Ustekinumab Research Articles

P521 Effectiveness of ustekinumab as therapy for chronic antibiotic refractory pouchitis

Abstract Background Up to 10% of patients with ulcerative colitis who undergo a proctocolectomy with ileal pouch-anal anastomosis, will develop chronic antibiotic refractory pouchitis (CARP). As there is a large unmet need in the management of these patients, we evaluated the efficacy and safety of induction and maintenance therapy with ustekinumab (UST). Methods We performed a prospective, multicentre, open-label study of patients with CARP (mPDAI ≥5 with an endoscopic subscore ≥2) . Patients received a weight-range-based infusion of UST at baseline (~6mg/kg) and subcutaneous injections of 90mg UST every 8 weeks thereafter until week 48. Patients underwent a pouchoscopy at baseline, week 16 and week 48, with assessment of the modified pouchitis disease activity index (mPDAI). The primary endpoint was the proportion of patients achieving steroid-free remission (mPDAI <5 and reduction by ≥2 points from baseline) at week 16. For this abstract we focus on the secondary endpoints at week 48 including the proportion of patients achieving steroid-free remission and response (reduction of mPDAI by ≥2 points from baseline) using a non-responder imputation. For patients still continuing UST at week 48, we evaluated the change in symptomatic and endoscopic mPDAI subscore, C-reactive protein (CRP) and faecal calprotectin levels compared to baseline. Descriptive statistics and paired nonparametric tests (Wilcoxon signed-rank) of changes from baseline were performed. Results We enrolled 22 patients (59% male, median age 42.2 years, median time after surgery 8.2 years). Twelve (54.5%) patients had previously been treated with biologics for CARP (table 1). At week 16, steroid-free remission was achieved in 27.3% of patients. At week 48, steroid-free remission was achieved in 36.4% and response in 54.5% of patients. In the 14 patients continuing UST at week 48, a significant decrease in total mPDAI (4 (1.8-7.3) vs. 8 (8-10), p<0.001), clinical subscore (1 (0-2.3) vs. 3 (2-4), p=0.001), and endoscopic subscore (3 (1.8-4.3) vs. 6 (4.8-6), p=0.001) was observed compared to baseline (figure 1). Faecal calprotectin (129 (80-344) vs. 229 (139-541) mg/kg, p=0.17) and CRP (2.5 (1.3-4.4) vs. 3.8 (1.6-9.3) mg/L, p=0.09) levels did however not decrease significantly (figure 2 and 3). Three serious adverse events (hospitalization for subobstruction, worsening pouchitis and choledocholithiasis) were recorded, but were not considered related to UST. Conclusion In this open-label pilot study in patients with CARP, maintenance therapy with UST showed a clinical and endoscopic effect in half of the patients, but was not associated with changes in inflammatory biomarkers. These promising results warrant confirmation in a placebo-controlled study with UST for the treatment of CARP.

P473 Corticosteroid-free clinical remission rates with guselkumab maintenance therapy in patients with moderately to severely active Crohn’s disease: Week 48 analyses from the phase 2 GALAXI 1 study

Abstract Background Corticosteroids are often used in Crohn’s disease (CD) to control inflammation. However, they are associated with adverse events; thus, achieving and maintaining remission without corticosteroids is a major treatment goal. GALAXI 1, a phase 2b, double-blind, placebo (PBO)-controlled study, evaluated efficacy and safety of guselkumab (GUS), a selective interleukin-23p19 subunit antagonist, in patients (pts) with moderately to severely active CD. Primary efficacy and safety data were presented previously. Here, we report corticosteroid-free clinical remission rates through Week (Wk) 48. Methods Pts with moderately to severely active CD were randomised in a treat-through design to GUS 200, 600, 1200mg; ustekinumab (UST) ~6mg/kg; or PBO intravenous (IV) induction followed by maintenance dosing (GUS 200mg IV-->GUS 100mg subcutaneous [SC] every 8 weeks [q8w], GUS 600mg IV-->GUS 200mg SC q4w, GUS 1200mg IV-->GUS 200mg SC q4w, UST ~6mg/kg IV-->UST 90mg SC q8w, PBO nonresponders-->UST ~6mg/kg IV-->UST 90mg SC q8w, PBO responders-->PBO SC q4w). Corticosteroid tapering was mandatory from Wk12 if medically feasible. Efficacy endpoints included corticosteroid-free CD Activity Index (CDAI) clinical remission (<150) and pt-reported outcome (PRO)-2 remission at Wk48 in the primary efficacy population. Pts randomised to PBO were not included in Wk48 efficacy analyses. GALAXI 1 was not powered to evaluate efficacy differences between treatment groups at Wk48; UST was a reference arm. Analyses were prespecified but not multiplicity controlled. Results At Wk48, 55.7-71.4% of pts in the GUS dose groups achieved corticosteroid-free CDAI clinical remission (Table 1). Similar rates were observed when the corticosteroid-free duration was ≥30 or ≥90 days before Wk48. Among pooled pts in CDAI clinical remission at Wk48 in the GUS groups, 115/120 (95.8%) were corticosteroid free. At Wk48, 49.2-68.3% of pts in the GUS dose groups achieved corticosteroid-free PRO-2 remission (Table 1). Among pooled pts in PRO-2 remission at Wk48 in the GUS groups, 105/110 (95.5%) were corticosteroid free. Outcomes in the reference UST group are shown in Table 1. Among pts in the GUS dose groups, 30.2-39.3% were using corticosteroids at Wk0 (median prednisone equivalent dose 20.0mg/d in each group); at Wk48, 60.0-78.9% of these pts met corticosteroid-free criteria (Table 2). Conclusion High rates of corticosteroid-free CDAI clinical and PRO-2 remission were achieved at Wk48 in the GUS dose groups. Among pts in clinical remission, most were corticosteroid free. Nearly all pts maintained corticosteroid-free CDAI clinical remission for ≥90 days. GUS IV induction followed by SC maintenance therapy also effectively reduced corticosteroid use at Wk48.

