bluuebunny/crossref_metadata_2025_split huggingface dataset:
OP34 Mirikizumab demonstrates rapid improvements in bowel urgency severity, bowel urgency frequency, and stool deferral time in patients with moderately-to-severely active Ulcerative Colitis: 12-week interim results from the phase 3b LUCENT-URGE trial
Authors: Danese S , Dignass A , Laharie D , Limdi J K , Kempinski R , Lewis J D , Younes Z , Cohen E , Alaka K , Eastman W J , Tian T , Kayhan C , Rubin D , Dubinsky M 
Published: January 2025

Abstract

Background
Bowel urgency (BU) is a common, under-recognized and debilitating symptom among patients with ulcerative colitis (UC). LUCENT-URGE is a Phase 3b, open-label, single-arm 28-week (W) study in adults with moderately-to-severely active UC and BU (Urgency Numeric Rating Scale [UNRS] ≥3) at baseline treated with mirikizumab (MIRI) (NCT05767021). BU was assessed using the validated UNRS1 and 2 new BU assessments: BU Frequency (BUF) and Stool Deferral Time (SDT). These 3 BU measures (UNRS, BUF, SDT) and clinical endpoints provide a more comprehensive understanding of BU and the impact of MIRI treatment. Here, we report W12 interim analysis results.

Methods
Patients were treated with intravenous (IV) MIRI 300 mg at W 0, 4 and 8, followed by 200 mg subcutaneous at W12 and every 4 weeks up to W28. The primary endpoint, BU severity (UNRS) at W12, was assessed by change from baseline. BUF improvement was assessed by change from baseline at W12. SDT was reported in minutes and categorized as (4) Severe: &lt;1 min; (3) Moderate-Severe: 1-2 min: (2) Moderate: 2-5 min; (1) Mild: 5-15 min; (0) None: ≥15 minutes.

Results
172 patients were enrolled from 8 countries. At baseline, mean (± standard deviation [SD]) modified Mayo score [MMS]) was 6.8±1.3; 64% of patients had severe disease activity (MMS 7-9), mean duration of UC was 8.0±8.2 years, mean UNRS score was 6.9 ±1.6, mean BUF was 6.9±3.7. UNRS, BUF, and SDT improved from baseline to W12 (Figure 1). At W12, 63% patients achieved clinical response and 44% achieved both clinical response and UNRS clinically meaningful improvement (≥3 point decrease). Correlations between UNRS and BUF, and between UNRS and SDT at baseline, W12, and W12 change from baseline were of similar magnitude (Spearman correlation coefficient range: 0.43-0.68). The safety profile of MIRI observed in LUCENT-URGE was consistent with the profile previously reported.

Conclusion
In patients with moderately-to severely active UC and BU, MIRI demonstrated improvement in BU measures with a decrease by more than 50% in BUF after 12W of treatment. Selecting patients with urgency and targeting BU improvement is a novel strategy to assess response to therapy for UC. Broader associations between BU and quality of life, UC symptoms, histopathologic findings, and gene expression data will be explored upon completion of the W28 LUCENT-URGE study.

References
1.Dubinsky MC, Shan M, Delbecque L, et al. Psychometric evaluation of the Urgency NRS as a new patient-reported outcome measure for patients with ulcerative colitis. J Patient Rep Outcomes 2022; 6(1): 114.
DOP008 High clinical and endoscopic remission rate with Vedolizumab in early CD patients: the 2nd interim analysis from a prospective multicenter interventional Study (EARLY CD)
Authors: Liu J , Guo H , Li Y , Zhu L , Jia Y , Zhang H , Zhang H , Huang Q , Gao X , Cao Q 
Published: January 2025

Abstract

Background
Early treatment with advanced therapy prior to the development of complications such as stricture and fistula, is associated with better disease prognosis in patients (pts) with Crohn’s disease (CD). This study (EARLY CD) aims to evaluate the efficacy and safety of Vedolizumab (VDZ) as first line therapy in pts with early CD.

Methods
EARLY CD is a prospective, single-arm, multicenter, interventional study (ChiCTR2200063233). Target enrollment was 172 pts and all pts will receive up to 50 weeks of VDZ treatment with dose optimization (additional dose at week 10 if no clinical response, and switch to Q4W if secondary loss of response at maintenance). Main inclusion criteria for early CD are disease duration less than 18 months, no previous use of immunosuppressive agents and advanced treatment, no complications such as fistula or stricture (except for inactive perianal fistula). Primary endpoint was clinical and endoscopic remission at week 52, together with several secondary endpoints including clinical and endoscopic response, transmural healing assessed by MRE, and improvements in both PRO and QoL. This second interim analysis was conducted when all 172 enrollments were completed.

