bluuebunny/crossref_metadata_2025 huggingface dataset:
A187 PROPHYLACTIC PHAGE TREATMENT ENHANCES SUB-THERAPEUTIC EFFICACY OF BUDESONIDE AGAINST E. COLI DRIVEN COLITIS IN MICE COLONIZED WITH A DEFINED MICROBIOTA
Authors: Jackson K , Galipeau H , Hann A , Bording Jorgensen M , Coombes B , Hosseinidoust Z , Verdu E
Published: February 2024

Background

Patients with IBD are increasingly experiencing treatment failures on frontline therapies. While corticosteroids are an effective frontline intervention, 16% of patients fail to respond, and 20%–30% show only partial responses. Bacteriophages have recently garnered attention as a potential adjunctive therapy for IBD to target bacterial strains associated with IBD, including adherent-invasive Escherichia coli (AIEC).

Aims

Our aim was to determine whether prophylactic bacteriophage therapy could enhance the therapeutic efficacy of a sub-therapeutic dose of budesonide in a gnotobiotic mouse model of E. coli-driven colitis.

Methods

Adult germ-free C57BL/6 mice were co-colonized with altered Schaedler-like flora (ASF) plus E. coli NRG857c, a Crohn’s disease-associated bacterial isolate. Three weeks later, mice were treated with phage HER259 (1x109 PFU/dose; 0.1% bicarbonate) 3 times/ week or vehicle (PBS with 0.1% bicarbonate) 3 times/ week (n=5/group). Mice were then exposed to low-dose dextran sulfate sodium (2%; DSS) in drinking water for 5 days, followed by 2 days of water. All mice were administered a subtherapeutic dosage of 2ug/day of Budesonide halfway through DSS exposure to endpoint. Mice were monitored daily for weight loss, stool consistency, and fecal occult blood. At sacrifice, colon tissue was collected for histological analysis.

Results

Compared with budesonide treatment alone, prophylactic phage treatment, followed by a sub-therapeutic dose of budesonide, led to reduced stool consistency scores (p ampersand:003C0.001) and reduced presence of occult blood (p ampersand:003C 0.001). No difference in fecal E. coli load was observed between groups. At endpoint, the combined phage-budesonide treatment was associated with lower histological scores as compared with mice treated with budesonide alone (p ampersand:003C 0.01).

Conclusions

While underlying mechanisms remain elusive, our results suggest a beneficial effect of prophylactic phage intervention to the subsequent administration of a frontline immunosuppressive compound used to treat IBD. Future work will investigate the mechanisms by which adjunctive phage therapy can enhance existing therapies used to treats colitis, to better inform clinical guidelines.

Funding Agencies

CIHR
A190 HELICOBACTER PYLORI INDUCES AN AUTO-REACTIVE PHENOTYPE IN PINK1 DEFICIENT MICE THAT CORRELATES WITH MOTOR DYSFUNCTION
Authors: Kazanova A , Bessaiah H , Sung J , Gavino C , Pei J , Recinto S , Miller W , Burns L , Zhu L , Stratton J , Gruenheid S
Published: February 2024

Background

Parkinson’s disease (PD) is a chronic neurodegenerative disorder. Several genetic predispositions, including the PTEN-induced kinase 1 (PINK1) mutation, have been implicated in early onset family cases. Besides the loss of dopaminergic neurons in the brain, PD patients have a unique immune phenotype that includes increased inflammation, blood serum, brain levels of proinflammatory cytokines, brain infiltration with cytotoxic CD8 T cells, and loss of regulatory T cells (Treg) and their anti-inflammatory phenotype.

The role of the gut microbiota and gastrointestinal infections are increasingly recognized as a cofactor in PD. One of pathogens associated with the risk of PD is Helicobacter pylori. The prevalence of this Gram-negative bacteria in PD patients is higher than in the general population and its eradication in PD patients improves motor function.

Loss of the PD-associated PINK1 alters induced Treg function in vitro. We previously have shown that in PINK1 knock-out (KO) mice, gut infection with Gram-negative bacteria, Citrobacter rodentium, induces mitochondrial antigen presentation (MitAP) to the CD8 T cells that later infiltrate the brain. In this model, PINK1 KO mice develop a Parkinson-like L-DOPA-responsive motor phenotype after four C. rodentium infections.

Aims

Here we aimed to scrutinize potential role of the H. pylori infection in the induction of motor dysfunction and disbalanced immune tolerance in PINK1 KO mice.

Methods

In addition to standard behavioural testing, at 2- and 6-months post-infection we performed a multiplex cytokine analysis of gastric homogenates and spectral flow cytometry of gastric lamina propria, mesenteric lymph nodes, blood, spleen, and brain infiltrating immunocytes. As well as in vitro immunocytes response and function assays to H.pylori exposure in PINK1 KO and wild-type (WT) littermate controls.

Results

We show that infection with H. pylori causes a long-lasting inflammation in the stomach; and local and systemic immune phenotype that remains 6 months post-infection. This phenotype, though present in some WT infected mice, is higher in PINK1 KOs and similarly to PD patients includes a decrease in Treg proportion, FoxP3 downregulation in regulatory T cells, Gata3+ CD4 T cell loss, as well as increase of circulating mitochondrial antigen-specific CD8 T cells. Moreover, the immune phenotype in the H. pylori infected PINK1 KO mice correlates with motor dysfunction and CD8 T cell brain infiltration with no such association seen in the WT mice.

Conclusions

These results provide insight to the gut-immunity-brain axis in the pathogenesis of Parkinson’s disease, and further investigate the role of Gram-negative bacteria in the establishment of immune tolerance-autoreactivity balance.

