bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP66 Disease course of Ulcerative proctitis in children: A population based study on behalf of the SIGENP IBD Group
Authors: Martinelli M , Fedele F , Romano C , Aloi M , Lionetti P , Alvisi P , Panceri R , Bramuzzo M , Illiceto M , Bosa L , Norsa L , Pastore M , Graziano F , Arrigo S , Felici E , Gatti S , Fuoti M , Strisciuglio C , Dipasquale V , D’Arcangelo G , Scarallo L , Labriola F , Miele E 
Published: January 2022

Abstract

Background
Ulcerative proctitis (UP), defined as a colonic location limited to the rectum, is a poorly investigated condition in children, usually considered as a minor form of Ulcerative Colitis (UC). The aim of the present study was to compare the disease course of paediatric patients affected by UP at diagnosis with the other UC locations.

Methods
This multicentre retrospective observational study has been carried out starting from the data prospectively registered in the IBD Registry of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP). Seventeen IBD referral centres adhering to the registry were included in the study. Patients age 0 to 18 years, who were diagnosed with UC according to the Porto criteria starting from January 1, 2009, to May 1st, 2021 were identified. Only children with a minimum follow-up of 12 months were included in the study. Once enrolled, children were subsequently divided in two groups based on Paris classification: group 1 (E1) and group 2 (E2, E3 and E4).

Results
Eight-hundred-eighty-five children were finally included in the study (median age at diagnosis: 11.2 years, range: 0–18 years; M/F: 434/451), of whom 176 (19.8%) belonging to group 1 and 709 (80.1%) to group 2. The median age at diagnosis was significantly higher in group 1 when compared to group 2 [11.9 (0–18) versus 11 (0–18) years, respectively; (p&lt;0.001)]. At diagnosis, the induction therapy was significantly different with 68 (39.5%) patients of group 1 undergoing steroid therapy versus 505 (71.2%) of group 2 (p&lt;0.001) and 79 (41.9%) of group 1 practising only mesalamine respect to 186 (26.2%) of group 2 (p&lt;0.001). A higher number of children from group 2 started immunosuppressive or biologic therapy as maintenance therapy at diagnosis [Group 1: 11 (6.2%) versus 173 (24.4%), respectively; (p&lt;0.001)]. The median follow-up of our cohort was 4.5 years (range 1–13 years). At the last follow-up, 67/176 (38%) children with UP showed an extension of their disease location without significant difference when compared to group 2 [265 (37.5%); p=0.9], while 81 (45%) children from Group 1 were under immunosuppressive or biologic therapy versus 566 (79.8%) from group 2 (p&lt;0.001). Five children (3%) of Group 1 underwent colectomy during the follow up versus 45 (6.9%) of Group 2 (p=0.06).

Conclusion
UP is a frequent location of paediatric onset UC and the risk of endoscopic extension of proctitis is similar to the more extensive forms. A considerable number of patients with UP required immunosuppressive or biologic therapy during the follow-up and no significant difference was observed in terms of surgery. Overall, UP cannot be considered as a minor form of UC.
DOP67 First-line infliximab is cost-effective compared to conventional treatment in paediatric Crohn’s Disease – Results from the TISKids study
Authors: Vuijk S , Jongsma M , Hoeven B , Cozijnsen M , van Pieterson M , de Meij T , Norbruis O , Groeneweg M , Wolters V , van Wering H , Hummel T , Stapelbroek J , van der Feen C , van Rheenen P , van Wijk M , Teklenburg S , Poleij M , Escher J , de Ridder L 
Published: January 2022

Abstract

Background
First-line infliximab (FL-IFX) induction treatment combined with azathioprine (AZA) is more effective to achieve clinical remission without treatment escalation at week 52 compared to conventional induction treatment (CONV) (Exclusive Enteral Nutrition or prednisone) combined with AZA in children with moderate-to-severe Crohn’s disease (CD). FL-IFX may lead to higher treatment costs compared to conventional treatment. However, data on cost-effectiveness of FL-IFX in children with CD is still limited. Therefore, our aim is to investigate the cost-effectiveness of FL-IFX in comparison with CONV. We hypothesized that cost effectiveness of FL-IFX is comparable to CONV in children with newly diagnosed moderate-to-severe CD in the first two years after treatment.

