bluuebunny/crossref_metadata_2025_split huggingface dataset:
P573 Change in fatigue in patients with Ulcerative Colitis or Crohn’s disease initiating vedolizumab or other biologic therapy: Data from Belgian registry patients
Authors: Louis E , Bossuyt P , Colard A , Caenepeel P , Baert F , Hantson A , Van Gassen G , Zhou J , Vermeire S 
Published: January 2023

Abstract

Background
Fatigue in patients (pts) with ulcerative colitis (UC) and Crohn’s disease (CD) is associated with decreased quality of life. This analysis aimed to describe fatigue evolution and identify factors associated with time to fatigue disappearance or fatigue persistence at 1 year among pts initiating vedolizumab (VDZ) or other biologic treatment (tx).

Methods
Post-hoc analysis of fatigue registry data of Belgian pts being followed in a prospective real-world safety study (PASS; NCT02674308). Pts ≥18 years with UC or CD initiating VDZ or other biologics with no prior VDZ exposure were included. Pts completed the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and physicians collected disease characteristics at baseline and 6-month intervals (4.5-year follow-up). Fatigue persistence was defined by 2 consecutive FACIT-F scores of &lt;40, and fatigue disappearance (in pts with baseline fatigue) by a FACIT-F score of &gt;40. Factors associated with time to fatigue disappearance and fatigue persistence at 1 year were assessed using multivariate regression.

Results
This analysis included 465 pts with UC (n=174) or CD (n=291) who initiated VDZ (n=259) or other biologic tx (n=206) at registry enrolment (Table 1 for baseline characteristics). Change in FACIT-F scores among all pts (Figure 1) showed an improvement in fatigue in the first 6-months following tx initiation before stabilising for the remainder of the study. The Kaplan-Meier estimate for time to fatigue disappearance (Figure 2) indicated fatigue disappearance occurred in 2.1%, 6.2% and 14.2% of pts with baseline fatigue at 6, 12 and 24-months respectively. In pts with baseline fatigue, lower likelihood of fatigue persistence was associated with achieving clinical remission (OR 0.31 [0.16, 0.60]). Probability of fatigue disappearance per unit of time was estimated to be higher in pts with UC vs CD (HR 1.53 [1.07, 2.21]) and in pts achieving vs not achieving clinical remission (HR 2.02 [1.18, 3.48]) and lower in pts with vs without extra-intestinal manifestations at baseline (HR 0.62 [0.39, 0.99]). No associations were observed between fatigue persistence/disappearance and tx group, demographics, disease duration, tx history, use of other medication, history of or active fistula, IBD surgery or clinical response.

Conclusion
These real-world findings suggest fatigue in pts initiating VDZ or other biologic therapy for UC or CD improves in the first 6 months of treatment before stabilising over time. Clinical remission was associated with a lower likelihood of fatigue persistence and shorter time to fatigue disappearance.
P575 Effect of etrasimod on immune cell subsets in colonic tissue of patients with ulcerative colitis: immunophenotyping analysis of colon biopsy samples from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials
Authors: Siegmund B , Komori H K , Abreu M T , Vermeire S , Dotan I , Goetsch M , Crosby C , Ryan R , Woolcott J , Danese S 
Published: January 2023

Abstract

Background
Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). Etrasimod reversibly sequesters specific lymphocyte subsets in lymph nodes, reducing circulating lymphocytes and resulting in fewer immune cells available to traffic to the gastrointestinal tract. To better understand how etrasimod reduces inflammation in UC, the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials included a per protocol exploratory immunophenotyping biomarker analysis in fixed-formalin paraffin-embedded (FFPE) colon biopsies.

Methods
In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). Characterization of immune cell types in colon biopsies were assessed at baseline, week 12, and week 52 (ELEVATE UC 52 only) by Epiontis ID, an epigenetic immune monitoring method. Biomarker levels for each lymphocyte subset were evaluated between responders vs nonresponders, defined by achievement of clinical efficacy criteria within each treatment group, using t-tests and nominal P values.

