bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonadherence Is Common in Patients With Apparent Resistant Hypertension: A Systematic Review and Meta-analysis
Authors: Bourque Gabrielle , Ilin Julius Vladimir , Ruzicka Marcel , Hundemer Gregory L , Shorr Risa , Hiremath Swapnil
Published: January 2023

Background

The prevalence of medication nonadherence in the setting of resistant hypertension (RH) varies from 5% to 80% in the published literature. The aim of this systematic review was to establish the overall prevalence of nonadherence and evaluate the effect of the method of assessment on this estimate.

Methods

MEDLINE, EMBASE, Cochrane, CINAHL, and Web of Science (database inception to November 2020) were searched for relevant articles. We included studies including adults with a diagnosis of RH, with some measure of adherence. Details about the method of adherence assessment were independently extracted by 2 reviewers. Pooled analysis was performed using the random effects model and heterogeneity was explored with metaregression and subgroup analyses. The main outcome measured was the pooled prevalence of nonadherence and the prevalence using direct and indirect methods of assessment.

Results

Forty-two studies comprising 71,353 patients were included. The pooled prevalence of nonadherence was 37% (95% confidence interval [CI] 27%–47%) and lower for indirect methods (20%, 95% CI 11%–35%), than for direct methods (46%, 95% CI 40%–52%). The study-level metaregression suggested younger age and recent publication year as potential factors contributing to the heterogeneity.

Conclusions

Indirect methods (pill counts or questionnaires) are insufficient for diagnosis of nonadherence, and report less than half the rates as direct methods (direct observed therapy or urine assays). The overall prevalence of nonadherence in apparent treatment RH is extremely high and necessitates a thorough evaluation of nonadherence in this setting.
iEnhancer-SKNN: a stacking ensemble learning-based method for enhancer identification and classification using sequence information
Authors: Wu Hao , Liu Mengdi , Zhang Pengyu , Zhang Hongming
Published: January 2023

Enhancers, a class of distal cis-regulatory elements located in the non-coding region of DNA, play a key role in gene regulation. It is difficult to identify enhancers from DNA sequence data because enhancers are freely distributed in the non-coding region, with no specific sequence features, and having a long distance with the targeted promoters. Therefore, this study presents a stacking ensemble learning method to accurately identify enhancers and classify enhancers into strong and weak enhancers. Firstly, we obtain the fusion feature matrix by fusing the four features of Kmer, PseDNC, PCPseDNC and Z-Curve9. Secondly, five K-Nearest Neighbor (KNN) models with different parameters are trained as the base model, and the Logistic Regression algorithm is utilized as the meta-model. Thirdly, the stacking ensemble learning strategy is utilized to construct a two-layer model based on the base model and meta-model to train the preprocessed feature sets. The proposed method, named iEnhancer-SKNN, is a two-layer prediction model, in which the function of the first layer is to predict whether the given DNA sequences are enhancers or non-enhancers, and the function of the second layer is to distinguish whether the predicted enhancers are strong enhancers or weak enhancers. The performance of iEnhancer-SKNN is evaluated on the independent testing dataset and the results show that the proposed method has better performance in predicting enhancers and their strength. In enhancer identification, iEnhancer-SKNN achieves an accuracy of 81.75%, an improvement of 1.35% to 8.75% compared with other predictors, and in enhancer classification, iEnhancer-SKNN achieves an accuracy of 80.50%, an improvement of 5.5% to 25.5% compared with other predictors. Moreover, we identify key transcription factor binding site motifs in the enhancer regions and further explore the biological functions of the enhancers and these key motifs. Source code and data can be downloaded from https://github.com/HaoWuLab-Bioinformatics/iEnhancer-SKNN.
Is it Time to Migrate to Liquid Chromatography Automated Platforms in the Clinical Laboratory? A Brief Point of View
Authors: Papp Lajos-Attila , Imre Silvia , Bálint István , Lungu Andreea-Ioana , Mărcutiu Petra-Edina , Papp Júlia , Ion Valentin
Published: January 2023

Liquid chromatography coupled to mass spectrometry already started to surpass the major drawbacks in terms of sensitivity, specificity and cross-reactivity that some analytical methods used in the clinical laboratory exhibit. This hyphenated technique is already preferred for specific applications while finding its own place in the clinical laboratory setting. However, large-scale usage, high-throughput analysis and lack of automation emerge as shortcomings that liquid chromatography coupled to mass spectrometry still has to overrun in order to be used on a larger scale in the clinical laboratory. The aim of this review article is to point out the present-day position of the liquid chromatography coupled to mass spectrometry technique while trying to understand how this analytical method relates to the basic working framework of the clinical laboratory. This paper offers insights about the main regulation and traceability criteria that this coupling method has to align and comply to, automation and standardization issues and finally the critical steps in sample preparation workflows all related to the high-throughput analysis framework. Further steps are to be made toward automation, speed and easy-to-use concept; however, the current technological and quality premises are favorable for chromatographic coupled to mass spectral methods.
OP06 Multiomic interrogation of the epithelium in active Ulcerative Colitis reveals dysregulated myeloid cells associated with non-response to anti-Tumour Necrosis Factor therapy.
Authors: Jha D , Al-Taie Z , Krek A , Eshghi S , Tankelevich M , Meringer H , Cossarini F , Canales-Herrerias P , Livanos A E , Polydorides A D , Martin J , Ko H M , McBride J , Hackney J , Colombel J F , Argmann C , Suarez-Farinas M , Petralia F , Mehandru S
Published: January 2023

Background

While the majority of Ulcerative Colitis (UC)-related mucosal studies have focused on whole intestinal tissues or the lamina propria (LP), epithelial compartment (EC)-specific studies are largely lacking. Here, we have defined EC-associated molecular and cellular dynamics during inflammation and studied their response to anti-tumor necrosis factor inhibitor (TNFi) therapy.

