Introduction

Studies estimating the healthcare costs associated with eosinophilic esophagitis (EoE) in real world practice are currently lacking in a European context.

Aims & Methods

We aimed to evaluate real-world healthcare resource utilization and costs associated with EoE in Spanish patients recruited in the EoE CONNECT registry during the first year of diagnosis.
Data from participants of the EoE CONNECT registry in their first year of diagnosis were used. EoE CONNECT is a multi-center, international, observational, prospectively-maintained registry of pediatric and adult patients diagnosed with EoE run by EUREOS. We identify, measure and value healthcare resources of Spanish participants from the healthcare provider perspective. To avoid the deleterious effects of the Covid-19 pandemic and post-pandemic on waiting lists and functioning of healthcare systems, only patients diagnosed between January 1, 2017 and December 31, 2018 were included.
Direct healthcare costs were estimated using local and official unit costs. Resource valued included specialist medical and emergency visits, hospital admissions, pharmacy treatments, medical urgent transport, upper gastrointestinal endoscopies, biopsies and other complementary diagnostic tests. Descriptive analyses of healthcare costs were performed by EoE phenotype, age, and the EoE patients’ volume of the site where they were cared for. Healthcare cost differences were assessed using the t-test, assuming unequal variances. Furthermore, healthcare cost differences were tested using multivariate regression models, including phenotype, age, and the healthcare center for each healthcare cost. All costs were expressed in 2018 euros, and updated according to health-related inflation unit rates.

Results

We included 302 patients (75% male), 82% adults (mean age 35 years), and 54% treated in high-volume sites in the healthcare costs analysis. After one year from diagnosis, 61% of patients were in clinico-histological remission (CHR), 28% never achieved CHR, 10% had active EoE despite they achieved CHR before with another treatment, and 1% were never evaluated for histological response. The mean annual healthcare costs per patient were €1,842.07 (median costs=€1,729.21; SD=795.69). Overall, 68% (€1,253.45) of total healthcare costs were due to upper GI endoscopies (including cost of biopsies), followed by medical visits and pharmacy treatments, €292.68 (16%) and €198.49 (11%) respectively. Direct costs were significantly higher in the pediatric population than in the adult patients (€2,101.51 vs. €1,784.29), yielding €317.22 (95%CI: 117.79 to 516.64; p=0.002) extra cost per pediatric patient, mainly due to anesthesia and hospital stay for recovery.
Significantly lower healthcare costs were found for patients treated in low-volume sites (€1,723.92 vs. €1,941.48; cost differences: -217.56, 95%CI: -402.11 to -33.02, p=0.002). No differences in healthcare costs by EoE phenotype were found (€18.19 higher in structuring phenotypes, p=0.86). Regression analysis confirmed differences in healthcare costs identified in descriptive analysis, especially related to the upper GI endoscopies’ costs, being €354.93 lower in adults (p<0.001), and €189.34 higher in high-volume centres (p=0.004).

Conclusion

EoE patients require high healthcare resources during the first year of diagnosis, mainly due to the need for upper GI endoscopies with biopsies and medical visits. Despite of high direct healthcare costs, active EoE remains in over 1/3 patients at the end of this first year. The chronicity of EoE could spread substantial cost over several years.

Introduction

Besides analgesia, opioids affect gastrointestinal (GI) motility, including decreased bowel peristalsis and delayed gastric emptying. Peripherally acting mu-opioid receptor antagonists, like naloxegol, are approved for treating opioid-induced constipation.

Aims & Methods

We aimed to evaluate the effects of naloxegol on opioid-induced lower GI tract dysfunction using magnetic resonance imaging (MRI) to assess changes in colonic volumes in healthy volunteers (HV).
In this double-blind, randomised, three-way crossover study, 15 HV complete three study visits, separated by ≥1 week washout, with administration of 25 mg naloxegol + 60 mg codeine, 60 mg codeine + placebo, or double placebo. During each visit, five abdominal MRI scans (each 20 min.) are obtained at 30 min intervals, at baseline, after drug intake, after a standardized 44 g oatmeal and 100 mL Nutridrink (313 kCal) meal, after a second drug dose, and after a bisacodyl 10 mg suppository administration. Colonic segmental volumes were quantified from all MRI scans using Entrolytics (Motilent, London, UK) in the ascending, transverse, descending, and rectosigmoid colon. We recorded the passage of stool during the study visit. Results are presented as medians with min. and max. P-values <0.05 are considered statistically significant. Adjusted p-values are used in case of post-hoc analysis.

