bluuebunny/crossref_metadata_2025 huggingface dataset:
A249 PARADOXICAL PSORIASIS FOLLOWING ANTI-TNFΑ THERAPY IN INFLAMMATORY BOWEL DISEASE AND ASSOCIATION WITH AN IL-23 RECEPTOR VARIANT: A PRELIMINARY REPORT
Authors: Natt N , Wilson A
Published: February 2024

Background

Patients with inflammatory bowel disease (IBD) who receive anti-tumor necrosis factor (TNF) α therapy are at risk of developing drug-related psoriatic skin lesions known as paradoxical psoriasis (PP). This is a severe unpredictable adverse drug event that often leads to discontinuation of anti-TNFα therapy. To date, there are no tools for identifying high-risk individuals. Variation in the IL-23 receptor (IL23R) gene has been linked to psoriasis onset and may be implicated in PP.

Aims

To evaluate the frequency of the IL23R variant (IL23R1142Gampersand:003EA) in anti-TNFα exposed IBD patients who develop PP versus those who do not. Clinical variables associated with PP development will also be assessed.

Methods

A case-control study is ongoing, including anti-TNFα-exposed adult IBD patients. Participants are divided based on the development of PP (cases n=11; controls n=48, identified to date, 500 additional patients will be screened). All participants were retrospectively genotyped for the occurrence of the IL23R1142Gampersand:003EA variant. Clinical variables and outcomes were assessed from the time of anti-TNFα exposure for at least one year of follow-up or to the time of anti-TNFα discontinuation.

Results

To date, we have included 59 adult IBD patients treated with infliximab or adalimumab. Eleven patients developed PP after a median duration of treatment of three months with anti-TNFα therapy. The most common presentations were guttate, plaque, and pustular psoriasis. Six patients had PP that involved 50% or more of their body surface area (BSA). Nine participants discontinued their anti-TNFα therapy due to PP. None of the cases had a personal or family history of psoriasis. PP patients were similar to controls with respect to age, sex, ethnicity, IBD type, disease duration, and concurrent immunomodulator use. The variant genotype occurred more frequently in PP patients compared to controls (54.5% vs. 4.2%, OR 27.6, 95%CI 4.3-145.4). Those with the variant genotype also had more extensive psoriasis compared to wildtypes (mean BSA 61% vs. 25%, p=0.045).

Conclusions

In this preliminary analysis, there was an increased frequency of the IL23R1142Gampersand:003EA variant in patients who developed PP compared to those who did not after anti-TNFα exposure. We did not identify any other clinical variables associated with development of PP. Interpretation of these results is limited by the small sample size. Completion of this study may help clarify the association between PP and the IL23R gene as well as other clinical risk factors implicated in PP development.

Funding Agencies

None
A250 CYTOKINE MULTI-OMICS AND MACHINE LEARNING IDENTIFY MIP1ALPHA AS A NOVEL MEDIATOR IN INFLAMMATORY BOWEL DISEASE
Authors: O'Brien E M , Potdar C , Mulder D
Published: February 2024

Background

Macrophage inflammatory protein 1 alpha (MIP1a) is a proinflammatory cytokine previously related to murine models of inflammatory bowel disease (IBD), but not definitively in the human disease. MIP1a acts as a chemoattractant of immune cells from the blood to the gut mucosa. We aimed to delineate the alterations to MIP1a and macrophages in relation to a range of IBD severity.

Aims

To characterize the changes to MIP1a production and localization in response to disease activity in IBD.

Methods

Both IBD (n=63) and control patients (n=118) were enrolled in this study (HSREB 6033229). Cytokine profiles were investigated using a 17-plex multi-fluorescent bead-based immunoassay (FirePlex, Abcam, Cambridge, UK) on serum from a subset of patients. Disease activity and macrophage levels were extracted from the clinical record. Activity was quantified using the Physician Global Assessment Score. Machine learning (ML) was performed with custom R scripts utilizing the tidymodels package (version 1.1) to determine the optimal model. Immunohistochemistry (IHC) was used to localize MIP1a in patient biopsies and quantified using QuPath software (v0.4).

Results

An extreme gradient boost ML model was found to have optimal sensitivity and specificity for predicting disease activity based on serum cytokine levels. Within this model lower levels of serum MIP1a were associated with higher severity of IBD activity. However, in GI mucosal biopsies, the percentage of MIP1a positive cells in colon tissue increased with the severity of IBD. Macrophage concentrations in the peripheral blood were higher in patients on prednisone, and relatively similar across all other medications used in our cohort.

Conclusions

With the data collected, we identify MIP1a as a possible prognostic tool for quantifying IBD activity.

Funding Agencies

CIHR
A252 DRUG DISCONTINUATION AND PERSISTENT SYMPTOMS AMONG THE USERS OF BIOSIMILAR AND LEGACY ANTI-TNF DRUGS IN A REAL-WORLD CANADIAN IBD COHORT
Authors: Oketola B , Lukusa L , Birck M , Neville A , Leung Y , Narula N , Afif W , Bernatsky S , Singh H
Published: February 2024

Background

Biosimilars and their reference originator drugs are increasingly used for inducing and maintaining remission in Inflammatory Bowel Diseases (IBD). Persistent symptoms, such as fatigue and joint pain, have been reported among individuals with IBD in remission. However, there is limited data on the persistence of symptoms among long-term users of biological therapy.

Aims

We report on drug discontinuation and persistent symptoms among a multicentre cohort of IBD patients 12 months after initiating anti-TNF originators or biosimilars.

