bluuebunny/crossref_metadata_2025_split huggingface dataset:
P530 Proactive therapeutic drug monitoring of anti-TNF agents is associated with higher mucosal healing rates in Crohn’s disease
Authors: Brinar M , Sabic M , Turk N , Grgic D , Domislovic V , Cukovic Cavka S , Kozmar A , Krznaric Z 
Published: May 2021

Abstract

Background
Reactive therapeutic drug monitoring (TDM) is routinely used in managing secondary loss of response to anti-TNF agents. Proactive TDM use has been associated with better clinical outcomes but its use in routine practice is still controversial. We aimed to investigate whether using proactive TDM strategy will result in higher mucosal healing and clinical remission rates.

Methods
After review of electronic case files, all patients that received anti-TNF treatment for active disease from 01.01.2017-01.02.2021. and responded to induction were included. Patients starting treatment for postoperative prophylaxis were excluded from the study. In the proactive group TDM was performed in week 14 and patients with subtherapeutic trough levels were dose optimized and underwent subsequent TDM measurments until the target trough level was reached. In the reactive group TDM was performed in the case of loss of response. Mucosal healing was defined as SES CD 3 for patients with CD and Mayo endoscopic score of £ 1 for UC patients. Clinical remission after 52 weeks was defined by the attending physician.

Results
A total of 161 IBD patients were included, 109 patients with CD and 52 patients with UC. There were 69 patients in the proactive group and 92 patients in the reactive group. No significant difference regarding age at diagnosis, age at treatment initiation, disease duration , prior immunomodulator use and time do endoscopy was observed between groups. A higher proportion of patients in the proactive group achieved mucosal healing but the difference between groups was not significant in the total cohort (proactive 52.4% vs reactive 42.2%; p=0.250). A significantly higher proportion of CD patients (n=109) in the proactive group achieved mucosal healing compared to the reactive group (56.8% vs 34.8%; p=0.039). No significant difference in mucosal healing rates between the groups was observed in UC cases. No significant difference in clinical remission rates was observed between the proactive and reactive group in the total cohort, CD and UC patients respectively.

Conclusion
Proactive TDM strategy is a valuable tool in managing CD patients resluting in higher rates of mucosal healing. Further studies are needed to define the optimal timepoints for proactive TDM.
P551 Lack of adherence to infliximab in inflammatory bowel disease patients contributes to loss of response in Crohn’s disease
Authors: Ferreiro Iglesias R , Gonzalez-Lopez J , Calvino-Suarez C , Mauriz-Barreiro V , Baston-Rey I , Cruz R , Dominguez-Munoz J E , Barreiro-de Acosta M 
Published: May 2021

Abstract

Background
Lack of adherence in patients with inflammatory bowel disease (IBD) is a relevant problem in our clinical practice. Non-adherence to anti-TNF increases healthcare costs. The aim of this study was both to measure adherence and also to study the factors and consequences related to non-adherence in patients with IBD under maintenance treatment with infliximab (IFX).

Methods
A prospective, observational cohort study was designed and patients with IBD under treatment with IFX were consecutively included. Adherence was measured with pharmacy refills and Morisky Medication Adherence Scale-8 (MMAS-8). Patients were systematically asked about adherence and the mean displacement days, the accumulated delay, the mean delay and the medication possession ratio (MPR) were calculated. MPR was calculated by dividing the number of days supplied within the refill interval by the number of days in the actual refill interval over 24 months. Potencial risk factors for non-adherence were evaluated: age, gender, disease duration, site of disease, behaviour of Crohn’s disease (CD), smoking status, educational level, marital status, type of housing, extraintestinal manifestations, previous surgery, concomitant treatments, anxiety and depression. Relapse was defined as a Harvey Bradshaw score &gt; 4 in CD and a partial Mayo &gt; 2 in ulcerative colitis (UC). The Mann-Whitney Wilcoxon U Test was used to distinguish the intergroup differences. Correlations were evaluated with Spearman rank correlation coefficients.