Results
Colon biopsies were collected and analysed from 276 subjects in ELEVATE UC 52 (179 etrasimod, 97 PBO) and 150 subjects in ELEVATE UC 12 (97 etrasimod, 53 PBO). Etrasimod induced significant changes from baseline (nominal P value &lt;0.05) in colonic T- and B-cell subsets at week 12 in ELEVATE UC 52 and ELEVATE UC 12 (Figure 1), which were maintained through week 52 in ELEVATE UC 52. At week 12, etrasimod induced significant reductions from baseline (nominal P value &lt;0.05) in colonic T- and B-cell subsets expressing IL17A, FOXP3, CCR7, CXCR3, and LRP5A in responders vs nonresponders (Table 1). At week 12, etrasimod, but not PBO, induced significant reductions from baseline (nominal P value &lt;0.05) in colonic CD8B-expressing T cells in responders vs nonresponders in ELEVATE UC 52; these trends were maintained through week 52. Significant effects on CXCR3, FOXP3, and LRP5A were observed in responders vs nonresponders in ELEVATE UC 12.

Conclusion
In this per protocol exploratory analysis of two independent phase 3 trials, etrasimod induced changes from baseline in colonic tissue T- and B-cell subsets in subjects with UC, with nominally significant reductions observed in those who met response criteria. The reduction in activated immune cells in colonic tissue in responders suggests etrasimod induces a reduction in local inflammation that could contribute to remission. These findings are the first to report changes to immune cell subsets in colonic tissue in response to a S1P receptor modulator.
P577 A Phase 1b Study to Evaluate Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of the Nucleotide-binding oligomerization domain, Leucine rich Repeat containing X1 (NLRX1) agonist NX-13 in Ulcerative Colitis
Authors: Peyrin-Biroulet L , Danese S , Colombel J F , Rieder F , Yarur A , Verstockt B , Lichtiger S , Mosig R , Cataldi F , Feagan B 
Published: January 2023

Abstract

Background
NLRX1 is a mitochondrial membrane protein whose activation reduces oxidative stress and decreases effector cell differentiation and cytokine release. NX-13 is a first-in-class, orally active, gut selective NLRX1 agonist with low systemic exposure. In preclinical studies of IBD, NX-13 effectively reduced inflammatory responses and disease severity. A phase 1a study (healthy subjects) showed NX-13 to be well tolerated with low systemic drug exposure suggesting a gut-selective drug delivery. We report the results of a phase 1b study in patients with Ulcerative colitis (UC) on the safety, target engagement and clinical efficacy of NX-13.

Methods
In this double-blind trial, 36 patients with active UC (Total Mayo Score [MCS] 4-10; Mayo endoscopic subscore [MES] 2-3) were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Modified Release (MR) or Placebo to be taken QD for 4 weeks (safety visit at week 5). Biologic exposed patients, stable 5’ASAs dose and corticosteroids (oral ≤20mg/day prednisone or equivalent) were permitted. IV or topical corticosteroids use was prohibited. Primary endpoints were safety and pharmacokinetic (PK) analysis. The study was not powered for clinical efficacy, however MCS, histopathologic Geboes score, and NLRX1, cytokine, and gene expression were obtained at baseline and day 28 in exploratory analyses (Table 1).

Results
During the 5-week observation period, no serious adverse events (AEs) were reported. All AEs were classified as mild or moderate and were most common in the 500mg MR group. One patient was withdrawn before week 5 due to a flare of UC. IR dose plasma PK levels peaked at 1hour, while the MR dose was absorbed later and maintained a low exposure longer. Qualitative immunohistochemical analysis showed target engagement as indicated by increase of NLRX1 at all doses. Symptomatic efficacy was seen in 8/11 patients in the 250mg group with a PRO (RB+SF) score of 0 at week 4. The decrease in MCS was 2.1-3.4 in the NX-13 arms vs 1 point with placebo (Fig 1A) while clinical response rates ranged from 27-72% amongst the active arms with no placebo responders, though no dose-response relationship was observed (Fig 1B). Endoscopic response ranged from 27-40% (Fig 1C), with 5/32 dosed patients being in endoscopic remission. Histologic remission largely paralleled endoscopic response and cytokine and mRNA levels support target engagement.

Conclusion
In patients with active UC, NX-13 was well-tolerated and target engagement was achieved. The exploratory efficacy endpoints indicated rapid clinical, endoscopic, and histologic improvement at week 4, relative to placebo. This novel mechanism of action will be further evaluated in a phase 2 study.
P583 Tofacitinib for acute severe ulcerative colitis: a systematic review
Authors: Ovesen P D , Brynskov J , Seidelin J B , Steenholt C 
Published: January 2023

Abstract

Background
Treatment of acute severe ulcerative colitis (ASUC) comprising iv steroids, second line infliximab or cyclosporin, and finally colectomy, has remained unchanged for nearly two decades and without improvements in colectomy rates. Tofacitinib (TOFA), a pan JAK-inhibitor, has emerged as a potential new treatment option for ASUC. We conducted a systematic review to assess efficacy, safety, and integration in current ASUC algorithms.

