bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP43 Extended induction in the True North OLE study: ozanimod efficacy in biologic-naive and biologic-experienced patients
Authors: Dignass A , Regueiro M , Colombel J F , Jain A , Canavan J B , Wu H , Lawlor G , Osterman M T , Vermeire S , Rubin D T 
Published: January 2023

Abstract

Background
Prior exposure to biologics can influence response to subsequent lines of advanced therapies. Previous analyses showed that patients who did not achieve clinical response following 10 weeks of ozanimod treatment in the phase 3 True North (TN) study benefited from extended induction with open-label ozanimod in the TN open-label extension (OLE) study. As the impact of prior biologic exposure on outcomes with extended induction is unknown, the aim of this analysis was to evaluate that question.

Methods
Clinical nonresponders to ozanimod at TN Week (W) 10 entered the OLE (data cutoff: January 10, 2022, at which point the disposition was available until OLE W94 for all patients). Data were analysed in patients with and without prior biologic exposure at baseline. Disease activity was assessed at TN W0 (baseline) and at W10 (OLE entry). Symptomatic clinical response and remission were evaluated through OLE W94, and multiple clinical, endoscopic, and histologic endpoints were evaluated at OLE W46 and W94 using observed case (OC) and nonresponder imputation (NRI) analyses.

Results
A total of 220 patients with prior biologic information entered the OLE after not achieving clinical response at TN W10 (biologic-naive, n=122; biologic-experienced, n=98). Disease activity at baseline was generally consistent between biologic-naive and experienced patients. About half of the ozanimod W10 nonresponders in both groups achieved symptomatic clinical response by OLE W5, with a higher proportion of biologic-naive patients maintaining response until OLE W94 in both OC and NRI analyses (Figure 1). Higher proportions of biologic-naive patients also sustained symptomatic clinical remission until OLE W94 in both OC and NRI analyses. In OC analysis, a higher proportion of biologic-naive patients achieved all clinical, endoscopic, and histologic endpoints at OLE W46 compared with biologic-experienced patients; by OLE W94, however, the proportions of patients who achieved all clinical, endoscopic, and histologic endpoints were generally consistent, regardless of prior biologic exposure (Figure 2). As expected, a smaller proportion of patients achieved the efficacy endpoints in the NRI analysis, with proportions being higher in biologic-naive patients; response rates were sustained between OLE W46 and W94 in each group.

Conclusion
Both biologic-naive and -experienced clinical nonresponders to ozanimod at the end of induction demonstrated response to extended induction with ozanimod. Delayed response was durable for up to 2 years of continuous ozanimod treatment in both groups, with higher proportions achieved in biologic-naive patients.
P006 Engineered propionate-producing bacteria attenuates murine colitis by modulating the immune function of resident macrophages via histone deacetylase
Authors: Feng Z , Wang X , Kang G , Zhao J , Ye Y , Liu L , Huang H , Cao X 
Published: January 2023

Abstract

Background
Most inflammatory bowel disease (IBD) patients are unable to maintain long-term remission by current treatment. Propionate has been proven to be able to exert anti-inflammatory effects in intestinal inflammation, but direct supplement of propionate has actual disadvantages including low bioavailability and poor sustained effect, et. al.

Methods
In this study, the genes related to acetate synthesis and metabolism were knocked out through the double plasmid CRISPR/cas9 gene editing system to increase the yield of propionate to ultimately form the engineered propionate-producing bacteria (EPB). The dextran sulfate sodium（DSS）-induced colitis model was used to explore the protective effect of EPB in vivo. Flow cytometry was used to evaluate the ratio of resident macrophage. Peritoneal macrophage and RAW264.7 cell lines were used to explore the effect and mechanism of EPB on the immune function of macrophages in vitro. Real-time polymerase chain reaction (RT-PCR) was performed to detect the expression of several cytokines in colon tissue and cells. Enzyme-linked immunosorbent assay (ELISA) was used to detect the level of cytokines in the cell supernatant. Western bolt was used to detect the levels of histone deacetylase protein and transcription factor GATA6.

