bluuebunny/crossref_metadata_2025_split huggingface dataset:
P981 Risankizumab, but not ustekinumab or vedolizumab, downregulates IL-23-induced mucosal pathogenic Th17 cells in patients with Crohn’s disease
Authors: Noviello D , Dusetti I , Pivorunas V , Lovati A E , Ciafardini C , Amoroso C , Conforti F , Piazza O Sed N , Vecchi M , Facciotti F , Paroni M , Caprioli F 
Published: January 2024

Abstract

Background
We recently described an interleukin(IL)-23-inducible pathogenic subset of CCR6+CXCR3-CCR5+ mucosal T helper (Th)17 cells (pTh17) infiltrating Crohn’s disease (CD) inflamed mucosa and specifically activated in response to Adherent-Invasive Escherichia Coli. pTh17 cells are functionally and phenotypically distinct from CCR6+CXCR3-CCR5- Th17 cells (cTh17) and from IL-12-induced CCR6+CXCR3+ Th1/17 subset. Here, we investigated pTh17 cells' recirculation into the bloodstream, localization into the intraepithelial lymphocyte (IEL) compartment, and in-vivo modulation by different biological therapies.

Methods
Adult patients with active CD initiating either vedolizumab as per clinical practice or ustekinumab and risankizumab during the SEQUENCE trial were prospectively recruited at Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano. In vedolizumab-treated patients, peripheral blood and intestinal biopsies were collected at baseline and at the end of induction. In ustekinumab- and risankizumab-treated patients, intestinal biopsies were collected outside study protocol assessments at baseline and week 24. Endoscopic response was defined as a greater than 50% decrease in the Simple Endoscopic Score from baseline. Peripheral blood mononuclear cells, lamina propria mononuclear cells (LPMC), and IEL were isolated and analyzed through flow cytometry.

Results
Overall, 34 CD patients were assessed. Demographic and baseline disease characteristics are summarized in Table 1. At baseline, as compared with cTh17, pTh17 cells: 1. are rarely found in the peripheral blood and express low levels of CCR9 and α4β7, 2. express high levels of tissue-resident markers CD69+CD103+ in the mucosa, and 3. infiltrate the IEL layer upon binding of CD103 with E-cadherin. Baseline pTh17 cells were upregulated in patients not achieving vedolizumab-induced endoscopic response. Upon vedolizumab treatment, a selective downregulation of mucosal cTh17 cells but not pTh17 was observed. Remarkably, risankizumab induced a specific downregulation of pTh17 cells, but not cTh17, in both LPMC and IEL layers. Conversely, ustekinumab reduced Th1/17 mucosal subsets, but not pTh17 cells (Figure 1).

Conclusion
pTh17 cells are largely unable to recirculate through the bloodstream, express markers of gut-tissue residency, and infiltrate the IEL compartment. IL-23 neutralization by risankizumab specifically downregulates mucosal pTh17 cells, as compared with vedolizumab and ustekinumab. Our immunologic results might provide mechanistic clues to vedolizumab latency effect in CD, and potentially explain early signs of risankizumab superiority over ustekinumab in the SEQUENCE study in terms of endoscopic response at 24 weeks.
P997 New Objective Assessment of perianal Crohn’s disease, Perianal Lesion Index; PLI
Authors: Yokoo T , Yoshikawa S , Masuda T , Terauchi S , Uchida H , Nakao T , Yamaoka K , Inagaki M , Tani T , Okamoto K , Inatsugi N 
Published: January 2024

Abstract

Background
In the previous survey, decisions of biological treatment (Bio) success for perianal Crohn’s disease (pCD) were made by the patient’s subjective improvement and physician’s assessment, so it lacks objectivity. Moreover, physicians, surgeons, and proctologists are related to treating pCD. This aspect is the difficulty of the treatment of pCD. We need a common assessment for each area’s doctor. We aimed to develop a new objective assessment of pCD, including endoscopic findings, and assess the efficacy of the newly launched Bio except anti-TNFα agents for pCD.

Methods
Usually, perianal abscesses and fistula are derived from ulcers in the lower rectum and anal canal, so we adapted SES-CD to the location and checked discharge and needs of setons, and finally scored it (Table 1). We named this assessment Perianal Lesion Index; PLI.
We retrospectively evaluated 20 pCD patients who received Ustekinumab (UST) and Vedolizumab (VDZ) from March 2017 to March 2023 at our institute. We checked each patient’s PLI, CRP, LRG, and CDAI and compared them before starting Bio and eight weeks after initiation of Bio using a paired T-test. Finally, we used the Pearson correlation coefficient to examine the correlation between PLI and conventional serum biomarkers and CDAI.

