Introduction

Swallowed topical corticosteroids (STC) are a treatment option for eosinophilic esophagitis (EoE); however, they are associated with side effects and some patients (pts) may not respond. Dupilumab demonstrated improvements in histologic, symptomatic, and endoscopic features in adult and adolescent pts with EoE over 24 weeks (Phase 3 LIBERTY EoE TREET study, NCT03633617) and is approved in the US and EU for the treatment of EoE. Here we assess the effect of long-term dupilumab on histologic, symptomatic, and endoscopic aspects of EoE in pts with/without prior use of STC and with/without prior inadequate response, intolerance, or contraindication to STC.

Aims & Methods

In Part B, pts received dupilumab 300 mg or placebo weekly (qw) for 24 weeks (W24). Eligible pts who completed Part B entered Part C and received dupilumab 300 mg qw for 28 weeks (W52). Clinicians categorized pts as with/without prior STC use and with/without prior inadequate response, intolerance, or contraindication to STC at screening. Assessed outcomes were: proportion of pts achieving ≤6 and <15 eosinophils per high-power field (eos/hpf), absolute change in Dysphagia Symptom Questionnaire (DSQ) score, mean change in Endoscopic Reference Score (EREFS), and Histologic Scoring System (HSS) grade/stage scores.

Results

In Part B, 80 pts received dupilumab and 79 placebo; in Part C, 74 continued dupilumab and 37 switched from placebo to dupilumab. Among pts who enrolled in Part C from Part B, 70% (78/111) had prior STC use. At W24, dupilumab improved vs placebo proportion of pts achieving ≤6 eos/hpf (with prior STC use 69% vs 7%, without 57% vs 0%), <15 eos/hpf (92% vs 11%, 83% vs 0%), and DSQ score (absolute mean [SD] change -27.3 [-15.8] vs -13.6 [12.5], -23.1 [15.6] vs -19.6 [15.0]). Pts continuing dupilumab in Part C further improved at W52: proportion achieving ≤6 eos/hpf (with prior STC use 86%, without 81%) and DSQ score (absolute mean [SD] change ‑31.4 [15.8], ‑27.7 [14.6]); all pts achieved <15 eos/hpf regardless of prior STC use. Pts switching from placebo to dupilumab at W24 improved at W52: proportion achieving ≤6 eos/hpf (with 70%, without 60%), <15 eos/hpf (82%, 70%), and DSQ score (‑26.1 [12.6], ‑29.9 [8.4]). At W52, EREFS and HSS grade/stage scores further improved or were maintained in pts continuing dupilumab and improved in pts switching to dupilumab (Table). Similar results were observed in pts with/without prior inadequate response, intolerance, or contraindication to STC.

Table. Peak eosinophil count in patients with or without prior swallowed topical corticosteroid use to Week 52

Conclusion

Dupilumab 300 mg qw for 52 weeks led to histologic remission (<6 eos/hpf) and sustained improvements in histologic, symptomatic, and endoscopic aspects of EoE, regardless of prior use or inadequate response, intolerance, or contraindication to STC.

Disclosure

AJB: Dr Falk Pharma, Norgine, Nutricia, Sanofi, SST, and Thelial – research funding; Alimentiv, Aqilion, AstraZeneca, Dr. Falk Pharma, Laborie, Medtronic, Regeneron Pharmaceuticals Inc., and Sanofi – consulting fees.
ESD: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Celgene/Receptos/BMS, GSK, Meritage, Miraca, Nutricia, Regeneron Pharmaceuticals Inc., Revolo, Shire/Takeda – research funding; Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, Gossamer Bio, GSK, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nextstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron Pharmaceuticals Inc., Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio – consulting fees; Allakos, Holoclara, and Invea – educational funding.
IH: Allakos, AstraZeneca, Calyx/Parexel, Eli Lilly, Ellodi/Adare Pharma, EsoCap, Gossamer Bio, GSK, Nextstone, Pfizer/Arena Pharmaceuticals, Phathom, Receptos/BMS, Sanofi/Regeneron Pharmaceuticals Inc., and Shire/Takeda – consulting fees; Allakos, Ellodi/Adare Pharma Solutions, Receptos/BMS, Regeneron Pharmaceuticals Inc., and Shire/Takada – research funding.
AJL: Dr Falk Pharma and EsoCap – consulting fees; Dr Falk Pharma, Ellodi Pharmaceuticals, Regeneron Pharmaceuticals Inc. – research funding.
CS: Adare Pharmaceuticals Inc., AstraZeneca, Calypso, Dr. Falk Pharma, EsoCap, GmbH, and Regeneron Pharmaceuticals Inc. – consulting fees.
AS, EM, JM, and XS: employees of Regeneron Pharmaceuticals Inc. and may hold stock and/or stock options in the company.
EL and LG: employees of Sanofi and may hold stock and/or stock options in the company.

Introduction

Eosinophilic esophagitis (EoE) is a chronic, type-2 inflammation-driven esophageal disease causing dysphagia and esophageal dysfunction. Patients with inflammatory bowel disease (IBD) or other type-2 inflammatory disorders may have an increased risk of EoE, but prevalence data are limited. This study examines the prevalence of dysphagia and EoE in patients with type-2 inflammatory diseases or IBD.

