Introduction

The use of ustekinumab (UST) and vedolizumab (VDZ) as first line therapies for inflammatory bowel disease (IBD) is increasing due to safety reasons and contraindications of anti-TNFs. However, there are no studies assessing their efficacy and safety in clinical practice in this setting.

Aims & Methods

Aims: Therefore, our aims were to describe the features of those patients not previously exposed to biologicals who were treated with VDZ or UST and to evaluate their efficacy and safety profile in this scenario.
Methods: Observational, retrospective and multicenter study based on the ENEIDA registry (a large, prospectively maintained database of the Spanish Working Group in IBD –GETECCU). All IBD patients not previously exposed to biological agents who started VDZ or UST as first-line biological treatment, were identified from the database. Disease activity at baseline and different time points from the beginning of UST/VDZ use, as well as development of side effects, were carefully reviewed from medical records.Descriptive statistics were used, followed by non-parametric comparisons by chi-square test.

Results

Out of 29,450 IBD patients ever exposed to any biological drug included in the ENEIDA registry at the time of data extraction, 406 patients met the inclusion criteria, 149 (36.7%) treated with UST and 257 (63.3%) with VDZ, as first line biological therapy.
At baseline, 46.3% UST and 41.8% VDZ were women (P=ns), median age at the beginning of UST was 60 years (IQR 45-73) and, 61.5 years (IQR 47-71) in VDZ. UST was more frequently used in Crohn’s disease (CD) (92.6% vs. 41%; P<0,001); conversely, VDZ was used significantly more often in ulcerative colitis (UC) (7.4% UST vs 59% VDZ; P<0,001). A higher proportion of extensive UC (81.8% UST vs 45;7% VDZ, P=0.029) and perianal disease (14.1% UST vs. 5.5% VDZ; P=0.002) was observed in the UST group. A past history of malignancy was common and evenly observed in both study groups (UST 33% vs VDZ 35.7%; P=ns), as were other comorbidities (47.7% UST vs 53.3% VDZ; P=ns). Concomitant immunosuppressants were used in 14% with UST and 13.9% with VDZ (P=0.671), and 32.4% and 49% were concomitantly treated steroids at the beginning of UST and VDZ, respectively (P=0.001). No differences were observed regarding disease clinical activity at baseline as assessed by the Harvey Bradshaw index (HBI) in CD and partial Mayo score (PMS) in UC. Endoscopic assessment was available in 106 (54.3%) CD patients and 132 (65.4%) UC patients, most of them having endoscopic activity (90% UST vs 91,8% VDZ ;P=ns).
During follow-up 37.8% UST vs. 46.5% VDZ required dose-escalation (P=0.024). No differences were observed regarding early and long-term clinical remission between UST and VDZ for both diseases (UC: week 14, 50% UST vs 68.5% VDZ; week 56, 83.3% UST vs 89% VDZ) (CD: week 14, 96.7% UST vs 92.7% VDZ; week 56, 74.6% vs 61.9% VDZ).
At the end of follow-up (median 21 months [IQR 13-41]) UST vs. 20.5 months [IQR 8-38.7]), treatment persistence was significantly higher among UST users (67.8% vs 43.2%; P=0.006).
Only 1.5% of patients discontinued UST because of adverse effects compared to 5.1% with VDZ (P=0.053).

Conclusion

In clinical practice, VDZ and UST are used as first-line therapies at older ages than anti-TNFs and mostly in patients with comorbidities or a past history of malignancy. Even in this scenario, both treatments have a good safety profile and a high persistence of treatment, although UST shows a higher persistence and a lower rate of treatment discontinuation due to side effects.

Disclosure

I have served as a speaker, consultant and advisory member for or has received research funding from Takeda, Gilead, Janssen, Faes Farma, FalK and MSD

Introduction

Complete removal of pancreatic duct stones is the goal of endoscopic treatment for chronic pancreatitis (CP), which is mainly performed by endoscopic retrograde cholangiopancreatography (ERCP), and is completed with either a basket or a balloon catheter. However, choosing which catheter primarily depends on the operators' preference, and the evidence is still scarce. Thus, this study compared the efficacy and safety of these two devices for pancreatic duct stone extraction.

