bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP44 Tofacitinib versus corticosteroids for induction of remission in moderately active ulcerative colitis (ORCHID): A prospective randomized open-label pilot study
Authors: Singh A , Midha V , Mahajan R , Kaur K , Singh D , Sood A 
Published: January 2023

Abstract

Background
The exact positioning of tofacitinib in the therapeutic algorithm is still unclear. We evaluated the efficacy of tofacitinib in comparison to corticosteroids for induction of remission in patients with moderately active UC.

Methods
This was a randomized, parallel-group active-controlled pilot study comparing the efficacy and safety of corticosteroids and tofacitinib in inducing remission in adults with moderately active UC (defined as total Mayo clinic score 6-9). Patients were randomly assigned to receive corticosteroids (prednisolone, starting 40 mg daily and tapered by 5 mg every week over 8 weeks) or tofacitinib (10 mg twice daily) for 8 weeks. The primary endpoint was composite remission (defined as total Mayo clinic score≤2, with an endoscopic subscore of 0 and fecal calprotectin&lt;100 mcg/g) at 8 weeks. Clinical remission (defined as Mayo clinic score ≤2) and clinical response (defined as a decrease of 30% in the Mayo clinic score from baseline or more and 3 or more points, along with either a rectal bleeding subscore of 0 or 1 or a decrease in the rectal bleeding subscore of 1 point or more) at week 8 were also evaluated. Follow-up assessments for efficacy and safety were done at weeks 2, 4, and 8.

Results
Seventy-eight patients (mean age 37.78±13.94 years, 42[53.84%] males; 43 assigned to tofacitinib and 35 to corticosteroids group) were enrolled. At week 8, there was no significant difference in the proportion of patients achieving composite remission in the two treatment groups (7 of 43, 16.28% in the tofacitinib group versus 3 of 35, 8.57% in the corticosteroid group; p=0.31). Clinical remission at week 8 was achieved in 18 of 43(41.86%) patients receiving tofacitinib and 13 of 35 (37.14%) patients receiving corticosteroids (p=0.67). Clinical response was seen in 28 of 43(65.12%) and 25 of 35(71.42%) patients in the tofacitinib and corticosteroid groups, respectively(p=0.55). No difference was observed in the median number of days required to achieve symptomatic remission between the two groups (10[IQR 7-18.75] and 10[IQR 5-12.5] days for tofacitinib and corticosteroids, respectively;p=0.25). One patient in the tofacitinib and corticosteroid group discontinued treatment due to the development of pulmonary tuberculosis and pustular acne, respectively. Another patient receiving tofacitinib developed herpes zoster. No serious adverse events or major adverse cardiovascular events were observed.

Conclusion
In patients with moderately active ulcerative colitis, there is no difference between the efficacy and safety of tofacitinib and corticosteroids for induction of remission. Tofacitinib can be used as a first-line therapy for inducing remission in moderately active UC. (CTRI Registration number: CTRI/2021/10/037641)
DOP45 Predicting late responders to filgotinib in patients with moderately to severely active Ulcerative Colitis: A post hoc analysis of SELECTION and SELECTIONLTE
Authors: Matsuoka K , Löwenberg M , Fumery M , Takatori Y , Fujitani Y , Oortwijn A , Faes M , Jamoul C , Hibi T 
Published: January 2023

Abstract

Background
Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor approved for the treatment of ulcerative colitis (UC) in Europe and Japan. Previous analyses of the SELECTION programme showed that, in patients with moderately to severely active UC, C-reactive protein, rectal bleeding and stool frequency at day 7 predicted response to FIL at week 10,1 and that patients who did not respond to FIL induction benefited from an additional 12 weeks of FIL 200 mg.2 This post hoc analysis was conducted to identify factors associated with late response to FIL.

Methods
The SELECTION programme comprises a phase 2b/3, randomized, double-blind, placebo (PBO)-controlled study (SELECTION; NCT02914522) and its open-label, long-term extension (SELECTIONLTE; NCT02914535). Adult patients aged 18–75 years were randomized to FIL 100 mg, FIL 200 mg or PBO once daily for 11 weeks in the induction study. This post hoc analysis only included patients receiving FIL 200 mg who did not have clinical remission or a Mayo Clinic Score (MCS) response at week 10 of induction and who subsequently entered SELECTIONLTE on FIL 200 mg. Patient characteristics at induction baseline and changes in surrogate markers of response from baseline to week 4 of induction were compared between patients who had observed partial MCS (pMCS) response (pMCS late responders) or observed non-response (pMCS non-responders) at week 12 of SELECTIONLTE using univariate and multivariate logistic regression models.

