Introduction

The BIOSTOP Trial is a prospective, multicenter, randomized, controlled, open-label study conducted in Norway to evaluate the two-year outcomes of tumor necrosis factor-alpha (anti-TNF) antibody withdrawal in patients with ulcerative colitis (UC) in sustained clinical and endoscopic remission. Prior non-randomized studies have suggested that approximately half of such patients maintain remission after anti-TNF discontinuation and that reintroduction of anti-TNF therapy is generally effective and safe in the event of relapse.

Aims & Methods

A total of 174 UC patients in confirmed clinical and endoscopic remission were enrolled across 19 gastroenterology centers between June 2017 and December 2020 and randomized 1:1 to either continue or discontinue anti-TNF therapy. Eligibility criteria included at least 12 months of first-line anti-TNF maintenance treatment, clinical remission, fecal calprotectin <200 µg/g, and endoscopic remission (Mayo endoscopic score 0 or 1). Two-year follow-up data were available for 172 patients (86 in each group). In 156 of the patients endoscopies were available for central reading (77 in the withdrawal group and 79 in the maintenance group). The primary endpoint was sustained endoscopic remission at two years.

Results

At two years, central reading of follow-up colonoscopies confirmed endoscopic remission in 64 of 77 patients (83%, 95% CI 71.8 – 93.1) in the anti-TNF withdrawal group, compared to 77 of 79 patients (96 %, 95 % CI 92.1 – 100.8) in the anti-TNF maintenance group. The non-inferiority primary endpoint of the study was thus not met. During the study period, 48% of patients in the withdrawal group and 88% in the maintenance group remained in sustained clinical and endoscopic remission without relapse. Among the 45 patients in the withdrawal group who experienced endoscopic confirmed relapse, 28 (62%) resumed anti-TNF therapy, with 26 achieving both clinical and endoscopic remission. Additionally, 10 of 13 patients with mild relapses achieved endoscopic remission with optimized non-biologic therapy. There were no difference in serious adverse events between the groups.

Conclusion

After two years, 83% of patients in the anti-TNF withdrawal group and 96% in the maintenance group were in clinical and endoscopic remission, including those who experienced flares and achieved new remission after reintroduction of anti-TNF or optimized non-biologic therapy. Nearly half of the patients maintained remission without anti-TNF, and the majority of relapses were effectively managed. These findings suggest that anti-TNF withdrawal is a safe option for selected UC patients in confirmed remission, provided they are monitored closely.
Trial Registration: ClinicalTrials.gov Identifier: NCT03011268; EudraCT Number: 2016-001409-18. Trial completion date: 31 January 2025.

Disclosure

No disclosures

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

Up to 40% of patients with acute severe ulcerative colitis (ASUC) do not respond to infliximab (IFX)(1) presumably due to insufficient drug exposure (1, 2). We investigated whether personalised IFX induction using predefined serum concentrations was superior to standard dosing.

Aims & Methods

In this prospective, multi-centre trial, adult IFX-naive steroid-refractory ASUC patients were randomised 1:1 to standard (SD) or personalised IFX dosing (PD). After an initial 5 mg/kg IFX infusion, SD was 5 mg/kg IFX at week 2 and 6. In PD, additional 5 mg/kg IFX infusions were administered guided by a Bayesian pharmacokinetic algorithm (iDose™) aiming at IFX serum concentrations >28 ug/mL day 0-28 and >15 ug/mL day 29-42 (3). The primary composite endpoint was clinical and endoscopic response at day 42 (Lichtiger score <10 and ≥3 points drop and UCEIS ≥2 points drop from baseline). Video-endoscopies were performed at baseline, day 42 and 182 and scored by 2 expert readers (XR) with adjudication by a third XR and post hoc also by the DovaVision UC AI tool (AI-R)(4). Key secondary endpoints were day 42 clinical response, day 42 endoscopic response, day 182 clinical remission (Lichtiger ≤3), day 182 endoscopic remission (UCEIS ≤1 on all components), and safety.

Results

48 patients were randomised (23 PD/25 SD) and 31 completed the 26-week study (19 PD/12 SD). Patient characteristics were comparable. Median cumulative IFX dose until day 42 was 18.41 mg/kg [1.77, 20.27] for PD vs 13.79 mg/kg [10.38, 14.82] for SD. The primary composite endpoint at day 42 was not met with XR (57% in PD vs 44% in SD; p=0.564). However, AI-R showed a significantly higher composite response rate in PD (74% in PD vs 32% in SD; p=0.0047). PD showed higher day 42 clinical response vs SD (91% vs 64%; p=0.039). Day 42 endoscopic response was observed in 57% in PD vs 44% in SD (p=0.564) with XR and 74% in PD vs 32% in SD with AI-R (p=0.0047). The proportion of patients in clinical and endoscopic remission at day 182 was higher in PD than in SD (65% vs 36%; p=0.082). Day 182 endoscopic remission with AI-R was higher in PD (52% in PD and 20% in SD; p=0.0337). SAEs occurred in 9% of patients on PD vs 20% of patients on SD. Following an interim analysis, the trial was discontinued based on futility.

Table 1. Baseline characteristics

Conclusion

Personalised IFX dosing was superior to standard dosing in ASUC when endoscopies were read by AI. This is the first IBD study where the primary endpoint, missed by expert assessment, was overturned and met by AI assessment instead. This demonstrates the potential of AI to fundamentally improve clinical trial methodology.

References

1. Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59(1):49-54.
2. Papamichael K, Van Stappen T, Vande Casteele N, Gils A, Billiet T, Tops S, et al. Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol. 2016;14(4):543-9.
3. Ungar B, Mazor Y, Weisshof R, Yanai H, Ron Y, Goren I, et al. Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis. Aliment Pharmacol Ther. 2016;43(12):1293-9.
4. Byrne M, Requa J, Panaccione R, Panes J, Bressler B, East JE, et al. Development and Validation of a novel AI-based computer vision solution for Ulcerative Colitis severity scoring on video for real world using high-volume expert-annotated video frames. United European Gastroenterol J. 2025 Oct.

Disclosure

This project received grant support from Pfizer Inc. and research support from Baysient LLC, Buhlmann Laboratories and Dova Health Intelligence.