Introduction

In patients with disorders of the gut-brain interaction abdominal bloating is a visceral sensation (sensation of pressure/fullness), whereas visible abdominal distension is a somatic manifestation with abnormal postural tone (abdominophrenic dyssynergia, i.e., diaphragmatic push and abdominal wall relaxation). Abdominophrenic dyssynergia can be corrected by a simple non-instrumental technique, and our aim was to determine the relation of distension and bloating responses over time.

Aims & Methods

In a randomized, placebo-controlled, parallel trial (ClincalTrials.gov number NCT06150638) 40 consecutive patients (34 women, 6 men; age range 18–58 years) with disorders of gut-brain interaction complaining of visible abdominal distension were randomized to receive biofeedback or placebo. Patients in the biofeedback group were explained the mechanism of distension, and were taught to relax the diaphragm and contract the abdominal wall, using an original audiovisual support and hands-on guidance by a trained operator. In the placebo group, sham measurements of abdominal and thoracic motion were performed, and a pill of placebo was administered. Three 30-min sessions were performed over a 4-week intervention period, with instructions to perform daily exercises (biofeedback group) or to take placebo three times a day (control group) at home. After the intervention, patients allocated to the placebo group were offered biofeedback treatment. After receiving biofeedback treatment, patients in both groups were instructed to continue practicing these same exercises over time, and were followed up: visible abdominal distension and sensation of abdominal pressure/fullness (bloating) were measured at 1 and 3 months using 10-cm scales for 7 consecutive days, and the mean values (±SE) were calculated.

Results

After undergoing the three treatment sessions, abdominal distension improved in the biofeedback group (n=19; by 24±7 %), but not in the placebo group (n=20; 8±3 % change; p=0.025 vs feedback group). In the 20 patients randomized to placebo, subsequent biofeedback treatment improved abdominal distension (by 35±7 %). Follow-up in all patients after biofeedback (n=36) showed a sustained improvement in abdominal distension and bloating sensation at 1 month (by 39±5 % and 36±7 %, respectively; p<0.001 vs before treatment for both), and at 3 months (by 37±5 % and 34±8 %, respectively; p<0.003 vs before treatment for both).

Conclusion

In patients with disorders of gut-brain interaction, correction of abdominophrenic dyssynergia by a simple, non-instrumental technique, produces a sustained improvement of visible abdominal distension, associated with a concomitant improvement of bloating sensation.

Disclosure

I have the following Conflict of Interest to declare: Coloplast, Schwabe

Introduction

Irritable bowel syndrome (IBS), which affects between 5 and 10% of the population according to the Rome III or IV diagnostic criteria, manifests as chronic abdominal pain associated with altered bowel transit. Moderate or severe IBS significantly impair the quality of life of patients, who are often dissatisfied with conventional treatments. In search of more effective solutions, many are turning to complementary and alternative approaches, such as hypnotherapy, whose effectiveness is well-established. Among these approaches, osteopathy, adopted by nearly 40% of patients in France, attracts growing interest. Single-centre studies with small sample sizes (30 to 40 patients) have reported promising but miscellaneous results, suggesting an improvement in symptoms and an effect on rectal sensitivity (1), or a transient effect on the severity of IBS (2).

Aims & Methods

Our study aims to evaluate the efficacy of visceral osteopathy on the severity of IBS symptoms in a French multicentre study. The trial, conducted as part of the 2015 National Hospital Clinical Research Program (PHRCN-PHRC-15-294), included adult patients suffering from IBS according to Rome III criteria and with moderate or severe IBS (IBS-SSS of 175 to 500 points at baseline). Patients were randomised into two groups: one with visceral osteopathy (three sessions performed over one month, two weeks apart) and one with placebo manipulation performed by the same osteopaths. Clinical characteristics (age, gender, BMI, IBS subtype according to bowel movements), anxiety (Spielberger State-Trait Anxiety Inventory, STAI-1 and STAI-2) and depression (Beck Depression Inventory or BDI II) levels, quality of life (IBS-QOL, ranging from 0 to 100, with 100 corresponding to the best quality of life), and IBS severity (IBS-SSS) were recorded. The primary objective of the study was the improvement in the IBS-SSS severity score at 2 months (1 month after the end of osteopathy). The effects on anxiety and depression levels as well as on quality of life were secondary objectives. The number of subjects to be included was calculated at 210 patients.

Results

Six centres included a total of 156 patients* (78 per group): mean age of 46 (± 15) years, 73% of women, 60% with IBS-C, 17% with IBS-D, 15% with IBS-M, and 8% with IBS-U. The mean IBS-SSS severity score was 336 (± 66) points (27.1% moderate severity and 72.9% severe with IBS-SSS > 300), with no difference between the two groups. Before inclusion, 61% of patients felt that osteopathy would be effective for their condition. At 2 months, the absolute decrease in the severity score (primary endpoint) was similar in both groups (52.4 ± 97.6 vs. 48.6 ± 98.9 points, p-value = 0.975), suggesting a placebo effect, as were the state-trait anxiety levels and quality of life (secondary endpoints).
* The monitoring committee terminated the study after a futility analysis on the first 156 patients because the study message could not be changed by including additional patients out of a planned total of 210.