Results
EPB exhibited enhanced propionic acid production. In vivo results showed that EPB group had less barrier damage and less inflammatory infiltration than control groups indicating it could prominently ameliorate DSS-induced colitis. EPB promoted the production of anti-inflammatory cytokine IL-10 and reduced the production of IL-2、IL-5 and IL-6 in DSS-induced mice. In the further exploration of the effects of EPB, we found that EPB increased the proportion of resident macrophages (F4/80hiCD11bhi) in the peritoneal cavity, And the transcription factor GATA6, which is specific express in peritoneal macrophages, was detected in the intestinal tissue. Moreover, we investigated the effects of EPB on peritoneal macrophages in vitro and found EPB not only affected the cytokine production ability of resident macrophages but also reduced cell apoptosis. Further analysis showed the regulatory effect of EPB on macrophages is associated with G protein-coupled receptors 41/43 and histone deacetylase 2 (HDAC2), which is closely related to propionate. GPR41/43 inhibitor weakened the effects of EPB on macrophages, while HDAC inhibitor trichostatin A (TSA) exerted a similar effect to EPB.

Conclusion
The engineered propionate-producing bacteria (EPB) could attenuate DSS-induced colitis in the mouse by modulating the immune ability of resident macrophage and the production of classic inflammation-related cytokines, which indicates an effective and safe treatment strategy for ulcerative colitis.
P062 Antibody responses to SARS-CoV-2 vaccination outperform responses induced by natural infection in patients with IBD receiving immunosuppressive medications: a report from the ICARUS-IBD consortium.
Authors: González Cueto E , Matthew E , Wellens J , Martinez Pazos V , Thompson C , Klenerman P , Cadwell K , Colombel J F , Satsangi J , Wong S Y ,   ICARUS-IBD consortium
Published: January 2023

Abstract

Background
The effects of immunosuppressive medications on immune responses to COVID-19 vaccination in patients with inflammatory bowel diseases (IBD) have been reported. However there is little data on immune responses in naturally infected SARS-CoV-2 patients compared with vaccination. We compared in a longitudinal study SARS-CoV-2 antibody and T cell responses in naturally-infected vs. vaccinated IBD patients.

Methods
110 IBD patients enrolled at the Icahn School of Medicine at Mount Sinai were prospectively followed with serial blood collection between May 2020, and February 2022. Samples were screened by ELISA to determine seropositivity, and stratified by infection, vaccination status, and IBD medications. Subsequently, ELISA-based inhibition assay and pseudotyped SARS-CoV-2 microneutralization assays were used to determine the inhibition and neutralization capacity of the seropositive individuals for wild type (WT) delta variant (Dv) and Omicron. Cellular responses were measured by IFN-γ ELIspot using nucleocapsid and spike peptide libraries.

Results
Overall, 64 patients had Crohn’s Disease and 46 had Ulcerative Colitis (UC), 69 were naturally infected. Only Anti-TNF (N=52), Ustekinumab (N=16), and Vedolizumab (VDZ) (N=33) treatment groups were considered. Only US-available vaccinations were included. Double-vaccinated IBD patients showed greater neutralizing responses to SARS-CoV-2 WT and Dv than naturally-infected individuals (p=0.0003, p=0.0025). Moreover, double-vaccinated individuals had greater neutralizing reactions against WT than DV (p 0.017) and Omicron (p 0.001) variants. Following natural infection, there were no differences between treatment groups in neutralization response, however those double-vaccinated on anti-TNF had lower neutralization than VDZ (p=0.008). Neutralization responses were maintained for a period of 8 months following natural infection and double vaccination. SARS-CoV-2 spike T cell responses were significantly higher in naturally infected (p=0.009) and double vaccinated individuals (p=0.005), with no significant differences between treatment groups (p&lt;0.999).

Conclusion
After a second vaccine dose, IBD patients showed stronger neutralizing antibody titers than naturally infected patients. Those on anti-TNF exhibited lower neutralizing responses than VDZ. T-cell responses were similar in infected and double-vaccinated subjects after vaccination or infection. These data imply COVID-19 immunization provides additional serological protection over natural infection.
P079 Attenuation of inflammation and histologic production-dependent improvement by engineered high acetate producing Saccharomyces boulardii in DSS-induced colitis
Authors: Deleu S , Trindade de Carvalho B , Jacobs I , Arnauts K , Deprez L , Vissers E , Lenfant M , De Hertogh G , Huys G , Thevelein J , Raes J , Vermeire S ,   MIMOSA
Published: January 2023

Abstract

Background
It has been hypothesized that the probiotic potential of the yeast Saccharomyces boulardii (Sb) is associated with its acetate production. This SCFA is of interest in IBD due to its cross-feeding potential with beneficial butyrate-producing bacteria and low toxicity to epithelial cells . Our previous in vitro work supports this hypothesis (Deleu et al, 2022) but still requires in vivo validation. Therefore, we evaluated the effect of different engineered Sb strains producing variable amounts of acetate in DSS-induced colitis in mice.

