bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP010 Optimizing the switch from escalated intravenous to subcutaneous infliximab: a population pharmacokinetics–pharmacodynamics study
Authors: Wang Z , Ferrante M , Vermeire S , Dreesen E 
Published: January 2025

Abstract

Background
The standard subcutaneous (SC) infliximab (IFX) of 120 mg bi-weekly (Q2W) has shown non-inferior pharmacokinetics (PK) and comparable efficacy to the intravenous (IV) IFX of 5 mg/kg Q8W in clinical trials. However, it remains unclear whether patients on escalated IV dosing regimens can transition to standard SC dosing without losing therapeutic response. This study aims to elucidate the dose–exposure–response relationship during IV-to-SC switching of IFX in patients with Crohn’s disease (CD) and ulcerative colitis (UC) through population pharmacokinetics–pharmacodynamics (popPK–PD) modelling and simulation.

Methods
Data were collected from healthy volunteers in two single-dose Phase I studies ([1]; NCT03446976) and patients with IBD in a two-part Phase I study (NCT02883452). In patients with IBD, frequent PK sampling was conducted during switching from 5 mg/kg IV IFX to Q2W SC IFX injections of 120/180/240 mg in Part 1 and 120/240 mg in Part 2. Faecal calprotectin (FC) was measured in patients at baseline, week (w)2, w6, and Q8W thereafter until w54. Endoscopic remission (ER) was assessed at screening, w22/30, and w54. We performed popPK–PD modelling and simulation (n=1000) using NONMEM to evaluate post-switch FC time courses and probabilities of ER.

Results
A total of 253 healthy volunteers and 179 patients (101 CD, 78 UC) contributed 7351 IFX and 1201 FC concentrations. IFX clearance increased with decreasing serum albumin, increasing body weight, and presence of neutralizing antibodies. FC levels decreased when overall IFX exposure (not just IFX trough concentrations) increased. Lower FC at w14 were associated with increased probabilities of ER in patients with UC, but not CD.
Simulations showed that the standard IV-to-SC switch at w6 of IFX therapy further decreases FC and results in a significantly higher probability of ER at w22/30 (54% if no switch vs 63% if switch) (Figure 1). Simulations also showed that patients on escalated Q6W/Q8W IV maintenance regimens can switch to 120 mg Q2W SC infliximab without FC increasing (Figure 2A). Patients on Q4W IV infliximab require SC dose escalation to either 120 mg QW or 240 mg Q2W to avoid an increase in FC (Figure 2B).

Conclusion
Infliximab trough concentrations are only a surrogate for therapeutic response, with overall infliximab exposure being the true driver. Therefore, the higher trough concentrations on standard SC dosing are needed to compensate for the lower SC peak concentrations. Standard SC dosing is superior to standard IV IFX dosing as evidenced by lower FC and higher ER rates (in patients with UC). Patients on Q6W and Q8W IV regimens can switch to standard SC IFX without an increase in FC.

References
[1] Westhovens R et al., [P0387] Poster presented at UEGW 2017.
DOP014 Efficacy and safety up to 3 years of risankizumab maintenance treatment in patients with moderately to severely active ulcerative colitis: interim results from phase 3 COMMAND open-label extension study
Authors: Atreya R , Louis E , Loftus Jr. E V , Rubin D T , Dubinsky M , Hisamatsu T , Kalabic J , Mendez P , Chen S , Shah S , Morisset P , Duan W R , Panaccione R 
Published: January 2025

Abstract

Background
Risankizumab (RZB), a high-affinity humanised IgG1 monoclonal antibody targeting interleukin-23 p19, has shown sustained efficacy and an acceptable safety profile for patients (pts) with ulcerative colitis (UC).1 This interim analysis reports efficacy data at week (wk) 0 and wk 96, as well as safety data of the COMMAND (NCT03398135) open-label extension (OLE).

Methods
The COMMAND OLE enrolled pts who completed 52-wks maintenance dosing in the COMMAND substudies or entered directly from the induction study.1 All pts received RZB180 subcutaneous (SC) starting at OLE wk 0, except pts who had prior rescue therapy (single RZB 1200 mg intravenous [IV] dose then RZB360 Q8w) who continued RZB360 in the OLE. The OLE was not designed to compare RZB180 and RZB360 groups. The data cut-off date for this interim analysis was as of June 30, 2024. Efficacy endpoints assessed were clinical remission (CR) per AMS, clinical response per AMS, endoscopic improvement, endoscopic remission, and corticosteroid-free CR per Partial AMS up to wk 96. Data are reported as observed prior to RZB rescue therapy during OLE. The safety analysis also includes pts who directly entered the OLE from induction; presented as events/100 pt years (E/100 PY).

