bluuebunny/crossref_metadata_2025 huggingface dataset:
OP21 Positivity thresholds of total infliximab and adalimumab anti-drug antibody assay: The prevalence of clearing and transient anti-drug antibodies in a national therapeutic drug monitoring service
Authors: Nice R , Chanchlani N , Green H , Bewshea C , Kennedy N , Ahmad T , Goodhand J , McDonald T , Perry M
Published: January 2020

Background

Anti-drug antibodies can affect biopharmaceutical pharmacokinetics by increasing or decreasing drug clearance. Drug-tolerant (total), unlike drug-sensitive (free), antibody assays permit antibodies to be measured in the presence of a drug. We sought to confirm the positivity threshold of our total anti-tumour necrosis factor (TNF) antibody ELISA assays in a sample of healthy volunteers and to use this threshold to report the prevalence of clearing and transient antibodies in patients treated with infliximab and adalimumab.

Methods

Serum was obtained from a random sample of 498 anti-TNF-naïve healthy adults recruited to the Exeter Ten Thousand study and tested for total anti-drug antibodies to infliximab and adalimumab. Using recommendations for confirmatory anti-drug antibody validation, we used bootstrapping to calculate the 80% one-sided lower confidence interval [CI] of the 99th centile to define assay thresholds.

We used paired drug and anti-drug antibody levels derived from our national therapeutic drug monitoring service to report the distribution of clearing (antibody positive, drug negative) vs. non-clearing (antibody positive, drug positive) antibodies. In patients with at least two test results, antibodies were classified as transient (single positive test with subsequent negative test) or persistent (at least two positive tests).

Results

The 80% one-sided lower CI of the 99th centile titre for total anti-drug antibody to infliximab and adalimumab were 8.7 AU/ml and 5.9 AU/ml, respectively. Using the manufacturer’s recommended threshold of 10 AU/ml for both total anti-TNF antibody assays, in healthy individuals, the prevalence of positive antibodies to infliximab and adalimumab was 1% (5/498) and 0.2% (1/498), respectively. Using the manufacturer’s threshold, at the time of last testing, of 7447 and 4054 patients treated with infliximab and adalimumab; 20.9% (n = 1,554) and 8.0% (n = 326) had clearing antibodies and 26.5% (n = 1973) and 12.1% (n = 490) had non-clearing antibodies, respectively (Figure 1). Using our newly defined threshold in the same cohorts; 21.1% (n = 1573) and 8.4% (n = 339) had clearing antibodies and 28.0% (n = 2083) and 20.0% (n = 812) had non-clearing antibodies, to infliximab and adalimumab, respectively. Amongst patients with at least two tests, most developed persistent antibodies (Figure 2). Irrespective of anti-TNF drug, or threshold used, less than 10% patients developed transient antibodies.

Conclusion

We report lower positivity thresholds for the IDKmonitor® total anti-TNF antibody ELISA assays than the manufacturer, in particular, for adalimumab. Transient antibody formation is uncommon: most patients develop persistent anti-drug antibodies that lead to drug clearance.
OP32 Mincle signalling promotes intestinal mucosal inflammation through induction of macrophage pyroptosis and neutrophil chemotaxis in Crohn’s disease
Authors: GONG W , Guo K , Ren J
Published: January 2020

Background

Macrophage-inducible C-type lectin (Mincle) signalling plays a proinflammatory role in different organs such as the brain and liver, but its role in intestinal inflammation remains unknown.

Methods

We studied the characteristics of Mincle signalling expression in CD patients and experimental colitis. The functional role of Mincle signalling in the intestine was addressed in experimental colitis models in vivo by using mice with Mincle knock out (Mincle−/−), neutralising anti-Mincle antibody, Mincle pharmacologic agonist and RNA-seq genome expression analysis. Bone marrow-derived macrophages were collected from mice and used to further verify the effect of Mincle signalling in macrophages.

Results

Mincle signalling was significantly elevated in active human CD and experimental colitis, and macrophages were the principal leukocyte subset that up-regulates Mincle signalling. Mincle deficiency ameliorated the colitis by reducing induced macrophage pyroptosis (Figure 1), whereas activation of Mincle with the pharmacologic agonist worsened the intestinal inflammation (Figure 2). Moreover, the ex vivo studies confirmed that Mincle signalling activation promoted and its absence restricted release of proinflammatory cytokines from pyroptosis of macrophage (Figure 3). Finally, Mincle/Syk signalling could promote the production of chemokines to recruit neutrophils by activating Mitogen-Activated Protein Kinase (MAPK) during inflammation (Figure 4).

Conclusion

Mincle signalling promotes intestinal mucosal inflammation through induction of macrophage pyroptosis and neutrophil chemotaxis. Modulation of the Mincle/Syk axis emerges as a potential therapeutic strategy to target inflammation and treat CD.
OP39 Treatment of ulcerative colitis With AMT-101, a novel oral interleukin-10 immunomodulatory fusion biologic that traffics across the intestinal epithelium
Authors: Mrsny R , Kanwar B , Mahmood T
Published: January 2020

Background

While different chronic inflammatory diseases can be correlated with distinct pro-inflammatory cytokines, interleukin-10 (IL-10) represents a central anti-inflammatory cytokine capable of modulating many pro-inflammatory signals. Previous clinical efforts to capture the benefit of IL-10 in suppressing the pro-inflammatory state in inflammatory bowel disease (IBD) patients have been limited by dose-limiting systemic side effects.