Methods

We enrolled and followed individuals with IBD (ampersand:003E18 years) who initiated therapy with infliximab or adalimumab, bio-originators/biosimilars, between January 2019 and March 2023. We determined the rate of discontinuation of therapy, persistent symptoms, and quality of life (QoL) after 12 months. Difference in effect estimates (proportions and means) between the two groups (originators versus biosimilars) was determined.

Results

181 individuals with IBD (CD = 58%, female = 46%, Caucasian = 85%) were enrolled. 62% were biologic-naïve at initiation. Of the 119 participants who completed a 12-month follow-up visit, about 19% (n = 34) discontinued drug use (all were infliximab users). Insufficient disease control was the most common reason for drug discontinuation (18.2%, n = 33). There was a significant reduction in the number of corticosteroid users at follow-up in both originator (rate ratio: 0.33, 95% confidence interval (CI): 0.16-0.49) and biosimilar users (rate ratio: 0.22, 95% CI: 0.14-0.30). With our limited power, we were unable to detect significant reductions in ER visits and hospitalizations in the first year after initiation of anti-TNF agents compared to that in the preceding year. The severity of pain/discomfort anywhere and the frequency of fatigue and anxiety/depression was not significantly reduced at 12 months in either of the groups. The percentage of those reporting moderate/severe abdominal pain was reduced among biosimilar users (46% to 20%; rate ratio of 0.26, 95% CI: 0.15-0.38), and originator users (28% to 13%, rate ratio 0.16, 95% CI: -0.02, 0.33). The proportion of those reporting rectal urgency at least some of the time was also reduced among both originators (30% at baseline to 9% at follow-up) and biosimilar users (33% to 17%). There was a significant improvement in QoL scores among both originator users (mean difference (MD) 13.0, 95% CI: 6.00-22.0) and biosimilar users (MD 10.0, 95% CI: 6.00-14.0) on the SIBDQ. This improvement was replicated on the EQ-5D only among biosimilar users.

Conclusions

Our study results suggest that even though the use of anti-TNF drugs leads to improvement in QoL, there may be no reduction in some symptoms, such as fatigue, anxiety, depression.

Funding Agencies

CIHR
A262 THE EXCESS USE OF PROTON-PUMP INHIBITORS IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE
Authors: Singh N , Nugent Z , El-Matary W , Singh H , Shaffer S , Bernstein C
Published: February 2024

Background

Proton-pump inhibitors (PPI) use can impact the gut microbiome, thus, it is possible that use in children may be associated with an increase in pediatric IBD.

Aims

We investigated the common gastrointestinal symptoms that result in a PPI prescription in pediatrics prior to a diagnosis of IBD and the degree to which children with IBD use excess PPIs compared to controls either prior to or post a diagnosis of IBD.

Methods

The University of Manitoba IBD Epidemiology Database includes all Manitobans diagnosed with IBD 1984-2018 with age, sex, and geographic-matched controls. PPI prescription data were assessed from April 1995 onwards in children diagnosed with IBD prior to age 18.

Results

PPI were dispensed prior to IBD diagnosis in 9% of 614 children diagnosed with IBD and 0.8% of 5718 controls (P ampersand:003C0.0001) with the median age being 15 years. Children with Crohn’s disease were no more likely to have been PPI-users pre-diagnosis (10%) than persons with ulcerative colitis (8%, p=0.57). Relative PPI use increases within 1-year of an IBD diagnosis (rate ratio, RR=22.4 (95% CI 13.6-37); P ampersand:003C 0.001) compared with 3-5 years pre-IBD (RR=4.9, 95% CI 1.4-16.7) and 1-3-year pre-IBD (RR=2.5, 95% CI 1.01-6.2). The percent of children being prescribed a PPI increased the more they visited a physician, which was associated with increased likelihood of being prescribed a PPI. PPI use was similar for the various gastrointestinal diagnoses in cases of IBD and controls. PPI users prior to a diagnosis may have less severe disease than non-PPI users. We found they were less likely to be hospitalized (HR 0.36, 95% CI 0.19 – 0.68; P = 0.002). There was no difference among children who had surgery for their IBD whether they were PPI users prior to IBD diagnosis compared to non-users.

Conclusions

PPI use was commonly prescribed for a variety of gastrointestinal complaints, similarly in cases and controls. Children with IBD have many more contacts for gastrointestinal diagnoses than controls even for 5 years prior to their diagnosis. This raises the possibility that PPIs are prescribed indiscriminately for gastrointestinal complaints since their use was not restricted to complaints warranting PPI use, or that PPIs are prescribed for early symptoms that are secondary to IBD.

Funding Agencies

None
A264 IDENTIFYING CLINICAL PREDICTORS FOR SUCCESS OF EXCLUSIVE ENTERAL NUTRITION INDUCTION THERAPY IN PEDIATRIC CROHN DISEASE
Authors: Suarez Suarez R G , McClement D G , Huynh H , Griffiths A , Shaikh A , Otley A , Jacobson K , Sherlock M , Mack D , Deslandres C , El-Matary W , deBruyn J , Walters T , Wine E
Published: February 2024

Background

Current treatments for IBD focus on reducing inflammation, mostly through suppression of the immune system. Exclusive enteral nutrition (EEN) is recognized as the first line therapy for mild-to-moderate luminal pediatric Crohn disease patients pCD. Although EEN is safe, as it does not suppress the immune system, it poses considerable challenges to patients, mostly due to palatability and monotony of the formula and treatment costs. Moreover, the efficacy of EEN varies greatly from patient to patient. Therefore, there is a need to distinguish between responders and non-responder patients.

Aims

Identify clinical features associated with efficacy of EEN induction therapy and apply machine learning to build a classifier to identify EEN non-responders.

