Endoscopic Response Research Articles

P542 Clinical decision support tool guided selective intensive induction strategy of ustekinumab in patients with Crohn’s disease: real-world evidence

Abstract Background Clinical decision support tool (CDST) of ustekinumab (UST) can predict the possibility of drug response1. However, the potential benefits of initial intensification induction therapy (IIT) to improve clinical outcomes for different responders has not been explored2. We aimed to evaluate the effectiveness and safety of the strategy of initial IIT for Crohn’s disease patients who exhibit varying responses based on UST-CDST. Methods This is a multicenter retrospective study included active Crohn’s disease patients who were low, intermediate and high probability responders according to UST-CDST (Figure 1). IIT was defined as intensive induction by 2 or 3 initial doses of a weight-based intravenous UST. The patients treated with standard therapy (ST) were identified as controls. The primary endpoint was corticosteroid-free clinical remission (CFCR) at week 24. The secondary endpoint was clinical remission, clinical response, endoscopic remission, endoscopic response, and CRP normalization at week 24. Propensity-matched analyses were applied to ensure comparability. Results A total of 296 patients were included, with 69 patients receiving IIT and 227 patients receiving ST. At week 24, in low-intermediate probability responders, IIT group was associated with higher rates of CFCR (72.3% vs 43.0%, OR 3.47 [95%CI 2.15-5.68], clinical remission (77.3% vs 47.1%, OR 3.82 [95%CI 2.33-6.37]), clinical response (78.1% vs 60.1%, OR 2.37 [95%CI 1.43-3.97]), endoscopic remission (50.6% vs 22.4%, OR 3.55 [95%CI 1.65-7.92]) and endoscopic response (83.1% vs 44.1%, OR 6.23 [95%CI 2.75-15.26]). CRP normalization were comparable. In high probability responders, all end points did not demonstrate statistically significant differences (Table 1). The cut-off UST trough concentration for predicting corticosteroid-free clinical remission was determined to be 1.43µg/mL, with an area under the curve (AUC) of 0.612, a sensitivity of 55.0%, and a specificity of 70.0%. No serious adverse events occurred. Conclusion Initial dose intensification induction in low-intermediate responders based on UST-CDST was superior to the ST in both clinical and endoscopic remission at week 24, which provide a novel strategy for stratifying patients at baseline. 1. Park J, Chun J, Yoon H, Cheon JH. Feasibility of a Clinical Decision Support Tool for Ustekinumab to Predict Clinical Remission and Relapse in Patients With Crohn's Disease: A Multicenter Observational Study. Inflamm Bowel Dis. 2023;29(4):548-554. 2. Ren H, Kang J, Wang J, et al. Efficacy of Ustekinumab Optimization by 2 Initial Intravenous Doses in Adult Patients With Severe Crohn's Disease [published online ahead of print, 2023 Aug 24]. Inflamm Bowel Dis. 2023; izad184.

P700 The efficacy of adalimumab combined with surgery for rectovaginal fistula in Crohn's disease：a single-center retrospective study

Abstract Background To assess the efficacy of adalimumab(ADA)combined with surgery in the treatment of Crohn's disease patients with rectovaginal fistulas. Methods A single-center retrospective study. The baseline data of patients with Crohn’s rectovaginal fistulas who visited the Anorectal Department of the Affiliated Hospital of Nanjing University of Chinese Medicine from January 2020 to July 2022 and accepted ADA combined with surgery treatment were included. Crohn’s disease Activity Index(CDAI), perianal disease activity index(PDAI) and inflammatory parameters, including Erythrocyte sedimentation rate(ESR) and C-reactive protein(CRP), were statistically analyzed at weeks0, 48. Follow-up was performed every 8 weeks. The outcomes included clinical response, clinical remission, fistula response, fistula remission, fistula remission under MRI, endoscopic response and endoscopic remission. Results A total of 43 RVF patients were included, 53.4% (23/43) patients were treated with Seton,44.1% (19/43) patients were treated with Advancement flap and 2.3%(1/43) patient was treated with Fecal diversion, with a median follow-up of 11.0 (2.5-15.0) months. After 48 weeks of treatment, CDAI[325(262,397)vs.197(134,396)], PDAI[8(6,9) vs. 5(3,6)], ESR[31(8,50) mm/h vs. 10(4,28)mm/h]and CRP[4.62(0.85, 14.45)mg/L vs.0.5(0.5,2.14)mg/L] were significantly lower than 0 week (Table 1) . CDAI, PDAI, ESR and CRP at the 48th week of treatment were significantly lower than those before treatment (p<0.05). At the last follow-up, 62.7%(27/43) patients achieved clinical response, 30.2%(13/43) achieved clinical remission. Meanwhile 69.7%(30/43) of patients achieved fistula response,32.5%(14/43) achieved fistula remission(Table 2),and 25.5%(11/43) achieved fistula remission under MRI; A total of 37 patients completed endoscopic re-examination, including 54.0% (20/37) of patients with endoscopic response and 24.3%(9/37) with endoscopic remission. Conclusion ADA combined with surgery is effective in the treatment of patients with Crohn’s rectovaginal fistulas.

P981 Risankizumab, but not ustekinumab or vedolizumab, downregulates IL-23-induced mucosal pathogenic Th17 cells in patients with Crohn’s disease

Abstract Background We recently described an interleukin(IL)-23-inducible pathogenic subset of CCR6+CXCR3-CCR5+ mucosal T helper (Th)17 cells (pTh17) infiltrating Crohn’s disease (CD) inflamed mucosa and specifically activated in response to Adherent-Invasive Escherichia Coli. pTh17 cells are functionally and phenotypically distinct from CCR6+CXCR3-CCR5- Th17 cells (cTh17) and from IL-12-induced CCR6+CXCR3+ Th1/17 subset. Here, we investigated pTh17 cells' recirculation into the bloodstream, localization into the intraepithelial lymphocyte (IEL) compartment, and in-vivo modulation by different biological therapies. Methods Adult patients with active CD initiating either vedolizumab as per clinical practice or ustekinumab and risankizumab during the SEQUENCE trial were prospectively recruited at Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano. In vedolizumab-treated patients, peripheral blood and intestinal biopsies were collected at baseline and at the end of induction. In ustekinumab- and risankizumab-treated patients, intestinal biopsies were collected outside study protocol assessments at baseline and week 24. Endoscopic response was defined as a greater than 50% decrease in the Simple Endoscopic Score from baseline. Peripheral blood mononuclear cells, lamina propria mononuclear cells (LPMC), and IEL were isolated and analyzed through flow cytometry. Results Overall, 34 CD patients were assessed. Demographic and baseline disease characteristics are summarized in Table 1. At baseline, as compared with cTh17, pTh17 cells: 1. are rarely found in the peripheral blood and express low levels of CCR9 and α4β7, 2. express high levels of tissue-resident markers CD69+CD103+ in the mucosa, and 3. infiltrate the IEL layer upon binding of CD103 with E-cadherin. Baseline pTh17 cells were upregulated in patients not achieving vedolizumab-induced endoscopic response. Upon vedolizumab treatment, a selective downregulation of mucosal cTh17 cells but not pTh17 was observed. Remarkably, risankizumab induced a specific downregulation of pTh17 cells, but not cTh17, in both LPMC and IEL layers. Conversely, ustekinumab reduced Th1/17 mucosal subsets, but not pTh17 cells (Figure 1). Conclusion pTh17 cells are largely unable to recirculate through the bloodstream, express markers of gut-tissue residency, and infiltrate the IEL compartment. IL-23 neutralization by risankizumab specifically downregulates mucosal pTh17 cells, as compared with vedolizumab and ustekinumab. Our immunologic results might provide mechanistic clues to vedolizumab latency effect in CD, and potentially explain early signs of risankizumab superiority over ustekinumab in the SEQUENCE study in terms of endoscopic response at 24 weeks.

