bluuebunny/crossref_metadata_2025 huggingface dataset:
Results for the London investigation into dielectric scanning of lesions study of the MARIA® M6 breast imaging system
Authors: Sidebottom Richard , Webb Donna , Bishop Briony , Mohammed Kabir , Allen Steven
Published: January 2024

Objectives

Determine the proportion of breast cancers for which MARIA® findings correspond to the cancer, with stratification by breast density and histological type. Investigate performance in symptomatic lesions. Gain patient feedback on experience with MARIA®.

Methods

MARIA® uses a radio frequency antennae array to measure signal attenuation and back scatter to build up a 3D map of tissue dielectric values. The study was a prospective, single-centre, interventional, post-approval device study.

Recruitment

Patients were eligible if they were attending symptomatic breast clinic or had confirmed or suspected breast cancer from any referral source. Recruitment between May 2018 and March 2020.

Reading

Regions of higher signal compared to background or distinct by shape were considered candidates for lesion correspondence. Up to 4 candidate regions per breast were annotated in likelihood order for representing a true lesion.

Results

389 patients were recruited, and 6 excluded. 114 patients recruited with breast cancers (2 bilateral, 5 multicentric). 57 (47%) malignant lesions showed correspondence between the MARIA® signal and the cancer. Higher correspondence was seen in invasive (50%) than in situ (29%) disease. There was no reduction in correspondence at higher breast density. Reduced signal correspondence in the central scan volume and for small lesions. MARIA® scanning was well tolerated.

Conclusions

We believe that MARIA® signal corresponds to a malignant lesion in 47% of breast cancers examined.

Advances in knowledge

Our study, the largest to date for this type of technology, demonstrates successes and limitations of this MARIA® M6 version.
Association between vitiligo and risk of retinal detachment: a population-based cohort study in Taiwan
Authors: Chen Ching-Li , Wu Chun-Ying , Chen Yen-Ling , Chen Chih-Chiang , Chang Yun-Ting , Wu Chen-Yi
Published: January 2024

Background

Vitiligo is reportedly associated with several ocular abnormalities. However, the relationship between vitiligo and retinal detachment (RD) remains unclear.

Objectives

To examine the risk of RD in patients with vitiligo.

Methods

A nationwide population-based cohort study was conducted using data from the Taiwan National Health Insurance Database from 2007 to 2018. A total of 21 132 patients with vitiligo were matched in a 1 : 4 ratio with people without vitiligo by age, sex and comorbidity propensity score. Cumulative incidence and Cox proportional hazard models were used to investigate the risk of RD in patients with vitiligo. Subgroup analysis was performed.

Results

The cohort with vitiligo had a significantly higher rate of RD than the cohort without vitiligo [adjusted hazard ratio (aHR) 1.44, 95% confidence interval (CI) 1.20–1.72; P < 0.001]. Patients with vitiligo who required treatments such as phototherapy, systemic corticosteroids or immunosuppressants exhibited an even greater risk of RD (aHR 1.57, 95% CI 1.16–2.14; P = 0.004).

Conclusions

Our study revealed a 1.44-fold increased risk of RD in patients with vitiligo, with an even higher risk in patients receiving phototherapy, systemic corticosteroids or immunosuppressants. The risk remained consistently higher over a 10-year follow-up period.
Scaling patterns of cortical folding and thickness in early human brain development in comparison with primates
Authors: Demirci Nagehan , Holland Maria A
Published: January 2024

Across mammalia, brain morphology follows specific scaling patterns. Bigger bodies have bigger brains, with surface area outpacing volume growth, resulting in increased foldedness. We have recently studied scaling rules of cortical thickness, both local and global, finding that the cortical thickness difference between thick gyri and thin sulci also increases with brain size and foldedness. Here, we investigate early brain development in humans, using subjects from the Developing Human Connectome Project, scanned shortly after pre-term or full-term birth, yielding magnetic resonance images of the brain from 29 to 43 postmenstrual weeks. While the global cortical thickness does not change significantly during this development period, its distribution does, with sulci thinning, while gyri thickening. By comparing our results with our recent work on humans and 11 non-human primate species, we also compare the trajectories of primate evolution with human development, noticing that the 2 trends are distinct for volume, surface area, cortical thickness, and gyrification index. Finally, we introduce the global shape index as a proxy for gyrification index; while correlating very strongly with gyrification index, it offers the advantage of being calculated only from local quantities without generating a convex hull or alpha surface.
The relationship between gray/white matter contrast and cognitive performance in first-episode schizophrenia
Authors: Kobayashi Haruko , Sasabayashi Daiki , Takahashi Tsutomu , Furuichi Atsushi , Kido Mikio , Takayanagi Yoichiro , Noguchi Kyo , Suzuki Michio
Published: January 2024

Previous postmortem brain studies have revealed disturbed myelination in the intracortical regions in patients with schizophrenia, possibly reflecting anomalous brain maturational processes. However, it currently remains unclear whether this anomalous myelination is already present in early illness stages and/or progresses during the course of the illness. In this magnetic resonance imaging study, we examined gray/white matter contrast (GWC) as a potential marker of intracortical myelination in 63 first-episode schizophrenia (FESz) patients and 77 healthy controls (HC). Furthermore, we investigated the relationships between GWC findings and clinical/cognitive variables in FESz patients. GWC in the bilateral temporal, parietal, occipital, and insular regions was significantly higher in FESz patients than in HC, which was partly associated with the durations of illness and medication, the onset age, and lower executive and verbal learning performances. Because higher GWC implicates lower myelin in the deeper layers of the cortex, these results suggest that schizophrenia patients have less intracortical myelin at the time of their first psychotic episode, which underlies lower cognitive performance in early illness stages.
An Eco-Friendly RP-HPLC Method Development and Validation for Quantification of Favipiravir in Bulk and Tablet Dosage Form Followed by Forced Degradation Study
Authors: Sangani Monika B , Patel Nirav
Published: January 2024

