bluuebunny/crossref_metadata_2025 huggingface dataset:
Reported evidence of greenness co-benefits on health, climate change mitigation, and adaptation: a systematic review of the literature
Authors: Kınay Pelin , Ji John S
Published: January 2022

This systematic review aims to appraise the quality of evidence on greenness co-benefits of climate change and health. Although there is evidence of the co-benefits of greenness on climate change and health, the research is of poor quality when it comes to addressing the connections and identifying mediators of greenness and climate change mitigation associations. The evaluation sought to identify areas where there was little or no evidence to guide future research. Current published studies mainly cover six health outcome categories (birth outcomes, physical activity, mental wellbeing, obesity, mortality, and cognitive function). For adaptation, greenness and climate change, associated studies included (a) cooling down effects and urban heat island impacts, (b) air quality improvement, and (c) flood mitigation. For each outcome, we performed a systematic search of publications on Web of Science, PubMed, Google Scholar, and Science Direct databases from 2000 to July 2021. After retrieving records in which full papers were assessed and non-English articles were excluded, a total of 173 articles, including research articles and reviews, were chosen. To ascertain the strength of the evidence, all interventions were assessed using the GRADE approach. The quality of evidence ranged from moderate to high for most categories of health outcomes (birth outcomes, mental wellbeing, mortality). GRADE assessment provided low-quality evidence for studies on air quality, flood mitigation, physical activity, and obesity due to poor study design (observational or limited data) and high heterogeneity (some data provided variability), and the review concluded that there is insufficient evidence on firm recommendations for public health interventions. Due to a huge amount of low-quality evidence and several areas of overlapping study, this evaluation recognized the co-benefits of greenness on climate change and health as an understudied field and hence as a research gap. The evidentiary foundation for greenness-climate change mitigation links was generally weak. Future research on climate change greenness co-benefit interventions should pay special attention to flood prevention, air quality interactions, and health effects including physical activity and obesity.
The potential function of post-fledging dispersal behavior in first breeding territory selection for males of a migratory bird
Authors: Patchett Robert , Styles Patrick , Robins King Joanna , Kirschel Alexander N G , Cresswell Will
Published: January 2022

One possible hypothesis for the function of post-fledging dispersal is to locate a suitable future breeding area. This post-fledging period may be particularly important in migratory species because they have a limited period to gather information prior to autumn migration, and in protandrous species, males must quickly acquire a territory after returning from spring migration to maximize their fitness. Here we use color-ring resightings to investigate how the post-fledging dispersal movements of the Cyprus wheatear Oenanthe cypriaca, a small migratory passerine, relate to their first breeding territory the following year when they return from migration. We found that males established first breeding territories that were significantly closer to their post-fledging location than to their natal sites or to post-fledging locations of other conspecifics, but these patterns were not apparent in females. Our findings suggest that familiarity with potential breeding sites may be important for juveniles of migratory species, particularly for the sex that acquires and advertises breeding territories. Exploratory dispersal prior to a migrant’s first autumn migration may contribute toward its breeding success the following year, further highlighting the importance of early seasonal breeding on fitness and population dynamics more generally.
OP06 The influence of different prednisolone tapering algorithms on the effectiveness of infliximab in patients with Ulcerative Colitis – A real-world cohort study
Authors: Ovesen P D , Ilvemark J F K F , Attauabi M , Seidelin J B
Published: January 2022

Background

Data regarding the influence of prednisolone tapering on clinical outcomes among patients with ulcerative colitis (UC) are limited. We aimed to investigate the influence of different prednisolone tapering algorithms on the effectiveness of infliximab (IFX) among patients with UC.

Methods

This Danish retrospective single-center study included all patients with UC who were treated with IFX between 2009 and 2019 at Herlev University Hospital. The patients were grouped according to the prednisolone tapering: standard (≤5 mg/week), fast (>5 mg/week), or direct discontinuation after an initial course of less than one week. Finally, we included a control group of patients treated with IFX monotherapy. The primary outcome was corticosteroid-free clinical remission at weeks 14 and 52 defined as a partial Mayo score ≤1. Variables with a p-value ≤0.20 in univariable regression analysis were included in multivariable analysis. A subgroup analysis containing patients with acute severe ulcerative colitis (ASUC) treated with at least 40 mg of prednisolone at initiation of IFX was performed.

Results

The study included 148 patients with UC of whom 81 (54.7%) were treated with prednisolone at the initiation of IFX. No association between prednisolone tapering and corticosteroid-free clinical remission with IFX at weeks 14 or 52 was observed (Figure 1 and Table 2). However, a higher proportion of patients in the standard tapering group achieved a C-reactive protein (CRP) level less than 5 mg/L at week 14 as compared with the fast-tapering group (23/23 (100%) vs. 14/18 (77.8%); p=0.03) and directly discontinuation group (6/10 (60%); p=0.03). This difference was not explained by prednisolone usage. In addition, none of the patients within the standard tapering regime (0/24; 0%) had severe activity at week 14 whereas this was seen in 4/19 (21.1%) in the fast tapering regime (p=0.03). In the subgroup analysis of 33 patients with ASUC, the standard tapering algorithm was associated with higher clinical remission as compared with the fast tapering regime at week 14 (9/14 (64.3%) vs. 5/19 (27.8%); p=0.02) and clinical response or remission at week 52 (12/14 (85.7%) vs. 7/19 (36.8%); p=0.01, Figure 2).