P807 HLA type impact on immunization and efficacy of ustekinumab in IBD patients: a multicenter study

Abstract Background About 30% of patients treated with ustekinumab will present primary or secondary failure. Outcomes and frequency of ustekinumab immunization are still controversial. Some HLA types (especially DQA1*05) appear to be predictive factors of anti TNFα immunization. This study aimed to assess the impact of HLA type on the risk of immunization and on the efficacy of ustekinumab. Methods IBD patients treatede with ustekinumab in Saint-Etienne and Lyon hospitals were included between 2017 and 2023. Ustekinulab through level was measured by ELISA and HLA type (DQA1, DQB1, DRB1) determined by PCR. Anti-drug antibodies (ADA) detection was done using both a "drug sensitive" assay (ELISA) and an innovative "drug tolerant" method based on anti human lambda chain. Data about clinical, biological (CRP, fecal calprotectin) and endoscopic responses were retrospectively collected. Results Among the 115 patients included (43% males, mean age of 40 years old), 98 had Crohn disease. Nighty-eight percent of the patients were previously treated with at least one anti-TNFα and 33% of them were immunized. In this study, 43 patients were immunized against ustekinumab with the "drug tolerant" assay and only 2 with the "drug sensitive" method. Immunization tended to reduce (not significatively) clinical, biological and endoscopic responses. Ustekinumab through level was significately higher for patients with good clinical (p = 0.009) and biological (p = 0.036). HLA DQA1*05 or DRB1*03 carriage was associated with higher risk of immunization (OR = 5.13, p = 0.048 / OR = 5.36, p = 0.006) and with a trend to decrease clinico-biological response. Other HLA types, notable DQA1*01 tended to be associated with a lower immunization (OR = 0.7, p=0.3) and a better response (OR = 2.55, p = 0.018). A small group involved (26 patients), combination therapy at induction had no significant benefit in terms of immunization prevention or therapeutic response. Sub-groups analysis seemed to confirm some HLA types involvement, by breaking free of imbalances due to haplotype transmission. Conclusion Our study suggests the usefulness of ustekinumab monitoring and a more common immunization than previously described. HLA type seem to influence immunization and ustekinumab response. Some specific HLA types and patients profiles tend to be associated with a higher risk of immunization not only to anti-TNFα but also to ustekinumab.

P854 Tofacitinib demonstrates preliminary efficacy in induction of remission in chronic pouchitis

Abstract Background Pouchitis is common following total proctocolectomy for ulcerative colitis (UC) and ileal pouch-anal anastomosis (IPAA) and generally responds to antibiotics. However, up to 20% of patients develop either antibiotic-dependent or antibiotic-refractory pouchitis, collectively referred to as chronic pouchitis. Methods We report our preliminary induction results from a multi-center open label induction with randomized withdrawal trial to assess the efficacy of tofacitinib in chronic pouchitis. All eligible participants received 10mg tofacitinib twice daily for 8 weeks, with an additional 8 weeks of therapy given to patients with an inadequate initial clinical response. The primary endpoint was clinical response (a reduction of clinical PDAI≥2) at week 8. Secondary endpoints included endoscopic response (a reduction of endoscopic PDAI≥2), mPDAI remission (modified pouchitis disease activity index (mPDAI)≤ 4 and a reduction of mPDAI≥2), mPDAI response (a reduction of mPDAI≥2) and improvement in health-related quality of life (HRQoL) using the short inflammatory bowel disease questionnaire (SIBDQ). Serum cytokine levels was analyzed using LEGENDplex human inflammation panel 1. Univariate analysis was performed to identify clinical and biochemical predictors of response to tofacitinib. Results A total of 33 patients with chronic pouchitis (Table 1) were included in the preliminary analysis. The clinical and endoscopic response rates at week 8 were 55% and 58% respectively, with a median improvement of 1 (p<0.05) and 3 (p<0.05) respectively (Figure 1). The mPDAI remission rate was 49% at week 8 with an mPDAI response rate of 73%. Endoscopic responders exhibited significant improvements in endoscopic oedema, granularity, friability, and mucous exudate (p<0.05). There was significant improvement in HRQoL, with the median SIBDQ score increasing from 35 at baseline to 54 at week 8 (p<0.05). Eleven patients received a further 8 weeks of therapy with a clinical response rate of 36%, yielding an overall response rate including extended induction of 67%. Univariate analysis did not reveal significant differences in baseline characteristics, clinical, or biochemical markers between responders and non-responders. However, a history of corticosteroid use (p=0.08) and high baseline levels of faecal calprotectin (p=0.15) demonstrated a non-significant association with treatment response. Elevated baseline serum levels of IL-1b, IFN-a and IL-33 were associated with a treatment response at week 8 (p<0.05). Conclusion Tofacitinib demonstrated preliminary efficacy in inducing both clinical and endoscopic response in patients with chronic pouchitis who have undergone IPAA for UC.

