Challenges in IBD Research 2024: Preclinical Human IBD Mechanisms.

Preclinical human inflammatory bowel disease (IBD) mechanisms is one of 5 focus areas of the Challenges in IBD Research 2024 document, which also includes environmental triggers, novel technologies, precision medicine, and pragmatic clinical research. Herein, we provide a comprehensive overview of current gaps in inflammatory bowel diseases research that relate to preclinical research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in IBD interception, remission, and restoration. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. This preclinical human IBD mechanisms section identifies major research gaps whose investigation will elucidate pathways and mechanisms that can be targeted to address unmet medical needs in IBD. Research gaps were identified in the following areas: genetics, risk alleles, and epigenetics; the microbiome; cell states and interactions; barrier function; IBD complications (specifically fibrosis and stricturing); and extraintestinal manifestations. To address these gaps, we share specific opportunities for investigation for basic and translational scientists and identify priority actions.

To address the unmet medical needs of patients with inflammatory bowel diseases (IBD) and move toward cures, preclinical human-relevant research must center on mechanistic questions pertinent to patients with IBD in the 3 areas of disease interception, remission, and restoration.

Challenges in IBD Research 2024: Pragmatic Clinical Research.

Pragmatic clinical research is 1 of the 5 focus areas of the Challenges in IBD Research 2024, a multidisciplinary effort by scientists, clinicians, patients, and funders to identify priorities for patient-centric research. This summary provides a comprehensive overview of current gaps in inflammatory bowel disease (IBD) clinical research and actionable approaches to address them. This review is focused on identifying research that is needed to achieve the best outcomes for patients in clinical practice. Research gaps include understanding the needs of understudied patient groups and addressing barriers to care so all patients receive optimal care, validating and using biomarkers to enable early diagnosis and result in better outcomes for adults and children with IBD, and determining the optimal sequencing of treatments (medical, surgical, adjunct) in children and adults. Inclusive pragmatic research is needed to address these gaps and lead to improvements in patient care and outcomes for all populations of patients with IBD.

Pragmatic clinical research focuses on improving evidence for how to best treat patients to improve quality of life and disease outcomes in real-world practice. This includes evaluating and improving healthcare delivery and decreasing barriers for all patients.

Challenges in IBD Research 2024: Novel Technologies.

Novel technology is one of the five focus areas of the Challenges in Inflammatory Bowel Disease (IBD) Research 2024 document. Building off the Challenges in IBD Research 2019 document, the Foundation aims to provide a comprehensive overview of current gaps in IBD research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in interception, remission, and restoration for these diseases. The document is the result of a multidisciplinary collaboration from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. Specifically, the Novel Technologies section focuses on addressing key research gaps to enable interception and improve remission rates in IBD. This includes testing predictions of disease onset and progression, developing novel technologies tailored to specific phenotypes, and facilitating collaborative translation of science into diagnostics, devices, and therapeutics. Proposed priority actions outlined in the document include real-time measurement of biological changes preceding disease onset, more effective quantification of fibrosis, exploration of technologies for local treatment of fistulas, and the development of drug delivery platforms for precise, location-restricted therapies. Additionally, there is a strong emphasis on fostering collaboration between various stakeholders to accelerate progress in IBD research and treatment. Addressing these research gaps necessitates the exploration and implementation of bio-engineered novel technologies spanning a spectrum from materials to systems. By harnessing innovative ideas and technologies, there's a collective effort to enhance patient care and outcomes for individuals affected by IBD.

Technology drives medical progress, solving clinical challenges and enhancing patient care in inflammatory bowel disease (IBD). Collaborative efforts focus on addressing research gaps to improve interception, restoration, and remission rates, utilizing innovative technologies for better patient outcomes.

Overview to Challenges in IBD 2024-2029.