Methods
Systematic search in MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Clinicaltrials.gov until August 17, 2022, including all studies reporting original observations on JAK-inhibitor use, notably tofacitinib, for ASUC defined according to Truelove and Witts criteria. Primary outcome was colectomy-free survival. Individual patient data from case reports were pooled and collectively analyzed.

Results
Of 853 publications identified, 20 studies (seven single case reports and eight case series resulting in data from 42 patients; one combined retrospective and prospective GETAID cohort study of 55 patients; one retrospective study of 40 cases and 113 matched controls; one pediatric retrospective cohort study of 11 patients; two ongoing trials) involving 148 patients (female 44-60%, age median 28-34 years, disease duration 5-10 years) treated with second- or third line tofacitinib for ASUC were included.
Colectomy-free survival was 78% from 90-day onwards in the pooled cohort of individual cases (Figure); GETAID cohort 85% 30-day, 79% 90-day, 74% 180-day; and 63% in the pediatric cohort. The case-control study observed lower 90-day colectomy risk among TOFA treated (HR 0.28 [0.10-0.28], p=0.018).

The majority received second line TOFA rescue therapy after initial failure to iv steroids (n=65), and with previous failure to one or more biologics, notable infliximab (n=62, 95%). There was no difference in colectomy rates between patients treated with second or third line TOFA (n=15 (23%) vs. n=1 (8%), p=0.44). Tofacitinib persistence at follow-up was 68-91%, clinical remission 35-69%, endoscopic remission 55%, and without reports of novel or severe safety signals (Table).

Conclusion
Tofacitinib appears to result in high short-term colectomy-free survival among refractory ASUC patients and may have potential in the future treatment of patients otherwise deemed for colectomy. Efficacy was comparable to first line ASUC therapy with iv steroids, but observations are limited, uncontrolled and with short follow-up. High-quality studies are needed.
P587 Intestinal ultrasound (IUS) and magnetic resonance imaging (MRI) for monitoring of response to therapy in luminal Crohn’s disease – a systematic review.
Authors: Lovett G , Schulberg J D , Hamilton A L , Wilding H E , Kamm M A , Wright E K 
Published: January 2023

Abstract

Background
Mucosal and transmural healing are associated with better outcomes in Crohn’s disease. Magnetic resonance imaging (MRI) and intestinal ultrasound (IUS) provide non-invasive cross-sectional assessment of disease activity and transmural healing. This systematic review addresses the utility of MRI and IUS in the assessment of disease activity and transmural healing in response to drug therapy when compared to endoscopy in patients with luminal Crohn’s disease.

Methods
Database searches were undertaken (Medline, Embase, Emcare, APA PsycInfo, CINAHL, Cochrane Library) following the PRISMA statement. Studies with ≥10 luminal Crohn’s disease patients with paired endoscopy and imaging (MRI or IUS) following treatment initiation were included. Records were screened on title and abstract, then full text by two independent reviewers.

Results
5760 records were identified, 1707 duplicates removed, 1468 excluded; 2585 screened on title and abstract, 65 underwent full text review, resulting in 24 studies meeting inclusion criteria. 10 studies examined IUS, 12 examined MRI and 2 compared both. There was good correlation between IUS and endoscopic remission with biologic and or thiopurine treatment (k = 0.63, P&lt;0.001; k = 0.73, P&lt;0.001), and good correlation for IUS score and Simple Endoscopic score-Crohn’s disease (SESCD) at baseline and reassessment (r=0.521; P&lt;0.001). Early reduction in bowel wall thickness (BWT) at 4-8 weeks of anti-TNF therapy predicted endoscopic response at 12-38 weeks (AUROC 0.77; OR 10.80 P=0.012). Significant reductions in BWT after 2 weeks of anti-TNF therapy was associated with clinical and endoscopic response at 14 weeks. A significant reduction in BWT as early as 4 weeks with ustekinumab therapy correlated with endoscopic response at 48 weeks (k = 0.21; 95%CI 0.04-0.38). IUS transmural remission rates were higher in colonic disease than terminal ileal disease (OR 2.59; 95%CI 1.43-4.70, P&lt;0.05). MRI MaRIA score had a high accuracy for predicting endoscopic remission (AUROC 0.967; sensitivity 93%, specificity 77%, P&lt;0.05). Intestinal healing detected by MRI and endoscopy after 1 year of anti-TNF was predictive of long-term clinical remission (sensitivity 75%, specificity 72%; P=0.02). The simplified MaRIA score correlates with endoscopic response and was responsive to change after drug therapy (r=0.72; 95%CI 0.53-0.85).

