Introduction

Celiac disease (CD) is an autoimmune disorder triggered by gluten ingestion in genetically predisposed individuals, leading to chronic intestinal inflammation. It affects about 1% of the global population and is often undiagnosed in childhood due to the absence of symptoms, with around 65% of cases in Italy going unnoticed. Early screening is a key tool for timely diagnosis and preventing long-term complications. In this perspective, the D1Ce Screen pilot study follows Italian Republic Law 130/2023, which mandates screening for pre-symptomatic CD and type 1 diabetes (T1D) in the general paediatric population through autoantibody measurements in capillary blood. Paediatric screening is a key tool for early detection and the prevention of long-term complications, associated with late or missed diagnosis. Individuals who tested positive for CD and T1D -specific autoantibodies will undergo further clinical evaluation at the regional specialized center to confirm the diagnosis

Aims & Methods

Primary objective of D1Ce Screen study is to assess, feasibility, acceptability and sustainability of a nationwide screening program, for the evaluation of undiagnosed CD cases and presymptomatic T1D. To assess operational aspects D1Ce Screen evaluates the involvement of primary care pediatricians (PCPs), blood sample collection accuracy and acceptability for families measuring anxiety, depression and quality of life through 3 validated questionnaires.
This is an observational multicenter study to screen 5,363 children in four Italian regions (Lombardy, Marche, Campania, Sardinia), distributed into three classes of age (2-2.9, 6-6.9, and 10-10.9 years), corresponding to peaks of seroconversion for these diseases. For eligibility, the inclusion criterion is age. T1D is the exclusion criterion. Voluntary PCPs were responsible for recruitment of participants, administration of informed consents and questionnaires, execution of blood drawing by finger prick, capillary blood collection and sample shipment. Specific T1D and CD autoantibodies are measured by ELISA in capillary samples. In addition, HLA DQ2 and DQ8 HLA typing is performed on dried blood spot (DBS).

Results

PCPs initially accepting to participate were 565, with 428 (75,7%) completing the study. Enrolled children were 5534, with 91,1% within the target age. The gender distribution was 49.4% females, 50.6% males. Samples suitable for analysis (adequacy for at least one assay) were 89% of the total collected. Most of DBS samples were suitable for HLA typing. The target of families undergoing questionnaire evaluation of 2% has been exceeded.

Conclusion

The D1Ce Screen pilot study provides evidence supporting the feasibility of a nationwide screening initiative. The active collaboration of PCPs, the high level of participation from families, and the efficient implementation of capillary blood sampling procedures were key contributors to its success. These findings confirm the potential for scalability of a paediatric screening program for T1D and CD within the framework of the Italian National Health Service. Early detection and timely initiation of a gluten-free diet in children diagnosed with CD are essential to preventing long-term complications and improving health outcomes.

References

Bosi E, Catassi C. Screening type 1 diabetes and celiac disease by law. Lancet Diabetes Endocrinol. 2024 Jan;12(1):12-14. doi: 10.1016/S2213-8587(23)00354-6

Introduction

TPM502 is a mixture of three distinct nanoparticles, each coupled with one celiac disease (CeD)-relevant gluten peptide, representing immunodominant and deamidated CD4⁺ T cell epitopes. TPM502 targets liver sinusoidal endothelial cells, which are unconventional antigen-presenting cells capable of inducing antigen-specific tolerance.

Aims & Methods

TCeD21 (NCT00565136) was a phase 2a double-blind, randomized, placebo-controlled study in HLA-DQ2.5-positive adults with confirmed CeD on a gluten-free diet. Patients achieving a predefined IL-2 response to a single dose (6 g) gluten challenge (GC1) were randomized into four cohorts to receive two intravenous infusions with escalating doses of TPM502 or placebo on day (D) 1 and D15. The GC was repeated 7 days after the second TPM502 dose (GC2). Peripheral blood mononuclear cells collected from each patient at predefined timepoints were analyzed by high-dimensional (30-color) flow cytometry, before and after HLA-DQ2.5-gliadin-specific tetramer (tet) enrichment, using surface staining for various phenotypic markers. The study aimed to characterize the phenotypes of gluten-specific T cells in CeD patients before and after TPM502 treatment to assess its immunomodulatory effects.