Results
Of the pts who entered the OLE (RZB180, N = 701; RZB360, N = 302), approximately 40% of pts had the opportunity to reach OLE wk 96 as of the cut-off date. At OLE wk 0 and 96, a similar proportion of patients in the RZB180 group achieved clinical and endoscopic outcomes (Figure 1A). In the RZB360 group, the percent of pts achieving clinical and endoscopic endpoints increased from OLE wk 0 through OLE wk 96 (Figure 1B). Similar rates of serious AEs, severe AEs, and AEs leading to discontinuation of study drug were reported in the RZB180 group and the RZB360 group with no new safety risks identified (Table 1).

Conclusion
In this interim analysis of the OLE, a sustained benefit was observed with long-term RZB treatment up to 96 wks. The long-term safety profile for RZB remains consistent and supports the long-term use.

References
1. Louis E et al. JAMA 2024;332(11):881-897
DOP015 Consistency and Quality of Inflammatory Bowel Disease care in Australasia; Towards Benchmarking, Crohn’s Colitis Cure Data Insight’s Program
Authors: Su W K , McNamara J , Wilson W , Wark G , Lynch K , Su H , Forbes A , Lawrance I , An Y K , Dutt S , Brett L , Walker G , Andrews J M , Connor S J , Ghaly S 
Published: January 2025

Abstract

Background
Inflammatory bowel disease (IBD) is a global health issue with Australia (AUS) and New Zealand (NZ) having amongst the highest prevalence rates worldwide. Our study examined the quality, safety, and consistency of care amongst ten Australasian centres.

Methods
Crohn’s Colitis Care (CCCare) is a cloud-based IBD-specific electronic medical record (EMR) used in Australasia. Deidentified data prospectively entered by clinicians and consumers during routine clinical practice were retrospectively analysed. Key performance indicators (KPI) were compared across two time periods, baseline (1st October 2021 to 30thSeptember 2022) and follow up periods (1st October 2023 to 30th September 2024). Centres with over 100 people with IBD with an assessment during the last 14-month period were included.

Results
At the end of the follow up period, 6794 people with IBD were included, 55.8% (n=3790) with Crohn’s Disease, 41.3% (n=2808) with Ulcerative Colitis and 2.9% (n=196) with IBD-Unclassified. There was an even gender distribution with 49.0% (n=3329) male, 48.2% (n=3276) female and 2.8% (n=189) did not have gender documented. The median age was 42 years (IQR 32 – 57) with a median disease duration of 11.3 years (IQR 5.6 – 19.7). The majority of people resided in AUS (71.2%, n=4834) and 28.8% (n=1960) in NZ.
Across the two study periods, the proportion of people receiving an advanced therapy remained stable (53.2% vs 52.9%, p=0.76), however the number of people on dose escalated (DE) therapy increased (25.1% vs 28.5%, p &lt; 0.001). In parallel, steroid use decreased; 12.4% vs 10.5%, p &lt; 0.01. There was a reduction in the rate of hospital admissions (4.1% vs 2.6%, &lt; 0.001) and surgeries (3.6% vs 1.6%, p &lt; 0.001). There were no differences in the rates of endoscopic (53.1% vs 54.7%, p=0.34) and radiologic remission (41.0% vs 43.0%, p=0.49).
There was a significant reduction in the completion of healthcare maintenance across all sites with a fall in overall covid vaccination (36.9% vs 29.8%, p&lt;0.001), influenza vaccination (20.1% vs 5.0%, p&lt;0.001) and skin care checks (12.0% vs 4.0%, p&lt;0.001). There was no significant difference in the proportion of people currently smoking (10.5% vs10.9%, p=0.54).

Conclusion
Observed clinical improvements, including reduced steroid use, admissions, and surgeries, coincided with increased DE therapy, reflecting a shift toward tailored healthcare. Post-pandemic reduction in healthcare maintenance likely reflects provider and consumer fatigue. Implementing a value-based IBD management approach with continuous KPI monitoring via digital tools like CCCare is essential for optimizing outcomes, highlighting trends, and identifying areas for improvement in healthcare delivery.
DOP017 Infliximab induction fails to reach targets in Perianal Fistulizing Crohn’s Disease: first results from the ATLANTIC study
Authors: Mulders L , Anjie S I , Chevallot-Beroux M , Loeff F , Mathot R A , D'Haens G R , Gecse K B 
Published: January 2025

Abstract

Background
In perianal fistulizing Crohn’s Disease (PFCD), higher serum concentrations of infliximab (IFX) have been associated with better outcomes. In clinical practice, the majority of PFCD patients receive dose intensification. However, the pharmacokinetics of IFX treatment in PFCD has not been described specifically. We hypothesized that patients with PFCD have altered IFX pharmacokinetics, compared to Crohn’s disease patients without perianal fistulizing disease (CD).

