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.

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.

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.

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.

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.

Implications of recurrent SARS-CoV-2 outbreaks for IBD management.

The initial phases of the global SARS-CoV2 pandemic had significant implications for the management of patients with inflammatory bowel disease (IBD). This impact is likely to be sustained and far-reaching across all models of care. Initial questions about the risk of SARS-CoV2 infection, and COVID-19 complications, in patients taking maintenance anti-TNFs, JAK inhibitors and other immune modulators have preliminary data. Current models for SARS-CoV-2 transmission predict intermittent outbreaks until 2022, which could disrupt clinical care and negatively affect outcomes for many patients across the globe. This review summarises changes in IBD clinical practice that will be required during the 'post-peak' phase of viral pandemics.

Health Maintenance Consensus for Adults With Inflammatory Bowel Disease.

BACKGROUND: With the management of inflammatory bowel disease (IBD) becoming increasingly complex, incorporating preventive care health maintenance measures can be challenging. The aim of developing these updated recommendations is to provide more specific details to facilitate their use into a busy clinical practice setting. METHOD: Fifteen statements were formulated with recommendations regarding the target, timing, and frequency of the health maintenance interventions in patients with IBD. We used a modified Delphi method and a literature review to establish a consensus among the panel of experts. The appropriateness of each health maintenance statement was rated on a scale of 1 to 5 (1-2 as inappropriate, and 4-5 as appropriate) by each panelist. Interventions were considered appropriate, and statements were accepted if ≥80% of the panelists agreed with a score ≥4. RESULTS: The panel approved 15 health maintenance recommendations for adults with IBD based on the current literature and expert opinion. These recommendations include explicit details regarding specific screening tools, timing of screening, and vaccinations for adults with IBD. CONCLUSIONS: Patients with IBD are at an increased risk for infections, malignancies, and other comorbidities. Given the complexity of caring for patients with IBD, this focused list of recommendations can be easily incorporated in to clinical care to help eliminate the gap in preventative care for patients with IBD.

Exosomes in Intestinal Inflammation.

Exosomes are 30-150 nm sized vesicles released by a variety of cells, and are found in most physiological compartments (feces, blood, urine, saliva, breast milk). They can contain different cargo, including nucleic acids, proteins and lipids. In Inflammatory Bowel Disease (IBD), a distinct exosome profile can be detected in blood and fecal samples. In addition, circulating exosomes can carry targets on their surface for monoclonal antibodies used as IBD therapy. This review aims to understand the exosome profile in humans and other mammals, the cargo contained in them, the effect of exosomes on the gut, and the application of exosomes in IBD therapy.

P033 Moving the Needle on Speaker Diversity at AIBD.

BACKGROUND: Diversity of invited speakers at academic conferences is a topic of increased focus in recent years. While there have been efforts to improve speaker diversity, an evaluation of this in the IBD field has not been undertaken to date. We aimed to address gaps in knowledge of speaker gender, race, and experience at a major annual IBD conference over time. METHODS: AIBD program brochures from 2014 to 2020 were reviewed by two providers to evaluate speaker demographic information including gender, race, topic of discussion, institutional affiliation, and, for those trained in gastroenterology, years post-fellowship. In addition, the proportion of all-male panels was calculated. As a comparator, the proportion of female speakers and all-male panels was then compared to a control conference run by the same CME organization (Personalized Therapies in Thoracic Oncology). RESULTS: The percentage of female speakers of any specialty at AIBD increased from 25% in 2016 to 39% in 2020. Female adult gastroenterologist speakers increased from 12% in 2015 to 27% in 2020. The percentage of all gastroenterologists that are female in the US is 19%. All-male panels also decreased from an average of 47% in 2014-2017, to 11% in 2018-2020. As a comparator, 47% of speakers at the control conference were female and there were no all-male panels in 2020. For race, in any given year an average of 13% of speakers were Asian, 5% Hispanic/Latinx, and 1% Black. This remained static over time. The percentage of Asian, Hispanic/Latinx, and Black gastroenterologists in the US is 29%, 5%, and 6%, respectively. Average years of experience of speakers at AIBD appeared relatively static, with a mean of 15 years since fellowship training per speaker. CONCLUSION: From 2014-2020, the proportion of female speakers at AIBD has increased to over one third in main programming. There remains room for improvement, particularly in increasing the racial and ethnic diversity of speakers and inviting more gastroenterologists in the early stages of their careers.

