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HIGH IL12 AND TH1-RESTRICTED IL23 RECEPTOR EXPRESSION IN THE INTESTINAL LAMINA PROPRIA CELLS IDENTIFIES CROHN’S DISEASE PATIENT’S RESPONDER TO USTEKINUMAB

Sara Onali 1, Nicola Raho 1, Amalia Di Petrillo 1, Claudia Carpineti 1, Erica Loddo 1, Marta Cadoni 1, Massimo Claudio Fantini 1

Affiliations

1 Università degli Studi di Cagliari, Monserrato, Italy

Summary

AI Generated

In this 12-patient prospective study, higher baseline expression of IL12 cytokine subunits and Th1-restricted IL23 receptor in lamina propria was associated with clinical remission at 16 weeks in Crohn's disease patients treated with ustekinumab.

At week 16, 50% (6/12) of CD patients achieved clinical remission (HBI <5) following ustekinumab treatment.
Patients who achieved remission had significantly higher baseline expression of IL12 cytokine subunits p40 and p35 compared to non-remitters (p=0.001 for both).
IL23 receptor expression in Th1 cells was significantly higher in remitters (18.0%) compared to non-remitters (5.8%; p=0.009), while expression in other cell types showed no difference between groups.
No statistically significant difference was found in overall IL12 and IL23 receptor RNA expression between remitters and non-remitters.
This single-center study enrolled CD patients with active luminal disease who had substantial prior anti-TNF exposure (45.4% IFX, 63.6% ADA) and long disease duration (mean 18.9 years).

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This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

Crohn’s disease (CD) is a chronic relapsing disorder of the gastrointestinal tract characterized by excessive inflammation sustained by the induction and expansion of Th1 and Th17 cells. Ustekinumab (UST), a fully humanized monoclonal antibody approved for the treatment of CD patients, inhibits both IL12 and IL23, two cytokines involved in the Th1 and Th17-mediated immune response, by targeting the common subunit p40. To be effective UST needs, in addition to the expression of target cytokines, the presence of cells responsive to IL12 and IL23, therefore we focused our attention on the expression of IL12 and IL23 receptors in target cells.

Aims & Methods

This study aimed at correlating the expression of IL12 and IL23 and their receptors in the lamina propria Th1, Th17 and innate lymphoid cells (ILCs) from CD patients’ biopsies collected before UST treatment start to the clinical disease activity evaluated after 16 weeks of therapy.
This is a prospective, observational, single-center open-label study. All CD patients with clinical indications to receive UST for active luminal disease were enrolled. Patients had baseline endoscopy to confirm disease activity by SES-CD and to collect biopsies to isolate LPMC. Clinical remission to therapy was assessed at week 16 and defines as Harvey Bradshaw Index (HBI) <5. IL12 (p40 and p35) and IL23 (p40 and p19) cytokines subunits and IL12 (IL12Rb1 and IL12Rb2) and IL23 (IL12Rb1 and IL23R) receptors subunits was evaluated in remitters (R) and not remitters (NR) by real-time PCR. Moreover, IL12Rb2 and IL23R expression was analyzed in Th1 (defined as CXCR3⁺/CCR6^-), Th17 (CXCR3^-/CCR6⁺); Th1/Th17 (CXCR3⁺/CCR6⁺), ILCs (127⁺/161⁺) by flow cytometry. Differences between groups were analyzed by Mann-Whitney test and statistical significance was considered for p<0.05.

Results

From April 2019 to April 2022, 12 CD patients were enrolled in the study. Clinical and demographic characteristics are described in Table 1. At week 16 6/12 (50%) patients were in remission. There was no statistically significant difference in il12rb2, il12rb1, and il23r RNA expression between R and NR. Regarding cytokines subunits, p40 and p35 expression was significantly higher in R than in NR (p=0,001). p19 expression in R was higher as compared to NR although the difference did not reach statistical significance. No difference in Th and ILCs subgroups frequencies between R and NR was observed by flow cytometry. IL12Rb2 and IL23R were equally expressed by Th17, Th1/Th17, ILC1, and ILC2/3 cells in the two groups. In contrast, IL23R expression in Th1 cells was significantly higher in R group (18.0%) as compared to NR (5.8%; p=0.009).

