bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP43 Impact of Inflammatory Bowel Diseases on the phenotype and severity of psoriasis and spondyloarthropathies
Authors: Attauabi M , Damsgaard Wewer M , Bendtsen F , Seidelin J B , Burisch J 
Published: May 2021

Abstract

Background
It is unclear whether inflammatory bowel diseases (IBD) affect the phenotype and severity of co-occurring axial spondyloarthropathies (axSpA) and psoriasis. Therefore, we aimed to investigate the characteristics of axSpA and psoriasis in relation to co-occurring IBD.

Methods
The systematic review and meta-analysis were conducted according to Cochrane’s recommendations. PubMed and EMBASE were searched from database inception till January 2020 for studies reporting disease phenotype and severity of axSpA and psoriasis in association with co-occurrence of IBD. Meta-analyses were performed using a random-effects model. Quality of the studies was assessed by the Newcastle-Ottawa Scale (NOS).

Results
The electronic search yielded 12,220 studies which were narrowed down to 152 after screening based on study titles and abstracts. Of these, a full-text review identified 20 eligible studies, including twelve and eight studies describing characteristics of axSpA and psoriasis, respectively, in relation to IBD.
AxSpA was identified among a total of 321 and 8,660 patients with and without a co-occurring IBD, respectively, and the studies’ mean NOS score was 6.8, including seven and five studies of moderate and high quality, respectively. The meta-analysis demonstrated that presence of co-occurring IBD was associated with an increased risk of dactylitis (risk ratio (RR)=2.06 (95%CI 1.24–3.42), I2=0%), but not enthesitis (RR=0.93 (95%CI 0.48–1.81), I2=86%). Furthermore, IBD was associated with a significantly lower Bath Ankylosing Spondylitis Radiology Index (mean difference (meandiff) -2.28 (95%CI -3.26-(-1.30)), p&lt;0.01, I2=0%), better Schober’s test results (meandiff 0.80 (95%CI 0.64–1.49), p&lt;0.01, I2=0%), and a lower finger to floor distance (meandiff -6.36 (95%CI -10.36-(-2.36)), p&lt;0.01, I2=0%).
The phenotype of psoriasis was assessed among 680 and 222,279 patients with and without a co-occurring IBD. The mean NOS score was 7.4, including two studies of moderate methodological quality, while the remaining six studies were of high quality. The presence of IBD was associated with a significantly less frequent presentation of psoriasis in the nails (RR=0.14 (95%CI 0.05–0.42), I2=0%) but not psoriatic arthritis (RR=0.94 (95%CI 0.27–3.31), I2=75%). Finally, the presence of IBD was associated with a milder phenotype of psoriasis (RR=1.41 (95%CI 1.02–1.96), p=0.04, I2=70%).

Conclusion
This is the first systematic review with meta-analysis investigating the impact of IBD on the disease phenotype and severity of psoriasis and axSpA. Our data suggest that IBD modifies psoriasis and axSpA to be milder and emphasizes the importance of a multidisciplinary approach to patients with psoriasis or axSpA and co-occurring IBD.
DOP46 Sustainability rate of immunomodulators monotherapy in patients with Crohn’s Diseases: A population-based analysis from the epi-IIRN cohort
Authors: Atia O , Friss C , Mendelovici A , Shteyer E , Yogev D , Ledderman N , Greenfeld S , Kariv R , Loewenberg Weisband Y , Gabay H , Nevo D , Matz E , Dotan I , Turner D 
Published: May 2021

Abstract

Background
Immunomodulators (IMM), including thiopurines and methotrexate (MTX), have been long used to maintain remission in Crohn’s disease (CD), both associated with remission, but also with toxicity and therapeutic failure. We aim to compare the sustainability of thiopurines and MTX commenced as monotherapy in patients with CD, and to explore predictors of sustainability.

Methods
This study was performed on data from four Health Maintenance Organizations (HMOs), covering 98% of the Israeli population. We included all biologic-naïve CD patients diagnosed after 2005 and treated with IMM monotherapy for at least three months. Sustainability was defined as continues IMM treatment without switching therapy, adding biologics or requiring surgery. In addition, at most one short steroid course was allowed. Cox regression model was used to explore estimated predictors to sustainability. To compare sustainability rate between thiopurines and MTX we used propensity score (PS) matching, and thereafter Cox regression model.