Results
The male-to-female ratio was 4.0, the average age at the treatment initiation was 35. Eighteen patient’s diseases were located in the small and large intestines, 10 patients were penetrating type, and 2 patients were stenotic type. We used UST for 16 patients and VDZ for 4 patients. Seven patients were naïve for Bio, 8 patients were treated by one Bio, and 5 patients were treated by two Bio.PLI was positively correlated with CRP (r=0.59, p&lt;0.001) but not correlated with LRG (r=0.77, p=0.077) and CDAI (r=0.35, p=0.07). The pretreatment average PLI was 8.5 and significantly decreased to 3.9 (p&lt;0.001) 8 weeks after Bio initiation. There was a significant change in CRP (3.1 to 0.9, p =0.03) but not CDAI (193 to 147, p=0.2). There were significant PLI changes in each treatment group; the UST group’s PLI change was 8.3 to 3.1 (p&lt;0.001), and the VDZ group's PLI was 9.5 to 8.0 (p=0.02) (Figure 1).

Conclusion
PLI seems to be an objective assessment for pCD, and it was positively correlated to CRP. We could assess each drug’s efficacy for pCD. Further investigation is needed to establish PLI’s accuracy, and we hope this assessment will contribute to the choices of Bio for pCD and the evaluation of its efficacy
P1000 A meta-analysis and systematic review of 5-aminosalicylates withdrawal in Inflammatory Bowel Disease
Authors: Arzivian A , Kerkham A , Tran Y , Rubin D , Leong R 
Published: January 2024

Abstract

Background
5-aminosalicylic acids (5-ASA) are the first-line agents in mild-to-moderate ulcerative colitis (UC). They are not recommended for Crohn’s disease (CD) or moderate-to-severe UC. 5-ASAs are the most prescribed medication for all patients with inflammatory bowel diseases (IBD). Its continuous use is associated with significant cost, adverse effects, and delay in treatment escalation. Recent analyses suggest no benefit of 5-ASA use in patients escalated to more advanced therapies. Hence, 5-ASA withdrawal was suggested, but the outcomes remain unclear. We aimed to perform a meta-analysis of 5-ASA withdrawal in patients with IBD and compare the risk of disease relapse in different cohorts of patients.

Methods
A search for articles was conducted in five medical databases, studies were selected, and their quality was assessed. Studies were divided into six clinically relevant cohorts depending on the type of IBD and other treatments used; the relative risk of relapse for individual studies in each cohort was analysed.

Results
1714 studies were identified; 27 were included in the meta-analysis. Withdrawal of oral 5-ASA monotherapy was associated with a 60% increased risk of relapse. Similarly, withdrawal of rectal 5-ASA had a relative risk of relapse of 2.03. When combined with immunomodulators and/or biologics in UC or CD, oral 5-ASA withdrawal was not associated with an increased risk of relapse. Patients on combined oral 5-ASA and immunomodulators had a higher risk of relapse in the 5-ASA continuation group across three studies; this can be attributed to the persistence of oral 5-ASA use in patients with more severe disease, delaying the appropriate escalation to advanced therapies. Two studies reported no increased risk of colorectal cancer when 5-ASA was withdrawn either as monotherapy or when combined with other treatments.

Conclusion
Oral or rectal 5-ASA monotherapy in UC should not be discontinued. 5-ASA withdrawal does not increase relapse in patients with UC or CD escalated to immunomodulator and/or biological treatment. Oral 5-ASA continuation combined with immunomodulators delays escalation to advanced therapy. Available data suggest that 5-ASA withdrawal does not increase the risk of colorectal cancer; however, this must be considered carefully in patients with unmodifiable risk factors.
P1015 Subcutaneous infliximab effectively manages clinical outcomes of Inflammatory Bowel Disease independently of various confounding factors
Authors: Buisson A , Cummings F , Subramanian S , Rahmany S , Fumery M , Kwon B , Park S , Lee Y N , Smith P J 
Published: January 2024

Abstract

Background
Since its approval, many inflammatory bowel disease (IBD) patients have been treated with subcutaneous (SC) infliximab (IFX), but the association of various confounding factors with clinical outcomes is still elusive.