Baseline CD patients characteristics	N=12
Male	7 (58,3%)
Mean Age (range)	52,6 (31-73)
Mean duration of disease yrs (range)	18,9 (10-32)
Previous Anti TNFs exposure IFX ADA	6 (45,4%) 8 (63,6%)
Disease Characteristics* Localization L1 L2 L3 P Behaviour B1 B2 B3	7 (63,6%) 3 (27,3%) 2 (18,2%) 4 (33,3%) 4 (33,3%) 4 (33,3%) 4 (33,3%)
PCR mean level and range (gr/dl)	12,2(0,2-90)
HBI, mean (range) SES-CD mean (range)	10 (17-4) 10 (5-14)

Conclusion

In CD patients treated with UST, high IL12 and Th1-restricetd IL23R expression in the lamina propria cells was associated with remission at week 16.

Disclosure

This study is supported by Janssen.

Conference

UEG Week Copenhagen 2023

Topics

IBD

Submission format

Abstract

Session

There are always openings (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

More Like This:

OBEFAZIMOD IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: EFFICACY AND SAFETY ANALYSIS FROM THE 96-WEEK OPEN-LABEL MAINTENANCE PHASE 2B STUDY

Josianne Nitcheu

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

OZANIMOD-EXPOSED PATIENTS WITH ULCERATIVE COLITIS UNDERGOING TOTAL COLECTOMY EXHIBIT UNIQUE HISTOLOGIC CHANGES IN LYMPH NODES

David T. Rubin

IMPACT OF CMV DETECTION IN COLONIC BIOPSIES ON CLINICAL OUTCOMES IN ACUTE SEVERE ULCERATIVE COLITIS

Carmen Tung

Waste manager: The police in endoscopy?

Anastasia Tsalouka

PERSONALIZED INTESTINAL ORGANOID AND IMMUNE CELL CO-CULTURE MODEL FOR EVALUATION OF BIOLOGICAL THERAPY EFFICACY IN ULCERATIVE COLITIS PATIENTS

Ruta Inciuraite

UEG Presentation

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OBEFAZIMOD IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: EFFICACY AND SAFETY ANALYSIS FROM THE 96-WEEK OPEN-LABEL MAINTENANCE PHASE 2B STUDY

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OBEFAZIMOD IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: EFFICACY AND SAFETY ANALYSIS FROM THE 96-WEEK OPEN-LABEL MAINTENANCE PHASE 2B STUDY

Severine Vermeire 1, Josianne Nitcheu 2, Paul GINESTE 2, Sheldon Sloan 2, Hartmut Ehrlich 2, Bruce E. Sands 3

Affiliations

1 University Hospitals Leuven, Leuven, Belgium

2 Abivax, Paris, France

3 Icahn School of Medicine at Mount Sinai, New York, United States

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Abstract

Introduction

Obefazimod is an oral small molecule that modulates inflammation by upregulating a specific anti-inflammatory micro-RNA (miR-124). Obefazimod has demonstrated safety and efficacy in patients with moderate-to-severe ulcerative colitis (UC) in the randomized, placebo-controlled, phase 2b induction study (1). This analysis presents data at week 96 after subjects enrolled in the open-label (OL) maintenance study.

Aims & Methods

Patients received placebo or obefazimod 25mg, 50mg or 100mg once daily (od) during the 16-week induction Phase 2b and, irrespective of their clinical response, could enter the optional OL 96-week maintenance study with obefazimod 50mg od. A total of 217 patients were enrolled into this study from January 13, 2020 onwards. Patients were followed monthly for safety and efficacy. Non-responder imputation (NRI) was used for missing efficacy data.

Results

Of 222 patients who completed the phase 2b induction study, 217 (97.7%) were enrolled in the OL maintenance study. 30/217 (13.8%) subjects dropped out prior to week 48, 6 subjects did not qualify the second year of treatment (non-responders) and 17/181 (9.4%) subjects dropped out between week 48 and week 96. All dropouts were considered as treatment failures for this analysis. 164 subjects completed the second year of treatment. Main efficacy results are presented in the Table below.

