bluuebunny/crossref_metadata_2025 huggingface dataset:
P533 Relation between TL1A expression in intestinal mucosa, and endoscopic severity and clinical course in ulcerative colitis
Authors: Shimodaira Y , Yoshida T , Watanabe K , Takahashi S , Fukuda S , Koizumi S , Matsuhashi T , Iijima K
Published: January 2023

Background

TL1A is a TNF super family member cytokine encoded by TNFSF15 and reported to be a disease susceptibility gene for IBD. The relationship between TL1A expression and IBD pathophysiology, clinical course, endoscopic findings was not sufficiently clear. The aim of this study was to clarify the correlation between TL1A expression in the intestinal mucosa of UC and endoscopic severity, clinical severity, and clinical course.

Methods

The subjects were patients with UC who were visiting our hospital. Mucosal samples were biopsied from rectum with lower gastrointestinal endoscopy, and TL1A gene expression was examined by RT-PCR. We analyzed the relationship between patients’ background, clinical symptoms, blood test findings, and mucosal activity and TL1A expression.

Results

A total of 77 specimens obtained with individual colonoscopy from 61 cases were included. Median age was 43, 36 cases were males, duration of disease was 2 years, the number of pancolitis was 54, median partial mayo score (pMayo) was 3, and the level of CRP was 1.5 mg/L. The number with Mayo endoscopic subscore (MES) of 0, 1, 2, and 3 were 14, 27, 24, and 12, respectively, and the mean TL1A expression was 1.76-, 1.09-, and 1.17-times higher in MES 1, 2, and 3 than in MES 0, respectively. TL1A expression was significantly higher in MES 1 than in MES 0 and MES 2. TL1A expression was significantly lower in the active group (pMayo 4 or higher) compared to the clinically low disease activity group (pMayo 3 or lower). TL1A expression was significantly lower with CRP ≥0.03 compared to CRP <0.03. TL1A expression was significantly higher in those with MES 1 at the initial onset than in those with MES 2 and 3. Eight cases were compared before and after induction therapy, and TL1A expression increased 1.9-fold after induction therapy. No correlation was found between the use of biologics and small molecular compounds and the expression of TL1A.

Conclusion

Relatively low activity in UC revealed higher mucosal expression of TL1A. TL1A is known to be secreted from various cell types such as macrophages and lymphocytes. It was suggested that the source of cell types and the amount of expression would alter according to the degree of inflammation.
P555 Systematic review with meta-analysis: The impact of cancer treatments on the disease activity of inflammatory bowel diseases
Authors: Grimsdottir S , Attauabi M , Dahl E K , Burisch J , Seidelin J B
Published: January 2023

Background

The association between cancer treatments and exacerbation of IBD is unclear. We aimed to evaluate the effects of cancer treatments on the disease activity of IBD.

Methods

We performed a systematic review of the literature on cancer therapy in patients with pre-existing IBD. Electronic searches of PubMed, Cochrane Library, and Embase were combined with manual searches (September 2021). Meta-analysis was performed using the random-effects model. The primary outcome was flares of IBD following cancer therapy. Secondary outcomes were need for IBD-related hospitalization, surgery, and initiation or intensification of steroid or biological treatments to manage IBD flares.

Results

In total, 33 studies were included in the systematic review, comprising 1,298 patients with IBD who received cancer treatment (Figure 1). The overall occurrence of IBD flares following cancer treatment was 30% (95% confidence interval (CI) 23-37%, Figure 2). IBD flares resulted in utilization of systemic steroids and biologic therapies among 25% and 10%, respectively, and in discontinuation of cancer treatment among 8% of patients (Figures 3a and 3b). Finally, risk of gastrointestinal toxicity following immune check point inhibitor treatment (ICI) was increased in patients with IBD compared to patients without IBD (RR=3.62, 95% CI 2.89-4.78) (Figure 4). Despite this, the studies generally reported that flares were manageable.

FIGURE 1. Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) flow diagram summarizing study selection.

FIGURE 2: Forest plot of incidence of IBD flares following cancer therapy, grouped by cancer treatment.

