bluuebunny/crossref_metadata_2025 huggingface dataset:
P449 Minimally invasive IPAA in UC: Preliminary results from a referral center
Authors: Fortuna L , Bottari A , Ficari F , Cricchio M , Cianchi F , Scaringi S
Published: January 2023

Background

Minimally invasive approaches in performing restaurative total proctocolectomy in Ulcerative Colitis(UC) have been increasingly adopted. In particular, the robotic approach could be used with more benefits in proctectomy with ileal pouch anal anastomosis (IPAA). In fact, the robotic device seems to potentially overcome all the limitations found in laparoscopic and conventional open surgery. The aim of our study was to compare and evaluate early and late functional postoperative outcomes and complications after IPAA, performed with open, laparoscopic and robotic techniques in UC patients.

Methods

At our institution, 397 UC patients who underwent restorative proctocolectomy with IPAA during the period 1986-2022, consecutively treated either with open surgery, laparoscopic or robotic techniques were enrolled. The incidence of early (<30 days) and late (>30 days) postoperative complications (intestinal occlusion, haematoma/wound infection, anastomotic dehiscence), hospital stay and an assessment about continence, autonomic nerve damage, incidence of pouchitis and cuffitis was evaluated.

Results

About the 397 patients, 344 underwent conventional open IPAA, 31 laparoscopically and 22 robotically. Comparable early and late postoperative surgical complications were recorded among the different techniques [early and late complications respectively 24/53 (45,2%) and 146/344(42,4%)] in minimally invasive and open groups. Minimally invasive surgery showed a better outcome regarding wound infections [0/53 (0%)], anastomotic dehiscence and reduced length of stay but open surgery demonstrated a better result on early and late intestinal occlusion [8/53 (15%)vs 22/344 (6,39%)] and anastomotic stenosis [5/53 (9,43%) vs 15/344 (4,36%)]. Lastly, the rate of cuffitis was higher in open surgery than in the minimally invasive group [(3/53 (5,66%) vs 46/344(13,37%)] and within these, robotic approach seems to show better results compared to laparoscopy.

Conclusion

UC patients undergoing IPAA could benefit from a minimally invasive surgical approach. Our experience confirms that robotics seems to be related to hopeful outcomes both in the short and long term period, even if more studies are needed to refine the promising results.
P451 Early infliximab trough levels in paediatric IBD patients predict sustained remission
Authors: Bevers N , Aliu A , Wong D , Derijks L , Winkens B , Vreugdenhil A , Pierik M , van Rheenen P
Published: January 2023

Background

Therapeutic drug monitoring (TDM) is an approach to improve treatment effectiveness of anti-TNF therapy in Inflammatory Bowel Disease (IBD), but timing and threshold trough levels (TL) are still subject of investigation, especially in paediatric populations.

The aims of our study were (1) to analyse induction – and post-induction infliximab TLs (respectively after 6 and 14 weeks) to predict sustained biochemical and clinical remission between 6 and 12 months in paediatric patients with IBD, and (2) to define paediatric threshold TLs at these timepoints.

Methods

We performed a retrospective study in 70 anti-TNF naïve paediatric IBD patients from two centres who were treated with an induction scheme of 5 mg/kg on 0, 2 and 6 weeks, and subsequently every approximately 8 weeks. We measured infliximab TLs at week 6 and 14 combined with (non)-invasive markers for disease activity. Patients were in sustained biochemical and clinical remission when they were asymptomatic and had normalised CRP and faecal calprotectin between 6 and 12 months after initiating therapy. Receiver operating characteristic (ROC) analysis was used to determine infliximab TL thresholds that best predicted sustained biochemical remission.

Results

Median infliximab TL at 6 and 14 weeks were higher for children in sustained remission versus children who were not (TL6 p=0.028 and TL14 p=0.028). Area under the ROC curve (AUROC) for infliximab TL6 and TL14 to predict sustained biochemical remission was 0.68 (95% Confidence Interval [CI] 0.53-0.83) and 0.67 (95%CI 0.53-0.82), respectively (Figure 1 and 2). The optimal infliximab thresholds were 13.2 mg/L and 6.9 mg/L for TL6 and TL14, respectively, yielding a sensitivity and specificity of 70% and 68% for TL6 and 57% and 76% for TL14.

Figure 1 ROC curve of infliximab trough level at 6 weeks for predicting sustained remission between 6 months to 12 months.

Figure 2 ROC curve of infliximab trough level at 14 weeks for predicting sustained remission between 6 months to 12 months.

Conclusion

In children with IBD treated with a regular infliximab induction scheme, infliximab TLs at week 6 and 14 both predicted sustained clinical and biochemical remission between 6 and 12 months after initiating therapy. TDM and early dose optimization may improve infliximab effectiveness and drug survival.
P453 The significance of the concentration of antibodies to infliximab on the frequency of loss of response when alternating the original drug infliximab and its biosimilar in patients with ulcerative colitis.
Authors: Zviaglova M , Knyazev O , Kagramanova A , Lischinskaya A , Podolskaya D , Nanaeva B
Published: January 2023

Background

Biosimilars are analogues of biopharmaceutical drugs, with a close, but not identical, parent molecule. Biosimilars offer greater access to affordable treatment for inflammatory bowel disease, while being comparable in efficacy and safety to brand-name products. However, switching from original genetically engineered biological drugs (GEBD) to biosimilars requires study and analysis.

