bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP72 Safety, tolerability and efficacy of anti-TL1A antibody PF-06480605 in treatment of ulcerative colitis: The open-label, multicentre, Phase 2a TUSCANY study
Authors: Danese S , Klopocka M , Scherl E J , Romatowski J , Allegretti J R , Peeva E , Vincent M S , Schoenbeck U , Xi L , Ye Z , Hassan-Zahraee M , Rath N , Li G , Neelakantan S , Banfield C , Lepsy C , Chandra D , Hung K E 
Published: January 2020

Abstract

Background
Widespread disruption of the mucosal immune system is central to the pathogenesis of ulcerative colitis (UC). One component, tumour necrosis factor (TNF) α-like ligand 1A (TL1A), is upregulated at the site of active disease in UC. Treatment of preclinical rodent models with anti-TL1A antibodies decreases disease activity, highlighting their therapeutic potential for UC. PF-06480605 is a first-in-class fully human immunoglobulin G1 monoclonal antibody targeting TL1A.

Methods
The Phase 2a, open-label, multicentre, single-arm TUSCANY study (NCT02840721) evaluated the safety, tolerability and efficacy of PF-06480605 in treatment of moderate to severe UC. Participants received 500 mg intravenous (IV) PF-06480605 every 2 weeks (Q2W) for a total of 7 doses, with a 14-week follow-up period. Primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and endoscopic improvement (EI) (Mayo endoscopic subscore [centrally read] of ≤1 without friability) at Week 14, respectively. Secondary efficacy endpoints included remission (total Mayo score ≤2, with no individual subscore &gt;1) and endoscopic remission (Mayo endoscopic subscore = 0) at Week 14. Transcriptomic profiling on intestinal biopsies was performed.

Results
Of the 50 participants who received PF-06480605, 42 completed the study. The majority were male (56.0%) and white (96.0%), with a mean age of 40.0 years and prior experience of anti-TNF inhibitors (72.0%). Pancolitis (48.0%) and left-sided colitis (32.0%) were the most common forms of UC at baseline. There were 109 TEAEs, of which 18 were treatment-related. Aside from worsening UC, the most common TEAE by system organ class was arthralgia, which occurred in 6 participants, and 1 was treatment-related. Treatment-emergent serious adverse events were reported in 3 participants, and considered treatment-related in 1 participant (Table 1). No malignancies or deaths were reported. At Week 14, statistically significant EI was observed in 38.2% of participants (Table 2). The proportions of participants achieving remission and endoscopic remission at Week 14 were 24.0% and 10.0%, respectively. Transcriptomic analyses demonstrated normalisation towards a non-inflamed transcriptome in participants with EI.

Conclusion
PF-06480605 exhibited an acceptable safety and tolerability profile and statistically significant EI in participants with moderate to severe UC. These results warrant further evaluation in subsequent studies.
DOP73 Efficacy and safety of escalation to tofacitinib 10 mg BID for patients with UC following loss of response on 5 mg BID maintenance therapy: Results from OCTAVE open-label, long-term extension study
Authors: Sands B E , Moss A C , Armuzzi A , Marshall J K , Lindsay J O , Sandborn W J , Danese S , Zeroncio M , Modesto I , Salese L , Lawendy N , Zhang H , Su C 
Published: January 2020

Abstract

Background
Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib have been demonstrated in patients with moderate to severe UC in three Phase 3 studies (OCTAVE Induction 1 and 2 [NCT01465763; NCT01458951]; OCTAVE Sustain [NCT01458574]) [1]. Here, we present updated efficacy and safety data of tofacitinib dose escalation in patients with UC participating in an ongoing, open-label, long-term extension (OLE) study (OCTAVE Open, NCT01470612) [2].

Methods
We present updated data from the dose-escalation subpopulation of the OLE study (as of May 2019; database not locked) comprising patients who achieved clinical response (CR) following 8 weeks of tofacitinib 10 mg twice daily (BID) induction therapy, entered OCTAVE Sustain receiving tofacitinib 5 mg BID, experienced treatment failure between Week 8 and Week 52, and subsequently entered OCTAVE Open with escalation to tofacitinib 10 mg BID. Treatment failure was defined as an increase of ≥3 points from maintenance study baseline total Mayo score, plus an increase of ≥1 point in both rectal bleeding subscore and centrally read endoscopic subscore (ES), and an absolute ES of ≥2 after ≥8 weeks of maintenance therapy. CR, mucosal healing (MH) and remission (R) were evaluated at Months 2, 12, 24 and 36 of OCTAVE Open (non-responder imputation and last observation carried forward [NRI-LOCF] and observed data). Safety was evaluated throughout the study.

