bluuebunny/crossref_metadata_2025_split huggingface dataset:
P376 Efficacy of ozanimod in vedolizumab-exposed patients with ulcerative colitis: a phase 3 True North post hoc analysis
Authors: Sands B E , Jain A , Ahmad H A , Osterman M , Memaj A , Canavan J B , Axelrad J E 
Published: January 2023

Abstract

Background
Ozanimod (OZA), an oral sphingosine 1-phosphate receptor modulator that prevents lymphocyte migration to inflamed tissues, is approved for the treatment of patients with moderate to severe ulcerative colitis (UC) in the European Union and United States. The phase 3 True North (TN) randomised trial showed that OZA was effective and well tolerated in these patients. OZA efficacy in patients who have been exposed to vedolizumab (VDZ-exp), an integrin receptor antagonist that interferes with lymphocyte trafficking to the gut, has not yet been described. This post hoc analysis of TN examined OZA efficacy in VDZ-exp patients.

Methods
In TN, patients were randomised to oral once-daily OZA 0.92 mg (equivalent to OZA HCl 1 mg) or placebo (PBO; Cohort 1) or to open-label OZA (Cohort 2) during the induction period (IP). Patients with a clinical response to OZA at Week 10 were rerandomised to OZA or PBO in the maintenance period (MP). Efficacy at Week 10 (IP) and Week 52 (MP) in the VDZ-exp subgroup was calculated. Differences in proportions between OZA and PBO at Week 10 were based on the Cochran-Mantel-Haenszel (CMH) test, stratified by corticosteroid use at screening and prior anti-tumor necrosis factor (anti-TNF) use. Differences between OZA/OZA and OZA/PBO at Week 52 were based on the CMH test stratified by both remission status and corticosteroid use at Week 10.

Results
TN included a total of 185 VDZ-exp patients (Cohort 1: PBO, n=35; OZA, n=63; and Cohort 2: OZA, n=87). Baseline demographics and clinical characteristics were balanced across treatment groups. In the VDZ-exp subgroup, 52% of patients had extensive disease at baseline, 78% had a Mayo endoscopic score of 3, 85% were previously exposed to anti-TNF, and 61% were receiving corticosteroid at baseline. At Week 10, OZA (Cohort 1) was numerically more effective vs PBO for all endpoints in VDZ-exp pts (Figure 1A). Notably, in the subgroup of patients previously exposed to VDZ as a first-line advanced therapy, clinical response at Week 10 was achieved in 50% (6/12) of OZA pts in Cohort 1 and 42% (5/12) of OZA patients in Cohort 2. At Week 52, a higher proportion of VDZ-exp patients on continuous OZA achieved all efficacy endpoints vs the OZA/PBO group, with significant differences shown for most endpoints. OZA/OZA vs OZA/PBO differences at Week 52 were larger than OZA vs PBO differences at Week 10 (Figure 1B).

Conclusion
This post hoc analysis of the phase 3 TN study found that OZA was effective in UC patients who previously failed VDZ, including those who failed VDZ alone or following other advanced therapies. Future studies evaluating OZA in VDZ-exp patients are warranted.
P377 Changes over time in the Lémann Index and the Inflammatory Bowel Disease-Disability Index in patients with Crohn’s disease
Authors: Wils P , Cartier L , Azahaf M , Hambli S , Branche J , Gérard R , Desreumaux P , Louvet A , Nachury M 
Published: January 2023

Abstract

Background
Crohn’s disease (CD) is a progressive, transmural disorder that leads to intestinal damage (fistula, abscesses, stenosis) and worsens the patient’s quality of life. The Lémann Index (LI, assessing cumulative bowel damage in CD) and the Inflammatory Bowel Disease-Disability Index (IBD-DI) have recently been validated. The objective of the present study was to assess changes over time in the LI and the IBD-DI and to identify factors associated with these changes.

Methods
In a cohort of 130 patients with CD being followed up prospectively at Lille University Hospital (Lille, France), the LI and the IBD-DI were evaluated first in 2016 (assessment #1, results previously published) and then again between September 2020 and October 2021 (assessment #2). Factors associated with the differences in the LI and IBD-DI were probed with a Mann-Whitney test or a bivariate analysis of variance. Survival curves for the progression of CD (surgery, drug-related events) were plotted according to the Kaplan-Meier method. Spearman’s coefficient was calculated as a guide to the strength of the correlation between the LI and the IBD-DI.