Methods

The Canadian Children Inflammatory Bowel Disease Network prospectively enrolled and followed new onset pediatric IBD cases. Prospective data for 308 pCD with EEN as their first treatment for CD are available. Patients with weighted Pediatric CD Activity Indexes (wPCDAI) collected after at least 4 weeks on EEN were compiled into a dataset (n=108). For this analysis, treatment response was defined as a wPCDAI reduction of at least 12.5 points of a patient’s wPCDAI baseline score.

The dataset includes 26 features for each of the 108 pCD patients at time of diagnosis. This included blood test results (Hgb, ESR, CRP, Alb, Htc, Plt), Paris Classifications, height, and weight Z-scores, as well as wPCDAI, SES-CD (simple endoscopic score, CD), PGA (physician global assessment), and Mayo scores.

Odds ratios were calculated to determine whether any features were associated with response to EEN induction therapy. Then, the most relevant features were identified with regularization techniques and a machine learning classifier for predicting response to EEN was built.

Results

Results showed that the appropriate subset of features to include for optimal accuracy over model simplicity are n=4 (PUCAI, PGA, SES-CD scores, and hematocrit). Also, an increase in PGA score (e.g., moving from “mild disease” to “moderate disease”) was associated with an increase in the chance of EEN failure (OR 3.1, 95% CI [1.7,5.8], p=0.0001). The best classifier for predicting EEN response was a random forest consisting of 20 decision trees. The classifier achieved an area under the ROC curve of 0.75 ± 0.07

Conclusions

Our results suggest that it is possible to produce a classifier capable of predicting EEN clinical remission with an accuracy over 60%. Higher PGA, PUCAI, and SES-CD scores show potential for predicting patients less likely to respond to EEN induction. This research has the potential to provide better quality of life for children who live with IBD.

Funding Agencies

CIHRIMAGINE SPOR Network , Women and Children's Health Research Institute
A268 1 YEAR FOLLOW-UP OF PEDIATRIC ULCERATIVE COLITIS USING INTESTINAL ULTRASOUND
Authors: Thornton S , Isaac D , Hudson A , MacKay D , Kuc A , Carroll M W , Wine E , Huynh H
Published: February 2024

Background

Intestinal ultrasound (IUS) is an emerging tool that offers a non-invasive method for monitoring inflammatory bowel disease in pediatric patients, with increasing popularity worldwide. Assessment of IUS for monitoring pediatric Ulcerative Colitis (UC) has been previously limited to small samples of patients with no long-term follow up.

Aims

This project aims to utilize intestinal ultrasound assessments obtained at routine time points to determine changes in IUS parameters within 12 months of study enrollment in newly diagnosed children with UC, and their relationship to biochemical markers, clinical assessments, and endoscopic findings.

Methods

Pediatric patients with suspected ulcerative colitis were prospectively enrolled through the Edmonton Pediatric IBD Clinic. Participants underwent IUS, clinical assessments, bloodwork for biomarkers, and fecal calprotectin (FCP) testing at baseline, 1-, 3-, 6-, and 12-month visits, as well as endoscopy at baseline and 6-12 months. In each IUS assessment, the bowel wall thickness (BWT), presence of hyperemia, abnormal haustrations, and fat wrapping was determined in 4 bowel segments (right, transverse, descending, and sigmoid colon). The Pediatric Ulcerative Colitis Activity Index (PUCAI) scores and Ulcerative Colitis Intestinal Ultrasound Scores (UC-IUS) were calculated at each visit.

Results

42 patients (55% male) were included. Median UC-IUS total scores and BWT alone improved in all bowel segments over the study period. For the most affected bowel segment for all patients, median percent reduction of BWT was 39.6%, 34.2%, 33.7%, and 42.5%, at the 1-, 3-, 6-, and 12-month assessment respectively. The biggest decrease in UC-IUS scores and BWT occurred with the initiation of therapy between baseline and 1-month. UC-IUS scores significantly correlated with endoscopy at 12-months, clinical assessments at all time points, and biochemical markers of disease at all time points over the 12-month study period (pampersand:003C0.05). BWT measurement alone also had significant correlation with endoscopy at 12 months; clinical assessment at 1-, 3-, and 6-months; and with biochemical markers at every time point (pampersand:003C0.05). Patients with inflammatory bowel markers (indicated by elevated FCP (ampersand:003E250)) at 12-months were found to have significantly thicker BWT and UC-IUS scores at 3- and 6-months.

Conclusions

BWT and UC-IUS performed well in pediatric patients with newly-diagnosed UC, with UC-IUS scores and BWT measurements alone correlating significantly with endoscopic, clinical, and biochemical disease activity over the 12-month study period. BWT alone performed similarly to total UC-IUS scores. This data suggests that IUS can offer a non-invasive method to monitor long-term pediatric UC disease severity.

Funding Agencies

TRIANGLE, WCHRI, Stollery Children's Hospital Foundation.
A269 SEX-DEPENDENT EFFECT OF PANCREASTATIN INHIBITION ON COLON MUCOSAL INTEGRITY IN HOMEOSTATIC CONDITION
Authors: Tshikudi D M , Hitchinson H , Hesampour F , Ghia J
Published: February 2024

Background

Sex bias in inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) epidemiology is well known. Pancreastatin (PST), an epithelial cells-derived peptide overexpressed in IBD patients, regulates the endoplasmic reticulum (ER) and survival signalling involved in CRC. Pancreastatin inhibitor 8 (PSTi8), an inhibitor of PST, showed promising anti-inflammatory effects in IBD male mice model. However, no data exists regarding PST’s role in colon mucosal regeneration and epithelium maintenance.