Aim

To determine the concentration of antibodies to infliximab in patients with UC receiving infliximab by one trade name (TN) and when alternating infliximab and its biosimilars and to determine the frequency of loss of response during the year of observation.

Methods

In the Department of inflammatory bowel diseases of the A. S. Loginov Moscow Clinical Scientific Center of the Moscow Healthcare Department, were observed 38 patients with IBD, who regularly received the original drug infliximab (IFX) -group 1 (n=20), group 2 a group of patients (n=18) alternated the original drug infliximab and its biosimilar.The level of antibodies to IFX in the blood serum before the next scheduled administration of the drug 10 months after inclusion in the study by enzyme immunoassay using the Shikari Quantitative Determination of Infliximab (Q-INFLIXI) and Shikari Quantitative Determination of Antibodies to Infliximab (Q-ATI) kits (Matriks Biotek). The loss of response was assessed by clinical, laboratory and instrumental data. Comparative analysis was carried out by the method of four-field tables using non-parametric statistical tests.

Results

Of the 20 patients with UC of the 1-st group, 3 (15.0%) had antibodies to IFX, on average, its concentration was 8.5 ± 2.2 ng/ml (normal values <5 ng/ml). Of the 18 patients of the 2nd group 10 (55.5%) antibodies to IFX were detected, on average - 187.9 ± 38.2 ng/ml. (OR - 0.141; 95% CI 0.030-0.658; x2 - 6.923, p= 0.023).During the year of observation among patients of the 1st group receiving the original IFX, the loss of response occurred in 2 (10.0%) patients with UC. Of the patients of the 2nd group, the loss of response occurred in 8 (10.0%) (RR - 0.139; 95% CI 0.025 - 0.785; x2 - 5.797; p = 0.017).

Conclusion

The concentration of antibodies to infliximab is higher in patients with UC when alternating IFX and its biosimilars than in patients with UC who regularly receive IFX by one TN. The frequency of loss of response when alternating infliximab and its biosimilars is significantly higher in patients with UC who regularly receive the drug for one TN.
P460 Preoperative nutrition supplementation may prevent one-year endoscopic recurrence in Crohn’s disease patients
Authors: Inniss S , Simpson K , Fragkos K , Wood C , Smith A , Rahman F
Published: January 2023

Background

Despite improved postoperative management, endoscopic recurrence after surgery remains common in Crohn’s disease (CD) patients [1]. It is widely accepted that patients receiving preoperative nutrition supplementation are less likely to experience postoperative complications [2]. However, little is known about the long-term effects of preoperative nutrition supplementation on surgery. In this study we aimed to assess the long-term effects of preoperative nutrition supplementation on endoscopic recurrence.

Methods

Single centre retrospective data was collected between 2015 and 2021 on patients who had surgical resection with ileocolonic anastomosis. Follow up data was retrospectively collected at 12 months after surgery. Endoscopic recurrence was defined as a Rutgeerts score of 2 or more. Statistical analysis included demographics and inferential analyses. Missing data was attributed to the absence in clinic notes.

Results

This study included 50 CD patients [50.0% male, median age of 31.0 (18.0-68.0), 81.8% non-smokers] who had ileocolonic anastomosis. Most patients had ileocolonic CD (76.0%, 38/50) and either stricturing (46.0%, 23/50) or penetrating (26.0%, 13/50) disease behaviour. Almost half (49.0%, 24/49) of CD patients received preoperative nutrition supplementation prior to surgery, with 61.9% on oral nutrition supplementation. No statistical difference was found between the demographics of patients receiving nutrition supplementation and patients without nutrition supplementation, p>0.05 (table 1). Endoscopic recurrence was observed in 43.5% (10/23) of patients at 12 months. 80.0% (8/10) of patients who experienced endoscopic recurrence did not receive preoperative nutrition supplementation (figure 1). Logistic regression indicated that patients receiving nutrition supplementation may be 84.4% less likely to experience endoscopic recurrence at 12 months compared to patients without nutrition supplementation (OR 0.16 (CI 0.023-1.056)(p=0.057)). The type of preoperative nutrition supplementation did not significantly impact endoscopic recurrence (p>0.05).

Conclusion

Preoperative nutrition supplementation may reduce the risk of endoscopic recurrence one year after surgical resection. The use of preoperative nutrition is highly recommended for all CD patients undergoing surgery. More extensive research is needed to confirm study findings.
P462 Delayed Responders with Ustekinumab in Ulcerative Colitis Have Increased Inflammatory Burden but Similar Long-term Outcomes as Early Responders
Authors: Wong E , Dulai P , Marshall J , Jairath V , Reinisch W , Narula N
Published: January 2023

Background

Differences in one-year outcomes among early compared to delayed responders to vedolizumab have been demonstrated in ulcerative colitis. However, it is unclear whether differences exist with ustekinumab, and what factors differentiate delayed responders from non-responders.

Methods

This was a post-hoc analysis of patient-level data from the UNIFI clinical trial. Ustekinumab-treated patients with clinical response, defined as reduction in total Mayo score ≥30% and ≥3 points from baseline with reduction in rectal bleeding subscore (RBS)≥1 or RBS≤1, at week 8 were deemed early responders and their outcomes were compared with delayed responders (week 8 non-responders who subsequently responded at week 16). The primary outcome assessed was one-year clinical remission (CR), defined as total Mayo score ≤2 and no subscore >1. Other one-year clinical, endoscopic, and histologic outcomes were also assessed. Outcomes were compared using t-tests and biomarkers compared using one-way repeated measures analysis of variance.