Results
Ninety patients with mean age 46 years (range: 22–85) were included. 49 (54.4%) were women and 63 (70%) had CD. Anxiety occurred in 38.9% of patients and depression in 78.9%. Three quarters of the patients were in clinical remission at inclusion. After 24 months of follow-up, 82 (91.1%) had delayed some dose of treatment, 35 (38.9%) had delayed on at least 7 days some dose of treatment, and 11 (12.2%) had not received some of the scheduled doses. The MPR was 87% (range 46–100). Lack of adherence was related to loss of response to IFX in CD (p = 0.035), but not in UC (p=0.078). In UC, lack of adherence was related with anxiety (p=0.046). The Spearman’s correlation between older age and non-adherence was 0.53 (p=0.006) in UC and 0.1 (p=0.308) in CD.

Conclusion
Lack of adherence is related to loss of response to IFX in CD. Non-adherence to IFX is high and strongly associated with age in UC. Older patients with UC are more prone to lack of adherence.
P603 Patient characteristics and adverse effects in biologic treatment of Crohn’s Disease and Ulcerative Colitis: A nationwide Danish cohort study years 2015–2018
Authors: Bjørn Jensen C , Jarlov Jensen K , Wennerström C , Sommer K J , Burisch J , Petersen J 
Published: May 2021

Abstract

Background
Biological therapies have demonstrated effectiveness in the treatment of Crohn’s Disease (CD) and Ulcerative Colitis (UC), but comparative analyses of the various treatments remain limited.

Methods
Using Danish national registries, we performed a nationwide cohort study including all bio-naïve individuals diagnosed with UC or CD initiating treatment with infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ), golimumab (GOL), or ustekinumab (UST) during 2015–2018. The hazard ratios (HR) of hospitalization, surgery, and start of corticosteroid therapy were explored using Cox regression adjusted for health-related and socio-economic parameters at treatment initiation.

Results
More than 90% of 1,836 CD and 1,886 UC patients had IFX as first-line treatment. Patients with ADA, VDZ, UST or GOL as first-line treatment were older at diagnosis and start of biologic treatment. A larger proportion were women, had higher education, and had previously had IBD surgery.
We observed a higher risk of all-cause hospitalization (HR: 1.56 (95% CI: 1.16; 2.10)) among CD patients with ADA as first-line treatment compared to IFX. No risk difference was observed of IBD hospitalization, IBD related surgery, or use of corticosteroids between ADA- and IFX-treated CD patients. We observed no risk difference between ADA- and IFX-treated UC patients for any outcomes. For both CD and UC patients, analyses of VDZ were based on very low number of cases and the results were inconclusive. Analyses of GOL and UST were not possible because of low numbers.
Second-line treatment with VDZ compared to ADA among CD patients previously treated with IFX showed no risk difference of all-cause hospitalization (1.32 (0.91; 1.92)), IBD hospitalization (1.27 (0.68; 2.35)), IBD related surgery (1.41 (0.69; 2.85)), or use of corticosteroids (0.70 (0.27; 1.82)). Among UC patients, second-line VDZ was associated with an increased risk of IBD related surgery (1.94 (1.01; 3.71)), but not of all-cause hospitalization (0.77 (0.48; 1.24)), IBD hospitalization (0.75 (0.38; 1.46)), or corticosteroid use (0.92 (0.37; 2.28)) compared to ADA.

Conclusion
We observed increased risk of hospitalization among CD patients treated with ADA compared to IFX, and increased risk of IBD-related surgery in UC patients receiving VDZ as second line treatment compared to ADA. The differences in key baseline characteristics patients initiating biologic treatment with ADA, VDZ, UST or GOL compared to IFX might reflect differences in disease state, that justify deviations from treatment guideline. It should be further investigated if the associations are an effect of differences in treatment efficacy and safety or confounding by differences in disease state at treatment start.
P656 Epidemiology and outcomes associated with local surgical and intersphincteric ligation procedures for complex cryptoglandular fistulas: A systematic literature review
Authors: Iglay K , Bennett D , Kappelman M , Karki C , Cook S 
Published: May 2021

Abstract

Background
Studies suggest that complex cryptoglandular fistulas (CCF) are difficult to treat, resulting in higher intervention failure rates and functional disability. This systematic literature review (SLR) assessed the epidemiology of cryptoglandular fistula and outcomes associated with local, surgical and intersphincteric ligation procedures for treatment of CCF.

