Five women had active disease at conception and one patient flared during pregnancy. There were 23 live births. Complications were observed in 25% of pregnancies [premature rupture of membranes, pre-eclampsia, miscarriage, elective termination and stillbirth] and in 35% of infants [prematurity, intra-uterine growth retardation, small for gestational age and congenital malformations including hip dysplasia, pulmonary valve stenosis and Hirschprung's disease]. Vedolizumab was continued throughout pregnancy in two females and stopped in the 1st and 2nd trimester in five and 16 patients, respectively. For live born children, the median [interquartile range] gestational age, weight and Apgar score 5 min after birth were 39 [37-39.6] weeks, 3270 [3080-3585] grams and 10 [9-10], respectively., Conclusions: Although several complications were observed, both in mothers and in newborns, no firm conclusions can be drawn. Awaiting prospective and controlled registries, vigilance and strict follow-up of pregnant patients treated with vedolizumab seems mandatory.

Background: Mucosal IL-13 Receptor alpha 2 ( IL13RA2 ) mRNA expression is one of the best predictive markers for primary non-responsiveness to infliximab therapy in patients with inflammatory bowel disease (IBD). The objective of this study was to understand how IL-13Rα2, a negative regulator of IL-13 signaling, can contribute to IBD pathology. Methods: IL13RA2 knockout (KO) and wild type (WT) mice were exposed to dextran sodium sulfate (DSS) in drinking water to induce colitis. Furthermore, mucosal biopsies and resection specimen of healthy individuals and IBD patients before the start of anti-tumor necrosis factor (anti-TNF) therapy were obtained for immunohistochemistry and gene expression analysis. Results: After induction of DSS colitis, IL13RA2 KO mice had similar disease severity, but recovered more rapidly than WT animals. Goblet cell numbers and mucosal architecture were also more rapidly restored in IL13RA2 KO mice. In mucosal biopsies of active IBD patients, immunohistochemistry revealed that IL-13Rα2 protein was highly expressed in epithelial cells, while expression was restricted to goblet cells in healthy controls. Mucosal IL13RA2 mRNA negatively correlated with mRNA of several goblet cell-specific and barrier genes, and with goblet cell numbers. Conclusions: The data suggest that IL-13Rα2 on epithelial cells contributes to IBD pathology by negatively influencing goblet cell recovery, goblet cell function and epithelial restoration after injury. Therefore, blocking IL-13Rα2 could be a promising target for restoration of the epithelial barrier in IBD.

Background & Aims: Trough concentrations of vedolizumab were found to correlate with clinical response in phase 3 studies of patients with ulcerative colitis (UC) or Crohn's disease (CD). Nevertheless, there are no solid data to support monitoring of vedolizumab trough concentrations in treated patients. We investigated the correlation between vedolizumab exposure and response in a real-world population and aimed to identify patient factors that affect exposure and response., Methods: We performed a retrospective cohort study of 179 consecutive patients (66 with UC and 113 with CD) who began vedolizumab therapy from September 1, 2015, through October 1, 2016, at University Hospitals Leuven, Belgium. Serum concentrations of vedolizumab were measured before all infusions up to week 30. Effectiveness endpoints included endoscopic healing (UC, Mayo endoscopic sub-score ≤1; CD, absence of ulcers), clinical response (physicians' global assessment), and biologic response or remission (based on level of C-reactive protein) and were assessed at week 14 (for patients with UC) and week 22 (for patients with CD). A stepwise forward addition-backward elimination modeling approach was performed to identify factors independently associated with vedolizumab exposure and response., Results: Vedolizumab trough concentrations >30.0 μg/mL at week 2, >24.0 μg/mL at week 6, and >14.0 μg/mL during maintenance therapy associated with a higher probability of attaining the effectiveness endpoints for patients with UC or CD (P < .05). Higher body mass and more severe disease (based on high level of C-reactive protein and low level of albumin and/or hemoglobin) at the start of vedolizumab therapy associated with lower trough concentrations of vedolizumab over the 30-week period and a lower probability of achieving mucosal healing (P < .05). Mucosal healing was achieved in significantly more patients with UC than patients with CD, even though a diagnosis of UC was not an independent predictor of higher vedolizumab trough concentrations., Conclusions: In a retrospective study of 179 patients with CD or UC, we observed a correlation between vedolizumab exposure