bluuebunny/crossref_metadata_2025_split huggingface dataset:
P169 Circulating eNAMPT predicts anti-TNF response in IBD patients: possible place in therapy of anti-eNAMPT antibody
Authors: Travelli C , Cascetta G , colombo G , Alessi A , Caputo E , Lenti M V , Pasini A , Porta C , Ribaldone D , Pastorelli L , Di Sabatino A , Genazzani A , Caviglia G P , Stocco G 
Published: January 2024

Abstract

Background
extracellular Nicotinamide phosphoribosyltrasferase (eNAMPT) is a cytokine with paracrine and autocrine effects on different cell types. Importantly, eNAMPT levels are increased in patients suffering of Inflammatory Bowel Diseases (IBD). Biologic drugs have been found effective in many IBD patients; however, a large proportion of patients with severe disease fail to achieve remission due to lack of drug response, loss of response, drug intolerance, or severe side effects that require cessation of therapy. Therefore, there is a clinical need for predictive response biomarkers as well as for new therapeutic strategies.

Methods
First, we investigated the expression of NAMPT in biopsies, in stools and the secretion of eNAMPT in serum in four cohorts of IBD patients. Second, we investigated if circulating eNAMPT levels correlate with the clinical response to biologics (infliximab, adalimumab, ustekinumab, vedolizumab). Clinical response is defined as a reduction of &gt;2 points in HBI (for CD) and in pMAYO (for UC) from baseline. Third, we have developed a monoclonal anti-eNAMPT antibody and we have evaluated its preclinical efficacy in acute and chronic preclinical models of IBD.

Results
We have determined the levels of circulating eNAMPT in three cohorts of patients that were not controlled by DMARDs and were treated with infliximab (IFX, cohort 1 and 3) or adalimumab (ADA, cohort 2). Notably, we confirmed a pronounced variability through the cohorts, identifying a group of patients with eNAMPT serum levels comparable with healthy adult populations and a group that showed elevated levels of eNAMPT. Performing a ROC curve analysis, a cutoff of 4.5 ng/ml can be extrapolated to discriminate these two populations.
Noteworthy, 100% patients with levels of eNAMPT below 4.5 ng/ml were responsive to infliximab/adalimumab. In contrast, anti-TNF therapy failed either at 14 or 22 weeks in some patients with high circulating levels of eNAMPT, indicating that high systemic eNAMPT might be associated with an increased risk of resistance to anti-TNF therapy. Notably, we found also that eNAMPT levels in stools of IBD patients are elevated compared to healthy subjects.
Then, we have developed and validated a candidate monoclonal antibody (called C269) which bind to eNAMPT, block is cytokine activity and reduces IBD symptoms, immune infiltrate and fibrosis in DSS and DNBS models.

Conclusion
Our data demonstrate that eNAMPT serum levels correlate with the clinical response to anti-TNF therapies suggesting that eNAMPT is not a simple by- stander of IBD, and that local and serum eNAMPT could be define as a biomarker to define the responsiveness to biologics. Notably, its neutralization might be a pharmacological strategy worth investigating.
P173 Characterization of the gut microbiota and the colonic immune response in acute severe ulcerative colitis : the multi-omics ITAC project
Authors: Riviere P , Dallmann-Sauer M , Enaud R , Bessissow T , Treton X , Uzzan M , Poullenot F , Zerbib F , Laharie D , Schurr E 
Published: January 2024

Abstract

Background
Limited understanding exists regarding the pathogenesis of acute severe ulcerative colitis (UC). Microorganisms are proposed as potential triggers due to the resemblances to infectious colitis and the essential role played by gut microbiota in UC-related inflammation. Our aim was to identify microbiome elements and host factors associated with acute severe UC.

Methods
This was a prospective study across three referral centers comparing two UC patient groups: acute severe hospitalized UC (as per Truelove and Witts criteria) and non-severe UC. We analyzed gut microbiota using 16S rRNA gene sequencing and conducted single-cell RNA-Seq on rectal biopsies in a subgroup of patients to uncover cellular subtypes and pathways involved in mucosal inflammation. We utilized whole blood RNA-Seq to investigate the host pathways involved in mediating systemic inflammation.