Aims & Methods

This single center retrospective cohort study reviewed the records of 452 consecutive CP patients who underwent ERCP for the first time, from February 2012 to December 2021. A propensity score-matched analysis (1:1) was performed using age, sex, diabetes mellitus, steatorrhea, pancreatic duct stricture, pancreas divisum, ESWL prior to stone extraction, number of stones, size and location of stones as variables. Finally, 101 patients with basket and 101 with balloon catheter were analyzed. The primary outcome was the clearance rate of pancreatic stones; the secondary outcomes were ERCP peri-procedural outcomes and complications.

Results

The rate of complete clearance was comparable between two groups (86.1% [87/101] vs 84.2% [85/101], P = 0.692). In patients with stones ≥ 2cm before extracorporeal shock wave lithotripsy (ESWL), the rate of complete clearance was significantly higher in balloon than in basket group (100% [19/19] vs 70.0% [14/20], P = 0.031). No significant difference was found in partial (odds ratio [OR] 0.8; 95% confidence interval [CI], 0.3-2.1; P = 0.603) and unsuccessful clearance(OR 1.9; 95% CI, 0.6-5.8; P = 0.274). In multivariate analysis, ESWL prior to stone extraction was the only independent predictor of complete clearance (OR, 2.3; 95% CI, 1.2-4.3; P = 0.013). In ERCP peri-procedural outcomes analysis, no significant difference were found in rates of difficult cannulation (1.0% vs 3.0%, P = 0.614), endoscopic sphincterotomy (53.5% vs 49.5%, P = 0.573), dilation of stenosis (26.7% vs 32.7%, P = 0.357), and extraction through the minor papilla (13.9% vs 10.9%, P = 0.522) between basket and balloon catheter groups. For patients with pancreatic duct stenosis, the rates of clearance were comparable between two groups. The rates of complications were also similar in pancreatitis (6 [5.9%]/9 [8.9%], P = 0.421), infection (0 [0.0%]/1 [1.0%], P = 1.000), and perforation (0 [0.0%]/2 [2.0%], P = 0.477) between the two groups; no bleeding or basket impaction was detected.

Table 2. The Impact Factors for Rate of Complete Clearance Between Basket and Balloon Catheter Groups

Conclusion

Basket and balloon catheters showed similar efficacy and safety for pancreatic stone extraction, while the balloon catheter was superior to the basket if the stone size was ≥ 2cm before ESWL. ESWL prior to stone extraction was an independent predictor for pancreatic stone extraction.

References

1. Beyer G, Habtezion A, Werner J, et al. Chronic pancreatitis. Lancet 2020;396:499-512.
2. Ross AS, Kozarek RA. Therapeutic pancreatic endoscopy. Digestive and Liver Disease 2010;42:749-756.
3. Dumonceau JM, Delhaye M, Tringali A, et al. Endoscopic treatment of chronic pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Updated August 2018. Endoscopy 2019;51:179-193.
4. Ishiwatari H, Kawakami H, Hisai H, et al. Balloon catheter versus basket catheter for endoscopic bile duct stone extraction: a multicenter randomized trial. Endoscopy 2016;48:350-7.
5. Ozawa N, Yasuda I, Doi S, et al. Prospective randomized study of endoscopic biliary stone extraction using either a basket or a balloon catheter: the BasketBall study. J Gastroenterol 2017;52:623-630.
6. Sharma R, Sharma V, Singhal U, et al. Outcomes of balloon vs basket catheter for clearance of choledocholithiasis: a systematic review and meta-analysis. Endosc Int Open 2022;10:E1447-e1453.
7. Zhao ZH, Hu LH, Ren HB, et al. Incidence and risk factors for post-ERCP pancreatitis in chronic pancreatitis. Gastrointest Endosc 2017;86:519-524.e1.
8. Wang D, Ji JT, Zou DW, et al. Extracorporeal shock wave lithotripsy as rescue for a balloon dilator trapped in the pancreatic duct. Endoscopy 2015;47 Suppl 1:E604-6.

Introduction

Mirikizumab (miri), a p19-directed IL-23 antibody, showed efficacy in ulcerative colitis (UC)¹. Miri modulates transcripts associated with disease activity and anti-TNF resistance in UC and increases expression of transcripts associated with healthy mucosa². Here, we evaluate the transcription profile of patients with UC who respond to placebo (PBO, 20.6%) or miri 200mg treatment (59.7%) versus non-responders and build a model that can predict response in patients with UC.

