bluuebunny/crossref_metadata_2025_split huggingface dataset:
P696 Design and rationale for the multicentre, randomised, controlled VERDICT trial to determine the optimal treatment target in patients with ulcerative colitis
Authors: Jairath V , Zou G , Radulescu G , Sigler J , Mcfarlane S C , Adsul S , Freire M , Peyrin-Biroulet L , Colombel J F , Moran G W , Sebastian S , Travis S , Vermeire S , Sandborn W J , D’Haens G R , Feagan B G 
Published: January 2023

Abstract

Background
Symptoms, endoscopy, histology, and biomarkers are used to evaluate disease activity and response to therapy in ulcerative colitis (UC). Histologic disease activity may persist in ~25% of patients with normal-appearing endoscopic mucosa, and observational studies demonstrate an association between the achievement of histologic remission (vs endoscopic remission alone) and a lower risk of complications. These findings suggest that histologic remission may be a distinct treatment target. The aim of the VERDICT trial is to determine the optimal treatment target in UC to inform clinical practice and future drug development.

Methods
The primary objective of the multicentre, randomised, controlled VERDICT trial (Figure 1) is to determine whether a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone in moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score &lt;2B.0) + endoscopic remission + symptomatic remission (Group 3). Therapy is administered according to a treatment algorithm that is dependent on each patient’s existing UC treatment regimen at study entry (Figures 2-4). Early introduction of vedolizumab and dose escalation to a maximum of 300 mg every 4 weeks until the assigned treatment target is reached are central to each algorithm. There are 3 opportunities, 16 weeks apart (weeks 16, 32, or 48), to achieve the treatment target. Urine, stool, mucosa, and serum samples are collected at these follow-up time points and at baseline for subsequent biomarker and prediction model development.

Results
The primary efficacy outcome is the time from treatment target achievement to a UC-related complication, defined as a UC-related hospitalisation, colectomy, need for rescue therapy, or treatment-related or other complication. This composite outcome will be compared among treatment target Groups 1 and 3 using the Cox proportional hazard model analysis. The trial was initiated in September 2020, and 660 patients are planned for enrolment. Of these, ~50% are currently enrolled at 55 sites across 10 North American and European countries. Prespecified interim analyses will be conducted when the first 50 patients in each group reach weeks 16, 32, and 48.

Conclusion
The VERDICT trial in active UC is designed to determine the optimal treatment target to inform clinical practice, drug trials, and future evidence-based recommendations.
P704 The effect of antiTNFα and anti-integrin agents on liver steatosis in inlamatory bowel disease patients with non-alcoholic fatty liver disease
Authors: Mitrovic M , Marković S , Kalaba A , Zarić D , Kralj Đ , Milić A , Svorcan P 
Published: January 2023

Abstract

Background
Non-alcoholic fatty liver disease (NAFLD) has been recognized as a common condition in inflammatory bowel disease (IBD) patients and could contribute to their overall morbidity. Anti-TNFα and anti-integrin agents have been the cornerstones of IBD therapy with proven clinical efficacy, but it΄s effect on liver steatosis is still unclear. Therefore this study aimed to evaluate the impact of anti-TNFα and anti-integrin agents on liver steatosis in IBD patients with proven NAFLD.

Methods
A total of 32 IBD patients with NAFLD, naive to biologic agents, 21 with an established diagnosis of ulcerative colitis, and 11 with Crohn’s disease were prospectively recruited for the study. NAFLD was defined by a baseline attenuation (ATT) coefficient measured by shear-wave (SW) elastometry of 0.63 dB/cm/MHz or higher and a baseline alanine aminotransferase (ALT) of more than 40 IU/L for males and 35 IU/L for females. The exclusion criteria were alcohol use (consuming &gt; 40 g alcohol/day for men and &gt; 20 g/day for women in the preceding 12 months), concomitant chronic viral hepatitis, the presence of hepatic carcinoma, biliary disease, drug use, and hypothyroidism. A total of 11 patients were treated with Adalimumab, 9 patients with Infliximab, and 12 patients with Vedolizumab. The SW elastometry and laboratory exams were performed at the moment of therapy induction and after the 6-month course of therapy.

Results
The anti-TNFα treatment significantly reduced liver steatosis according to the ATT coefficient dynamic (0.70±0.07 vs 0.66±0.03 dB/cm/MHz, p=0.021) and ALT level dynamic came on the verge of statistical significance (44±7 vs 40±6 IU/L, p=0.058). We did not observe a significant difference between the Infliximab- and Adalimumab-treated patients. The anti-integrin agent, Vedolizumab, had no impact on liver steatosis (0.66±0.03 vs 0.67±0.04 dB/cm/MHz) and ALT level dynamic (47±4 vs 45±5, p=0.29). Both groups of agents had no impact on patients’ lipid profile dynamic. We found no correlation between liver steatosis level and CRP and fecal calprotectin dynamic.