P698 Effectiveness and Safety of Ustekinumab for Ulcerative Colitis: A Brazilian Multicentre Real-World Observational Study

Abstract Background Real-world data on the effectiveness and safety of ustekinumab (UST) in ulcerative colitis (UC) are lacking in Latin America. In this study, we aimed to describe the effectiveness and safety of UST in a real-world multicentre cohort of Brazilian patients with UC. Methods We conducted a multicentre retrospective observational cohort study, including patients with moderate to severe UC (Total Mayo score 6-12, with an endoscopic subscore of 2 or 3) who received UST. The co-primary endpoints were clinical remission, defined as a total Mayo score ≤2 at 1 year, with a combined rectal bleeding and stool frequency subscore of ≤1, and endoscopic remission (endoscopic Mayo subscore of zero) within one year from baseline. Secondary endpoints included clinical response between weeks 12-16, endoscopic response within one year of starting UST, steroid-free clinical remission at week 52, and biochemical remission at week 52. We also evaluated UST treatment persistence and safety. Results A total of 50 patients were included (female, n=36, 72.0%), with a median disease duration of 9.2 years (1-27). Most patients had extensive colitis (n=38, 76.0%), and 43 (86.0%) were steroid-dependent at baseline. Forty patients (80.0%) were previously exposed to biologics (anti-TNF drugs, n=31; vedolizumab [VDZ], n=27). The co-primary endpoints of clinical remission and endoscopic remission at 1 year were achieved by 50.0% and 36.0% of patients, respectively. Clinical response at weeks 12-16 was 56.0%, endoscopic response, steroid-free clinical remission, and biochemical remission at week 52 were 68.0%, 67.4%, and 50.0%, respectively. The UST treatment persistence rates at 24 months was 73.7%. During the follow-up, 10 patients (20.0%) were hospitalized, mostly due to disease progression, and three patients required colectomy. Nine patients (18.0%) discontinued the drug mainly due to a lack of effectiveness. Twenty-six adverse events (AEs) were reported, 15 of which were considered as serious AEs. Conclusion This is the first real-world experience study to report the effectiveness and safety of UST specifically in a Latin American population. In this real-world cohort of difficult-to-treat UC patients, UST was associated with improvements in clinical, biochemical, and endoscopic outcomes. The safety profile was favorable, consistent with the known profile of UST.

P706 Tofacitinib in Moderate to Severe Ulcerative Colitis patients naïve to biological therapy: A prospective real world analysis of efficacy and safety

Abstract Background Tofacitinib is an oral non-selective Janus Kinase inhibitor approved for Ulcerative colitis (UC) after the failure of biological therapy. Tofacitinib as first line therapy in biologic naive patients has not been evaluated. Methods We conducted a prospective study to assess the safety and efficacy of Tofacitinib as first line therapy in biologic naive moderate to severe UC. Tofacitinib was given at a dose of 10mg BD for 8 weeks followed by de-escalation to 5mg BD maintenance in responders. Dose escalation was done for relapses. Demographics, disease characteristics, concomitant medication, adverse events, severity and time to relapse were recorded. Clinical response and remission (defined as partial Mayo score: PMS decrease ≥2 and PMS ≤1 respectively) were measured at 4 weeks, 8 weeks, 24 weeks and 52 weeks. Endoscopic response (UCEIS score decrease ≥2) and remission (UCEIS 0-1) were assessed at 1 year. Time to event analysis was done to evaluate the cumulative rate of clinical response. Results 176 patients (136 biologic naive, 58% male; median age 40y [IQR:31-48y]) were included. Median baseline PMS and UCEIS score were 5 (IQR: 5-7 and 4-6 respectively) (Table 1). Of the biologic naïve cohort, clinical response was achieved in 68.4% and 79.4% at 4 and 8 weeks respectively. Clinical remission was achieved in 45.6%(4-weeks) and 55% (8-weeks). Maintenance of remission was seen in 44.1% and 32.4% in 24 and 52 weeks respectively (Fig1A). There was a significant reduction in PMS from baseline to end of 8-weeks (p<0.001) (Fig 1B). Corticosteroid-free clinical remission was achieved in 64.8% at 24-weeks. 106 patients (77.9%) maintained response till last follow-up. 11 relapsed after dose de-escalation (median time of 5m [range 3-22m]. 7/11 responded to dose escalation to 10mg. Endoscopic response was noted in 62.5% and remission in 33.9% with significant reduction in UCEIS from baseline to 52-weeks(p<0.001) (Fig 1B). Severe and minor adverse events were noted in 4 and 3 patients respectively (Table 1). Overall 1/3 of patients discontinued therapy at 24-weeks (14%) and 52 weeks (10%). No significant difference in proportion of clinical or endoscopic remission was observed between the biologic naïve and those with history of prior biologic usage (n=31, median time from withdrawal of biologics to Tofacitnib initiation=9 months). Conclusion Tofacitinib was effective in induction of clinical remission in more than half of biologic naive, moderate to severe UC . Three-fourth of these patients continued to be in remission at one year with few serious adverse events. Tofacitinib can be considered as upfront oral therapy after failure of conventional management.

OP40 Transcriptomic signature of response to vedolizumab in patients with moderate-to-severe ulcerative colitis: Results from an international, multicentre, retrospective cohort study

Abstract Background Transcriptomic analysis has the potential to facilitate drug development and clinical decision making in inflammatory bowel disease. Current understanding of pharmacodynamic response to vedolizumab is limited by a lack of publicly available mucosal biopsy RNA samples/sequencing data and corresponding clinical information. We aimed to identify gene signatures associated with response to vedolizumab in ulcerative colitis (UC) patients by pooling data from 3 international sites. Methods Patients receiving vedolizumab for the treatment of moderate-to-severe UC at Hospital Clínic de Barcelona (IDIBAPS), Mount Sinai Hospital (MSH), and University of California, San Diego (UCSD) with baseline and post-treatment (week 14 [± 4 weeks]) mucosal biopsy RNA-sequencing data and Mayo Clinic endoscopic subscores (MCES) were eligible for inclusion. Endoscopic response was defined as an MCES <1. Demographic and clinical data were collected. Differential expressed genes (DEGs) between baseline and week 14 were identified using linear mixed models with a >1.5 or <-1.5-fold change (adjusted P-value <.05). Enrichment was performed using Reactome pathway analysis and a previously published UC gene signature (adjusted P-value <.05).1 Analyses were performed using R version 4.3.0. Results Twenty-three patients were included (IDIBAPS: n=12; MSH: n=8; UCSD: n=3). Site-specific differences in sex, surgical history, and corticosteroid use were observed (Table). Analysing data by site yielded a relatively small number of DEGs between baseline and week 14 (IDIBAPS=57 [27 up-regulated, 30 down-regulated]; MSH=0; UCSD=0) among endoscopic responders (IDIBAPS: n=5; MSH: n=7; UCSD: n=2). Combining data from the 3 sites increased the number of DEGs among endoscopic responders at week 14 (n=14) to 1162 (662 up-regulated and 500 down-regulated). The down-regulated DEGs were enriched for genes involved in 37 of 103 up-regulated Reactome pathways in UC, including neutrophil degranulation, interleukin-4 and interleukin-13 signalling, interleukin-10 signalling, and integrin cell surface interactions. The up-regulated DEGs were enriched for genes involved in 1 of 39 down-regulated Reactome pathways in UC (Drug ADME). Conclusion We defined a pharmacodynamic signature using mucosal biopsies from UC patients who had endoscopic response to vedolizumab at week 14. The signature was enriched for several, but not all, pathways involved in UC. In addition to providing insight into vedolizumab’s mechanism of action, we underscored the utility of multi-site collaboration to access data, increase statistical power, and enhance the generalizability of research findings. Reference: 1. Linggi et al. Sci Rep 2021;11:18243.