FIGURE 3: Forest plot of incidence of need for initiation of a) systemic steroids or b) initiation or intensification of biologic therapyfor managing IBD flares following cancer treatment.

FIGURE 4: Forest plot of risk ratios of GI toxicities following cancer treamtment in patients with IBD vs patients without IBD.

Conclusion

Current data indicate a high proportion of patients with IBD experiencing a flare following the start of cancer treatment. Patients with IBD were at increased risk of gastrointestinal toxicity following ICI treatment compared to those without IBD. However, cancer therapy-induced IBD flares were manageable and should not preclude appropriate cancer treatments.
P560 Curcumin-QingDai combination for patients with active ulcerative colitis: A randomized double-blinded placebo-controlled trial
Authors: Ben-Horin S , Salomon N , Karampekos G , Viazis N , Lahat A , Ungar B , Eliakim R , Kriger-Sharabi O , Reiss-Mintz H , Yanai H , Dotan I , Zittan E , Maharshak N , Hirsch A , Weitman M , Mantzaris G J , Kopylov U
Published: January 2023

Background

The herbal extracts Curcumin and QingDai (QD, Indigo) were previously shown to be effective in mild-moderate and in moderate-severe ulcerative colitis (UC), respectively. We evaluated the efficacy and safety of a combination of curcumin-QingDai (CurQD) in patients with active UC.

Methods

This was a two parts trial. Part 1 was an open label study of 4 weeks CurQD in patients with active UC, defined by a Simple Clinical Colitis Activity Index (SCCAI) score ≥5 and a modified Mayo endoscopic sub-score≥2. Part 2 was a placebo-controlled trial conducted in two centers in Israel and Greece, that randomized active UC patients at a 2:1 ratio to either enteric-coated CurQD 3gr/day or an identical placebo for eight weeks. The co-primary outcome at week 8 was clinical response (reduction in SCCAI of ≥3 points) and an objective evidence of response (Mayo endoscopic subscore improvement of ≥1 or 50% calprotectin reduction from baseline). Responding patients continued either curcumin or placebo alone for additional 8 weeks as maintenance treatment. Expression of Cyp1A1 in rectal mucosa was assessed as a measure of aryl-hydrocarbon receptor (AhR) pathway activation. Curcumin purity, and indigo and indirubin content in CurQD were confirmed by LC-MS/MS.

Results

There were 59 patients enrolled in the two study parts. In efficacy analysis of part 1, 7/10 responded including 3/10 who achieved clinical remission. For part 2, 95 patients were screened and 42 were included and randomized (48.8% biologics and/or immuno-modulators experienced, 36.6% biologics-experienced). The co-primary outcome was achieved in 43% and 8% of CurQD and placebo patients, respectively (p=0.033). Clinical response was observed in 85.7% versus 30.7% (p<0.001), 50% calprotectin-reduction in 46.4% versus 15.4% (p=0.08) and endoscopic improvement in 75% versus 20% (p=0.036), in the CurQD and placebo groups, respectively. The overall rate of adverse events was comparable between the groups. Among week-8 responders to CurQD, additional 8 weeks of treatment with curcumin alone resulted in 93%, 80% and 40% with maintained clinical response, clinical remission and clinical-biomarker response, respectively, at week 16. CurQD treatment uniquely resulted in activation of the AhR pathway, as gauged by a signficantly up-regulated expression of CYP1A1 in the rectal mucosa, which was not observed among patients receiving placebo, 5ASA or biologic drugs.

Conclusion

In this randomized controlled trial, combination CurQD was found to be effective for inducing remission in active UC patients. Induction of AhR may merit further study as a potential treatment target in active UC
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

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 <40, and fatigue disappearance (in pts with baseline fatigue) by a FACIT-F score of >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

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 <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 <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 <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

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

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

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<0.001; k = 0.73, P<0.001), and good correlation for IUS score and Simple Endoscopic score-Crohn’s disease (SESCD) at baseline and reassessment (r=0.521; P<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<0.05). MRI MaRIA score had a high accuracy for predicting endoscopic remission (AUROC 0.967; sensitivity 93%, specificity 77%, P<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