Funding Agencies

ASAP
A192 'GLYCOCAGED' DRUGS: PHARMACOKINETICS AND TRANSLATIONAL POTENTIAL FOR PEOPLE WITH IBD
Authors: Ma W , Luzentales-Simpson M , Menzies S C , Wang C , Kothandapani J , Haskey N , Gibson D , Brumer H , Sly L M
Published: February 2024

Background

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract. Despite the alarming global increase in IBD burden with 1 in 121 Canadians affected, no cure exists. Systemic administration of anti-inflammatory drugs like corticosteroids is a front-line therapy for inducing remission. However, these drugs are limited in their application by deleterious off-target side effects. To target the drug to sites of inflammation and reduce systemic uptake, we developed a microbiome-cleavable, glycoconjugate drug delivery system, termed GlycoCage. We have demonstrated that GlycoCaged dexamethasone (Dex, a potent steroid), is effective at reducing inflammation at 10-fold lower doses than its uncaged counterpart in the SHIP-deficient (SHIP-/-) mouse model of CD-like intestinal inflammation.

We hypothesize that GlycoCaged technology can expand the therapeutic window of IBD drugs by lowering effective doses and eliminating side effects.

Aims:

1) Quantify Dex in systemic circulation.

2) Assess status of inflammation outside of the gut in SHIP-/- mice treated with caged Dex.

3) Measure decaging activity in people with IBD.

Methods

To compare systemic distribution of Dex to caged Dex, we orally gavaged SHIP+/+ and SHIP-/- mice with 3 mg/kg of Dex or the molar equivalent of caged Dex and collected serum for LC-MS/MS analysis at multiple timepoints post oral gavage. In addition to CD-like ileitis, SHIP-/- mice spontaneously develop enlarged mesenteric lymph nodes (MLNs) and inflamed lungs. After daily treatment of Dex or caged Dex for 2 weeks, MLNs and lungs were collected and analyzed for size and histopathology. We also obtained stool samples from healthy control participants and people with IBD to investigate the prevalence of prodrug-cleaving activity by direct enzymatic activity assay using fluorogenic resorufin as a prodrug proxy. Data from people with IBD were stratified to fecal calprotectin.

Results

Unlike free dexamethasone, caged dexamethasone did not enter systemic circulation or impact inflammation outside of the gut in SHIP-/- mice. All people have decaging activity that is not affected by IBD or the individual’s disease activity.

Conclusions

Our results highlight a novel glycoconjugated prodrug strategy to improve and broaden treatment options for people with IBD. In the future, we will evaluate GlycoCaged Dex in a mouse model of colitis and test the efficacy of other GlycoCaged drugs.

Funding Agencies

CCCGlycoNet
A199 ALKAL2/ALK AXIS PROMOTE PERSISTENT VISCERAL PAIN
Authors: Defaye M , Abdullah N , Svendsen K , Soussi L , Dickemann A , Altier C
Published: February 2024

Background

Long-lasting changes in neural pain circuits precipitate the transition from acute to chronic pain in patients living with inflammatory bowel diseases (IBDs). While significant improvement in IBD therapy has been made to reduce inflammation, a large subset of patients continues to suffer throughout quiescent phases of the disease. Peripheral and central mechanisms contribute to the transition from acute to chronic pain during clinical remission. In the search of new treatments, we previously found that targeting the anaplastic lymphoma kinase (ALK) receptor could have therapeutic value for persistent pain conditions.

Aims

Here we investigated whether ALKAL2 (ALK ligand) /ALK signaling axis regulates chronic visceral pain.

Methods

We used the post-inflammatory dextran sodium sulfate (DSS) mouse model of colitis as a well-established rodent model of chronic visceral pain, in which animals display increased VHS 5 weeks after DSS administration in the absence of inflammation as described in IBD patients. To assess the role of ALKAL2/ALK signalling in chronic visceral pain, we pharmacologically blocked ALK receptor using clinically available compound Lorlatinib in the postcolitis model. Moreover we genetically depleted ALKAL2 in gut-innervating nociceptors that express the heat sensitive transient receptor potential vanilloid type 1 (TRPV1) channel, using shRNA vectorized in cell type specific Adeno-associated Viruses.

Results

We showed that ALKAL2 expression was significatively enhanced in lumbosacral (LS) dorsal root ganglia (DRG) sensory neurons in the post-colitis model. In naïve mice, ALKAL2 administration induced visceral hypersensitivity in an ALK dependant manner. In addition, depletion of ALKAL2 in TRPV1 nociceptors or blocking ALK with the clinically available compound Lorlatinib, reversed visceral hypersensitivity in the post-colitis model. Accordingly, phosphorylation of ALK receptor occurring at the LS of the spinal dorsal horn was reduced.

Conclusions

Overall, these findings provide novel insights into the mechanisms underlying the transition from acute to chronic visceral pain in IBD. Our work could generate a portfolio of clinically available anti-cancer drugs, including Lorlatinib, as novel pain therapeutics. Repurposed ALK inhibitor could facilitate pain management in in individuals with IBD.

Funding Agencies

CIHR
A200 EXPOSURE TO CANNABIS SMOKE IN UTERO AFFECTS THE DEVELOPMENT OF THE ENDOCANNABINOID SYSTEM IN THE GASTROINTESTINAL TRACT
Authors: Ratcliffe E , Sunil M , Podinic T , Kasinska J , Hirota J , Raha S
Published: February 2024

Background

Recreational use of cannabis has been legalized in Canada since 2018. Increasing numbers of women are using cannabis while pregnant, with reported rates ampersand:003E10%. There is a disconnect with societal perceptions, with up to one third of women believing that cannabis is safe for use in pregnancy, but with preclinical and clinical studies demonstrating negative neurodevelopmental outcomes. A key component of gut-brain axis regulation is found in the endocannabinoid system (ECS), of which receptors, ligands and enzymes are extensively distributed throughout the gastrointestinal (GI) tract and are actively involved in GI motility and sensation.

