Introduction

​Pancreas inflammation is frequently brought on by sustained intraductal pressure, which is mostly caused by gallstones or ERCP, a minimally invasive diagnostic technique. It has been demonstrated that in mice, this brief pressure reduces tight junction integrity through calcineurin. Another effector protein of intraluminal pressure is the mechanosensitive Ca²⁺ channel PIEZO1, which senses cell elongation, increases Ca²⁺ influx, and hence controls both epithelial cell division and apoptosis. However, the development of treatment approaches that specifically target post-ERCP and gallstone-induced pancreatitis has been hampered in recent years due to challenges in in vitro modeling of pressure-related changes.

Aims & Methods

Therefore, our aim was to use apical-out organoids (hPOCs) generated from human pancreas to demonstrate the pressure-related disease processes ex vivo.
Pancreatic tissue samples were collected from 3 cadaver donors and used for establishment of hPOCs. Polarity switching of organoids was induced by Matrigel removal. Conventional and apical-out hPOCs were compared by RNA-sequencing and fluorescent live cell imaging. Gene expression changes in response of 1 µM PIEZO1 activator (YODA1) treatment were measured by qRT-PCR in apical-out hPOCs.

Results

Polarity switching reduced PIEZO1 expression, although decreasing intraluminal pressure and therefore cell elongation reduced expression of cytoskeletal and cell cycle related genes such as ACTB, VCL, LPXN, LMNA, and cyclin gene family members. In the same experiment, pro-inflammatory cytokines like CXCL1, CXCL2, CXCL3, and CXCL8 were found to be downregulated. We demonstrated that polarity switching resulted in enhanced Cl^- efflux via CFTR and ANO1 due to the absence of sustained intraluminal pressure maintained by basal secretion in the closed lumen of conventional organoids. The production of pro-inflammatory cytokines in apical-out hPOCs was reversed upon pharmacological activation of PIEZO1 by YODA1, indicating that PIEZO1 is responsible for the development of the inflammation-like pre-stimulated phenotype of apical-in hPOCs.

Conclusion

Altogether, our results suggest that conventional organoid cultures, previously used as physiologically relevant models, may represent a pressure-induced inflammatory state by overexpressing elements of the epithelial innate immune response, while polarity switching of organoids may overcome the previous limitations and open new perspectives in modelling pressure-induced pancreatitis in vitro.

Introduction

Only a small number of trials have been conducted on the use of SC Infliximab in IBD with a lack of data to directly compare with IV Infliximab. These trials have focused upon patients newly started on Infliximab. There has been an under representation of patients who have been established on IV Infliximab for a longer period of time and then undergone SC switch as well as higher risk patient groups including those with Perianal Disease and Escalated Dosing Regimens of IV Infliximab. We conducted the largest study completed so far in the UK comparing the efficacy, pharmacokinetics and safety of SC with IV Infliximab in IBD .The novelty of SC Infliximab use in the UK combined with the scarcity of units currently using this treatment and critical study outcomes at 1 year only becoming available in May 2023 have prompted us to submit this as a late breaking abstract.

Aims & Methods

Retrospective cohort study of 306 patients in established clinical remission receiving Infliximab at an IBD centre in the UK during May 2023. Efficacy was assessed using objective biomarkers (CRP, FCP), clinical disease activity scores (HBI/SCCAI) at Baseline, 3-6, 12-15 months and treatment persistence. Pharmacokinetics was assessed through treatment discontinuation secondary to Anti-Drug Antibody formation and changes in serum drug levels. Safety was assessed through the frequency of treatment related side effects. Statistical analyses included; Descriptive, Wilcoxon, ANOVA, Regression, KMC/Log Rank and MWU Test. Ethical approval was not required.

Results

199 patients were on SC Infliximab and 107 patients on IV Infliximab. The Efficacy of SC Infliximab was demonstrated through no significant change in the CRP and FCP from baseline when compared to values at 3-6 months and 12-15 months (CRP (p = 0.344)) (FCP (p = 0.301)). Higher rates of treatment persistence were reported on SC Infliximab when compared to the IV group (87% SC vs 35% IV, p < .001). This difference persisted when escalation of the IV dose was excluded as the reason for the failure of treatment persistence (87% SC vs 76% IV, p = .001). An increase in drug levels on treatment was found to be a significant factor for treatment persistence in the SC group (p = .001) (OR 31.77). However, perianal disease and the dosing of IV Infliximab prior to SC switch were not significant factors for treatment persistence in the SC group (Perianal Disease ((p= .757) (OR 1.2)) (Dosing of IV Infliximab (p = .513) (OR 0.67)). There were significant differences between the SC and IV Infliximab group when comparing drug levels on treatment (p=<.001), the CRP at 3-6/12 (p=<.001) and the FCP at 3-6/12 (p=<.001). Those on SC Infliximab had a significant increase in drug levels on treatment not observed in the IV group with higher drug levels and more frequent increase in drug levels (SC (p = <.001) (Median 6 Before, Median 14 After) (83.2%)), (IV (p = .085) (Median 3.1 1^st, Median 4.8 2^nd) (54.4%)). Furthermore, Anti-Drug Antibody (ADA) formation leading to treatment discontinuation was less frequently observed on SC Infliximab (2% SC vs 20% IV). Treatment discontinuation due to side effects was less frequent in those on SC Infliximab (3% SC vs 13% IV).

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Conclusion

SC switch should be considered in patients who are in established clinical remission on IV Infliximab as offering an effective and safe alternative, even in higher risk patients, with an increase in serum drug levels predictive of treatment success. The SC route displays different pharmacokinetic properties to IV which are favourable given the lower rates of treatment discontinuation.

References

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