Methods
Patients with CD and PFCD starting standard dose intravenous IFX (5 mg/kg at week 0,2,6, thereafter every 8 weeks) were enrolled. Pre-infusion samples were collected from the second infusion (week 2) until 26 weeks to measure IFX trough level (TL), and anti-drug antibodies if IFX TL was below 1.0 μg/mL (radioimmunoassay). Target TL during induction were 20 μg/mL at week 2, 15 μg/mL at week 6, and at week 14 10 μg/mL for PFCD and 5.0 μg/mL for CD patients. Statistical analysis included unpaired T-tests and Mann-Whitney U tests for numerical differences, and chi-square tests (X²) for differences in proportions.

Results
A total of 149 patients were included (63 PFCD, 86 CD), and a total of 761 serum samples were analyzed. Patient demographics, including age, disease duration and treatment characteristics were largely comparable between groups, only luminal disease activity and use of concomitant immunomodulators were higher in CD patients (see Table 1).
During induction, target IFX TL were achieved in significantly lower proportion of PFCD compared to CD patients (43% vs. 57%, p=0.038). At week 14, median serum IFX concentrations were significantly lower in PFCD patients (2.8 μg/mL, IQR 1.0-5.4) compared to CD patients (4.8 μg/mL, IQR 2.0–6.6) (p = 0.014) (Figure 1). At week 14, target IFX TL in PFCD patients were achieved in only 9% (5/57) and 46% (36/78) of CD patients (p&lt;0.0001).
Anti-drug antibodies were detected in 16% (10/63) of PFCD patients and 12% (10/86) of CD patients (p=0.169) after a median of 20 weeks (IQR 9-28), which were transient in 35% (7/20) of patients during follow-up.

Conclusion
During induction, standard infliximab dosing results in lower TL in PFCD, compared to CD. The previously suggested target IFX concentration at week 14 is only reached in a fraction of PFCD patients. This may contribute to a prolonged disease burden and may necessitate alternative dosing strategies in PFCD.
DOP019 Reduced Gut Microbial Amino Acid Auxotrophies and Enhanced Tryptophan Degradation in Inflammatory Bowel Disease
Authors: Waschina S , Harris D , Starke S , Homeister L , Schuchardt S , Tran F , Verstockt B , Ananthakrishnan A , Vermeire S , Rosenstiel P , Schreiber S , Aden K 
Published: January 2025

Abstract

Background
Microbial amino acid auxotrophies, the inability of certain gut bacteria to synthesise essential amino acids, are important microbiome features contributing to gut microbial diversity and stability.1 Their relationship with inflammatory bowel disease (IBD), including Ulcerative Colitis (UC) and Crohn’s Disease (CD), remains poorly understood.

Methods
Stool and serum samples were collected from healthy controls (HC, n=190) and IBD patients from two longitudinal biologic therapy exposure (Baseline, Week 14) cohorts in Kiel, Germany (nUC=26, nCD=29) and Leuven, Belgium (nUC=63). Additional stool metagenomes from a Boston, US cohort (nUC=49, nCD=65) were included. Stool DNA underwent shotgun metagenomic sequencing. Metagenomic data were processed with the ATLAS workflow for metagenome-assembled genomes (MAGs) inference and quantification. Serum metabolomes were analysed using the Biocrates MxP Quant 500 Kit. Microbial auxotrophies and amino acid degradation pathways were predicted using genome-scale metabolic modelling.2

Results
Amino acid auxotrophies were prevalent in the human gut microbiome, with Tryptophan (Trp) auxotrophies being the most common. Patients with IBD showed reduced auxotrophies compared to HC, with CRP levels correlating with more pronounced reductions in Trp auxotrophies. Metagenomic profiling revealed a distinct enrichment of amino acid degradation genes in IBD, particularly for Trp-degrading enzymes such as Tryptophan decarboxylase and Tryptophan transaminase. These changes correlated with specific serum metabolites, particularly aromatic compounds, indicating a strong interconnection between microbial and host amino acid metabolism.