and response. These findings support monitoring of vedolizumab trough concentrations to predict patients' outcome., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The Trough Concentration Adapted Infliximab Treatment (TAXIT) trial demonstrated that maintaining infliximab trough concentrations at 3 to 7 μg/mL is most effective at inducing remission in patients with inflammatory bowel diseases (IBDs), with fewer flares than clinic-based dosing. We performed a follow-up analysis of study participants to explore the correlation between trough dosing strategy and mucosal healing, continued infliximab use, and rates of hospitalization, surgery, and steroid use., Methods: This was a retrospective single-center study of 226 patients with IBD who completed the maintenance phase of TAXIT, performed at the University Hospitals of Leuven in Belgium. Baseline patient characteristics, laboratory test results, and endoscopic data were obtained at the end of that study between June 2012 and December 2013 (n = 125). Long-term outcome data (IBD-related hospitalization, abdominal surgery, and systemic steroid use) were collected from the time of the last TAXIT study visit (August 2012-April 2013) until April 1, 2016. We also collected data on continued use of infliximab and trough concentrations., Results: At baseline, 91% of patients in the clinic-based dosing group and 90% of patients in the trough concentration-based dosing group had mucosal healing. After a median follow-up time of 41 months (interquartile range, 39-42 mo), infliximab treatment was continued by 81 of 108 patients (75%) from the clinic-based dosing group and 86 of 107 (80%) from the trough concentration-based dosing group. However, within 1 year, infliximab was discontinued by 10 of 27 patients (37%) from the clinic-based dosing group and 2 of 21 patients (10%) from the trough concentration-based dosing group (P = .04). The rates of hospitalization, surgery, and steroid use were below 15% in both groups., Conclusions: At the end of a trial of clinic-based dosing vs trough concentration-based dosing of infliximab in patients with IBD, most patients had mucosal healing. Most patients (≥75%) in both groups continued taking infliximab for more than 3 years after the trial, but a significantly higher proportion of patients in the clinic-based dosing group discontinued infliximab in the first year after the end of the trial. Both groups had low rates of hospitalization, surgery, and steroid use., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The advent of anti-TNF agents has dramatically changed the treatment algorithms for IBD in the last 15 years, but primarily and more importantly secondary loss of response is often observed. Fortunately , new treatment options have been actively explored and some have already entered our clinical practice. In the class of anti-cytokine agents, the anti-IL12/IL23 monoclonal antibodies (mAbs) have entered clinical practice with the anti-p40 mAb ustekinumab in Crohn's disease (CD). Also, more selective anti-IL23 agents (anti-p19) have shown efficacy and are being further developed, in contrast to agents inhibiting IL-17 downstream which have failed in clinical trials despite their clear efficacy in psoriasis (Verstockt et al. in Expert Opin Biol Ther 17(1):31-47, 2017; Verstockt et al. in Expert Opin Drug Saf 16(7):809-821, 2017). Following up on the efficacy of the anti-adhesion molecule vedolizumab, etrolizumab (anti-beta-7 integrin) and PF-00547659, an anti-MadCam mAb, are being developed (Lobaton et al. in Aliment Pharmacol Ther 39(6):579-594, 2014). Oral anti-trafficking agents, such as ozanimod, targeting the S1P receptor responsible for the efflux of T-cells from the lymph nodes, have also shown efficacy in patients with ulcerative colitis (UC) (Sandborn et al. in N Engl J Med 374(18):1754-1762, 2016). Oral agents inhibiting cell signaling have been explored successfully in IBD. Tofacitinib, a non-selective oral Janus kinase (JAK) inhibitor, is effective in patients with UC and several other more or less selective Jak1, 2 and 3 inhibitors are being developed for the treatment of CD and UC (Sandborn et al. in N Engl J Med 376(18):1723-1736, 2017; Vermeire et al. in Lancet 389(10066):266-275, 2017; De Vries et al. in J Crohns Colitis 11(7):885-93, 2017). Finally, despite initial disappointing results with systemic administration of mesenchymal stem cells, Alofisel, adipose tissue derived, allogeneic mesenchymal stem cells, locally injected in perianal fistula tracts, induce long-lasting beneficial effects and the drug has been approved in Europe (Panes et al. in Gastroenterology, 2017). In summary, the quest for new treatment options in IBD is very active and justified by the high medical need and unresolved problems patients are facing.

