bluuebunny/crossref_metadata_2025_split huggingface dataset:
P738 Response to etrasimod treatment in ulcerative colitis is associated with a reduction of circulating B and pro-inflammatory T cells: a single-cell-based post-hoc sub-analysis of the ELEVATE UC 52 trial
Authors: Weidinger C , Milek M , Hecker J , Haag L M , Freise I , Obermayer B , Beule D , Ryan R D , Crosby C , Siegmund B 
Published: January 2024

Abstract

Background
Etrasimod (ETR) is an oral, once-daily, selective sphingosine 1-phosphate receptor 1,4,5 (S1PR) modulator for the treatment of moderately to severely active ulcerative colitis (UC). The mechanism of action is based on a retention of lymphocytes in lymphatic tissue hindering circulating lymphocytes from entering the gut and causing inflammation. However, the effect of ETR on immune cell function and composition is not well characterized. In addition, it is unknown whether the response of UC patients to ETR treatment is associated with specific immune cell signatures.

Methods
Single-cell RNA sequencing (scRNAseq), mass cytometry (CyTOF) and clinical data integration were used to characterize the effects of 12 weeks of treatment with ETR on the immune composition and function of peripheral blood mononuclear cells (PBMCs) collected from 15 UC patients at weeks 0 and 12 during the ELEVATE UC Phase 3 clinical trial. As an exploratory cohort, PBMCs from 5 UC patients reaching the primary endpoint of clinical remission at week 12 (modified Mayo score &lt;2), 5 UC patients not responding to ETR treatment (modified Mayo score &gt;2) and 5 placebo-treated UC patients were included. 30 samples were processed for scRNAseq; additionally, 28 blood samples were ex-vivo stimulated with ionomycin/PMA for 4 h and cytokine production was assessed by CyTOF. To determine the effects of ETR in UC patients, immune cell function and composition were compared intra-individually between weeks 0 and 12. Subsequent comparisons between ETR responders, non-responders and placebo-treated UC patients were performed to discriminate responders from non-responders.

Results
Significant reductions in T and B cell subsets, along with increases in the abundance of dendritic and monocytic cells, were observed in responders by week 12 of -treatment. Importantly, ETR treatment significantly reduced circulating T cells producing pro-inflammatory cytokines, including TNFα and IFNγ, and S1PR modulation led to a mitigation of naïve and effector memory CD4 and CD8 T cells in ETR-treated UC patients achieving clinical remission. In contrast, patients not responding to ETR treatment had significantly higher frequencies of both naïve and TNFα-producing CD4 T cells by week 12.

Conclusion
In line with the described role of S1PR in lymphocyte trafficking, single-cell analyses of circulating immune cells from ETR-treated UC patients confirmed a significant reduction in B cells and pathogenic T cell subsets after ETR treatment providing an in-depth cellular characterization of S1PR modulation in UC patients thereby contributing to a better understanding of the key mechanism of action of ETR. However, these findings require validation in larger cohorts.
P758 Effectiveness and tolerability of methotrexate monotherapy in Crohn’s disease patients: A multicenter observational study
Authors: Park J , Jaeyoung C , Soo Jung P , Jae Jun P , Tae Il K , Won Ho K , Hyuk Y , Jae Hee C 
Published: January 2024

Abstract

Background
Methotrexate monotherapy is recommended as a maintenance therapy for Crohn’s disease (CD). However, long-term follow-up data are scarce. We aimed to examine the effectiveness and tolerability of methotrexate monotherapy in 94 CD patients from three IBD Clinics in Korea.

Methods
Patients with active CD treated with methotrexate monotherapy were included. Clinical characteristics, laboratory indicators, endoscopy indices were evaluated at baseline, 6, 12, and 24 months. Independent factors associated with long-term clinical and endoscopic outcomes were determined.