P108 Response to vedolizumab in ulcerative colitis is associated with reduced neutrophil extracellular traps formation and IL-1β production: insights from NEUTROVED study

Abstract Background Vedolizumab (VDZ) is a humanized mAb against integrin α4β7. VDZ inhibits gut inflammation by impeding intestinal T-cell homing, however, recent data suggest that effects of α4β7 blocking extend beyond T-cells to alterations in innate immunity. Neutrophils are key components of innate immune response and inflammation in ulcerative colitis (UC). Studies have provided evidence linking neutrophils with UC pathogenesis, through autophagy induction and production of IL-1β-enriched neutrophil extracellular traps (NETs). NEUTROVED aimed to investigate the effects of VDZ treatment on neutrophils that may be associated with clinical and endoscopic response. Methods Patients with moderate-to-severe UC who received VDZ in standard medical care were evaluated in two timepoints, 24 hours before treatment initiation (T1) and at week 14 of treatment (T2). Clinical/endoscopic scores and common laboratory indexes were evaluated. In parallel, RNA-sequencing in peripheral neutrophils was performed, and markers of NETs in plasma and intestinal biopsies were assessed. Results In total 5 patients completed the study until today (Table 1). In T2, 4 patients demonstrated complete remission, and one patient had mild disease. No adverse events were recorded. RNA-sequencing analysis of paired samples revealed 248 significantly downregulated and 109 upregulated genes in peripheral neutrophils after VDZ treatment. Bioinformatics analysis using the GeneCodis4 web-based tool revealed that downregulated DEGs clustered mainly in immune-related pathways, including neutrophil degranulation, Toll-like receptor cascades, signaling by interleukins, NETs formation, and HIF-1 signaling pathway, while upregulated DEGs were involved in RNA metabolism-related processes, and the ribosome biogenesis pathway. A comparative analysis between these differentially expressed genes (DEGs) and our previous RNA-sequencing data of peripheral neutrophils isolated from active UC patients (n=24) highlighted a set of 168 DEGs as restored targets after VDZ therapy. Of note, several unique genes implicated in neutrophil activation, including IL-1 signaling components, were found significantly downregulated after VDZ therapy. In line with the abovementioned transcriptome alterations, markers of NETs and IL1β-bearing NETs in plasma and colonic tissue were significantly reduced, recapitalizing clinical and endoscopic response to VDZ. Conclusion Response to VDZ treatment in UC is related to anti-inflammatory actions on neutrophils characterized by reduced NETosis and IL-1β production through NETs. Further mechanistic studies investigating the possible effects of VDZ on innate immunity and neutrophil-mediated responses are warranted.

P824 Association between visceral adipose tissue and disease duration, clinical activity, and response to various biological agents in inflammatory bowel disease

Abstract Background The relationship between body fat composition and inflammatory bowel disease (IBD) progression, medical response, and prognosis is widely acknowledged. Visceral adipose tissue (VAT) has been shown to be profoundly responsible of most of the obesity-associated metabolic derangements, however it is also related to severity of inflammation. Although VAT can be estimated using computerized tomography, abdominal bioimpedance is a new and reliable technique without expense and radiation exposure. We investigated whether VAT is linked to the disease activity in severe IBD and the short-term response to biological therapies. Methods We prospectively evaluated 65 IBD patients, (n=26 with ulcerative colitis (UC) and n=39 with Crohn’s disease (CD) who had moderate-severe disease activity) at baseline before the initiation of biological therapy. We quantified VAT using abdominal bioimpedance (ViScan). VAT and other body fat metric measures (BMI, total and free fat mass, abdominal fat mass) were also analyzed. The response to biological agents was assessed by clinical (Mayo and CDAI) and endoscopical (mucosal healing) scores at 3 months. Results Out of the 65 patients, 22 individuals (33.8%) exhibited clinical and/or endoscopic response after 3 months. Among responders and non-responders, there was a comparable approximation of disease location (p=0.321) and behavior (p=0.239). Patients with CD had slightly lower levels of VAT, BMI, and free fat mass compared to those with UC. In non-responders with UC, VAT levels were lower than in responders, whereas in non-responders with CD, VAT levels were higher than in responders. No distinction was observed in the VAT response among other classes of biologics, including anti-TNF, ustekinumab, and vedolizumab. Conclusion In summary, VAT parameters using bioimpedance (ViScan) were found to be correlated with the disease activity and reliably identified IBD patients who responded well to various biological treatment in the short-term. Therefore, human fat indices might be novel biomarkers for disease severity and response to therapy.

P983 Treatment of patients with moderate-to-severe Crohn’s disease with subcutaneous infliximab leads to an endoscopic response across all segments of the colon and terminal ileum: A post hoc analysis of the LIBERTY-CD study