In this work, an eco-friendly simple, precise reverse phase high-performance liquid chromatography (HPLC) method has been developed and validated for Favipiravir in bulk and tablet dosage form followed by its force degradation study. The proposed method was validated to obtain official requirements including stability, accuracy, precision, linearity, robustness and selectivity as per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidelines. The estimation was developed on C (18) column reversed-phase using the mobile phase composition as methanol:water (10:90 v/v). The flow rate was set as 1 ml/min, and the maximum absorption was observed at 323 nm using Shimadzu Photo Diode Array detector. The Favipiravir, drug showed a precise and good linearity at the concentration ranges of 10–50 μg/mL. The Revearse Phase High Perforance Liquid Chromatography assay showed the highest purity ranging from 99.90 to 100.02% for Favipiravir, tablet dosage form, and 100.15% was the mean percentage purity. The percent recovery was found within the acceptance limit of (98.6–100.0%). Intra- and inter-day precision studies of the method were less than the maximum allowable limit percentage of relative standard deviation ≤ 2.0. The Favipiravir retention time was found to be 5.00 min. To examine the stability of the drug, various forced degradation studies were conducted on Favipiravir Active Pharmaceutical Ingredient. The developed method was validated according to the ICH guidelines. A very quick, cost-effective, precise and accurate HPLC method for the determination of Favipiravir has been developed and validated in compliance with ICH guidance Q2.
Antibiotic Prescribing Patterns for Respiratory Tract Illnesses Following the Conclusion of an Education and Feedback Intervention in Primary Care
Authors: Harrigan James J , Hamilton Keith W , Cressman Leigh , Bilker Warren B , Degnan Kathleen O , David Michael Z , Tran David , Pegues David A , Dutcher Lauren
Published: January 2024

Background

A study previously conducted in primary care practices found that implementation of an educational session and peer comparison feedback was associated with reduced antibiotic prescribing for respiratory tract diagnoses (RTDs). Here, we assess the long-term effects of this intervention on antibiotic prescribing following cessation of feedback.

Methods

RTD encounters were grouped into tiers based on antibiotic prescribing appropriateness: tier 1, almost always indicated; tier 2, possibly indicated; and tier 3, rarely indicated. A χ2 test was used to compare prescribing between 3 time periods: pre-intervention, intervention, and post-intervention (14 months following cessation of feedback). A mixed-effects multivariable logistic regression analysis was performed to assess the association between period and prescribing.

Results

We analyzed 260 900 RTD encounters from 29 practices. Antibiotic prescribing was more frequent in the post-intervention period than in the intervention period (28.9% vs 23.0%, P < .001) but remained lower than the 35.2% pre-intervention rate (P < .001). In multivariable analysis, the odds of prescribing were higher in the post-intervention period than the intervention period for tier 2 (odds ratio [OR], 1.19; 95% confidence interval [CI]: 1.10–1.30; P < .05) and tier 3 (OR, 1.20; 95% CI: 1.12–1.30) indications but was lower compared to the pre-intervention period for each tier (OR, 0.66; 95% CI: 0.59–0.73 tier 2; OR, 0.68; 95% CI: 0.61–0.75 tier 3).

Conclusions

The intervention effects appeared to last beyond the intervention period. However, without ongoing provider feedback, there was a trend toward increased prescribing. Future studies are needed to determine optimal strategies to sustain intervention effects.
OP07 Consistent IBD treatment approaches across South Asian and White ethnicities despite phenotypic variations: a study of 33,157 patients using the IBD BioResource
Authors: Balarajah S , Martinez-Gili L , Alexander J , Mullish B , Perry R , Li J , Marchesi J , Parkes M , Orchard T , Hicks L , Williams H
Published: January 2024

Background

The current evidence suggests ethnic distinctions in IBD phenotype, and differences in the provision of treatment have been reported. This multi-centre cohort study utilised the UK IBD BioResource dataset to evaluate phenotypic differences between South Asian (SA) and White (WH) IBD, and to explore if these were associated with differences in treatment.

Methods

Phenotypic and outcome data were extracted from the IBD BioResource. Chi2 (categorical data) and Mann-Whitney U (continuous data) tests were used. Propensity score matching (PSM) accounted for age at diagnosis, sex, smoking status, disease location and behaviour and perianal disease (CD). Differences in medication use (multivariable logistic regression) and surgical outcomes (Kaplan-Meier and Cox regression analysis) were assessed in propensity-matched (PM) cohorts.

Results

33,157 (31,932 WH; 1225 SA) individuals were included (48.1% CD, 45.4% UC, 6.5% IBD-U). UC was the predominant disease subtype in SA (UC, SA 57.3% vs WH 44.9%, p<0.001). SA were younger at diagnosis [CD, SA 24 (IQR 17-36) vs WH 26 (IQR 19-39) years, p<0.001; UC, SA 29 (IQR 22-38) vs WH 35 (25-48) years, p<0.001]. SA CD had less ileal disease (SA 30.3% vs WH 38.4%, padj=0.008), and more perianal involvement (SA 38.5% vs WH 32.3%, p=0.009) than WH. SA CD had less stricturing disease (SA 16.9% vs WH 25.6%, padj<0.001). SA UC were more likely to have extensive disease (SA 41.7% vs WH 34.1%, padj<0.001). Initial analyses in non-PSM cohorts showed that fewer SA CD underwent surgery [SA (n=157,37.4%) vs WH (n=7532,50.4%), p<0.001], and that similar proportions of SA (n=33,5.1%) and WH (n=747,5.5%; p=0.15) UC underwent a colectomy.