Aims

Here, we investigated the impact of PSTi8 treatment on colonic epithelial cells in male and female mice under homeostatic conditions.

Methods

Male and female C57BL/6 mice were treated with PSTi8 (2.5mg/mL/kg, i.r.) or PBS for six days. Epithelial cells’ proliferation (Ki67) and differentiation (cytokeratin-20) were measured by immunofluorescence. Genetic markers for differentiated epithelial cells (goblet Muc2 and Tuft Dclk1), stem cells (fast-cycling Lgr5, reserve Hopx and fetal-like Ly6a), stem cell regulator (BMP4), epithelial cells lineage commitment (Atoh1, Hes1, Gfl1), ER activation (ATF6), and apoptosis (CHOP) were tested by qRT-PCR.

Results

PSTi8 treatment decreased epithelial cell proliferation in both sexes. The inhibition of PST lowered the differentiation of epithelial cells and mucus production and increased tuft cell gene expression in females but not in male mice. In females, PSTi8 treatment increased fast-cycling stem cells but lower reserve and fetal-like stem cells in both sexes. In addition, PST inhibition significantly downregulated BMP4, which regulates epithelial cell differentiation, in females while not altering its expression in males. In contrast, PSTi8 treatment significantly increased transcription factors regulating epithelial cells' self-renewal and lineage commitments Hes1 and GFI1 in females but decreased Atoh1 in both sexes. PST inhibition enhanced gene expression of ER stress molecules ATF6 and CHOP in female and ATF6 in male mice. CHOP remained unaltered by PST inhibition in males.

Conclusions

PSTi8 alters colonic epithelial regeneration, differentiation, and thus maintenance in a sex-dependent manner.

Funding Agencies

CIHRChildren’s Hospital Research Institute of Manitoba (CHRIM)/Research Manitoba
A270 RISK FACTORS FOR COLORECTAL NEOPLASIA DEVELOPMENT IN INFLAMMATORY BOWEL DISEASE PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS: A CASE-CONTROL STUDY
Authors: van Lierop L , Derks M , te Groen M , Tran C , Lytvyak E , Montano Loza A , Hoentjen F
Published: February 2024

Background

Patients with inflammatory bowel disease (IBD) and concomitant primary sclerosing cholangitis (PSC-IBD) have a 25-year cumulative risk of up to 50% to develop colorectal neoplasia (CRN). Mucosal inflammation is an important driver of CRN development in IBD, but it is unknown whether this also applies to PSC-IBD patients.

Aims

We aimed to assess the impact of active mucosal inflammation per colonic segment and endoscopic remission on CRN risk.

Methods

This is a single-center case-control study, including cases with PSC-IBD with CRN, and controls with PSC-IBD without CRN. Exclusion criteria were a CRN diagnosis prior to IBD or PSC diagnosis, familial CRC syndromes, and insufficient endoscopic follow-up (ampersand:003C2 available colonoscopy reports, and for cases, ampersand:003C2 available endoscopy reports before CRN diagnosis). Data was collected on demographics, IBD and PSC disease characteristics, and IBD medication use. Data from all available colonoscopy and sigmoidoscopy reports between 2002 and 2023, including endoscopic and histologic disease severity, disease extent, and CRN lesions, was collected. The primary outcome was a diagnosis of CRN, secondary outcomes included CRN grade and location, inflammatory burden per colonic segment harboring CRN, and colonic surgery.

Results

We included 247 PSC-IBD patients (163 ulcerative colitis, 80 Crohn’s disease) with a median follow-up of 6.3 years (IQR: 4.1-12.6) and 6 endoscopic procedures (IQR: 4.0-8.0). Median disease duration was 19 years for IBD (IQR: 11.0-26.0) and 13 years for PSC (IQR: 7.0-18.0). In 50 cases a total of 113 CRN lesions were observed, of which 11 (10%) were advanced CRN (aCRN; HGD or CRC). 23 patients (45%) were diagnosed with ampersand:003E 1 lesion while 45 lesions (40%) were identified in the right-sided colon, 27 (24%) in the transverse colon, 28 (25%) in the left-sided colon, and 10 (9%) in the rectum (3 lesions unknown). Endoscopic remission was observed in 24 cases (48%) during the 2 endoscopies prior to lesion detection vs. in 83 controls (42%) for their last 2 endoscopies. Of all CRN lesions, 39 (35%) were found in a colonic segment with confirmed previous endoscopic and/or histologic inflammation during the 1-2 endoscopies prior to lesion detection (31 low-grade and 8 aCRN). Of the 32 patients who underwent (sub)total colectomy or proctocolectomy, 20 (63%) had an indication due to CRN diagnosis. Mortality was 13% (n=32) during follow-up.

Conclusions

The risk for CRN and associated colectomy is high in PSC-IBD. Active mucosal inflammation preceded CRN in the affected colonic segment in only 35% of the lesions. Future expansion and additional analysis of our cohort will focus on the impact of persistent endoscopic remission and impact of biologic therapy on CRN risk in PSC-IBD.

Funding Agencies

None
A271 EFFECT OF ANTI-TNF AGENTS ON DNA METHYLATION IN PERIPHERAL BLOOD OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Venner J , Francis J , Rumore J , Sargent M , Jones M , Bernstein C
Published: February 2024

Background

Despite the success and ongoing use of tumor necrosis factor inhibitors (TNFi) in the treatment of inflammatory bowel disease (IBD), there are no predictors of response to therapy. While much research has gone into understanding genetic risks for IBD, less work has been done exploring epigenetic associations with treatment. Hence, we wondered whether epigenetic changes were associated with failure of TNFi in IBD.

