bluuebunny/crossref_metadata_2025_split huggingface dataset:
P409 FMT induced increase in gut microbial diversity and Clostridia is associated with clinical response in patients with ulcerative colitis – results from STOP Colitis trial
Authors: Quraishi M N , Quince C , Hewitt C , Beggs A , Gerasimidis K , Sharma N , Hawkey P , Oo Y , Ives N , Manzoor S , Loman N , Hansen R , Hart A , Gaya D , Iqbal T 
Published: January 2022

Abstract

Background
Findings from five randomised trials using faecal microbiota transplantation (FMT) in adults with ulcerative colitis (UC) demonstrate therapeutic potential. The optimum methodology for administration of FMT is unclear. We describe a prospective, three centre, open-label randomised trial (STOP-Colitis pilot) that compared tolerability and efficacy of nasogastric (NG) versus colonic (COLON) routes of administration and identified potentially important host microbial interactions.

Methods
Adult participants with active UC (partial Mayo score of ≥4 and ≤8) were randomised for administration of, 8 infusions of FMT over an, 8 week period either via the naso-gastric (NG) or colonic (COLON) route. Each patient was matched to a single FMT donor. Clinical response was defined as ≥3 point and ≥30% reduction in full Mayo score at week, 8 compared to baseline. Changes in faecal gut microbial diversity (Shannon’s diversity) and composition before/after FMT were analysed with, 16S rRNA sequencing. Correlation between datasets was evaluated with Kendall’s Tau coefficient.

Results
Sixteen patients were randomised to NG;, 14 to COLON FMT. Seven participants in the NG and, 2 in the COLON arm withdrew before completion. Clinical response was achieved in, 9/12 [75%] for COLON vs, 2/8 [25%] for NG)., 12/14 (86%) COLON participants were protocol-adherent compared with, 8/16 (50%) for NG. For the COLON patients (N=8) an increase in alpha diversity was observed (P=0.01). For those patients that responded to FMT overall (N=9) there was a significant increase in alpha diversity (P&lt;0.005) and lower faecal calprotectin levels in responders vs. non-responders (week, 4 to week, 8 mean, 508.6 ug/g vs, 853.6 ug/g respectively; P=0.03). Overall, there was a negative association between calprotectin levels and alpha diversity (tau =-0.29; P &lt;, 0.005). Operational taxonomic units belonging to Clostridia deriving from the Christensenellaceae and Lachnospiracae families correlated with both reduced calprotectin and had high engraftment frequency (both false discovery rate corrected P&lt;0.10). In a cohort of patients with mucosal immune cell analysis Clostridia positively correlated with gut homing Treg populations and negatively correlated with Th17 cells populations (P&lt;0.005), suggesting that this group may play an important role in the immune response to FMT in UC.

Conclusion
This pilot study suggests that in participants with active UC, FMT delivered via the colonic route appears to be better tolerated than via NG with a greater efficacy signal. There are signals linking gut microbial diversity and taxa belonging to Clostridia (short chain fatty acid producers) with clinical response, calprotectin and a shift towards an immunoregulatory phenotype.
P440 Loss of response and dose escalation of infliximab and adalimumab in Ulcerative Colitis patients: A Systematic Review and Meta-analysis
Authors: Savelkoul E , Thomas P , Derikx L , Den Broeder N , Römkens T , Hoentjen F 
Published: January 2022

Abstract

Background
Anti-Tumour necrosis factor agents are essential therapeutics in moderate-to-severe Ulcerative Colitis (UC). Annual loss of response (LOR) and dose escalation (DE) risk in UC patients have not been systematically evaluated. This study aimed to assess the annual LOR rate and DE rate for infliximab (IFX) and adalimumab (ADA) in UC.

Methods
A systematic search of PubMed, EMBASE and Cochrane Library was conducted from January, 2000 to July, 2021. Clinical trials and cohort studies assessing IFX and/or ADA use in adult UC patients were included if these reported LOR rates or DE rates. The primary outcomes included (1) the annual LOR per patient-year of IFX and ADA in UC patients and (2) the annual DE rates per patient-year of IFX and ADA. LOR was only assessed in patients who had primary response to IFX or ADA as defined by the authors. LOR was reported as defined by the authors and then categorized in three definition groups:, 1) treatment discontinuation due to LOR, 2) treatment intensification defined as dose escalation and/or treatment switch and/or surgery, because of LOR and, 3) increase of clinical, biochemical and/or endoscopic disease activity. Dose escalation was defined as any dose increase or interval shortening as reported by the authors. Summary estimates were calculated using random effects models.