Results
Methotrexate was administered orally (70.2%) or parenterally (29.8%). The mean methotrexate induction dose was 15.3 ± 0.4 mg per week, and the mean duration of therapy was 26.2 months. Of 76 patients who were treated for &gt;6 months, the clinical remission rates were 76.3%, 74.6%, and 80.0% at 6, 12, and 24 months, respectively, by per protocol analysis. The mean CRP levels were 7.5 ± 1.3, 5.3 ± 1.2, 3.8 ± 0.7, and 2.6 ± 0.5 mg/L at 0, 6, 12, and 24 months, respectively. Of 31 patients who underwent follow-up endoscopy after 27.5 months, the endoscopic remission rate was 38.7%. Baseline hemoglobin level &lt; 10 g/dL was a significant independent factor negatively associated with clinical remission at 6 (odds ratio [OR]: 0.023, 95% confidence interval [CI]: 0.003-0.206, p = 0.001) and 12 (OR, 0.079; 95% CI: 0.009-0.699, p = 0.023) months. Parenteral administration was a significant independent factor positively associated with clinical remission (OR: 11.231, 95% CI: 1.027-122.811, p = 0.047) and endoscopic remission (hazard ratio: 4.711, 95% CI: 1.398-15.874, p = 0.012) at 12 months.

Conclusion
Methotrexate monotherapy was effective and tolerable as a maintenance therapy in CD patients.
P762 Risk of Infection After Acute Severe Ulcerative Colitis in East Asia and Australia/New Zealand: AOCC and ANZIBDC collaboration study
Authors: Kim S J , Kim D H , Park S H , Kim K O , Lee Y J , Song E M , Kim E S , Lee H S , An Y K , Begun J , Ruddick-Collins L , Fernandes R , Liu J , Cao Q , Kobayashi T , Wei S C 
Published: January 2024

Abstract

Background
Infection is one of the concerns in the treatment of inflammatory bowel disease, and advanced age and immunosuppressants are known to be risk factors for infection. However, there has been no studies on infection after acute severe ulcerative colitis (ASUC) and its associated factors. The aim of this study was to investigate infection and associated factors in ASUC patients, as well as differences in infection risk between regions of East Asia and Australia/New Zealand (ANZ).

Methods
We retrospectively analyzed patients with ASUC diagnosed according to Truelove Witt criteria from January 2015 to September 2022. We identified the overall incidence of infection and related risk factors, and then analyzed the differences by two regions.

Results
A total of 676 ASUC patients (329 in East ASIA, 347 in ANZ) were enrolled. Overall infections within 1 year after ASUC occurred in 65 patients (9.6%). Clostridioides difficile (C. diff) infection (17/65, 26%), CMV colitis (14/65, 21%), and pneumonia (7/65, 10%) were most common infections. Risk factor associated with infection was combination therapy with anti-TNF agent and thiopurine at discharge (hazard ratio [HR] 5.225, 95% confidential interval [CI] 2.469-11.059, P&lt;0.001). The group with infections exhibited worse outcomes, including a higher readmission rate (39.3% vs. 92.2%, p &lt; 0.001), readmission due to ulcerative colitis (UC) (16.3% vs. 31.3%, p = 0.004), UC-related mortality (0.9% vs. 9.6%, p &lt; 0.001), and overall mortality during the follow-up period (1.1% vs. 13.8%, p &lt; 0.001, Table 1).
In comparative analysis between East Asia and ANZ, there was no difference in the incidence of infection (7.6% vs 11.5%, p=0.083) and infection related mortality (1% vs 0.3%, p=1.000) within 1 year after ASUC. CMV colitis (10/25, 40%) and C. difficile infection (6/25, 24%) were common in East Asia while C.difficile infection (11/40, 27%) and skin infections (7/40 17%) occurred frequently in ANZ. The risk factors for infection in East Asia were anti TNF at discharge (HR 3.684, 95% CI 1.434-9.465, P=0.007) and CMV infection (HR 3.587, 95% CI 1.136-11.333, P=0.03), but the risk factors for infection in ANZ were combination therapy with anti TNF and thiopurine at discharge. (HR 7.911, 95% CI 3.397-11.333, P=&lt;0.001, Figure 1).