Methods

We have designed a chimaera of human IL-10 genetically fused to a non-toxic and poorly immunogenic fragment of the cholix exotoxin, termed AMT-101, that demonstrated rapid receptor-mediated transcytosis in vitro and in vivo and could activate phospho-STAT3 in cells within the lamina propria following luminal administration (data not shown). Mice with oxazolone-induced colitis were dosed by oral gavage with AMT-101 daily for 12 days, at which time colon tissue and serum were examined for hallmarks of inflammation. Enteric-coated capsules were used to deliver either 1 or 5 mg of AMT-101 to the distal ileum of cynomolgus monkeys; serum was collected to examine PK and PD outcomes in this non-inflamed model.

Results

Histological changes of colonic tissue associated with oxazolone-induced colitis was blocked by the oral gavage of AMT-101. Increases in serum levels of pro-inflammatory cytokines IL-1b, IL-6, and IL-17A were blunted by AMT-101 treatment. Remarkably, endogenous IL-10 increased in this model in an attempt to correct inflammation, but this was also decreased by the delivery of AMT-101. Cynomolgus monkeys dosed orally with AMT-101 capsules showed very low serum levels compared with those observed after IV injection of 0.5 mg/kg AMT-101. Strikingly, serum levels of IL-1 receptor antagonist (IL-1RA) as an anti-inflammatory PD marker were increased to a greater extent following oral capsule dosing compared with IV administration.

Conclusion

These studies provide strong pre-clinical evidence that AMT-101 can effectively reach the intestinal lamina propria to delivery biologically-active IL-10 following transcytosis across the intestinal epithelium. Importantly, the gut-selective nature of the responses observed suggests AMT-101 may alleviate the previous issues of dose-limiting side effects observed with systemic administration of IL-10 and point to the intestinal lamina propria as a critical site of IL-10’s immunomodulatory actions. AMT-101 has advanced to the clinic and is currently being evaluated in a Phase1b trial in patients with active ulcerative colitis.
DOP04 Matching between donors and patients in faecal microbiota transplantation is important for long-term maintenance on ulcerative colitis
Authors: Ishikawa D , Okahara K , Takahashi M , Haga K , Nomura K , Shibuya T , Nagahara A
Published: January 2020

Background

We previously demonstrated that fresh-faecal microbiota transplantation (FMT) following triple-antibiotic therapy [amoxicillin, fosfomycin, and metronidazole (AFM); A-FMT] for ulcerative colitis (UC) patients induced changes in the phylum Bacteroidetes, which constitutes a critical factor correlated with clinical responses. Here, we analyse the short- and long-term efficacy of A-FMT comparing to AFM monotherapy, and we explore the concept of a beneficial donor for long-term maintenance.

Methods

This prospective and non-randomised control study was conducted from July 2014 to March 2017. Eligible patients were at least 20 years of age, with a diagnosis of active UC which were required a Lichtiger’s clinical activity index (CAI) of 5 or more, or with an endoscopic Mayo score of 1 or more. Patients’ spouses or relatives in the family were selected as donors. AFM was administered to patients with UC for 2 weeks, and up to 2 days before fresh FMT. Clinical response was defined as a decrease of CAI of 3 points or more, and remission was defined as 3 points or less. Maintenance of efficacy was defined as no exacerbation of CAI and no intensification of treatments.

Results

Seventy-nine patients completed protocol (A-FMT; n = 47, mono-AFM; n = 32). At 4 weeks after treatment, clinical response and remission were observed in 31 and 19 patients (65.9%, 40.4%) in A-FMT, which higher than in mono-AFM respectively (56.2%, 18.7%). The maintenance rate of clinical responder was shown to be significantly higher in A-FMT than in AFM at 12 months and 24 months after treatment (A-FMT vs. mono-AFM, p = 0.046 and 0.034, Wilcoxon test). In A-FMT, in case that the age difference between donor and patient is more than 11 years, maintenance rate was significantly lower than 0–10 age difference in A-FMT (≥11 vs. 0–10, n = 14, 16; p = 0.004 and p = 0.003, log-rank test). Siblings relationship has a significantly higher maintenance rate compared with parent–child relationship (Siblings vs. parent–child; n = 7, 13; p = 0.009 and p = 0.006, log-rank test).

Conclusion

A-FMT exhibited reassuring clinical outcomes in terms of short and long term. This is the first report of FMT to reveal the importance of matching between donors and patients for long-term maintenance on UC.
DOP06 Non-invasive identification of adherent-invasive E. coli in patients with Crohn’s disease
Authors: Buisson A , Vazeille E , Hébuterne X , Fumery M , Pariente B , Nancey S , Seksik P , Peyrin-Biroulet L , Allez M , Ballet N , Billard E , Rodriguez S , Pereira B , Barnich N
Published: January 2020

Background

Medications limiting the adhesion of ‘adherent and invasive E. coli’ (AIEC) represent potential strategies to treat Crohn’s disease (CD). However, the ileal AIEC identification is a time-consuming procedure, and the number of AIEC strains which colonise ileal CD mucosa remains unknown. There is an unmet need for non-invasive biomarkers to identify patients colonised by AIEC. We aimed to evaluate non-invasive biomarker of ileal AIEC colonisation in patients with CD.

Methods

This prospective and multi-centre study included CD patients requiring ileocoloscopy. Saliva, serum, stools and ileal biopsies were collected. Abundance and global invasive ability of ileal or faecal E. coli were performed. Isolated E. coli were characterised as AIEC or non-AIEC on I407 epithelial cells and THP1 macrophages. The ERIC-PCR profiles of ileal E. coli were performed. Ileal E. coli/CEACAM6 interaction was analysed by a yeast aggregation test and T84 assays (CEACAM6 protein expression, adhesion inhibition test with D-mannose). Quantification of serum anti-E. coli and ileal or salivary CEACAM6 was realised by ELISA.

