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Objectives: To investigate the effects of asperosaponin VI (AVI) on intestinal epithelial cell apoptosis and intestinal barrier function in a mouse model of Crohn's disease (CD)-like colitis and explore its mechanisms., Methods: Male C57BL/6 mice with TNBS-induced CD-like colitis were treated with saline or AVI (daily dose 150 mg/kg) by gavage for 6 days. The changes in body weight, colon length, DAI scores, and colon pathologies of the mice were observed, and the expressions of inflammatory factors and tight injunction proteins were detected using ELISA and RT-qPCR. The effects of AVI on barrier function and apoptosis of mouse intestinal epithelial cells and TNF‑α‑treated Caco-2 cells were analyzed using immunofluorescence staining, TUNEL assay, and Western blotting. Network pharmacology, TUNEL assay, and Western blotting were performed to explore and validate the therapeutic mechanisms of AVI for CD., Results: In the mouse models of CD-like colitis, AVI significantly improved body weight loss, colon shortening and DAI and tissue inflammation scores, alleviated intestinal villi and goblet cell injuries, and lowered the expressions of inflammatory factors. AVI treatment significantly reduced the loss of tight junction proteins and apoptosis in both mouse intestinal epithelial cells and TNF‑α-stimulated Caco-2 cells. KEGG enrichment pathway analysis suggested that the therapeutic effect of AVI on CD was associated with inhibition of PI3K/AKT/NF-κB pathway activation, which was confirmed by lowered expressions of p-PI3K, p-AKT, and p-p65 in AVI-treated mouse models and Caco-2 cells. In Caco-2 cells, Recilisib significantly blocked the inhibitory effect of AVI on the PI3K/AKT/NF-κB pathway and TNF-α-induced apoptosis, and AKT1 knockdown experiment confirmed the role of the PI3K/AKT pathway for mediating the activation of downstream NF-κB signaling., Conclusions: AVI can improve TNBS-induced CD-like colitis in mice by reducing intestinal epithelial cell apoptosis and intestinal barrier damage via inhibiting the PI3K/AKT/NF-κB signaling pathway.

The unknown mechanism that controls intestinal barrier dysfunction in individuals with Crohn's disease (CD) plays a crucial role in the onset of intestinal inflammation. Testin, an intercellular linker protein, has the potential to protect epithelial barrier function. This study aimed to analyse the effects of Testin on CD-like colitis and explore the possible underlying mechanism. Colon samples from CD patients and trinitrobenzene-sulfonic acid (TNBS)-treated mice were collected to examine changes in Testin expression. To assess the therapeutic effects of Testin on CD-like colitis in mice, we examined the symptoms of enteritis, performed histological analysis, and evaluated intestinal barrier permeability. The ability of Testin to stabilize tight junction (TJ) proteins was investigated via immunofluorescence and western blotting. We conducted in vivo and in vitro experiments using colonic organoids and blocking techniques to explore how Testin safeguards the integrity of the intestinal barrier. Testin expression was downregulated in the colons of CD patients and TNBS-treated mice. Increasing Testin expression led to amelioration of colitis symptoms and reduced the production of inflammatory cytokines in the colons of TNBS-induced colitis model mice. Furthermore, increased Testin expression resulted in decreased depletion of TJ proteins (ZO-1 and Claudin-1) and promoted the effectiveness of the intestinal barrier in mice with TNBS-induced colon damage and in lipopolysaccharide (LPS)-stimulated colonic organoids. Elevated Testin levels inactivated the JNK/P38 signalling pathway, potentially contributing to the beneficial impact of Testin on the intestinal barrier. Testin can inhibit the loss of TJ proteins in CD mice by inactivating the JNK/P38 pathway. These findings help to clarify how Testin alleviates CD-like colitis in mice by protecting intestinal barrier function. These findings could lead to the use of a new treatment approach for CD in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the effect and potential mechanisms of α-cyperone (CYP) on Crohn's disease (CD) -like colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) in mice., Methods: The mice were randomly and evenly divided into wild type (WT), TNBS, CYP and 5-aminosalicylic acid (5-ASA) groups, with 10 mice in each group. The symptoms of enteritis, the function and structure of the intestinal barrier, and the expression levels of inflammatory factors, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and gamma-interferon (IFN-γ), in the colon were assessed. The lipopolysaccharide (LPS)-induced inflammation model of Caco2 cells was constructed and the cells were divided into Control, LPS and LPS+CYP groups. The expression levels of tight junction protein and inflammatory factors in each group were assessed. Gene Ontology (GO) functional enrichment analysis was conducted to predict the possible pathways of action and potential molecular mechanisms of CYP, and to verify them in vivo and in vitro ., Results: In the in vivo study, compared with those of the TNBS group, the body mass and colon length of mice in the CYP group and the 5-ASA group were significantly increased, while the disease activity scores and histological inflammation scores were significantly decreased ( P <0.05). The level of lucifcein-glucan isothiocyanate and the bacterial translocation rate (in the liver, the spleen, and mesenteric lymph nodes) were significantly decreased, while the transepithelial electric resistance (TEER) value and the expression levels of zonula occluden protein-1 (ZO-1), and claudin-1 were significantly increased ( P <0.05). The expression of inflammatory factors was significantly decreased ( P <0.05). In the in vitro study, compared with those of the LPS group, the TEER value and the expression of ZO-1 and claudin-1 in the Caco2 cells in the LPS+CYP group were significantly increased ( P <0.05). The expression of inflammatory factors was significantly decreased ( P <0.05). Enrichment analysis showed that CYP was correlated with inflammatory response ( P <0.001). Western blot results showed that CYP could significantly reduce the expression of key proteins in toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway in vivo and in vitro ( P <0.05)., Conclusion: CYP may protect the intestinal barrier by antagonizing the inflammatory response of the intestinal mucosa through regulating the expression of the TLR4/NF-κB signaling pathway, thereby alleviating TNBS-induced CD-like colitis in mice., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Office of Journal of Sichuan University (Medical Sciences).)

Current treatments for patients in the active phase of Crohn's disease (CD) include conventional treatments and biological treatments. Infliximab (IFX), a TNF-α antagonist, is recommended to induce remission in patients with moderate-to-severe CD who have not responded to conventional therapy. IFX terminates the inflammatory cascade by inhibiting the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and caspase signaling pathways and increases the apoptosis of activated T cells in inflamed tissues.

Background and Aims: This posthoc analysis of the GEMINI and VISIBLE studies in ulcerative colitis (UC) and Crohn's Disease (CD) assessed exposure-efficacy of vedolizumab intravenous (IV) and subcutaneous (SC)., Methods: A previously described population pharmacokinetic model was used to predict average serum and trough concentrations at steady state (C av,ss , C trough,ss ) and simulate the transition from vedolizumab IV to SC. Efficacy was defined as clinical remission at week 52: complete Mayo score ≤ 2 points and no individual subscore > 1 point (UC), and CD activity index score ≤ 150 points (CD)., Results: Data were from 1968 patients (GEMINI 1 [ n  = 334], VISIBLE 1 [ n  = 216], GEMINI 2 [ n  = 1009], VISIBLE 2 [ n  = 409]) who received maintenance treatment with vedolizumab IV-Q8W, IV-Q4W, SC-Q2W, or placebo. Model-predicted C av,ss for IV-Q8W and SC-Q2W was similar in UC and CD. C av,ss was higher for IV-Q4W than IV-Q8W and SC-Q2W. C trough,ss values from IV and SC aligned well with pooled observed C trough by treatment group in UC and CD. C av,ss was equivalent for SC and IV. For UC and CD, efficacy rates were greater in patients in the highest quartiles of vedolizumab exposure for both formulations., Conclusion: Exposure-efficacy relationships for IV and SC vedolizumab administration were comparable, confirming that both are equally effective during maintenance treatment.

Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are chronic diseases associated with increased morbidity and reduced quality of life. Age may represent a risk factor for adverse events, due to the multimorbidity and polypharmacy, common in elderly patients. Elderly are often not included in clinical trials evaluating efficacy and safety of study drugs for the treatment of inflammatory bowel diseases. Several drugs, such as aminosalicylates, systemic corticosteroids, immunosuppressant drugs, biological drugs and Janus Kinase inhibitors, are available for the management of inflammatory bowel diseases. Therefore, with the increasing spectrum of therapeutic options it is important to analyze the evidence regarding the safety of the use of these agents in elderly patients. Selection of immunosuppressive therapy is a challenge in the management of elderly patients with inflammatory bowel diseases, for whom biologics with a lower risk of infection or cancer, such as vedolizumab and ustekinumab, may be preferred in elderly patients. Concomitant therapies and comorbidities must be thoroughly investigated before initiating any immunosuppressive or biological therapy in order to minimize the risk of drug-drug interactions. This review aimed to provide an overview of the safety of thiopurines, methotrexate and target therapies as well as their drug-drug interactions in patients with inflammatory bowel diseases.

Objective To investigate the regulatory role of natural plant compound prunetin (PRU) on the intestinal epithelial inflammation and the barrier structure in Crohn's disease-like colitis. Methods A lipopolysaccharide (LPS)-induced inflammatory injury model of colonic organoids and a 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis model were established to evaluate the effects of PRU on the intestinal epithelial inflammation and intestinal barrier. In addition, network pharmacological predictions, combined with in vitro and in vivo studies, were used to analyze the molecular mechanisms by which PRU modulates intestinal epithelial inflammation and intestinal barrier in CD-like colitis. Results PRU inhibited the release of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in LPS-induced colonic organoids, and ameliorated the colitis symptoms in TNBS-induced mice, including body mass loss, elevated disease activity index and increased inflammation scores. Meanwhile, PRU promoted the expression of tight junction proteins (ZO-1 and claudin-1) and improved their translocation restoration in LPS-induced colonic organoids and TNBS-induced intestinal epithelial cells, while maintaining the intestinal barrier structure. Mechanistically, PRU targeted the Toll-like receptor 4 (TLR4) and inhibited the activation of the TLR4/myeloid differentiation primary response gene 88 (MyD88) signaling pathway. Conclusion PRU can antagonize TLR4/MyD88 signaling, thereby inhibiting intestinal epithelial inflammation and protecting against intestinal barrier damage, which helps ameliorate Crohn's disease-like colitis.