Conclusion
The incidence of infection within 1 year after ASUC is 9.6%, and combination therapy of anti-TNF and thiopurine at discharge is a risk factor. Infections were associated with poor prognosis including mortality. There was no difference in the incidence and mortality rates of infections between East Asia and ANZ while the types of infections and related risk factors were different.
P765 A Novel Monoclonal Antibody Drug Candidate SPY001 Targeting Integrin ɑ4β7 for the Treatment of IBD Demonstrates Prolonged Half-Life in Non-Human Primates
Authors: Zhu E , Rios D , Vaz R , Friedman J , Nguyen D , Spencer A , Oh J , Shaheen H 
Published: January 2024

Abstract

Background
Background: Antagonism of the interaction between the cellular adhesion integrin ɑ4β7 and endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) has proven to be relatively safe and effective in the treatment for Crohn’s disease (CD) and ulcerative colitis (UC). Additional benefit may be gained from an ɑ4β7 antagonist given via the subcutaneous (SC) route at extended intervals (eg, every 8 to 12 weeks) during maintenance therapy.

Methods
The humanized monoclonal IgG1 antibody SPY001 binds to the same ɑ4β7 epitope as vedolizumab and includes a YTE modification within the Fc region to increase its serum half-life via increased affinity for the neonatal Fc receptor (FcRn), thereby favoring recycling into the circulation over degradation. Half-life extension was evaluated via pharmacokinetic analysis in Tg276 transgenic mice (hemizygous for human FcRn) following a single intravenous bolus dose of SPY001 (10 mg/kg, 5 mg/kg, 1 mg/kg) and in cynomolgus monkeys following a single bolus dose of SPY001 (150 mg/kg), given by either intravenous (IV) and subcutaneous (SC) administration. PK simulations in humans were based on allometric scaling of SPY001 clearance observed in cynomolgus monkey and conducted in MATLAB.

Results
In Tg276 mice, the half-life of SPY001 was 10-11 days across all dose cohorts compared to approximately 3 days for vedolizumab. In cynomolgus monkeys, the half-life of SPY001 was 19-23 days following a single IV or SC infusion, a significant increase over the reported half-life of 10 days for vedolizumab in cynomolgus monkeys. Based on allometric scaling of the clearance of SPY001 observed in this study, predictive simulations of SPY001 PK in humans suggested that Q8W-Q12W SC dosing at 300 mg would be able to achieve a C6-wks, induction ≥ 35 mg/mL and Ctrough, ss ≥ 6 mg/mL for simulated patients covering a large range of body weights and albumin concentrations.

Conclusion
SPY001 is a novel humanized monoclonal IgG1 with an extended half-life over that of vedolizumab in Tg276 mice and cynomolgus monkeys. It offers the potential for effective and safe treatment of CD and UC with the advantage of infrequent SC dosing. Further preclinical and clinical studies are warranted to demonstrate this potential.
P788 The effect of etrasimod on faecal calprotectin and high-sensitivity C-reactive protein: Results from the ELEVATE UC clinical programme
Authors: Jairath V , Rubin D T , Verstockt B , Çekin A H , Abreu M T , Lees C W , Fellmann M , Woolcott J C , Crosby C , Wu J , Bhattacharjee A , Herman D , Gu G , Siegmund B 
Published: January 2024

Abstract

Background
Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here, we present a post hoc analysis of efficacy data from two phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12,1 assessing associations with faecal calprotectin (fCAL) and high-sensitivity C-reactive protein (hsCRP) and responses to etrasimod in patients (pts) with UC.

Methods
In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), pts aged 16–80 years with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg once daily or placebo. Efficacy endpoints of clinical remission, clinical response and endoscopic improvement-histological remission (EIHR) were measured at Wk 12 (both trials analysed separately) and Wk 52 (ELEVATE UC 52). Differences in median fCAL and hsCRP between responders and nonresponders (based on criteria for each endpoint) were assessed. Wilcoxon p values were calculated for responder analyses. Sensitivity and specificity based on fCAL and hsCRP concentrations were presented as receiver operating characteristic (ROC) curves with area under the curve (AUC).

