bluuebunny/crossref_metadata_2025_split huggingface dataset:
OP04 Efficacy of upadacitinib in ulcerative colitis: A phase 3 post hoc analysis of biologic- and anti-TNF-inadequate response patients
Authors: Vermeire S , Danese S , Hébuterne X , D’Haens G , Takeuchi K , Finney-Hayward T , Klaff J , Holweg C T J , Rubin D T 
Published: January 2023

Abstract

Background
Upadacitinib (UPA), an oral selective and reversible Janus kinase inhibitor, has demonstrated efficacy with a well-characterised safety profile in patients (pts) with moderately to severely active ulcerative colitis (UC) in a Phase 3 clinical trial program.1,2 This post hoc analysis evaluated UPA in pts with an inadequate response (IR; persistently active UC despite ≥1 induction regimen of infliximab, adalimumab, golimumab, vedolizumab or ustekinumab), loss of response, or intolerance to ≥1 biologic (bio-IR) or anti-TNF agent (anti-TNF-IR) in the Phase 3 trials.

Methods
Pts with a clinical response to UPA 45 mg once daily (QD) following 8-week (wk) induction therapy in U-ACHIEVE or U-ACCOMPLISH were subsequently randomised to placebo (PBO), UPA 15 mg or UPA 30 mg QD in U-ACHIEVE Maintenance.1,2 Here, we evaluated the efficacy of UPA after 8-wk induction and 52-wk maintenance therapy in non-bio-IR pts, bio-IR pts and the subset of anti-TNF-IR pts within the bio-IR population.

Results
Overall, 508 bio-IR pts (51% overall) and 464 anti-TNF-IR pts (91% of bio-IR population) were analysed after induction, and 336 bio-IR pts (49% overall) and 306 anti-TNF-IR pts (91% of bio-IR population) were analysed after maintenance. UPA was significantly more efficacious than PBO across all endpoints analysed at Wk 8 of induction in the non-bio-IR, bio-IR and anti-TNF-IR subgroups (Figure 1; Table 1). At Wk 52 of maintenance, both UPA doses were more efficacious than PBO across subgroups for the primary endpoint of clinical remission per Adapted Mayo score (Figure 2). Adjusted response rate differences for both UPA doses vs PBO were generally similar across most endpoints at Wk 8 of induction and Wk 52 of maintenance for the non-bio-IR, bio-IR and anti-TNF-IR subgroups. At Wk 52 of maintenance, UPA 30 mg QD had numerically better efficacy than 15 mg QD across all endpoints except change from baseline in faecal calprotectin in non-bio-IR patients, with generally similar results for non-bio-IR, bio-IR and anti-TNF-IR pts (Table 2).

Conclusion
In pts with UC, significantly more pts achieved clinical remission after 8-wk induction and 52-wk maintenance therapy with UPA than PBO in non-bio-IR, bio-IR and anti-TNFIR pts. Generally similar efficacy was observed between the bio-IR and anti-TNF-IR pts, which was consistent with the previously published overall population.1,2 These findings suggest that UPA is efficacious for UC regardless of prior therapy with anti-TNF agents or other biologics.
OP17 Upadacitinib Improves Endoscopic Outcomes in Patients with Moderate to Severely Active Crohn’s Disease Irrespective of Previous Failure to Respond to Biologics or Conventional Therapies
Authors: Feagan B G , Horst S , Dryden G , Lindsay J O , Ferrante M , Dubenco E , Lacerda A P , Ford S , Anyanwu S I , Zhou Q , Liu J , Chen M , Schreiber S 
Published: January 2023

Abstract

Background
Upadacitinib (UPA), an oral, reversible JAK inhibitor, demonstrated superior efficacy compared to placebo (PBO) in patients with moderate to severe Crohn’s disease (CD) in 2 multicentre, phase 3 induction (U-EXCEL and U-EXCEED), and 1 maintenance (U-ENDURE) trial.1-3 This sub-analysis assessed endoscopic outcomes in patients with or without a history of biologic failure (inadequate response or intolerance) among those receiving UPA treatment.