The mission of the Crohn's & Colitis Foundation is to cure Crohn's disease and ulcerative colitis and to improve the quality of lives of patients living with these diseases-in other words, to care and cure. To achieve these missions, there is a need to identify and prioritize research gaps and approaches to address these gaps, which is the aim of Challenges in IBD 2024. The Foundation convened close to 80 experts in inflammatory bowel disease (IBD), including researchers, clinicians, patients and caregivers, funders, industry representatives, and Foundation scientific staff and organized them into 5 workgroups, one for each of the 5 Challenges topics: Preclinical Human IBD Mechanisms, Environmental Triggers, Precision Medicine, Novel Technologies, and Pragmatic Clinical Research. The findings of these groups outline a research agenda that intends to change the research paradigm in IBD by introducing 2 concepts in the course of IBD that warrant specific focus: interception (during the preclinical phase) and restoration of normal physiology after remission is achieved. We hope these reviews will stimulate innovations in our understanding and management of IBD.

Challenges in IBD Research 2024: Precision Medicine.

Precision medicine is part of 5 focus areas of the Challenges in IBD Research 2024 research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and pragmatic clinical research. Building on Challenges in IBD Research 2019, the current Challenges aims to provide a comprehensive overview of current gaps in inflammatory bowel diseases (IBDs) research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in interception, remission, and restoration for these diseases. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient-centric research prioritization. In particular, the precision medicine section is focused on the main research gaps in elucidating how to bring the best care to the individual patient in IBD. Research gaps were identified in biomarker discovery and validation for predicting disease progression and choosing the most appropriate treatment for each patient. Other gaps were identified in making the best use of existing patient biosamples and clinical data, developing new technologies to analyze large datasets, and overcoming regulatory and payer hurdles to enable clinical use of biomarkers. To address these gaps, the Workgroup suggests focusing on thoroughly validating existing candidate biomarkers, using best-in-class data generation and analysis tools, and establishing cross-disciplinary teams to tackle regulatory hurdles as early as possible. Altogether, the precision medicine group recognizes the importance of bringing basic scientific biomarker discovery and translating it into the clinic to help improve the lives of IBD patients.

Precision medicine is the practice of getting the most suitable drug or treatment option to each individual patient at the right time. In Crohn's disease and ulcerative colitis, we need to learn more about the diversity of patients to deliver precision medicine.

Challenges in IBD Research 2024: Environmental Triggers.

Environmental factors play an important role in inflammatory bowel diseases (IBD; Crohn's disease, [CD], ulcerative colitis [UC]). As part of the Crohn's & Colitis Challenges 2024 agenda, the Environmental Triggers workgroup summarized the progress made in the field of environmental impact on IBD since the last Challenges cycle in this document. The workgroup identified 4 unmet gaps in this content area pertaining to 4 broad categories: (1) Epidemiology; (2) Exposomics and environmental measurement; (3) Biologic mechanisms; and (4) Interventions and Implementation. Within epidemiology, the biggest unmet gaps were in the study of environmental factors in understudied populations including racial and ethnic minority groups and in populations witnessing rapid rise in disease incidence globally. The workgroup also identified a lack of robust knowledge of how environmental factors may impact difference stages of the disease and for different disease-related end points. Leveraging existing cohorts and targeted new prospective studies were felt to be an important need for the field. The workgroup identified the limitations of traditional questionnaire-based assessment of environmental exposure and placed high priority on the identification of measurable biomarkers that can quantify cross-sectional and longitudinal environmental exposure. This would, in turn, allow for identifying the biologic mechanisms of influence of environmental factors on IBD and understand the heterogeneity in effect of such influences. Finally, the working group emphasized the importance of generating high-quality data on effective environmental modification on an individual and societal level, and the importance of scalable and sustainable methods to deliver such changes.

Environmental factors are important in inflammatory bowel diseases. It is a high priority to identify environmental factors impacting different disease stages and in different populations, develop biomarkers for such exposures, and generate evidence for modifying them to improve outcomes.

Colorectal polypectomy and endoscopic mucosal resection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2024.