Conclusion
In the short term, we observed potential beneficial effects of anti-TNFα agents on liver steatosis of IBD patients with proven NAFLD.
P722 Symptom-based disease trajectories Identify a population of early super-responders in ulcerative colitis achieving complete disease control under targeted therapy
Authors: Tran F , Brard R , Flechsenhar K , Aden K , Rosenstiel P , Agueusop I , Schreiber S 
Published: January 2023

Abstract

Background
Clinical trials with advanced therapies typically document the efficacy of induction and maintenance therapies as landmark endpoints. In ulcerative colitis (UC), independent assessments of clinical remission, endoscopic improvement, inflammatory biomarker, and histologic response are used, while little is known about the individual patient benefit. Disease control (DC) as a composite of symptomatic, biochemical, and morphologic remission becomes important to achieve for patients. By analysing their symptom trajectories towards the new outcome DC, distinct subpopulations of the seemingly uniform therapy response phenotype in UC can be identified. In a prospective cohort, we investigate UC patients using symptoms (i.e., partial Mayo Clinical Score (PCMS)) to detect different trajectories that may lead to DC.

Methods
231 UC patients from Kiel Campus of University Hospital Schleswig-Holstein receiving first time induction and maintenance therapy with anti-TNF, anti-IL-12/23, anti-Integrin or JAK inhibitors (JAKi) between 2010-2022 were enrolled. Patients were assigned by clinical choice to their therapy and received standard care: Symptoms were assessed by PCMS with laboratory investigations at each visit (every 4-12 weeks) and endoscopies (at week 0, 14, 52) were evaluated using Mayo endoscopic score (eMayo) and histology assessment with Nancy index (NI). We defined DC at week 52 (DC52) as the combination of eMayo =0, NI =0-1, PMCS =0-1, C-reactive protein &lt;5 mg/l and leucocyte counts 2.5-12/nl. We performed ANOVA and unpaired Wilcoxon tests at each timepoint as well as ROC analyses to identify thresholds discriminating different trajectories.

Results
24.2% (56) of patients achieved DC52, while 25.6% (59) reached week 52 without DC and 50.2% (116) changed therapy within 52 weeks due to inefficacy. We identified an early separation of PMCS trajectories between DC52 (2.07, ±0.27SEM) vs. non-DC52 (3.49, ±0.27SEM) already 6 weeks after induction (p &lt;0.001; Figure 1&2). At week 6, PMCS ≤2 (41.76% vs. 14.06%; sensitivity 0.47, specificity 0.76) and PMCS change from baseline &gt;3 (40.24% vs. 16.92%; sensitivity 0.79, specificity 0.60) were associated with higher rates of DC52 vs. non-DC52. Linking DC52 with prospective outcomes, we observed higher rates of clinical remission (75.00% vs. 27.12%) and DC at week 104 (57.14% vs. 20.34%) in DC52 vs. non-DC52.

Conclusion
In this real-world cohort, DC52 was characterized by early drop of PMCS and a higher likelihood of DC until week 104. While our results await replication, the observation of discrete super-response trajectories leading to DC could give rise to algorithmic trials investigating early change of therapy for patients not joining an ideal trajectory as early as week 6.
P736 Factors associated with partial Mayo Clinic Score over time in patients with Ulcerative Colitis treated with filgotinib in the phase 2b/3 SELECTION trial
Authors: Peyrin-Biroulet L , Louis E , Hisamatsu T , Jamoul C , Santermans E , Harris K , de Haas A , Oortwijn A , Feagan B 
Published: January 2023

Abstract

Background
Responses to ulcerative colitis (UC) treatments vary considerably between individuals, and factors associated with a stable response are not well defined. Filgotinib (FIL) is an oral, Janus kinase 1 preferential inhibitor approved in the EU and the UK as a UC therapy. We aimed to identify factors associated with partial Mayo Clinic Score (pMCS) over time in FIL-treated patients with UC in the phase 2b/3 SELECTION trial (NCT02914522).

