bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP63 Efficacy and safety of iron carboxymaltose on chronic fatigue in patients with inflammatory bowel disease: a randomised controlled trial
Authors: Fiorino G , Allocca M , Gilardi D , Alfieri M , Danieli P , Furfaro F , Roda G , Loy L , Zilli A , Radice S , Peyrin-Biroulet L , Danese S 
Published: January 2020

Abstract

Background
Patients with inflammatory bowel diseases (IBD) have an altered quality of life, also due to chronic fatigue (CF). Iron administration is effective in iron deficiency associated with CF in patients with heart failure. Our hypothesis was that iron administration in patients with iron-deficiency could improve CF and quality of life in IBD patients.

Methods
This was a phase 2, randomised, placebo-controlled, double-blind trial. Adult patients with established IBD diagnosis in clinical remission (HB &lt;5; Mayo clinical score ≤2) from ≥ 6 months, CF symptoms (MFI-20&gt; 13), martial deficiency (ferritin &lt;100 µg/l, or &lt;300 µg/l if transferrin saturation&lt;20%), but not anaemia, were eligible. Patients were randomised to receive 200 mg of i.v. iron carboxymaltose (ICM) or placebo (PBO) every month up to 6 months. The primary objective was to compare the rate of patients in CF remission (Multidimensional Fatigue Inventory, MFI-20 &lt;13) between the 2 groups. Secondary objectives were CF response (MFI-20 decrease of ≥4 points, but MFI-20 total &gt;13) at week 24 and CF remission (MFI-20 &lt;13) at week 12. Evolution of anxiety and depression and change in the quality of life at weeks 4, 12 and 24 from baseline trough week 24 were also assessed. The calculated sample size was 36 patients (18 for each treatment arm).

Results
Forty-six patients were screened, 30 patients completed 24 weeks of treatment (21 Crohn’s disease, 9 ulcerative colitis). Baseline characteristics were not different among the two groups. Between patients treated with ICM vs. PBO, 2/15 patients vs. 0/15 respectively were in CF remission at week 24 (13% vs. 0%, p = 0.46). CF response was observed in 7/15 patients treated with ICM vs. 10/15 patients with PBO (47% vs. 67%, p = 0.46). At week 12, 1/17 vs. 0/17 patients were in CF remission (6% vs. 0%, p = 0.96), and 12/17 vs. 10/17 (71% vs. 59%, p = 0.90) showed CF response. At the study completion, ferritin restoration was found in 12/14 patients (86%) treated with ICM vs. 1/15 (7%) receiving PBO (p &lt; 0.001). No significant differences in terms of anxiety, depression and quality of life restoration were found between the two groups at week 12 and 24. A total number of 69 adverse events (AEs) were reported in 17 patients (37 mild, 31 moderate, 1 severe), only 5 were related to the study treatment (3 nausea, 1 gastric pain, 1 arthralgia), and only 1 (nausea) led to study drug discontinuation.

Conclusion
Intravenous ICM is not effective in treating CF in IBD patients, with no significant adverse events. ICM was more effective than PBO in restoring ferritin in the majority of IBD patients.

Funding
This study was funded by the ECCO Vifor Grant 2017.
DOP68 Thiomyristoyl ameliorates colitis by blocking the differentiation of Th17 cells via STAT3/IL-6 signal pathway
Authors: XU Y , zhang M , Xu G , Zou X 
Published: January 2020

Abstract

Background
The pathogenesis of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), has not been fully elucidated, but a strong correlation between IBD and the immune dysregulation of the host has been persistently detected. Sirtuin 2 (SIRT2), a histone deacetylase, has recently been found to play an important role in inflammation, infection and immunomodulatory. As a potent SIRT2-specific inhibitor, thiomyristoyl (TM) has an extensive anticancer activity, but its anti-inflammatory property remains unclear.

Methods
Human peripheral blood mononuclear cells (PBMC) were differentiated into T helper 17 (Th17) cells in vitro and were treated with TM simultaneously. Interleukin (IL)-17A in the culture supernatant, the ratio of T cells, the levels of phosphorylated-signal transducer and activator of transcription (p-stat3) and phosphorylated-nuclear factor kappa-B (p-NF κB) were determined by enzyme-linked immunosorbent assay (ELISA), flow cytometry or western blotting, respectively. Then, colitis C57BL/6J mice induced by 2.5% dextran sulphate sodium salt (DSS) were treated with TM, and were evaluated by disease activity index (DAI) and haematoxylin-eosin (HE) staining. T-cell subsets in the mice spleen, IL-6, IL-10 and IL-17A in serum, related factors retinoic acid receptor-related orphan receptor-γ t (ROR-γt), forkhead box protein P3 (FOXP3), IL-17A, interferon γ γ (IFN-γ), IL-23, IL-10 and hypoxia-inducible factor (HIF)-1α in mice colon were measured by flow cytometry, ELISA, quantitative real-time polymerase chain reaction (Q-PCR) and western blotting, respectively.