Results

Overall, 102 CD patients were enrolled in this study and 25.8% of them exhibited ileal AIEC colonisation (AIEC+). The abundance and global invasive ability of ileal mucosa-associated E. coli were higher in AIEC+ CD patients compared with CD patients without AIEC (AIEC−) (p = 0.0065 and p = 0.0007, respectively). There was no difference between faecal abundance and invasive ability of E. coli between AIEC+ and AIEC− patients. The ERIC-PCR profiles of ileal E. coli showed that CD AIEC+ were for 78% of them colonised by not more than 2 clonal AIEC strains. In addition, AIEC were able to interact with CEACAM6 by binding D-mannose residues and to induce CEACAM6 expression in T84 cells (p = 0.0009 and p = 0.0185, vs. non-AIEC; respectively). This was also supported by adhesion inhibition test. Serum anti-E. coli level was higher for CD AIEC+ (vs. CD AIEC-). Ileal CEACAM6 level were positively correlated with abundance of ileal associated E. coli in AIEC+ patients (r = 0.4000; p = 0.0362) and with salivary CEACAM6 level (r = 0.4690; p < 0.0001). The non-invasive biomarker ‘serum anti-E.coli/salivary CEACAM6’ index was higher for CD AIEC+ (p = 0.0174; vs. CD AIEC-). A cut-off value < 1.34 × 10−6 eliminated the presence of ileal AIEC with a high negative predictive value (90% CI95% [69%–95%]).

Conclusion

Our study reported that identification of faecal AIEC cannot replace identification of AIEC from ileal biopsies, most of AIEC infection are mono or bi-clonal (≤ 2 strains) and that non-invasive biomarker such as ‘serum anti-E.coli/salivary CEACAM6’ index could be helpful to screen CD patients for AIEC infection.
DOP07 Long-term results of 4.5 years of faecal microbiota transplantation for treatment of refractory ulcerative colitis
Authors: Uygun A , Karakaya M F , Erdal H , Celebi G , Sakin Y S , Artuk C , Ozturk K , Gulsen M
Published: January 2020

Background

Faecal microbiota transplantation (FMT) provides replacement of pathogenic bacteria with more favourable microbiomes in recipients with dysbiosis. The aim of the present study was to prospectively investigate the efficacy of FMT by assessing the clinical and endoscopic response in patients with ulcerative colitis (UC) who had failed anti-inflammatory, immunosuppressive and TNF-α inhibitors (Infliximab, Adalimumab, Vedolizumab) therapy.

Methods

In this prospective and uncontrolled study, 116 patients with UC were enrolled. All medications except mesalazine were discontinued 1 week before FMT. Colonoscopy was performed both before and after FMT. To assess the efficacy of FMT, Mayo scores were calculated at weeks 0, 24 and 48. A total of 400–600 ml of extracted fresh faecal suspension was administered into the 20 to 30  cm of terminal ileum of recipients.

Results

After 4.5 years of FMT experience with 116 patients, who have completed their 6 months after 236 procedures of FMT for treatment of UC, 42 of the 116 patients showed full clinical response (100% clinical + laboratory + endoscopically full response) (per-protocol analysis 37.1%), (intention-to-treat analysis 36.2%) at Week 48 and 33 of the 116 patients achieved clinical and endoscopic remission (laboratory 70%, clinically and endoscopically 50–75% improvement) (per-protocol analysis 29.2%), (intention-to-treat analysis 28.4%) at Week 48. Thirty-eight of the 116 patients were accepted as nonresponders at the end of Week 48 (per-protocol analysis 29.2%), (intention-to-treat analysis 32.7%) and 3 patients (2.5%) were lost to follow-up. There was no significant difference among donors concerning both the rate of clinical remission and clinical response. At 4.5 years, serious side effects were observed on 2 patients, 1 colon perforation and 1 toxic megacolon; both were directed to surgery. In 48 weeks’ follow-up, 31 patients (26.7%) experienced mild adverse events after FMT, such as elevated white blood cell counts and ESR, nausea, abdominal pain and high fever, all were managed conservatively.

Conclusion

FMT could be considered as a promising rescue treatment modality before surgery in patients with refractory UC. Our research is the first in the world for the treatment of UC resistant to medical treatment before surgery. Also, it is the first research to show the long-term results of FMT. FMT appears to be significantly safer and more tolerable than the immunosuppressive and TNF-α inhibitors therapy in patients with UC.
DOP08 Deep remission in paediatric Crohn’s disease is associated with increased abundance of dialister species and increased valerate
Authors: Taylor H , McDonald J , Serrano Contreras J I , Li J , Marchesi J , Hart A
Published: January 2020

Background

Deep remission, or the absence of mucosal inflammation on endoscopy, is associated with improved long-term outcomes in paediatric Crohn’s disease (pCD). In pCD faecal calprotectin level <100 mg/l is a validated non-invasive marker of deep remission and is a therapeutic target used in clinical practice. The microbiome in pCD has been extensively compared with controls and is known to have reduced diversity, high instability, and depleted short-chain fatty acid (SCFA) producers. This study investigates variation in microbiome, metabolome and protease activity associated with deep remission.

Methods

Children aged 3–18 years with established pCD on infliximab were recruited. Stool samples were cooled immediately, aliquoted, and frozen at −80oC within 4 h. Deep remission status was assigned if the calprotectin level was under 100 mg/l. 16S sequencing and analysis used Illumina MiSeq (V1-2 primers), DADA2, and STAMP. ¹H-NMR spectral profiles were used to develop partial-least-squares discriminant-analysis with Monte-Carlo cross-validation (MCCV-PLS-DA) models. Metabolome microbiome correlation used Storey’s method for multiple testing correction and a threshold of │RHO│≥ 0.5 with q < 0.05. Protease activity was assayed by comparing the breakdown of fluorescein labelled casein against trypsin standards.