Background and Aims: Ongoing efforts to break the therapeutic ceiling in inflammatory bowel disease include combination therapy approaches. Dual-targeted therapy (DTT) has been reported in case reports and small case series. This report describes our experience with ustekinumab (UST) and upadacitinib (UPA) as DTT in patients with Crohn's disease (CD)., Methods: In this retrospective, observational study, we reviewed medical records of patients with CD treated with combined UST and UPA between April 2021 and July 2022. Clinical remission was defined as Harvey-Bradshaw Index (HBI) ≤ 4, and clinical response was defined as decrease in HBI ≥ 3 or physician's assessment of clinical response., Results: We identified 10 CD patients treated with UST/UPA, with median follow-up period of 10 months (interquartile range (IQR) 7.3-12). Median age was 35.5 years (IQR 28.3-43.8) and median number of prior biologic treatment exposures was 4 (IQR 4-5). Indications for UST/UPA were active CD (n = 6), extraintestinal manifestations (EIM) (n = 2), and both active CD and EIM (n = 2). Five of six patients with active CD achieved clinical remission with UST/UPA. Two patients with active EIM (joint pain) achieved resolution of their symptoms. One patient exhibited improvement in both conditions. Three patients developed mild respiratory symptoms and one experienced bowel obstruction. Two patients developed nausea resulting in de-escalation of treatment interval or discontinuation altogether., Conclusion: Based on our case series, combination therapy with UST and UPA may be effective and appears safe in refractory Crohn's disease and for patients with co-existing extraintestinal manifestations., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Crohn's disease (CD) involves activation of mast cells (MC) and NF-кB in parallel with the PPAR-α/NLRP3 inflammasome/IL-1β pathway in the inflamed colon. Whether polyphenols from maqui ( Aristotelia chilensis ) represent a natural alternative treatment for CD is unclear. Therefore, we used an animal model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD-like colitis to investigate protective effects of maqui extract through monitoring NLRP3 inflammasome and MC activation in colon tissue., Methods: Maqui extract was administered via orogastric route to mice after (post-Treatment group) or prior (pre-Treatment group) to TNBS-induction. Colon pathology was characterized by histoarchitectural imaging, disease activity index (DAI), and assessing NF-кB, p-NF-кB, PPAR-α/NLRP3 expression and IL-1β levels., Results: Compared to mice treated with TNBS alone administration of anthocyanin-rich maqui extract improved the DAI, colon histoarchitecture and reduced both colon wet-weight and transmural inflammation. Induction with TNBS significantly increased colonic NLPR3 inflammasome activation, while co-treatment with maqui extract (either post- or pre-Treatment) significantly downregulated NLRP3, ASC and caspase-1 levels, which manifested as reduced colonic IL-1β levels. Supplemented maqui extract marginally diminished NF-кB activity in epithelial cells but reached statistical significance in immune cells (as judged by decreased NF-кB phosphorylation). PPAR-α signaling was largely unaffected by Maqui whereas MC infiltration into the colon mucosa and submucosa decreased and their level of degranulation was suppressed., Conclusion: These outcomes show the post- and pre- Treatment effect of a polyphenolic extract rich in anthocyanins from maqui the acute phase of TNBS- induced CD-like colitis is linked to suppression of the NLRP3 inflammasome and reduced MC responses. These data indicate that maqui extract represents a potential nutraceutical for the treatment of inflammatory bowel disease (IBD)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ortiz-Cerda, Argüelles-Arias, Macías-García, Vázquez-Román, Tapia, Xie, García-García, Merinero, García-Montes, Alcudia, Witting and De-Miguel.)

Background: We tested whether proton pump inhibitors (PPIs) are associated with enteric infections among those with inflammatory bowel disease (IBD), after adequately accounting for baseline differences between PPI users and nonusers., Methods: This was a self-controlled case series, with each patient serving as their own control. Ambulatory patients with IBD were included if they were tested for enteric infection by multiplex polymerase chain reaction testing panel (GIPCR) and/or Clostridoides difficile toxin PCR from 2015 to 2019 and received PPIs for some but not all of this period. Rates of enteric infections were compared between the PPI-exposed period vs pre- and post-PPI periods identical in duration to the exposed period. Conditional Poisson regression was used to adjust for time-varying factors., Results: Two hundred twenty-one IBD patients were included (49% ulcerative colitis, 46% Crohn's disease, and 5% indeterminate colitis). The median PPI duration was 7 months (interquartile range 4 to 11 months). A total of 25 (11%) patients had a positive GIPCR or C. difficile test in the PPI period, 9 (4%) in the pre-PPI period, and 8 (4%) in the post-PPI period. Observed incidence rates for enteric infections were 2.5, 7.4, and 2.2 per 100 person years for the pre-PPI, PPI, and post-PPI periods, respectively (adjusted incidence rate ratios, 2.8; 95% confidence interval [CI] 1.3-6.0) for PPI vs pre-PPI and 2.9 (95% CI, 1.3-6.4) for PPI vs post-PPI). The adjusted absolute excess risk associated with PPIs was 4.9 infections per 100 person years., Conclusions: Proton pump inhibitors were associated with a 3-fold increased risk for enteric infection among those with IBD but had a modest absolute risk., (© The Author(s) 2023. 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 & Aims: Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated receptor 1 (PAR 1 ) increases in inflammatory bowel disease. The present study investigated the therapeutic effects of PAR 1 antagonism on colitis-associated carcinogenesis., Methods: A colitis-associated carcinogenesis model was prepared in mice by treatment with azoxymethane (AOM) and dextran sulfate sodium (DSS). PAR 1 antagonist E5555 was administered in long- and short-term protocol, starting on the day of AOM injection and 1 week after completing AOM/DSS treatment, respectively. The fecal samples were collected for metagenome analysis of gut microbiota. The intestinal myofibroblasts of the Crohn's disease patients were used to elucidate underlying cellular mechanisms. Caco-2 cells were used to investigate a possible source of PAR 1 agonist proteinases., Results: AOM/DSS model showed weight loss, diarrhea, tumor development, inflammation, fibrosis, and increased production of inflammatory cytokines. The β-diversity, but not α-diversity, of microbiota significantly differed between AOM/DSS and control mice. E5555 alleviated these pathological changes and altered the microbiota β-diversity in AOM/DSS mice. The thrombin expression was up-regulated in tumor and non-tumor areas, whereas PAR 1 mRNA expression was higher in tumor areas compared with non-tumor areas. E5555 inhibited thrombin-triggered elevation of cytosolic Ca 2+ concentration and ERK1/2 phosphorylation, as well as IL6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in intestinal myofibroblasts. Caco-2 cell-conditioned medium contained immunoreactive thrombin, which cleaved the recombinant protein containing the extracellular domain of PAR 1 at the thrombin cleavage site., Conclusions: PAR 1 antagonism is proposed to be a novel therapeutic strategy for treatment of inflammatory bowel disease and its associated carcinogenesis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The patient was a 21-year-old man who had been diagnosed with Crohn's disease and received infliximab and azathioprine six years earlier. He was admitted with fever and fatigue. Peripheral blood examination showed LDH 2,473 U/l and thrombocytopenia, and contrast-enhanced computed tomography (CT) showed hepatosplenomegaly. Bone marrow biopsy and liver biopsy showed CD4+CD56+TCRγδ＋CD8 - atypical cells, leading to a diagnosis of hepatosplenic T-cell lymphoma (HSTCL). The patient was refractory to CHOP and DA-EPOCH, and therefore received cord blood transplantation with myeloablative conditioning. CT showed reduced in hepatosplenomegaly and peripheral blood examination showed LDH 165 U/l and plt 180,000/µl, so the patient was discharged on day117. HSTCL is a tumor of immature γδT cells with a Vδ1 mutation in the spleen, and immunodeficiency has been implicated in its pathogenesis. Patients with inflammatory bowel disease treated with azathioprine are known to have an increased risk of lymphoproliferative disease. In this case, use of immunosuppressive drugs for Crohn's disease may have caused malignant transformation of γδ cells in the intestinal epithelium. Although the patient was refractory to chemotherapy, he was able to achieve remission with early cord blood transplantation and long-term survival is expected.

Background: Short-term efficacy and safety of brazikumab (MEDI2070), a human monoclonal antibody and anti-p19 subunit inhibitor of interleukin-23, was demonstrated in a phase 2a trial in patients with moderate-to-severe active Crohn's disease (CD). We report brazikumab long-term safety and tolerability from the open-label period of this phase 2a study., Methods: Patients who completed the 12-week, double-blind induction period were eligible for inclusion in an open-label period where all patients received subcutaneous brazikumab (210 mg) every 4 weeks for 100 weeks. Patients had moderate-to-severe active CD and had failed or were intolerant to ≥ 1 anti-tumour necrosis factor alpha (TNFα) agent. Safety assessments included treatment-emergent adverse events (TEAEs); further assessments were pharmacokinetics and immunogenicity., Results: Of the 104 patients who entered the open-label period, 57 (54.8%) continued to the end of the open-label period and 47 (45.2%) discontinued brazikumab. The most common reasons for discontinuation were lack of response (14.4%), patient decision (12.5%), and TEAEs (11.5%). In total, 44 (84.6%) in the group switching from placebo to brazikumab (placebo/brazikumab) and 43 (82.7%) in the group continuing brazikumab (brazikumab/brazikumab) experienced 1 or more TEAEs. Most TEAEs were mild-to-moderate in severity. Common TEAEs included nasopharyngitis and headache. Numbers of treatment-emergent serious adverse events (TESAEs) were similar between groups. Infections occurred in 40.4% of patients in the placebo/brazikumab group and 50% in the brazikumab/brazikumab group. There were 5 TESAEs of infection, none of which were opportunistic. No major adverse cardiac events, malignancies, or deaths were reported., Conclusions: Brazikumab was well tolerated with an acceptable safety profile over a 100-week period in patients with moderate-to-severe active CD who failed or were intolerant to 1 or more anti-TNFα agents., Trial Registration: NCT01714726; registered October 26, 2012., (© 2023. The Author(s).)

Background: Therapeutic drug monitoring (TDM) has the potential to improve efficacy and diminish side effects. Measuring methotrexate-polyglutamate (MTX-PG) in erythrocytes might enable TDM for methotrexate in patients with Crohn's disease (CD)., Aim: To investigate the relationship between MTX-PGs and methotrexate drug survival, efficacy and toxicity METHODS: In a multicentre prospective cohort study, patients with CD starting subcutaneous methotrexate without biologics were included and followed for 12 months. Primary outcome was subcutaneous methotrexate discontinuation or requirement for step-up therapy. Secondary outcomes included faecal calprotectin (FCP), Harvey Bradshaw Index (HBI), hepatotoxicity and gastrointestinal intolerance. Erythrocyte MTX-PGs were analysed at weeks 8, 12, 24 and 52 or upon treatment discontinuation., Results: We included 80 patients with CD (mean age 55 ± 13y, 35% male) with a median FCP of 268 μg/g (IQR 73-480). After the 12-month visit, 21 patients (26%) were still on subcutaneous methotrexate monotherapy. Twenty-one patients stopped because of disease activity, 29 because of toxicity, and four for both reasons. Five patients ended study participation or stopped methotrexate for another reason. A higher MTX-PG 3 concentration was associated with a higher rate of methotrexate drug survival (HR 0.86, 95% CI 0.75-0.99), lower FCP (β -3.7, SE 1.3, p < 0.01) and with biochemical response (FCP ≤250 if baseline >250 μg/g; OR 1.1, 95% CI 1.0-1.3). Higher MTX-PGs were associated with less gastrointestinal intolerance. There was no robust association between MTX-PGs and HBI or hepatotoxicity., Conclusions: Higher MTX-PG 3 concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX-PG 3 could be used for TDM if a target concentration can be established., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Many clinical factors can contribute to the efficacy of medical therapy in Inflammatory Bowel Disease (IBD). We assessed their effects on the efficacy of vedolizumab therapy in a cohort of patients with IBD., Methods: We conducted a retrospective study on patients between 18 and 80 years of age with ulcerative colitis (UC) or Crohn's disease (CD) who were seen in the IBD program at Houston Methodist in Houston, TX and treated with vedolizumab for at least 6 months from 2018 to 2022. We investigated factors prior to the initiation of therapy that best predicted treatment response, with an emphasis on vitamin D levels and examined several variables including patients' demographics and clinical information on disease location and severity and nutritional status before and after the initiation of vedolizumab. Post-treatment data were gathered after a minimum of 6 months of vedolizumab therapy. The clinical parameters used for the study were the Harvey-Bradshaw Index for CD and the Activity Index for UC., Results: There were 88 patients included in our study of whom 44 had CD and 44 had UC.; median age was 39.5 (31.0, 53.25) years; 34% patients were male; and 80.7% were Caucasian. All patients received an induction dosing of 300 mg vedolizumab at 0, 2, and 6 weeks then maintenance dosing as standard of care every 8 weeks. Among UC patients with vitamin D ≥ 30 ng/mL at the initiation of vedolizumab therapy, UC Endoscopic Index of Severity (UCEIS) scores after 6 months of therapy were significantly lower than in those who had low pre-treatment vitamin D levels (1.5 vs. 3.87, p = 0.037). After treatment, vitamin D levels improved more significantly in the higher pre-treatment vitamin D group, with a median level of 56 ng/mL, than in the lower pre-treatment vitamin D group, with a median level of only 31 ng/mL ( p = 0.007). In patients with CD with vitamin D ≥ 30 ng/mL at the initiation of vedolizumab therapy, we found higher iron saturation (12 vs. 25%, p = 0.008) and higher vitamin B12 levels (433.5 vs. 885 pg/mL, p = 0.003) than in those with vitamin D < 30 ng/mL. After treatment, CD patients with high pre-treatment vitamin D levels had significantly higher vedolizumab levels (27.35 vs. 14.35 μg/mL, p = 0.045) than those with low pre-treatment vitamin D. Post-treatment scores and inflammatory markers in CD patients (HBI, CRP, ESR, and SES-CD) were lower in those who had lower baseline vitamin D., Conclusions: Our results show higher pre-treatment vitamin D levels predicted significant endoscopic improvement in patients with ulcerative colitis (UC). Improving vitamin D levels lowered C-reactive protein levels significantly in CD patients. Higher vitamin D levels were seen after treatment in both UC and CD patients. Vitamin D can play a role in clinical and endoscopic outcomes and should be assessed routinely and optimized in patients with IBD.