1: ESGE recommends cold snare polypectomy (CSP), to include a clear margin of normal tissue (1-2 mm) surrounding the polyp, for the removal of diminutive polyps (≤ 5 mm).Strong recommendation, high quality of evidence. 2: ESGE recommends against the use of cold biopsy forceps excision because of its high rate of incomplete resection.Strong recommendation, moderate quality of evidence. 3: ESGE recommends CSP, to include a clear margin of normal tissue (1-2 mm) surrounding the polyp, for the removal of small polyps (6-9 mm).Strong recommendation, high quality of evidence. 4: ESGE recommends hot snare polypectomy for the removal of nonpedunculated adenomatous polyps of 10-19 mm in size.Strong recommendation, high quality of evidence. 5: ESGE recommends conventional (diathermy-based) endoscopic mucosal resection (EMR) for large (≥ 20 mm) nonpedunculated adenomatous polyps (LNPCPs).Strong recommendation, high quality of evidence. 6: ESGE suggests that underwater EMR can be considered an alternative to conventional hot EMR for the treatment of adenomatous LNPCPs.Weak recommendation, moderate quality of evidence. 7: Endoscopic submucosal dissection (ESD) may also be suggested as an alternative for removal of LNPCPs of ≥ 20 mm in selected cases and in high-volume centers.Weak recommendation, low quality evidence. 8: ESGE recommends that, after piecemeal EMR of LNPCPs by hot snare, the resection margins should be treated by thermal ablation using snare-tip soft coagulation to prevent adenoma recurrence.Strong recommendation, high quality of evidence. 9: ESGE recommends (piecemeal) cold snare polypectomy or cold EMR for SSLs of all sizes without suspected dysplasia.Strong recommendation, moderate quality of evidence. 10: ESGE recommends prophylactic endoscopic clip closure of the mucosal defect after EMR of LNPCPs in the right colon to reduce to reduce the risk of delayed bleeding.Strong recommendation, high quality of evidence. 11: ESGE recommends that en bloc resection techniques, such as en bloc EMR, ESD, endoscopic intermuscular dissection, endoscopic full-thickness resection, or surgery should be the techniques of choice in cases with suspected superficial invasive carcinoma, which otherwise cannot be removed en bloc by standard polypectomy or EMR.Strong recommendation, moderate quality of evidence.

Hot avulsion versus argon plasma coagulation for the management of the non-ensnarable polyp: A multicenter, randomized controlled trial.

Background and Aim: Snare resection of nonlifting colonic lesions often requires supplemental techniques. We compared the success rates of neoplasia eradication using hot avulsion and argon plasma coagulation in colonic polyps when complete snare polypectomy had failed. Methods: Polyps that were not completely resectable by snare polypectomy were randomized to argon plasma coagulation or hot avulsion for completion of resection. Argon plasma coagulation was delivered using a forward shooting catheter, using a nontouch technique (flow 1.2 L, 35 watts). Hot avulsion was performed by grasping the neoplastic tissue with hot biopsy forceps and applying traction away from the bowel wall while using EndoCut I or soft coagulation for avulsion. Surveillance colonoscopies were performed at 6, 12, and 18 months. Results: From November 2013 to July 2017, 59 patients were randomized to argon plasma coagulation (28) or hot avulsion (31). The median age was 69 (60-75), with 46% being female. The median residual tissue size was 10 mm (6-12). The residual adenoma rate at 6 months (hot avulsion 6% vs argon plasma coagulation 21% P = 0.09) and 18 months was not different between the groups (6.6% vs 3.6% P = 0.25). One patient in the argon plasma coagulation arm was diagnosed with metastatic cancer of likely colorectal origin despite benign histology in the original polypectomy specimen, supporting the importance of tissue acquisition. Conclusion: Both hot avulsion and argon plasma coagulation are effective and safe modalities to complete resection of non-ensnarable colonic polyps.

Medical management of painful achalasia: a patient-driven systematic review.