Criteria	Definition	All patients (NRI) N=217
Clinical remission	MMS : stool frequency sub-score ≤1, RBS = 0 and endoscopic sub-score ≤1	52.5%
Endoscopic improvement	Endoscopic sub-score ≤1	59.0%
Endoscopic remission	Endoscopic sub-score = 0	35.9%
Clinical response	Decrease from baseline in the MMS ≥ 2 points and ≥30% from baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1	70.5%

MMS: Modified Mayo score ; NRI: Non-responder imputation ; RBS: rectal bleeding sub-score
Among the 168 patients with no clinical remission after week 16 induction, 81 (48.2 %) achieved de novo clinical remission at week 96 of the OL maintenance study. Among the 49 patients with clinical remission after induction, 33 (67.3 %) maintained remission at week 96.
In total, 149 /217 subjects (68.7 %) reported at least one treatment emergent adverse events (TEAE) over 2 years of treatment. TEAEs leading to study discontinuation were reported in 17 subjects (7.8 %) and serious adverse events (SAEs) were reported in 18 subjects (8.3 %). The most frequent TEAEs (≥ 5 %) were COVID-19 (14.3 %), headache (11.5%), ulcerative colitis (7.8 %) and nasopharyngitis (6.9 %). No new safety risks were identified over these 96 weeks.

Conclusion

Results from this 96-week analysis of the OL maintenance Phase 2b study confirmed long-term efficacy of obefazimod 50 mg od, with durable clinical remission, as well as a favorable long-term safety profile.

References

Vermeire S, Sands B, Tilg H et al. ABX464 (obefazimod) for moderate-to-severe, active ulcerative Colitis: a phase 2b, double-blind, randomised, placebo-controlled induction trial and 48 week, open-label extension. Lancet Gastroenterol Hepatol 2022, 7 (11): 1024-1035

Disclosure

Bruce E Sands reports consulting fees from Abbvie, Alimentiv , Amgen, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Target RWE,Teva, TLL Pharmaceutical, Ventyx Biosciences; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Janssen, Pfizer, Takeda; research grants and consulting fees from Theravance Biopharma; and stock options from Ventyx Biopharma.
Séverine Vermeire has received grants from AbbVie, J&J, Pfizer, Takeda and Galapagos; Séverine Vermeire has received consulting and/or speaking fees from: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma.

Event

UEG Week Copenhagen 2023

Topics

Endoscopy Histopathology IBD

Submission format

Abstract

Session

The new kids on the block for IBD: Part 1

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

More Like This:

OBEFAZIMOD IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: EFFICACY AND SAFETY ANALYSIS FROM THE 96-WEEK OPEN-LABEL MAINTENANCE PHASE 2B STUDY

Josianne Nitcheu

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

OZANIMOD-EXPOSED PATIENTS WITH ULCERATIVE COLITIS UNDERGOING TOTAL COLECTOMY EXHIBIT UNIQUE HISTOLOGIC CHANGES IN LYMPH NODES

David T. Rubin

IMPACT OF CMV DETECTION IN COLONIC BIOPSIES ON CLINICAL OUTCOMES IN ACUTE SEVERE ULCERATIVE COLITIS

Carmen Tung

Waste manager: The police in endoscopy?

Anastasia Tsalouka

PERSONALIZED INTESTINAL ORGANOID AND IMMUNE CELL CO-CULTURE MODEL FOR EVALUATION OF BIOLOGICAL THERAPY EFFICACY IN ULCERATIVE COLITIS PATIENTS

Ruta Inciuraite

UEG Presentation

New

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BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

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BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

E.A.M. (Noortje) Festen 1, Paola Pibiri 2, Roy Oelen 2, Werna T. C. Uniken Venema 3, Emilia Bigaeva 1, Monique G.P. Van der Wijst 2, Maria Paraskevopoulou 4, Klaas Nico Faber 2

Affiliations

1 UMCG, Groningen, Netherlands

2 University Medical Center Groningen, Groningen, Netherlands

3 Zuyderland Medisch Centrum, Leuven, Belgium

4 Takeda Pharmaceuticals, Acton, United States

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Abstract

Introduction

Ulcerative colitis (UC) and Crohn’s disease (CD) share chronic intestinal inflammation but differ in clinical behavior and treatment response. Although single-cell RNA sequencing (scRNA-seq) studies have advanced understanding of IBD biology, limited sample sizes have hindered robust comparison of shared versus disease-specific mechanisms. We therefore performed a large-scale meta-analysis of gut mucosal scRNA-seq datasets to define common inflammatory architecture and divergent immune programs in UC and CD.

Aims & Methods

Gut mucosal scRNA-seq datasets from two CD and two UC cohorts were integrated using a standardized computational workflow for preprocessing, harmonization, and downstream analysis. Cell-type annotation, differential abundance and gene expression analyses, pathway enrichment, and cell–cell communication inference were performed to compare inflamed and non-inflamed tissue within each disease and identify shared versus disease-specific programs.