Methods

EC-focused analyses that included total RNA sequencing (RNAseq), single-cell (sc) RNAseq, spatial transcriptomics (ST), microscopy and flow cytometry (FC) were performed in a cohort of UC patients (n=103) and healthy controls (HC, n=116); Primary Cohort (PC). Inflammation-associated signatures were validated in an internal validation cohort (VC-1; UC, n= 401; HC, n = 243). Additionally, 3 distinct validation cohorts (VC-2a, n=23; VC-3b, n=48; VC-4c, n=214) were used to determine cellular and molecular phenotypes that were associated with TNFi-treatment response.

a. Gut, 2018; PMID-27802155

b. Am J Gastroenterol., 2011; PMID- 21448149

c. Lancet Gastroenterol Hepatol., 2022; PMID: 34798036

Results

Total RNAseq and scRNA seq analyses and FC revealed distinct immune perturbations in the EC of patients with UC, including a major increase in neutrophils, monocyte-macrophages (MoMac) and inflammatory macrophages, while EC-resident, homeostatic gd T cells were significantly reduced (Fig 1A, B). ST identified significantly reduced frequencies of mature epithelial subtypes in UC and significantly increased co-localization between multiple cell types, including epithelial cells and myeloid cells (Fig 1C), that was confirmed by microscopy (Fig 1D).

A signature of 255 EC inflammation-associated genes was derived that reversed with TNFi. This included treatment associated reduced expression of genes such as CSF3R, FCGR3B, MZB1, PDPN, TREM, FPR2 with a concomitant increased expression of genes like BEST4, CA2, SLC16A1, UGT1A10 (Fig 1E). Interrogation of UC-associated inflammatory cell types within VC-2, VC-3, and VC-4 demonstrated that reduction in neutrophils, MoMac, macrophages, DCs and plasma cells and an increase in epithelial cells was associated with TNFi response. Furthermore, early (W8-W10) reductions in myeloid cell- and plasma cell-associated genes was associated with TNFi response (Fig 1F, G).

Conclusion

Detailed multiomic characterization of the EC in UC reveals myeloid cell-, plasma cell- and epithelial cell-associated modules that are associated with non-response to TNFi and charts a course to define rational drug sequencing and combinations in UC.
OP08 Mucosal healing with vedolizumab in inflammatory bowel disease patients with chronic pouchitis: Evidence from EARNEST, a randomized, double-blind, placebo-controlled trial
Authors: Jairath V , Feagan B G , Silverberg M S , Danese S , Gionchetti P , Löwenberg M , Bressler B , Ferrante M , Hart A , Lindner D , Escher A , Jones S , Shen B , Travis S
Published: January 2023

Background

Mucosal healing (MH) is an important treatment goal for inflammatory bowel disease (IBD). Vedolizumab (VDZ), a gut-selective anti-lymphocyte trafficking agent, has shown potential to achieve MH.1,2 EARNEST, a randomized double-blind placebo-controlled trial of VDZ in chronic pouchitis,3 offers a robust dataset systematically collected from the inflamed pouch mucosa to further explore the impact of VDZ treatment on MH.

Methods

EARNEST evaluated intravenous VDZ (300 mg) vs placebo (PBO) administered at weeks 0, 2, 6, 14, 22, and 30, in adult patients (pts) with active chronic pouchitis despite antibiotic therapy after proctocolectomy and ileal pouch-anal anastomosis for ulcerative colitis. Endoscopic imaging was captured and centrally read at baseline, Week (W) 14, and W34. Total ulceration and SES-CD (modified to apply to a single segment) were evaluated. Microscopic inflammation was also evaluated using the Pouchitis Disease Activity Index (PDAI) histological component. Pre-specified exploratory endpoints included changes in total ulceration and SES-CD remission (score ≤2); MH was defined post-hoc as SES-CD=0 plus PDAI histology score ≤1 (none/mild polymorphic nuclear leukocyte infiltration and no ulceration). Fecal calprotectin (FCP) levels were explored by MH status. PDAI remission (score <7 and ≥3 point-reduction from baseline) and Inflammatory Bowel Disease Questionnaire (IBDQ) remission (score ≥170) were assessed in pts with/without MH at W14.

Results

In total, 98 pts had endoscopic evaluations (VDZ n=48; PBO n=50). Ulcers/erosions were higher in VDZ pts at baseline with a greater reduction at W14 and W34 with VDZ vs PBO (Table 1). More pts treated with VDZ vs PBO achieved reduction in ulcerated surface area, complete absence of ulceration/erosions and SES-CD remission. At W14, 7/42 (16.7%) pts had MH on VDZ vs 1/40 (2.5%) on PBO. All 7 VDZ pts with MH at W14 were in PDAI remission at W14 and W34; 6/7 (85.7%) pts achieved IBDQ remission at W14 and 5/7 (71.4%) achieved IBDQ remission at both W14 and W34. Of the 35 VDZ-treated pts without MH at W14, 11/35 (31.4%) achieved PDAI remission at W14, 11/35 (31.4%) at W34, and 9/35 (25.7%) at both W14 and W34; 13/35 (37.1%) achieved IBDQ remission at W14, 17/35 (48.6%) at W34, and 12/35 (34.3%) at both W14 and W34. MH was associated with FCP ≤250 µg/g while ~40-60% of pts without MH had FCP >250 µg/g (Table 2).