Results
Forty-one patients (23 (56%) female, median (interquartile range IQR) age 42 (34 – 57) years were included: 19 with acute severe UC and 22 with non-severe UC. Compared to patients with non-severe UC, those with acute severe UC displayed distinct gut microbiota with reduced diversity, increased Proteobacteria (Escherichia/Shigella genus), and decreased Lachnospiraceae and Ruminococcaceae. In severe cases (n=4 - 13,047 cells), single-cell RNA-Seq analysis of rectal biopsies revealed distinctive patterns compared to non-severe cases (n=5 - 18,433 cells): plasmablasts showed an altered transcriptomic profile with heightened IgG expression, and there was an expanded cluster of interleukin (IL) 26 expressing T cell population. Innate immune cells exhibited a pro-inflammatory profile marked by increased expression of the IL1B gene. In blood samples, we observed no distinct differentiation of transcriptomic profiles between severe and non-severe cases.

Conclusion
Our multi-omics study reveals key cellular and bacterial components in acute severe UC pathogenesis. We identified Proteobacteria, especially Escherichia coli as a potential pathobiont in acute severe UC. At the colonic level, we observed an increased IgG/IgA ratio, while both T cells and innate immune cells indicated a pro-Th17 mucosal environment. Enhanced systemic inflammation in acute severe UC was not reflected by specific changes in immune circulating cells. These insights may pave the way for future research focusing on microbiome modulation, interventions targeting plasmablasts, or nuanced inhibition of the Th17/IL-23 axis in acute severe UC.
P186 Comparative Analysis of Clinical Phenotypes and Pathogenic Features between Late-Onset and Infantile-Onset Monogenic Inflammatory Bowel Disease
Authors: Xiao F , Liu H , Xu J , Shen Y , Liao J 
Published: January 2024

Abstract

Background
Previous research on monogenic IBD (m-IBD) has mainly focused on very-early-onset IBD (VEO-IBD) and Montreal classification A1 type IBD patients. In non-A1 type (age &gt; 16y) late-onset IBD patients, some individuals also exhibit IBD manifestations due to monogenic mutations. Here we systematically review the literature, using infantile-onset monogenic IBD patients as a control, to explore the genetic characteristics, clinical presentations, and treatment strategies of late-onset monogenic IBD.

Methods
Based on the onset age of IBD, m-IBD was categorized into infantile-onset (IO, &lt;2 years) and late-onset (LO, &gt;16 years as non-A1 type based on Montreal classification) groups. A systematic review was conducted to analyze the gastrointestinal (GI) clinical features of detailed cases published from January 1990 to June 2023 and to summarize the correlation between genetic pathogenesis and onset ages.

Results
512 m-IBD cases (398 IO and 114 LO) associated with 87 genes were included. Of these genes, 25 out of 87 genes were found to cause both IO and LO conditions. Crohn’s disease (CD) was the predominant type of IBD, account for 42.2% of IO and 44.7% of LO cases. Difficult-to-treat IBD patients showed similar rates (17.4% for IO and 13.0% for LO). However, infantile-onset cases were predominantly associated with complex perianal disease (13.5%), while late-onset cases were linked to postoperative recurrence following surgical resections (10.6%). Anti-inflammatory medicine and biologics were the main strategies, but in infantile-onset (IO) cases, immunosuppressants (57.9%), parenteral nutrition (26.8%), gastroenterostomy (20.2%), and HSCT (24.6%) were more frequently utilized compared to late-onset (LO) cases, where intestinal resection (37.8%) was more prevalent. Homozygosity was the predominant zygosity type (39.9% in IO and 39.3% in LO), while heterozygosity was more prevalent in LO cases (28.9%) compared to IO cases (13.3%) (p&lt;0.05). Most of the genes associated with median onset ages of IBD before 2 years were causative genes for primary immunodeficiency (PID), whereas significantly lower rate of PID genes mutation was found in LO cases (26/27, 96.3% vs. 6/11, 54.5%, p= 0.005).

Conclusion
m-IBD patients predominantly present with CD, ulceration and atypical pathology, colon involvement, and difficult to treat regardless of onset ages, but vary in terms of family history, GI symptoms, location of the lesion, polyps and villous atrophy, type of complications, treatment options, and type of Difficult-to- treat IBD.
P188 Cumulative inflammatory burden as a risk factor for colorectal neoplasia in inflammatory bowel disease patients with primary sclerosing cholangitis: a multi-center case-control study
Authors: Van Lierop L , Derks M E W , te Groen M , Tran C D , Lytvyak E , Dijkstra G , Montano-Loza A J , Hoentjen F 
Published: January 2024

Abstract

Background
Inflammatory bowel disease (IBD) patients with concomitant primary sclerosing cholangitis (PSC-IBD) have a 25-year cumulative risk of up to 50% to develop colorectal neoplasia (CRN). Mucosal inflammation is an important driver of CRN, but it is unknown whether this also applies to PSC-IBD patients. We aimed to assess the impact of chronic mucosal inflammation per colonic segment on CRN risk in PSC-IBD patients.