Conclusion

This study demonstrated no overall impact of prednisolone tapering algorithms on short and long-term effectiveness of IFX in patients with UC. However, standard tapering resulted in lower CRP levels and fewer cases of severe disease activity in the overall cohort and higher rate of short and long-term clinical response among ASUC patients, as compared with fast tapering regimes. Taken together, the data indicate that longer corticosteroid exposure in patients with high disease burden might improve IFX responses.
OP31 Dietary and Multi-Omic characterization of new onset treatment naive Crohn Disease identifies factors that may contribute to disease pathogenesis
Authors: Haberman Ziv Y , Braun T , Amir A , Levhar N , Malik A , Neuman S , Picard O , Yavzuri M , Efroni G , Hadar R , Ben-Horin S
Published: January 2022

Background

Crohn Disease (CD) prevalence is rising worldwide. As altered genetics are improbable, this phenomenon likely relates to environmental-dietary changes linked with gut microbiome. We aimed to define host and microbial factors at CD diagnosis.

Methods

Multiomics analyses of SOURCE cohort including clinical, biomarkers (CRP, fecal calprotectin), food frequency questionnaire (FFQ), serum metabolomics, mucosal terminal ileum (TI) transcriptomics, and fecal and mucosal biopsy samples for 16S microbial amplicon sequencing.

Results

25 newly-diagnosed CD and 33 controls (median age 28 years, 50% males). Gender, age, and BMI did not differ between groups, but CRP (p=0.001) and calprotectin (p=E-10) were significantly higher in CD. FFQ results showed that compared to controls, pre-diagnosis CD patients consumed significantly more added sugar (g/day), starch (g/day) nitrite (mg/day), and significantly less vitamin K, D, vegetables, and olive oil (Fig 1). Microbial analyses highlighted significant differences (FDR<0.1) in amplicon sequence variants (ASVs) abundance between stool and biopsies samples (73 ASVs) and between CD and Controls samples (82 ASVs). Biopsy vs. stool samples were enriched for Veillonella, Fusobacterium, Neisseria, and Ruminococcus gnavus. CD showed higher abundance of Enterobacteriaceae and Ruminococcus gnavus with reduction of several Ruminococcaceae and Lachnospiraceae taxa (Fig. 1). Ileal transcriptomics differential expression (FC>1.5, FDR<0.05) replicated previous results with significant induction in CD of DUOX2, CXCL9, and DEFB4A and pathways linked to innate and adaptive immunity, and to extracellular matrix. CD down regulated genes included GUCA2B, SLC10A2, and GSTA1, and pathways linked with epithelial transporters. Serum metabolomics highlighted significant variations (FDR<0.25) in Linoleic acid, aKG, Tryptophan, nicotinamide, Docosahexaenoic acid, oxalate, and GABA between CD and controls. We next tested for significant association (FDR<0.25) between diet and multi-OMICs (Fig. 2). Associations between gut microbiome and TI transcriptomics, and serum metabolomics showed that Erysipelotrichacea taxa positivity correlated with serum oxalate, and TI expression of CEACAM6 and DUOX2. Associations between diet and TI transcriptomics and serum metabolomics indicated that B12, tryptophan and riboflavin consumptions were negatively associated with the bile acid transporter SLC10A2 in the TI, and vegetables consumption was positively associated with oxalate degrading Oxalobacter.

Conclusion

Conclusions: FFQ identifies difference in diet at the onset of CD that may contribute to pathogenesis. Integration between dietary and OMICs layers disclosed novel correlations warranting further exploration.
DOP19 Myeloid and lymphoid cell abnormalities persist in the intestinal mucosa of patients who recover from COVID-19 infection
Authors: Meringer H , Tokuyama M , Tankelevich M , Martinez-Delgado G , Jha D , Livanos A E , Canales-Herrerias P , Cossarini F , Mehandru S
Published: January 2022

Background

Although respiratory failure is the hallmark of severe disease, it is increasingly clear that Coronavirus Disease 2019 (COVID-19) is a multi-system disorder. The presence of gastrointestinal (Gl) involvement by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been suggested by epidemiological, clinical, non-human primate, in-vitro (enteroid) and ex-vivo (human biopsy) studies. Having recently documented persistence of SAR-CoV-2 within the intestinal epithelium 7 months after infection, here we aimed to study mucosal immune cell abnormalities in individuals with prior history of COVID-19.

Methods

Individuals with previous COVID-19 diagnosis (by either RT–PCR or seroconversion) and controls (without RT-PCR or serological evidence of prior COVID-19 infection) undergoing endoscopic evaluation were recruited into the study (Table 1,2). Colonic and small intestinal (duodenal and ileal) biopsies were analyzed by multiparameter flow cytometry for mucosal immune cell populations including myeloid cells (classical and non-classical monocytes, dendritic cell subsets), T cells (subsets and activation state), B cells (including plasma cells). Persistence of viral antigens was determined by immunofluorescence microscopy (n=30) using a previously published anti-nucleocapsid (NP) antibody.

Results

Thirty subjects with a previous history of COVID-19 (post-COVID), median of 4 months from diagnosis (range 1–10 months), were recruited and compared with 40 normal volunteer (NV) controls. Relative to controls, post-COVID subjects displayed higher frequencies of classical (CD14+) monocytes in both, the colon and the small bowel, while significantly higher frequencies of conventional dendritic cells (cDC) 1 (lin-HLA-DRhiCD14-CD11c+CD141+) and cDC2 (lin-HLA-DRhiCD14--CD11c+CD1c+) were noted in the colon only. Among T cell subsets, CD8+ tissue resident memory T cells (CD8+CD69+CD103+) were significantly increased in colon of post-COVID subjects compared to NV. Among B cell subsets, plasma cells (CD3-CD27+CD38hi) trended higher (p=0.06), while mucosal B cells (CD3-CD19+) were significantly lower in the terminal ileum of post-COVID subjects compared to NV. Finally, with IF, we detected SARS-CoV-2 NP in 10 out of 30 (33%) of post-COVID subjects (Figure 1). There were no significant correlations of these cell populations with either time after the infection or IF positivity.