Results
101 patients were included. More than half of the included patients had a long-standing disease (&gt;15 years), 35% had ano-perineal involvement and 56% had a history of resection. Clinical activity was reported in 40% of patients at assessment#2. The median time interval between the two evaluations was 4.2 years. The LI (assessed in 61 patients) did not change significantly (median: 9.6 at #1 vs. 9.3 at #2; p = 0.14). The LI increased for 16 patients (26%), decreased for 26 (43%) and was stable for 19 (31%). Persistent clinical activity was the only factor significantly associated with worsening of the LI (p=0.01). A LI &gt;7.9 was not associated with CD progression. The IBD-DI score (assessed in 98 patients), decreased significantly over time (median: 23.2 at #1 vs. 21.4 at #2; p = 0.006). The IBD-DI decreased for 59 patients (60.2%), increased for 37 (37.8%) and was stable for two (2%). Factors associated with improvement in the IBD-DI were younger age at diagnosis, a longer time interval before initiation of the first biologic, drug optimization, and exposure to combination therapy. There was no correlation between LI and the IBD-DI (r 0.125, p=0.27).

Conclusion
This is the first cohort study assessing changes over time in both the LI and the IBD-DI in CD patients. After more than 4 years of follow-up, the LI appeared to be stable and the IBD-DI decreased, without correlation between the indices. Persistent clinical activity was associated with worsening LI reinforcing the interest in monitoring these patients.
P381 Ustekinumab trough levels are associated with sonographic transmural healing in Pediatric Inflammatory Bowel Disease
Authors: Kellar A , Aronskyy I , Dubinsky M C , Dolinger M T 
Published: January 2023

Abstract

Background
Transmural healing (TH) assessed by intestinal ultrasound (IUS) is associated with improved inflammatory bowel disease (IBD) outcomes. This study evaluates the relationship between ustekinumab trough levels (UTL) and sonographic TH in children with IBD treated with ustekinumab (UST).

Methods
Children (&lt;18 years) with IBD treated with maintenance UST and undergoing IUS examination and serum UTL (Prometheus Labs, CA) at a single tertiary center between July 2020 and October 2022 were prospectively recruited. Children who underwent IUS and UTL on 2 events &gt;6 months apart were included in a per-event analysis. Primary outcome was the comparison of UTL between children with and without TH, defined as bowel wall thickness (BWT) ≤3 mm and no hyperemia (BWH) on color Doppler, using the Mann-Whitney U test. Area under the receiver operating curve (AUROC) determined the optimal UTL cut-point to detect TH. Secondary outcome was the comparison of UTL for each IUS parameter. Descriptive statistics summarized the data as frequencies and percentages for categorical variables and median [interquartile range] for continuous variables. A p-value of significance was set to &lt;0.05.

Results
Overall, 50 IUS exams on 129 bowel segments were performed in 44 children with IBD, 34:10 Crohn’s disease (CD):ulcerative colitis (UC)/IBD-U treated with UST, median [IQR] age 14.9[13.2-16.6] years, 22(50%) female, and disease duration 3.83[1.98-5.32] years (Table 1). 18(41%) children were treated with standard dose UST of 90mg every 8 weeks and had significantly lower UTL compared to 26(59%) treated with escalated dosing of 90 mg every 4 or 6 weeks (7.4[4.8-12.7] ug/ml vs. 11.6[6.1-19.3] ug/ml, p=0.002). Median time between UTL and IUS was 0 days [0-11.25]. Overall, 24(55%) children (18(53%) CD, 6(60%) UC/IBD-U) achieved TH. Higher UTL was associated with TH (13.1[6.1-17.5] ug/ml) compared to children without TH (5.7[4.2-13.9] ug/ml; p=0.010) (Figure 1A). Higher UTL was also associated with TH in children with CD (11.7[5.3-17.0] ug/ml) compared to children with CD without TH (5.5[4.2-11.0] ug/ml; p=0.013) (Figure 1B). Optimal UTL cut-point to detect TH was 11.4 ug/ml for all children (AUROC=0.647, sensitivity=62%, and specificity=69%) and children with CD (AUROC=0.661, sensitivity=59%, specificity=79%). Median UTL for all children was associated with lymphadenopathy (p=0.02) but no other individual IUS parameters (Table 2).