Methods
Nine week old female C57/Bl6 mice (N=120) were allocated to 12 treatment groups receiving drinking water or 2.75% DSS in combination with PBS (control), Baker’s yeast (non-probiotic control), SDH1 (non-acetate producing Sb), ENT (transient acetate producing Enterol strain-probiotic control), SbP (high acetate producing Sb) and ENT3 (extra high acetate producing Sb). Disease activity including weight loss, diarrhoea and the presence of occult blood was scored daily. On day 7, the DSS groups were transferred to regular drinking water and on day 14 mice were sacrificed. Colonic tissue and blood were collected for resp. histologic and cytokine analysis.

Results
Disease activity, determined by the area under the curve, in DSS subgroups was lower for SbP compared to PBS and Baker’s yeast (both p&lt;0.05). Remarkably, Sb SDH1 showed even higher disease activity compared to the Sb strains ENT, SbP and ENT3 (all p&lt;0.05). At sacrifice, macroscopic damage score in DSS subgroups was lower for SbP and ENT3 (both p&lt;0.05) compared to Sb SDH1 and the colon weight/length-ratio was decreased for ENT and SbP compared to Sb SDH1 (resp. p=0.06 and p=0.08). Higher histologic inflammation was noted in the non- or only transient-acetate producing strains on DSS compared to healthy PBS control (all p&lt;0.05), whereas this increase was not observed for both high-acetate producing strains SbP and ENT3 on DSS (p=NS). Lower IL1β, IL2 and IL4 concentrations for DSS groups on SbP and ENT3 compared to DSS groups on Sb SDH1 and ENT were observed (all p&lt;0.05). In contrast, IL10, TNFα and KC/GRO were lower for the DSS groups on Sb SDH1 and ENT compared to DSS groups on SbP, ENT3, and even PBS for IL2 and 4 (all p&lt;0.05).

Conclusion
Engineered high acetate producing Sb strains show a significant trend towards improved attenuation of DSS-induced colitis compared to the parent Sb strain on disease activity, macroscopic damage score and show production-dependent response on histology. Mixed pro-inflammatory serum profiles were observed potentially pointing in the direction of other effects of acetate accumulation. Together with our previous in vitro work, these data indicate a role for Sb-produced acetate in attenuating inflammation.
P095 Newly discovered gut matrikines from Crohn’s disease intestinal tissue induce cell proliferation, activation and inflammatory response in intestinal myofibroblasts in vitro
Authors: Papatheodoridi M , Giuffrida P , Canetti D , Yutaka Y , Hodgetts H , Di Sabatino A , Johnston H , Verona G , Rendell N , Al-Akkad W , Frenguelli L , Hall A , Luong T , Sampietro G , Pinzani M , Rombouts K , Belloti V , Mazza G 
Published: January 2023

Abstract

Background
The interaction between intestinal myofibroblasts (iMFBs) and extracellular matrix (ECM) changes contributes to Crohn’s disease (CD) fibrosis, but the exact mechanisms are not yet clear. Our group recently discovered a selection of matrix-derived peptides (matrikines) that specifically appear in the intestinal tissue of patients with CD fibrostenosis.1 Here, we evaluate the in vitro effect of 19 matrikines (with various bioactivity likelihood) on primary human intestinal myofibroblasts (IMFBs), key cells in CD fibrosis.

Methods
Primary human iMFBS (500K/mL, Passage 4, Novabiosis) were cultured in serum-free medium (SFM) (DMEM high glucose, 1% sodium pyruvate, 1% non-essential aminoacids, 1% Antibiotics-Antimycotics and 3mg Gentamicin), complete medium (SFM with 10% fetal bovine serum), PDGF-bb 10ng/mL or treated with each of the matrikines at 10, 50, 100 μg/mL for 24hours. The effect of each matrikine on cell proliferation, gene expression and migration was assessed by BrdU, qPCR and Transwell assays, respectively. RNA sequencing data was analysed using the GSEA software.

Results
The effect on iMFBs proliferation and viability was tested with each of the 19 matrikines at 3 different doses (Table 1).