P782 Ustekinumab in Ulcerative colitis: a real-life effectiveness study across multiple Belgian centers (SULTAN)

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon.1 Ustekinumab (UST), a monoclonal antibody against the p40 subunit of interleukin (IL) 12 and 23 has shown in the UNIFI trials to be effective and safe in patients with moderate-to-severe UC.2 Real-life data are still limited.3 The aim of this study was to assess the real-world effectiveness and safety of UST in patients with UC across Belgian hospitals. Methods In this multicentric, retrospective observational study, patients with UC who received UST from September 2020 onwards were included. Clinical and biochemical response was assessed at baseline, week 8, 16 and 52. The primary endpoint was steroid-free remission defined as partial Mayo score of ≤ 2 with no subscore > 1 at week 16. Secondary endpoints included clinical and biochemical response (defined respectively as a decrease in partial Mayo score ≥ 3 points and ≥ 3 plus a decrease in rectal bleeding score ≥ 1 or an absolute rectal bleeding score ≤ 1 and a decline of 50% or more in CRP and/or fecal calprotectin). Results 107 patients with moderate-severe UC (86% patients with ≥ S2 severity) were included across 16 participating centers. Median disease duration was 10 years (1-73y) and 69 (64%) of patients had previously failed 2 or more biologicals. At week 16, 35 patients reached the primary endpoint of steroid-free clinical remission (33%), while 67 had a clinical response (62.6%) (Fig 1). There was a statistically significant decline in partial mayo score (median at baseline 6.0 range (1-9); W16 2.0 (0-9, p<.001), CRP (3.85 mg/L (0.4-181) vs 3.15 (0.88-10.3); p<.001) and calprotectin (1040 (13-6000) vs 300 (3.8-2980); p<.001) (Fig 2 and 3). Biochemical response was seen in 41 patients (38%). No predictors for steroid-free remission could be identified. At the end of follow-up at week 52, 75 patients were still treated with UST (70%). Reasons for discontinuation were primary non-response (N=18 (17%), loss of response (N=8 (7.5%) and adverse events (N=2 (1.9%)). No predictor for UST failure could be identified. Eight patients needed to be referred for colectomy (7.5%). In 7 patients dose optimization via IV reinduction occurred. No difference in occurrence of extra-intestinal manifestations was noted during treatment, severe infections occurred in 1 patient (0.9%). No other new safety signals were observed. Conclusion In this multi-centric, real-life cohort with highly refractory UC patients, UST was associated with a clinical response rate of 63% at 16 weeks while steroid-free remission was achieved in 33% of patients. No important new safety signals were observed.

P054 Secreted inflammatory protein profiles following treatment of ex-vivo human inflammatory bowel disease explants with licenced biologic therapies

Abstract Background Patient-derived inflammatory bowel disease (IBD) ex-plants have potential for biomarker and therapy discovery. Infliximab (IFX), ustekinumab (USTK) and vedolizumab (VDZ) are biologic therapies licenced for the induction and maintenance of remission in ulcerative colitis (UC) and Crohn’s disease (CD). All are efficacious in IBD despite differing mechanisms of action. Treatment of IBD explants ex-vivo with licensed biologic therapies may result in further insights into their mechanism of action. We aimed to evaluate the effect of IFX, USTK and VDZ on inflammatory protein secretion profiles in ex-vivo human IBD ex-plants. Methods Patients with IBD, undergoing endoscopy, were prospectively recruited. Biopsies were collected from the sigmoid and IBD ex-plants generated as per previously described methods. IBD explants were then co-cultured for 24 hours with an IgG control vehicle, IFX, USTK and VDZ. After 24 hours, tissue conditioned media (TCM) from IBD explants was collected. TCM secreted inflammatory protein profiles were quantified using 54 V-plex ELISA (Meso Scale Diagnostics, USA). Secreted inflammatory protein profiles were compared between IgG vehicle (control) and USTK, IFX, VDZ treated ex-plants. All continuous variables are presented as median [interquartile range (IQR)]. P values < 0.05 were considered significant in analyses. Results 37 patients with IBD were included (51% CD, 49% UC); age (median, [IQR]) 41[33-53] years, 49% male; disease duration (median, [IQR]) 9 [5-14] years; 51% of patients were anti-TNF naïve. TNF-a secretion was significantly lower in IBD explants treated with IFX compared with IgG control, p=0.006. IL-23 secretion was significantly lower in IBD explants treated with USTK compared with IgG control, p=0.043. Biologic therapy ex-vivo resulted in significant differences in angiogenesis and vascular injury panel biomarkers compared to control; CRP, VEGF-A and SAA. Pro-inflammatory cytokines and chemokines were also significantly decreased with ex-vivo biologic therapy compared to control; IL-2, IL-10, IL-6, MCP-1, IL-1a, TNF-a and MDC. Three Th17 panel proteins were significantly decreased with ex-vivo biologic therapy compared to control; IL-22, IL-17A, IL17A Gen B. Conclusion The statistically significant decrease in both TNF-a and IL-23 secretion with ex vivo IFX and USTK treatment respectively demonstrates that the IBD explant model recapitulates expected IBD disease biology and therapy responses. These data demonstrate that treatment with licenced biologic therapies ex-vivo reduces multiple pro-inflammatory cytokines, chemokines and secreted proteins in IBD explants. Further study is required to completely understand the effects of licenced biologic therapies on the IBD tissue microenvironment.