Aims

We tested the hypothesis that exposure to cannabis smoke in utero could influence the expression of ECS components in the developing GI tract.

Methods

We developed a “real world” cannabis smoke inhalation model in which CD-1 pregnant mouse dams were exposed daily to a delta-9-tetrahydrocannabinol (THC)-dominant strain of cannabis in a smoking chamber unit, from embryonic days 6 (E6) to E18. Control mice were placed in a restraining cage and exposed to room air for the equivalent time-period. Dams were sacrificed at E18, fetuses removed and the fetal GI tract (from stomach to distal colon) collected for RNA extraction. Key components of the ECS were investigated by developing a NanoString Custom CodeSet, including receptors (cannabinoid receptors 1 and 2; CB1 and CB2, transient receptor potential vanilloid type 1; TRVP1, GPR55) and enzymes (diacylglycerol lipase; DAGL, fatty acid amide hydrolase; FAAH, monoacylglycerol lipase; MAGL, N-acylphosphatidyletanolamine phospholipase D; NAPE-PLD). Samples (n=per litter; 7 cannabis-exposed and 8 control) were processed in the Farncombe Metagenomics Facility and NanoString data analyzed using nSolver Analysis Software.

Results

We found a significant increase in the expression of ECS receptors in the cannabis-exposed compared to control GI tract at E18, including CB2 (pampersand:003C0.05), TRPV1 (pampersand:003C0.05) and GPR55 (pampersand:003C0.0005). Interestingly, no significant change in mRNA expression was detected for CB1. We also found a significant increase in mRNA encoding the full panel of ECS enzymes, including DAGL (pampersand:003C0.005), FAAH (pampersand:003C0.05), MAGL (pampersand:003C0.05) and NAPE-PLD (pampersand:003C0.005) in cannabis-exposed compared to control GI tract.

Conclusions

In conclusion, we have found a significant increase in mRNA expression in a panel of key ECS receptors and enzymes in the GI tract at a point of maximal exposure to cannabis in utero. Future research will be needed to further characterize potential impacts on postnatal GI development and function.

Funding Agencies

CIHRThe Azrieli Foundation
A201 AORTO-ESOPHAGEAL FISTULA AS A COMPLICATION OF ESOPHAGEAL VARICEAL BANDING
Authors: Al Salmi U , Stallwood C , Khan K
Published: February 2024

Aims

This is the first reported case of bleeding from an aorto-esophageal fistula as a consequence of ischemic esophageal ulceration post esophageal variceal banding.

Methods

A 46-year-old male presented with epigastric pain for one-week, which was not associated with fever, jaundice, or symptoms of GI bleed. He was hemodynamically stable with an unremarkable exam and basic labs. He underwent a CT scan which showed chronic portal vein thrombosis extending from the main portal vein into the superior mesenteric vein and evidence of portal hypertension, along with massive esophageal varices. Anticoagulation was not started due to risk of GI bleed.

Upper endoscopy confirmed the presence of three columns of large esophageal varices in the distal and mid esophagus, the largest was 3 cm in size. There was no stigmata of recent bleeding and no gastric varices. Seven bands were applied. CT abdomen was repeated on the seventh day of admission, showing extension of portal vein thrombosis. As such, the thrombosis team started a low dose of anticoagulation.

(dalteparin 7500 IU). He tolerated it well and showed no signs of bleeding prior to discharge.

The day after discharge, the patient presented again with an episode of melena. Examination was remarkable for tachycardia, hypotension and melena. Hemoglobin was stable. Patient was admitted with impression of upper GI bleed most likely secondary to post banding ulcer. He was started on medical therapy. Anticoagulation was held. Next day, the patient had an episode of hematemesis with large amount of blood and clots. Emergent upper endoscopy showed active bleeding in the distal esophagus. Further examination showed a full-thickness, 7 mm defect in the lower esophagus with fresh red blood emptying from it into the esophagus (Figure 1). Thoracic surgery was consulted and suspected a perforated esophageal ulceration at the site of previous banding, with an aorto-esophageal fistula. Patient deteriorated immediately and passed away. The cause of death was cardiac arrest secondary to acute blood loss anemia.

Results

AEF is a recognized cause of upper GI bleeding with a high mortality rate. While rare, it can occur secondary to ischemic esophageal ulcer post EV banding.

Conclusions

This is the first reported case of an aorto-esophageal fistula as a consequence esophageal variceal band ligation. While extremely rare, this complication should be considered as a potentially fatal complication of variceal banding, especially in the setting of a diseased or previously repaired aorta.
A202 A CASE OF MYCOBACTERIUM WOLINSKYI PULMONARY INFECTION SECONDARY TO LONG-STANDING ACHALASIA IN AN IMMUNOCOMPETENT PATIENT
Authors: Bowron J C , Sadowski D C
Published: February 2024

Background

Achalasia is an esophageal motility disorder resulting in chronic esophageal obstruction and stasis. Rapidly growing mycobacterium (RGM) pulmonary infections have been previously observed in individuals with underlying gastro-esophageal motility disorders. To date, pulmonary Mycobacterium wolinskyi infection (MWI) in the setting of achalasia has not previously been reported.

Aims

Our aim is to present a novel case of M. wolinskyi pneumonia in a patient with achalasia. We also searched the medical literature to identify previously reported associations between achalasia, chronic regurgitation symptoms and MWI. M. wolinskyi is an emerging clinical concern among RGMs. While primarily associated with post-operative, prosthetic joint and skin and soft tissue infections, M. wolinskyi pulmonary infections have not been documented to date in an immunocompetent patient.

