Introduction

Current guidelines provided information on the management of patients with gastrointestinal bleeding, in particular focusing on admission, endoscopic management and medical treatment during the hospital stay. So far, 11-15% of patients treated for GIB required a new hospitalization for a new bleeding episode.

Aims & Methods

The aim of the study is to verify if the management in a dedicated practice after hospital discharge for gastrointestinal bleeding reduces further bleeding and costs. This is an ambispective cohort single center study, including patients observed between May 2022 and September 2023 in our clinical practice dedicated to gastrointestinal bleeding. We enrolled consecutive patients with overt gastrointestinal bleeding or iron deficiency anemia affected by vascular lesions. The effectiveness was defined as a composite endpoint including iron supplementation, blood transfusion, medical treatment and number of hospital stay. Costs were evaluated starting from Diagnosis Related Groups (DRG) codes. The cost effectiveness analysis and ICER has been calculated using the ICERconf.EXE software (Software Prescriptions, c/o Bob Obenchain, California, USA).

Results

In our institute 602 patients with gastrointestinal bleeding were evaluated between May 2022 and September 2023, of these 79 were included in the study. The mean age was 73.8 years (SD±10,8), 46% were female. The source of bleeding was angiodysplasia in 63% of patients, GAVE in 9% (Gastric Antral Vascular Ectasia), erosions in 9%. After the introduction in the dedicated practice, the re-bleeding decrease from 1.3 episodes to 0.2 episodes, p<0.001. The cost average after the practice was 4074 euro (SD ±5485), the average cost before the practice was 4885 euro (SD ±4567), it has been observed a cost saving after the management in the dedicated practice, C diff= -751 euro. The average effectiveness after practice was 8.7 (SD±1.06) and the average effectiveness before the practice was 7.3 (SD ±1.3) with the E diff= 1.47, p<0.001.

Conclusion

The dedicated practice for patients with gastrointestinal bleeding provides effectiveness in reducing transfusion, iron supplementation and hospitalization with a consistent cost reduction.

Clinical Case Summary

Background & aim: Gastric ischemia is a rare but often overlooked cause of abdominal pain. We present a case of chronic ischemic gastritis due to severe mesenteric arterial stenosis, highlighting the importance of early recognition and interventional management.
Methods: A 77-year-old female with type 2 diabetes mellitus and dyslipidemia presented with a 1-month history of severe postprandial epigastric pain, progressive in intensity, leading to significant weight loss and liquid diet dependence. She denied vomiting or bowel habit changes. Esophagogastroduodenoscopy(EGD) revealed severe erythematous, edematous mucosa with multiple scattered clean-based ulcers and erosions in the stomach and duodenum. CT angiography demonstrated severe atherosclerotic changes, including near-complete stenosis of the celiac trunk and significant narrowing of the superior mesenteric artery (SMA).
Results: A multidisciplinary team, including surgery and interventional radiology, decided on superior mesenteric angioplasty. The procedure involved abdominal aortogram, selective SMA arteriogram, and angioplasty with placement of two metallic stents, achieving successful revascularization. Post-procedure, the patient was discharged on dual antiplatelet therapy. Follow-up showed complete resolution of symptoms, improved appetite, and weight gain. Repeat EGD revealed significant mucosal healing, confirming the success of revascularization.
Conclusion: Chronic ischemic gastritis is an underdiagnosed entity that should be considered in patients with postprandial abdominal pain and weight loss, especially with vascular risk factors. Early recognition and intervention can lead to significant symptom relief and improved outcomes. This case emphasizes the role of endovascular interventions in managing ischemic gastroduodenopathy.

References

Clinical Gastroenterology and Hepatology 2014;12:246–252
Ribas BM,. Severe ischemic gastritis caused by chronic mesenteric ischemia. J Vasc Bras. 2023;22:e20230002

Introduction

Immune checkpoint inhibitors (CPI) have revolutionised cancer outcomes, but frequently trigger immune related adverse effects, including life-threatening colitis. Tissue resident memory (TRM) T cells are key cells involved in the pathogenesis of CPI-induced colitis (CPI-C), but the mediators they produce to facilitate disease are poorly defined.

Aims & Methods

We utilised our previously published in vivo pre-clinical model of CPI-C, which occurs when mice are given combination anti-CTLA4 and anti-PD1 and a proinflammatory microbiota mix, to define the role of the Granzyme A/B cytotoxicity pathway in disease. Disease was induced in wildtype (WT) and Granzyme A/B double knockout (GzmAB^-/-) mice. Clinical outcomes (colon and spleen mass, histology and infiltrating neutrophils) from these mice were assessed to measure the severity in disease. T cell populations were also analysed using flow cytometry.