P684 Extra intravenous reinduction of ustekinumab on an already shortening interval is an effective optimisation strategy for patients with refractory Crohn’s disease

Abstract Background Designing treatment optimisation strategy for ustekinumab (UST) is challenging. We aimed to evaluate the efficacy and safety of extra weight-based intravenous reinduction of UST on an already shortening interval in patients with refractory Crohn’s disease (CD). To the best of our knowledge, this is the first study to report optimised UST treatment in a Chinese population. Methods This was a single-center retrospective observational study. Dosing optimisation strategies were designed for CD patients showing partial or loss of response to standardised UST with a shortened interval of every-8-week (q8w) dosing, or an extra weight-based intravenous reinduction followed by q8w subcutaneous administration. Clinical, biochemical, and endoscopic findings and trough concentrations of UST were analyzed. Results Dose optimisation strategies were developed for 27 out of 64 patients; 13 patients required a shortened q8w interval and 14 patients required intravenous reinduction. Crohn’s disease activity index [96.5 (39.8,156.3) vs. 158.0 (101.5,175.3), P=0.009] and C-reactive protein [3.3 (1.1,7.0) vs. 4.8 (0.5,15.1), P=0.023] levels decreased significantly after intravenous reinduction, while the trough concentration of UST increased [1.8 (1.2,8.6) vs. 1.1 (0.2, 6.4), P=0.009]. Clinical and endoscopic remission was achieved in 57.1% (8/14) and 33.3% (2/3) of patients, respectively, while 53.8% (7/13) and 25.0% (2/8) of patients achieved clinical and endoscopic remission at around week 8 in the q8w cohort, respectively. The incidence of patient-reported adverse effects was 3.7%. (Figure 1) Conclusion Intravenous reinduction improved clinical and endoscopic remission safely and effectively in patients showing poor response to standardised UST treatment, which should be an optimal rescue optimisation strategy before switching to biologics targeting other pathways.

P578 Exploring duration of corticosteroid withdrawal in definitions of corticosteroid-free remission endpoints in ustekinumab clinical trials: results from the IM-UNITI, UNIFI, and SEAVUE trials

Abstract Background Remission off steroids is a major treatment goal in inflammatory bowel disease. In the recent CORE-IBD consensus,1 the preferred definition of “corticosteroid-free” remission in clinical trials was withdrawal ≥12 weeks before the assessment timepoint. We evaluated the rates of corticosteroid-free remission according to three different definitions (ie, cross-sectional, ≥30, and ≥90 days) in the analysis of the corticosteroid-free remission endpoint using data from the IM-UNITI and SEAVUE trials of patients with Crohn’s disease (CD) and the UNIFI trial of patients with ulcerative colitis (UC). Methods In IM-UNITI and UNIFI, patients with moderate-to-severe CD and UC, respectively, who had previously responded to ustekinumab (UST) induction were randomized to placebo (PBO), UST 90mg SC q12w, or UST 90mg SC q8w. In SEAVUE, biologic naïve patients with moderate-to-severe CD were randomized to adalimumab 160mg SC at week 0, 80mg SC at week 2, and 40mg SC q2w or UST ~6mg/kg IV at week 0 and 90mg SC q8w. Each trial included protocols for mandatory corticosteroid tapering after the induction phase unless medically inappropriate (required in IM-UNITI and UNIFI starting at week 8 and recommended in SEAVUE starting at week 8 but required starting at week 16). Corticosteroid-free remission was defined as clinical remission (CDAI<150 in IM-UNITI and SEAVUE and a Mayo score ≤2 with no individual subscore >1 in UNIFI) and not receiving steroids at the assessment timepoint or ≥30 or ≥90 days before the assessment timepoint. Corticosteroid-free remission at week 44 was a major secondary endpoint in IM-UNITI and UNIFI (both cross-sectional). Corticosteroid-free remission (≥30 days before week 52) was a major secondary endpoint in SEAVUE. Results The proportions of patients who achieved corticosteroid-free remission were consistent, regardless of the corticosteroid-free duration used in the assessment (Tables 1 and 2). The results were consistent for both ustekinumab treatment groups (q12w and q8w) and placebo in the pivotal IM-UNITI and UNIFI studies (Table 1) and for both ustekinumab and adalimumab groups in the SEAVUE study (Table 2). Conclusion In CD and UC clinical trials of ustekinumab maintenance, which included protocol-mandated corticosteroid tapering regimens, corticosteroid-free remission results at 1 year were similar regardless of the corticosteroid-free duration used in the outcome definition.

P818 Survival of ustekinumab treatment based on concomitant immunomodulator use

Abstract Background Given the low immunogenicity of ustekinumab (UST), it has been suggested that it is not necessary to add an immunomodulator (IMM). However, there is little scientific evidence on whether the efficacy of combined UST+IMM treatment may be greater than in monotherapy, due to the concomitant action of both drugs. The aim of the study was to evaluate the survival of UST treatment with and without concomitant IMM. Methods Patients with stable follow-up at Hospital Universitario La Paz (Madrid), with Crohn’s disease (CD) and previous or current treatment with UST, since May 2016, were retrospectively included. Results A total of 137 patients were included. Table 1 shows the baseline characteristics. In 98 patients (71.53%) UST indication was induction of remission; in 22 (16.06%) post-surgical recurrence treatment; in 5 (3.65%) it was prescribed as post-surgical recurrence prophylaxis; and in the remaining 12 (8.76%) the indication was for other reasons. At the time of analysis, 91 (66.42%) patients were still on active treatment and 46 (33.58%) had discontinued treatment (of which 9 due to primary failure, 27 due to secondary loss of response, 9 due to adverse events, 1 due to remission). 89 patients (64.96%) did not receive concomitant IMM. Whilst, 48 (35.04%) received concomitant treatment with an IMM. The mean time of IMM treatment was 9.16 years (SD 6.76). UST treatment had a mean duration of 2.19 years (SD 1.35) in patients receiving concomitant IMM; while it was of 1.67 years (SD 1.02) in those who did not receive concomitant IMM; being this statistically significant (p=0.0124) (Figure 1). When performing a multivariate analysis by linear regression, the only variables that negatively influenced UST survival were age at diagnosis (Coef. -0.36; p=0.028), perianal disease (Coef. -0.29; p=0.198) and location rather than L1 (Coef. 0.2; p=0.072). However, concomitant IMM use had a positive influence (Coef. 0.45; p=0.032). Conclusion In our experience, the survival of ustekinumab is greater in combined treatment with immunosuppressant, being also the only independent variable associated with a greater durability of the drug.