Results
Our search yielded, 26,320 potentially relevant articles. We analysed, 50 unique studies (IFX (n=35) or ADA (n=23)) assessing LOR (IFX:, 24 cohort studies, ADA:, 21 cohort studies) or DE (IFX:, 21 cohort studies, ADA:, 16 cohort studies). Follow-up among all studies ranged from, 38 to, 350 weeks. The pooled annual LOR for IFX was, 11.2% (95% CI [0.082–0.153], Figure, 1). LOR per category was as follows:, 8.3% (95% CI [5.3–13.3]) for discontinuation (n=16), 18.6% (95% CI [11.5–29.8]) for treatment intensification (n=6), 19.3% (95% CI [14.3–26.0]) for increase in clinical/biochemical/endoscopic activity (n=2). The pooled annual LOR for ADA was, 15.1% (95% CI [0.103–0.220], Figure, 2). LOR per category was as follows:, 12.0% (95% CI [7.1–19.9]) for discontinuation (n=16), 43.6% (95% CI [21.8–87.2]) for treatment intensification (n=3), 11.6% (95% CI [4.0–33.9]) for increase in clinical/biochemical/endoscopic activity (n=2). Annual pooled DE rates were, 14.7% (95% CI [10.4–20.7]) for IFX and, 21.3% (95% CI [15.6–29.0]) for ADA.
Figure, 1 - Infliximab

Figure, 2 - Adalimumab

Conclusion
The overall pooled annual LOR in UC patients was, 11% for IFX and, 15% for ADA. LOR rates varied among different used definitions. Annual dose escalation rates were, 15% for IFX and, 21% for ADA. Future studies in this field should focus on a universal definition of LOR and report time to loss of response.
P451 Evaluating drug sustainability, efficacy and safety of biologic agents in elderly patients with Inflammatory Bowel Disease: a single center retrospective study
Authors: Golovics P , LeBlanc J F , Drügg Hahn G , Wetwittayakhlang P , Qatomah A , Wang A , Boodaghians L , Liu J , Al Ali M , Wild G E , Afif W , Bitton A , Lakatos P L , Bessissow T 
Published: January 2022

Abstract

Background
Despite the advancement in pharmacological management of Inflammatory Bowel Disease (IBD), the efficacy and the side effects of the biologics are rarely studied in the elderly population. Our aim was to evaluate retrospectively the drug sustainability, efficacy, and safety of the biologic therapies in the elderly IBD population.

Methods
Consecutive elderly (&gt; 60 years old) IBD patients, treated with biologics (infliximab, adalimumab, vedolizumab, ustekinumab) followed at the McGill University IBD Center were included between January 2000 and 2020. The efficacy of treatment was measured using clinical and biochemical parameters. Response and remission variables were measured at three distinct time points from the start date of the biologic agent, as in 3, 6–9 and 12–18 months. Patients required a minimal follow-up period of three months. Adverse events (AE) or serious adverse events (SAE) occurring within three months of the last biologic dose were considered to be related to the biologic agent.

Results
We identified a total of 147 elderly patients with IBD treated with biologic agents (109 Crohn’s disease (CD) and 38 ulcerative colitis (UC)). Disease location was predominantly ileocolonic (47.7%) in CD and pancolitis(63.2%) in UC. 47.6% of elderly IBD patients had attempted at least 1 biologic agent (Table1). The mean duration of biologic treatment was 157.5 (SD:148)weeks. Steroid exposure varied from 34% at the start of biologic therapy to 19% at 3 months, 16.3% at 6–9 months and 6.5% at 12–18 months.’ The remission rates at 3, 6–9 and 12–18 month were not significant between the biologic therapies. Kaplan-Meyer analysis did not show statistical difference for drug sustainability (p=0.195)(Figure1), time to adverse event (p=0.158) (Figure2) or infection rates (p=0.973) (Figure3) between all four biologics studied. The most common AEs led to discontinuation were loss of response, infusion or injection reaction and infection.