Results

We generated disease-specific atlases comprising more than 405,000 cells from approximately 190 patients with CD and 313,000 cells from approximately 72 patients with UC. Across both diseases, inflammation followed a shared remodeling program marked by epithelial cell loss, expansion of immune populations, and activation of immune-related pathways. Despite this common inflammatory framework, immune execution diverged by disease. In CD, CD8+ T cells declined in inflamed tissue, whereas in UC they expanded together with other immune subsets. B cells showed a similar contrast, with enrichment of innate and stress-response pathways in CD versus adaptive and humoral immune programs in UC. Monocytes added further specificity, with strong enrichment of JAK-STAT signaling observed only in UC. Consistently, cell-cell communication analysis indicated stronger adaptive immune interactions in UC than in CD.

Conclusion

UC and CD share a common inflammation-associated tissue remodeling program, but diverge in the immune pathways and cellular interactions that dominate the inflamed mucosa. These findings provide a systems-level framework for understanding IBD heterogeneity and may help prioritize phenotype-specific therapeutic targets.

References

1. Martin, J. C. et al. Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy. Cell 178, 1493-1508.e20 (2019).
2. Smillie, C. S. et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 178, 714-730.e22 (2019).
3. Jaeger, N. et al. Single-cell analyses of Crohn’s disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions. Nat. Commun. 12, 1921 (2021).
4. Calviño-Suárez, C. et al. Exploration of JAK/STAT pathway activation in ulcerative colitis reveals sex-dependent activation of JAK2/STAT3 in the inflammatory response. Front. Immunol. 16, 1609740 (2025).

Event

UEG Week Barcelona 2026

Topics

Gut Microbiota Mechanisms & Personalised Medicine Immunology IBD

Submission format

Abstract

Session

New insights into IBD mechanisms

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

More Like This:

OBEFAZIMOD IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: EFFICACY AND SAFETY ANALYSIS FROM THE 96-WEEK OPEN-LABEL MAINTENANCE PHASE 2B STUDY

Josianne Nitcheu

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

OZANIMOD-EXPOSED PATIENTS WITH ULCERATIVE COLITIS UNDERGOING TOTAL COLECTOMY EXHIBIT UNIQUE HISTOLOGIC CHANGES IN LYMPH NODES

David T. Rubin

IMPACT OF CMV DETECTION IN COLONIC BIOPSIES ON CLINICAL OUTCOMES IN ACUTE SEVERE ULCERATIVE COLITIS

Carmen Tung

Waste manager: The police in endoscopy?

Anastasia Tsalouka

PERSONALIZED INTESTINAL ORGANOID AND IMMUNE CELL CO-CULTURE MODEL FOR EVALUATION OF BIOLOGICAL THERAPY EFFICACY IN ULCERATIVE COLITIS PATIENTS

Ruta Inciuraite

UEG Presentation

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OZANIMOD-EXPOSED PATIENTS WITH ULCERATIVE COLITIS UNDERGOING TOTAL COLECTOMY EXHIBIT UNIQUE HISTOLOGIC CHANGES IN LYMPH NODES

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OZANIMOD-EXPOSED PATIENTS WITH ULCERATIVE COLITIS UNDERGOING TOTAL COLECTOMY EXHIBIT UNIQUE HISTOLOGIC CHANGES IN LYMPH NODES

Nathaniel Aviv Cohen 1, Christopher R. Weber 2, Jason X. Cheng 2, David Choi 1, Nicole M. Garcia 1, Natalie Choi 1, David T. Rubin 1

Affiliations

1 University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, United States

2 University of Chicago Medicine, Chicago, United States

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Abstract

Introduction

Ozanimod regulates lymphocyte egress from the spleen and lymph nodes into the systemic circulation. The histologic changes which occur in the lymph nodes of patients on these therapies is unknown.

Aims & Methods

We aimed to describe histologic changes in lymph nodes from patients with UC who were treated with ozanimod and underwent subsequent colectomy due to treatment-refractory disease. This retrospective study included patients with UC undergoing total colectomy for treatment-refractory disease who were treated with ozanimod within the 2 months prior to colectomy and a cohort of patients with UC undergoing colectomy who did not have ozanimod exposure. Histology of the lymph nodes from the mesentery of colectomy specimens were reviewed blindly by a hematophatologist (JXC) and an expert GI pathologist (CRW). Histopathological parameters were scored and 2-tailed student’s unpaired t-test was used to determine significance between groups. Demographic and clinical data were recorded.

