bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP30 Long-term outcomes of Crohn’s perianal fistulas treatment: anti-TNF with surgical closure versus anti-TNF alone (PISA-II) - A patient preference RCT
Authors: Meima - van Praag MD E , Stoker J , D’Haens G , Gecse K , Dijkgraaf M , Bemelman W , Buskens C 
Published: January 2022

Abstract

Background
The PISA-II trial showed that anti-TNF induction combined with surgical closure induces MRI healing more frequently than anti-TNF alone at 18 months follow-up (FU) and that this was associated with no recurrences at the time. The aim of this study was to compare long-term outcomes of both treatment arms.

Methods
In this FU study, data were collected from patients who participated in the PISA-II trial, a multicentre, international patient preference randomised controlled trial that compared anti-TNF induction combined with surgical closure to anti-TNF therapy alone as treatment for Crohn’s perianal fistulas. FU data were collected from the time of enrolment in the PISA-II trial until November 2021. Primary outcome was radiological healing at MRI and secondary outcomes included long-term clinical closure, recurrences, anti-TNF trough levels (suboptimal level was defined as infliximab &lt;5.0ug/ml, adalimumab &lt;5.9ug/ml), incontinence (improved, decreased or never had), and a decisional regret scale.

Results
Long-term FU data were collected from 88 out of 94 patients included in the PISA-II trial, 35/38 in the surgical closure arm and 53/56 in the anti-TNF treatment arm. Median FU was 5 years (IQR 4–7). During long-term FU radiological healing occurred in significantly more patients in the surgical closure arm (40% vs 17%; P=0.018). Long-term clinical closure occurred in 71% in the surgical closure arm and in 60% in the anti-TNF treatment arm (P=0.533). Recurrences occurred in 20% in the surgical closure arm and in 36% in the anti-TNF treatment arm (P=0.111). One patient with radiological healing developed a recurrence (4.3%) vs 12/57 (21.1%) patients with clinical closure. Trough levels were available in 32/53 patients treated with anti-TNF. Around the time of recurrence a suboptimal anti-TNF serum trough level occurred in 6/10. In the surgical closure arm, 6 patients had more and 6 patients had less incontinence problems after treatment, comparable to the 5 patient in the anti-TNF treatment arm with more and 8 with less incontinence problems. All patients in the surgical closure arm who completed the questionnaire (strongly) agreed that undergoing surgery was the right decision and 79% of the patients in the anti-TNF arm (strongly) agreed, 14% neither agreed nor disagreed and 7% disagreed that anti-TNF treatment was the right decision.

Conclusion
This study further supports the previous finding that anti-TNF induction combined with surgical closure should be considered in patients with Crohn’s perianal fistulas as long-term outcomes are favourable. Interestingly, surgical closure does not seem to be correlated to decreased continence, and all patients agreed that surgery was the right decision.
DOP49 Context-dependent roles of High-mobility group box 1 (HMGB1) during intestinal inflammation and carcinogenesis
Authors: Zierz E , Foelsch K , Pelczar P , Qi M , Alawi M , Clauditz T , Gagliani N , Huber S , Huebener P ,   Huebener
Published: January 2022

Abstract

Background
HMGB1 is a ubiquitously expressed nucleoprotein with proinflammatory functions following cellular release. The protein is passively released during tissue necrosis, acting as a damage-associated molecular pattern, but can also be actively secreted by immune cells. Stool and serum HMGB1 levels have been suggested as markers of both inflammatory bowel disease (IBD) activity and colorectal cancer (CRC) invasiveness, and antibody-mediated HMGB1 neutralization was beneficial in animal models of IBD. We explored context-dependent functions of HMGB1 in the injured intestine using novel experimental mice with cell-specific genetic HMGB1 deficiency.

Methods
To circumvent the postnatal lethality of global HMGB1 deficiency in animals, we used the Cre-lox system to generate enterocyte-specific (Hmgb1ΔIEC , Villin-Cre) and myeloid cell-specific (Hmgb1ΔLysM , LysM-Cre) HMGB1-knockout mice. Animals were subjected to well-established models of acute (DSS, Citrobacter rodentium) and chronic (AOM+DSS, CD45RBhigh T cell transfer colitis, Apc+/min) intestinal injury, followed by clinical, endoscopic, histological and molecular analysis. HMGB1 expression was assessed in human IBD and CRC specimens.

