Introduction

The advent of biologics and small molecule inhibitors targeting immunologic mechanisms has revolutionized the landscape of inflammatory bowel diseases (IBD) treatment. However, a significant proportion of patients remain primary non-responders and initial responders can relapse over time. Combining treatments with different mechanisms of action holds potential to increase the clinical response rates in IBD patients. The aim of this study was to examine the potential utility of combining distinct anti-inflammatory mechanism(s) with α4β7 integrin inhibition in IBD. We utilized the clinically relevant CD4⁺CD45RB^hi T cell transfer (TCT) colitis mouse model, which has been used to validate the preclinical monotherapy efficacy of these agents for IBD.

Aims & Methods

At initiation of TCT colitis, Rag2^-/- mice received anti-α4β7 monoclonal antibody (mAb) alone, or in combination with subtherapeutic doses of an anti-IL12p40 mAb, an anti-IL23p19 mAb, or a small molecule inhibitor (SMi) of TYK2 (deucravacitinib, BMS-986165) for 7 weeks. Colitis development was evaluated via readouts including body weights, gross colon weight by length ratios, transcriptomic analysis of the colonic tissue, and histopathological scores.

Results

In monotherapy settings, treatment with anti-α4β7 significantly inhibited the development of moderate to severe colitis in mice. This was reflected by improved body weights, gross colon weight/length ratios, and histopathology scores (sum of inflammation, erosion, hyperplasia, and gland loss scores) compared to vehicle controls. The combination treatment of anti-α4β7/IL12p40 was the most robust, indicated in part by a highly consistent therapeutic response across study animals, surpassing the therapeutic efficacy of both anti-α4β7 monotherapy and other combination treatments with anti-IL23p19 or TYK2 SMi. On the other hand, anti-α4β7/IL23p19 and anti-α4β7/Tyk2 SMi showed only moderately improved efficacy, compared to anti-α4β7 monotherapy. Finally, tissue transcriptomic analysis revealed involvement of mechanistic pathways related to efficacy, including T cell activation/differentiation for all groups with inhibitors but to different degrees. Additionally, combination treatments showed differences focused within cytokine signaling, innate immune receptor signaling, and antigen presentation pathways.

Conclusion

Inhibition of cytokines IL12/IL23, which drive effector Th1 and Th17 responses, and regulate innate and Jak-STAT signaling, in combination with blockade of the cell trafficking integrin α4β7, resulted in significantly increased protection from colitis compared to monotherapy groups. Combining these agents with different mechanisms of action offers a rational approach to test these combinations for potential increased therapeutic activity in patients with IBD.

Disclosure

All authors are employees and shareholders of Morphic Therapeutic, Waltham, MA, USA.

Introduction

There is conflicting data on the risk factors linked to Gastroesophageal Reflux Disease (GERD) and Functional Dyspepsia (FD). Studies that explore the association between anxiety/depression and GERD phenotypes (Esophagitis/EE and Non-Erosive Reflux Disease/NERD), FD, and Rome-IV syndromes are scarce.

Aims & Methods

The aim was to evaluate the association between epidemiological factors and comorbidities with GERD phenotypes, FD, and Rome-IV syndromes, as well as the relationship of these processes with anxiety/depression.
338 participants were selected from 357 patients referred to three tertiary centers in Granada (Spain) for endoscopic assessment. A gastroenterologist individually interviewed each participant prior to the procedure and administered three validated questionnaires (GERD-Q, Rome-IV, and HADS) to detect the presence of GERD, FD, and anxiety/depression, respectively.

Results

45/338 patients were controls, 198/58.6% were classified as GERD, 81/24.0% EE (49/14.5% symptomatic, and 32/9.5% asymptomatic), 117/34.6% NERD, 176/52.1% FD (43/12.7% epigastric pain syndrome, 36/10.7% postprandial distress syndrome, and 97/28.7% overlapping syndrome). 81 patients were mixed GERD-FD. Multivariate analysis found significant independent associations: age in NERD and FD; sex in EE, asymptomatic EE and FD; body mass index in NERD and FD; alcohol in EE; anxiety/depression in FD; use of calcium channel antagonists in EE; and inhalers in FD. We compared controls vs different groups/subgroups finding significantly more anxiety in NERD, FD, all Rome-IV syndromes, and mixed GERD-FD; more depression in FD, overlapping syndrome, and mixed GERD-FD; and higher levels of anxiety+depression in NERD, FD, overlapping syndrome, and mixed GERD-FD.

Table: Multivariate analysis (logistic regression) of factors associated with different groups and subgroups of GERD and FD

Conclusion

The existence of shared demographic and psychopathological risk factors in Non-Erosive Reflux Disease (NERD) and Functional Dyspepsia (FD) implies that they could be part of the same pathophysiological spectrum. The prevalence of anxiety was higher in NERD, while anxiety and depression were more frequent in FD. These results suggest that psychological therapy could be a supportive strategy for both conditions.