Conclusion
Intestinal ultrasound and magnetic resonance imaging are reliable non-invasive modalities for assessing transmural healing in Crohn’s disease and accurate in monitoring response to drug therapy. Early changes in ultrasound are predictive of response to treatment. Intestinal ultrasound can monitor response to biologic induction.
P590 ADVANCED-UC TRIAL: AppenDectomy Vs ANti TNF-a in inducing Clinical and EnDoscopic remission in left-sided Ulcerative Colitis – A Randomized Clinical Trial
Authors: Luglio G , Rispo A , Tropeano F P , Cricrì M , Castiglione F , De Palma G D 
Published: January 2023

Abstract

Background
A considerable amount of evidence supports the immunomodulatory role of the appendix in the development and course of Ulcerative Colitis. Indeed, the appendix could act as either a reservoir for commensal bacteria or as the "priming site” for the cytokine production and the immunological cascade triggering inflammation in the colon. Therefore a potential role of the appendix in etiopathogenesis, treatment, prophylaxis and in the colectomy rate in UC has been hypothesized. Given the lack of randomized data on the topic, the ADVANCED-UC trial aims to assess to role of appendectomy in inducing remission in refractory left sided Ulcerative Colitis.

Methods
Consecutive patients with left-sided UC refractory to conventional treatment and candidate to biologics will be randomized in the standard group (anti-TNF alpha) or in the intervention group (laparoscopic appendectomy). Primary endpoints: Steroid Free Clinical Remission, Endoscopic remission and Assessment of Quality of Life at 3 and 12 months. Secondary endpoints: Clinical Response, Failure Rate, Complication rate and Histological Remission at 3 and 12 months; Colectomy rate at 12, 24 and 60 months. To obtain a significance level of 5% and a test power of 90%, it is required a sample size of 148 patients (74 patients per group), assuming a 25% success rate in the control group and a 50% success rate in the experimental group. The study has been already approved by our local IRB (num. 340/21) and has been granted with the Spring Award from the Surgical Research Network by the Crohn’s and Colitis Foundation (CCF). We plan to start the enrollment in 2023 and we are currently recruiting potential participating centers, to run a multicenter, randomized controlled trial

Results
The findings of this study could support a change of treatment paradigm for patients refractory to conventional therapy: indeed, while an appendectomy can protect UC patients from the future use of expensive or potentially dangerous drugs, or even major surgery, the initial additional costs and potential side effects of appendectomy will be offset by substantial health gains and reduced costs later in time. On the other hand, patients undergoing appendectomy which do not experience disease remission and are forced to start biologics will be followed up for the evaluation of the colectomy rate to evaluate the possible synergic effect of appendectomy and biologics in reducing the need for total colectomy in the long term.

Conclusion
The aim of this study is to define the role and effects of laparoscopic appendectomy as a therapeutic option in patients with UC refractory to conventional therapy who are candidates, in the first instance, for biologic anti-TNF-a therapy.
P602 Achievement of stringent histologic and composite endpoints in subjects with moderately to severely active ulcerative colitis treated with etrasimod: a post hoc analysis of the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials
Authors: Magro F , Peyrin-Biroulet L , Sands B E , Danese S , Jairath V , Goetsch M , Bhattacharjee A , Wu J , Ferreira Branquinho D , Modesto I , Feagan B G 
Published: January 2023

Abstract

Background
In ulcerative colitis (UC), persistent histological activity is associated with higher rates of relapse and long-term complications, even when endoscopic remission is achieved; therefore, histological healing is a potentially important treatment target. Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator for the treatment of moderately to severely active UC. This post hoc analysis of the phase 3 ELEVATE programme evaluated the efficacy of etrasimod according to different histologic and composite endpoints.

Methods
In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 utilized a treat-through design comprising a 12-week induction period followed by a 40-week maintenance period. ELEVATE UC 12 comprised a 12-week induction period. A key secondary endpoint was the achievement of endoscopic improvement-histologic remission (EIHR). In this post hoc analysis (baseline MMS 5-9), efficacy of etrasimod was compared to PBO at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12 using additional histologic and composite endpoints defined in Table 1.