Conclusion

In this first randomised multicentre study, visceral osteopathy was no more effective than a placebo manipulation in improving the severity of IBS, psychological comorbidities, or quality of life.

References

(1) Attali et al. Treatment of refractory irritable bowel syndrome with visceral osteopathy: Short-term and long-term results of a randomized trial. Journal of Digestive Diseases 2013; 14; 654–661. doi: 10.1111/1751-2980.12098
(2) Florance et al. Osteopathy improves the severity of irritable bowel syndrome: a pilot randomized sham-controlled study. European Journal of Gastroenterology & Hepatology 2012 ; 24 (8) : p 944-949. DOI: 10.1097/MEG.0b013e3283543eb7

Disclosure

Nothing to disclose

Introduction

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus. Inflammation in EoE has been associated with potential risk of esophageal cancer (EC), with controversial results by the most recent studies [1] [2] [3].

Aims & Methods

The aim of this study was to estimate the true risk burden of EC in EoE, further investigating the confounding role of overlapping gastroesophageal reflux disease (GERD) or Barrett Esophagus (BE) on EC occurrence. We conducted a retrospective multicenter cohort study on aggregated data of EoE patients accessing the global federated health research network “TriNetX”, with access to electronic medical records from approximately a hundred million patients across large healthcare organizations (HCOs), based on the ICD-10 code (K20.0), from January 1^st 2000 until March 31^st 2025. We inferred the risk of EC, by comparing two different EoE cohorts: cohort A including EoE diagnosis (excluding eosinophilic gastrointestinal disorders [EGIDS]), not applying any other restrictive criteria; cohort B with only pure EoE diagnosis excluding any instance of GERD (K21.0) and Barrett esophagus (BE) (K22.7) or other EGIDS. The control cohort comprised patients encountered in outpatient clinic for undefined issues (Z00), without diagnosis of EoE/BE or pre-cancerous lesions. We used propensity score nearest neighbor greedy matching, adjusting for PPI use, family history of GI cancer, age, sex, other esophageal diseases (K22.0) and GERD status. Kaplan-Meyer (KM) curves with censoring were built for time-to-event analysis. Log Rank test was used to compare KM curves. Hazard Ratios (HRs) and Risk Ratio (RR) estimation for EC risk were calculated and compared. Sub-analyses for squamous-cell cancer (SCC) vs adenocarcinoma, and for EC location in the esophagus (distal, medium and proximal) were implemented.

Results

After 1:1 propensity score matching, 92,447 patients with EoE (with or without GERD) (cohort A) (mean age 38.9±20.7 years, M 59.7%, previous history of malignant GI neoplasm 2.7%, GERD 40.4%, other esophageal diseases 14.9%, PPI use 40.4%; all p>0.05 with control group) and 32,270 patients pure EoE (without GERD/BE) (cohort B) (mean age 33.9±19.3 years, M 64.7%, previous history of malignant GI neoplasm 1.2%, GERD 0%, other esophageal diseases 8.3%, PPI use 23.2%; all p>0.05 with control group), were compared with controls subjects. Mean follow-up of cohort A was 1298.6 days compared to 1046.5 days in cohort B. The total number of EC occurrences in cohort A were 44 in EA group compared to 31 in the control group, resulting in a HR of 1.676 (1.058-2.657, 95%CI), while a non-significant RR of 1.419 (0.896, 2.247, 95%CI). The KM survival analysis resulted significant (log-rank test p=0.026). Interestingly, when comparing cohort B (pure EoE without GERD or BE) with the control group, only 10 instances of EC in both groups where encountered during the follow-up, with a non-significant HR of 0.893 (0.290-2.754 95%CI) with no difference in the KM survival analysis (p= 0.844). No differences in sub-analysis for squamous cell or adenocarcinoma cancer, neither for EC occurrence in different esophageal localizations were detected.

Conclusion

The results from this global retrospective study on more than 90,000 EoE patients, confirmed the irrelevant risk of EC in pure EoE. The mild association reported in other studies may be likely due to EoE overlap with GERD/BE. No specific surveillance for EC seems needed in EoE when GERD and BE are not present.

References

1. Albaneze N, Cotton CC, Anderson C, Katzka DA, Dellon ES. No Association Between Eosinophilic Oesophagitis and Oesophageal Cancer in US Adults: A Case-Control Study. Aliment Pharmacol Ther. 2025 Jan;61(2):363-368. doi: 10.1111/apt.18431. Epub 2024 Dec 4. PMID: 39629856; PMCID: PMC11680457.
2. Zhou MJ, Hsing AW, Clarke JO. Prevalence and predictors of Barrett's esophagus and esophageal cancer in patients with eosinophilic esophagitis. Dis Esophagus. 2025 Jan 7;38(1):doae120. doi: 10.1093/dote/doae120. PMID: 39775829.
3. Uchida AM, Schuman SS, Pyne A, Peterson K, Carlson M, Garber JJ, Roelstraete B, Ludvigsson JF. Risk of Cancer Diagnosis in Patients With Eosinophilic Esophagitis Using a Nationwide Swedish Population Cohort. United European Gastroenterol J. 2024 Dec;12(10):1378-1387. doi: 10.1002/ueg2.12713. Epub 2024 Nov 20. PMID: 39565026; PMCID: PMC11652337.