Results
Of 944 patients enrolled in the OLE study, the dose escalation subpopulation comprised 59 patients. In these patients, CR, MH and R rates 36 months after dose escalation were, respectively, 40.7%, 39.0% and 30.5% for NRI-LOCF and 95.2%, 86.4% and 66.7% for observed data (Table). Of these 59 patients, 29 had prior tumour necrosis factor inhibitor (TNFi) failure; in these patients, CR, MH and R rates at Month 36 were, respectively, 51.7%, 51.7% and 41.4% for NRI-LOCF, and 100.0%, 92,3% and 75.0% for observed data. Incidence rates for safety events and pt-years’ exposure are reported in the table.

Conclusion
For most patients who lost initial CR to tofacitinib 10 mg BID induction therapy while on tofacitinib 5 mg BID maintenance therapy, including those with prior TNFi failure, dose-escalation back to 10 mg BID recaptured CR by Month 2 and was generally maintained over 3 years. The safety profile with tofacitinib 10 mg BID in the dose-escalation subpopulation was generally consistent with that in the overall study population, although there was a numerically higher rate of herpes zoster. These analyses are limited by low pt numbers and the absence of a comparator arm.

References
DOP78 Intestinal surgery rates in ulcerative colitis and Crohn’s disease in the era of biologics: A Danish Nationwide Register Study from 2003 to 2016
Authors: Vadstrup K , Alulis S , Borsi A , Olsen J , Jørgensen T R , Munkholm P , Qvist N 
Published: January 2020

Abstract

Background
Biologic response modifiers (biologics) has been introduced as potent drugs for the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). Whether this has resulted in a reduction in the need for surgical treatment is controversial. This study aims to explore the surgery rates of patients diagnosed with CD and UC between 2003 and 2015 and correlate to those treated with biologics or not in Denmark with a follow-up until 2016.

Methods
This national register study included patients diagnosed between 2003 and 2015 and followed up until 2016, identified in the Danish National Patient Registry (NPR). Biologic therapies available in (parts of) the study period were infliximab, adalimumab, vedolizumab and golimumab. Surgery rates were identified through three types: bowel resections (code KJFB), total colectomies (code KJFH) and resections and excisions of the rectum (code KJGB). The share of patients undergoing surgery or initiating and receiving biologic treatment in each year was analysed. Additionally, patients undergoing surgery were stratified to receiving biological treatment in a period before the surgery or not and the time to first surgery was investigated.

Results
Among 10,302 CD patients and 22,144 UC patients, 2,328 CD patients and 2,128 UC patients underwent intestinal resection. Numbers were driven by the two first surgery codes (97% for CD and 93% for UC), and &gt;1 resection was observed in 20% of the CD cases and more in the UC cases (40%), as expected due to reoperations. In the same period, 2,939 and 2,504 patients were treated with biologics for CD and UC, respectively, with an increase observed over the years. The vast majority were treated with an anti-TNF-α biologic, as vedolizumab was not approved in Denmark before 2015. We observed similar surgery rates of patients receiving biologics compared with those not treated with biologics. However, the time period from diagnosis to first intestinal surgery was observed to be longer for the patients treated with biologics (Figure1).

Conclusion
The number of patients undergoing intestinal resections or initiating biologic treatments after diagnosis increased throughout the study period for the full population. The risk of intestinal resections was similar in the group of patients who received biologicals compared with the group who did not, but the treatment seemed to postpone surgery in both diseases.
DOP82 Macrophages in Crohn’s disease mesentery are predominantly inflammatory and produce calprotectin
Authors: Bloemendaal F M , Becker M , Koelink P J , van der Bilt J D , Bemelman W A , D’Haens G R A M , Buskens C J , Wildenberg M E 
Published: January 2020

Abstract

Background
Alterations in the mesentery of Crohn’s disease (CD) patients have long been described, although the functional importance of this tissue is less clear. Some studies hypothesise an anti-inflammatory role for enhanced mesentery, whereas others consider a more pathologic function, given its close proximity to the inflamed intestine. Better phenotypic and functional evaluation of the cells present in this tissue is warranted to improve our understanding of its role in disease. We have previously shown a disproportionate presence of macrophages in CD mesorectum. In this study, we aimed to better characterise the phenotype and function of the macrophages in the mesentery in CD.

