bluuebunny/crossref_metadata_2025_split huggingface dataset:
P888 Evaluating patient access to infliximab subcutaneous in inflammatory bowel disease
Authors: Jang M , Yoo H , Kwon T 
Published: January 2023

Abstract

Background
Infliximab(IFX) subcutaneous(SC) was developed as a novel formulation biosimilar added to the intravenous(IV) infliximab. Infliximab is one of the most effective treatments in IBD and approval of subcutaneous formulation was expected to bring greater patient convenience, yet it had to overcome its hurdles in Health Technology Assessment (HTA) in the absent of the SC originator. This research aims to evaluate patient access to IFX SC based on time-to-reimbursement decision post market authorization in July of 2021.

Methods
The pricing database, IQVIA MIDAS® data and epidemiology data were combined to analyze patient access in 32 countries. We evaluated 1) status of the reimbursement 2) volume consumed in a country 3) average period from marketing authorisation to positive reimbursement decision 4) reason for delayed access.

Results
Since the market authorization, positive reimbursement decisions were made in 18 countries among 31 European countries including UK. Among them, patients who reside in 15 countries had records of utilization of IFX SC in the year of 2022. About 74.76% of IBD patients is eligible for reimbursement of CT-P13 SC among the assumed 1,023,765 IBD patients in Europe. Average time from market authorisation to positive reimbursement decision by health authorities were 9 months(2-17) in the case of IFX SC which suggests delayed reimbursement compared to biosimilars. Although most of the European countries offered shortened or simplified HTA pathways to biosimilars, most of the countries did not have clear guidance on pricing of the novel biosimilars. Several countries failed to provide IFX SC after a positive reimbursement decision because the procurement system failed to differentiate a novel biosimilar with different strength and form from the existing biosimilars in same molecule. This may have deterred the market entry; countries where adopted national tender grouped IFX SC with IFX IV(Norway, Hungary) or extended procurement basket to all available IBD treatment(Denmark and Lithuania).

Figure: Reimbursement status of infliximab subcutaneous in European countries

Conclusion
There are apparent differences in patient access to IFX SC among European countries. Biosimilars promises to bring improved patient access to biologics, however, pricing of bio-betters or bio-innovators could be convoluted that efforts are still warranted in order to bring the drug into the market within shortest possible time. Although IBD treatment options are expanding, IFX is still widely used. Adding another SC treatment may improve patient convenience and quality of life and thus, overall improved access to the drug is imperative for equitable use.
P890 Prevalence and Characteristics of Extra-intestinal Manifestations in a single cohort of Italian Patients with Inflammatory Bowel Disease
Authors: Marino M , Sigura E , Castagnaviz E , Dottor F , Colombo A , Solito S , Terrosu G , Buda A , Berretti D 
Published: January 2023

Abstract

Background
Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder comprised of Crohn disease (CD) and ulcerative colitis (UC). Patients with IBD may present extraintestinal manifestations (EIMs) that may affect different district such as joints, skin, eyes, and hepatobiliary area. Our objective is to characterize and determine the prevalence of EIMs in our cohort of patients affected with IBD

Methods
The study population consisted of IBD patients who were followed in one single tertiary Centre in North East Italy. Retrospectively demographic and clinical characteristics of patients were analysed. The diagnosis of EIMs was based on standard criteria and on specialist consultation.

Results
Our registry has 904 patients with IBD (M/F 484/420), 536 have UC (59,29%), 355 CD (39,26%) and 13 unclassified IBD (1.43%). Among them 170 patients (18,80%) presented at least one EIMs, 82 of 536 (15,29%) with UC and 81 of 335 (24,17%) with CD. The median age of these patients was 48 years old (36-57) and EIMs were more prevalent in females (55.6%) and in patients with younger age (57.7% with age range between 17-40 y.o.). In most of the patients (67.64%) were present more than one EIMs. Regarding the type of EIMs, the articular ones were by far the most frequent (67.7%) than followed by other manifestations: mucocutaneous (32.4%), hepatobiliary (11.2%), ocular (10.0%), pancreatic (5.9%), coagulation (3.5%), pulmonary (2.4%), muscular (1.2%), hearing loss (1.2%) and cardiac (1.2%). Furthermore EIMs were also more prevalent in smokers [p &lt;0.001], patients with extensive UC [p = 0.008] and patients with major IBD-related surgery [p = 0.015]