Aims

Describe the association of TNFi response with DNA methylation in patients with IBD.

Methods

Participants ≥18 years with IBD (N=169) were selected from the Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects (IMAGINE) Strategy for Patient Oriented Research (SPOR) Network. At enrollment participants completed a questionnaire that included their disease diagnosis, therapy, smoking history, and disease activity using the validated IBD Symptom Inventory (IBDSI). Patients provided whole blood samples that were processed for and run on Illumina DNA methylation arrays.

Results

The 169 patients were in three treatment groups: TNFi naïve (N=98, never exposed to an anti-TNF agent), TNFi responder (N=32, inactive disease on anti-TNF agent), and TNFi nonresponder (N=39, active disease not on any biologic at time of enrollment). The mean symptom score (SIBDSI) was different across the three groups (pampersand:003C0.001): TNFi nonresponders having a higher SIBDSI (24 ± 6.1) than the TNFi naïve (9.1 ± 5.5) or responder (8.3 ± 4.3) treatment groups. Relative proportions of leukocyte populations were estimated using DNA methylation. CD4 and CD8 T cell and B cell counts were higher (pampersand:003C0.05) in the nonresponders and responders versus TNFi naïve group. Neutrophil counts were lower (pampersand:003C0.05) in the TNFi nonresponders and responders compared to the TNFi naïve group (Figure 1). There was a trend towards increased epigenetic estimates of age acceleration (pampersand:003E0.05) in nonresponders versus responders and TNFi naïve patients, likely driven by disease activity (data not shown). Epigenome-wide analysis of the three groups revealed 16 CpGs for responder versus naïve (e.g. CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1), and two CpGs for nonresponders versus responders (Table 1). This includes a CpG for guanine nucleotide-binding protein subunit gamma-2 (GNG2) that was shared between the two comparisons.

Conclusions

Exposure to TNFi is associated with changes in peripheral leukocyte populations independent of response to treatment, indicating a TNFi effect. This implies that anti-TNF treatment is having some effect on patients even if there is clinical nonresponse. Differentially expressed CpGs implicates possible markers of response to treatment, particularly CDKAL1, a gene that has been associated with TNFi response in psoriasis.

Funding Agencies

Guts and Roses Charity
A275 THE POTENTIAL MECHANISTIC ROLES OF SPHINGOLIPIDS IN HEALTHY FIRST-DEGREE RELATIVES OF PATIENTS WITH CROHN'S DISEASE
Authors: Xue M , Lee S , Neustaeter A , SHAO J , Huynh H , Griffiths A , Turner D , Madsen K , Moayyedi P , Steinhart H , Bitton A , Mack D , Jacobson K , Ropeleski M , Cino M , Bernstein C , Panaccione R , Bressler B , Turpin W , Croitoru K
Published: February 2024

Background

Crohn's Disease(CD) features a complex etiology intertwining genetic, environmental, and immunological dimensions. Sphingolipids (SPs) are pivotal lipid molecules within cell membranes and various biological processes, including cell growth, apoptosis, and inflammatory responses. While our prior research identified SPs as significant risk factors for CD onset, their pre-clinical influence on CD risk biomarkers and potential role in pathogenesis remains unclear

Aims

To identify the relationship between SPs and established CD risk factors

Methods

We used samples from healthy first-degree relatives(FDRs), followed in a nested case-control cohort from the Crohn's Colitis Canada- Genes, Environment, Microbial(GEM) project, matching those who developed CD(n=77) with control FDRs(n=303) based on age, sex, follow-up time, and geographic location. 59 SPs were selected from serum metabolites measured via an untargeted metabolomics platform. We used partial Spearman correlation to identify relationships between SPs and CD risk factors: i)intestinal permeability via the urinary fractional excretion ratio of lactulose to mannitol(LMR); ii)gut subclinical inflammation using fecal calprotectin(FCP); iii)systemic inflammation with C-reactive protein(CRP); iv)microbiome composition through fecal 16S rRNA sequencing and v)serum protein profile using the Olink® Proximity Extension Assay platform. A two-sided qampersand:003C0.05 was considered significant

Results

We identified 38 positive correlations between CRP and SPs across various sub-pathways, including Ceramides, Sphingomyelins and Hexosylceramides(0.117≤rho≤0.342, 1.37×10−09≤q≤0.042). One SP Ceramide(d18:1/16:0) correlated positively with FCP(rho=0.201, q=0.012). Moreover, two SPs, N-palmitoyl-sphingosine (d18:1/16:0) and glycosyl-N-(2-hydroxynervonoyl)-sphingosine (d18:1/24:1(2OH)), correlationed with Peptoclostridium genus (rho=0.465 and -0.245, q=1.47×10−16 and 0.028 respectively). All SPs correlated with one or more proteins, most positively between Sphingosine-1-phosphate and non-receptor tyrosine kinase(rho=0.637, q=1.98 ×10−36) and most negatively between sphingadienine and Chymotrypsin-C protein(rho=-0.334, q=4.11×10−8). No significant correlations emerged between SPs and LMR

Conclusions

We identified correlations between SPs and CD risk factors. The correlation with CRP suggests SPs might contribute to systemic inflammatory pathways related to CD. Moreover, correlations with the bacterial taxa highlight SPs' potential role in regulating microbial composition. Extensive correlations with proteins emphasize the pivotal impact of SPs on their function. This study may offer new insights into CD prevention

Funding Agencies

CCC, CIHR
A276 A SYSTEMATIC REVIEW OF THE ASSOCIATION BETWEEN EOSINOPHILIC ESOPHAGITIS AND INFLAMMATORY BOWEL DISEASE
Authors: Yanofsky R P , Jogendran R , Hoxha T , Pathak A , Orchanian-Cheff A , Tandon P
Published: February 2024

Background

Inflammatory bowel disease (IBD) and eosinophilic esophagitis (EoE) are chronic inflammatory conditions of the gastrointestinal tract. IBD and EoE have been linked to other autoimmune conditions. There has been conflicting evidence on whether these two diseases are associated.

