bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP89 Effects of ferric derisomaltose and ferric carboxymaltose on hypophosphatemia in iron-deficiency anaemia due to Inflammatory Bowel Disease: A Phase IV randomised clinical trial
Authors: Zoller H , Wolf M , Blumenstein I , Primas C , Lindgren S , Thomsen L L , Reinisch W , Iqbal T 
Published: May 2021

Abstract

Background
Intravenous iron can correct iron deficiency anaemia (IDA) in inflammatory bowel disease (IBD). Certain formulations are associated with hypophosphatemia, but this has not previously been investigated in a randomised clinical trial in IBD. The aim of this randomised, double-blind trial was to compare the risk of hypophosphatemia with ferric derisomaltose/iron isomaltoside 1000 (FDI) vs ferric carboxymaltose (FCM) in patients with IDA due to IBD.

Methods
Adults with IBD and IDA (haemoglobin [Hb] &lt;13g/dL; s-ferritin ≤100ng/mL) who were unsuitable for oral iron treatment were recruited at outpatient clinics in 5 European countries. Patients were randomised 1:1 to FDI or FCM (1000mg at baseline and 500 or 1000mg at Week 5 based on weight and iron need at baseline). The primary endpoint was the incidence of hypophosphatemia (s-phosphate &lt;2.0mg/dL) from baseline to Week 5. Additional endpoints included biomarkers of bone and mineral metabolism, Hb concentrations, fatigue score, and adverse events (AEs).

Results
Of 97 patients enrolled (mean age 42.1 years; 52.6% female; 39.2% Crohn’s disease; 60.8% ulcerative colitis), 48 received FDI and 49 FCM. The incidence of hypophosphatemia was significantly lower for FDI than FCM (8.3% vs. 51.0%; p&lt;0.0001). After the first dose, biomarker responses (least squares mean change from baseline) were significantly less pronounced after FDI than FCM: s-phosphate decreased less with FDI than FCM, with a nadir at Week 1 (FDI, -0.49mg/dL; FCM, -1.33mg/dL; p&lt;0.0001); urinary fractional excretion of phosphate increased less at Week 1 (FDI, 2.58%; FCM, 9.22%; p=0.0021); intact fibroblast growth factor 23 increased markedly over the first day only with FCM (FDI, -8.54pg/mL; FCM, 149.31pg/mL; p&lt;0.0001); 1,25-dihydroxyvitamin D decreased less with FDI than FCM, with a nadir at Week 1 (FDI, -16.39pg/mL; FCM, -30.83pg/mL; p&lt;0.0001); parathyroid hormone increased only in the FCM group, with a peak at Week 2 (FDI, -2.22pg/mL; FCM, 14.28pg/mL; p=0.011). Bone-specific alkaline phosphatase increased more with FCM than FDI at Week 2 (p=0.0025), with the difference persisting at Week 10 (p=0.0041). Hb increased in both groups and were comparable at all time points. Improvements from baseline in fatigue score were greater for FDI than FCM at Weeks 5 and 7 (both p&lt;0.01). Incidence of AEs were comparable (FDI, 91.7%; FCM, 89.8%).

Conclusion
In IDA due to IBD, FDI resulted in significantly lower incidence of hypophosphatemia than FCM. FDI and FCM lead to similar increases in Hb concentration. In contrast to FDI, FCM treatment led to persistent changes in bone biomarkers, suggesting possible long-term adverse effects on bone health. ClinicalTrials.gov Identifier: NCT03466983. Supported by Pharmacosmos A/S (Holbæk, Denmark).
OP25 Efficacy of filgotinib in patients with Ulcerative Colitis by line of therapy in the phase 2b/3 SELECTION trial
Authors: Peyrin-Biroulet L , Dotan I , Hibi T , Taliadouros V , Oortwijn A , Zhao S , Zhang J , Hsieh J , Feagan B 
Published: May 2021

Abstract

Background
Patients with ulcerative colitis (UC) often do not respond to treatment or lose response over time, and thus switch between therapies with various mechanisms of action (MoAs).1 Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor in development as a UC treatment. We assessed the efficacy of FIL in biologic (bio)-naïve and bio-experienced patients with UC, and in bio-experienced patients with failure of 1 or ≥2 biologics or 1 or 2 MoAs.