Methods
In SELECTION, adults with moderately to severely active UC received FIL 200 mg (FIL200), FIL 100 mg (FIL100) or placebo once daily for 11 weeks in Induction (IND) Study A (biologic-naive) or B (biologic-experienced).1 Patients in clinical remission or with a Mayo Clinic Score (MCS) response at week 10 could enter the 47-week Maintenance (MNT) Study. To evaluate factors associated with pMCS during MNT this post hoc analysis used a mixed model for repeated measures (MMRM), which included fixed effects of time, IND dose (FIL200 or FIL100), the factor of interest and pMCS at IND baseline, and correlated patient residual errors. For categorical factors, the least-squares mean difference with 95% confidence interval (CI) and the overall type III p value were calculated. For continuous factors, the difference in pMCS for a one-unit change in the factor of interest was estimated with 95% CI. Multiplicity adjustment of p values was not performed.

Results
Data from 371 patients treated with FIL200 (n=199) or FIL100 (n=172) were included. Previous use of at least one biologic therapy or a tumour necrosis factor antagonist/vedolizumab, and week 10 MCS subscores of ≤1 were associated with higher pMCS over time than their respective reference categories (p&lt;0.0001; Table 1). Over time, pMCS was 0.45 units higher in patients assigned to IND Study A versus IND Study B (p=0.0002). Week 10 endoscopic score ≤1, Geboes histologic remission and Inflammatory Bowel Disease Questionnaire total score &gt;170 were associated with lower pMCS over time than their respective reference categories (p≤0.0001). Change from baseline in pMCS at week 10 and faecal calprotectin levels at week 10 were positively associated with pMCS over time (p&lt;0.0001; Table 2). Patient-reported outcome (PRO) measures at week 10 were negatively associated with pMCS over time (p≤0.0001).

Conclusion
History of previous biologic therapy, and week 10 assessments (endoscopic, clinical, biomarker and PRO) were among the factors influencing pMCS over the course of 1 year of FIL treatment, consistent with previous findings from trajectory modeling.2 Further MMRM analyses may help to identify patients who benefit most from FIL treatment.
1. Feagan BG et al. Lancet 2021;397:2372–84.
2. Schreiber S et al. MP443 [abstract]. UEGJ 2022;10:459.
P741 Do gastroenterology services need published standards for provision of antenatal care in patients with Inflammatory Bowel Disease? A local evaluation of UK practice
Authors: Tolan M , Nartey J , Dattoo M , King D , de Silva S 
Published: January 2023

Abstract

Background
Inflammatory bowel disease (IBD) is common with 0.5-1% of the UK living with the disease. Poor disease control can result in adverse pregnancy outcomes including low birth weight and preterm labour. It is essential that pregnant patients with IBD receive care from physicians experienced in management of antenatal IBD. Furthermore patients must be equipped with the knowledge to make decisions on their care and the care of their new-born. Audit standards by Selinger et al 20201 for the British Society of Gastroenterology (endorsed by the British Maternal and Fetal Medicine Society) have been published for UK practice but local service standards are unknown.

Methods
Pregnant patients with Crohn’s disease (CD) and Ulcerative Colitis (UC) between 2017-2020 were identified with ICD-10 and OPSC-4 codes for a hospital with 650 inpatient beds and a catchment area of 450,000 with around 4,600 births per annum. The service was assessed against a 90% compliance standard for documentation of: a decision on biological therapy during pregnancy; discussion on mode of delivery (MoD); antenatal live vaccine counselling; and breast-feeding advice.

Results
48 eligible patients were identified. Mean birth weight and delivery date were in line with the national average with no preterm births. 41 of 48 patients (85%) were in remission at the time of conception. 9 of 25 CD pregnancies were on biologics at conception and 7 of 9 (78%) discontinued this by 24-weeks gestation; one continued vedolizumab to 30-weeks and received antenatal vaccine counselling; one continued ustekinumab to 34-weeks. 4 out of 23 UC pregnancies were on biologics at conception; all ceased biologics by 24-weeks and vaccine counselling was not indicated. Only one published standard was achieved, with decision on biologics in pregnancy discussed in 100% (13/13). 3 standards were not met; MoD discussion (23%, 11/48); antenatal vaccine counselling (50%, 1/2); and breast-feeding advice (4%, 2/48).