Results
A total of 4,891 (1,551 [32%] pediatric-onset and 3,340 [68%] adults) IMM-treated patients were included with 37,825 person-years of follow up, of whom 4,339 (89%) were treated with thiopurines and 552 (11%) with MTX. The median time from CD diagnosis to initiation of IMM was 6.1 months (IQR 1.7–19.7), and the median course duration was 11.9 months (6.1–25.3). Sustainability rate was recorded in 92% of patients after 6 months from initiation of IMM and 81%, 69% and 65% at one, three and five years, thereafter. The most common type of failure was escalation to biologics (67%), while 17% required repeated steroid courses and 15% underwent surgery. Sustainability was associated with earlier initiation of IMM during the disease course (HR 0.98 [95%CI 0.97–0.985]) and lack of steroids at initiation of IMM (HR 0.7 [95%CI 0.6–0.8]). A PS adjusted analysis that included 337 thiopurnes-treated patients individually matched with 337 MTX-treated patients, showed sustainability was significantly better with thiopurines (HR 0.7 [95%CI 0.5–0.8]).

Conclusion
Two thirds of biologic-naïve CD patients treated with IMM monotherapy sustain this treatment after five years, especially when initiated early during the disease course. Sustainability was more likely in those treated with thiopurines compared with MTX.
DOP71 Fungal and bacterial gut microbiota in paediatric onset Inflammatory Bowel Disease introduced to infliximab
Authors: Ventin-Holmberg R , Höyhtyä M , Saqib S , Korpela K , Nikkonen A , Salonen A , de Vos W M , Kolho K L 
Published: May 2021

Abstract

Background
Paediatric Inflammatory Bowel Disease (PIBD), including Crohn’s Disease (CD), Ulcerative Colitis (UC) and IBD undefined (IBDU) is increasing worldwide and is characterized by an onset inflammation in the gastrointestinal tract. The patients may present severe symptoms such as abdominal pain, diarrhoea and bloody stool. No defined pathogenesis has been established for PIBD, but an imbalanced intestinal microbiota is strongly associated to the disease. Anti-tumour necrosis factor alpha (TNF-α) is an effective drug to treat inflammation in IBD, but up to half of the patients do not have a long-term response to the drug. Presently, there are no methods available to predict the TNF-α response. Here we have investigated the biomarkers of the gut fungal and bacterial microbiota, which are largely unexplored in paediatric patients, particularly for the fungal microbiota, with the aim to find possible predictors of drug response.

Methods
The gut microbiota composition of 30 PIBD (25 CD, 2 UC and 3 IBDU) patients at the Children′s Hospital, University of Helsinki receiving the anti-TNF-α drug infliximab (IFX) was studied by MiSeq sequencing targeting the bacterial 16S rRNA gene and fungal ITS region separately from faecal samples collected before the start of treatment and two and six weeks after treatment initiation. The response to IFX was evaluated by a faecal calprotectin value below 100 µg/g at week six after treatment initiation. The fungal MiSeq sequencing data was processed by using the DADA2 pipeline, annotated to the BLAST database and analysed using the package mare. The bacterial MiSeq sequencing data was analysed using mare and annotated to the SILVA database.

Results
Both the fungal and bacterial microbiota differed significantly between responders compared to non-responders to IFX, further validated by high predictive power (area under curve &gt; 0.8) for therapy response. This difference was characterized by an increase in short-chain fatty acid producing bacteria, such as bacteria in the class Clostridia in the responders at baseline. This was observed as elevated Faecalibacterium and Subdoligranulum genera in particular of responders at baseline. Additionally, Candida was increased while Saccharomyces was decreased in non-responders at the end of the study. Finally, we observed that the interkingdom correlations differed between response groups to IFX.

Conclusion
Our results strengthen the proposal that the gut microbiota composition of PIBD patients could predict the response to anti-TNF-α treatment in the future.
P037 Nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion properties of MORF-057 support its clinical development as an oral selective α4β7 integrin inhibitor
Authors: Jones J , Lee D , Smukste I , Cui D , Bursavich M G , Troast D , Zhong C , Wong J E , Mangada M M , Bain G , Lippa B , Ray A S , Rogers B N 
Published: May 2021

Abstract

Background
MORF-057 is a potent and selective small molecule inhibitor of the α 4β 7 integrin. Using a receptor occupancy (RO) assay under physiologically relevant conditions, MORF-057 achieves 90% α 4β 7 RO at approximately 10 nM in human whole blood. The current studies evaluate nonclinical pharmacokinetics (PK) and properties of absorption, distribution, metabolism, and excretion (ADME) to enable dose/exposure projection to humans.