Background: Crohn's disease perianal fistulae (CD-PAF) occur in 25% of patients and are notoriously challenging to manage. Tumor necrosis factor inhibitors are first line agents., Aims: The aim of this study was to compare infliximab (IFX) versus adalimumab (ADA) efficacy in CD-PAF healing over time., Methods: A retrospective study at two large-tertiary medical centers was performed. Inclusion criteria were actively draining CD-PAF and initial treatment with IFX or ADA following CD-PAF diagnosis. The primary endpoints were perianal fistula response and remission at 6 and 12 months. Secondary endpoints included biologic persistence over time and dose escalation at 6 and 12 months., Results: Among 151 patients included in the study, 92 received IFX and 59 received ADA as first line agents after CD-PAF diagnosis. At 6 months, the 64.9% of the IFX group and 34.8% of the ADA group demonstrated CD-PAF clinical improvement (p < 0.01). Univariate and multivariate analyses demonstrated significant differences among the IFX and ADA groups for clinical response at 6-months and 12-months (p = 0.002 and p = 0.042, respectively). There were no factors that predicted response, with the exception of concomitant immunomodulator affecting the 6-month clinical response (p = 0.021). Biologic persistence, characterized by Kaplan Meier methods, was significantly longer in the IFX group compared to the ADA group (Log-rank p = 0.01)., Conclusion: IFX induction and maintenance is associated with higher rates of response and remission in CD-PAF healing as well as higher treatment persistence compared to ADA. Additionally, our study supports the use of concomitant immunomodulator therapy for CD-PAF healing and remission., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Primary and secondary non-response to anti-tumor necrosis factor (TNF) therapy is common in patients with Crohn's disease (CD), yet limited research has compared the effectiveness of subsequent biological therapy., Objective: We sought to compare the effectiveness of vedolizumab and ustekinumab in anti-TNF-experienced patients with CD, focusing on patient-prioritized patient-reported outcomes (PROs)., Methods: We conducted a prospective, internet-based cohort study nested within IBD Partners. We identified anti-TNF-experienced patients initiating with CD vedolizumab or ustekinumab and analyzed PROs reported approximately 6 months later (minimum 4 months, maximum 10 months). Co-primary outcomes were Patient-Reported Outcome Measurement Information System (PROMIS) domains of Fatigue and Pain Interference. Secondary outcomes included patient-reported short Crohn's disease activity index (sCDAI), treatment persistence, and corticosteroid use. Inverse probability of treatment weighting (IPTW) was used to control for a number of potential confounders and incorporated into linear and logistic regression models for continuous and categorical outcomes, respectively., Results: Overall, 141 vedolizumab and 219 ustekinumab initiators were included in our analysis. After adjustment, we found no differences between treatment groups in our primary outcomes of Pain Interference or Fatigue or the secondary outcome of sCDAI. However, vedolizumab was associated with lower treatment persistence (OR 0.4, 95% CI 0.2-0.6) and higher corticosteroid use at follow-up assessment (OR 1.7, 95% CI 1.1-2.6)., Discussion: Among anti-TNF experienced patients with CD, Pain Interference or Fatigue was not significantly different 4-10 months after starting ustekinumab or vedolizumab. However, reduced steroid use and increased persistence suggest superiority of ustekinumab for non-PRO outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There is a need to better understand the positioning of biologic therapies for long-term outcomes in biologic-naïve Crohn's disease (CD). We assessed the comparative effectiveness of infliximab and ustekinumab among induction responders for 1-year outcomes., Methods: This post hoc analysis included data from 220 biologic-naïve CD participants with response to induction therapy from 2 clinical trial programs. Participants achieving 1-year clinical remission (CR) (Crohn's disease activity index <150), corticosteroid-free CR, normalization of fecal calprotectin (FC), endoscopic response (Simple Endoscopic Score for CD decrease ≥50% from baseline), and endoscopic remission (ER) (Simple Endoscopic Score for CD <3) were compared. Multivariate logistic regression evaluated the likelihood of achieving the outcomes adjusted for confounders. Propensity score matching created a cohort with similar distribution of baseline covariates., Results: One-year CR and corticosteroid-free CR rates were similar between infliximab-treated and ustekinumab-treated patients (CR, 66 of 110 [60.0%] vs 63 of 110 [57.3%]; adjusted odds ratio [aOR], 1.15; 95% CI, 0.67-1.98; P = .681; corticosteroid-free CR, 11 of 28 (39.3%) vs 27 of 51 [52.9%]; aOR, 0.58; 95% CI, 0.23-1.47; P = .251). Compared with ustekinumab-treated patients, infliximab-treated participants were more likely to achieve 1-year endoscopic response (43 of 92 [46.7%] vs 6 of 30 [20.0%], aOR, 3.59; 95% CI, 1.34-9.66; P = .011) and ER (31 of 92 [33.7%] vs 4 of 30 [13.3%]; aOR, 3.35; 95% CI, 1.07-10.49; P = .038). Among patients with FC ≥250 mg/kg at baseline, normalization (<250 mg/kg) at 1-year was similar between groups. Similar results were observed within the propensity matched population for all analyses., Conclusions: Treatment with infliximab and ustekinumab among induction responders achieved 1-year CR with similar efficacy, but infliximab may confer greater benefit for endoscopic outcomes. Findings should be interpreted with caution as our analyses were unpowered., (© 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.)

Objective: The aim of the study was to characterize the drug utilization and switch patterns of biological treatment of ulcerative colitis (UC) and Crohn's disease (CD)., Methods: Using Danish national registries, this nationwide study included individuals diagnosed with UC or CD, bio-naïve at the initiation of treatment with infliximab, adalimumab, vedolizumab, golimumab, or ustekinumab in 2015-2020. Hazard ratios of discontinuing the first treatment or switching to another biological treatment were explored using Cox regression., Results: Among 2995 UC patients and 3028 CD patients, infliximab was used as a first-line biologic treatment in 89% of UC patients and 85% of CD patients, followed by adalimumab with 6%, vedolizumab with 3%, and golimumab with 1% for UC, and adalimumab with 12%, vedolizumab with 2%, and ustekinumab with 0.4% for CD.When comparing adalimumab as the first treatment series to infliximab, there was a higher risk of treatment discontinuation (excluding switch) among UC patients (hazard ratio: 2.02 [95% confidence interval: 1.57; 2.60]) and CD patients (1.85 [1.52; 2.24]). When comparing vedolizumab to infliximab, there was a lower risk of discontinuation for UC patients (0.51 [0.29-0.89]), and for CD patients, although not significantly (0.58 [0.32-1.03]). We observed no significant difference in the risk of switching to another biologic treatment for any of the biologics., Conclusion: More than 85% of UC and CD patients initiating biologic therapy had infliximab as their first-line biologic treatment, in accordance with official treatment guidelines. Future studies should explore the higher incidence of treatment discontinuation of adalimumab as the first treatment series.Key summarySeveral biologic therapies are available in the treatment of ulcerative colitis and Crohn's disease.Clinical guidelines stipulate that infliximab should be the first-line biologic therapy.Drug utilization studies comparing biologic therapies head-to-head are sparse.In Denmark, during 2015-2020 infliximab remained the most widely used biologic treatment, with adalimumab being second.One in four patients experienced more than one biologic during the study period.The risk of discontinuation of biologic treatment (and not starting a new biologic) was higher for initiators of adalimumab.Clinical and social background factors available from the registers could not account for the observed risk difference in discontinuation.

Surgery in Crohn's disease may be the cause of short bowel syndrome that may lead to kidney dysfunction. Dual biologic therapy is rarely needed to control activity. We present a case of a 61-year-old steroid dependent (A2L1B3p) female who had undergone surgery on three occasions: ileocecal resection (resection of 15 cm of terminal ileum); resection of right and left colon up to sigmoid; proctectomy with intersphincteric resection along with ileostomy due to a rectovaginal fistula. She had been previously treated with prednisone, azathioprine, methotrexate, infliximab and adalimumab but the treatment was discontinued owing to adverse effects. Vedolizumab was started, showing good control of the luminal activity but the rectovaginal fistula recurred. Treatment changed to ustekinumab, the fistula activity was controlled but the mucosa activity recurred. 11 months after commencing with ustekinumab, vedolizumab was added to the treatment and complete remission was achieved for three years. Simultaneously, the patient developed renal dysfunction derived from the short bowel syndrome that led to chronic kidney failure. In the face of potential renal replacement therapy, a new therapy with 2.5 mg/sc/d teduglutide was started achieving stable figures of creatinine and normalization of the glomerular filtration rate.

Background: Recombinant zoster vaccine (RZV) is recommended for all adults ≥19 years of age who are at increased risk for HZ, including patients with inflammatory bowel disease (IBD)., Methods: A Markov model was constructed to compare the RZV cost-effectiveness with no vaccination in patients with Crohn's Disease (CD) and ulcerative colitis (UC). A simulated cohort of 1 million patients was used for each IBD group at ages 18, 30, 40, and 50. The primary objective of this analysis was to compare RZV cost-effectiveness in patients with CD and UC, comparing vaccination to no vaccination., Results: Overall, vaccination is cost-effective for both CD and UC, with the incremental cost-effectiveness ratio (ICERs) below $100,000/quality-adjusted life years (QALY) for all age cohorts. For patients with CD, 30 years of age and older, and those with UC 40 years and older, vaccination was both more effective and less expensive than the non-vaccinated strategy (CD ≥30: ICERs $6183-$24,878 and UC ≥40: ICERs $9163-$19,655). However, for CD patients under 30 (CD 18: ICER $2098) and UC patients under 40 (UC = 18: ICER $11,609, and UC = 30: $1343), costs were greater for vaccinated patients, but there was an increase in QALY. One-way sensitivity analysis of age indicates that cost break-even occurs at age 21.8 for the CD group and 31.5 for the UC group. In probabilistic sensitivity analysis, 92% of both CD and UC simulations indicated that vaccination was preferred., Conclusion: In our model, vaccination with RZV was cost-effective for all adult patients with IBD., (© 2023 John Wiley & Sons Ltd.)

