Introduction

The gut virome has been previously linked to the development of Crohn's disease (CD), a type of Inflammatory Bowel Disease (1). Recent findings have implicated the expansion of Caudovirales as a potential trigger for CD (2). However, despite speculations regarding molecular mimicry, there has been insufficient investigation into the causal connection between Caudovirales and CD. This lack of understanding stems from the absence of robust data on the immunological effects of Caudovirales and the technical difficulties associated with analyzing protein structures, which have impeded efforts to establish a definitive causal relationship. Consequently, there remains a critical gap in our comprehension of how the virome contributes to CD.

Aims & Methods

In this study, we aimed to investigate the differences in T-cell dynamics between patients with Crohn's disease (CD) and normal controls to explore the potential mechanistic link between CD and Caudovirales. We considered three possible mechanisms: oligoclonal expansion, typically associated with antigen-driven clonal expansion; polyclonal expansion, which can give rise to self-antigen targeting cells; and the absence of T-cell expansion, which would suggest the involvement of other immune mechanisms. By examining T-cell dynamics, we sought to gain insights into the immune processes at play in the pathophysiology of CD. To investigate clonal expansion, we used pcDelta, a near-coincidence statistic originally developed for evaluating T-cell receptor (TCR) clonotype skewing following antigen exposure. The amount of near-sequence similarity is a surrogate for the degree of clonal expansion to a particular antigen and can thus be used for this purpose.
CDR3 sequences of the beta chain of T-cell receptors (TCRs) specific to various viral antigens were obtained from the Immune Epitope Database (IEDB), a rigorously curated repository of TCR sequences with annotated antigen specificities. Additionally, disease-specific CDR3 sequences were compiled from a comprehensive review that consolidated TCR clonotypes isolated from individuals diagnosed with Crohn's disease (CD), drawn from multiple studies. Using pcDelta, we quantified the near-sequence similarity at the amino acid level between TCRs from CD patients and those specific to various viral antigens, comparing these similarities to those observed in healthy controls. To account for the varying numbers of epitope-specific TCRs, subsampling was performed, and a pcDelta value was calculated for each sample.

Results

Our results showed significantly increased near-sequence similarity (p-value < 0.001) across all viral antigens for the CDR3 sequences of TCR isolated from healthy controls as opposed to patients with CD, suggesting oligoclonal expansion to some unknown antigens in patients with CD. Relative T-cell expansion between the various viral antigens within each group was preserved, consistent with the above findings.

Conclusion

The significant decrease in near-sequence similarity between the CDR3 sequences of patients with CD and viral antigens as opposed to healthy controls is suggestive of oligoclonal expansion, consistent with the idea in the literature of molecular mimicry. However the source of the antigen leading to oligoclonal expansion is yet to be identified. Isolating T-cells from individuals exposed to Caudovirales and analysing the TCR Repertoire might prove useful in identifying the source antigen. Future investigations could also employ structural modelling or functional assays to elucidate the impact of molecular mimicry in CD.

References

(1) Diculescu, M., Manuc, T.-E. and Manuc, M. (2016) ‘Recent insights into the molecular pathogenesis of Crohn&#39;S disease: A review of emerging therapeutic targets’, Clinical and Experimental Gastroenterology, p. 59. doi:10.2147/ceg.s53381.
(2) Errico, C., Massimino, L., Facoetti, A., Nicolò, S., et al. (2024) ‘P057 caudovirales may trigger molecular mimicry mechanisms in crohn’s disease’, Journal of Crohn’s and Colitis, 18(Supplement_1), pp. i325–i325. doi:10.1093/ecco-jcc/jjad212.0187.

Introduction

EUS-guided Gastroenterostomy (EUS-GE) represents a recent breakthrough in therapeutic endosonography, with most existing data derived from retrospective studies focused on short-term technical outcomes. Limited information is available on long-term outcomes, the need for reinterventions and modifications of Lumen Apposing Metal Stents (LAMS) over time.

Aims & Methods

All consecutive EUS-GE performed in a single institution with the Wireless Simplified Technique (WEST) between 2020 and 2024 were enrolled in a prospective registry (PROTECT, ClinicalTrials.gov NCT04813055), with efficacy and safety outcomes assessed every 60 days. The primary outcomes were symptom recurrence after initial clinical success (rate, proportion) and dysfunction-free survival (DyFS) estimated using Kaplan Meier curves. Endoscopic LAMS reassessments were used to calculate the time to first modification of the stent and surrounding tissues, whilst Radiologic imaging was used to estimate the change in stent calibre (linear regression).