Results

Interim analysis on 8 HVs (mean age 36±5y, 75% females) revealed that two subjects made stool on 2 mornings before the study visit. Four subjects passed stool in the double placebo group (2 postprandial, 2 post-bisacodyl), and 2 of them passed stool in the other 2 groups as well, around the same time. A significant scan x group effect was found for the whole colon volumes (p<0.05). More specifically, there was a significant difference in median ascending colon volumes between the scans (p=0.03), and especially in the double placebo group (Table). Although there was no significant difference in the median transverse colon volumes, bisacodyl led to a significant decrease in descending colon volume (p<0.0001), more specifically in the naloxegol+codein group and the double placebo group (ps<0.05), but not in the codein+placebo group. No significant differences in volumes of the rectosigmoid were detected.

Conclusion

Interim MRI analysis of 8 HVs suggests different colonic motility responses across groups and timepoints. Toilet visits were suppressed in both codeine groups. Different responses to drug and food intake were found in the ascending and descending colon between the naloxegol+codein and double placebo group on one hand compared to the codein+placebo group. Expansion and analysis of the full number of subjects will further clarify insights into the acute colonic responses to opioids and potential reversal by naloxegol.

Introduction

Gastric emptying is controlled by phasic gastric contractions which occur at a frequency of ~3 cycles per minute (cpm) in phase with gastric slow waves. Tests to measure slow waves cannot directly detect abnormal contractions. The Atmo Capsule possesses an accelerometer that measures changes in capsule orientation and can thus detect gastric contractions. We analyzed accelerometer data to define its capability to characterize gastric contraction frequency and amplitude in patients with suspected dysmotility, and to assess if frequency or amplitude vary in relation to transit delay.

Aims & Methods

Gut transit was measured by the Atmo Capsule in 209 subjects: 48 with predominant upper GI (UGI) symptoms alone (suspected gastroparesis), 21 with lower GI (LGI) symptoms (suspected slow colon transit) alone, and 140 with combined UGI+LGI symptoms. This analysis utilized data from subjects recording valid gastric emptying time (GET) measures and did not incur protocol deviations affecting gastric transit. Delays in GET were categorized as: normal, <5 h; delayed, 5-10 h; severely delayed, ≥10 h. Fast Fourier Transformation (FFT) of the accelerometer data allows for the identification and analysis of the dominant gastric frequency and amplitude using 10-minute windows and a cutoff frequency of 4.5 cpm. Variability of frequency and amplitude measures were estimated by calculating interquartile range (IQR) and range (max-min) values and were analyzed in relation to presenting symptoms and gastric emptying delays.

Results

Gastric data from 190 subjects were suitable for analysis: gastric contractions with dominant frequencies of 3.30 cpm (IQR 0.47, range 1.47) and amplitudes of 0.10 arbitrary units (au) (IQR 0.04, range 0.14) were detected in 185 (97%) of subjects. Mean contraction frequency tended to be higher in those with delayed GET compared with no delay (p=0.016) and severe delay (p=0.005) (Table 1). Frequency IQR (p=0.002) and range (p=0.002) were higher for GET delay vs. no delay, while range was higher in severe GET delay vs no delay (p<0.001). Mean amplitude was higher in subjects with severe GET delay compared with normal delay (p=0.008) and normal transit (p=0.001). Amplitude IQR and range were both higher in those with severe GET delay compared with normal delay (p=0.002; p=0.001) and no delay (p<0.001 for both). Frequency metrics were similar irrespective of predominant symptoms. Amplitude means (p=0.022), IQR (p=0.030) and range (p=0.0004) were higher for UGI vs. LGI symptoms.

Table 1. Dominant gastric frequencies and amplitudes in relation to gastric emptying delays. Data shown as median (interquartile range) and analyzed via Kruskal-Wallis test.

Conclusion

The Atmo Capsule accelerometer reliably characterizes 3 cpm gastric contraction frequency and amplitude in subjects with proposed delays in gut transit. Increased variabilities in contraction frequency and amplitude were defined in those with severely delayed gastric emptying and increased amplitude variability was found for predominant upper GI symptoms. We propose these higher variations identified by accelerometry may reflect hypomotility or contractile dropout, suggesting additional clinical utility of the Atmo Capsule in suspected gastroparesis.