Conclusion
Altered microbial metabolism in IBD is characterised by reduced Trp auxotrophies and increased Trp degradation. This suggests a microbial imbalance where Trp degraders outcompete auxotrophic genotypes, potentially contributing to IBD pathology. Understanding the shifts in amino acid requirements and degradation by the gut microbiome provides new insights into microbiome-host co-metabolism in IBD and may inform future therapeutic strategies targeting nutrient essentialities of gut microorganisms.

References
1. Starke S, Harris DMM, Zimmermann J, Schuchardt S, Oumari M, Frank D, Bang C, Rosenstiel P, Schreiber S, Frey N, Franke A, Aden K, Waschina S. Amino acid auxotrophies in human gut bacteria are linked to higher microbiome diversity and long-term stability. The ISME Journal. 2023;17(12):2370-2380. doi:10.1038/s41396-023-01537-3
2. Zimmermann J, Kaleta C, Waschina S. gapseq: informed prediction of bacterial metabolic pathways and reconstruction of accurate metabolic models. Genome Biol. 2021;22(1). doi:10.1186/s13059-021-02295-1
DOP021 Appendectomy regulates intestinal flora-bile acid axis inhibits macrophage lipid metabolism and improves Ulcerative Colitis
Authors: Chu F , Hailong C 
Published: January 2025

Abstract

Background
The specific role of the appendix as both an immune organ and a reservoir for gut microbiota in inflammatory bowel disease (IBD) remains elusive. Recent clinical studies have demonstrated that appendectomy can alleviate refractory ulcerative colitis and reduce the rate of colon surgical resection in patients. However, the underlying mechanisms are still unclear. This study aims to comprehensively explore the precise regulatory mechanisms of appendectomy in the process of colonic inflammation.

Methods
Appendectomy was performed on C57BL/6 mice followed by induction of dextran sulfate sodium (DSS)-induced colitis. Changes in colon length, body weight, and other parameters were evaluated.Quantitative real-time polymerase chain reaction (qPCR), western blot, and immunofluorescence staining were employed to assess production of pro-inflammatory cytokines and the level of colonic mucosal barrier markers. Public databases were utilized for bioinformatics analysis. Transcriptomic, 16S rRNA, and metabolomic sequencing were conducted.

Results
Appendectomy increased colon length, body weight, and enhanced mucosal barrier integrity in mice with colitis, indicating alleviation of colitis. 16S rRNA sequencing indicated significant differences in microbial taxa such as Mucispirillum, Bacleroides, Clostridium_sensu_stricto_1, Romboutsia genus, Turcicibacter. Metabolomics analysis suggested that secondary bile acids accumulation. Both tanscriptome sequencing and metabolomics analysis enriched in lipid metabolism.

Conclusion
This study highlights the critical role of' appendectomy in regulating gut microbiota and lipid metabolism, and its contribution to the remission of UC. Appendectomy may hold promise as a therapeutic approach for mitigating colonic inflammation and improving disease outcomes in patients with UC.

References
1. Agrawal M, Allin KH, Mehandru S, Faith J, Jess T, Colombel JF. The appendix and ulcerative colitis - an unsolved connection. Nat Rev Gastroenterol Hepatol. 2023;20(9):615-624. doi:10.1038/s41575-023-00774-3
2. Arjomand Fard N, Armstrong H, Perry T, Wine E. Appendix and Ulcerative Colitis: a Key to Explaining the Pathogenesis and Directing Novel Therapies?. Inflamm Bowel Dis. 2023;29(1):151-160. doi:10.1093/ibd/izac106
3. Parian A, Limketkai B, Koh J, et al. Appendectomy does not decrease the risk of future colectomy in UC: results from a large cohort and meta-analysis. Gut. 2017;66(8):1390-1397. doi:10.1136/gutjnl-2016-311550
4. Elmahdi R, Jess T, Andersena NN. Appendectomy in Your First-degree Relative Protects You Against UC. J Crohns Colitis. 2019;13(12):1585. doi:10.1093/ecco-jcc/jjz089
DOP024 Transport of pks+ E. coli derived genotoxin colibactin from bacteria into host cell
Authors: Schloderer J , Neurath M , Günther C 
Published: January 2025

Abstract

Background
Colorectal cancer (CRC) is among the most prevalent cancer worldwide with a rapidly increasing frequency. Many studies have highlighted a close association between CRC, inflammatory bowel diseases (IBD), and alterations in gut microbial composition. Among these, particular attention has been drawn to B2 serotype Escherichia coli and other pks-positive Enterobacteriaceae. These bacteria carry a genetic island encoding a multi-enzyme assembly line responsible for the non-ribosomal synthesis of colibactin, a peptide-polyketide hybrid molecule that acts as a potent genotoxin. Colibactin alkylates double-stranded DNA, causing inter-strand crosslinks, double-strand breaks (DSB), and a specific mutational signature commonly found in CRC. Despite the growing knowledge about colibactin synthesis and its mode of action, the mechanism by which it is delivered from bacteria to the host epithelium remains unclear. Here, we hypothesize a small-particle carriage system to overcome the instability of colibactin and the physical obstacle posed by the mucus layer.

