Introduction

Loss of parietal cells causes the development of spasmolytic polypeptide-expressing metaplasia (SPEM) through transdifferentiation of chief cells. Slc26a9 is a member of Slc26a family with highly expression in the parietal cells to maintain gastric mucosal homeostasis (Liu et al., DDW 2019, 2020 and 2022). Our previous study showed that SLC26A9 deficiency causes gastric intraepithelial neoplasia in mice. (Liu et al., Cellular oncology 2022). However, the role of Slc26a9 in SPEM is never investigated.

Aims & Methods

Explore the role of Slc26a9 in SPEM. Slc26a9^fl/fl mice were crossed with Atp4b-Cre to generate parietal cell-specific Slc26a9 knockouts in Slc26a9^fl/fl/Atp4b-Cre mice in a mixed genomic background. Histopathology, immunohistochemistry (IHC), immunofluorescence (IF), Flow cytometry analysis, qPCR and single-cell sequencing were performed in Slc26a9^fl/fl mice and Slc26a9^fl/fl/Atp4b-Cre mice. Macrophage polarization markers and cytokine-related markers were detected by qPCR and Western-blot. Slc26a9 was overexpressed by adeno-associated virus and chronic SPEM model was established by using IL-33.

Results

Compared with Slc26a9^fl/fl mice, Slc26a9^fl/fl/Atp4b-Cre mice exhibited autoimmune gastritis (strongly loss of parietal cells, oxyntic atrophy followed with lymphocyte infiltration) at 1month, accompanied with H⁺/K⁺-ATPaseb and intrinsic factor lost. Flow cytometry analysis showed that CD4⁺T cells that infiltrated the Slc26a9^fl/fl/Atp4b-Cre stomach expressed the TCR (TCRVa2/TCRVb2) specific for the H⁺/K⁺-ATPase peptide. With advanced of age, Slc26a9^fl/fl/Atp4b-Cre mice displayed SPEM and hypergastrinemia at 6 months, followed with gastric alarmin IL-33 released and upregulation of SPEM markers, TFF2 and MUC6. Identification of gastric epithelial cell lineages using scRNA-seq and unbiased clustering showed that a variety of immune cell types. qPCR revealed significantly upregulation of macrophage molecular markers (F4/80, CD86, CD163), followed with the significantly upregulation of polarization markers of M2 macrophages and related chemokines in Slc26a9^fl/fl/Atp4b-Cre mice, including Arg1, Klf4, Fizz1, Ym1, Mrc1, CCL24 and CCL22 when compared with Slc26a9^fl/fl mice. Moreover, double immunofluorescence confirmed that M2 polarized markers F4/80⁺CD163⁺ cells were significantly accumulated in Slc26a9^fl/fl/Atp4b-Cre mice. At the same time, there was a corresponding increase in M2 macrophages capable of secreting IL-33. Notably, overexpression of Slc26a9 in IL-33-induced chronic SPEM model reduced SPEM formation and suppressed IL-33 downstream immune signaling as well as decreased M2 macrophages polarization. These results suggested that parietal cell-selective Slc26a9 deletion in mice caused SPEM development by promoting polarization of M2 macrophages via IL-33 upregulation.

Conclusion

Parietal cell-selective Slc26a9 deficiency in mice lead to the development of SPEM via IL-33 signaling. We speculated that Slc26a9 plays an important protective role in stabilizing gastric mucosal immunity and gastric epithelial cell homeostasis.

Introduction

After first anti-TNFɑ (aTNF) failure in ulcerative colitis (UC), switching to a different mechanism of action (MoA) could decrease the rates of failure and discontinuation compared to a second aTNF and with a better safety profile.

Aims & Methods

We performed a retrospective and multicenter study (6 Andalusian sites). Patients diagnosed of UC who had failed a first biological therapy with an aTNF and started a second-line biological therapy with another aTNF or a different MoA such as ustekinumab (UST), vedolizumab (VDZ), tofacitinib and filgobinib (JAK) were included. The aim of our study was to evaluate the long-term durability of a different MoA compared to a second aTNF after a first-line therapy failure with aTNF.

Results

185 patients with UC were included. There were no significant differences between both groups in terms of age, sex, extension of disease, extraintestinal manifestations or IMIDs, smoking habit or HLA-DQA1*05. The only significant difference was disease duration (9 years MoA vs 12 years in second aTNF, p=0.02). 80 patients received a different MoA (37 VDZ, 24 UST, 19 JAK) and 105 a second aTNF (34 IFX, 60 ADA, 11 golimumab). Duration of first aTNF, although non-significant (p=0.06), tended to be shorter in the MoA group (7 months vs 12 months in aTNF group). The most frequent cause of suspension of first aTNF in the MoA group was primary failure (46% vs 31%, p= 0.02) and in the second aTNF group was secondary failure (51% vs 35%, p=0.02). The follow-up mean was 22.4 months in the group of a different MoA and 23.3 months in the second aTNF group. 60% of patients discontinued the second-line biological treatment, 64% with aTNF vs 35% with a different MoA. Durability of therapies in the group of different MoA was significatively longer compared with second aTNF (50% vs 31.4%, p=0.036) (figure 1). UST showed the best durability (66.7%), followed by JAK (63.2%), IFX (52.9%), VDZ (32.4%), ADA (21.7%) and golimumab (18.2%), with significant differences (p=0.03). Reasons for discontinuation were primary failure in 29.7% (63.6% second aTNF vs 36.4% different MoA), secondary failure in 25.9% (64.5% second aTNF vs 35.5% different MoA) and intolerance or adverse events in 6.4% (66.6% second aTNF vs 34.4% different MoA). Adverse events were reported in 12 patients, 8 with aTNF a 4 with other MoA (2 vs 0 infusion reactions, 1 vs 1 mild infections, 2 vs 1 respiratory adverse effects, 1 vs 1 cutaneous reactions, 1 vs 0 musculoskeletal effects, 1 vs 1 neoplasia).