P396 Ustekinumab Is A Promising Option For The Treatment Of Postoperative Recurrence Of Crohn’s Disease

Abstract Background Postoperative recurrence (POR) following ileocolonic resection is a major concern in patients with Crohn's disease (CD). The role of Ustekinumab (UST) as therapeutic option for the POR of CD is currently unknown Methods All consecutive CD patients with a baseline colonoscopy at 6-12 months from ileocolonic resection showing POR with Rutgeerts score ≥ i2 who were treated with UST after the baseline colonoscopy, and with an available post-treatment endoscopy, were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD). The primary outcome was endoscopic success, defined as reduction of at least one point of Rutgeerts score. The secondary outcome was clinical failure, assessed at the end of follow-up and defined in case of occurrence of one of the following: mild clinical relapse (Harvey-Bradshaw Index 5-7), clinically relevant relapse (Harvey-Bradshaw Index > 7), UST discontinuation due to adverse events, need for new resection. Results Fifty-nine patients started UST for the management of POR. Five patients were excluded due to the absence of the baseline colonoscopy, 5 were excluded due to absent or mild POR (i.e. Rutgeerts score i0 or i1), and 5 patients were excluded due to short follow-up and the consequent absence of post-treatment colonoscopy. Finally, 44 patients were included (mean follow-up: 17.8 ± 8.4 months). The baseline postoperative colonoscopy showed an intermediate severity of recurrence (Rutgeerts score i2) in 25.0% of patients, and a severe recurrence (Rutgeerts score i3 or i4) in 75.0% of patients. Only 5 patients (11.4%) were naïve to biologics, while most had previous failure to one (61.4%), two (15.9%), or three (11.4%) biologics. The post-treatment colonoscopy was performed after a mean of 14.5 ± 5.5 months following initiation of UST. Endoscopic success was reported in 22 out of 44 (50.0%) patients, of whom 12 (27.3%) achieved a Rutgeerts score i0 or i1. None of these 22 patients with endoscopic success fulfilled the criteria for clinical failure. Clinical failure at the end of follow-up was reported in 12 out of 44 patients (27.3%); none of these 12 patients had achieved endoscopic success at post-treatment colonoscopy. At univariate Cox regression analysis, the number of previous biologics (HR 2.59 per-unit increase, 95% CI 1.33-5.03; p=0.005), previous surgery (HR 3.45, 95% CI 1.37-8.84; p=0.008), and need for steroids at baseline (HR 3.13, 95% CI 1.03-10.87; p=0.044) were associated with clinical failure at the end of follow-up. Conclusion Ustekinumab could be a promising option for the treatment of POR of CD

P678 Ustekinumab therapy improves the nutritional status in patients with Crohn's Disease. A prospective study

Abstract Background Patients with Crohn’s disease (CD) display high rates of nutritional deficiencies and metabolic imbalances, primarily due to mucosal damage induced by inflammation. In particular, the loss of lean muscle mass configures a condition known as sarcopenia, which is not necessary associated with a low Body Mass Index (BMI). The presence of sarcopenia has been associated with a worst outcome of IBD. At present, no studies evaluated the impact of Ustekinumab (UST) in terms of its effects on body composition. The aim of this prospective study was to evaluate whether UST treatment could modify the parameters of body composition assessed by Bioelectrical Impedance Assay (BIA) in patients with CD. In particular, we evaluated phase angle, which represents the most clinically established impedance parameter and it might be considered as a reliable and optimal marker of nutritional status. Methods We prospectively enrolled all consecutive CD patients treated with UST at our center, following the current guidelines. BIA was performed at baseline and at week 48, assessing Body Cellular Mass (BCM), total body water, phase angle and BMI. At the same time-points, a colonoscopy was performed in order to evaluate the therapeutic outcome in terms of mucosal healing, defined as a Simple Endoscopic Score for CD <2. We evaluated also clinical remission, defined as a Harvey-Bradshaw Index <5 at week 48. Results Out of 44 patients enrolled, 26 (59%) presented clinical remission and 22 (50%) achieve mucosal healing at the end of follow up. No significant differences were observed at baseline in all the BIA parameters between responders and non-responders. Phase angle increased over time in responders, while this was not observed in non-responders (test for the interaction between time and outcome, p-value=0.010 and 0.008 for clinical remission and mucosal healing, respectively). The same differential increase was observed for BCM (test for the interaction between time and outcome, p-value=0.037 and 0.076 for clinical remission and mucosal healing, respectively). No other significant differences were observed regarding the other BIA parameters. Conclusion UST therapy seems to be able to modify body composition of patients with CD. In particular, the increase in phase angle in responders suggests that a significant improvement of nutritional status occurred in these patients. Our results are in line to what was shown by a previous study performed in patients with psoriasis treated with UST.

P618 Long-term real-world data of Ustekinumab in Ulcerative Colitis – the Stockholm Ustekinumab study – STOCUSTE

Abstract Background Background: Ustekinumab (UST) is an anti-interleukin-12/23 antibody in the treatment of inflammatory bowel disease (IBD), mainly used in patients failing anti-TNF-agents. The STOCUSTE study includes patients treated at four hospitals in Stockholm to provide long-term real-world data. Methods Methods: This was a retrospective study including patients diagnosed with ulcerative colitis and treated with UST between years 2016 and 2021. The patients were followed from start of UST until withdrawal of treatment for any reason, or until end of study follow-up, July 31, 2021.We assessed disease activity; Physician Global Assessment (PGA); Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score, laboratory parameters and drug persistence. The primary outcome was remission (PGA = 0) and response (decrease PGA ≥ 1 from baseline) at 3 and 12 months, respectively. Results Results: 96 patients, 44 women and 52 men were included. The patients had either extensive colitis (68%), left-sided colitis (29%) or proctitis (3%). All but two patients were anti-TNF-experienced; 94 (98%) had failed ≥1, 59 (61%) ≥2 and 34 (35%) ≥3 anti-TNF-drugs. At inclusion 92 patients (96%) had active disease and 4 patients were in remission, 48 (50%) were on oral or topical corticosteroids, 13 (14%) had thiopurines. At 12 months only 9% were on oral or topical corticosteroids. Among patients who were treated with UST, 9/71 (6%) were in remission at 3 months, and 26/33 (78%) patients were in remission at 12 months. Withdrawal from treatment during the first 12 months was 36 (38 %), mainly due to persisting disease activity (20%); 8% were withdrawn due to adverse events, 2% needed bowel surgery, and 2% were lost to follow up. Conclusion Conclusions: In this group of difficult-to-treat patients with ulcerative colitis, Ust was shown to be effective in the majority, with high drug persistence at 12 months in combination with a favorable safety profile.