Conclusion

VDZ was associated with better control of markers of inflammation vs PBO, based upon improvements in endoscopic/histologic outcomes in the pouch mucosa, as well as improved outcomes reported by pts. These effects of VDZ in the pouch mucosa are consistent with those observed in the wider patient population with IBD.
OP15 Efficacy of ustekinumab for Ulcerative Colitis through 4 years: Final clinical and endoscopy outcomes from the UNIFI long-term extension
Authors: Danese S , Afif W , Abreu M , Sandborn W , Miao Y , Zhang H , Panaccione R , Hisamatsu T , Scherl E , Leong R , Rowbotham D , Arasaradnam R , Peyrin-Biroulet L , Sands B , Marano C ,   UNIFI Investigators
Published: January 2023

Background

Ustekinumab (UST) is an interleukin12/23p40 antagonist approved for treatment of moderate to severe Ulcerative Colitis (UC). Here we report final clinical outcomes based on the Mayo score, including the endoscopy subscore, from the UNIFI long-term extension (LTE) study through 4 years of UST treatment.

Methods

Overall, 523 intravenous UST induction responders were randomised to subcutaneous maintenance therapy: 175 placebo (PBO); 172 UST 90 mg every 12 weeks (q12w); 176 UST 90 mg q8w. A total of 284 UST patients (pts) completed week (wk)44 and continued treatment in the LTE; pts receiving PBO were discontinued after study unblinding. Starting at wk56, randomised pts with UC worsening could receive a dose adjustment: PBO to UST q8w, UST q12w to UST q8w, and UST q8w to UST q8w (sham adjustment). Outcomes based on the Mayo score (including endoscopy assessed by a local reader) were evaluated at the final efficacy visit (wk200); pts who had treatment failure (i.e., had ostomy or colectomy or discontinued UST due to lack of therapeutic effect or worsening UC) before wk200 were also included, and they were imputed as nonresponders. Clinical remission was defined as a Mayo score ≤2 points and no individual subscore >1; clinical response as a decrease in Mayo score of ≥30% and ≥3 points from induction baseline with either a decrease in rectal bleeding subscore of ≥1 from induction baseline or a rectal bleeding subscore of 0 or 1; modified Mayo score (without Physician’s Global Assessment subscore) response as a decrease in modified Mayo score of ≥30% and ≥2 points from induction baseline with either a decrease in rectal bleeding subscore of ≥1 from induction baseline or a rectal bleeding subscore of 0 or 1; and endoscopic improvement as an endoscopy subscore of 0 or 1.

Results

Among 205 pts who were randomised to UST at maintenance baseline and continued treatment in the LTE, who either had Mayo score data (including endoscopy) at wk200 or had experienced treatment failure, 58.0% were in clinical remission, 80.0% were in clinical response, 79.5% were in modified Mayo score response, and 67.3% showed endoscopic improvement (Figure 1). Using an alternative “as observed case” analysis (without imputation for treatment failures), among 171 randomised pts who continued UST treatment through LTE and had an endoscopy score at wk200, 69.6% were in clinical remission, 95.9% were in clinical response, 95.3% were in modified Mayo score response, and 80.7% showed endoscopic improvement.

Conclusion

Among these pts with a history of moderate to severe UC who continued UST treatment, approximately 2/3 or more were in clinical remission, clinical response, and/or demonstrated endoscopic improvement at 4 years.
OP21 COVID-19 morbidity/mortality and vaccination against SARS-CoV-2 in patients with Inflammatory Bowel Disease in Poland: Nationwide Data
Authors: Kucha P , Walkiewicz D , Wieszczy P , Reguła J , Zagórowicz E
Published: January 2023

Background

According to the international recommendations, patients with inflammatory bowel disease (IBD) should be vaccinated against SARS-CoV-2 at the earliest opportunity to do so. The aim of this study was to assess the morbidity and mortality from COVID-19 in the adult IBD population in Poland with respect to their vaccination status.

Methods

We conducted a retrospective analysis of administrative health claims collected by the National Health Fund, the sole public payer in Poland. We identified adult IBD patients as of December 31th, 2021 who had at least two or more records with K50 or K51 code and two or more prescriptions for IBD drugs reimbursed or else intestinal surgery preceding the record. The vaccination status in 2021 was assessed using the database maintained by the Ministry of Health. We examined the vaccination process against SARS-CoV-2 among IBD patients along with morbidity and mortality from COVID-19. We conducted a Cox proportional hazard model analysis to determine the hazard ratio of SARS-CoV-2 infection, hospitalization and death in respect to the vaccination status during the autumn wave of the COVID-19 pandemic (October–December 2021).

Results

As of December 31th, 2021 there were 93 068 adult patients diagnosed with IBD. The vaccination rate in IBD patients was significantly higher than in the general population of Poland (72.1% vs 63.8%; p<0.001) and grew with age, reaching the top value among those aged 70-79 years (88.2%) [Figure 1]. 87 353 IBD patients were included into the Cox proportional hazard analysis of autumn pandemic wave, during which there were 4 042 registered COVID-19 cases in IBD population. The peak value of a weekly average of incidence rate of COVID-19 was lower for vaccinated IBD patients (7.4/10000) than for unvaccinated ones (13.0/10000). The risk of being infected was significantly lower for vaccinated IBD patients (HR 0.53; 95%CI 0.5-0.57; p<0.001). The cumulative risk of being positively tested for COVID-19 shows Figure 2. The most notable protective effect of vaccination against SARS-CoV-2 was found in patients aged 60-69 years (HR 0.47; 95%CI 0.39-0.55) and in those aged 80 years and above (HR 0.44; 95%CI 0.32-0.63). The risk of hospitalization due to COVID-19 was also significantly lower among the vaccinated IBD patients (HR 0.48; 95%CI 0.31-0.74, p<0.0001). The risk of death due to COVID-19 was more than 3 times decreased in vaccinated IBD patients in comparison to the remaining IBD population (HR 0.29, 95%CI 0.17-0.43, p<0.001) [Table 1].

