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CHANGING THE COURSE OF CROHN’S DISEASE WITH AN EARLY USE OF ADALIMUMAB: THE CURE STUDY FROM THE GETAID

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CHANGING THE COURSE OF CROHN’S DISEASE WITH AN EARLY USE OF ADALIMUMAB: THE CURE STUDY FROM THE GETAID

Bénédicte Caron 1, Elodie Jeanbert 1, Florian Poullenot 2, Yoram Bouhnik 3, Lucine Vuitton 4, Catherine Reenaers 5, Stephane NANCEY 6, pierre Blanc 7, Xavier Roblin 8, Stéphanie Viennot 9, Jean-Louis Dupas 10, Anne Laure Pelletier 11, Arnaud Bourreille 12, Jacques Moreau 13, Jerome Filippi 14, Maria Nachury 15, Guillaume Bouguen 16, Marion Simon 17, Ludovic Caillo 18, Anthony Buisson 19, Laurianne Plastaras 20, Vered Abitbol 21, Alexandre Aubourg 22, Médina Boualit 23, David Laharie 24, Laurent Peyrin-Biroulet 25

Affiliations

1 Nancy University Hospital, Vandoeuvre les Nancy, France

2 Bordeaux University Hospital, Bordeaux, France

3 CHU Beaujon Dept. of IBD and Nutrition, Clichy, France

4 Besançon university hospital gastroenterology, Courbevoie, France

5 Assistants en formation gastro, réseau Ulg - CHU Sart Tilman, Assistants en formation gastro, réseau, Lantremange, Belgium

6 Lyon University Hospital, Pierre Benite, France

7 Hopital Saint Eloi, Montpellier, France

8 University of St. Etienne Dept. de Gastroenterologie, Saint Etienne, France

9 CHRU de Caen HGE 19è étage, Caen Cedex, France

10 CHU Nord Amiens, Amiens, France

11 Hopital Beaujon, Paris, France

12 Hopital Hotel Dieu Et Hme - Hge Aile Sud, Nantes Cedex 1, France

13 Centre Hospitalier Universitaire de Toulouse, Hopital Rangueil, Toulouse, France

14 Hopital de lAchet Dept. de Gastroenterlogie Dept. de Nutrition Oncologie, Nice Cedex 3, France

15 CHRU Lille, Courbevoie Cedex, France

16 CHU Pontchaillou, Rennes, France

17 Institut Mutualiste Montsouris, Paris, France

18 CHU DE NIMES, Nîmes, France

19 CHU Estaing Clermont-Ferrand, Clermont-ferrand, France

20 Chu Colmar, Colmar, France

21 Hopital Cochin Gastroentérologie AP-HP, Paris Cedex 14, France

22 Cabinet Medical, Chambray Les Tours, France

23 Ch Valenciennes, Valenciennes Cedex, France

24 CHU de Bordeaux Hopital Haut-Leveque Dept. de Gastroenterologie, Pessac cedex, France

25 Inserm U1256, Nancy University Hospital, Vandoeuvre-les-Nancy, France

Summary

AI Generated

In this first prospective trial of adalimumab withdrawal in early Crohn's disease, only 4% of patients maintained deep remission at 2 years after stopping a 12-month course of treatment.

Among 171 biologic-naïve patients with early CD (less than 24 months since diagnosis), 22.2% achieved deep remission after 12 months of adalimumab.
Of the 31 patients who achieved deep remission at 12 months and discontinued adalimumab, only 7 (22.6%) maintained deep remission one year after stopping treatment.
Overall, just 7 of 171 patients (4%) were in deep remission off adalimumab at 2 years from treatment initiation.
No serious adverse events were reported, and no predictive factors for loss of deep remission after discontinuation were identified.
Median time to clinical relapse after adalimumab discontinuation was 14 months.
The authors conclude that anti-TNF therapy should not be discontinued, even in patients with early Crohn's disease.

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Abstract

Introduction

Crohn's disease (CD) is a disabling and destructive disease. Early intervention associated with tight monitoring appear to the best way to achieve deep remission and to prevent disease progression. Whether anti-TNF (tumor necrosis factor) therapy can be interrupted in patients with early CD who have undergone a period of prolonged deep remission is unknown.