Background: The Western dietary pattern, characterized by high consumption of fats and sugars, has been strongly associated with an increased risk of developing Crohn's disease (CD). However, the potential impact of maternal obesity or prenatal exposure to a Western diet on offspring's susceptibility to CD remains unclear. Herein, we investigated the effects and underlying mechanisms of a maternal high-fat/high-sugar Western-style diet (WD) on offspring's susceptibility to 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced Crohn's-like colitis., Methods: Maternal dams were fed either a WD or a normal control diet (ND) for eight weeks prior to mating and continued throughout gestation and lactation. Post-weaning, the offspring were subjected to WD and ND to create four groups: ND-born offspring fed a normal diet (N-N) or Western diet (N-W), and WD-born offspring fed a normal (W-N) or Western diet (W-W). At eight weeks of age, they were administered TNBS to induce a CD model., Results: Our findings revealed that the W-N group exhibited more severe intestinal inflammation than the N-N group, as demonstrated by a lower survival rate, increased weight loss, and a shorter colon length. The W-N group displayed a significant increase in Bacteroidetes, which was accompanied by an accumulation of deoxycholic acid (DCA). Further experimentation confirmed an increased generation of DCA in mice colonized with gut microbes from the W-N group. Moreover, DCA administration aggravated TNBS-induced colitis by promoting Gasdermin D (GSDMD)-mediated pyroptosis and IL-1beta (IL-1β) production in macrophages. Importantly, the deletion of GSDMD effectively restrains the effect of DCA on TNBS-induced colitis., Conclusions: Our study demonstrates that a maternal Western-style diet can alter gut microbiota composition and bile acid metabolism in mouse offspring, leading to an increased susceptibility to CD-like colitis. These findings highlight the importance of understanding the long-term consequences of maternal diet on offspring health and may have implications for the prevention and management of Crohn's disease. Video Abstract., (© 2023. The Author(s).)

Background: There is an increasing incidence of inflammatory bowel disease (IBD) for which environmental factors are suspected. Antibiotics have been associated with development of IBD in earlier generations, but their influence on IBD risk in adults is uncertain., Objective: To assess the impact of antibiotic exposure, including dose-response, timing and antibiotic class, on the risk of IBD in all individuals aged ≥10 years., Design: Using Denmark nationwide registries, a population-based cohort of residents aged ≥10 years was established between 2000 and 2018. Incidence rate ratios (IRRs) for IBD following antibiotic exposure were calculated using Poisson regression., Results: There were a total of 6 104 245 individuals, resulting in 87 112 328 person-years of follow-up, and 52 898 new cases of IBD. Antibiotic exposure was associated with an increased risk of IBD as compared with no antibiotic exposure for all age groups, although was greatest among individuals aged 40-60 years and ≥60 years (age 10-40 years, IRR 1.28, 95% CI 1.25 to 1.32; age 40-60 years, IRR 1.48, 95% CI 1.43 to 1.54; age ≥60 years, IRR 1.47, 95% CI 1.42 to 1.53). For all age groups a positive dose-response was observed, with similar results seen for both ulcerative colitis and Crohn's disease. The highest risk of developing IBD was seen 1-2 years after antibiotic exposure, and after use of antibiotic classes often prescribed to treat gastrointestinal pathogens., Conclusion: Antibiotic exposure is associated with an increased risk of IBD, and was highest among individuals aged 40 years and older. This risk increased with cumulative antibiotic exposure, with antibiotics targeting gastrointestinal pathogens and within 1-2 years after antibiotic exposure., Competing Interests: Competing interests: ASF: Research support from Crohn’s and Colitis Foundation; consultant for GLG, M3, Janssen, Guidepoint. JF: consultant Vedanta Biosciences and Innovation Pharmaceuticals; Scientific Advisory Board Vedanta Biosciences. JC: research grants from AbbVie, Janssen Pharmaceuticals and Takeda; payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microba, Novartis, PBM Capital, Pfizer, Sanofi, Takeda, TiGenix, Vifor; holds stock options in Intestinal Biotech Development., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Crohn's disease (CD) is a chronic inflammatory bowel disease characterized by relapsing and remitting inflammation that leads to progressive bowel damage. Despite advances in medical treatment for CD, many patients require surgical intervention. Most studies of surgery rates are from patients treated with anti-tumor necrosis factor alpha (anti-TNFα) treatments, with comparatively little data on the surgery rates of patients treated with vedolizumab and ustekinumab. SOJOURN aimed to estimate the hazard rate and incidence of the first CD-related surgery following initiation of treatment with vedolizumab or ustekinumab in biologic-naïve patients with CD., Methods: SOJOURN was a retrospective, observational cohort study examining administrative claims data from the Optum® Research Database between July 1, 2017 and March 31, 2020. Included participants were adults with a diagnosis of CD and a claim for vedolizumab or ustekinumab (defined as the index treatment) between January 1, 2018 and December 31, 2019, with no claims for a biologic in the 6 months before initiation of this treatment. The variable follow-up started on the day after the index date and continued until whichever came first of discontinuation of the index treatment, surgery event, switching of the index treatment, initiation of combination biologic treatment, disenrollment, or March 31, 2020. The time to the first CD-related surgery on biologic treatment was estimated by Kaplan-Meier analysis. The hazard ratio and incidence rate ratio of CD-related surgery for each treatment cohort was compared using a Cox proportional hazards model and a Poisson regression model, respectively., Results: Of the 1,122 included patients, 578 received vedolizumab and 544 received ustekinumab. After 1 year of the variable follow-up, 7.7% of patients receiving vedolizumab and 11.6% of patients receiving ustekinumab had undergone a CD-related surgery. Vedolizumab was associated with a 34.2% lower hazard rate of surgery (hazard ratio 0.658, 95% confidence interval [CI] 0.436-0.994, p = 0.047) and a 34.5% lower incidence of surgery (rate ratio 0.655, 95% CI 0.434-0.988, p = 0.044) than ustekinumab., Conclusions: This real-world analysis of biologic-naïve patients with CD suggests that vedolizumab is associated with greater effectiveness in reducing the rate of CD-related surgery than ustekinumab., (© 2023. The Author(s).)

The susceptibility, risk factors, and prognosis of COVID-19 in patients with inflammatory bowel disease (IBD) remain unknown. Thus, our study aims to assess the prevalence and clinical outcomes of COVID-19 in IBD. We searched PubMed, EMBASE, and medRxiv from 2019 to 1 June 2022 for cohort and case-control studies comparing the prevalence and clinical outcomes of COVID-19 in patients with IBD and in the general population. We also compared the outcomes of patients receiving and not receiving 5-aminosalicylates (ASA), tumour necrosis factor antagonists, biologics, systemic corticosteroids, or immunomodulators for IBD. Thirty five studies were eligible for our analysis. Pooled odds ratio of COVID-19-related hospitalisation, intensive care unit (ICU) admission, or death in IBD compared to in non-IBD were 0.58 (95% confidence interval (CI) = 0.28-1.18), 1.09 (95% CI = 0.27-4.47), and 0.67 (95% CI = 0.32-1.42), respectively. Inflammatory bowel disease was not associated with increased hospitalisation, ICU admission, or death. Susceptibility to COVID-19 did not increase with any drugs for IBD. Hospitalisation, ICU admission, and death were more likely with 5-ASA and corticosteroid use. COVID-19-related hospitalisation (Odds Ratio (OR): 0.53; 95% CI = 0.38-0.74) and death (OR: 0.13; 95% CI = 0.13-0.70) were less likely with Crohn's disease than ulcerative colitis (UC). In conclusion, IBD does not increase the mortality and morbidity of COVID-19. However, physicians should be aware that additional monitoring is needed in UC patients or in patients taking 5-ASA or systemic corticosteroids., (© 2022 John Wiley & Sons Ltd.)