Conclusion

Adult patients with IBD were more likely to get vaccinated against SARS-COV-2 than adults in the general population of Poland. The vaccination significantly decreased the risk of the infection, hospitalization and death due to COVID-19.
OP22 The risk of cancer in pediatric-onset immune-mediated inflammatory diseases – a nationwide Danish study from 1980-2018.
Authors: Ehrström A , Jansson S , Malham M , Wewer V
Published: January 2023

Background

A higher risk of cancer has been reported among patients with adult-onset immune-mediated inflammatory disease (IMID). However, data on cancer risk in paediatric-onset IMIDs (pIMID) are scarce. In this nationwide study from 1980 to 2018, we investigated the risk of cancer in the Danish pIMID population compared to controls from the background population.

Methods

PIMID was defined as patients registered in the Danish National Patient Registries with one or more of the following diagnoses: inflammatory bowel disease (pIBD), rheumatic disease (pRD), or autoimmune idiopathic liver disease (pAILD) before their 18th birthday. Each case was matched with up to 10 controls from the background population. Cancer diagnoses were verified using the Danish Cancer Registry. Risk of cancer was calculated using Cox proportional regression analysis and presented as hazard ratios (HR) with 95% confidence intervals (95% CI).

Results

We identified 13 216 cases, consisting of 5 811 pIBD (44%), 7 241 pRD (55%) and 347 pAILD (2%), and 114 502 controls. Median age at diagnosis was 12.5 years. Follow-up time was 11.1 and 10.5 years for cases and controls, respectively. The risk of overall cancer in pIMID compared to the background population was HR 2.1 (95%CI: 1.8-2.4), p<0.001. The risk of cancer was HR 2.4 (95%CI: 2.0-3.0), p<0.001 in pIBD, ascribed to colorectal-, liver-, skin cancer and lymphoma, HR 1.6 (95%CI: 1.2-2.1), p=0.002 in pRD, ascribed to lymphoproliferative cancer, and HR 5.7 (95%CI: 2.5-13.1), p<0.001 in pAILD, ascribed to liver and skin cancer. Patients with multiple IMID had an increased risk of cancer compared to patients with only one pIMID diagnosis (HR 2.8 [95%CI: 1.9-4.1], p<0.001).

Conclusion

PIMID was associated with a twofold increased risk of cancer, ascribed to colorectal cancer in pIBD, liver cancer and skin cancer in pIBD and pAILD, and lymphoproliferative cancer in pIBD and pRD.
OP28 Children and young adults with inflammatory bowel disease have an increased incidence and risk of developing mental health conditions: a UK population-based cohort study
Authors: Cooney R , Tang D , Barrett K , Russell R K
Published: January 2023

Background

While it is widely recognised that inflammatory bowel disease (IBD) is associated with depression and anxiety, the burden of mental health conditions in children and young adults with IBD remains unclear. This study assessed this burden using UK population-based data.

Methods

A retrospective observational study was performed using a large UK primary care dataset (Optimum Patient Care Research Database). Children and young adults aged 5–25 years diagnosed with IBD between 2010 and 2020 were propensity score matched with up to four population controls. The association between IBD and incident depression, anxiety disorder (AD), eating disorders, body image disorders, attention-deficit disorders, behavioural disorders, adjustment disorders, acute stress disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), self-harm, parasuicide (including suicide), sleep disturbance and ‘any mental health condition’ (a composite consisting of all these mental health conditions) was investigated. Absolute risk was derived using Kaplan-Meier analysis. Relative risk of all outcomes up to 10-years in the IBD cohort versus controls was estimated using adjusted Cox proportional hazards models controlling for age, sex, socioeconomic status, ethnicity, and other conditions (asthma, atopic dermatitis, allergic rhinitis, thyroid disease, epilepsy, diabetes mellitus, cancer, juvenile idiopathic arthritis, systemic lupus erythematosus, ankylosing spondylitis, and psoriatic arthritis).

Results

3,898 young patients with incident IBD were matched to 15,571 controls. IBD patients were significantly more likely to develop PTSD (adjusted Hazard Ratio [aHR] 2.47, 95% CI 1.23-4.94), eating disorders (aHR 1.85, 95% CI 1.05-3.26), self-harm (aHR 1.49, 95% CI 1.00-2.21), sleep disturbance (aHR 1.40, 95% CI 1.15-1.71), depression (aHR 1.34, 95% CI 1.16- 1.56), AD (aHR 1.25, 95% CI 1.06-1.48), and ‘any mental health condition’ (aHR 1.28, 95% CI 1.12-1.46) (Figure 1). In subgroup analysis, male sex, and IBD patients aged 12 to 17 appear to have the greatest additional risk for developing mental health conditions (Figure 2) and Crohn’s disease had a higher risk than ulcerative colitis (aHR 1.32, 95% CI 1.10-1.58 and aHR 1.19, 95% CI 0.95-1.49 respectively).