PSM was used to match 355 SA to 355 WH in CD, and 525 SA to 525 WH in UC. Variables were well-balanced. There were no differences in 5-ASA, corticosteroid, thiopurine, anti-TNF or Vedolizumab use (Table 1). In CD, 126 (36.5%) SA and 152 (44.7%) had surgery. Survival analysis in CD showed no difference in the time to surgery (Fig 1A, log-rank 0.28). SA ethnicity was not associated with increased risk of surgery in CD (HR 0.82, 95% CI 0.63-1.07, p=0.14). In UC, 25 (4.8%) and 37 (7.1%) WH had a colectomy. There was no significant difference in the time to colectomy (Fig 1B, log-rank 0.12) nor was SA ethnicity associated with an increased risk of having a colectomy (HR 0.65, 95% CI 0.39-1.11, p=0.12).

Conclusion

In the largest analysis of SA IBD to date, we have demonstrated phenotypic differences associated with ethnicity. Accounting for these variations, we have shown comparable provision of medical and surgical treatment in SA and WH. These findings indicate consistent care of IBD patients from different ethnic backgrounds in the UK.
OP20 Postoperative endoscopic recurrence after resection of Crohn’s terminal ileitis with Kono-S or side-to-side functional end anastomosis: results of a Multicenter Prospective Randomized Trial
Authors: Trencheva K , Spinelli A , Kienle P , D'Hoore A , Luglio G , Flemming S , Scaringi S , Tropeano F , Christos P , Michelassi F
Published: January 2024

Background

A novel anastomosis (Kono-S) was described in 2003 in Crohn’s disease. Subsequent observations have suggested that this anastomosis is associated with lower endoscopic and surgical recurrence rates. The purpose of this study was to compare the endoscopic recurrence between the Kono-S and the side-to-side functional end anastomosis at 3-6 months after resection of Crohn’s terminal ileitis.

Methods

This was a prospective multi-center randomized trial conducted at eight international centers. Patients with Crohn’s terminal ileitis requiring elective ileocecal resection were randomized to a Kono-S (Group1) or a side-to-side functional end (Group2) anastomosis (Image1). Patients were discharged on no biologicals. Exclusion criteria included age (<18), pregnancy, recurrent or multisite Crohn’s disease, and need of postoperative treatment with biologicals. Data were collected prior to and during surgery, daily after surgery until discharge, at 30 days post-op, and at 3-6 months colonoscopy. Participating surgeons were instructed in the Kono-S technique through videos. Disease clinical activity was measured by Harvey Bradshaw Index (HBI). Endoscopic remission/recurrence was graded with the modified Rutgeerts score: endoscopic remission was defined as a Rutgeerts score of 0, 1, or 2a, and a Rutgeerts score of 2b or higher was considered a recurrence. All study sites had Institutional Review Board approval, ClinicalTrial.gov # NCT03256240.

Results

We enrolled 288 Crohn’s patients (50.7% female) with a median age of 34 (18-81). 154 patients were randomized to Group 1 (Kono-S) and 134 to Group 2 (Side-to-Side). 30 days follow-up was completed on 278 (96.9%) patients. The Kono-S group had a higher percentage of past smokers (57 vs.30, p = 0.007) and current smokers (33 vs.12, p = 0.004). The mean operative time was 22 minutes longer in the Kono-S group (154 vs.132 minutes; p = 0.386). There was no mortality. 233 (81%) patients underwent a colonoscopy at 3-6 months. There was no significant difference between the two groups in terms of endoscopic recurrence (p = 0.883) and HBI (p = 0.109) or in recurrence-free survival (Log Rank Mantel-Cox test p = 0.256) (Table 1). On multivariable analysis, current smokers had significantly higher odds for endoscopic recurrence at 3-6 months (OR= 2.80, [95% CI =1.10 - 6.92], p = 0.029).

Conclusion

Kono-S and Side-to-side anastomoses have similar endoscopic recurrence rates at 3-6 months. Independently of surgical techniques, smokers had a significantly higher rate of endoscopic recurrence at 3-6 months after surgery.
DOP26 Metagenomic and metabolomic profiles in IBD: understanding microbial and metabolic shifts from a large deeply phenotyped cohort
Authors: Marius B , Rolhion N , Creusot L , Lefevre A , Alonso I , Brot L , Danne C , Bourrier A , Parrot L , Mélanie D , Benech N , Nion-Larmurier I , Mclellan P , Landman C , Beaugerie L , Seksik P , Emond P , Kirchgesner J , Sokol H
Published: January 2024

Background

Alterations in gut microbiota composition and functions are involved in the pathogenesis of Inflammatory Bowel Disease (IBD) and the role of specific bacterial taxa has been particularly pointed out. The role of microbiota-derived metabolites, including those produced from tryptophan, are major actors in host-microbiota interactions in health and in IBD. Large studies analyzing both gut microbiota and metabolomics data are scarce.

Methods

In the current study, we analyzed a total of 764 individuals from Saint Antoine Hospital cohort, including 447 patients with Crohn's disease (CD), 262 patients with Ulcerative Colitis (UC) and 55 healthy subjects. We performed shotgun metagenomic sequencing on fecal samples and integrated the results with deep clinical phenotyping and targeted metabolomics data encompassing 294 different molecules.