Background: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy., Methods: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021., Findings: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded., Interpretation: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation., Funding: European Union's Horizon 2020., Competing Interests: Declaration of interests EL has received educational and research grants from Janssen, Pfizer, AbbVie, and Takeda, Fresenius-Kabi; speaker fees from AbbVie, Dr Falk Pharma, Ferring, Janssen, Pfizer, Celgene, Bristol Myers Squibb (BMS), Galapagos, and Takeda; advisory board fees for AbbVie, Celgene, Ferring, Janssen, BMS, Pfizer, Takeda, Gilead-Galapagos, Arena, and Elli Lilly; and consultancy fees from AbbVie. JS reports research support from European Commission Horizon 2020 programme. ND has received research grants from AbbVie, Janssen, and Takeda; speaker fees from AbbVie, Celltrion, Pfizer, Janssen, and Takeda; and advisory board fees from AbbVie, Dr Falk Pharma, and Janssen. BS has served as a consultant for AbbVie, Arena, BMS, Boehringer, CT Scout, Galapagos, Gilead, Janssen, Lilly, and PredictImmune; and has received speaker's fees from AbbVie, CED Service GmbH, Dr Falk Pharma, Ferring, Janssen, Materia Prima, Pfizer, and Lilly. GD'H reports consultancy activities for AbbVie, Agomab, Alimentiv, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, BMS, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, GlaxoSmithKline, Gossamerbio, Pfizer, Immunic, Johnson & Johnson, Origo, Polpharma, Procise Diagnostics, Prometheus laboratories, Prometheus Biosciences, Progenity, and Protagonist; speaker's bureau for AbbVie, Arena, Galapagos, Gilead, Pfizer, BMS, and Takeda; and fees for data monitoring board activities for Galapagos, AbbVie, Astrazeneca, and Seres Health. PB has received financial support for research from AbbVie, Amgen, Celltrion, Mylan, Pfizer and Takeda; lecture fees from AbbVie, Celltrion, Galapagos, Janssen, Lilly, Pentax, and Takeda; advisory board fees from AbbVie, Arena Pharmaceuticals, BMS, Celltrion, Dr Falk Pharma, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros. LV has received fees from AbbVie, Amgen, Biogen, Mylan, Takeda, MSD, Janssen, Pfizer, Ferring, and Galapagos. PI has received honoraria for talking on behalf of AbbVie, BMS, Celgene, Celltrion, Dr Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Lilly, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire, and Warner Chilcott; and for acting in an advisory capacity to AbbVie, Arena, Boehringer-Ingelheim, BMS, Celgene, Celltrion, Connect Biopharma, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott. SV has received consulting or lecture fees for AbbVie, Amgen, Sandoz, Janssen, MSD, Pfizer, Celltrion, and Takeda. CAL has received grants from Genentech, AbbVie, Eli Lilly, Pfizer, Roche, UCB Biopharma, Sanofi Aventis, Biogen IDEC, Orion OYJ, and AstraZeneca; grants and personal fees from Janssen, Takeda, and Ferring; and personal fees from Dr Falk Pharma, outside the submitted work. FB has received grant or research support from AbbVie, Amgen, Janssen, and Takeda; honoraria from AbbVie, Dr Falk Pharma, Arena, Celgene, Mundipharma, Ferring, Vifor, Janssen, Merck Sharp & Dohme, Pfizer, Norgine, and Takeda. MN received board membership, consultancy, or lecture fees from AbbVie, Amgen, Arena, Biogen, CTMA, Celltrion, Ferring, Fresenius, Janssen, Mayoli-Spindler, MSD, Pfizer, Sandoz, and Takeda. MF received consulting or lecture fees for AbbVie, Amgen, Biogen, Gilead, Sandoz, Janssen, MSD, Pfizer, Ferring, Lilly, Tillots, Celltrion, Fresenius, Galapagos, and Takeda. CG received consulting or lecture fees from AbbVie, Amgen, Celltrion, Biogen, Fresenius, Gilead, Janssen, MSD, Mylan, Pfizer, Takeda, and Vifor. SB-H has received advisory board or consulting fees from AbbVie, Takeda, Janssen, Celltrion, Pfizer, GlaxoSmithKline, Ferring, Novartis, Roche, Gilead, NeoPharm, Predicta Med, Galmed, Medial Earlysign, and Eli Lilly, and research support from AbbVie, Takeda, Janssen, Celltrion, Pfizer, and Galmed. J-FC has received research grants from AbbVie, Pfizer, and Takeda; payment for lectures from AbbVie, Amgen, Pfizer, and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Novartis, Otsuka, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development. EH has received lecture fees from Takeda, Janssen, and BMS; and consultant or advisory board fees from AbbVie, Gilead, and Janssen. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Crohn's disease has a substantial negative impact on health-related quality of life (HRQoL)., Aim: To examine the effects of risankizumab on HRQoL in Crohn's disease METHODS: We analysed data from patients with Crohn's disease from 12-week induction trials ADVANCE (N = 850) and MOTIVATE (N = 569) with risankizumab 600 mg or 1200 mg intravenous (IV) versus placebo IV and a 52-week maintenance trial FORTIFY (N = 462) with risankizumab 180 or 360 mg subcutaneous (SC) versus placebo SC. Outcomes included Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), 36-item Short Form Health Survey (SF-36), EuroQol 5-Dimension-5-Level (EQ-5D-5L) and work productivity. The mean change and percentages of patients achieving clinically meaningful improvement in all outcomes were determined at weeks 12 and 52., Results: At week 12, more patients in the risankizumab 600 or 1200 mg groups achieved IBDQ response than with placebo (ADVANCE: 70.2%, 75.5% vs. 47.8%, p ≤ 0.001; MOTIVATE: 61.7%, 68.5% vs. 48.2%, p ≤ 0.01) and FACIT-F response (ADVANCE: 51.3%, 48.0% vs. 35.7%, p ≤ 0.01; MOTIVATE: 44.2%, 49.1% vs. 33.7%, p < 0.05). These improvements persisted at week 52 with risankizumab maintenance treatment. Similar trends were observed for SF-36 physical and mental component summary scores, EQ-5D-5L and activity impairment within work productivity measures., Conclusions: Risankizumab induction therapy (600 or 1200 mg IV) led to clinically meaningful improvements in disease-specific and general patient-reported outcomes, including fatigue, in patients with moderate to severe Crohn's disease. These improvements were sustained after 52 weeks of risankizumab (180 or 360 mg SC) maintenance therapy., (© 2022 AbbVie Inc. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Etrolizumab is a gut-targeted anti-β7 monoclonal antibody targeting α4β7 and αEβ7 integrins. We aimed to compare the safety and efficacy of two doses of etrolizumab with placebo in patients with Crohn's disease., Methods: BERGAMOT was a randomised, placebo-controlled, double-blind, phase 3 study done at 326 treatment centres worldwide. We included patients aged 18-80 years with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220-480, and a mean daily stool frequency score of ≥6 or a mean daily stool frequency score of >3, and a mean daily abdominal pain score of >1, as well as the presence of active inflammation on screening ileocolonoscopy) who had intolerance, inadequate response, or no response to one or more of corticosteroids, immunosuppressants, or anti-TNF therapy within the past 5 years. BERGAMOT consisted of three induction cohorts (a placebo-controlled, double-blind exploratory cohort [cohort 1]; an active treatment cohort not containing a placebo control [cohort 2]; and a placebo-controlled, double-blind pivotal cohort [cohort 3]) and one maintenance cohort. In induction cohort 3, during the 14-week induction, patients were randomly assigned (2:3:3) to receive matched placebo, 105 mg etrolizumab subcutaneously every 4 weeks (at weeks 0, 4, 8, and 12) or 210 mg etrolizumab subcutaneously (at weeks 0, 2, 4, 8, and 12), stratified by concomitant treatment with oral corticosteroids, concomitant treatment with immunosuppressants, baseline disease activity, and previous exposure to anti-TNF therapy. To preserve masking, all patients received two injections at weeks 0, 4, 8, and 12 and one injection at week 2. Week 14 etrolizumab responders from all cohorts were re-randomly assigned (1:1) to receive 105 mg etrolizumab (etrolizumab maintenance group) or placebo (placebo maintenance group) every 4 weeks for 52 weeks; patients in the induction placebo group underwent a sham re-randomisation to preserve masking. During maintenance, randomisation was stratified by CDAI remission status, concomitant treatment with oral corticosteroids, induction dose regimen, and previous exposure to anti-TNF therapy. All participants and study site personnel were masked to treatment assignment for both induction and maintenance. Co-primary induction endpoints at week 14 (placebo vs 210 mg etrolizumab) were clinical remission (mean stool frequency ≤3 and mean abdominal pain ≤1, with no worsening) and endoscopic improvement (≥50% reduction in Simple Endoscopic Score for Crohn's Disease [SES-CD]). Co-primary maintenance endpoints at week 66 (placebo vs etrolizumab) were clinical remission and endoscopic improvement. Efficacy was analysed using a modified intention-to-treat (mITT) population, defined as all randomised patients who received at least one dose of study drug (induction) and as all patients re-randomised into maintenance who received at least one dose of study drug in the maintenance phase (maintenance). Safety analyses included all patients who received at least one dose of study drug. Maintenance safety analyses include all adverse events occurring in both induction and maintenance. This trial is registered with ClinicalTrials.gov, NCT02394028, and is closed to recruitment., Findings: Between March 20, 2015, and Sept 7, 2021, 385 patients (209 [54%] male and 326 [85%] white) were randomly assigned in induction cohort 3 to receive placebo (n=97), 105 mg etrolizumab (n=143), or 210 mg etrolizumab (n=145). 487 patients had a CDAI-70 response in any of the induction cohorts and were enrolled into the maintenance cohort, of whom 434 had a response to etrolizumab and were randomly assigned to placebo (n=217) or 105 mg etrolizumab (n=217). At week 14, 48 (33%) of 145 patients in the 210 mg induction etrolizumab group versus 28 (29%) of 96 patients in the placebo induction group were in clinical remission (adjusted treatment difference 3·8% [95% CI -8·3 to 15·3]; p=0·52), and 40 (27%) versus 21 (22%) showed endoscopic improvement (5·8% [-5·4 to 17·1]; p=0·32). At week 66, a significantly higher proportion of patients receiving etrolizumab than those receiving placebo had clinical remission (76 [35%] of 217 vs 52 [24%] of 217; adjusted treatment difference 11·3% [95% CI 2·7-19·7]; p=0·0088) and endoscopic improvement (51 [24%] vs 26 [12%]; 11·5% [4·1-18·8]; p=0·0026). Similar proportions of patients reported one or more adverse events during induction (95 [66%] of 143 in the 105 mg etrolizumab group, 85 [59%] of 145 in the 210 mg etrolizumab group, and 51 [53%] of 96 in the placebo group) and maintenance (189 [87%] of 217 in the etrolizumab group and 190 [88%] of 217 in the placebo group). During induction, the most common treatment-related adverse events were injection site erythema (six [4%] of 143 in the 105 mg etrolizumab group, four [3%] of 145 in the 210 mg etrolizumab group, and none of 96 in the placebo group), and arthralgia (two [1%], one [1%], and four [4%]). In the maintenance cohort, the most common treatment-related adverse events were injection site erythema (six [3%] of 217 in the etrolizumab group vs 14 [6%] of 217 in the placebo: group), arthralgia (five [2%] vs eight [4%]), and headache (five [2%] vs seven [3%]). The most common serious adverse event was exacerbation of Crohn's disease (14 [6%] of 217 patients taking placebo and four [2%] of 217 patients taking 105 mg etrolizumab in the maintenance cohort)., Interpretation: A significantly higher proportion of patients with moderately to severely active Crohn's disease achieved clinical remission and endoscopic improvement with etrolizumab than placebo during maintenance, but not during induction., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests WJS has received grants from Alimentiv, Arena, Boehringer Ingelheim, Celgene, Gilead, GSK, Janssen, Lilly, Pfizer, Prometheus, Roche/Genentech, Series Therapeutics, Shire, Takeda, and Theravance; personal fees from Alfasigma, Alimentiv, Alivio, Allakos, Amgen, Applied Molecular Transport, Arena, AstraZeneca, Atlantic Pharmaceuticals, Bausch Health, BeiGene, Bellatrix, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celgene, Celltrion, Celularity, ClostraBio, Codexis, Cosmo Pharmaceuticals, Equillium, Escalier Biosciences, Forbion, Galapagos, Gilead, Glenmark, Gossamer Bio, GSK, Immunic, InDex Pharmaceuticals, Inotrem, Intact Therapeutics, iota Biosciences, Janssen, Kiniksa, Kyverna, Landos Biopharma, Lilly, Morphic Therapeutics, Novartis, Ono, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer, Pharm-Olam, Progenity, Prometheus, Protagonist Therapeutics, Provention Bio, PTM Therapeutics, Quell Therapeutics, Reistone Biopharma, Roche/Genentech, Series Therapeutics Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sterna Biologicals, Sublimity, Surrozen, Takeda, Theravance, Thetis, Tillotts Pharma, UCB, Vedanta Biosciences, Ventyx Biosciences, Vivelix, Vividion, Vivreon Gastrosciences, Xencor, and Zealand Pharma; and stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Progenity, Prometheus, Protagonist Therapeutics, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, and Vivreon Gastrosciences. JP has received grants from MSD; consulting fees from AbbVie, Arena, Boehringer Ingelheim, Celgene, GSK, Janssen, MSD, Nestlé, Oppilan Pharma, Pfizer, Progenity, Roche/Genentech, Takeda, Theravance, and TiGenix; and other fees and support from AbbVie and Takeda. SD has received consulting fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Dr Falk Pharma, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Lilly, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor. ZS, AH, RJ-M, and CE are employees of Roche/Genentech and receive salary and stock options. MD has received speaker fees from AbbVie, Janssen, Pfizer, Roche, and Takeda; consulting fees from Bioclinica; and other fees and support from AbbVie, Chiesi, Ferring, Janssen, Roche, SOFAR, and Takeda. JFV has received grants from AbbVie, Applied Molecular Transport, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, and Takeda. DL has received grants from AbbVie, Amgen, Fresenius Kabi, and Takeda; speaker fees from AbbVie, Ferring, Fresenius Kabi, Galapagos, Janssen, Pfizer, Takeda, and Tillotts Pharma; consulting fees from AbbVie, Bristol Myers Squibb, Fresenius Kabi, Galapagos, Janssen, MSD, Pfizer, Roche, Takeda, and Tillotts Pharma; and other fees and support from AbbVie, Janssen, Pfizer, and Sandoz. CB has received grants from Roche; speaker fees from AbbVie and Janssen; and other fees and support from AbbVie, Janssen, and Takeda. RA has received grants from AbbVie, Biogen, InDex Pharmaceuticals, Takeda, and Tillotts Pharma; speaker fees from AbbVie, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Ferring, Fresenius Kabi, Galapagos, InDex Pharmaceuticals, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Samsung Bioepis, Takeda, and Tillotts Pharma; consulting fees from AbbVie, Arena, Biogen, Boehringer Ingelheim, Galapagos, InDex Pharmaceuticals, Janssen-Cilag, Kliniksa Pharmaceuticals, Lilly, Samsung Bioepis, Stelic Institute, and Takeda; and other fees and support from AbbVie, Biogen, Dr Falk Pharma, and Janssen-Cilag. RP has received speaker fees and consulting fees from Roche/Genentech. SV has received grants from AbbVie, Galapagos, Janssen, Pfizer, and Takeda; speaker fees from AbbVie, Galapagos, Janssen, Pfizer, Roche/Genentech, and Takeda; and consulting fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Gilead, GSK, Hospira, IMIDomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Roche/Genentech, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma, and Zealand Pharma. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Anti-TNF-α agents (e.g. infliximab, adalimumab, etanercept) are effective management options in various inflammatory and autoimmune diseases (e.g. inflammatory bowel disease). The occurrence during anti-TNF-α agent therapy of a new onset or exacerbation of an inflammatory condition that usually responds to this class of drug has been termed a paradoxical adverse event (PAE). A wide range of ophthalmic PAEs have been reported including uveitis, optic neuritis/neuropathy, scleritis, orbital myositis, retinal vasculitis, and others. The patient reported herein developed a dramatic orbital inflammatory PAE during his infliximab infusions, which manifested as an acute orbital apex syndrome with vision loss. Physicians using this medication should be aware of this serious vision-threatening PAE, and urgent therapy with high dose intravenous corticosteroids may be required.