Conclusion
Our service did not meet new standards for antenatal IBD care, demonstrating a need for improvement. We recommend that all IBD teams understand the expected service standards, perform a baseline service evaluation and develop clear patient pathways and departmental guidelines to identify pregnant patients with IBD. Clear patient information and close collaboration between obstetricians and gastroenterologists is essential to optimise the outcome for mother and baby.
1) Selinger C et al Standards for the provision of antenatal care for patients with inflammatory bowel disease: guidance endorsed by the British Society of Gastroenterology and the British Maternal and Fetal Medicine Society. Frontline Gastroenterology 2021;12:182-187 BMJ 2020
P742 Real-world evidence comparison on the effectiveness of ustekinumab vs anti-TNF or vedolizumab in ulcerative colitis: induction phase results from the prospective, observational RUN-UC study
Authors: Bokemeyer B , Plachta-Danielzek S , Howaldt S , Mohl W , Efken P , Ehehalt R , Kahl M , Krause T , Trentmann L , Lügering A , Schnoy E , Jochum C , Fajardo Salmon S , Hartmann P , Gilman E , Schreiber S 
Published: January 2023

Abstract

Background
Observational real-world evidence (RWE) studies on the effectiveness and safety of ustekinumab (UST) in ulcerative colitis (UC) are required in addition to RCTs, which are usually confined to selected patients and thus may not represent distinct treatment patterns and everyday clinical practice. For this reason, the prospective, controlled, propensity score (PS)-adjusted RUN-UC study was conducted in UC patients starting a newly initiated biologics therapy with a follow-up period of 3 years. The aim of the present analysis was to investigate the induction phase effectiveness of UST vs anti-TNF vs vedolizumab (VEDO) in UC in terms of clinical and steroid-free remission.

Methods
Between 2020-2022, 507 UC patients starting a new therapy with UST or other biologics were enrolled in 34 IBD-experienced centres across Germany. After exclusion of small molecules and missing outcomes, the final sample consisted of 317 patients. Response modified (reduction of partial Mayo score (pMayo) by ≥ 3 points from baseline to week-16 and a reduction of at least 30% or reaching remission at week-16), clinical remission (pMayo ≤ 1 plus a bleeding subscore=0), and steroid-free remission (pMayo ≤ 1, bleeding subscore=0 and no systemic use of steroids or oral budesonide during the last 8 weeks) were considered as outcomes. To reduce the effect of confounders, PS adjustment with inverse probability of treatment weighting (IPTW) was implemented. A weighted logistic regression was used, and the results were reported as odds ratio (OR) and 95% confidence interval (CI). Health-related quality of life was assessed by using the self-reported visual analogue scale (EQ-VAS) of the EQ-5D. Changes in EQ-VAS from baseline to week-16 were assessed with a linear model.

Results
101 UST (bio-naïve: 6), 106 anti-TNF (ADA: 24.5%, IFX: 65.1%, GOL: 10.4%) (bio-naïve: 70) and 110 VEDO (bio-naïve: 73) UC-patients were included. PS adjustment removed systematic differences between the three groups (UST/anti-TNF/VEDO: 44.9/43.8/48.1% males, 6.7/9.9/5.5% smokers, 7.9/12.5/9.3% EIM). The effectiveness of UST in terms of response, clinical and steroid-free remission was comparable to that of anti-TNF and VEDO at week 16 (Tab. 1). We observed a significant increase in EQ-VAS within all three groups (Tab. 2). The increase in the UST group was significantly higher than in the VEDO group and numerically higher than in the anti-TNF group.

Conclusion
In this prospective RUN-UC study, with propensity score weighted groups, UST showed similar induction phase effectiveness in comparison with anti-TNF and VEDO. Quality of life was significantly improved in the UST group vs VEDO and was numerically higher than anti-TNF after the induction phase.
P746 Identification of Altered Microbial Genera at Baseline in Adalimumab Clinical Remitters and an Absence of Change in Total Microbial Composition Post Induction Treatment in the SERENE UC Study
Authors: Morsy Y , Pivorunas V , Leitner C , Birchler T , Guay H , Scharl M 
Published: January 2023

Abstract

Background
The gut microbiome plays an integral role in the pathogenesis of Inflammatory Bowel Disease (IBD). However, there have been a limited number of studies investigating the composition of the gut microbiome in anti-TNF-treated Ulcerative Colitis (UC) patients. The aims of this study were to 1) identify novel microbial baseline predictors of clinical response and remission to Adalimumab treatment, and 2) assess the impact of Adalimumab induction treatment on the gut microbiome of UC patients.

Methods
The SERENE UC study (NCT02065622) compared the efficacy of higher adalimumab dosing regimens to the standard regimen in patients with moderately to severely active UC. 16S rRNA gene sequencing was performed on 204 stool samples from 107 UC patients at baseline and Week 8. An ANOVA test followed by Tukey HSD was used to compare microbial content within (baseline) or across (baseline vs Week 8) visits between clinical remitters (n=16), clinical responders (n=38), and patients who failed to respond to Adalimumab treatment (n=53). Clinical response was defined as a full Mayo score decrease of ≥3 points and ≥30% from baseline, plus ≥1-point decrease in rectal bleeding score or absolute bleeding score ≤1 at Week 8. Clinical remission was defined as a full Mayo score ≤2 with no sub-score &gt;1 at Week 8.