Results

Twenty-one children were included; 10 were in deep remission and 11 had active disease. There were no significant differences in age, disease duration, treatment, or BMI between groups. Mean height z score was lower in those with active disease (p = 0.015). There was no significant difference in α diversity between groups, and non-metric multidimensional scaling of weighted unifrac distance identified no difference in community composition (PERMANOVA p = 0.317). The relative abundance of Dialister species was higher in those with deep remission (3.4 vs. 0.4%, q = 0.033). Dialister abundance was positively correlated with valerate concentration. MCCV–PLS-DA was able to effectively discriminate metabolome profiles from active and deep remission patients (R2 = 0.87, Q2 = 0.51); valerate and glutamate were increased in deep remission, ethanol and lysine were decreased. There was a trend towards increased protease activity in patients with active disease (p = 0.054).

Conclusion

Dialister species are enriched in pCD in deep remission and are associated with significant metabolome changes, including increased valerate. Valerate, like other SCFAs, has known anti-inflammatory properties and has previously been implicated in effective C. difficile treatment. This study supports an association between Dialister abundance, valerate and mucosal healing in pCD. A trend towards higher protease activity in active disease also warrants further investigation.
DOP28 Understanding the molecular mechanisms of anti-TNF treatment failure in patients with Crohn’s disease: A pilot serum proteomic analysis of the PANTS cohort
Authors: Lin S , Chanchlani N , Invergo B M , Anderson M W , Guay H M , Reppell M , Butler J W , Goodhand J R , Ahmad T , Kennedy N A
Published: January 2020

Background

Proteomic biomarkers have been linked to anti-TNF treatment failure, but previous studies have been insufficiently powered to stratify associations by drug level. The Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) is a prospective UK-wide study investigating treatment failure in 1610 anti-TNF naïve patients. We aimed to identify proteomic markers of treatment failure.

Methods

We sampled patients with primary non-response (PNR) (n = 223) and remission (n = 219) who had a baseline CRP ≥4 mg/l and/or calprotectin >100 µg/g. PNR was defined at week 14 as ongoing steroids, or both of HBI failed to fall by ≥3 points or to ≤4 and CRP failed to fall by ≥50% or to ≤3 mg/l. Non-remission at week 54 was defined as HBI >4 and CRP >3 mg/l and no steroids. Targeted serum proteomic analysis of 180 proteins using Olink Inflammation and Immune Response panels were performed. Mann–Whitney U tests were used to identify baseline proteins that predicted PNR and non-remission. Sub-group analyses stratified by drug level were undertaken. Pharmacokinetic (PK) failure was defined as PNR with low drug level (infliximab level <2 mg/l, adalimumab level <6 mg/l) and pharmacodynamic (PD) failure as PNR despite adequate drug level. Significant proteins were entered into multivariable logistic regression models and Bayesian information criterion (BIC) with backward stepwise selection were used to build predictive models of treatment failure. We applied 10-fold cross-validation to test the models. P-values of < 0.05 were considered significant.

Results

Elevated fibroblast growth factor 21 (FGF21) (OR 1.3, CI 1.1–1.4, p = 3.4 × 10–5) and interleukin-10 receptor subunit α (IL10RA) (OR 1.6, CI 1.2–2.1, p = 6.3 × 10–4) predicted PNR (Figure 1). At week 14, FGF21 (OR 1.5, CI 1.3–1.9, p = 1.8 × 10–6) and IL10RA (OR 1.8, CI 1.3–2.3, p = 5.8 × 10–5) levels were also associated with PNR.

Sub-group analyses showed baseline FGF21 (OR 1.4, CI 1.2–1.7, p = 2.0 × 10–4) predicted PK failure and that IL10-RA (OR 1.6, CI 1.1–2.2, p = 6.7 × 10–3) predicted PD failure (Figure 2).

In separate models, non-remission at week 54 was predicted by baseline (FGF21; OR 1.3, CI 1.1–1.4, p = 1.4 × 10–4, IL10-RA; OR 1.5, CI 1.1–2.0, p = 3.6 × 10–3) and week 14 (FGF21; OR 1.4, CI 1.2–1.7, p = 3.6 × 10–4, IL10-RA; OR 1.7, CI 1.3–2.4, p = 1.7 × 10–4) FGF21 and IL10-RA levels. Model validation of baseline FGF21 and IL10-RA showed an area under the curve of 0.61 (CI 0.57–0.64) for PNR and 0.60 (CI 0.56–0.64) for non-remission at week 54.

Conclusion

Our study identified FGF-21 and IL10-RA as proteins of interest associated with PK and PD treatment failure, respectively. Functional studies to determine the molecular mechanism driving dysregulation of these proteins are required.
DOP31 Serum protein markers for early and differential IBD diagnosis validated by machine learning approaches
Authors: Verstockt S , Verplaetse N , Raimondi D , Verstockt B , Glorieus E , De Decker M , Hannes L , Ballet V , Vandeput E , Moreau Y , Ferrante M , Laukens D , Mana F , De Vos M , Vermeire S , Cleynen I
Published: January 2020

Background

The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions with a polygenic and multifactorial pathogenesis. Intensified treatment early in the disease course of IBD results in better outcomes. This is, however, challenged by the diagnostic delay faced in IBD, and especially in CD. Therefore, markers supporting early and differential diagnosis are needed. In this study, we aimed to discriminate IBD patients from non-IBD controls, and CD from UC patients, using serum protein profiles combined with an IBD polygenic risk score.

Methods

Patients naïve for immunosuppressives and biologicals, and without previous IBD-related surgery were prospectively included within 3 months after diagnosis, across three Belgian IBD referral centres (PANTHER study). We collected serum from 127 patients (88 CD, 39 UC) and 66 age- and gender-matched non-IBD controls. Relative serum levels of 576 unique proteins were quantified (OLINK). Proteins were ranked according to (1) adjusted (adj.) p values obtained from differential expression analysis; (2) importance scores from machine-learning feature-selection algorithms (univariate feature selection, logistic regression with L2 penalty and Random Forest). For all individuals, a weighted IBD polygenic risk score (PRS) was calculated (PRSice 2.0) for the 242 known IBD risk loci. Receiver operating characteristics (ROC) and area under the curve (AUC) analysis were performed to measure the performance of top-ranked proteins and the IBD PRS (R package ROCR).