Methods
PubMed and Embase were searched to identify articles published in the past 5 years (2015–2020) relating to incidence or prevalence of cryptoglandular fistula and outcomes of surgical interventions for CCF (PROSPERO registration number CRD42020177732). Outcomes of interest included fistula closure/healing, recurrence, surgery failure, post-operative pain and faecal incontinence. The interventions included anal flap procedures, fistulectomy, fistulotomy, primary sphincteroplasty, modified Park’s technique, LIFT or BIOLIFT, and TROPIS. Two trained reviewers used pre-specified eligibility criteria to identify studies for inclusion and evaluate risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. Data were extracted for a range of variables, including study type and design, population, outcomes and limitations.

Results
In total, 148 studies were identified that met a priori eligibility criteria for all cryptoglandular fistulas and all intervention types. Of these, two reported incidence or prevalence of cryptoglandular fistulas and 18 reported outcomes for the interventions of interest in CCF. Prevalence of cryptoglandular fistulas was reported as 1.35 per 10 000 patients without Crohn’s disease, and 52.6% of patients without IBD were found to progress from anorectal abscess to fistula over 12 months. Studies examining the clinical outcomes reported primary healing rates of 57.4–100.0%, recurrence rates of 4.9–61.0% and failure rates of 2.8–18.0% of patients. Only five studies reported post-operative pain as a clinical outcome. Overall, these studies suggest patients experience no or minimal longer-term post-operative pain. In studies reporting post-operative faecal incontinence following anal mucosal flap procedures, observed incontinence rates were low, as measured using Wexner or Miller scoring. None of the studies involving fistulectomy measured faecal incontinence.

Conclusion
This SLR provides a summary of outcomes from a selected group of surgical interventions for CCF. Healing rates vary according to surgery type; however, differences in study design and heterogenous definitions prevent direct comparison. Overall, the published literature indicates low to modest rates of CCF recurrence and limited data on faecal incontinence and longer-term post-operative pain.
Sponsor: Takeda Pharmaceuticals USA, Inc.
P669 Effect of vedolizumab therapy on whole blood transcriptional profiles in patients with Inflammatory Bowel Disease
Authors: Haglund S , Söderman J , Almer S 
Published: May 2021

Abstract

Background
Vedolizumab (VDZ) is one of many new biological drugs used in patients with inflammatory bowel disease who fail more conventional therapy. Despite proven efficacy, subgroups of patients show limited clinical benefit from VDZ. Here, we hypothesized that differences in clinical response to VDZ therapy might be reflected in changes in gene expression in whole blood which potentially could serve as easy accessible candidate biomarkers.

Methods
Transcriptional profiles of 20 patients (Crohn’s disease 13, ulcerative colitis 7) were established by sequencing of RNA isolated from stabilized whole blood collected at baseline (T0), and at follow-up at week 10–12 (T1) following three infusions of VDZ. Clinical response was defined as a decrease of &gt; 3 in the simplified Harvey Bradshaw Index or in the Simple Clinical Colitis Activity Index at T1 compared with T0. Differently expressed genes were identified by using the R packages Rsubread, edgeR and limma with hg38 as reference genome. Pathway analyses were done by gene set enrichment analysis (GSEA, Broad Institute) using Reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Routine laboratory parameters were obtained.

Results
Overall, two genes were down-regulated (IGLV2-23 &gt; 2-fold) and four genes were up-regulated (ADAMTS5 &gt; 2-fold) at follow up (FDR &lt; 0.05). This was attributed to regulation in responders (n=9), but not in non-responder (n=11). In responders, 55 genes were down-regulated (25 genes &gt; 2-fold, e.g. IGHV3-74) and 146 genes were up-regulated (8 genes &gt; 2-fold, e.g. OLFM1) at T1 vs. T0. However, at T0 there were no differences between responders and non-responders suitable as predictive biomarkers. Nevertheless, 89 KEGG pathways were differently enriched between study groups at baseline, and up to 44 pathways within the groups when studying the transcriptional profiles over time (FDR &lt; 0.075). The plasma-concentration of VDZ was not associated with the clinical outcome, and was not correlated with the dose of VDZ (mg/kg bodyweight).

Conclusion
There is a strong need for reliable and predictive biomarkers in decision making for personalised medicine. Our study shows that VDZ affects the transcriptional profile in blood of patients responding to treatment, whereas no gene regulation was noticed in non-responders. It also suggests that whole blood is not optimal for identifying predictive pre-treatment biomarkers based on individual genes in patients with need for this integrin inhibitor. However, treatment outcome may depend on several interacting genes, illustrated by the identification of significant pathway differences between study groups, both at baseline (T0) as well as in response to treatment (T1). Further studies are needed to confirm our findings.
P670 Identification of two additional susceptibility loci for Crohn’s disease in Koreans
Authors: Lee H S , Jung S , Ye B D , Baek J , Park D , Park S H , Yang S K , Song K 
Published: May 2021

Abstract

Background
Genome-wide association studies (GWAS) have identified more than 240 susceptibility loci associated with IBD mainly in Caucasians, however, there are limited studies in other populations.