P381 Ustekinumab trough levels are associated with sonographic transmural healing in Pediatric Inflammatory Bowel Disease

Abstract Background Transmural healing (TH) assessed by intestinal ultrasound (IUS) is associated with improved inflammatory bowel disease (IBD) outcomes. This study evaluates the relationship between ustekinumab trough levels (UTL) and sonographic TH in children with IBD treated with ustekinumab (UST). Methods Children (<18 years) with IBD treated with maintenance UST and undergoing IUS examination and serum UTL (Prometheus Labs, CA) at a single tertiary center between July 2020 and October 2022 were prospectively recruited. Children who underwent IUS and UTL on 2 events >6 months apart were included in a per-event analysis. Primary outcome was the comparison of UTL between children with and without TH, defined as bowel wall thickness (BWT) ≤3 mm and no hyperemia (BWH) on color Doppler, using the Mann-Whitney U test. Area under the receiver operating curve (AUROC) determined the optimal UTL cut-point to detect TH. Secondary outcome was the comparison of UTL for each IUS parameter. Descriptive statistics summarized the data as frequencies and percentages for categorical variables and median [interquartile range] for continuous variables. A p-value of significance was set to <0.05. Results Overall, 50 IUS exams on 129 bowel segments were performed in 44 children with IBD, 34:10 Crohn’s disease (CD):ulcerative colitis (UC)/IBD-U treated with UST, median [IQR] age 14.9[13.2-16.6] years, 22(50%) female, and disease duration 3.83[1.98-5.32] years (Table 1). 18(41%) children were treated with standard dose UST of 90mg every 8 weeks and had significantly lower UTL compared to 26(59%) treated with escalated dosing of 90 mg every 4 or 6 weeks (7.4[4.8-12.7] ug/ml vs. 11.6[6.1-19.3] ug/ml, p=0.002). Median time between UTL and IUS was 0 days [0-11.25]. Overall, 24(55%) children (18(53%) CD, 6(60%) UC/IBD-U) achieved TH. Higher UTL was associated with TH (13.1[6.1-17.5] ug/ml) compared to children without TH (5.7[4.2-13.9] ug/ml; p=0.010) (Figure 1A). Higher UTL was also associated with TH in children with CD (11.7[5.3-17.0] ug/ml) compared to children with CD without TH (5.5[4.2-11.0] ug/ml; p=0.013) (Figure 1B). Optimal UTL cut-point to detect TH was 11.4 ug/ml for all children (AUROC=0.647, sensitivity=62%, and specificity=69%) and children with CD (AUROC=0.661, sensitivity=59%, specificity=79%). Median UTL for all children was associated with lymphadenopathy (p=0.02) but no other individual IUS parameters (Table 2). Conclusion Higher maintenance UTL are associated with sonographic TH in children with IBD. Future prospective studies are needed to determine if targeting higher UTL levels during induction and maintenance UST therapy promotes TH.

OP03 Highly stable epigenome-wide peripheral blood DNA methylation signatures accurately predict endoscopic response to adalimumab, vedolizumab and ustekinumab in Crohn’s disease patients: The EPIC-CD study

Abstract Background Despite the proven efficacy of biological treatments in Crohn’s disease (CD), many patients fail to respond or lose response over time. Therefore, predictive biomarkers for treatment efficacy would be of extreme value. Previous epigenome-wide association studies associated differential DNA methylation with CD-specific phenotypes, suggesting a potential use in classification and prediction of response to treatment. Methods We prospectively collected and measured longitudinal peripheral blood DNA methylation profiles of 184 adult CD patients prior to (T1) and after a median of 28 weeks (T2) following biological treatment with Adalimumab (ADA), Vedolizumab (VEDO) or Ustekinumab (USTE) in a discovery (n=88) and independently collected internal validation cohort (n=96) using the Illumina EPIC BeadChip array. Response (R) was defined as the combination of endoscopic response (≥50% reduction in SES-CD score) and steroid-free clinical response (≥3 point drop in 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). Biomarker identification and classification analyses were performed using stability selection gradient boosting on samples taken at T1 whereas samples taken at T2 and intraclass correlation (ICC) data were used to assess long-term stability of our identified CpG loci1. Results A total of 58 ADA-patients (NR=29, NNR=29), 64 VEDO-patients (NR=36, NNR=28) and 62 USTE-patients (NR=30, NNR=32) were included. Prior to treatment, at T1, we identified distinct panels of 100 ADA-, 22 VEDO- and 68 USTE-associated CpG loci that, in combination, predict clinical- and endoscopic response with high accuracy (AUC ADA=0.73, VEDO=0.89 and USTE=0.94) upon validation. Notably, for these CpG loci, methylation levels did not significantly differ between T1 and T2, implicating stability during both induction and maintenance treatment, irrespective of inflammatory status and therapeutic intervention. In addition, the majority of these CpG loci (>60%) demonstrated long-term hyper stability (ICC-values ≥0.90). Furthermore, genes annotated to the CpGs of interest suggest drug specific involvement in TNF-signaling, endothelial cell-cell adhesion, integrin dependent T-cell homing, the innate immune system and Th17/Treg differentiation, corroborating to the mode of action of each drug. Conclusion Here, we report on 3 validated panels of highly stable, epigenetic biomarkers that predict clinical and endoscopic response in CD patients treated with ADA, VEDO or USTE. Additional external- and clinical validation as part of EPIC-CD and the OMICROHN clinical trial are currently ongoing.