Aims & Methods

The primary objective was to evaluate the sustained deep remission rate one year after discontinuation of a 12-month course of adalimumab in adult patients with early CD who achieved deep remission at 12 months after treatment induction and who were already in clinical remission and biomarker remission at 6 months.
We carried out a multicentre prospective GETAID cohort study. All patients had early luminal CD less than 24 months since diagnosis, and were naïve to biologics. The primary study endpoint was percentage of patients with sustained deep remission one year after stopping a 12-months course of adalimumab (+/- 3 months) in adult patients with early-stage CD who achieved deep remission without therapeutic intervention (i.e. no surgery, no clinical flare-up, no introduction of CD-related treatment, no need for adalimumab optimization) AND who were already in clinical remission (CDAI < 150) and biomarker remission (CRP < 5 mg/L and fecal calprotectin < 250) at 6 months. A clinical flare-up was defined as a CDAI > 220 or an increase in CDAI between two subsequent visits > 70.

Results

A total of 171 patients received treatment with adalimumab between March 2015 and March 2019.
In this cohort, 39.2% (67/171) were active smokers. The median disease duration was 4 [2-9] months. CD location was ileal (42.7%, 73/171), colonic (12.3%, 21/171), and ileo colonic (44.4%, 76/171). Twenty-one patients (12.3%) had perianal disease. The majority of patients had an inflammatory phenotype (71.3%, 122/171). At inclusion, median CRP level was 9.0 [3.0-24.0] mg/L, and median fecal calprotectin was 440.5 [159.0-838.0] µg/g.
Overall, 38/171 (22.2%) of patients achieved deep remission after a 12-month course of adalimumab. From those who achieved deep remission, 7 patients did not discontinue adalimumab. In this study, 7/31 (22.6%) patients maintained their deep remission for one year after their treatment discontinuation (24 months from initiation of adalimumab). Among the whole cohort, only 4% (7/171) of patients were in deep remission off adalimumab at 2 years. Median time between adalimumab discontinuation and the first clinical relapse was 14 months. No predictive factor associated with loss of deep remission in the year following treatment discontinuation was identified. No serious adverse event was reported.

Conclusion

In this first prospective trial exploring withdrawal of advanced therapy in early CD, 22.6% achieved deep remission at one year with adalimumab; among them, about a quarter maintained deep remission at two years. These results demonstrate that anti-TNF therapy should not be discontinued, even in patients with early CD.

Event

UEG Week Berlin 2025

Topics

IBD Mechanisms & Personalised Medicine

Submission format

Abstract

Session

Clinical management of IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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1 Hannover Medical School, Hannover, Germany

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UEG Week Berlin 2025

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Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

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Affiliations

1 University of Medicine and Pharmacy Craiova, Craiova, Romania

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Abstract

Event

UEG Week Berlin 2025

Topics

Nurses Pancreas Radiology & Imaging

Session

Hot topics in European gastroenterology

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

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2025

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Update on hepatorenal syndrome

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Affiliations

1 UCL Institute of Hepatology, University College London, UK, London, United Kingdom

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Abstract

Event

UEG Week Berlin 2025

Topics

Hepatobiliary

Session

What's new in complications in chronic liver disease in 2025?

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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GUT MYCOBIOME SIGNATURES PREDICT NEOADJUVANT IMMUNOCHEMOTHERAPY RESPONSE IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA: A MACHINE LEARNING APPROACH WITH EXPERIMENTAL VALIDATION

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GUT MYCOBIOME SIGNATURES PREDICT NEOADJUVANT IMMUNOCHEMOTHERAPY RESPONSE IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA: A MACHINE LEARNING APPROACH WITH EXPERIMENTAL VALIDATION

le liu 1, Liping Liang 2, Shijie Mai 3

Affiliations

1 Zhujiang Hospital, Southern Medical University, Guangzhou, China

2 Guangzhou First People's Hospital, Guangzhou, China

3 Nanfang Hospital, Southern Medical University, Guangzhou, China

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Abstract

Introduction

Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis despite advances in neoadjuvant immunochemotherapy (NICT). With highly variable treatment responses, identifying reliable predictive biomarkers remains crucial. While gut microbiome influences on immunotherapy efficacy are increasingly recognized, the specific role of the fungal microbiome (mycobiome) in NICT outcomes for ESCC remains unexplored, representing a significant gap in developing personalized treatment strategies.

Aims & Methods

This study aimed to characterize gut mycobiome signatures in ESCC patients and develop fungal biomarker-based predictive models for NICT response. We conducted ITS2 sequencing on 136 fecal samples collected from 68 ESCC patients (pre- and post-NICT) and 19 healthy controls (HC). Patients were stratified as responders (R, n=26) or non-responders (NR, n=42) based on tumor regression grade (TRG) scores. We performed comprehensive analyses of mycobiome diversity, composition, co-occurrence networks, and functional pathways across groups. The Boruta algorithm was employed for feature selection to identify fungal biomarkers, followed by multilayer perceptron (MLP) machine learning with five-fold cross-validation to develop predictive models. Additionally, ESCC xenograft models were established to investigate gut mycobiome-immune interactions through fecal microbiota transplantation (FMT) and targeted fungal manipulation experiments.