Conclusion
Our study confirm that about one-fifth of patients with IBD may have associated EIMs with rheumatic manifestations, by far, the most frequent symptom. CD and female patients with severe Crohn's disease represent the group with the highest risk of developing EIMs followed by smokers, extensive UC and with previous major IBD surgery. These patients should therefore be specially monitored and referred to the corresponding specialist when suggestive symptoms appear.
P892 Characteristics and trend of Inflammatory Bowel Disease epidemiology for 30 years from 1991 to 2020: A single-center experience analysis in Incheon, Korea
Authors: Na S Y , Choi H , Ji J S , Kim S Y 
Published: January 2023

Abstract

Background
Inflammatory bowel disease (IBD) in Asia is different from that of the West in incidence, prevalence, clinical features, and genetic mutations. The purpose of this study was to investigate changes in the characteristics and trends in patients with IBD over 30 years in a single center in Incheon, Korea.

Methods
Among 1,070 IBD patients (Crohn’s disease [CD] 286; ulcerative colitis [UC] 784) who visited from Jan 1991 to Dec 2020, 773 patients (CD 204; UC 569) who were first diagnosed and followed for more than 1 year were enrolled. The demographic characteristics and trends of IBD patients for 30 years of IBD were analyzed retrospectively by dividing them into three periods.

Results
In CD, the age at diagnosis gradually decreased from 24.7±5.1 years in 1990-2000 to 21.9±9.5 years in 2011-2020 (p-trend=0.025), but there was no significant change in UC (p-trend=0.177). The male-to-female ratio showed a tendency to increase from 0.7 to 1.5 in UC (p-trend=0.002) over 30 years. The UC/CD ratio gradually decreased from 6.4 in 1991-2000, 2.6 in 2001-2010, and 2.5 in 2011-2020. In CD, the colonic phenotype gradually decreased with the recent period (35.7%, 26.2%, and 15.2%, respectively; p&lt;0.01), but there was no difference in disease behavior (p=0.482). At the time of diagnosis, 35.8% of CD patients had a history of perianal abscess/fistula. In UC, there was no change in disease extent according to the periods, and the overall proctitis, left-sided, and pancolitis were 46.2%, 30.2%, and 23.6%, respectively. For the severity of UC, mild disease gradually increased; by 34.4% in 1991-2000, 47.0% in 2001-2010, and 60.1% in 2011-2020, respectively (p&lt;0.001).

Conclusion
The incidence and prevalence of IBD in Korea have continued to increase over the past three decades. Age, male-to-female ratio, phenotype, and severity at the time of diagnosis of IBD in Korea are constantly changing.
P896 Inflammatory Bowel Disease in the elderly, a survey of elderly patient demographics, disease-related complications and compliance with vaccination and screening services
Authors: Elwood S , Clarke M , Lukose T , Lardner C , Mc Gettigan N , Boland K , Patchett S 
Published: January 2023

Abstract

Background
Inflammatory Bowel Disease (IBD) in the elderly (&gt;60yrs) is becoming more prevalent in concordance with the ageing population and the rising incidence of IBD. An increasing number of patients are receiving a diagnosis of IBD in later years in addition to those with known IBD transitioning to elderly. The presentation, disease course, risk of complications and choice of medical therapies differ in this group from younger cohorts. We aimed to examine patient demographics and the incidence of adverse effects/complications amongst elderly IBD patients. We also sought to identify appropriate vaccination rates and uptake with screening services.

Methods
In a single tertiary centre, IBD patients aged &gt;60 attending the outpatient clinic or admitted acutely were invited to complete an anonymous written survey.