Methods
To identify additional susceptibility loci in Asians, we expanded our previous study design (comprising a total of 1,621 patients with Crohn’s disease [CD] and 4,419 controls), followed by replication in an additional 582 patients with CD and 845 controls. To determine biological processes associated with candidate genes for CD, we conducted pathway analyses by MAGMA using the results obtained through the current meta-analyses and the summary statistics of the largest meta-analysis in the European population as input.

Results
The meta-analysis of Korean GWAS identified two novel susceptibility loci for CD at rs2240751 in the MFSD12-C19orf71-FZR1-DOHH region on 19p13 (pcombined = 3.03 × 10–8) and rs6936629 in the RFX6-GPRC6A-FAM162B region on 6q22 (pcombined = 3.63 × 10–8), of which rs6936629 showed significant association in European population (p = 1.88 × 10–4). Comparisons of the top 10 pathways for CD between the Korean and European data showed that MHC class Ⅱ protein complex, antigen binding, and response to antigenic stimulus-related pathways were more significant in the Korean population (Figure 1A), whereas cytokine and transcription factor-related pathways were more significant in the European population (Figure 1B).

Conclusion
Our findings provide additional biological insight into CD pathogenesis and support the importance of studying IBD genetics in diverse populations.
P679 The keystone bacterium Christensenella minuta improves colitis in in vivo preclinical Inflammatory Bowel Disease models
Authors: Kropp C , Le Corf K , Relizani K , Tambosco K , Martinez C , Chain F , Rawadi G , Langella P , Claus S , Martin R 
Published: May 2021

Abstract

Background
There is increasing evidence that microbiome-based therapies can correct dysbiosis and reduce inflammation associated with Inflammatory Bowel Diseases (IBD). In particular, the human commensal family of Christensenellaceae bacteria has been reported as missing in several cohorts of Crohn’s disease patients, indicating that it may have a role in maintaining microbial symbiosis in this population. To assess its potential for IBD management, we used the reference type species Christensenella minuta DSM 22607 to examine its anti-inflammatory properties.

Methods
We first performed two distinct independent preclinical colitis models: i) a moderate DNBS-induced colitis model in mice and ii) a severe TNBS-induced colitis model in rats. To decipher the mechanisms of action of C. minuta underlying the observed effects, we determined its ability to produce short chain fatty acids (SCFA) at different growth phases and we assessed its capacity to modulate the inflammatory response of human colonic cells.

Results
Our results showed that in both rodent models, C. minuta prevented intestinal damages by decreasing macroscopic scores, reduced colonic inflammation by limiting neutrophils infiltration in the colon and stimulated mucosal healing. We also confirmed that C. minuta is a high acetate and moderate butyrate producer. Finally, we showed that C. minuta displayed potent anti-inflammatory properties by decreasing the secretion of the pro-inflammatory cytokine IL-8 through NF-kB inhibition in HT-29 cells.

Conclusion
Together, these results revealed for the first time the strong anti-inflammatory properties of C. minuta and confirm its high potential as an innovative microbiome-based biotherapy for IBD.
P682 Antibiotic resistome profiles of fecal Escherichia coli isolates in association with Crohn’s disease
Authors: Siniagina M , Markelova M , Boulygina E , Laikov A , Khusnutdinova D , Abdulkhakov S , Grigoryeva T 
Published: May 2021

Abstract

Background
In recent years, there was a growing interest in the modulation and manipulation of the intestinal flora to treat patients through fecal microbiota transplantation (FMT). Unfortunately, 2 cases of bacteremia via FMT in 2019 occurred in patients due to extended-spectrum beta–lactamase–producing E. coli from the same stool donor. However, one of the recipients did not get an active infection. So, the association between health status and bacterial ability to resist chemicals requires further investigations.