Introduction

Recently, a novel self-assembling peptide hemostatic gel has become available in Japan. However, the safety and efficacy of this novel self-assembling peptide hemostatic gel remain unclear for bleeding after EST.

Aims & Methods

The aim of this study was to evaluate the safety and efficacy of a novel self-assembling peptide hemostatic gel for bleeding after EST, and compared to conventional endoscopic hemostasis technique.
This retrospective study was carried out between January 2019 and October 2022. Patients who developed bleeding associated with EST were enrolled. The patients were divided into two groups based on the hemostasis techniqueused: a conventional hemostasis technique (Group A) or a novel self-assembling peptide hemostatic gel hemostasis technique (Group B).

Results

A total of 62 patients (Group A, n=36; Group B, n=26)were included. Endoscopic hemostasis was initially obtained in 72.2% (26/32) of patients in Group A and in 88.4% (23/26) of patients in Group B, with no significant difference (P=0.1211). However, the procedure time was significantly shorter in Group B (mean, 9.38 min) compared with Group A (mean, 15.4 min) (P=0.0103).There were no significant differences in the severity of bleeding between the two groups (P=0.4468). post-EST bleeding was observed in 6 patients (Group A, n=4; Group B, n=2). although there was no significant difference (P=0.6532), adverse events were more frequently observed in Group A (n=12) than in Group B (n=1).

Conclusion

PuraStat application for EST bleeding might be safe and effective, and comparable to the conventional endoscopichemostasis technique, although further prospectiverandomized trial is needed.

Introduction

Delayed bleeding is a frequently observed complication after endoscopic mucosal resection of large adenomas of colorectum and duodenum. Even though the associated mortality is low, delayed bleeding causes significant morbidity and use of health care resources. Clip closure of the resection field reduces delayed bleeding, but it is time consuming and often complete closure is not achieved. Hemostatic gels and powders can be applied quickly and easily. These agents are in use for the treatment of active bleeding, but it is unknown, whether they will also prevent delayed bleeding when applied to the resection field prophylactically.

Aims & Methods

We conducted a randomized controlled trial of patients undergoing hot-snare endoscopic mucosal resection of flat lesion in the duodenum and colorectum at 15 centers in Germany. Lesions had to be non-pedunculated and measure at least 10 mm in the duodenum and 20 mm in the colorectum. Immediately after resection was completed patients were randomized to hemostatic gel application (intervention group) or no prophylaxis (control group). The primary endpoint was clinically significant delayed bleeding rate (CSDB) within 30 days after resection. Secondary endpoints included transfusion requirements, other complications, wound healing and lesion recurrence.

Results

A total of 233 patients were included in the trial. We performed a planned interim analysis when 200 patients were available for evaluation of the primary end point; at this point we stopped enrollment in the trial due to futility. Of the 200 patients included in the interim analysis, 100 (88 colorectal, 12 duodenal) were included in the intervention group and 100 (88 colorectal, 12 duodenal) in the control group. Groups were comparable in terms of patient age, sex, comorbidities, and lesion localization. CSDB occurred in 13 cases (13%) in the intervention group and in 6 cases (6%) in the control group. This difference was not statistically significant (p=0.146 Fisher’s Exact Test). CSDB rates for colorectal lesions were 10% vs. 4.5% (intervention vs. control group) and for duodenal lesions 33% vs. 17%. Follow-up for patients already enrolled is continuing and data lock for the full study cohort is expected in May 2024. The full data set will be presented at UEG Week.

Conclusion

The application of a hemostatic gel following endoscopic mucosal resection of large non-pedunculated lesions in the duodenum and colorectum does not reduce the rate of CSDB.

Disclosure

OM and TVH have received lecture fees from Puramatrix (the company producing Purastat gel). TW has received lecture fees from Fuji (the company marketing Purastat in Germany).

Introduction

Intestinal ultrasound (IUS) has proven to be a valuable tool for accurately detecting intestinal damage and characterizing disease behavior in Crohn’s disease (CD). IUS scoring systems for CD activity have been developed, however all the studies had methodological flaws. Therefore, studies comparing and validating the existing IUS scores in CD patients are required.

Aims & Methods

In this study, we aimed to compare two main existing scores, Bowel Ultrasound Score (BUSS) and International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) in patients with ileal CD using the simplified endoscopic activity score for CD (SES-CD).
An observational cross-sectional study was performed to evaluate the disease activity in adult CD patients with ileal involvement between November 2019 and February 2024. All patients had undergone ileocolonoscopy and IUS, the time interval between the two procedures was lower than 10 days. Receiver operating characteristic (ROC) curve analyses was performed for BUSS and IBUS-SAS to predict SES-CD ≤2 for CD.

