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Background: Adalimumab, a fully human tumor necrosis factor (TNF) antagonist, is an effective treatment for patients with Crohn disease who are naive to the chimeric TNF antagonist, infliximab. No anti-TNF agent has been evaluated prospectively in patients with Crohn disease who had responded to another anti-TNF agent and then lost that response or were intolerant of the agent.Objective: To determine whether adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who have symptoms despite infliximab therapy or who cannot take infliximab because of adverse events.Design: 4-week, randomized, double-blind, placebo-controlled trial (November 2004 to December 2005).Setting: 52 sites in the United States, Canada, and Europe.Patients: 325 adults 18 to 75 years of age who had a history of Crohn disease for 4 months or more that was moderate to severe at baseline (Crohn's Disease Activity Index [CDAI] score, 220 to 450 points).Intervention: Patients were randomly assigned to receive induction doses of adalimumab, 160 mg and 80 mg, at weeks 0 and 2, respectively, or placebo at the same time points.Measurements: The primary end point was induction of remission at week 4. Decreases in CDAI score by 70 or more and 100 or more points (secondary end points) were also measured.Results: A total of 301 patients completed the trial. Twenty-one percent (34 of 159) of patients in the adalimumab group versus 7% (12 of 166) of those in the placebo group achieved remission at week 4 (P < 0.001). The absolute difference in clinical remission rates was 14.2 percentage points (95% CI, 6.7 to 21.6 percentage points). A 70-point response occurred at week 4 in 52% (82 of 159) of patients in the adalimumab group versus 34% (56 of 166) of patients in the placebo group (P = 0.001). The absolute difference in 70-point response rates was 17.8 percentage points (CI, 7.3 to 28.4 percentage points). Two of 159 patients in the adalimumab group and 4 of 166 patients in the placebo group discontinued treatment because of adverse events. No patients in the adalimumab group and 4 of 166 patients in the placebo group had a serious infection.Limitations: The trial did not directly compare alternative active treatments and did not evaluate maintenance of response or long-term immunogenicity of adalimumab.Conclusion: Adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who cannot tolerate infliximab or have symptoms despite receiving infliximab therapy. For more information on adalimumab in Crohn disease, click here. ClinicalTrials.gov registration number: NCT00105300. [ABSTRACT FROM AUTHOR]

Objective: To compare efficacy and tolerability of a loperamide/simethicone (LOP/SIM) combination product with that of loperamide (LOP) alone, simethicone (SIM) alone, and placebo (PBO) for acute nonspecific diarrhea with gas-related abdominal discomfort.Research Design and Methods: In this multicenter, double-blind, 48-h study, patients were randomly assigned to receive two tablets, each containing either LOP/SIM 2 mg/125 mg (n = 121), LOP 2 mg (n = 120), SIM 125 mg (n = 123), or PBO (n = 121), followed by one tablet after each unformed stool, up to four tablets in any 24-h period. The primary outcome measures were time to last unformed stool and time to complete relief of gas-related abdominal discomfort. For time to last unformed stool, an unformed stool after a 24-h period of formed stools or no stools was considered a continuance of the original episode (stricter definition) or a new episode (alternate definition).Results: A total of 483 patients were included in the intent-to-treat analysis. The median time to last unformed stool for LOP/SIM (7.6 h) was significantly shorter than that of LOP (11.5 h), SIM (26.0 h), and PBO (29.4 h) (p < or = 0.0232 in comparison with survival curves) using the alternate definition; it was numerically but not significantly shorter than that of LOP (p = 0.0709) and significantly shorter than that of SIM and PBO (p = 0.0001) using the stricter definition. LOP/SIM-treated patients had a shorter time to complete relief of gas-related abdominal discomfort than patients who received either ingredient alone or placebo (all p = 0.0001). Few patients reported adverse events in the four treatment groups, none of which were serious in nature. Potential study limitations include the ability to generalize study results to the population at large, variability in total dose consumed, and subjectivity of patient diary data.Conclusions: LOP/SIM was well-tolerated and more efficacious than LOP alone, SIM alone, or placebo for acute nonspecific diarrhea and gas-related abdominal discomfort. [ABSTRACT FROM AUTHOR]