Aims & Methods

In this prospective, multicentric, questionnaire-based screening study, patients from the departments of gastroenterology, pulmonology, dermatology, and otolaryngology at the Medical University of Vienna, as well as from the Allergy Center Floridsdorf, were screened for dysphagia using the validated brief esophageal dysphagia questionnaire (BEDQ). The primary endpoint was the prevalence of clinically relevant dysphagia, defined as a BEDQ score ≥10 or a history of bolus impaction in the past year. Endoscopy was offered to symptomatic patients without recent biopsies. Patient characteristics and differences in absolute eosinophil count, eosinophilic cationic protein (ECP), and IgE levels were analyzed using independent-samples T-tests.

Results

A total of 690 patients (45.7% female, mean age 54.5 years) were screened; 54.4% had IBD, 20.2% allergic rhinitis, 16.4% asthma, 8.7% atopic dermatitis, 6.4% chronic rhinosinusitis with nasal polyps (CRSwNP), and 5.2% IgE-mediated food allergy with multiple diagnoses possible. Overall, 5.1% (n=35) exhibited clinically relevant dysphagia. EoE was previously diagnosed in 2.0% (n=14), including four patients with clinically relevant dysphagia. Among the remaining 31 patients, eight had prior endoscopies ruling out EoE, seven underwent endoscopy revealing two new EoE cases, and 16 are still awaiting gastroscopy. No significant differences in IgE, eosinophilic count, or ECP were found between patients with EoE, those with dysphagia, and asymptomatic individuals.

Conclusion

Patients with IBD and type-2 inflammatory diseases exhibit a high prevalence of dysphagia. While EoE is more common than in the general population, most dysphagia remains unexplained. Systematic dysphagia screening in this high-risk population may reduce diagnostic delay.

Introduction

Surveillance is recommended in patients with colonic inflammatory bowel disease (IBD) given their increased risk of colorectal cancer (CRC). Present risk stratification strategies do not discriminate sufficiently between risk groups. We aimed to develop and validate a dynamic multivariable prediction model for advanced colorectal neoplasia (aCRN, including high-grade dysplasia and CRC) in IBD.

Aims & Methods

We pooled data from six existing surveillance cohort studies (two unpublished).^1-3 Patients with IBD and an indication for CRC surveillance were included if they underwent at least one follow-up procedure. Exclusion criteria included prior aCRN, prior colectomy, or an unclear indication for surveillance. Predictors were selected based on the results of a recent meta-analysis,⁴ frequency, and data availability: extensive disease, prior dysplasia (indefinite for dysplasia or low-grade dysplasia), primary sclerosing cholangitis, male sex, IBD type, post-inflammatory polyps, age, and maximal endoscopic inflammation. A dynamic prediction model was developed using a landmarking approach based on Cox proportional hazard modelling.⁵ Model performance was assessed with Harrell’s c-statistic and by calibration curves, adjusted for optimism by internal cross-validation. In a sensitivity analysis model performance was assessed in data ≥2010 only (internal validation). Generalizability across the surveillance cohorts was evaluated by internal-external cross-validation.

Results

The surveillance cohorts encompassed time periods 1973-2021 and comprised 3,731 patients (54% male sex; 75% ulcerative colitis or IBD-unclassified and 25% Crohn’s disease) with a median follow-up of 5.7 years (interquartile interval 3.3-9.6; 26,336 patient-years of follow-up); 146 individuals were diagnosed with aCRN (see table 1 for patient characteristics). The final model contained eight predictors, with a cross-validation median c-statistic of 0.74 and 0.75 and calibration slope of 0.77 and 0.83 for, respectively, a 5- and 10-year prediction window in overall analyses. Calibration plots showed good calibration. Ninety percent of 10-year predicted aCRN risks were between 0.9 and 18.7%. Model discrimination improved in data ≥2010 and calibration results remained unchanged (48% of all procedures ≥2010). Internal-external cross-validation results showed medium discrimination and reasonable to good calibration.

Conclusion

We generated a model based on clinical factors that predicts future aCRN risk, with moderate to good model discrimination and good calibration. However, generalizability results vary and are impacted by varying cohort sizes and should be interpreted with caution. Future research should focus on formal external validation, relate predicted aCRN risks to surveillance intervals, and investigate the impact of this new model in daily clinic prior to clinical application.