Abstract Background Mucosal healing (MH) has been associated with positive long-term clinical and surgical outcomes in patients (pts) with Crohn’s disease (CD).1 Patterns of MH vary by therapeutic agent, with limited efficacy in the terminal ileum.2–4 This post hoc analysis aimed to investigate the pattern of endoscopic MH across intestinal segments in pts who received subcutaneous (SC) infliximab (IFX) maintenance treatment in the Phase 3 LIBERTY-CD study. Methods LIBERTY-CD demonstrated superior efficacy of SC CT-P13 120 mg every 2 weeks (Q2W) vs placebo (PBO) after IV IFX induction for clinical remission and endoscopic response at Week (W) 54.5 This post hoc analysis evaluated centrally read and batch analysed Simple Endoscopic Score for Crohn's Disease (SES-CD) values obtained at screening, W22 and W54 for 5 ileocolonic segments (rectum; left, transverse and right colon; and terminal ileum). Pts with missing data or who underwent dose escalation to SC IFX 240 mg Q2W upon loss of response from W22 were imputed as non-responders. Endoscopic complete MH (CMH; defined as SES-CD=0) or partial MH (PMH; defined as ≥50% decrease in the SES-CD from screening) were evaluated for segments that had endoscopic abnormalities at screening (segmental SES-CD ≥1 at screening). Results were analysed descriptively. Results Among all randomised pts (N=343; SC CT-P13: n=231, PBO: n=112), the most frequently affected segment at screening was the left colon (187/343; 54.5%), followed by the right colon (185/343; 53.9%), rectum (163/343; 47.5%), terminal ileum (156/343; 45.5%) and transverse colon (134/343; 39.1%). In an analysis of all affected segments, endoscopic CMH rates were higher with SC CT-P13 vs PBO (Figure 1A). Endoscopic CMH rates in the terminal ileum at W54 were 46.7% and 19.6% in the SC CT-P13 and PBO arm, respectively (p=0.0014). PMH rates were also significantly higher in the SC CT-P13 arm across all segments at W22 and W54 (Figure 1B), with rates in the terminal ileum of 64.8% and 33.3% in the SC CT-P13 and PBO arm, respectively (p=0.0003). Conclusion SC IFX 120 mg Q2W led to high and consistent endoscopic MH rates across all segments, including the terminal ileum. Early observation of endoscopic MH (at W22) underscores the potency of SC IFX treatment. Further studies are warranted to investigate the association between segmental MH and long-term outcomes. 1Otte ML et al. World J Gastroenterol 2023;29:1157–72. 2Danese S et al. Gastroenterology 2019;157:1007–18. 3Reinisch W et al. J Crohns Colitis 2017;11:425–34. 4Wu Y et al. Therap Adv Gastroenterol 2020;13:1756284820976923. 5Hanauer SB et al. Gastroenterology 2023;164(S6):S220–1.

P1044 Mirikizumab Pharmacokinetics and Exposure-Response in a Phase 2 Study in Patients With Moderately to Severely Active Crohn’s Disease

Abstract Background Mirikizumab (miri) is a humanized anti–interleukin-23-p19 monoclonal antibody approved for the treatment of ulcerative colitis (UC) and under development for Crohn’s disease (CD). This analysis characterises miri pharmacokinetics (PK) and the relationship between miri exposure and efficacy response using data from a phase 2 trial in adults with moderately to severely active CD. Methods AMAG was a randomised, double-blind, placebo-controlled trial conducted in 14 countries. Patients received placebo, miri 200 mg, 600 mg, or 1000 mg as induction regimens administered intravenously (IV) every 4 weeks (Q4W) through Week 12, followed by 36 weeks of maintenance treatment with continuous treatment of miri 200 mg, 600 mg, or 1000 mg IV or miri 300 mg administered subcutaneously (SC) Q4W. PK parameters were analysed by non-linear mixed-effects modelling. Covariate effects on miri exposure were evaluated using simulation-based estimations. Exposure-response (ER) for patients achieving endoscopic response by Simple Endoscopic Score for Crohn’s Disease (SES-CD) at Weeks 12 and 52 were assessed using logistic regression models. Results 186 patients were included. The estimated systemic clearance (CL), central volume of distribution (V), and SC bioavailability (F) were 0.022 L/hr, 3.31 L, and 33.4%, respectively. Lower baseline values for SES-CD (indicative of a less severe CD) were associated with reduced CL. Lower body weight and higher albumin levels were also associated with reduced CL. Higher body weight was associated with higher V and lower baseline body mass index correlated with higher SC F. Impacts on PK parameters were small relative to random variability and not considered clinically relevant. The model-based ER analyses for endoscopic response probability at Week 12 detected a significant treatment effect relative to placebo (p<0.001) and a significant ER (p=0.001) in a dose range of 200-1000 mg. The ER analyses indicated near maximal efficacy for IV dose between 600 mg and 1000 mg during the Induction Period. There was no significant relationship between miri exposure and the probability of achieving endoscopic response by SES-CD at Week 52, indicating exposures produced by the maintenance doses provided similar efficacy. Conclusion Miri PK characteristics in adults with active CD were consistent with miri UC studies. Overall, none of the covariates identified as being significantly correlated with miri PK parameters were considered clinically relevant. No patient factors evaluated in this analysis justify dose adjustment. These findings support the miri induction dose 900 mg IV Q4W and maintenance dose 300 mg SC Q4W selected for phase 3 CD study.

P998 Phase 2 basket design study evaluating the efficacy and safety of an anti-TL1A antibody (TEV-48574) in moderate to severe ulcerative colitis or Crohn's Disease (RELIEVE UCCD)

Abstract Background TEV-48574 is a human antibody that targets tumor necrosis factor (TNF)-like ligand 1A, also known as TNF superfamily member 15 (TNFSF15). TEV-48574 is being evaluated in the first basket design trial in IBD. The basket design is uniquely suited for the efficient assessment of TEV-48574 as evidence suggests that TL1A signaling plays a key role in both ulcerative colitis (UC) and Crohn’s disease (CD). TL1A signaling is not a primary driver but an amplifier of inflammation; thus, targeting TL1A should mitigate excessive immune responses while leaving baseline immunity intact. Originating in oncology trials, the basket trial design has emerged as a new efficient approach for testing treatment efficacy in different disease indications with potentially common molecular mechanisms. The basket design approach allows the evaluation of multiple indications in a single study design that provides adequate support for initiation of confirmatory studies. Additionally, the basket design allows for shared sites and institutional review boards, data collection and analyses under consistent conditions. Herein, we describe the phase 2b basket trial evaluating TEV-48574 in UC and CD (clinicaltrials.gov NCT05499130), currently ongoing along with a long-term extension study (LTE)(NCT05668013). Methods In this double-blind placebo-controlled global study, TEV-48574 or placebo is administered subcutaneously to adults (n = 240) diagnosed with moderate-to-severe IBD (UC (n = 120) or CD (n = 120)). Patients who meet pre-specified inclusion/exclusion criteria are randomized to either one of two TEV-48574 dose regimens or placebo in a 1:1:1 ratio (stratified by diagnosis (UC or CD) and previous exposure to advanced IBD therapy(biologics and small molecules)) for 14 weeks. Patients who complete the 14-week induction period have the option to enter the LTE, consisting of a 44-week maintenance period for responders and a re-induction period for non-responders. Primary efficacy endpoints are induction of clinical remission (a modified Mayo Score of ≤2 points for UC), and endoscopic response (a reduction in Simple Endoscopic Score for Crohn's Disease (SES-CD) of ≥ 50% from baseline) for CD, at week 14. A Bayesian approach will be used to compute posterior probabilities for the response endpoints within each indication. Additional endpoints include safety assessments, measures of clinical response, biomarkers, pharmacokinetics, and immunogenicity. Results Conclusion TEV-48574 is a potential novel treatment option for patients with UC and CD that may have dual antifibrotic and anti-inflammatory effects. The phase 2 basket study design offers an efficient approach to advance TEV-45874to confirmatory phase 3 studies.

