bluuebunny/crossref_metadata_2025_split huggingface dataset:
P393 Effect of filgotinib on anaemia in patients with Ulcerative Colitis in SELECTION
Authors: Loveikyte R , de Haas A , Oortwijn A , Eskens B , Jamoul C , Muller K , van der Meulen-de Jong A 
Published: January 2023

Abstract

Background
Patients with ulcerative colitis (UC) often have anaemia owing to inflammation and/or blood loss.1 Filgotinib (FIL) is a once-daily, oral, Janus kinase (JAK) 1 preferential inhibitor approved for the treatment of UC, which may be associated with fewer haematological events than pan-JAK inhibitors. In the phase 2b/3 SELECTION trial (NCT02914522),2 FIL 200 mg (FIL200) was well tolerated and effective vs placebo (PBO) in patients with UC. This post hoc analysis of SELECTION data compared haematological events across the FIL and PBO treatment arms.

Methods
In SELECTION, adults with moderately to severely active UC were randomized 2:2:1 to receive FIL200, or FIL 100 mg, or PBO once daily for 11 weeks during induction. FIL responders (clinical remission or a Mayo Clinic Score response at week 10 [W10]) were rerandomized to continue their induction FIL dose or PBO in the 47-week Maintenance (MNT) Study. PBO responders continued PBO during MNT. This analysis evaluated the proportions of patients with haematological events (anaemia, leukopenia, lymphopenia, neutropenia and thrombocytopenia) at baseline (BL), W10 and W58. Haematological events were defined based on the relevant laboratory parameters being below the lower limit of normal. For anaemia at W10 and W58, patients were further stratified by rectal bleeding (RB) status (no: RB subscore=0; yes: RB subscore ≥1) at W10 and W58, respectively.

Results
At BL, ~50% of patients had anaemia in all treatment arms. Among these patients, the proportion without anaemia at W10 was similar across the FIL and PBO arms (25.0–30.7%; Table 1). Among patients without BL anaemia, the proportion with anaemia at W10 was also similar across all arms (12.1–17.3%). Among patients without RB at W10, the proportion of patients with a change in anaemia status from BL to W10 was also similar across arms. At W58, the proportion of patients with anaemia was similar across all arms, although ~40% of patients overall had missing data (Table 2). At BL, &lt;5% of patients had leukopenia across all treatment arms (Tables 3 and 4). Lymphopenia, neutropenia and thrombocytopenia were also uncommon at BL (&lt;10%, &lt;4%, and &lt;1% of patients, respectively). Among patients without these four haematological events at BL, &lt;5%, &lt;6%, 4% and ~1%, respectively, had them at W10.

Conclusion
Treatment with JAK1-preferential FIL up to W58, was not associated with anaemia, thought to occur via JAK2 inhibition, in patients overall and in those without RB at W10, compared with PBO. The small numbers of patients with haematological events excluding anaemia at BL limit rigorous inter-arm comparison.
1. Malesza IJ et al. Nutrients 2022;14:3478. 2. Feagan BG et al. Lancet 2021;397:2372–84.
P396 Ustekinumab Is A Promising Option For The Treatment Of Postoperative Recurrence Of Crohn’s Disease
Authors: Macaluso F S , Grova M , Mocciaro F , Di Mitri R , Privitera A C , Distefano M E , Vitello A , Camilleri S , Ferracane C , Pluchino D , Belluardo N , Giangreco E , Fries W , Viola A , Cappello M , Amato L , Bertolami C , Ventimiglia M , Renna S , Casà A , De Vivo S , Orlando A ,   Sicilian Network for Inflammatory Bowel Disease (SN-IBD)
Published: January 2023

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 &gt; 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
P412 Time trend in clinicopathological features and prognosis of Ulcerative Colitis associated neoplasia: A nationwide cohort in Japan
Authors: Komatsu K , Shinagawa T , Noguchi T , Uchino M , Ikeuchi H , Okabayashi K , Tanaka S , Futami K , Itabashi M , Watanabe K , Nagahara H , Okita Y , Shimada Y , Mizuuchi Y , Okamoto K , Yamada K , Sato Y , Mizushima T , Kimura H , Takahashi K , Hida K , Kinugasa Y , Ishida F , Okuda J , Daito K , Yamamoto T , Yamamoto S , Koyama F , Hanai T , Komori K , Shida D , Arakaki J , Akagi Y , Yamaguchi S , Ueno H , Matsuda K , Ajioka Y , Sugihara K , Ishihara S ,   The Study Group for Inflammatory Bowel Disease Associated Intestinal Cancers by the Japanese Society for Cancer of the Colon and Rectum
Published: January 2023