Results

We observed strong changes in the taxonomic composition and functional capabilities of the microbiota in CD and UC patients compared to healthy subjects. Besides disease itself, the most important drivers of microbiota composition were the disease location (Montreal classification), recent antibiotic treatment, disease activity (flare vs remission) and history of ileocecal resection. Interestingly, IBD diagnosis explained much more the variations of microbiota functions than taxonomy. The decrease in microbiota diversity was stronger in CD than in UC. In parallel to a decreased amount of Faecalibacterium in IBD, we also observed a decrease in the diversity of Faecalibacterium strains, with a stronger decrease in CD. Our multifactorial analysis revealed specific microbial taxa and functions affected by disease-related factors. We particularly identified many correlations between tryptophan metabolites and microbial abundance. Targeted gene analysis of tryptophan-related enzymes in metagenomes further supported these findings. A network analysis considering bacterial taxa and metabolites revealed profound alterations in IBD with some specificities between CD and UC.

Conclusion

We pointed out new microbiome and metabolome alterations associated with IBD, with some phenotype specificities. Overall, our findings provide crucial information and a substantial resource for understanding the interactions between the host and microbiome in the context of IBD.
DOP46 Tofacitinib for hospitalized acute severe Ulcerative Colitis – the TRIUMPH study
Authors: Narula N , Peerani F , Hansen T , Bessissow T , Bressler B , Arun A , Schmit M , Castelli J A , Marshall J K
Published: January 2024

Background

Tofacitinib is a rapidly acting Janus kinase (JAK) inhibitor with several case series reporting effectiveness in patients with acute severe ulcerative colitis (ASUC). However, there remains a paucity of prospective data evaluating its efficacy and rapidity of onset in ASUC.

Methods

The TRIUMPH study is a phase 4 prospective interventional trial of tofacitinib in ASUC conducted in five hospitals across Canada (Clinicaltrials.gov: NCT04925973). Patients with ASUC (biologic naïve and experienced) refractory to three days of intravenous corticosteroids (Modified Truelove-Witts Severity Index [MTWSI] > 10 despite steroids) were eligible for enrollment. Patients were treated with tofacitinib 10mg bid and assessed daily while in hospital. The primary outcome was day 7 clinical response (MTWSI reduction of > 3 from baseline and < 10). Secondary outcomes included rapidity of clinical and biomarker improvements over the first 7 days, colectomy over the course of one year, and corticosteroid-free clinical remission (total Mayo score < 2), endoscopic improvement (endoscopic Mayo score 0 or 1), and adverse events at 3, 6, and 12 months.

Results

This is an interim analysis as the study has been fully recruited with six-month follow-up available for all participants. 24 patients with ASUC were recruited and received tofacitinib 10mg bid. The mean total baseline Mayo score was 10.1 (SD 1.4) and all patients had a baseline Mayo endoscopic subscore of 2 (25%, 6/24) or 3 (75%, 18/24). One third of the patients (8/24) had previous anti-TNF failure. Day 7 clinical response was achieved in 58.3% (14/24) patients. The mean number of days to achieve clinical response was 2.4 days (SD 1.3). Marked reduction in C-reactive protein was observed in responders as soon as one day after tofacitinib initiation compared to non-responders (Figure 1). Colectomy occurred in 16.7% (4/24) patients by day 7 and 25% (6/24) by six months. At six months, 45.8% (11/24) patients remained on tofacitinib (including 78.6% (11/14) of day 7 responders), with 33.3% (8/24) having achieved endoscopic improvement and corticosteroid-free clinical remission. A total of six patients reported adverse events, one of which was considered severe (stroke at day 3 after initiation of tofacitinib).

Conclusion

Tofacitinib may be an effective induction strategy in patients hospitalized with steroid-refractory ASUC. Randomized controlled trials are needed to compare JAK inhibitors with infliximab for steroid refractory ASUC.
DOP53 Long-term Efficacy and Safety of Risankizumab in Patients With Moderate to Severe Crohn's Disease up to 3 Years of Treatment: Results From the FORTIFY Open-Label Long-term Extension
Authors: Ferrante M , Panaccione R , Colombel J F , Dubinsky M , Hisamatsu T , Lindsay J O , Song A , Neimark E , Zhang Y , Kligys K , Crowley J , Duan W R , D’Haens G
Published: January 2024

Background

The ongoing FORTIFY maintenance open-label extension (OLE) substudy evaluates the long-term efficacy and safety of risankizumab (RZB), a p19 interleukin-23 inhibitor, for treatment of moderate to severe Crohn’s disease (CD). Here, we report 2-year results of FORTIFY OLE.

Methods

The FORTIFY (NCT03105102) OLE enrolled patients (pts) who completed 52-wks maintenance dosing in the FORTIFY substudies or RZB phase 2 OLE.1,2 All pts received 180 mg subcutaneous (SC) RZB every 8 wks (Q8w), starting at wk56, except for pts who had prior rescue therapy (single 1200mg intravenous [IV] RZB dose then 360mg SC Q8w) who continued 360mg SC Q8w in the OLE. Pts with inadequate response (increased symptoms plus objective marker of inflammation) during the OLE could receive rescue therapy as described above. Pooled data from both treatment groups (RZB 180 mg & 360 mg SC) were assessed. Clinical outcomes were evaluated every 24 wks (endpoint definitions in Figure footnote). Endoscopy was performed every 96 wks. Results are reported as observed. Efficacy data for pts receiving rescue therapy in the OLE were included up to rescue initiation. Safety was assessed through the cutoff date of 05MAR2023. As this trial is ongoing, most patients have not reached the wk152 study visit. Any treatment-emergent adverse events (TEAEs) reported on or after the first dose in the OLE were analysed.