Methods

We present a retrospective clinical case description of our case. We carried out a literature review from 1999 to Oct 2023, with the keywords "M. wolinskyi and infection.

Results

A 34-year-old male presented with a several-month history of productive cough, exertional dyspnea, fatigue, and unintentional weight loss of 17 kg over the past 6 months. Despite multiple courses of oral and intravenous antibiotics, there was no clinical improvement. His medical history included long-standing achalasia requiring previous pneumatic dilations. On admission, his chest X-ray revealed bilateral interstitial and alveolar infiltrates with consolidation. Routine microbiology and viral panels were negative. CT scan showed widespread bilateral consolidation and a dilated and fluid-filled esophagus. A timed barium swallow demonstrated dilated esophagus with irregular tertiary contractions and limited GE-J opening.

Sputum cultures were positive for MWI on day 8 of admission (BACTEC MGIT). This was confirmed with lung biopsy demonstrating MWI with necrotizing granulomatous inflammation. The patient was prescribed a 12-month course of doxycycline, trimethoprim-sulfamethoxazole, and ciprofloxacin. Inpatient pneumatic dilation to 35 mm was performed. At discharge, his swallowing was subjectively improved, and a follow-up swallowing study noted improvement with no evidence of regurgitation.

Conclusions

Chronic esophageal obstruction provides an ideal lipid-rich environment for RGM infections. Related mycobacterial species have been isolated in pulmonary infections have been linked to chronic esophageal obstruction. To date, no cases of M. wolinskyi pulmonary infection with achalasia have been reported. We present a unique case of M. wolinskyi pulmonary infection in an immunocompetent patient with chronic achalasia, adding to our understanding of this emerging clinical concern.

Funding Agencies

None
A211 INCREASED RATES OF PPI DEPRESCRIPTION OVER TIME IN PATIENTS WITH UPPER GI BLEEDS
Authors: Kecskemeti K , Borgaonkar M , Mcgrath J
Published: February 2024

Background

Proton Pump Inhibitors (PPIs) are commonly used for various indications, including prophylaxis of upper GI bleeding. We aimed to assess if there has been more PPI deprescription in recent years in patients treated for Upper GI Bleeds (UGIB).

Aims

Our study aimed to assess the frequency of PPI deprescription in patients treated with endoscopic therapy for UGIBs. We hypothesized that there was a higher rate of PPI deprescription in recent years.

Methods

This retrospective cohort study analyzed patients who received endoscopic treatment for UGIB between the years 2015-2022. All patients who were treated with endoscopic therapy for an UGIB from two academic GI practices were included. PPI deprescription was defined as a 50% dose reduction, frequency reduction or complete medication discontinuation in the past 3 months or longer in established PPI users. To assess trends, the cohort was divided into group 1 (2015-2018) and group 2 (2019-2022). Data were analysed using SPSS and chi-squared testing was used to compare categorical variables.

Results

Data were collected from 301 UGIB treated endoscopically. The mean age was 66.4 ± 13.5 years with 64% males and 36% females. Patients from group 1 had a deprescription rate of 2% (2/101 cases). Patients from group 2 (2019-2022) had a deprescription rate of 16% (32/200 cases) (pampersand:003C0.001).

Conclusions

There was a higher rate of PPI deprescription in patients treated for UGIB in the second time period. Reasons for the increased rate of PPI deprescription require further investigation.

Chi-Squared of PPI Deprescription for entire cohort

Fisher Exact test: P value ampersand:003C0.001

Funding Agencies

None
A214 AGE, SEX AND POSITION INFLUENCE UPPER ESOPHAGEAL SPHINCTER PRESSURES
Authors: Pokraka K , Woo M , Randall D
Published: February 2024

Background

Upper esophageal sphincter (UES) function may be evaluated using high resolution manometry (HRM) to measure manometric parameters specific to the UES. The UES parameters are not well established however there is evidence suggesting a relationship between the UES parameters and esophageal motility disorders as well as UES parameters and symptoms including dysphagia, globus sensation and reflux. The Esophageal Symptom Questionnaire (ESQ-30) is a validated tool in the assessment of esophageal symptoms and measures the frequency and severity of dysphagia, reflux and globus through three separate sub-scales (ESQ-D, ESQ-R, ESQ-G respectively).

Aims

We aimed to identify the relationship between UES manometric variables and patient demographic variables (age, sex) as well as patient symptoms including broad categories of globus sensation, dysphagia and reflux.

Methods

Retrospective analysis of consecutive reports from HRM studies performed between October 2021 – March 2023 who provided consent for inclusion in the motility databank and completed ESQ-30 questionnaires. All values expressed as median (IQR: 25-75-centile). Values were compared with the non-parametric Mann-Whitney U test. Relationships between manometric diagnosis, UES pressures and symptomatology were explored.

Results

681 patients underwent esophageal manometry and completed the ESQ-30 questionnaire. These patients were 442 (65%) female (mean age 54.6 +/- 14.8 years). Over the study period, 318 patients underwent esophageal HRM in the upright position and were diagnosed according to CCv3 and 361 patients underwent HRM in the supine position and were diagnosed by CCv4 manometric criteria.

UES mean basal pressure was significantly higher in females than males (64.6 [42.3-89.1] vs 68.4 [48.4-96.1], p = .015) as well as in the supine position (77.5 [55.9-101.0] vs. 56.0 [38.7-80.3]. UES mean basal pressure was negatively correlated with age (R2 -.28 p ampersand:003C .001).

In terms of esophageal symptomatology, dysphagia scores (ESQ-D) were negatively correlated with UES mean basal pressure (R2 -.15, p ampersand:003C .001).