Results
In ELEVATE UC 52 and ELEVATE UC 12, 289 and 238 pts received etrasimod and 144 and 116 received placebo, respectively. Baseline fCAL and hsCRP concentrations were similar across cohorts and levels decreased with etrasimod treatment (median change from baseline at Wk 52 [ELEVATE 52]; -710.56 mg/kg and -0.49 mg/L for fCAL and hsCRP, respectively). Following etrasimod, Wk 12 (both studies) and Wk 52 (ELEVATE UC 52), median fCAL and hsCRP were significantly lower in responders vs nonresponders for all efficacy endpoints (fCAL [ELEVATE UC 52] shown in Table; all endpoints p&lt;0.01). At Wk 4, pts receiving etrasimod who were subsequent responders for efficacy endpoints at Wk 12 had lower median fCAL concentrations vs nonresponders in both trials (all p&lt;0.001; Figure). A similar trend was observed for Wk 4 median fCAL concentrations and responders for efficacy endpoints at Wk 52 (ELEVATE UC 52). Across endpoints in both trials, ROC analyses indicated that both fCAL and hsCRP were consistent in predicting short- and longer-term outcomes, with more pronounced associations at Wk 52.

Conclusion
In phase 3 trials in pts with UC, fCAL and hsCRP levels decreased with etrasimod treatment. ROC analyses indicated association between fCAL and hsCRP and treatment response at all endpoints, and demonstrated significantly lower fCAL and hsCRP values in responders. These data demonstrate the utility of fCAL and hsCRP to predict and monitor disease control in pts with UC treated with etrasimod.
Reference
1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171.
P789 Impact of risk factors for Janus kinase inhibitor use identified by the Pharmacovigilance Risk Assessment Committee on the safety and efficacy of ozanimod in patients with moderately to severely active ulcerative colitis
Authors: Siegmund B , Kuehbacher T , Armuzzi A , Hart A , Bressler B , Feagan B G , Wu H , Ahmad H A , Osterman M T , Charles L , Poehler A M , Jain A , Danese S 
Published: January 2024

Abstract

Background
With the emergence of oral small molecule therapies for ulcerative colitis (UC), there is a need for identification of favourable safety and efficacy profiles for these therapies. The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency reassessed the benefit–risk of Janus kinase inhibitor (JAKi) use based upon data showing increased risk of major adverse cardiovascular (CV) events (MACE) and cancer with tofacitinib. Accordingly, the PRAC identified criteria for which a JAKi should be used only if no alternatives are available or used with caution. This analysis of the phase 3 True North (TN) study (NCT02435992) evaluated the safety and efficacy of ozanimod (OZA) by the presence of JAKi PRAC criteria in patients with moderately to severely active UC.

Methods
Analyses were performed in TN patients comparing those with ≥1 vs no JAKi PRAC criteria at TN baseline (BL). The criteria included age ≥65 y, history of major CV problems, history of CV risk factors (eg, hypertension, high-density lipoprotein cholesterol &lt;40 mg/dl, diabetes mellitus), current or former smoker, and history of cancer. Safety was monitored through Week (W) 52 and efficacy endpoints were assessed at W10 and W52 in patients receiving OZA or placebo (PBO).

Results
At TN BL, 491 patients had ≥1 JAKi PRAC criteria and 521 had no JAKi PRAC criteria. BL patient characteristics were generally similar across groups, but the ≥1 JAKi PRAC criteria group was older (46-48 y vs 36-37 y), with more male patients (62-72% vs 52-61%) and longer UC disease duration (7-9 y vs 6-7 y) vs the no JAKi PRAC criteria group. Treatment-emergent adverse events (TEAEs) occurring during the induction and maintenance periods are shown in Table 1. Overall, TEAE rates were slightly higher in patients with ≥1 vs no JAKi PRAC criteria; however, rates of serious TEAEs and TEAEs leading to treatment discontinuation were similar. Bradycardia and hypertension rates were slightly higher in patients with ≥1 vs no JAKi PRAC criteria; rates of other CV and thromboembolic events and cancer were similar between groups. At W10, OZA was more effective than PBO for clinical remission and response, with slightly greater treatment differences in patients with ≥1 vs no JAKi PRAC criteria (Figure 1A). At W52, more OZA/OZA pts achieved all endpoints vs OZA/PBO pts, with slightly greater treatment differences in patients with ≥1 vs no JAKi PRAC criteria (Figure 1B).

