Introduction

No single pharmacological approach is currently available for the treatment of inflammatory bowel disease (IBD) in active and maintenance stages. As evidence is growing on the immuno-modulatory activities of the G-protein coupled receptor GPR120 and on its role in modulating the pathophysiology of IBD, its potential as a therapeutic target for this disease is worthy of exploration.

Aims & Methods

Herein, we have developed DFL23806, a new GPR120 selective small molecule agonist, and propose it as a potential therapeutic approach for IBD. We employed our in-house proprietary Exscalate platform for molecular docking simulations to define the site and mode of binding of the compound with the receptor and used in vitro studies and in vivo models (murine dextran sodium sulfate (DSS)-induced acute and chronic colitis and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis models) to characterize the mechanism of action of our molecule and evaluate its therapeutic effects.

Results

DFL23806 is a selective agonist of human and mouse GPR120 that can activate both the G-protein dependent and independent signaling (β-arrestin pathway) of the receptor. DFL23806 has been designed to have high metabolic stability and reach the ileum and colon at optimal concentrations that allow for the activation of GPR120 while, notably, delaying its internalization. This can lead to prolonged periods of signal transduction compared to other commercially available GPR120 agonists and amplification of signaling effects. In vivo, intrarectal treatment with DFL23806 exerted consistent immunomodulatory action in DSS-induced acute colitis in mice. Moreover, oral treatment with DFL23806 significantly inhibited both DSS- and TNBS-induced chronic colonic inflammation and fibrosis by improving the disease activity index, endoscopic score, and reducing body weight loss and colonic tissue damage. Interestingly, DFL23806 treatment also modulated the composition of microbiota, inhibiting the concentration of pathogenic bacteria, and rescued intestinal dysbiosis induced by TNBS.

Conclusion

These results suggest that the stimulation of GPR120 could be an effective strategy for managing colitis, and that DFL23806 has great potential as a therapeutic for the treatment of IBD.

Disclosure

The authors are employees of Dompé farmaceutici s.p.a., Italy. The company has interests in the development of GPR120 selective agonist for the treatment of IBD and metabolic diseases.

Introduction

Infection by Leishmania spp. in patients diagnosed with inflammatory bowel disease (IBD) is an uncommon infectious complication. The use of anti-TNF-α is well known risk factor for Leishmania infection (LI), particularly in some endemic areas, but only a few case series have been reported in the literature, mainly in the Mediterranean basin.

Aims & Methods

Aim: To evaluate the main demographic, IBD-disease features and risk factors as well as LI disease characteristic and required treatment among IBD patients who develop LI.
Methods: This is a retrospective, observational, multicenter study conducted in twenty-five Spanish hospitals, promoted by the Young Group of GETECCU, including patients diagnosed with IBD and subsequent diagnosis of LI.

Results

We collected a total of 73 patients, 48 of them were men (65.8%) with a mean age of 48 ± 15.06 years. 92% of patients resided in the Mediterranean basin, an endemic area of Leishmania. Only 1 patient was born outside of Spain. Nineteen percent of patients were smokers and 16.4% had some comorbidities.
Fifty patients had Crohn's disease (CD) (68.5%) with ileocolonic involvement (30.1%) and inflammatory behaviour (45.2%) and 42.9% had perianal disease. 94% of CD patients were on clinical remission at the time of LI diagnosis. In addition, 23 patients had ulcerative colitis (UC) (31.5%), being extensive colitis the most frequent extent (78.3%), and all of them were on clinical remission or had mild disease activity. 69 patients (94.5%) were under immunosuppressive and/or biologic treatment during the 6 months prior to the LI. 6.8% were on immunosuppressants monotherapy, 42.5% in combotherapy and 38.4% under biologic monotherapy. Regarding biological treatment, 97% of patients were under AntiTNF and only 2 patients were under treatment with Ustekinumab.
Regarding the characteristics of LI, 62 patients presented cutaneous involvement (85%), 9 visceral (12%) and the rest presented mucocutaneous involvement.
Symptoms associated to LI were fever (9.6%), abdominal pain (4.1%) and constitutional syndrome (8.2%), moreover 24.7% required hospital admission. Regarding the location of the skin lesions, the most frequent were the upper limbs (35.6%) followed by lower limbs (30.1%).
The treatment used for LI was systemic amphotericin in 60.3% of patients and pentavalent antimonials in 35.4%; the remaining patients were treated with other treatments, including miltefosine. LI solved at one month in 33 patients (45.2%) and at one year in 95.3% of patients, and only 11% of patients had recurrent LI.
Treatment was stopped temporarily in 38.4% of patients and definitively in 27.4%, starting Ustekinumab (36.8%), Vedolizumab (15.8%) and antiTNF (10.6%) and the rest of the patients remained without biological treatment after the LI.