Results
In total, 160 patients were included (102 [63.8%] pMCS late responders and 58 [36.3%] pMCS non-responders) (Table 1). In univariate analysis, prior use of biologics was not significantly associated with late response to FIL. Changes in surrogate markers of response showed that none were significantly associated with late response (Figure 1). In multivariate analysis of baseline characteristics, older age was positively associated with late response to FIL (odds ratio [OR]: 1.042, 95% confidence interval [CI]: 1.011–1.073, p = 0.007), while body mass index (BMI) &lt; 18.5 kg/m2 (OR: 0.041, 95% CI: 0.003–0.519, p = 0.014) was negatively associated with late response.

Conclusion
In SELECTION programme participants, older age was positively associated with late response to FIL 200 mg and BMI &lt; 18.5 kg/m2 was negatively associated with late response. These factors should be taken into account when monitoring patients on FIL with insufficient response at week 10. No other strong predictors were identified. The results of this analysis should be interpreted in the context of previous findings.1
1. Feagan B et al. United European Gastroenterol J 2022;10(S8):462–3
2. Vermeire S et al. United European Gastroenterol J 2021;9(S8):215–6
DOP53 Community types of the human gut virome are associated with endoscopic outcome in UC patients
Authors: Jansen D , Falony G , Vieira-Silva S , Simsek C , Marcelis T , Machiels K , Caenepeel C , Raes J , Severine V , Matthijnssens J 
Published: January 2023

Abstract

Background
Inflammatory bowel diseases (IBD) are a group of chronic inflammatory diseases of the gut. The pathophysiology is unknown; however, it is thought to result from an inappropriate immune reaction to the commensal gut microbiota. Community-typing is a common practice in bacteriome analysis allowing for the stratification of individuals based on their gut microbiome (eg., ‘enterotyping’). A viral counterpart of these enterotypes might allow stratification of individuals based on their gut virome. The aim of the present study is to investigate the existence of such viral community types and assess the impact of therapeutic outcome (and other covariates) on the gut virome in IBD patients.

Methods
Fecal samples were selected from 181 patients undergoing immunomodulatory therapy, and a baseline (pre-intervention) and a primary endpoint (post-intervention) have been collected for each patient. Viral metagenomics and deep sequencing were performed following viral enrichment with the NetoVIR protocol. Redundancy analysis and Dirichlet Multinomial Mixtures were applied to determine covariates of the virome composition and to condense the gut virota into viral community types, respectively.

Results
IBD patients were stratified based on unsupervised machine learning into two viral community types. Community type CA showed a low α-diversity and a high relative abundance of Caudoviricetes [non-CrAss] phages and was associated to the dysbiotic Bact2-enterotype. Community type CrM showed a high α-diversity and a high relative abundance of Caudoviricetes [CrAss] and Malgrandaviricetes phages. The gut virome variation was explained by several factors: patients’ individuality (75.8%), disease location (1.4%), age (0.5%) and faecal moisture (0.3%), with diagnosis not showing a non-redundant effect. Despite our expectations the choice of biological therapy did not show an association with the virome variation. During post-interventional analysis, endoscopic outcome (0.5%) was associated to gut virome variation as well. Remitting UC, but not CD, patients revealed a high percentage of community type CrM, a high Shannon diversity and a low phage lysogenic potential. Conversely, non-remitting UC, but not CD, patients revealed a high percentage of community type CA, a low Shannon diversity and a high lysogenic potential.

Conclusion
These findings suggest that viral community-typing allows for stratification of IBD patients based on their gut virome composition and might be a valuable tool to better understand IBD subtypes or as a potential future biomarker.
DOP60 Environmental risk factors for Inflammatory bowel disease: A large prospective case-control study in India
Authors: Banerjee R , Pal P , Prakash N , Mudigonda S , Joseph S , Patel R , Khalil M , Komawar A , Korikana S , Mekala D , Akki Y , Gaddam A , Valluri S 
Published: January 2023

Abstract

Background
Increasing urbanization and westernization of lifestyles have been implicated for the rising incidence of IBD in the developing world. However real world data is very limited. We planned a comprehensive assessment of environmental exposures in a large cohort of patients with and without IBD in India to identify key risk factors.

