bluuebunny/crossref_metadata_2025_split huggingface dataset:
OP02 The breastmilk proteomics of women with Inflammatory Bowel Disease (IBD) and its impact on fecal calprotectin and microbiota composition in their babies
Authors: Guedelha Sabino J , Tarassishin L , Agrawal M , Eisele C , Barré A , Dubinsky M , Stone J , Nair N , Debebe A , Hawkins K , Rendon A , Hu J , Colombel J F , Peter I , Torres J 
Published: January 2022

Abstract

Background
Breastmilk (BM) is a complex fluid that contributes to shaping the immune system of the offspring. BM composition depends on stage of lactation, maternal health status and diet, environment, and genetics. Limited data exists on the composition of the BM from women with IBD and its potential impact on the newborn’s microbiome composition.

Methods
The MECONIUM (Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome) study is a prospective cohort study including pregnant women with IBD, pregnant healthy control (HC), and their offspring. BM samples were collected 2 weeks post-delivery. Stool samples from the offspring were collected throughout the first 3 years of life and used to assess faecal calprotectin (fCal) and gut microbiota composition (16S). Targeted proteomics of the BM samples was performed with the Olink inflammation panel (92 protein biomarkers). Correlations between specific proteins in the BM, fCal and 16S were assessed using non-parametric tests. Multiple testing correction was performed with false discovery rate (FDR). MaAsLin2 R package was used for multivariate testing.

Results
236 BM samples were analysed: 174 from HC, 37 Crohn’s disease (CD), 25 ulcerative colitis (UC). Thymic stromal lymphopoietin (TSLP), a cytokine with an important role in the maturation of T cells, was significantly lower in BM of women with IBD vs HC (FDR p=0.0017). The levels of TSLP in the BM of the mothers correlated negatively with infant fCal at year1 (rho=-0.20, p=0.01), and with the relative abundance of Cronobacter (MaAsLin2 FDR 0.1) of the offspring at month 1. Chemokine (C-C motif) ligand 20 (CCL20), which acts in chemotaxis of dendritic cells and T-cells and B-cells, was also significantly lower in women with CD vs HC (FDR 0.013) and in women with CD vs UC (p=0.014). Matrix metalloproteinase-1 (MMP-1), a collagenase involved in the breakdown of extracellular matrix, was also lower in BM of women with CD (p=0.009) and a negative correlation was observed between the levels of MMP1 and fCal at 3 months and 1 year (rho=-0.20 and -0.18, p=0.01 and 0.02, respectively). Osteoprotegerin (OPG), higher in BM of women with UC (p=0.018), was positively correlated with Streptococcus (MaAsLin2 FDR p=0.2) and negatively correlated with Bacteroides and Parabacteroides (MaAsLin2 FDR p=0.03 and 0.1) in the offspring at month 1.

Conclusion
The proteomic profile of BM of women with IBD is distinct from that of women without IBD. BM composition may influence offspring’s’ gut microbiome signatures and fCal level at different timepoints. These findings suggest that BM composition may impact the offspring’s intestinal immune system maturation and microbiome development, and warrant further research.
OP05 Outcome of induction therapy with vedolizumab in children: Results from the prospective, multi-centre VEDOKIDS study
Authors: Shavit Z , Stein R , Aloi M , Ledder O , Focht G , Urlep D , Hyams J , Broide E , Vais B , Levine J , Shouval D , Matar M , Assa A , Rosh J , Hussey S , Markowitz J , Yerushalmy-Feler A , Miele E , Shaoul R , Russell R K , Turner D 
Published: January 2022

Abstract

Background
Limited data are available on the use of Vedolizumab (VDZ) in paediatric Crohn’s Disease (CD) and Ulcerative Colitis (UC). We evaluated the effectiveness and safety of VDZ to induce remission at week 14 in the prospective, multicenter VEDOKIDS study.