Conclusion

The usage of antiTNF is associated to LI in IBD patients, but LI could also happen under inmunossupresants or ustekinumab therapy. Although cutaneous involvement is the most frequent manifestation, 12% of patients have visceral involvement or LI recurrences. This infectious complication should be considered in IBD patients in endemic areas.

Disclosure

No Conflict of Interest.

Introduction

Mirikizumab was approved for the treatment of Ulcerative colitis (UC) in May 2023. However, real-world data especially in biological-experienced patients, is scarce.

Aims & Methods

We aimed to determine treatment efficacy and persistence on Mirikizumab in mostly treatment-experienced UC patients.
All patients, who were treated for UC in the inflammatory bowel disease (IBD) outpatient clinic of the University Hospital Frankfurt from 07/23-03/23 were retrospectively analyzed. Data on clinical (Simple Clinical Colitis Activity Index (SCCAI)) and biochemical disease activity (fecal calprotectin (FC)) as well as patient history were collected. Patients were followed-up for at least 12 weeks.

Results

Twenty-one patients with UC were included. Eighteen patients had already received at least one biological agent prior to starting Mirikizumab. Thirteen patients were exposed to ≥ 2 biological agents and even 6 patients to ≥ 4 biological agents prior to starting Mirikizumab. Two patients received Mirikizumab as a first line treatment. Eight patients were treated with Ustekinumab prior to the therapy with Mirikizumab. Ten patients received oral steroids as concomitant treatment. The median SCCAI at the start of induction was 7 (1-18). We report a reduction in clinical disease activity to 2 (0-11) at week 12 based on the preliminary data of the SCCAI. Median SCCAI and FC levels are shown in table 1.
Biochemical disease activity was assessed with FC levels. The median FC level at the start of the induction was 642 (14-2100). At week 12 the median FC level was 253 (21-2100) and 330 (9-2100) at week 12. Intravenous induction therapy was extended in 11 patients, with 10 patients receiving 6 infusions. Four patients were re-induced after having previously received Mirikizumab subcutaneously. One patient discontinued treatment after an extended induction due to a primary non-response. One patient reported new nodulous skin lesions after the treatment with Mirikizumab.

Conclusion

We report preliminary real-world data on the treatment with Mirikizumab. In our interim analysis Mirikizumab proves to be an effective and safe treatment in biological-experienced UC patients.

Disclosure

AK reports consulting and lecturer fees and travel grants from Takeda, Janssen-Cilag, Celgene/BMS GmBH, AbbVie, Falk Foundation and Galapagos, RL reports consulting and lecturer fees and travel grants from AbbVie, Janssen-Cilag , KF reports consulting and lecturer fees from Vifor Pharma, Immundiagnostik AG, MSD/Merck, Takeda, BMS GmbH Pharmacosmos, AbbVie, Celgene/BMS, SZ reports consultancy and speaker’s bureau fees from AbbVie, Allergan, Biomarin, Gilead, Intercept, Janssen-Cilag, MSD/Merck, Novo Nordisk, SoBi and Theratechnologies and IB reports consulting and lecturer fees from Takeda, AbbVie, Amgen, Biogen, Janssen-Cilag, Celgene/BMS GmBH, Celltrion, Falk Foundation, Fresenius Kabi, Galapagos, Lilly, Pharmacosmos and Pfizer, KS reports consulting fees and clinical studies from Abbvie, BMS, Cymabay, Chemomab, Calliditas, Falk, Ipsen, Jannsen-Cilag, Gilead, GDK, MSD, Roche, VIR, MSD, AD none