Results

164 EUS-GEs (median age 66 [60-74], male 52.4%, malignant indication 99.4% [pancreatic cancer 73.2%, metastatic 58.3%]) were included. A 20 mm LAMS was used in 98.8%, dilated up to 18 mm in 98.8% of cases. Technical and Clinical success rates were 98.8% and 96.3%, respectively. Adverse events (AEs) were registered in 15.2% (procedure-related 6.1%, severe/fatal 3.7%).
Over a median follow-up of 112 [40-190] days, symptom recurrence occurred in 9.1%, but was related to stent dysfunctions in 10/154 (6.5%) cases. Stent dysfunctions happened after a median of 231 [67-321] days from the procedure, all of which (100%) were successfully managed endoscopically. Estimated DyFS at 6 and 12 months was 97.5% and 82.6%, respectively.
Among 38 patients undergoing endoscopic LAMS re-evaluation for different reasons, tissue reactions on the gastric or jejunal side were observed in 34.2% after a median of 190 [33-351] days, and LAMS ingrowth was seen in 13.2% after a median of 421 [250-560] days. A total of 132 CT scans from 75 patients were analysed, with regression analysis revealing a reduction in LAMS diameter of ≈ 0.25 mm + 0.03 every 2 months (F-test p<.0001).

Conclusion

In the natural history of EUS-GE, subclinical LAMS changes and tissue reactions can be frequently detected during follow-up along with a progressive narrowing of LAMS diameter. However, most of these modifications are asymptomatic, with a 6.5% rate of endoscopic reinterventions, all performed successfully. Analysis of these curves may be helpful to plan scheduled reinterventions, especially in cases with benign indication or in long-term survivors.

Introduction

Positive effects on markers of metabolic dysfunction–associated steatotic liver disease (MASLD) have already been demonstrated for sodium–glucose cotransporter-2 (SGLT2) inhibitors. Pre-clinical evidence from rodent models also suggests MASLD benefits of endothelin-A receptor antagonism. Zibotentan, the most selective endothelin A receptor antagonist, is currently under clinical investigation in combination with dapagliflozin for treatment of chronic kidney disease (CKD) and for liver cirrhosis. Advanced CKD is also recognized to occur concomitantly with liver cirrhosis.

Aims & Methods

The aim of this exploratory analysis was to evaluate the effect of zibotentan combined with dapagliflozin and dapagliflozin alone on a non-invasive measure of MASLD in patients with CKD recruited into the ZENITH-CKD phase 2b study.

447 patients in the ZENITH-CKD study were treated for 12 weeks with either zibotentan 0.25 mg in combination with dapagliflozin 10 mg (n = 91), or zibotentan 1.5 mg in combination with dapagliflozin 10 mg (n = 179), or dapagliflozin 10 mg alone (active control) (n = 177). The primary outcome was urinary albumin creatinine ratio at week 12. The presented results are from patients with non-alcoholic fatty liver disease fibrosis score (NFS) > 0.675, indicating high risk for advanced fibrosis and included 39 patients treated with combination therapy with either dose of zibotentan, and 27 patients treated with dapagliflozin alone.

Results

Conclusion

A reduction in NFS was observed in this small exploratory analysis of patients with CKD and high risk for advanced liver fibrosis across all three active arms of the study. These data support further exploration of the effects of zibotentan and dapagliflozin in patients with liver cirrhosis as part of the ongoing ZEAL part B study. Further data from both the CKD and liver study programs are awaited.

Disclosure

PA, PG, EW, KP, JO, KF and SR are employees of, and hold stakes in, AstraZeneca. HJLH has received funding from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novartis. HJLH has received consulting fees from Alexion, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Dimerix, Eli Lilly, Janssen, Novartis, Novo Nordisk, Roche, Travere Therapeutics and Vifor Pharma.

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) with stent placement is the current standard for drainage of distal malignant biliary obstruction (MBO), but carries a significant risk of post-procedural pancreatitis.[1] EUS-guided choledochoduodenostomy (EUS-CDS) is increasingly used as a promising alternative, but comparative studies are still scarce.[2,3] While previous studies have mainly focused on stent patency, the current study aims to evaluate whether EUS-CDS is superior to ERCP in achieving a textbook outcome for the patients, indicating an optimal post-procedural course.