Methods
Eligible patients had average daily stool frequency [SF] ≥4 and/or abdominal pain score [APS]≥2, plus a Simple Endoscopic Score for CD (excluding the presence of narrowing component) ≥6 [≥4 for isolated ileal disease]). Patients received UPA 45 mg once daily (QD; UPA45) or PBO (2:1) for 12 weeks (wks). Patients that achieved SF/APS clinical response after 12 weeks of treatment with UPA45 (≥ 30% decrease in daily very soft/liquid SF and/or ≥ 30% decrease in daily abdominal pain APS with neither worse than baseline) were re-randomized (1:1:1) to UPA 30 mg QD (UPA30), UPA15 mg QD (UPA15) or PBO for 52 wks of maintenance. Endoscopic response\ remission were evaluated by central reading at wk 12 induction and wk 52 maintenance. Adverse events (AEs) were assessed through wk 52. Statistical significance in comparisons was not assessed due to an inability to control for type I error in subgroup analysis.

Results
Baseline characteristics/demographics were similar across treatment groups. In the pooled induction population (U-EXCEED+U-EXCEL), 72.0% UPA45 and 71.5% PBO patients had history of prior biologic failure. In U-ENDURE, 73.4% UPA15, 75.6% UPA30, and 76.4% PBO patients had history of prior biologic failure. In patients without or with biologic failure, UPA demonstrated higher rates for endoscopic response compared to PBO at wk 12 (52.0%, 35.7% UPA45 vs 16.2%, 5.3% PBO, Figure 1A) and wk 52 (Figure 1B). Similarly, in patients without or with a history of biologic failure, UPA exhibited higher rates of endoscopic remission at wk 12 (36.0%, 19.6% UPA45 vs. 10.1%, 2.8% PBO, Figure 1A) and wk 52 (Figure 1B). Differences from PBO were found in endoscopic response or remission in patients that remained in response/remission from the entry of maintenance to wk 52 for either dose, regardless of prior history of biologic failure (Figure 1C). UPA treatment was well-tolerated, with no new safety risks observed compared to the known safety profile of UPA (Tables 1-2).

Conclusion
Upadacitinib achieved clinically meaningful endoscopic outcomes, which were maintained up to 1 year, irrespective of a patient’s prior biologic treatment, with an acceptable safety profile.
OP40 PRA023 Demonstrated Efficacy and Favorable Safety as Induction Therapy for Moderately to Severely Active UC: Phase 2 ARTEMIS-UC Study Results
Authors: Sands B , Peyrin-Biroulet L , Danese S , Rubin D T , Vermeire S , Laurent O , Luo A , Nguyen D , Lu J D , Wiechowska-Kozlowska A , Leszczyszyn J , Kempinski R , Kierkus J , Ma C , Ritter T , Feagan B G , Targan S 
Published: January 2023

Abstract

Background
Tumor necrosis factor-like cytokine 1A (TL1A) is an upstream regulator of pro-inflammatory cytokines and fibrosis signals. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases using a precision medicine approach with a companion diagnostic (CDx). This Phase 2 placebo-controlled, multi-center, double-blind study aimed to assess the efficacy and safety of PRA023 for induction treatment in adults with moderately to severely active ulcerative colitis (UC).

Methods
Key eligibility criteria included a modified Mayo Score of 4-9, a centrally read (with adjudication) endoscopy subscore of ≥ 2, a rectal bleeding subscore of ≥ 1, and a history of insufficient response, loss of response, and/or intolerance to conventional and/or advanced (approved biologics and JAK inhibitors/S1P modulators) therapies (≤ 4 advanced agents from ≤ 3 classes). Patients were stratified by prior biologic exposure status (yes/no) and CDx status (yes/no) and randomized 1:1 to placebo or intravenous PRA023 (1000mg on Day 1, 500mg at Weeks 2, 6, and 10). The primary endpoint was clinical remission at week 12. Analyses of all ranked secondary endpoints, the first being endoscopic improvement (endoscopy score of ≤ 1), were multiplicity controlled.