Results

ESCC patients demonstrated significant mycobiome dysbiosis compared to healthy controls, characterized by reduced fungal alpha diversity and distinct beta diversity patterns. At baseline, ESCC patients showed enrichment of Rhodotorula minuta, Actinomucor elegans, and several Candida species. Responders exhibited significantly higher baseline fungal diversity than non-responders, with enrichment of Meyerozyma, Candida boidinii, Trichosporon dermatis, and Cryptococcus species, whereas non-responders showed predominance of Saccharomyces, Nakaseomyces, and pathogenic Candida species (C. glabrata, C. parapsilosis, C. albicans). Responders also displayed more complex, stable fungal co-occurrence networks with higher density and clustering coefficients. Post-NICT, both groups showed partial recovery of mycobiome diversity, with significant increases in beneficial fungal taxa. Functional pathway analysis revealed distinct metabolic profiles between responders and non-responders. Using the Boruta algorithm, we identified 23 genus-level and 22 species-level fungal biomarkers that demonstrated high predictive value. The MLP model based on genus-level markers achieved AUCs of 90.2% (training) and 91.9% (test), while the species-level model showed comparable performance. In animal experiments, mice receiving R-FMT exhibited reduced tumor growth and enhanced CD8+ T cell infiltration compared to NR-FMT recipients. Notably, Candida boidinii supplementation synergized with anti-PD-1 therapy, while Saccharomyces depletion enhanced treatment sensitivity.

Conclusion

Our findings establish the gut mycobiome as a powerful predictor of NICT response in ESCC, with machine learning models achieving >90% accuracy using fungal biomarkers. Experimental validation not only confirms mechanistic links between specific fungi and antitumor immunity but also demonstrates that targeted mycobiome modulation can enhance immunotherapy efficacy. This dual approach of prediction and intervention offers a novel framework for precision oncology in ESCC, potentially transforming clinical decision-making and treatment outcomes in this challenging malignancy.

References

1. Li J, Xu J, Zheng Y, et al. Esophageal cancer: Epidemiology, risk factors and screening. Chin J Cancer Res. 2021; 33(5): 535-547.
2. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012; 366(22): 2074-2084.
3. Schroeder W, Ghadimi M, Schloesser H, et al. Long-Term Outcome After Histopathological Complete Response with and Without Nodal Metastases Following Multimodal Treatment of Esophageal Cancer. Ann Surg Oncol. 2022.
4. Rosner S, Liu C, Forde PM, Hu C. Association of Pathologic Complete Response and Long-Term Survival Outcomes Among Patients Treated With Neoadjuvant Chemotherapy or Chemoradiotherapy for NSCLC: A Meta-Analysis. JTO Clin Res Rep. 2022; 3(9): 100384.
5. Coker OO, Nakatsu G, Dai RZ, et al. Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer. Gut. 2019; 68(4): 654-662.
6. Dohlman AB, Klug J, Mesko M, et al. A pan-cancer mycobiome analysis reveals fungal involvement in gastrointestinal and lung tumors. Cell. 2022; 185(20): 3807-3822.
7. Wurster S, Albert ND, Kontoyiannis DP. Candida auris Bloodstream Infection Induces Upregulation of the PD-1/PD-L1 Immune Checkpoint Pathway in an Immunocompetent Mouse Model. Msphere. 2022; 7(2): e81721.

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Gut Microbiota Immunology Mechanisms & Personalised Medicine Oesophagus

Submission format

Abstract

Session

Oncobiome

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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UEG Presentation

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MICROPLASTIC-INDUCED ALTERATIONS IN GUT MICROBIOME AND METABOLISM: INSIGHTS FROM AN EX VIVO BIOREACTOR MODEL

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MICROPLASTIC-INDUCED ALTERATIONS IN GUT MICROBIOME AND METABOLISM: INSIGHTS FROM AN EX VIVO BIOREACTOR MODEL

Christian Pacher-Deutsch 1,2, Kristina Žukauskaitė 1,2, Cigdem Akar 2, Maximilian Nepel 2, Lukas Kogler 1,3,4, Hansjörg Habisch 2, Serena Ducoli 5, Stefania Federici 5, Tobias Madl 2,6, Verena Pichler 1,3, Angela Horvath 1,2, Vanessa Stadlbauer 1,2,6