Achalasia is a rare esophageal disorder characterized by abnormal esophageal motility and swallowing difficulties. Pain and/or spasms often persist or recur despite effective relief of the obstruction. A survey by UK charity 'Achalasia Action' highlighted treatments for achalasia pain/spasms as a key research priority. In this patient-requested systematic review, we assessed the existing literature on pharmacological therapies for painful achalasia. A systematic review of the literature using Medline, Embase and Cochrane databases was performed to identify studies evaluating pharmacological therapies for achalasia. Methodological quality of included randomized controlled trials was assessed using the Cochrane Risk of Bias tool. In total, 70% (40/57) of survey respondents reported experiencing pain/spasms. A range of management strategies were reported. Thirteen studies were included in the review. Seven were randomized controlled trials. Most studies were >30 years old, had limited follow-up, and focussed on esophageal manometry as the key endpoint. Generally, studies found improvements in lower esophageal pressures with medications. Only one study evaluated pain/spasm specifically, precluding meta-analysis. Overall risk of bias was high. The achalasia patient survey identified that pain/spasms are common and difficult to treat. This patient-requested review identified a gap in the literature regarding pharmacological treatments for these symptoms. We provide an algorithm for investigating achalasia-related pain/spasms. Calcium channel blockers or nitrates may be helpful when esophageal obstruction and reflux have been excluded. We advocate for registry-based clinical trials to expand the evidence base for these patients.

Speaker Diversity and Audience Ratings at a National Inflammatory Bowel Diseases Conference.

BACKGROUND: There is a need to improve speaker diversity at gastroenterology conferences, but little public data exist to quantify this. In addition, the perception of diverse speakers by conference audiences is not appreciated. We sought to identify time trends in speaker profiles and audience ratings at a national inflammatory bowel diseases conference. METHODS: Faculty profiles and audience feedback forms from 2014 to 2020 were reviewed for an annual inflammatory bowel diseases meeting. Speaker demographics including gender, race, and years of experience post-training were collected. Continuing medical education surveys were examined for audience ratings of speakers' knowledge level and teaching ability. RESULTS: Six years of data were collected, including 560 main program faculty and 13 905 total feedback forms. The percentage of female speakers increased from 25% in 2016 to 39% in 2020. All-male panels decreased from 47% in 2014 to 2017 to 11% in 2018 to 2020. Racial diversity of speakers remained unchanged (13% Asian, 5% Hispanic/Latinx, 1% Black). In audience feedback forms, female speakers from all sessions were perceived as having equal knowledge base and teaching ability compared with male speakers. However, speakers with <10 years of experience post-training were viewed as less knowledgeable and with poorer teaching abilities compared with more senior faculty. CONCLUSIONS: Gender diversity at inflammatory bowel disease conferences is improving. However, there remain significant gaps, particularly in racial diversity and improving perceptions of early-career speakers. These data should inform program committees for future gastroenterology conferences.

Personalizing therapy selection in inflammatory bowel disease.

INTRODUCTION: Inflammatory bowel disease (IBD) is a complex disease, caused by aberrant immune responses to environmental stimuli where genetic, metabolomic, and environmental variables interact to cause mucosal inflammation. This review sheds light on the different drug and patient related factors that affect personalization of biologics in IBD treatment. AREAS COVERED: We utilized the online research database PubMed to carry out literature search pertaining to therapies in IBD. We incorporated a combination of primary literature as well as review articles and meta-analyses in writing this clinical review. In this paper, we discuss the mechanisms of action for different biologics, the genotype and phenotype of patients, and pharmacokinetics/pharmacodynamics of drugs, as factors that influence response rates. We also touch upon the role of artificial intelligence in treatment personalization. EXPERT OPINION: The future of IBD therapeutics is one of precision medicine, based on the identification of aberrant signaling pathways unique to individual patients as well as exploring the exposome, diet, viruses, and epithelial cell dysfunction as part of disease pathogenesis. We need global cooperation for pragmatic study designs as well as equitable access to machine learning/artificial intelligence technology to reach the unfulfilled potential of IBD care.

Comparison of Over-the-Scope Clips to Standard Endoscopic Treatment as the Initial Treatment in Patients With Bleeding From a Nonvariceal Upper Gastrointestinal Cause : A Randomized Controlled Trial.