Conclusion
Higher maintenance UTL are associated with sonographic TH in children with IBD. Future prospective studies are needed to determine if targeting higher UTL levels during induction and maintenance UST therapy promotes TH.
P388 Shear wave elastography predicts short-term response to induction therapy in patients with Crohn’s disease
Authors: Sagami S , Morikubo H , Miyatani Y , Fukuda T , Asonuma K , Maeda M , Yoko Y , Karashima R , Hojo A , Nakano M , Hibi T , Kobayashi T 
Published: January 2023

Abstract

Background
Endoscopy has been used to assess the disease activity of Crohn's disease (CD) but may not be sufficient considering the transmural nature of its inflammation. Bowel ultrasonography (BUS) has been reported to reflect disease activity of CD and long-term outcomes. We performed a prospective study to determine whether BUS can predict short-term clinical response to induction therapy.

Methods
Consecutive CD patients with active ulcers in endoscopy requiring induction therapy (Anti-TNF antibody, IL-12/23 p40 antibody, integrin inhibitor, prednisolone) were prospectively enrolled at a single center from October 2018 to July 2022. Short-term clinical response was defined by a reduction of Crohn’s disease activity index &gt; 70 at week 8. Ultrasonographic findings (bowel wall thickness (BWT), colour Doppler signal (CDS), and shear wave elastography (SWE) were recorded for the most severely affected segment at baseline, week 1, and 8 and compared between responders and non-responders.

Results
Seventeen out of 29 patients were classified as responders at week 8. There was no difference in BWT and CDS at baseline, week 1, and 8 between responders and non-responders (Table 1). In contrast, responders had lower baseline SWE compared with non-responders (2.7±0.3 vs. 3.8±0.3, p=0.02). Adjusted by the prior exposure to biologics, the lower SWE at baseline was associated with clinical response at week 8 (adjusted odds ratio associated with 0.1 m/s increase: 0.9, p=0.018) (Table 2). SWE did not change over time regardless of response for 8 weeks.

Conclusion
Lower intestinal wall stiffness as measured by SWE is an independent predictor of short-term clinical response.
P390 Ustekinumab modulates IL-12 and IL-23-related cell type-specific inflammatory transcriptional states in Ulcerative Colitis induction therapy
Authors: Richards D , Venkat S , Freeman T C , Mcrae B , Hoops T , Marano C , Branigan P 
Published: January 2023

Abstract

Background
Ustekinumab (UST) is a monoclonal antibody specific for the p40 subunit of interleukin (IL)-12 and IL-23. In a randomised phase 3 trial (UNIFI; NCT02407236) in patients with moderate-to-severe ulcerative colitis (UC), UST was shown to be more effective for inducing and maintaining clinical remission than placebo. There has yet to be a mechanistic understanding of p40 blockade in inflammatory bowel disease. Here, we investigated the underlying molecular mechanism of action of UST in UC.

Methods
Paired colon biopsies for transcriptomic analysis were obtained at screening and week 8 in patients who received a single intravenous induction treatment of placebo (n=145 subjects), UST 130 mg (n=155 subjects), or a weight-range-based dose (approximated to UST 6 mg/kg of body weight; n=171 subjects). Tissue transcriptional profiles were determined using Affymetrix microarrays. Transcriptional changes were analysed in the context of cell type-specific co-expression modules derived from single cell UC data. Gene set variation analysis (GSVA) was used to quantitatively assess changes in specific biologic modules in the context of endoscopic and histologic-endoscopic mucosal improvement (HEMI) responder and non-responder analyses. Nichenet, which predicts ligand–target gene links, was used with single cell UC data to identify ligands that are predicted to be associated with our cell type-specific modules.