Affiliations

1 Center for Biomarker Research in Medicine (CBmed), Graz, Austria

2 Medical University of Graz, Graz, Austria

3 University of Vienna, Vienna, Austria

4 Medical University of Vienna, Vienna, Austria

5 University of Brescia, Brescia, Italy

6 BioTechMed-Graz, Graz, Austria

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Abstract

Introduction

Microplastic particles (MPs), defined as plastic fragments smaller than 5 mm, are pervasive pollutants that accumulate in ecosystems and the human food chain (1). Literature points at various health risks, including the induction of carcinogenesis (2). Emerging evidence from animal models (3) suggests that MPs may influence the gut microbiome, but the impact on the human gut microbiome remains poorly understood.

Aims & Methods

This study aimed to evaluate how various MP types influence gut microbial composition and metabolism using an ex vivo bioreactor model, with a focus on exploring potential carcinogenic effects arising from MP–microbiome interactions.
Stool samples from healthy donors were used to inoculate bioreactor cultures, which were maintained under anaerobic conditions for five days with daily nutrient feeding. These cultures were exposed to five common MP types—polystyrene (PS), polypropylene (PP), low-density polyethylene (LDPE), poly(methyl methacrylate) (PMMA), and polyethylene terephthalate (PET)—at concentrations mimicking both estimated human exposure (4) and higher doses to assess dose-dependence. Cell viability and total bacterial counts, as well as culture pH, were measured throughout the experiment. To further explore potential microbiome and metabolic alterations, 16S rRNA gene sequencing and targeted metabolomics were performed.

Results

MP exposure did not lead to significant changes in total or viable bacterial cell counts. However, MP-treated cultures exhibited a consistent and significant decrease in pH compared to controls, suggesting changes in microbial metabolic activity. Microbiome sequencing revealed plastic-type-dependent alterations in microbial composition, with certain bacterial taxa increasing or decreasing in abundance depending on the MP type. These shifts occurred across multiple genera within diverse families, including Lachnospiraceae, Oscillospiraceae, Enterobacteriaceae, and Ruminococcaceae, with the majority of changes occurring withing the phylum Bacillota. These compositional changes were accompanied by shifts in the metabolomic profiles, some of which correlated with the observed pH changes. Several plastic types induced changes in valeric acid levels, while individual MP types were associated with alterations in distinct metabolites such as uracil, lactic acid, and acetic acid.

Conclusion

This study demonstrates that MPs can affect gut microbial activity and metabolism without significantly altering overall bacterial abundance in the short term. The variation in microbiome response across plastic types highlights the complexity of MP-microbiome interactions. Changes in faecal pH are known to be associated with various gastrointestinal diseases (5). Interestingly, some of the MP-induced changes in microbial composition resembled patterns linked to diseases such as depression and colorectal cancer. In contrast, other changes showed patterns that differed from those typically associated with conditions like Parkinson’s disease and irritable bowel syndrome, highlighting the complexity of these associations and the dependency on the context. The bioreactor model provided a controlled environment for identifying direct MP-microbiome interactions; however, in humans, additional factors like diet, immune response, and individual microbiome variations play a role in determining long-term effects. Exposure duration may also play a critical role in shaping the extent and nature of microbiome alterations (6), underscoring the need for further research into the effects of chronic MP exposure and associated health risks.

References

(1) Mamun, A. A., Prasetya, T. A. E., Dewi, I. R., & Ahmad, M. (2023). Microplastics in human food chains: Food becoming a threat to health safety. The Science of the total environment, 858(Pt 1), 159834. https://doi.org/10.1016/j.scitotenv.2022.159834
(2) Kumar, R., Manna, C., Padha, S., Verma, A., Sharma, P., Dhar, A., Ghosh, A., & Bhattacharya, P. (2022). Micro(nano)plastics pollution and human health: How plastics can induce carcinogenesis to humans?. Chemosphere, 298, 134267. https://doi.org/10.1016/j.chemosphere.2022.134267
(3) Hirt, N., & Body-Malapel, M. (2020). Immunotoxicity and intestinal effects of nano- and microplastics: a review of the literature. Particle and fibre toxicology, 17(1), 57. https://doi.org/10.1186/s12989-020-00387-7
(4) Senathirajah, K., Attwood, S., Bhagwat, G., Carbery, M., Wilson, S., & Palanisami, T. (2021). Estimation of the mass of microplastics ingested - A pivotal first step towards human health risk assessment. Journal of hazardous materials, 404(Pt B), 124004. https://doi.org/10.1016/j.jhazmat.2020.124004
(5) Yamamura, R., Inoue, K. Y., Nishino, K., & Yamasaki, S. (2023). Intestinal and fecal pH in human health. Frontiers in Microbiomes, 2, 1192316.
(6) Yin, L., Yang, M., Teng, A., Ni, C., Wang, P., & Tang, S. (2025). Unraveling Microplastic Effects on Gut Microbiota across Various Animals Using Machine Learning. ACS nano, 19(1), 369–380. https://doi.org/10.1021/acsnano.4c07885