Conclusion

Innate and adaptive immune cell abnormalities persist in the intestinal mucosa of post-COVID subjects for up to 10 months and may reflect viral persistence or immune cell dysregulation in the intestines. These findings have major implications for understanding the pathogenesis of long term sequela of COVID-19, including long-haul COVID.
DOP21 Potential mechanisms linking biological therapies on SARS-CoV-2 susceptibility in Inflammatory Bowel Disease patients
Authors: Pisani L F , Mola S , Crespi G , Caprioli F , Pastorelli L , Annunziata M L , Manfredi M , Porta C
Published: January 2022

Background

The current novel coronavirus (SARS-CoV-2) pandemic is an ongoing global health crisis, which represents an important challenge for the whole society and mankind. Patients with inflammatory bowel disease (IBD) are treated with immunosuppressive drugs that are usually associated with more severe viral infections. However, the effects of the different therapies on the risk of SARS-CoV-2 infection and Covid-19 severity in IBD patients are still under investigation.

Methods

Between April 2020 and April 2021, 238 IBD patients (N=145 with Crohn disease and N=93 with Ulcerative colitis) of the North Italy area have been enrolled. Both serum samples (N=238 IBD patients and N=45 healthy donors) and colon biopsies from inflamed and non-inflamed mucosa (N=88 IBD patients N=20 non-IBD control) have been collected. To evaluate the exposure to SARS-CoV-2, both clinical data and seroprevalence of anti-SARS-CoV-2 Ab have been analyzed. Serum samples were analyzed by untargeted metabolomics analysis and the frequency of a serum metabolomics signature associated with protection were evaluated in IBD versus healthy donors. Moreover, gene expression analysis of key proteins for virus entry (ACE2, TMPRSS2, TMPRSS4, ADAM17) were analyzed by qPCR in the gut mucosa biopsies of IBD patients.

Results

The seroprevalence of anti-SARS-CoV-2 Ab in our cohort of IBD patients (10/238) indicates an overall lower incidence of COVID-19 in comparison with the general population of Lombardy. Accordingly, we observed that the serum metabolomics signature associated with protection was more frequent in IBD patients treated with anti-TNF (N=50, 70%), than healthy controls (N=45, 50%). Gene expression analysis of the proteins involved in SARS-CoV-2 entry also indicated that IBD patients treated with anti-TNF (N=14) had a lower mucosal level of SARS-CoV-2 receptor ACE2 and its sheddase ADAM17 than non-IBD subjects along with higher expression of the proteases TMPRSS2 and TMPRSS4. Moreover, vedolizumab-treated patients (N=7) showed a significant lower expression of ACE2, TMPRSS2 and TMPRSS4 than controls, whereas ADAM17 levels were similar.

Conclusion

Our study indicates that IBD population treated with biologics has an overall lower risk to contract SARS-CoV-2 infection. Future studies to gather the mechanisms underpinning the effects of biologics on the expression of the proteins involved in SARS-CoV-2 viral entry in association with the specific metabolomics signature of viral susceptibility might shed light on potential targets to increase resistance in higher risk subgroups of patients.
DOP29 A novel predictive scoring system of venous thromboembolism after surgery for Inflammatory Bowel Disease: A NSQIP-IBD registry analysis
Authors: Cheong J Y , Connelly T , Prien C , Jia X , Valente M , Bhama A , Lightner A , Holubar MD- MS S
Published: January 2022

Background

Patients undergoing colorectal surgery for inflammatory bowel disease (IBD) are recognized to have an increased risk of venous thromboembolism (VTE). The aim of this study was to determine the perioperative risk factors for VTE and to create a predictive scoring system for VTE in the IBD cohort.

Methods

The NSQIP-IBD registry from 2017–2020 was used to identify patients for the study. Demographics, operative and outcomes data of IBD patients undergoing colectomies for IBD were analyzed. Student t and χ 2 tests were used for univariate analysis. A logistic multivariate regression model was performed using all significant variables to develop a predictive scoring system of VTE.

Results

5003 patients (51.9% male, mean age 42.7, 57.3% Crohn’s / 42.7% ulcerative colitis) were included in the study. 125 (2.49%) developed VTE. The univariate analysis is presented in Table 1. On multivariate analysis ASA grade, ulcerative colitis, sepsis, serum sodium <139 mmol/L, an open abdomen and preoperative inter hospital transfer were associated with greater risk of VTE. An open abdomen postoperatively was associated with the highest odds of developing a VTE [2.69 (1.20 – 5.39, p=.009)]. Using these 6 significant factors, a risk model was created. The risk of VTE with one risk factor was 0.7% and 1.8% with two risk factors. The risk of VTE increased to 3.6% and 4.5% with three and four risk factors respectively. With five and six risk factors, the risk of VTE increased exponentially to 10.9%, 25% respectively (Figure 1).

Conclusion

This study affirms that multiple perioperative and operative factors increase the risk of VTE after surgery for IBD. We present a novel model which demonstrates a cumulative risk increasing exponentially when more than five risk factors are present.
DOP32 Biologic treatment does not reduce the risk of postoperative peristomal pyoderma gangrenosum in Crohn’s Disease patients
Authors: Iesalnieks I
Published: January 2022

Background

To assess the risk of postoperative peristomal pyoderma gangrenosum in Crohn’s disease patients undergoing bowel resection with formation of an ostomy.