Methods
We included patients from the TISKids international randomized controlled trial in which children with moderate-to-severe CD were treated with either FL-IFX (Inflectra, biosimilar of IFX) or CONV.(1) Patients included outside of the Netherlands (n=6) or patients with serious comorbidity besides CD were excluded from this analysis (n=2). Data on healthcare consumption and costs were obtained per hospital for all included patients until week 104. Direct health-related costs were collected, including hospital visits, drug costs, laboratory tests, endoscopies and surgeries. The effectiveness of treatment was assessed by mean weighted paediatric CD activity index (wPCDAI) and faecal calprotectin (fcal) levels (µg/g) measured over time until week 104. This analysis was performed by a mixed model. Moreover, time to additional anti-tumor necrosis factor-α (anti-TNF) treatment up to 104 weeks after inclusion was assessed.

Results
In this analysis, 89 patients were included, 44 in the FL-IFX group and 45 in the conventional treatment group. There were no significant differences between the two groups at baseline. Interestingly, the mean costs were similar for FL-IFX (€34,783) and CONV (€34,923) after two years, p=0.97 (Figure 1). Mean fcal levels were lower for FL-IFX compared to CONV over two years (416 vs. 625, p=0.03). The mean wPCDAI scores over two years were numerically lower for FL-IFX compared to CONV (5.95 vs. 10.34, p=0.01), but this difference became smaller over time. Furthermore, the time to (re)start anti-TNF treatment was significantly longer in the FL-IFX group (median 68 weeks) compared to the conventional treatment group (median 32 weeks) (p=0.02) (Figure 2).

Conclusion
Treatment with FL-IFX is cost-effective compared to conventional treatment in the first two years after diagnosis in children with moderate-to-severe CD.

Reference
1. Jongsma MME et al. Gut. 2020 Dec 31; DOI: 10.1136/gutjnl-2020–322339. / PMID: 33384335
DOP71 Low occurrence of colectomy with long-term (up to 4 years) golimumab treatment in patients with moderate-to-severe active Ulcerative Colitis: Data from the PURSUIT maintenance and long-term extension studies
Authors: Weinstein C L , Meehan A G , Lin J , Govoni M , Qureshi Z P 
Published: January 2022

Abstract

Background
In a previous real-world study of long-term (up to 4 years) treatment with golimumab (GLM) in ulcerative colitis (UC), patients reported a low overall colectomy incidence (5.8%).1 This analysis evaluates the incidence of colectomy among patients with moderate-to-severe active UC in the PURSUIT-maintenance (-M)2 and long-term extension (-LTE)3 studies.

Methods
Eligible PURSUIT-M trial participants completed a 6-week GLM induction trial without requiring colectomy.4,5 Responders to GLM induction were randomised 1:1:1 to GLM 50 mg, 100 mg, or placebo (PBO) maintenance for up to 1 year, administered every 4 weeks (q4w). Nonresponders to GLM or PBO induction received GLM 100 mg; responders to PBO induction received PBO (each administered q4w for up to 1 year). Participants experiencing loss of clinical response during maintenance were eligible for one treatment intensification (switch from PBO to GLM 100 mg, or GLM dose increase). Participants who completed PURSUIT-M were eligible to continue their treatment in the 3-year PURSUIT-LTE study. Colectomy (total or partial) was a prespecified outcome in PURSUIT-M; serious adverse event narratives and safety summaries were also examined for reports of colectomy (total or partial). For PURSUIT-LTE, serious adverse event narratives and safety summaries were examined for reports of colectomy (total or partial). The reasons for colectomy were not collected systematically in PURSUIT-M or -LTE. Descriptive information on colectomies was assessed and reported.

Results
A total of 60 (4.9%) colectomies were reported among the 1228 patients who enrolled in the 1-year PURSUIT-M study, including 672 participants who continued into the 3-year LTE study. The table shows the distribution of colectomies by study phase, induction responder status, initial treatment assignment, and treatment prior to colectomy. The colectomy rate during the 3-year extension was lower than that observed during the maintenance phase of the study [1.3% (9/672) compared to 4.2% (51/1228)].

Conclusion
Consistent with previously reported data, this retrospective evaluation of colectomy data from the PURSUIT-M and -LTE studies in patients with moderate-to-severe active UC demonstrated a low occurrence of colectomy with long-term (up to 4 years) GLM treatment. The limited number of colectomies observed in the LTE study occurred predominantly in patients with more severe disease at baseline (induction non-responders) who had been receiving GLM 100 mg.
References
1. Iborra M, et al. SciRep. 2020;10:17774
2. Sandborn WJ, et al. Gastroenterol. 2014;146:96–109
3. Reinisch W, et al. J Crohn’s Col. 2018;12:1053–1066
4. Sandborn WJ, et al. Gastroenterol. 2014;146:85–95
5. Rutgeerts P, et al. Aliment Pharmacol Ther. 2015;42:504–514
DOP73 A comparative efficacy and safety analysis of subcutaneous infliximab and vedolizumab in patients with Crohn’s Disease and Ulcerative Colitis
Authors: Peyrin-Biroulet L , Arkkila P , Armuzzi A , Atreya R , Danese S , Ferrante M , Guardiola J , Jahnsen J , Louis E , Lukáš M , Reinisch W , Roblin X , Smith P J , Kwon T S , Kim J Y , Yoon S W , Kim D H 
Published: January 2022