Conclusion

Young IBD patients have a significantly higher incidence and risk of new mental health conditions. Mental health remains a critically overlooked aspect of IBD patient management. Further research into identifying optimal monitoring tools and support for these patients is required to improve patient care.
OP32 The gut virome-colonizing Orthohepadnavirus genus is associated with ulcerative colitis pathogenesis and induces intestinal inflammation in vivo
Authors: Facoetti A , Massimino L , Palmieri O , Fuggetta D , Spanò S , D'Alessio S , Furfaro F , D'Amico F , Zilli A , Fiorino G , Noviello D , Latiano A , Bossa F , Pirola A , Mologni L , Piazza R , Abbati D , Perri F , Bonini C , Peyrin-Biroulet L , Malesci A , Danese S , Ungaro F
Published: January 2023

Background

Ulcerative colitis (UC) is a chronic inflammatory disorder with an unknown etiology1. Over recent years, a growing body of evidence has been pinpointing gut virome dysbiosis as a fundamental component in its progression2, although its role during the early phases of chronic inflammation is far from being fully defined. Therefore, we sought to investigate the role of a virome-associated protein encoded by the Orthohepadnavirus genus, the Hepatitis B virus X protein (HBx)3, during UC aetiopathogenesis.

Methods

HBx positivity of UC patient-derived blood and gut mucosa was assessed by RT-PCR and Sanger sequencing correlated with clinical characteristics by multivariate analysis. Transcriptomics was performed on HBx-overexpressing endoscopic biopsies from healthy donors.

C57BL/6 mice underwent intramucosal injections of liposome-conjugated HBx-encoding plasmids or the control. Multidimensional flow cytometry analysis was performed on colonic samples from HBx-treated and control animals. Transepithelial electrical resistance measurement, proliferation assay, ChIP-Seq, and RNA-Seq were performed on in vitro models of the gut barrier.

Results

HBx was detected in about 45% of patients with UC (Figure 1) and found to induce colonic inflammation in mice (Figure 2A-2D), while its silencing reverted the colitis phenotype in vivo (Figure 2E-2H). HBx acts as a transcriptional regulator in epithelial cells (Figure 3), provoking barrier leakage and altering inflammatory response (Figures 3 and 4).

Conclusion

This study paves the way for the understanding of the aetiopathogenesis of UC and provides a brand-new standpoint that looks at the virome as a target for tailored treatments, possibly leading to an entirely new approach to therapeutic intervention.

References:

1. Massimino L, Lamparelli LA, Houshyar Y, et al. The Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) framework. Nat Comput Sci 2021;1:511–5. doi:10.1038/s43588-021-00114-y

2. Ungaro F, Massimino L, D’Alessio S, et al. The gut virome in inflammatory bowel disease pathogenesis: From metagenomics to novel therapeutic approaches. United European Gastroenterol J 2019;7:999–1007. doi:10.1177/2050640619876787

3. Ungaro F, Massimino L, Furfaro F, et al. Metagenomic analysis of intestinal mucosa revealed a specific eukaryotic gut virome signature in early-diagnosed inflammatory bowel disease. Gut Microbes 2019;10:149–58. doi:10.1080/19490976.2018.1511664
OP34 Enteral Nutrition Compared with Steroids in Children with Crohn’s Disease – In Israel: a nationwide study from the epi-IIRN
Authors: Plotkin L , Lujan R , Focht G , Greenfeld S , Loewenberg Weisband Y , Lederman N , Matz E , Dotan I , Turner D
Published: January 2023

Background

Studies have shown that exclusive enteral nutrition (EEN) treatment is as effective to corticosteroids (CS) for induction of remission in pediatric Crohn's disease (CD) with fewer side effects, but long-term outcome data are scarce. In this nationwide study we aimed to compare the risk of complicated disease course (CDC) after 2 years of follow-up in children with CD receiving EEN or CS as induction therapy.

Methods

Data of children diagnosed with CD in the epi-IIRN cohort between 2005-2020 were retrieved from the 4 Israeli Health-Maintenance-Organizations covering 98% of the population. The primary outcome was CDC defined as CD-related surgery, steroid-dependency, or need for more than one biologic class during 2 years post-diagnosis. Secondary outcomes included hospitalizations, and the use of biologics (any). Additionally, anthropometrics, labs reflecting nutrition (i.e., Alb and HGB), and growth were assessed at repeated visits until 2 years thereafter. To account for confounding by indication bias, we compared children with similar baseline characteristics based on Propensity Score (PS) individual matching. Time to CDC outcome was evaluated using Kaplan-Meier survival curves and compared by the log-rank test. A Cox proportional hazard model was sought to assess the relationship between the type of induction and time to CDC outcome.

Results

A total of 785 children with CD were induced after diagnosis with either EEN (n=410) or CS (n=375); mean age 13.3±3.5 years, 59% males. PS successfully matched 116 pairs of whom 85 (36%) had CDC. The survival probability of CDC at 6, 12,18, and 24 months was higher in the CS group compared to the EEN group at all time points (5%vs4%, 12% vs 10%, 22% vs 3%, and 27% vs.16%, respectively p=0.045; fig. 1). In a Cox multivariable model adjusted by year of diagnosis, CS induction treatment was similarly associated with higher hazard of CDC by 2 years (HR 1.8 [95%CI 1.01-3.25]). The survival probability of hospitalization was also higher in the CS group at 6,12,8, and 24 months (16% vs 9%, 20% vs 12%, 25% vs 14%, and 27% vs. 15%, respectively, p=0.024; fig.2). There was no difference in time to biologics (p=0.96, n=59 (51%) in EEN, n=57 (49%) in CS) and anthropometric data (Table 1). Significant improvements were observed in HGB and Alb levels for the EEN group during the first 3 months from diagnosis compared with the CS (p=0.046 and p=0.035 respectively) (table 1).