Objective: To evaluate the clinical relevance of antidrug antibodies (ADAs) measured using a drug-tolerant assay in a post hoc analysis of the Trough Concentration (TC) Adapted Infliximab Treatment (TAXIT) randomised controlled trial., Design: ADA in serum samples (n=221) of 76 patients enrolled in TAXIT, who presented with an infliximab TC <3 µg/mL at screening, were reanalysed after optimisation and at the end of the study using a drug-tolerant ADA assay. Patients underwent dose escalation to achieve therapeutic TCs between 3 µg/mL and 7 µg/mL prior to randomisation. Patients were grouped into quartiles (Q1-4) according to ADA concentration at screening., Results: Using a drug-tolerant assay, the immunogenicity detection rate increased from 21% (drug-sensitive assay) to 63% at screening, from 0% to 51% after optimisation and from 3% to 42% at the end of TAXIT. Patients in ADA Q4 required a higher cumulative infliximab dose (2390 (880-2998) mg) to achieve target TCs, resulting in a higher drug cost (€10 712 (4120-13 596)) compared with ADA-negative patients (€2060 (1648-3296)) and patients in ADA Q1/Q2 (€2060 (1648-4120)/€2060 (1751-3296), p<0.001). However, all but one patient belonging to ADA Q4 were also ADA-positive using a drug-sensitive assay., Conclusions: Upon dose intensification, low concentration ADAs, not detectable using a drug-sensitive assay, disappear in more than half of the patients over time and are clinically non-relevant. In contrast, high concentration ADAs which are typically also detected in a drug-sensitive assay, persist over time and necessitate a higher cumulative dose and drug cost. In the latter group, proactive drug switching may be more cost-efficient., Clinical Trials Register: 2011-002061-38; Post-results., Competing Interests: Competing interests: TVS is a PhD fellow of Flanders Innovation and Entrepreneurship (VLAIO, Flanders). GVA, MF and SV are senior clinical researchers of the FWO. NVC received consultancy fees from Boehringer Ingelheim, Pfizer, UCB and Takeda. GVA received financial support for research from Abbott and Ferring Pharmaceuticals, lecture fees from Janssen, MSD and Abbott, and consultancy fees from PDL BioPharma, UCB Pharma, Sanofi-Aventis, Abbott, Abbvie, Ferring, Novartis, Biogen Idec, Janssen Biologics, NovoNordisk, Zealand Pharma A/S, Millenium/Takeda, Shire, Novartis and Bristol Mayer Squibb. MF received financial support for research from Takeda, lecture fees from MSD, Janssen, Abbvie, Boehringer-Ingelheim, Ferring, Chiesi, Tillotts, Zeria and Mitsubishi Tanabe, and consultancy fees from MSD, Janssen, Abbvie, Boehringer-Ingelheim and Ferring. SV received grant support from MSD, Abbvie and Takeda, lecture fees from Abbvie, MSD, Ferring Pharmaceuticals, Takeda, Hospira and consultancy fees from Abbvie, Takeda, Pfizer, Ferring Pharmaceuticals, Shire Pharmaceuticals Group, MSD, Hospira, Mundipharma, Celgene, Galapagos, Genentech/Roche. AG has served as a speaker for MSD, Janssen Biologicals, Pfizer, Takeda and Abbvie, as consultant for UCB and has received Investigator Initiated Research Grants from Pfizer., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Endoplasmic reticulum [ER] stress was shown to be pivotal in the pathogenesis of inflammatory bowel disease. Despite progress in inflammatory bowel disease [IBD] drug development, not more than one-third of patients achieve steroid-free remission and mucosal healing with current therapies. Furthermore, patient stratification tools for therapy selection are lacking. We aimed to identify and quantify epithelial ER stress in a patient-specific manner in an attempt towards personalised therapy., Methods: A biopsy-derived intestinal epithelial cell culture system was developed and characterised. ER stress was induced by thapsigargin and quantified with a BiP enzyme-linked immunosorbent assay [ELISA] of cell lysates from 35 patients with known genotypes, who were grouped based on the number of IBD-associated ER stress and autophagy risk alleles., Results: The epithelial character of the cells was confirmed by E-cadherin, ZO-1, and MUC2 staining and CK-18, CK-20, and LGR5 gene expression. Patients with three risk alleles had higher median epithelial BiP-induction [vs untreated] levels compared with patients with one or two risk alleles [p = 0.026 and 0.043, respectively]. When autophagy risk alleles were included and patients were stratified in genetic risk quartiles, patients in Q2, Q3, and Q4 had significantly higher ER stress [BiP] when compared with Q1 [p = 0.034, 0.040, and 0.034, respectively]., Conclusions: We developed and validated an ex vivo intestinal epithelial cell culture system and showed that patients with more ER stress and autophagy risk alleles have augmented epithelial ER stress responses. We thus presented a personalised approach whereby patient-specific defects can be identified, which in turn could help in selecting tailored therapies., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background: Vedolizumab (VDZ) has been approved for the treatment of patients with moderate-to-severe Crohn's disease and ulcerative colitis. The GEMINI trials reported a low prevalence of anti-VDZ antibodies (AVA). However, the AVA assays used in GEMINI were drug sensitive, resulting in a possible underestimation of the rate of AVA formation. This study aimed to monitor immunogenicity of VDZ in a real-life cohort using a drug-resistant AVA assay., Methods: Using a combination of VDZ/AVA complex precipitation and acid dissociation, a drug-resistant assay for AVA detection in the presence of high VDZ concentrations has been developed and analytically validated. The assay was applied on serum samples of 179 VDZ-treated patients with inflammatory bowel disease to evaluate the prevalence and time course of AVA., Results: A dose-response curve ranging from 25 to 1600 ng/mL using 1/125 diluted serum was obtained, allowing the detection of AVA concentrations up to 200 μg/mL of MA-VDZ19C11 equivalents, a calibrator antibody to VDZ. This assay was highly AVA specific and drug resistant. Four of 179 VDZ-treated patients (2.2%) were AVA positive and AVA were detected already after the first VDZ infusion. AVA were all transient in these patients without need for any dosage optimization. There was no correlation between VDZ and AVA concentrations in the AVA-positive samples., Conclusions: AVA appear from the first VDZ infusion onward and disappear over time. The low prevalence of AVA suggests that immunogenicity does not influence response to treatment.