BACKGROUND: Current endoscopic methods in the control of acute nonvariceal bleeding have a small but clinically significant failure rate. The role of over-the-scope clips (OTSCs) as the first treatment has not been defined. OBJECTIVE: To compare OTSCs with standard endoscopic hemostatic treatments in the control of bleeding from nonvariceal upper gastrointestinal causes. DESIGN: A multicenter, randomized controlled trial. (ClinicalTrials.gov: NCT03216395). SETTING: University teaching hospitals in Hong Kong, China, and Australia. PATIENTS: 190 adult patients with active bleeding or a nonbleeding visible vessel from a nonvariceal cause on upper gastrointestinal endoscopy. INTERVENTION: Standard hemostatic treatment (n = 97) or OTSC (n = 93). MEASUREMENTS: The primary outcome was 30-day probability of further bleeds. Other outcomes included failure to control bleeding after assigned endoscopic treatment, recurrent bleeding after initial hemostasis, further intervention, blood transfusion, and hospitalization. RESULTS: The 30-day probability of further bleeding in the standard treatment and OTSC groups was 14.6% (14 of 97) and 3.2% (3 of 93), respectively (risk difference, 11.4 percentage points [95% CI, 3.3 to 20.0 percentage points]; P = 0.006). Failure to control bleeding after assigned endoscopic treatment in the standard treatment and OTSC groups was 6 versus 1 (risk difference, 5.1 percentage points [CI, 0.7 to 11.8 percentage points]), respectively, and 30-day recurrent bleeding was 8 versus 2 (risk difference, 6.6 percentage points [CI, -0.3 to 14.4 percentage points]), respectively. The need for further interventions was 8 versus 2, respectively. Thirty-day mortality was 4 versus 2, respectively. In a post hoc analysis with a composite end point of failure to successfully apply assigned treatment and further bleeds, the event rate was 15 of 97 (15.6%) and 6 of 93 (6.5%) in the standard and OTSC groups, respectively (risk difference, 9.1 percentage points [CI, 0.004 to 18.3 percentage points]). LIMITATION: Clinicians were not blinded to treatment and the option of crossover treatment. CONCLUSION: Over-the-scope clips, as an initial treatment, may be better than standard treatment in reducing the risk for further bleeding from nonvariceal upper gastrointestinal causes that are amenable to OTSC placement. PRIMARY FUNDING SOURCE: General Research Fund to the University Grant Committee, Hong Kong SAR Government.

Effectiveness and safety of cold snare polypectomy and cold endoscopic mucosal resection for nonpedunculated colorectal polyps of 10-19 mm: a multicenter observational cohort study.

BACKGROUND : Cold snare polypectomy (CSP) is the standard of care for the resection of small (< 10 mm) colonic polyps. Limited data exist for its efficacy for medium-sized (10-19 mm) nonpedunculated polyps, especially conventional adenomas. This study evaluated the effectiveness and safety of CSP/cold endoscopic mucosal resection (C-EMR) for medium-sized nonpedunculated colonic polyps. METHODS : A prospective multicenter observational study was conducted of all morphologically suitable nonpedunculated colonic polyps of 10-19 mm removed by CSP/C-EMR between May 2018 and June 2021. Once resection was complete, multiple biopsies were taken of the margins circumferentially and centrally. The primary outcome was the incomplete resection rate (IRR), based on residual polyp in these biopsy specimens. Secondary outcomes were recurrence rate at first surveillance colonoscopy and rates of adverse events (AEs). RESULTS : CSP/C-EMR was performed for 350 polyps (median size 15 mm; 266 [76.0 %] Paris 0-IIa classification) in 295 patients. Submucosal injection was used for 87.1 % (n = 305) of polyps. Histology showed 68.6 % adenomas, 26.0 % sessile serrated lesions (SSLs) without dysplasia, 4.0 % SSL with dysplasia, and 1.4 % hyperplastic polyps. The IRRs based on margin or central biopsies being positive were 1.7 % (n = 6) and 0.3 % (n = 1), respectively. The polyp recurrence rate was 1.7 % (n = 4) at first surveillance colonoscopy - completed for 65.4 % (n = 229) of polyps at a median interval of 9.7 months. AEs occurred in 3.4 % (n = 10) of patients: four with post-polypectomy pain; three self-limiting post-polypectomy bleeds; two post-polypectomy-syndrome-like presentations; and one intraprocedural bleed treated with clips. There were no perforations. CONCLUSION : CSP/C-EMR for morphologically suitable nonpedunculated colonic polyps of 10-19 mm is effective and safe, including for conventional adenomas. Rates of incomplete resection and recurrence were low, with few AEs. Studies directly comparing this method with hot snare resection are required.