Conclusion
Current biologic therapies were not different with regards to drug sustainability and safety in the elderly IBD population. Based on these results, we are not able to suggest a preferred sequencing order among biologicals.
P459 High inadequate surveillance rates in colitis-associated advanced neoplasia: a multicenter retrospective cohort study
Authors: Te Groen M , Derks M E , Peters C P , Dijkstra G , De Vries A C , Römkens T E , Horjus C S , De Boer N K , De Jong M E , Nagtegaal I D , Derikx L A , Hoentjen F 
Published: January 2022

Abstract

Background
Although colorectal cancer (CRC) surveillance is embedded in IBD practice, a subset of patients still develops advanced neoplasia (AN; high-grade dysplasia (HGD) and/or CRC). We aimed to determine the most plausible explanations for AN in IBD patients through assessment of inadequate surveillance.

Methods
A search of the nationwide histopathology registry of the Netherlands (PALGA) was used to identify IBD patients with AN in seven hospitals. Patients with ulcerative colitis (UC), Crohn’s disease (CD), or IBD-unclassified (IBD-U) from 1 January 1991 until 1 October 2020 were eligible for inclusion. Exclusion criteria comprised familial CRC or AN prior to IBD diagnosis. A root-cause analysis based on the World Endoscopy Organizations’ recommendations was performed to determine inadequate surveillance prior to the first AN, including lack of cecal intubation, insufficient bowel preparation (BBPS&lt;6 or according to colonoscopy report) and active endoscopic inflammation. Interval inadequacy was assessed according to most recent BSG guideline including a six month margin. Associations were assessed with a binary regression model.

Results
We included 179 patients with AN (figure 1). Of these, 22 patients (12.3%) were diagnosed with AN before surveillance was indicated. Inadequate surveillance was present in 122 patients (68.2%, n=50 HGD, n=72 CRC), of whom 47 patients (26.3%) did not receive any surveillance colonoscopy before AN diagnosis. A delayed surveillance interval was identified in 44 patients (24.6%), with a median deviation from surveillance recommendations of 19.0 months (IQR 9.5–28.5 months). Furthermore, 56 patients (31.3%) had active inflammation, three had insufficient bowel preparation, and two patients had an incomplete colonoscopy. Younger age at diagnosis (annual OR 0.96, 95% CI 0.94–0.98, p&lt;0.01) and post-inflammatory polyps (OR 2.14 95% CI 1.06–4.32, p=0.03) were independently associated with inadequate surveillance. By contrast, prior indefinite for dysplasia or low-grade dysplasia was associated with adequate surveillance (OR 0.36, 95% CI 0.17–0.76, p&lt;0.01). Finally, 35 patients (19.6%) had interval or surveillance AN despite adequate surveillance (diagnosed during a diagnostic procedure or surveillance colonoscopy, respectively).
Figure 1. Root-cause analysis flowchart

Conclusion
The majority of IBD patients with AN in our cohort had prior inadequate surveillance. This observation underlines the importance of adequate surveillance and guideline adherence.
P463 Serum and mucosal Serpin E1 concentration correlates with endoscopic activity in inflammatory bowel disease - potential new activity marker
Authors: Jójárt B , Molnár T , Kata D , Szabó V , Varga Á , Resál T , Bacsúr P , Szántó K , Földesi I , Molnár T , Maléth J , Farkas K 
Published: January 2022

Abstract

Background
Inflammatory bowel disease (IBD) is characterized by an unregulated immune response generating unbalance cytokine homeostasis. Analysis of patient-specific cytokine profiles may open new therapeutic targets or identify biomarkers that distinguish responders from non-responders before initiating therapy. Therefore, the aim of the present study was to determine cytokine profile of IBD patients and identify cytokines with predictive potential.

Methods
Blood and biopsy samples were obtained from 79 clinically active IBD patients and 28 controls without IBD. Inclusion criteria included change of therapy or initiation of new treatment for IBD patients. Organoid culture (OC) was generated from 5 clinically active IBD patients and 5 controls. Cytokine Array was used to analyse cytokine expression patterns. Total protein and mRNA were isolated from biopsies and from OCs. Protein levels were measured by ELISA and gene expression by qRT-PCR in serum, mucosa and in OCs.