Introduction

Endoscopic submucosal dissection (ESD) is the first-line treatment for superficial gastric lesions with a negligible or very low risk of lymph node metastasis. However, a permanent risk of developing metachronous lesions persists. We intend to analyze the risk factors associated with the development of metachronous lesions in a population of patients undergoing ESD.

Aims & Methods

Prospective cohort study conducted at a single centre, involving patients who underwent gastric ESD for lesions between 2017 and 2023, with a follow-up period of ≥ 6 months. Lesion characteristics were analyzed, including the rate of metachronous lesions, and logistic regression was performed to identify risk factors associated with the development of metachronous lesions.

Results

Included 78 ESDs performed on gastric epithelial lesions (59% female), with a mean age of 70.3±7.9 years. Regarding family history of gastric adenocarcinoma, 17.9% of patients had a first-degree relative. Among the analyzed lesions: 42.3% measured between 0-20mm, 57.7% ≥ 20mm; 12.8% were sessile, 71.8% flat and 15.4% depressed; 19.2% were located in the cardia, fundus or body, 21.8% in the incisura angularis and 59% in the antrum. Regarding histological findings: 42.3% low-grade dysplasia, 30.8% high-grade dysplasia, 23.1% intramucosal adenocarcinoma and 3.8% adenocarcinoma with submucosal invasion. Nine metachronous lesions (11.5%) were detected, with a median time of occurrence of 24 [13-32] months. In the analysis of risk factors, statistical significance was found for location outside the antrum (21.6% vs. 1.9%; p=0.002) and the presence of adenocarcinoma (23.8% vs. 7%; p=0.039), but not for size ≥20mm (13.7% vs. 5.1%; p=0.178) or ulceration of the lesion (9.1% vs. 10.1%; p=0.915). Logistic regression analysis revealed that only location outside the antrum had a significant risk for the development of metachronous lesions (OR 13.4; 95% CI: 1.4-127.1).

Conclusion

Given the permanent risk of developing metachronous lesions, the identification of associated risk factors is important as it may eventually allow for the adaptation of surveillance programs.

Introduction

Liver transplant is the only definitive treatment for chronic liver disease (CLD). Referral to a hepatologist for consideration for liver transplant should be made when a patient with CLD experiences a hepatic decompensation or has a MELD score ≥ 15. Failure to refer in a timely manner can result needing a liver transplant evaluation (LTE) in the inpatient setting while a patient is experiencing acute decompensation.

Aims & Methods

We aimed to compare the clinical presentation of patients undergoing LTE in the inpatient setting versus the outpatient setting to identify potential risk factors for requiring urgent evaluation. A list of all LTEs performed at our institution between 10/2017-8/2021 was obtained. Medical records were preliminarily reviewed for evaluation setting (Inpatient vs. Outpatients); evaluations for re-transplantation and acute liver failure were excluded. After all Inpatients (n=159) were identified, Outpatients (n=159) were selected at random to create a sample matched for age, gender, race, and ethnicity (n=318). Data were collected using our institutions electronic medical record and outside health records as obtained during LTE process. “Prior decompensations” refers to the number of the following clinical decompensations experienced prior to the time of LTE: ascites, hepatic encephalopathy (HE), variceal/acute UGIB, SBP and HRS. Categorical variables and continuous were compared between using Fisher’s Exact test, and student’s T test, respectively.