Results
IBD and CRC biopsies exhibited high levels of HMGB1 expression in epithelia, immune cells, tumor cells and the peritumoral stroma. HMGB1 deficiency from enterocytes and myeloid cells did not alter Citrobacter- or T cell transfer-induced enterocolitis, when epithelial injury was comparably low. In contrast, Hmgb1ΔIEC mice exhibited aggravated DSS-induced colitis, as evidenced by severe weight loss as well as exacerbated neutrophil- and monocyte-driven mucosal inflammation compared to Hmgb1f/f . Whole tissue RNA sequencing indicated defective cellular proliferation in injured Hmgb1ΔIEC intestines. In the AOM+DSS-model, Hmgb1ΔIEC had a comparable tumor burden to Hmgb1f/f , whereas Hmgb1ΔLysM had significantly fewer and smaller tumors, potentially linked to metabolic alterations in the tumor micromilieu. In the Apc+/min model, enterocyte HMGB1 deficiency effectuated more and larger tumors, whereas leukocyte HMGB1 did not affect tumor load.

Conclusion
Contrasting antibody-mediated HMGB1 neutralization in animal models of IBD, our findings from genetic HMGB1 deletion studies reveal a critical role of enterocyte HMGB1 in the maintenance of the intestinal barrier during severe colitis. Impaired epithelial regeneration or inefficient local immune cell expansion in Hmgb1ΔIEC may account for the aggravated phenotype. HMGB1 from enterocytes and immune cells context-dependently affect maladaptive intestinal would healing, potentially mediated by cell-intrinsic and -extrinsic mechanisms that warrant further investigation.
DOP57 Development and validation of a convolutional neural network for the automatic detection of enteric ulcers and erosions in capsule endoscopy: A multicentric study
Authors: Afonso J , Mascarenhas M , Ribeiro T , Cardoso P , Gonçalves R , Ferreira J , Andrade A P , Mascarenhas Saraiva M , Cardoso H , Macedo G 
Published: January 2022

Abstract

Background
Capsule endoscopy (CE) is the gold-standard for the evaluation of the enteric mucosa in patients with suspected or known inflammatory bowel disease, particularly Crohn’s disease. Ulcers and erosions of the small bowel are common findings and their identification in CE is paramount for an accurate disease stratification.
Several artificial intelligence (AI) algorithms have been developed to aid endoscopists to detect lesions in different endoscopic modalities. With this project we intend to develop and test an AI algorithm for the automatic identification of ulcers and erosions in the small bowel mucosa.

Methods
A total of 2565 CE exams from two different centers (1483 from São João University Hospital and 1082 from ManopH Gastroenterology Clinic) were used to develop the Convolutional Neural Network (CNN). 55320 frames of the enteric mucosa were obtained, 18396 containing enteric ulcers and erosions, and 36924 containing normal mucosa. 90% of the frames were used to develop the training dataset and 10% were used to test the network. The patients included on the training dataset were excluded from the testing dataset. This patient split brings the technology performance closer to that of a real-life setting. The output provided by the CNN was compared to the classification provided by a consensus of experts.

Results
Our model was able to automatically detect ulcers and erosions in the enteric mucosa with an accuracy of 93.2%, sensitivity of 90.4% and a specificity of 93.9%. The mean processing time for the validation dataset was 29 seconds (approximately 306 frames/second).
An example of the output obtained after the network application can be seen in Figure 1.

Conclusion
The authors developed a CNN for the automatic identification of enteric ulcers and erosions in CE videos and tested it in AI naïve patients. This represents an evolution in the technology readiness level into a real-life clinical setting, that will surely improve the diagnostic yield of CE exams, which will ultimately translate into better patient care.
DOP79 Biomarkers for IBD using OLINK Proteomics inflammation panel: Preliminary results from the COLLIBRI consortium
Authors: Sudhakar P , Salomon B , Verstockt B , Ungaro R , Aden K , D’Haens G , Komori K , Guay H , Silverberg M , Vermeire S , Halfvarson J 
Published: January 2022

Abstract

Background
Circulating serum proteins have provided insights into disease pathogenesis and are being used to identify prognostic, diagnostic and therapeutic biomarkers for chronic inflammatory diseases. With this pilot project, the Collaborative IBD Biomarker Research Initiative (COLLIBRI) consortium aimed to unravel disease heterogeneity in inflammatory bowel disease (IBD).