Results
By week 8, both UST treatment arms induced a greater magnitude of transcriptional changes associated with Th17, Th1 cytotoxicity, myeloid inflammatory, epithelial inflammatory, and inflammatory fibroblast modules compared with placebo. Ligand-target gene predictions indicate IL-12 and IL-23 are associated with changes in the Th1 cytotoxicity and Th17 module expression, respectively. Population level molecular changes in both UST treatment arms are consistent with endoscopic and HEMI response at week 8. When evaluating sub-groups stratified by endoscopic improvement or HEMI status, significant changes were observed in transcriptional modules in both UST responders and UST non-responders identifying mechanistic processes associated with dual blockade of IL-12 and IL-23 following exposure to UST. Placebo non-responders showed no significant changes.

Conclusion
Molecular analysis of colon biopsies from UC patients after UST induction revealed IL-12 and IL-23-related transcriptional changes associated with Th1 cytotoxicity and Th17 biology. By leveraging UC single cell derived transcriptional modules, we have identified key disease-relevant processes that significantly changed with UST treatment, regardless of response status and have extended the mechanistic understanding of p40 blockade in UC.
P394 Long-term perineal reoperation and wound healing after proctectomy or ileal pouch-anal anastomosis extirpation in patients with Inflammatory Bowel Disease – a retrospective multicentre study
Authors: Berghog J , Hermansson M , Risto A , Strömbäck J , Unger D , Gustafsson H , Hagavall M , Landerholm K , Buchwald P , Nordenvall C , Myrelid P , Block M ,   Swedish Organization for the study of IBD (SOIBD)
Published: January 2023

Abstract

Background
Patients with inflammatory bowel disease (IBD) may need to undergo proctectomy or ileal pouch-anal anastomosis (IPAA) extirpation with known short- and long-term perineal complications such as wound dehiscence, delayed healing, sinus formation and fistulas. This study aimed to examine perineal complications after proctectomy or IPAA extirpation.

Methods
This Swedish retrospective, multicentre study included IBD patients ≥18 years undergoing proctectomy or IPAA-extirpation between January 1st 2000 and December 31st 2019 at four hospitals. Medical records were reviewed and perineal wound healing was assessed at 3, 6, 12 and 24 months. Primary endpoint was need for perineal re-operation due to complications. Predefined factors associated with reoperation was assessed.

Results
Four hundred and fifty-one patients (257 males) were included in the study. After 3, 6, 12 and 24 months 70%, 75%, 80% and 88% had healed. Forty-nine (11%) patients underwent re-operation for perineal wound complication. Low age and short duration of IBD were significantly associated with the risk of reoperation (p&lt;0.001 and p=0.032). Crohn′s disease was more common (55%) in the group that underwent re-operation compared to 41% in the no-reoperation group but not statistically significant (p=0.06). Most patients that underwent re-operation demonstrated a wound complication or perineal wound secretion within 30 days of surgery; 90% vs 48% ;p&lt;0.001[KL1] and 80% vs 37%; p&lt;0.001 [KL2] respectively. Following re-operation, the perineal wound healed in 45% (22/49).

Conclusion
At long-term follow-up 88% had healed perineal wound and only 11% had required perineal reoperation. Wound complications and secretion within 30 days of surgery seem unfavourable and predict reoperation and incomplete perineal healing.
P400 Identifying Nutritional targets in Crohn’s disease: INTICO1: a time-limited trial of exclusive enteral nutrition during adult CD remission
Authors: McDonnell M , Westoby C , Sartain S , Giannasca P , Corthésy J , Grzywinski Y , Frézal A , Capt P , Cummings F , Wootton S 
Published: January 2023

Abstract

Background
During clinical remission in adult Crohn’s disease (CD), impaired health reacted quality of life and fatigue is common, and the nutritional state may be affected by factors such as restrictive eating and altered anatomy from previous inflammation or surgeries. Adults with CD in clinical remission do not routinely undergo nutritional assessments or intervention. The INTICO1 study used a time-limited trial of exclusive enteral nutrition (EEN) to expose and explore nutritionally sensitive aspects of in adults with CD during remission. The extent to which the nutritional state relates to the quality of CD remission and the potential role for nutritional therapies is neither well described nor understood.

Methods
This was a single arm longitudinal observation study with a dietary intervention. 24 adults in CD remission (Harvey Bradshaw &lt;5, faecal calprotectin &lt;250) underwent assessment of nutritional state at 3 time points; after habitual diet (assessment 1), after 7 days of polymeric EEN (assessment 2) and after a 2-week gradual return to habitual diet (assessment3). Assessments comprised food diary analysis, anthropometry, bio-electrical impedance analysis, routine pathology measures of micronutrient concentration, and patient reported outcome measures (PROMs).