Disclosure

These authors disclose the following: Braden Kuo, Anthony J. Lembo, Eammon M.M. Quigley, Satish S.C. Rao, and William D. Chey serve on the Medical Advisory Board of Atmo Biosciences. Michael Cline and Baharak Moshiree served on the Medical Advisory Board of Atmo Biosciences. Braden Kuo has received funding from NIH, Vanda, Atmo Biosciences, and Takeda and has consulted for Evoke, Takeda, Ironwood, Novo Nordisk, Cindome, and Neurogastrx. Thomas Abell has received funding from Gastric Dysrhythmias, Neurogastrx, NIH GpCRC, and Vanda and has consulted for Enterra Medical, Novo Nordisk, Nuvaira, and Vanda. Anthony J. Lembo has received funding from Ardelyx, Biomerica, GSK, Ironwood, Takeda, and Vibrant and holds stock with Allurion, Bristol Myer Squibb, and J&J. Abigail Stocker has received funding from Cindome, Enterra Medical, and Vanda. William D. Chey has received funding from Atmo Biosciences, Commonwealth Diagnostics Intl, QOL Medical, and Salix; has consulted for AbbVie, Ardelyx, Biomerica, Comvita, Gemelli, Ironwood, Nestle, QOL Medical, Phathom, Redhill, Salix, Vibrant, and Takeda; has filed patents with My Nutrition Health, Digital Manometry, and Rectal Expulsion Device; and holds stock options with Coprata, Evinature, Food Marble, Kiwi Bioscience, and Modify Health. The remaining authors disclose no conflicts.

Introduction

Although traditionally regarded as a vestigial organ, the appendix is increasingly recognized for its potential role in modulating gut immunity and contributing to the development of significant inflammatory or neoplastic intestinal diseases [1]. However, the underlying mechanisms linking the appendix to these immune and pathological processes remain poorly understood. This study aimed to investigate the relationship between the local immune microenvironment and the mutational landscape of rectal carcinomas in the context of prior or progressive appendectomy status.

Aims & Methods

This study aimed to investigate the relationship between the local immune microenvironment and the mutational landscape of rectal carcinomas in the context of prior or progressive appendectomy status.
Patients enrolled in the IMMUNOREACT 1 and 2 studies (NCT04915326 and NCT04917263, respectively) were stratified according to appendectomy status. Immunohistochemical analysis was performed to assess a range of immune markers, including CD3, CD4, CD8, CD8β, Tbet, FoxP3, PD-L1, MSH6, PMS2, and CD80. Additionally, flow cytometry was employed to evaluate the percentage of epithelial cells expressing CD80, CD86, CD40, HLA-ABC, or HLA-DR, as well as to quantify activated CD8+ T cells, CD4+ Th1 cells, and regulatory T cells (Tregs). Non-parametric tests were used.

Results

In this cohort, 41 patients out of 163 underwent appendectomy for other causes (e.g. appendicitis) before having been diagnosed with a rectal cancer. When the two groups were compared for microenvironmental features, in the normal mucosa of patients who had a previous appendectomy there was a higher rate of epithelial cells expressing HLA-abc (p=0,04) and a higher expression of CTLA4 on CD3+ T cells (p=0,03) when compared to appendectomy-naive patients. Within the rectal cancer tissue, a higher expression of CD86 on epithelial (cancer) cells expression was found in patients who already had an appendectomy (p=0,03). In therapy naïve patients, previous appendectomy was associated to a higher activation of CD4+ T helpers (expression of CD25), (p=0.04), and to tendency of higher rate of epithelial cells expressing HLA-abc (p=0,06) and of T cells expressing CTLA-4 (p=0.08). In patients who had neoadjuvant therapy, lower level of PD-L1 on the leukocyte surface were observed in patients who had a previous appendectomy (p=0.039).

Conclusion

Our findings suggest that prior appendectomy may be associated with distinct alterations in the local immune microenvironment of rectal carcinomas, including increased expression of antigen-presenting and immune-regulatory molecules such as HLA-BC, CTLA4, and CD86. In therapy naïve patients, appendectomy seem to increase the activation of T helper cells counterbalanced by an increase of the number of T cells expressing CTLA-4. These immune shifts in both tumour tissue and adjacent healthy mucosa support the hypothesis that the appendectomy may in somehow alter the interaction between epithelia cells and intraepithelial T cells. Further trancriptomic ​analysis will shed light on the effect of appendectomy on mucosal microevironment of ​rectal cancer patients.