Results

Following statistical analysis, 243 serum proteins were found to be differentially expressed (adj. p < 0.05) between IBD patients and controls. Three top-ranked markers were also identified as top 10 ranked proteins by all feature-selection algorithms, and resulted in a significant AUC of 93% (95% CI: 89–97%) to distinguish IBD from controls. While adding the IBD PRS did not further contribute (AUC 93% [95% CI: 89–97%]), the top-ranked protein on its own had a strong discriminative power with an AUC of 87% (95% CI: 82–92%). When comparing UC and CD, we found 15 differentially expressed proteins. Two proteins ranked within the top 10 across all feature-selection algorithms. This two-marker panel could discriminate UC from CD with an accuracy of 88% (95% CI: 82–96%). Adding the IBD PRS did not further improve the prediction model (AUC=88% [95% CI: 81–96%]).

Conclusion

Machine learning approaches validated top differentially expressed serum proteins with diagnostic potential in IBD. We identified a three-marker panel classifying IBD patients and non-IBD controls, and a two-marker panel discriminating UC from CD.
DOP36 Family-specific host genetic and gut microbial signatures have a beneficial role in early identification of familial inflammatory bowel diseases
Authors: SHIN G Y , Park Y M , Ha E , Gu K N , Kim K , Lee C K , Kim H J
Published: January 2020

Background

Familial IBD may have its own signatures with respect to host genetic variants and/or gut microbiome. However, available data focussing on this topic is still limited, particularly for Asian patients with familial IBD. We aimed to investigate the possible host genetic and gut microbial signatures in familial IBD through a combined analysis of genomic and metagenomic profiles.

Methods

All patients were affiliated with a prospectively recruited cohort of patients with IBD (NCT03589183) and met the diagnostic criteria of Crohn’s disease (CD) or ulcerative colitis (UC). We constructed a unique family cohort comprising ≥2 affected individuals with familial IBD and ≥1 their unaffected, healthy first-degree relative (FDR) in each family. Whole-exome sequencing for rare variants followed by a genome-wide single-nucleotide polymorphism analysis for common variants was performed. A polygenic risk score (PRS) was calculated separately in Crohn’s disease (CD), ulcerative colitis (UC) or IBD. Gut microbial community was analysed by 16s rRNA sequencing of stool samples.

Results

Eight Korean families comprising 16 with familial IBD (12 concordant IBD, 4 discordant IBD) and 9 FDRs were included for analysis. Whole-exome sequencing identified four family-specific candidate genes (LAMA5, MYO15B, TTN, and WDR66) with rare missense variants that were transmitted preferentially to the affected FDRs in at least ≥3 families (Figure 1). An in silico analysis identified the deleterious effect of the identified variants on the gene products including LAMA5 (SIFT = 0, PolyPhen-2 = 0.72). The patients with CD, but not those with UC, had a significantly higher mean PRS than controls (PRS = 2.137 vs. 0.742, p-value = 0.030). Metagenomic sequencing revealed significant differences in α- and β-diversity of gut microbiota among the patients with CD, those with UC, and unaffected FDRs (all p < 0.05), showing lower microbial richness in the patients with familial IBD (p = 0.02). In various taxonomic levels, compared with unaffected FDRs, the patients with familial IBD showed the significantly differential abundance of several gut bacteria (all corrected p < 0.05; Figure 2).

Conclusion

Family-specific host genetic and gut microbial signatures have a beneficial role in early-identification of familial IBD (NCT03515070).
DOP37 Neoplastic lesions outside diseased area in inflammatory bowel disease patients: A national cohort study
Authors: Cremer A , Demetter P , De Vos M , Rahier J F , Baert F , Moreels T , Macken E , Louis E , Vermeire S , Franchimont D
Published: January 2020

Background

Patients with inflammatory bowel diseases (IBD) are at increased risk of dysplasia and colitis-associated cancer (CAC). The presentation of (pre)neoplastic lesions (low-grade dysplasia (LGD), high-grade dysplasia (HGD) or colorectal cancer (CRC) is reported to vary depending if the lesions are located inside disease area (IDA) or outside diseased area (ODA). The primary aim was to analyse the characteristics and prognostic of IDA compared with ODA neoplastic lesions in a large cohort of IBD patients.

Methods

We performed a multicentre retrospective pathological data collection from 7 tertiary referral regional or academic IBD centres in Belgium. Clinical, endoscopic and pathological data were retrieved through retrospective electronic chart review. From the IBD pathology databases, 1183 colorectal lesions were identified in 541 IBD patients: 415 developed dysplasia (77%) and 126 CRC (23%) during their follow-up. Biopsies and surgical specimen were centrally reviewed by an expert IBD pathologist to confirm the diagnosis of dysplasia and/or CRC.

Results

Demographic and clinical variables of the study population are summarised in Table 1. More patients with IDA lesions had HGD (9%) or CAC (27%) during their follow-up compared with the group of patients with ODA lesions (3% of HGD and 11% of CRC) (p < 0,0001). Mortality was higher in patients with IDA than in those with ODA lesions (p < 0.05). When comparing IBD patients with IDA lesions and CAC (=111) to those with ODA lesions and sporadic CRC (n = 15), median age at IBD diagnosis was lower (29 (IQR:22–49) vs. 41(IQR:28–54) years; p = 0.0001). Characteristics of the 1183 neoplastic lesions are summarised in Table 2. IDA lesions were more frequently non-visible, non-polypoid and ≥ 1 cm than ODA lesions (p < 0.0001). ODA sporadic CRC was more frequently located in the right colon compared with IDA CAC (5/16 (31%) vs. 21/133 (16%), p < 0.01).