Methods
This study is a part of a wider epidemiologic colonoscopic screening program for detection of IBD on all symptomatic patients attending the hospital and specially conducted rural health camps. A detailed questionnaire based survey of environmental risk factors including diet, smoking, antibiotic use, hygiene status, microbial exposures, vaccination, water supply, rural/urban residence was conducted prior to colonoscopy. The risk factors were compared among the IBD and non IBD patients with normal colonoscopy. Univariate logistic regression was done initially adjusting for age and sex followed by multivariate analysis to estimate adjusted ORs (aOR) and 95% CIs.

Results
13421 completed environmental risk questionnaire.1306 IBD(576 CD;730 UC) cases diagnosed.12115 with normal colonoscopy served as the controls.
In multivariate model, current smoking(aOR 5.66; 95% CI 4.41-7.26),ex-smoking (aOR 1.79;1.24-2.58), regular alcohol intake (aOR 1.82, 1.14-2.9), non-vegetarian diet(aOR 1.8; 1.48-2.23),daily bakery/fast food consumption(aOR 1.57; 1.31-1.88),soft drink consumption(&gt; 2/week)(aOR 1.37,1.14-1.66), delivery by cesarean section (aOR 1.49, 95% CI 1.28-1.76), antibiotic use(&lt;1 yr age) (aOR1.33;1.1-1.58), exposure to pets(aOR 1.68;1.39-2.03), Western toilets (aOR3.52, 2.56-3.58)and childhood infections (aOR 1.74; 1.45-2.028) increased risk of UC (Fig 1, 2). Increased risk of CD was seen with current smoking(aOR 6.16; 95% CI 4.68-8.11), ex-smoking(aOR2.15; 1.43-3.22),non-vegetarian diet (aOR 1.69;1.34-2.13), soft drink consumption(&gt; 2/week)(aOR 1.84,1.51-2.24),daily bakery/fast food consumption(aOR 2.24;1.85-2.71), oral contraceptive pill use (aOR 3.79, 1.29-12.17) antibiotic use (&lt;1 year age)(aOR 1.27; 1.04-1.54),exposure to pets(aOR 1.79; 1.45-2.2), caesarean section(aOR 1.48;1.23-1.77), Western toilets (aOR 2.98, 2.47-3.59), non-human milk exposure (&lt;6 months age) (aOR 1.28, 1.03-1.6) and childhood infections(aOR 2.51; 2.1-3.04)(Fig 3, 4). Breastfeeding &gt;6 months, daily fruit consumption and daily exercise were protective for both UC and CD (Fig1-4).Rural habitat was not protective for development of IBD both UC and CD.

Conclusion
This large prospective case control study of IBD risk factors in India identifies environmental triggers including childhood immunological, hygiene and dietary factors which modulate risk of IBD later in life.
DOP79 Alternative polygenic forms of Inflammatory Bowel Disease are not captured by current generations of polygenic risk scores
Authors: Mateos B , Gaite A , Rodríguez-Lago I , Marigorta U M 
Published: January 2023

Abstract

Background
Polygenic risk scores (PRSs) have emerged as a promising tool to ascertain individuals at high risk of developing IBD. However, the sensitivity of current PRSs is limited, and will likely remain so in the immediate future. The default expectation is that patients not captured by PRSs must be enriched for rare variants with strong effects and/or environmental risk factors. We set out to investigate an alternative scenario, namely that combinations of common variants in non-GWAS genes conform population of patients that are missed by large genetic studies for the main forms of the disease.

Methods
MAGMA was used to identify genes from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) GWAS. We selected a sort of monogenic IBD genes1 which were significant for IBD (pval ≈ 10-4) but do not overlap with polygenic IBD genes. These genes were compared using DESeq tool on two transcriptomic databases: RISK (Crohn’s disease (CD) onset vs non-IBD) and PROTECT (ulcerative colitis (UC) onset vs 52 weeks). A second DESeq analysis was performed between patients with high against low expression of these 13 genes. We explored these genes using in-silico predicted expression based on eQTL in 9 different tissues for UK Biobank (UKBB) population, comparing UKBB individuals according to disease and polygenic risk score status.