Results

Alcohol was the most common CLD etiology (42.1% Inpatient, 48.4% Outpatient). Inpatients tended to live further from our center than Outpatients (p=0.079). Inpatients had significantly higher MELD-Na scores (27.1 ± 8 vs. 13.3 ± 6; p<0.0001). Malnutrition was more common in 5.6 times more common in inpatients than outpatients (OR 5.6, 95% CI 2.9-10.8, p<0.001).. A similar proportion of patients had 1 hospitalization. But inpatients were 3 times as likely to have had ≥ 1 liver-related hospital admission prior to LTE (p<0.0001). Inpatients had significantly more prior decompensations than Outpatients prior to inpatient LTE (3.2 ± 1.4 vs. 1.8 ± 1.1, p<0.001), with the greatest differences in SBP and HRS.

Conclusion

Multiple liver-related hospitalizations and malnutrition may be considered a risk factor for ultimately needing inpatient LTE and should be taken seriously by health care providers caring for patients with CLD. Episodes of SBP and HRS should prompt providers to consider immediate or urgent LTE referral regardless of other factors.

References

Multiple liver-related hospitalizations may be considered a risk factor for ultimately needing inpatient LTE and should be taken seriously by health care providers caring for patients with CLD. Episodes of SBP and HRS should prompt providers to consider immediate or urgent LTE referral regardless of other factors.

Disclosure

D Devuni has received grant funding from Sequana Medical and receives grant support from the NIAAA (AA017986-11), both for research unrelated to this work.

Introduction

The quality of colonoscopy is influenced by patient and operator factors. Studies investigating operator attentional fatigue on adenoma detection rate (ADR) have yielded conflicting results.

Aims & Methods

This study aims to compare ADR, polyp detection rate (PDR) and sessile serrated lesion detection rate (SSLDR) and complication rates between elective colonoscopies performed early and late in the list, across multiple operators (n>15), over 10 years, in a tertiary Brisbane (Australia) hospital.
A retrospective study was conducted on elective colonoscopies performed between 2012 and 2022 at The Prince Charles Hospital. ‘Early procedures’ are defined as procedures starting in the first hour of the first procedure starting and ‘late procedures’ are defined as procedures starting within the last hour of the last procedure starting. This pre-defined early and late procedures were used as surrogate markers for operator fatigue, accounting for a possible non-linear relationship between time and onset of fatigue, as well as the variation in number of colonoscopies performed every hour. Timing and the order of colonoscopy were used as alternative surrogates, in a secondary analysis.
Logistic regression was performed on all categorical outcome variables, and Poisson regression was modelled on continuous outcome variables, due to their non-linear distribution. Multivariate analysis included all potential confounding variables related to outcomes of interest. Statistical significance was defined as a P-value less than 0.05. Statistical analyses were performed using the SAS® statistical software (SAS Institute Inc, USA).
Exclusion included; surveillance for IBD and elective ESD.

Results

In total, 15 proceduralist (11 gastroenterologists, 4 surgeons) performed 39, 206 elective colonoscopies from 2012 to 2022. The baseline characteristics of patients, year and procedure sessions are similarly distributed between the early and late groups.
Multivariant analysis found significant associations between late procedures and lower adenoma detection rates, polyp detection rates and SSL detection rates. After adjusting for age, gender, proceduralist, year, morning or afternoon procedure, and bowel preparation quality, PDR, ADR and SDR remain 20-28% lower in late colonoscopies compared with early ones. We also found that age, gender, proceduralist, year and bowel preparation independently affected ADR in multivariant analysis. However, morning or afternoon ADRs did not significantly differ after adjusting for other variables. Proceduralist were found to be the only additional significant variable for SDR in multivariant analysis. There was no significant association between timing of procedures and major adverse events.