Results

As of the cutoff date, 1147 pts entered the OLE, of which 203 (17.6%) pts received rescue therapy during the OLE. Clinical response and remission rates were generally maintained with RZB from wks 56 to 152 (CD activity index [CDAI] clinical response, 85.8% to 86.5%, respectively; enhanced clinical response, 88.6% to 89.2%; CDAI clinical remission, 68.5% to 77.6%; stool frequency/abdominal pain score clinical remission, 64.4% to 71.0%) (Figure). At wks 56 and 152, respectively, rates of endoscopic response were 53.4% and 74.2%, endoscopic remission were 37.5%, and 58.9%, and ulcer-free endoscopy were 31.0% and 50.0%. There were no new trends for exposure-adjusted rates of TEAEs, and rates of adjudicated major cardiovascular adverse events, malignancies, serious infections and hepatic events remained stable with no new safety risks identified. There were no events of active tuberculosis, serious hypersensitivity, or adjudicated anaphylactic reaction. Three deaths occurred during the OLE (see Table footnote), all assessed by investigators as unrelated to study drug.

Conclusion

Pts receiving long-term RZB maintenance therapy in FORTIFY demonstrated sustained clinical and endoscopic efficacy with at least 3 years of treatment. The safety profile is consistent and supports long-term RZB treatment.

1doi: 10.1093/ecco-jcc/jjab093

2doi: 10.1016/S0140-6736(22)00466-4.
DOP63 Mortality in Pediatric-onset Immune-Mediated Inflammatory Disease – A Nationwide Study
Authors: Malham M , Jansson S , Ingels H A S , Jørgensen M H , Roed N , Wewer A V , Fox M P
Published: January 2024

Background

Patients with pediatric-onset immune-mediated inflammatory diseases (pIMID) show more aggressive phenotypes compared to patients diagnosed as adults. Despite this, data on mortality is extrapolated from patients diagnosed in adulthood, which might underestimate the actual risk. We aim to estimate the effect of pIMID compared to reference individuals from the general population on the long-term risk of all-cause mortality.

Methods

A population-based cohort study using the nationwide Danish health care registers. We included all patients diagnosed with pIMID in Denmark from 1980 to 2018 and matched them to up to ten reference individuals from the general population (with no recorded IMID) based on sex, age at diagnosis, and area of residence. Exposure was pIMID, defined as ICD codes indicative of autoimmune hepatitis, primary sclerosing cholangitis, Crohn’s disease, ulcerative colitis, juvenile idiopathic arthritis, system lupus erythematosus, or vasculitis registered before age 18.

The primary outcome was all-cause mortality. The secondary outcome was cause-specific mortality. Cox survival analysis was used to estimate hazard ratios (HR) and Aalen survival analysis to estimate rate differences with corresponding 95% confidence intervals (CI) adjusted for the year of diagnosis and family income.

Denmark has universal free health care, and health care data can be accessed through the nationwide health registers, continuously updated since 1980.

Results

We included 11,581 individuals diagnosed with pIMID, and 99,665 matched reference individuals, accounting for 1,371,994 person-years of follow-up. Median age at pIMID diagnosis was 12.6 years (IQR: 7.9 – 15.9). During follow-up, 152 pIMID patients and 316 reference individuals died, resulting in an all-cause mortality adjusted HR (aHR) of 3.8 (95% confidence interval [CI]: 3.1-4.7) compared to reference individuals without pIMID. This corresponded to 7.8 (95%CI: 6.1-9.5) additional deaths per 10,000 person-years. The strongest associations were found for gastrointestinal disorders (aHR 22.8 [95%CI: 9.6-64.1]), gastrointestinal cancers (aHR 19.2 [95%CI: 5.0-74.2]), and lymphoproliferative diseases (aHR 6.8 [95%CI: 2.8-16.8]). The aHR of suicide was 2.9 (95%CI: 1.6-5.0).

Conclusion

Patients diagnosed with pIMID have a four-fold increased risk of mortality when followed into adulthood. This underlines the severe disease course of pIMID and highlights the need for lifelong multidisciplinary care.
DOP70 Prevalence and severity of bowel urgency in Crohn’s Disease: Results from the Communicating Needs and Features of IBD Experience (CONFIDE) Survey
Authors: Dubinsky M C , Gibble T , Travis S , Panaccione R , Hibi T , Bleakman A P , Panni T , Kayhan C , Favia A D , Atkinson C , Schreiber S , Rubin D T
Published: January 2024

Background

Bowel urgency (BU) affects patients with Crohn’s disease (CD); however, its prevalence and severity are unclear. Here, data from Communicating Needs and Features of IBD Experiences (CONFIDE) study were used to understand the burden and impact of BU among patients with moderate-to-severe CD.

Methods

CONFIDE is an online, quantitative, cross-sectional survey exploring the experiences and impact of symptoms on patients with CD or ulcerative colitis in Europe (France, Germany, Italy, Spain, and UK), United States (US) and Japan. Criteria based on previous treatment, steroid use, and/or hospitalization defined moderate-to-severe CD. Patients were asked about bowel movement deferral time with response options ranging from able to wait ≥15 minutes (mins) to sometimes unable to make it to the bathroom in time. Patients currently experiencing BU (in last month) rated BU severity in the last 3 days using the Urgency Numeric Rating Scale (NRS, 0-10), a content-validated patient-reported instrument. CD data from Europe and US are presented here using descriptive statistics.

Results

Surveys were completed by 547 European (male [M]=55.4%, mean age 38 years) and 215 US (M=54.9%, mean age 40.9 years) patients with CD. Current BU (over the past month) was reported by 38% of patients in Europe and 42.3% in US. More than one-third of all patients in both Europe and US reported that over the last 3 days, they needed to get to the bathroom within 5 mins, and 1.8% European and 2.8% US patients were sometimes unable to make it to the bathroom in time. Among patients who reported currently experiencing BU, 46% reported the need to get to the bathroom within 5 mins and 3% reported sometimes being unable to make it to the bathroom in time in both Europe and US. Shorter deferral times were reported by those with higher mean Urgency NRS scores (Table). Mean (SD) Urgency NRS scores in patients with a deferral time <5 mins vs those with a deferral time >5 mins were 7.0 (1.7) vs 6.5 (2.1) among European and 7.3 (1.5) vs 6.7 (1.9) among the US patients. Most European and US patients reported experiencing BU, BU-related accidents, and/or wearing diaper/pad/other protection due to fear/anticipation of BU-related accidents at least once a month in past 3 months (Figure).