Methods
Totally, 63 E. coli strains from 32 fecal samples (14 CD patients and 18 controls) were whole-genome sequenced on the Miseq platform (project #0671-2020-0058). The strains were tested against 15 antibiotics by a disc-diffusion assay according to EUCAST guidelines. E. coli ATCC 25922 was used as a control. Antibiotic resistance genes were predicted by the Resistance Gene Identifier and CARD database.

Results
All strains tested were susceptible only to meropenem (Figure 1). The proportion of multidrug-resistant strains in CD patients and controls did not differ significantly. Strains from both groups differed in sensitivity to amikacin and levofloxacin (Fisher’s exact test, p&lt;0.1). Ciprofloxacin, widely used in therapy, was less effective against CD-derived strains (15%) compared to controls (3%). The inefficiency of fluoroquinolones could be due to plasmid-associated genes (qnrS1, qnrB19) and mutations in chromosome genes (gyrA, parC). Several strains carried aminoglycoside transferase genes, but only 1 CD-derived strain was non-sensitive. Susceptibility to tetracyclines did not differ between groups, and almost all strains, growing on the antibiotic, contained efflux pump genes (tetA, tetB, tetD, tetR). About half of the strains from both groups were active against penicillins carrying genes for class A (TEM-1, TEM-150) and D beta-lactamases (OXA-1). TEM-150 was only in control strains. Cephalosporin-resistant strains were in both groups and harbored AmpC type β-lactamases. Almost all strains had multidrug efflux systems (MdtEF-TolC, EmrAB-TolC, EmrKY-TolC, AcrAB-TolC), MdtG and AcrD efflux pumps, and their regulators. Although all strains contained pmrF and pmrC genes, only 1 CD-derived strain was non-sensitive to polymyxin.

Figure 1. Antibiotic resistance of E. coli strains (in %, * - p &lt; 0.1)

Conclusion
Thus, the differences in susceptibility between CD- and control-derived strains were revealed. However, E. coli strains from healthy subjects contained antibiotic resistance genes and demonstrated activity against antibiotics of various categories, which might be crucial and should be taken into account for a safe and effective therapy in the treatment of CD.
Randomized Controlled Trial Substudy of Cell-specific Mechanisms of Janus Kinase 1 Inhibition With Upadacitinib in the Crohn’s Disease Intestinal Mucosa: Analysis From the CELEST Study
Authors: Aguilar Daniel , Revilla Lluís , Garrido-Trigo Alba , Panés Julian , Lozano Juan J , Planell Núria , Esteller Miriam , Lacerda Ana P , Guay Heath , Butler James , Davis Justin Wade , Salas Azucena 
Published: May 2021

Abstract

Background
Janus kinase (JAK) inhibition shows promise for treatment of patients with moderate to severe Crohn’s disease. We aimed to provide mechanistic insights into the JAK1-selective inhibitor upadacitinib through a transcriptomics substudy on biopsies from patients with Crohn's disease from CELEST.

Methods
Seventy-four patients consented to this optional substudy. Ileal and colonic biopsies were collected during endoscopy at screening and week 12 or 16. RNA isolated from 226 samples was analyzed by RNAseq, with additional qPCR analysis. Additional biopsies from patients with Crohn's disease receiving anti-tumor necrosis factor (anti-TNF; n = 34) and healthy controls (n = 10) were used for qPCR. Single-cell RNAseq public profiles were used to evaluate treatment effects on specific cellular subsets, associations with endoscopic improvement, and indirect comparisons with the anti-TNF-treated cohort.

Results
In involved areas of mucosa with endoscopic remission after upadacitinib treatment, 1156 and 76 protein-coding genes were significantly regulated (false discovery rate &lt; 0.05) at week 12/16 in colonic and ileal biopsies, respectively (60 overlapped), compared with baseline. Upadacitinib did not significantly affect transcriptomes of noninvolved intestinal areas. CELEST patients (mostly anti-TNF-refractory) showed baseline differences in gene expression compared with a separate cohort of biologic-naïve patients. Notably, upadacitinib reversed overexpression of inflammatory fibroblast and interferon-γ effector signature markers.

Conclusions
Upadacitinib modulates inflammatory pathways in mucosal lesions of patients with anti-TNF-refractory Crohn's disease, including inflammatory fibroblast and interferon-γ-expressing cytotoxic T cell compartments. This substudy is the first to describe the molecular response to JAK1 inhibition in inflammatory bowel disease and differential effects relative to anti-TNF treatment. (Clinical trial identifier: NCT02365649)