The Surface Morphology of Large Nonpedunculated Colonic Polyps Predicts Synchronous Large Lesions.

BACKGROUND & AIMS: Large (≥20 mm) nonpedunculated colorectal polyps (LNPCPs) may have synchronous LNPCPs in up to 18% of cases. The nature of this relationship has not been investigated. We aimed to examine the relationship between individual LNPCP characteristics and synchronous colonic LNPCPs. METHODS: Consecutive patients referred for resection of LNPCPs over 130 months until March 2022 were enrolled. Serrated lesions and mixed granularity LNPCPs were excluded from analysis. Patients with multiple LNPCPs resected were identified, and the largest was labelled as dominant. The primary outcome was the identification of individual lesion characteristics associated with the presence of synchronous LNPCPs. RESULTS: There were 3149 of 3381 patients (93.1%) who had a single LNPCP. In 232 (6.9%) a synchronous lesion was detected. Solitary lesions had a median size of 35 mm with a predominant Paris 0-IIa morphology (42.9%) and right colon location (59.5%). In patients with ≥2 LNPCPs, the dominant lesion had a median size of 40 mm, Paris 0-IIa (47.6%) morphology, and right colon location (65.9%). In this group, 35.8% of dominant LNPCPs were non-granular compared with 18.7% in the solitary LNPCP cohort. Non-granular (NG)-LNPCPs were more likely to demonstrate synchronous disease, with left colon NG-LNPCPs demonstrating greater risk (odds ratio, 4.78; 95% confidence interval, 2.95-7.73) than right colon NG-LNPCPs (odds ratio, 1.99; 95% confidence interval, 1.39-2.86). CONCLUSIONS: We found that 6.9% of LNPCPs have synchronous disease, with NG-LNPCPs demonstrating a greater than 4-fold increased risk. With post-colonoscopy interval cancers exceeding 5%, endoscopists must be cognizant of an individual's LNPCP phenotype when examining the colon at both index procedure and surveillance. CLINICALTRIALS: gov, NCT01368289; NCT02000141; NCT02198729.

Lower gastrointestinal function after surgery for deep endometriosis: A prospective cohort study.

OBJECTIVE: To prospectively compare long-term lower gastrointestinal function before and after laparoscopic surgery for deep endometriosis (DE). METHODS: In this prospective observational study we followed 149 patients with confirmed DE who were treated surgically. Patients completed the International Consultation on Incontinence Questionnaire Anal Incontinence Symptoms and Quality of Life Module (ICIQ-B) before surgery, and 6 weeks, 6 months, and 12 months after surgery. Bowel pattern, bowel control, and bowel impact on quality of life summary scores were compared before and after surgery. RESULTS: Bowel pattern score showed an increasing improvement at all time points after surgery, from a mean pre-operation score of 4.8 ± 2.0 to 4.4 ± 1.8 at 6 weeks, 4.2 ± 1.8 at 6 months, and 4.2 ± 1.2 at 12 months. Bowel impact on quality of life significantly improved from pre-surgery mean score of 5.5 ± 6.0 to 4.2 ± 5.5 at 6 weeks and 4.4 ± 5.4 at 6 months. Direct lower gastrointestinal endometriosis involvement and worse initial function were associated with larger improvements in scores following surgery. CONCLUSIONS: Lower gastrointestinal function significantly improved after surgical treatment of DE. Further research is needed to confirm our findings and to better characterize the sub-groups of patients for whom surgery will have a beneficial effect on their bowel function.

Erratum: Cold snare polypectomy of colorectal polyps ≤ 10 mm on clopidogrel: Australian and New Zealand randomized controlled trial.

[This corrects the article DOI: 10.1055/a-1813-1019.].