P682 A Retrospective Comparison of Different Treatment Modalities in Patients with Chronic Pouchitis

Abstract Background Chronic pouchitis affects ~30% of patients post total colectomy with ileal pouch anal anastomosis (IPAA) surgery. Treatment with anti-TNF, anti-integrin α4β7, anti-IL-12/23, or Crohn's disease exclusion diet (CDED), have shown promise in different studies. We aimed to compare the efficacy of these treatments in a real-world context and to detect factors that can aid in treatment choices. Methods A retrospective cohort study encompassing demographic, clinic, endoscopic, histologic and lab values of adult ulcerative colitis (UC) patients post-IPAA surgery with chronic pouchitis, treated with biologics or CDED at the Tel Aviv Medical Center. Data were collected at baseline, 12, 26, and 52 weeks of treatment. Primary outcomes were assessed using the modified Pouchitis Disease Activity Index (mPDAI). mPDAI response was defined as a reduction from baseline of ≥2 points, while mPDAI remission was defined as mPDAI response in addition to mPDAI score ≤4. Results Therapeutic interventions among 51 patients included CDED (n=10), vedolizumab (n=21), ustekinumab (n=7) and adalimumab (n=13) [Table 1]. At 12 and 26 weeks, overall mPDAI response rates were 52% and 48%, respectively, with no significant difference between groups. At 52 weeks, mPDAI response rates were significantly higher for ustekinumab and vedolizumab (60% and 55%, respectively) compared with adalimumab and CDED (27.3% and 0%, respectively), p=0.043. Fecal calprotectin reduction at week-26 was greatest for ustekinumab (93%), followed by vedolizumab (73%), adalimumab (55%), and CDED (-13%), p=0.003. Treatment persistence over 150 weeks was significantly higher for ustekinumab (100%) compared with adalimumab (46%), vedolizumab (33%), and CDED (20%), p<0.001 [Figure 1]. The predominant cause for treatment discontinuation was secondary loss of response (50%), followed by primary non-response and surgical complications (14.7% each), poor compliance (11.8%), side-effects (5.9%), and development of antibodies (2.9%). Patients without prior biologic or immunomodulator treatment for pouchitis had significantly higher mPDAI response rates at 12 weeks (90%, p=0.016 and 73.3%, p=0.03, respectively). Patients with surgical pouch complications showed a trend towards lower mPDAI-defined response rates at 12 weeks (25% vs. 64.7%; p = 0.064). Conclusion Ustekinumab and vedolizumab demonstrate higher likelihood of maintaining long-term clinical and endoscopic response, along with greater reduction in fecal calprotectin compared with adalimumab and CDED. Biologic and immunomodulator therapy-naïve patients achieved higher induction response rates.

P1074 Impact of body mass index (BMI) on clinical outcomes and drug levels in patients with Crohn’s disease receiving maintenance treatment with subcutaneous infliximab: A post hoc analysis of the LIBERTY-CD study

Abstract Background Obesity and high levels of visceral adipose tissue are associated with lower response rates to intravenous (IV) infliximab (IFX).1 Subcutaneous (SC) IFX is a novel formulation that demonstrated superiority to placebo as maintenance therapy in patients (pts) with moderate-to-severe active Crohn’s disease (CD) in the Phase 3 LIBERTY-CD study. Assessing efficacy of SC IFX by BMI is important as, unlike the IV formulation, pts receive a fixed dose. This post hoc analysis aimed to assess the association between BMI and the efficacy of SC IFX therapy. Methods Data from LIBERTY-CD (NCT03945019) were analysed; 231 pts from the SC IFX arm were divided into four subsets by their BMI: underweight (BMI <18.5 kg/m2, n=27); normal (18.5–24.9 kg/m2, n=133); overweight (25–29.9 kg/m2, n=53); obese (≥30 kg/m2, n=18). Co-primary endpoints at Week (W) 54 (clinical remission [CD Activity Index (CDAI) score <150]; endoscopic response [≥50% decrease in Simple Endoscopic Score for CD (SES-CD) from baseline (BL)]) and W54 change from BL in CDAI score were assessed by BMI subset. Correlations between BMI and CDAI score, SES-CD or median trough level of infliximab (TLI), and the impact of BMI on W54 TLI, were evaluated. Analyses were conducted in a descriptive manner. Results At W54, there were no statistically significant differences in co-primary endpoints or change from BL in CDAI score across BMI subsets, despite descending trends in rates of achieving co-primary endpoints, change in CDAI score and TLI with increasing BMI (Table). From the underweight to obese subsets, clinical remission rates were 63.0%, 66.2%, 58.5% and 44.4% (p=0.125), endoscopic response rates were 55.6%, 36.1%, 41.5% and 27.8% (p=0.207) and median changes from BL in CDAI score were −227.3, −212.9, −196.2 and −204.5 (p=0.358). No significant correlations were observed between BMI and CDAI score (Pearson r=0.0972/p=0.141; Spearman rank r=0.0619/p=0.349) or BMI and SES-CD (Pearson r=0.0446/p=0.507; Spearman rank r=0.0375/p=0.577), while there was a weak, but significant, negative correlation between BMI and TLI (Pearson r=−0.2808/p<0.001; Spearman rank r=−0.2829/p<0.001) (Figure). Additionally, there was a significant difference in median W54 TLI across BMI subsets from underweight to obese (17.0, 13.6, 9.3 and 6.6 µg/mL; p=0.007) (Table). Conclusion While there was a significant difference in TLI across BMI subsets, there was no statistically significant impact of BMI on W54 clinical or endoscopic outcomes. These results could be explained by the relatively high TLI achieved with the SC formulation. Further larger and longer-term studies including pts with morbid obesity and utilising body composition assessment are warranted. 1Yarur A et al. Gastroenterology 2023;165:963–75.