Methods
PK studies were conducted in mouse, rat, dog, and monkey following intravenous (IV) and oral administration. ADME studies were conducted in vitro and in rats using carbon-14 [14C] labeled MORF-057. MORF-057 levels were quantified using liquid chromatography coupled with tandem mass spectrometry. Human PK was predicted based on body weight allometry, well-stirred and semi-physiological models.

Results
MORF-057 exhibited low to moderate clearance (CL) in animals with species dependent volume of distribution (Vdss) resulting in half-lives of 1.1 to 2.7 hours (Table 1). Following an oral dose, absorption was high with bioavailability ranging from 15% to 49%. MORF-057 is highly protein bound and distribution of [14C]MORF-057 derived radioactivity in rat was predominantly in the small intestine wall, liver, and stomach wall. Rifampin, an inhibitor of organic anion transporting polypeptides, decreased MORF-057 clearance by 3-fold in monkeys suggesting MORF-057 elimination involves hepatic uptake transport. MORF-057 is further cleared via CYP3A metabolism followed by biliary/fecal elimination of metabolites. MORF-057 is predicted to have moderate bioavailability (40%) and CL (6.5 mL/min/kg) in humans. Wajima transformation shows good agreement of the normalized PK across animal species, with a predicted human concentration-time profile supporting &gt;90% α 4β 7 RO at trough following 200 mg twice daily dose (Figure 1).

Conclusion
These data demonstrate that MORF-057 is well absorbed and PK properties in animals support the potential for achieving high α4β7 RO following oral administration in humans. These nonclinical results provided a basis for the progression of MORF-057 into a first-in-human Phase 1 clinical study assessing safety, pharmacokinetics, and receptor occupancy (results being reported separately).
P057 CRL4DCAF2 promotes cell proliferation and limits the development of colitis
Authors: Wang C , Yao L , Zhang Y , Cao Q 
Published: May 2021

Abstract

Background
Ulcerative colitis (UC) is an idiopathic intestinal inflammatory disease, which leads to chronic intestinal mucosal barrier damage. More and more evidences show that ubiquitination of proteins regulates the occurrence and development of intestinal inflammation. DCAF family proteins could form E3 ubiquitin ligase with CRL4-DDB1 to regulate cell growth, differentiation, apoptosis and other life activities. CRL4DCAF2 is a crucial regulator in cell cycle regulation, but there are few studies on its application in intestinal epithelium. This study aims to explore the specific mechanism of CRL4DCAF2 in regulating the proliferation and repairment of intestinal epithelial cells.

Methods
DSS - induced colitis in mice was used as the experimental model in vivo. HCT116 and SW480 cell lines were used as experimental models in vitro studies.The Cre-loxP system was used to construct a mouse model of intestinal epithelium-specific DCAF2 knockout. The intestinal mucosa biopsy specimens of 11 normal patients and 11 UC patients were collected. In addition, qRT-PCR, Western blot, RNA-seq and immunofluorescent staining were used to detect the expression levels of target genes in human colon biopsy specimens, mouse colon tissues, HCT116 or SW480 cells

Results
DCAF2 gene was highly expressed in the colon of mice. The occurrence and development of DSS-induced experimental colitis was accompanied by a significant down-regulation of DCAF2 protein expression in colon. DCAF2 mRNA level was significantly decreased in UC patients. Mouse with intestinal epithelial-specific knockout of DCAF2(i.e. DCAF2IEC-KO) suffered from embryonic death. Compared with wild-type adult C57BL/6J mice, DCAF2IEC-KD mouse showed more severe intestinal inflammation in DSS-induced colitis model. CCK-8 test, PI staining and EDU staining flow cytometry experiments showed that the proliferation of intestinal epithelial cells with DCAF2 overexpression was faster than that of the control (P &lt; 0.05) in HCT116 and SW480 cell lines, while in knockdown of DCAF2 models, the opposite results were obtained. Its effect may be related to the ubiquitination of p21. At the same time, MLN4924 in vivo and in vitro experiments further verified our experimental results. Combined with RNA-seq and Western blot, we also found that DCAF2 may reduce the symptoms of colitis by maintaining the stability of autophagy.