Results
Compared with the positive control group, the levels of IL-17A in culture supernatant, the percentage of Th17, the levels of p-stat3 and p-NF kappa B in cell lysate were lower in the TM group. Compared with PBS-treated colitis mice, TM-treated colitis mice had longer colons, fewer weight-losses, lower DAI and histopathologic scores. Interestingly, although the expression of IFN-γ, IL-17A, and ROR-γt was inhibited in the colons of TM-treated mice, the level of FOXP3 did not change. Consistently, the percentage of spleen Th17 cells was decreased in the TM group while the percentage of Treg cells was not affected. In addition, the TM group had reduced levels of IL-23 and HIF-1α, and an increased level of IL-10 in the colon, compared with colitis group.

Conclusion
TM ameliorates DSS-induced experimental colitis by blocking the differentiation of Th17 cells, which may be associated with the STAT3/IL-6 signal pathway. SIRT2 may represent a potential target for the treatment of IBD.
DOP76 Corticosteroid sparing effects of ustekinumab therapy for ulcerative colitis through 2 years: UNIFI long-term extension
Authors: Peyrin-Biroulet L , Sandborn W , Sands B , Scherl E , Marano C , O’Brien C , Zhang H , Johanns J , Zhou Y , Abreu M , Arasaradnam R P , Rowbotham D S , Leong R W L , Danese S 
Published: January 2020

Abstract

Background
Ustekinumab (UST) is an IL12/23 blocker approved for Crohn’s disease and ulcerative colitis (UC). In the UNIFI maintenance study of patients with moderate–severe UC, &gt;90% of the patients who achieved clinical response or remission at week 44 were able to eliminate corticosteroids, an important goal of therapy. In this analysis, we describe the corticosteroid (CS) sparing effects of UST treatment through week 92 among patients who were treated in the UNIFI long-term extension (LTE).

Methods
Responders to UST 8 weeks after IV induction entered the maintenance study and were randomised to UST 90mg SC (q12wks or q8wks) or PBO. Patients who did not respond to UST IV induction received a dose of UST 90mg SC at week 8 and were evaluated at week 16. Those in clinical response at week 16 (delayed responders), were not randomised on entry into the maintenance study and received UST 90mg q8wk. All patients who completed week 44 of the maintenance study were eligible to enter the LTE and continue to receive the same dose. Patients could receive UST dose adjustment during the LTE (q12wk to q8wk or q8wk to q8wk [sham dose adjustment]) from week 56 onward. Patients who remained on PBO were discontinued from the LTE after maintenance study unblinding. During the maintenance study, CS tapering was recommended for all patients receiving CS at maintenance baseline. At week 92 of the LTE, CS-free symptomatic remission rates and CS use were calculated using intention-to-treat analyses with a dose adjustment considered to be a treatment failure and with a dose adjustment not considered to be a treatment failure.

Results
Of the 284 patients in the randomised population who were treated with UST in the LTE, 139 were receiving CS at maintenance baseline. Of these, 92.8% (n = 129) were CS-free at week 92. CS-free symptomatic remission rates at week 92 are summarised in Table 1. Results were similar for the q8wk and q12wk maintenance doses. Of the UST-treated patients who were in symptomatic remission at week 92, 98.4% (182/185) were CS-free; similar results were seen when dose adjustment was not considered to be a treatment failure. Of the 116 delayed responders (non-randomised population) who continued to receive UST in the LTE, 92 patients were in symptomatic remission at week 92; of whom, 94.6% (87/92) were CS-free.

Conclusion
UST maintenance therapy, with both q8wk and q12wk dosing regimens, was effective in reducing and eliminating the use of CS in patients with UC. Nearly all patients in the LTE who were in symptomatic remission at week 92, were not taking steroids.
DOP88 Visceral fat area correlates well with anti-TNFα drug levels and secondary loss of response in Crohn’s disease patients
Authors: Lim Z , Welman C , Raymond W , Thin L 
Published: January 2020

Abstract

Background
A high body mass index (BMI) is known to adversely affect anti-TNFα trough levels and secondary loss of response (SLOR); however, the literature is scarce in defining what aspect of body mass determine these outcomes. We hypothesise that a large visceral fat area is associated with a lower anti-TNFα level and a higher rate of SLOR. Our aim was to determine the impact of fat and muscle compartment areas on these outcomes.