P147 Trends in choice of first line biologic therapy for patients with Inflammatory Bowel Disease. An observational cohort study

Abstract Background Biologic therapies have revolutionised the management of Inflammatory Bowel Disease (IBD) with increasing utilisation over the last decade. The anti-Tumour Necrosis Factor-alpha (anti-TNF) agents (Infliximab (IFX) and Adalimumab (ADA)) as well as newer agents (Ustekinumab (UST) and Vedolizumab (VED)) all have well demonstrated safety and efficacy profiles in the management of IBD. The choice of an optimal first line biologic remains unclear due to lack of comparative randomised trials and real-world studies; however, certain patient and disease characteristics may influence this choice. The aims of this study were to explore temporal trends in choice of 1st-line biologic therapy and factors that influence this choice. Methods A retrospective observational cohort study of all patients with IBD that commenced induction and completed at least one maintenance dose of a biologic therapy between 1st January 2015 and 31st December 2021. Relevant patient and disease-specific factors were collected, including patient comorbidities (ischaemic heart disease, malignancy and opportunistic infections) at time of diagnosis, for each eligible patient. Factors affecting choice of biologic therapy were compared using ANOVA and c2 test. Results 280 patients were included, with 50.7% being male and median age of IBD diagnosis of 29 years. There was a progressive increase in biologic use over time, with 15 patients commencing1st biologic therapy in 2015, rising to 58 patients in 2021. UST has overtaken IFX and ADA as first line choice for Crohn’s disease (CD) since its introduction in 2018 (Figure 1). IFX has remained preferred first line therapy for ulcerative colitis (UC) over VED and ADA, with stable trend in choice over time. Factors with significant differences in choice of first line biologic therapy included age (UST for older age of commencement), IBD subtype (higher proportion of patients commencing ADA had CD, whereas higher proportion of patients commencing VED had UC), disease location (VED was preferred for colonic over ileal CD), and malignancy (UST was preferred) (Table 1). Conclusion - There has been a steady rise in the number of patients commencing biologic therapies, with an average increase of 24% per year from 2015 to 2021. - Ustekinumab has replaced anti-TNF therapy as the preferred first line biologic for Crohn’s disease; a trend likely secondary to the comparatively favourable safety profile of ustekinumab. Ustekinumab was preferred in older patients and those with history of malignancy. - Infliximab remains the preferred first line therapy for ulcerative colitis with stable trends in choice. - The presence of perianal disease was not a significant factor affecting choice.

DOP51 Mucosa-associated microbial signatures associate with objective response prior to the start of anti-TNFα but not vedolizumab or ustekinumab in Crohn’s disease patients

Abstract Background Crohn’s disease (CD) is a complex immune-mediated disease of the gastrointestinal tract where the gut microbiome plays an important role. Current biological treatment options in CD include the anti-TNFα agents adalimumab (ADA) and infliximab (IFX), vedolizumab (VDZ), and ustekinumab (USTE). Finding biomarkers to predict therapy response is still a clinical unmet need, as the majority of CD patients fail to reach endoscopic remission within 1 year of treatment. While the majority of studies focus on fecal samples, mucosa-adherent bacterial signature could bring forth stable biomarkers. In this study, we sought to identify signatures of the adherent microbiome in intestinal biopsies aimed at differentiating responders (R) from non-responders (NR), prior to the start of biological treatment. Methods We prospectively collected paired ileal and colonic biopsies (stored snapfrozen in -80 ºC) from adult CD patients scheduled to start anti-TNFα (IFX and ADA), VDZ and USTE treatment during baseline endoscopies. After 6-12 months of follow-up, patients were classified as either R or NR based on endoscopic response (≥50% reduction in SES-CD score) in combination with steroid-free clinical response (≥3 point drop in HBI or HBI ≤4) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a basal CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Microbiome composition of the biopsies was determined using 16S RNA gene V3V4 amplicon sequencing. Results For the anti-TNFα cohort, we included in total 36 CD patients (21R and 18 NR), for VDZ cohort a total of 44 patients (28 R and 16 NR) and for USTE cohort a total of 40 patients (20R and 20 NR).When comparing α-diversity and β-diversity between R and NR, we did not find significant differences in ileal and colonic samples at baseline for the VDZ and USTE cohorts. Notable, for the anti-TNFα cohort (table 1), we obtained significant differences when comparing α-diversity (p=0.028) and β-diversity between R and NR. We demonstrated differences between colonic R and NR in taxa abundance for ASVs associated with the phyla Bacteroidetes, Firmicutes, Fusobacteria, Proteobacteria (figure 1). Furthermore, ASVs associated with Firmicutes, Bacteroidetes, Actinobacteria are different in abundance between ileal R and NR (figure 2). Figure 1: Differential taxa abundance colonic R vs NR anti-TNFα Figure 2: Differential taxa abundance ileal R vs NR anti-TNFα Figure 3: graphical summary Conclusion Here, we investigated the microbial signature of R and NR before the start of treatment of three separate cohorts and we demonstrated that the mucosa-associated microbiome differentiates R and NR to anti-TNFα therapy. Further analyses as part of the EPIC Pioneer study, are ongoing.

P510 Comparative effectiveness of Ustekinumab against other biologics in Inflammatory Bowel Disease: a propensity score analysis.