Abstract

Background
With an increase in the number of Ulcerative Colitis (UC) patients in Japan, UC associated neoplasia (UCAN) cases have been accumulated. Laparoscopic surgery for sporadic advanced colorectal cancer was approved in 2002 and biologic agents have been approved for UC from 2010 in Japan. However, few reports have ever examined the time trend using a large patient cohort. We aimed to clarify time trend in clinicopathological features and prognosis of UCAN with a nationwide cohort. This study was conducted as a sub-analysis of the nationwide retrospective study across 47 institutions from the Japanese Society for Cancer of the Colon and Rectum.

Methods
A total of 1,139 UCAN patients were identified in the nationwide cohort from 1983 to 2020. Clinicopathological features, 5-year cancer specific survival (CSS) and overall survival (OS) were compared among the following three groups by the period of UCAN diagnosis, before 2000, 2001-2010 and 2011-2020 (the results are shown in this order).

Results
The number of UCAN patients registered in the database were 59, 340 and 740 in each period. Age at UCAN diagnosis (47, 51, 54, median, p&lt;0.01) and the disease duration from UC diagnosis to UCAN diagnosis (14.3, 16.0, 17.5 years, mean, p&lt;0.01) increased through the study periods. The rate of a surveillance colonoscopy as a diagnostic procedure (36.2%, 58.6%, 72.8%, p&lt;0.01) increased without a change in the ratios of early (pathological stage 0-I) neoplasia (60.7%, 59.5%, 62.2%, p=0.72). Laparoscopic surgery became a dominant surgical procedure in the recent cases (1.7%, 33.2%, 47.7%, p&lt;0.01) without an increase in postoperative complication rate (39.7%, 29.2%, 29.8%, p=0.26). Improvement in 5-year CSS (77.2%, 87.5%, 90.7%, p&lt;0.05) and OS (77.2%, 84.3%, 88.5%, p&lt;0.05) was observed. Among pathological stage III patients, better curative resection rate (66.7%, 92.6%, 97.1%, p&lt;0.01) and the more use of adjuvant chemotherapy in the last decade (50.0%, 58.5%, 76.6%, p&lt;0.05) were observed.

Conclusion
Longer duration of UC before the diagnosis of UCAN was observed in recent cases, which might be due to the improvement of medical therapy, including biologic agents. Minimally invasive surgery prevailed without an increase in postoperative complications. Curative resection and adjuvant chemotherapy might play a role in improvement of 5-year CSS and OS.
P463 Crohn’s disease–associated anorectal cancer has a poor prognosis with high local recurrence: a subanalysis of the Nationwide Japanese Study
Authors: Ogino T , Mizushima T , Sekido Y , Fujii M , Eguchi H , Nezu R , Ikeuchi H , Uchino M , Futami K , Okamoto K , Ajioka Y , Sugihara K , Ishihara S ,   The Study Group for Inflammatory Bowel Disease Associated Intestinal Cancers by the Japanese Society for Cancer of the Colon and Rectum
Published: January 2023

Abstract

Background
Cancer is the worst prognostic factor for patients with Crohn’s disease (CD). Previous studies of CD-associated colorectal cancer (CRC) have involved only small numbers of patients, and no large series have been reported. The aims of this study are to clarify the prognosis and clinicopathological features of CD-CRC compared with sporadic CRC using a large nationwide database from the Japanese Society for Cancer of the Colon and Rectum.

Methods
A large nationwide database covering data from 1980 to 2020 was used to identify patients with CD-CRC (n=233) and sporadic CRC (n=129,783). The clinicopathological features, 5-year overall survival (OS), and 5-year recurrence free survival (RFS) for patients with CD-CRC were compared with these outcomes in sporadic CRC. The data were further analyzed based on tumor location in the colon (CC) or anus/rectum (RC). Propensity score (PS) matching was used to account for selection bias. A binomial logistic regression model was used to estimate the PS, using the nine effective covariates: age at cancer diagnosis, sex, CEA, surgical treatment, adjuvant chemotherapy, tumor depth, lymph node metastasis, distant metastasis, and residual tumor.