Methods
We enrolled children (age 0–18 years) with CD or UC commenced on VDZ with a standardized dosing of 177mg/BSA up to 300mg at 0, 2, 6 and q8 weeks thereafter. Non-responders had their dose escalated to q4wks at the discretion of the local physician. Explicit demographic, clinical and safety data were prospectively recorded via REDcap. Clinical remission was defined as steroid- and EEN-free remission (i.e. wPCDAI&lt;12.5 or PUCAI&lt;10) without the need for new medications. Complete remission was defined as clinical remission with normal CRP and ESR. Predictors of response were explored by Logistic regression.

Results
128 children were enrolled, 60 (47%) with CD, and 68 (53%) with UC (58 (45%) males, mean age 13.8±3.6, 93 (73%) failed previous anti-TNF, median disease duration 2.3 years (IQR 0.9–4.7)). Using the ITT principle, clinical and complete remission rates for CD at week 14 were 30% and 20%, respectively, and for UC 50% and 38%, respectively (Fig 1). Clinical remission rates of those receiving VDZ as first line biologics versus second line were 57% and 34%, respectively (p=0.019; Fig 2); the corresponding complete remission rates were 49% and 23% (p=0.004).
In the UC group, disease activity at baseline measured by the PUCAI predicted clinical remission at week 14 (OR=0.95, 95%CI 0.93–0.98; median baseline PUCAI 15 (IQR 0–30) in those achieving remission and 45 (20–55) in those who did not; p=0.002). ESR (OR=0.94, 95%CI 0.89–0.98; p=0.009) and a trend towards extensive disease (L3 vs. L1 and L2; OR 0.14, 95%CI 0.18–1.036, p=0.054) predicted clinical remission in CD.
During the 14 weeks, 113 adverse events (AE) were recorded in 58 children: 28 AEs were possibly related to VDZ, all of which were mild-moderate and only 3 (11%) led to discontinuation of VDZ (leukocytoclastic vasculitis, myalgia and dyspnea). There were 18 serious AEs, only one was graded as possibly related to VDZ (headache). There were 18 non-serious cases (19%) of upper respiratory infections (pharyngitis, tonsilitis, parotitis, and otitis media) and one Campylobacter jejuni which was graded as serious.

Conclusion
In this prospective multicenter study, VDZ was safe and effective for inducing remission in a refractory cohort of paediatric IBD, more so in UC. Disease severity and extent at baseline may predict clinical response.
OP17 Maintenance phase propensity score adjusted effectiveness and persistence at week-52 in biologic-naïve Ulcerative Colitis patients treated with vedolizumab or anti-TNF (VEDO IBD-study)
Authors: Plachta-Danielzik S , di Giuseppe R , Bokemeyer B , Efken P , Mohl W , Krause T , Hoffstadt M , Ehehalt R , Trentmann L , Schweitzer A , Jessen P , Franzenburg S , Hartmann P , Schreiber S 
Published: January 2022

Abstract

Background
In this real-world-evidence (RWE) study we aimed to analyse the persistence of biologic therapy in biologic-naïve ulcerative colitis (UC) patients and to compare 1-year effectiveness of vedolizumab (VDZ) and anti-TNF.

Methods
Between 2017 and 2020, 1200 consecutively enrolled biologic-naïve and biologic- experienced patients with UC and Crohn′s disease (CD) were prospectively included in the VEDOIBD-Registry from 45 IBD-experienced centres across Germany. After exclusion of bio-experienced patients, CD and missing outcomes, the final sample consisted of 274 biologic-naïve UC-patients with 1-year follow-up data. Switchers of a drug were considered as treatment failure (modified intention-to-treat analysis; mITT) while switchers were excluded from per protocol analysis (PP). Clinical response modified (reduction of partial Mayo score (pMayo) from baseline to 1-year by &gt;3 points or a reduction of at least 30% compared to baseline or reaching remission at 1-year) and (steroid-free) remission rates (pMayo ≤1 plus a bleeding subscore=0 (and no systemic use of steroids or budesonide at 1-year)) were predefined 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).

