bluuebunny/crossref_metadata_2025_split huggingface dataset:
P799 Use of anti-TNF agents may reduce a risk of venous thromboembolism in Korean patients with inflammatory bowel disease: A nationwide population-based study from the National Health Insurance Database
Authors: Kim H M , Kim S Y , Kim H S , Lee J K , Park S H , Moon J S , Cho Y S , Kang D R 
Published: January 2020

Abstract

Background
Inflammatory bowel disease (IBD) has a risk of venous thromboembolism (VTE) compared with healthy controls, which justify prophylaxis in practice. There are few data on VTE in Asian IBD patients including Koreans. We aimed to investigate the incidence of VTE and the potential risk factors in Korean IBD patients.

Methods
A nationwide population-based cohort study was performed using claims data from the National Health Insurance service in Korea for 10 years, from 2006 to 2015. VTE, Crohn’s disease (CD) and ulcerative colitis (UC) were operationally defined by using ICD-10 codes, codes for Rare and Intractable Diseases registration, and pharmaceutical prescriptions for IBD-specific drugs. Control group was defined as age- and sex-matched health insurance subscribers without IBD for the same period. The hazard ratio (HR) for the risk of VTE was calculated after adjusting for covariates such as age, sex, rural area, comorbidities, Charlson Comorbidity Index (CCI), admission, and therapeutic drugs use for IBD using multivariate Cox proportional hazard regression.

Results
A total of 45,037 patients were diagnosed with IBD (13,850 CD and 31,187 UC), and 133,019 were defined as controls. VTE occurred in 411 (0.91%) in IBD, 106 (0.76%) in CD, and 305 (0.98%) in UC, whereas 641 (0.48%) in controls. In univariate analysis among IBD patients, old age (&gt;59 years: HR = 6.256), female sex (HR = 1.537), low income (HR = 1.3090), high CCI (&gt;3 score: HR = 4.053), steroid use (HR = 1.872), emergency care (HR = 1.513) and hospitalisation (HR = 1.352) significantly increased a risk of VTE. However, anti-TNF agent use (HR = 0.611) significantly decreased a risk of VTE. In multivariate analysis with adjustment among all subjects, CD (HR = 15.833) and UC (HR = 8.125) significantly increased a risk of VTE compared with controls.

Conclusion
Our study demonstrates that VTE is significantly high in Korean IBD patients compared with controls. In addition, old age, female sex, low income, high CCI, steroid use, emergency care, and hospitalisation are suggested as risk factors of VTE in IBD. Interestingly, use of anti-TNF agents may reduce risk of VTE, which should be considered for prophylaxis strategy suitable for Korean IBD patients.
P801 Treatment patterns of complex perianal fistula in Crohn’s disease in five European countries: the PREFACE study, a retrospective chart review
Authors: Ferrante M , Siproudhis L , Poggioli G , Reinshagen M , Milicevic S , Roset M , Thun B , Bent-Ennakhil N , D′Ambrosio R , Fernandez-Nistal A , Panes J 
Published: January 2020

Abstract

Background
Presence of fistulas in Crohn’s disease (CD) is an indicator of poor prognosis; 22.1% of CD patients suffer from fistulising disease1 with high variability in complex perianal fistula (CPF) prevalence2. There is limited information available about the management of CPF in a real-world setting. This study describes the treatment patterns of patients with CPF in CD in Europe.

Methods
Retrospective medical chart review of consecutive patients with CD receiving treatment for a new episode of CPF during the period (September 2011 to September 2014), in Belgium, France, Germany, Italy and Spain. Index date was defined as the date of treatment initiation for a new episode of CPF during the eligibility period. Data was collected from CD diagnosis to at least 3 years after index date (except for deceased or lost to follow-up patients) to describe patient characteristics and treatments used for all CPFs episodes since CD diagnosis.

Results
A total of 386 patients (51% female) were included with a mean (SD) age of 38 (13) and 10 (9) years since CD diagnosis. At CD diagnosis, 28% of patients had ileal, 29% colonic and 39% ileocolonic involvement; 24% of study patients had anal or perianal fistula. Prior to index date, 42% of patients had at least one surgery, being partial resection of small bowel the most common one. ASA-5, anti-TNFs and immunosuppressants were used for CD or complications in 47%, 48% and 42% of patients. Patients presented 584 CPFs during the study period. More than half of these CPFs were trans-sphincteric (60%). Out of the 584 CPFs, 92% were treated with at least one surgical intervention (most frequent: 56% long-term seton placement, 46% surgical drainage), and 86.6% with at least one medical treatment. Medical treatments most frequently used for CPFs or CD and complications (overlapping a CPF episode) were anti-TNFs (49%), antibiotics (44%) and immunosuppressants (26%).

