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

Introduction

Gastroenterologists generally undergo gastroenterology (GI) training during their childbearing years, making pregnancy while training a highly important topic regarding family-work balance. The aim of this study is to assess the challenges GI trainees encounter during pregnancy and parenthood.

Aims & Methods

A questionnaire was sent out via social media and email, targeting doctors who were pregnant or had a pregnant partner during their GI training in the last 10 years.

Results

Forty-six women (mean age 35.5 ±3.76, 93.4% from European countries). Of these, 56.5% had one pregnancy during training, 30.4% had two and 13.1% had three pregnancies. Fifteen males (mean age 35.2 ±3.76, 93.3% from European countries) also answered the questionnaire. Age at first pregnancy was similar between males (30.6 years) and females (30.5 years).
Most women (84.7%) reported worrying that they would be perceived negatively when they asked for changes in their work schedule due to the pregnancy. While 67.4% reported that their colleagues were accommodating, only 56.5% felt that it was easy to talk to their training coordinators about the pregnancy. Furthermore, 69.5% were concerned that the pregnancy would negatively impact their training.
Nearly all women participants (97.8%) were working more than 40 hours before the pregnancy. Of these, 78.2%, 63% and 32.6% continued to work more than 40 hours per week in the first, second and third trimesters, respectively. Worryingly, 56.5% had at least one complication during pregnancy or delivery. Participants reported several hazards that weren’t addressed during pregnancy, namely exposure to non-scavenged anaesthetic gases (47.8%), scope locator (36.9%), blood-borne illnesses (34.8%) and radiation (15.2%), and long endoscopy sessions (28.2%).
Of the participants who had returned to work after the birth of the child (n=44 females, n=15 males), men worked full-time more often than women (92.9% vs 59.5%, p=0.02).
Both genders had difficulty coping with parenthood, with only 19% of women and 33.3% of men stating that it was easy to adapt to being back at work and having a young child (p=0.25). They also reported feeling less productive at work than before (females: 54.8%, males: 40%, p=0.32).
Regarding the responsibility of caring for the child when they are unwell, 92.9% of the men reported that the child is taken care of by the other partner. In contrast, women reported it was themselves (36.4%) or other relatives (34.1%) who took care of the child; only 12.6% stated it was her partner who did it. Women reported feeling guilty towards colleagues for taking time off work to be with their child (35% females vs 6.7% males, p=0.03.)
Trainees felt that having children will impair their career progress (56.1% females, 40% males, p=0.29). However, females were more often convinced that having children made them appear less ambitious than their peers (60.4%), compared to males (26.7%), (p=0.02).

Conclusion

Pregnant trainees face numerous concerns during their pregnancy, both physical and psychological. Training centres need to carry out a formal risk assessment for all pregnant trainees to address possible hazards. Whilst parenthood strongly impacts on both male and female trainees, women tend to carry more burden regarding care for the child. There is the need to support and normalize pregnancy and parenthood during training, to achieve a healthy family-life-work balance.