Methods
This is a multi-center case-control study including cases with PSC-IBD and CRN and controls with PSC-IBD without CRN. Subjects were included from 8 medical centers in Canada and the Netherlands. Exclusion criteria were a CRN diagnosis prior to IBD or PSC diagnosis, familial CRC syndromes, and &lt;2 available colonoscopy reports. Data was collected on demographics, IBD and PSC disease characteristics, CRN lesions, and endoscopy reports between 1977 and 2023. Pan-colonic and segmental (right colon, transverse colon, left colon, rectum) endoscopic cumulative inflammatory burden scores were calculated as the sum of (mean) endoscopic inflammation severity between colonoscopies x length of the surveillance interval until index procedure. The index procedure was the colonoscopy during which CRN was detected (cases) or randomly selected and matched for disease duration (controls). The primary outcome was a CRN diagnosis, secondary outcomes were CRN grade and location, time to CRN (Kaplan-Meier curve), pan-colonic cumulative inflammatory burden, cumulative inflammatory burden per colonic segment harboring CRN, and colonic surgery.

Results
We included 335 PSC-IBD patients (224 UC, 101 CD) with a median follow-up of 8 years (IQR: 5.0-14.0) and 6 endoscopies (IQR: 4.0-8.0). Median disease duration was 19.5 years for IBD (IQR: 11.0-26.0) and 13 years for PSC (IQR: 7.0-19.0). Advanced neoplasia (HGD or CRC) was found in 35 out of 102 cases (34%). Fifty-six (55%) cases were diagnosed with &gt; 1 lesion, and 43 (42%) had ≥ 1 right-sided lesion. Median time to index CRN was 17 years (IQR: 8.0-24.0). Sixty-six patients underwent (sub)total colectomy or proctocolectomy, including 49 (74%) due to CRN diagnosis. There was no difference in pan-colonic cumulative inflammatory burden scores (mean scores: 4.7 (cases) and 3.7 (controls); P=0.21, 95%-CI: -2.52-.56) and segmental scores (mean scores: 4.9 (cases) and 4.1 (controls); P=0.27, 95%-CI: -2.29-.65) between cases and controls. Mortality was 13% (n=45.)

Conclusion
In this large multi-center cohort study, the risk for CRN-associated colectomy in PSC-IBD was high, while pan-colonic and segmental cumulative inflammatory burden scores were not associated with CRN risk.
P192 Personalizing treatment for predicting response to infliximab in children with Crohn’s disease using proteomic biomarkers
Authors: Winter H , Baldassano R N , Pfeffkorn M D , Wali P , Verstraete S G , Picoraro J A , Washek M A , Kumar N , Mortan W , Havard- Jr M , Blystone L , Trombler B , Pursley C , Lin X , Dillon S T , Gu X , Otu H H , Ngo L , Libermann T A 
Published: January 2024

Abstract

Background
Identifying minimally invasive diagnostic biomarkers that predict and monitor response to TNF inhibitors would enable treatment to be personalized and increase knowledge of the biological pathways associated with response or lack thereof.

Methods
Children and adolescents with Crohn’s disease who started treatment with infliximab (IFX) were enrolled in a prospective, multi-center (n=6) trial to identify biomarkers that predict response to IFX. Electronic case report forms were prepared by Studytrax (Macon, GA). Subjects &lt;18 years of age were diagnosed with Crohn’s disease using standard clinical/pathologic criteria. Clinical evaluation and serum samples were obtained prior to initiation of IFX, after induction (dose 4), at six months, and after one year or at the time of treatment withdrawal. There were 119 subjects enrolled and 102 subjects completed induction. Non-responders (n=15) were defined prior to the 4th infusion as having a PCDAI &gt; 10, an elevated Physician Global Assessment (PGA) or requiring dose escalation or medication change. Responders at the 4th infusions were either in remission (PUCAI ≤ 10) or were described as quiescent by PGA. Using the 7k SomaScan (SomaLogic; Boulder, CO) proteomics platform, quantitative protein profiles were generated from banked pre-treatment (V1) and after the three-dose induction (V2) to identify candidate protein biomarkers predictive of therapeutic response. Associations between the 7,310 proteins detected with SomaScan and response to IFX were assessed using t test. Response predictor models were developed using linear regression with backward selection. We report our preliminary findings from a discovery cohort of 56 subjects who completed induction.