Methods

All patients with Crohn’s disease undergoing intestinal resection with formation of an ostomy were included in the present retrospective analysis. The data collection was performed prospectively. All cases of pyoderma gangrenosum were identified by clinical examination and documented on photographs. “Extended colectomies” were total colectomy and proctocolectomy.

Results

Between 2009 and 2021, 99 patients underwent intestinal resections with formation of an ostomy – 95 ileostomies and 4 colostomies. Ileocolic resections were performed in 62 patients, small bowel resections in 2 and colorectal resections in 35 patients. Additional abdominoperineal rectal resections were performed in 19 out of latter 35 patients. At the time of surgery, 31 patients were on biological treatment, 19 on steroids. Postoperatively, 10 patients (10%) developed peristomal pyoderma gangrenosum – all during first 3 postoperative months and all in presence of an ileostomy. By univariate analysis, abdominoperineal resection (26% vs. 9%, p=0.03), presence of colonic disease (20% vs. 2%, p=0.005), preoperative biological treatment (24% vs. 4%, p=0.008), extended colectomy (27% vs. 5%, p=0.008), non-stricturing/non-penetrating disease (35% vs. 5%, p=0.002) were associated with an increased risk of peristomal pyoderma gangrenosum. By multivariate analysis, preoperative intake of biologic treatment (Hazard Ratio 5.5, p=0.03), and non-stricturing/non-penetrating disease (HR 8.3, p=0.006) were associated with the risk of postoperative pyoderma gangrenosum.

Conclusion

Crohn’s disease patients with colonic disease undergoing bowel resections for non-stricturing/non-penetrating disease are at high risk to develop peristomal pyoderma gangrenosum during the early postoperative period. Preoperative biological treatment does not decrease the risk of pyoderma formation; moreover, it might even increase it.
DOP39 Effect of baseline disease characteristics on clinical outcomes in moderate-to-severe Ulcerative Colitis treated with upadacitinib: Results from a Phase 3 trials programme
Authors: Higgins P , Colombel J F , Reguiero M , Parkes G , Ilo D , Philips C , Yao X , Cheng E , Schreiber S
Published: January 2022

Background

Upadacitinib (UPA) is an oral, once-daily (QD), selective Janus kinase inhibitor that has demonstrated efficacy in the induction and maintenance treatment of Ulcerative Colitis (UC). This analysis aimed to assess the impact of baseline UC characteristics on clinical outcomes following UPA therapy.

Methods

Patients (pts) with moderately to severely active UC who had failed conventional or biological treatment were enrolled in two randomised, double-blind (DB), placebo (PBO)-controlled, Phase 3, 8-week induction studies of UPA 45 mg QD vs PBO. Pts achieving a clinical response (decrease from baseline in Adapted Mayo score ≥2 points and ≥30% from baseline, plus a decrease in rectal bleeding score [RBS] ≥1 or an absolute RBS ≤1) at Week (Wk) 8 entered a 52-week, randomised, DB, PBO-controlled, Phase 3 maintenance study, and received UPA 15 mg QD, UPA 30 mg QD, or PBO. The primary efficacy endpoint was clinical remission per Adapted Mayo score at Wk 8 (induction) and at Wk 52 (maintenance). Pre-specified (PS) and post hoc (PH) analyses were conducted by baseline disease activity (full Mayo score ≤9 or >9) (PS), extent (PS), duration (<2, 2–5, >5–10, >10 years [yrs]) (PH), and high-sensitivity C-reactive protein (hs-CRP) level (≤5 or >5 mg/L) (PH).

Results

988 pts were included in the induction studies, and 451 in the maintenance study. The treatment difference between UPA 45 mg QD and PBO excluded zero for all subgroups at Wk 8 (Figure 1). Wk 8 remission rates were lower for full Mayo score >9 vs ≤9, and for CRP >5 vs ≤5 mg/dL, with minimal effects of disease extent or duration. Wk 52 maintenance of remission rates were greater with UPA 15 mg and 30 mg QD vs PBO (16–44% and 30–50% difference, respectively), and with UPA 30 vs UPA 15 mg QD. This incremental benefit of the 30 mg dose was greater in pts with severely (full Mayo score >9) vs moderately active disease (Figure 2); 15 mg and 30 mg demonstrated similar efficacy in pts with Mayo score <9. Statistically non-significant numerical advantages for UPA 30 mg vs UPA 15 mg maintenance were seen in all subgroups, with the exception of hs-CRP >5 mg/L.

Conclusion

UPA 45 mg QD is an effective induction treatment for UC, regardless of baseline disease characteristics. Both 15 and 30 mg UPA doses are effective maintenance regimens, regardless of baseline disease characteristics. However, the 30 mg dose shows a trend towards increased benefit vs 15 mg in pts with Mayo score >9 and extensive disease. This analysis suggests that while UPA 15 mg may be most appropriate for patients with UC with a low inflammatory burden (per full Mayo score and extent), the 30 mg dose may be more appropriate for those with a high one.
DOP59 Development of a novel Ulcerative Colitis (UC) endoscopic activity prediction model using machine learning (ML)
Authors: Colombel J F , Rubin D , Schott J P , Gottlieb K , Erisson L , Prucka B , Phillips S , Kwon J , Ng J , McGill J
Published: January 2022

Background

Previous studies have described machine learning (ML) models to predict how human readers would score disease activity in UC using the endoscopic Mayo Score (eMS). So far, none employed deep human annotation that considers all the endoscopic features making up the eMS. Here we report the results of an ML model that is trained on eMS features using centrally read endoscopies.