Abstract

Background
CT-P13 is the first and only subcutaneous (SC) formulation of infliximab (IFX) which received EMA approval in July 2020 for the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). This study compares efficacy and safety between IFX SC and vedolizumab (VDZ) in moderate-to-severe CD or UC patients using data from the pivotal study of IFX SC, VISIBLE 2 and recently presented systematic literature review and meta-analysis [1].

Methods
This comparative study analyses 7 randomised controlled trials. The IFX SC trial (NCT02883452) was compared with the VDZ trials including GEMINI II, GEMINI III, VISIBLE 2 for CD and GEMINI I, VISIBLE 1, and VARSITY for UC. VISIBLE 2 was added in this analysis as it was published after the presented meta-analysis. In all studied VDZ trials, only responders at week 6 continued to receive maintenance treatment except VARSITY trial, which followed a treat-through design.
Crohn’s Disease Activity Index (CDAI)-70, CDAI-100 response and clinical remission for CD, and clinical response, clinical remission, and mucosal healing for UC at week 6 (induction) and 1 year (week 50–54, maintenance) were compared between IFX SC and VDZ for evaluating efficacy. Discontinuation due to lack of efficacy and safety profiles over 1 year were also assessed.

Results
In the patients with CD, IFX yielded significantly better efficacy results in the induction phase compared to VDZ with non-overlapping 95% confidential interval while IFX SC displayed better results, although statistically non-significant during the maintenance phase (Table 1). In UC, similar efficacy was shown between the treatments during both induction and maintenance phase (Table 2). The proportion of patients discontinued due to lack of efficacy was significantly higher in VDZ compared to IFX SC in both CD (IFX SC 5% and VDZ 32%) and UC (IFX SC 3% and VDZ 15%) over 1 year (Tables 1,2).
The safety profiles were generally comparable between IFX SC and VDZ. Similar proportion of patients experienced serious adverse event (9% and 14% in CD; 12% and 11% in UC in IFX SC and VDZ). The proportion of patients experiencing serious infection between the treatments was also similar in both CD and UC (Tables 3,4).

Conclusion
Better efficacy was shown in IFX SC compared to VDZ in CD, while a similar efficacy was shown in UC. A significantly higher proportion of patients were discontinued due to lack of efficacy in VDZ compared to that of IFX SC over 1 year. Safety profiles over 1 year were generally comparable between IFX SC and VDZ in both indications.

Reference
1. Peyrin-Biroulet, L. (2021). P0414 Efficacy and safety of infliximab and vedolizumab in patients with inflammatory bowel diseases: a systematic review and meta-analysis. Poster presented at: 2021 UEG Week.
DOP89 Infliximab and ustekinumab clearance during induction predicts post-induction endoscopic outcomes in patients with Crohn’s Disease
Authors: Wang Z , Kantasiripitak W , Verstockt B , João S , Ferrante M , Declerck P , D’Haens G , Laharie D , Vermeire S , Dreesen E 
Published: January 2022

Abstract

Background
Monitoring of monoclonal antibody clearance has been hypothesised to be an appealing approach for predicting treatment outcomes in patients with inflammatory bowel diseases. We aimed to investigate the benefits of monitoring infliximab and ustekinumab clearance in patients with Crohn’s disease (CD) based on data from clinical trials.

Methods
Data were obtained from patients with moderate-to-severe CD starting infliximab (n=108)1 or ustekinumab (n=80)2 therapy. Endoscopic remission (CD Endoscopic Index of Severity &lt;3) and endoscopic response (≥50% decrease from baseline in simple endoscopic score for CD) were assessed at week (w)12 and w24 of infliximab and ustekinumab therapy, respectively. A priori prediction (based on covariate data only; at w0) and a posteriori prediction (Bayesian forecasting using measured drug concentrations; during treatment) were performed using previously built population pharmacokinetic models (NONMEM 7.5).3,4 Covariates of fecal calprotectin, albumin, CD activity index, and antibodies towards infliximab (ATIs) were used to estimate infliximab clearance. Albumin and body weight were used to estimate ustekinumab clearance.