Conclusions

Age, sex and position may influence UES manometric pressures. The finding of higher UES pressures in the supine position may reflect a mechanism for decreasing proximal reflux. The decreased UES basal pressure with age is possibly related to changes in the integrity of the neuromuscular system. Having a better understanding of the poorly understood normal UES dynamics and how this changes in motility disorders may allow us to more specifically target areas for treatment.

Funding Agencies

None
A218 TRADING ONE PROBLEM FOR ANOTHER? THE EMERGENCE OF LYMPHOCYTIC ESOPHAGITIS IN A PEDIATRIC PATIENT WITH EOSINOPHILIC ESOPHAGITIS AFTER TREATMENT WITH DUPILUMAB
Authors: Strauss J , Brundler M , McKenzie L S
Published: February 2024

Background

Eosinophilic esophagitis (EoE) is a Th2 driven chronic, inflammatory disorder defined by esophageal dysfunction and a peak eosinophil count (PEC) ≧ 15 eosinophils/high-power field on biopsy. Dupilumab, a human monoclonal antibody that inhibits IL-4 and IL-13 signaling was recently approved for use in Canada in children with EoE. There is limited data on the histologic abnormalities found with reintroduction of dietary triggers on dupilumab.

Aims

To describe emergence of lymphocytic esophagitis without eosinophilia observed during food reintroduction in a pediatric patient with EoE on dupilumab.

Methods

Case report and literature review.

Results

We present a 14-year-old boy with extensive food allergies, eczema, asthma and treatment refractory EoE. After failing to improve with proton-pump inhibitor (PPI), food elimination diet and topical steroids, he was started on an elemental formula with concomitant PPI. This resulted in symptomatic and histologic remission, however food restriction led to poor quality of life.

The patient was started on dupilumab 200 mg every 2 weeks and had a dramatic improvement in his disease course. Over 2 years on treatment, several allergic foods were reintroduced with normal histologic biopsies. However, two dietary challenges led to the emergence of lymphocytic esophagitis with basal zone hyperplasia (BZH) and dilated intercellular spaces (DIS), but no eosinophilia. Subsequent removal of the dietary antigen and endoscopic reassessment led to normal biopsies, without lymphocytic or eosinophilic infiltration.

Lymphocytic esophagitis is rare in children and the etiology is unknown; it is characterized by increased intraepithelial lymphocytes without eosinophils or neutrophils, and associated spongiosis. The emergence of lymphocytic esophagitis was unexpected and subsequent normalization of histology with removal of an antigen suggests that the lymphocytic pattern observed was driven by the allergic food. This may indicate that IL-4/IL-13 antagonism by dupilumab affects other immune signaling pathways, resulting in a lymphocytic-predominant inflammatory response upon exposure to allergic food antigens.

Conclusions

Dupilumab is a promising new medication in the management of pediatric EoE, particularly in the extremely atopic patient. In our case, the use of dupilumab led to improved antigen tolerance and quality of life. However, the emergence of lymphocytic esophagitis was unexpected, and the natural history and prognosis of this condition is not well defined. This is the first case to describe the emergence of lymphocytic esophagitis in a patient treated for eosinophilic esophagitis with dupilumab, and its subsequent resolution with dietary exclusion.

Funding Agencies

None
A219 EARLY CANADIAN EXPERIENCE WITH BALLOON CRYOTHERAPY FOR BARRETT’S ESOPHAGUS
Authors: Sullivan R , Fazal A , Gupta M , Belletrutti P , Wong C
Published: February 2024

Background

Balloon Cryotherapy (bCr) is a novel endoscopic treatment modality for Barrett’s esophagus (BE) associated dysplasia. Cryotherapy offers an additional approach, particularly in cases refractory to or with an anatomical impediment to radiofrequency ablation (RFA), currently first line in endoscopic eradiation therapy (EET). The use of bCr is new in Canada and it was introduced in Alberta in February 2023.

Aims

To present the early experience of bCr use for BE from a provincial Canadian cohort.

Methods

An Alberta health technology assessment approved bCr, which was then incorporated into the provincial BE treatment algorithm. Indications for bCr include: 1) RFA-refractory, 2) anatomical impediment to RFA, 3) need for concomitant biopsy/EMR, and 4) pain with RFA. All patients who underwent bCr for BE in Alberta from February to September 2023 at two tertiary care centers were included. Data on demographics, BE lesion characteristics, prior BE treatments, and bCr use are presented.

Results

During the 8-month period, 22 patients underwent a total of 32 bCr treatments. The median age was 68, with 77% of patients being male. At baseline, 81% had long-segment BE (≥3 cm), with a median maximal BE length of 7cm. The majority had baseline histology of high-grade dysplasia (HGD) (n=11, 50%), followed by low-grade dysplasia (LGD) (n=5, 22%), T1a (n=4, 18%), T1b (n=1, 4.5%), and intestinal metaplasia (IM) (n=1, 4.5%). All patients had previously received EET, with 77% undergoing a combination of EMR, RFA, APC, and/or ESD. Most had received RFA (n=18, 81%, median sessions=5) and EMR (n=13, 59%, median sessions=2). Some had prior APC (n=10, 45%, median sessions=1) and one had ESD. Prior to bCr, most patients had converted to short-segment (ampersand:003C3cm) BE (n=16, 72%), and histology was predominately IM (31%), followed by visible BE though no biopsy (27%), HGD (22%), T1a (13%), and LGD (4.5%). The primary indication for bCr was RFA-refractory BE (n=17, 77%), followed by anatomical impediment to RFA (n=4, 18%), and concomitant EMR (n=1, 4%). No procedures were aborted due to technical difficulties and there were no major adverse events such as perforation, bleeding, or pain requiring hospitalization. Among those with follow-up after a bCr session (n=19, 59%), one reported pain, two reported self-limited dysphagia, and one had a stricture requiring dilation. Of the 7 patients with post-bCr endoscopy, all had no dysplasia on the first set of biopsies (no IM, n=4; IM, n=2; indefinite for dysplasia, n=1).