Methods
Conditioned media (CM) from pks+ and isogenic pks- bacteria were harvested, filtered, and ultracentrifuged to isolate distinct fractions, including vesicle and soluble portions. These fractions were tested for their ability to induce DNA DSBs in patient-derived colon organoids, which were detected by γH2AX staining. To more closely match in vivo exposure conditions, we created apical-out converted organoids in addition to classical basal-out growth. This approach allowed us to simulate and compare exposure to surfaces accessible before and only after the loss of barrier integrity, a typical hallmark of IBD.

Results
Our experiments demonstrated that basal application of bacterial isolates caused increased signs of cellular stress and genetic damage, independent of colibactin. In apical-out organoids, several fractions of the cell-free bacterial supernatant, but only those derived from pks+ E. coli, were able to reliably induce double-strand breaks.

Conclusion
Even though the genotoxic effect following CM treatment was substantially less pronounced than in co-culture experiments, our results suggest that the transfer of colibactin between bacteria and epithelium might not depend exclusively on direct physical contact, as suspected by other studies. The data support the presence of a mid-distance carriage system that is not limited by the size of bacteria and can therefore cross the intestinal barrier. Beyond that, we demonstrated that intestinal organoids are overall more susceptible to immunological stress by bacterial components when exposed at their basal surface, which indicates a significant bias in studies relying solely on classical organoid culture as an experimental system.
DOP025 Subjects sharing bacterial amplicon sequence variants exhibit differences in their IgA and IgG coating of gut bacteria, with enrichment of IgG binding for bacteria typically found in the oral cavity
Authors: Levhar N , Hadar R , Braun T , Efroni G , Ben-Horin S , Amir A , Haberman Y 
Published: January 2025

Abstract

Background
IgA is the predominant antibody in the gut, coating a larger proportion of intestinal bacteria. IgG is found in lower concentrations but tends to increase with gut inflammation. We aimed to characterize IgA- and IgG-coated gut microbial compositions in healthy controls and evaluate coating variations of shared bacteria across individuals.

Methods
We established a protocol for isolating IgA- and IgG-bound fecal bacteria, using magnetic streptavidin beads coated with biotin anti-human IgA or IgG (Fig. 1A). The initial stool, as well as the negative (unbound) and positive (IgG- or IgA-bound bacteria) fractions, were analyzed by 16S rRNA sequencing. For differential abundance, a non-parametric, permutation-based rank mean test was applied (dsFDR&lt;0.25).

Results
Fecal samples from 13 healthy subjects (Mean age 40.6 years, 54% males) were simultaneously incubated with anti-human IgA- or IgG- coated beads. Within-sample variability was quantified using three different fecal aliquots per subject, and several controls were included throughout the process. Paired differential abundance between the positive and the negative IgA fractions identified 46 amplicon sequence variants (ASVs) bacteria significantly higher in the positive fraction (IgA bound) and 44 ASVs significantly higher in the negative fraction. To better characterize the bound and unbound ASVs, we calculated term enrichment f-scores using the dbBact knowledge base (PMID: 37326027). This indicated enrichment of bacteria consistently reported as IgA-bound in previous publications, implicating the validity of our separation of Ig-bound bacteria (Fig. 1B). Similar analysis for the IgG-bound bacteria, identified 58 and 49 differentially abundant ASVs in the positive and negative fractions, respectively, with significant enrichment of bacteria previously noted to show IgA-coating and of salivary/oral bacteria among IgG-bound bacteria (Fig. 1C). Using the Ig-coating index (ICI; PMID: 25171403) of each `shared` ASV (detected in more than two subjects), we noted large inter-individual variance among the controls, with 42.4% ASVs showing significant inter-individual variance in IgA-coating (FDR&lt;0.1; Fig. 2A) and 30.3% ASVs with significant inter-individual variance in IgG-coating (FDR&lt;0.1; Fig. 2B).

Conclusion
Healthy subjects show variations in the immunoglobulin coating of bacteria, even among shared ASVs, indicating a personalized immune-bacterial repertoire. However, it is still unclear if this variation contributes to the gut microbiome composition variations seen between subjects. In addition, we observed preferential enrichment for immunoglobulin coating of bacteria typically found in the oral cavity.