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

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<0.001) and at week 52 (ELEVATE UC 52: 32.8% vs 8.9%; P<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<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<0.001 and 10.4% vs 4.5%, P=0.030; week 52 ELEVATE UC 52: 18.2% vs 5.2%; P<0.001) and disease clearance (week 12 ELEVATE UC 52 and UC 12: 8.4% vs 1.5%, P<0.001 and 9.9% vs 4.5%, P=0.042; week 52 ELEVATE UC 52: 18.6% vs 3.7%; P<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

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<0.05) and clinical response (46[23-79]/ vs. 14[6–45] eosinophils/hpf, P<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 >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
P624 Investigating the symptom burden among European patients with moderate-to-severe Crohn’s disease using a real-world survey
Authors: Burisch J , Hart A , Sturm A , Knight H , Rudolph C , Meadows R , Oortwijn A , Weatherby S , Rolph R , Dawod F , Armuzzi A
Published: January 2023

Background

Despite treatment, patients with Crohn’s disease (CD) experience symptoms that affect their health-related quality of life (HRQoL). Understanding how CD affects HRQoL reveals valuable insight into disease impact. We aimed to examine the disease burden in patients with moderate-to-severe CD in remission vs not in remission using real-world, gastroenterologist (GE)- and patient-reported data.

Methods

Data were drawn from the Adelphi Inflammatory Bowel Disease (IBD) Disease Specific Programme,1 a point-in-time survey conducted in France, Germany, Italy and Spain from October 2020 to March 2021. GEs collected data from the next 5–8 consecutive patients (≥18 years old, not involved in clinical trials) with a CD diagnosis who they saw in clinical practice. GEs reported patient demographics, clinical characteristics (including remission status) and treatment history. Patients completed questionnaires on their treatment satisfaction, symptoms and HRQoL (Short Inflammatory Bowel Disease Questionnaire [SIBDQ] and EQ-5D scores). Scores were compared among patients in remission vs not in remission using propensity score matching (PSM).

Results

Overall, 133 GEs reported on 538 patients with CD (Table 1). Overall, 66.0% of patients were employed, and of those not working, 24.3% were not working due to CD. Most patients (70.9%) had received ≥2 lines of treatment and 43.3% of patients were receiving a tumour necrosis factor (TNF) inhibitor. Of 427 patients from whom complete data were available and were therefore included in PSM analyses, 70.0% (n=299) were in remission. Although patients in remission were generally less likely than those not in remission to experience CD symptoms, they were still moderately likely to experience symptoms such as fatigue/tiredness and abdominal pain (Figure 1). Similarly, whilst patients in remission had better mean SIBDQ and EQ-5D scores than those not in remission, their scores still indicated diminished HRQoL (Figure 2). Of patients for whom symptom data were provided, 39.2% were either not satisfied with their current treatment or believed that better disease control could be achieved. A higher proportion of patients who were dissatisfied with their treatment reported residual symptoms than those who were satisfied, especially abdominal pain, non-bloody diarrhoea and fatigue/tiredness (Figure 3). Characteristics of patients in remission with mucosal healing were similar regardless of whether remission was confirmed by endoscopy.

Conclusion

A substantial proportion of patients with CD, even those in remission, experience high symptom burden and diminished HRQoL despite treatment. There is a need for therapies that provide more comprehensive disease control.

1. Anderson P et al. Curr Med Res Opin 2008:24;3063–72.
P631 Long-term safety of vedolizumab versus other biologic agents in ulcerative colitis (UC) and Crohn’s Disease (CD): Results from a large multinational prospective observational study
Authors: Louis E , Sebastien S , Siegmund B , Bossuyt P , Danese S , de Boer N , Loftus E , Moum B , Peyrin-Biroulet L , Schreiber S , Zhou J , Wernicke J , Angellotti E , Siegel C
Published: January 2023

Background

Vedolizumab (VDZ) is a gut-selective humanised monoclonal anti-α4β7 integrin antibody for treatment of UC and CD. This post-authorization safety study (PASS) compared long-term safety in patients (pts) treated with VDZ or other biologics for UC or CD.