Results
Compared with sporadic cases, patients with CD-CRC were younger, more often had RC, multiple lesions, and mucinous adenocarcinoma. R0 resection was less common with CD-CRC (77.43%) vs sporadic CRC (90.99%; P&lt;0.001). Five-year OS was worse with CD-CRC vs sporadic CRC (53.99% vs 71.17%, P&lt;0.001). Evaluation by tumor location showed significantly worse 5-year OS and RFS with CD-RC compared with sporadic RC, whereas 5-year OS and RFS in CD-CC vs sporadic CC was comparable. A higher recurrence was found with CD-RC (39.57%) compared with sporadic RC (21.97%, P&lt;0.001), but the recurrence rates did not differ between CD-CC and sporadic CC. The most frequent sites of recurrence in CD-RC were local. Following PS matching, 5-year RFS with CD-RC was significantly worse than with sporadic RC (52.41% vs 78.74%, P&lt;0.001), but 5-year RFS did not differ between CD-CC and sporadic CC (81.07% vs 82.04%, P=0.900).

Conclusion
Poor prognosis with CD-CRC is attributable primarily to RC and high local recurrence. Local control is indispensable to improving prognosis.
P479 Reliability and responsiveness of histologic disease activity indices in Crohn’s Disease
Authors: Solitano V , Schaeffer D F , Hogan M , Pai R K , Zou G , Pai R K , Vande Casteele N , Parker C E , Remillard J , Christensen B , Panaccione R , Sands B E , D’Haens G , Feagan B G , Ma C , Jairath V 
Published: January 2023

Abstract

Background
The operating properties of histologic indices are poorly characterized in Crohn’s disease (CD) and no validated index exists. We assessed the reliability and responsiveness of histologic indices/items, developed an exploratory index, and compared different methods of scoring.

Methods
Using baseline and week 12 histologic image sets from the EXTEND placebo-controlled trial, blinded central readers scored 4 histologic indices (the Global Histologic Activity Score [GHAS], Geboes Score [GS], Robarts Histopathology Index [RHI], and Nancy Index [NHI]) and 3 additional novel items identified by an expert panel (mucin depletion, basal plasmacytosis, and pyloric gland metaplasia in the ileum). Reliability and responsiveness were evaluated for a global score (4 colonic segments + ileum), colonic score (4 colonic segments) and ileal score (ileum only) using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Change was defined using treatment assignment and improvement in histologic disease activity as measured on a 100-mm visual analogue scale (VAS) in responsiveness testing. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an ICC ≥0.4 and AUC ≥0.56. The VAS served as the dependent variable.

Results
Paired histologic images were analysed from 55 subjects. Inter-rater reliability was substantial to almost perfect (ICC=0.73-0.85) and responsiveness was small to large (treatment assignment AUC=0.50-0.65; VAS AUC=0.71-0.94). The GHAS, GS, RHI, and NHI reached the minimum threshold for reliability (ICC ≥0.4) and responsiveness (AUC ≥0.56) regardless of whether the global and colonic scores were calculated using the worst affected segment, average of the included segments, or sum of the included segments (Table 1-3). Five items were tested as candidate predictors. Three exploratory indices were developed, each consisting of 3 items: a global index (neutrophils in the lamina propria, neutrophils in the epithelium, and erosion/ulceration), colonic index (chronic inflammatory infiltrate, neutrophils in the lamina propria, and erosion/ulceration) and ileal index (chronic inflammatory infiltrate, neutrophils in the epithelium, and erosion/ulceration). The novel indices highly correlated with the GHAS, GS, RHI, and NHI, with correlation coefficients ≥0.80 (Table 4).