Conclusion

This is the largest single-centre study on operator fatigue and its effect on colonoscopy quality. Although the minimum standards for ADR was achieved, ‘late procedures’ have statistically significant lower ADR, PDR and SSLDR compared to ‘early procedures’. There was no difference in the complication rates between ‘early procedures’ and ‘late procedures’.
This study highlights the detrimental effect of fatigue in later procedures affecting the quality of colonoscopies and may be applicable in principal to other procedural based clinical work. Importantly, this may or perhaps will or is having an impact on patient safety, satisfaction, outcomes and clinical KPI’s for the operators and hospital administrators.

Disclosure

None

Introduction

Urgency is not an IBD Patient Reported Outcome (PRO) in the STRIDE II but it has been assessed at baseline and as an outcome measure in recent pivotal RCTs with newer biologicals and targeted synthetic small molecules in both Crohn’s disease CD) and ulcerative colitis (UC). However, although it is reasonable to assume that UC patients or CD patients with rectal involvement may complain for severe urgency, urgency has been assessed even in patients with Crohn’s ileitis (iCD).

Aims & Methods

The aim of this study was to assess whether urgency is reported by iCD patients with flares or quiescent disease in a Real-World (RW) setting. This prospective, pilot, RW study included CD patients with solely L1 phenotype. L1 location was documented by ileocolonoscopy, histology and, imaging (MRE, US, or capsule endoscopy). Patients with colonic and/or rectal disease, perianal involvement and complicated ileal disease were excluded. Patients were interviewed by office visits during disease flare [HBI>5, CRP <5mg/dl, faecal calprotectin (FC)>250μg/g faecal tissue and SES-CD for terminal ileum >3 if colonoscopy was performed within a month prior to the visit) and during clinical remission (HBI<5, CRP <5mf/dl and FC <200μg/g and ileal SES-CD=0, in a recent ileocolonoscopy). The presence of and severity of urgency was recorded by a Symptom Rating Score of 0-10 (absent to very severe). The presence and severity of abdominal pain, the number and consistency of stools, nocturnal stools, blood and/or mucus in the stools, and the feeling of inadequate evacuation were sought by a structed questionnaire.

Results

During a 15-month period, 85 iCD patients [45 males, median age (range) 33 (18-65) years, median (range) disease duration 9 (0.6-25) years] were enrolled in the study. Patients were receiving a wide range of treatments, including anti-TNF agents (n=35), ustekinumab (N=25), vedolizumab (N=5), azathioprine (n=10), budesonide (n=5) and mesalazine (n=15). Fifty patients had a flare, 65 were in remissionand 30 patients were interviewed sequentially in flare and remission of disease. All patients in disease flare reported abnormal classical PROs of CD. Moderate to severe urgency [median score 5, range 4-8] was reported by 5/50 (10%) patients with disease flare, 8/65 (12%) patients with disease remission and 2/30 (6.5%) patients who were interviewed during flare and remission of disease. 3/50 patients with urgency during a flare of CD did not report urgency during disease remission. Six of the 8 patients who were interviewed only with iCD in remission and reported urgency had concurrently typical Irritable Bowel Symptoms (IBS, abdominal pain relieved by defecation, alternating diarrhoea/constipation, inadequate bowel emptying).

Conclusion

This prospective, pilot, real-world study shows that the reliability of urgency as classical PRO in patients with iCD is questioned and raises doubts whether urgency should be included in the spectrum of PROs for patients with iCD both in RCTs and in RW studies. Validation of the terminology in different ethnic languages may also pose additional barriers in patient understanding and reporting the symptom in the presence of additional IBS-type symptoms. Large studies are needed to assess if urgency is present in patients with iCD and how reliably is reported especially in multinational RCTs.

Disclosure

Dr GJ Mantzaris: Research grants: AbbVie, Genesis, Merck Sharp & Dohme, Takeda; advisor/speaker: AbbVie, Aenorasis, Dr Falk, Ferring, Hospira, Janssen, Merck Sharp & Dohme, MYLAN, Pfizer, Takeda, Vianex.
Dr A Loukou: Nothing to declare