BACKGROUND: The endoscopic substudy of the ACCENT I (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen) Crohn's disease trial examined the effects of infliximab on mucosal inflammation and mucosal healing, and assessed their impact on outcomes. DESIGN: ACCENT I was a randomized, double-blind, parallel group study. SETTING: This study took place at multiple centers in North America, Europe, and Israel. MAIN OUTCOME MEASUREMENTS: Ileocolonoscopic examinations were performed at weeks 0, 10, and 54. Complete mucosal healing was defined as the absence of all mucosal ulcerations. The end point of principal interest was the proportion of patients randomized as responders with mucosal healing at week 10. The proportion of responders who demonstrated mucosal healing at week 54 or at both weeks 10 and 54 is also summarized. Changes in Crohn's disease endoscopic index of severity (CDEIS) scores from baseline to week 10 and 54 were calculated for all patients in this substudy. RESULTS: Complete mucosal healing by week 10 occurred in significantly more week 2 responders who had received 3 doses of infliximab compared with a single dose (31% vs. 0%, p = 0.010). A significantly higher proportion of week 2 responders in the combined scheduled maintenance group had complete mucosal healing at week 54 compared with the episodic group (50% vs. 7%, p = 0.007). The results for all patients are consistent with those for week 2 responders only. Significantly greater improvement in the CDEIS occurred with scheduled maintenance compared with episodic treatment at week 10 (p

Recognizing, diagnosing, and managing inflammatory bowel disease can all be problematic. Understanding the hallmarks of the disease and keeping up-to-date on the key medical therapies will help you deliver better care. [ABSTRACT FROM AUTHOR]

Whether you treat or refer patients with Crohn's disease or ulcerative colitis, an update on a recent series of medical and surgical advances will help your management of these perplexing conditions. [ABSTRACT FROM AUTHOR]

Gastrointestinal immune-related adverse events (GI irAEs) are common manifestations of immune checkpoint inhibitor (ICI) toxicity. We present a comprehensive systematic review of the incidence, management, and clinical course of irAEs across the entire GI system, including the luminal GI tract, liver, and pancreas. MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library were used to conduct this review. All studies pertaining to GI irAEs were included. Both abstracts and full manuscripts were eligible if they included human subjects and were written in the English language. Articles not available in English, animal studies, or research not specific to GI toxicity of immunotherapy were excluded. We excluded certain article types depending on whether stronger evidence was available in the literature for a specific toxicity, for example, if prospective studies were available on a topic, retrospective studies and case reports were excluded. We extracted a final 166 articles for our review and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for data reporting. Risk of bias tools were not used to evaluate the extracted studies given the narrative nature of this manuscript, but each study was critically appraised by the manuscript writer. We detail the incidence, presentation, evaluation, management, and outcomes of the various GI toxicities that may arise with ICI therapy. Specifically, we discuss the characteristics of upper GI toxicity (esophagitis and gastroenteritis), lower GI toxicity (colitis), hepatobiliary inflammation, pancreatitis, and rarer forms of GI toxicity. We hope this review serves as a useful and accessible clinical tool that helps physicians familiarize themselves with the nuances of gastrointestinal/hepatic/pancreatic ICI toxicity diagnosis and management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: It is unclear if steroid tapering protocols can affect clinical trial outcomes in ulcerative colitis [UC], particularly fixed versus adaptive steroid tapering. Fixed steroid tapering involves incremental dose decreases at prespecified intervals, and adaptive steroid tapering uses investigator discretion as determined by the patient's response., Methods: In this post-hoc analysis from six clinical trials of UC [VARSITY, ACT 1, PURSUIT, GEMINI1, OCTAVE, and ULTRA2], responders to induction therapy with baseline corticosteroid use were considered as the primary population of interest. Adjustments were made to account for treat-through versus re-randomisation designs, and multivariate regression was performed to account for other potential confounding variables. The primary outcome was corticosteroid-free clinical remission [CR] at 1 year, and secondary outcomes were CR and endoscopic improvement., Results: There was a total of 861 patients who had achieved clinical response after induction and were using corticosteroids. Within multivariate analysis, patients using adaptive steroid tapering regimens were less likely to achieve corticosteroid-free CR at 1 year (odds ratio [OR] 0.66 [95% confidence interval, CI, 0.48-0.92], p = 0.015) but had increased odds for achieving CR at 1 year (OR 1.9 [95% CI 1.43-2.52], p < 0.001). The steroid tapering regimen was not associated with achievement of endoscopic improvement at 1 year., Conclusions: Among patients with UC on corticosteroids in clinical trials, patients using adaptive steroid weaning regimens were less likely to achieve corticosteroid-free CR at 1 year but more likely to achieve CR at 1 year. Consideration should be given to implementing mandatory fixed steroid weaning protocols in future clinical trials of UC., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: The disease severity index (DSI) for inflammatory bowel disease (IBD) combines measures of disease phenotype, inflammatory activity, and patient-reported outcomes. We