Methods
We collected mesenteric specimens from Crohn’s disease, ulcerative colitis (UC) and non-inflammatory bowel disease (IBD) patients, undergoing surgical bowel resections. In IBD patients, mesentery was collected contiguous to the inflamed region of the intestine, in non-IBD patients, mesentery adjacent to the resection margin. Macrophages were sorted by flow cytometry as CD45+ CD66b-CD14+CD11b+ cells. Sorted cells were analysed by expression profiling and functional analysis.

Results
Macrophages were present in all analysed tissues. Within the population, a discriminating expression pattern for CD11b was present, dividing CD14+ macrophages in a CD11bhigh and a CD11bdim subset. Transcriptional profiling and gene set enrichment showed the CD11bhigh population to be consistent with IFN-induced pro-inflammatory macrophages, while the CD11bdim population was most consistent with IL4-induced regulatory macrophages. Among the top upregulated genes in CD11bhigh macrophages were S100A8 and S100A9, the two heterodimeric subunits for calprotectin. Flow cytometry confirmed higher expression of calprotectin in the CD11bhigh population also on the protein level. Functionally, CD11bdim macrophages showed higher phagocytic capacity, again consistent a role in tissue repair. Strikingly, the CD11bdim subset was diminished significantly in the mesentery of CD patients, with a near absence in some patients, while the profile in UC was comparable to non-IBD patients.

Conclusion
Mesenteric macrophages contain two populations, CD11bhigh with a pro-inflammatory profile and CD11bdim with a regulatory profile. In the mesentery of CD patients, the CD11bdim population was strongly decreased, consistent with a pro-inflammatory role for this tissue.
P004 PN-943, an oral α4β7 integrin antagonist, inhibits MAdCAM1-mediated proliferation and cytokine release from CD4+ T cells independent of trafficking
Authors: CHENG L , Venkataraman S , Zhao L , Lee L , Tang T , Liu D , Mattheakis L 
Published: January 2020

Abstract

Background
PN-943, an oral gastrointestinal (GI) -restricted peptide antagonist of α4β7 integrin, is being developed for the treatment of inflammatory bowel disease (IBD). Blockade of α4β7 binding to mucosal addressin cell adhesion molecule-1 (MAdCAM1) is thought to treat IBD by preventing extravascular migration of blood T cells into the inflamed GI mucosa. Recent evidence suggests the involvement of other mechanisms. Saturation of circulating T-cell α4β7 by vedolizumab is not sufficient for optimal efficacy; and PTG-100, a PN-943 analogue, showed evidence of clinical and histological remission in ulcerative colitis patients at sub-saturating blood receptor occupancy (%RO). Here, we assessed the potential of a local GI-acting function of α4β7 by evaluating the ability of PN-943 to inhibit MAdCAM1-mediated CD4+ T-cell proliferation and cytokine production.

Methods
Primary CD4+ T cells were labelled fluorescently and incubated with plate-bound anti-CD3 alone or together with MAdCAM1 with or without inhibitors for three days. Phenotype, distribution of T-helper (Th) subsets and %RO analyses were conducted by flow cytometry. Supernatant cytokine levels were quantified by multiplex assays.

Results
MAdCAM1 combined with anti-CD3 markedly enhanced proliferation of CD4+ T cells compared with anti-CD3 alone (n = 7, 12–64%). Immune phenotyping revealed that proliferation occurred in both CD45RO- naïve and CD45RO+ memory T cells and was restricted to the β7+ population with successive cycles of proliferation showing increased β7 expression. Amongst the proliferated memory T cells, the percentage of the IFNγ-producing Th1 subset was higher than IL-17A-producing Th17 and IL-4-producing Th2 subsets. Multiplex profiling identified several cytokines, including but not limited to IL-6, IL-13, GM-CSF, and TNFα, whose release were promoted by MAdCAM1. PN-943 abolished MAdCAM1-mediated stimulation (n = 4, IC50 4.6 nM). The inhibitory effects were associated with lowered β7 expression indicative of internalisation by PN-943. Blockade was not observed with an inactive analogue indicating dependency on PN-943 binding to α4β7. Consistent with the requirement for a locally acting drug, 30 mg/kg oral dosing in mice demonstrated high exposure (n = 6, 39 nM) and occupancy of T-cell α4β7 (n = 6, 92%) in the GI compared within the blood.