Conclusions

Our early experience with bCr demonstrates there is a need for additional EET for BE. Cryotherapy, in accordance with gastroenterology society guidelines, is a promising next step in the BE algorithm. In our provincial cohort, bCr has shown technical success, and preliminary data suggests that it is safe and effective in ablating resistant BE segments.

Funding Agencies

None
A222 CLINICAL EFFECTIVENESS AND SAFETY OF USTEKINUMAB IN YOUTH WITH REFRACTORY INFLAMMATORY BOWEL DISEASE IN SAUDI ARABIA: A RETROSPECTIVE COHORT STUDY
Authors: Alhadab A A , Almarhoon A , AlAlwan A , Hammo A
Published: February 2024

Background

Inflammatory bowel disease (IBD) incidence and prevalence have been increasing worldwide with higher disease severity observed in pediatrics. Limited data exists on the effectiveness of ustekinumab (UST) in children.

Aims

To describe the effectiveness and safety of UST in pediatric patients with IBD.

Methods

A retrospective, single-center cohort study was conducted between January 2017 and February 2022. The study included patients ≤16 years of age who were treated with off-label UST and followed up for a minimum of one year. Clinical remission was defined as a decrease in the score on the Pediatric Crohn's Disease (CD) and Pediatric Ulcerative Colitis (UC) Activity Indices to ≤10 at week 52.

Results

A total of 13 patients who had failed anti-TNFα therapy were included, 8 (61.5%) with CD and 5 (38.5%) with UC. The median age of the patients was 13y (IQR: 11.5 to 14). UST treatment was initiated at a median of 3y (IQR: 2.3 to 7) after diagnosis. Ten patients (76.9%) achieved clinical remission. There were no statistically significant differences in baseline characteristics between patients who achieved and did not achieve clinical remission. Biochemical remission was achieved in 6 patients (46.2%). C-reactive protein levels decreased significantly in the remission group and insignificantly in the non-remission group. No significant changes were observed in erythrocyte sedimentation rate, albumin, or hemoglobin. BMI improved (Fig 1) and the need for corticosteroids significantly decreased after UST therapy in the remission group (P = 0.014). Endoscopy conducted post-treatment in 7 patients confirmed remission in 6 patients, with one patient showing clinical remission but not endoscopic remission. Adverse events included two instances of infection and once case of headache.

Conclusions

UST was effective as a secondary biologic therapy for the induction and maintenance of remission in patients with anti-TNFα refractory IBD. At one year, 84% of patients remained on UST with no severe adverse reactions reported. Future prospective large-scale studies are necessary to assess the therapeutic positioning and optimal dosing regimens of UST in pediatric IBD.

Figure 1. Change in BMI Z-score throughout the study (P value of interaction = 0.049).

Funding Agencies

None
A223 DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE AND PRIMARY SCLEROSING CHOLANGITIS AT THE OTTAWA HOSPITAL
Authors: Alrifae Y , Sambhi G , Benchimol E I , Ricciuto A , Murthy S
Published: February 2024

Background

Primary sclerosing cholangitis (PSC) is present in up to 8% of individuals with inflammatory bowel disease (IBD). Characteristics of this population are unique and data are limited.

Aims

To describe the demographic and clinical characteristics of all individuals with PSC-IBD managed at The Ottawa Hospital (TOH).

Methods

A chart review was performed for 132 patients with PSC-IBD followed at TOH between January 1998 and July 2023.

Results

Of 132 individuals with PSC-IBD identified at TOH, 26.5% had Crohn’s disease (CD), 68.2% had ulcerative colitis (UC) and 5.3% had IBD-unclassified. Median age at diagnosis were 25.3 (IQR 20.94) for IBD and 33.84 (IQR 23.98) for PSC, and 66.7% of all patients were male. More than 17% had a co-morbid autoimmune disease other than IBD or PSC. Of those with CD, roughly 15% had fibrostenotic or penetrating complications and 17% had perianal disease at the time of IBD diagnosis. Only 28% ever had a liver biopsy, whereas the majority were diagnosed with PSC by cholangiography. PSC distribution was isolated intrahepatic in 47%, isolated extra-hepatic in 5.1% and mixed intra/extra-hepatic in 38.5%. Clinically significant portal hypertension was present in 11.5% at PSC diagnosis, while 27.3% and 16.7% developed cirrhosis and liver decompensation, respectively by last follow-up. 17.4% underwent liver transplant, of which 30.4% developed PSC recurrence post-transplant.

Conclusions

Our study showed that the majority of PSC-IBD patients are young males with UC. Co-morbid autoimmune diseases are common while isolated extra-hepatic PSC is uncommon. Cirrhosis, liver decompensation and liver transplant are frequent occurrences in this population. PSC recurrence post-transplant is observed in more than 30% of patients.

Funding Agencies

None
A224 CHARACTERIZATION OF VERY-EARLY-ONSET INFLAMMATORY BOWEL DISEASE IN CHILDREN ampersand:003C6 YEARS OF AGE: A SINGLE CENTER EXPERIENCE
Authors: Alsaedi K S , Sant'Anna A , Ahmed N
Published: February 2024

Background

Very-early-onset inflammatory bowel disease (VEO-IBD), diagnosed before the age of six years old, presents a distinct subtype of pediatric inflammatory bowel disease (IBD). This chronic inflammatory condition is believed to result from an abnormal immune response triggered by environmental factors including the gut microbiota, in genetically susceptible individuals.

Aims

This study aims to analyze the clinical characteristics and management of VEO-IBD patients in a tertiary medical center, evaluating disease presentation, localization and treatment strategies.