Conclusion

EEN as induction therapy in pediatric CD is associated with a lower long-term risk of complicated disease course and larger improvement in HGB and Alb but not in growth parameters compared with CS, even when adjusting to baseline disease severity and patients characteristics.
OP36 Real-world evidence on comparative effectiveness of Ustekinumab vs anti-TNF in Crohn’s disease with propensity score adjustment: two-year maintenance phase results from the prospective observational RUN-CD study
Authors: Bokemeyer B , Plachta-Danielzik S , Deppe H , Mohl W , Teich N , Hoffstadt M , Schweitzer A , von der Ohe M , Gauss A , Atreya R , Krause T , Blumenstein I , Fajardo Salmon S , Hartmann P , Gilman E , Schreiber S
Published: January 2023

Background

Within the framework of the prospective real-world RUN-CD registry on the effectiveness and safety of ustekinumab (UST) in Crohn’s disease (CD), a total of 901 CD-patients undergoing a newly initiated biologics therapy were enrolled in 44 IBD-experienced centers from all over Germany between 2017-2020 with a follow-up of 3 years. Here, the results on the effectiveness of the maintenance therapy over 24 months are presented as a real-world evidence (RWE) comparison of CD-patients with UST vs anti-TNF.

Methods

After exclusion of other biologics than UST and anti-TNF and missing outcomes (HBI), the final sample consisted of 550 CD patients. Clinical remission (HBI ≤ 4) was the predefined endpoint at month 24 and additionally, switching of biologics therapy was considered as an outcome failure. Patients were analysed on a modified intent-to-treat basis (mITT; switchers considered as outcome failure). To reduce the effect of confounders, propensity score (PS) adjustment with inverse probability of treatment weighting (IPTW) was implemented. A weighted logistic regression was used, and the results were reported as odds ratio (OR) and 95% confidence interval (CI). Quality of life was assessed using the self-reported visual analogue scale (EQ-VAS) of the EQ-5D with changes from baseline to 2 years.

Results

308 UST (naïve: 27) and 242 anti-TNF (naïve: 162) CD-patients were included (ADA: 61.2%, IFX: 38.8%). The number of switches within 24 months was significantly lower with UST than with anti-TNF (27.6% vs 37.1%; p=0.038), and especially with IFX, whereby the difference between UST and IFX (27.6% vs 46.7%; p=0.003) proves to be statistically significant (Fig. 1). Clinical remission at two years was not statistically different for the overall UST vs anti-TNF groups (51.2% vs 54.4) (numerically higher in biologic-naïve UST- vs anti-TNF-patients, without statistically significance) (Tab. 1). Remission rates were similar for UST vs ADA, while they were significantly higher for UST vs IFX (54.4% vs 37.9%; p=0.008) (Tab. 2), and also significantly higher for ADA vs. IFX (58.2% vs 37.9%; p=0.003). As a sign of an improved QoL we observed a significant increase in EQ-VAS within both treatment groups. However, a similar increase in EQ-VAS was observed with UST and anti-TNF (+14.2 vs +12.3; p=0.147).

Conclusion

In this prospective two-year RWE comparison clinical remission was, also due to more frequent switches within the IFX group, significantly higher with UST when compared with IFX and higher with ADA than with IFX. Considering the effectiveness results of UST and the proven favourable safety profile, UST can be considered a first-line targeted therapy for CD.
OP39 Safety of ustekinumab in IBD: Final pooled long-term safety analysis through 5 years in CD and 4 years in UC
Authors: Ghosh S , Feagan B , Ott E , Gasink C , Marano C , Miao Y , Sandborn W , Danese S , Abreu M , Sands B
Published: January 2023

Background

Long-term efficacy of ustekinumab (UST) has been reported in Crohn’s disease (CD) through 5 years (yrs)1 and in ulcerative colitis (UC) through 4 yrs.2 A previous pooled analysis of long-term safety data reported a favorable UST safety treatment profile for inflammatory bowel disease (IBD).3 Here, we present results of the final cumulative analysis of long-term safety data from UST studies through up to 5 yrs in CD and 4 yrs in UC.

Methods

Data from 6 phase 2/3 UST IBD studies were pooled. In phase 3, patients (pts) received a single IV placebo (PBO) or UST (130mg or ~6mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90mg q8w or q12w). Concomitant immunomodulators and corticosteroids were permitted. All pts who received ≥1 dose of UST were included. Safety outcomes are summarized and presented using number of events per 100 patient-years (PY) of follow-up and corresponding 95% confidence interval (CI).

Results

In this final pooled UST IBD safety data, 2575 pts were treated with UST with 4826 PYs of follow-up. Rates of key safety events, including MACE and malignancies, were similar between PBO and UST or not higher for UST (Table 1).

The most frequently occurring adverse events (AEs) in either group (excluding diseases under study) were headache (PBO 16.66 vs. UST 11.60), arthralgia (PBO 15.91 vs. UST 11.23), abdominal pain (PBO 13.79 vs. UST 9.86), nausea (PBO 11.35 vs. UST 7.13), and pyrexia (PBO 11.35 vs. UST 5.91); infections were nasopharyngitis (PBO 17.82 vs UST 19.10) and upper respiratory tract infection (PBO 11.78 vs UST 9.80). The most frequently reported serious infections of anal abscess, pneumonia, cellulitis, and abdominal abscess were no higher in the UST group than PBO, except gastroenteritis (PBO 0.11 vs UST 0.25). No lymphomas were reported. Nine deaths were reported in UST-treated pts (0.00 [0.00, 0.32] PBO vs. 0.19 [0.09, 0.35] UST), 6 in CD and 3 in UC (all considered unrelated to study agent).