Results

We included 642 ustekinumab-treated patients, including 321 (50%) early responders, 115 (17.9%) delayed responders, and 205 (32.1%) non-responders (Table 1). No differences were observed for one-year CR among early vs. delayed responders [132/321 (41.1%) vs. 40/115 (34.8%), p=0.233], nor for any other outcome assessed (Table 2). Similar findings were observed among delayed responders regardless of weight-based vs. fixed ustekinumab induction dose (Table 3). Compared to early responders, delayed responders had more severe endoscopic disease at baseline as measured by the MES [88/115 (76.5%) vs. 206/321 (64.2%), p=0.015] and were more likely to have abnormal CRP at baseline based on a threshold > 3mg/L [83/115 (72.2%) vs. 183/321 (57%), p=0.004]. Compared to non-responders, delayed responders had a significant decline in CRP (F(4, 844), p<0.0001) and fecal calprotectin (F(4, 818), p<0.0001) through week 16 (Figure 1).

Conclusion

Compared with early ustekinumab responders, delayed responders had greater inflammatory burden at baseline. Early and delayed responders have similar one-year outcomes. Biomarker decline can be observed in delayed responders and help differentiate them from non-responders. The decision to prolong ustekinumab among initial non-responders should be informed with biomarkers and weighing the overall risk to benefit.
P466 Efficacy and safety outcomes in patients with moderate to severe ulcerative colitis stratified by ethnicity and race: a pooled analysis of data from GEMINI 1, VARSITY, and VISIBLE 1
Authors: Mukherjee R , Khan R M Q , Liu J J , Ananthakrishnan A N , Lichtenstein G R , Uddin S , Young L , Boules M , Adamson P , Reeves V
Published: January 2023

Background

Ulcerative colitis (UC) is an inflammatory bowel disease with an estimated prevalence of 181 cases per 100,000 adults in the USA. Hispanic or Latino individuals comprise 19% of the US population and 24% of individuals are races other than White; however, the efficacy and safety of advanced therapies for UC in these populations remains uncertain because of their underrepresentation in clinical trials. Underrepresentation has the potential to bias evidence towards therapies with understudied efficacy and safety in minority ethnic and racial groups. This post hoc analysis used pooled clinical trial data of advanced therapies in patients with UC stratified by ethnicity and race in order to identify differential efficacy and safety outcomes among the populations investigated.

Methods

GEMINI 1, VARSITY, and VISIBLE 1 were phase 3 or 3b clinical trials investigating vedolizumab (intravenous or subcutaneous) versus placebo or adalimumab in patients with moderately to severely active UC. Data from these trials were pooled to create three cohorts of patients who received adalimumab, vedolizumab, or placebo. The number and proportion of patients with each efficacy and safety outcome at week 52 were reported for each of the treatment cohorts, stratified by ethnicity and race. Ethnicity and race were self-reported in the three trials.

Results

Overall, 1,358 patients were included in the pooled treatment cohorts. Of the 465 patients with available ethnicity information, only 40 patients (8.6%) reported their ethnicity as Hispanic or Latino. Efficacy and safety outcomes were similar when stratified by ethnicity with some exceptions (Table 1). When stratified by race, efficacy and safety outcomes were similar among White and Asian patients (Table 2). In the vedolizumab cohort, 47.3% and 47.1% of White and Asian patients, respectively, had mucosal healing. Some differences were observed in the efficacy and safety outcomes of Black patients compared with White and Asian patients; however, the treatment cohorts included fewer than 10 Black patients.

Conclusion

In the GEMINI 1, VARSITY, and VISIBLE 1 trials, efficacy and safety outcomes were similar among racial and ethnic groups, with the exception of Black patients. However, this analysis was limited by the small sample size of patients of races other than White, as well as the limited availability of ethnicity information, which prevented robust comparisons of outcomes between patients of different ethnicities and races. Future clinical trials of advanced therapies should aim to recruit and report a diverse patient population with UC who are representative of the patients who will receive these treatments.
P471 A Transcriptome-dependent Prognostic Model of Response in Patients with Ulcerative Colitis
Authors: Johnson T , Reinisch W , Steere B , Milch C , Harris C , Morris N , D'Haens G , Huang K , Krishnan V
Published: January 2023

Background

Mirikizumab (miri), a p19-directed IL-23 antibody, showed efficacy in ulcerative colitis (UC)1. Miri modulates transcripts associated with disease activity and anti-TNF resistance in UC and increases expression of transcripts associated with healthy mucosa2. Here, we evaluate the transcription profile of patients with UC who respond to placebo (PBO, 20.6%) or miri 200mg treatment (59.7%) versus non-responders and build a model that can predict response in patients with UC.