Results
172 pts were recruited with a median follow-up of 7.1 months (IQR 3.3-11.7). Mean age was 30.9 years, 73.8% were male. Mean CDAI score at baseline was 245.97 and SES-CD score was 9.7 (table). Clinical and endoscopic remission rates reached 83.8% and 48.7% at week 14, with further increase to 92.1% and 71.1% at week 52 (figure). Early clinical improvement was observed, with both abdominal pain score (APS) and loose stool frequency score (LSFS) started to decline from week 1, APS decreased by 50.6% (from 44.9 to 22.2), LSFS decreased by 56.1% (from 32.5 to 14.26). From week 1 to week 52, IBDQ improved from 157.8 to 185.9, self-rated health status EQ visual analogue scale increased from 72.3 to 85.4, and self-reported fatigue score assessed by FACIT improved from 38.1 to 43.9. Twenty pts have completed MRE evaluation both at baseline and week 52, with MaRIA score showing a decline from 23.9 to 20.3. Adverse events occurred among 20 pts (11.6%), including exacerbation of perianal disease that required surgical drainage (n=6), arthralgia (n=4), infection (n=7), GI bleeding (n=1), acute appendicitis (n=1), and elevated transaminase (n=1).

Conclusion
This is the first study worldwide to prospectively evaluate the efficacy of VDZ as first-line therapy among bio-naïve pts with early CD. Interim analysis showed promising results including high clinical and endoscopic remission rates through week 52, together with early PRO response and improvement in quality of life.
DOP011 Colectomy rates of newly diagnosed Finnish Ulcerative Colitis patients are decreasing
Authors: Kontola K , Oksanen P , Huhtala H , Helavirta I , Ilus T 
Published: January 2025

Abstract

Background
The effect of biological medication on colectomies is still unclear. Our aim was to determine colectomy risk in newly diagnosed Finnish ulcerative colitis (UC) patients and compare the risk of prebiological and biological era.

Methods
We used the registry of Social Insurance Institution of Finland to find newly diagnosed UC patients. Data on colectomies were collected from the Finnish Institute for Health and Welfare. Patients were stratified according to the UC diagnosis year and the availability of biological medication in Finland to three groups: 2000-2005 (prebiological), 2006-2012 (only infliximab available) and 2013-2020 (multiple advanced therapies available). We defined the subgroups as paediatric (aged &lt;20), adults (aged 20-59), and the elderly (aged ≥60).

Results
We identified 32,108 UC patients and 2,195 colectomies performed on them. The 1-, 5- and 10-year cumulative colectomy risks were 1.0%, 4.7% and 7.3%, respectively. Throughout the study period, the risks were declining with the incidence rate ratio (IRR) 0.98 (p=0.009) in 1-year, IRR 0.97 (p&lt;0.001) in 5-year and IRR 0.97 (p&lt;0.001) in 10-year colectomy risk. Colectomy rates were lower in advanced therapy era (IRR 0.76 (p = 0.048) in 1-year and IRR 0.70 (p &lt;0.001) in 5-year risk) and the 10-year risk also in infliximab era (IRR 0.87 (p = 0.010)) . The paediatric population had lower risk of surgery in advanced therapy era (IRR 0.33 (p =0.021) in 1 and 0.43 (p &lt;0.001) in 5 years) , whereas the risk of the elderly stayed constant (IRR 1.33 (p =0.400) in 1 and IRR 1.12 (p =0.553) in 5 years postdiagnosis).

Conclusion
The risk of colectomy among newly diagnosed UC patients has decreased along the 21st century. This could be due to the use of advanced therapy options and more active treatment strategies.
DOP013 Risk of immune mediated inﬂammatory diseases associated with anti-TNFs and ustekinumab in Crohn’s disease: a nationwide population-based cohort study
Authors: Kirchgesner MD- PhD J , Giboin C , Curmin R , Tubach F 
Published: January 2025

Abstract

Background
Biologics have been variously associated with an increased risk of paradoxical immune mediated inﬂammatory diseases (IMIDs) in patients with Crohn’s disease (CD). While this risk has been assessed in cohort studies for tumor necrosis factor inhibitors (anti-TNF), only case reports have reported the paradoxical occurrence of IMIDs in patients treated with ustekinumab. The aim of this study was to assess the risk of an incident second IMID in patients with CD treated with anti-TNF and ustekinumab.