Results
Of the 135 patients in the full analysis data set, 60/67 (89.6%) in the placebo arm and 68/68 (100%) in the PRA023 arm completed the 12-week Induction Period. Baseline characteristics were similar with minor differences in the proportion of patients with baseline endoscopy score of 3 and prior exposure to ≥ 3 advanced therapies (Table 1). A significantly greater proportion of patients who received PRA023 achieved the primary endpoint of clinical remission (26.5% PRA023 vs. 1.5% placebo, ∆25.0%, p &lt; 0.0001) at Week 12 (Table 2). In addition, substantially more patients who received PRA023 achieved the key secondary endpoint of endoscopic improvement (36.8% PRA023 vs. 6.0% placebo, ∆30.8%, p &lt; 0.0001). All remaining ranked secondary endpoints were met (Table 2). The rates of treatment-emergent adverse events (AEs) were similar between the two arms with no serious AEs or AEs leading to study drug discontinuation in the PRA023 arm (Table 3). There were no safety signals identified from the study.

Conclusion
PRA023 was effective with favorable tolerability for the induction of clinical remission and endoscopic improvement in moderately to severely active UC. A Phase 3 study will be conducted to confirm these findings. Recruitment is ongoing for the CDx+ expansion cohort of the study to assess the effectiveness of the CDx, designed to select patients with a higher probability of responding to PRA023.
DOP03 Unfermented β-fructan fibres can induce gut inflammation and tumorigenesis in select Inflammatory Bowel Disease patients mediated by gut microbiota
Authors: Voisin A , Mahmood R , Jeanson T L , Bernstein C , Armstrong H ,   IBD Clinical and Research Centre
Published: January 2023

Abstract

Background
Dietary fibres are not digested in the bowel; they are fermented by microbes, typically promoting gut health. However, IBD patients have altered gut microbiota composition and can experience sensitivity to consumption of fibres. Our previous findings offered the first mechanistic evidence that if dietary β-fructans (inulin and oligofructose) are not fermented by gut microbes in IBD patients, these fibres can induce inflammation. This diet-induced inflammation could have serious repercussions as chronic inflammation creates a mutagenic environment that promotes progression to colorectal cancer (CRC). We hypothesized that unfermented β-fructans cause tumorigenesis and promotion of IBD progression to CRC.

Methods
We examined pathways associated with response to β-fructan in a randomized controlled trial examining β-fructan supplementation (15g/day) in UC patients in remission (RNA sequencing). We validated pathways of interest in IBD patient colonic biopsies cultured ex vivo with β-fructans (targeted proteomics and mesoscale discovery). We examined structural changes (microscopy; e.g., tumorigenic architecture) in these biopsies. Further, cell invasion, migration, and proliferation were examined using scratch wound assays and chick chorioallantoic membrane assays (CAM; n=10 embryos per treatment).

Results
CRC-related pathways (SLIT2/MAPK and SOS1) were induced and anti-tumour gene RPS27A was reduced only in biopsies from remission UC patients who entered relapse following consumption of β-fructans (endpoint versus baseline), not those in the placebo arm who relapsed. Pathways were validated in IBD patient colonic biopsies cultured ex vivo demonstrating oligofructose produced more significant effects than inulin; response correlated with disease severity. Inulin and oligofructose further influenced the processes of migration and invasion reflective of the tumorigenic process of epithelial to mesenchymal transition and risk of CRC.