Results
Pro-inflammatory cytokines were not detected in control samples, whereas in IBD biopsies the cytokine profiles enabled the discrimination between inflamed or non-inflamed areas. The mucosal expression of Serpin E1 was detected in all inflamed biopsy samples, whereas it was below the detection limit in healthy subjects. In responders Serpin E1 gene expressions were significantly (p&lt;0.001) lower than in non-responders. On the other hand, we were not able to detect significant changes between responders and non-responders in gene expression of TNF-α, IL-1β, IL-6 and TGF-β. In responders, mucosal Serpin E1 concentration significantly decreased (p&lt;0,05) after the initiation of therapy compared to non-responders. Serum and mucosal Serpin E1 concentrations were significantly higher in patients with endoscopically and clinically active disease compared to inactive (endoscopic: p&lt;0.0001, clinical: p&lt;0.05). Correlation analysis revealed that serum Serpin E1 level correlates with disease activity (p&lt;0.01). In OCs the level and expression of Serpin E1 was lower in healthy organoids compared to OCs generated from inflamed samples.

Conclusion
Our results suggest that serum and mucosal Serpin E1 expression reflects endoscopic activity in IBD, which could be used to follow-up disease activity and possibly therapeutic response. Organoids mimicked the expression of Serpin E1 in the original biopsies suggesting that OCs can be used to study the effect of Serpin E1 inhibition.
P479 Trends in medication use and treatment patterns in Chinese patients with Inflammatory Bowel Diseases: A multicenter cohort study from 1999 to 2020
Authors: Yao L , Shao B , Cao Q 
Published: January 2022

Abstract

Background
The temporal changes in medication use and therapeutic paradigm in patients with Inflammatory bowel disease (IBD) have not been well elucidated in China over the past two decades. Therefore, we aimed to identify the temporal changes in medication use and treatment patterns for Chinese patients with IBD and to evaluate the factors associated with initial drug strategies.

Methods
A multicenter retrospective cohort study was conducted among Chinese patients newly diagnosed with Crohn’s disease (CD) and ulcerative colitis (UC) from January 1999 to December 2019. Medication utilization, treatment patterns, and associated factors with initial drug strategies were investigated.

Results
Prescriptions of 5-aminosalicylates (ASA) and corticosteroids (CS) gradually decreased, whereas prescriptions of immunosuppressants (IMS) and infliximab (IFX) increased in patients with CD. Except for stable prescriptions of ASA and CS, IMS and IFX increased since 2007 in patients with UC. Subgroup (N=957) analyses revealed that treatment patterns went through notable changes from ASA to IMS or IFX in patients with CD, while ASA and CS were still steadily prescribed in patients with UC. Logistic regression analyses revealed that perianal and gastrointestinal surgeries before diagnosis, disease behavior, and disease location were associated with different initial therapeutic strategies in patients with CD. However, medications before diagnosis, disease location, and diagnostic year might affect initial strategies in patients with UC.

Conclusion
Parallel to increasing uses of IMS and IFX in IBD over past two decades, a significant decrease in uses of ASA and CS were observed in CD, but not in UC. Treatment strategies analyses provided a unique insight in understanding long-term therapeutic patterns in the Chinese population.
P489 Temporal trends of colectomy for ulcerative colitis in the multi-drug era; a population based cohort study
Authors: Jenkinson P , Plevris N , Lyons M , Gros B , Derikx L , Constantine-Cooke N , Jones G , Lees C 
Published: January 2022

Abstract

Background
We are now in the multi-drug era for ulcerative colitis (UC). The use of advanced therapies for UC has dramatically increased over the last 6 years. NICE approvals of anti-TNF and anti-α4β7 therapy (both in 2015) were followed by IL12/23 (2019) and janus kinase inhibitors (2020). The aim of this study was to describe the impact of this change in patterns of advanced therapy prescribing on colectomy rates for UC within a well defined population-based cohort.

Methods
The Lothian IBD registry (LIBDR) is a manually validated, prevalent dataset compiled through capture-recapture methodology (Jones et al. 2018) that is &gt;95% complete for the 907,580 residents of NHS Lothian (mid-2019 population estimates). The LIBDR contains measured prevalence between 2008–2018, estimated prevalence from 2018–2028 (derived from Autoregressive integrated moving average {ARIMA} modelling). All patients with a diagnosis of UC who underwent a colectomy in Lothian, Scotland between 01/01/2005 and 31/102021 were identified by interrogating multiple clinical and administrative databases. Linear and segmental regression analyses were used to identify the annual percentage change (APC) and temporal trends (statistical joinpoints) in colectomy rates.

