Introduction

Vedolizumab (VDZ) is efficacious to induce and maintain clinical remission in Crohn’s disease (CD). However, prospective data about its efficacy including endoscopy in early CD are lacking.

Aims & Methods

We conducted a prospective multi-centre international (Belgium, the Netherlands and Hungary) open label trial comparing the efficacy and safety of VDZ therapy in patients with early or late moderate-severe active CD (Crohn’s Disease Activity Index [CDAI] 220-450 and presence of ulcers at endoscopy). Early CD was defined as diagnosis <2 years and treatment naïve or only treated with corticosteroids and/or immunomodulators; late CD was defined as diagnosis >2 years and previously treated with corticosteroids, immunomodulators and anti-tumor necrosis factor agents. Patients received intravenous VDZ (300 mg) at weeks 0-2-6 and q8 weeks thereafter for a total of 52 weeks, with an extra infusion at w10 in the absence of a CDAI drop <70. Ileocolonoscopy was performed at baseline, w26 and w52 and all procedures were centrally read. The sample size was calculated for 1/3 early and 2/3 late CD. An extremely strict primary composite endpoint was used: proportion of patients with clinical and endoscopic remission (CDAI≤150 and Simple Endoscopic Score for CD [SES-CD]<4) at both w26 and w52. Key secondary endpoints included the proportion of patients with absence of ulcers, proportion of patients with endoscopic response (SES-CD reduction ≥50%) at w26 and w52 and safety.

Results

We recruited 86 early and 174 late CD patients, of whom 52 early and 104 late CD patients completed w52 (insufficient clinical response and adverse events were the main reasons for early withdrawal). Baseline characteristics including disease activity parameters were similar across both groups (median total SES-CD 9 [6-17] and 12 [7-17], median CDAI 254.7 [235.7-287.2] and 259 [235.2-314.5] for early and late CD, respectively), apart from disease duration and age (median disease duration 0 [0-1] and 11 [5.5-15.5], median age 29.5 [23.8-45.3] and 36 [28-48] for early and late CD, respectively). The primary endpoint was reached in 31.4% vs. 8.6% (p=0.001; ITT) and 45.0% vs. 16.0% (p<0.001; per protocol [PP]) of patients with early vs. late CD (Table 1). All key secondary endpoints were also met in favour of patients with early CD (Table 1). Serious adverse events (SAEs) occurred in 4.7% of patients with early vs. 27% of patients with late CD (p<0.0001) and included infection (1.2 vs 7.5%) bowel obstruction (0 vs 2.3%), exacerbation of CD (2.3 vs 4%), abdominal pain (0 vs 1.7%) and malignancy (0 vs 1.7%).

Table 1. Primary composite endpoint and key secondary endpoints (ITT and PP analysis)

Conclusion

VDZ treatment is more effective and safer in early than in late CD (IIS Funded by Takeda Nederland B.V. [IISR-2014-100757]; LOVE-CD EudraCT number 2014-005376-29).

Disclosure

GD: served as advisor and/or speaker for Abbvie, Alimentiv, Astrazeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Polpharm, Prometheus biosciences, Prometheus laboratories, Procise diagnostics, Protagonist, Sandoz, Setpoint, Spyre, Takeda, Tillotts and Ventyx.
ML: consultancy/ lecture fees from Abbvie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, Tillotts. Central reader for Alimentiv. Grant received from Galapagos and NFU.
FB: reports grants/research supports from AbbVie, Amgen, Takeda, Janssen, honoraria or consultation fees from AbbVie, Amgen, Arena, MSD, Celgene, Kabi-Fresenius, Takeda, Ferring, Pfizer, Norgine, Janssen and participation in a company sponsored speaker's bureau for AbbVie, MSD, Takeda, Ferring, Pfizer, Janssen.
PB: has received research grants from AbbVie, Amgen, Celltrion, Mylan, Pfizer, and Takeda; lecture fees from AbbVie, Celltrion, Janssen, Lilly, and Takeda; and consulting fees from AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros.
FH: has served on advisory boards or as speaker for Abbvie, Janssen, MSD, Takeda, Pfizer, Celltrion, Teva, Sandoz, Amgen and Pendopharm, and has received independent research funding from Janssen, Abbvie, Pfizer and Takeda.
EC: has no conflicts of interest.
LO: has no conflicts of interest.
MH: has no conflicts of interest.
TM: has received speaker’s honoraria from MSD, AbbVie, Egis, Goodwill Pharma, Takeda, Pfizer, Janssen, Sandoz, MundiPharma, Phytotec, Roche, Fresenius and Teva.
SV: financial support for research from: AbbVie, J&J, Pfizer, Takeda and Galapagos and receives speakers’ and/or consultancy fees from: AbbVie, Abivax, AbolerlsPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, Astrazeneca, BioraTherapeutics, BMS, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech Roche, Gilead, GSK, Hospira, lmidomics, Janssen, J&J, Lilly, Materia Prima, Mestag Therapeutics, Microbiotica, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance, Tillots Pharma AG, VectivBio, Ventyx, Zealand Pharma.