Results
28 patients surveyed to date. 61% (n=17) had a diagnosis of UC. 54% were female (n=15). Mean age was 67.5, while mean age at diagnosis was 50 (range 19-65). 25% (n=7) received a diagnosis of IBD after 60 years, of which 57% were female. Mean BMI was 25.9. 25% (n=7) reported an infection in the last 6 months, all of whom required treatment with antibiotics. There was only one case of infection requiring hospitilisation, a patient on biologic therapy who developed a clostridium difficile infection. COVID-19 affected 39% (n=11), none required hospitilisation. 21% (n=6) report 2 or more comorbidities, of which 50% report a recent infection requiring treatment. All patients who required IBD surgery (n=5) had a high BMI. 57% (n=16) had a smoking history, with 14% (n=4) being active smokers. Infliximab and salofalk granules were the most prescribed IBD treatments. 46% were on biologics (n=13), with anti-TNF being the most common (29%). 25% (n=7) reported steroid use in the last year while 14% were not currently on IBD treatment. 21.4% (n=6) reported prior malignancy, skin cancer being most common. 50% of cancer sufferers were smokers. 100% have had a minimal of two COVID-19 vaccines. 64% (n=18) have had a flu-vaccine in the last 12 months with 75% (n=21) report annual flu-vaccine uptake. 61% (n=17) had the pneumococcal vaccine. Bowel screening participation was 46.5% (n=13).

Conclusion
Smoking, high BMI and multiple comorbidities were common in elderly IBD patients. Infections were common in this cohort and typically required treatment with antibiotics, however, were rarely severe or required hospitalisation. Severe infections were seen in those on biologic therapy. Biologics were commonly prescribed to elderly IBD patients. Skin cancer was the most common malignancy. There was suboptimal uptake with vaccinations and bowel screening.
P897 Longitudinal multi-tissue transcriptomic study reveals patient-specific drug response determinants in Inflammatory Bowel Disease patients
Authors: Cervera Seco L M , Sánchez Mayor M , Corraliza A M , Salas A , Panés J , Marigorta U M 
Published: January 2023

Abstract

Background
Despite the lack of understanding of Inflammatory Bowel Disease (IBD) pathogenesis, association studies have made inroads into the elucidation of the genetic component of disease diagnosis. The corresponding determinants of drug response, in turn, remain obscure. Primary response is low, secondary loss of response is prevalent and remission rates are low (30% of patients roughly). Along with the expanding repertoire of drugs, it is critical to develop a strategy to reveal the factors contibuting to drug response at the patient level. Our goal is to understand drug response in IBD looking to establish a precision medicine strategy to assign patients a specific treatment based on their transcriptomic profile.

Methods
We carried out a longitudinal follow-up of 147 IBD patients, from whom we sampled 264 intestinal biopsies and 119 blood extracts. Patients were exclusively treated with one of the three main available biologics: 248 with infliximab (anti-TNF), 47 with ustekinumab (anti-IL12/IL23) and 88 with vedolizumab (anti-α4β7). RNA-seq profiles were obtained at three different times (baseline, 14 weeks and 46 weeks after treatment initiation), resulting in 232, 92 and 59 samples, respectively. Differential expression analysis and pathway enrichment analysis were performed to get drug-specific genes and response signatures.

Results
The initial exploratory analysis confirms that tissue is the main determinant of expression variability among patients. As for longitudinal response, anti-TNF-specific features are quintessentially inflammatory, especially involved in translation and immune pathways, while response to ustekinumab is associated with extracellular recognition. Of note, vedolizumab-specific profiles strikingly differ between biopsy and blood samples. We also revealed that drug response is determined during first weeks of treatment, as up- and down-regulated genes are shared across time points. This may entail huge consequences in the clinic since the determination of response could be assessed earlier. Using clinical activity to define responders, we identified around 200 differentially expressed genes that could predict response to infliximab at time zero. We also improved our understanding regarding individual response by carrying out trend analyses based on connectivity scores that identify individual-specific regulated pathways.

Conclusion
While we identified common patterns across time in enriched pathways, we could discern specific drug response profiles. Besides providing a renewed understanding of the molecular effects of biological drugs, we propose that personalised models predicting response are feasible, and a promising venue to develop therapeutic guidelines of biologics in IBD.
P902 Native American Mapuche ancestry is related to higher IBD risk in Chileans
Authors: Pérez T , Bustamante M L , Magne F , Travisany D , Alvarez-Lobos M , Hernandez-Rocha C , Azocar L , Aguilar N , Espino A , Estela R , Escobar S , Zazueta A , Baez P , Silva V , Arriagada E , Barahona C , Zollner L , Miquel J F , Lorenzo-Bermejo J 
Published: January 2023

Abstract

Background
Most genetic association studies rely on Caucasian, African and Asian individuals with inconsistent results depending on the population investigated, suggesting that genetic susceptibility to inflammatory bowel disease (IBD) may depend on interactions between ethnicity and genetic-environmental factors. Aim: To explore the contribution of genetic ancestry to IBD risk in Chileans. Aim: To explore the contribution of genetic ancestry to IBD risk in Chileans.