References

1. Collard MK, Tourneur-Marsille J, Uzzan M, Albuquerque M, Roy M, Dumay A, Freund JN, Hugot JP, Guedj N, Treton X, Panis Y, Ogier-Denis E. The Appendix Orchestrates T-Cell Mediated Immunosurveillance in Colitis-Associated Cancer. Cell Mol Gastroenterol Hepatol. 2023;15(3):665-687.

Introduction

Ingestible sensors hold the promise to revolutionize the monitoring of gastrointestinal diseases, including inflammatory bowel disease (IBD). These miniature electronic capsules could provide a minimally-invasive, cost-effective, and patient-friendly alternative to traditional endoscopic procedures, with the promise of greatly enhancing disease tracking and management.

Aims & Methods

To enable real-time, minimally-invasive monitoring of gut health, we developed the Gastrointestinal Smart Module (GISMO), a highly miniaturized ingestible sensor (3 times smaller than video capsules) that measures redox balance, pH, and temperature throughout the GI tract.
Redox balance plays a key role in regulating the intestinal barrier and mediating interactions among the host, immune system, and gut microbiota. In conditions like IBD, gastrointestinal cancers, and irritable bowel syndrome (IBS), disruptions in immune response and shifts in the gut microbiome can destabilize the balance of oxidants and antioxidants^1,2. This imbalance leads to oxidative stress, detectable through altered redox signals.
After validation in both lab and pre-clinical models, the GISMO system was tested in healthy participants.

Results

In this first-in-human trial, 66 sensors were administered to 15 healthy participants. The GISMO system demonstrated feasibility, safety, and ease of use. Participants reported ease in swallowing the sensors and expressed willingness to ingest multiple capsules. No device-related adverse events occurred throughout the study. GISMO is the first device capable of measuring in vivo redox balance, providing high-resolution data every 20 seconds. The data revealed consistent profiles from an oxidative environment in the stomach to a strongly reducing environment in the colon. This group of self-reported healthy volunteers exhibited low inter- and intra-subject variability, providing a reliable baseline for future comparative studies in patient populations.

Conclusion

This trial marks the first in vivo measurement of redox balance along the human gut, paving the way for new insights into the role of redox balance in maintaining gut homeostasis, inflammation, and the gut microbiome. The ability to conduct frequent and simple monitoring could revolutionize the way gastrointestinal diseases are tracked and managed.

References

1. Campbell, E. L. & Colgan, S. P. Control and dysregulation of redox signalling in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 16, 106–120 (2019).
2. Bourgonje, A. R. et al. Oxidative Stress and Redox-Modulating Therapeutics in Inflammatory Bowel Disease. Trends Mol Med 26, 1034–1046 (2020).

Disclosure

AE, FL, NVH, RA have filed a patent application on sensing in the gastrointestinal tract with the European (EP4197437A1) and U.S. (US20230190178A1) patent office. FL, AE, and RS have filed a patent application on measuring and localizing inflammation in the gut (application no. EP 24217111.4) with the European patent office. TTo, IDCM, AE, FL have filed a patent application on localization of an ingestible device (application no. EP24222150.5).

Introduction

A large proportion of Inflammatory Bowel Disease (IBD) patients also develop liver diseases, predominantly primary sclerosing cholangitis (PSC), and more than 80% of PSC patients also have IBD. Coexistence of both diseases in patients, increase of five times the risk of developing a colorectal cancer, and causes liver transplantation failure. Both of IBD and PSC have no curative treatment yet, and the impact of IBD on liver homeostasis and reciprocally the impact of PSC on intestinal barrier (IB) remain largely unknown.