Conclusion
Almost one fourth of the patients with CPF already had anal or perianal fistulas at CD diagnosis. Based on ECCO guidelines it was expected that almost all CPFs in CD patients should be treated with anti-TNF with or without surgical intervention. However, the use of anti-TNF during CPF episodes was lower than expected. Surgical drainage and seton placement were performed in a majority of patients in at least 3 years following treatment intensification, with a low rate of other types of surgery. Almost two third of CPFs were trans-sphincteric and if inadequately treated, sphincter function may be compromised.
P807 UCEIS is associated with PRO2, partial Mayo and SCCAI remission in UC: preliminary results from a prospective study
Authors: Golovics P A , Gonczi L , Reinglass J , Verdon C , Afif W , Wild G , Bitton A , Seidman E , Bessissow T , Lakatos PhD P L 
Published: January 2020

Abstract

Background
Optimal management of patients with ulcerative colitis (UC) requires the accurate assessment of disease activity. Endoscopic evaluation is considered the gold standard approach, but it is invasive. We aimed to determine the operating characteristics of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), to quantify the cut off most closely correlated with clinical remission or activity and determine agreement with the Mayo endoscopic subscore (MES), Baron score, clinical scores and biomarkers.

Methods
136 patients were included prospectively (age: 48 (IQR38-61) years, duration 12 (4–19)years, 63 females, 53.7% extensive disease, 40.4% on biologicals) at the time of the colonoscopy. Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Mayo endoscopic subscore (MES), Baron scores were calculated, as well as the2 item patient reported outcome (PRO), partial MAYO, Simple Clinical Colitis Activity Index (SCCAI). CRP and faecal calprotectin (FCAL) was available in 58.1 and 33.8% of patients. 20.7% had clinical flare, treatment was escalated in 17.8% of patients. ROC analysis and K-statistics were performed and Spearman’s correlation was calculated.

Results
UCEIS was strongly associated to PRO2 SF (AUC:0.866), RBS (AUC:0.921), PRO2 combined remission (AUC:0.905), partial MAYO (AUC:0.956) and SCCAI (AUC:0.907) remission in a ROC analysis. A UCEIS of ≤3 was identified as the best cut-off to identify RBS subscore of 0, or total PRO2 remission (RBS 0 and SF ≤1), partial MAYO (≤2) and SCCAI (≤2.5) remission, while a UCEIS≥4 identified active disease frequently needing change in medical therapy. A moderate agreement was found between UCEIS and MES (K=0.451) or Baron (K=0.499) scores. Correlation between FCAL and UCEIS (coeff:0.743, p &lt; 0.0001) was strong, while modest only with CRP (coeff:0.333, p = 0.01).

Conclusion
A UCEIS was strongly associated with clinical remission defined as PRO2, SF, RBS, partial Mayo or SCCAI with best agreement with RBS and partial Mayo remission. A UCEIS of ≤3 was identified as a cut-off for quiescent disease, while a UCEIS≥4 identified active disease, which can support clinical decision-making based on endoscopic findings. Agreement between UCEIS and FCAL was strong, while agreement with UCEIS and MES/Baron scores was moderate.
P814 Incidence and significance of fatigue in patients with IBD
Authors: Kokkotis G , Bekiari D , Bletsa M , Gizis M , Perlepe N , Athanasiou V , Kounadis G , Koutsounas I , Kolios G , Bamias G 
Published: January 2020

Abstract

Background
Fatigue is common in IBD patients, even in clinical remission and adversely affects the quality of life. For this reason, it has been suggested to use fatigue questionnaires as PROS (patient reported outcomes). We aimed to study the degree of fatigue in IBD patients and identify factors that are positively or negatively related to its presence.

Methods
Patients with IBD (men: 51.6%, Crohn’s Disease: 65.2%, age: 36.7 years median, 18.1–72 yrs range), with a regular f-up in our Department completed the Fatigue Severity Scale, IBD Fatigue self assessment 1 & 2, short IBDQ and Short Health Scale upon consensus. Two groups of patients were studied: Group A, patients attended the IBD outpatient clinic (121 patients / 144 questionnaires) and Group B, patients attended the infusion centre for biological therapy (55 patients / 414 questionnaires). The SPSS-23 statistical programme was used to identify correlations between fatigue and various clinical-laboratory parameters of patients.