Background and Aims: The efficacy of current biologics may be limited by targeting only one pathway. Pentoxifylline [PTX] interferes with tumour necrosis factor [TNF] gene expression. We performed a randomised, placebo-controlled pilot study to determine if PTX plus vedolizumab [VDZ] in patients with Crohn's disease [CD] is safe and improves response compared with VDZ monotherapy., Methods: Thirty adult patients with active CD were randomised to VDZ/PTX or VDZ/placebo and followed for 24 weeks. Endoscopic activity and inflammatory cytokines were measured at baseline and Week 24. Descriptive statistics were used to determine estimates of effect., Results: Demographics were similar but baseline disease activity was higher in the VDZ/PTX group. There was no difference in clinical remission at Week 14 (60.0% vs 66.67%, odds ratio [OR] 0.76, 95% confidence interval [CI] 0.16, 3.51) or steroid-free clinical remission at Week 24 in patients receiving VDZ/PTX. Improved clinical response was noted in the VDZ/PTX group at Weeks 6, 14, and 24 [Week 6: 20% vs 6.67%, Week 14: 26.67% vs 6.67%, Week 24: 40% vs 20%]. The rate of endoscopic remission was similar between the groups [40% vs 33.33%], with a greater mean decrease in Simple Endoscopic Score-CD [SES-CD] and C-reactive protein [CRP] with VDZ/PTX [SES-CD -3.17 vs -0.15, CRP -5.56 vs 0.46]. An increase in serum TNF-α concentration was observed with VDZ/placebo group; PTX mitigated this effect. No serious adverse events occurred., Conclusions: VDZ/PTX did not provide benefit over VDZ monotherapy in clinical or endoscopic remission but appeared to improve clinical response and was safe. These data should inform a fully powered study., (© 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: Ozanimod, an oral sphingosine 1-phosphate receptor modulator currently approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis, showed clinical, endoscopic, and histological benefit in the phase 2 STEPSTONE trial for Crohn's disease (CD). We aim to describe the trial design of the YELLOWSTONE phase 3 program evaluating the safety and efficacy of ozanimod in patients with moderately to severely active CD., Methods: The YELLOWSTONE program consists of phase 3, randomized, double-blind, placebo-controlled induction (NCT03440372 and NCT03440385) and maintenance (NCT03464097) trials and an open-label extension (OLE) study (NCT03467958). Patients with inadequate response or intolerance to ≥1 CD treatment are randomized to receive daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo for 12 weeks during induction. Those who respond to ozanimod are rerandomized to continue ozanimod or placebo maintenance therapy for 52 weeks. Patients who do not meet criteria for maintenance, experience relapse during maintenance, or complete maintenance or ≥ 1 year of STEPSTONE are eligible for open-label treatment for up to 234 weeks. Efficacy endpoints include clinical, endoscopic, and histologic outcomes., Results: Expected 2023 (induction studies), 2024 (maintenance study), and 2026 (OLE)., Conclusion: YELLOWSTONE will provide pivotal phase 3 data on the safety and efficacy of ozanimod in patients with moderately to severely active CD using state-of-the-art methods, including centrally read endoscopic and histologic measurements, along with subjective assessments of symptom control based on the Crohn's Disease Activity Index. These studies could enable approval of ozanimod as a new CD therapy., Clinical Trial Registration Numbers: NCT03440372, NCT03440385, NCT03464097, NCT03467958., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Brian G. Feagan has consulted for AbbVie, ActoGeniX, Albireo, Amgen, AstraZeneca, Avaxia Biologics, Baxter, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Calypso, Celgene, Elan, enGene, Ferring Pharma, Roche/Genentech, gIcare Pharma, Gilead, Given Imaging, GSK, Ironwood, Janssen, Johnson & Johnson, Lexicon, Lilly, Merck, Millennium, Nektar, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Sanofi, and UCB, and is a director at Robarts Clinical Trials. Stefan Schreiber has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Fresenius, Galapagos/Gilead, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist, ProventionBio, Takeda, and Theravance Biopharma. Anita Afzali has served as a consultant for AbbVie, Takeda, Janssen, Pfizer, Bristol Myers Squibb, Eli Lilly, Gilead, TLL Pharmaceuticals, Arena Pharmaceuticals, and DiaSorin, and has received speaker fees from AbbVie, Takeda, Janssen, Pfizer, and Bristol Myers Squibb. Florian Rieder has consulted for Adnovate, AgomAb, Allergan, AbbVie, Arena, Boehringer Ingelheim, Celgene/Bristol Myers Squibb, CDISC, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, GuidePoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Janssen, Koutif, Mestag Therapeutics, Metacrine, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, Redx Pharma, Roche, Samsung, Surmodics, Surrozen, Takeda, TechLab, Theravance, Thetis, UCB, Ysios Capital, and 89bio. Jeffrey Hyams served on advisory boards for Janssen, Pfizer, and Boehringer Ingelheim and as a consultant to Takeda, Bristol Myers Squibb, Thetis, and Eli Lilly. Kanthi Kollengode, Jared Pearlman, Vladimir Son, and Cecilia Marta are employees of Bristol Myers Squibb. Douglas C. Wolf has received honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Arena, Celgene/Bristol Myers Squibb, Janssen, Pfizer, Prometheus, Takeda, and UCB. Geert G. D'Haens has consulted for AbbVie, Cellceutix, Celgene, Endo, Ferring, Gilead, Janssen Ortho Biotech, Eli Lilly, American Regent, Merck, Morphic, Pfizer, Prometheus Laboratories, Romark, Salix Pharmaceuticals/Valeant, Shire Pharmaceuticals, Takeda, and UCB; conducted research for UCB, Janssen Ortho Biotech; editor (honorarium) Gastroenterology and Hepatology (Gastro-Hep Communications), Springer Science and Business Media; received book royalties from SLACK, Inc., and Professional Communications, Inc., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Anti-tumour necrosis factor (TNF) agents are associated with increased infection risk among elderly IBD patients, but little is known about non anti-TNF biologics in this cohort. We examined the safety and effectiveness of ustekinumab in elderly Crohn's patients., Methods: This retrospective multi-centre cohort study included Crohn's patients ≥60-years old who commenced ustekinumab. We recorded Harvey-Bradshaw index (HBI), concomitant steroid therapy, treatment persistence and new infections or malignancies. Primary outcome was serious infections requiring hospitalisation., Results: Seventy patients were included, with median age of 68 years. 43 (61.4%) had prior anti-TNF exposure, and 15 (21.4%) vedolizumab. Median treatment duration was 12 months, totalling 84 patient-years. Nine serious infections were reported, incidence 106.7/1000 patient-years. Systemic steroids were associated with increased risk of serious infections [odds ratio (OR) 7.83, 95% confidence interval (CI): 1.44-44.32, P = 0.02]. There were 27 "non-serious" infections; 321.4/1000 patient-years. Charlson co-morbidity index (OR 1.49, 95% CI: 1.05-2.12, P = 0.03) and steroid exposure (OR 44.10, 95% CI: 1.75-1112.10, P = 0.02) increased non-serious infection risk (P &lt; 0.05). Mean HBI improved from 8.13 to 4.64 at 6 months and 4.10 at last follow up (P &lt; 0.0001). 12-month treatment persistence was 55.7% (N = 39); 34 (48.6%) were steroid-free., Conclusion: Ustekinumab was safe and effective in a cohort of elderly Crohn's disease patients. Infections were mostly mild, not resulting in therapy discontinuation. Serious infection risk was comparable to previously reported rates with anti-TNF agents. Steroid exposure was associated with an increased serious infection risk., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Ethnopharmacological Relevance: Mume Fructus (MF) is a well-known traditional Chinese medicine used to treat chronic cough, prolonged diarrhea, and other inflammation-related diseases. We previously confirmed the anti-colitis effect of its ethanol extract on a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced Crohn's disease (CD) rat model. However, the active ingredients and underlying mechanisms of MF remain unknown., Aim of the Study: To clarify the material basis and potential mechanism of the ethanol extract of MF (MFE) in alleviating CD and its complications, such as lung injury and intestinal obstruction., Materials and Methods: MF was extracted with 80% ethanol aqueous solution and separated with 0, 40, and 100% ethanol aqueous solutions. MFE and its fractions were screened in a TNBS-induced CD rat model. For the bioactive fraction, the chemical composition was identified and quantified using ultrahigh-performance liquid chromatography coupled with diode-array detection and quadrupole time-of-flight tandem mass spectrometry. Interleukin (IL)-1β, IL-6, IL-17, transforming growth factor (TGF)-β, and lipopolysaccharide (LPS) levels in the colon, lungs, and/or plasma were detected using enzyme-linked immunosorbent assays. The expression levels of zonula occludens-1 (ZO-1) and occludin in the colon were measured using immunohistochemical staining, and the intestinal microbiota and short-chain fatty acid (SCFA) levels were analyzed using 16S rRNA gene sequencing and gas chromatography/mass spectrometry., Results: The 40% ethanol fraction of MF (MFE40), which mainly contained methyl citrate, ethyl citrate, and caffeoylquinic acid ethyl esters, was identified as the active fraction that could alleviate CD in rats. MFE40 could ameliorate inflammation and fibrosis in the colon and lung tissues by inhibiting the secretion of cytokines, such as IL-1β, IL-6, IL-17, and TGF-β, along with intestinal obstruction and lung injury in CD rats. The possible mechanisms of MFE40 were related to increased expression of ZO-1 and occludin in the colon, reduction in plasma LPS levels, and restoration of SCFAs via reduction in the relative abundance of Adlercreutzia, Clostridium&#95;sensu&#95;stricto&#95;1, Erysipelatoclostridium, Faecalibaculum, norank&#95;f&#95;Erysipelotrichaceae, Phascolarctobacterium Coriobacteriaceae&#95;UGG&#95;002, and Allobaculum and increase in the relative abundance of Escherichia shigella, Christensenella, Acetivibrio&#95;ethanolgignens, and Butyricicoccus. MFE40 had no significant influence on the inflammatory factors in healthy rats., Conclusions: Citrate esters and hydroxycinnamate esters are the main active constituents of MFE40. MFE40 exhibited a remission effect on CD rats and inhibited intestinal obstruction and lung injury via anti-inflammatory effects and regulation of the intestinal microbiota-gut-lung homeostasis., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Aims: Both methotrexate and tioguanine can be considered as treatment options in patients with Crohn's disease after failure of conventional thiopurines. This study aimed to compare tolerability and drug survival of methotrexate and tioguanine therapy after failure of conventional thiopurines in patients with Crohn's disease., Methods: We conducted a retrospective, multicentre study, including patients with Crohn's disease initiating monotherapy methotrexate or tioguanine after failure [all causes] of conventional thiopurines. Follow-up duration was 104 weeks or until treatment discontinuation. The primary outcome was cumulative therapy discontinuation incidence due to adverse events. Secondary outcomes included total number of [serious] adverse events, and ongoing monotherapy., Results: In total, 219 patients starting either methotrexate [n = 105] or tioguanine [n = 114] were included. In all 65 [29.7%] patients (methotrexate 43.8% [46/105 people], tioguanine 16.7% [19/114 people], p <0.001) discontinued their treatment due to adverse events during follow-up. Median time until discontinuation due to adverse events was 16 weeks (interquartile range [IQR] 7-38, p = 0.812). Serious adverse events were not significantly different. Patients treated with methotrexate experienced adverse events more often [methotrexate 83%, tioguanine 46%, p <0.001]. Total monotherapy drug survival after 104 weeks was 22% for methotrexate and 46% for tioguanine [p <0.001]., Conclusions: We observed a higher cumulative discontinuation incidence due to adverse events for methotrexate [44%] compared with tioguanine [17%] in Crohn's disease patients after failure of conventional thiopurines. The total adverse events incidence during methotrexate use was higher, whereas serious adverse events incidence was similar. These favourable results for tioguanine treatment may guide the selection of immunosuppressive therapy after failure of conventional thiopurines., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: Subcutaneous (SC) vedolizumab is effective in inflammatory bowel diseases (IBD) when administered after induction with two infusions., Aim: To assess the effectiveness, safety and pharmacokinetics of a switch from intravenous (IV) to SC maintenance vedolizumab in patients with IBD METHODS: In this prospective cohort study, patients with IBD who had ≥4 months IV vedolizumab were switched to SC vedolizumab. We studied the time to discontinuation of SC vedolizumab, adverse events (AEs), changes in clinical and biochemical outcomes and vedolizumab concentrations at baseline, and weeks 12 and 24., Results: We included 82 patients with Crohn's disease (CD) and 53 with ulcerative colitis (UC). Eleven (13.4%) patients with CD and five (9.4%) with UC discontinued SC vedolizumab after a median of 18 (IQR 8-22) and 6 weeks (IQR 5-10), respectively. Four patients with CD switched to a different drug due to loss of response, nine switched back to IV vedolizumab due to adverse events, and three due to needle fear. Common AEs were injection site reactions (n = 15) and headache (n = 6). Median clinical and biochemical disease activity remained stable after the switch. Median serum vedolizumab concentrations increased from 19 μg/ml at the time of the switch to 31 μg/ml 12 weeks after the switch (p < 0.005)., Conclusions: Switching from IV to SC vedolizumab maintenance treatment is effective in patients with CD or UC. However, 9% of patients were switched back to IV vedolizumab due to adverse events or fear of needles., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aims: To date, there are no systematic pharmacokinetic [PK] data on vedolizumab in paediatric inflammatory bowel disease [IBD]. We report results from HUBBLE, a dose-ranging, phase 2 trial evaluating the PK, safety and efficacy of intravenous vedolizumab for paediatric IBD., Methods: Enrolled patients [aged 2-17 years] with moderate to severe ulcerative colitis [UC] or Crohn's disease [CD] and body weight ≥10 kg were randomized by weight to receive low- or high-dose vedolizumab [≥30 kg, 150 or 300 mg; <30 kg, 100 or 200 mg] on Day 1 and Weeks 2, 6 and 14. Week 14 assessments included PK, clinical response and exposure-response relationship. Safety and immunogenicity were assessed., Results: Randomized patients weighing ≥30 kg [UC, n = 25; CD, n = 24] and <30 kg [UC, n = 19; CD, n = 21] had a baseline mean [standard deviation] age of 13.5 [2.5] and 7.6 [3.2] years, respectively. In almost all indication and weight groups, area under the concentration curve and average concentration increased ~2-fold from low to high dose; the trough concentration was higher in each high-dose arm compared with the low-dose arms. At Week 14, clinical response occurred in 40.0-69.2% of patients with UC and 33.3-63.6% with CD in both weight groups. Clinical responders with UC generally had higher trough concentration vs non-responders, while this trend was not observed in CD. Fourteen per cent [12/88] of patients had treatment-related adverse events and 6.8% [6/88] had anti-drug antibodies., Conclusions: Vedolizumab exposure increased in an approximate dose-proportional manner. No clear dose-response relationship was observed in this limited cohort. No new safety signals were identified., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background and Aims: Optimal management of patients with inflammatory bowel disease [IBD] after anti-tumour necrosis factor [TNF] discontinuation due to severe induced skin lesions is unclear. Our study aimed to describe dermatological and IBD evolution after anti-TNF discontinuation for this side effect., Methods: We conducted a multicentre retrospective study including consecutive IBD patients who discontinued anti-TNF due to severe induced skin lesions. Our objectives were to determine factors associated with dermatological remission [complete disappearance of skin lesions] and with IBD relapse in patients with inactive disease at inclusion, notably the impact of an early switch to another biological agent within 3 months of anti-TNF discontinuation., Results: Among the 181 patients [134 women, 160 Crohn's disease] included in the 13 participating centres, dermatological remission occurred in 110 [62%] patients with a median [interquartile range, IQR] interval of 8.0 [6.8-11.0] months. Scalp location was independently associated with less remission of skin lesions (hazard ratio [HR] = 0.64 [95% CI 0.43-0.94], p = 0.02) while early switch was independently associated with a higher probability of remission of skin lesions (HR = 1.64 [95% CI 1.1-2.5], p = 0.02). Among the 148 patients with inactive IBD at inclusion, disease relapse occurred in 75 [51%] patients with a median [IQR] interval of 26.0 [23.0-39.1] months. Survival rates without IBD relapse at 1 year were 85.8% [95% CI 77.5-94.9] in the early switch group and 59.3% [95% CI 48.9-71.9] in the other group [p < 0.01]., Conclusions: Early switch to a new biological is associated with a higher probability of healing of anti-TNF-induced skin lesions and significantly reduces the risk of IBD relapse., (© 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: Therapy with two concomitant biologicals targeting different inflammatory pathways has emerged as a new therapy option for treatment refractory inflammatory bowel disease (IBD). Data on the efficacy and safety of dual biological therapy (DBT) are scarce and are investigated in this study., Materials and Methods: Data on all patients treated with a combination of two biologicals in four Finnish tertiary centres were collected and analysed. Remission was assessed by a physician on the basis of biomarkers, endoscopic evaluation and alleviation of symptoms., Results: A total of 16 patients with 22 trials of DBT were included. Fifteen patients had Crohn's disease. The most common combination of DBT was adalimumab (ADA) and ustekinumab (USTE; 36%) with median follow-up of nine months (range 2-31). Altogether seven (32%) patients were in remission at the end of follow-up and in two trials response to DBT was assessed to be partial with the relief of patient symptoms. In a total of four trials DBT reduced the need for corticosteroids. The majority of patients achieving a response to DBT were treated with the combination of ADA and USTE (56%). At the end of follow-up all nine (41%) patients responding to DBT continued treatment. Infection complications occurred in three patients (19%)., Conclusion: DBT is a promising alternative treatment for refractory IBD, and half of our patients benefitted from it. More data on the efficacy and safety of DBT are needed especially in long-term follow up.