Results

GzmAB^-/-mice showed a significant reduction in disease features compared to WT mice, with reduced colon mass, reduction in infiltrating neutrophils and fewer inflammatory monocytes. Flow cytometry analysis of the T cell compartment revealed a significant reduction in both bulk CD4 and CD8 T cells and also CD4 and CD8 tissue resident memory T cells in both the cLP and IEL in GzmAB^-/-mice treated with CPI-C in comparison to WT mice treated with CPI-C. GzmAB^-/-mice treated with CPI-C also had a reduction in IFNγ and TNFα production from both CD4 T cells and CD8 T cells. These data highlight the importance of granzymes in inducing the disease phenotype in CPI-C. In order to investigate whether CD4 T cells or CD8 T cells were more important, we depleted these cells in vivo in WT mice treated with CPI-C at both 1 and 3 weeks. Here, we found that WT mice with CD4 T cells depleted got significantly worse disease with colon masses increasing and there being increased infiltrating neutrophils. There was an increase in cytotoxic cytokines being produced by CD8 T cells when CD4 T cells were depleted. However, when CD8 T cells were depleted, there was no change in any clinical features or cytokine production from CD4 T cells.

Conclusion

Using GzmAB^-/- mice we have demonstrated that CPI-colitis is at least partially dependent on the granzyme cytotoxicity pathway. Targeting the cells that produce granzyme in the colon of patients with CPI-colitis might offer an attractive novel treatment option for patients with CPI-colitis.

References

1. Lo, J.W., Cozzetto, D., Alexander, J.L. et al. Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis. Nat Commun 14, 6719 (2023). https://doi.org/10.1038/s41467-023-41798-2
2. Luoma A. M. et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 182, 655-671.e22 (2020).
3. Sasson, S. C. et al. Interferon-gamma-producing CD8(+) tissue resident memory T cells are a targetable hallmark of immune checkpoint inhibitor-colitis. Gastroenterology 161, 1229–1244.e1229 (2021).
4. Gupta T, Antanaviciute A, Hyun-Jung Lee C, et al. Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis. Cancer Cell. 2024 May 13;42(5):797-814.e15. doi: 10.1016/j.ccell.2024.04.010. PMID: 38744246.

Introduction

Tumor necrosis factor-like ligand 1A (TL1A) is a member of the Tumor necrosis factor (TNF) superfamily implicated in the pathogenesis of inflammatory bowel disease (IBD) as a key amplifier of the effector function of several immune cells. TL1A can be expressed by various immune cells, including macrophages, dendritic cells, and some T cell subsets, and exists either as a membrane-bound or as a cleaved soluble trimer. TL1A signals predominantly by activating NF-kB pathway via the only known functional receptor, death receptor 3 (DR3), which has restricted expression mostly on effector T cells and innate lymphoid cells (ILCs). Afimkibart is a fully human anti-TL1A antibody that has shown clinical benefit in Phase 2 clinical studies and specifically blocks the activity of trimeric forms of TL1A. Monomeric TL1A has also been described; however, the relevance of monomeric TL1A in DR3 signaling and disease is unclear. This study aimed to understand the functional characteristics of both monomer and trimer TL1A species in primary cells and cell lines.

Aims & Methods

Immunoassays were used to measure the detection of TL1A species in IBD serum. Recombinant human monomeric and trimeric TL1A proteins were assessed for binding to afimkibart using SPR and in cellular assays using primary immune cells and cell lines for nuclear factor-kappa B (NF-κB) signaling and interferon-gamma (IFNγ) production.

Results

In functional cellular assays with primary immune cells, we demonstrate that trimeric recombinant human TL1A (rhTL1A) protein causes significant NF-κB signaling in human peripheral T lymphocytes, and in the presence of interleukin 12 (IL12) and interleukin 18 (IL18) co-stimulation, a significant increase of IFNγ production by human primary peripheral blood mononuclear cells (PBMCs). In line with the mechanism of action, both the NF-κB signaling and IFNγ production are blocked by afimkibart. In contrast, only high concentrations of monomeric rhTL1A, >100 ng/ml, induced moderate NF-κB signal and demonstrated a minimal increase in IFNγ production above IL12 + IL18 stimulation alone. However, this activity was blocked by afimkibart. Lastly, afimkibart blocks endogenous soluble and membrane-bound TL1A.