Results
There were 15/56 (27%) non-responders and 41/56 (73%) responders at V2 after IFX induction. SomaScan analysis of the 56 individuals identified sets of differentially expressed proteins discriminating between non-responders and responders at both V1 and V2 and also defined protein signatures that changed from V1 to V2 for responders and non-responders, respectively. Strikingly, only responders demonstrated significant decreases in pro-inflammatory pathways at V2 compared to V1, thereby correlating well with anticipated reduced inflammation in responders. A 6-protein linear regression model performed with an AUC of 0.99 for predicting IFX response at pre-treatment V1.

Conclusion
In a discovery cohort from a multicenter, prospective trial of children and adolescents treated with infliximab, a comprehensive proteomics platform was able to identify serum proteins that are highly associated with response to infliximab and accurately predict response prior to treatment.
P197 Exploring diet categorisations and their influence on flare prediction in IBD, using Sparse Group LASSO
Authors: Stevens C L , Adriaans G M C , Spooren C E G M , Peters V , Pierik M J , Dijkstra G , Almeida R J , Jonkers D M A E , Campmans-Kuijpers M J E 
Published: January 2024

Abstract

Background
Diet is an important environmental factor that may affect flare occurrence in inflammatory bowel disease (IBD), but analyses are hindered by its complexity. Different a priori and a posteriori dietary assessment tools can be used, such as dietary quality scores and dietary pattern analyses. The Sparse Group LASSO (SGL) might be a novel method combining an a priori and an a posteriori approach. In this study, we aim to explore the SGL method to study whether different food categorisations, representing different dietary patterns, can predict flares in patients with IBD.

Methods
Baseline data on habitual dietary intake and longitudinal data on disease course was collected over a period of 24 months from two cohorts from the Northern and Southern provinces of the Netherlands. Collected food items were classified into 22 food groups. These were further classified into 3 diet categorisations, representing different dietary patterns: model 1. Plant vs animal vs mixed; model 2. Potentially healthy vs neutral vs potentially unhealthy; model 3. Ultra-processed vs not ultra-processed. The SGL parameter ‘lambda’ identifies important groups using a priori group information, while allowing for only a subset of variables within a group to be important predictors.

Results
Of 724 eligible patients, 427 were in remission at baseline and could be included in the SGL analyses. 106 patients (65.1% female, 34% ulcerative colitis, mean age 43.3 ± 14.7 years) developed a flare within 11.2 ± 6.6 months of follow-up. There was a significant higher crude food intake of red meat (p=0.028) and vegetables (p=0.027) in patients who developed a flare compared to those remaining in remission. Prediction models were moderate with AUC varying between 0.425 and 0.542 for model 1, 0.512 and 0.562 for model 2 and 0.451 and 0.612 for model 3 (Table 1). All models showed red meat, legumes and vegetables as the first selected predicting variables. Unexpectedly, legumes and vegetables predicted a higher risk on flares independently of their categorisation. This was robust in our data and confirmed by Kaplan-Meier survival analyses. Notably, clinical confounders sex and kilocalorie intake had the highest predictive values in all 3 models.

Conclusion
Categorisation of the same food groups and food items in different ways influences the predictive value of the SGL method. For the present study, categorising according to ultra-processed and not ultra-processed achieved the best prediction model, though still moderate. The current exploration of the SGL method showed that food might not be the most important predictor of flares in IBD. However, red meat, legumes and vegetables were the most important dietary influencers in these cohorts.
P209 Work productivity and unmet needs of treated ulcerative colitis patients: A Japan National Health and Wellness Survey study
Authors: Kim H , Huang Z , Qin F , Arokianathan F M N , Kamiya Y , Wang D , Hiraoka S 
Published: January 2024

Abstract

Background
Ulcerative colitis (UC), a subset of inflammatory bowel disease (IBD), is a chronic, immune-mediated disease process which causes inflammation and ulceration of the large intestine. In Japan, the annual prevalence of UC in 2014 showed a ten-fold increase in more than 10 years. Despite current treatments, patient-reported disease challenges persist. This study investigated the disease burden and unmet needs of treated UC patients in Japan.

Methods
This cross-sectional, observational study used existing data from the online, self-administered Japan National Health and Wellness Survey conducted in 2017, 2019, and 2021. Respondents were aged ≥18 years, with self-reported UC and had undergone/were on treatment [5-Aminoslicyclic acid (5-ASA), steroids, immunomodulators (IMs), biologics (Bio)/Janus kinase inhibitors (JAKi), or others]. Data pertaining to demographics and clinical characteristics, medication adherence, health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), and indirect cost were collected and analysed.