Methods

This was a prospective, observational, multicentre, cohort study in pts with UC or CD starting treatment with VDZ or other biologics (NCT02674308, EUPAS6469). Pts were biologic naïve (VDZ=35%, Other biologic=65%) or had prior exposure to biologics other than VDZ and were followed for up to 7 yrs. Pts were treated under usual standard of care as directed by their physician with no discontinuation from the study due to physician-directed treatment changes. The primary safety outcome was serious infections and was compared between cohorts using a Cox proportional hazards model adjusted by propensity score (with other biologics as reference). Secondary safety outcomes were adverse events (AE) of special interest (AESI) as listed in Tables 2 and 3.

Results

In total, 5208 patients were enrolled across 21 countries between Mar 2015 and Jul 2019. The full analysis set comprised 5008 pts (VDZ=2502; other biologic=2506) and mean (SD) study duration was 37.4 (14.1) months. Consistent with the observational nature of the study and the current standard of care, the baseline characteristics in the two cohorts were imbalanced (Table 1). The overall treatment-emergent Adverse Event (AE) rate was 61.3% (VDZ) and 59.5% (other biologic), with serious AEs in 27.5% (VDZ) and 25.7% (other biologic), respectively. In UC pts, the incidence rate (IR) of serious infections were: 0.014 (95% CI: 0.010, 0.019) [VDZ] and 0.015 (0.010, 0.023) [other biologic], with a hazard ratio (HR) of 1.018 (0.931, 1.114), p=0.70 (Table 2). In CD pts, corresponding findings were 0.012 (95% CI: 0.008, 0.017) [VDZ] and 0.006 (95% CI: 0.004, 0.009) [other biologic] with HR of 1.035 (0.959, 1.117), p=0.38 (Table 3). The incidence of primary and secondary safety outcomes is reported in Table 2 for UC and Table 3 for CD. There were no safety issues relating to pregnancy and no cases of PML observed. There were 19 deaths in the VDZ cohort (1 case of pneumonia deemed as treatment-related); and 13 deaths in the other biologic cohort, 2 cases deemed treatment-related (one case septic shock and pneumonia; one case non-small cell lung cancer). Clinical outcomes and quality of life (QoL) measures were comparable between cohorts.

Conclusion

In this long-term, prospective, real-world observational study of a large multinational population under routine standard of care there was no new safety signal identified in relation to VDZ. Results are consistent with the known safety profile of VDZ.
P638 Effectiveness and safety of risankizumab induction therapy for 100 patients with Crohn’s disease: a GETAID multicentre cohort study
Authors: Fumery M , Defrance A , Roblin X , Altwegg R , Caron B , Hebuterne X , Carmen S , Meyer A , Nachury M , Laharie D , Nancey S , Le Berre C , Serrero M , Geyl S , Gilletta C , Ah Soune P , Duveau N , Uzza M , Abitbol V , Biron A , Tran Minh M L , Paupard T , Vuitton L , Elgharabawy Y , Peyrin-biroulet L ,   GETAID
Published: January 2023

Background

Phase III trials have demonstrated the efficacy of risankizumab in moderate-to-severe Crohn’s disease (CD), but no real-world data are currently available. We aimed to assess the short-term effectiveness and safety of risankizumab in patients with CD.

Methods

From May 2021 to May 2022, all patients with refractory luminal CD treated with risankizumab in 22 French GETAID centers were retrospectively included. The primary endpoint was steroid-free clinical remission at week 12 (Harvey-Bradshaw (HB) score < 5). Secondary endpoints included clinical response (≥ 3-point decrease of HB score and/or (HB) score < 5), biological remission (CRP ≤ 5 mg/L), need for CD-related surgery, and adverse events.