Methods
Serum samples were cross-sectionally obtained from 3,390 individuals (Crohn’s disease (CD), n=1815; ulcerative colitis (UC), n=1170; healthy, n=405) recruited at nine centres from Sweden and Belgium. Relative levels of 92 proteins were analysed using the Proseek Multiplex Inflammation I Probe kit 96x96 (Olink Proteomics, Uppsala, Sweden) and reported as arbitrary units, i.e., normalised protein expression on a log2 scale. Using a multivariate integrative approach, we identified protein signatures distinguishing CD and UC samples and attempted to identify clusters or subgroups within patients. Recruiting centre, cohort and batch information were considered for the integrative analysis. Optimisation was performed for identifying the number of components and features per component using 5-fold cross-validation and Leave-One-Group-Out-Cross-Validation, respectively. Information on transcriptional regulators was retrieved from the ReMap project using the orthogonal regulatory resource ChEA3.

Results
A panel of 8 proteins was identified which could segregate CD and UC patients (Figure 1). FGF19 exhibited a consistent trend of expression (downregulated in CD) across all batches of datasets. An integrated AUC of 72.5% was achieved across the different batches of samples used in the study with the highest AUC (79.2%, P-value 8.5e-07) being recorded for a single batch of samples (CD = 42, UC = 56). On a centre-specific dataset, the cross-centre integrated signature achieved an AUC of 75.1%. We identified three transcription factors (MEF2A, BATF, NFKB2), of which the two latter ones are known to modulate intestinal inflammation and which could potentially regulate the expression of at least half of the genes encoding the proteins in the predictive 8-protein panel.

Conclusion
We identified an integrated proteomic biomarker panel capable of separating CD and UC patients. Through further integration of confounder variables along with using other supervised and unsupervised approaches, subsequent analyses may further refine the molecular heterogeneity among CD and UC patients. Our results demonstrate the need for large datasets to identify relevant clusters of patients with IBD, since the diagnosis exhibits a high degree of clinical heterogeneity.
*Equally contributed
P040 Reduced serological response to COVID-19 vaccines in patients with IBD is further diminished by TNF inhibitor therapy; Early results of the VARIATION study (VAriability in Response in IBD Against SARS-COV-2 ImmunisatiON)
Authors: Doherty J , Stack R , O’ Morain N , Girod P , Tosetto M , Inzitari R , Sheridan J , Cullen G , Buckley M , Mulcahy H , Ryan E J , Daghfal D , Doran P , O Morain C , Doherty G 
Published: January 2022

Abstract

Background
Patients with inflammatory bowel disease (IBD) have attenuated responses to current vaccinations. There is a limited body of evidence suggesting patients with IBD receiving TNF antagonists have an attenuated response to vaccination against COVID-19. We sought to determine the impact of IBD and various medications for the treatment of IBD on antibody responses to vaccination against COVID-19.

Methods
Patients with IBD (n=270) and healthy controls (HC, n=116) were recruited prospectively and quantitative antibody responses were assessed following 1st and 2nd doses of COVID-19 vaccination. The impact of IBD and medications for treatment of IBD on vaccine response rates was investigated.

Results
All HC seroconverted post complete vaccination [100%]. A small proportion of patients with IBD failed to seroconvert [2%]. Median IgG spike protein (SP) antibody levels post-complete vaccination in our IBD cohort was significantly lower than HC [2,613 AU/mL versus 6,871 AU/mL, p=&lt;0.001]. A diagnosis of IBD and viral-vector vaccine use were independently associated with lower IgG SP antibody levels. Patients with IBD receiving anti-TNF therapy had significantly lower IgG SP antibody levels [2444.6 AU/mL] than IBD patients not receiving these agents [3867.6 AU/mL]. Patients with IBD not receiving TNF inhibitors still showed attenuated responses compared to HC receiving a similar vaccine [p = &lt; 0.001].[Figure 1]. IgG SP antibody levels in our IBD cohort reduced rapidly during follow up.