Methods

793 full-length videos were obtained from 249 patients with UC who participated in NCT02589665, a phase 2 trial with mirikizumab in patients with UC and associated with centrally read (single reader) eMS (CReMS) as the primary dataset. After cleaning for usable frames, the data were split into training, validation and testing subsets. The ML workflow consisted of annotation, segmentation, and classification (e.g., erosions, ulcers, erythema, vascular pattern, and bleeding). Human image classification and segmentation with bounding boxes and was subjected to quality control adjudicated by one of three IBD specialists, generating more than 60,000 eMS-relevant annotation labels. The model was evaluated on a test set of 147 videos using the CReMS, and a consensus set of 94 test videos, where CReMS and annotator reported eMS (AReMS) were in agreement without adjudication. The primary objective of the model was a categorical prediction of endoscopically inactive disease (eMS 0 & 1) compared with active disease (eMS 2 & 3). The secondary objectives of the model were to predict endoscopic healing (eMS 0) and to predict severe disease (eMS 3).

Results

The model performances are in Table 1. On the full test set of 147 videos, the model predicted inactive disease compared with active disease with an accuracy of 84%, positive predictive value (PPV) of 80%, and negative predictive value (NPV) of 85%. In the subset of 94 videos with CreMS and AReMS consensus, the model predicted inactive disease compared with active disease with an accuracy of 89%, PPV 87%, and NPV of 90%. In this same subset, the model predicted endoscopic healing and severe disease with an accuracy of 95% and 85%, PPVs of 86% and 82% and NPVs of 95% and 87%, respectively. For the secondary objectives in the full set of 147 videos, the model predicted endoscopic healing and severe disease with an accuracy of 90% and 80%, PPVs of 44% and 86%, and NPVs of 95% and 86%, respectively.

Conclusion

We have developed a ML predictive model of the eMS in UC using centrally read videos and demonstrate excellent distinction between active and inactive disease, and clear discrimination between other levels of endoscopic activity. We propose that this unique ML approach to endoscopic assessment be considered as a substitute to human central reading in future clinical trials.
DOP61 Development and validation of novel models in prediction of intravenous corticosteroids resistance in patients with Acute Severe Ulcerative Colitis
Authors: Yu S , Li H , Li Y , Xu H , Tan B , Tian B , Dai Y , Tian F , Qian J
Published: January 2022

Background

Early prediction of intravenous corticosteroid (IVCS) resistance in Acute severe ulcerative colitis (ASUC) patients could reduce costs and delay in rescue therapy. However, most prediction models for ASUC were at high risk of bias with a lack of external validation. This study aims to construct and validate a model that accurately predicts IVCS resistance using various statistical methods.

Methods

A retrospective cohort of patients who were diagnosed with ASUC and had undergone IVCS treatment between March 2012 to January 2020 was established. Predictors evaluated included age, gender, race, medications before admission, infections, and laboratory data at baseline and during IVCS treatment, and endoscopic outcomes relied on blinded centralized endoscopy reading. The LASSO regression was used in feature selection for multivariate logistic regression model. Models based on machine learning methods (decision tree and random forest [RF]) were also constructed. Internal validity was confirmed and model performances were compared. External validation was conducted using data using an independent cohort from a tertiary referral centre.

Results

A total of 129 patients were included in the derivation cohort. During index hospitalization, 102 (79.1%) responded to IVCS, and 27 (20.9%) failed; 16 patients underwent colectomy, 6 received cyclosporin, and 5 succeeded with IFX as rescue therapy. Ulcerative Colitis Endoscopic Index of Severity (UCEIS; odds ratio [OR] 5.39, 95% confidence interval [CI] 2.52–14.0, p<0.001) and C-reactive protein (CRP) level on the third day (OR 1.05, 95% CI 1.03–1.08, p<0.001) were selected by LASSO regression and identified as the only two independent predictors of IVCS resistance in logistic regression. The decision tree model identified a UCEIS higher than 6.5 points and CRP level at day 3 higher than 33.57 mg/dL as the proxy for IVCS resistance. UCEIS and CRP level at day 3 were also the most important predictors in the RF model. Areas under the curve receiver operating characteristic (AUC) of logistic model, decision tree model, and RF model were 0.64 (95% CI 0.49–0.80), 0.81 (95% CI 0.71–0.90), and 0.88 (95% CI 0.82–0.95), respectively. A validation cohort of 65 ASUC patients were established, and the AUC of the models in external validation were 0.57 (95% CI 0.45–0.70), 0.70 (95% CI 0.61–0.80), and 0.71 (95% CI 0.48–0.94), respectively.

Conclusion

In patients with ASUC, UCEIS and CRP level at day 3 of IVCS treatment appeared to allow the prompt prediction of likely IVCS nonresponders. Machine learning-based models outperformed the traditional statistical model in the prediction. The models may aid therapeutic decision-making in ASUC patients.
DOP62 Efficacy of biologic drugs in short-duration versus long-duration Inflammatory Bowel Disease: A systematic review and an individual-patient data meta-analysis of randomized controlled trials
Authors: Ben-Horin S , Novack L , Mao R , Guo J , Zhao Y , Sergienko R , Zhang J , Kobayashi K , Hibi T , Chowers Y , Peyrin-Biroulet L , Colombel J F C , Kaplan G G K , Chen M H
Published: January 2022

Background

Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may associate with higher efficacy, especially in Crohn’s disease (CD).