Results
Patients achieving endoscopic remission at w12 had significantly lower infliximab clearance and higher infliximab serum concentration at w2 and w6 of treatment (P &lt;0.05, Table 1). Patients achieving endoscopic response at w24 had significantly lower ustekinumab clearance at w4 and w8, as well as a significantly larger reduction in clearance relative to w0 (P &lt;0.05, Table 1). However, ustekinumab serum concentrations at w4 and w8 were similar between patients with and without endoscopic response (P &gt;0.2, Table 1).
Most patients with an early increase in infliximab clearance (16/22; 73%) and ustekinumab clearance (27/29; 93%) did not reach the endoscopic endpoint (P &lt;0.05; Table 2). However, a decrease in clearance was no guarantee for endoscopic remission during infliximab therapy (false predictive rate 46%) and response during ustekinumab therapy (false predictive rate 69%).
The infliximab clearance after start of induction therapy (at w2 and w6) was significantly higher in patients who developed ATIs during induction therapy (Figure 1).

Conclusion
Lower infliximab and ustekinumab clearance (absolute as well as relative to w0) early during induction predict more favourable endoscopic outcomes. In patients treated with ustekinumab, clearance monitoring may better predict endoscopic response at w24 as compared to standard therapeutic drug monitoring.
References1. D’Haens et al.Gastroenterology 2018
2. Verstockt et al. J Crohns Colitis 20193. Dreesen et al. Br J Clin Pharmacol 20214. Wang et al. Br J Clin Pharmacol 2021.
P001 Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on the IL23/IFNg axis
Authors: Lo J , Cozzetto D , Madgwick M , Sieh J Y X S , Olbei M , Alexander J L , Miguens Blanco J , Kudo H , Ibraheim H , Liu Z , Castro Seoane R , Goldin R , Marchesi J , Korcsmaros T , Lord G , Powell N 
Published: January 2022

Abstract

Background
Immune checkpoint inhibitors (CPI) have revolutionised cancer treatment, with previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off target immune-mediated tissue injury, particularly at the barrier surfaces. CPI-induced colitis is a common a serious complication.

Methods
To probe the impact of immune checkpoints on intestinal homeostasis mice were challenged with combination anti-CTLA4 and anti-PD-1 immunotherapy, manipulation of the intestinal microbiota and antibody blockade/depletion studies. Colonic immune responses were profiled using RNA-sequencing, including high-resolution single cell analyses, and flow cytometry.

Results
CPI colitis was dependent on the composition of the intestinal microbiota and was characterized by remodelling of mucosal lymphocytes with induction of polyfunctional lymphocyte responses characterized by expression of interferon-g (IFNg), other pro-inflammatory cytokines/chemokines (Il22, Il17a Ccl3, Ccl4 and Ccl9) and cytotoxicity molecules (Gzmb, Gzma, Prf1, Nkg7). In comparison with mucosal lymphocytes in the steady state, polyfunctional lymphocytes from both CD4+ and CD8+ lineages upregulated costimulatory molecules and checkpoint molecules in CPI-colitis, indicating that these cells are usually very tightly regulated. CPI-colitis was attenuated following depletion of effector lymphocytes or following blockade of the IL23/IFNg axis.

Conclusion
This study provides new mechanistic insights into CPI-colitis, identifying polyfunctional, cytotoxic lymphocytes as key mediators of disease. Therapeutic targeting of their effector response or regulatory networks, including the IL23/IFNg axis holds the key to preventing and reversing CPI-colitis.
P008 Modulation of Wnt signaling via a Wnt mimetic improved epithelial healing without causing hyperplasia in a mouse colitis model
Authors: Lu C , Xie L , Shah D , Newman M , Baribault H , Yeh W C , Li Y 
Published: January 2022

Abstract

Background
Disruption of the colon epithelial barrier is a characteristic of ulcerative colitis (UC), allowing luminal microbes to come into contact with intestinal immune cells resulting in inflammation. All approved UC treatments are anti-inflammatory drugs and because they do not directly heal the epithelial barrier, the intestinal immune system continues to be exposed to gut microbes, resulting in low remission rates. Physiological Wnt signaling is fundamental to intestine epithelial homeostasis and renewal. Modulation of Wnt signaling might present an opportunity to achieve histological remission, which is associated with an improved clinical course, in UC. Previously, in vivo overexpression or administration of exogenous R-Spondin (RSPO), which amplifies Wnt signaling by increasing the amount of Wnt receptors on the cell surface, was reported to show effects on the intestine epithelium and helped regenerate intestine epithelium in various injury models. However, RSPO was also reported, to induce hyperplasia in normal intestine epithelium. Wnt signaling may also be modulated with recently developed Wnt mimetics which mimic endogenous Wnt proteins and activate downstream β-catenin signaling upon engaging with receptors of Wnts. The objective of the current study was to compare the effect of these two approaches in an acute DSS model.