Conclusion
DCAF2 is low expressed in patients with ulcerative colitis, which may promote the activation and proliferation of intestinal epithelial cells. It could maintain autophagy stability, and restore intestinal barrier, thus alleviate the development of ulcerative colitis
P144 Clock gene expression levels inversely correlate with disease activity in ulcerative colitis and Crohn’s disease
Authors: Weintraub Y , Cohen S , Chapnik N , Anafy A , Yerushalmy-Feler A , Ben-Tov A , Dotan I , Riva T , Froy O 
Published: May 2021

Abstract

Background
Pathophysiological mechanisms active in inflammatory bowel disease (IBD), such as mucosal barrier repair, innate and adaptive immune responses, intestinal motility and gut microbiome, all exhibit diurnal variations. Chronic disruption of the molecular clock augment inflammatory response. We have shown that newly diagnosed, naïve to treatment, young IBD patients showed reduced clock gene expression in both inflamed and non-inflamed intestinal tissues and in peripheral White Blood Cells (WBC). This reduction correlated with disease activity. Our aim in this study was to determine whether certain clock genes correlate with disease activity scores or inflammatory markers in Crohn’s disease (CD) vs. ulcerative colitis (UC).

Methods
17 patients with CD and 13 with UC, 8–22 years old, were recruited. Patients were evaluated upon diagnosis and during medical treatment. Disease activity scores, C-reactive protein (CRP) and fecal calprotectin (Fcal) levels were measured and WBC were analysed for clock gene (CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2) expression. Clock gene expression levels were correlated to disease activity scores (clinically active vs. remission), CRP levels (&lt;5 mg/l vs. &gt;5 mg/l) and Fcal levels (&lt; 250 μg/mg vs. &gt;250 μg/mg) in CD (21 samples) and UC (20 samples).

Results
In UC, BMAL (p&lt;0.008), CLOCK (p&lt;0.02), CRY1 (p&lt;0.002), CRY2 (p&lt;0.0009), PER1 (p&lt;0.003) and PER2 (p&lt;0.003) showed decreased expression when Fcal levels were &gt; 250 μg/mg. When compared with the clinical status and CRP levels, only BMAL1 showed reduced expression (p&lt;0.003 and p&lt;0.001, respectively). In CD, clinical status correlated with clock gene expression: CLOCK (p&lt;0.035), PER1 (p&lt;0.001) and CRY1 (p&lt;0.028) were reduced in active disease. CRP and Fcal did not correlate with clock gene expression.

Conclusion
Altered levels of certain clock genes were demonstrated in young CD and UC patients in exacerbation vs. remission. In UC, Fcal levels inversely correlated with all major circadian genes and partially with clinical status and CRP levels. In CD patients clock gene expression inversely correlated with clinical status.
P214 Faecal S100A12 as a non-invasive marker of inflammatory activity in pediatric Inflammatory Bowel Disease
Authors: Casertano M , Cenni S , Caprio A M , Oglio F , Pacella D , Miele E , Martinelli M , Staiano A , Strisciuglio C 
Published: May 2021

Abstract

Background
Calgranulin-C (S100A12) is a new faecal marker of inflammation that is potentially more specific for Inflammatory Bowel Disease (IBD) than calprotectin, since it is only released by activated granulocytes. In recent years it has been confirmed that the S100A12 has comparable sensitivity and specificity to fecal calprotectin (FC) in adult patients with IBD. The aim of our study was to evaluate concentration of faecal S100A12 and calprotectin (FC) to see which of the two tests best correlated to inflammation in IBD children.

Methods
Between September 2019 and March 2020, we prospectively enrolled all IBD pediatric patients, both Crohn’s Disease (CD) and Ulcerative Colitis (UC). Blood and faecal samples were collected in order to evaluate serological markers of inflammation, faecal S100A12A and FC. S100A12 and FC were determined by enzyme-linked immunosorbent assay (ELISA).