Methods
We identified individuals with CD and no other IMIDs switching after a first anti-TNF to either a second anti-TNF or ustekinumab based on the French administrative healthcare databases 2008-2022. The primary outcome was the occurrence of a second IMID, including inflammatory rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and polymyalgia rheumatica), skin diseases (psoriasis, hidradenitis suppurativa, and vitiligo), neurologic diseases (multiple sclerosis, myasthenia gravis), thyroiditis, connective tissue diseases, and vasculitis. Follow-up started from treatment switch until occurrence of a second IMID, treatment withdrawal, or December 31, 2022. A lag period of 3 months was considered to minimize protopathic bias. Hazard ratios for the risk of second IMID were calculated, following 1:1 propensity score (PS) weighting, in order to control for confounders including demographics, previous and baseline IBD disease activity, co-treatment exposure, and comorbidities.

Results
Among 13,994 CD patients included, 10,712 (76.5%) and 3,282 (23.5%) patients were exposed to a second anti-TNF and ustekinumab, respectively. The overall proportion of women was 59.6%. Mean age at cohort entry was 38.0 (SD, 13.8) and 41.6 years (SD, 14.8) in the anti-TNF and ustekinumab groups, respectively. The median follow-up was 5.7 years (IQR, 3.3-9.1). Overall, 578 incident second IMID occurred (incidence rates: 23.2 per 1000 PY, person-years), mainly consisting in psoriasis (350, 60.6%) and ankylosing spondylitis (117, 20.2%). The cumulative incidence of second IMID after 10 years of follow-up was 9.85% (confidence interval 95% [8.84-10.85]). All covariates included in the PS model were balanced with an absolute standardized difference lower than 0.1. The risk of second IMID was lower in patients exposed to ustekinumab compared to those exposed to a second anti-TNF (HR=0.63 CI 95%[0.48-0.81], p-value&lt;0.001).

Conclusion
Based on a population-based and propensity score weighted cohort of 13,994 CD patients, exposure to ustekinumab was associated with a lower risk of second IMID compared to anti-TNF.
DOP018 Etrasimod for the treatment of Ulcerative Colitis: Up to 4 years of safety data from the global clinical programme
Authors: Vermeire S , Rubin D T , Regueiro M D , Takeuchi K , Walsh A , Kotze P G , Charabaty A , Goetsch M , Lazin K , Wu J , Tsamos G , Segovia M , Branquinho D , Danese S 
Published: January 2025

Abstract

Background
Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). The long-term safety, tolerability and efficacy of etrasimod are being evaluated in an ongoing open-label extension (OLE) study.1 We report an updated cumulative safety analysis from the etrasimod UC clinical programme with a maximum of 4 years of exposure.

Methods
Patients who received etrasimod in completed phase 2 (OASIS; OASIS OLE), phase 3 (ELEVATE UC 52; ELEVATE UC 12) and ongoing ELEVATE UC OLE (data cutoff 30 Aug 2023) and ES101002 OLE (data snapshot 30 Aug 2022) studies were included. Treatment-emergent adverse event (TEAE) frequency and exposure-adjusted incidence rates (IRs) per 1 patient-year (PY) were analysed.

Results
A total of 1196 patients received ≥1 dose of etrasimod 1 mg or 2 mg once daily with a mean (standard deviation) exposure of 70.66 (54.36) weeks, and 1619.5 PYs of total exposure. Demographics and baseline characteristics are reported in Table 1. Most TEAEs were nonserious and rarely led to discontinuation. The IRs of TEAEs of interest were generally low (Table 2). Serious infections and herpes zoster infections were infrequently reported (all IR ≤0.02). Three patients experienced four nonserious events of macular oedema (0.3%, IR &lt;0.01), including one event leading to discontinuation that resolved. One patient experienced two nonserious events of cystoid macular oedema (&lt;0.1%; IR &lt;0.01) that resolved. Malignancies were uncommon and included five patients with serious events (0.4%), two patients with squamous cell carcinomas and one with basal cell carcinoma. Eleven patients (0.9%) had alanine aminotransferase (ALT) levels &gt;3 times the upper limit of normal (ULN) at two consecutive post-baseline visits. Notably, no patients exhibited &gt;3× ULN in either ALT or aspartate aminotransferase and &gt;2× ULN in total bilirubin (laboratory criteria for Hy’s law). TEAEs leading to death were reported in three patients (all deemed unrelated to treatment). No serious adverse events of hypertension or bradycardia were reported. No events of second-degree Mobitz type 2 atrioventricular (AV) block or third-degree AV block occurred.