Results
Assessment 1 (habitual diet) identified individuals with multiple inadequacies of intake (7% (26/368)) micronutrients bloods below the normal laboratory range (see table for analytes) reduced lean mass, low phase angle (PhA) and excessive fatigue (reduced SF-36 vitality). At assessment 2 (post EEN), subjects had fewer deficiencies 4% (16/368), with significant increases seen in Vitamins A, D, E, B2, B6, B9 and the minerals Ca, Cu, Po4 and Se. At visit 3 (return to free diet), micronutrient concentrations reverted toward assessment 1 level, although B6 and B9 remained significantly higher (pairwise comparison visit 1 vs visit 3). BIA measures of nutritional status (PhA) and the SF36 physical function score improved 1 and 2 (5.2 vs 5.4 p&lt;0.01 and 95 v100 p&lt;0.05) and returned to baseline levels on return to free diet (Assessment 3).

Conclusion
A time-limited trial (7 days) of EEN, given in this setting of adults in CD remission led to changes in micronutrient biochemistry, objective improvement in the bioelectrical properties of the body (increased phase angle) and an improvement in fatigue among the subjects as captured by the SF36-PF. The study suggests that impaired nutritional state and excessive fatigue is likely to be prevalent among adults with CD during remission and may be sensitive to nutritional intervention.
P402 A Pilot Study on the Effect of Colesevelam on the Microbiome in Primary Terminal Ileal Resected Crohn’s Disease
Authors: Kumar A , Quraishi M N , Al-Hassi H O , Elasrag M , Segal J P , Jain M , Steed H , Butterworth J , Farmer A , McLaughlin J , Beggs A , Brookes M 
Published: January 2023

Abstract

Background
Surgery plays a pivotal role in ileal Crohn’s disease despite the risk of endoscopic recurrence following an ileocaecal resection greater than 65% within 12 months of surgery. More than 90% of Crohn’s patients have a concomitant diagnosis of bile acid diarrhoea following an ileal resection. This pilot study aimed to assess whether the use of bile acid sequestrants in post-operative Crohn’s patients with bile acid diarrhoea can alter the microbiome and prevent disease recurrence.

Methods
Post-operative Crohn’s patients with symptoms of diarrhoea underwent 75SeHCAT testing for bile acid diarrhoea. If positive (75SeHCAT &lt; 15%), patients were treated with colesevelam and stool samples were collected at 4-weeks, 8-weeks and 6-12 months post-treatment. If negative (75SeHCAT &gt; 15%), treatment was not given and were reviewed in clinic as per local guidelines. Patients underwent a 6-12 months post-operative colonoscopy where mucosal biopsies were taken. Disease activity was established using the endoscopic Rutgeert’s score, with disease remission defined as Rutgeerts score &lt; i2 and disease recurrence ³ i2. Faecal and mucosal 16S ribosomal RNA gene analysis was undertaken to assess a/b-diversity and microbial composition.

Results
A total of 44 faecal samples and 44 mucosal biopsies were sequenced from 14 patients. 1/10 patients on colesevelam and 2/4 patients not on colesevelam demonstrated disease recurrence. There was no significant difference in a/b-diversity pre- and post-treatment. Pre-treatment, the three most abundant bacterial classes in all patients were Bacteroidia, Clostridia and Gammaproteobacteria (Figure 1). Following 6-12 months of treatment, out of the 9 patients on colesevelam, 5/9 (55.6%) had a reduction in Bacteroidia, 9/9 (100%) had an increase in Clostridia, and 7/9 (77.8%) had a reduction in Gammaproteobacteria. Of the two patients not given colesevelam, ½ (50%) showed a reduction in Bacteroidia, increase in Clostridia and a reduction in Gammaproteobacteria.

Conclusion
This small pilot study demonstrated that patients who were given colesevelam, a bile acid sequestrant, were more likely to be in disease remission at their 6-12 months colonoscopy review. Furthermore, treatment with colesevelam may have a role in altering the microbiome to help maintain remission states in post-operative Crohn’s disease. Larger mechanistic studies are now needed to confirm these findings and demonstrate statistical significance.