Results

Among the 100 patients included, all have been previously exposed to anti-TNF agents, 94 to vedolizumab, 98 to ustekinumab (all exposed to at least three biologics) and 61 had previous intestinal resection. All but three (97%) received a 600 mg risankizumab intravenous induction at weeks 0-4-8. At week 12, steroid-free clinical remission was observed in 45.8% of patients, clinical remission in 58% and clinical response in 78.5%. Absence/mild abdominal pain with normal stool frequency was noted in 50% of patients at week 12. Biological remission was observed in 50% of patients. Six patients discontinued risankizumab before the week 12 visit due to lack of efficacy. CD-related hospitalization was needed in six patients, and three underwent intestinal resection. In multivariable analysis, only a history of ustekinumab loss of response (vs primary failure) (Odds Ratio (OR), 2.80 ; 95%CI, 1.07 – 7.82; p=0.041) was significantly associated with clinical remission at week 12. Twenty adverse events (AE) occurred in 20 patients including 7 serious AE corresponding to 6 CD exacerbation and one severe hypertension.

Conclusion

In a cohort of highly refractory patients with luminal CD and multiple prior drug failures including ustekinumab, risankizumab induction provided clinical response in about 3 out of 4 patients and steroid-free clinical remission in about half of patients.
P639 Percutaneous drainage vs surgery as definitive treatment for anastomotic leak after intestinal resection in patients with Crohn’s disease.
Authors: Belvedere A , Dajti G , Larotonda C , Angelicchio L , Rizzello F , Gionchetti P , Poggioli G , Rottoli M
Published: January 2023

Background

Anastomotic leak remains one of the most relevant complications after intestinal resection for Crohn’s disease (CD). While surgery has always been considered the standard treatment for perianastomotic abscess or collection, percutaneous drainage (PD) has been proposed as a potential alternative.

The aim of this study was therefore to compare the success rate of percutaneous drainage with that of surgery for the management of anastomotic leak in CD patients.

Methods

Retrospective, single-centre study including all consecutive patients who were diagnosed with an anastomotic leak as a complication of intestinal resection for CD between 2004 and 2022. Patients requiring emergency surgery due to generalised peritonitis or clinical instability were excluded. Anastomotic leak was defined as a perianastomotic fluid collection confirmed by radiological findings within 30 days from surgery. Patients underwent either PD or surgery as a primary treatment for the complication. The success after PD was defined as the removal of the drainage with clinical and radiological resolution of the complication. The need for further surgical treatment was considered as a failure in both groups.

Primary aim: to compare the success rate of PD vs surgery. Secondary aims: to compare the outcomes at 90 days after the procedures; to identify the variables associated with the indication to PD.

Results

Among the 47 patients included, 25 (53%) underwent PD and 22 (47%) surgery. Table 1 shows the outcomes by the procedure.

Success rate was 84% in PD and 95% in surgery group (p=0.20). The median time to success was 14 days after PD (drainage removal) and 12.5 days after surgery (discharge) (p=0.92). Similar rates of post-procedure medical (12% vs 18%, p=0.55) and surgical (24% vs 36%, p=0.62) complications were shown. An ileostomy was required in 91% of surgery cases. At 90 days, similar rates of discharges (100% vs 95%, p=0.28), readmissions (8% vs 0%, p=0.18) and reoperations (16% vs 9%, p=0.48) were observed between PD and surgery cases, respectively.

In the multivariate analysis (Table 2), PD was more likely to be performed in patients whose anastomotic leak was diagnosed later after surgery (OR 1.25, 95%CI 1.03-1.53, p=0.027), in those who underwent an ileo-colic anastomosis alone (OR 3.72, 95%CI 2.29-12.45, p=0.034) and in those who were treated after 2016 (OR 6.36, 95%CI 1.04-39.03, p=0.046).

Conclusion

The present study confirms that PD is a safe and effective procedure to treat anastomotic leak and perianastomotic abscess in CD patients. Surgery, in particular, is associated with a high risk of stoma formation, which would require a subsequent operation. PD should be indicated in all eligible patients as an effective alternative to surgery.
P655 MadCAM1 Negativity of Lamina Propria Endothelial Cells is Associated with Non-Response to Vedolizumab in Inflammatory Bowel Disease Patients
Authors: Zelinkova Z , Podmanicky D , Berakova K , Kadleckova B
Published: January 2023

Background

Vedolizumab (VDZ), a monoclonal antibody against α4β7 integrin has been shown to be effective in inducing and maintaining remission in inflammatory bowel disease (IBD). By blocking α4β7, it is preventing the homing of lymphocytes through binding to mucosal vascular adressin cell adhesion molecule 1 (MadCAM1) localised on the intestinal endothelial cells. We have previously reported that MadCAM1 is expressed to various extent on lamina propria endothelial cells of IBD patients and that this expression is stable over time. The aim of the present study was to analyse whether expression of MadCAM1 was related to the response to VDZ in IBD patients.