Methods

In the phase 2 AMAC trial (NCT02589665), patients were randomized 1:1:1:1 to receive intravenous PBO (N=63), 50mg miri (N=63), or 200mg miri (n=62) with possible exposure-based dose increases or fixed 600mg miri (n=61) at Week (W)0, 4 and 8. Colonic biopsies were collected at baseline, W12, and W52. An Affymetrix HTA2.0 microarray measured gene expression. Limma comparing values at baseline and W12 determined differentially expressed genes (DEGs). DEGs maintaining their W12 expression level through W52 among responders in either the PBO and miri 200mg arms were designated as similarly expressed genes (DEGSEGs).

XGBoost models3 were trained to predict clinical response (decrease in 9-point Mayo subscore [rectal bleeding, stool frequency, endoscopy] of ≥2 points and ≥35% from baseline [BL] with either a decrease of RB subscore of ≥1 or an RB subscore of 0 or 1) using baseline levels of DEGSEGs and TNF biomarkers. Leave-one-out cross validation of the models using AMAC data and validation experiments by training on the PROTECT data4 then predicting in AMAC were used to evaluate our models.

Results

Miri 200mg responders were associated with 84 DEGSEGs, PBO responders were associated with 26 DEGSEGs, and 21 DEGSEGs were common to both. When using the PROTECT data as the training data and AMAC data as the validation cohort (Figure A), we were able to achieve high ROC-AUC and PR-AUCs using the top 36 (FC > 1.5) miri DEGSEGs (PR-AUC=0.78), TNF biomarkers (PR-AUC=0.91), or combined (PR-AUC=0.93) gene sets as the features (Figure B-E) and found that the response prediction was significantly higher in AMAC responders vs. non-responders (Figure F).

Conclusion

Baseline transcript features were predictive of clinical response in patients with UC treated with miri 200mg and our model distinguished responders from non-responders. Future studies may further validate this model.

References:

1 Sandborn WJ, et al. Gastroenterology. 2020;158(3):537-549.e10

2 Steere B, et al. J Crohns Colitis. 2020;S103-S104

3 Chen T, et al. Proceedings of the 22nd ACM SIGKDD International Conference. 2016;7285-794

4 Hyams JS, et al. Lancet Gastroenterol Hepatol. 2017;2(12):855-868
P478 Platelet-related indicators for predicting vedolizumab response in patients with Ulcerative Colitis
Authors: Jiao J , Liu W , Wang B , Cao H
Published: January 2023

Background

Ulcerative Colitis (UC) combine both inflammation and coagulation in their pathogenesis and clinical manifestations. Although platelets (PLT) are well known for their role in hemostasis, there are a rising number of studies supporting their considerable role as inflammatory amplifiers in chronic inflammatory conditions. However, whether PLT are related to the efficacy of biologic agents is unknown. This study aimed to investigate whether platelet ratio before and after induction therapy can be predictive biomarkers for the therapeutic outcomes of vedolizumab therapy in UC.

Methods

Patients with moderate-to-severe UC receiving vedolizumab in our hospital between November 2020 and November 2022 were retrospectively evaluated. Patients with concomitant corticosteroid treatment≥20 mg, immunomodulators, or other conditions that could modify the platelet count were excluded. The primary endpoint was clinical response at the end of the induction period (at 14 weeks). We analyzed the association between platelet count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP), fecal calprotectin, and the clinical efficacy of vedolizumab. The above indicators between the response and nonresponse groups were compared via a univariate analysis. The independent risk factors of nonresponse were identified via a multivariate analysis.

Results

Seventy-one patients with moderate-to-severe active UC started treatment with vedolizumab and 20 patients (28.2%) experienced loss of response (LOR) after induction therapy. The platelet count, albumin, CRP, NLR, PLR, MLR, and Particul Mayo score between the LOR and response groups significantly differed. The Platelet ratio before and after induction therapy cut-off value of 1.077 was predictive of LOR, using receiver operating characteristic analysis (sensitivity:78.0%, specificity:81.8%). A univariate analysis revealed a significant relationship between LOR and the platelet ratio (P＜0.05). Multivariate analysis indicated the platelet ratio as an independent prognostic factor for LOR (OR=11.219, 95% CI:3.316-37.959, P＜0.05).

Conclusion

Platelet ratio before and after induction therapy is a useful prognostic marker in patients with moderate-to-severe active UC treated with vedolizumab, and may contribute to appropriate use of vedolizumab LOR. A large sample from multiple centers is needed to validate the association between platelet-related measures and the rate of vedolizumab response.
P490 Etrasimod for the treatment of ulcerative colitis: up to 2.5 years of pooled safety data from global clinical trials
Authors: Vermeire S , Peyrin-Biroulet L , Panés J , Regueiro M , Kotze P G , Charabaty A , Goetsch M , Shan K , Wu J , McDonnell A , Woolcott J , Danese S
Published: January 2023

Background

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). The safety and efficacy of etrasimod for the treatment of moderate to severe UC has been evaluated in the OASIS phase 2 and ELEVATE phase 3 placebo (PBO)-controlled trials. Long-term safety and efficacy of etrasimod for UC are being evaluated in an ongoing, open-label extension (OLE) study. We report an integrated analysis of the cumulative safety profile observed during the clinical development programme.