Results
158 VDZ and 116 anti-TNF (ADA: 27.6%, IFX: 57.8%, GOL: 14.7%) biologic-naïve UC-patients were included in this prospective RWE comparing the effectiveness of VDZ vs anti-TNF. Until week 52 significantly more patients switched to another biologic-drug in the anti-TNF group than in the VDZ group (40.5% vs 16.5%; p&lt;0.001) (Fig. 1). In mITT, clinical response at 1-year was significantly higher in VDZ than in anti-TNF treated patients (61.7% vs. 40.3%; OR 2.39 (95% CI 1.39–4.10)). VDZ also tended to be superior to anti-TNF for (steroid-free) remission (Tab. 1; p=0.058 (p=0.051)). In the PP-analysis, VDZ showed numerically higher 1-year effectiveness, but this did not reach statistical significance (Tab. 1). Analysing week-14 induction phase responders (Tab. 2), VDZ had numerically higher effectiveness rates compared to anti-TNF but without significant difference.

Conclusion
The 1-year maintenance findings suggested, in line with our previous induction phase data, only moderate long-term effectiveness in both groups. However, besides the significant response data, VDZ showed numerically higher remission rates compared to anti-TNF though only borderline significant. The higher treatment persistence of VDZ vs anti-TNF, along with the higher effectiveness, may suggest VDZ as a first-line biologic therapy option in UC patients.
OP26 Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 LUCENT-1 study
Authors: D’Haens G , Kobayashi T , Morris N , Lissoos T , Hoover A , Li X , Arora V , Milch C , Sandborn W J , Sands B E 
Published: January 2022

Abstract

Background
Anti-IL23p19 inhibitors are emerging as promising treatment options for ulcerative colitis (UC). Mirikizumab (miri) is a humanized, IgG4 monoclonal antibody directed against the p19 subunit of IL-23, a key mediator in the pathogenesis of inflammatory bowel diseases. We assessed the induction efficacy and safety of miri with a Phase 3, multi-center, randomized, parallel-arm, double-blind, placebo (PBO)-controlled trial (LUCENT 1; NCT03518086) in patients with moderately to severely active UC (Modified Mayo Score 4–9 points and centrally read Mayo endoscopic subscore ≥2) who had inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, biologic therapies, or tofacitinib.

Methods
Adult patients (N=1281) were randomized in a 3:1 ratio to receive blinded intravenous administration of 300 mg miri or PBO every 4 weeks for 12 weeks. Randomization was stratified by biologic failure status, baseline (BL) corticosteroid use, BL disease activity as measured by modified Mayo score, and world region. The primary objective was to test the hypothesis that miri was superior to PBO in inducing clinical remission at Week 12. Key secondary objectives were clinical response, endoscopic remission, symptomatic remission, clinical response in biologic-failed patients, histologic-endoscopic mucosal improvement, and improvement in bowel urgency at Week 12 (see Figure for endpoint definitions). Mixed Model for Repeated Measures was used to assess urgency; the Cochran-Mantel-Haenszel test, with missing data imputed as nonresponse, was used to assess all other outcomes.

Results
BL characteristics were balanced across the two treatment groups. A significantly greater proportion of patients treated with miri achieved clinical remission at Week 12 (Miri: 24.2%; PBO: 13.3%; Δ=11.1 [99.875%CI: 3.2, 19.1]; p=0.00006). Miri-treated patients achieved all key secondary endpoints, including a significantly greater average reduction in bowel urgency severity compared to PBO (p&lt;0.00001). The frequencies of treatment-emergent adverse events in miri-treated patients were similar to PBO. There were numerically fewer serious adverse events (Miri: 27 [2.8%], PBO: 17 [5.3%]) and discontinuations due to adverse events (Miri: 15 [1.6%], PBO: 23 [7.2%]) in miri-treated patients compared to PBO. There were 2 colon malignancies in the miri arm (0.2%) and no deaths during the treatment period.