References

1. Choi CR, Al Bakir I, Ding NJ, et al. Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study. Gut 2019;68:414-422.
2. Mahmoud R, Shah SC, Ten Hove JR, et al. No Association Between Pseudopolyps and Colorectal Neoplasia in Patients With Inflammatory Bowel Diseases. Gastroenterology 2019;156:1333-1344 e3.
3. Ten Hove JR, Shah SC, Shaffer SR, et al. Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with inflammatory bowel disease with long-standing colitis: results of a 15-year multicentre, multinational cohort study. Gut 2019;68:615-622.
4. Wijnands AM, de Jong ME, Lutgens M, et al. Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis. Gastroenterology 2021;160:1584-1598.
5. van Houwelingen, H., & Putter, H. (2012). Dynamic Prediction in Clinical Survival Analysis (1st ed.). CRC Press. https://doi.org/10.1201/b11311:

Disclosure

Laurent Beaugerie: Research grants: Biogen, Celltrion, Takeda, Ferring, Celltrion, Viatris; Personal fees: Takeda, Nordic Pharma, Janssen, BMS, and Viatris.
Charles N. Bernstein: Dr Bernstein is supported by the Bingham Chair in Gastroenterology. Dr. Bernstein has served on advisory Boards for AbbVie Canada, Amgen Canada, Bristol Myers Squibb Canada, Eli Lilly Canada, Roche Canada, Janssen Canada, Sandoz Canada, Takeda Canada, and Pfizer Canada; Educational grants from Abbvie Canada, Amgen Canada, Bristol Myers Squibb Canada, Ferring Canada, Organon Canada, Pfizer Canada, Takeda Canada, and Janssen Canada. Speaker’s panel for Abbvie Canada, Janssen Canada, Pfizer Canada, and Takeda Canada. Received research funding from Abbvie Canada, Amgen Canada, Sandoz Canada, Takeda Canada, and Pfizer Canada.
Steven H. Itzkowitz: Dr Itzkowitz has served on Advisory Board for Exact Sciences Corporation and a consultant for Geneoscopy. He has received research support from Exact Sciences Corporation and Freenome.
Julien Kirchgesner: Lecture fees from Janssen and Lilly, and consulting fees from Roche, Gilead, Pfizer, Janssen, Celltrion, Lilly, Takeda, and Abbvie.
Cyriel Y. Ponsioen: Received grant support from Gilead and Perspectum and speaker’s fees from Tillotts

Introduction

Long-standing inflammatory bowel disease (IBD) patients have a 2-3-fold increased risk of developing colorectal cancer¹. IBD patients with high-risk colorectal colitis-associated neoplasia (HR-CAN), including non-polypoid lesions and large (>20 mm) non-pedunculated colon polyps, are often not amenable to conventional resection techniques, such as polypectomy and endoscopic mucosal resection, considering the increased risk of complications and progression to submucosal invasive cancer².

Aims & Methods

Aim of this study was to evaluate safety, effectiveness, and feasibility of endoscopic submucosal dissection (ESD) of HR-CANs in IBD patients. In this real-world, multicenter, retrospective study, we included consecutive IBD patients referred to nine Tertiary Italian Endoscopy Centers (2014-2023) to undergo an advanced endoscopic resection (AER), including ESD and hybrid-ESD (hESD), for HR-CANs. The primary outcome was rate of en bloc resection, R0 resection and adverse events (AEs). The secondary outcome was rate of post-AER surgery, local recurrence, and metachronous lesions. En bloc resection was defined as excision of the targeted lesion in a single specimen. R0 resection was defined as resection with lateral and deep margins free of dysplasia/neoplasia on histopathology. Among AEs, we considered bleeding and perforation.

Results

A total of 90 HR-CANs (90% non-polypoid, 79% left-side colon, mean size 35.5 mm ± 16.5 mm, 17% invasive pit-pattern) in 86 patients with colonic IBD (57% male, aged 61 yrs ± 12 yrs, 86% ulcerative colitis, with a disease duration of 183 months ± 109 months, 18% active disease at endoscopy) were included. ESD and hESD were performed in 82% and 18% of cases. The final histopathological diagnoses after AER were serrated sessile lesions in 14.5%, low-grade dysplasia in 31%, high-grade dysplasia in 39%, adenocarcinoma in 14.5%, and squamous cell carcinoma in 1% of cases. En bloc resection and R0 resection were achieved in 97% and 86% of cases. AEs occurred in 29% (n=26) of cases: 20 intraprocedural (13 bleedings and 7 perforations, all managed endoscopically) and 6 postprocedural (4 bleedings treated endoscopically and 2 perforation that required surgery). After a mean follow-up of 23 months, local recurrence and metachronous lesions occurred in 7% (n=6) of cases (3 local recurrences and 3 metachronous lesions). Post-AER surgery was required in 14% (n=13) of cases (7 for histopathology, 2 for complications, 2 for recurrences, 2 for refractory IBD).

Conclusion

Our findings showed that AER, including ESD and hESD, of HR-CANs when performed in Tertiary Endoscopy Centers was safe and effective in patients with colonic IBD, reducing the risk of recurrence and the need for surgery.

References

1. Shah SC, Itzkowitz SH. Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management. Gastroenterology. 2022 Mar;162(3):715-730.e3. doi:10.1053/j.gastro.2021.10.035.
2. Bak MTJ, et al. Endoscopic management of patients with high-risk colorectal colitis-associated neoplasia: a Delphi study. Gastrointest Endosc. 2023 Apr;97(4):767-779.e6. doi:10.1016/j.gie.2022.12.005.

Disclosure

Nothing to declare.