Results
At week 12 and at week 52, significant improvements with etrasimod were observed in histologic outcomes, including EIHR (with and without eosinophils), histologic remission, histologic-endoscopic mucosal improvement (HEMI), endoscopic normalization-histologic remission (with and without eosinophils), and disease clearance (Figure 1). In both studies, etrasimod was superior to PBO in achievement of HEMI at week 12 (ELEVATE UC 52 and UC 12: 27.7% vs 8.9%, and 25.7% vs 10.7%, both P&lt;0.001) and at week 52 (ELEVATE UC 52: 32.8% vs 8.9%; P&lt;0.001). Etrasimod was also superior to PBO in achievement of histologic remission at week 12 (33.9% vs 9.6%) and at week 52 (30.7% vs 14.1%, both P&lt;0.001) in ELEVATE UC 52, but not ELEVATE UC 12. Etrasimod was superior to PBO using the more stringent endpoints of endoscopic normalization-histologic remission (week 12 ELEVATE UC 52 and UC 12: 10.6% vs 1.5%, P&lt;0.001 and 10.4% vs 4.5%, P=0.030; week 52 ELEVATE UC 52: 18.2% vs 5.2%; P&lt;0.001) and disease clearance (week 12 ELEVATE UC 52 and UC 12: 8.4% vs 1.5%, P&lt;0.001 and 9.9% vs 4.5%, P=0.042; week 52 ELEVATE UC 52: 18.6% vs 3.7%; P&lt;0.001).

Conclusion
In this post hoc analysis, etrasimod was superior to PBO for achievement of stringent composite endpoints including EIHR, endoscopic normalization-histologic remission, and disease clearance in both ELEVATE UC 52 and ELEVATE UC 12.
P623 Mucosal eosinophils as markers of post-induction vedolizumab response in paediatric Ulcerative Colitis
Authors: Musto F , Ranalli M , Giordano C , Bianchi E , Veraldi S , Oliva S , D’Arcangelo G , Aloi M 
Published: January 2023

Abstract

Background
Vedolizumab (VDZ) is commonly used as an off-label therapy in children with ulcerative colitis (UC) but no predictive factors of response are available. Vedolizumab binds α4β7 integrin and blocks the migration of T-lymphocytes and other cells, including eosinophils, which are involved in the UC inflammatory process. The aim of our study was to explore the predictive value of pre-therapy mucosal eosinophil count on the response to vedolizumab induction therapy in a paediatric population with UC

Methods
This is a retrospective, monocentric study, including children with UC treated with VDZ in the Paediatric Gastroenterology Unit of Policlinico Umberto I Hospital – Sapienza University of Rome. Histopathological data were analyzed for eosinophil counts in high power fields (hpf) in the cecum, transverse colon, sigma, and rectum prior to VDZ treatment. Clinical remission and response were evaluated at week 14 based on the PUCAI score.

Results
Twenty-five UC patients treated with VDZ were enrolled. All patients had failed previous anti-TNF therapy. Median baseline eosinophil count was 21 eo/hpf (5-60) in the cecum, 20 eo/hpf (6-68) in transverse colon, 44 eo/hpf (12-77) in sigma and 31 eo/hpf (9-67) in rectum. Baseline median eosinophil mucosal count in sigma was significantly higher in patients in remission (51[30-82]/ vs. 19[8.5–46] eosinophils/hpf, P&lt;0.05) and clinical response (46[23-79]/ vs. 14[6–45] eosinophils/hpf, P&lt;0.05) at week 14, compared to non-responders. At univariate and multivariate analysis, the number of eosinophils in sigma was confirmed to predict clinical remission [OR=1.0 (95%CI:1.00-1.087), p: 0.03), also independently to concomitant steroid use [OR: 1.06 (95%CI: 1.00-1.122) p: 0.047). The ROC curve identified a risk threshold value for eosinophil count in sigma &gt;23 eosinophils/hpf, with a sensitivity of 85.7% and specificity of 66.7% (Youden’s index 0.83) with an area under the curve (AUC) of 0.778

Conclusion
Mucosal eosinophil abundance in sigma may predict remission to vedolizumab induction in paediatric UC. More studies are warranted to confirm these preliminary results and further investigate the role of mucosal eosinophils as a marker of therapeutic response and in the pathogenesis of UC