bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP09 Models for predicting Crohn Disease (CD) exacerbation using serum and fecal metabolomics
Authors: Levhar N , Hadar R , Braun T , Efroni G , Naamneh R , Agranovich B , Talan Asher A , Selinger L , Picard O , Lahat A , Eliakim A , Kopylov U , Ben-Horin S , Amir A , Haberman Y 
Published: January 2024

Abstract

Background
Metabolites, produced endogenously or derived from the gut microbiome, are key mediators and effectors of many cellular functions, but there are only scant data on their temporal changes along CD course. We analyzed the dynamics of serum and fecal metabolome in a prospective cohort of quiescent CD patients over 2 years or until the occurrence of a clinical flare, aiming to identify whether changes in the metabolome precede and predict a clinical relapse.

Methods
Untargeted metabolomics was performed using LC/MS. Multivariate analyses in MaAsLin2 were applied to identify differentially abundant metabolites between CD cases who relapsed and those who remained in remission. Our models used the "Leave-One-Out" approach to compensate for over-fitting bias.

Results
We included 110 serum samples and 232 fecal samples from 44 CD participants recruited in remission (mean age 31.73 years, 59% males; Table 1). The median follow-up time was 630 days (IQR 500-808). Demographic, biomarkers, and treatment exposures were not significantly different between the 11 that experienced flare during follow-up and the 33 that remained in remission throughout. We compared the metabolomics between relapsers and non-relapsers using only preflare samples after excluding samples from a particular subject in the "Leave-One-Out" approach. The top 3 metabolites in each direction and comparison and their abundance preflare in the non-relapsers and relapsers are shown (Fig. 1A-B). We then calculated a flare index for that excluded subject, using the sum peak area ratio of all metabolites that were increased and decreased preflare. A receiver operating characteristic (ROC) area under the curve (AUC) using the "individual" flare index after z-score normalization was able to predict a subsequent flare with AUC=0.73, 95% CI 0.52-0.93 for serum metabolomics (Fig. 1C) compared with AUC=0.62 (95% CI 0.40-0.84) for CRP and AUC=0.74 (95% CI 0.54-0.94) for FCP, in the same sampling cohort. For the stool sampling cohort, metabolomics predictive accuracy was AUC=0.75 (95% CI 0.5-0.99; Fig. 1D) compared with AUC=0.67 (95% CI 0.49-0.84) for CRP and AUC=0.71 (95% CI 0.55-0.86) for FCP. Survival plot analyses after selecting Youden point based on ROC (Fig. 1C-D) showed moderately better performance for fecal flare index with log-rank Hazard Ratio (HR) of 8.20 (95% CI 1.98-34.20), than for the serum with HR of 3.45 (95% CI 1.5-11.37).

Conclusion
In a prospective cohort of quiescent CD patients, we identified metabolites in the serum and feces that were incorporated in models that can predict CD flare. These can be used to guide personalized preemptive therapy intensification and provide insight into the underlying mechanism of CD flares.
DOP29 Capsule endoscopy-guided proactive treatment versus standard treatment of patients with quiescent Crohn’s Disease: The CURE-CD randomized controlled trial
Authors: Ben-Horin S , Lahat A , Ungar B , Ukashi O , Yablecovitch D , Amitai M M , Haberman Y , Selinger L , Talan-Asher A , Kriger-Sharabi O , Naftali T , Ron Y , Yanai H , Dotan I , Kopylov U , Eliakim R 
Published: January 2024

Abstract

Background
Optimal strategies for treat-to-target in Crohn’s disease (CD) are still being sought. We aimed to examine the value of capsule endoscopy (CE) to guide proactive treatment optimization in patients with CD

Methods
A prospective randomized controlled clinical trial with temporally-restricted blinding. Patients with CD involving the small bowel who were in clinical remission (CDAI&lt;150) for over three months were enrolled. Baseline clinical, biomarker, imaging, patency capsule and CE assessments were performed. ‘High risk’ patients, defined as CE Lewis score ≥350 were randomized to either proactive treatment optimization or continued standard care for 24 months. ‘Low risk’ patients with Lewis score&lt;350 continued their standard care. All patients repeated CE every six months for 24 months. Primary outcome was the rate of clinical exacerbation (CDAI increase&gt;70 points and CDAI&gt;150 or hospitalization/surgery) in the standard-care versus the proactive-care sub-groups of high-risk patients, at 24 months. Secondary outcomes included risk of flare in the low-risk versus the standard-care high-risk arms, and predictive profiles for flare of calprotectin, MRI, intestinal ultrasound and Lewis score.