Results
485 patients underwent colectomy for UC between 2005 and October 2021 (Fig 1). Colectomy rates per 100 UC patients fell from 1.47 colectomies in 2005 to 0.25 in 2021 (p=0.009). The colectomy APC decreased by 4.1% per year between 2005 and 2014 and 18.5% per year between 2014 and 2021 (Figure 2). Temporal trend analysis (2005–2021) identified a significant joinpoint in colectomy rates in 2014 (p=0.009) (Figure 2).

Figure 1 Absolute number of colectomies for UC per year between 2005–2021. Linear regression showing colectomy numbers (solid line) and 95% confidence intervals (dashed lines) constrained at 2014.

Figure 2, Colectomy rates per 100 UC patients from 2005–2021. Joinpoint regression separated at inflection point at 2014 (solid line).
Between 2005 and 2007, 0 / 100 patients undergoing colectomy received maintenance biologic treatment prior to the admission for colectomy. Between 2019 and 2021, 19 / 33 (57.8%) patients received maintenance biologic therapy prior to colectomy (Figure 3).

Figure 3. Percentage of colectomy patients who had been treated with at least 1 maintenance biologic prior to surgery.

Conclusion
This population based cohort study has shown a significant reduction in the rate of colectomy for UC that has coincided with the introduction of biologic medication. Whilst we cannot ascribe causality, within this study the timeline of falling colectomy rates closely parallels the rapid increase in the use of biologic medication.
P493 The synthetic glycan KB295 optimises microbiome composition and function in ulcerative colitis: Results from a proof of principle human study
Authors: Meisner J , Miller K , Lee J , Jose A , Giuggio M , McComb M , Humphries E , Rosini M , Wingertzahn M , Shanahan F , van Hylckama Vlieg J E T , Dowling M 
Published: January 2022

Abstract

Background
Ulcerative colitis (UC) pathogenesis involves genetic susceptibility, immune-mediated tissue injury, and gut microbiota disturbances. Most approved therapies modify host immunity, rather than directly targeting the microbiota. Faecal microbiota transplantation provides encouraging evidence for the therapeutic potential of gut microbiome modulation. Gastrointestinal tract bacteria are ecologically differentiated by their ability to use specific glycans as growth substrates, making glycans a promising and safe alternative to target the microbiome. To explore this, we used an ex vivo faecal microbiota culture system to identify a synthetic glycan (KB295) with desirable microbiological activity and conducted a proof of principle study (NCT04508413) of safety and tolerability of KB295 in patients with UC.

Methods
In ex vivo studies, faecal microbial communities from healthy subjects were incubated anaerobically (negative control) ± KB295. Taxa counts from shotgun metagenomic sequencing data were used to evaluate microbial response to KB295. Short-chain fatty acid (SCFA) levels were also assessed. KB295 was evaluated in an open-label single-arm study in adult patients with mild to moderate UC. KB295 was ingested over an 8-wk period. Objectives included KB295 safety (primary) and effect on gut microbiota composition and faecal biomarkers.

Results
In ex vivo studies, KB295 increased SCFA levels across 10 faecal samples to a median of 47.0 vs 15.2 mM with negative control, including increases in acetate, propionate, and butyrate levels. Metagenomic sequencing showed pathobiont depletion in the family Enterobacteriaceae with KB295 to a median relative abundance of 10.8% vs 38.2% with negative control. Pathobiont depletion was associated with enrichments of diverse genera in the phyla Bacteroidetes and Firmicutes. In patients with UC (n=12), KB295 was well tolerated with generally mild adverse events (AEs). The most frequently occurring AEs were bowel habit changes, flatulence, and headache. Median faecal calprotectin and lactoferrin levels decreased by 69.0% (n=11) and 86.0% (n=6), respectively, from screening to end of the KB295 intake. Consistent with our ex vivo results, of the patients for whom we have data to date, the relative abundance of the faecal pathobiont family Enterobacteriaceae decreased in 5 of 5 participants, and the commensal genus Parabacteroides was enriched in 4 of 5 participants.

Conclusion
Our results establish a proof of principle for the glycan modulation of gut microbiome composition and function and provide insight into the potential utility of this strategy in patients with UC. The safety and tolerability of KB295, along with evidence of reduced inflammation, support a phase 2 study, which is planned.