Aims & Methods

In the phase 2 AMAC trial (NCT02589665), patients were randomized 1:1:1:1 to receive intravenous PBO (N=63), 50mg miri (N=63), or 200mg miri (n=62) with possible exposure-based dose increases or fixed 600mg miri (n=61) at Week (W)0, 4 and 8. Colonic biopsies were collected at baseline, W12, and W52. An Affymetrix HTA2.0 microarray measured gene expression. Limma comparing values at baseline and W12 determined differentially expressed genes (DEGs). DEGs maintaining their W12 expression level through W52 among responders in either the PBO and miri 200mg arms were designated as similarly expressed genes (DEGSEGs).
XGBoost models³ were trained to predict clinical response (decrease in 9-point Mayo subscore [rectal bleeding, stool frequency, endoscopy] of ≥2 points and ≥35% from baseline [BL] with either a decrease of RB subscore of ≥1 or an RB subscore of 0 or 1) using baseline levels of DEGSEGs and TNF biomarkers. Leave-one-out cross validation of the models using AMAC data and validation experiments by training on the PROTECT data⁴ then predicting in AMAC were used to evaluate our models.

Results

Miri 200mg responders were associated with 84 DEGSEGs, PBO responders were associated with 26 DEGSEGs, and 21 DEGSEGs were common to both. When using the PROTECT data as the training data and AMAC data as the validation cohort, we were able to achieve high ROC-AUC and PR-AUCs using the top 36 (FC > 1.5) miri DEGSEGs (PR-AUC=0.78), or combined (PR-AUC=0.93) gene sets as the features and found that the response prediction was significantly higher in AMAC responders vs. non-responders.

Conclusion

Baseline transcript features were predictive of clinical response in patients with UC treated with miri 200mg and our model distinguished responders from non-responders. Future studies are underway to validate this model.

References

1. Sandborn WJ, et al. Gastroenterology. 2020;158(3):537-549.e10.
2. Steere B, et al. J Crohns Colitis. 2020;S103-S104.
3. Chen T, et al. Proceedings of the 22^nd ACM SIGKDD International Conference. 2016;7285-794.
4. Hyams JS, et al. Lancet Gastroenterol Hepatol. 2017;2(12):855-868.

Disclosure

TJ and KH report no conflicts of interest. WR reports grant support and personal fees from Abbott Laboratories, AbbVie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik, and Merck Sharp & Dohme, and personal fees from Aptalis, Celltrion, Danone Austria, Elan, Ferring, Mitsubishi Tanabe Pharma Corporation, Otsuka, PDL BioPharma, Pharmacosmos, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Bioclinica, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Covance, Galapagos, Genentech, Gilead Sciences, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Nestle, Novartis, Ocera, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Second Genome, SetPoint Medical, TiGenix, UCB, Zyngenia, and 4SC. BS, CH, NM, and VK are employees and shareholders of Eli Lilly and Company. CM is a former employee of Eli Lilly and Company. GD has served as an advisor for: AbbVie, Ablynx, Active Biotech, AgomAb Therapeutics, Allergan, AlphaBiomics, Amakem, Amgen, AM-Pharma, Applied Molecular Therapeutics, Arena Pharmaceuticals, AstraZeneca, Avaxia Biologics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Cosmo Pharmaceuticals, Dr. Falk Pharma, DSM Pharmaceuticals, Echo Pharmaceuticals, Eli Lilly and Company, enGene, Exeliom Biosciences, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Immunic Therapeutics, Johnson & Johnson, Kintai Therapeutics, Lycera, Medimetrics, Medtronic, Merck Sharp & Dohme, Mitsubishi Pharma, Mundipharma, Nextbiotics, Novo Nordisk, Otsuka, Pfizer, PhotoPills, ProciseDx, ProDigest, Progenity, Prometheus Laboratories/Nestlé, Protagonist Therapeutics, RedHill Biopharma, Robarts Clinical Trials, Salix Pharmaceuticals, Samsung Bioepis, Sandoz, Seres Therapeutics/Nestec/Nestlé, Setpoint, Shire, Takeda, Teva, TiGenix, Tillotts Pharma AG, Topivert, Versant, and Vifor Pharma; and received speaker fees from: AbbVie, Biogen, Ferring Pharmaceuticals, Galapagos NV/Gilead Sciences, Johnson & Johnson, Merck Sharp & Dohme, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts Pharma AG, and Vifor Pharma.