Results
Out of 118 screened patients, 60 were enrolled (20 in each of the three arms). Treatment intensification in CE-determined high-risk group, who were allocated to proactive treatment, comprised biologic dose-escalation (n=11/20), starting a biologic (8/20) or swapping a biologic (1/20) at study entry. Notably, 9/20 proactive-group patients underwent a second optimization following detected inflammation on subsequent semi-annual CE studies. Clinical exacerbation by 24 months (primary outcome) occurred in 5/20 (25%) of the high-risk proactive-treatment group versus 14/20 (70%) of the high-risk standard-care group (OR=0.14, 95%CI 0.04-0.57, p=0.006). For secondary outcomes, the rate of clinical flare in the standard-care low-risk group was numerically but not significantly lower than in standard-care high-risk group (9/20 versus 14/20, respectively, OR 0.3, 0.1-1.3, P=0.11). Among all patients continuing standard care, baseline CE Lewis score was higher among relapsers versus non-relapsers (median 450, IQR [225-900] versus 225, [135-600], respectively, p=0.03). Of 251 CE ingested, there was a single (0.4%) temporarily-retained CE, which resolved spontaneously.

Conclusion
In a randomized strategy-finding controlled trial, proactive treatment optimization based on CE findings in patients with CD in remission, proved safe and superior for prevention of disease exacerbation compared with continued standard care. NCT03555058
P091 Single-cell metabolic phenotyping of monocytes and macrophages in Crohn’s disease
Authors: Haag L M , Lehmann M , Walling S , Kunkel D , Hecker J , Huck A , Glauben R , Weidinger C , Kuehl A A ,   T. TRR241 IBDome Consortium, Siegmund B 
Published: January 2024

Abstract

Background
Crohn’s disease (CD) is a chronic inflammatory disease, which can affect any part of the gastrointestinal tract. It is characterized by alterations in the innate and adaptive immune systems. Changes in both monocyte and macrophage (MΦ) populations have been reported in CD patients. However, the precise contribution of these cells to disease pathogenesis and progression remains unclear. Our hypothesis is that in CD, the local environment affects the metabolism of monocytes and MΦ. Furthermore, we believe that the cell’s metabolism is essential for the phenotypic and functional identity of these cells. The aim of this study is to analyze and compare the metabolic signatures of peripheral blood monocyte subsets and tissue MΦ in CD patients with ileitis (iCD), deep remission (rCD) and healthy controls (HC).

Methods
A total of 28 adults from the IBDome5 cohort were analyzed, consisting of 10 individuals with iCD, 8 with rCD and 10 HC. Suspension mass cytometry was utilized to analyze peripheral blood mononuclear cells (PBMCs) using a 34-marker panel targeting key proteins and rate-limiting enzymes across multiple metabolic pathways. In addition, we conducted further analysis on intestinal tissue obtained during ileocolonoscopy using imaging mass cytometry. This allowed for the application of a similar marker panel to compare the metabolic states of tissue-resident MΦ (ongoing analysis) with the identified signatures found in peripheral blood.

Results
Peripheral blood samples of CD patients and HC were analyzed. FlowSOM clustering of CD45+ events discriminated 11 major clusters of PBMCs. Reclustering based on CD14 and CD16 allowed the identification of 4 monocyte clusters, including classical monocytes. Classical monocytes exhibited unique metabolic signatures that distinguished them from other monocyte populations. Ongoing investigations targeting metabolic signatures in the monocyte-MΦ compartment will determine whether disease states differ significantly between the single disease entities.

Conclusion
Single-cell phenotyping using suspension and imaging mass cytometry can assess metabolic states of the monocyte-MΦ compartment in CD and HC. Such insights may provide novel markers for monitoring disease activity and reveal potential therapeutic targets.
P127 Sphingosine-1-Phosphate Receptor Blockade with Etrasimod alters Lymphocyte Trafficking in Crohn's Disease: Insights from High-Dimensional Phenotypic Mapping
Authors: Nikolakis D , Pruijt M J , Aberkrom V E R , de Voogd F A E , Branquinho D , Crosby C , Teichert C , van de Sande M G H , Grootjans J , D'Haens G R A M 
Published: January 2024