Results
The starting point based on MAGMA analysis led to the detection of 13 monogenic IBD genes which may partially participate in polygenic forms of the disease. The transcriptomic analyses, based on stratification according to the levels of these 13 genes, implied that these genes participate in regulatory programmes that are particularly heterogeneous and variable among cases. The detected differentially expressed genes are associated with immune processes and receptors, inflammation transporters, and digestive problems, as well as skin development, humoral response, extracellular matrix, and mitochondrial component. The TWAS-based estimation analyses hint that low-PRS patients are indeed enriched for common variants associated with higher pathogenic levels at the 13 selected genes.

Conclusion
Although polygenic risk scores may play a valuable role in patient management, our study hints at the presence of patients with common polygenic forms that are not captured by current genetic risk estimators.
1. Chrissy B. et al, 2022. Gastroenterology.
DOP81 Unaffected ileal transcriptomics in Crohn's disease is associated with the response to anti-TNF therapy
Authors: Lee H S , Lee Y , Baek J , Kim Y , Park S , Jung S , Kim K K , Hwang S W , Lee J L , Park S H , Yang S K , Han B , Song K , Yoon Y S , Ye B D 
Published: January 2023

Abstract

Background
We aimed to assess the gene expression profiles of uninflamed small bowels in patients with Crohn’s disease (CD) to identify its accompanying molecular alterations.

Methods
We performed RNA sequencing of the uninflamed small bowel tissues obtained from 70 patients with ileal CD, and 9 patients with colon cancer (non-CD controls) during bowel resection. Differentially expressed gene (DEG) analyses were performed using DESeq2. Gene set enrichment, correlation, and cell deconvolution analyses were applied to identify modules and functionally enriched transcriptional signatures of CD.

Results
A comparison of CD patients and non-CD controls revealed that of the 372 DEGs, 49 protein-coding genes and 5 lncRNAs overlapped with the IBD susceptibility loci. The pathways related to immune and inflammatory reactions were upregulated in CD, while metabolic pathways were downregulated in CD. Compared with non-CD controls, CD patients had significantly higher proportions of immune cells, including plasma cells (P=1.15×10-4), and a lower proportion of epithelial cells (P=1.12×10-4). Co-upregulated genes (M14 module) and co-downregulated genes (M9 module) were identified in CD patients. The M14 module was enriched in immune-related genes and significantly associated with the responses to anti-TNF therapy. Intestinal tissue transcriptomic analysis of 3 independent cohorts, identified M14 module upregulation in non-responders at baseline, which was predictive of response with acceptable discrimination ability (area under the curve of 77~83%).

Conclusion
The differences in gene expression and cellular composition between CD patients and non-CD controls imply significant molecular alterations, which are associated with the response to anti-TNF treatment.
DOP85 Crohn's Disease Strictures Respond to Drug Treatment and Treat-to-Target Intense Combination Therapy is More Effective than Standard Anti-TNF Therapy. Two year results of the STRIDENT Randomised Controlled Trial.
Authors: Schulberg J , Hamilton A , Wright E K , Holt B , Lovett G , Sutherland T , Ross A , Vogrin S , Kamm M 
Published: January 2023

Abstract

Background
The randomised STRIDENT (Stricture Definition and Treatment) trial showed that Crohn’s disease symptomatic strictures are responsive to anti-TNF therapy with most patients clinically improved after 12 months treatment with adalimumab +/- thiopurine. Treat to target intensification resulted in greater stricture morphology improvement. We present here 2 year (from study entry) follow up to assess response durability and risk of surgery.

Methods
Patients with symptomatic Crohn’s disease strictures and associated inflammation (elevated faecal calprotectin and CRP) were assessed with imaging (intestinal ultrasound and MRI) and ileo-colonoscopy. The Obstructive Symptom Score (OSS) was used for clinical assessment. Patients were randomised 2:1 to high dose adalimumab induction (160mg weekly for 4 weeks) followed by 40mg fortnightly plus thiopurine, with adalimumab dose increase at 4 and/or 8 months if evidence of ongoing inflammation, versus standard dose adalimumab monotherapy. The primary endpoint was improved OSS at 12 months. Patient interview was conducted at 24 months, assessing drug treatment, symptoms, need for endoscopic therapy, hospitalisation and surgery.