aimed to validate the DSI and assess its utility in predicting a complicated IBD course., Methods: A multicenter cohort of adults with IBD was recruited. Intraclass correlation coefficients (ICCs) and weighted Kappa assessed inter-rater reliability. Cronbach's alpha measured internal consistency of DSI items. Spearman's rank correlations compared the DSI with endoscopic indices, symptom indices, quality of life, and disability. A subgroup was followed for 24 months to assess for a complicated IBD course. Area under the receiver operating characteristics curve (AUROC) and multivariable logistic regression assessed the utility of the DSI in predicting disease progression., Results: Three hundred and sixty-nine participants were included (Crohn's disease [CD], n = 230; female, n = 194; mean age, 46 years [SD, 15]; median disease duration, 11 years [interquartile range, 5-21]), of which 171 (CD, n = 99; ulcerative colitis [UC], n = 72) were followed prospectively. The DSI showed inter-rater reliability for CD (ICC 0.93, n = 65) and UC (ICC 0.97, n = 33). The DSI items demonstrated inter-rater agreement (Kappa > 0.4) and internal consistency (CD, α > 0.59; UC, α > 0.75). The DSI was significantly associated with endoscopic activity (CDn=141, r = 0.65, P < .001; UCn=105, r = 0.80, P < .001), symptoms (CDn=159, r = 0.69, P < .001; UCn=132, r = 0.58, P < .001), quality of life (CDn=198, r = -0.59, P < .001; UCn=128, r = -0.68, P < .001), and disability (CDn=83, r = -0.67, P < .001; UCn=52, r = -0.74, P < .001). A DSI of 23 best predicted a complicated IBD course (AUROC = 0.82, P < .001) and was associated with this end point on multivariable analyses (aOR, 9.20; 95% confidence interval, 3.32-25.49)., Conclusions: The DSI reliably encapsulates factors contributing to disease severity and accurately prognosticates the longitudinal IBD course., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background and Aims: This systematic review aims to elucidate the use of corticosteroids in randomized clinical trials (RCTs) evaluating biologics and small molecules for inflammatory bowel disease (IBD). We analyzed corticosteroid use during both the induction and maintenance phases, highlighting areas needing standardization and improvement in clinical research., Methods: We selected placebo-controlled phase 3 RCTs involving adults with moderate to severe IBD. These studies included detailed reports on corticosteroid use during induction and maintenance phases, with clinical remission and/or corticosteroid-free clinical remission (CSF-CR) as primary endpoints., Results: Initially, 324 studies were identified and refined to 26 RCTs after screening. Analysis revealed variability in corticosteroid administration. Over time, corticosteroid use showed a decreasing trend (Spearman ρ = -0.42, P = .045). Studies allowing higher corticosteroid doses (up to 40 mg/day of prednisone or equivalent) reported a higher proportion of corticosteroid users (51.8%, range: 42.9%-61%) compared to those excluding patients on doses >20 mg/day (37.5%, range: 31.6%-51.8%; P = .007) or >30 mg/day (41.1%, range: 29.6%-53.7%; P = .023). Trials with mandatory tapering protocols showed a narrower gap between overall clinical remission and CSF-CR rates, with an average difference of 6% in the group without mandatory tapering and 1.2% in the group with forced tapering (T-test P = .038; Cohen's d ≈ 1.1)., Conclusions: This review highlights the variability in corticosteroid use across RCTs and its impact on evaluating new IBD therapies. Standardizing tapering protocols and defining CSF-CR are essential for accurate outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Patients with ulcerative colitis (UC) who are hospitalised for acute severe flares represent a high-risk orphan population., Aim: To provide guidance for clinical trial design methodology in these patients., Methods: We created a multi-centre consortium to design and conduct a clinical trial for a novel therapeutic intervention (hyperbaric oxygen therapy) in patients with UC hospitalised for moderate-severe flares. During planning, we identified and addressed specific gaps for inclusion/exclusion criteria; disease activity measures; pragmatic trial design considerations within care pathways for hospitalised patients; standardisation of care delivery; primary and secondary outcomes; and sample size and statistical analysis approaches., Results: The Truelove-Witt criteria should not be used in isolation. Endoscopy is critical for defining eligible populations. Patient-reported outcomes should include rectal bleeding and stool frequency, with secondary measurement of urgency and nocturnal bowel movements. Trial design needs to be tailored to care pathways, with early intervention focused on replacing and/or optimising responsiveness to steroids and later interventions focused on testing novel rescue agents or strategies. The PRECIS-2 framework offers a means of tailoring to local populations. We provide standardisation of baseline testing, venous thromboprophylaxis, steroid dosing, discharge criteria and post-discharge follow-up to avoid confounding by usual care variability. Statistical considerations are provided given the small clinical trial nature of this population., Conclusion: We provide an outline for