Conclusion

Patients with moderate-to-severe CD reported similar experiences of BU in the Europe and US, with most patients reporting currently experiencing BU and wearing diaper/pad/protection due to fear of BU-related accidents at least once a month. Patients currently experiencing BU had short deferral times, often having to reach the bathroom in ≤5 mins. Given the substantial burden and impact, BU should be considered when assessing patients with CD.
P016 Reduction of mucosal (active) eosinophils, B cells and T cells after vedolizumab therapy in patients with ulcerative colitis
Authors: Jacobs I , Cremer J , Ferrante M , Sabino J , Vermeire S , Breynaert C , Vanuytsel T , Verstockt B
Published: January 2024

Background

Patients with ulcerative colitis (UC) are often treated with biological therapies or small molecules. Knowledge about the impact of these therapies on the intestinal and peripheral blood immune cell composition is scarce. Therefore, we investigated how advanced therapies modulate immune cell distribution in UC patients.

Methods

We included 30 UC patients (53% male, median age 42 years) who started a biological or small molecule. Before the first drug administration, mucosal colonic biopsies and a peripheral blood sample were obtained. At the end of induction, colonic biopsies and peripheral blood were sampled again. Patients starting adalimumab (n=2), infliximab (n=3), vedolizumab (n=11), ustekinumab (n=6), ozanimod (n=2) and the JAK inhibitors filgotinib (n=3) and tofacitinib (n=3) were included. Endoscopic improvement was defined as a Mayo endoscopic subscore of 0-1 at the end of induction. From the biopsies, a single-cell suspension was made. Intestinal and circulating immune cells were characterized via flow cytometry. Statistical analysis was performed using a paired t-test.

Results

Independent of the mechanism of action (MOA), patients responding to therapy showed a decrease of colonic granulocytes (neutrophils (p<0.0001) (Figure 1A), basophils (p<0.0001) (Figure 1B) and eosinophils (p=0.008) (Figure 1C)), active eosinophils (p=0.002) (Figure 1D)), B cells (p=0.05) (Figure 1E), regulatory T cells (p<0.0001) (Figure 1F) and T helper (Th) 2 cells (p=0.02) (Figure 1G), balanced with an increase of Th1 cells (p=0.03) (Figure 1H). In peripheral blood, eosinophils increased in patients not responding to therapy (p=0.05) (Figure 1I). Furthermore, we observed that only patients starting vedolizumab (n=11) showed a decrease in colonic eosinophils (p=0.02) (Figure 1J), active eosinophils (p=0.002) (Figure 1K), B cells (p=0.03) (Figure 1L) and T cells (p=0.004) (Figure 1M). Considering only non-vedolizumab patients (n=19), we did not observe this effect.

Conclusion

UC patients responding to advanced therapies showed a different intestinal immune cell distribution compared to non-responders, regardless of MOA. Vedolizumab therapy furthermore decreased several mucosal immune cell subsets that migrate to the gut through α4β7-MAdCAM-1 binding. While the effect of vedolizumab on B cells and T cells was previously described, we have now potentially identified an additional eosinophil-reducing effect in the colon.
P028 A pathogenic role of activated mucosal-associated invariant T cells in an animal model of Inflammatory Bowel Disease
Authors: Yasutomi Y , Chiba A , Haga K , Murayama G , Makiyama A , Kuga T , Nagahara A , Nagaishi T , Miyake S
Published: January 2024

Background

It is known that the mucosal-associated invariant T (MAIT) cells are the innate-like T cells that are restricted by the major histocompatibility complex-related molecule 1 (MR1), and that these cells express a semi-invariant T cell receptor. We have previously reported that the activation status of the circulating MAIT cells in patients with Ulcerative Colitis (UC) is associated with disease activity, and these cells infiltrate the inflamed colonic mucosa. These findings imply that MAIT cells are involved in the pathogenesis of Inflammatory Bowel Disease (IBD). However, the role of MAIT cells in the setting of IBD has not been revealed. Therefore, we investigated the role of MAIT cells in an animal model of UC.

Methods

To this end, we utilized MR1 deficient mice (MR1-/-), which lack MAIT cells, and isobutyl 6-formyl pterin (i6-FP), which is a synthetic antagonistic MR1 ligand. MR1-/- on the C57BL/6 background, their littermate wild-type controls, and C57BL/6 mice were sensitized by rectal administration of oxazolone to induce colitis. These were then administered an oral i6-FP. Splenocytes (SPL) and colonic lamina propria lymphocytes (LPL) were isolated from mice receiving i6-FP to measure cytokine production. MR1-/-, i6-FP-treated mice and their controls were orally administered FITC-dextran to analyze intestinal permeability. The peripheral blood mononuclear cells (PBMC) from the patients with UC were also isolated to study the effect of i6-FP on cytokine production by MAIT cells.

Results

MR1 deficiency or i6-FP treatment resulted in reduced severity of oxazolone-induced colitis. Mice treated with i6-FP resulted in reduced MAIT cell production of pro-inflammatory cytokines such as IFN-g and TNF in both SPL and colonic LPL. Similar results were also observed in PBMC isolated from the patients with UC when incubated with i6-FP. Although MR1 deficiency resulted in increased intestinal permeability, i6-FP administration did not affect gut integrity in mice.