Methods

Safety outcomes included adverse event (AE) frequency and exposure-adjusted incidence rates (EAIRs) of AEs of interest determined based on safety data from PBO-controlled trials and OLE trials. Patients who received PBO or etrasimod (1 or 2 mg) were analysed as two cohorts: patients who received either PBO or etrasimod as part of one phase 2 study (etrasimod 1 or 2 mg for 12 weeks; NCT02447302) or two phase 3 studies (etrasimod 2 mg for 12 or 52 weeks; NCT03945188 and NCT03996369) were reported as the PBO-controlled cohort, and all patients who received ≥1 dose of etrasimod in the all UC cohort (studies above, NCT02536404, NCT03950232, and open-label period of NCT04176588; data cut-off January 31, 2022). Patients may have participated in >1 study.

Results

Overall, 956 patients received ≥1 dose of etrasimod with 769.3 patient years (PY) of exposure with demographics for both cohorts reported in Table 1. In the PBO-controlled cohort, a total of 629 and 314 patients received etrasimod and PBO, respectively, with 288.1 and 115.1 PY of exposure. Mean (SD) exposure per patient was 23.9 (18.5) and 19.1 (15.1) weeks for etrasimod and PBO, respectively. Of the 956 patients who received etrasimod in the all UC cohort, mean (SD) exposure was 42.0 (27.5) weeks. Rates for AEs, serious AEs, and infections (including serious infections, opportunistic infections, and herpes zoster) were similar between treatment arms and between the PBO-controlled and all UC cohorts (Table 2). Eleven (1.8%) etrasimod-treated patients reported events of bradycardia (EAIR=0.04) in the PBO-controlled cohort (9 of 11 events were asymptomatic); no events were reported in PBO-treated patients. Other AEs of special interest including hypertension and macular oedema were similar between treatment arms and with the all UC cohort.

Conclusion

Etrasimod in patients with moderately to severely active UC was overall well tolerated and had an acceptable safety profile that did not appear to change with longer-term treatment of up to 2.5 years. In the PBO-controlled cohort, serious infections and herpes zoster were more commonly reported among PBO patients.
P492 Subcutaneous infliximab (CT-P13 SC) as maintenance therapy for ulcerative colitis: A Phase 3, randomized, placebo-controlled study: Results of the LIBERTY-UC study
Authors: Sands B E , Hanauer S B , Colombel J F , Sandborn W , Schreiber S , Danese S , Klopocka M , Kulynych R , Kierkus J , Soltysiak A , Smolinski P , Gonciarz M , Sreckovic S , Valuyskikh E , Horynski M , Gasbarrini A , Kim S , Bae Y , Lee S , Lee J H , Lee J , Lee S J , Lee S G , Kim J M
Published: January 2023

Background

CT-P13 subcutaneous (SC) infliximab formulation was developed to provide patients with a convenient option for treatment. Previous studies have shown efficacy and safety of CT-P13 SC comparable to CT-P13 intravenous (IV) in inflammatory bowel disease (IBD)1 and rheumatoid arthritis2. This study aimed to demonstrate superiority of CT-P13 SC over placebo in maintenance therapy after induction therapy of CT-P13 IV in patients with ulcerative colitis (UC).

Methods

Patients with moderately to severely active UC (modified Mayo score 5 to 9 with endoscopic subscore of ≥ 2 points) were enrolled LIBERTY-UC (NCT04205643) and treated with open label CT-P13 IV 5 mg/kg at Weeks 0, 2 and 6 as induction therapy. At Week 10, patients who had a clinical response, defined as decrease in modified Mayo score from baseline of at least 2 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 point, were randomised in a 2:1 ratio to receive either CT-P13 SC 120 mg (CT-P13 SC) or placebo SC arms every 2 weeks up to Week 54. The primary endpoint was clinical remission at Week 54. The key secondary endpoints of clinical response, endoscopic-histologic mucosal improvement, and corticosteroid-free remission were assessed at Week 54. Safety was evaluated up to Week 54.

Results

A total of 548 patients were enrolled. Among them, 438 patients (79.9%) responded to CT-P13 IV induction dosing and were randomised (294 in CT-P13 SC arm and 144 in placebo arm, respectively) at Week 10. The rate of clinical remission at Week 54 was significantly greater in CT P13 SC (43.2%) compared to placebo (20.8%) (P<0.0001). Clinical response, endoscopic-histologic mucosal improvement and corticosteroid-free remission also showed statistically greater improvement with CT-P13 SC treatment group, compared to placebo treatment group (Table 1).

The safety profile during maintenance phase was generally comparable between CT-P13 SC and placebo arms (table 2). No deaths were reported.

Conclusion

CT-P13 SC was more effective than placebo for clinical remission, clinical response, endoscopic histologic mucosal improvement, and corticosteroid-free remission at Week 54 in patients with moderately to severely active UC. No new safety concerns were identified. These results demonstrate that the CT-P13 SC provides both a robust clinical benefit and the convenience of SC administration to patient with moderately to severely active UC.

1 Schreiber et al., 2021. Gastroenterology 2021;160:2340–23

2 Westhovens et al., 2020. Rheumatology 2020;00:1
P493 QUASAR Induction Study 1 Cumulative Response to Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis
Authors: Peyrin-Biroulet L , Rubin D , Lichtenstein G , Shipitofsky N , Huang K H , Germinaro M , Wilson R , Zhang H , DuVall G A , Cao Q , Allegretti J , Feagan B , Hisamatsu T , Panés J , Dignass A , Bressler B , Sands B ,   QUASAR Investigators
Published: January 2023

Background

Guselkumab (GUS), an IL-23p19 antagonist, had greater efficacy than placebo (PBO) in achieving clinical response and clinical remission at Week (Wk) 12 in the randomized, controlled Phase 2b QUASAR Induction Study 1 (NCT04033445) in patients with moderately to severely active ulcerative colitis (UC).1 Patients who were not in clinical response at Wk 12 received GUS treatment through Wk 24. Here, we report GUS cumulative efficacy and safety results for Induction Study 1.