P900 A PROOF-OF-CONCEPT, PLACEBO-RANDOMIZED CONTROLLED TRIAL TARGETING ADHERENT AND INVASIVE ESCHERICHIA COLI (AIEC) WITH ANTIBIOTICS IN CROHN’S DISEASE: the TEOREM TRIAL

Abstract Background Adherent-invasive E. coli (AIEC) are found in the ileal mucosa of 21-63% of patients with ileal Crohn’s disease (CD) vs 0-16% of controls. This trial tested the efficacy of antibiotics targeting AIEC in CD patients with ileal involvement, colonized by AIEC. Methods Eligible patients had endoscopically active (CDEIS ≥8) ileal or ileocolonic CD and either a clinically inactive, or mild to moderately active disease that responded to budesonide or prednisolone. AIEC search was performed on ileal biopsies, by phenotypical assays. The primary endpoint was the endoscopic overall response at week 12, defined as segmental response in at least 1 segment, and < 20% increase of CDEIS in other segments. Segmental response was defined by decrease ≥ 50% of surface of ulcerations, or loss of deep ulcerations (if any). Secondary endpoints were ΔCDEIS ≥ 50% in at least 1 segment with CDEIS ≥ 8 at baseline, and remission (CDEIS < 6 in all segments). Endoscopic endpoints were assessed by a central, anonymous and blinded scoring of video recordings of colonoscopies at preinclusion and week 12. Patients were randomized 1/1 between oral Ciprofloxacin 500 mg bid + Rifaximin 800 mg bid and double placebo for 12 weeks. In this subgroup of patients selected for AIEC colonization, we were in search of a strong signal of efficacy. We hypothesized that 60% of patients in the experimental arm and 25% of those in the placebo arm would reach the primary endpoint. 31 patients in each arm were planned to demonstrate such a difference. Results Between May 2016 and June 2021, 155 patients were screened, of whom 91; 27 were AIEC positive and 24 patients (12 in each arm) were randomized in 10 centres. 17 patients had a clinically active disease. All AIEC strains of randomized patients were sensitive to ciprofloxacin and rifaximin. Clinical and endoscopic characteristics were similar in the 2 arms. 2 patients did not have colonoscopy at week 12 (1 tendinitis and 1 had no colonoscopy during the COVID pandemic). 7/10 patients cleared AIEC at week 12 in the experimental arm, vs 6/12 in the placebo arm. The 3 patients who received antibiotics and remained AIEC+ after antibiotics acquired resistance to ciprofloxacine. Results are displayed in the table. There was no association between AIEC clearance and endoscopic endpoints. A Bayesian, post hoc analysis showed that the probability to obtain a 35% difference in the primary endpoint between the two arms of the trial was of 25%. Conclusion Antibiotics were not statistically superior to placebo to achieve endoscopic response and remission in patients with ileal CD colonized with AIEC. There was no association between AIEC clearance and endoscopic endpoints. Differences were numerically in favour of antibiotics.

P146 Latent activation of the extrinsic coagulation pathway in patients with ulcerative colitis

Abstract Background Ulcerative colitis (UC) is associated with an increased risk of venous thromboembolism. We investigated the correlation of UC severity with latent activation of the extrinsic coagulation pathway and colonic stromal tissue factor (TF) expression. Methods Plasma exosomes, microparticles (EM), TF protein, activities of EM-bound TF (EM-TF) and FVIIa, as well as TF mRNA (F3) in primary colonic stromal cells in culture were measured. Disease extent by Montreal classification, medications, UC clinical activity by partial Mayo score (PMS), endoscopic severity by the MS endoscopic component (eMS; loss of response defines as ≥2), quality of life by the short IBD questionnaire- SIBDQ, complete blood count, CRP, ESR and albumin were retrieved. Statistical significance (p) was assessed with the following tests: Student’s t for 2 groups with normally distributed values, Mann-Whitney U if not, Wilcoxon test for paired data. Correlation of continuous against scale variables was assessed with Pearson’s or Spearman’s r and corresponding p values for linear or logarithmic continuous variables, respectively. Results Plasma was obtained from 38 UC patients (31 males, disease duration 151±25 months, 14 with extensive colitis, 5 current smokers) and 28 healthy blood donors (HBD; 20 males) who served as controls. TF mRNA (F3) was measured in primary colonic stromal cells in culture from 12 UC patients (11 males, disease duration 169±53 months, 8 with extensive colitis, 1 current smoker) and from 7 controls undergoing screening colonoscopy. UC patients had 4- and 3.7- times more exosomes and microparticles than controls, respectively (A). TF protein correlated with PMS (r 0.443), albumin (-0.362), ESR (0.353), PLT (0.575) and endoscopic UC severity (0.468; B). EM-TF activity was 1.6-times higher (C) and correlated to disease extent (E3: 1.9 x E2), albumin (-0.624), endoscopic severity (0.422; D) and SIBDQ (-0.64). Downstream, FVIIa activity was 2.2-times higher. Refractory-to-treatment patients had 5.8-, 1.5-, 2.1- times higher TF protein (E), MP-TF, FVIIa activity, respectively. Within responders, the need for steroids or biologics correlated with 2.2-times higher MP-TF activity. Colonic stromal cells from patients with UC maintained a 2.2-times higher F3 (F), which correlated to PMS (0.56), albumin (Spearman’s r -0.543), endoscopic severity (M3: 8.3 x M2). All the aforementioned were statistically significant with a < 0.05. Conclusion The extent of spontaneous activation of the extrinsic coagulation pathway is associated with clinical and endoscopic UC activity and response to treatment. TF in colonic stromal cells mirrors its systemic activity and indicates the possible contribution of such cells to increased TF plasma bioactivity.

P592 Higher predictive power of epigenetic signatures for response to vedolizumab and ustekinumab in anti-TNF naïve patients with active Crohn’s disease

Abstract Background Despite the significant progress in IBD care with biological therapies, the current 'trial-and-error' method remains suboptimal. Previous results from our EPIC-CD study demonstrated that two distinct epigenetic panels of 25 and 68 DNA methylation markers, respectively, were associated with (non-)response to vedolizumab (VDZ) and ustekinumab (USTE) in active Crohn’s disease (CD)1. Data from clinical trials have demonstrated that response rates in patients naïve to biological treatment are higher. We therefore aimed to evaluate the performance of our models in bionaive and anti-TNF exposed subpopulations. Methods We prospectively measured peripheral blood DNA methylation profiles from 184 adult CD patients prior to treatment with VDZ or USTE in a discovery (n=126) and independent validation (n=58) cohort using the Illumina EPIC BeadChip array. Between 26 and 52 weeks, patients were categorized as responders or non-responders based on a combination of endoscopic response (≥50% reduction in SES-CD score), steroid-free clinical response (≥3-point drop in Harvey-Bradshaw Index (HBI) or HBI ≤4 AND no systemic steroids), and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Epigenetic biomarker identification and classification analyses were conducted through stability selection gradient boosting on the discovery cohort. Subsequently, the performance of the identified epigenetic biomarkers was assessed independently on the validation cohort, with patients stratified by prior anti-TNF exposure. Results Out of the 58 patients in the validation cohort, 25 received treatment with VDZ, and 33 with USTE, with 52% (n=13) and 36% (n=12) respectively naïve to anti-TNF treatment. Baseline characteristics between anti-TNF naive and anti-TNF exposed patients showed no significant differences, despite a slight significant age difference in the vedolizumab group, where anti-TNF exposed patients were significantly younger (table 1). In the overall independent validation cohort, the prediction models demonstrated an AUC of 0.75 for both VDZ and USTE. However, after stratification by prior anti-TNF exposure, we observed increased performance of our models among anti-TNF naive patients for both VDZ (AUCnon-exposed=0.85 versus AUCexposed=0.66) and USTE (AUCnon-exposed=0.97 versus AUCexposed=0.63 (figure 1). Conclusion Our findings demonstrate that prior anti-TNF exposure leads to somewhat reduced predictive power of our epigenetic models for Vedolizumab and Ustekinumab response. The predictive models may therefore find its optimal application in bio-naive patients, although they remain significant in anti-TNF exposed patients.