Conclusion
In this phase 3 UC study, 300mg miri IV demonstrated statistically significant and clinically meaningful improvements vs PBO in all primary and key secondary endpoints across clinical, endoscopic, histologic, and symptomatic measures, with an acceptable safety profile.
OP27 A Phase 1 Study Evaluating the Bioequivalence of the Proposed Commercial and Clinical Formulations of Etrasimod 2mg, and the Effect of Food on the Pharmacokinetics of the Proposed Commercial Formulation in Healthy Volunteers
Authors: Lee C , Ramaiya A , Tang Y , Sapone A , Shan K , Randle A , Grundy J 
Published: January 2022

Abstract

Background
Etrasimod (ETR) is a once-daily, oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders including ulcerative colitis, Crohn’s disease, eosinophilic esophagitis, and atopic dermatitis. This study evaluated the single-dose bioequivalence of the proposed commercial and clinical formulations of ETR 2mg in the fasted state, and the effect of food on the pharmacokinetics of the proposed commercial formulation.

Methods
This 3-treatment, 3-period crossover Phase 1 study enrolled 18 healthy adults (18–55 years: 10 males/8 females). Participants were randomized to 6 treatment sequences (3 participants/sequence: ABC, BCA, CAB, ACB, BAC, CBA) consisting of Treatment A (single-dose ETR 2mg clinical formulation, fasted), Treatment B (single-dose ETR 2mg proposed commercial formulation, fasted), and Treatment C (single-dose ETR 2mg proposed commercial formulation, fed). Treatments were administered on Days 1, 10, and 19 to allow 8-day washout periods between treatments. In the fed state (Treatment C), all participants received an FDA-standard high-fat, high-calorie meal. Blood samples for determination of ETR concentration were collected at prespecified timepoints to 168 hours post dose. Analysis of variance was performed on log-transformed Cmax, AUC0-last, and AUC0-∞ values to determine geometric least squares mean ratios (GLSMR) of Test/Reference and associated 90% confidence intervals (CI) to assess bioequivalence and food effects. Safety and tolerability of ETR were also evaluated.

Results
Bioequivalence: The 90% CI for the GLSMR of ETR Cmax and AUC plasma exposure measures, comparing the proposed commercial vs clinical formulations, were within the accepted 80%–125% range (GLSMR and 90% CI) for establishing bioequivalence (Table 1). Median Tmax for Treatments A and B were both 4 hours. Food Effect: The 90% CI for the GLSMR of ETR Cmax and AUC plasma exposure measures, comparing the proposed commercial formulation under fed vs fasted conditions, were within the accepted 80%–125% range for establishing no food effect (Table 2). Median Tmax for Treatment C was 6 hours. Safety and Tolerability: All treatment-emergent adverse events (AEs) were mild (except 1 moderate AE [headache]). One participant had an AE leading to study drug discontinuation. There were no serious AEs or deaths.

Conclusion
Based on results from this study, the proposed commercial and clinical formulations of ETR 2mg were bioequivalent in terms of rate and extent of absorption. No significant differences were demonstrated in ETR exposure for the proposed commercial formulation under fed and fasted conditions. All treatments were generally safe and well tolerated.
OP29 Peripheral blood DNA methylation biomarkers accurately predict clinical- and endoscopic response to vedolizumab in a real-life cohort of Crohn’s Disease patients
Authors: Joustra V , Hageman I , Li Yim A , Levin E , Satsangi J , Adams A , De Jonge W , Henneman P , D’Haens G 
Published: January 2022

Abstract

Background
Despite the proven efficacy of vedolizumab (VDZ), only 29% and 36% of the Crohn’s disease (CD) patients present corticosteroid-free clinical- and endoscopic remission, respectively. Therefore, predictive biomarkers for treatment success would be of extreme value. Previous studies have identified aberrant DNA methylation associated with CD-specific phenotypes, suggesting that the methylome may be useful for classification and prediction of VDZ treatment response. Here, we sought to identify such DNA methylation biomarkers that can predict clinical- and endoscopic response to VDZ in CD patients.