Introduction

Advanced combination treatment (ACT), defined as the use of two biologics or a biologic and a small molecule drug with distinct mechanisms of action, is increasingly adopted for refractory inflammatory bowel disease (IBD) and overlapping immune-mediated inflammatory diseases (IMIDs). Despite promising clinical results, the immunological consequences of ACT remain poorly characterized. Here, we investigated how two ACT regimens—anti-TNF + anti-integrin and anti-TNF + anti-IL-23—shape the peripheral CD3⁺ T cell landscape at single-cell resolution, with a focus on clonotype architecture, repertoire diversity, and antigen specificity.

Aims & Methods

We aim to characterize the peripheral CD3⁺ T cell transcriptional landscape and clonal architecture in patients with refractory IBD who achieved clinical response following initiation of two different ACT regimens: anti-TNF + anti-integrin α4β7 and anti-TNF + anti-IL-23. Peripheral blood mononuclear cells (PBMCs) were collected from six patients with Crohn’s disease who achieved clinical response to ACT. Four patients received anti-TNF + anti-integrin α4β7, and two received anti-TNF + anti-IL-23. CD3⁺ T cells were isolated and analyzed via single-cell RNA sequencing (scRNA-seq) coupled with paired T cell receptor (TCRα/β) sequencing. Cell state annotations were performed using supervised deconvolution against the scIBD reference atlas, and TCR repertoire metrics (diversity, clonality, evenness) were computed to assess clonal expansion dynamics.

Results

All patients included demonstrated clinical improvement, underscoring the immunological relevance of the findings. Single-cell transcriptomic and TCR repertoire profiling uncovered distinct treatment-specific patterns in peripheral T cell states and clonal architecture. In the anti-TNF + α4β7 group, there was marked enrichment of CD4⁺ tissue central memory T cells (CD4⁺ tissue-Tcm) and CD4⁺ naïve T cells (CD4⁺ Tn), along with greater TCR diversity, reduced clonal dominance, and enhanced repertoire evenness. In contrast, the anti-TNF + IL-23 group exhibited a marked enrichment of CD8⁺ naive T cells (CD8⁺ Tn) and a repertoire characterized by reduced diversity and pronounced oligoclonal expansion.

Conclusion

In difficult-to-treat IBD patients who achieved clinical response to ACT, distinct patterns of immunological remodeling emerged depending on the therapeutic combination. Treatment with anti-TNF + anti-integrin was associated with a diversified, polyclonal T cell repertoire consistent with a systemic rebalancing of the adaptive immune response, whereas anti-TNF + anti-IL-23 drove more focused, oligoclonal expansions indicative of selective immune activation. These divergent signatures underscore mechanistically distinct pathways of immune reprogramming and highlight the potential of T cell–based immuno-profiling to inform the rational selection of biologic combinations. Incorporating single-cell and TCR repertoire analyses into ACT trials may enable a precision medicine framework for optimizing treatment strategies in IBD.