Methods

Eligible patients had moderately to severely active UC (modified Mayo score of 5 to 9 with a Mayo endoscopy subscore ≥2) at baseline. Patients were randomized 1:1:1 to IV GUS 200mg, 400mg, or PBO at Wks 0, 4, and 8. Patients who were not in clinical response to IV induction at Wk 12 received GUS treatment (PBO IV→GUS 200mg IV; GUS 200mg IV→GUS 200mg SC; GUS 400mg IV→GUS 200mg SC) at Wks 12, 16, and 20 and were evaluated at Wk 24 (Figure 1). Matching IV or SC PBO was administered to maintain the blind.

Results

Three hundred thirteen patients were randomized and treated at baseline. Demographic and disease characteristics at baseline were similar among the treatment groups, and approximately 50% had a prior inadequate response or intolerance to advanced UC therapy. At Wk 12, clinical response was achieved by 61.4% (62/101) and 60.7% (65/107) of patients randomized to GUS 200mg and GUS 400mg IV vs 27.6% (29/105) of patients randomized to PBO IV (both p<0.001). Of the patients in the GUS groups who were not in clinical response at Wk 12, 54.3% (19/35) in the GUS 200mg IV→200mg SC group and 50.0% (19/38) in the GUS 400mg IV→200mg SC group achieved clinical response at Wk 24. Clinical response at Wk 12 or 24 was achieved by 80.2% of patients who were randomized to GUS 200mg IV and 78.5% of patients who were randomized to GUS 400mg IV. For patients who received PBO IV→GUS 200mg IV, clinical response at Wk 24 (65.2%) was similar to Wk 12 clinical response following GUS 200mg IV induction (61.4%). The most frequent adverse events among all GUS-treated pts (n=274) were anemia (7.7%), headache (5.1%), worsening UC (4.4%), COVID-19 (3.6%), arthralgia (2.9%) and abdominal pain (2.6%) which are consistent with Wk 12 results.

Conclusion

Overall, approximately 80% of patients randomized to receive GUS achieved clinical response at Wk 12 or 24. Continued treatment with SC GUS allowed 50-54.3% of IV GUS Wk 12 clinical nonresponders to achieve clinical response at Wk 24. No new safety concerns for GUS were identified.
P496 Antenatal thiopurine exposure in women with IBD is associated with intrahepatic cholestasis of pregnancy
Authors: Rosiou K , Broglio G , Lever G , Chiu C M , Stocker L J , Chipeta H , Glanville T , Selinger C P
Published: January 2023

Background

Pregnant women with Inflammatory Bowel Disease (IBD) continue thiopurines to maintain remission. Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder of pregnancy, often causing distressing maternal symptoms and with potential implications for pregnancy outcome. Case studies have reported treatment-resistant intrahepatic cholestasis of pregnancy in thiopurine-exposed IBD pregnancies. We aimed to investigate whether thiopurines are associated with an increased risk of ICP and the course of ICP in the setting of thiopurine therapy.

Methods

Single-centre retrospective cohort study comparing incidence and course of ICP in thiopurine exposed vs non-exposed patients with IBD and compared with age-matched pregnant controls.

Results

The IBD cohort consisted of 386 pregnancies in 243 patients with IBD, with 386 age-matched controls without IBD. In patients with IBD, ICP was more common amongst thiopurine exposed pregnancies (n=10 9.0% vs n=5 1.8%; OR 5.34 [1.78-16.02]; p=0.021). Only thiopurine exposure was associated with the development of ICP. Age, disease activity, IBD phenotype, previous surgery, mesalazine, biologic, and steroid exposure were not associated. All thiopurine exposed ICP cases (of which 4 received ursodeoxycholic acid) improved symptomatically without thiopurine discontinuation.

The incidence of ICP was significantly lower in women without IBD compared with women with IBD (n=5 1.3% vs n=15 4.1%; p=0.039). Thiopurine-exposed IBD patients had higher odds of experiencing ICP compared to non-IBD controls (n= 10 9.0% vs n=5 1.3%; OR 7.55 [2.52-22.57]; p<0.001). IBD patients not exposed to thiopurines had a comparable ICP incidence to controls (n-=5 1.8% vs n=5 1.3%; p=0.75). Severe ICP (total serum bile acids ≥40 µmol/l) occurred in 80% of thiopurine exposed patients, vs 40% in non-exposed (p=0.25), vs 20% in controls (p=0.09). We found no evidence of an unfavourable course of ICP in thiopurine exposed IBD cases. Median week of delivery was not significantly different among ICP cases in all three groups (p=0.39).