Abstract

Background
The blockade of lymphocyte trafficking from the lymph nodes (LNs) towards the intestinal mucosa is an effective approach for the treatment of ulcerative colitis (UC). Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor (S1PR) modulator, which is currently also under investigation for Crohn’s disease (CD).
The therapeutic mechanism of action of S1PR modulators in the context of inflammatory bowel disease (IBD) is not completely understood. It is hypothesized that both B and T- cell populations are affected by this treatment and are retained in the peripheral LNs, reducing circulating lymphocytes and resulting in fewer immune cells available to traffic in the gastrointestinal tract. Etrasimod has been reported to induce a partial and selective reduction of lymphocyte subsets in the blood of healthy subjects, but the direct effect of S1PR modulators on LN leukocytes has not been evaluated. The aim of this study was to investigate changes in leukocyte subpopulations in peripheral LNs and peripheral blood (PB) in response to S1PR inhibition with etrasimod in patients with CD.

Methods
CD patients with moderate to severe disease activity, participating in the Phase 2, double-blinded, non-placebo-controlled portion of the CULTIVATE trial, were eligible for this sub-study. At baseline and after 14 weeks of etrasimod induction treatment (2 or 3 mg/day), 10cc of PB and 4 ultrasound guided biopsy samples of an inguinal LN were obtained. The isolated peripheral blood mononuclear cells (PBMCs) and LN leukocyte populations, were analyzed at single cell level via high-dimensional immunophenotyping through mass cytometry (CyTOF) at both timepoints.

Results
We observed that in the LNs, the numbers/percentages of naïve, central and effector memory T-helper cells, as well as, of CD8+ naïve T-cells were increased after treatment with etrasimod. There was a decrease in the proportion of these cell populations in peripheral blood. Circulating naïve and memory B-cells were reduced, while these subsets where also slightly reduced in the LN compartment. Innate immune cell populations were not significantly altered.

Conclusion
Etrasimod induction treatment resulted in an increase of both naïve and central memory T-lymphocyte subsets in inguinal LNs, with a corresponding decrease in the periphery. The effect on the frequency of B-cells was not consistent in the LNs and PB, while innate immunotypes and T-regs, were not significantly affected. Despite the limited sample size, these selective effects were consistent with previously published PB immunophenotyping studies with etrasimod.
This study was conducted as a collaboration between Amsterdam UMC and Pfizer.
P193 Fatigued patients with Inflammatory Bowel Disease exhibit distinct systemic antibody epitope repertoires
Authors: Griesbaum M G , Vogl T , Andreu-Sánchez S , Klompus S , Kalka I N , Leviatan S , van Dullemen H M , Visschedijk M C , Festen E A M , Faber K N , Dijkstra G , Weinberger A , Segal E , Weersma R K , Bourgonje A R 
Published: January 2024

Abstract

Background
Patients with inflammatory bowel diseases (IBD) frequently experience fatigue, affecting up to 80% of those with active disease and approximately 50% with quiescent disease. The exact cause of IBD-associated fatigue is often unknown, making clinical management very challenging. In this study we aimed to explore whether patients with quiescent IBD reporting fatigue exhibit specific systemic antibody responses, which could provide insight into immune reactivities underlying fatigue.

Methods
Systemic antibody epitope repertoires were profiled in 327 patients with IBD (156 Crohn’s disease [CD]; 171 ulcerative colitis [UC]) leveraging phage-display immunoprecipitation sequencing (PhIP-Seq) against 344,000 rationally selected peptide antigens. Fatigue severity was assessed on a 10-point Likert scale, ranging from 1 (no fatigue) to 10 (highest fatigue severity). Quiescent IBD was defined as clinical (Harvey-Bradshaw Index [HBI] &lt;5 or Simple Clinical Colitis Activity Index [SCCAI] &lt;2.5) and biochemical remission (C-reactive protein [CRP] &lt;5 mg/L) at time of sampling. Multivariable logistic regression analyses, allowing adjustment for potential confounding factors e.g. age, sex, and smoking, were performed to identify associations between fatigue and systemic antibody responses.