Results
There were no differences in alpha diversity in terms of richness and evenness when comparing samples from patients across response categories, or alpha and beta diversity when comparing paired samples from patients pre- and post-treatment. In addition, principal coordinate analysis of the microbiome did not highlight any clustering of the samples between response groups or visits. When stratifying patients by clinical response status at Week 8, we identified 4 genera that were significantly altered at baseline in the clinical remitters compared to the clinical responders and/or non-responders, including Dorea, Ruminococcus torques group, Subdoligranulum, and Collinsella. Unexpectedly, when comparing paired pre- and post-treatment samples within a response group, we failed to detect any significant changes on the total microbiome composition regardless of response status at Week 8.

Conclusion
These findings suggest that baseline microbial composition is significantly altered in UC patients who achieve clinical remission, but that Adalimumab treatment does not significantly alter the composition of the gut microbiome after 8 weeks of treatment. Future work is focused on achieving a deeper understanding of the gut landscape in UC patients treated with Adalimumab through 1) investigation of bacterial, viral, and fungal composition by metagenomics, and 2) integration of serum metabolomics data.
P752 Predictors of time to relapse upon ozanimod withdrawal in patients with moderately to severely active ulcerative colitis
Authors: Vermeire S , Abraham B , Bressler B , Reinisch W , Axelrad J E , Jain A , Memaj A , Akukwe L , Liu W J , Osterman M T , Canavan J B , Sands B E 
Published: January 2023

Abstract

Background
Ozanimod (OZA) is approved in the EU, US, and other countries for the treatment of moderately to severely active ulcerative colitis (UC) in adults based on the phase 3 True North (TN) trial. Data on time to disease relapse in patients (pts) who withdrew OZA treatment in TN were previously reported (Sands BE et al. Am J Gastroenterol. 2022;17(suppl):S506-7). The objective of this post hoc analysis was to identify predictive and prognostic variables of time to disease relapse in the TN maintenance period (MP).

Methods
Pts in TN were randomised to once-daily oral OZA 0.92 mg or placebo (PBO) in a double-blind manner or to open-label OZA for a 10-week induction period. Those with clinical response to OZA at Week 10 were then rerandomised to continue OZA (OZA/OZA) or switch to PBO (OZA/PBO) in the MP. Disease relapse was defined as an increase in partial Mayo score of ≥2 points from Week 10, absolute partial Mayo score ≥4, Mayo endoscopy subscore (MES) ≥2, and exclusion of other causes of increased disease activity unrelated to UC. Time to disease relapse was estimated using the Kaplan-Meier method in both MP groups. The saturated Cox proportional-hazards model for assessing predictors of time to disease relapse included demographics, disease characteristics, prior medications, and laboratory and efficacy variables at the end of the induction period. Insignificant terms at α=0.05 were removed via backward elimination.

Results
The OZA/OZA arm (n=230) had a slightly higher proportion of pts with baseline severe endoscopic disease than the OZA/PBO arm (n=227). Otherwise, baseline and Week 10 characteristics were balanced across MP arms (Tables 1 and 2). In multivariable analyses, corticosteroid use at Week 10 was prognostic for time to relapse (P&lt;0.0001; no interaction with individual treatment arms). MES &gt;1 and clinical response but not remission at Week 10 were also assessed as prognostic variables, but these did not achieve statistical significance at α=0.05 (P=0.071 and P=0.171, respectively). Relapse rates were low and similar regardless of prior biologic exposure in the OZA/OZA arm. Prior biologic exposure was an independent predictor of time to relapse after withdrawal of OZA in the OZA/PBO arm (P=0.027) (Figure 1). For OZA/PBO pts, Week 16 Kaplan-Meier estimates and 95% CI of no relapse were 83.8% (76.7–88.8%), 72.1% (54.4–83.9%), and 48.5% (30.8–64.1%) for the biologic-naive, 1 failed biologic, and ≥2 failed biologics groups, respectively.

Conclusion
Increasing numbers of prior biologics were predictive of increased rates of disease relapse in pts who discontinued OZA. Pts with UC, especially those with prior biologic failures, should minimise OZA discontinuation to mitigate the risk of disease relapse.