Methods
SELECTION (NCT02914522) was a phase 2b/3 double-blind, randomised, placebo-controlled trial comprising two induction studies and a maintenance study. Adults (18–75 years) with moderately to severely active UC were randomised 2:2:1 to FIL 200 mg, FIL 100 mg or placebo (PBO) once daily for 11 weeks in Induction Study A (bio-naïve) and B (bio-experienced). Patients in either clinical remission or Mayo Clinic Score (MCS) response at week 10 (responders) could enter the Maintenance Study. Responders who received induction FIL were re-randomised 2:1 to continue their induction regimen or PBO through week 58. Responders who received induction PBO continued PBO. We assessed clinical remission and MCS response at weeks 10 and 58 in bio-naïve patients and bio-experienced patients with failure of 1 or ≥2 biologics and 1 or 2 MoAs (TNF antagonists and vedolizumab). All p values for subgroup analyses are nominal.

Results
At week 10, clinical remission was achieved by a significantly higher proportion of bio-naïve and -experienced patients treated with FIL 200 mg than PBO (Figure 1a). A higher proportion of bio-experienced patients with 1 biologic or MoA failure treated with FIL 200 mg than PBO achieved clinical remission at week 10 (p&lt;0.05); a smaller treatment effect was seen in patients with ≥2 biologic or 2 MoA failures (Figure 1b). None of these comparisons reached p&lt;0.05 for FIL 100 mg. Higher proportions of patients treated with either dose of FIL than PBO achieved MCS response at week 10 in all (sub)groups (Figure 2). At week 58, higher proportions of bio-naïve and -experienced responders, and bio-experienced responders with ≥2 biologic or 2 MoA failures treated with maintenance FIL 200 mg than PBO achieved clinical remission (p&lt;0.05) (Table 1). Higher proportions of responders treated with maintenance FIL 200 mg than PBO achieved MCS response at week 58 in all (sub)groups.

Conclusion
FIL 200 mg was effective in inducing and maintaining clinical remission in bio-naïve and -experienced patients. Induction results suggest FIL 200 mg is most effective in bio-naïve patients, and those who switch after failure of 1 biologic or MoA. Interpretation of week 58 data is limited by low patient numbers.

Reference
P012 Low frequencies of circulating inhibitory TIGIT+CD38+ effector T cells identify an immunologically distinct subgroup of pediatric patients with severe Crohn’s disease
Authors: Heredia M , Costes L , Tindemans I , Aardoom M , Klomberg R , Kemos P , Joosse M , van Haaften D , Tuk B , Ruemmele F , Croft N , Escher J , de Ridder L , Samsom J 
Published: May 2021

Abstract

Background
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a T cell driven intestinal inflammation. Current T cell suppressive therapeutic regimens are moderately successful due to a large clinical heterogeneity amongst patients. Detailed understanding of aberrant inflammatory and inhibitory T-cell responses in individual patients is lacking. Previously, we have shown that, in healthy individuals, 40% of peripheral blood CD38+ (CD62LnegCD4+) effector T cells, which are enriched for intestinal antigen specificity, express the inhibitory molecule T cell immunoglobulin and ITIM domain (TIGIT). TIGIT+CD38+ effector T cells have a regulatory function, produce IL-10 and express multiple co-inhibitory receptors. Conversely, TIGITnegCD38+ effector T cells are enriched in inflammatory IFN-γ producing cells. In a small cohort of pediatric-onset IBD patients, low frequencies of TIGIT+CD38+ effector T cells were associated with a reduced duration of clinical remission. We hypothesize that a subgroup of IBD patients has reduced frequencies of circulating inhibitory TIGIT+CD38+ effector T cells, reflecting a distinct pathogenesis associated with a more severe disease course.

Methods
In the Rotterdam PIBD-SETQuality cohort of newly diagnosed pediatric IBD patients (CD: n=37; UC: n=16), patients with suspicion of IBD but negative diagnosis (n=12) and age-matched healthy controls (n=22), we monitored TIGIT+ and TIGITnegCD38+ effector T cells in peripheral blood and collected plasma at diagnosis and during immunosuppressive therapy.