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

Background: We describe a case of acute hypoxic respiratory failure due to drug induced lung disease secondary to ustekinumab, which is a monoclonal antibody used to treat psoriasis, psoriatic arthritis, and inflammatory bowel disease., Case Presentation: A 33-year-old man with a history of Crohn's disease presented with fevers, myalgias, and abdominal pain, and subsequently developed acute hypoxemic respiratory failure approximately 2 weeks after restarting ustekinumab for his Crohn's disease. Cross-sectional chest imaging showed ground glass opacities and bilateral consolidations. Due to progressive hypoxia, he ultimately required intubation and mechanical ventilation. Broad infectious and autoimmune work up was negative, making drug induced interstitial lung disease (DILD) the leading consideration. He was treated with high dose steroids with dramatic improvement in his respiratory status. At follow up, his imaging findings had largely resolved, and his pulmonary function tests were normal., Conclusions: For patients presenting with acute hypoxic respiratory failure, it is critical to identify the underlying cause. In addition to testing for common respiratory infections that can cause respiratory failure, patients should also be evaluated for risk factors for developing atypical or opportunistic infections as well as inflammatory pneumonitis. Due to receiving ustekinumab, our patient was both at risk for developing an opportunistic infection as well as DILD. Although rare, DILD is a recognized toxicity of ustekinumab. Ustekinumab can cause significant lung injury, as in our patient, but with steroids and avoidance of future doses of the medication, our patient demonstrated good recovery. Reassuring outcomes have similarly been described in the literature; however, this case provides further details about outcomes with long-term follow-up clinical, imaging, and pulmonary function testing data available. We recommend consideration of high dose steroids for these patients for whom DILD is suspected., (© 2022. The Author(s).)