Methods
Crohn’s disease (CD) patients who were prescribed standard doses of an anti-TNFα agent [5 mg/kg, 8 weekly infliximab (IFX) or 40 mg EOW of adalimumab (ADA)] from 1 February 2015 to 30 June 2018 were examined retrospectively. Primary responders with a minimum therapy duration of 12 weeks, at least 12 months of follow-up and a trough level within 6 months of a CT or MRI, were eligible for inclusion. The primary outcome was the trough level and the secondary outcome was time to SLOR, defined as a need to dose escalate, change out of class, requiring ≥3 courses of corticosteroids in a 12-month period, or surgery. Patients were followed until they met a SLOR or the census date of 30 June 2019. Visceral fat area (VFA), subcutaneous fat area (SFA) and skeletal muscle area (SMA) were measured on the CT/MRI at the L3 vertebral level in cm2 by a radiologist blinded to the clinical outcome and corrected for patient height (cm2/m2).

Results
Of 813 patients prescribed an anti-TNFα agent in the study period, data from 69 eligible CD patients were included for analysis. The median age was 43.5 ± 16.2 years, and 42 (60.9%) were males. Forty-four (63.8%) and 25 (36.2%) patients were treated with IFX and ADA respectively. The mean BMI was 26.9 ± 5.2. Univariate analysis of infliximab trough levels found that total fat area, VFA, visceral fat index [VFI (VFA/height in m2)] and VFA/SMA ratio were inversely correlated with anti-TNFα trough level (p &lt; 0.05). No association was found between ADA trough level and muscle/fat areas. After multivariate adjustment for CRP, albumin, presence of antibodies, concurrent immunomodulator use and gender, IFX levels were inversely associated with VFA [-0.021 (−0.038, −0.003) p = 0.025], VFI [−0.066 (−0.119, −0.013) p = 0.016] and VFA/SMA [−3.805 (−7.132, −0.477) p = 0.026] but not BMI [−0.232 (−0.520, 0.055) p = 0.11). No association was found for ADA trough levels. Kaplan–Meir analyses showed a trend towards a shorter time to SLOR with an increasing tertile of VFI in both IFX and ADA treated patients.

Conclusion
Visceral fat area corrected for height (VFI) is a better determinant of anti-TNFα trough levels and SLOR than BMI.
P001 The novel DYRK1a inhibitor VRN024219 alleviates disease severity on the IBD mouse models by modulating T-cell differentiation
Authors: Seo D H , Ma H W , Kim S , Kim D H , Kim H K , Lee S H , Kim S , Ahn J Y , Yoon S H , Kim D K , Cheon J H 
Published: January 2020

Abstract

Background
DYRK1A belongs to dual-specificity tyrosine (Y) phosphorylation regulated kinase (DYRK) family which is known to be activated through autophosphorylation of tyrosine residues in the activation loop and phosphorylates their substrates on serine and threonine residues. Other members of this family include DYRK1B, DYRK2, DYRK3, and DYRK4. Studies have revealed that DYRK kinase family plays an important role in regulating cell proliferation and apoptosis. DYRK1A has been reported to be strongly expressed in the brain and known to regulate various functions. However, the role and underlying mechanisms of DYRK1a in inflammation in general, specifically in IBD, remain poorly understood. Accordingly, we present the underlying mechanisms of DYRK1a on the course of IBD by using the novel DYRK1a inhibitor VRN024219.

Methods
First, we tested the effects of our compound VRN024219 on T-cell differentiation using naïve CD4 T cells extracted from the mouse spleen. Then we assessed the efficacy and mechanism of VRN024219 on the dextran sodium sulphate (DSS) and T-cell transfer-induced experimental colitis that mimics human ulcerative colitis (UC), comparing to that of Tofacitinib. Finally, we evaluated the effect of VRN024219 on pro-inflammatory cytokines such as interleukin (IL) −17A, IL-6, and tumour necrosis factor (TNF) α expressed by peripheral blood mononuclear cells (PBMCs) from 20 UC patient samples (Severance Hospital, Seoul, Korea).

