bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP74 Initial Clearance of infliximab is a predictor for the time of formation of anti-drug antibodies
Authors: Kutschera M , Primas C , Reinisch S , Novacek G , Kim S H , Lee S H , Lee J H , Reinisch W , Mould D R 
Published: May 2021

Abstract

Background
Treating patients with biologics like infliximab (IFX), may cause the formation of antidrug antibodies (ADA). ADA are associated with faster drug clearance, reduced treatment efficacy and increased risk of infusion-related side effects. The aim of this study is to identify possible predictors for ADA-formation.

Methods
A time to first detection of ADA model was developed by using data from a Phase 3 clinical trial of biosimilar CT-P13 and originator infliximab comparing efficacy and safety in moderately to severely active Crohn’s disease (CD). We analyzed data from 220 patients initiating IFX. Seven subjects with ADA present at baseline were discarded. The following baseline covariates were evaluated in this analysis: age, weight, first estimated drug clearance, disease duration, dose, sex and concomitant immune-modulators. Continuous covariates were divided into lower quartile, inter-quartile range, and upper quartile bins. Kaplan-Meier survivor estimates were plotted by bin. The data was then modeled parametrically with NONMEM by constructing a full model which was further refined using the Wald’s Approximation Method algorithm. Hazard ratios and probability of ADA at time points of interest were calculated for significant covariates.

Results
Initial IFX clearance, concomitant immunomodulators and IFX dose were identified as being statistically significant predictors of the time to first ADA. The model suggested that the hazard of ADA increases by 61% for every increase on 0.1 L/day in clearance, it decreases by 41% with concomitant administration of immunomodulators and decreases by 29% for every increase in dose of 100 mg. Thus, for a patient with initial IFX clearance of 0.2 L/day, no immunomodulators and a dose of 328 mg, the average time to first ADA is 374 days (range 221–451). If clearance is 0.4 L/day under the same conditions, then ADA onset is 144.5 days (range 90–216). Increasing the starting dose to 428 mg would improve the time to onset to 203 days (range 110–337). Again, under the same conditions, adding immunomodulator would increase the time to onset to 354 days (range 214–451).

Conclusion
We have identified initial infliximab clearance as an independent predictor for onset of ADA in CD patients. Our results suggest that early assessment of clearance should guide treatment optimization with IFX in patients with CD, including the addition of concomitant immunosuppressants or increasing the dose during induction.
N03 Information flow experiences during COVID-19 in IBD patients: a prospective observational study
Authors: Geens P , De Dycker E , Paps A , Lambrechts T , Sabino J , Ferrante M , Vermeire S 
Published: May 2021

Abstract

Background
During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, several patients contacted members of the IBD team with coronavirus disease 2019 (COVID-19) related questions. Some patients intended to cancel scheduled IBD clinic outpatient visits or endoscopic examinations and/or stop or postpone their medication. We surveyed the need for information by IBD patients during the SARS-CoV-2 pandemic and the role of the IBD team in this regard.

Methods
We performed an anonymous survey at the IBD department of our tertiary referral center. The questionnaire contained 15 closed questions, including on basic demographic data, medication use, testing for COVID-19, information sources, and intention to stop or postpone medication or follow-up. The questionnaire was available to all adult patients attending the IBD outpatient clinic and infusion unit from July 1st until October 30th 2020. All questionnaires were collected before the second COVID-19 wave. Patients on subcutaneous medication that did not attend the IBD clinic during these months were contacted via e-mail.

Results
We collected 965 questionnaires. The majority of patients (44.3%) was 18–40 years old. There were more patients with Crohn’s disease (66%) than ulcerative colitis (32%) and IBD unclassified (2%). Demographics and medication use are presented in table 1. A third of the patients (31.7%) was tested for SARS-CoV-2, of whom 8.3% tested positive. Twenty-six percent of patients considered they had higher need for information about COVID-19 than the general population. News websites were a source of information about COVID-19 for 52.5% of patients, followed by hospital websites (43.8%), direct contact with the IBD physician (24.6%), direct contact with the IBD nurse (23.1%), and state sponsored websites (20.9%). In fact, 35.9% of patients contacted the IBD nurse since the start of the pandemic. The majority of patients reported they were satisfied by the information (80.5%) and/or reassured (85%) by the IBD nurse. Ten percent of patients had considered to stop IBD medication due to the pandemic, and 80% of these refrained to do so following the advice of the IBD nurses. Finally, 12.5% of the patients expressed true fear of hospital visits due to the pandemic, which was associated with female gender and higher need for information.