Objectives: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A (IL-17A), has shown significant efficacy in the treatment of psoriatic arthritis (PsA) and sustained long-term clinical response without unexpected new safety outcome for an IL-17A inhibitor. Here, we report the updated safety profile of ixekizumab up to 3 years in patients with PsA., Methods: This is an integrated safety analysis from four clinical trials in patients with PsA who received at least one dose of ixekizumab. Treatment-emergent adverse events (TEAEs) and selected adverse events (AEs) exposure-adjusted incidence rates (EAIRs) per 100 patient-years up to 3 years of exposure are reported., Results: A total of 1401 patients with a cumulative ixekizumab exposure of 2247.7 patient-years were included in this analysis. The EAIR of patients with ≥1 TEAE was 50.3 per 100 patient-years and most TEAEs were mild to moderate in severity. Serious AEs were reported by 134 patients (EAIR=6.0). The most reported TEAEs were nasopharyngitis (EAIR=9.0) and upper respiratory tract infection (EAIR=8.3). Infections in general and injection site reactions were the most common TEAEs; the incidence rates of serious cases were low (EAIR ≤1.2). The EAIRs of malignancies (EAIR=0.7), inflammatory bowel disease (EAIR=0.1) including ulcerative colitis and Crohn's disease, depression (EAIR=1.6), and major adverse cerebro-cardiovascular events (EAIR=0.5) were low. As assessed, based on year of exposure, incidence rates were decreasing or constant over time., Conclusions: In this analysis, the overall safety profile and tolerability of ixekizumab are consistent with the known safety profile in patients with PsA. No new or unexpected safety events were detected., Trial Registration Number: NCT01695239, NCT02349295, NCT02584855, NCT03151551., Competing Interests: Competing interests: AAD reports consulting and advisory boards for AbbVie, Amgen, Aurinia, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, GlaxoSmithKline, Janssen, MoonLake, Novartis, Pfizer and UCB; and research grants from AbbVie, Eli Lilly and Company, GlaxoSmithKline, Novartis, Pfizer and UCB. BC has received grant/research support from Novartis, Pfizer and Roche-Chugai; served as a consultant for AbbVie, Eli Lilly and Company, Gilead Sciences, Janssen, Pfizer, Roche-Chugai and Sanofi; and served on speakers’ bureaus for Bristol Myers Squibb, Eli Lilly and Company, Gilead Sciences, Merck Sharp & Dohme, Pfizer and Roche-Chugai. APA, DZ, RB, AMG and ATS are shareholders and employees of Eli Lilly and Company. G-RRB is a consultant for Eli Lilly and Company, Janssen, Novartis and Pfizer; and has received research funding from Eli Lilly and Company., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with Crohn's disease (CD) experience intestinal inflammation. Ontamalimab (SHP647), a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1, is a potential novel CD treatment. OPERA II, a multicenter, open-label, phase 2 extension study, assessed the long-term safety and efficacy of ontamalimab in patients with moderate-to-severe CD., Methods: Patients had completed 12 weeks of blinded treatment (placebo or ontamalimab at 22.5, 75, or 225 mg subcutaneously) in OPERA (NCT01276509) or had a clinical response to ontamalimab 225 mg in TOSCA (NCT01387594). Participants received ontamalimab at 75 mg every 4 weeks (weeks 0-72), then were followed up every 4 weeks for 24 weeks. One-time dose reduction to 22.5 mg or escalation to 225 mg was permitted at the investigator's discretion. The primary end points were safety and tolerability outcomes. Secondary end points included changes in serum drug and biomarker concentrations. Efficacy end points were exploratory, and used non-responder imputation methods., Results: Overall, 149/268 patients completed the study. The most common adverse event leading to study discontinuation was CD flare (19.8%). Two patients died; neither death was considered to be drug related. No dose reductions occurred; 157 patients had their dose escalated. Inflammatory biomarker concentrations decreased. Serum ontamalimab levels were consistent with known pharmacokinetics. Remission rates (Harvey-Bradshaw Index [HBI] ≤ 5; baseline, 48.1%; week 72, 37.3%) and response rates (baseline [decrease in Crohn's Disease Activity Index ≥ 70 points], 63.1%; week 72 [decrease in HBI ≥ 3], 42.5%) decreased gradually., Conclusions: Ontamalimab was well tolerated; treatment responses appeared to be sustained over 72 weeks.ClinicalTrials.gov ID: NCT01298492., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background and Aims: 5-aminosalicylates (5-ASA) are frequently used in the management of Crohn's disease (CD). We used a de-identified administrative claims database to compare patterns and outcomes of continuing versus stopping 5-ASA in patients with CD who escalated to anti-metabolite monotherapy., Methods: Patients with CD on 5-ASA who were new users of anti-metabolite monotherapy and followed for at least 12 months from OptumLabs® Data Warehouse. Three patterns of 5-ASA use were identified: stopped 5-ASA, short-term 5-ASA (use for < 6 months after starting anti-metabolites), or persistent 5-ASA (use for > 6 months after starting anti-metabolites). Outcomes (need for corticosteroids, risk of CD-related hospitalization and/or surgery, treatment escalation to biologic therapy) were compared using Cox proportional hazard analysis adjusting for key covariates, with a 12-month immortal time period., Results: Of 3036 patients with CD who were new-users of anti-metabolite monotherapy, 667 (21.9%), 626 (20.6%), and 1743 (57.4%) stopped 5-ASA, used 5-ASA transiently or persistently, respectively. Compared to patients who stopped 5-ASA after starting anti-metabolites, persistent 5-ASA use was associated with a higher risk of corticosteroid use (HR, 1.24 [1.08-1.42]), without an increase in risk of CD-related hospitalization (HR, 1.21 [0.98-1.49]), CD-related surgery (HR, 1.28 [0.90-1.80]) or treatment escalation (HR, 0.85 [0.62-1.20]). Sensitivity analyses using a 3-month window after initiation of anti-metabolites to classify patients as continuing vs. stopping 5-ASA showed similar results. Residual confounding by disease severity could not be excluded., Conclusion: 5-ASAs are frequently continued long-term even after escalation to anti-metabolite therapy in patients with CD but offer no clinical benefit over stopping 5-ASA., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The efficacy and safety profile of ustekinumab (UST) in Crohn's disease (CD) is favorable; however, data in elderly patients are lacking. We aimed to assess the safety and efficacy of UST in elderly CD., Methods: We performed a retrospective cohort study of CD patients classified as elderly (age ≥ 65 years at UST initiation) or nonelderly (<65 years) treated at a large, tertiary referral center. Outcomes assessed were clinical (measured by physician global assessment [PGA]) and steroid-free response, remission, adverse events, and postsurgical complications were compared by age category. Multivariable regression modeling and survival analysis was also performed., Results: In total, 117 patients (elderly n = 39, nonelderly n = 78) were included in the study. Elderly patients had predominantly moderate disease (87.2%), while nonelderly had a higher proportion of severe disease activity (44.9%) (p = 0.001), though no differences in baseline endoscopic activity, prior biologic use, or steroid or immunomodulator use at baseline existed (p > 0.05 all). While nearly 90% patients in both groups experienced clinical response to UST, compared to nonelderly, elderly patients were less likely to achieve complete clinical remission (28.2% vs. 52.6%, p = 0.01). On regression modeling, age was not associated with clinical outcomes (p > 0.05 all). Mucosal healing was achieved in 26% elderly and 30% nonelderly patients (p = 0.74). There were no significant differences in infusion reactions (2.6% vs. 6.4%, p = 0.77), infection (5.2% vs. 7.7%, p = 0.7), or postsurgical complications (p = 0.99) by age category., Conclusion: UST is safe and effective in elderly CD. Although limited by sample size and retrospective design, such real-world data can inform biologic positioning in this IBD population., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background/aims: Originator-adalimumab, an established treatment for patients with Crohn's disease (CD), showed no difference in efficacy or adverse events versus adalimumab biosimilar SB5 (SB5-adalimumab) over 10 weeks (W) of treatment. To understand the long-term effectiveness of SB5-adalimumab in CD, patients switched from originator-adalimumab to SB5-adalimumab were compared with patients remaining on originator-adalimumab over 104 W., Methods: Data on patients aged ≥18 years, diagnosed with CD and treated at ISCARE, were collected prospectively from July 2018 to January 2021. Primary outcome: clinical disease activity at W52, measured by Harvey-Bradshaw index (HBI). Secondary outcomes: C-reactive protein (CRP), faecal calprotectin (FC) and adalimumab concentrations at W10, 26, 52 and 104, and treatment persistence. To ensure comparable cohorts, patients were propensity score (PS)-matched for age, gender and disease activity., Results: After matching, 54 patients remained per cohort. At W52, mean (SD) HBI score was 3.2 (2.5) for originator-adalimumab and 4.0 [3.6] for SB5-adalimumab (difference [95% CI] -0.78 [-2.8, 1.3]; n = 18/cohort); no clinically meaningful differences in CRP, FC or drug concentrations were noted. Kaplan-Meier's estimates (95% CI) of remaining on treatment were originator-adalimumab: 0.870 (0.785-0.965) versus SB5-adalimumab: 0.648 (0.533-0.789) at W52 and significantly lower for SB5-adalimumab versus originator-adalimumab ( p < .001) over 104 W. Local skin reaction events/pain was the main reason for treatment discontinuation in the SB5-adalimumab cohort ( n  = 20/54 [37%])., Conclusions: These long-term results of CD patients receiving originator-adalimumab or following nonmedical switch to SB5-adalimumab show similar therapeutic effects on clinical disease activity, biological parameters and pharmacokinetic profile in both cohorts from 52 to 104 W. A separation in persistence was observed beyond W26, mainly due to differences in local reactions at the injection site.

Background and Aims: There are limited comparative data for infliximab and vedolizumab in inflammatory bowel disease patients., Methods: We conducted a systematic review and meta-analysis to compare the efficacy and safety of infliximab and vedolizumab in adult patients with moderate-to-severe Crohn's disease or ulcerative colitis., Results: We identified six eligible Crohn's disease and seven eligible ulcerative colitis trials that randomised over 1900 participants per disease cohort to infliximab or vedolizumab. In the Crohn's disease and ulcerative colitis cohorts, infliximab yielded better efficacy than vedolizumab for all analysed outcomes (CDAI-70, CDAI-100 responses, and clinical remission for Crohn's disease and clinical response and clinical remission for ulcerative colitis) during the induction phase, with non-overlapping 95% confidence intervals. In the maintenance phase, similar proportions of infliximab- or vedolizumab-treated patients achieved clinical response, clinical remission, or mucosal healing in both Crohn's disease and ulcerative colitis. For the safety outcomes, rates of adverse events, serious adverse events, and discontinuations due to adverse events were similar in infliximab- and vedolizumab-treated patients in both diseases. The infection rate was higher in infliximab for Crohn's disease and higher in vedolizumab when treating patients with ulcerative colitis. There was no difference between the treatments in the proportions of patients who reported serious infections in both indications., Conclusions: Indirect comparison of infliximab and vedolizumab trials in adult patients with moderate-to severe Crohn's disease or ulcerative colitis demonstrated that infliximab has better efficacy in the induction phase and comparable efficacy during the maintenance phase and overall safety profile compared to vedolizumab., (© 2022. The Author(s).)

Biologics and immunomodulators (IMM) are generally considered the most effective therapies for the treatment of ulcerative colitis and Crohn's disease. However, despite the efficacy of these therapies, many patients either have a primary lack of response or a secondary loss of response to these medications. Therapeutic drug monitoring (TDM) is a systematic approach to managing such patients. In this review, we summarize the latest data on TDM, including reactive and proactive TDM, in patients with inflammatory bowel disease on biologics and/or IMM., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The temporal trends in medical treatment and long-term outcomes of patients with Crohn's disease (CD) have not been well elucidated in China over the past 2 decades. Accordingly, we aimed to evaluate the treatment paradigm and long-term clinical course of Chinese patients with CD in a hospital-based cohort., Methods: All adult patients newly diagnosed with CD (n = 1338) between 1999 and 2019 in the Sir Run Run Shaw Hospital were included in this cohort. Medication utilization, disease outcomes, and risk factors were investigated., Results: Overall, 48.7%, 35.6%, 67.8%, and 61.6% of patients used 5-aminosalicylates (5-ASA), corticosteroids, thiopurines, and infliximab (IFX), respectively. The cumulative risk of 5-ASA and corticosteroid initiation decreased during follow-up, whereas that of IFX initiation increased. Throughout a median follow-up duration of 26.4 (interquartile range, 12.0-49.2) months, a total of 486 and 300 patients underwent hospitalization and surgery, respectively. Of the 1097 patients with B1/B2 disease behavior at diagnosis, 10.3% experienced phenotype progression. The hospitalization rate decreased after 2015; however, surgery and phenotype progression rates did not significantly change. A Cox regression analysis indicated that IFX use since diagnosis was a contributing factor for lower rates of hospitalization and phenotype progression, whereas thiopurine use was associated with a lower surgery rate., Conclusions: Infliximab use was observed to increase as 5-ASA and corticosteroid use decreased. Additionally, hospitalization rates decreased following temporal changes in IFX management, yet the surgery and phenotype progression rates remained the same., (© The Author(s) 2021. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous studies have shown that antibiotic use and enterocolitis increase the risk of developing inflammatory bowel disease (IBD) in western countries. However, these risk factors have not yet been identified in Asian populations. This study aimed to investigate the risk of IBD development associated with antibiotic use and enterocolitis in Japan. A Japanese health insurance claims database was used to identify patients recently diagnosed with Crohn's disease (CD) and ulcerative colitis (UC) along with five matched participants without IBD. Episodes of antibiotic use and enterocolitis for 1 and 2 years before the date of diagnosis were analyzed using a conditional regression test. A total of 371 patients with CD and 2420 with UC were included. The adjusted odds ratio (AOR) increased in association with antibiotic use to 1.61 (95% confidence interval [CI] 1.26-2.05) and 1.20 (95% CI 1.09-1.31) and enterocolitis to 3.40 (95% CI 2.60-4.44) and 2.14 (95% CI 1.88-2.43) in 1 year in CD and UC, respectively. The risk associated with antibiotics was independent of the number or type of antibiotics, and the risk associated with enterocolitis did not differ with the pathogen that caused the disease. However, prior exposure to antibiotic use and enterocolitis was associated with an increased risk of developing IBD., (© 2022. The Author(s).)

Background & Aims: Guselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis. This study evaluated the efficacy and safety of guselkumab in patients with moderately to severely active Crohn's disease with inadequate response or intolerance to conventional or biologic therapy., Methods: GALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients 1:1:1:1:1 to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. Change from baseline in Crohn's Disease Activity Index score (primary end point), clinical remission, clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, endoscopic response (major secondary end points), and safety in guselkumab-treated patients vs placebo were evaluated through week 12. Ustekinumab was a reference arm., Results: Of 309 patients evaluated, approximately 50% had disease refractory to prior biologic therapy. At week 12, significantly greater reductions in Crohn's Disease Activity Index from baseline (least squares means: 200 mg: -160.4, 600 mg: -138.9, and 1200 mg: -144.9 vs placebo: -36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each guselkumab group vs placebo (Crohn's Disease Activity Index <150; 57.4%, 55.6%, and 45.9% vs 16.4%; all, P < .05). Greater proportions of patients receiving guselkumab achieved clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, and endoscopic response at week 12 vs placebo. Efficacy of ustekinumab vs placebo was also demonstrated. Safety event rates were generally similar across treatment groups., Conclusions: At week 12, all 3 dose regimens of guselkumab induced greater clinical and endoscopic improvements vs placebo, with a favorable safety profile., Clinicaltrials: gov, Number: NCT03466411., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)