framework decisions made for the hyperbaric oxygen trial in patients hospitalised for UC flares. Future research should focus on the remaining gaps identified., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. The LIBERTY studies aimed to demonstrate superiority of CT-P13 SC vs placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC)., Methods: Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately to severely active CD or UC and inadequate response or intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks 0, 2, and 6. At week 10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until week 54 (maintenance phase) using prefilled syringes. (Co-) primary end points were clinical remission and endoscopic response (CD) and clinical remission (UC) at week 54 (all-randomized population)., Results: Overall, 396 patients with CD and 548 patients with UC received induction treatment. At week 54 in the CD study, statistically significant higher proportions of CT-P13 SC-treated patients vs placebo-treated patients achieved clinical remission (62.3% vs 32.1%; P < .0001) and endoscopic response (51.1% vs 17.9%; P < .0001). In the UC study, clinical remission rates at week 54 were statistically significantly higher with CT-P13 SC vs placebo (43.2% vs 20.8%; P < .0001). Achievement of key secondary end points was significantly higher with CT-P13 SC vs placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified., Conclusions: CT-P13 SC was more effective than placebo as maintenance therapy and was well tolerated in patients with moderately to severely active CD or UC who responded to CT-P13 IV induction., Clinicaltrials: gov, Numbers: NCT03945019 (CD) and NCT04205643 (UC)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: This study assessed whether baseline triggering receptor expressed on myeloid cells [TREM-1] whole blood gene expression predicts response to anti-tumour necrosis factor [anti-TNF] therapy in patients with ulcerative colitis [UC] or Crohn's disease [CD]., Methods: TREM-1 whole blood gene expression was analysed by RNA sequencing in patients with moderately to severely active UC or CD treated with adalimumab in the Phase 3 SERENE-UC and SERENE-CD clinical trials. The predictive value of baseline TREM-1 expression was evaluated and compared according to endoscopic and clinical response vs non-response, and remission vs non-remission, at Weeks 8 and 52 [SERENE-UC], and Weeks 12 and 56 [SERENE-CD]., Results: TREM-1 expression was analysed in 95 and 106 patients with UC and CD, respectively, receiving standard-dose adalimumab induction treatment. In SERENE-UC, baseline TREM-1 expression was not predictive of endoscopic response [p = 0.48], endoscopic remission [p = 0.53], clinical response [p = 0.58], or clinical remission [p = 0.79] at Week 8, or clinical response [p = 0.60] at Week 52. However, an association was observed with endoscopic response [p = 0.01], endoscopic remission [p = 0.048], and clinical remission [p = 0.04997] at Week 52. For SERENE-CD, baseline TREM-1 expression was not predictive of endoscopic response [p = 0.56], endoscopic remission [p = 0.33], clinical response [p = 0.07], or clinical remission [p = 0.65] at Week 12, or endoscopic response [p = 0.61], endoscopic remission [p = 0.51], clinical response [p = 0.62], or clinical remission [p = 0.97] at Week 56., Conclusions: Baseline TREM-1 gene expression did not uniformly predict adalimumab response in SERENE clinical trials. Further research is needed to identify potential blood-based biomarkers predictive of response to anti-TNF therapy in patients with inflammatory bowel disease., Clinicaltrials.gov Identifiers: NCT02065622; NCT02065570., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Neutrophil (PMN) tissue accumulation is an established feature of ulcerative colitis (UC) lesions and colorectal cancer (CRC). To assess the PMN phenotypic and functional diversification during the transition from inflammatory ulceration to CRC we analyzed the transcriptomic landscape of blood and tissue PMNs. Transcriptional programs effectively separated PMNs based on their proximity to peripheral blood, inflamed colon, and tumors. In silico pathway overrepresentation analysis, protein-network mapping, gene signature identification, and gene-ontology scoring revealed unique enrichment of angiogenic and vasculature development pathways in tumor-associated neutrophils (TANs). Functional studies utilizing ex vivo cultures, colitis-induced murine CRC, and patient-derived xenograft models demonstrated a critical role for TANs in promoting tumor vascularization. Spp1 (OPN) and Mmp14 (MT1-MMP) were identified by unbiased -omics and mechanistic studies to be highly induced in TANs, acting to critically regulate endothelial cell chemotaxis and branching. TCGA data set and clinical specimens confirmed enrichment of SPP1 and MMP14 in high-grade CRC but not in patients with UC. Pharmacological inhibition of TAN trafficking or MMP14 activity effectively reduced tumor vascular density, leading to CRC regression. Our findings demonstrate a niche-directed PMN functional specialization and identify TAN contributions to tumor vascularization, delineating what we believe to be a new therapeutic framework for CRC treatment focused on TAN angiogenic properties.

