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

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
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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.

Introduction

The human gut microbiome consists of a diverse range of microorganisms, including not only bacteria but also viruses, archaea and fungi. Among these, bacteria have been shown to have a significant impact on the health or disease status of the host. However, despite increasing evidence for the role of fungi in liver disease, inflammatory bowel disease and cancer, little is known about the interactions between bacteria and fungi.

Aims & Methods

In this study, we aimed to investigate in depth the interkingdom relationship between fungal and bacterial communities in the gut of healthy monozygotic and dizygotic twins using a novel merging analysis method. Faecal samples from 106 twin pairs were analysed using 16S rRNA gene sequencing for bacteria and ITS sequencing for fungi. To enable a comprehensive analysis of the interactions between these two microbial communities, we adapted a novel merging normalisation method and linked it to systematic dietary and environmental characteristics.

Results

The implementation of the merging normalisation method allowed for an in-depth comparison of the fungal and bacterial communities independent of the low read counts. In direct comparison, bacteria were significantly more abundant and diverse than fungi, with Bacteroides and Prevotella being the most dominant bacterial genera. Within the fungal community, Candida was the most abundant genus in the cohort, followed by Geotrichum, while Saccharomyces was less abundant. Other fungal genera were detected sporadically between individuals. Most bacterial taxa showed a negative correlation with both Candida and Geotrichum at some level of abundance. For example, Bacteroides showed no antagonism towards Candida when its relative abundance was below 5%, whereas genera such as Prevotella (rho=-0.16, p=0.02), Alistipes (rho=-0.16, p=0.02) and Faecalibacterium (rho=-0.17, p=0.01) showed antagonistic interactions with Candida at relative abundances as low as 0.1%. These correlations were calculated across different abundances of the interacting fungi and bacteria, showing that negative associations increased with higher abundance (up to rho=-0.6 for Alistipes). An interkingdom network analysis further revealed a complex dynamic involving the three most abundant genera - Bacteroides, Prevotella and Candida - which showed mutually antagonistic relationships.

Conclusion

The implementation of the novel, easy-to-use merging analysis provided an in-depth view of the interactions between bacterial and fungal communities in the human gut, which are predominantly antagonistic in nature. The bacterial community appears to use several mechanisms to protect the gut environment from fungal colonisation.

Disclosure

Nothing to disclose