Results
A total of 105 different antibody-bound peptides were associated with fatigue (nominal P-value&lt;0.05), albeit none passed adjustment for multiple comparisons. Among these antibodies, 50 (47.6%) were found to be less frequent in highly fatigued patients (fourth quartile, Q4), while 55 (52.4%) were identified as more frequent in highly fatigued patients compared to those with low fatigue scores (first quartile, Q1). Among highly fatigued patients, antibody responses were primarily directed towards viral antigens, notably several antigens from Epstein-Barr virus (EBV), as well as bacterial antigens, including functional proteins from Streptococcus and Staphylococcus species. Fatigued patients with CD exhibited elevated systemic antibody responses against allergens, Staphylococcus, Pseudomonas aeruginosa, and Shigella spp. Fatigued patients with UC showed higher frequencies of antibody responses against herpes simplex virus (HSV), influenza viruses, and few responses against allergens and Streptococcus bacteria. These results remained materially unchanged when repeating analyses in patients with quiescent IBD.

Conclusion
This study may suggest a potential role of viral antigens, particularly EBV, in the pathophysiology of fatigue in patients with IBD. However, larger confirmatory studies are needed to validate these findings. PhIP-Seq may represent a valuable strategy to approach the investigation of immune responses underlying complex symptoms such as fatigue.
P280 Comparative responsiveness of disease activity indices in moderately-to-severely active Ulcerative Colitis: a post-hoc analysis of the UNIFI trial
Authors: Solitano V , Panaccione R , Sands B E , Wang Z , Zou G , Peyrin-Biroulet L , Danese S , Cornfield L J , Feagan B G , Singh S , Jairath V , Ma C 
Published: January 2024

Abstract

Background
Clinical, endoscopic, histological, and composite instruments are used to measure disease activity in ulcerative colitis (UC). We compared responsiveness of the Mayo Clinic Score (MCS), modified Mayo Clinic Score (mMS), partial Mayo Clinic Score (pMS), Robarts Histopathology Index (RHI), and UC-100 score after treatment with ustekinumab in patients with moderately-to-severely active UC.

Methods
Publicly available data from the phase 3 UNIFI induction trial (NCT02407236) comparing the efficacy and safety of ustekinumab versus placebo in patients with moderate-to-severe UC were obtained from Vivli (Vivli ID #7549) and Yale University Open Data Access Project (#2021-4848). Post-hoc analyses were performed on patient level data to ascertain outcomes of interest. Treatment assignment was the criterion for change in evaluation of responsiveness, which was quantified using the probability of a treated patient having a larger change than a placebo patient (win probability [WinP]) and estimated using nonparametric methods. Extent of responsiveness was interpreted according to Cohen’s benchmarks as very small (WinP&lt;0.56); small (0.56≤ WinP&lt;0.64); medium (0.64≤ WinP&lt;0.71); and large (WinP≥0.71).

Results
Data from 961 patients with moderately-to-severely active UC randomised in UNIFI were included. At baseline, 319 patients received placebo and 624 patients received ustekinumab. A total of 912 (94.9%) patients completed the induction trial. Overall mean baseline index scores were: MCS 8.9 (±1.6), mMS 6.6 (±1.3), pMS 6.2 (±1.4), RHI 16.6 (±8.1), and UC-100 score 71.4 (±16.5) (Table). The UC-100 demonstrated a large degree of responsiveness (WinP 0.72 [95% CI: 0.66, 0.78]). The MCS (0.68 [0.62, 0.73]), mMS (0.69 [0.63, 0.75]), and pMS (0.65 [0.59, 0.71]) demonstrated similar, medium effect sizes (all comparisons p&gt;0.05) (Figure). The RHI alone had a relatively small effect size (WinP 0.63 [0.56-0.70]). Among individual UC-100 components (Mayo Clinic stool frequency subscore, Mayo Clinic endoscopic subscore, and RHI), the endoscopic score was most responsive (WinP 0.59 [0.36-0.82]). The combination of endoscopy and RHI was associated with a medium degree of responsiveness (WinP 0.69 ([0.34, 1.00]).

Conclusion
UC disease activity indices are similarly responsive to change. Depending on trial design and measurement feasibility, different instruments can be considered optimal for evaluation of efficacy. The mMS is similarly responsive to the MCS without including the physician global assessment and may be more appropriate for determining trial eligibility and defining primary endpoint, whereas the UC-100 may be more appropriate for measuring treatment effect when an objective continuous measure is needed.
P346 Assessing Brain Morphology in Functional Gastrointestinal and Inflammatory Bowel Disorders Using Functional Magnetic Resonance Imaging (fMRI)
Authors: Piotrowicz G , Skrobisz K , Naumczyk P , Markiet K , Sabisz A , Rydzewska G , Szurowska E 
Published: January 2024

Abstract

Background
Functional gastrointestinal disorders (FGIDs) and non-specific inflammatory bowel diseases (IBD) are increasingly common in young adults. Studies have shown abnormal interhemispheric interactions in FGIDs and altered Default Mode Network (DMN) connectivity in brain regions linked to gastric sensations and emotional regulation. This study explores these neural mechanisms in FGIDs and IBDs, focusing on chronic visceral pain and its association with DMN reorganization.