Results

From our series of 45 patients treated with ozanimod, 6 (13%) required surgery for treatment-refractory disease. Colectomy specimen data were available for 5 patients (1 patient had surgery at an outside center). Lymph node specimens from 6 control patients with UC who had colectomy were also examined. Demographic and clinical data are summarized in Table 1. The duration of ozanimod therapy prior to surgery ranged from 6 to 24 weeks. Histologic examination of lymph nodes showed that patients treated with ozanimod had significantly greater extent of dilated sinuses (p=0.03) and greater degrees of sinus histiocytosis (p=0.03) compared with control patients. In addition, there was a tendency towards more Castleman-like angiotrophic hyperplasia, plasma cell infiltration and subcortical interfollicular expansion in ozanimod treated patients (not statistically significant).

Ozanimod Case 1	50^A	14^B	Female^C	Extensive colitis^D	Infliximab, adalimumab, ustekinumab, vedolizumab^E	6^F	Treatment refractory disease^G
Ozanimod Case 2	20	2	Male	Left sided colitis	Infliximab, vedolizumab, tofacitinib	12	Treatment refractory disease
Ozanimod Case 3	34	5	Female	Left sided colitis	Infliximab, ustekinumab, tofacitinib, vedolizumab	24	Treatment refractory disease
Ozanimod Case 4	24	2	Male	Extensive colitis	Infliximab, vedolizumab, tofacitinib, ustekinumab	16	Treatment refractory disease
Ozanimod Case 5	37	16	Male	Extensive colitis	Infliximab, adalimumab, ustekinumab, vedolizumab	8	Treatment refractory disease
Control Case 1	47	1	Male	Left sided colitis	Infliximab, vedolizumab, upadacitinib	n/a	Treatment refractory disease
Control Case 2	68	36	Male	Left sided colitis	Infliximab, ustekinumab, vedolizumab	n/a	Treatment refractory disease
Control Case 3	30	26	Female	Extensive colitis	Infliximab, golimumab, vedolizumab, tofacitinib	n/a	Treatment refractory disease
Control Case 4	32	4	Female	Left sided colitis	Infliximab, adalimumab	n/a	Treatment refractory disease
Control Case 5	29	5	Male	Extensive colitis	Adalimumab, ustekinumab, vedolizumab, tofacitinib	n/a	Treatment refractory disease

Table 1: Demographic and clinical data of patients with UC receiving ozanimod and control patients who underwent total colectomy
^AAge (years); ^B Disease Duration (years); ^C Sex; ^D Disease Extent; ^E Prior Advanced Therapies; ^F Duration of ozanimod therapy (weeks); ^G Reason for colectomy

Conclusion

This study identifies unique histologic changes in the lymph nodes of patients with UC treated with ozanimod. These changes could be in keeping with the known mechanism of action of ozanimod and suggests that other inflammatory pathways were driving their disease activity in these patients. The significance of the changes, particularly the Castleman-like features, needs to be further investigated.

Disclosure

NAC has served as a consultant for Iterative Health, Takeda and Seres Pharmaceuticals and has received travel support from Pfizer.
CRW, JXC, DC, NMG, and NKC, have no relevant disclosures.
DTR has received grant support from Takeda; and has served as a consultant for AbbVie, Alimentiv Inc., Altrubio, Amgen, Arena Pharmaceuticals, Aslan Pharmaceuticals, Boston Consulting Group, Boehringer Ingelheim Ltd., Bristol-Myers Squibb, Buhlmann Diagnostics Corp., Celgene, ClostraBio, Connect BioPharma, Datos Health, EcoR1, Ferring Pharma, Genentech/Roche, Gilead Sciences, IBD RPM dba Chronicles Health, IAG, Iterative Health, Janssen Pharmaceuticals, Kaleido Biosciences, Lilly Eli & Co, Menten AI, Pfizer, Prometheus Biosciences, Reistone Biopharma, Sangamo Therapeutics, Shanghai Pharma Biotherapeutics USA, Syneos, Takeda, Target RWE, Techlab Inc., and Trellus Health.