Abstract Background Background: Increasing evidence supports the use of Ustekinumab (USTK) in patients with moderate to severe Crohn’s disease (CD) and Ulcerative colitis (UC). Comparison of USTK against other biologics is still lacking. Methods AIMS: to perform a propensity score analysis (PSA) for comparison of USTK against conventional Infliximab (IFX), proactive IFX and vedolizumab in CD and UC Methods retrospective study including patients under Ustekinumab (n=71), Vedolizumab (n=98), conventional IFX (n=70) and proactive IFX (n=148). PSA correcting for age, gender, IBD subtype, previous biologic exposure was performed for each comparison. We compared the rates of fecal calprotectin (Fc) remission (<150 µg/g), treatment discontinuation, hospitalization, and surgery at 52 weeks of treatment. Primary non-responders were excluded. Results Results: after PSP, ustekinumab showed lower rates of treatment discontinuation compared to vedolizumab (7.4% vs 37%, P< 0.001) with a trend for higher rates of Fc remission (42.6% vs 25.9%, P=0.104). Ustekinumab showed higher rates of Fc remission compared to conventional IFX (53.8% vs 19.2%, P= 0.020) with a trend for lower rates of hospitalization (7.7% vs 30.8%, P= 0.075). There were no differences between ustekinumab and proactive IFX in any of the clinical outcomes. Conclusion Conclusion: taking into account the potential limitations of PSP, our results suggest that ustekinumab may be as effective as proactive IFX with some benefits compared to vedolizumab and conventional IFX.

P615 The safety and efficacy of ustekinumab combined with sphincter-preserving surgery for perianal fistulizing Crohn’s disease:a single-center retrospective study

Abstract Background To assess the clinical efficacy and safety of ustekinumab(UST) combined with sphincter-preserving surgery in the treatment of perianal fistulizing Crohn’s disease(pfCD). Methods A single-center retrospective study. The baseline data of pfCD patients who met the inclusion and exclusion criteria and visited the Anorectal Department of the Affiliated Hospital of Nanjing University of Traditional Chinese Medicine from January 2020 to March 2022 were collected. Patients were assessed for fistula response and remission by rectal magnetic resonance image(MRI) and perianal disease activity index(PDAI). Patients' fistula response and remission were assessed by rectal MRI and PDAI. Patients were assessed for clinical response and remission by using Crohn's disease activity Index( CDAI). Patients' anal function was assessed by using the Wexner score. The differences in CDAI,PDAI and inflammatory parameters, including C-reactive protein(CRP) and erythrocyte sedimentation rate(ESR), at 0 week, 8 weeks and 16 weeks were statistically analyzed. Results A total of 64 pfCD patients were included. Fistula response was 23.4% (8 weeks), 40.6% (16 weeks), and 51.6% (follow-up endpoint); fistula remission was 21.9% (follow-up endpoint); fistula MRI remission was 9.3% (follow-up endpoint); clinical response was 68.8% (8 weeks) and 79.7% (16 weeks); and clinical remission was 46.9% (8 weeks) and 59.4% (16 weeks). CDAI, PDAI and inflammatory parameters at the 8th and 16th week of treatment were significantly lower than those before treatment (p<0.05). There was no significant difference in postoperative anal function (p<0.05). The incidence of adverse events was 1.6%. Conclusion UST combined with sphincter-preserving surgery is safe and effective in the treatment of pfCD.This therapy can effectively improve the fistula condition and systemic manifestations.

P811 Combination biological or small molecule therapy in patients with refractory inflammatory bowel disease: a multicenter Brazilian experience

Abstract Background This preliminary study describes the Brazilian experience on dual biologic therapy or small molecule combined with a biologic therapy in patients with inflammatory bowel disease (IBD) refractory to multiple biologics. Methods We identified patients from 6 IBD centers in Brazil between April 2020 and November 2022 who received treatment with a combination of two biologics or a biologic and a small molecule drug due to refractory disease or concomitant immunomediated condition. The primary endpoint was clinical remission at week 16, defined as a total Mayo score of ≤2 for UC and Harvey-Bradshaw Index (HBI) <4 for CD. Secondary endpoints were improvement in disease activity scores and biomarkers. Adverse events were monitored and summarized descriptively. Results Twenty-nine patients were identified (69% CD, n=20), 51.8% female, mean age 38.8 years old [SD= ± 14.8 years]). Seventy per cent (n=14) had penetrating behavior among CD patients. Twenty-seven had failed to, at least, one anti-TNF; 79.9% had failed to ustekinumab (UST), and 34.5% to vedolizumab (VEDO). Twenty-six patients were treated with combination advanced therapy due to loss of response to biologics and three patients had concomitant ankylosing spondylitis. The most common combination used was UST+ADA (n=12, 41.4%), followed by UST+VEDO (n=6, 21.7%). Mean treatment time was 53.8 weeks (SD= 40.4 weeks, CI 95% [37.5 – 70]). At week 16, clinical remission rates were 80% and 66% for CD and UC, respectively. All patients under VEDO + UST combination achieved clinical remission at 16w, in both diseases. Baseline HBI mean was 10.8 (SD= ± 3.6 points; CI 95% [9.1- 12.5]), decreasing to a mean of 5.5 at week 16 (SD= ± 3.5 points; CI 95% [3.8 - 7.2]) and plateauing at 7 by week 24 (SD= ±5.4 CI 95% [3.4- 10.6]). There was a notable decrease in HBI at week 16 (p< 0.001) and a significant decrease at week 24 (p= 0.02) compared to baseline. Mean CRP at week 16 was significantly lower than baseline in CD (17.4mg/dL vs 5.5 mg/dL, p=0.001) and numerically lower in UC (from 14.3mg/dL to 9.9mg/dL, p= 0.5). Fecal calprotectin decreased from 2509mcg/g to 1472mcg/g in both groups (p=0,2). In addition, all patients with ankylosing spondylitis showed symptomatic remission. No new safety signals were identified during follow-up Conclusion Despite combination of advanced therapies in IBD is not yet recommended by treatment guidelines, this strategy seems to be a promising option for patients with refractory IBD or concomitant autoimmune disease. Our data indicate that further investigation in this direction is worthwhile.