Results

Total 56 adult patients with ileal CD were included in the study, 38 patients (67.9%) were male, the median age was 40.5 (IQR 26-46.75) years and the median duration of the disease was 8.4 (IQR, 4.93-10.29) years. In the endoscopically remission (SES-CD ≤2) group; the median BUSS was 2.63 (IQR 2.12-3.45) and the median IBUS-SAS was 14 (IQR, 11.3-18.4), while in the endoscopically active (SES-CD >2) group; the median BUSS was 5.67 (IQR, 3.47-7.76) and the median IBUS-SAS was 49.7 (IQR, 23.3-72.65). The median BUSS and median IBUS-SAS in the endoscopically remission group were significantly lower than those of the endoscopically active group (p< 0.001, for both). The cut-off value for BUSS to determine endoscopic remission (SES-CD ≤2) was 3.9 (AUC: 0.839, 95% CI: 0.737-0.941, sensitivity: 92%, specificity: 73%, p < 0.001), while the cut-off value for IBUS-SAS to establish endoscopic remission (SES-CD ≤2) was 24.4 (AUC: 0.871, 95% CI: 0.780-0.962, sensitivity: 100%, specificity: 73%, p < 0.001).
There was a very high positive correlation between BUSS and IBUS-SAS (r=0.914, p<0.001), a high positive correlation between BUSS and SES-CD (r=0.659, p<0.001), a moderate positive correlation between BUSS and CRP (r=0.577, p<0.001). There was a high positive correlation between IBUS-SAS and SES-CD as well as IBUS-SAS and CRP (r=0.728, p<0.001 and r=0.657, p<0.001 respectively).

Conclusion

In this study, we found that the most accurate cut-off value for BUSS was 3.9 and the most accurate cut-off value for IBUS-SAS was 24.4 in CD patients with endoscopic remission (SES-CD ≤2) group. Also, we have confirmed that both BUSS and IBUS-SAS significantly correlate with endoscopic activity in a real-world cohort.

Introduction

The BELCOMID study recruited immune mediated inflammatory disease (IMID) patients during the COVID19 pandemic. Patients were evaluated before vaccination, after onset of the vaccination campaign and after onset of booster vaccinations. Clinical data, Nucleocapsid(N-)antibodies and Spike(S-)antibodies were assessed.

Aims & Methods

Current subgroup analysis aimed to firstly, explore factors associated with N-/S-antibody response in IMID patients with different COVID19 vaccination status. Five patient groups were identified. G1: no vaccination before the vaccination campaign, G2: complete baseline vaccination, G3: 1 booster, G4: 2 boosters, G5: patients refusing every vaccine even after the booster campaign. We report on influence of IMID treatment and smoking status.
Secondly, we explored influence of SARS-CoV2 infection and vaccination on IMID flare-up.

Results

Demographics of 2165 recruited IMID patients are shown in Table.
After baseline vaccination (G2) odds of N-seroconversion were higher in patients treated with combined IMM/TIMT (OR2.52, p=0.023). No other association with N-seroconversion was found.
Mean S-antibody titre increased progressively from G2 to G4. After completed baseline vaccination (G2), odds of S-antibody seroconversion were lower in those treated with TIMT (OR0.28, p=0.0079) particularly rituximab (OR0.0354, p<0.001), IMM (OR0.276, p<0.001), combined IMM/TIMT (OR0.156, p<0.001) and systemic steroids (OR0.183, p<0.001). IMID flare prior to vaccination was associated with lower risk of S-seroconversion (RR0.94, p<0.001). By contrast, mean S-titre was higher for those treated with antiIL23 (mean ratio 2.17, p=0.011) and vedolizumab (mean ratio 1.84, p<0.001) in G2.
After 1 booster (G3), lower odds of S-seroconversion remained with rituximab (OR0.0368, p<0.001), IMM (OR0.222, p=0.0014), combined IMM/TIMT (OR0.15, p<0.001) or systemic steroids (OR0.0637, p<0.001). Vedolizumab was associated with lower odds of being in the lowest S-titer quartile (OR0.206, p<0.001). Odds for S-antibody seroconversion with anti-TNF were higher compared to rituximab both for patients in G2 (OR26.3, p<0.001) and G3 (OR27.5, p<0.001).
Patients who received 2 boosters (G4) all had S-seroconversion and no IMID treatment modality was associated with higher odds of being in the lowest quartile.
After baseline vaccination (G2) smokers had higher risk of being in the lowest S-antibody titer quartile (RR1.45, p=0.0098). This observation persisted after 1 booster (G3)(RR1.42, p=0.0122) but was no longer noticed after 2 boosters (G4).
After start of booster vaccinations, 25.17% of patients had experienced IMID flare-up in the previous months. No significant association between IMID flare-up rate and previous SARS-CoV2 infection was found. There was no increased risk of IMID flare-up with additional booster vaccination. However, patients who received 2 booster vaccines showed a lower RR for IMID flare-up compared to those who only received 1 booster (RR0.70, p=0.0067).

Conclusion

Certain immune-modulating treatment modalities and smoking may blunt serologic COVID19 vaccination responses. However, this is overcome by repeated booster vaccination without increased risk of IMID flare-up.

Disclosure

The BELCOMID study group received research grants from following pharmaceutical companies: Almirall, Roche, Janssen, Pfizer, Eli Lilly, Amgen, Biogen, Mylan, LEO Pharma. These companies had no role in study design, conduct nor reporting of results.