Event

UEG Week Copenhagen 2023

Topics

IBD

Submission format

Abstract

Session

IBD: From principles to therapy

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

More Like This:

OBEFAZIMOD IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: EFFICACY AND SAFETY ANALYSIS FROM THE 96-WEEK OPEN-LABEL MAINTENANCE PHASE 2B STUDY

Josianne Nitcheu

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

OZANIMOD-EXPOSED PATIENTS WITH ULCERATIVE COLITIS UNDERGOING TOTAL COLECTOMY EXHIBIT UNIQUE HISTOLOGIC CHANGES IN LYMPH NODES

David T. Rubin

IMPACT OF CMV DETECTION IN COLONIC BIOPSIES ON CLINICAL OUTCOMES IN ACUTE SEVERE ULCERATIVE COLITIS

Carmen Tung

Waste manager: The police in endoscopy?

Anastasia Tsalouka

PERSONALIZED INTESTINAL ORGANOID AND IMMUNE CELL CO-CULTURE MODEL FOR EVALUATION OF BIOLOGICAL THERAPY EFFICACY IN ULCERATIVE COLITIS PATIENTS

Ruta Inciuraite

UEG Poster

Standard Poster

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IMPACT OF CMV DETECTION IN COLONIC BIOPSIES ON CLINICAL OUTCOMES IN ACUTE SEVERE ULCERATIVE COLITIS

Carmen Tung 1, Michael Yulong Wu 1, Christopher John Kiely 1, Steffanie Nario 1

Affiliations

1 Royal North Shore Hospital, St Leonards, Australia

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Abstract

Introduction

Patients with ulcerative colitis (UC) are at an increased risk of cytomegalovirus (CMV) infection. CMV infection in acute severe ulcerative colitis (ASUC) may worsen disease severity and clinical outcomes. Current guidelines recommend colonic biopsies for the exclusion of CMV in all patients with ASUC. One study found that CMV positivity in ASUC was associated with greater need for rescue therapy, longer hospital length of stay (LOS) and higher readmission rates but found no difference in rate of colectomy.¹ We aimed to investigate the impact of positive CMV result on clinical outcomes in patients presenting with ASUC.

Aims & Methods

A retrospective review included all ASUC presentations to a quaternary hospital over a 10-year period based on modified Truelove and Witts’ criteria. ASUC presentations were grouped based on CMV positivity as determined by colonic biopsy. Data on pre-admission medications was collected. Data was collected on rates of rescue therapy, referral to colorectal surgery, colectomy, total parenteral nutrition (TPN). Outcomes assessed included intensive care unit (ICU) admission, 30- and 90-day readmission rates, 30- and 90-day mortality rates and mean LOS.

Results

A total of 172 ASUC presentations were identified. Of these, 133 had available colonic biopsy CMV results. 11 patients (8%) had positive CMV. Positive CMV result was significantly associated with increased need for TPN (36% vs 11%, p=0.02), ICU admission (27% vs 5%, p=0.004) and referral to colorectal surgery (82% vs 43%, p=0.01). Patients with CMV had longer LOS (27.1±14.0 vs 11.0±7.4, p=0.003). There were no significant differences in rates of rescue therapy, inpatient colectomy, readmission or mortality rates. 9 of the patients (82%) were treated with ganciclovir or valganciclovir. Patients on maintenance advanced UC therapies, including biologics and small molecule inhibitors, had significantly higher rate of CMV (22% vs 5%, p=0.01). Biologic therapy alone was associated with higher rate of CMV (24% vs 7%, p=0.02), whereas small molecule inhibitor alone was not (p=0.6). Pre-admission use of 5-aminosalicylates, high dose steroids, thiopurines or combination therapies were not associated with CMV positivity.

Table 1: Comparison data of clinical outcomes in ASUC between patients with and without CMV positivity on colonic biopsy

	CMV on biopsy		p-value
	Positive	Negative
Rescue therapy (n)	7 (64%)	44 (36%)	p=0.07
TPN (n)	4 (36%)	14 (11%)	p=0.02*
Referral to colorectal surgery (n)	9 (82%)	52 (43%)	p=0.01*
Inpatient colectomy (n)	3 (27%)	14 (11%)	p=0.13
ICU admission (n)	3 (27%)	6 (5%)	p=0.004*
Readmission at 90 days (n)	4 (40%)	23 (19%)	p=0.11
Mortality at 90 days (n)	1 (9%)	2 (2%)	p=0.11
Length of stay (days)	27.1 ± 14.0	11.0 ± 7.4	p=0.003*

Conclusion

Patients with CMV positive colonic biopsies tend to require more inpatient interventions, including increased need for TPN, ICU admission, referral to colorectal surgery and longer hospital length of stay. Despite more complex admission course of ASUC patients with concurrent CMV infection, these patients were not observed to have worse outcomes than those without CMV diagnosis. Maintenance biologic and small molecule inhibitor use was associated with higher rates of CMV, reflecting the immunosuppressant effects of advanced UC therapies. CMV detection needs to be considered as a potential exacerbating factor in disease severity.