Conclusion

Herein, we demonstrate that afimkibart blocks NF-kB signaling and IFNγ production induced by TL1A stimulation. While some signaling activity was observed at high concentrations of monomeric TL1A protein, we hypothesize that any signaling observed with monomeric form is likely due to the formation of trimers, which are efficiently blocked by afimkibart. Overall, any monomeric TL1A present should not be functionally active nor be available as a sink for afimkibart, thus preserving the optimal pharmacokinetic (PK) and pharmacodynamic (PD) properties needed for effective target inhibition.

Disclosure

All the authors are employees of Genentech-Roche.

Introduction

Colectomy is the primary treatment for dysplastic lesions in inflammatory bowel disease (IBD). Since the development of advanced endoscopic techniques, the management of dysplasia is evolving. Endoscopic submucosal resection (ESD) could be used in selected cases at referral centres as an alternative to colectomy. However, the feasibility and safety in IBD remains limited.

Aims & Methods

To evaluate en-bloc resection rate and the need of colectomy due to ESD failure in IBD.
Secondary aims: to assess the complications of ESD, the local recurrence of dysplastic lesions, the presence of synchronous and metachronous lesions and the risk of IBD relapse following the procedure.
Multicentre, retrospective study of IBD patients who underwent ESD for suspected colonic dysplastic lesions at least one month before the inclusion date. Patients with total colectomy before ESD, invisible dysplasia at the time of ESD, or pregnancy were excluded. En-bloc resection rate and colectomy due to ESD failure at the short term were evaluated by logistic regression analysis. The risk of IBD relapse was evaluated by Cox regression analysis.

Results

Sixty patients from 22 centres were included: 47 with ulcerative colitis, 11 with Crohn’s disease and 2 with IBD-unclassified. The mean age at ESD was 64 years (SD 13). The majority of the lesions (n=33, 55%) were located in rectum. Fifty lesions (83%) were located in areas previously inflamed. En-bloc and R0 were achieved in 58 (97%) and 50 patients (83%), respectively. Colectomy due to ESD failure was required in 5 patients (8.3%), all of them occurred within 6 months after ESD. No risk factors were associated with colectomy in multivariable analysis, including inflammatory activity, IBD treatments or characteristics of the lesions. Complications occurred in 17 patients (28%): 3 did not required any treatment, 6 required pharmacologic therapy, 6 needed endoscopic or radiologic intervention, and 2 underwent surgery (Table 1). No deaths were reported.
At least one surveillance colonoscopy after ESD was performed in 42 patients (70%). Local recurrence was observed in 2 patients (4.7%) while other dysplastic lesions were detected in 11 (26%) during the follow-up (median 1.5 years, IQR 0.5-3.4). All these lesions were removed endoscopically. Synchronous and metachronous lesions were identified in 4 (20%) and 9 patients (19%), respectively. IBD relapse occurred in 8 patients during the follow-up, with an incidence rate of 7% person-year (CI 95%:3-13). The occurrence of relapses was gradually throughout the follow-up period.

Table 1. Complications of endoscopic submucosal dissection

Conclusion

ESD avoids colectomy in 90% of IBD patients with dysplastic lesions. One-third of the patients experienced complications, all of them resolved with no sequelae. Given the risk of new dysplastic lesions, ongoing monitoring with surveillance colonoscopies is recommended.

Disclosure

María José García has received financial support for travelling and educational activities from Janssen, Pfizer, AbbVie, Takeda, Kern Pharma, Faes Farma and Ferring.
Edoardo Vincenzo Savarino has served as speaker for Abbvie, Abivax, Agave, AGPharma, Alfasigma, Apoteca, Biosline, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Galapagos, Johnson&Johnson,consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, Dr. Falk, Eli Lilly, Fenix Pharma, Ferring, Giuliani, Grunenthal, Johnson&Johnson, JB Pharmaceuticals, Merck & Co, Nestlè, Pfizer, Reckitt Benckiser, Sanofi/Regeneron, SILA, Sofar, Takeda, Unifarco; he received research support from Bonollo, Difass, Pfizer, Reckitt Benckiser, Sanofi/Regeneron, SILA, Sofar, Unifarco, Zeta Farmaceutici.
Irene González-Partida has received support for conference attendance and speaker fees from AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Janssen, MSD, Kern, Pfizer, Shire, Takeda, Teva and Tillotts Pharma AG.
Alicia López has served as speaker for Chiesi, Takeda, ABBVIE, Lilly. I have received support for conference attendance from Pfizer, Lilly, Kern Pharma, Falk, Ferring, and Janssen
Jordina Llao has received educacional suport from Abbvie, Tillots, Ferring and Lilly.