Results
Among 293 treated UC patients in Japan, most were conventional treatment users (84%) and 29% were living with UC for ≥15 years. Despite active treatment, 91% of patients reported UC as bothersome to a certain degree, 35% reported having moderate-to-severe disease severity post-treatment, and 55% reported ≥1 persisting UC symptom. Treated patients reported EuroQoL-5-dimension visual analogue scale scores of 68. Depression and anxiety were reported in ≥35% of patients and majority (68%) of employed patients reported work productivity impairment. On average, employed UC patients reported 30-40% WPAI on a weekly basis, resulting in a mean indirect cost of 1.12 million Japanese yen (€8,799) per patient annually. Males, moderate-to-severe disease activity, and low treatment adherence (&lt;80%) were associated with increased WPAI (p&lt;0.05). In comparison to 5-ASA users, Bio/JAKi users had the highest work impairment, while steroid and IM users had higher activity impairment (p&lt;0.05).

Conclusion
The overall HRQoL scores were lower than the average Japanese healthy population and the indirect cost due to work productivity impairment was high, equating to approximately 1/5 of the average household income. Those with lower treatment adherence consistently reported the highest work and activity impairment. The findings implicate a high disease burden and unmet needs affecting Japanese UC patients despite currently available treatments, suggesting the importance of a new convenient treatment for optimising UC outcomes. Additionally, workplace accommodations and understanding of employers on UC could assist in improving work productivity of UC patients.
P218 Development of Magnetic Resonance Imaging based index to differentiate Crohn’s disease associated perianal fistula and cryptoglandular perianal fistula
Authors: Singh A , Kakkar C , Bhardwaj A , Bonaffini P A , Goyal M , Marwah M , Sachdeva A , Bansal N , Mahajan R , Midha V , Sood A 
Published: January 2024

Abstract

Background
Magnetic resonance imaging (MRI) is the standard for evaluating perianal fistulae. Perianal fistula can be the first manifestation of CD, and needs to be differentiated from non-CD associated perianal fistula. This study sought to identify the variations in MRI characteristics of perianal fistulas in patients with and without inflammatory bowel disease (IBD), considering the potential implications for treatment decisions.

Methods
This was a single-center cross-sectional analysis of patients who underwent pelvic MRI for assessment of perianal fistula between January 2021 and June 2022 at Dayanand Medical College and Hospital (DMCH), Ludhiana, India. Patients who underwent dedicated MRI fistula protocol were included. Patients with prior anal resection or anastomosis, anorectal tumor, or equivocal imaging findings that could not be definitely assessed as a fistula were excluded. The following features were assessed: anatomic type of fistula (Parks classification), luminal origin (hour clock position), anal verge distance, signs of acute inflammation, circumference of anus involved by inflammation, presence of rectal inflammation, and abscess.

Results
Between January 2022 and December 2022, a total of 287 MRI scans were conducted to assess for perianal fistulae. Out of these, 119 MRI scans met the eligibility criteria and 32(26.89%) were associated with an established clinical diagnosis of CD. A higher proportion of females had CD-associated perianal fistula compared to non-CD perianal fistula. A significantly greater percentage of CD-associated perianal fistulas exhibited supra-levator extension, multiple and branched fistula tracts, and ≥2 internal and external openings. Patients with CD had higher prevalence of concurrent perianal abscess, proctitis, anorectal strictures, and a greater number of clock hours of inflamed anal circumference, compared to patients with cryptoglandular fistula. (Table 1) On multivariate logistic regression analysis, female sex, ≥2 internal openings, proctitis and height of the mucosal origin of the fistula from the anal verge &gt;1.85 cm independently predicted the perianal fistula to be associated with CD. We constructed the DMCH index as follows:
DMCH index: (3xfemale sex) + (3x≥2 internal openings of the fistula tract) + (6xrectal wall thickening) + (2xheight of mucosal origin of the fistula from anal verge &gt;1.85 cm)
The DMCH index greater than 7 identified the perianal fistulae associated with CD with a sensitivity of 84% and specificity of 91% [Area under curve 0.91; 95% CI 0.85-0.97; P&lt; 0.0001].(Figure 1)

Conclusion
The DMCH index identifies CD associates perianal fistula with a high level of accuracy. These findings require validation and confirmation in independent, multi-reader studies.