Endogenous antisense RNA curbs CD39 expression in Crohn's disease.

CD39 is an ectonucleotidase that initiates conversion of extracellular nucleotides into immunosuppressive adenosine. CD39 is expressed by regulatory T (Treg)-cells, where it mediates immunosuppression, and by a subset of T-helper (Th) 17-cells, where it limits pathogenicity. CD39 is regulated via single-nucleotide-polymorphisms and upon activation of aryl-hydrocarbon-receptor and oxygen-mediated pathways. Here we report a mechanism of CD39 regulation that relies on the presence of an endogenous antisense RNA, transcribed from the 3'-end of the human CD39/ENTPD1 gene. CD39-specific antisense is increased in Treg and Th17-cells of Crohn's disease patients over controls. It largely localizes in the cell nucleus and regulates CD39 by interacting with nucleolin and heterogeneous-nuclear-ribonucleoprotein-A1. Antisense silencing results in CD39 upregulation in vitro and amelioration of disease activity in a trinitro-benzene-sulfonic-acid model of colitis in humanized NOD/scid/gamma mice. Inhibition/blockade of antisense might represent a therapeutic strategy to restore CD39 along with immunohomeostasis in Crohn's disease.

Mesalamine in the Initial Therapy of Ulcerative Colitis.

Inflammatory bowel disease is a chronic disorder of intestinal inflammation and includes Crohn's disease and ulcerative colitis. The goal of therapy is to induce and maintain remission, which is achieved with conventional therapies. Mesalamine is considered a first-line therapy for ulcerative colitis. Clinical trials have confirmed its efficacy and safety in patients with mild to moderate ulcerative colitis. Doses of more than 2.4 g/d achieve significantly higher rates of clinical and endoscopic remission, with a decreased risk of relapse. Serious adverse effects are rare, but nonadherence is common. Mesalamine is considered safe in pregnancy, excluding formulations with dibutyl phthalate.

Development of Entrustable Professional Activities for Advanced Inflammatory Bowel Disease Fellowship Training in the United States.

BACKGROUND: The level of inflammatory bowel disease (IBD) training in general gastroenterology fellowship is often insufficient to prepare trainees to deliver advanced IBD care in practice. Advanced IBD fellowships have been developed to fill this training gap, but there is no established curriculum, and significant variability exists across programs. Entrustable professional activities (EPAs) are practical and realistic objectives that define essential tasks of a specialty that physicians should master to be competent during independent practice. The American College of Gastroenterology (ACG) and Crohn's & Colitis Foundation (Foundation) established a task force to develop and appraise EPAs for advanced IBD fellowship. METHODS: Entrustable professional activities were developed using a multistep approach in a similar manner to other specialties. Initial EPAs identified via focus groups were evaluated, critiqued, and changed using an iterative model of feedback. The final EPAs were selected after the task force conducted a 3-phase modified Delphi method consisting of 2 sequential rounds of web-based voting and an in-person consensus meeting. RESULTS: Ten EPAs for advanced IBD fellowship were established including detailed descriptions with the associated knowledge, skills, and attitudes for each that can serve as curricular milestones. CONCLUSION: Ten EPAs describing the core work of an advanced IBD fellowship-trained physician have been established by a multisociety task force. Creating EPAs for an advanced curriculum comes with unique challenges, particularly the need to prevent duplication of prior training competencies while demonstrating the potential for unique milestones.

Impact of Clinical Pharmacists in Inflammatory Bowel Disease Centers During the COVID-19 Pandemic.