References

1. Huang D, Rennie M, Krasovec A, Nagubandi S, Liu S, Ge E, Khehra B, Au M, Sivagnanam S, Kwan V, Rogge C, Mitrev N, Kariyawasam V. Impact of cytomegalovirus on outcomes in acute severe ulcerative colitis: a retrospective observational study. Ther Adv Chronic Dis. 2024 Mar 28;15:20406223241233203. doi: 10.1177/20406223241233203. PMID: 38560721; PMCID: PMC10981253.

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

Predicting outcomes in IBD (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Josianne Nitcheu

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

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Waste manager: The police in endoscopy?

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PERSONALIZED INTESTINAL ORGANOID AND IMMUNE CELL CO-CULTURE MODEL FOR EVALUATION OF BIOLOGICAL THERAPY EFFICACY IN ULCERATIVE COLITIS PATIENTS

Ruta Inciuraite

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Waste manager: The police in endoscopy?

Anastasia Tsalouka 1

Affiliations

1 University General Hospital Attikon, Athens, Greece

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Abstract

Event

UEG Week Copenhagen 2023

Topics

Endoscopy Nurses

Session

Green endoscopy

Published

2023

More Like This:

OBEFAZIMOD IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: EFFICACY AND SAFETY ANALYSIS FROM THE 96-WEEK OPEN-LABEL MAINTENANCE PHASE 2B STUDY

Josianne Nitcheu

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

OZANIMOD-EXPOSED PATIENTS WITH ULCERATIVE COLITIS UNDERGOING TOTAL COLECTOMY EXHIBIT UNIQUE HISTOLOGIC CHANGES IN LYMPH NODES

David T. Rubin

IMPACT OF CMV DETECTION IN COLONIC BIOPSIES ON CLINICAL OUTCOMES IN ACUTE SEVERE ULCERATIVE COLITIS

Carmen Tung

Waste manager: The police in endoscopy?

Anastasia Tsalouka

PERSONALIZED INTESTINAL ORGANOID AND IMMUNE CELL CO-CULTURE MODEL FOR EVALUATION OF BIOLOGICAL THERAPY EFFICACY IN ULCERATIVE COLITIS PATIENTS

Ruta Inciuraite

UEG Presentation

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

PERSONALIZED INTESTINAL ORGANOID AND IMMUNE CELL CO-CULTURE MODEL FOR EVALUATION OF BIOLOGICAL THERAPY EFFICACY IN ULCERATIVE COLITIS PATIENTS

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

Not sure what you can access? Learn more about account types.

PERSONALIZED INTESTINAL ORGANOID AND IMMUNE CELL CO-CULTURE MODEL FOR EVALUATION OF BIOLOGICAL THERAPY EFFICACY IN ULCERATIVE COLITIS PATIENTS

Deimantė Tilindė 1, Ruta Inciuraite 1, Ugne Kulokiene 1, Indre Aleknaviciene 1, Vytautas Kiudelis 2, Laimas Virginijus Jonaitis 2, Juozas Kupcinskas 2, Jurgita Skieceviciene 1

Affiliations

1 Lithuanian University of Health Sciences/Institute for Digestive Research, Kaunas, Lithuania

2 Lithuanian University of Health Sciences, Kaunas, Lithuania

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Abstract

Introduction

Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting 5 million people worldwide, characterized by mucosal inflammation that can extend throughout the colon [1]. Current treatments often have limited efficacy or severe side effects [2]. As, there are no established criteria for selecting the most effective treatment for IBD, innovative preclinical drug testing systems are of major importance.

Aims & Methods

The aim of this study was to evaluate the effects of biological therapy using ulcerative colitis patient-derived personalized co-culture models of colonic epithelial and immune cells under inflammatory conditions.

The effects of upadacitinib (UPA) and ozanimod (OZA) were tested in personalized co-cultures of colonic epithelial cells and macrophages derived from UC patients (n=12) and control (Con) individuals (n=11). Inflammation was induced with inflammatory cytokines TNF-α (10 ng/mL) and IFN-γ (10 ng/mL). Barrier integrity was measured by transepithelial electrical resistance (TEER). Expression of TNF-α, CCL5, and CXCL9 genes was evaluated using qRT-PCR. Secretion of cytokines in the epithelial cells and macrophages culture media was investigated using a flow cytometry-based target protein assay. Data comparison was conducted using the Shapiro-Wilk test and the Wilcoxon rank-sum test. A difference between the values was considered significant when p ≤ 0.05 or padj. ≤ 0.05.