Methods
192 Chilean IBD patients were genotyped using Illumina’s Global Screening Array. Genotype data was combined with similar information from 3147 population-based Chilean controls from a published study on gallstones, body mass index, c-reactive protein and gallbladder cancer in Chileans (Barahona et al., Hepatology 2021). The individual proportions of Aymara, African, European and Mapuche ancestry were estimated using the software ADMIXTURE (supervised estimation). Using the statistical software R version 4.2.1, we calculated the odds ratios (OR) and 95% confidence intervals (CI) for gender, as well as age and ancestry proportions grouped into quartiles using the library “epitools”.

Results
Table 1 shows the investigated characteristics of the study population and their association with IBD risk. For example, the 1st and 3rd quartiles of the proportion of Mapuche ancestry in IBD patients were 24.7% and 34.2%, respectively, and the corresponding OR was 2.30 (95%CI 1.52-3.48) for the lowest versus the highest group.

Conclusion
The type and proportion of Native American ancestry in Chileans seems to be associated with IBD risk.
P907 NOD2 mutations are associated with the development of inflammatory and progressive digestive tract damage in Crohn’s disease
Authors: Behnisch S , Reiner J , Witte M , Holle A , Schäffler H , Huth A , Jaster R , Lamprecht G 
Published: January 2023

Abstract

Background
Single-nucleotide polymorphisms (SNP) of the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene are associated with higher risk for Crohn′s disease (CD). It has also been reported that they are more likely to associate with specific phenotypes such as stricturing or perianal disease and the need for resection surgery. The aim of our study was to investigate if these NOD2 variants are associated with higher cumulative bowel damage in Crohn’s disease.

Methods
We performed NOD2 genotyping in a cohort of 150 patients with CD from a tertiary care center in Germany. The risk polymorphisms SNP 8 (R702W, rs2066844), SNP 12 (G908R, rs2066845), and SNP 13 (1007fs, rs2066847) were screened for. The Lémann-Index (LI) was calculated to estimate digestive tract damage of each patient. Additionally, we collected the following data: age at diagnosis, disease location and behaviour using the Montréal classification, and the disease duration.

Results
Fifty patients carried at least one of the three SNPs. In the univariate analysis, the LI of patients with at least one risk-SNP was not significantly different from the LI in patients without a risk-SNP (NOD2 WT), 13.62 ± 15.10 vs. 11.57 ± 13.08, p=0.196. Also, after stratification for the single polymorphisms, the LI was not significantly different in patients with vs. patients without SNP. However, variants of NOD2 were associated with a higher LI in patients with non-stricturing, non-penetrating disease behavior (Montréal classification B1), 2.61 ± 2.80 vs. 0.85 ± 1.82, p=0.007. Importantly, in the presence of SNP13 a strong correlation between the LI and disease duration was found, rp = 0.69. In contrast, only a weak correlation was detectable in the presence of NOD2 WT, rs = 0.30 (figure 1). The LI was significantly higher in patients with SNP13 and an early disease onset than in patients who were first diagnosed at a higher age.

Conclusion
NOD2 risk polymorphisms are associated with a high LI during non-stricturing, non-penetrating disease behaviour. In line with this, we observed higher digestive tract damage in patients with CD diagnosis at a young age in patients with the polymorphism SNP13. Finally, our data suggest that particularly SNP13 predisposes to progressive damage accumulation over the disease course.
P916 Small bowel permeability improvement is associated with microbial changes seen in mild to moderate active paediatric Crohn’s disease patients on nutritional therapy
Authors: Verburgt C , Dunn K , Sigall Boneh R , Wine E , Benninga M , de Jonge W , Van Limbergen J 
Published: January 2023

Abstract

Background
Barrier disruption leading to impaired intestinal permeability in Crohn’s Disease (CD) has been associated with various processes, including (pro-inflammatory) cytokine production, impaired mucus production and altered tight junction protein expression. A recent study showed that healthy first-degree relatives of CD patients had abnormal intestinal permeability which was associated with altered gut microbiome composition. We have previously reported that intestinal permeability improves with nutritional therapy (by either Crohn’s disease exclusion diet (CDED) or exclusive enteral nutrition (EEN)). We hypothesized this improvement in permeability might be associated with changes in the gut microbiome caused by nutritional therapy.