Results
One hundred seventeen consecutive children, 46 (39%) with CD and 71 (61%) with UC were enrolled in the study. The mean age was 14.6 years (range:5–18), 44% female. Twenty three children were in clinical relapse (20%). No significant differences in S100 A12A levels were found between the UC and the CD groups (mean ±ds 25 ±32mcg/ml vs 34 ±27 mcg/ml respectively, p=0.22).In the UC group we found a statistically significant correlation of both calprotectin and S100A12 with CRP (r=0.253, p=0.044 and r=0.252, p=0.040, respectively). In CD group we found that both calprotectin and S100A12 correlated with hemoglobin (r= -0.343, p=0,024; r=-0.401, p 0.008 respectively), hematocrit (r=-0.361, p=0,046; r=-0.434, p=0.015, respectively), fibrinogen (r=0.499, p&lt; 0,001; r=0.325, p =0.038, respectively), and white blood cells count (r=0.309, p=0.044; r=0.394, p=0.021, respectively). Moreover, in CD group, FC correlated with CRP (r=0.431, p=0.004) and erythrocyte sedimentation rate (r=0.430, p=0.004). Finally, S100A12 correlated with platelet count both in CD and UC group (r=0.351, p=0.021and r=0.254, p=0.038, respectively) IBD children in clinical relapse had higher values ​​of S100A12 and FC than patients in remission (66±47 mcg/ml vs 43±42 mcg/ml, p=0.05 and 260±192 mg/Kg vs 166±169 mg/Kg, p=0.046, respectively)

Conclusion
Our preliminary data show that both faecal S100A12 and FC are useful non-invasive biomarkers which reflect inflammatory activity of IBD children. Our future aim is to evaluate the correlation of S100A12 and endoscopic finding in order to further clarify its role in the diagnosis and the management of pediatric IBD.
P353 Pan-enteric capsule endoscopy enables assessment of mucosal healing after biologic treatment initiation in Crohn’s disease
Authors: Volkers A , Bosuyt P , de Jong J , D’Haens G , Löwenberg M 
Published: May 2021

Abstract

Background
Pan-enteric capsule endoscopy (pan-CE) visualizes the entire gastrointestinal tract and provides an attractive alternative to conventional ileocolonoscopy to evaluate luminal disease activity in Crohn’s disease (CD). An earlier study showed that pan-CE is feasible, safe and well tolerated by CD patients. The aim of the present study was to assess the Sensitivity TO measure Change (STOC) in mucosal disease activity using pan-CE in CD.

Methods
Patients with CD and active disease based on symptoms (i.e. Crohn’s disease activity index (CDAI) &gt;150) and inflammatory biomarkers (i.e. C-reactive protein (CRP) &gt;5 mg/L and/or fecal calprotectin (fCal) levels &gt;250 mg/kg) underwent pan-CE, using the second-generation Pillcam colon capsule, prior to and 8-12 weeks after treatment initiation with infliximab, adalimumab or vedolizumab. Luminal disease activity was assessed using the Crohn’s disease endoscopic index of severity (CDEIS) and the simple endoscopic score for Crohn’s disease (SES-CD), expanded with two segments for the jejunum and pre-terminal ileum. Sensitivity to detect mucosal change was assumed if the standardized effect size was &gt;0.8. Correlations between the evolution in CDAI, CRP and fCal with endoscopic activity scores before and after treatment initiation were calculated.

Results
Twenty-eight patients underwent pan-CE of whom two withdrew consent and four did not start biologic therapy. Twenty-two patients (78.6%) started biologic treatment and underwent pan-CE twice. Median duration between treatment initiation and pan-CE was 11 weeks (IQR: 9.8-12 weeks). Half of patients (11/22) were female and the median age was 24 years (IQR=22-38 years). The standardized effect size was 1.11 for CDEIS and 1.36 for SES-CD. Median CDEIS scores decreased from 6.8 (IQR=4.6-11.2) to 3 (IQR=0.9-6.0, p=0.01). Median SES-CD scores decreased from 15.5 (IQR=9.8-22.5) to 6 (IQR=2.8-11.3, p=0.001). SES-CD score per segment decreased significantly for colon segments, not for small bowel segments (figure 1). The difference in CDAI, CRP and fCal outcomes before and after treatment did not correlate with the change in CDEIS and SES-CD.

Conclusion
Pan-CE is useful to assess luminal disease activity in CD patients who embark on biological treatment. Pan-CE is sensitive to monitor mucosal healing outcomes and might therefore replace ileocolonoscopy for this indication in CD patients.