Conclusion

The current studies indicate that MAIT cells have a pathogenic role in colitis and suppressing activation of these cells may reduce the severity of colitis without affecting gut integrity. Thus, MAIT cells may be potential therapeutic targets for IBD including UC.
P048 Identification of IL36RN missense mutations in Crohn’s disease patients as a potentially new drug target for treating rare patients with over-activation of the IL36 signaling cascade
Authors: Hecker J , Saurenbach J , Letizia M ,   T. TRR241 IBDome Consortium, Löscher B S , Franke A , Koop K , Neufert C , Schütz A , Siegmund B , Weidinger C
Published: January 2024

Background

The interleukin 36 (IL-36) family includes the agonists IL-36α, IL-36β, IL-36γ, which activate the NF-κB pathway and the natural antagonist IL-36RA, which inhibits IL-36 signaling. While missense mutations in the gene encoding IL-36RA (IL36RN) are associated with severe skin inflammation, their role in Crohn’s disease (CD) is currently unknown. Therefore, we here investigated if IL36RN mutations contribute to inflammation in CD and whether IL-36 signaling might represent a potential drug target for personalized therapy.

Methods

Mutations in IL36RN were identified by whole exome sequencing (WES) followed by targeted Sanger sequencing. Peripheral blood mononuclear cells (PBMCs) of affected patients were analyzed by mass cytometry and serum cytokines were measured by ELISA. Identified IL36RN mutations were characterized by overexpression experiments and functional assays. Clinical and molecular responses of one IL-36RN mutant patient to combined treatment with spesolimab and certolizumab pegol was assessed by fecal calprotectin, endoscopy, RNA sequencing and mass cytometry at week 0 and 12 of treatment.

Results

In a cohort of 47 ulcerative colitis patients, 177 CD patients and 34 healthy controls, we identified 3 CD patients with heterozygous missense mutations in IL36RN (IL-36RA S113L, IL-36RA P76L and IL-36RA L133I). In the patient carrying the IL-36RA S113L variant, we detected elevated serum levels of IL-18 and IL-23, as well as an increased frequency of TH17 cells in PBMCs, suggesting an overactivation of the IL-36 pathway. Overexpression experiments showed that IL-36RA S113L causes decreased expression of IL-36RA, resulting in increased IL-36 signaling. The patient was therefore treated with 1200 mg of the IL-36R blocking antibody spesolimab every 4 weeks and 200 mg of certolizumab pegol biweekly on the basis of an Out Of Scope request. This approach resulted in reduced intestinal inflammation and a reduction in the frequency of pro-inflammatory myeloid cells in PBMCs.

Conclusion

In this study, we show that pathogenic IL36RN mutations are present in a subset of CD patients and that blocking IL-36 signaling may represent a personalized therapeutic approach for this rare subset of patients in whom conventional biologic therapies have failed.

Disclaimer

Boehringer Ingelheim was given the opportunity to review the abstract for medical and scientific accuracy as well as intellectual property considerations in relation to the potential mention of BI substances. Boehringer Ingelheim had no role in the design, analysis or interpretation of the results in this study. Spesolimab was made available on the basis of an out of scope request. Boehringer Ingelheim was given the opportunity to review this abstract as a courtesy.
P144 Modulation of Immunometabolism via NLRX1 or PLXDC2: Novel Bimodal Mechanisms for the Treatment of Inflammatory Bowel Diseases
Authors: Danese S , Colombel J F , Rieder F , Peyrin-Biroulet L , Siegmund B , Vermeire S , Dubinsky M , Schreiber S , Yarur A , Panaccione R , Feagan B , Mosig R , Cataldi F , Verstockt B
Published: January 2024

Background

Immunometabolism exerts a bimodal action at the interface of extracellular immune response and intracellular metabolism. It controls both intracellular processes and extracellular inflammatory responses by regulating both cellular energy supply & demands, factors that determine how a cell responds to the extracellular signals. Hence, immunometabolic pathways represent an attractive target as a gate of entry & checkpoint for the inflammatory cascade. Nucleotide-binding oligomerization domain, Leucine Rich repeat containing X1 (NLRX1) & PLeXin Domain-Containing protein 2 (PLXDC2) have been identified in immunometabolic pathways for multiple cell types in immune mediated inflammatory diseases (IMIDs) and inflammatory bowel diseases (IBD)2,3. The goal of this analysis was to compare these two key immunometabolic pathways.

Methods

For both programs, in vitro murine T cell & macrophage differentiation & in vivo mouse dextran sodium sulfate (DSS) colitis models, gene expression, metabolic profiles & cytokine expression were assessed.

Results

NX-13, a novel NLRX1 agonist, resulted in regulation of cellular metabolism: activation of mitochondrial genes such as mt-nd3 & odgh, and concomitant down-regulation of glucose uptake by murine T cells (Fig1A). Simultaneously, NLRX1 stabilization by NX-13 increased antioxidant enzyme expression & reduced reactive oxygen species in T cells. NX-13 specifically reduced effector T cell differentiation (Fig1B) & inflammatory cytokine expression, while Treg differentiation was increased. Ultimately, these bimodal effects converge to dampened colitis severity scores in acute DSS colitis (Fig1C). PLXDC2 activation by LABP-69 directly reduced glycolysis, reflected by decreased extracellular acidification & oxygen consumption in bone marrow-derived macrophages (BMDM) stimulated with lipopolysaccharide (LPS, Fig1D). LABP-69 also reduced superoxide levels in BMDM. Of note, PLXDC2 activation downregulated cellular expression of the inflammatory cytokines TNFα & IFNγ by T cells (Fig1E). The PLXDC2 agonist PX-04 decreased inflammation in acute DSS colitis in mice as shown by disease activity score (Fig1F).