Conclusion
Our findings suggest that intolerance and avoidance of fibres in select IBD patients occurs specifically in patients whose gut microbiota do not support fermentation of dietary fibres resulting in increased presence of unfermented dietary fibres in the gut. Here we show that these β-fructan fibres commonly touted as beneficial prebiotics can elicit gut inflammation and tumorigenesis in this subset of IBD patients, suggesting consumption of these fibres should be avoided in these patients.
DOP10 Early intestinal resection in Crohn’s Disease is not associated with severe long-term disease course
Authors: Grellier N , Kirchgesner J , Uzzan M , Mclellan P , Stefanescu C , Lefèvre J H , Panis Y , Sokol H , Beaugerie L , Treton X , Seksik P ,   ERIC
Published: January 2023

Abstract

Background
Crohn’s Disease patients (CD) with early complicated behaviour (stenosis and/or fistula) are thought to have a more severe long-term disease course. To address this question, we focused on ileal CD that requires early intestinal resection after diagnosis. We aimed to assess the impact of the time to surgery from diagnosis on the risk of severe disease course in patients with ileal CD undergoing a primary ileocecal resection (ICR) or ileal resection (IR).

Methods
All CD patients who underwent ICR or IR between January 2001 and December 2015 and followed in two Inflammatory Bowel Disease (IBD) tertiary centres in France were included. Data were retrieved using dedicated IBD database and patients’ medical records. Early resection was defined as a surgery performed within 6 months after diagnosis. Two control groups with patients who underwent the first surgery between 6 months and 2 years and between 2 and 5 years after diagnosis were enrolled. The primary outcome was second intestinal resection. Secondary outcomes included the need for biologic treatments after initial intestinal surgery. Patients were followed from the date of first surgery until September 2022. Kaplan Meier survival analysis and log-rank test were used to estimate the survival without second intestinal resection and biologic initiation according to the time of first intestinal resection to diagnosis.

Results
Among 404 patients who underwent ICR or IR within 5 years after diagnosis, 130 (32.2%) patients had undergone surgery within 6 months after diagnosis (Group A), 138 (34.2%) patients between 6 months and 2 years (Group B) and 136 (33.7%) patients between 2 and 5 years (Group C). Clinical data are shown in Table 1. The cumulative risk of a second ICR or IR ten years after the first surgery was 25.2% (95% CI 12.5 - 40.2) in group A, 16.6% (5.1 - 33.9) in group B and 22.8% (9.8 – 39.1) in group C, without statistically significant difference (p = 0.25) (Figure 1). The risk of biological exposure after the first surgery was not significantly different in the three groups (p = 0.12) (Figure 2). The cumulative risk to start a biologic therapy at ten years was 46.2% (35.0 – 56.6) in group A, 39.0% (26.2 – 51.5) in group B and 48.0% (36.3 – 58.8) in group C.

Conclusion
In a bicentric cohort with long-term follow-up, intestinal resection within 6 months of CD diagnosis was not associated with an increased risk of second surgery as compared to patients with primary ICR/IR later after diagnosis. Furthermore, patients with early intestinal resection did not need more biological therapies after the first surgery. These data suggest that early intestinal resection in CD is not a predictor of poor long-term prognosis compared to late resection.
DOP12 Validation of radiomics features on MR enterography characterizing inflammation and fibrosis in stricturing Crohn’s disease
Authors: Sleiman J , Chirra P , Gandhi N , Gordon I O , Viswanath S , Rieder F ,   Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium
Published: January 2023

Abstract

Background
MR enterography (MRE) accurately detects Crohn’s disease (CD) strictures, yet its ability to differentiate inflammatory from fibrostenotic components within a CD stricture is limited. Artificial intelligence in cross sectional imaging, termed radiomics, is a quantitative image extraction analysis technology creating an opportunity to enhance characterization of strictures on routine MRE exams. We present a study on machine-reader evaluation of MRE to distinguish inflammation and fibrosis in CD strictures via quantitative radiomic features and compare radiomics performance to central radiologist scoring of MRE.