Results
Problematic fatigue (FSS&gt; 36) was reported by 46.5% of patients. No difference was observed between Crohn’s disease and Ulcerative Colitis or between the two groups of patients. There were statistically significant correlations between fatigue and disease activity (R = 0.428, P &lt;0.001) and HGB (R = −0.177, p &lt; 0.001). Fatigue was significantly associated with quality of life based on the short IBDQ and SHS questionnaires (R = −0.655, p &lt; 0.001 and R = 0.485, p &lt; 0.001 respectively). There was also a statistically significant relationship of both fatigue and quality of life with parameters such as female sex (p &lt; 0.01), arthralgia (p &lt; 0.05) and biological agent treatment (p &lt; 0.05), while quality of life was statistically significant related with the disease type (P =0.01) too. Sequential measurements showed that the quality of life and fatigue rate were consistently maintained in patients with remission under biological therapy.

Conclusion
In the group of IBD patients we studied, a significant correlation with various clinical characteristics was observed. The presence of fatigue is a factor associated with poor quality of life for patients.
P816 Association of autoimmune rheumatic disease with inflammatory bowel disease: a nationwide population-based study
Authors: Baek D , Lee H S , Park S B , Song H K , Jang B I , Bae J H , Goong H J , Kang H S , Jung S H , Kim T O , Song G A , Park E Y 
Published: January 2020

Abstract

Background
Increasing evidence demonstrated that inflammatory bowel disease (IBD) has a shared genetic background with autoimmune rheumatic diseases (ARDs). However, the association between these two disease entities is not vigorously elucidated. The aim of this study is to investigate the prevalence and association between IBD and ARDs.

Methods
A nationwide population-based cross-sectional study was performed using the Korean National Health Insurance Claims database according to ICD-10 codes (Table 1). The prevalence of ARDs, including systemic lupus erythematosus (SLE), inflammatory myositis (polymyositis (PM) and dermatomyositis (DM)), systemic sclerosis (SSc), Sjogren’s syndrome (SjS), ankylosing spondylitis (AS), and rheumatoid arthritis (RA), was determined in patients with inflammatory bowel disease, compared with general populations.

Results
A total of 82,480 IBD patients (57,382 patients with ulcerative colitis and 25,098 with Crohn’s disease) were enrolled. The analysis revealed that patient with IBD had higher risk of being concomitantly affected by AS and RA (Table 2). Other ARDs, such as SLE, inflammatory myositis, SSc, and SjS were not associated with IBD.

Conclusion
This nationwide population-based study demonstrated that RA and AS showed higher incidence in IBD patients. This result suggests that etiopathogenesis of IBD might be shared with RA and AS.
P820 An easy and rapid targeted next generation sequencing-based genotyping assay for the validated IBD risk loci
Authors: Verstockt S , Hannes L , Deman S , Wollants W J , Souche E , Verstockt B , van der Werf I , Hoischen A , Ferrante M , Vermeire S , Cleynen I 
Published: January 2020

Abstract

Background
Inflammatory bowel diseases (IBD) are complex genetic diseases for which 242 susceptibility loci have been identified thus far. For translational or functional follow-up studies it can be of interest to know the genotype of specific variants. For other studies a composite genetic risk score–the polygenic risk score–is of value. There currently is a gap in technology to genotype a few hundred variants in a flexible and cost-effective way. We therefore developed a genotyping assay for the 242 validated IBD susceptibility loci.

Methods
Using MIPgen v.1.1, we designed molecular inversion probes (MIPs) covering 269 independent variants from the 242 IBD loci. MIP libraries were prepared according to Neveling et al. (Clin Chem. 2017), followed by paired-end sequencing using a MiSeq® System (Illumina). In the pilot studies, 16 IBD patients were genotyped, and results were compared with available immunochip (ichip) data. Genotypes for the covered variants were obtained using an in-house developed pipeline, and performance metrics were assessed (incl. genotyping call rate, percentage off-target reads and concordance with ichip-based genotypes). After optimisation, we genotyped 279 individuals (168 IBD patients and 111 non-IBD controls). We also calculated a weighted IBD polygenic risk score (PRSice 2.0) for these.