Conclusion

Thiopurine exposure was associated with a significantly increased risk of ICP amongst patients with IBD compared to non-exposed IBD patients and age-matched general population controls. The course of ICP was not significantly different in thiopurine exposed cases. Clinicians involved in the management of patients with IBD should be aware of the potential risk for ICP and assess bile acids when symptoms occur. Prospective studies are required to understand the potential relationship between thiopurine metabolites and ICP.
P498 Ustekinumab Real World Evidence Study (UndieS): study design with information about positioning and the choice of ustekinumab
Authors: Young D , Booker C , Samaan M , Limdi J , Kok K , Donovan F , Hart A , Smith M , Bodger K , Batchelor J , Cummings F
Published: January 2023

Background

Strict eligibility criteria of phase 3 trials limit the external validity of their results. Well-designed real-world studies are intended to complement these by describing the effectiveness and safety of these medicines in routine clinical practice. As therapeutic options for the treatment of Crohn’s disease (CD) expands, the ideal sequence of medications, and the influences on this, needs defining.

Methods

UndieS is a phase IV, multi-centre, prospective, observational study of patients with CD initiated on ustekinumab as part of their routine care. 600 participants will be recruited from 22 centres across the UK with a follow-up period of 2 years. Assessments at baseline and weeks 8, 16/20, 56, 80 and 104 include modified Harvey-Bradshaw Index (mHBI), IBD-Control, Treatment Satisfaction Questionnaire for Medication and PRO-2. The primary outcome is steroid-free remission (mHBI ≤ 4) at one year. Secondary outcome measures include describing changes in disease activity, PROs and tolerability.

Results

Recruitment started in March 2020 with 437 patients recruited so far. The summary baseline characteristics are 50% male, median (range) age at consent 41 (18-91) years (14% > 65 years), median mHBI 5 (0-39). The median duration of Crohn’s disease before starting ustekinumab was 8 (0-60) years. Disease location (as per Montreal classification) is: L1: 35%, L2: 20%, L3: 44% and isolated L4: 1%. 24% of participants reported perianal disease. The proportion of participants using concomitant immunomodulators or oral corticosteroids on starting ustekinumab (15% and 11% respectively) is lower than in the UNITI clinical trial program.

59% of participants had a disease activity score suggesting that they would not meet the threshold required for entry into UNITI and suggested by NICE for moderately-to-severely active CD, although 81% of these had evidence of inflammation. Inadequate response to or adverse effects from a previous treatment was a common indication (52% of participants).

32% of the participants are bio-naïve; 64% and 10% have previous exposure to anti-TNF and vedolizumab respectively and 6% have been exposed to both. Details of prior biologic exposure is shown in figure 1. The most common reasons for the specific choice of ustekinumab were intolerance to immunomodulators and concern about infection risk. Bio-naïve patients were older (median 45 vs. 39 years; p=0.02) and had a shorter disease duration (7 vs. 9 years; p=0.04) than those with prior biologic exposure.

Conclusion

Our cohort is representative of those patients with CD being treated with ustekinumab in a real-world setting. Some important differences between these patients and those recruited to phase 3 clinical trials are identified.
P506 Endoscopic and clinical outcomes of upadacitinib in patients with moderate to severe Crohn’s disease by baseline disease severity
Authors: Siegmund B , Patel K , Torres E A , Lakatos P L , Seidelin J , Fleisher M , Ford S , Remple V , Lacerda A P , Anyanwu S , Garrison A , Panés J
Published: January 2023

Background

Upadacitinib (UPA) is an oral selective Janus kinase inhibitor with demonstrated efficacy in induction and maintenance treatment of Crohn’s disease (CD). This post hoc analysis assessed the efficacy of UPA in patients with CD by baseline (BL) disease severity.

Methods

In the U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) induction studies, patients with moderate-to-severe CD and intolerance/inadequate response to biologic therapy (both studies) and/or conventional therapy (U-EXCEL) received UPA 45 mg once daily (QD) or placebo (PBO) for 12 weeks. Patients who achieved clinical response to UPA induction were re-randomised in a maintenance study (U-ENDURE, NCT03345823) to receive UPA 15 mg QD, UPA 30 mg QD, or PBO for 52 weeks. Clinical remission and endoscopic response were evaluated in subgroups stratified by BL disease characteristics: Crohn’s Disease Activity Index (CDAI), very soft/liquid stool frequency (SF), abdominal pain score (APS), and Simple Endoscopic Score for CD (SES-CD). Patients from the U-EXCEL and U-EXCEED studies were pooled for analysis.

Results

Among 1021 patients with moderate-to-severe CD (UPA 45 mg, n=674; PBO, n=347), week 12 clinical remission and endoscopic response rates were significantly higher for patients receiving UPA 45 mg vs PBO regardless of BL disease severity (nominal P <.01), except SES-CD <6 (UPA, n=35; all had ileal disease only per the inclusion criteria) (Figure 1). UPA efficacy rates were higher compared with PBO across BL CDAI, with variable treatment effects. Patients with lower BL SF achieved clinical remission and endoscopic response with UPA 30 mg at higher rates than those with higher BL SF at week 12 and week 52. At week 12, the absolute efficacy rates and treatment differences for clinical remission and endoscopic response were generally similar across BL APS. Patients with higher BL SES-CD (≥15) generally achieved higher rates of clinical remission and endoscopic response at week 12 with UPA vs PBO than those with lower BL SES-CD (6–14). At week 52, clinical remission and endoscopic response rates were generally higher for patients receiving UPA vs PBO and most were consistent with a dose-response relationship (Figure 2). Generally, larger treatment differences between UPA and PBO were observed for patients with the most severe disease per SES-CD.