Methods

A systematic review and individual-patient-data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (Oct 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction-of-remission in patients with short-duration (≤18months) versus long-duration disease (>18months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients’ characteristics on the primary outcome. Study PROSPERO registration: CRD42018041961.

Results

We obtained data from five biologics drug manufacturers and included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab or vedolizumab (6,168 CD, 3,227 UC patients). In CD, induction-of-remission rates were higher in pooled placebo and active arms’ patients with short-disease duration≤18 months (41.4%, 244/589) compared with disease-duration>18months (29.8%, 852/2857, meta-analytically estimated OR=1.33, 95%CI:1.09–1.64). The primary outcome, proportional biologic/placebo treatment effect on induction-of-remission, was not different in short-duration disease ≤18 months (n= 589, OR 1.47, 95%CI:1.01–2.15) compared with longer disease-duration (n=2857, OR 1.43, 95%CI:1.19–1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cut-offs and when modelled for individual-patients’ co-variates, including prior anti-TNFs exposure. In exploratory post-hoc analysis comparing patients with colonic-CD (L2) versus small-bowel L1 CD (and excluding ileo-colonic L3 disease) the OR for induction-of-remission in long-duration disease>18months compared with short-duration disease was 0.62 for small-bowel CD (95%CI: 0.42; 0.91) but was not significant in pooled colonic CD population (OR=0.94, 95%CI: 0.66; 1.34)

Conclusion

This Individual patient level meta-analysis of clinical trials of multiple biologics found there are higher rates of induction-of-remission in early CD for both biologics and placebo, resulting in a treatment-to-placebo effect ratio which is similar across different disease durations. No such relationships between disease-duration and outcomes is found in UC
DOP63 Real World Effectiveness, Safety and Pharmacokinetics of Switching Intravenous Vedolizumab Maintenance treatment to Subcutaneous Vedolizumab Therapy for Inflammatory Bowel Disease
Authors: Volkers A , Straatmijer T , Duijvestein M , Sales A , Levran A , van Schaik F , Jeroen M , Gecse K , Ponsioen C , Grootjans J , Hanzel J , Tack G , Jansen J , Hoentjen F , de Boer N , van der Marel S , Dijkstra G , Oldenburg B , Löwenberg M , van der meulen A , D’Haens G
Published: January 2022

Background

Subcutaneous (SC) formulation of vedolizumab (VDZ) is available for Crohn’s disease (CD) and ulcerative colitis (UC). We assessed the efficacy, safety, and pharmacokinetic (PK) profiles of patients with inflammatory bowel diseases (IBD) who switched from intravenous (IV) to SC VDZ treatment in two prospective, real world cohorts.

Methods

The primary cohort is an ongoing open-label, real life, prospective single centre cohort study. As a validation cohort, we used the Initiative on Crohn and Colitis (ICC) registry, a prospective, observational, nationwide registry including patients switching from IV to SC VDZ. In both cohorts, patients receiving IV VDZ maintenance for >4 months were offered to switch treatment to SC VDZ, 108 mg every 2 weeks. In the primary cohort, assessment of clinical, biochemical and PK parameters took place at baseline, at approximately 10 weeks following the switch and at the physician’s discretion thereafter. In the ICC cohort, follow up visits were at week 12 and 24. The primary endpoint was the proportion of patients discontinuing SC VDZ at week 24.

Results

In total, 78 (50 CD (64%) and 28 UC (36%)) and 54 patients (29 CD (54%) and 25 UC (46%)) were included in the primary and ICC cohort respectively (table 1). During follow up, 8 (10.3%) of the primary cohort and 6 (11.1%) patients of the ICC cohort stopped VDZ SC during follow-up time till week 24, after a median treatment duration of 18 (IQR=5–19) and 10 (IQR=7–15) weeks, respectively. Treatment withdrawal was most often caused by adverse events (AE), in total for 8 out of 132 patients (6%) (table 2). Four patients had loss of response to SC VDZ. Three of these patients had biochemical disease activity at initiation of SC therapy. Reported AEs included headache and injection related reactions. The median VDZ concentration increased from 11 ug/mL (IQR=9.4–20) to 28 ug/mL (IQR=24.3–31.2, p<0.0001) and from 20 ug/mL (14.3–26.3) to 34.6 ug/mL (26.8–42.9) (p<0.01), between baseline and visit 1 in the primary and validation cohort, respectively (figure 1).

Conclusion

The present abstract reports real world experience of switching IV to SC VDZ maintenance treatment in IBD patients in two observational Dutch cohorts. VDZ concentrations were significantly higher after the switch to SC VDZ. A switch from IV to SC VDZ appears to be effective and safe. However, a proportion of patients switched back to IV VDZ due to injection related AEs.
DOP72 The association of anti-tumor necrosis factor and thiopurine therapy with the risk of lymphoma among Inflammatory Bowel Disease patients: A nation-wide study from the epi-IIRN
Authors: Waterman M , Lavi I , Harel S , Focht G , Loewenberg Weisband J , Greenfeld S , Kariv R , Ledderman N , Matz E , Keinan-Boker L , Eizenstein S , Dotan I , Turner D , Levi Z
Published: January 2022

Background

To clarify the risk of lymphoma in patients with inflammatory bowel diseases (IBD) exposed to anti-tumor necrosis factor (anti-TNF) and/or thiopurines we aimed to evaluate the Israeli IBD population.