Aims & Methods

The aims of the study were to investigate the impact of (1) mouse models of IBD on liver homeostasis and (2) the impact of mouse models of PSC on IB integrity. Two models of colitis have been used. A model was conducted by adding 3% DSS in drinking water for five days, followed by two days of regular water. The second model of colitis was performed using a pre-sensitizing step involving subcutaneous injection of 2% oxazolone and five day later, a rectal injection of 1.5% oxazolone. As PSC mouse models, we used intra-peritoneal injection of 1µL/g mice weight of CCl₄ twice a week for 8 weeks and another model with a 0.1% diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate within diet for 3 weeks. Colitis and cholangitis severities were monitored by food consumption, macroscopic observations as well as calculation of Disease Activity Index which sum up scores of weight loss, bleeding and stool consistency. Fecal samples were tested for calprotectin and lipocalin by ELISA to estimate gut inflammation. Intestinal permeability (IP) was investigated in vivo by estimation of FITC-Dextran quantity in mice’s sera after oral administration and at mice sacrifice in ileum and colon tissues by measuring the flux of fluorescein sodium salt in Ussing chamber. To study liver homeostasis, we performed pathological analysis (H&E and Sirius red staining), and real-time PCR with a focus on fibrosis markers, bile acids metabolism and metabolic pathways.

Results

IBD models induced strong alteration of colonic homeostasis including increased fecal markers of inflammation (Calprotectin and Lipocalin-2) and tissues mRNA expression of inflammatory cytokines (Ifng…). These models of colitis were also accompanied by elevated IP and impaired liver genes expression level of fibrosis (Col3a1) and fatty acids metabolism (Fasn…), as well as cholesterol and bile acids transporters (Abcb11…). This was found to be correlated with impaired enterohepatic circulation of bile acids in the gut. Furthermore, an increase expression of mRNA markers of inflammation (Cxcl1…) was only observed in the liver of the DSS colitis model. However, no alteration of liver homeostasis, including infiltrated immune cells or fibrosis was revealed by histological analysis. PSC mouse models induced strong alterations of liver homeostasis and were associated with altered gut homeostasis shown by a strong increased IP.

Conclusion

Our data demonstrate that IBD colitis models impair liver homeostasis, while PSC models disrupt intestinal integrity. The data obtained from both IBD and PSC models demonstrated a significant increase in intestinal permeability, thereby underscoring it’s potential as an association between those diseases. Further investigations are ongoing in ours models as a next step will be to study a combination of both protocols to explore disease progression and severity.

References

Rabiee, Anahita, and Marina G Silveira. “Primary sclerosing cholangitis.” Translational gastroenterology and hepatology vol. 6 29. 5 Apr. 2021, doi:10.21037/tgh-20-266
Kim, You Sun et al. “Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gut-liver axis.” Experimental & molecular medicine vol. 55,7 (2023): 1380-1387. doi:10.1038/s12276-023-01042-9

Introduction

This study aims to assess the impact of antithrombotic therapy on endoscopic findings in patients hospitalized for upper gastrointestinal bleeding.

Aims & Methods

We carried out a prospective, single-center cross-sectional study including 332 patients between June 2020 and February 2025. Patients were classified as antithrombotic (AT) users if they were receiving antiplatelet agents (such as low-dose aspirin or thienopyridines) and/or anticoagulants (including vitamin K antagonists, direct oral anticoagulants, or heparin).

Results

The mean age of the study population was 59 ± 16.7 years, with a marked male predominance (77.1%). Among them, 63 patients (19%) were receiving antithrombotic (AT) therapy—41 on antiplatelet agents and 39 on anticoagulants. Patients in the AT group were significantly older (68 vs. 57 years; p < 0.001) and had a higher burden of comorbidities (75.8% vs. 16.7%; p < 0.001). However, there were no significant differences between the AT and non-AT groups regarding the presence of active bleeding at endoscopy (12.7% vs. 16.8%; p = 0.425) or the need for endoscopic hemostasis (7.9% vs. 16%; p = 0.1).
In multivariate analysis, after adjustment for age, sex, comorbidities, active bleeding, and AT use, only the presence of active bleeding was independently associated with the need for endoscopic hemostasis. Specifically, active bleeding at endoscopy increased the odds of requiring hemostasis by 26-fold (OR: 26, 95% CI: 12.9–62.15; p < 0.001), whereas AT therapy was not an independent predictor (OR: 0.386, 95% CI: 0.105–1.42; p = 0.154).

Conclusion

In older patients receiving antithrombotic therapy and admitted for upper gastrointestinal bleeding, the risk of active bleeding during endoscopy and the need for endoscopic hemostasis do not appear to be increased.