Introduction

Despite the increasing incidence of Crohn’s disease (CD), its early immune disturbances have not been described yet. The preclinical period provides an opportunity to gain insight into the initial processes involved in the pathogenesis of the disease.

Aims & Methods

The main aim of our study was to describe how the subclinical inflammatory process is modifying the individual’s immunologic environment while the patient is still on preclinical period. We analysed scRNASeq data from peripheral blood mononuclear cells (PBMC) of patients with incidentally-diagnosed CD according to ECCO criteria during the colorectal cancer screening programme, after histologic confirmation. Their gene expression profile was compared to healthy individuals acquired from publicly available datasets. The analytical pipeline included merging of the datasets followed by batch correction concerning integration from different studies, quality control and filtering, and finally cell-type annotation and differential gene expression analysis.

Results

Two patients with CD (mean age 53,5 years) and 2 healthy controls were included. We observed distinct transcriptomic profile in preclinical patients compared to controls, with small intragroup differences. The cell-type annotation identified B cells (B), CD4+ and CD8+ T-cells (CD4T, CD8T), dendritic cells (DC), monocytes (Mono) and natural killer cells (NK). The analytical pipeline included 17,021 cells (B:3,274, CD4T:5,798, CD8T:3,476, DC:315, 2, Mono:928, NK:3,230) and 3000 quantified genes. Considering each cell type individually, we identified 49 differentially expressed genes (DEG) between CD patients and controls (B:39, CD4T:37, CD8T:41, DC:42, Mono:37, NK:37), from which 30 were DEGs in all cell types.
Building on the list of 49 detected DEGs, we report three insights into the preclinical period of the disease.
First, pathway analysis revealed significant enrichment of the pathway that is related to immunoregulatory interactions between lymphoid and non-lymphoid cells, and functional annotation analysis identified gene products that are related to immunological defense. Second, we identified significant transcriptomic alterations in genes that have previously been related to the symptomatic phase of IBD, or reported as potential biomarkers. Third, after performing principal component analysis we observed greater separation between the patients groups in the CD8T cells compared to the other cell-types.

Conclusion

This study reveals the initial transcriptomic profiles and the main pathways that precede the onset of symptomatic inflammatory bowel disease. Our findings may help in identifying potential targets for early disease intervention.

Introduction

Epstein-Barr virus (EBV) associated gastric cancer (GC) has been reported to be about 5-16% of all gastric cancers with good prognosis compared to EBV-negative GC. The aim of this study was to evaluate the clinicopathological characteristics of EBV-positive GC including survival analysis in the prospective observational cohort study in a tertiary hospital in South Korea.

Aims & Methods

Total 4,586 patients who underwent EBV in situ hybridization (EBV-ISH) testing among 14,613 patients diagnosed with GC were prospectively enrolled at Seoul National University Bundang Hospital from 2003 to 2023. Data including age, sex, smoking, cancer type and stage, tumor size and location, histologic type, molecular features (p53 expression and MSI), and survival information including causes of death were collected and analyzed.

Results

EBV-positive cancer group showed significant differences compared to EBV-negative cancer group. That is, they showed higher proportion of males (p<0.001), predominant presence in the proximal stomach (p<0.001), higher proportion of undifferentiated cancer (p<0.001), and lower cancer stage (p=0.004) (Table). In Cox multivariate analyses, age (HR 1.022, p<0.001), tumor size (HR 1.118, p<0.001) along with cancer stage (stage 2 HR 5.843, p<0.001; stage3 HR 15.570, p<0.001; stage4 HR 50.075, p<0.001, respectively) were significant risk factors for GC-specific mortality, while EBV positivity was inversely correlated (HR 0.537, p=0.023). In the survival analyses, EBV-positive cancer group showed statistically significant survival advantages over EBV-negative cancer group in both overall (p=0.016) and gastric cancer-specific survival (p=0.005)

Conclusion

EBV-positive GC group was associated with male sex, proximal location, poorly differentiated histology and lower cancer stage, and showed significantly better prognosis than EBV-negative gastric cancer. EBV might play a role in the gastric carcinogenesis to make less metastasis resulting in better survival.