REAL-WORLD EXPERIENCE FOR BIOLOGIC USE IN IBD IN THAI: A SINGLE-CENTER EXPERIENCE

Abstract BACKGROUND Biologics have been used for the treatment of inflammatory bowel disease (IBD) worldwide; however, their use is still limited in Southeast Asia. This study aimed to describe the pattern of biologic use and outcomes in a tertiary referral center in Thailand. METHOD All patients with IBD who used biologics from the first case in 2012 to present in our center were enrolled. The data were prospectively collected since 2017; the data of patients before 2017 were retrospectively reviewed. The treatment outcomes comprised cumulative clinical, endoscopic, radiologic response or remission, and quality of life assessed by SIBDQ. Furthermore, the biologic persistence was reported. RESULTS Of 296 cases currently in the IBD clinic, 85 used biologics, including infliximab (IFX), vedolizumab (VDZ), and ustekinumab (UST). The mean age was 44.4 years, and 62% were male. Fifty-eight (68.2%) had Crohn’s disease (CD) and 27 (31.8%) had ulcerative colitis (UC). In CD, 58% had ileocolonic disease, 48% had bowel stricture, 29% had fistula, and 19% had perianal diseases. In UC, 19% had left-sided colitis, and 81% had extensive colitis. Most patients (97%) failed conventional treatment. In CD, 60%, 31%, and 8.6% use IFX, VDZ, and UST as the first biologic, respectively. While 81.5% of UC used VDZ and 18.5% used IFX. Concomitant immunomodulator was used in 77.6%. The median duration of the first biologic use was 12.6 months. The outcomes of the treatment were shown in Table 1. The overall cumulative clinical response and remission at 1 year were 94% and 63%, respectively, without significant differences among each biologic. The cumulative rate of endoscopic remission was 29%, 64%, and 82% at 1, 3, and 5 years, respectively, also without significant differences among each biologic (p=0.21). However, subgroup analysis in Crohn’s disease showed a trend of a better endoscopic remission rate for IFX and UST when compared to VDZ (p=0.15). The radiologic remission rate was only 12% of 25 patients who underwent CT enterography. The SIBDQ increased from 52.0 to 57.4 after 1 year of treatment. Thirty-six (42%) stopped the medicine. As shown in Figure 1, the overall cumulative rate of biologic discontinuation was 19% and 39% in the first and second year, respectively, without significant differences among biologics. However, the reason for drug discontinuation was different as all adverse events occurred in only patients using IFX. CONCLUSION Biologics were mostly used in refractory patients in this cohort. The outcomes were comparable to those previously reported in western. Current biologics could significantly improve patients’ symptoms, quality of life, and mucosal healing, but not transmural healing. The adverse events were less in newer biologics.

Ustekinumab Promotes Radiological Fistula Healing in Perianal Fistulizing Crohn's Disease: A Retrospective Real-World Analysis.

There is insufficient evidence to confirm the efficacy of ustekinumab (UST) in promoting fistula closure in perianal fistulizing Crohn's disease (CD) patients. We aimed to evaluate the efficacy of UST in a real-world setting. The data were retrospectively analyzed. Intestinal clinical and endoscopic changes were evaluated. Fistula radiological outcomes were determined using the Van Assche score. A total of 108 patients were included, 43.5% of whom had complex perianal fistulas. Intestinal clinical and endoscopic remission was achieved in 65.7% and 31.5% of patients, respectively. The fistula clinical remission and response rates were 40.7% and 63.0%, respectively, with a significant reduction in Perianal Crohn's disease Activity Index [5.0(3.0, 8.0) vs. 7.5(5.0, 10.0), p < 0.001] and Crohn's Anal Fistula Quality of Life [23.5(9.3, 38.8) vs. 49.0(32.3, 60.0), p < 0.001]. Radiological healing, partial response, no change, and deterioration were observed in 44.8%, 31.4%, 13.4%, and 10.4% of patients, respectively. The cut-off UST trough concentration for predicting fistula clinical remission was 2.11 μg/mL with an area under the curve of 0.795, a sensitivity of 93.3%, and a specificity of 67.6%. UST is efficacious in promoting radiological fistula closure in patients with perianal fistulizing CD. A UST trough concentration over 2.11 μg/mL was correlated with a higher likelihood of perianal fistula clinical remission.

Real-World Effectiveness and Risk Factors for Discontinuation of Ustekinumab in Ulcerative Colitis

Introduction: Ustekinumab (UST) has been approved for the treatment of moderate-to-severe ulcerative colitis (UC). Real-world data showing the effectiveness and safety of UST are necessary to confirm the results of clinical trials for applicability in daily clinical practice. Although some studies have reported real-world evidence of UST, only few studies have confirmed its effectiveness in the real world. The aim of this study was to assess the short- and long-term effectiveness, durability, safety, and risk factors for discontinuation of UST in UC in clinical practice. Methods: This was a retrospective, single-center, observational study. From March 2020 to January 2023, all consecutive patients with active UC who were treated with UST at Nagoya University Hospital were included. The primary outcome was the clinical remission rate at weeks 2–8 and weeks 24–48. The secondary outcomes included clinical response, persistence of UST therapy, endoscopic changes during follow-up, risk factors for UST discontinuation, and occurrence of any adverse events. The clinical effectiveness was evaluated using the Lichtiger score. Results: A total of 31 patients were included in this study. The clinical remission rates were 9.7%, 29.0%, 54.8%, and 64.5% at weeks 2, 8, 24, and 48, respectively. Twelve (38.7%) patients discontinued UST during the follow-up period. The probability of continuing UST was 93.5%, 80.6%, 77%, and 70% at weeks 2, 8, 24, and 48, respectively. The major reason for discontinuation of UST was primary failure (75.0%). A high baseline C-reactive protein (CRP) level was a significant risk factor for the discontinuation of UST. No adverse events were observed in this study. Conclusion: UST is effective for patients with UC. High CRP levels were identified as a risk factor for UST discontinuation. The findings of this study would help clinicians to select appropriate treatment options for patients with UC by identifying the risk factors for treatment discontinuation.