Methods

A retrospective descriptive study was conducted of 28 VEO-IBD patients diagnosed between January 2001 and January 2019 at our institution. Data was abstracted including patient demographics, clinical features, laboratory and histological parameters, treatment, and disease classification based on the revised Porto Criteria.

Results

Among the 28 patients, Crohn’s disease (CD) was the predominant diagnosis (89%) with predominantly colonic involvement. Thiry-two percent of patients had isolated colitis whereas the upper gastrointestinal (UGI) tract was involved in 57% of the cohort, approximately one third had involvement of the small bowel. The most common presenting symptoms were rectal bleeding and diarrhea, both occurred in 65% of the patients. Patients were followed for a mean duration of 115 months. Despite prior assumptions of its severity, VEO-IBD patients in this cohort responded well to conventional treatments in which 64% were induced with steroid therapy, 25% received biologics and 35% received immunomodulators. Surgical interventions were relatively infrequent. Only 2 patients out the 28 VEO-IBD patients underwent surgery for refractory colitis, one of them in the 1st 2 years of life. There were limited genetic testing results which made it difficult to know our incidence of monogenic IBD. However, only 5 of our patients had full genetic workup done in other centers for research purposes with 1 patient being diagnosed with monogenic IBD consistent IPEX syndrome.

Conclusions

This study highlights the unique clinical profile of VEO-IBD, with CD being the prevalent diagnosis in this age group in our population. Our cohort did not have a more severe phenotype, emphasizing that there is significant variation within this group Understanding the predictors of response is needed in individual patients with VEO-IBD is vital for tailored management and improved outcomes in this young population.

Funding Agencies

None
A225 ASSESSMENT OF BEDSIDE INTESTINAL ULTRASOUND IN MONITORING CROHN’S DISEASE ACTIVITY
Authors: Ashrafinia N , Guzowski T , Fowler S
Published: February 2024

Background

Bedside intestinal ultrasound (IUS) is an evolving modality in monitoring disease activity and assessing complications in inflammatory bowel disease (IBD). The easy-tolerability and immediate accessibility to results for expedited clinical decision-making contribute to the growing global attraction of IUS integration into IBD care. Fecal calprotectin (FC) is a known, non-invasive tool to assess disease activity in IBD. However, it comes with limitations.

Aims

To assess the efficacy of IUS in monitoring Crohn’s Disease (CD) compared to FC level.

Methods

We conducted a retrospective observational study in patients with confirmed CD at a certified IUS gastroenterologist’s outpatient clinic in Saskatoon. Patients’ charts undergoing IUS between February 2022 and April 2023 were reviewed. Patients with CD and available FC results within a month of IUS performance were identified. Age, gender, disease character, clinical symptoms (Harvey-Bradshaw Index (HBI)), FC levels, and IUS bowel wall thickening (BWT) were collected. The cut-off for FC levels and BWT for disease activity were ampersand:003E250 μg/g and ampersand:003E3 mm, respectively. The correlation between IUS BWT and FC levels was analyzed based on the Pearson correlation.

Results

Among a total of 178 chart reviews, 71 patients were identified. The median age was 49 years, 52.1% were males and 47.8% were females. 35 (49.3%) ileal CD, 35 (49.3%) ileocolonic and 1 (1.4%) colonic CD were identified. The HBI score verified 67.6% mild disease, 19.7% moderate, 11.2% in remission, and 1.4% severe disease. The Pearson correlation coefficient (r) between FC levels and BWT findings on IUS was r = 0.29 (P ampersand:003C0.0001), indicating a weak positive correlation.

Conclusions

A positive but weak correlation exists between bowel wall thickening in IUS and FC level in monitoring CD. Recognizing FC limitations, future multi-center, larger cohort studies need to be done to investigate this correlation further.

Funding Agencies

None
A246 EXAMINING BARRIERS TO PHYSICAL ACTIVITY IN PEDIATRIC INFLAMMATORY BOWEL DISEASE PATIENTS
Authors: Morin S , Byra M , Issenman R , Timmons B , Obeid J
Published: February 2024

Background

Inflammatory bowel disease (IBD) poses significant challenges to pediatric patients, affecting their physical and psychological well-being. Physical activity can be an essential component of managing IBD, yet its adoption among this population remains suboptimal. Understanding the factors that influence physical activity levels in youth with IBD, particularly barriers to engagement, is crucial.

Aims

(1) Describe physical activity levels in pediatric IBD, and (2) assess the relationship between physical activity and barriers to physical activity in youth with IBD.

Methods

We recruited patients between the ages of 7-17 years with a single confirmed diagnosis of IBD. Participants completed a barriers to physical activity questionnaire adapted from Zabinski et al. (2003). Each item was scored on a scale from 1 to 5, to yield a total barriers score and subdomain scores for body-related, convenience, resource, social, fitness, and disease-related barriers; each score presented as an average out of 5. Lower scores indicated lower barrier burden. Participants also wore accelerometers during waking hours for 7 consecutive days to quantify daily average total physical activity (TPA), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA). Descriptive statistics and multiple regression analyses were used to determine the relationship between physical activity and barriers to physical activity.

Results

Forty-nine youth completed the study (31% females; age: 14.77±1.98 years). Physical activity levels were low (TPA: 146.6±49.5 min/day; LPA: 104.2±33.4 min/day; MVPA: 42.4±21.2 min/day), with only 21% of participants meeting the 24-hour movement guidelines of 60 min/day of MVPA. Total and resource barriers both significantly predicted TPA (total: β=-47.76, p=0.004; resource: β=-48.30, pampersand:003C0.001), LPA (total: β=-29.01, p=0.01; resource: β=-29.68, pampersand:003C0.001), and MVPA (total: β=-18.75, p=0.01; resource: β=-18.62, pampersand:003C0.001). Fitness barriers significantly predicted TPA (β=-41.48, p=0.016) and MVPA (β=-22.01, p=0.008). Body-related, convenience, social, and disease-related barriers did not significantly predict TPA, LPA, or MVPA.