Conclusion

Neoplastic lesions outside the diseased area were more likely to be visible, polypoid, < 1cm, in the right colon and diagnosed at endoscopy than inside disease area lesions. A lower prevalence of HGD and Cancer were reported with neoplastic lesions outside the diseased area.
DOP38 Prevalence of fatigue in a severe inflammatory bowel disease cohort highly exposed to biologics
Authors: Liefferinckx C , El hamdi M , Fassin M , Cremer A , Minsart C , Amininejad L , Wambacq V , Van Gossum A , Franchimont D
Published: January 2020

Background

In addition to physical and psychological factors, systemic inflammation, anaemia and/or malnutrition contribute to fatigue in Crohn’s disease (CD) and ulcerative colitis (UC). Despite recent advances in the management of the disease activity, fatigue is a major disabling symptom for inflammatory bowel disease (IBD) patients.

Methods

The aim of this prospective study is to evaluate the prevalence of IBD patients suffering from fatigue in a tertiary IBD referral centre and delineate its contributing factors. All patients with a confirmed IBD diagnosis were eligible. A given written consent has been obtained for each patient (P2019/053). Fatigue evaluation was assessed by FACIT-F. Self-report questionnaires were used to assess different factors related to fatigue: disease activity was assessed by patient-reported outcomes (PRO), anxiety by State and Trait Spielberger scores, depression by Beck score (BDI-II), sleep quality by Insomnia severity index (ISI) and Epworth scale, and quality of life by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Biological values including haemoglobin, C-reactive protein (CRP), thyroid-stimulating hormone (TSH), folic acid and B12 vitamin were collected when available.

Results

Demographic data of the 128 included patients are presented in Table 1. This cohort was characterised by a high prevalence of CD complicated behaviours and UC pancolitis. 84.4% of patients (n = 108) were exposed to biologics at the time of completion of the questionnaire.

The prevalence of fatigue was 65.6% stratified as severe (FACIT-F <20) and moderate (FACIT-F 20–40) in 21.1% and 44.5%, respectively. Fatigue was clearly associated with active disease in CD, anxiety, depression, poor quality of life, insomnia and somnolence but not with active disease in UC. All biological values were within normal ranges and did not influence fatigue. Older age at diagnosis was associated with lower FACIT-F score while disease duration was not (Table 2). No correlation was found between fatigue and any specific biologics (p = 0.08).

Conclusion

This prospective study reported a fatigue prevalence of 65.6% in a severe IBD cohort highly exposed to biologics. Beyond disease activity in CD, psychological factors (whether they are causes or consequences) such as anxiety, depression, poor quality of life and insomnia were associated with fatigue.
DOP45 Increased prevalence but not incidence of myocardial infarction and stroke in patients with inflammatory bowel diseases in Quebec in 1996–2015
Authors: Verdon C , Reinglas J , Filliter C , Coulombe J , Gonczi L , Afif W , Wild G , Seidman E , Bitton A , Bessissow T , Brassard P , Lakatos P L
Published: January 2020

Background

Chronic inflammatory diseases have been linked to increased risk of atherothrombotic events, but the risk associated with inflammatory bowel disease (IBD) is conflictive. We, therefore, examined the risk of and risk factors for myocardial infarction (MI) and stroke in patients with IBD in Quebec.

Methods

We used the public health administrative database from the Province of Québec to identify newly diagnosed IBD patients between 1996 and 2015 with established case ascertainment algorithm. Incidence and prevalence of stroke and myocardial infarction were defined using ICD codes found in primary, secondary care visits or admission. Comorbidity analysis was performed by both using a logistic regression or a Poisson model with outcome rates for 1000 person-years adjusted for age and sex along with one comorbidity of interest, or with medical therapy as a time-varying variable. Significant variables (p < 0.05) were added to a multivariable models along with age and sex. Analyses were run overall and stratified by disease type. Incidence rate ratios, 95% CIs and p-values were computed.

Results

In total, 34 644 newly diagnosed IBD patients (CD: 59.5%) were identified. The prevalence but not incidence rates of MI was higher in IBD (prevalence at the end on 2013: 3.98%, OR:2.03 95% CI: 1.92–2.15, incidence: 0.234 per 1000 patient-years) compared with the background Canadian rates (prevalence in 2012–2013: 2.0%, incidence: 0.220 per 1000 patient-years), while the prevalence and incidence rates of stroke were not significantly higher in IBD (prevalence in 2012–2013: 2.98%, OR: 1.15 95% CI:1.08–1.23, incidence: 0.122 per 1000 patient-years vs Canadian rates: (prevalence in 2012–2013: 2.60%, incidence: 0.297 per 1000 patient-years). We identified age, sex, hyperlipidaemia and hypertension (p < 0.001 for each) as risk factors for developing MI and stroke in both CD and UC. Diabetes was identified as an additional risk factor for MI in CD and stroke in UC. Exposure to biologicals was associated with a higher incidence of MI compared with the non-treatment group (IRR: 1.51, 95% CI: 0.82–2.76, p = 0.07) in the insured IBD population.

Conclusion

Increased prevalence but not incidence of MI and no increased risk of stroke was identified in this population-based IBD cohort from Quebec. Risk factors for both MI and stroke included age, sex, hyperlipidaemia, hypertension and diabetes in IBD. Exposure to biologicals, reflecting disease severity in administrative databases, was associated with a higher incidence rate ratio for MI in IBD.
DOP46 Impact of a genetic burden on familial aggregation of inflammatory bowel disease
Authors: Lee H S , Hannes L , Vancamelbeke M , Ballet V , Ferrante M , Vermeire S , Cleynen I
Published: January 2020

Background

Family history of inflammatory bowel disease (IBD) is the strongest risk factor for IBD. There currently, however, is limited understanding of the contribution of genetic risk to familial aggregation of IBD. We aimed to evaluate the association between the IBD polygenic risk score (PRS) and familial IBD, and determine its contribution to familial IBD.