Methods

A nested case-control study on the epidemiology cohort of the Israeli IBD Research Nucleus (epi-IIRN) including all 4 Health Maintenance Organizations in Israel linked to the Israeli Cancer Registry. Patients diagnosed since 1.1.2005 until 31.12.2015 (42,954 patients) were included and followed until 31.12.2017. Each lymphoma case was matched to 30 non-lymphoma IBD patients by age, gender, IBD subtype, and date of earliest evidence of IBD in the database. Patients with other risk factors for lymphoma, or lymphoma diagnosis prior to IBD diagnosis were excluded (figure 1). Conditional logistic regression was used to compute the association of drug exposure (anti-TNF, thiopurines and combination) with diagnosis of lymphoma. Patients without exposure to anti-TNF and/or thiopurines in each group served as reference within each group. Additionally, sub-group analyses by gender, age group at inclusion (≤48, 49–64, ≥65), time from last drug exposure (≤90 days, 91–365 days, >365 days) were done.

Results

The final nested cohort included 5556 IBD patients (185 lymphoma cases matched to 5,371 without lymphoma). Mean follow-up (F/U): 5.5±3.5 years, 50% with Crohn’s disease, mean age at database entry 52.6±17.80 years. Anti-TNF-only exposure was documented in 4.3% (8/185) of lymphoma cases vs. 2.6% (145/5,371) of controls OR 1.97, CI 0.93–4.16, p=0.07; in males the ORs were 2.84 (CI 1.17–6.92 p=0.04) and increased to OR 3.48 (CI 1.55–7.88, p=0.002) for males <48 years and OR 2.87 (CI 1.53–5.37, p=0.001) for patients with last exposure ≤90 days (figure 2). Exposure to combination anti-TNF+thiopurines occurred in 8.6% (16/185) of lymphoma cases vs. 5.3% (282/5,371) of controls OR 2.09 (CI 1.17–3.73, p=0.013). Males on anti-TNF-thiopurine combination had OR of 3.42 (CI 1.37–8.52, p=0.003) and in sequential (non-overlapping exposure to both thiopurines and anti-TNFs during F/U) combination an OR of 2.74 (CI 1.02–7.35 p=0.02). Thiopurine-only exposure occurred in 15.1% (28/185) of lymphoma cases vs. 13.5% (726/5,371) of controls, OR 1.32 (CI 0.86–2.03, p=0.20). Males on thiopurines had an OR of 1.75 (CI 1.02–2.99, p=0.05). The risk increased further in males <48 years OR 2.17 (CI 1.01–4.66, p=0.047) and in males aged≥65 OR 3.50 (CI 1.55–7.82, p=0.002). Females were not at risk for lymphoma (figure 3).

Conclusion

This nationwide study suggests that exposure to anti-TNF therapy alone or in combination with thiopurines may be associated with an increased risk of lymphoma, but only in males, especially when last exposure occurred within 90 days.
DOP82 Achievement of steroid-free remission in patients with moderately to severely active Crohn’s Disease during treatment with risankizumab
Authors: Schreiber S W , Cross R , Panaccione R , D’Haens G , Bossuyt P , Colombel J F , Louis E , Dubinsky M , Kligys K , Neimark E , Song A , Zambrano J , Cheng E , Ferrante M
Published: January 2022

Background

The efficacy and safety of risankizumab (RZB) as induction and maintenance therapy for patients with moderately to severely active Crohn’s disease (CD) has been documented. Steroid-free clinical remission is an important additional treatment goal in CD. The efficacy of RZB by baseline steroid use during induction and steroid-free outcomes during maintenance was examined.

Methods

In ADVANCE (NCT03105128) and MOTIVATE (NCT03104413), patients with moderately to severely active CD received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients with clinical response to RZB were re-randomised in a 52-week maintenance study (FORTIFY; NCT03105102) to subcutaneous (SC) RZB or PBO (ie, withdrawal). Patients receiving steroids (maximum prednisone or equivalent ≤ 20 mg/day; budesonide ≤ 9 mg/day) at baseline of the induction studies maintained stable doses for the 12-week study duration. A mandatory steroid taper per protocol was initiated at the beginning of maintenance for patients receiving steroids during induction. Patients losing clinical response (per investigator assessment) after initiation of taper could have their steroid dose increased up to the induction baseline dose. This analysis included patients who received RZB 600 mg IV in ADVANCE or MOTIVATE and patients who received RZB 360 mg SC in FORTIFY. Endpoints reported included clinical remission (defined by CD Activity Index [CDAI] or stool frequency/abdominal pain score [SF/APS] criteria) at week 12 of induction by baseline steroid use, steroid-free clinical remission (CDAI or SF/APS), steroid-free endoscopic response, and steroid-free endoscopic remission at week 52 of maintenance. Steroid discontinuation rates over 52 weeks of maintenance were also assessed.

Results

Induction of clinical remission at week 12 with RZB 600 mg IV in ADVANCE or MOTIVATE was independent from baseline steroid use (Figure 1).Clinical remission rates (CDAI or SF/APS) at week 12 were similar for patients using steroids vs those who were not (33.8%–42.0% vs 34.9%–46.6%; Figure 1). Steroid use decreased over time in FORTIFY, with a greater proportion of patients receiving RZB 360 mg SC discontinuing steroids at week 52 vs withdrawal (PBO SC; Figure 2A). Rates of steroid-free clinical remission (P ≤ .012), steroid-free endoscopic response (P < .001), and steroid-free endoscopic remission (P < .001) were significantly higher with RZB 360 mg SC vs withdrawal (PBO SC) at week 52 of maintenance (Figure 2B–2C).