Conclusion
The α4β7-MAdCAM1 interaction promoted β7+CD4+ T-cell proliferation and cytokine release, which may contribute to chronic inflammatory responses occurring in the diseased gut of IBD patients independent of T-cell trafficking. PN-943 inhibition of MAdCAM1-mediated signalling through α4β7 supports the potential therapeutic advantages for an oral GI-restricted approach, whereby PN-943 is delivered locally and directly blocks α4β7 function in the GI.
P005 Regulators of the guanylate cyclase pathway are potential novel markers of mucosal healing in IBD
Authors: Jeffery L E , Shivaji U N , Zardo D , Acharjee A , Nardone O M , Smith S C , Gkoutos G , Visweswariah S S , Ghosh S , Iacucci M 
Published: January 2020

Abstract

Background
Intestinal guanylate cyclase C (GC-C) present in epithelial cells has been shown to have a role in gut homeostasis. The downstream effects of activation of GC-C are due to production of cyclic-GMP. GC-C is encoded by the gene GUCY2C, mutations in which are implicated in Familial Diarrhoea Syndrome and noted as risk factors for Crohn’s disease. GUCY2C and its activator, GUCA2A have been shown to be downregulated in IBD. We hypothesised that regulation of this pathway might be important in remission and response to therapy.

Methods
Forty-four patients with IBD and 7 patients with polyps (controls) at University Hospitals Birmingham, UK were recruited under ethical consent. Relevant demographic and clinical data were extracted from the hospital EMR. All patients had disease activity recorded on endoscopic examination of mucosa and intestinal biopsies collected for analysis. Mucosal healing was defined as MES = 0 (UC) and SES-CD &lt;6 (CD). Of 44 patients, 14 had matched baseline and 12-week post-biologic therapy assessment and had tissues collected. Intestinal biopsies were analysed by 3’RNA-sequencing using the Illumina Nextseq sequencer. FASTQ files were generated through BaseSpace and reads de-multiplexed, trimmed, aligned, and quantified using the GeneGlobe (Qiagen) workflow. Expression was compared between groups using either Wilcoxon tests or Kruskal–Wallis with Dunn post-hoc analysis as appropriate.

Results
Expression of Guanylate cyclase activators GUCA2A and GUCA2B in patients who showed mucosal healing was equivalent to controls, but GUCA2A was down-regulated in those with active disease (non-healing) (p = 0.006). The same pattern was observed for transcriptional regulators of GUCY2C, including HNF4A (p = 0.0248) and CDX2 (0.0062). Correspondingly, GUCY2C was reduced in non-healing mucosa, although the difference was not significant (Figure 1). In patients who responded to biologic therapy, both GUCA2A (p = 0.0234) and GUCA2B (p = 0.0117) were increased at follow-up but no change was observed for those who did not respond. Change in GUCY2C expression did not reach statistical significance in either group, although an increase was observed for a large proportion of responders.

Conclusion
Our findings suggest that regulation of the Guanylate Cyclase pathway may be involved in the restoration of a stable mucosa in IBD and that expression of its regulators may be used to indicate response to treatment.
P009 The innate cytokines IL-1α and TNF-α induce the expression of Oncostatin M and its type II receptor in human colonic subepithelial myofibroblasts
Authors: Filidou E , Kokkotis G , Tarapatzi G , Boulkou M , Arvanitidis K , Drygiannakis I , Valatas V , Koutroubakis I , Vradelis S , Kolios G , Bamias G 
Published: January 2020

Abstract

Background
Oncostatin M (OSM), a cytokine of the IL-6 family, has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Specifically, OSM and its receptor, OSMR, are elevated in inflamed colonic regions of IBD patients; in addition, high OSM expression at baseline has been associated with failure to respond to anti-TNF. OSMR expression localised in stromal cells of the intestinal lamina propria. Our aim was to investigate the expression of OSM and its receptors subunits, OSMR, LIFR and gp-130 in primary subepithelial myofibroblasts (SEMFs) and test whether this expression is regulated by the innate cytokines, IL-1α and TNF-α.