Results
When VRN024219 was treated to splenocyte, the compound significantly downregulated Th17 and enhanced T reg cell differentiation. Protein levels of IL-17a, IL-6, and TNF α were increased in the DSS-induced colitis mice, whereas administration of DYRK1a inhibitor VRN024219 substantially improved clinical score than that of Tofacitinib-treated group. Additionally from T-cell transfer-induced colitis model, VRN024219 treated group demonstrated a larger population of ROR γ T-cell than that of tofacitinib Finally, the protein levels of proinflammatory cytokines were significantly down-regulated in VRN024219 treated 20 patient samples.

Conclusion
Our data provide clear evidence that the novel DYRK1a inhibitor plays a protective role in DSS- and T-cell transfer-induced colitis which was closely related to a Th17/Treg modulation. Thus, VRN024219 might a promising candidate for a new drug for IBD.
P020 MAM, an anti-inflammatory protein derived from Faecalibacterium prausnitzii as a biomarker in Crohn’s disease?
Authors: McLellan P , Lavelle A , Brot L , Straube M , de Sordi L , Grill J P , Bourrier A , Kirchgesner J , Chatel J M , Beaugerie L , Sokol H , Seksik P 
Published: January 2020

Abstract

Background
The intestinal microbiota of patients with Crohn’s disease (CD) is characterised by a specific dysbiosis, including the loss of Faecalibacterium prausnitzii (F. prau), a major bacterium with anti-inflammatory properties. MAM protein (microbiotia anti-inflammatory molecule) produced by F. prau has recently been identified as partially carrying the anti-inflammatory activity of this bacterium. The description of microbiota for diagnostic purposes in CD is currently difficult to achieve. MAM could be a biomarker of dysbiosis. Our goal was to study the expression of MAM in the intestinal ecosystem and to evaluate its interest as a biomarker.

Methods
An in silico approach was used to determine primers of MAM gene sequences specific to two currently known phylogroups (I and II) of F. prau. Faecal samples were collected from a monocentric cohort of CD patients in flare (n = 24) and in remission (n = 24) and from healthy controls (n = 12). To measure MAM expression in vivo in the microbiota, we extracted total RNA and DNA from each sample and performed quantitative PCR (qPCR) with MAM primers (I and II), F. prau primers and universal bacterial primers. We compared the relative expression (ΔCt) of MAM mRNA and DNA with qPCR to the overall amount of bacteria in faecal samples.

Results
MAM analyses of F. prau phylogroup II were the most informative. We observed that the relative expression of MAM mRNA was statistically lower in active patients 5.84 × 10−5 [95% CI 3.8 × 10−6–2.1 × 10−3] and in remission 5.36 × 10−5 [95% CI 2.5 × 10−8–1.9 × 10−2] compared with healthy controls 5.42 × 10−4 [95% CI 8.5 × 10−5–9.1 × 10−2], (p = 0.004). There was no difference in ΔCt between flare and remission in CD patients. The most relevant relative expression threshold was 1.6 × 10−4. At this threshold, sensitivity was 81%, specificity 76%, positive predictive value 94% and negative predictive value 47%. In multivariate analysis, the relative expression of MAM was an independently associated with the diagnosis of CD; OR 2.961 [95% CI 2.026–4.831] (p = 0.003). Using relative expression of MAM DNA, we found a significant decrease in the flare group compared with remission patients and controls. We found a negative correlation of MAM DNA expression with CRP (p = 0.0053) and HBI (p = 0.025).

Conclusion
Our results showed that the loss of MAM RNA expression is observed in CD patients. Moreover, MAM DNA detection was associated with CD activity parameters. This opens up the prospect of an ecological biomarker of CD based on the expression of molecules from the intestinal ecosystem. These results will need to be validated in larger independent cohorts and their specificities compared with other pathological situations.
P021 The influence of short-chain fatty acids produced by commensal bacteria on macrophage phenotype
Authors: Jukes C , Ricci L , von Coburg E , Nasr M , Walker A W , Duncan S H , Hegazy A N 
Published: January 2020

Abstract

Background
Macrophages are dynamic immune cells that react to environmental signals to adapt to their environment. Among this diverse array of signals are multiple bacterially derived metabolites including short-chain fatty acids (SCFAs) in the gastrointestinal tract. It has been previously shown that butyrate, one of several SCFAs produced by bacteria, is able to drive an antimicrobial phenotype in macrophages. However, it is still unknown which bacterial species are able to drive this impact and whether this effect can be recapitulated in vivo. The identification of a common molecular signature that drives this phenotype may allow us to easily identify bacteria with this beneficial phenotype and give insight into potential therapeutic strains.