Methods
We prospectively recruited adult CD patients that initiated VDZ treatment following a baseline colonoscopy in two cohorts: a discovery and validation cohort. Peripheral blood DNA methylation profiles were measured prior to treatment (T1), and after a median of 22 weeks (T2) using the Illumina Infinium HumanMethylation EPIC BeadChip array. Response (R) was defined as the strict combination of endoscopic- (≥50% reduction in SES-CD score) and steroid-free clinical response (≥3 point drop in HBI and HBI ≤4 AND no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Twenty-one patients had deep remission (DR), defined as a combined endoscopic- (SES-CD≤2) and steroid-free clinical remission (HBI ≤4, no systemic steroids). Biomarker identification and classification analyses were performed using stability selection gradient boosting.

Results
In total, 64 CD patients were enrolled (discovery 16R/14NR and validation 20R/14NR). Both cohorts were comparable for age, sex and smoking status. Forty-nine (77%) patients had previously failed an anti-TNF agent. All patients had measurable serum vedolizumab concentration at T2 (median 14.5 (6.9 – 21.3) µg/mL). Through classification analysis at T1, we were capable of discriminating R from NR with high predictive performance (25 CpGs, AUC 0.88, F1-score of 0.84, PPV of 0.91 and NPV of 0.85). When analysing the methylome of patients in deep remission, we identified 23 CpGs with high predictive performance upon independent validation (F1-score 0.80, PPV of 0.71 and NPV of 0.86). Investigating the CpGs of interest implicated genes involved in endothelial cell-cell adhesion and integrin dependent T-cell homing, corroborating VDZ’s mode of action.

Conclusion
We demonstrate two novel 25- and 23-feature panels of epigenetic biomarkers that accurately predict response or deep remission to vedolizumab respectively. Similar analyses on infliximab, adalimumab and ustekinumab are currently ongoing as part of the EPIC-CD study.
OP33 Effect of upadacitinib (UPA) treatment on extraintestinal manifestations (EIMs) in patients with moderate-to-severe Ulcerative Colitis (UC): Results from the UPA Phase 3 programme
Authors: Colombel J F , Cao Q , Ghosh S , Reinisch W , Zhou W , Ilo D , Shu L , Yao X , Rubin D T 
Published: January 2022

Abstract

Background
EIMs are common in patients with UC and are associated with impaired quality of life. This analysis evaluated the impact of treatment with the selective Janus kinase 1 inhibitor UPA on EIMs in patients with moderate-to-severe UC.

Methods
Data were included from two induction studies (U-ACHIEVE Induction [NCT02819635] and U-ACCOMPLISH [NCT03653026]) and a maintenance study (U-ACHIEVE Maintenance). Patients with moderate-to-severe UC were randomised 2:1 to 8 weeks’ induction treatment with UPA 45 mg once daily (QD) or placebo. Patients with a clinical response to induction were re-randomised (1:1:1) to 52 weeks’ maintenance treatment with UPA 15 mg or 30 mg QD, or placebo. The presence of EIMs (peripheral arthropathy, axial arthropathy, episcleritis, uveitis, iritis, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, oral aphthous ulcers, primary sclerosing cholangitis, autoimmune hepatitis, venous thromboembolism, chronic obstructive pulmonary disease, bronchiectasis, nephrolithiasis and anaemia) was captured in the EIM form at the start of induction (baseline) and at every visit up to Week 52. The induction study results were pooled for analysis.