Methods

All IBD patients treated with VDZ in one referral IBD centre were included. The biopsies or resection specimen from the inflamed intestinal tissue were stained by immunohistochemistry for MadCAM1 expression. Clinical response to vedolizumab was assessed in patients with the minimal treatment duration of 10 weeks and the response rate between patients with positive and negative MadCAM1 were analyzed by Fisher`s exact test.

Results

In total, 92 IBD patients were treated with VDZ; for 83 of them intestinal biopsies or surgical specimen were available for assessment of MadCAM1 expression. In four patients (5%) no expression of MadCAM1 was detected, remaining 79 patients expressed MadCAM1 to various extent.

Overal, 30 patients (36%) were non-responders to VDZ treatment. With regards to MadCAM1 expression, 67% of patients expressing MadCAM1 responded to VDZ (53 patients) while none of the patients negative for MadCAM1 responded to treatment (p=0.0171).

Conclusion

Lack of MadCAM1 expression in intestinal endothelium is associated with clinical non-response to vedolizumab.
P660 Body composition and health-related quality of life in adult Crohn’s Disease during clinical remission: The INTICO2 cohort study
Authors: McDonnell M , Sartain S , Westoby C , Katarachia V , Davis C , Cummings F , Wootton S
Published: January 2023

Background

A reduction in the absolute or relative mass of lean tissue or muscle mass in the context of disease and/or malnutrition are well-described features associated with poor prognosis. Conversely, excessive adiposity may lead to metabolic disease, increased inflammation and has been linked to adverse CD outcomes. Bioelectrical impedance analysis (BIA) allows estimation of fat-mass index (FMi kg/m2) and fat-free mass index (FFMi kg/m2) which can be expressed standardised as Z scores using device-specific age and gender reference ranges. Here we report the body composition and relationship between BMI, elevated FMi and reduced FFMi Z scores and patient reported outcome measures in an adult cohort in CD clinical remission.

Methods

194 adult CD outpatients in clinical and biochemical remission were recruited from a single tertiary IBD service (Harvey Bradshaw Index <5 and calprotectin <250µg) as part of the INTICO2 observational study. 55 had undergone previous intestinal resection, 81 were on biological therapy, 67 immunomodulator and 33 both. Subjects needed to be in intestinal continuity and not currently receiving either exclusive or partial EN or IV nutrition. Body composition was assessed using BIA (seca mBCA 515) and expressed as FMi and FFMi Z scores. Health and disease-related quality of life was assessed using Short Form 36 (SF36) and the fatigue-specific PROM FACIT-F.

Results

The Median BMI of the cohort was 26.1 (18.0-48.9) Kg/m2. One subject was underweight (≤18.5) by BMI, 37% of patients (71/194) were overweight (BMI ≥25), of which 47 (24% of cohort) were obese (BMI≥30). 16/97 of men and 11/97 of women were below the 5th centile (SDS score <-2) for age and sex matched values for FFMi, respectively. Of the 27 individuals with reduced lean mass, 20 had a normal BMI (20-25), 2 were overweight (25-30). 14/97 and 21/97 of women were above the 95th centile for FMI Z-scores (SDS score >2), all had BMI over 30. Excessive fatigue was present among the population affecting 25% (49/194). FMiz was correlated to excessive fatigue among women (r- 0.236 p<0.05), but there was no relationship to FFMiZ among either sex.

Conclusion

While weight loss is a recognised presentation of CD, this characterisation of a large outpatient adult cohort in remission found the commonest BMI-defined malnutritional states to be overweight or obese. In the population of individuals with predominantly normal or elevated BMI, sarcopenia was common, masked by excessive adiposity and may not have been appreciated without BIA assessment of body composition. Body composition analysis estimates of excessive age and sex matched adiposity was correlated to excessive fatigue, which was common in the population.