Methods
The ASSEMBLE project is an initiative to combine multi-national real-world cohort datasets and analyse the effectiveness and safety of SC IFX therapy. In the ASSEMBLE-1 database analysis, three studies from France and the United Kingdom1-3 were integrated to assess the clinical outcomes up to 6 months (6M) after switching from IV to SC IFX. Clinical remission was defined as Harvey-Bradshaw Index (HBI) or modified HBI (mHBI) &lt;5 for Crohn’s disease (CD) and Simple Clinical Colitis Activity Index (SCCAI) or partial Mayo score (PMS) &lt;3 for ulcerative colitis (UC). Treatment persistence was assessed by Kaplan-Meier survival analysis. After adjustment with inverse probability of treatment weights (IPTW), the association of various parameters on clinical outcomes was assessed with marginal structural models (MSMs), by comparing the estimated marginal means (EMMs) of remission rates at 6M between patients in each subgroup.

Results
The data of 428 patients were pooled from the three datasets (70.6% CD, 29.4% UC). 85.4% of patients were in clinical remission before switching to SC IFX with median HBI or mHBI of 1 (IQR 0,2) for CD and median SCCAI of 2 (IQR 1,3) or PMS of 0 (IQR 0,0) for UC. The overall clinical remission and persistence rates at 6M after switching were 84.7% and 94.5%, respectively. Pre-switch IV IFX regimens, immunomodulator (IMM) use, age, baseline fecal calprotectin (FC) level, or baseline C-reactive protein (CRP) level were not associated with persistence. Persistence rate was &gt;90% regardless of body mass index (BMI), although it was higher for patients &lt;25 kg/m2 BMI (98.1%). Assessment with MSMs indicated that the clinical remission rate of CD, but not UC, was expected to be significantly lower only if patients were treated with escalated IV IFX before switching rather than standard 5 mg/kg Q8W regimen (p=0.01; Table 1). No association with high BMI, IMM use, age, ≥150 μg/g FC, and ≥5 mg/L CRP was found in both CD and UC (Table 1). Perianal disease was not associated with CD remission either.

Conclusion
The ASSEMBLE-1 results confirm that switching from IV to SC IFX is well accepted and effectively manages the clinical outcomes of the disease regardless of various confounding factors in IBD patients. However, further studies are warranted to explore the association of pre-switch IV IFX regimens with clinical outcomes. [1] Smith et al. J Crohns Colitis 2022 [2] Buisson et al. Clin Gastroenterol Hepatol 2023 [3] Rahmany et al. Gastroenterology 2023.
P1017 Upadacitinib as rescue therapy for the treatment of Acute Severe Colitis in an acute care setting
Authors: Clinton J , Motwani K , Schwartz S , McCarthy P , Axelrad J , Cross R , George L 
Published: January 2024

Abstract

Background
Inflammatory bowel disease is a chronic, relapsing and remitting inflammatory disorder that despite advances in medical therapy often requires hospitalization for treatment of acute flares with intravenous corticosteroids. Many patients will not respond to corticosteroids and require infliximab or cyclosporine as rescue therapy. If medical therapy fails, definitive surgical management is required. Recently, Janus Kinase inhibitors, including upadacitinib, have been proposed as an alternative rescue therapy given their rapid onset of action. The aim of this study was to evaluate the efficacy of upadacitinib as an alternative rescue therapy for acute severe colitis.

Methods
We conducted a retrospective review of 12 inflammatory bowel disease patients admitted for acute severe colitis who received upadacitinib induction therapy. The rates of surgery, repeat or prolonged steroid use, and re-admission within 90 days of index hospitalization were measured. The need for re-induction with upadacitinib, change in medical therapy, rates of clinical remission, change in 6-point partial Mayo score, and laboratory markers of inflammation were measured as secondary outcomes. Statistical analysis of primary and secondary endpoints was performed with descriptive analysis.

Results
Five patients met the primary composite endpoint including four patients requiring surgery and one additional patient being unable to withdraw steroids within 90 days of hospital discharge. One patient required re-induction with upadacitinib within 90 days and no patients required change in medical therapy within 90 days. Of the patients who did not undergo surgery, 63% were in clinical remission within 90 days and showed clinical improvement with decreased 6-point partial Mayo scores at the post-discharge visit (4.75 during admission vs. 1.25 at post discharge visit, p&lt;0.0001). There were no adverse reactions reported in relation to upadacitinib administration during the study period.