Aims

The purpose of the current study is to perform a systematic review evaluating the incidence of co-existing IBD and EoE. To determine whether the relationship between IBD and EOE is unique for autoimmune conditions, we also evaluated the relationship between other autoimmune conditions such as rheumatoid arthritis and atopic dermatitis and EOE.

Methods

A comprehensive search strategy was conducted on July 10, 2023 using MESH terms for eosinophilic esophagitis and IBD, autoimmune disorders or connective tissue disorders in Ovid MEDLINE; Ovid Embase; Cochrane Database of Systematic Reviews (Ovid); and Cochrane Central Register of Controlled Trials (Ovid). The primary outcome was defined as the frequency of concomitant IBD and EOE compared to the frequency of IBD alone. Secondary outcomes included the frequency of concomitant autoimmune conditions and EOE compared the frequency of the autoimmune condition alone, as well as the examination of clinical, biomarker, and endoscopic outcomes of patients with concomitant IBD and EOE compared to patients with IBD alone.

Five independent reviewers participated in study selection applying eligibility criteria and selecting studies for inclusion. Duplicate items were removed and title and abstracts screening occurred. Any publication deemed potentially relevant by was carried forward to the full-text review. Discrepancies were resolved by consensus.

Results

Our systematic search identified 2144 potential studies. After screening titles, we were left with 268 studies. Following full text review, 50 studies remained which included 9 articles and 19 abstracts on IBD and EOE, and 8 articles and 14 abstracts on other autoimmune conditions and EOE.

The 9 articles on IBD and EOE consisted of 6 retrospective cohort, 1 prospective cohort, 1 case-control and 1 case series study. 8 of the studies were conducted in the United States and 1 was conducted in Italy. There were 4 studies on adult populations, 4 studies on pediatric populations, and 1 study in both. There was a total of 133,451,249 patients evaluated, the majority being from one study (n=133,308,339 patients). The number of concomitant IBD and EOE patients per study ranged from 5 to 3506 patients and the number of IBD patients without EOE ranged from 33 to 701,601 patients. In the general population, the number of EOE patients alone per study ranged from 33 to 102,048. Completion of data extraction and statistical analysis is ongoing.

Conclusions

There may be an association between IBD and EOE. Further data analysis is ongoing.

Funding Agencies

None
A279 WHY LIVER TRANSPLANT RECIPIENTS DIE: A QUALITY ASSURANCE REVIEW
Authors: Aboalfaraj N , Talab R , Marquez V , Chahal D , Hussaini T , Dmitriew M , Yoshida E
Published: February 2024

Background

Liver transplant techniques have significantly advanced over time, enhancing patient survival rates. In 2022, 99 liver transplants were performed in British Columbia (BC), ranking second in organ transplants. In BC, mortality rates for liver transplant recipients are 9.4% at one year, 15.6% at three years, 21% at five years, and 31% at ten years. However, a knowledge gap exists about the causes of post-transplant deaths in BC. This study aims to explore the primary mortality causes among these recipients over the last decade.

Aims

This study aims to investigate the leading causes of mortality among liver transplant recipients in British Columbia between 2013 and 2023. The objective is to identify areas for improvement and to develop strategies to decrease mortality rates.

Methods

We conducted a retrospective observational study including all patient deaths among liver transplant recipients in BC between January 1, 2013, to August 31, 2023. Secondary data from the BC Transplant database were used for this analysis.

Results

Over a ten-year period, 320 deaths were recorded in liver transplant recipients in BC. On average, patients were 53.5±12.96 years. Additionally, 60% of these individuals were male. Deaths occurred, on average, 8.6 ± 8.05 years after the patients received their transplants. Malignancy emerged as the primary cause of death, representing 24.7% of all fatalities. Together, multi-organ failure (12.5%), sepsis (11.3%), and cardiovascular issues (6.9%) made up close to one-third of the total deaths. Thirty-one patients (9.7%) died due to liver-related causes. The most common causes of graft loss were hepatitis C recurrence (6/31) and allograft rejection (8/31). Unfortunately, the cause of death was unknown in a significant proportion of patients (67/320), with nearly one-third (10/31) of all liver-related mortalities lacking a clear documented etiology.

Conclusions

Our study elucidated the causes of death in liver transplant recipients in British Columbia over the past decade. Cancer-related mortality, multi-organ failure, sepsis, cardiovascular events, and liver allograft failure were among the most common causes of death in this patient population. Hepatitis C recurrence and allograft rejection were common etiologies for liver-related mortality. The significant proportion of patients with undetermined or undocumented causes of death is of concern. These findings underscore the necessity for enhanced oncological surveillance, rigorous patient evaluation, and a potential re-evaluation of post-transplant care, especially in managing infections and cardiovascular health. The substantial "unknown" causes of death emphasize a need for better data capture provincially.