Conclusion

Efficacy of RZB induction therapy was independent of baseline steroid use. RZB maintenance promotes high rates of steroid-free clinical and endoscopic outcomes, demonstrating a benefit of RZB treatment in CD.
DOP86 Mirikizumab-induced upregulation of colonic transcripts correlates with improvements in stool frequency in a phase 2 study of patients with moderately to severely active Ulcerative Colitis
Authors: Steere B , Powell N , Higgs R , Wang Y C , Milch C , Sandborn W J , Sands B E , Reinisch W , D’Haens G , Krishnan G
Published: January 2022

Background

We have previously shown that treatment with mirikizumab (miri), a p19-directed IL-23 antibody, significantly downregulates inflammatory genes associated with disease activity and upregulates genes expressing epithelial transporter proteins in colonic tissue in patients with ulcerative colitis (UC). Here we explored the correlation between the expression of colonic mucosa genes and stool frequency (SF), a symptom reflective of disease activity, during the 12-week induction period of a Phase 2 study of patients with moderately to severely active UC (NCT02589665).

Methods

Patients were randomised 1:1:1:1 to receive intravenous placebo (PBO), miri 50mg or 200mg with possibility of exposure-based dose increases, or fixed miri 600mg every 4 weeks for 12 weeks. SF was reported daily by patients and transformed on a 4-level ordinal scale [0–3] representing increased SF above their normal or healthy baseline (BL). Patient colonic biopsies (PBO N=58, miri 50mg N=52, 200mg N=51, 600mg N=54) were collected at BL and Week (W)12, and gene expression measured using an Affymetrix HTA2.0 microarray workflow. BL and W12 gene expression or SF values were pooled and associations identified based on non-parametric Kendall’s tau. Pathway analysis (Hallmark and Reactome) of correlated genes was performed using over-representation analysis. p values of enrichment were determined by hypergeometric distribution test and adjusted for multi-testing with Benjamini-Hochberg procedure. Differential gene expression after miri treatment was determined by paired t-test comparing expression levels at BL and at W12 using data from the 200mg treatment group.

Results

A total of 267 genes were correlated with SF (|tau| >0.3 and qval <0.001). Of these, 212 were positively correlated (high expression associated with high SF) and 55 were negatively correlated (high expression associated with low SF). The 212 transcripts that were positively correlated with SF were uniformly and consistently downregulated with miri treatment, while the 55 transcripts that negatively correlated with SF, were consistently upregulated with miri treatment (Table 1). Biological pathways significantly associated with the miri-responsive transcripts that correlated with SF included inflammatory response, extracellular matrix dysregulation, neutrophil degranulation and cytokine signaling pathways, especially TNF and IL6 pathways (Table 2).

Conclusion

This is the first study to identify colon-based transcripts that correlate with a clinical disease activity measure, stool frequency, and it demonstrates that treatment with miri may upregulate genes associated with normalization of SF and down regulate genes associated with inflammation in colonic tissue samples of patients with UC.
DOP88 Long-term real-world data of ustekinumab in Crohn’s Disease – the Stockholm ustekinumab study – STOCUSTE
Authors: Bello F , Lördal M , Johansson F , Sabhan H , Muhsen S , Borin A , Forsberg O , Wennerström C , Söderman C , Almer S
Published: January 2022

Background

Ustekinumab (UST), an anti-interleukin-12/23 antibody, has successfully been introduced in the treatment of IBD, mainly in patients failing anti-TNF-agents. The STOCUSTE study includes IBD patients treated with UST at four teaching hospitals in Stockholm to provide long-term follow-up data. Here, we report the outcome in Crohn’s disease over the first 12 months.

Methods

This retrospective study includes patients diagnosed with Crohn’s disease and treated with UST who were followed until withdrawal of treatment for any reason, or until end of study, July 31, 2021. Disease activity (Harvey-Bradshaw Index (HBI); Physician Global Assessment (PGA), laboratory parameters and drug persistence were assessed. The primary outcome was remission (HBI ≤4; PGA = 0) and response (decrease HBI ≥3; PGA ≥1 from baseline) at 3 and 12 months, respectively.

Results

120 patients, 61 women (51%), with a median age of 27 (IQR 27) at start of UST were included. All patients had luminal disease and 19 (16%) also fistulizing disease. 109 (91%) had failed ≥1 and 59 (49%) ≥2 anti-TNF drugs. In addition, 50 patients (42%) failed vedolizumab. At inclusion, 106 (88%) had active disease; 40 (33%) were on corticosteroid treatment and 22 (18%) on thiopurines.

The persistence on UST was high, 93% at 3 months and 56% at 12 months. Of patients on UST at 3 months, 38% were in remission, and, at 12 months, 53%. An additional 26% were in response at 12 months. Of the 40 patients initially on corticosteroids, 17 (43%) and 28 (70%) had stopped steroids at 3 and 12 months, respectively. The median faecal calprotectin level declined from 272 (90–1763) at baseline to 75 (49–99) µg/g at 3 months (p<0.01). There was a slight decrease in CRP over 12 months, from 3 (2–12) to 1 (1–2) mg/l, together with increases in haemoglobin and serum albumin (n.s).

Withdrawal from treatment during the first 12 months was 44% (53/120), mainly due to persisting disease activity. Four patients were withdrawn due to adverse events, three needed bowel surgery, two had malignancy and one patient suffered from systemic infection.

Conclusion

In this group of difficult-to-treat patients with Crohn’s disease, UST was shown to be effective in the majority, with high drug persistence at 12 months in combination with a favorable safety profile.