Methods
Paediatric participants with mild-to-moderate CD from a prospective clinical trial evaluating nutritional therapy (with CDED+PEN or EEN) for induction of remission were included (NCT01728870). A lactulose/mannitol (L/M) test for intestinal permeability was performed at weeks 0 and 3 by administering a sugar solution containing lactulose (5 g) and mannitol (1 g) followed by urine collection for LC-MS/MS analysis. A cut-off L/M ratio 0.025 was used (Leibovitzh, Gastroenterology 2022). We compared 16S rRNA (V4V5) changes of dietary responders between weeks 0 and 6 to identify microbial changes associated with improved intestinal permeability.

Results
Paired L/M ratios were available for 53 patients (26 CDED+PEN and 27 EEN). Normal L/M ratios were seen in 15/26 (58%) of CDED+PEN patients and 15/27 (56%) of EEN patients at baseline, which improved to 19/26 (73%) in CDED+PEN and 17/27 (63%) in EEN (generalized linear model, p=0.574) at week 3. Notably, 7/11 (63%) CDED+PEN patients with abnormal intestinal permeability at baseline normalised, compared to 5/12 (41%) patients in the EEN group (NS). Dietary response has been shown to be associated with significant increases in Clostridia and decrease in Gammaproteobacteria (Gastroenterology 2019). Of dietary responders, intestinal permeability “non-improvers” showed no significant changes in microbial composition, whereas “improvers” showed significant increases in different genera of Eubacteriales (Clostridia), accompanied by increase in Alphaproteobacteria (all p&lt;0.05,LDA &gt;2) at week 6.

Conclusion
A subset of patients with paediatric CD have impaired intestinal barrier function and disrupted intestinal permeability. Achieving clinical remission and improvement in intestinal permeability share features of microbiome correction. Further study to characterise the effect of the microbiome and metabolome (including whole metagenome analysis) on intestinal permeability, particularly within a dysbiotic state such as CD, is warranted.
P929 Gut mucosal microbiota composition in Inflammatory Bowel Disease introduced to infliximab
Authors: Ventin-Holmberg R , Lindholm J , Eberl A , Taina S , Saavalainen P 
Published: January 2023

Abstract

Background
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastro-intestinal tract with the main subtypes Crohn’s disease (CD) and ulcerative colitis (UC). IBD is growing rapidly in incidence and prevalence throughout the world and is strongly associated with an imbalance of the gut microbiota, although the pathogenesis is unknown. There are multiple conventional treatments, but moderate to severe IBD is treated successfully with anti-tumor necrosis factor alpha (TNF-α) infliximab (IFX). Many have studied the fecal microbiota in relation to IFX treatment, but studies on the mucosal microbiota composition during IFX treatment are scarce. Additionally, there is a problem that up to half of the patients receiving IFX do not have a good long-term response. There are no methods available to predict the response to IFX, which would be crucial to save from both high costs and possible side-effects. Previously, predictive markers of IFX response have been mostly investigated from the fecal microbiota composition.

Methods
Here the aim was therefore to investigate the mucosal microbiota composition of the gut during IFX treatment and to determine whether the gut mucosal microbiota composition differed between responders and non-responders to IFX. This was investigated in an exceptional cohort including 72 IBD patients from whom biopsy samples from both small- and large intestine and fecal samples were collected before, during and after IFX treatment. The IFX response was determined clinically and by colonoscopy at week 12 after start of treatment.
The microbiota composition was determined by MiSeq sequencing targeting the 16S conserved rRNA regions of DNA extracted from the biopsies using an optimized repeated bead-beating isolation method. Additionally, the already published fecal fungal and bacterial microbiota composition was also included to get further comparison between these.

Results
Interestingly, the preliminary results of the mucosal bacterial microbiota also show that there is a significant difference between the response groups (p &lt; 0.05), similar to the fecal microbiota composition. Thus, the IFX response groups could be distinguished based on the fecal and mucosal microbiota composition.

Conclusion
These results could, together with previously published results, provide an urgently needed diagnostic tool for IFX response prediction.