Conclusion
Etrasimod remains well tolerated in patients with moderately to severely active UC, with a favourable safety profile that has not changed with longer-term treatment exposure for up to 4 years.

References
1. Vermeire S et al. J Crohns Colitis 2023; 17: i619–i620.
Pfizer’s generative artificial intelligence tool MAIA was used to assist production of the abstract first draft. Authors reviewed/edited and take responsibility for the content.
DOP022 Shared and Distinct Features of the Gut Microbiome in Immune-mediated Inflammatory Diseases: Initial Analysis from the INTEGRATE Cohort Study
Authors: Kim H S , Kim J E , Nam B , Oh S J , Kim B H , Park S K , Lee S W , Jo S , Lee J Y , Bae J W , Lee Y A , Park D I , Kim T H , Lee C K 
Published: January 2025

Abstract

Background
Inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) share overlapping pathophysiological mechanisms as immune-mediated inflammatory diseases. While gut microbial dysbiosis has been implicated in both conditions, the shared and distinct features of the oral-gut microbiome axis remain poorly understood. This study aims to characterize the oral and gut microbial signatures and their relationship with environmental factors in IBD and AS to identify common pathogenic pathways and disease-specific patterns.

Methods
The INTEGRATE study is a nationwide prospective observational study in Korea targeting recruitment of 1,100 IBD patients, 700 AS patients, and 2,244 healthy controls over five years (Table 1). Systematic collection includes clinical data and biological samples (saliva, stool, blood, intestinal tissues) for multi-omics analyses. Microbial characterization employs full-length 16S rRNA gene sequencing and shotgun metagenomics for saliva and stool samples, complemented by metabolomic analyses of saliva, stool, and plasma. This initial analysis includes gut microbiome data from 254 IBD patients, 156 AS patients, and 194 healthy controls.

Results
Alpha diversity analysis revealed a gradient pattern, with IBD patients showing lowest gut microbiome diversity, AS patients intermediate, and healthy controls highest (p&lt;1.0e-12 for all indices, Fig. 1). In IBD patients, alpha diversity significantly correlated with disease activity indices (Harvey-Bradshaw Index score in Crohn's disease, total Mayo score in ulcerative colitis) and inflammatory markers (CRP, r=-0.13, p=0.042). Blood urea nitrogen levels showed positive correlation with alpha diversity in both IBD (r=0.21, p=0.00062) and AS cohorts (r=0.20, p=0.015). Beta diversity analysis demonstrated distinct clustering patterns (UniFrac distance), with AS patients positioned intermediately between IBD patients and healthy controls (Healthy vs IBD: R²=0.0502, Healthy vs AS: R²=0.0148, IBD vs AS: R²=0.0198; all p=0.001). Species-level analysis through full-length 16S rRNA sequencing identified specific taxa (Clostridium bolteae, Blautia hansenii) significantly enriched in both IBD and AS patients compared to controls.

Conclusion
Our initial analysis demonstrates distinct gut microbiome signatures across IMIDs, with a clear diversity gradient and shared taxonomic features between IBD and AS. These findings, coupled with specific clinical correlations, provide a foundation for understanding common pathogenic pathways. Ongoing multi-omics analyses and quantitative microbiome profiling will further elucidate the role of the oral-gut microbiome axis in these IMIDs, potentially identifying novel microbial biomarkers for precision medicine.
DOP023 Bifidobacterium-candida warfare in the gut of patients with ulcerative colitis
Authors: Jangi S , McDermott L , Shum A , Stiff K , perera L , Friedman S , Kumamoto C 
Published: January 2025

Abstract

Background
C. albicans is identified more frequently in the gut of patients with active ulcerative colitis (UC), and may drive inflammation through activation of specific fungal receptors in the intestine. Pathogenic expansion of C. albicans in UC may occur due to loss of specific protective bacterial strains. Prior work has suggested that Bifidobacterium species may antagonize Candida species. However, relationships of Bifidobacterium species with Candida species in patients with UC are not known, and whether Bifidobacterium may mechanistically suppress C. albicans growth is unclear.

Methods
We utilized data from the Study of a Prospective Adult Research Cohort with IBD to interrogate relationships between fungal and bacterial species during varying inflammatory phases of UC. Relative abundances of fungal and bacterial taxa was obtained from 18 internal transcribed spacer sequences and shotgun sequences. Spearman’s correlations between fungal and bacterial relative abundance were performed. To further assess observed bacterial-fungal correlations in vitro, cell-free supernatants from lab-derived and patient-derived strains were utilized to assess their suppressive ability in competitive assays.