Results

Samples from 36 patients completing the study (12 placebo, 24 TPM502) were analyzed across five timepoints. In the placebo group, tet⁺ CD45RA^-CD62L^-CD4⁺ T (Ttet) cells increased after both GCs. By contrast, the TPM502 cohorts exhibited elevated Ttet cell numbers before GC2 (D22) but showed limited expansion afterward (D29), suggesting that TPM502 treatment may prevent further activation-induced expansion. Moreover, the frequency of activated Ttetcells—indicated by activation markers CD38, ICOS, and OX40—significantly decreased across all TPM502 dose levels after GC2 compared to the placebo group (fold change D22 vs D29, all p < 0.0001 by Kruskal-Wallis test). Notably, the diminished gluten response of Ttet cells post-treatment was accompanied by enhanced expression of co-inhibitory receptors TIGIT and PD-1 (D-21 vs D29, p < 0.0001), along with reduced CD127 expression (p < 0.01), indicative of decreased cell survival. These phenotypic changes, consistent with T cell exhaustion or anergy, persisted until study end and were visibly distinct from those in the placebo group, as illustrated by the heatmap of delta log-transformed flow cytometry data of Ttet cells across timepoints, clustered hierarchically. Gliadin-specific CD4⁺ regulatory T cells (CD25⁺CD127^- Ttet) and CD39⁺ Ttet cells increased post-treatment at the highest TPM502 dose, suggesting the induction of regulatory states in these T cells. Moreover, pre-enriched samples showed reduced activation of αEβ7⁺ γδ⁺ and CD8⁺ Tcells after GC2 at the highest TPM502 dose, suggesting potential bystander effects.

Conclusion

Data from the first longitudinal tetramer-based flow cytometry analysis in CeD patients provide evidence that TPM502 induces antigen-specific tolerance through T-cell immunomodulation. These results corroborate other pharmacodynamic outcomes generated in this study, including a significant and dose-dependent reduction in ex vivo IL-2 and IFN-γ secretion by gluten-specific T cells after treatment. In addition to a good safety and tolerability profile of TPM502, this nanoparticle-mediated induction of antigen-specific tolerance may provide a novel therapeutic avenue to treat celiac disease.

Introduction

The achievement of histological remission (HR) is a key treatment goal in ulcerative colitis (UC), as it is suggestive of better disease management and predicts response to therapy.
The absence of neutrophils in epithelium and lamina is crucial to define HR. However, the role of neutrophil number and localisation remains unclear. We aimed to develop a novel artificial intelligence (AI)-driven system to automate neutrophil detection, localisation, and quantification, supporting assessment of HR and enable the prediction of response to therapy.

Aims & Methods

We developed an AI-driven system by integrating two deep learning models to (1) segment whole slide images (WSIs) into epithelium, crypts and lamina propria and to (2) detect and quantify neutrophils. Outputs from these models were combined to compute neutrophil densities in the lamina propria, epithelium, and overall tissue. The optimal neutrophil density cut-offs to assess disease activity (Geboes score >2B.0) in UC patients were identified in the AMAC phase 2 Mirikizumab trial, and subsequently validated in the multicentre prospective PICaSSO cohort study. Cut-offs to determine treatment response at weeks 12 and 52 (histological improvement [HI; Geboes score ≤3.1] and histological remission [HR; Geboes score ≤2B.0]), were also evaluated.

Results

Table 1 shows the system diagnostic performance in assessing disease activity and predicting response to therapy at W12 and W52 in the Mirikizumab cohort.
303 WSIs from active UC patients from the multicentre, randomised, double-blind, parallel-arm, placebo-controlled phase 2 clinical trial of Mirikizumab were analysed. The model yielded a DICE SØrensen of 0.57 for segmentation, precision of 82.3% and recall of 77.0% for neutrophil detection. The system identified an overall optimal neutrophil density cut-off (cells/mm²) predictive of disease activity of >21.7.0 (>10.1 and >30.4 for epithelium and lamina propria, respectively), with an accuracy of 86% (85% and 85%, respectively). Further validation in the multicenter PICaSSO cohort yielded to similar results.
Moreover, the overall optimal cut-off to predict histological remission at W52 was <20.8 (<10.4 and <27.9 for epithelium and lamina propria, respectively), with an accuracy of 82.0% (81% and 80%, respectively).

Conclusion

Our novel AI-based system demonstrates strong potential as an automated tool to detect, localise, and quantify neutrophils to assess histological activity and predict response to therapy in a clinical trial UC cohort and real-world settings. This framework could be applied in clinical trials and routine clinical practice, offering objective guidance for personalised management in UC patients.