Methods

We included 54 multiple-affected families (≥3 first-degree relatives affected) of European ancestry, including 189 affected IBD patients (156 Crohn’s disease; 33 ulcerative colitis), and 133 unaffected relatives. For all individuals, Immunochip genotypes were available. Weighted PRSs with estimates derived from literature were calculated using PRSice-2.0, including clumping and different p-value thresholds (pT) to select which variants to include in the score. Explained variance (Nagelkerke pseudo-R²) was calculated across different pTs. To account for possible intra-familial correlations, the association between PRS and familial IBD was evaluated in age- and sex-adjusted generalised mixed regression models including family as random effects. Sporadic cases (n = 1768) and non-IBD controls (n = 868) with Immunochip genotypes were used for comparison.

Results

Using pT = 0.05 for PRS calculation, we found that affected relatives had a higher PRS than unaffected relatives (p = 1.00 × 10−2), sporadic cases (p = 4.58 × 10−2), and non-IBD controls (p < 2.20 × 10−16) (Figure 1a and b). The risk of disease in families increased by 1.23-fold (95% confidence interval (CI) 1.21–1.24) for every incremental standard deviation in PRS. Individuals in the highest quartile had a 3.45 times higher risk of IBD (95% CI 1.77–6.72) than those in the lowest quartile. However, the proportion of the explained variance between affected and unaffected family members was smaller than that of sporadic IBD and non-IBD controls; and the best pT was different for familial or sporadic IBD. In familial IBD, the best-fit PRS was at pT = 6.90 × 10−3 and explained 5.3% (Figure 1c, p = 3.07 × 10−4) of variance, whereas, in sporadic IBD, the best-fit PRS was at pT = 0.08 and explained 16.7% (Figure 1d, p = 8.48 × 10−63). For sporadic IBD, a typical increase in the proportion of variance explained was seen with more liberal p-value thresholds and levelling off at ~pT = 0.1 (Figure 1d). What was striking, however, was that in familial IBD this additive genetic variance was only observed until pT = 0.01, after which explained variance dropped dramatically (Figure 1c).

Conclusion

Higher IBD polygenic risk increases the risk for familial IBD as it does for sporadic IBD. In sporadic IBD, the increased risk is defined by variants of all p-value levels (until ~pT = 0.1). In familial IBD, the difference between those affected or not is in the higher-effect variants (p < 0.01).
DOP50 The landscape of somatic mutations in non-neoplastic IBD-affected colon
Authors: Olafsson S , McIntyre R E , Coorens T , Butler T , Robinson P , Lee-Six H , Sanders M , Arestang K , Dawson C , Tripathi M , Strongili K , Hooks Y , Stratton M R , Parkes M , Martincorena I , Raine T , Campbell P J , Anderson C A
Published: January 2020

Background

Under normal physiological conditions, colonic crypts accrue ~40 somatic mutations for every year of life. That somatic mutations contribute to the development of cancer is well established, but their patterns, burden and functional consequences in diseases other than cancer have not been extensively studied and our understanding of the effects of chronic inflammation on the mutational profile and clonal structure of the colon is limited. Here, we investigated how the recurrent cycles of inflammation, ulceration and regeneration seen in IBD impact the mutational and clonal structure of intestinal epithelia.

Methods

We isolated and whole-genome sequenced ~400 individual colonic crypts from 46 IBD patients and compared these to ~400 crypts from 41 non-IBD controls. We compared the mutation burden, mutational signature exposure, clonal structure and cancer driver mutation landscape in crypts from actively and previously inflamed regions with crypts dissected from controls.

Results

We estimated the base substitution rate of affected colonic epithelial cells to be doubled after IBD onset. This change was primarily driven by acceleration of mutational processes ubiquitously observed in normal colon (Figure 1), and we did not detect an IBD-specific mutational process. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimetre-scale clonal expansions, even in the absence of mutations in KRAS, TP53 and APC (Figure 2). We discovered that mutations in ARID1A, PIGR and ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, were under positive selection in colonic crypts from IBD patients (Figure 3). With the exception of ARID1A, these genes and pathways have not been previously associated with cancer risk. A previously published mouse model of ZC3H12A suggests that LoF mutations in this gene may facilitate healing of affected mucosa without promoting tumorigenesis. This could make the encoded protein an attractive drug target. The observed enrichment of mutations in PIGR and IL17 and TLR pathways suggests that somatic mutations may initiate, maintain or perpetuate IBD pathogenesis through disruption of microbe-epithelial homeostasis.

Conclusion

Our results provide new insights into the consequences of chronic intestinal inflammation on the mutational profile and clonal structure of colonic epithelia. We identify the mutagens driving the increase in mutation burden and mutations which are under positive selection in the context of inflammation. Our results suggest that studying somatic mutations in the colon can reveal putative drug targets and pathogenic mechanisms for IBD.
DOP55 A real-world comparison of the effectiveness and safety of vedolizumab and anti-TNF therapies in early treatment initiation with first-line biologic therapy in ulcerative colitis: Results from EVOLVE
Authors: Mantzaris G , Bressler B , Kopylov U , Bassel M , Brett N , Colby C , Lopez C , Saha S , Kifnidi C , Agboton C , Adsul S , Demuth D , Luo M , Wang S , Yarur A
Published: January 2020

Background

Evidence suggests that early treatment (Tx) with biologic agents in Crohn’s disease improves long-term clinical outcomes. However, there is less evidence in ulcerative colitis (UC), and data comparing early Tx with first-line biologic vedolizumab (VDZ) to anti-tumour necrosis factor (anti-TNF) in real-world settings is needed. This study compared the clinical effectiveness and safety of UC patients who initiated VDZ or an anti-TNF as a first-line biologic within 2 years following diagnosis.