Conclusion
We found that two-thirds of patients treated with upadacitinib 45mg daily for acute severe colitis were able to avoid surgery during the index admission and within 90 days post-discharge. Of the patients who were able to avoid surgery, most were able to taper steroids, did not require readmission within 90 days of index hospitalization and were in clinical remission within 90 days. Upadacitinib may be effective salvage therapy for acute severe colitis, but larger controlled trials are required to validate these results.
P1035 CT-based radiomics signature of visceral adipose tissue and bowel lesions for identifying patients with Crohn’s disease resistant to infliximab
Authors: Wang Y , Zhou Z , Luo Z , Li X 
Published: January 2024

Abstract

Background
Data describing the effect of visceral adipose tissue (VAT) on infliximab treatment response in patients with Crohn’s disease (CD) remains scarce. We aimed to develop and validate a VAT-based radiomics model (RM) using computed tomography (CT) images to identify CD patients at high risk of primary nonresponse to infliximab, and explored whether it can improve the prediction efficacy of an established bowel lesions-based RM.

Methods
This retrospective study included 231 CD patients (training cohort, n=112; internal validation cohort, n=48; external validation cohort, n=71) from two tertiary centers. Machine-learning VAT model and bowel model were developed separately to identify CD patients with primary nonresponse to IFX. A comprehensive model incorporating VAT and bowel radiomics features was further established to verify whether CT features extracted from VAT would improve the predictive efficacy of bowel model. Area under the curve (AUC) and decision curve analysis were used to compare the prediction performance. Clinical utility was assessed by integrated differentiation improvement (IDI).

Results
VAT model and bowel model exhibited comparable performance for identifying patients with primary nonresponse in both internal [AUC: VAT model vs bowel model, 0.737(95% CI, 0.590-0.854) vs. 0.832 (95% CI, 0.750 - 0.896)] and external validation cohort [AUC: VAT model vs. bowel model, 0.714(95% CI, 0.595-0.815) vs. 0.799(95% CI, 0.687-0.885)], exhibiting a relatively good net benefit. The comprehensive model incorporating VAT into bowel model yielded a satisfactory predictive efficacy in both internal [AUC,0.840(95%CI, 0.706-0.930)] and external validation cohort [AUC,0.833(95%CI, 0.726-0.911)], significantly better than bowel alone (IDI=4.2% and 3.7% in internal and external validation cohorts, both P&lt;0.05).

Conclusion
VAT has an effect on IFX treatment response. It improves the performance for identification of CD patients at high risk of primary nonresponse to IFX therapy with selected features from RM.
P1051 The role of Resection Margins in Crohn`s Disease – A potential risk factor for Disease Recurrence?
Authors: Kelm M , Buck V , Benatzky C , Schöttker K , Rosenfeldt M , Germer C T , Nusrat A , Meining A , Flemming S 
Published: January 2024

Abstract

Background
Postoperative disease recurrence after ileocecal resection for Crohn`s Disease is a major issue for all disciplines. While adequate therapeutic strategies are lacking, further criteria are necessary to improve the identification of patients at risk for disease recurrence. In line with that, the exact role of positive resection margins as a potential risk factor on disease recurrence remains unclear since current evidence is heterogenous.

Methods
All patients who received ileocecal resection due to localized terminal ileitis Crohn at the Department of Surgery at the University Hospital of Wuerzburg between 2014 and 2021 were evaluated. Primary endpoints were severe endoscopic (Rutgeerts-Score &gt;2) and surgical recurrence (re-operation due to Crohn`s Disease) during follow up. Positive resection margins were identified by two independent pathologists and defined by the following criteria as international consensus: neutrophils localized in the epithelium, cryptitis, and/or plexitis.

Results
214 patients received ileocecal resection at the Department of Surgery. Of those, 159 patients were finally included for analysis with a median follow up of 35 months. Postoperative morbidity was not affected by inflammation at the resection margins. However, positive resection margins resulted in significantly increased rates of severe endoscopic recurrence at six months (2.0% versus 15.6%, p=0.02) and overall (4.2% versus 19.6%, p=0.001). Additionally, positive margins resulted in significantly increased rates of surgical recurrence (0% versus 4.5%, p=0.04).

Conclusion
Positive resection margins in Crohn`s Disease are associated with increased rates of severe endoscopic and surgical recurrence and should therefore be considered as risk factor for postoperative disease recurrence.
P1053 Ustekinumab trough concentration could predict the aggravation of endoscopic severity after de-escalation in the sub-analysis of CD-EXTEND study
Authors: Kato S , Tagawa K , Yamaga N , Yakabi K , Nagoshi S 
Published: January 2024

Abstract

Background
De-escalation was a useful strategy for improving patient’s QOL and reduction of medical expenses. However, endoscopic data after de-escalation of ustekinumab (UST) has not been reported. The aim of this study was to elucidate UST trough concentration for the prediction of endoscopic aggravation after de-escalation of UST.