Conclusion
The 4 existing indices were similarly reliable and responsive in measuring CD histologic activity, regardless of the method for calculating global and colonic scores and could be used in clinical trials. Attempts at novel index development did not offer benefit over current histologic indices.
P491 Efficacy and safety of upadacitinib for the treatment of fistulas and fissures in patients with Crohn’s disease
Authors: Colombel J F , Irving P , Rieder F , Panaccione R , Schwartz D , Hayashi R , Zhu X , Lacerda A P , Dubcenco E , Marced E , Hecht P , Feng T , Berg S , Reinisch W 
Published: January 2023

Abstract

Background
Intestinal and perianal fistulas and fissures are associated with significant morbidity and decreased quality of life in patients with Crohn’s disease (CD). We evaluated rates of fistula and fissure improvements with upadacitinib (UPA), an oral selective Janus kinase inhibitor, in patients with CD who had fistulas or fissures at baseline in phase 3 induction and maintenance trials.

Methods
In the U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) phase 3 induction trials, patients with moderate-to-severe CD were randomized to UPA 45 mg once daily (QD) or placebo (PBO) for 12 weeks. Patients who achieved clinical response after 12 weeks of induction were eligible for U-ENDURE (NCT03345823) and rerandomized to UPA 30 mg QD, UPA 15 mg QD, or PBO for an additional 52 weeks of maintenance treatment. Fistula activity was assessed by presence of external openings and draining upon gentle compression. Presence of perianal fissures was also assessed. The proportion of patients with external closure of fistula openings, complete resolution of draining, and ≥ 50% reduction in draining was recorded at weeks 12 and 52. Endpoints were analyzed using non-responder imputation.

Results
Of 1021 enrolled patients, 143 patients had fistulas (124 [86.7%] perianal; 19 [13.3%] enterocutaneous) and 54 patients had perianal fissures at baseline. The proportion of patients who achieved external closure of fistula openings was higher with UPA vs PBO at week 12 (Fig 1A) and at week 52 (Fig 2A). The proportion of patients who achieved complete resolution of draining and ≥ 50% reduction in draining was higher with UPA vs PBO at week 12 (Fig 1B and 1C) and at week 52 (Fig 2B and 2C). A higher proportion of patients achieved complete resolution of fissures with UPA vs PBO at week 12 (Fig 1D) and at week 52 (Fig 2D). At weeks 12 and 52, a higher proportion of patients with fistulas treated with UPA vs PBO achieved clinical remission and endoscopic response (Fig 1E and 2E). Rates of adverse events (AEs), serious AEs, or AEs leading to study drug discontinuation were similar in UPA groups compared with PBO during the induction and maintenance periods. Rates of abscess formation were 1.8% with UPA 45 mg and 6.8% with PBO at week 12, and 3.0% with UPA 30 mg, 6.4% with UPA 15 mg, and 2.5% with PBO at week 52.

Conclusion
Among patients with CD complicated with fistulas and/or fissures at baseline, UPA treatment led to higher rates of external closure of fistula openings, resolution of draining, and healing of fissures, along with clinical remission and improvements in luminal disease compared with PBO. No new safety concerns were identified.
P531 A model-based tool for guiding infliximab induction dosing to maximise long-term deep remission in children with inflammatory bowel diseases
Authors: Kantasiripitak W , Wicha S G , Thomas D , Hoffman I , Ferrante M , Vermeire S , van Hoeve K , Dreesen E 
Published: January 2023

Abstract

Background
Adequate infliximab (IFX) concentrations during induction treatment are predictive for deep remission (corticosteroid-free clinical and endoscopic remission) at six months in children with Crohn’s disease (CD) and ulcerative colitis (UC).1 Under standard IFX induction dosing, children often have low IFX trough concentrations.2 Model-informed precision dosing (MIPD) is advocated as a promising IFX dosing strategy. We aimed to develop and validate an MIPD framework for guiding paediatric IFX induction treatment.

Methods
Data from 31 children (4-18 years, 15-76 kg, 20:11 CD:UC) receiving standard IFX induction dosing (5 mg/kg at week [w]0, w2, and w6) were repurposed.1 Eight paediatric population pharmacokinetic models were evaluated (six 2-compartment models and two 1-compartment models). Modelling and simulation were used to identify exposure targets, an optimal sampling strategy, and to develop a multi-model prediction algorithm for implementation into an MIPD software tool.3 A role for IFX clearance monitoring was evaluated.