Methods
The study included patients with functional dyspepsia (FD), N=18; irritable bowel syndrome (IBS), N=20 and IBD, N=18 alongside a control group of 18 healthy volunteers. Selection criteria included the Rome III Criteria for FGIDs and various diagnostic tests for IBDs. MRI scans were conducted using a 3T Achieva TX Scanner, applying standard T1 and T2 sequences without contrast agents. Functional imaging utilized T2 Gradient Echo-Planar Imaging.

Results
DMN analysis showed no anterior-posterior split. Significant differences were observed in the IBD group compared to controls, particularly in the left superior frontal gyrus. When comparing all patient groups with controls, increased DMN connectivity was noted in the left cingulum and supplementary motor area. These areas were also significant when comparing only FGIDs patients with controls, indicating altered DMN connectivity in these disorders. Please see: Figure 1 and Table 1.

Conclusion
The study highlights differences in DMNs between patient and control groups, especially in the left superior frontal gyrus, left cingulum, and left supplementary motor area. All disease groups showed variations from controls in the DMN pattern within the left cingulum. Significant differences in the DMN of the supplementary motor area were observed in functional gastric disease groups compared to controls. These findings suggest a link between brain areas involved in sensorimotor processes and symptoms of FD and IBS, providing insights into the neural basis of these conditions. Despite varied changes, common features differentiating the entire study group from healthy controls were identified. This condensed version focuses on the key aspects of your original text, ensuring that the main findings and methodology are clearly presented within the character limit.
P360 Prevalence and risk factors for fatigue in patients with inflammatory bowel disease and endoscopic healing
Authors: Yzet C , Brazier F , Meudjo E , Robert C , Moreau C , Derval E , Richard N , Fumery M 
Published: January 2024

Abstract

Background
Fatigue is a frequent symptom among patients with inflammatory bowel disease (IBD). While the recent STRIDE II international guidelines consider disability-free and normal quality of life as therapeutic targets, the degree of endoscopic healing required to limit fatigue is unknown. The aim of this study was to investigate the prevalence of fatigue and its determinants in a cohort of IBD patients with endoscopic healing.

Methods
We conducted a single-center cross-sectional study between January 2019 and June 2023. All consecutive IBD patients with endoscopic healing Crohn's disease (CD, CDEIS &lt;4) and ulcerative colitis (UC, Mayo ≤ 1) were assessed for disability (IBD-disk) the day of the colonoscopy. Fatigue and severe fatigue were defined by an IBD-Disk energy subscore &gt;5 and &gt;7, respectively.

Results
166 patients were included, of whom 64% (107/166) had CD. The majority of patients were treated with anti-TNF (91/166, 55%), half of them in combination therapy (44/166). The prevalence of fatigue and severe fatigue were 39% (65/166) and 23.5% (39/166) respectively, with no significant difference between CD and UC (p=0.59). The prevalence of fatigue in patient with partial endoscopic healing (Mayo 1 and CDEIS&gt;0 and &lt;4)) and with complete healing (Mayo 0, CDEIS 0) was 44.4% (24/54) and 36.6% (41/112) p =0.424.In multivariate analysis, factors associated with fatigue were female gender (OR=4.2, [1.1; 16.5], p= 0.040), presence of joint pain (OR=4.36, [1.0; 18.2], p= 0.04), sleep disturbance (OR =26.2, [5.5; 124.4], p &lt;0.0001). Younger age (OR=0.95, [0.9; 0.99], p= 0.023) was associated with a significantly lower risk of fatigue. In multivariate analysis, severe fatigue was associated with female gender (OR=3.2, [1.1; 9.2], p= 0.026), the presence of joint pain (OR=2.9, [1.1; 8.1], p= 0.037) or sleep disorders (OR =11.3, [3.6; 35.9], p &lt;0.0001).

Conclusion
One third of IBD patients with endoscopic healing suffer from fatigue. Female gender, arthralgia and especially sleep disorders are risk factors for fatigue. These results argue in favor of a holistic management of IBD patients.