Among 9 most likely-bioactive matrikines (M1-M9) (Figure 1), M1, M4, M7, M8 and M9 induced the highest effect in cell proliferation and were selected for further experiments. Gene expression assays showed upregulation of ACTA2 with M1 or M7 and upregulation of COL1A1 with M1, M7 or M8, indicating activation of the iMFBs (Figure 2).

Transwell assays also showed that M1, M4 and M8 induce iMFB cell migration.
A total of 1948, 1024, 460, 570, and 2749 differentially expressed genes (DEGs) were identified in iMBFs treated with M1, M4, M7, M8 and M9 vs no treatment, showing enrichment in pathways related to “smooth muscle contraction”, “fibroblast growth factor”, “cell migration”, “collagen formation”, “elastin formation” and “ECM organization”; most of which were also enriched by complete medium and/or PDGFbb that served as positive controls. However, pathways related to “proinflammatory and profibrotic mediators” or “vascular permeability” were only enriched in iMFBs treated with M1, M4, M8 and M9 or M1 and M9, respectively (Figure 3).

Conclusion
A selection of newly discovered CD-specific matrikines induce activation of iMFBs as well as inflammatory response and endothelial changes, suggesting an important role and therefore their potential value as biomarkers in the progression of intestinal fibrostenosis.
P119 Perianal Crohn’s disease and the development of colorectal and anal cancer: A systematic review and meta-analysis
Authors: Johansen M P ,   Martha Pollen Johansen Mads Damsgaard Wewer Andreas Nordholm-Carstensen Johan Burisch
Published: January 2023

Abstract

Background
Over the course of their disease, 15-30% of patients with Crohn's disease(CD) develop Perianal Crohn's disease (pCD). In approximately 5% of patients, perianal fistula is the only manifestation of their CD. Previous studies have found that perianal involvement results in an 11-fold increased risk for anal cancer. The aim of this systematic review was to assess the literature on the incidence and risk factors for colorectal cancer and anal cancer in patients with perianal Crohn’s disease.

Methods
A systematic review of the literature was performed using PubMed, Embase and Google Scholar. A meta-analysis was then conducted using a random-effect model.

Results
Five studies were included in the systematic review. Of the total patients, 26.5% had perianal Crohn’s disease. The median follow-up was 6 years. In total, 127 cases of colorectal cancer were found [0.43% of the included Crohn’s disease patients]. Perianal involvement was present in 50% of colorectal cancer patients [0.89% of the population]. Three of the studies specified the cancer to be rectal or anal, which were present in 68 and 24 cases [0.3% and 0.1% of patients], respectively. In a subgroup analysis of rectal and anal cancer, perianal involvement was most frequent in anal cancer, accounting for 46% of the cases. In the rectal cancer group, 37% had perianal involvement. The higher incidence of colorectal cancer in patients with perianal Crohn’s disease was confirmed in a meta-analysis.

Conclusion
Half of the patients with colorectal cancer and anal cancer were found to have perianal Crohn’s disease. In patients with perianal involvement, there was a higher percentage of anal cancer compared with rectal cancer. These results support the theory that patients with perianal Crohn’s disease are at increased risk for developing colorectal and anal cancer. Studies collecting more detailed data regarding patients and their cancers are needed to further specify the disease course.
P126 Ask twice: The importance of repeated faecal calprotectin testing prior diagnostic colonoscopy in an adult inception cohort
Authors: Rimmer P , Cheesbrough J , Quraishi M N , Sharma N , Cooney R , Love M , Iqbal T 
Published: January 2023

Abstract

Background
Elevated Faecal Calprotectin (FCP) is established as a valuable tool in differentiating Inflammatory Bowel Disease (IBD) from Irritable bowel syndrome (IBS) and monitoring IBD activity. Initial implementation studies in the UK demonstrated benefit from repeat testing to exclude false positives. This is not currently mandated by IBD consensus guidelines. Growing waiting times are increasing pressure to include a single result in straight to test pathways. No one level for significant elevation is defined with levels between 100-250ug/g used. We present our experience of the real-world utility of FCP used in a primary care referral pathway.

Methods
From Jan 2021-Nov 2022, new referrals were streamed into a rapid access ‘Inception IBD’ clinic on the basis of symptoms and raised FCP. A repeat FCP (kit sent in advance) was brought to the first appointment, with same day processing using the Buhlmann fCAL Turbo Test. Results and accompanying diagnosis and outcome data was collected prospectively. There was no standardised testing interval but median time from referral to review was 34 days.