Methods
In this retrospective single center study 51 patients (n=34 for discovery; n=17 for validation) had confirmed stricturing CD (using CONSTRICT criteria) on MRE. Surgical histopathology scoring of specimens within 15 weeks of MRE exam (range 0-100, scores ≥70 =severe) was used as the reference standard for both inflammation and fibrosis. An expert abdominal radiologist blinded to clinical and histopathologic results provided a global visual analog scale (VAS, 0-100) assessment of stricture inflammation and fibrosis. 2164 3D radiomic features were extracted from the stricture regions on MRE, from which the most relevant feature subsets were identified via cross-validated machine learning analysis in the discovery cohort for differentiating between severe vs mild inflammation and fibrosis. Radiomic features and VAS scores were evaluated against pathology-defined inflammation and fibrosis in the validation cohort.

Results
Clinical variables including sex, age, Montreal classification and stricture type across discovery and validation groups can be found in Table 1. The median time from MRE to surgical resection was 7.1 90-15) weeks. 43% of strictures in the overall cohort were classified as severe for inflammation and 43% had severe fibrosis. Two distinct sets of radiomic features capturing textural heterogeneity (patterns, local entropy) within strictures were significantly associated with severe inflammation or severe fibrosis (p&lt;0.01). For inflammation, AUC for discovery and validation were 0.69 and 0.67, respectively (Figure 1). For fibrosis, AUC for discovery and validation were 0.83 and 0.77, respectively (Figure 2). The radiologist VAS had an AUC of 0.71 for identifying inflammation and AUC 0.46 for identifying fibrosis. Combining radiomic features and radiologist VAS had no significant impact on predictor performance.

Conclusion
Radiomic analysis may support the identification of fibrosis, but not inflammation in stricturing CD compared to radiological visual assessment. This tool may offer a novel way to stratify patients for future anti-fibrotic therapies.
DOP13 Plasma metabolite fingerprint could discriminate inflammatory bowel disease patients from healthy subjects
Authors: Farkas K , Endre G , Bacsur P , Resál T , Kocsmárszky-Koósz V , Tömösi F , Tóth E , Rutka M , Bálint A , Fábián A , Bor R , Szepes Z , Goretity Á , Thibodeau I , Molnár T 
Published: January 2023

Abstract

Background
Inflammatory bowel diseases (IBD, Crohn’s disease [CD], ulcerative colitis [UC]) are chronic immune-mediated systemic diseases with unknown aetiology. In the past few years, experimental studies revealed associations of human serum and plasma metabolites’ with IBD with a possible discriminative power between IBD and healthy subjects. Our study focused on the utility of plasma metabolome profiling as a diagnostic marker in patients with different phenotypes.

Methods
IBD patients were enrolled in a double-centre prospective cohort study. Large number of healthy subjects were included to reduce methodological bias. Blood samples were obtained at baseline and stored at –20°C and plasma metabolites were measured by high performance liquid chromatography coupled with tandem-mass spectrometry (HPLC-MS/MS). Logistic regression, minimum redundancy maximal relevance (mRMR), principal component analysis (PCA), and linear discriminant analysis (LDA) were used to calculate discriminative power.

Results
Plasma metabolome profile of 26 IBD (13 UC and 12 CD) patients and 168 HC participants were analyzed, and 388 metabolites were measured. 33 and 58% of CD patients and 31 and 39% of UC patients had clinical and endoscopic activity based on clinical (mean pMayo: 2.8±3.4, CDAI: 56±62) and endoscopic (mean PanMayo: 7.4±13.3 and SES-CD: 7.3±8.2) indices. Low plasma level of cysteine (CV=-0.36; p&lt;0.01), triglycerides (CV=-0.19; p&lt;0.01) and hexosylceramide (HexCer(d18:1/23:0); CV=-0.18; p&lt;0.01), while high level of arginine (CV=0.3; p&lt;0.24), hexosylceramide (HexCer(d18:2/23:0); CV=0.2; p=0.02), glutamate (CV=0.19; p&lt;0.01) and lactate (CV=0.16; p=0.01) were significantly associated with IBD. According to mRMR analysis, cysteine (p&lt;0.001), triglyceride (p&lt;0.01), and HexCer(d16:1/22:0); (p&lt;0.001) ranked highest in terms of feature importance (discriminative power). Based on the 16 metabolites considered to be of the highest discriminative power, the healthy and the IBD groups were well separated (PC1=18.2%, PC2=14.7%; Figure 1.).