Funding Agencies

None
A291 ANA-NEGATIVE AUTOIMMUNE HEPATITIS IN A 30-YEAR-OLD FEMALE: A DIAGNOSTIC CHALLENGE
Authors: Islam A H , Mortuza R , Arab J
Published: February 2024

Background

Autoimmune Hepatitis (AIH) is a chronic liver condition arising from the immune system's attack on liver cells. Its diagnosis is typically supported by the presence of autoantibodies, notably ANA. However, cases have been identified where AIH occurs in the absence of these conventional serologic markers. Prior studies have reported that ANA-negative AIH patients showed more acute presentations and higher frequencies of histologic acute hepatitis compared to those with positive autoimmune serology. As such, ANA-negative subset of patients presents a diagnostic challenge but highlights the evolving understanding of autoimmune processes in liver diseases.

Aims

To detail the clinical presentation, investigative measures, and treatment approach in a an otherwise healthy 30-year-old female diagnosed with ANA-negative autoimmune hepatitis.

Methods

The diagnostic approach included clinical symptomatology, biochemical tests, imaging via abdominal ultrasound, and histopathological evidence from an ultrasound-guided liver biopsy

Results

The patient presented initially with epigastric pain, jaundice, and pruritus over two weeks. Blood tests revealed acute hepatitis: ALT at 2723 U/L[JA1] , AST at 1428 U/L, and hyperbilirubinemia at 503 μmol/L, with GGT and ALP remaining normal. An abdominal ultrasound presented a typical liver morphology and biliary system. Initial autoimmune liver disease panels, including ANA, and viral hepatitis screenings, returned negative results. Furthermore, the patient's medication and drug history provided no additional clues for drug-induced aetiologies. For more conclusive diagnostics, an US-guided liver biopsy was performed during the admission revealing moderate acute hepatitis characterized by both interface hepatitis and lobular inflammation, prompting the suspicion for ANA-negative AIH. Initiating prednisone treatment (40 mg daily) based on clinical and biopsy evidence led to a significant reduction in liver enzymes and bilirubin. By the time of her discharge, her primary residual symptoms were mildly controlled jaundice and pruritus. She was transitioned to a tapering dose of prednisone, and Azathioprine was later added to her regimen. Subsequent close follow up revealed complete resolution of her symptoms. Notably, a 7-month follow-up unveiled a previously undetected AIH marker: ASMA with a titre of 1:80.

Conclusions

ANA-negative AIH, as showcased in this case, emphasizes the importance of a thorough and iterative diagnostic approach. Traditional serological markers may not always be present, necessitating reliance on a combination of clinical presentations and histopathology. Regular follow-ups and periodic re-evaluations are essential. This approach is crucial for pinpointing the diagnosis, guiding effective therapeutic interventions, and ultimately ensuring positive outcomes for patients navigating complex autoimmune liver conditions.

Funding Agencies

None
A293 PREVALENCE OF METABOLIC ASSOCIATED STEATOTIC LIVER DISEASE AND ITS IMPACT ON ADVERSE OUTCOMES IN PRIMARY BILIARY CHOLANGITIS PATIENTS
Authors: Kaviani R , Wong Y , Shreekumar D , Mason A , Montano Loza A , Lytvyak E
Published: February 2024

Background

Metabolic associated steatotic liver disease (MASLD) is highly prevalent among Canadians, thus making coexistence with other liver diseases inevitable. Primary biliary cholangitis (PBC) is the most common autoimmune liver disease diagnosed in one out of 1,000 women above 40. The impact of concomitant MASLD on liver outcomes in patients with PBC is unclear.

Aims

We aimed to determine the prevalence of MASLD among patients with PBC and the association between concomitant liver disease and adverse liver outcomes.

Methods

PBC patients diagnosed between 1984 and 2023 and followed up at the University of Alberta with vibration-controlled transient elastography data available were included. MASLD was diagnosed if the Controlled Attenuation Parameter ≥288 dB/min with at least one cardio-metabolic criteria, based on elevated body mass index, blood pressure, and abnormal glycemic and lipid tests. Proportions were compared using chi-square, medians – Mann-Whitney test. We utilized a Cox hazards regression model to calculate hazard ratios and determine associations between MASLD and the development of cirrhosis or decompensation, need for liver transplant, or death.

Results

A total of 115 patients (87.0% females, age at diagnosis 52.3±11.5 years) followed over a median duration of 11.0 [range 0.1-39.7] years) were included. The prevalence of MASLD (33.0% [n=38]) was higher in females than males (35.0%[n=35] vs. 20.0%[n=3]; p=0.249). The prevalence of cirrhosis at diagnosis was twice as high among PBC patients with MASLD than those without (26.3%[n=10] vs. 13.0%[n=10]; p=0.076). No difference was observed in the frequency of decompensation at diagnosis (8.8%[n=3] vs. 6.3%[n=4]; p=0.638). Cirrhosis frequency (50.0% vs. 50.6%; p=0.948) and decompensation (38.2% vs.37.1%; p=0.912) over the course of the disease were similar between PBC patients with and without MASLD. There was no association between MASLD and development of cirrhosis (HR0.51, 95%CI 0.23-1.13; p=0.095), decompensation (HR0.81, 95%CI 0.37-1.76; p=0.596), liver transplantation (HR0.72, 95%CI 0.19-2.72; p=0.628), or death (HR0.69, 95%CI 0.22-2.16; p=0.519). PBC patients with MASLD have comparable event-free (median 10.7 [3.1-30.8] vs. 10.7 [0.1-23.3] years; p=0.684) and overall survival (median 11.3 [3.2-39.7 vs. 10.7 [0.1-23.3] years; p=0.456).

Conclusions

Every third patient with PBC had MASLD, which tended to be more prevalent among females. We did not observe any significant differences in the development of adverse liver outcomes between patients with PBC and concurrent MASLD in comparison to those without. Studies with larger sample sizes are necessary to further explore the potential impact of MASLD on liver outcomes.