INTRODUCTION: To characterize the clinical pharmacists' impact on caring for patients with inflammatory bowel disease during COVID-19. METHODS: A clinical pharmacist's encounters between March 17 and April 14, 2020, were audited to determine encounter frequency and indication. RESULTS: The clinical pharmacist addressed COVID-19 and inflammatory bowel disease treatment concerns with 140 patients, conducted 34 medication education and monitoring visits, reviewed 141 patients' charts and helped rescheduled 18 patients who missed their biologic infusion, transitioned 12 patients to home infusions, and assisted 5 patients with medication access. DISCUSSION: Clinical pharmacists embedded in gastroenterology practices permit for continued optimal patient care during a pandemic.

Modulation of lymphocyte-mediated tissue repair by rational design of heterocyclic aryl hydrocarbon receptor agonists.

Aryl hydrocarbon receptor (AHR) is an essential regulator of gut immunity and a promising therapeutic target for inflammatory bowel disease (IBD). Current AHR agonists are inadequate for clinical translation due to low activity, inadequate pharmacokinetics, or toxicity. We synthesized a structurally diverse library and used integrated computational and experimental studies to discover mechanisms governing ligand-receptor interaction and to design potent drug leads PY109 and PY108, which display physiochemical drug-likeness properties, desirable pharmacokinetic profiles, and low toxicity. In a murine model of dextran sulfate sodium-induced colitis, orally administered compounds increase interleukin-22 (IL-22) production and accelerate mucosal healing by modulating mucosal adaptive and innate lymphoid cells. AHR and IL-22 pathway induction was confirmed using RNA sequencing and characterization of the lymphocyte protein-protein interaction network. Significant induction of IL-22 was also observed using human T cells from patients with IBD. Our findings support rationally designed AHR agonists for IBD therapy.

Cathelicidin Mediates a Protective Role of Vitamin D in Ulcerative Colitis and Human Colonic Epithelial Cells.

BACKGROUND: Vitamin D plays a protective role in ulcerative colitis (UC) patients through unclear mechanisms. Cathelicidin is an antimicrobial peptide induced by 1,25(OH)D2. Our goal was to evaluate the link between cathelicidin and vitamin D-associated clinical outcomes in UC patients, explore vitamin D induction of cathelicidin in human colon cells, and evaluate the effects of intrarectal human cathelicidin on a murine model of colitis. METHODS: Serum and colonic cathelicidin levels were measured in UC patients and correlated with clinical and histologic outcomes. Human colon cells were treated with 1,25(OH)2D and production of cathelicidin and cytokines were quantified. Antimicrobial activity against Escherichia coli from cell culture supernatants was measured. Mice were treated with intrarectal cathelicidin, and its effects on DSS colitis and intestinal microbiota were evaluated. RESULTS: In UC patients, serum 25(OH)D positively correlated with serum and colonic cathelicidin. Higher serum cathelicidin is associated with decreased risk of histologic inflammation and clinical relapse but not independent of 25(OH)D or baseline inflammation. The 1,25(OH)2D treatment of colon cells induced cathelicidin and IL-10, repressed TNF-α, and suppressed Escherichia coli growth. This antimicrobial effect was attenuated with siRNA-cathelicidin transfection. Intrarectal cathelicidin reduced the severity of DSS colitis but did not mitigate the impact of colitis on microbial composition. CONCLUSIONS: Cathelicidin plays a protective role in 25(OH)D-associated UC histologic outcomes and murine colitis. Cathelicidin is induced by vitamin D in human colonic epithelial cells and promotes antimicrobial activity against E. coli. Our study provides insights into the vitamin D-cathelicidin pathway as a potential therapeutic target.

Management of Asymptomatic Terminal Ileitis.

Ileal intubation is often performed during screening colonoscopies. This had led to the recognition of mild ileitis in many asymptomatic patients. The natural history and clinical significance of this finding are not well established, and there are no guidelines on whether these patients merit further work-up or an interval surveillance colonoscopy. This conundrum was presented and discussed on @MondayNightIBD. In this article, we review the specific literature on the topic and make reference to the informed opinions of the convo participants. We propose an #IBDAlgorithm for management of asymptomatic ileitis.