Conclusion
Treatment cessation and anxiety could be avoided by direct interaction with the IBD nurses and in particular with the IBD nurse as first point of contact for the patient. Patients with IBD may profit from an optimized information platform with scientifically correct information addressing the concerns of this specific population.
N11 Complementary and alternative methods to improve quality of life in patients with inflammatory bowel diseases: a systematic literature review
Authors: Martinato M , Comoretto R I , Zampieri A , Monaco E , Barberio B , Azzolina D , Savarino E , Gregori D 
Published: May 2021

Abstract

Background
Inflammatory Bowel Diseases (IBD) shoved an increasing incidence in the last decade. They can occur at any age, but especially between 15 and 30. They have multifactorial aetiology, including genetic, intestinal bacterial, immunological and environmental causes. These diseases present invasive and often disabling symptoms. Typically, patients complained of abdominal pain, diarrhoea and rectal bleeding, and frequently they present complications such as malabsorption, malnutrition, water and electrolyte imbalances accompanied by nausea and vomiting, and intestinal obstruction or stricture. Moreover, the effects of IBD extend to the systemic level, with extraintestinal manifestations generally located at the musculoskeletal apparatus, skin or eyes, as well as psychiatric complications, including depression and anxiety. There is no definitive cure for IBD, and the severity of symptoms affect patients’ well-being, compromising their quality of life (QoL) which is, in fact, generally lower as compared to healthy population. This leads patients to search for self-care methods that allow them to achieve greater control and management of the disease, i.e., complementary and alternative methods (CAMs).

Methods
The purpose of the paper is to investigate the efficacy of mind-body CAMs in improving the QoL of patients suffering from IBD. Therefore, we focused on CAMs’ impact on the psychological and physical spheres of the subjects, considering outcomes such as anxiety, depression, stress, gastrointestinal symptoms and QoL. A systematic literature review was performed consulting the online databases PubMed, Cinahl, Cochrane, and Google Scholar regarding interventional studies performed in the last twenty years.

Results
312 papers were identified and 21 of them were selected according to inclusion criteria applied to title and abstract. 8 of them were then excluded after full-text assessment according to exclusion criteria. The interventions described in the 13 papers included fell within the dimension of mind-body techniques in the sphere of mindfulness and relaxation. A quantitative synthesis was not performed because, among the identified evidence, the treatment effect is never reported for more than two studies. Overall, time-correlated positive developments were recorded in all the outcomes considered in patients with a greater degree of psychological stressors at the initial assessment, guaranteed an increase in the QoL or an avoidance of impairment of QoL during flare-ups.

Conclusion
Mind-body CAMs have the potential to allow patients suffering from IBD to improve their compromised QoL. However, this area needs further investigation, carrying out more homogeneous studies, with larger samples and longer intervention and follow-up periods.
N13 Living in rural communities with Inflammatory Bowel Disease: Perspectives on healthcare use and access to care from patients and providers in one Canadian province
Authors: Rohatinsky N , Russell B , Boyd I , Dickson A , Fowler S , Peña-Sánchez J N , Quintin C L , Risling T , Wicks K , Wicks M 
Published: May 2021

Abstract

Background
Living with Inflammatory Bowel Disease (IBD) requires lifelong, repeated interactions with the healthcare system. Individuals with IBD living in rural areas are often disadvantaged with limited access to IBD-related healthcare services in their local communities which can result in poor health outcomes. Furthermore, these individuals encounter additional out of pocket expenses to travel to urban centres for care. There is limited information about the experiences of access to IBD-related care from the perspectives of patients and providers living in rural communities. The purpose of this study was to examine healthcare utilization and access to care in individuals with IBD who reside in rural areas within one Canadian province.

Methods
The qualitative results from a larger patient-oriented, mixed methods study will be reported. Seventeen individuals residing in rural communities from one Canadian province were recruited to participate. Fourteen individuals living with IBD and three healthcare providers were interviewed and shared their experiences on IBD-related access to care and healthcare use. Data was collected prior to the pandemic. Interview data was analyzed using thematic analysis to identify common themes.

