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

Primary aim: To assess the retention rate of ustekinumab treatment in patients with ulcerative colitis (UC).
Secondary aims: To assess the short-term effectiveness, the durability of response, and the tolerability of ustekinumab in clinical practice.

Aims & Methods

Retrospective, multicenter study including UC patients who had received the first ustekinumab dose at least 16 weeks before inclusion. Patients were followed-up from the first ustekinumab dose to treatment discontinuation or last visit, whichever came first. Only patients with active disease [Partial Mayo Score (PMS)>2] at ustekinumab start were considered in the effectiveness analysis. Clinical effectiveness was based on PMS. Patients who stopped ustekinumab before their last visit were considered non in remission at subsequent time points (negative imputation).

Results

376 patients have been included so far (91% had PMS >2 at ustekinumab start, 96% had been exposed to biologics, and 25% had failed to anti-TNF, vedolizumab and tofacitinib). At baseline, 50% of patients were under mesalamine, 24% under steroids, and 6% under thiopurines. 74% of patients started the maintenance treatment with 90 mg every-8-weeks, and 5% with 90 mg every-12-weeks subcutaneously; 8% of patients received ustekinumab intravenously as maintenance treatment from the beginning. 100 patients (27%) withdrew ustekinumab during follow-up [median=12 months (m)]. Incidence rate of ustekinumab discontinuation was 21% per patient-year of follow-up. The probability of maintaining ustekinumab was 98% at 1 m, 90% at 6 m, 78% at 12 m, 71% at 18 m, and 66% at 24 m. Main reasons for ustekinumab withdrawal were primary non-response (42%) and loss of response (30%). Anaemia at baseline (HR=1.7, 95%CI=1.1-2.6) was associated with higher risk, while concomitant treatment with mesalamine was associated with lower risk (HR=0.6, 95%CI=0.4-0.9), of ustekinumab discontinuation. The proportion of patients in clinical remission (CR) was 37% at week (w) 4, 49% at w 8, and 48% at w 16. To have moderate-severe vs. mild disease activity at baseline (OR=0.2, 95%CI=0.1-0.4) and to have failed to both anti-TNF and vedolizumab (OR=0.6, 95%CI=0.4-0.9) were associated with lower CR at week 16. A total of 83 (31%) patients among those with active disease at baseline and with at least response during the induction, lost response during a median follow-up of 12 months (IQR=6-18 months). The probability of maintaining response was 82% at 6 m, 72% at 12 m, and 61% at 24 m. The incidence rate of loss of response was 27% per patient-year of follow-up. In the multivariate analysis, to have achieved CR during the induction was the only variable associated with lower risk of loss of response (OR=0.5, 95%CI=0.3-0.9). The dose was escalated in 61% of patients with loss of response, and 82% improved (53% had CR); an intravenous reinduction was given in 19%, and 50% improved (31% had CR). The proportion of patients in CR during follow-up was 58% at 12 m, 48% at 24 m, and 41% at 36 m. A total of 69 patients (18%) had at least one adverse event, being infections the most frequent ones (8%). Ustekinumab was withdrew in 5 (1.3%) patients.

Conclusion

In the largest study performed so far on ustekinumab in UC in real life, ustekinumab has shown to be effective in inducing remission even in highly refractory UC patients. A relevant proportion of patients discontinue the treatment, mostly due to primary failure and loss of response. Dose escalation is effective to regain response after loss of efficacy. The safety profile is similar to that previously reported.

Disclosure

This is an investigator-initiated study with financial support from Janssen (CNTO1275UCO4008).