Conclusion

UPA induction and maintenance therapy improved clinical and endoscopic outcomes vs PBO in patients with moderate-to-severe CD, across levels of disease severity. Data for the small subgroup of patients with SES-CD <6 should be interpreted cautiously given lower mucosal healing rates in isolated ileal CD.1

Reference:

1. Atreya R, et al.Curr Res Pharmacol Drug Discov. 2022;3:100097.
P509 Surgery and biologic prescription rates for Crohn's disease in Lothian, Scotland; an updated population-based cohort study.
Authors: Jenkinson P , Plevris N , Lyons M , Gros Alcalde B , Derikx L , Constantine-Cooke N , Arnott I , Jones G , Lees C
Published: January 2023

Background

Recent years have seen a shift in Crohn’s disease (CD) management to earlier initiation of biologic therapy using a treat to target strategy. We have previously published a population based cohort showing a reduction in CD surgery rates and increase in biologic prescribing over time.

Methods

The aim of this study was to identify trends in rates of surgery and biologic prescription in CD over time in a population-based cohort. All incident CD cases diagnosed between 01/01/2000 and 31/12/2017 were identified from the Lothian IBD registry . Abdominal surgeries and biologic prescription from diagnosis to July 31st 2022 were identified from national coding data and the EHR.. The cohort was divided into quartiles by date of diagnosis: 2000-04, 2005-08, 2009-13 and 2014-17; comparison was performed using the log rank test.

Results

560/1753 (30.3%) incident CD cases underwent resectional surgery over a median of 12 years follow-up (IQR 8-14). The overall cumulative incidence rates of first surgery at 1, 5, and 10 years were 7.41% (95% CI, 3.4%–10.4%), 16.1% (12.2%-19.6%), and 29.9% (25.2%–34.4%), respectively. When comparing temporal trends there was a significant reduction in surgical rates by date of diagnosis (logrank p <0.00) (Fig 1). There was no difference in the rate of repeat surgery between cohorts (p=0.156).

Fig 1. Kaplan–Meier curves for risk of first surgery in Crohn’s disease during follow-up of cohorts defined by year of diagnosis.

A total of 703/1753 patients (34.3%) were prescribed biologics. The rates of first biologic prescription at 1, 5, and 10 years were 8.2% (CI:, 4.4%– 12.3%), 22.2% (18.8%-25.6%), and 34.7% (31.4%–37.8%) respectively. When comparing temporal trends, there was a significant increase in biologic prescription rates by date of diagnosis (logrank p <0.001; Figure 2). Biologic prescription in the first year after diagnosis rose significantly over time from 1.0% in the earliest cohort to 22.2% in the latest.

Fig 2. Kaplan–Meier curves for risk of first biologic in Crohn’s disease during follow-up of cohorts defined by year of diagnosis.

Conclusion

We have identified a significant increase in the cumulative incidence of biologic prescription and use of biologics earlier in the patients IBD journey over time. This has been parallelled by a significant reduction in the incidence of first surgery which has been maintained with longer follow up.
P512 The counts of white blood cells are not predictive for long-term remission under treatment with thiopurines: a three year Japanese multi-center retrospective cohort study.
Authors: Kiyohara H , Yamazaki H , Moriya K , Akimoto N , Kawai S , Kobayashi T ,   IBD Terakoya Group
Published: January 2023

Background

Whether white blood cell (WBC) counts are predictors for the effectiveness of thiopurine treatment in ulcerative colitis (UC) has been inconclusive in previous studies with small sample sizes. We investigated the association between WBC counts and future relapses in UC patients in a large-scale multicenter study.

Methods

This retrospective cohort study enrolled a total of 723 UC patients in remission from 33 hospitals and followed up for three years. Relapse was defined as a need for treatment intensification. The risk of relapse was compared among patients with the baseline WBC counts<3000/µL (N=31), 3000–4000/µL (N=167), 4000–5000/µL (N=241), and ≥5000/µL (N=284) using a Cox regression model analysis. Moreover, exploratory analyses were conducted to identify other factors predicting relapse.

Results

During a median follow-up period of 1095 (interquartile range, 1032–1119) days, relapse occurred in 17.2% (125/723). In a crude analysis, WBC counts were not associated with relapse; hazard ratios (HRs) [95% confidence interval (CI)] were 1.50 [0.74–3.06], 1.02 [0.66–1.59] and 0.67 [0.43–1.05] in WBC<3000/µL, 3000–4000/µL, and 4000–5000/µL groups, respectively (WBC≥5000/µL group, as reference). Multivariable-adjusted analyses showed similar results; HRs [95% CI] were 1.21 [0.59–2.49], 1.08 [0.69–1.69], and 0.69 [0.44–1.07], in <3000/µL, 3000–4000/µL, and 4000–5000/µL group, respectively (Table 1). In the exploratory analyses, thiopurine use <1 year and a mean corpuscular volume <90 fL were predictors for relapse.

Conclusion

WBC counts were not predictors for future relapses in patients with UC treated with thiopurine as a maintenance therapy.
P521 Effectiveness of ustekinumab as therapy for chronic antibiotic refractory pouchitis
Authors: Outtier A , Louis E , Dewit O , Schops G , Verstockt B , Sabino J , Vermeire S , Ferrante M
Published: January 2023

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.