Conclusions

Our findings confirmed that youth with IBD are not engaging in enough physical activity. Importantly, we found those with higher total barrier, resource- and fitness-related barriers presented with 18-48 fewer minutes of daily physical activity. These findings highlight the need for tailored interventions aimed at reducing specific barriers to support physical activity participation in youth with IBD.

Funding Agencies

None
A247 THE IMPACT OF BIOLOGICS ON MATERNAL AND NEONATAL OUTCOMES IN PREGNANT PATIENTS WITH INFLAMMATORY BOWEL DISEASE AND THEIR ASSOCIATION WITH THERAPEUTIC DRUG LEVELS
Authors: Nabavian H , Eisen S , O'Connor K , Srikanth V , Huang V
Published: February 2024

Background

Biologic therapies are at the backbone of managing moderate to severe IBD and maintaining clinical remission. The data on the effects of biologic therapy on maternal and neonatal outcomes continues to be limited. To our knowledge, there have been no previous studies specifically investigating whether biologic therapeutic drug levels in pregnant patients are related to maternal and neonatal outcomes.

Aims

The objective of this study is to determine whether biologic use in pregnancy is associated with adverse maternal and fetal outcomes, and if those outcomes correlate to specific therapeutic drug levels.

Methods

In this study, we retrospectively evaluate patients at a high-volume pregnancy and inflammatory bowel disease centre at Mount Sinai Hospital in Toronto between January 1st, 2017 to December 31st, 2022. Primary outcomes include maternal complications, such as induction of labour, cesarean section, peripartum infections, placental abruption, preterm labour and pre-eclampsia. Secondary outcomes include neonatal complications, such as preterm birth, low birth weight (ampersand:003C2500g), congenital anomalies and the presence of neonatal infection. These outcomes will be compared to therapeutic drug levels measured in preconception, during pregnancy and post-partum.

Results

A total of 312 patients were included in our study, of which 152 were on biologic treatment for IBD. Of the biologics population, the majority of patients are on Remicade, followed by Humira and Stelara (Table 1). Preliminary data analysis reveals that there was no significant difference in the rate of miscarriages (10% vs. 6%, P= 0.1), cesarean section (44% vs. 38%, P=0.3) and preterm deliveries (12% vs. 14%, P=0.7) between the biologics vs. non-biologics patient groups. Next round of analysis will include secondary outcomes and therapeutic drug levels.

Conclusions

Through this study, we hope to add to the literature on the possible safety of maintaining biologic therapy during pregnancy in those with inflammatory bowel disease. The data on proactive therapeutic drug monitoring in pregnant patients may bring to light the importance of its inclusion in clinical decision-making algorithms.

Breakdown of therapies in the biologic patient group

Funding Agencies

None
A248 RISK OF ARRHYTHMIA IN INFLAMMATORY BOWEL DISEASE
Authors: Narous M , Nugent Z , Rabinovich-Nikitin I , Kirshenbaum L , Bernstein C
Published: February 2024

Background

Inflammatory bowel disease (IBD) has been shown to be associated with stroke or early atherosclerosis. Atrial fibrillation (AF), being the most common arrhythmia seen clinically, can be a consequence of systemic inflammation. The association between IBD and arrhythmia has been studied in recent literature with inconclusive evidence.

Aims

1. To determine the risk of arrhythmia (defined as AF, other supraventricular or ventricular tachycardia) in IBD.

2. To compare the risk of arrhythmia amongst IBD medications.

3. To assess mortality in IBD with arrythmia as compared to controls.

Methods

The risk of arrhythmia was determined in a retrospective population-based cohort study using the University of Manitoba IBD Epidemiology Database (11,432 IBD cases and 109,582 matched controls). Arrhythmia risk in IBD was adjusted for presence of comorbidities of the Charlson Comorbidity Index (CCI). The effect of IBD medications on the development of arrhythmia was assessed in a nested case-control study of individuals with IBD. Follow-up started on date of IBD diagnosis until arrhythmia diagnosis, emigration out of the province of Manitoba, death, or March 31, 2018. Cases were censored at date of first database identification of a diagnosis of heart failure or myocardial infarction. All-cause mortality was a secondary outcome compared across non-IBD controls and IBD cases with arrhythmia using proportional hazards regression analysis was done.

Results

Persons diagnosed with IBD were more likely than controls (HR 1.51; 95% CI 1.30-1.76) to develop arrhythmia. When controlling for CCI comorbidities, the significant association between IBD and arrhythmia remains. Medications including 5-ASA, thiopurines, and TNFa inhibitors were not associated with arrhythmia, with OR 0.99 (95% CI, 0.68-1.45), 1.06 (95% CI, 0.57-1.97), and 0.90 (95% CI, 0.31-2.61), respectively. All-cause mortality was slightly increased in persons with IBD in analyses unadjusted and adjusted for the presence of arrhythmia, with HR's of 1.13 (1.07-1.19) and 1.12 (1.06-1.18). Increased mortality was more pronounced in CD, but UC did not raise risk of mortality.

Conclusions

Persons with IBD have a higher risk of arrhythmia even prior to a diagnosis with heart disease. IBD medications did not raise risk of arrhythmia in our dataset. All-cause mortality, with the development arrhythmia as a time dependent variable, was significantly raised in CD as compared to non-IBD controls, but not in UC. Further data are necessary to establish the risk of arrhythmia in IBD, especially with stratification by setting of arrhythmia diagnosis and severity of IBD based on Montreal classification.

Funding Agencies

None