Conclusion
Patients with IBD who do not seroconvert post-vaccination against COVID-19 are a vulnerable cohort. Patient with IBD have attenuated serological responses to SARS-CoV-2 vaccination. Use of anti-TNF therapy further impacts IgG SP antibody levels. Impaired response to vaccination in our study highlights the importance of booster vaccination programmes for patients with IBD.
P075 Neutrophils prevent rectal bleeding in Ulcerative Colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis
Authors: Leppkes M , Lindemann A , Gößwein S , Paulus S , Roth D , Hartung A , Liebing E , Zundler S , Acera M G , Patankar J V , Mascia F , Scheibe K , Hoffmann M , Uderhardt S , Schauer C , Foersch S , Neufert C , Vieth M , Schett G , Atreya R , Kühl A A , Bleich A , Becker C , Herrmann M , Neurath M F 
Published: January 2022

Abstract

Background
Bleeding ulcers and erosions are hallmarks of active ulcerative colitis (UC). However, the mechanisms controlling bleeding and mucosal haemostasis remain elusive.

Methods
We used high resolution endoscopy and colon tissue samples of active UC (n = 36) as well as experimental models of physical and chemical mucosal damage in mice deficient for peptidyl-arginine deiminase-4 (PAD4), gnotobiotic mice and controls. We employed endoscopy, histochemistry, live-cell microscopy and flow cytometry to study eroded mucosal surfaces during mucosal haemostasis.

Results
Erosions and ulcerations in UC were covered by fresh blood, haematin or fibrin visible by endoscopy. Fibrin layers rather than fresh blood or haematin on erosions were inversely correlated with rectal bleeding in UC. Fibrin layers contained ample amounts of neutrophils co-aggregated with neutrophil extracellular traps (NETs) with detectable activity of peptidyl-arginine deiminases (PAD). Transcriptome analyses showed significantly elevated PAD4 expression in active UC. In experimentally inflicted wounds, we found that neutrophils underwent NET formation in a PAD4-dependent manner hours after formation of primary blood clots, and remodelled clots to immunothrombi containing citrullinated histones, even in the absence of microbiota. PAD4-deficient mice experienced an exacerbated course of DSS-induced colitis with markedly increased rectal bleeding (96 % vs 10 %) as compared to controls. PAD4-deficient mice failed to remodel blood clots on mucosal wounds eliciting impaired healing. Thus, NET-associated immunothrombi are protective in acute colitis, while insufficient immunothrombosis is associated with rectal bleeding.

Conclusion
Our findings uncover that neutrophils induce secondary immunothrombosis by PAD4-dependent mechanisms. Insufficient immunothrombosis may favor rectal bleeding in UC.
P274 Bioelectrical impedance analysis identifies low skeletal muscle index in patients with Inflammatory Bowel Disease
Authors: Nguyen A , Holt D , Burns M , Herath M , Gibson P R , Ebeling P , Milat F , Moore G 
Published: January 2022

Abstract

Background
Low skeletal muscle index (SMI) has been associated with increased need for surgery and post-surgical complications in patients with Inflammatory Bowel Disease (IBD). On dual energy X-ray absorptiometry (DXA), SMI is routinely calculated by dividing limb skeletal muscle mass (kg) by the square of the height (m2). Bioelectrical impedance analysis (BIA) provides a quick, inexpensive and radiation-free method to measure body composition. The aim of this study was to compare BIA with DXA to identify patients with low skeletal muscle mass and to show change over 14 weeks.

Methods
This single-centre prospective study recruited adult patients with IBD and adult controls, matched for gender. Active disease was defined as a faecal calprotectin of ≥150 μg/g. Active IBD patients undergoing biologic induction had repeat body composition measurements at least 14 weeks apart. All patients underwent single-frequency segmental BIA (Tanita BC-418) and DXA (GE Lunar Prodigy). A BIA-predicted SMI was calculated by dividing limb fat-free mass (kg) by the square of the height (m2).