Conclusion
In patients with UC, JAKi PRAC criteria were not associated with greater rates of MACE or cancer with OZA for up to 52 wk, nor did they affect OZA efficacy, suggesting that OZA is a safe and tolerable oral small molecule treatment option for such patients.
P815 Infliximab drug monitoring: proactive or reactive: a North West England NHS 3 trust retrospective study
Authors: Campbell R , Nelson E , Everall J , Ash N , Mountford J , Davies J 
Published: January 2024

Abstract

Background
Therapeutic drug monitoring (TDM) plays a vital role in the management of patients on Infliximab. (1) The British Society of Gastroenterology (BSG) recommends TDM assessment ideally takes place 2-4 weeks after the initial loading doses, however the European Crohns and Colitis Organisation (ECCO) do not make particular proactive or reactive recommendations for TDM. (1,2,3)

Methods
Three North West England NHS trusts retrospectively collected data on 75 patients who had Infliximab trough and antibody levels done within a 12 month time frame. The aim was to establish if collectively TDM was done proactively or reactively and the overall outcomes from the monitoring.

Results
The demographic profile gave us 37 females and 38 males with the disease distribution predominantly Crohns disease ( N=53). There were more participants in the 18-50 age range (N=53) with 22 patients being 31-40 years of age, less participants in the 51-70+ age range ( N=22). Dual therapy with either Mercaptopurine or Azathioprine accounted for 49 out of the 75 participants with a majority favouring Azathioprine. Clinical management and routine use of TDM was seen in 40.5% ( N= 54) of patients indicating proactive use of monitoring in this study. TDM was undertaken after induction and annually in 48 patients whilst the remaining 27 patients received monitoring as ‘maintenance’, this is similar to the BSG recommendations and in a study by Sagar et al in 2021 ( 4).

Conclusion
Although the three participating trusts may use differing assays for the TDM, the outcomes show that it is used proactively for the majority of patients after induction and annually in keeping with BSG recommendations (3). From the data collected a further examination of results regarding subcutaneous versus intravenous TDM outcomes is proposed as the trusts move towards providing patients with both modes of administration of Infliximab.
P824 Association between visceral adipose tissue and disease duration, clinical activity, and response to various biological agents in inflammatory bowel disease
Authors: Karakan T , Coşkun M , Bilican G , Demir B , Karataş A , Ekmen N , Moral K , Karakoç A , Cindoruk M 
Published: January 2024

Abstract

Background
The relationship between body fat composition and inflammatory bowel disease (IBD) progression, medical response, and prognosis is widely acknowledged. Visceral adipose tissue (VAT) has been shown to be profoundly responsible of most of the obesity-associated metabolic derangements, however it is also related to severity of inflammation. Although VAT can be estimated using computerized tomography, abdominal bioimpedance is a new and reliable technique without expense and radiation exposure. We investigated whether VAT is linked to the disease activity in severe IBD and the short-term response to biological therapies.

Methods
We prospectively evaluated 65 IBD patients, (n=26 with ulcerative colitis (UC) and n=39 with Crohn’s disease (CD) who had moderate-severe disease activity) at baseline before the initiation of biological therapy. We quantified VAT using abdominal bioimpedance (ViScan). VAT and other body fat metric measures (BMI, total and free fat mass, abdominal fat mass) were also analyzed. The response to biological agents was assessed by clinical (Mayo and CDAI) and endoscopical (mucosal healing) scores at 3 months.

Results
Out of the 65 patients, 22 individuals (33.8%) exhibited clinical and/or endoscopic response after 3 months. Among responders and non-responders, there was a comparable approximation of disease location (p=0.321) and behavior (p=0.239). Patients with CD had slightly lower levels of VAT, BMI, and free fat mass compared to those with UC. In non-responders with UC, VAT levels were lower than in responders, whereas in non-responders with CD, VAT levels were higher than in responders. No distinction was observed in the VAT response among other classes of biologics, including anti-TNF, ustekinumab, and vedolizumab.

Conclusion
In summary, VAT parameters using bioimpedance (ViScan) were found to be correlated with the disease activity and reliably identified IBD patients who responded well to various biological treatment in the short-term. Therefore, human fat indices might be novel biomarkers for disease severity and response to therapy.