Methods
Monocytes were differentiated into macrophages in the presence of SFCAs or bacterial supernatants from a wide range of gut commensals isolated from healthy human donors. RNA was isolated post-differentiation and gene expression screened using a defined gene panel using the Fluidgm Biomark system. In addition, cytokines present in the supernatant were measured by ELISA and the ability of the macrophages to kill intracellular bacteria determined. Currently, we are carrying out the same procedure using bone marrow-derived macrophages (BMDM) from mice in order to expand this work flow into the mouse system so that we can determine if bacteria identified can elicit their impact in vivo.

Results
We have screened numerous SCFAs alone and in combination in the bacterial killing assay to determine how these are able to influence macrophage phenotype. From these experiments, we have repeated the earlier observation that butyrate can increase macrophage killing of intracellular bacteria. In addition, we have identified four bacterial isolates that induce significantly increased microbial killing in macrophages. This is associated with the production of butyrate, acetate and formate. Using RNA from these different conditions, we are in the process of determining if there is a common molecular pathway by which this increased antimicrobial phenotype is driven.

Conclusion
Both SCFAs and SCFA producing bacteria are able to induce an antimicrobial phenotype in macrophages that increased the ability of these cells to kill intracellular pathogens. Identification of a common signature that drives these changes could help to screen bacterial isolates for this beneficial trait. Ongoing work hopes to identify such a signature, to enable us to screen large numbers of commensals using high-throughput molecular methods. This can then be verified using both in vitro and in vivo techniques.
P055 Effect of Mimosa caesalpiniifolia extract on DSS-induced colitis in Wistar rats
Authors: Garnevi Fávero A , Cordeiro T S , Silva K N , Cardili L , Silva M J D , Paiotti A P R 
Published: January 2020

Abstract

Background
Iinflammatory bowel disease (IBD) is a chronic disease characterised by dysregulation of the immune function response and imbalanced release of cytokines and unresolved inflammatory progress associated with the intestinal mucosa. In this way, new drugs are constantly tested as a novel treatment option. Mimosa caesalpiniifolia (MC) has been described as a potent analgesic, anti-inflammatory, anti-haemorrhagic, astringent, anthelmintic and diuretic. This study aimed to evaluate the effect of MC extract on dextran sulphate sodium (DSS)-induced colitis in Wistar rats.

Methods
Forty male Wistar rats were randomised into five groups: Sham; 5% DSS-induced colitis; control MC extract (125 mg/kg/day); 5% DSS-induced colitis treated with MC (125 mg/kg/day); 5% DSS-induced colitis treated with MC + 5-ASA (125 mg/kg/day for both). Colitis was induced by administration of 5% DSS (MP Biomedicals), diluted in drinking water and offered ad libitum for 5 days. MC plant extract was diluted in water and administered by oral gavage per 6 days. The leaf extracts were prepared in 70 gl ethanol and dried in a Buchi B19 Mini-spray dryer using 20% aerosol. The selection of the operating conditions used was followed by the Laboratory of Medicinal and Phytotherapeutic Plants of Unifal-MG. After the induction of colitis, body weight, general health status and faecal characteristics will be evaluated daily. All rats were euthanised on the ninth day of the experiment. The entire colon was dissected and fixed in 10% neutral-buffered formalin at room temperature and embedded in paraffin to provide sections for histological evaluation (Ethics Committee on the Use of Animals number 4362180119). The severity of colitis was evaluated in sections stained with Hematoxylin and Eosin. Parameters such as inflammation extent, regeneration and crypt damage were graded according to Dieleman et al. Statistical analysis was performed by one-way analysis of variance (ANOVA), followed by Tukey post hoc test using Graph Pad Prism (version 6.0).

Results
MC extract treatment reduced significantly the severity of DSS-induced colitis evidenced by a decreased in clinical symptoms (p &lt; 0.0001). The rats treated with MC extract showed a decreased in diarrhoea episodes and rectal bleeding. We observed histopathological changes of colon tissue between the DSS-treatment and control groups, however, without statistical significance. The MC extract treatment reduced the damage to the colonic tissue evidenced by a decreased of inflammatory cells, ulcerations, and goblet cell preservation.

Conclusion
MC extract reduces the clinical signs and suggests a potential anti-inflammatory effect on DSS-induced colitis.