References

[1] Santacroce G, Meseguer P, Zammarchi I, et al. P406 A novel active learning-based digital pathology protocol annotation for histologic assessment in Ulcerative Colitis using PICaSSO Histologic Remission Index (PHRI). Journal of Crohn's and Colitis, Volume 18, Issue Supplement_1, January 2024, Pages i843–i844
[2] Graham S, Vu QD, Jahanifar M, et al. CoNIC Challenge: Pushing the frontiers of nuclear detection, segmentation, classification and counting. Med Image Anal. 2024;92:103047.

Disclosure

MI received research grants and consultant fees from Olympus, Pentax, Eli Lilly, and Janssen. All other authors declare no competing interests.

Introduction

Risankizumab (RZB) is a highly specific humanized monoclonal antibody that targets the p19 subunit of interleukin-23 and was designed to have low immunogenicity and high bioavailability, allowing for less-frequent dosing, although the clinical implications of these modifications have not been studied. The FORTIFY maintenance open label extension (OLE) is an ongoing phase 3 substudy evaluating the long-term efficacy and safety of RZB in pts with moderate to severe Crohn’s disease (CD). Here, we report interim efficacy and safety results from the FORTIFY OLE following up to 4 years (yrs) of RZB treatment.

Aims & Methods

The FORTIFY (NCT03105102) OLE enrolled pts who completed 52 weeks (wks) of RZB maintenance.^1,2 Pts received subcutaneous (SC) RZB 180mg every 8wks (Q8w) starting at wk56, except for pts who received rescue therapy prior to or during the OLE; these pts received SC RZB 360mg Q8w (see Table footnote for rescue therapy details). Pooled data (180mg+360mg) were analyzed through wk144 of the OLE (wk200 of cumulative RZB treatment) using as observed (AO) and modified nonresponder imputation (mNRI, pts were considered nonresponders for visits after premature discontinuation of RZB due to the primary reason of lack of efficacy or adverse event limited to Crohn’s disease only, as well as initiation of rescue, while other missing data were handled by multiple imputation [MI]) methods (‘All Patients [No Rescue or Prior to Rescue]’ group in Table). For pts who received rescue therapy, only their data obtained prior to receiving rescue were included in the aforementioned AO and mNRI analyses (‘All Patients [No Rescue]’ group in Table). Data from pts on the day of or after rescue were analyzed separately and reported AO starting at the initiation of rescue (defined as the last nonmissing value prior to or on initiation of rescue) and every 24 wks post-rescue (‘Rescue’ group in Table). Safety was evaluated in all pts receiving any RZB treatment in the OLE. Treatment-emergent adverse events (TEAEs) reported on/after the first dose in the OLE were summarized (cutoff date: 30DEC2024).

Results

A total of 1112 pts (excluding 36 pts who received RZB rescue at entry to OLE) received ≥1 dose of RZB 180mg or 360mg in the OLE. Efficacy rates (per mNRI analysis) were stable from OLE wk0 to wk144 for clinical remission per stool frequency/abdominal pain score (SF/APS, 64.5% to 75.8%) and per CD Activity Index (CDAI, 68.6% to 82.8%), endoscopic response (55.1% to 73.8%), and endoscopic remission (39.0% to 58.8%) (Table). Pts who received rescue therapy in the OLE demonstrated clinical and endoscopic improvements over time. The profiles of TEAEs and AEs of special interest were consistent with the known safety profile of RZB.^3,4
​

Conclusion

Durable clinical and endoscopic efficacy was observed in pts with moderate to severe CD who completed up to 4 yrs of RZB maintenance therapy in the FORTIFY OLE. Pts who received rescue therapy in the OLE also showed clinical and endoscopic improvements by wk144. No new safety risks for RZB were identified, supporting its long-term use in treating CD.

References

1. Ferrante M, et al. J Crohns Colitis. 2021;15(12):2001-2010.
2. Ferrante M, et al. Lancet. 2022; 399(10340):2031–46.
3. Papp KA, et al. J. Am. Acad. Dermatol. 2023; 89(6):1149–58.
4. Ferrante M, et al. J Crohns Colitis. 2024;18(Supplement_1):i168–70.