DOP65 Infliximab plus azathioprine and quick steroids discontinuation versus azathioprine plus steroids in patients with acute severe Ulcerative Colitis responding to intravenous steroids: a parallel, open-label randomized controlled trial

Abstract Background In patients admitted for acute severe ulcerative colitis (ASUC) responding to intravenous (IV) steroids, the most effective treatment is unknown. In thiopurine-naive patients, thiopurines are appropriate to maintain remission according to current guidelines while the benefit of early infliximab (IFX) therapy remains to be established. Methods In this multicentre, parallel group, open-label randomised controlled trial, thiopurine and biologics-naïve adults admitted for ASUC defined by a Lichtiger score >10 were included between 2016 and 2021 if they responded to IV steroids. They were randomly assigned to receive either combination therapy with IFX and azathioprine (AZA) with a quick steroid discontinuation (IFX+AZA arm), or AZA and standardized steroid tapering regimen (AZA arm). The primary endpoint was treatment failure at W52, defined as absence of steroid-free clinical remission (MCS≤2 with no individual subscore >1), absence of endoscopic response (Endoscopic subscore ≤1), use of a prohibited treatment, adverse event leading to interruption of allocated treatment, colectomy or death. A sample size of 73 patients per group was initially calculated. Due to challenges in recruiting patient, the steering committee decided to prematurely terminate the study blindly of any study results, after including 64 patients. Results 64 were randomised (32 males, age of 34.5 [26.3-50.3] years, Lichtiger score of 13.0 [12-14], CRP of 29.0 [12.8-96.8] mg/L and serum albumin of 31.2 [27.7-35.6] g/L at baseline): 32 were assigned to IFX+AZA arm and 32 to AZA arm. In ITT population, treatment failure at w52 was observed in 81.5% in the AZA arm versus 53.3% in the IFX+AZA arm (OR 3.85 [1.15-12.88], p=0.03). Components of the composite primary endpoint are given in table 1. In PP population, treatment failure at week 52 was observed in 81.5% (22/27) in the AZA arm versus 50.0% (13/26) in the IFX+AZA arm (OR 4.40 [1.28-15.18], p=0.02). In total 121 adverse events (AE) were reported in 40 patients including 23 serious AE in 18 patients (11 in the IFX + AZA arm and 7 in the AZA arm, p=0.24) and 8 leading to treatment interruption (5 in the IFX+AZA arm and 3 in the AZA arm, p=0.39). Serious AE included infectious AE in 6 cases (1 in the AZA arm and 5 in the IFX+AZA arm, p=0.20) and UC relapse in 9 (4 in the AZA arm and 5 in the IFX+AZA arm, p=0.60). No death was reported. Conclusion At w52, combination therapy with IFX + AZA and quick steroids discontinuation was more effective than AZA with standard steroids tapering regimen to prevent treatment failure in patients with ASUC responding to IV steroids. Combination therapy with IFX and AZA should be encouraged in ASUC patients responding to IV steroids (EudraCT 2014-005212-42; study funded by Pfizer).

P576 Fecal calprotectin could predict clinical and endoscopic response to ustekinumab therapy

Abstract Background Ustekinumab (UST) is one of the most used biologic drugs for the treatment of Crohn’s Disease (CD) and Ulcerative Colitis (UC). However, not all patients achieve clinical remission and even less mucosal healing. There is currently scarce knowledge about the early markers of therapeutic response in this setting, with particular regard to mucosal healing. The aim of this multicenter study was to evaluate the role of fecal calprotectin (FC) as early predictor of mucosal healing. Methods We enrolled consecutive patients with CD or UC treated with UST for at least 48 weeks at four referral centers in the last 5 years. Therapeutic response was evaluated in terms of clinical remission (defined as a Partial Mayo Score <2 for patients with UC and as Harvey Bradshaw Index <5 for patients with CD, without concomitant corticosteroid therapy) and mucosal healing (defined as a Mayo Endoscopic Score <2 for UC and as the disappearance of ulcers for CD). We collected clinical and demographic data, as well as fecal calprotectin (FC) and C-Reactive Protein (CRP) levels at baseline and at week 24. Results Among 196 patients enrolled (73 [37.2%] women), 167 were affected by CD, whereas 29 by UC. Globally, 128 (65.3%) patients achieved clinical remission and 83 (42.3%) endoscopic remission at 48 weeks of treatment. There were no group differences in age, sex, BMI, baseline clinical and endoscopic indexes, or baseline CRP levels between patients achieving or not either clinical or endoscopic remission. Baseline calprotectin levels were lower in patients who achieved endoscopic remission (median [interquartile range] 391 [103, 1050] versus 825 [317, 1800] µg/mL,p=0.002). At week 24, lower calprotectin levels were observed in both the groups who achieved clinical (160 [50, 426] versus 439 [146, 1000] µg/mL,p<0.0001) and endoscopic remission (114 [43, 265] versus 392 [139, 912] µg/mL,p<0.0001) compared with non-responders. The effects of week-24 calprotectin levels on clinical remission (β= -0.003,p<0.0001) and endoscopic remission (β= -0.004,p<0.0001) remained significant in multivariable models adjusted for age, sex, and BMI. A cut-point of 268 µg/mL was identified as the optimal threshold of week-24 calprotectin for predicting clinical remission (sensitivity 65%, specificity 67%, ROC AUC 0.689), while a cut-point of 309 µg/mL was identified to predict endoscopic remission (sensitivity 79%, specificity 59%, ROC AUC 0.712). Conclusion Our data suggest that FC assessment after 24 weeks of treatment with UST could represent a promising early marker of response, even in terms of mucosal healing, in both CD and UC.