Aims & Methods

This single-center study included patients with distal MBO who underwent technically successful (1) EUS-CDS with a lumen apposing metal stent (LAMS) plus additional coaxial stent or (2) ERCP with fully covered self-expandable metal stent (FCSEMS) as part of the prospective SCORPION studies and SPHINX trial, respectively.[1,4] The primary endpoint was textbook outcome, defined as the absence of procedure- or stent-related adverse events (AEs), reinterventions, or hospital readmissions within 30 days of the procedure. Secondary endpoints included individual components of the primary outcome, mortality, time to initiation of treatment (e.g., systemic therapy or surgery), and textbook outcome at 90 days.

Results

A total of 144 patients were enrolled for EUS-CDS (n=49) or ERCP (n=95). Primary etiologies included pancreatic cancer (n=117, 81%) and distal cholangiocarcinoma (n=14, 10%). Coaxial stents used in the EUS-CDS group were FCSEMS (n=20) or double pigtail plastic stents (n=29). Textbook outcome was achieved in 44 patients (90%) in the EUS-CDS group and in 67 patients (71%) in the ERCP group at 30 days (RR 1.27, 95% CI 1.08-1.50). EUS-CDS led to fewer procedure- or stent-related AEs (RR 0.35, 95% CI 0.14-0.84) compared with ERCP, particularly post-procedure pancreatitis (0% vs. 23%). Other AEs, including perforation (2% vs. 0%), bleeding (0% vs. 0%), stent dysfunction with or without cholangitis (4% vs. 6%), and cholecystitis (4% vs. 3%) were similar between groups. Hospital readmission rate was lower in the EUS-CDS group (6% vs. 30%, RR 0.21, 95% CI 0.07-0.65), as was the length of hospital stay (mean 0.3 days [SD 1.3] vs. 1.8 days [SD 4.0], P=0.01). In-hospital mortality (8% vs. 5%), need for reinterventions (8% vs. 6%), and time to treatment initiation, either surgery or chemotherapy, did not differ (median 33 days [IQR 23-42] vs. 30 days [IQR 18-41]). At 90 days, textbook outcome was more often present in the EUS-CDS group when compared to ERCP however the difference was no longer significant (78% vs. 69%, RR 1.22, 95% CI 1.02-1.44).

Conclusion

EUS-CDS with LAMS and additional coaxial stent was superior to ERCP with FCSEMS in achieving textbook outcome at 30 days post-procedure. EUS-CDS resulted in less procedure- or stent-related AEs, particularly post-procedure pancreatitis, and consequently in fewer hospital readmissions and shorter hospital stay. Therefore, when expertise is available, EUS-CDS with coaxial stent placement could be considered as primary biliary drainage technique in patients with distal MBO.

References

1. Onnekink, A. M., Gorris, M., Bekkali, N. L., et al (2024). Endoscopic sphincterotomy to prevent post-ERCP pancreatitis after self-expandable metal stent placement for distal malignant biliary obstruction (SPHINX): a multicentre, randomised controlled trial. Gut, gutjnl-332695. https://doi.org/10.1136/gutjnl-2024-332695
2. Teoh, A. Y. B., Napoleon, B., Kunda, R et al (2023). EUS-Guided choledocho-duodenostomy using lumen apposing stent versus ERCP with covered metallic stents in patients with unresectable malignant distal biliary obstruction: a multicenter randomized controlled trial (DRA-MBO trial). Gastroenterology, 165(2), 473-482.e2. https://doi.org/10.1053/j.gastro.2023.04.016
3. Chen, Y., Sahai, A., Donatelli, G. et al (2023). Endoscopic Ultrasound-Guided Biliary Drainage of First Intent With a Lumen-Apposing Metal Stent vs Endoscopic Retrograde Cholangiopancreatography in Malignant Distal Biliary Obstruction: A Multicenter Randomized Controlled Study (ELEMENT Trial). Gastroenterology, 165(5), 1249-1261.e5. https://doi.org/10.1053/j.gastro.2023.07.024
4. Fritzsche, J. A., Fockens, P., Besselink, M. G. et al (2024). Optimizing EUS-guided choledochoduodenostomy with lumen-apposing metal stents for primary drainage of malignant distal biliary obstruction (SCORPION-IIp): a prospective pilot study. Gastrointestinal Endoscopy. https://doi.org/10.1016/j.gie.2024.10.012

Disclosure

Paul Fockens acted as a consultant for Cook Endoscopy and Olympus, outside the submitted work.
Roy L.J. van Wanrooij acted as a consultant for Boston Scientific. Jeanin E. van Hooft has received research support from Cook Medical and acted as lecturer for Cook Medical, Boston Scientific and Falk, and as consultant for Olympus. Rogier P. Voermans received a research grant and acted as consultant for Boston Scientific. All outside the submitted work. All other authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this abstract.