Results
Despite a genotyping call rate of 94.3%, the first pilot run suffered from a high rate of off-target reads (52.5%). After redesigning poorly-performing MIPs, off-target reads dropped to 9.4%, and the genotyping call rate increased to 97.5%. Concordance with genotypes previously obtained from ichip was 99.3%. When applying the optimised design on a larger scale (i.e. on the 279 individuals), we obtained similar performance metrics, with 8.0% off-target reads and a genotyping call rate of 97.3%. Moreover, upscaling resulted in a turnaround time of 2.5 working days/96 samples and a cost of €14/sample. The calculated IBD polygenic risk scores showed higher scores in patients as compared with controls (5.5E−03 vs. 4.0E−03, p = 8.80E−10; R² IBD polygenic risk score = 0.15, p = 1.28E−07), however with a large overlap between both groups. Quartile analysis showed that individuals within the highest quartile had an 8.1-fold (95% CI: 3.7–17.5) increase in risk towards IBD compared with individuals in the first quartile.

Conclusion
We developed a cost-effective genotyping assay for currently known IBD risk loci, with an integrated bioinformatics pipeline from raw sequencing data to individual genotypes and calculation of a polygenic risk score. Furthermore, this assay enables genotyping of individuals on a large scale while remaining flexible to implement newly identified genetic variants.
P822 Genetic analysis of ulcerative colitis in Japanese individuals using population-specific SNP array
Authors: Okamoto D , Kakuta Y , Takeo N , Moroi R , Kuroha M , Kanazawa Y , Hisashi S , Fuyuno Y , Umeno J , Hirano A , Torisu T , Nakamura M , Esaki M , Matsumoto T , Kinouchi Y , Masamune A 
Published: January 2020

Abstract

Background
Previous genome wide association studies (GWASs) have identified over 200 susceptibility loci for inflammatory bowel diseases (IBD), but studies in non-European population are limited. To clarify the genetic background of ulcerative colitis (UC) in the Japanese population, we conducted GWAS using a population specific SNP array (Japonica Array).

Methods
Discovery GWAS included 624 UC patients and 2004 healthy controls (HC) and replication study included 1075 UC patients and 419 HCs. We performed GWAS using a Japonica Array and the subsequent imputation with a Japanese population reference panel (referred to as 2KJPN). After GWAS, significant and candidate loci were identified and the representative top SNPs of each region were analysed in replication study and combined analysis. The probability of colectomy between genotypes of rs117506082, the top hit SNP at HLA loci, was analysed using the Kaplan–Meier method.

Results
In the GWAS, only the HLA loci showed genome wide significant association [rs117506082, p = 6.69E−28, OR=1.29, 95%CI=1.23–1.35]. 7 regions with nominal significance included 2 known loci: IL23R [rs76418789, p = 6.29E−7, OR=0.89, 95%CI=0.85–0.93], IRF8 [rs16940202, p = 1.03E−6, OR=1.07, 95%CI=1.04–1.10] and 5 novel loci: miR-622 [rs9560575, p = 8.23E−7, OR=1.06, 95%CI=1.04–1.09], 14q31 [rs117618617, p = 1.53E−6, OR=1.13, 95%CI=1.09–1.19], KAT6B [rs12260609, p = 1.81E−6, OR=1.06, 95%CI=1.04–1.09], PAX3-CCDC140-SGPP2 [rs7589797, p = 2.87E−6, OR=0.94, 95%CI=0.93–0.97], KCNA2 [rs118020656, p = 4.01E−6, OR=1.12, 95%CI=1.07–1.18]. Combined analysis revealed that the HLA loci [rs117506082, p = 1.10E−23, OR=3.43, 95%CI=2.99–3.83] and IL23R p.G149R [rs76418789, p = 9.03E−11, OR=0.51, 95%CI=0.42–0.63] had a genome wide significant association. The GG genotype of rs117506082 had a significantly lower probability for total colectomy compared with the GA+AA genotype (p = 1.72E−2).

Conclusion
IL23R p.G149R is a susceptibility locus for UC in Japanese individuals. The GG genotype of rs117506082 at HLA loci, a risk genotype for UC susceptibility, may predict a better clinical course.
P823 DNA methylation profiles accurately predict vedolizumab response and remain stable during induction and maintenance treatment in Crohn’s disease
Authors: Joustra V , Hageman I , Li Yim A , Gecse K , Lowenberg M , te Velde A , Satsangi J , de Jonge W , Henneman P , D’Haens G 
Published: January 2020

Abstract

Background
While the use of biologicals has revolutionised the treatment of Crohn’s disease (CD) in recent decades, many patients fail to respond or lose response over time. Predictors for treatment selection and/or success are lacking. Vedolizumab (VDZ) induces corticosteroid-free clinical remission in 29% and endoscopic remission in 36% of patients after 6 months. Accumulating evidence suggests that the epigenome, mainly DNA-methylation, is associated with certain CD phenotypes. Here, we investigated whether the DNA methylome of peripheral blood (PB) obtained from CD patients treated with VDZ was associated with clinical and endoscopic response or non-response to treatment.

