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

Inflammatory bowel disease (IBD), a chronic inflammatory disease of the gastrointestinal tract, is caused by various factors, including genetic factors and environmental factors, as well as dysregulated immune responses. LMT503, a novel organic small-molecule compound, has the potential to suppress pro-inflammatory cells and induce anti-inflammatory cells by modulating their cell metabolisms. We evaluated the anti-inflammatory effects of LMT503 in a murine adoptive T cell transfer-induced colitis model.

Aims & Methods

This study was conducted to evaluate the anti-inflammatory effect of LMT503 in the murine chronic colitis model. Naïve CD4⁺CD25^-CD45RB^high CD62L^high T cells that were isolated from wild-type mice by flow cytometry based-method and transferred to Rag1 knock-out mice by intraperitoneal injection to induce murine adoptive T cell transfer-induced colitis. LMT503 was orally administrated (50mg/kg, 100mg/kg) for 2 weeks starting at 5 weeks after naïve T cell transfer. The disease activity index (DAI) was checked daily, and histopathological score, macroscopic injury score, and colon length were evaluated upon sacrifice. Macrophages and T cells from the spleen were analyzed by flow cytometry. Gene expression in colon tissue was measured by qRT-PCR and cytokine profiles in plasma was measured by cytometric bead array. Myeloperoxidase (MPO) activity was measured using the MPO activity kit.

Results

Oral administration of LMT503 ameliorated adoptive T cell transfer-induced colitis in mice. The DAI, histopathological score, and macroscopic injury score were significantly decreased after the administration of LMT503 in a dose-dependent manner. The LMT503-treated group showed significantly increased mucin production in the colon. Th1, Th17 cells, and M1 macrophages in the spleen were suppressed, and M2 macrophages were induced by the administration of LMT503. MPO activity and gene expressions of pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in colon tissue were suppressed by the administration of LMT503. And the level of inflammatory cytokines, such as IL-2, TNF-α, and IFN-γ, in plasma were significantly suppressed by the administration of LMT503. Especially, LMT503 treatment significantly increased the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a), a master regulator of mitochondrial biogenesis, suggesting that LMT503 modulates cellular metabolism towards an anti-inflammatory metabolism.

Conclusion

Our data suggest that the anti-inflammatory effect of LMT503 ameliorates murine adoptive T cell transfer-induced colitis by modulating cellular metabolism and immune cell modulation. Therefore, LMT503 may be a novel therapeutic drug that opens new avenues for the treatment of IBD.

References

1. Erben U, Loddenkemper C, Doerfel K, et al. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol. 2014;7(8):4557-4576.
2. Ostanin DV, Bao J, Koboziev I, et al. T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade. Am J Physiol Gastrointest Liver Physiol. 2009;296(2):G135-G146.
3. Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011;186(7):4234-4243.
4. Burke JR, Cheng L, Gillooly KM, et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Sci Transl Med. 2019;11(502):eaaw1736.
5. Kiesler P, Fuss IJ, Strober W. Experimental Models of Inflammatory Bowel Diseases. Cell Mol Gastroenterol Hepatol. 2015;1(2):154-170.

Introduction

Despite new therapeutic strategies, substantial proportion of patients with ulcerative colitis (UC) undergo colectomy at some point. Restorative proctocolectomy with ileal pouch ano anastomosis (IPAA) is regarded as intervention of choice in these patients. However, the disease conversion to Crohn´s disease (CD) is reported in up to one third of these patients who necessitate immune suppressive treatment after IPAA. Considering the life-long need for immune suppressive therapy in these patients, ileo-rectal anastomosis (IRA) would represent a good alternative to IPAA in this specific group of patients. Todate, no data are available to predict the UC-CD conversion. One of the possibility to reduce the risk of performing IPAA in patients developing CD in pouch is to use the modified two-stage proctocolectomy approach and identify patients who develop CD endoscopically between colectomy and the restoration of continuity.

Aims & Methods

The aim of the present study was to assess the UC-CD conversion rate identified prior IPAA via ileoscopy.
All patients with UC operated in one tertiary IBD center between 2016 and 2021 were identified in medical records. The main outcome was CD detected at ileoscopy between the first stage operation, i.e. total colectomy with terminal ileostomy and the restoration of continuity either via IPAA or IRA. The ileoscopy was performed between three to six months after colectomy. The secondary outcome was the rate of conversion to CD after IPAA or IRA.

Results

Sixty patients underwent total colectomy (mean age 41 years, range 22-77; 62% were men); seven patients were lost to follow-up, finally the data from 53 patients were analysed. The majority of these patients (36 - 68%) underwent colectomy for therapy resistent chronically active UC, 9 (17%) patients for acute severe UC, 2 patients had benign colonic stenosis, 5 had high-grade dysplasia or colorectal cancer detected at surveillance colonoscopy and one patient had extensive pseudopolyposis.
All resection specimen were reviewed and no histopathological features of CD were found. Three out of the 53 (6%) ileoscopically assessed patients prior IPAA or IRA were diagnosed with CD in prestomal terminal ileum. During the further follow-up, additional 4 patients developped CD, two after IPAA, one with definitive ileostomy in prestomal ileum and one in neoterminal ileum after IRA.
In total 7 out of 53 patients in this cohort developped CD (13%). Using the two stage approach with ileoscopy between colectomy and restoration of continuity, three out of these seven patients with CD convertion in this cohort were detected prior the decision on the type of second-stage operation.