Methods
This CD-EXTEND study was a single-centre prospective observational study approved by the institutional review board of our hospital. Thirty CD patients who selected de-escalate UST treatment after administration of intravenous UST 6 mg/kg and subcutaneous UST 90mg every 8 weeks until 54 weeks were enrolled in this cohort. Endoscopic evaluation was performed at baseline and at one year. Endoscopic aggravation was defied as the increase of SES-CD score. Cut-off values of prediction for endoscopic aggravation was calculated by receiver operating characteristic (ROC) curve.

Results
Endoscopic evaluation could be evaluated in 25 patients. Endoscopic aggravation was recognized in 9 patients. There was no significant differences of patient’s characteristics and biomarkers including CRP, fecal calprotectin (FC) and Leucin-rich alpha-2-glycoprotein (LRG) between aggravated and non-aggravated groups at the baseline. However, trough concentration was significantly higher in aggravated group than non-aggravated group at the base line (1.5 ± 0.7 vs 2.8 ± 1.3 μg/mL, p=0.02). CRP, FC and LRG significantly increased in aggravated group, not in non-aggravated group. However, trough concentration significantly decreased in both aggravated and non-aggravated groups. Trough at one year was significantly lower in aggravated group than non-aggravated group (0.44 ± 0.3 vs 1.0 ± 0.71 μg/mL, p=0.02). Cut-off values of trough concentration of prediction for endoscopic aggravation at base line and at one year were 2.15 and 0.4 μg/mL, respectively.

Conclusion
UST trough concentration was a good prediction marker for endoscopic aggravation.
P1084 Persistence and efficacy of Ustekinumab in Crohn's disease after antiTNF failure. May the response of the second biologic therapy be better than the first one?
Authors: Latrás Cortés I , Saéz Hortelano J C , Suárez Álvarez P , García Prada M , Cano Sanz N , Ortega Valin L , Sierra Ausín M 
Published: January 2024

Abstract

Background
After antiTNF failure, a second antiTNF in Crohn's disease (CD) is effective to achieve and maintain remission, but only50% remain with the drug after 12 months of treatment. Ustekinumab (UST) has a better persistence as second-line treatment and is effective to induce and maintain long-term remission.

Methods
Retrospective and observational study retrieved from a prospective database of Crohn's disease patients treated with UST, after approval of Research Ethics Committee. Data were collected at the beginning of treatment and after 4, 8, 16, 24 weeks, 12, 24, 36, 48, 60 months and at the end of follow-up (UST discontinuation or March 2023 if treatment continues).

Primary Objective
evaluate the persistence with UST and clinical (Harvey-Bradshaw index (HBI)&lt;4) and biological remission (C-reactive protein (CRP)&lt;5 mg/dl and/or fecal calprotectin (FC)&lt;250 mg/kg) in each period of follow up.
Clinical remission in perianal disease was defined as absence of drainage both spontaneous and after soft pressure. Persistence of the first biologic therapy, reasons of treatment change, dose optimization, surgery, hospitalizations and adverse events were also evaluated.

Results
68 patients were included (Table 1).
Median survival of antiTNF is 1.65 years (IC95% 1.18-2.56). 72.06% patients receive antiTNF 1 year, 45.59% 2 years, 30.88% 3 years and only 8.82% are treated during 10 years.
Persistence with UST was longer than with antiTNF. 93.2% of patients receive UST 1 year, 89.4% 2 years and 86.1% 3 years.
There was a significant reduction of fecal calprotectin values during follow-up (p=0.0002).
7 patients with perianal disease achieved clinical remission (70.00%) and 4 complete fistula healing in magnetic resonance enterography (40.00%) at the end of follow-up.
60.29% patients received 90 mg every 8 weeks, but 36.76% required dose optimization (23.50% 90mg sq/4 weeks and 13.24%130mg/4 weeks ev).
86.76% continue UST at the end of follow-up, with a mean duration of treatment of 27.65 months (SD 18.27). 9 patients (13.24%) stopped treatment (1 primary non response, 5 loss of response, 3 adverse events).
11 patients (16.18%) needed surgery and hospitalization during follow up; 63.60% of them had stricturing disease.

Conclusion
Persistence with UST as a second line therapy was superior to antiTNF in first-line. 86.76% continued treatment with UST after 2 years. UST achieved early and long-term clinical remission in approximately two thirds of patients. 36.76% of patients required dose optimization. UST was effective in perianal disease after antiTNF failure.

Figure 1 shows clinical remission in patients with basal HBI&gt;4.