Conclusion

The final compilation of cumulative UST IBD safety data through 5 yrs in CD and 4 yrs in UC showed a safety profile that continued to be favorable and supports the well-established UST safety experience across all approved indications.

References:

1. Sandborn WJ, et al. Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn's Disease: The IM-UNITI Trial. Clin Gastroenterol Hepatol. 2022;20(3):578-590.e4.

2. Afif W, et al. Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results from The UNIFI Long-term Extension. UEGW 2023.

3. Sandborn WJ, et al. 129 Safety of Ustekinumab In IBD: Pooled Safety Analysis through 5 years in CD and 2 Years in UC. Gastroenterology. 2021;Supplement:S-35-S-36.
DOP01 The effect of vedolizumab on CD8 T cell repertoire homogeneity and blood-gut trafficking in patients with inflammatory bowel disease
Authors: Williams K , Shows D , Kongala R , Clarke A , Lord J
Published: January 2023

Background

Inflammatory bowel disease (IBD) causes T cell to infiltrate intestinal mucosa, but the heterogeneity of these cells is not understood at a clonal level. The anti-integrin α4β7 agent vedolizumab is believed to treat IBD by blocking this T cell infiltration from blood.

Methods

To understand the clonal distribution of T cells in IBD and how this is affected by vedolizumab, we studyined the T cell receptor (TCR) repertoire in CD8+ T cell subsets sorted from blood samples and colon mucosal biopsies via FACS. Inflamed or uninflamed colon segments from 15 ulcerative colitis and 13 Crohn’s disease patients were compared to colon biopsies from 11 people without IBD. In peripheral blood, we profiled purified α4β7+, α4β7- effector/memory, CD45RA+ terminal effector/memory (TEMRA) CD8 T cells, and mucosal-associated invariant T (MAIT) cells. In a separate cohort of 13 IBD patients, samples were obtained before and during vedolizumab therapy to determine its effect on the diversity and overlap of the TCR repertoires of blood and colon CD8+ T cells.

Results

CD8 TCR diversity in the mucosa and peripheral blood did not correlate with inflammation. CD8 TCR repertoire overlap between any two anatomically distinct locations of a person’s colon was consistently high, though often lower between inflamed and uninflamed sites. Repertoire overlap was also seen between the colon and each peripheral blood subpopulation studied, with the highest overlap seen for integrin α4β7+ T cells and the lowest for MAIT cells. Inflamed tissue overlapped more than uninflamed with each blood subpopulation. Vedolizumab did not affect the overlap between colon CD8+ T cells and circulating α4β7+ CD8 T cells, nor their TCR diversity, regardless of treatment efficacy. Indeed, flow cytometry revealed no relative depletion of effector/memory T cells in the colons of vedolizumab recipients. Instead, vedolizumab caused the depletion of rare naïve mucosal T cells and dendritic cells (DC) from the colonic mucosa.

Conclusion

CD8 T cell clones are spread homogenously throughout the colon. Although TCR repertoire overlap is greater within than between inflamed and uninflamed colon segments, a similar diversity of TCRs in both argues against local clonal expansion being the main source of excess T cells in inflamed mucosa. Rather, our data reveal increased TCR overlap between blood and inflamed mucosa to support the significance of T cell trafficking in IBD pathogenesis, particularly concerning experienced α4β7+ T cell populations. However, we surprisingly found neither gross nor clonal evidence that blockade of this trafficking is the mechanism by which vedolizumab treats IBD, instead finding only naïve T cells and DC to be depleted from the colonic mucosa in response to vedolizumab.
DOP06 Deep characterization of IL-23 pathway in different gut segments and associated plasma biomarkers in inflammatory bowel disease
Authors: Cairns J , Monkley S , Tian S , Angermann B , Liu Z , Öberg L , Muthas D , Cabrera C , Rapsomaniki E , Fernández Llaneza D , Olsson M , Paraskos J , Ellison G , Khan E , Duncan E A , Neisen J , Gehrmann U , Chamberlain C
Published: January 2023

Background

The role of Interleukin 23 (IL-23) in the pathogenesis of both Crohn’s disease (CD) and ulcerative colitis (UC) is well documented. However, more than half of patients do not respond or lose response to current anti-IL-23 treatments. Thus, we aimed to identify patients with IL-23-driven disease using gut segment-specific transcriptome analysis and quantification of IL-23 pathway cytokines in plasma to enable patient stratification in inflammatory bowel disease (IBD).

Methods

Analyses of real-world data from the Study of a Prospective Adult Research Cohort with IBD (SPARC IBD) obtained from the IBD Plexus program of the Crohn’s & Colitis Foundation including clinical, plasma biomarker (IL-22, IL-23, INF-γ, and IL-17A), and mucosal ileum and colon transcriptome data.

Results

To differentiate IL-23 from TNF-driven disease, we performed gene set variation analysis (GSVA) using IL-23 and TNF gene sets and ileal and colonic transcriptome data from 1230 CD and 664 UC patients. An IL-23, but not TNF, transcriptional module was enriched in ileal compared to colonic biopsies in CD (p < 0.001​). IL-23 pathway activity was significantly higher in uninflamed Ileal compared to colonic biopsies from CD patients (p < 0.001)​). Importantly, IL-23 pathway activity was increased in intestinal biopsies from macroscopically inflamed compared to uninflamed regions, from all gut segments in both CD and UC and correlated with the endoscopic score for both diseases (Fig 1). We also observed higher plasma IL-22 levels in both CD and UC patients with moderate to severely active disease compared with patients in remission (Fig 2). We found that tissue IL-23 pathway activity was linked to plasma biomarker levels in general. The subgroup of CD patients with elevated plasma IL-22 levels showed higher IL-23 pathway activity in the ileum (p=0.003) and colon (p=0.013). In UC, patients with elevated plasma IL-22 levels showed higher IL-23 pathway activity in the sigmoid colon (p=0.001), but not the cecum (p=0.141) (Fig 3).