Methods

This was a real-world, multi-country, retrospective chart review study in Canada, Greece and the United States where biologic-naïve UC patients (≥18 years old) were treated with VDZ or an anti-TNF (adalimumab, infliximab, golimumab) agent within 2 years following diagnosis (initiated Tx May 2014–March 2018). Clinical effectiveness and safety data were collected from Tx initiation to earliest of chart abstraction date, death, or 6 months post-Tx discontinuation (Canada only). Tx persistence was defined as the duration of time from treatment initiation to discontinuation. Analyses of cumulative rates of Tx persistence, clinical response, clinical remission and mucosal healing over 24 months were estimated using Kaplan–Meier analyses. Clinical response, remission and mucosal healing were assessed using pre-defined hierarchical algorithms of standard disease measures reported in the medical records. Analyses of incidence rates (per 100 person-years [PYs]) of disease exacerbations, disease-related surgeries, serious adverse events (SAEs) and serious infections (SIs) were performed. Adjusted analyses used inverse probability weighting to balance cohorts.

Results

This analysis included 176 UC patients (VDZ: 86; anti-TNF: 90) from 37 sites. Mean (SD) age at index date: VDZ, 41.4 (18.9); anti-TNF, 36.8 (15.6) years (p = 0.20) and the proportion male: VDZ, 58.1%; anti-TNF, 56.7% (p = 0.84). At 12 months, 72.9% and 58.1% continued VDZ and anti-TNF respectively (p = 0.03) (Figure 1A). Though there were no differences in clinical response, clinical remission or mucosal healing between VDZ and anti-TNF groups; VDZ patients were significantly less likely to experience disease exacerbations (HR = 0.47 [95% CI: 0.32–0.69]) and SAEs (HR = 0.37 [95% CI: 0.19–0.72]) (Figure 2). Adjusted outcomes (Figures 1C and D, and 2B) were similar to unadjusted outcomes.

Conclusion

EVOLVE is one of the first studies that compared early VDZ Tx to early anti-TNF Tx in biologic-naïve UC patients. Results showed VDZ was associated with higher persistence, lower likelihood of experiencing disease exacerbations and a more favourable safety profile. Thus, in early UC, Tx with VDZ may improve long-term clinical outcomes. Sample size limitations warrant further study.
DOP61 Tofacitinib, an oral, small-molecule Janus kinase inhibitor, in the treatment of ulcerative colitis: Analysis of an open-label, long-term extension study with up to 5.9 years of treatment
Authors: Lichtenstein G R , Loftus E V , Wei S C , Damião A O , Judd D , Lawendy N , Chan G , Zhang H , Wang W , Thorpe A J , Bloom S
Published: January 2020

Background

Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were demonstrated in patients with moderate to severe UC in 3 Phase 3 studies.1 Here, we present data from an ongoing, open-label, long-term extension (OLE) study.2

Methods

We present updated safety and efficacy data from the OLE study (OCTAVE Open, NCT01470612; as of May 2019, database not locked). Eligible patients included non-responders (Week 8 data) in OCTAVE Induction 1 and 2 (NCT01465763; NCT01458951) and completers (Week 52 data) or treatment failures (early-termination data) in OCTAVE Sustain (NCT01458574). Patients in remission (total Mayo score ≤2, no individual subscore >1, rectal bleeding [RB] subscore 0) at Week 52 of OCTAVE Sustain (central read) received tofacitinib 5 mg twice daily (BID); all others received 10 mg BID. Induction non-responders without clinical response (≥3-point and ≥30% decrease from induction study baseline total Mayo score, plus ≥1-point RB subscore decrease or absolute RB subscore ≤1) at Month 2 of the OLE study were withdrawn. Incidence rates (IRs) for adverse events (AEs) of special interest were calculated (no. of unique patients with events per 100 patient-years). Efficacy endpoints were derived from Mayo score (local read) with non-responder and last observation carried forward imputation (NRI-LOCF) [a].

Results

Of 944 patients who received ≥1 dose of tofacitinib, 769 (81.5%) received 10 mg BID (median duration [range]: 5 mg BID 1170 [36–2066]; 10 mg BID 668 [1–2159] days). In total, 338 (35.8%) and 93 (9.9%) patients discontinued due to insufficient clinical response and AEs (excl. worsening UC), respectively. IRs (95% confidence interval) in the Tofacitinib. All group were: deaths 0.18 (0.05, 0.47); serious infections 1.57 (1.08, 2.19); herpes zoster (non-serious and serious) 3.27 (2.54, 4.14); major adverse cardiovascular events 0.14 (0.03, 0.40); malignancies excl. non-melanoma skin cancer (NMSC) 0.92 (0.56, 1.42); NMSC 0.74 (0.43, 1.21); deep vein thrombosis 0.05 (0.00, 0.25); pulmonary embolism 0.18 (0.05, 0.47) (Table). At Month 36 (NRI-LOCF), 58.9% (n = 103) and 33.5% (n = 257) were in remission, 64.6% (n = 113) and 37.0% (n = 284) had mucosal healing (Mayo endoscopic subscore of 0 or 1) [b] and 66.9% (n = 117) and 40.2% (n = 309) showed clinical response, in the 5 and 10 mg BID groups, respectively.

Conclusion

Incidence of AEs remained generally consistent in patients with moderate to severe UC in the OLE study compared with a previous analysis.2 Data continue to support long-term efficacy with tofacitinib up to 36 months beyond Week 52 of OCTAVE Sustain.

References