SB5 is an approved biosimilar of adalimumab, a recombinant monoclonal anti-tumor necrosis factor (TNF) antibody. The approval of SB5 was based on the comparison with reference adalimumab in analytical studies, pharmacokinetic (PK) and immunogenicity assessments, and randomized controlled trials. Efficacy data was primarily obtained in patients with rheumatoid arthritis, and extended to include additional indications such as psoriasis, Crohn's disease, or ulcerative colitis by extrapolation. Following its approval, additional post-marketing data have been collected comparing SB5 with reference adalimumab. This review summarizes the clinical data on SB5 from randomized controlled trials and provides a comprehensive overview of the available post-approval data. In "real-world" settings, SB5 was as effective as its reference product across different indications and countries, treatment persistence was well maintained throughout studies, and no new safety concerns were identified. In both controlled and "real-world" settings, switching from reference adalimumab to SB5 was not associated with altered efficacy or clinical complications. In post-approval studies, the quality of SB5 was consistent over time, independent of the batch and process changes, and the SB5 autoinjector was preferred over other autoinjectors by both healthcare professionals and patients. Taken together, these data support the use of SB5 whenever reference adalimumab is appropriate and demonstrate that switching from reference adalimumab to SB5 is feasible., (© 2023. The Author(s).)

Background: Post-traumatic stress (PTS) is the psycho-physiological response to a traumatic or life-threatening event and is implicated in inflammatory bowel disease (IBD). IBD-PTS is present in up to 30% of white, non-Hispanic patients. The rates of IBD in Asian populations are expanding, making the exploration of IBD-PTS in this population imperative., Methods: Adult patients of South/Southeast (S/SE) Asian decent with IBD for more than 6 months were recruited online via social media and patient-support groups. Participants completed the post-traumatic stress disorder (PTSD) Checklist-5 (PCL-5), the United States National Institutes of Health's Patient-Reported Outcomes Measurement Information System (NIH-PROMIS) -43 profile and demographics. S/SE Asian participants were age and sex matched (1:2) with randomly selected white, non-Hispanic controls. Statistical analyses evaluated differences in IBD-PTS symptoms between groups, the relationship between disease severity and health-related quality of life (HRQoL) and predictors of IBD-PTS severity., Results: Forty-seven per cent of the 51 S/SE Asian participants met the diagnostic cut-off for PTSD on the PCL-5 compared to 13.6% of 110 IBD controls. The mean global score on the PCL-5 was three times higher in S/SE Asians. Patients of S/SE Asian decent were over five times more likely to have PTSD due to their IBD experiences than controls, nearly doubling when controlling for disease activity. More severe IBD-PTS was present in S/SE Asian patients with active disease and those with extraintestinal manifestations. Higher global levels of IBD-PTS were associated with poorer HRQoL in S/SE Asians where increased hyperarousal from IBD-PTS predicted more sleep disturbance., Conclusions: S/SE Asian patients are five times more likely to experience IBD-PTS than their white, non-Hispanic counterparts. Several cultural factors lead to IBD-PTS in S/SE Asian patients that must be considered by IBD providers. Preventing, screening for and treating IBD-PTS in this population appears warranted., (© 2023. Indian Society of Gastroenterology.)