Results
At baseline, 25.0% and 26.5% of patients in the UPA 45 mg QD and placebo induction groups had ≥1 EIM, while 24.3%, 26.6% and 24.8% of patients randomised to maintenance treatment with UPA 15 mg QD, UPA 30 mg QD or placebo, respectively, had ≥1 EIM (Table 1). The most common EIMs at baseline were anaemia, peripheral arthropathy and axial arthropathy; all other EIMs were reported in &lt;2% of patients (Table 1). The proportion of patients reporting resolution of any EIM, arthropathy (peripheral and axial) and anaemia at Week 8 was numerically greater with UPA 45 mg QD than placebo in the induction studies (Figure 1A). Resolution at Week 52 of any EIM in patients with ≥1 EIM at baseline was significantly increased with UPA 30 mg QD (p&lt;0.001), and numerically greater with UPA 15 mg QD, versus placebo (Figure 1B). In patients with arthropathy (peripheral or axial) at baseline, the proportion achieving resolution of arthropathy (peripheral and axial) at Week 52 was significantly increased with UPA 30 mg QD (p=0.010), and numerically higher with UPA 15 mg QD, versus placebo (Figure 1B). The same was true of anaemia resolution in patients with anaemia at baseline (p=0.019 for UPA 30 mg QD versus placebo; Figure 1B).

Conclusion
UPA treatment is effective in resolving EIMs in patients with UC. EIM symptom resolution was improved versus placebo following induction treatment with UPA 45 mg and after maintenance treatment with UPA 15 or 30 mg, with the 30 mg dose providing statistically significant improvements versus placebo.
DOP05 Morbid obesity, a new susceptibility factor for developing Inflammatory Bowel Disease. Results of a population-based study
Authors: Canete Pizarro F C , Vela E , Calafat M , Clèries M , Mañosa M , Domènech E 
Published: January 2022

Abstract

Background
Some genetic polymorphisms (present in less than 30% of patients) and environmental factors, such as tobacco exposure, have been identified to increase the susceptibility for developing inflammatory bowel disease (IBD), but it is suspected that there may be other still unknown environmental or epidemiological factors. In this sense, some studies suggested an increased incidence of IBD in individuals undergoing bariatric surgery (BS) for morbid obesity (MO). We aimed to assess whether BS or MO are associated with an increased risk of developing IBD.

Methods
All individuals resident in Catalonia (7.7 million inhabitants in 2021) with a diagnosis of obesity or MO within the period 2005–2020 were identified from the Catalan Public Health System Database. Children under the age of 18 and those diagnosed with IBD prior to the diagnosis of obesity or MO were excluded. Individuals BS and those with a new diagnosis of IBD were identified, and the likelihood of developing IBD was analyzed by Kaplan-Meier survival analysis. A Cox regression multivariable analysis was performed to assess independent risk factors for the development of IBD, Crohn’s disease (CD) and ulcerative colitis (UC).

Results
Three cohorts were identified: 94,473 individuals with MO; 1,009,256 with obesity; and 14,698 who underwent BS during the study period. A total of 4,277 new diagnoses of IBD were identified, of which 78 among individuals who underwent BS prior to IBD diagnosis (0.84 cases per 1000 person-years), 409 among individuals with OM but without BS (0.90 cases per 1000 person-years), and 3,790 in obese individuals (0.60 cases per 1000 person-years). The likelihood of developing IBD was significantly higher in patients with MO as compared with obese patients (HR 1.46; 95%CI 1.32–1.62). These differences were maintained when the likelihood of developing CD or UC were assessed separately. In the multivariable logistic regression analysis, MO (HR 1,68; CI95% 1.41–1.99), female gender (HR 1.17; 95%CI 1.05–1.31) and active smoking (HR 1.62; 95%CI 1.43–1.84) were associated with an increased risk of CD. In UC, MO (HR 1,36; 95%CI 1.19–1.55) and BS (HR 2.62; 95%CI 1.34–2.11) were independent risk factors, whereas female gender (HR 0.86; 95%CI 0.79–0.93) was an independent protective factor.

Conclusion
MO is an independent risk factor for the development of IBD, for both CD and UC, whereas BS seems to increase the risk only for UC.