Results
Many participants identified access to care challenges associated with living in rural communities. Communication, stressors and support systems, and coordination of care were identified as themes. Participants described disconnects in communication with and between healthcare providers. They suggested virtual technology was underutilized and was a cost-effective means to enhance communication. Participants experienced feelings of isolation and identified stressors while living in rural areas. They recommended the integration of formal and informal supports to ease stressors and promote mental well-being. Participants reported gaps in care and described a lack of accessible, multidisciplinary rural healthcare providers to optimize their IBD-related care and health outcomes. This lack of access to rural care resulted in frequent travel to access a variety of services. Recruitment and retention of rural care providers was identified as a strategy to enhance access to care.

Conclusion
Participants offered many suggestions to improve rural IBD-related care access within the healthcare system. These initiatives have great potential to increase quality of care, enhance quality of life, and reduce health system costs.
OP04 Safety analysis of filgotinib for Ulcerative Colitis: Results from the phase 2b/3 SELECTION study and phase 3 SELECTIONLTE long-term extension study
Authors: Schreiber S W , Watanabe M , Yun C , Zhou Y , Zhao S , Hsieh J , Moerch U , Rogler G , Loftus Jr E V 
Published: May 2021

Abstract

Background
Filgotinib (FIL) is an oral preferential Janus kinase (JAK) 1 inhibitor in development for the treatment of inflammatory diseases. FIL for the treatment of moderately to severely active ulcerative colitis (UC) was evaluated in the phase 2b/3, double-blind, placebo (PBO)-controlled SELECTION study (NCT02914522) and its long-term extension (LTE) study (NCT02914535). Here we report safety results from the FIL UC program.

Methods
Patients received FIL 100 mg, FIL 200 mg or PBO (2:2:1) once daily orally for up to 11 weeks for induction (cohort 1). At week 11, FIL induction responders were rerandomized 2:1 to continue FIL or receive PBO maintenance for 47 weeks (cohort 2). Week 10 non-responders and patients with worsening disease during the maintenance study were eligible for open-label FIL in the LTE. Patients completing the maintenance study could continue blinded dosing in the LTE. Cohort 3 comprised cohorts 1 and 2 and the LTE. Exposure-adjusted incidence rates (EAIRs) and exposure-adjusted event rates (EAERs) per 100 patient-years (PYs) were calculated for treatment-emergent adverse events (AEs) by treatment group in cohorts 1 and 2 (EAIR) and cohort 3 (EAER).

Results
In cohort 1, 1069 patients received FIL and 279 patients received PBO; baseline characteristics were generally similar across treatment groups (overall mean age, 43 years; mean UC duration, 8.4 years; mean Mayo Clinic Score, 9.0). EAIRs for AEs of interest were similar across treatment groups in cohorts 1 and 2 (Table 1). Treatment exposure for PBO, FIL 100 mg or FIL 200 mg in cohort 3 (i.e. cohorts 1 + 2 + the LTE) was 318, 360 and 1207 PYs, and median treatment duration was 12, 11 and 67 weeks, respectively. One case of pulmonary embolism occurred with FIL 200 mg induction and three venous thrombosis cases occurred with PBO maintenance/LTE (cohort 3) (Table 2). EAERs for all infections were similar across treatment groups, the most common being nasopharyngitis (Table 2). Opportunistic infections were rare. EAERs for serious infections were low across treatment groups (2.2 [PBO], 3.5 [FIL 100 mg], 2.2 [FIL 200 mg]), the most common being appendicitis (Table 2). EAERs for herpes zoster (HZ) were low in all treatment groups (0.3 [PBO], 0.3 [FIL 100 mg], 1.8 [FIL 200 mg]) (Table 2). HZ infections were cutaneous only and only one was serious. EAIRs for all infections in cohorts 1 and 2 were generally numerically higher for both PBO and FIL in patients over (vs under) 65 years old and in those with (vs without) biologic treatment failure (Figure 1).