Results
At diagnosis, approximately 50% of CD patients had strongly reduced frequencies of inhibitory TIGIT+CD38+ effector T cells compared to UC patients and age-matched controls. CD patients with low frequencies of TIGIT+CD38+ effector T cells at diagnosis needed earlier anti-TNF treatment with 73% of patients receiving anti-TNF treatment within 1 year versus 38% for patients with normal frequencies of TIGIT+CD38+ effector T cells. Inflammatory TIGITnegCD38+ effector T cells were enriched in Ki67, reflecting recent proliferation, and expressed chemokine receptors associated with inflammatory non-classical T-helper-1 IFN-γ hiIL-17lo producing cells. High frequencies of TIGITnegCD38+ effector T cells correlated with high plasma IFN-γ concentrations.

Conclusion
These results demonstrate that reduced frequencies of circulating inhibitory TIGIT+CD38+ effector T cells discriminate a subgroup of pediatric CD patients with high frequencies of inflammatory IFN-γ hiIL-17lo producing cells, high plasma IFN-γ concentrations, and in need of early anti-TNF treatment, possibly indicative of a distinct pathogenesis with a more severe disease course.
P017 Small bowel transcriptomics define similarities and divergent pathways between Crohn, environmental enteric dysfunction (EED), and celiac diseases, implicating role for the microbiome in the pathogenesis
Authors: Haberman Ziv Y , Iqbal N T , Braun T , Dexheimer P J , Hadar R , Rahman N , Syed S , Moskaluk C , Moore S R , Ali S A , Denson L A 
Published: May 2021

Abstract

Background
Crohn disease (CD), environmental enteric dysfunction (EED) and celiac disease are prevalent enteropathies linked to chronic gut inflammation. However, unlike celiac and Crohn that are prevalent in westernized countries, EED is seen in only in low- and middle-income countries of the developing world. Recent work has defined specific EED duodenal microbiota associated with stunting, and transmission of EED histologic changes and weight loss by microbial transfer to germ free mice.

Methods
We performed high throughput transcriptomics of 94 duodenal samples from the SEEM cohort:52 undernourished EED participants, 17 celiac and 25 healthy North American controls. We compared those to our previously reported transcriptomics of 248 newly diagnosed ileal CD from RISK. Comparison were performed between cases and controls within each cohort.

Results
Above 90% of the expressed protein coding genes are shared between duodenum samples within SEEM, and Crohn ileal within RISK enabling the anticipated comparison. A substantial number of the down-regulated genes in undernourished EED participants overlapped with celiac (212/481, 44%) and with Crohn Disease (249/481, 52%). Shared reduced signatures and functions included decrease in epithelial lipid metabolism, vitamins, and brush border transport signatures. Relative to celiac disease, suppression of antioxidant and detoxification genes were EED- and Crohn-specific, which include the reduction of metallothioneins (MT family) that buffer against toxic metals, and aldo-keto NADPH- genes (AKR1C family) involved in detoxification of environmental compounds. A smaller proportion of the EED up-regulated signal overlapped with celiac (85/781), and we noted a more significant overlap with Crohn disease (248/781, Chi squares p&lt;0.05). Relative to celiac disease, up-regulation of an innate anti-microbial DUOX2 and LCN2 gene, and of myeloid response signals, several CCL chemokines, and extracellular matrix signature were EED- and Crohn-specific. Consistent with this, greater level of DUOX2 protein was detected in duodenal biopsies from EED subjects vs. celiac and controls and in ileal CD vs. ileal controls. As opposed to the robust dysbiosis previously characterized in Crohn disease, we were unable to identify significant microbial signal in celiac patients in comparison to controls, while recent studies identified microbial patterns linked with EED.

Conclusion
We highlight important biologic signals widely overlapping between Crohn Disease (CD) and EED transcriptome in the small intestine, suggesting mechanisms involving altered gut microbiota. Inhibiting innate immune activation or reverting Crohn dysbiosis may be beneficial future therapy for Crohn Disease and EED.
P032 MiR-511 deficiency aggravates T cell transfer colitis in mice
Authors: Rahman S , Elfiky A , van Hamersveld P  H P , Verseijden C , Welting O , Meijer S L , Hakvoort T B M , de Jonge W J , Heinsbroek S E M 
Published: May 2021

Abstract

Background
MiR-511 is embedded in intron region 5 of the CD206/MRC1 gene, expressed by macrophage and dendritic cell populations. In this study, we aimed to investigate the effect of MiR-511 deficiency on intestinal inflammation in a murine T cell transfer colitis model.