Methods
Primary SEMFs were isolated from endoscopically-obtained colonic biopsies from healthy controls, set to culture and stimulated with 5ng/ml IL-1α and/or 50ng/ml TNF-α for 6 h. Total RNA was extracted and the mRNA transcripts for OSM, OSMR, LIFR and gp-130 were measured by reverse transcription-quantitative (RT-q) PCR.

Results
Unstimulated SEMFs had a basal expression of both OSM and its receptors subunits. IL-1α or TNF-α stimulations did not alter LIFR expression, but they induced a statistically significant upregulation of OSM, OSMR and gp-130. Specifically, the expression of OSM in SEMFs was significantly upregulated after stimulation with IL-1α alone or in combination with TNF-α (IL-1α: 11.48-fold increase, 8.29–26.05; IL-1α+TNF-α: 13.42-fold, 11.32–17.16; p &lt; 0.0001). Regarding the OSMR and gp-130 subunits [which form the type II receptor of OSM], OSMR mRNA was induced by TNF-α alone or in combination with IL-1α (TNF-α: 1.75-fold, 1.27–2.02, p &lt; 0.01; IL-1α+TNF-α: 2.06-fold, 1.83–2.34, p &lt; 0.0001), whereas gp-130 mRNA expression was increased under all stimulatory conditions (IL-1α: 1.94-fold, 1.46–2.07; TNF-α: 1.81-fold, 1.46–2.25; IL-1α+TNF-α: 1.59-fold, 1.31–2.51; p &lt; 0.01 for all comparisons).

Conclusion
Our results show that OSM and OSMR are expressed on primary human SEMFs and that they are upregulated under stimulation with innate pro-inflammatory cytokines. These data further support a potential role of this system of inflammatory mediators in the pathogenesis of intestinal inflammation.
P011 Dysbiosis and Goblet cells depletion triggers early intestinal barrier dysfunction that precedes gut inflammation in IL-10 deficient mice (IL-10−/−)
Authors: López Cauce B , Puerto M , García J J , Miranda-Bautista J , Vaquero J , Bañares R , Menchén L 
Published: January 2020

Abstract

Background
Interleukin-10 deficient mouse (IL-10−/−) is a widely used model of spontaneous ileocolitis that resembles human inflammatory bowel disease (IBD); intestinal barrier dysfunction is an early pathophysiological event, but its underlying mechanisms are still unknown. The objective of this work is to study the natural history of ileocolitis in IL-10−/−, and unravel the influence of intestinal barrier dysfunction and dysbiosis in the development of overt inflammation.

Methods
Wild-type (WT) and IL-10−/− mice were followed until sacrifice at 3, 5, 10, 20, 57 and 70 weeks of life. Bodyweight, colonic weight/length ratio and in vivo intestinal permeability (measured by rectal administration of FITC-dextran) were registered. After the sacrifice, the colon was harvested and the evaluation of the expression of inflammatory (interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), inducible nitric synthase (iNOS) and cyclooxygenase-2 (COX-2) and epithelial permeability (ZO-1, E-cadherin, Occludin, Claudins 2 and 7, and Reticulon-4B (RTN-4B) markers was performed by qPCR; expression of mucin-2 (MUC-2) and molecules involved in goblet cell maturation such as interleukin-18 (IL-18) and WAP Four-Disulphide Core Domain 2 (WFDC2), as well as the endoplasmic reticulum stress marker X-box-binding protein (Xbp)-1) by qPCR were also analysed. We also used colon slices for histologic evaluation with haematoxylin-eosin and alcian blue stainings. The microbiota composition was studied by sequencing of the V3-V4 regions of ribosomal 16S from faecal samples of all these mice.

Results
Compared with WT, IL-10−/− mice showed lower weight gain at all ages and a higher colonic weight/length ratio and histological evidence of inflammation at weeks 20 and 57. iNOS and IL-1b gene expression in the colon were significantly higher in IL-10−/− mice at weeks 10 and 20, respectively. Nevertheless, increased intestinal permeability was observed from week 10; the number of goblet cells and expression of MUC-2, IL-18, WFDC2 and XBP-1 were significantly lower in knockout mice from week 10. Moreover, dysbiosis in IL-10−/− mice began at week 5, increasing at 10 and showing the lowest diversity and appearance of pathogenic families at 20 weeks of age.

Conclusion
Dysbiosis and goblet cell depletion in the colon of IL-10−/− mice are associated with early intestinal barrier dysfunction, and precede overt gut inflammation in this animal model of IBD.