Event

UEG Week Berlin 2025

Topics

Gut Microbiota Colorectal

Submission format

Abstract

Session

The gut ecosystem: From pathogenesis to treatment

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

IMU-856, AN ORALLY AVAILABLE EPIGENETIC MODULATOR OF BARRIER REGENERATION, SHOWED POSITIVE EFFECTS ON GUT HORMONE LEVELS IN CELIAC DISEASE PATIENTS IN A PHASE 1 CLINICAL STUDY

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IMU-856, AN ORALLY AVAILABLE EPIGENETIC MODULATOR OF BARRIER REGENERATION, SHOWED POSITIVE EFFECTS ON GUT HORMONE LEVELS IN CELIAC DISEASE PATIENTS IN A PHASE 1 CLINICAL STUDY

Amelie Schreieck 1, Indira Pichetto Olanda 1, Doris Proebstl 2, Evelyn Peelen 1, Juliano Fonseca 1, Martina Wirth 1, Sara Elhag 1, Inge Kehler 1, Daniel Vitt 1, Hella Kohlhof 1, Andreas Muehler 1

Affiliations

1 Immunic AG, Gräfelfing, Germany

2 Former Employee Of Immunic Ag, Gräfelfing, Germany

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Abstract

Introduction

A dysfunctional intestinal mucosal barrier is a key pathophysiological hallmark and driver of a broad range of gastrointestinal diseases including celiac disease and inflammatory bowel disease. To date, there are no adequate treatment strategies to ameliorate impaired barrier function.
IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a histone/non-histone protein deacetylase which serves as a transcriptional regulator of intestinal barrier function and regeneration of bowel epithelium. IMU-856 may represent a new approach to treat gastrointestinal diseases with compromised barrier function.

Aims & Methods

This was a first-in-human, double-blind, randomized, placebo-controlled clinical trial of IMU-856 in healthy volunteers and patients with celiac disease. In the multiple ascending dose part, healthy human subjects were dosed once-daily for 14 consecutive days with IMU-856 at three different dose levels or placebo. Additionally, the Phase 1/1b study was designed to assess safety and tolerability of IMU-856 at two different dose levels in patients with celiac disease during periods of gluten-free diet and a 15-day gluten challenge. Further objectives included pharmacokinetics and the assessment of histological changes. Biomarkers reflecting intestinal enterocyte mass and function, nutrient absorption, and enteroendocrine hormones like GLP-1 were analyzed to assess potential effects on gut health.

Results

IMU-856 was safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. Treatment with IMU-856 protected against gluten-induced histologic deterioration, improved the health and metabolic function of intestinal enterocytes as measured by nutrient uptake and citrulline [1], and had positive effects on enteroendocrine cells increasing endogenous GLP-1 levels in a dose-dependent manner.

Conclusion

IMU-856 is a safe, highly selective and potent epigenetic modulator, improving the intestinal barrier function in patients with celiac disease undergoing a gluten challenge.
Positive effects of IMU-856 on gut hormones and various biomarkers for overall gut health including intestinal function and integrity were observed. Therefore, IMU-856 may offer extensive potential for treatment of gastrointestinal diseases with compromised intestinal barrier function and metabolic diseases.

References

1. Daveson AJM, Stubbs R, Polasek TM, Isola J, Anderson R, Tye-Din JA, et al. Safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856, a SIRT6 modulator, in coeliac disease: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial.

Disclosure

AS, MW, EP: employees of Immunic AG, option and shareholders of Immunic, Inc.
IPO, JF, IK, SE: employees of Immunic AG, option and/or shareholders of Immunic, Inc.
HK: employee of Immunic AG, shareholder of Immunic, Inc., co-inventor of patents for the drug in investigation
DP: option holder of Immunic, Inc.
DV, AM: employees of Immunic AG and Immunic, Inc., shareholders of Immunic, Inc., co-inventors of patents for the drug in investigation

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Immunology Mechanisms & Personalised Medicine Small Intestine & Nutrition

Submission format

Abstract

Session

Molecular medicine: Understanding the mechanism allows therapy

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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