Methods
A double MiR-511- and Rag-1 (knockout) KO mouse was generated and a T cell transfer colitis was induced by intraperitoneal injection of naïve T cells from donor WT mice. Since these mice lack mature T and B cells, first signs of inflammation appeared at week 3 after T cell injection. An endoscopy score was obtained to determine inflammation at week 3 and 5, respectively. The experiment was terminated at week 5 and severity of inflammation was assessed on the basis of weight loss, colon weight/length ratio, histology score, spleen weight and disease activity index. In addition, flow cytometry was performed for analysing immune cell populations (monocyte, macrophages, dendritic cells, neutrophils) in the colons of both control and colitis groups and T cells in the spleens of colitis group, respectively.

Results
Following the induction of T cell transfer colitis, colon weight/length ratio, spleen weight and endoscopic score were significantly increased in the double KO mice compared to Rag-1 KO control mice. A higher histology score and disease activity index in the double KO with no change in weight loss compared to Rag-1 KO control mice was observed. A significant increase in monocyte population in the colons of double KO was seen and increased numbers of monocytes was also observed in the double KO control group with no inflammation. Also, a higher influx of T cells in the double KO mice with a significant increase in Foxp3 and IL4 population was observed in the group with colitis.

Conclusion
MiR-511 deficiency aggravates intestinal inflammation compared to Rag-1 KO control mice. Also, a higher presence of monocyte as well as T cell populations were observed in these mice. Together these data show that MiR-511 is involved in the regulation of intestinal health. Future research will focus on underlying mechanisms.
P047 The ATG16L1 T300A polymorphism in Crohn’s Disease patients leads to abnormal autophagy flux in dendritic cells
Authors: Quiniou G , Dinet O , Cervantes O , Verdet M , Boschetti G , Viret C , Nancey S , Faure M , Rozieres A 
Published: May 2021

Abstract

Background
Crohn’s disease is a chronic inflammatory bowel disease, whose pathogenesis is largely determined by an inappropriate immune response towards luminal microbiota in genetically susceptible hosts, affecting in particular genes involved in the autophagy process. The autophagy-related ATG16L1 T300A variant is one of the most frequently associated polymorphisms with susceptibility to Crohn’s disease, but the functional consequences of this polymorphism on the dynamic properties of the autophagy flux remains unknown.

Methods
Using dynamic monitoring of LC3 lipidation, a key protein marker of autophagy, we have quantitatively analysed the autophagic flux of human primary dendritic cells, which are very potent antigen-presenting cells whose function is critical in Crohn’s disease.

Results
The detailed analysis of the dynamic properties of the autophagic flux reveal that the maturation process in dendritic cells from healthy subjects is associated with a decrease of the velocity and the intensity on the autophagy flux although the turnover of autophagosome formation was maintained, demonstrating the capacity of resilience of the autophagy flux for a maintenance of functional autophagy during maturation process. Strikingly, the expression of the ATG16L1 T300A variant, but not NOD2 R702W variant, in dendritic cells from patients with Crohn’s disease is associated with a disorder of the autophagic flux dynamics in immature dendritic cells, that was not modulated upon maturation. The lack of adaptation of the autophagy flux in ATG16L1 T300A expressing dendritic cells of Crohn’s disease patients, during their maturation was not associated with altered phenotypic acquisition of maturation markers but highlighted a very specific autophagic flux signature.

Conclusion
Dendritic cells of Crohn’s patients expressing the autophagy-related ATG16L1 T300A have an altered autophagy flux, that could affect their function and contribute to the pathogenesis of Crohn’s disease.
P078 Proteomics and Lipidomics Analysis Revealed Alterations of Complement Activation and Lipid Metabolism in peripheral blood mononuclear cells of Inflammatory Bowel Disease Patients
Authors: Notararigo S , Bravo S , Martin-Pastor M , Baston-Rey I , Quiroga-Castiñeira A , Dominguez-Munoz J E , Domínguez Medina E , Barreiro-de Acosta M 
Published: May 2021

Abstract

Background
The lack of interaction between immune system cells and microbiota is considered a key driver of the pathogenesis of inflammatory bowel disease (IBD). The association of age-associated B cells (ABC) from antigen-experienced B cells and autoimmunity is now well established. The increased demands in lipid metabolism during immune response and cell activation upon autoimmune signals leads to lipid tag modifications of proteins. In IBD patients, we observed an impairment of B cell development, identifying a transitional B cell subset expressing CD38Hi, CD24Hi and CD19+. We hypothesize that metabolic alterations of proteins and lipids during immune cell activation might be a relevant mechanism of autoimmune disease.