Results
A single FCP was available for 425 patients with a final diagnosis. Two pre-treatment FCPs were available in 185. Median initial FCP was 949ug/g in those subsequently diagnosed with IBD (Ulcerative colitis 1162ug/g, Crohn’s 893ug/g) vs 353ug/g in those without IBD. This difference heightened on retesting, with median FCP in IBD 749ug/g vs 34ug/g in non-IBD (Fig 1). FCP fell between 1st and 2nd measurement in 88.6% of patients who had IBD excluded.

In IBD, baseline FCP showed strong correlation with established disease activity markers (Fig 2).

Baseline FCP levels were significantly higher in IBD patients who went on to require biologic treatment (Mann-Whitney U 2763, p&lt;0.001).

A variety of FCP cut-off values were assessed (Fig 4). A two sample &gt;200ug/g cut off performed best as assessed by Area Under the Curve (AUC). However, sensitivity fell to 81.5% at this level.

Of 15 IBD patients who didn’t have two FCPs &gt;200ug/g, 7 had an increase between the 1st and 2nd FCP (median 147 vs 487ug/g). The remaining 8 comprised 4 ileal Crohn’s, 3 mild proctitis and 1 stricturing colonic Crohn’s in whom FCP failed to correlate with disease activity. Overall, 83% (48/58) of patients with increasing 1st to 2nd FCP were diagnosed with IBD.

Conclusion
Our data supports repeat testing of FCP to avoid unnecessary investigations adding to post COVID endoscopy backlogs. A cut off of two values &gt;200ug/g had the best overall performance but can miss a small number of IBD cases, particularly those with isolated ileal disease or a more indolent disease course. This cut off should not be used in those with a marked increase between 1st and 2nd result, where IBD is likely.
P162 Earlier (luminal) surgery is associated to reduced postoperative morbidity in ileocaecal Crohn’s disease: results from SURGICROHN – LATAM study
Authors: IBD Latam Consortium S , Avellaneda N L , Saddy Rodrigues Coy C , Sarubbi Fillmann H , Saad-Hossne R , Muñoz J P , García-Duperly R , Bellolio F , Rotholtz N , Rossi G , Marquez V J R , Cillo M , Lacerda-Filho A , Carrie A , Yuki Maruyama B , Sarubbi Fillmann L , Ferro E , Londoño-Schimmer E , Iglesias A , Bras Harriott C , Campana J P , Londoño Estrada D , Kotze P G ,   SURGICAL IBD LATAM CONSORTIUM
Published: January 2023

Abstract

Background
Early surgical resection is an emerging concept for patients with ileocaecal Crohn’s disease (CD). The aim of this study was to compare postoperative outcomes after ileocaecal resections between patients with luminal and complicated CD.

Methods
A retrospective analysis of patients operated for ileocaecal CD during an 8-year period in ten tertiary referral academic centres from Latin America was performed. Patients were allocated into 2 groups: those operated for early (luminal) disease (Early Crohn’s Disease -ECD-) and for complications of CD (Complicated Crohn’s disease -CCD-). A comparative analysis was performed regarding short-term outcomes of surgery, considering overall postoperative complications as main outcome.

Results
337 patients were included in the analysis, 60 (17.80%) in the ECD group. Smoking and exposure to perioperative biologic drugs were more prevalent in CCD group. CCD patients had increased requirement of urgent surgery (26.71 vs. 15%, p=0.056), longer operative time (164.25 vs. 90.53 minutes, p&lt; 0.01), lower rates of primary anastomosis (90.23 vs. 100%, p=0.012), increased rate of overall postoperative complications (33.21 vs. 16.67%, p=0.013), more reoperations (13.36 vs. 3.33%, p=0.026), and higher rates of major anastomotic fistulas and hospital stay. On multivariable analysis, smoking (p= 0.001,95%CI: 2.59-32.11), operative time (p=0.022,95%CI:1-1.02), associated procedures (p=0.036,95%CI:1.09-15.72) and intraoperative complications (p=0.021,95%CI:1.45-92.31) were independently related to presenting postoperative complications.

Conclusion
Early (luminal) ileocaecal resections were associated to lower rates of overall postoperative complications. Proper timing for surgery, avoiding delays in surgical indication can impact postoperative outcomes.