Results
We found that C. albicans is increased in active UC vs during remission (q-val &lt;0.05). Across all patients, 15 unique Bifidobacterium species were identified, including B. adolescentis, B. longum, and B. bifidum [Fig 1A]. The relative abundance of fecal B. adolescentis was negatively associated with C. albicans abundance in UC (p&lt;0.05) [1B]. Multiple strains of B. adolescentis were detected [1C], although these strains did not demonstrate significant genetic variability when compared to a reference marker [1D]. We further observed that cell-free supernatants from lab-derived strains of both Bifidobacterium adolescentis (ATCC 15703) and Bifidobacterium bifidum (ATCC 29521) were able to inhibit C. albicans (ATCC 18804) growth [2CD], while cell-free supernatants from control species Blautia producta (ATCC 27340) only showed partial inhibition of C. albicans [2B]. Using donated fecal samples from 7 patients with active UC, we were able to isolate in culture 11 separate isolates of Bifidobacterium strains (confirmed by MALDI-TOF), and 1 isolate of Candida species, with inhibitory assays between patient derived strains ongoing.

Conclusion
Bifidobacterium adolescentis is negatively associated with C. albicans in fecal samples from UC patients. Both B. adolescentis and B. bifidum strains completely suppress C. albicans growth in vitro. Bifidobacterium species may provide colonization resistance against C. albicans in the UC gut. Loss of Bifidobacterium strains may allow for C. albicans expansion which may contribute to inflammation and relapse.
DOP029 SPP1 in colitis-associated colon cancer
Authors: Manna S , Sehn M , Cardoso da Silva D , Liu X , Wiese J J , Heldt C , Siegmund B , Hummel M , Schumann M 
Published: January 2025

Abstract

Background
Colitis-associated carcinoma (CAC) is a major complication that arises in patients with a long-standing ulcerative colitis (UC) and Crohn’s disease (CD). Albeit numerous studies report mutational landscape of CAC, its transcriptomic landscape is poorly understood. Thus, to interrogate the tumour ecology & mechanisms behind CAC development, we adopted a muti-modal approach utilizing FFPE tissues from human CAC patients and colon organoids. We leveraged immunology bulk gene expression and spatial gene expression to derive a robust gene signature of CAC at a single cell resolution.

Methods
To comprehensively profile the CAC immune microenvironment, we created a comprehensive dataset (Nanostring) covering relevant clinical FFPE samples encompassing 40 patients suffering from either IBD or CAC, alongside inflammation-free healthy controls (10 patients/group). We observed a robust upregulation of the SPP1 (Secreted Phosphoprotein 1) gene encoding osteopontin (OPN) in CAC. Subsequently, we extended our methodology to spatially resolved transcriptomics (Xenium) using 5μm FFPE sections from CAC & UC patients (3 patients/group). This provided insights into the spatial and single cell expression of SPP1 and its target receptors at a subcellular resolution. Furthermore, we mapped the ligand-receptor pairs onto cell types to uncover SPP1 signalling in CAC. These findings were validated at a protein level by whole FFPE section confocal microscopy.

Results
Immunology gene expression (Nanostring) dataset revealed a strong upregulation of SPP1 gene encoding OPN in CAC as compared to UC and CD. Spatially resolved transcriptomics (Xenium) unveiled the spatial heterogeneity of SPP1 expression in CAC, that is primarily arising from CD68+ CD163+ macrophages in CAC (Fig 1B), validated through OPN/CD68 immunostainings. Ligand-receptor (LR) analysis revealed a distinct LR pairing focusing on SPP1, that is secreted (outgoing signal) macrophages to T cells (as incoming signal) via upregulated integrin and CD44-receptors (Fig 1D/E). Furthermore, CAC tumour cells surrounding the SPP1+ macrophages exhibited a distinct gene expression signature associated with T cell exclusion and immunosuppression in CAC (Fig 1C/FG).

Conclusion
We identified a CAC specific upregulation of SPP1 at both RNA and protein levels, expressed by CD68+ CD163+ macrophages. Mutually exclusive spatial location of SPP1/OPN+ macrophages and CD8+ T cells suggests a crucial indirect role of SPP1/OPN in mediating an immunosuppressive tumour microenvironment. We further uncovered CAC specific, single cell gene expression signature that has the potential to identify pre-malignant stages of CAC.