Conclusion

IL-23 pathway activity in different segments of the gut may contribute differently to pathogenesis in CD, while IL-23 pathway activity is similar across colonic segments in UC. The association between plasma biomarker levels and gut tissue IL-23 pathway activity suggests that quantifying plasma IL-22 levels could be a valuable tool to assess the efficacy of anti-IL-23 therapy in IBD.
DOP07 Targeting the canonical WNT signalling pathway as a potential novel therapy in Crohn′s associated fibrosis
Authors: Buck A , Weber M C , Friess H , Neumann P A
Published: January 2023

Background

Crohn’s disease (CD) is characterized by chronic recurrent intestinal inflammation that leads to progressive fibrotic remodelling of the intestinal wall. Despite advances in medical therapy for CD, 50% of patients still require surgical treatment after 10 years of disease mainly due to fibrosis-associated intestinal stenosis formation. A specific anti-fibrotic therapy does not yet exist, underlining the medical need for further research in this area. The exact mechanism of fibrosis development in CD fibrosis is not yet understood, but WNT signalling has been shown to play a critical role in fibrosis in other organs. However, the role of WNT-signalling in intestinal fibrosis and its potential druggability is not well characterized.

Methods

Bulk RNA sequencing was performed to uncover important mechanistic pathways participating in fibrosis development in surgical specimens from patients with fibrostenosing CD. Non fibrotic non-inflamed areas of the same patients served as controls. To elucidate the functional role of matrix producing fibroblasts, primary cells were isolated from both areas. Their fibrotic potential was further characterized by flow cytometry, immunofluorescence, and RNA sequencing. Protein levels of fibrosis markers as well as WNT target genes were assessed using immunofluorescence imaging techniques.

Results

Gene set enrichment (GAGE) revealed highly upregulated WNT-pathway (p adj < 0.0029) in CD fibrosis compared to matched normal tissue. Flow cytometry revealed an increased population of PDPN+, PDGFRa+ mesenchymal cells in fibrotic segments compared to non-fibrotic tissue. These cells preserve their fibrotic phenotype in vitro showing elevated expression of aSMA and COL1 in FACS. Functional and gene analysis showed upregulated migratory potential of fibrotic fibroblasts, as well as matrix production capabilities (VIM, COL1A1, FN1). RNA sequencing of tissue as well as fibroblasts revealed markedly elevated expression the Wnt1 effector WISP1, which is upregulated in fibrotic cells and tissue. In turn, WISP1 treatment of primary fibroblasts led to activation of the canonical WNT pathway, its target transcription factors and genes (LEF1, MMP7).

Conclusion

Fibrosis formation in CD patients is associated with activated WNT signalling. One druggable protein, a downstream target gene of WNT-signalling could be WISP1. This will be further investigated in our in vitro as well as in our in vivo model, to propose a novel therapy for reducing surgical intervention in CD patients.
DOP08 Cellular and molecular interaction of MAIT in mucosal tissue and their role in inflammatory bowel disease
Authors: Bosáková V , Frič J
Published: January 2023

Background

Inflammatory bowel disease (IBD) manifests as chronic inflammation of the gastrointestinal tract and is characterized by a deregulated immune response targeting the gut microflora. Mucosal-associated invariant T (MAIT) cells have been identified as a possible key player in IBD. Activated MAIT cells produce cytokines including IL-26, a newly discovered cytokine involved in the pathology of IBD. Interestingly, IL-26 is not expressed in mice and therefore its effect on the course of inflammation has not been yet fully investigated. Similarly, studies employing human cell cultures often provide limited results as they cannot fully mimic the complex three-dimensional structure of the intestinal tissue. A great hope is placed in the development of models of human diseases using organoids - 3D structures that better recapitulate the architecture and functionality of tissues.

Methods

Our laboratory recently described a model of intestinal inflammation based on human iPSCs-derived intestinal organoids (IOs). Taking advantage of this model, we investigate the influence of the cytokine IL-26 on the course of IBD. Moreover, we elucidate the influence of MAIT cells on the pathogenesis of IBD by studying their pathways of activation in vitro, and subsequently their interaction with inflamed tissues through the co-culture with IOs.

Results

After stimulation, IOs mimic the pro-inflammatory microenvironment and express various cytokines and chemokines. Moreover, IOs express MR1 which is recognised by the invariant TCR receptor of the MAIT cells. IOs express functional IL-26 receptor and respond to this cytokine.

MAIT cells isolated from human blood show production cytokines including IL-26 and effector molecules upon in vitro activation. Their response differs depending on the origin of the stimuli.

Conclusion

IOs form complex structures and immunocompetent environment allowing to study of intestinal inflammation. IOs consist of various cell types, but not immune cells. Taken together with MR1 and cytokines expression we show that IOs can activate MAIT cells, and they serve as a relevant model for in vitro study of their biology. Moreover, IOs respond to IL-26, so they also provide a relevant model to elucidate the role of this cytokine. We expect that this study will contribute to our understanding of the processes underlying the progression of IBD, and lead to the design of new therapeutic targets for the treatment of idiopathic intestinal inflammation.