References

Danese S, Solitano V, Jairath V, Peyrin-Biroulet L. The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment). Gut. 2022 Dec;71(12):2380-2387. doi: 10.1136/gutjnl-2022-327025. Epub 2022 Jun 14. PMID: 35701092.

Disclosure

Virginia Solitano has received speaker fees from Pfizer and consultancy fees from Johnson & Johnson. Vipul Jairath has received consultancy/advisory board fees from AbbVie, Alimentiv Inc., Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Topivert, Ventyx, and Vividion; and speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi. Silvio Danese has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenixa, UCB Inc, and Vifor; and lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer, and Takeda. The other authors have nothing to disclose.

Introduction

Endoscopic stenting proved to be a valid surgery-sparing approach for upper gastrointestinal benign pathological conditions, mainly refractory benign strictures and post-surgical transmural defects. Niti-S™ Beta-2™ EKxxxxFNT2 esophageal covered stents were specifically designed to treat these conditions preventing stent migration and embedment.

Aims & Methods

We conducted a monocentric retrospective analysis on prospectively collected data regarding patients undergoing EKxxxxFNT2 placement for benign indication between January 2019 and December 2024, considering demographic, anthropometric, clinical and technical variables, and evaluating safety and efficacy profiles.

Results

A total of 32 patients were included (M 53.1%, median age 63 years), 25 (78.1%) post-surgical. Indication for stent placement was leakage in 16/32 cases (50%), and stricture/compression and fistula both in 8/32 (25%). Most frequently applied stent (16/32, 50%) was Niti-S™ Beta-2™ EKxxxxFNT2 esophageal covered stent 24 mm x 200 mm. Technical success was achieved in 100% of the cases. No periprocedural AEs were registered, 4 stents (12.5%) migrated. Median time to oral refeeding was 4 days [IQR 2-10]. Stents were removed after a median time of 34 days [IQR 17.3-41.5]. Three patients (9.4%) died before stent removal. Overall clinical success rate was 26/32 cases (81.3%); anastomotic leakage as indication proved to be significantly more frequent among the unsuccessful group [5/6 (83.3%) VS 7/26 (26.9%), p=0.0012]. Two cases (8%) of stenosis relapse were reported, all successfully endoscopically treated.

Conclusion

Double-bump antimigratory Niti-S™ Beta-2™ EKxxxxFNT2 esophageal covered stents proved to be a safe, effective, and rapid therapeutic option for patients with complex benign upper gastrointestinal conditions.

References

Binda C, Jung CFM, Fabbri S, Giuffrida P, Sbrancia M, Coluccio C, Gibiino G, Fabbri C (2023) Endoscopic Management of Postoperative Esophageal and Upper GI Defects-A Narrative Review. Med Kaunas Lith 59:136. https://doi.org/10.3390/medicina59010136
Medas R, Ferreira-Silva J, Girotra M, Barakat M, Tabibian JH, Rodrigues-Pinto E (2023) Best Practices in Esophageal, Gastroduodenal, and Colonic Stenting. GE Port J Gastroenterol 30:19–34. https://doi.org/10.1159/000527202
Fuccio L, Hassan C, Frazzoni L, Miglio R, Repici A (2016) Clinical outcomes following stent placement in refractory benign esophageal stricture: a systematic review and meta-analysis. Endoscopy 48:141–148. https://doi.org/10.1055/s-0034-1393331
Spaander MCW, van der Bogt RD, Baron TH, Albers D, Blero D, de Ceglie A, Conio M, Czakó L, Everett S, Garcia-Pagán J-C, Ginès A, Jovani M, Repici A, Rodrigues-Pinto E, Siersema PD, Fuccio L, van Hooft JE (2021) Esophageal stenting for benign and malignant disease: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2021. Endoscopy 53:751–762. https://doi.org/10.1055/a-1475-0063
Boerlage TCC, Houben GPM, Groenen MJM, van der Linde K, van de Laar AWJM, Emous M, Fockens P, Voermans RP (2018) A novel fully covered double-bump stent for staple line leaks after bariatric surgery: a retrospective analysis. Surg Endosc 32:3174–3180. https://doi.org/10.1007/s00464-018-6034-2