Results
In the initial 12 months study 52 patients were randomised to the intensive and 25 to the standard treatment arm. 64/77 (83%) patients recorded an outcome at 12 months (13/77 (17%) withdrawn: 8 surgery, 5 other) 74/77 (96.1%) patients were followed up at a mean of 25.3 (IQR 24.4-26.3) months. Of these, 59 (79.7%) remained on adalimumab, 10 (13.5%) had switched to another biologic and 5 (6.7%) had ceased biologic therapy. For patients who were on adalimumab at 12 months the risk of surgery by 24 months was 15%. Of patients on adalimumab 40mg fortnightly at 12 months, 12/48 (25%) had been dose escalated by 24 months. Endoscopic balloon dilatation, hospitalisation or surgery was required in 6 (8.1%), 14 (18.9%) and 13 (17.5%) respectively; rates were not different between the standard and intensive treatment groups (P = 0.982). Median time to intestinal resection was 12.2 (IQR 6.9-18.6) months. Clinical responders at 12 months, compared to non-responders, had a reduced likelihood of surgery at 24 months (9% vs 42%, P=0.003).

Conclusion
Clinical response to adalimumab for structuring Crohn’s disease is durable in a majority of patients, with most patients remaining on adalimumab and avoiding surgery at two years. Rates of surgery were not different between the standard and intensive therapy arms. Clinical response to adalimumab at 12 months is an important predictor of future surgical risk.
P001 Obefazimod upregulates miR-124 and downregulates the expression of some cytokines in blood and rectal biopsies of patients with moderate-to-severe ulcerative colitis.
Authors: Santo J , Gineste P , Scherrer D , Nitcheu J , Ehrlich H , Sands B E , Vermeire S 
Published: January 2023

Abstract

Background
The oral small molecule obefazimod (ABX464) has demonstrated efficacy and safety in patients with moderate-to-severe ulcerative colitis (UC) in a randomized, placebo-controlled, 8-week phase 2b induction study1. We examined the effects of obefazimod on miR-124 and cytokines levels in blood (baseline, weeks 4 and 8) and rectal biopsies (baseline, week 8) of these patients.

Methods
Absolute quantification (QuantaSoft Pro) of the miR-124 copy number was performed by using droplet digital PCR technology on 644 rectal biopsy samples and 1104 whole blood samples from patients receiving obefazimod (25mg, 50mg or 100mg once daily) or placebo. A total of 15 cytokines (IL1b, IL13, IL17, IL6, IL10, IL23, MCP-1, IL34, CXCL-12, IL22, LIF, TGFb, GM-CSF, IFNg and TNFa) were examined by immunohistochemistry (IHC) on 208 rectal biopsies. For each cytokine, antibodies were tested for the chromogenic IHC detection on paraffin tissue sections; repeatability and reproducibility tests were conducted to validate protocols with robust signal. IHC signal was digitized and quantified with Halo® image analysis software. IL17 was also measured in blood samples using an ELLA immunoassay (Bio-Techne).

Results
The three tested doses of obefazimod (25mg, 50mg or 100mg once daily) significantly upregulated miR-124 in blood at week 1 (A) and 8 (B), and in rectal tissue at week 8 (C) (from p&lt;0.001 to p&lt;0.0001 vs. placeb

The three doses of obefazimod significantly reduced IL17 levels in blood of patients at week 1, 4 and 8 (from p&lt;0.01 to p&lt;0.0001 vs. placebo).

IHC protocols in rectal tissue were validated for 4 out of 15 cytokines: IL17, IL23, CXCL-12, INFg. Compared with baseline levels, an 8-week obefazimod treatment significantly down-regulated the expression of IL17 (at all doses, (from p&lt;0.05 to p&lt;0.001), IL23 (p&lt;0.01 at 50mg, p&lt;0.001 at 100 mg), and INFg (p&lt;0.001 at 50 mg).

Within obefazimod treated subjects, clinical responders showed higher reduction of IL-17A and IL-23 expression in rectal tissue than non-clinical responders at week 8 (reduction in MMS ≥2 points and ≥30% from baseline + decrease in rectal bleeding subscore ≥1 or absolute rectal bleeding subscore ≤1 point). No significant change was observed with CXCL-12.

Conclusion
The 8-week efficacy of obefazimod in patients with moderate-to-severe UC is associated with an increase in miR-124 expression in blood and tissue and with a decrease of IL17, IL23 and INFg in the colorectal tissue.
References:
1. Vermeire S, et al. ABX464 (obefazimod) for moderate to severe active ulcerative colitis: a randomised, placebo controlled phase 2b induction trial and 48 week extension. The Lancet Gastroenterology & Hepatology. 2022. https://doi.org/10.1016/S2468-1253(22)00233-3