Background & Aims: Ustekinumab is an effective treatment of Crohn's disease (CD). Of interest to patients is knowing how soon symptoms may improve. We analyzed ustekinumab response dynamics from the ustekinumab CD trials., Methods: Patients with CD received intravenous induction with ustekinumab ∼6 mg/kg (n = 458) or placebo (n = 457). Week 8 ustekinumab responders received subcutaneous ustekinumab 90 mg as the first maintenance dose or as an extended induction dose for nonresponders. Patient-reported symptom changes (stool frequency, abdominal pain, general well-being) within the first 14 days and clinical outcomes through week 44 were evaluated using the CD Activity Index., Results: After ustekinumab infusion, stool frequency improvement was significantly (P < .05) greater than placebo on day 1 and for all patient-reported symptoms by day 10. In patients with no history of biologic failure or intolerance, cumulative clinical remission rates increased from 23.0% at week 3 to 55.5% at week 16 after the subcutaneous dose at week 8. Corresponding cumulative rates for patients with a history of biologic failure or intolerance increased from 12.9% to 24.1%. Neither change from baseline in CD Activity Index score nor week 8 ustekinumab pharmacokinetics were associated with week 16 response. Among all patients who received subcutaneous ustekinumab 90 mg q8w, up to 66.7% were in clinical response at week 44., Conclusions: Ustekinumab induction provided symptom relief by day 1 post-infusion. Following ustekinumab infusion and a subcutaneous 90 mg injection, clinical outcomes continued to increase through week 16 and up to week 44. Regardless of week 8 clinical status or ustekinumab pharmacokinetics, patients should receive additional treatment at week 8., Clinicaltrials: gov numbers, NCT01369329, NCT01369342, and NCT01369355., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Crohn's disease [CD] is a debilitating, inflammatory condition affecting the gastrointestinal tract. There is no cure and sustained clinical and endoscopic remission is achieved by fewer than half of patients with current therapies. The immunoregulatory function of the vagus nerve, the 'inflammatory reflex', has been established in patients with rheumatoid arthritis and biologic-naive CD. The aim of this study was to explore the safety and efficacy of vagus nerve stimulation in patients with treatment-refractory CD, in a 16-week, open-label, multicentre, clinical trial., Methods: A vagus nerve stimulator was implanted in 17 biologic drug-refractory patients with moderately to severely active CD. One patient exited the study pre-treatment, and 16 patients were treated with vagus nerve stimulation [4/16 receiving concomitant biologics] during 16 weeks of induction and 24 months of maintenance treatment. Endpoints included clinical improvement, patient-reported outcomes, objective measures of inflammation [endoscopic/molecular], and safety., Results: There was a statistically significant and clinically meaningful decrease in CD Activity Index at Week 16 [mean ± SD: -86.2 ± 92.8, p = 0.003], a significant decrease in faecal calprotectin [-2923 ± 4104, p = 0.015], a decrease in mucosal inflammation in 11/15 patients with paired endoscopies [-2.1 ± 1.7, p = 0.23], and a decrease in serum tumour necrosis factor and interferon-γ [46-52%]. Two quality-of-life indices improved in 7/11 patients treated without biologics. There was one study-related severe adverse event: a postoperative infection requiring device explantation., Conclusions: Neuroimmune modulation via vagus nerve stimulation was generally safe and well tolerated, with a clinically meaningful reduction in clinical disease activity associated with endoscopic improvement, reduced levels of faecal calprotectin and serum cytokines, and improved quality of life., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Prolonged perineal wound healing following proctocolectomy in patients with inflammatory bowel disease (IBD) is a frustrating result for the medical team and patients who were hoping for improved quality of life. Prolonged healing, which lasts more than 6 months following proctocolectomy, is termed persistent perineal sinus (PPS) and typically necessitates further surgical management. Healing of the PPS is difficult due to the resulting "dead space" following proctocolectomy, necessitating the need to fill the void with viable tissue in an area with anatomic constraints. Here we provide a narrative review and comprehensively address the incidence, pathogenesis, and clinical and operative management of a PPS in patients with IBD following proctocolectomy. Operative methods discussed include surgical debridement, flap closure of the perineum, omental flap closure, and gracilis muscle transposition. It is necessary to further investigate and establish a gold standard of care for these patients., (© 2023 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)