Methods
An IBD cohort of patients in clinical remission under anti-TNF treatment was included in order to test metabolic and proteomic changes in peripheral blood mononuclear cells (PBMCs). Proteomic analysis was performed by Mass Spectrometry using a label free quantitative method (SWATH-MS analysis) and lead to identify a number of proteins underregulated (&lt; 0.6) and overexpressed (&gt; 1.5) fold change respect to control. Lipidomics of serum samples analyzed by proton Nuclear Magnetic Resonance spectroscopy (NMR)2 and multivariant statistics.

Results
Serum samples were obtained in Crohn disease (CD) n = 18, ulcerative colitis (UC) n = 9, before biological infusion and healthy controls (CTRL) n = 10. Proteins related with lipid metabolism like APOC2 for CD and APOB, APOA1 for UC, were differentially modulated. Significant differences in non-polar metabolites and lipids that phenotypically define CD and UC groups respect to CTRL were observed (Fig. 1)

Fig. 1 Orthogonal-Partial Least Square-Discriminant Analysis (OPLS-DA) of the global NMR data of the serum samples of groups CD and CTRL.
Indeed, proteins associated with complement activation like Complement Factor 1 and Complement C1q subcomponent subunit B were differentially expressed in CD group. These results were confirmed by lipidomic analysis, in which palmitic (Fig. 2) as well as other candidate lipids were more abundant in IBD groups than CTRL.

Fig 2. Differences of palmitic acid concentration in CD and UC patients vs CTRL (Bonferroni test showed statistical difference between CTRL vs. CD and CTRL vs. UC with p = 0.02 and p = 0.004 respectively).

Conclusion
Our study detected high levels of proteins regulating lipid metabolism and palmitic in IBD patients. This observation can be interpreted as part of deleterious alterations of proteins through palmitoylation during B-cell activation and might be a relevant mechanism of disease. Further exploration of palmitate catabolism might shed light to the mechanisms that result in immunometabolic disorders.
P083 High prevalence of ulcerative appendicitis in UC patients without colonic disease activity
Authors: Heuthorst L , Mookhoek A , Wildenberg M , D’Haens G , Bemelman W , Buskens C 
Published: May 2021

Abstract

Background
The aim of the current study was to assess histological features of appendices from patients with UC and its clinical relevance.

Methods
Patients with UC in remission and active UC (therapy refractory) that underwent an appendectomy in the frame of clinical trials between 2012–2019 were included. Histological features of UC appendices were compared to those of patients with acute appendicitis and colon carcinoma. The Robarts Histopathology Index score (RHI) was used to assess appendiceal inflammation. In patients with active UC, clinical and histological characteristics were compared between patients with and without endoscopic response after appendectomy.

Results
In total, 140 appendix specimens were assessed (n=35 UC remission, n=35 active UC, n=35 acute appendicitis, n=35 colon carcinoma). Histological features of appendices from UC patients looked like UC rather than acute appendicitis. The incidence of active appendiceal inflammation was not different between UC patients in remission versus active disease (53.7% versus 46.3%, p=0.45) and limited versus extensive disease (58.5% versus 41.5%, p=0.50). Endoscopic response, assessed in 28 therapy refractory patients, was more frequently seen in patients with higher RHI scores (RHI&gt;9 81.8% versus RHI≤9 9.1%, p=0.004) and limited disease (proctitis/left sided 63.6% versus pancolitis 36.4%, p=0.02).

Conclusion
The presence of active appendiceal inflammation is common in UC and not related to disease activity in the colon. More than 50% of UC patients in remission show active histological disease in the appendix. Favorable response to appendectomy for refractory UC was seen in cases with ulcerative appendicitis. These findings might support the role of the appendix as a driving force in UC.