Conclusion
FIL was well tolerated in patients with UC. Aggregation of AEs typical for pan-JAK inhibition was not observed, consistent with preferential JAK-1 inhibition with FIL.
OP36 Risankizumab therapy induces improvements in endoscopic endpoints in patients with Moderate-to-Severe Crohn’s Disease: Results from the phase 3 ADVANCE and MOTIVATE studies
Authors: Bossuyt P , Ferrante M , Baert F , Danese S , Feagan B G , Loftus Jr E V , Panés J , Peyrin-Biroulet L , Ran Z , Armuzzi A , D’Haens G R , Song A , Neimark E , Liao X , Zhou Q , Berg S , Wallace K , Panaccione R 
Published: May 2021

Abstract

Background
Endoscopic healing has become a critical treatment target in Crohn’s disease (CD). Risankizumab (RZB), a humanized immunoglobulin G1 monoclonal antibody against the p19 subunit of interleukin 23, is being investigated as a treatment for moderate-to-severe CD. This analysis assessed different endoscopic endpoints in patients treated with RZB induction therapy in two double-blind, randomised, placebo (PBO)-controlled studies (ADVANCE [NCT03104413] and MOTIVATE [NCT03105128]).

Methods
Patients with moderate-to-severe CD (CD Activity Index [CDAI] of 220–450, Simple Endoscopic Score for CD [SES-CD] ≥ 6 [≥ 4 for isolated ileal disease] excluding the narrowing component, and average daily [liquid/very soft] stool frequency [SF] ≥ 4 and/or average daily abdominal pain [AP] score ≥ 2) who had demonstrated prior inadequate response or intolerance to conventional and/or biologic treatment (ADVANCE) or to biologic treatment (MOTIVATE) were randomised 2:2:1 (ADVANCE) or 1:1:1 (MOTIVATE) to receive intravenous (IV) RZB 600 mg, RZB 1200 mg, or PBO at weeks 0, 4, and 8. This analysis evaluated the proportion of patients who achieved endoscopic remission ulcer-free endoscopy (ie, absence of ulcers), and composite endpoints of CDAI clinical response and endoscopic response, and enhanced clinical response and endoscopic response at week 12 (endpoints defined in Figure 1 footnotes). All endoscopies were centrally read by a blinded reviewer. Safety was assessed throughout the studies.

Results
In ADVANCE and MOTIVATE, 850 and 569 patients, respectively, were randomised and included in the intent-to-treat population for this analysis. At week 12 greater proportions of RZB- vs PBO-treated patients in both studies achieved endoscopic remission (P ≤ .001), ulcer-free endoscopy (P ≤ .01), CDAI clinical response and endoscopic response (P ≤ .001), and enhanced clinical response and endoscopic response (P ≤ .001; Figure 1). Treatment with RZB 600 mg or 1200 mg was well tolerated, and no new safety risks were identified.1,2

Conclusion
Induction therapy with IV RZB 600 mg or 1200 mg resulted in improved outcomes at week 12 compared with PBO as assessed by endoscopy and by composite endoscopic-clinical endpoints in patients with moderate-to-severe CD.

References
P027 Epithelial cells of patients with ulcerative colitis do not show an increased sensitivity after microbiota stimulation compared to non-IBD controls
Authors: Arnauts K , Lapierre C , Verstockt B , Verstockt S , Sudhakar P , Vermeire S , Verfaillie C , Sabino J , Ferrante M 
Published: May 2021

Abstract

Background
Alterations in the intestinal microbiota play a pivotal role in the pathogenesis of Inflammatory Bowel Diseases (IBD). Although there is a lot of interest in restoring dysbiosis, the effects of microbial alterations are not fully understood. In addition, it is known that epithelial cells from IBD patients maintain intrinsic defects1. For that reason, our aim was to unravel if epithelial cells of UC patients are more sensitive towards microbiota stimulation, compared to non-IBD controls.

Methods
Intestinal organoids of UC patients (n=8) and non-IBD controls (n=8) were grown as monolayers on Transwell inserts. Upon confluency (evaluated by transepithelial electrical resistance (TEER)), monolayers were stimulated for 24 hours with TNF-α (100 ng/ml), IL-1β (20 ng/ml) and Flagellin (1 µg/ml) to mimic inflammation. Fresh fecal samples of a selected donor (n=1, high microbial cell count and presence of selected phyla2) and UC patients (n=3, endoscopic sub-mayo ≥2) were filtered and stored in 0.9% NaCl. Monolayers were stimulated for 6 hours with 3.108 microbial cells (cell count by Flow Cytometry). RNA sequencing was performed by Truseq for Illumina. Differentially expressed genes (DEG) were studied by DESeq2 (FDR &lt;0.05).