Results
A total of 251 IFX concentrations were available (6-10 samples per patient). One patient had undetectable IFX concentrations at w6 and w12 but had no measurable antibodies to IFX (ATI). At six months after start of the IFX treatment, 58% (18/31) of patients achieved deep remission.
The measured IFX concentration at w12 was the best predictor and classifier for deep remission. A 7.5 mg/L IFX concentration target at w12 was associated with a 64% probability of deep remission at six months (Figure 1). With standard dosing, less than 80% of simulated children &lt;40 kg attained this target (Figure 2). Immunomodulator combo-therapy only subtly improved probability of target attainment. Presence of ATI lowered the target attainment considerably.
The w12 target was most accurately and precisely achieved by implementing MIPD at w6 using the w6 IFX concentration. The multi-model algorithm outperformed single models when optimising the w6 dose based on combined w2 and w4 concentrations. MIPD using only the w2 concentration resulted in biased and imprecise predictions. The predictive performance of the MIPD multi-model algorithm was robust to misspecification of ATI status.
IFX clearances at w6 and w12 were predictive for deep remission (P=0.02) (Figure 3).
An IFX module was added to the TDMx software tool to facilitate MIPD and clearance monitoring (https://tdmx.shinyapps.io/Infliximab_paediatric/).

Conclusion
A freely available, interactive, multi-model MIPD software tool is provided to facilitate IFX induction dosing and improve deep remission rates in children with CD and UC.
1van Hoeve et al. J Pediatr 2022.
2van Rheenen et al. J Crohns Colitis 2020.
3Kantasiripitak et al. CPT:PSP 2022.
P570 Safety and Effectiveness of Tofacitinib in Ulcerative Colitis: Real-world Data from TOFA-UC, a SN-IBD Study
Authors: Macaluso F S , D'Antonio E , Fries W , Viola A , Ksissa O , Cappello M , Muscarella S , Belluardo N , Giangreco E , Mocciaro F , Di Mitri R , Ferracane C , Vitello A , Grova M , Renna S , Casà A , Ventimiglia M , Orlando A ,   Sicilian Network for Inflammatory Bowel Disease (SN-IBD)
Published: January 2023

Abstract

Background
Real-world evidence is necessary to determine the safety and effectiveness of tofacitinib (TOFA) for the treatment of ulcerative colitis (UC) in clinical practice.

Methods
TOFA-UC is a multicenter observational study performed among the Sicilian Network for Inflammatory Bowel Disease (SN-IBD) on a prospectively maintained database. All consecutive patients with UC starting TOFA from its introduction in Sicily (June 2021) to June 2022 (12 months) were enrolled. The primary outcome was the assessment of safety, in terms of rate of adverse events (AEs). Secondary outcomes included the rates of clinical response, steroid-free clinical remission (based on partial Mayo score) and C-Reactive Protein (CRP) normalization after 8 weeks and at the end of follow-up, the rate of loss of response, and treatment persistence.

Results
111 patients were included (mean follow-up: 31.5 ± 15.2 weeks). Only 8 patients (7.2%) were naïve to biologics, while most had previous failures to one (27.0%), two (26.1%), three (32.4%), or four (7.2%) biologics. Nineteen adverse events were reported (17.1%; incidence rate: 28.6 per 100 patient-year), including 11 cases of hypercholesterolemia, 3 infections (no cases of herpes zoster reactivation), nausea in two patients, paresthesia in one case, one colorectal cancer and one pulmonary embolism. At week 8, the rates of clinical response, steroid free clinical remission, and CRP normalization were 74.8%, 45.0%, and 56.9%, respectively, and 68.5%, 51.4%, and 65.2%, respectively, at the end of follow-up. Eighteen patients experienced a loss of response after successful induction (21.7%; incidence rate: 33.2 per 100 patient-year). The dose was increased to 10 mg bid in 15 patients, and 7 of them recaptured the response. A total of 26 patients (23.4%) discontinued TOFA over time, of whom 3 due to AEs. At multiple model regression analysis, being former smoker (hazard ratio=4.03; 95% CI=1.36-10.25; p=0.015) was the only variable associated with higher risk of treatment discontinuation. No significant differences in all outcomes of effectiveness were detected when the subgroup of patients naïve to biologics or with only one previous line of biologic therapy was compared with those with at least two previous lines of biologics.

Conclusion
TOFA is safe and effective in patients with UC, including those with multiple previous failures to biological therapies.