Results
Of 48 patients with IBD, 54% had Crohn’s disease, 56% were male and median age was 29 (IQR 23–40) years. 28 had active disease, 16 inactive disease and 4 had no faecal calprotectin available. Patients with IBD and controls (n=30) had similar total body water, measured by BIA, and differed in albumin levels (39 vs 40.1 g/L, p=0.011). In IBD patients and controls, BIA total fat-free mass correlated strongly with DXA-derived fat-free mass (0.96 and 0.93, both p&lt;0.0001). The BIA-predicted SMI also correlated well with DXA-derived SMI (0.89 and 0.91, both p&lt;0.0001).

The correlation was stronger for Ulcerative Colitis (0.96) compared to Crohn’s disease (0.84). In patients with IBD, the mean difference between BIA-predicted SMI and DXA-derived SMI was 1.1 ± 0.6 kg/m2 with 95% limits of agreement, -0.1 to 2.3 kg/m2. Controls followed a similar trend with a mean difference of 0.5 ± 0.6 kg/m2 and 95% limits of agreement, -0.5 to 1.6 kg/m2.

The BIA-predicted SMI demonstrated a strong ability to identify low DXA-derived SMI for women with IBD (AUC: 0.98) and less so for men (AUC: 0.79). In 14 patients undergoing biologic treatment, change in DXA-derived SMI correlated with BIA-derived SMI (0.76, p=0.003).

Conclusion
An accurate estimate of SMI can be obtained with BIA as point-of-care in clinical practice. Further prospective studies with larger sample sizes are needed to determine the accuracy of BIA in monitoring changes of SMI during IBD treatment.
P327 Comparison of adalimumab drug levels and drug survival in proactive vs reactive therapeutic drug monitoring
Authors: Shields S , Dunlop A , Barry S , Galloway P , Seenan J P , Macdonald J 
Published: January 2022

Abstract

Background
The therapeutic landscape for inflammatory bowel disease (IBD) has expanded in recent years. The anti-TNF drug adalimumab remains one of the most commonly prescribed treatments. However, rates of loss of response to adalimumab are significant. Therapeutic Drug Monitoring (TDM) has emerged as a tool to prevent loss of response to treatment but there is no consensus on the optimum TDM testing strategy., 2 testing strategies are commonly used - proactive TDM (pTDM), performed during sustained clinical response and reactive TDM (rTDM), performed following loss of response. The aim of this work was to compare adalimumab drug levels (DL) and drug survival (DS) for patients exposed to pTDM compared to rTDM testing strategies.

Methods
Data for patients with IBD, treated with adalimumab, and exposed to TDM, was extracted from the Scottish Biologic TDM database. Patients were assigned to pTDM or rTDM groups based on the indication of their first TDM test. Prescribing information was extracted from the NHS Scotland Safe Haven homecare prescribing database. Homecare delivery dates were used to infer start and end dates of adalimumab treatment. Where adalimumab start date was before, 2017, a start date of, 1/1/2017 was used to coincide with the introduction of the Scottish TDM service. The study period was, 1/1/2017 to, 1/3/2020 giving a maximum duration of drug exposure of, 38 months. The most recent drug level was used for each patient to reflect the impact of the TDM strategy employed. SPSS was used to perform statistical analysis.

Results
367 patients were included for analysis, 190 males and, 177 females, 262 with Crohn’s disease and, 105 with Ulcerative Colitis., 314 patients were assigned to the pTDM group, and, 53 to the rTDM group. The mean DL across both groups was, 9.5 mcg/ml, with no significant difference seen between pTDM and rTDM groups (p=0.642). Median DS in the pTDM group was, 21 months versus, 15.6 months in the rTDM group. 277 patients (75.5%) remained on treatment at the end of the study, 244 (77.7%) in the pTDM group, versus, 33 (62.3%) in the rTDM group. DS was significantly higher in the pTDM group compared to the rTDM (p=0.004) group (Fig., 1), with divergence of the survival curve seen after, 6 months.

Conclusion
pTDM has been clearly favoured by clinicians from the outset of the TDM service. Whilst our data shows that DLs do not vary significantly between TDM groups, importantly, the DS with adalimumab is longer with pTDM as part of routine clinical care, when compared to rTDM. Further evaluation of clinical outcomes including steroid prescription, hospital admissions and surgery rates in the context of pTDM and rTDM strategies is therefore warranted, and in progress.