Methods
We prospectively recruited CD patients scheduled to start VDZ treatment at regular dosage and who underwent baseline endoscopy. PB was collected prior to treatment (T1) and at a median of 14 weeks (T2) into treatment. Additionally, a third PB sample was collected after a median of 79 weeks (T3) into treatment for 10 CD patients. DNA methylation was measured using the Illumina Infinium Methylation EPIC BeadChip. After a median 27 weeks of treatment, patients were characterised as responders (R) or non-responders (NR) based on endoscopic changes (R= ≥50% reduction in SES-CD score) combined with either steroid-free clinical remission (≥3 point drop in HBI, no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein and faecal calprotectin).

Results
We analysed data of 16 R and 14 NR patients, 53% of which were female with a median age of 37. No significant differences in age, sex or smoking were observed between R and NR. All patients had measurable serum VDZ concentration at the second endoscopy. To identify response-associated biomarkers, we performed elastic net regression through repeated cross-validation. We identified 38 differentially methylated probes (DMPs) associated with response (Figure a), 7 of which were located in gene promoters. Performance-wise the DMPs displayed a sensitivity of 0.86 and a specificity of 0.8 in predicting response (Figure b). Notably, the degree of methylation for the response-associated DMPs did not change after 14 weeks of treatment (n = 30), or even after 79 weeks (n = 10).

Conclusion
Here, we show that the DNA methylome in peripheral blood is associated with response to VDZ. As the difference in methylation remained stable during induction and maintenance treatment with VDZ, inflammation did not appear to affect the response-associated DMPs. Our observations provide evidence towards the establishment of epigenetic marks with predictive biomarker capabilities, paving the road towards personalised treatment selection in CD.
P824 Molecular predictors of anti-TNF treatment response in patients with Crohn’s disease
Authors: WALCZAK M , Lykowska-Szuber L , Plucinska M , Michalak M , Krela-Kazmierczak I , Zakerska-Banaszak O , Stawczyk-Eder K , Eder P , Dobrowolska A , Slomski R , Skrzypczak-Zielinska M 
Published: January 2020

Abstract

Background
Anti-tumour necrosis factor (anti-TNF) therapy has revolutionised the treatment of Crohn’s disease (CD). These drugs induce clinical and mucosal remission with high effectiveness, however almost 20–40% of patients do not respond to initial treatment. The exact mechanism of primary non-response is still unknown. The aim of the study was to investigate the impact of genetic interindividual differences on patients’ response. This will allow to identify molecular predictors of variable reaction to anti-TNF treatment.

Methods
DNA samples were obtained from 107 diagnosed and clinically characterised CD patients following anti-TNF therapy, where 12 of patients were classified as nonresponders. Based on long-range PCR libraries and next-generation sequencing (NGS), a panel of 23 genes belonging to TNF superfamily, proinflammatory factors, apoptosis-related proteins, signal transmission factors and receptors was analysed. After NGS, bioinformatical and statistical analysis were performed.

Results
In total, 598 single-nucleotide variants (SNP) for all analysed targets were identified. Patients’ nonresponse was associated with genotypes in 12 following loci (p ≤ 0.05): rs1061624 (OR: 4.22; 95% CI: 1.33–13.34) in TNFRSF1B gene, rs7896789 (OR: 0.27; 95% CI: 0.09–0.78) in FAS gene, rs2041747 (OR: 0.17; 95% CI: 0.04–0.80) in IL1R gene, rs373184583 (OR: 0.29; 95% CI: 0.09–0.82), rs12128686 (OR: 0.29; 95% CI: 0.09–0.82), rs7539036 (OR: 0.31; 95% CI: 0.11–0.87) and rs6672453 (OR: 0.31; 95% CI: 0.11–0.87) in FCGR3A gene, rs1071676 (OR: 2.47; 95% CI: 1.04–5.85), rs1143639 (OR: 2.47; 95% CI: 1.04–5.85), rs1143637 (OR: 2.47; 95% CI: 1.04–5.85) and rs1143634 (OR: 2.47; 95% CI: 1.04–5.85) in IL1B gene as well as rs55790676 (OR: 2.64; 95% CI: 1.02–6.83) in ADAM17 gene.

Conclusion
Obtained results suggest that molecular changes in genes involved in TNF activity may play an important role in response to anti-TNF treatment and be useful as molecular markers indicating potential patients’ response. Additionally, these results may contribute to better understanding the mechanism of monoclonal antibodies action in IBD treatment.