Methods
Utilizing a mouse acute DSS colitis model, we compared the epithelial healing effects of a Surrozen proprietary Wnt mimetic, R2M3-26, RSPO2, and combination treatments of R2M3-26 and RSPO2. Animals received 4% (wt/vol) dextran sulfate sodium (DSS) in drinking water for 7 days followed by 1% DSS in drinking water from day 8. Protein treatments began on day 4. Disease activity, body weight (BW), fecal score, and occult blood were measured daily. Animals were terminated on day 10 for colon and small intestine histology as well as a serum cytokine panel.

Results
DSS damage to the colon epithelium was visible by H&E stain at day 4 and day 7 and continued to progress. We observed reduced mRNA expression of Wnt target genes and Wnt ligands in the colon, suggesting compromised Wnt signaling in the tissue. R2M3-26, RSPO2, and the combination treatments were efficacious in improving Disease Activity Index (DAI) and reducing serum cytokine levels. However, both RSPO treatments and combination treatments caused hyperproliferation of epithelium in the small intestine and the colon, consistent with what was reported in normal mice.

Conclusion
The Surrozen Wnt mimetic, R2M3-26, repaired the DSS damaged colon epithelium without causing hyperproliferation of epithelial cells in the intestine, making it a potential therapeutic platform for IBD.
P009 Integrin-b7+ cytotoxic MAIT cells are expanded in the colon of Ulcerative Colitis patients, correlate with disease severity and are targeted by vedolizumab therapy
Authors: Hermangild Kottoor S , Ibraheim H , Polychronis P , Senthuran B , Jameson E , Samaan M , Irving P , Powell N 
Published: January 2022

Abstract

Background
Mucosal-associated invariant T (MAIT) cells are major histocompatibility complex (MHC) class Ib-restricted innate-like lymphocytes with anti-bacterial functions that are enriched at mucosal sites. Their role in ulcerative colitis (UC) is unknown.

Methods
Colonic biopsies and peripheral blood were collected from patients with active UC (n=34) and healthy control subjects (n=14). Peripheral blood mononuclear cells (PBMC) and Lamina propria mononuclear cells (LPMC) were isolated and activated in vitro with PMA/ionomycin followed by surface and intracellular staining and multiparametric flow cytometry analysis. T cell populations, including gamma delta T cells (TCR gamma delta+), iNKT cells (TCR Vα24-Jα18+), MAIT cells (TCR Vα7.2+ CD161+), CD4, CD8 T cells and their intracellular expression of IL17A, TNF, IFN-g, IL22, IL13 and granzyme B (GZMB) were determined. MAIT cells were further characterised as CD8+, CD4+, CD8 CD4 double positive (DP), CD8 CD4 double negative (DN) cells and expression of the gut homing integrin-b7.

Results
DN cells were the most common MAIT subset in the colon and were significantly increased in both UC patients and HC subjects compared to peripheral blood. In UC, DN MAIT cells exhibited a cytotoxic phenotype, with significantly higher production of Granzyme B (median 45.0% of cells) compared to DN MAIT cells in HC (median 17%, P&lt;0.005). DN MAIT cells in UC gut also co-produced significantly higher proportion of IL17A (median 22% in UC vs 7% in HC, P&lt;0.006) and TNF (median 61% in UC vs 10% in HC, P&lt;0.02) compared to DN MAIT cells from HC. In UC patients, the proportional abundance of cytotoxic DN MAIT cells accumulating in the colon significantly correlated with disease activity (UCEIS) score (r2=0.34, P&lt;0.0007).
The number of DN MAIT cells expressing integrin-b7 was also significantly higher in UC patients compared to HC (median 66% in UC vs 32% in HC, p&lt;0.001). In UC patients initiated on vedolizumab therapy, the proportional abundance of cytotoxic, DN MAIT cells accumulating in the colon significantly fell at week 14 in comparison with their pre-treatment abundance (median 25% vs 51%, P&lt;0.001). Following vedolizumab induction, the reduction in the abundance of colonic cytotoxic DN MAIT cells correlated with endoscopic improvement (r2=0.45, p=0.0085).

Conclusion
DN MAIT cells with cytolytic activity and augmented expression of multiple cytokines are enriched in the colon of UC patients in numbers that correlate with the magnitude of mucosal injury. Vedolizumab treatment reduces DN MAIT cell accumulation in the colon and the magnitude of reduction correlates with treatment response.