Funding Agencies

None
A305 ANONYMOUS LIVING LIVER DONATION IMPROVES ACCESS FOR MEDICALLY UNDERSERVED CHILDREN IN NEED OF LIVER TRANSPLANTATION
Authors: Yodoshi T , John T , Stunguris J , De Angelis M , Van Roestel K , Hensley J , Avitzur Y , Bandsma R , Jones N , Kamath B M , Ling S , Miserachs M , Ghanekar A , Cattral M , Sayed B , Ng V L
Published: February 2024

Background

Since our first pediatric anonymous non-directed live donor liver transplant (A-LDLT) performed in April 2005, 62 children have undergone live donor liver transplant (LDLT) with an anonymous non-directed graft. Anon-LDLT organs being allocated as per our deceased donor liver transplant (DDLT) wait list.

Aims

To evaluate clinical outcomes, recipient characteristics and social determinants of health of pediatric recipients of A-LDLT in comparison to those who received a directed LDLT (Dir-LDLT) and DDLT.

Methods

Retrospective analysis of all recipients of LDLT performed between January 2005 and March 2023. Demographic and clinical data included age, sex, race, ethnicity, single-parent households, primary diagnosis, recipient blood type, time on waiting list, post-LT intensive care unit (ICU) length of stay (LOS), time to extubation, and post-transplant comorbidities were assessed as covariates. A comparative analysis was conducted between children receiving A-LDLT, Dir-LDLT versus DDLT.

Results

A total of 422 (50% male, 57% white, 23% Asian, 7% Black, 5% indigenous) childrenunderwent LT during the study period. Biliary atresia (40%) and metabolic diseases (19%) were the commonest primary indications. A-LDLT was done in 62 children (15%) with no directed donor options. Dir-LDLT was in 174 children (41%). Of 186 DDLTs (44%), 25% were split grafts, 26% reduced, and 49% whole liver grafts. In A-LDLT recipients, the primary diseases were more frequently characterized by metabolic disorders (31%), while the incidence of acute liver failure was notably lower (0%). Recipients of Anon-LDLT were more often Indigenous recipients in comparison to Dir-LDLT or DDLT recipients (p=0.044). Anon-LDLT recipients were more frequently living in single parent households (18% vs 3% vs 10%, pampersand:003C0.001) and to require interpreter assistance (11% vs 3% vs 0.5%, pampersand:003C0.001) (Table), compared to children who received Dir-LDLT or DDLT. Median time on the wait list was longer for Anon-LDLT (92 days) compared to Dir-LDLT (62 days) and DDLT (72 days) recipients (p=0.004). Post-LT ICU LOS, time to extubation, other post-LT complications or patient prognosis were better in the A-LDLT and Dir-LDLT recipients than DDLT recipients.

Conclusions

This retrospective analysis of 422 children undergoing LT at a single institution confirms excellent patient and graft survival for A-LDLT recipients. Patients from Indigenous communities, single parent and households where English is a second language, are more frequently the beneficiaries of Anon-LDLT grafts. Anon-LDLT, as utilized in this single center analysis, benefits medically underserved pediatric patients who otherwise have limited access to the advantages of LT.

Funding Agencies

None
A307 NEUROGASTROENTEROLOGY & MOTILITY CAID (CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA) SYNDROME: A SEVERE LATE-ONSET PEDIATRIC INTESTINAL PSEUDO-OBSTRUCTION
Authors: adouane l , Poinsot P , Castilloux J , Faure C
Published: February 2024

Background

Pediatric intestinal pseudo-obstruction (PIPO) is a rare, heterogeneous and severe gut motility disorder. It is associated with a high morbidity and mortality rate. The etiology of PIPO can be either primary (sporadic or familial), secondary or idiopathic. In primary forms, 50 to 75% of patients will present symptoms in the first month of life and 80% by the end of the first year of life. In 2014, Chetaille et al. described the CAID syndrome related to a recessive SGOL1 mutation as a new form of PIPO associated with cardiac dysrhythmia.

Aims

Our aim is to describe the clinical presentation and the specific digestive and nutritional features of pediatric patients with SGOL1 mutation.

Methods

Monocentric, retrospective and descriptive study. We enrolled children and adolescents aged less than 18 years. All data were collected from patients’ files.

Results

8 patients were included (5 girls), two of them were first-degree related. They all had a typical clinical presentation of PIPO (excessive abdominal distension, abdominal pain and vomiting) but with a later onset than usually seen in primary PIPO (median (range) age: 6.3 years [2-15.6]). The median age (range) at diagnosis was 7.8 years [4-15.7]. In most patients contrast studies showed massively distended small bowel and colon. Antroduodenal manometry was performed in 6 patients and was abnormal with a neuropathic pattern. Others were diagnosed using the ESPGHAN criteria (2018 Jun;66(6):991-1019). All patients needed parenteral nutrition at a median (range) age of 11.8 years [6.5-15.9] due to failure to thrive, intestinal failure and electrolytic disorders. Seven patients needed an ileostomy. One out of 8 patients was off PN at 18 years. Three patients had sinus dysfunction: one at the time of PIPO diagnosis and two sometimes after. All of them required a pacemaker. One patient died in her twenties and it wasn’t related to PIPO or its possible complications.

Conclusions

Recessive SGOL1 mutation, a new cohesinopathy affecting the gut and heart rhythm, represents a late-onset but severe form of PIPO. It is usually associated with sinus dysfunction and cardiac dysrhythmia. However, digestive symptoms appear first. Long term outcome is still to describe.

Funding Agencies

None