Disclosure

E.V. received speaker and/or consulting fees from Sanofi/Regeneron, Falk Pharma, Apollo Therapeutics, and Aurora Biofarma. EVS received consulting fees from Dr Falk Pharma and Reckitt Benckiser; research support from Medtronic and Diversatek Healthcare. DAC.: Medtronic(Speaking, Consulting, License); Diversatek (Consulting); Braintree(Consulting); Medpace (Consulting); Phathom Pharmaceuticals(Speaking); Regeneron/Sanofi(Speaking). AJB received research funding from BMS, Sanofi/Regeneron, SST, and Dr. Falk Pharma and received speaker and/or consulting fees from Uniquity, Laborie, Medtronic, BMS, Dr. Falk Pharma, Calypso Biotech, Eupraxia, Aqilion, Alimentiv, Sanofi/Regeneron, Uniquity, Reckitt, AlfaSigma and AstraZeneca. All other authors did not have any disclosures.

Introduction

Human transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis, spurring development of the oral TG2 inhibitor ZED1227. In the phase 2a CEC-003/CEL study in CeD patients on a gluten-free diet (GFD), once-daily treatment with ZED1227 with gluten challenge (3 g/day) for 6 weeks led to significant improvement in the ratio of intestinal villous height to crypt depth (VH:CrD) versus placebo.¹ Despite adherence to a gluten-free diet, up to half of CeD patients report persistent symptoms often combined with varying degrees of small intestinal injury. Hence, potential treatments for CeD should ideally address these symptoms and improve mucosal injury.

Aims & Methods

The aim of the present study was a dose-ranging trial of ZED1227 in CeD patients with residual symptoms and villous atrophy despite a GFD. This was a double-blind, randomized, placebo-controlled phase 2b study. It enrolled adult CeD patients who had followed a GFD for at least one year and who experienced at least one moderate or severe gastrointestinal (GI) symptom in the month prior to baseline. All patients underwent an initial 5-week placebo run-in phase, followed by endoscopy and 1:1:1:1 randomization of patients with VH:CrD ≤2.5. Treatment was placebo thrice-daily (TID) or ZED1227 at doses of 10 mg TID, 25 mg TID, or 50 mg once-daily (QD) for 12 weeks. No gluten challenge was carried out. The primary endpoint was the rate of patients with both improvement by ≥ 0.4 in VH:CrD and improvement by ≥ 15% in either of two symptom scores (non-stool GI or diarrhea severity) on the celiac disease symptom diary (CDSD) from the end of the run-in phase to week 12. Key secondary endpoints included the change in VH:CrD, change in CDSD GI total severity score, and safety.

Results

A total of 397 patients were randomized to the 4 arms, of whom 92.7% completed treatment. The primary endpoint was achieved by 27.1% of patients receiving 10 mg ZED1227 TID, 16.9% for 25 mg TID, 25.3% for 50 mg QD, and 19.3% for placebo, with no significant differences between any treatment arm and placebo. The mean change in VH:CrD ratio from baseline was 0.21 for 10 mg ZED1227 TID, 0.17 for 25 mg TID, and 0.26 for 50 mg QD versus 0.12 for placebo. Within-group changes from baseline to week 12 were statistically significant within each arm, while the between-group difference in changes was significant only for 50 mg ZED1227 QD versus placebo (p<0.05). Similarly, mean changes in the CDSD GI total severity score were -0.96 with 10 mg ZED1227 TID, -0.95 with 25 mg TID, -1.20 with 50 mg QD, and -1.05 with placebo. Improvements within each arm were again statistically significant, with no significant differences between any treatment arm and placebo. There were no notable differences in the rates of adverse events or serious adverse events (SAEs) between the study arms, and no SAEs related to the study drug were reported.

Conclusion

The CEC-004/CEL study did not meet its primary endpoint of combined improvement in histology and symptoms. However, changes in the VH:CrD ratio achieved with 50 mg ZED1227 QD were statistically superior to placebo, consistent with the results of the prior CEC-003/CEL study. Significant within-group improvement from baseline to week 12 in both histologic and symptom outcomes within the placebo group underscored the challenges of clinical trials without deliberate gluten exposure in patients with the heterogeneous symptom and histology typical of partially treated CeD. The favorable safety profile of ZED1227 was confirmed, and no new safety concerns were identified.

References

1. Schuppan D, Maki M, Lundin KEA, Isola J, Friesing-Sosnik T, Taavela J, et al. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. N Engl J Med. 2021;385(1):35-45.

Disclosure

Sponsor of the trial: Dr. Falk Pharma GmbH
Acknowledgement: This research was supported by Takeda.