Results

In cell cultures stimulated with inflammatory cytokines, barrier permeability increased (TEER decreased – Con: by 452.03 Ω·cm², UC: 39.3 Ω·cm²), which partially recovered after removal of inflammatory factors (TEER increased – Con: by 65.91 Ω·cm2, UC – only 47.31 Ω·cm²). Epithelial integrity was restored after incubation with UPA and OZA (TEER increased – Con: by 116.82 Ω·cm² (UPA), by 193.77 Ω·cm2 (OZA); UC: by 226.64 Ω·cm2 (UPA), by 188.5 Ω·cm² (OZA)). At the molecular level, overnight stimulation with TNF-α and IFN-γ increased expression of CXCL9 gene in epithelial cells (UC: fold change (FC) = 3064.49 p_adj.= 2.07 x 10^-5; Con: FC = 664.44, p_adj.= 2.00 x 10^-2) and macrophages (UC: FC = 140.47 p_adj.= 0.01; Con: FC = 314.43, p_adj.= 0.01) in both groups. Co-culture treatment with UPA and OZA showed important trend of patient-specific responses to each therapeutic agent, which probably was the most important factor of non-significant values for observed changes in CCL5, CXCL9, TNF-α expression analysing summarized data. The flow cytometry-based target protein assay revealed that TNF-α and IFN-γ can influence inflammatory cytokine secretion in both epithelial cells and macrophages of UC patients and Control individuals, which can be further modified by novel biological therapy agents – UPA and OZA.

Conclusion

In conclusion, treatment with TNF-α and IFN-γ reduced epithelial barrier integrity and induced increased expression of inflammatory cytokines in epithelial cells and macrophages. Biological therapy (UPA or OZA) tended to restore disrupted barrier integrity. However, the response to novel biological therapy agents (UPA and OZA) on gene expression in both cell types and inflammatory cytokine levels in the cell culture media showed varying impacts and effectiveness, thereby revealing individualized responses of subjects to different biological preparations.

References

1. Le Berre C, Honap S, Peyrin-Biroulet L. Ulcerative colitis. Lancet. 2023 Aug 12;402(10401):571-584. doi: 10.1016/S0140-6736(23)00966-2. PMID: 37573077.
2. Singh S, Allegretti JR, Siddique SM, Terdiman JP. AGA Technical Review on the Management of Moderate to Severe Ulcerative Colitis. Gastroenterology. 2020 Apr;158(5):1465-1496.e17. doi: 10.1053/j.gastro.2020.01.007. Epub 2020 Jan 13. PMID: 31945351; PMCID: PMC7117094.

Disclosure

No conflict of interest to declare.

Event

UEG Week Vienna 2024

Topics

IBD Immunology Mechanisms & Personalised Medicine

Submission format

Abstract

Session

IBD: Latest news on a personalised approach

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

More Like This:

OBEFAZIMOD IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: EFFICACY AND SAFETY ANALYSIS FROM THE 96-WEEK OPEN-LABEL MAINTENANCE PHASE 2B STUDY

Josianne Nitcheu

BIOPSY-BASED SINGLE-CELL PROFILING OF ULCERATIVE COLITIS AND CROHN’S DISEASE REVEALS SHARED INFLAMMATORY ARCHITECTURE AND DISEASE-SPECIFIC IMMUNE PATHWAYS

Klaas Nico Faber

OZANIMOD-EXPOSED PATIENTS WITH ULCERATIVE COLITIS UNDERGOING TOTAL COLECTOMY EXHIBIT UNIQUE HISTOLOGIC CHANGES IN LYMPH NODES

David T. Rubin

IMPACT OF CMV DETECTION IN COLONIC BIOPSIES ON CLINICAL OUTCOMES IN ACUTE SEVERE ULCERATIVE COLITIS

Carmen Tung

Waste manager: The police in endoscopy?

Anastasia Tsalouka

PERSONALIZED INTESTINAL ORGANOID AND IMMUNE CELL CO-CULTURE MODEL FOR EVALUATION OF BIOLOGICAL THERAPY EFFICACY IN ULCERATIVE COLITIS PATIENTS

Ruta Inciuraite