bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

Background
Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). 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 &gt;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

Abstract

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&lt;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

Abstract

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&lt;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

Abstract

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&lt;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

Abstract

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% &gt; 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

Abstract

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 &lt;.01), except SES-CD &lt;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 &lt;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

Abstract

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 &lt;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 &lt;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

Abstract

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&lt;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&lt;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 &lt;3000/µL, 3000–4000/µL, and 4000–5000/µL group, respectively (Table 1). In the exploratory analyses, thiopurine use &lt;1 year and a mean corpuscular volume &lt;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.