Conclusion
Based on our results, plasma metabolite levels may help to discriminate IBD and healthy subjects. Integrative analysis of different biological samples may potentially predict IBD and could promote achieving personalized medicine. Further sample collections and analysis within this study can reveal discriminative metabolite fingerprints among IBD subtypes and correlations with activity as well.
DOP14 Identification and validation of a lipidomic signature as a novel diagnostic biomarker of paediatric Inflammatory Bowel Disease
Authors: Salihovic S , Nyström N , Bache-Wiig Mathisen C , Andersen S , Olbjørn C , Perminow G , Opheim R , Detlie T E , Huppertz-Hauss G , Bazov I , Kruse R , Lindqvist C M , Hedin C R H , Carlson M , Öhman L , Magnusson M , Keita Å V , Söderholm J D , D’Amato M , Orešič M , Repsilber D , Hyötyläinen T , Hoivik M L , Halfvarson J 
Published: January 2023

Abstract

Background
Improved diagnostic biomarkers are an unmet clinical need for paediatric inflammatory bowel disease (IBD). We therefore aimed to identify a diagnostic lipidomic signature of IBD in blood.

Methods
We performed a non-targeted liquid chromatography-time of flight mass spectrometry-based lipidomics (UPLC-QTOFMS) analysis of plasma samples from 211 treatment-naïve children with suspected IBD (Table 1). Discovery cohort: the Uppsala Children’s Hospital cohort (n=94); Validation cohort: children from the population-based IBSEN III inception cohort (n=117). All children underwent diagnostic workup for IBD in accordance with the ESPGHAN/Porto criteria. Multivariable and supervised machine learning were used to identify a diagnostic lipidomic signature and its performance was compared to clinically established biomarkers i.e., high sensitivity C-reactive protein (hsCRP) and faecal Calprotectin.

Results
The discovery cohort comprised of 58 children with IBD and 36 symptomatic controls without any discernible evidence of IBD. In the validation cohort, the corresponding numbers were 80 and 37. In a multivariable analysis, using regularized regression and discovery cohort data, a lipidomic signature comprising 30 lipid species was identified as influential in distinguishing IBD from symptomatic controls (Figure 1). Further, while examining both individual lipidomic species and lipidomic signatures in the discovery cohort, the highest diagnostic accuracy was observed for a short lipidomic signature comprising of only two lipid species, LacCer(d18:1/16:0) and PC(18:0p/22:6). When applied to the validation cohort, the short signature improved the diagnostic prediction of paediatric IBD (AUC=0.87 [95%CI 0.79-0.95]) compared to high-sensitivity C-reactive protein (hsCRP) alone (AUC=0.73 [95%CI 0.63-0.82]), P-value=0.0004. Adding hsCRP to the diagnostic model did not improve its performance (AUC=0.86) (Figure 2). Only 77 (66%) children from the validation cohort provided a stool sample, and among these children, the diagnostic capacity of the short lipidomic signature (AUC=0.88 95%CI 0.80-0.95) and faecal Calprotectin (AUC=0.93 95%CI 0.87-0.99) did not differ (P-value=0.22).

Conclusion
This study has identified and validated a diagnostic lipidomic signature of pediatric IBD that was superior to hsCRP and did not differ from faecal Calprotectin. This signature could be developed into an accessible and scalable blood test for paediatric IBD, particularly among patients unwilling to provide stool samples.