Results
Although TEER measurements indicated a higher epithelial cell permeability upon UC microbiota stimulation in UC patients compared to non-IBD controls (p=0.038; Mann-Whitney; Figure 1), we could not confirm this distinct response based on RNA sequencing data at principal component analysis (PCA). Several epithelial barrier genes were significantly upregulated between UC and non-IBD epithelium at nominal p-value, while only CLDN1 and 18 were significant for FDR &lt;0.05 (Figure 2). Clustering on PCA was driven by microbial treatment and not by epithelial origin (Figure 3). Inflamed monolayers of UC patients showed different baseline characteristics (129 DEG; e.g. HLA-G, MUC2, CLDN1, IL23A, PARP8; Figure 4A), but did not propagate in a different response upon microbiota exposure compared to non-IBD controls. Treatment with microbiota of UC patients (23 DEG; e.g. PARP9, TGFBI, ANXA13) or the selected donor (58 DEG; e.g. CCL5, CLDN18, TGFBI) only induced minor differences between epithelial cell types (Figure 4B).

Conclusion
We observed no different response in epithelial cells of UC patients towards microbiota stimulation compared to non-IBD epithelial cells on transcriptomic level. Further validation on barrier integrity is needed. We observed no indications that microbial treatment would be less beneficial to UC patients, based on the epithelial cell response. Addition of (patient specific) immune cells will contribute to unraveling host-microbiota interactions in IBD patients.

References
P071 Crohn’s Disease is associated with elevated levels of the pro-inflammatory CXCR3 ligands (CXCL9, 10 and 11) with an associated reduction in Paneth cell derived antimicrobial peptides in ex-vivo ileal biopsies
Authors: Jones F , Doherty G , McNamee E 
Published: May 2021

Abstract

Background
Despite an expanding array of treatment options, a significant proportion of patients with Crohn’s Disease (CD) fail to respond to currently available therapies, underpinning the importance of biological insights into disease pathogenesis. The pro-inflammatory chemokines CXCL9,10 and 11 bind to the CXCR3 receptor, highly expressed on effector T-cells. Mouse models of chronic ileitis have shown that CXCR3+ effector T cells drive the loss of paneth cells that play an important role in innate immunity and mucosal barrier function. In the TNFΔΔARE mouse ileitis-model, small molecule inhibition of the CXCR3 receptor reverses paneth cell loss and restores antimicrobial peptide levels. The aims of this study were to evaluate the role of chemokines that bind to CXCR3+ effector T-cells in adult patients with ileal CD compared to healthy controls and to assess the impact of these pro-inflammatory chemokines on paneth cell derived anti-microbial peptides.
Methods, 13 CD patients and 16 healthy controls attending for routine endoscopic evaluation were prospectively recruited at St.Vincent’s University Hospital, Dublin and ileal biopsies were collected in media. RNA was isolated from homogenised ileal biopsies (Quiagen kit), DNAse treated using DNAse I (Invitrogen) and reverse transcribed using M-MLV reverse transcriptase (Promega). Target cDNAs were quantified using an Applied BiosystemsTM QuantStudioTM 7 Flex Real-Time PCR System.

Results
We identified an increase in the relative mRNA expression of CXCR3 associated chemokines, with significantly higher levels of CXCL9, CXCL10 and CXCL11 in ileal CD patients compared to healthy controls. This coincides with a reduction in paneth cell-derived antimicrobial peptides with significantly lower levels of alpha defensins (DEFA5, DEFA6) and lysozyme in CD patients compared to healthy controls.

Conclusion
This study supports data from animal models and provides a hypothesis for the loss of paneth cells in patients with ileal CD. The reduction in paneth cell derived anti-microbial peptides may help to explain the altered microbiome and provide an explanation for the loss of mucosal barrier integrity in Inflammatory Bowel Disease (IBD). A greater understanding of the role of chemokines in the development of mucosal immunity and inflammation in IBD may allow the targeting of chemokines in novel therapeutic strategies.