Conclusion

Agents targeting immunometabolism demonstrate a novel, innovative concept with potential therapeutic applicability in IBD & other IMID. NLRX1 & PLXDC2 represent distinct pathways that modulate the intracellular metabolic state simultaneously with extracellular inflammation and hence can be targeted to break the inflammatory cascade to stop chronic inflammation. These bimodal MOAs will be studied further to understand how they may synergistically address multiple aspects of chronic immune diseases such as IBD.

1Chi Cell Mol Immunol (19)

2Leber et al. J Immunol 203(12)

3Tubau-Juni et al. J Immunol 206(Supp)
P196 Pregnancy and perinatal outcomes of Inflammatory Bowel Disease mothers in Taiwan - a nationwide health and welfare databases analysis
Authors: Wu H Y , Chen C N , Weng M T , Huang C B , Tsao P N , Wei S C
Published: January 2024

Background

The incidence of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), has exhibited a consistent rise in recent years across Asia and Taiwan. Existing literature suggests that women with IBD may experience suboptimal perinatal outcomes. However, the specific relationship between IBD in pregnant Taiwanese women and the subsequent health outcomes of their newborns remains unclear. This study aims to meticulously examine the association between maternal IBD and perinatal outcomes using extensive and representative health databases in Taiwan.

Methods

We utilized four large national representative health and welfare databases: 1) Maternal and Child Health Database, 2) Birth Certificate Database, 3) National Health Insurance Database, and 4) Catastrophic Illness Database. Data spanning from 2004 to 2018 were linked using encrypted personal IDs to establish a birth cohort during this period. Mothers identified with a registered IBD diagnosis (CD: ICD 9=555, ICD 10= K50.00-K50.919; UC: ICD 9=556.0-556.6 and 556.8-556.9, ICD 10= K51.00-K51.919) in the Catastrophic Illness Database were defined as cases, with a comparison group of healthy pregnant women matched 1:10 in the same birth year and maternal age. Statistical analyses were done by chi-square tests and conditional logistic regression models.

Results

Among the 3,059,647 births between 2004 and 2018, 146 newborns (126 UC; 20 CD) were born by mothers with a registered IBD diagnosis (Figure 1). No statistically significant differences were observed in stillbirth, preterm birth, cesarean delivery, low birth weight, small-for-gestational-age (SGA), large-for-gestational-age (LGA), and low Apgar scores when compared to the 1,460 matched healthy mothers (Table 1). The only significant difference was observed in the incidence of hypertensive disorders of pregnancy, with a lower prevalence in the IBD group compared to the control group (4.1% vs. 13.6%; p=0.001). Multivariate conditional logistic regression analysis disclosed no significant differences in the aforementioned perinatal outcomes. Subgroup analysis demonstrated that no difference was noted between the CD and UC groups.

Conclusion

Through this comprehensive analysis of long-term health and welfare databases in Taiwan, we found comparable perinatal outcomes between women with IBD and matched healthy women. The birth outcomes are also improved compared with previous studies. This may be associated with advancements in medical management for IBD in recent years. Further research is needed to explore the long-term neurodevelopmental outcomes of these newborns.
P222 Inflammatory Bowel Disease and cardiac function: a systematic review of literature with meta-analysis
Authors: Soares C , Fiuza J , Rodrigues C , Gil J , Craveiro N , Ministro P
Published: January 2024

Background

Morphological and functional cardiac involvement is rarely seen in inflammatory bowel disease (IBD) patients but there is evidence that IBD patients have an increased risk of cardiovascular events despite the lower prevalence of traditional cardiovascular (CV) risk factors when compared to the general population. Our systematic review and meta-analysis examined the relationship between IBD and cardiac function, namely incidence of heart failure (HF) and clinical and subclinical echocardiographic changes.

Methods

Two medical databases, PubMed and Scopus, were systematically searched up to September 2022 to identify all studies reporting heart failure and/or echocardiographic changes in IBD patients.

Results

We identified 1287 original papers and included 18 in our qualitative analysis. Through analysis of echocardiographic data, we found subtle systolic and diastolic changes in IBD patients. We also found higher vascular dysfunction with increased aortic stiffness, coronary microvascular dysfunction resulting in worse cardiovascular outcomes. This group had an increased risk for HF hospitalizations compared with general population. We have also performed a meta-analysis with 9 studies which included echocardiographic data. In the IBD population we found reduced E/A ratio (Std. MD -0.51, 95% CI: -1.00 to -0.02, p = 0.04, I2 = 87%, p<0.0001), higher values of E/E’ ratio (Std. MD 1.46, 95% CI: 0.86 to 2.07, p<0.00001, I2 = 80%, p=0.02). We evaluated left ventricular function using longitudinal global strain which was decreased in IBD patients (Std. MD 0.66, 95% CI: 0.48 to 0.84, p<0.00001, I2 = 0%, p= 0.55). Overall IBD patients had increased LA diameter (Std. MD 0.06, 95% CI: 0.12 to 0.24, p = 0.50, I2 = 20%), and an increased LA area (Std. MD 0.03, 95% CI: 0.24 to 0.29, p = 0.85, I2 = 0%), but no statistical significance was not reached. A significant increase in inter-atrial and right intra-atrial conduction delay was observed in IBD patients (Std. MD 0.88, 95% CI: 0.45 to 1.31, p<0.0001, I2 = 42%; Std. MD 0.9, 95% CI: 0.57 to 1.22, p < 0.00001, I2 = 0%, respectively). We found no significant bias in our analysis using CASP checklist.

Conclusion

There is significant evidence to conclude that the IBD population has increased risk for LV and atrial dysfunction, vascular changes, arrhythmias, and heart failure hospitalization. Screening with sensitive imaging like speckle tracking echocardiography could identify early subclinical changes. IBD is in fact a cardiovascular risk factor and tight inflammation control may reduce the risk.