Conclusion

Our study shows that after a first aTNF failure in UC, a switch to a biological therapy with a different MoA achieves longer survival compared to switching to a second aTNF, with less primary and secondary failure.

Introduction

Ulcerative colitis (UC) is a chronic and relapsing disease for which the number of biological therapies available are increasing over the years. Data comparing the effectiveness of a second anti-TNFɑ (aTNF) and the switch to a different mechanism of action (MoA) such as Ustekinumab (UST), Vedolizumab (VDZ), Filgotinib or Tofacibinib (JAK) is lacking.

Aims & Methods

We performed a retrospective and multicenter study (6 Andalusian sites). Patients diagnosed of UC who had failed a first biological therapy with an aTNF and started a second-line biological therapy with another aTNF or a different MoA (UST, VDZ, JAK) were included. Clinical response and remission were assessed at weeks 16 and 52. The aim of our study was to evaluate the effectiveness of a second-line biological therapy with aTNF compared to a different MoA after a first aTNF failure.

Results

185 UC patients were included. There were no differences in the demographic data except for disease duration (9 years with MoA vs 13 years in aTNF, p=0.02). As first aTNF, infliximab (IFX) was the most common in both groups (49% MoA group, 56% second aTNF), followed by adalimumab (ADA) (48% MoA group, 33% second aTNF). In the second aTNF group, immunomodulators were significatively more used (60% vs 38%, p=0.003). There were no differences in the concomitant use of steroids. 80 patients received a different MoA (37 VDZ, 24 UST, 19 JAK) and 105 a second aTNF (34 IFX, 60 ADA, 11 golimumab). At week 16, 52% of patients were in clinical response (70% with another MoA vs 54% with second aTNF, p=0.07; IFX 65%, ADA 53%, VDZ 68%, UST 71%, JAK 74%, p=0.07), being 15.6% more likely to achieve response with another MoA. Clinical remission at week 16 was obtained by 36% (39% with another MoA vs 33% with second aTNF, p=0.6; IFX 47%, ADA 30%, VDZ 35%, UST 46%, JAK 37%, p=0.1). At week 52, 48% achieved clinical response (51% with another MoA vs 45% with second aTNF, p=0.8; IFX 50%, ADA 42%, VDZ 49%, UST 54%, JAK 53%, p=0.5) and 39% were in clinical remission (40% with another MoA vs 38% with second aTNF, p=0.53; IFX 50%, ADA 32%, VDZ 35%, UST 38%, JAK 53%; p=0.06). When the effectiveness is analyzed by first aTNF used, independently of the aTNF, subsequent use of a different MoA achieves better results although not significant compared to a second aTNF. Partial Mayo and calprotectin showed a significant decrease at weeks 16 and 52 in both groups. Hemoglobin and albumin levels remained similar during follow-up in both groups.

Conclusion

Second-line biological therapy is effective regardless of biological therapy used in UC, but switching to a different MoA tend to achieve better results in terms of clinical response and remission compared to a second aTNF.

Introduction

Dilated CBD on non-invasive imaging with normal or borderline derangement of LFT and unremarkable physical signs has been always a diagnostic dilemma. In the clinical setting, however, to determine the presence of ductal calculi or importantly a tumor remains a significant dilemma; a balance must be struck between invasive ERCP, associated complications and potential inaccurate diagnosis. We made a protocol to do EUS prior to ERCP in all such cases, where the previous investigations did not give a conclusive evidence of the pathology. We studied the efficacy of EUS in such cases for reaching a conclusive diagnosis and avoid unnecessary ERCP and its incipient complications.

Aims & Methods

To evaluate the efficacy of EUS prior to ERCP for patients with dilated CBD and other inconclusive imaging with normal or borderline derangement of LFT.
A total of 900 patients were referred for ERCP in last 6 years with inconclusive imaging study for dilated CBD and normal to borderline deranged LFT’s.

Results

482 - CBD stones
08 - Pancreatic Malignancy
12 - Distal Cholangiocarcinoma
04 - CBD Sludge
34 - Ampullary Tumor
30 - Impacted Stone at ampulla
12 - Distal CBD polyps
06 - WON Compression
12 - Chronic Pancreatitis Related Stricture
86 - Presumed Spontaneous passage of stones,
44 - Type 1 Choledochal cyst,
60 - Periampullary diverticulum,
40 - Stones in Hartman’s pouch,
34 - Small ampullary adenoma,
16 - Duodenal ulcers with scarring
20 - Post cholecystectomy dilatation

ERCP was performed in 557 cases ( 61.9%) and avoided in 38.1%).
In the cases of pancreatic malignancy, distal cholangiocarcinoma, ampullary tumors, FNA was done and patients without cholangitis were not offered ERCP but subjected to surgery. Two patients with CBD sludge had cholangitis so ERC was done. Distal CBD polyps were removed at ERCP and two had intraductal ductal extensions so surgery was offered. Only two patients each with choledochal cyst and post duodenal ulcer scarring underwent ERC as they had cholangitis.

Conclusion

EUS has remarkable diagnostic yield in detecting etiology of dilated CBD and avoids unnecessary ERCP’s in patients with unidentified cause on other imaging modality.

Disclosure

The authors have nothing to disclose.