Disclosure

Marc Ferrante
Research grants from AbbVie, EG Pharma, Janssen, Pfizer, Takeda and Viatris. Consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, MRM Health, Merck Sharp and Dohme, Pfizer, Takeda and ThermoFisher. Speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen-Cilag, Merck Sharp and Dohme, Pfizer, Takeda, Truvion Healthcare and Viatris
Remo Panaccione
Consulting fees from AbbVie, Abbott, Alimentiv, Amgen, Arena, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Ferring, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Schering-Plough, Shire, Sublimity Therapeutics, Theravance, UCB, and Takeda; speaker fees from AbbVie, Arena, Celgene, Ferring, Gilead Sciences, Janssen, Lilly, Merck, Pfizer, Roche, Sandoz, Shire, and Takeda; and research/educational support from AbbVie, Ferring, Janssen, Pfizer, and Takeda. He has served on an advisory board for AbbVie, Amgen, Arena, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Sandoz, Shire, Sublimity Therapeutics, Takeda, and Theravance
Jean-Frederic Colombel
Research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; payment for lectures from AbbVie, Allergan, Amgen, Ferring Pharmaceuticals, Shire, and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Ferring Pharmaceuticals, Galmed Research, Genentech, GlaxoSmithKline, Imedex, Immunic, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Lilly, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development.
Marla Dubinsky
Consulting fees from AbbVie, Arena, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Gilead, Janssen, Pfizer, Prometheus Labs, and Takeda; and is founder and a shareholder of Trellus Health
Tadakazu Hisamatsu
Grant support from AbbVie, Daiichi-Sankyo, EA Pharma Co, Ltd. JIMRO, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Co., Ltd. Consulting fees from EA Pharma Co, Ltd., Janssen Research & Development, LLC., Gilead Sciences, Eli Lilly, Bristol Myers Squibb. Lecture fees from AbbVie, EA Pharma Co, Ltd, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co, Ltd.
James O. Lindsay
Consultant and an advisory board participant for AbbVie, Atlantic Healthcare, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead, GSK, Janssen, MSD, Napp, Pfizer, Shire, Takeda, and Vifor Pharma; has received speaker fees and sponsorship for academic meetings from AbbVie, Ferring Pharmaceuticals, Janssen, MSD, Napp, Norgine, Pfizer, Shire, Tillotts Pharma, and Takeda; and has received investigator-led research grants from AbbVie, Gilead, Pfizer, Shire and Takeda.
Geert D’Haens
Consultant for AbbVie, AgomAb, AstraZeneca, AM Pharma, AMT, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals,, GSK, Pfizer, Immunic, J&J, Origo, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, Protagonist and Ventyx; and has received speakers bureau fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Pfizer, Bristol Myers Squibb, and Takeda

Alexandra Song, Yi Yao, Yang Yang, Javier Zambrano, Fernando Aponte, and W. Rachel Duan are full-time employees of AbbVie and may own AbbVie stock or options.

Funding
AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and authors thank all the trial investigators and the patients who participated in this clinical trial.
Medical writing support was provided by Stephanie Parsons, PhD, an employee of AbbVie.

Introduction

Prospective evidence of the long-term efficacy of endoscopic submucosal dissection (ESD) for T1 colorectal cancer (CRC) is insufficient.

Aims & Methods

We aimed to evaluate long-term ESD outcomes for T1 CRC, focusing on the risk stratification criteria and necessity of additional surgery.
This large-scale, multicenter, prospective cohort study was conducted by Hiroshima GI Endoscopy Research Group. All consecutive patients who underwent colorectal ESD between January 2014 and December 2018 were included, and those with pathologically confirmed T1 CRC were analyzed. Patients were classified into low-risk and high-risk groups based on histopathological risk factors for lymph node metastasis in JSCCR guidelines. High-risk patients were categorized into those who underwent additional surgery (surgery group) and those who were followed up without surgery (follow-up group).

Results

Among 2357 patients who underwent ESD for 2478 early colorectal neoplasms, 431 were diagnosed with T1 CRC. Ten recurrences (2.6%) and five T1 CRC-associated deaths (1.3%) occurred in the high-risk group, with none in the low-risk group. Five-year cumulative overall and local recurrence rates were significantly higher in the follow-up versus surgery group (7.7% and 1.9%; P=0.019 versus 6.4% and 0%; P<0.001), with no local recurrence in the surgery group. Five-year overall survival was significantly worse in the follow-up group (79.5% and 95.2%; P<0.001), while no significant difference was found in 5-y disease-specific survival (98.5% and 98.5%; P=0.447).

Conclusion

No recurrence or mortality occurred in the low-risk group, suggesting that intensive surveillance may be unnecessary for these patients after curative ESD. Additional surgery could prevent local recurrence for high-risk T1 CRC, supporting a risk-based treatment approach.