Conclusion

The conversion from ulcerative colitis to Crohn`s disease occurs in a significant proportion of IBD patients after colectomy. Ileoscopy performed between the two stages of restorative proctolectomy is helpfull in detecting these patients and guiding the decision on the type of surgical intervention to restore continuity.

Disclosure

Nothing to disclose.

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

The current gold standard for diagnosis of Inflammatory bowel disease (IBD) is based on clinical and endoscopic evaluation as well as histologic and radiologic evaluation. However, endoscopic evaluation can be uncomfortable and carry some risks, especially in the pediatric population that requires general anesthesia in order to perform the procedure.

Aims & Methods

Our aim was to investigate whether serum biomarkers can differentiate between pediatric patients with and without IBD. Secondary aims were to determine whether there are biomarkers that can differentiate between Crohn's disease (CD) and Ulcerative colitis (UC), and whether we can predict progression to biologic treatment within one year from diagnosis using these biomarkers.
Pediatric patients undergoing a first diagnostic colonoscopy at British Columbia Children's Hospital (BCCH) between December 2019 and June 2022 were invited to participate in the study. A 2 ml blood sample was taken from each participant at the time of colonoscopy. Demographic and clinical data were collected from each patient. Blood samples were analyzed using the Legendplex^TM flow cytometry kits investigating which included 50 different inflammatory cytokines and chemokines associated with IBD. A prediction model was built via a supervised learning method to determine how well we can predict the different groups.

Results

One hundred pediatric patients participated in the initial study. Five were excluded from the analysis due to uncertain diagnosis. Median age was 13.36 years, 39 were females (41%) and 54 (56.84%) were diagnosed with IBD, with 35 (64.81%) diagnosed with Crohn's disease. On a univariate analysis and Volcano plot 6 biomarkers were found to be strongly associated with the diagnosis of IBD: IL22, IL8, TARC, GROA, MIG, and IL18. The cross-validated AUROC was 0.70. Using SPLS-DA the classification accuracy was improved to 0.84, and MIG was found to be the key biomarker to discriminate between pediatric IBD patients and non-IBD patients.
On a univariate analysis only TSLP was found statistically significant as a predictor of CD, and RANTES and TARC were found as negative predictors for initiating biologic treatment within one year of diagnosis. However, the prediction model did not predict well the subclasses nor progression to biologic treatment.

Conclusion

Using serum biomarkers can predict the diagnosis of Pediatric IBD. MIG was found to be the key biomarker in the prediction model.

Introduction

In recent years, the number of early-onset CRC (EO-CRC) diagnosed at the age of less than 50 years has been increasing. Previous studies suggest that EO-CRC may have higher malignant potentials and a worse prognosis than late-onset CRC. However, the reason why EO-CRC is regarded as aggressive cancer and result in delayed diagnosis remains unclear. We thought that both the lack of appropriate opportunities for screening or medical examination and the bias that was caused owing to being analyzed altogether regarding the different clinical stages could affect worse prognosis of EO-CRC. In this study, we focused on T1 cancer to highlight the essential features of EO-CRC to minimize the bias caused by the time of diagnosis.

Aims & Methods

This study is a secondary analysis of the main JSCCR (The Japanese Society for Cancer of the Colon and Rectum) project, “International joint research on lymph node metastasis in CRC”. Utilizing 4673 T1 CRC cases treated between July 2009 and December 2016 at 27 facilities belonging to JSCCR, we divided the patients into 5 groups according to age at the diagnosis: 49 years or younger, 50‒59 years, 60‒69 years, 70‒79 years, and 80 years or older. To analyze the clinicopathological features including sex, tumor location, macroscopic type, tumor size, histology, submucosal invasion depth, lymphatic/venous invasion, tumor budding, lymph node metastasis, and treatment methods, the Spearman’s correlation test was used. The difference of disease-free survival (DFS) between early-onset and later-onset CRC was also examined using log-rank test and Kaplan–Meier method.

Results

The cases of EO-CRC were 349 (7.5%). Among age groups, the proportion of rectum (from 49 years or younger to 80 years or older;44.1%, 42.0%, 36.6%, 29.0%, and 12.0%, respectively; P <0.05), protruded type (62.2%, 59.1%, 54.9%, 48.4%, 45.9%; P <0.05), and frequency of lymph node metastasis (10.0%, 7%, 8.0%, 7.0%, 4.6%; P <0.05) were decreased as the age group increased. In terms of sex, the proportion of male tends to decrease as the age group increased (57.9%, 60.8%, 63.5%, 57.0%, 52.7%, respectively; P <0.05). No significant differences were found among the five age groups for tumor size, histology, submucosal invasion depth, vascular invasion, tumor budding, recurrence rate, and treatment. No significant difference was observed regarding DFS between the two groups (5-year DFS; 98.7% for EO-CRC and 94.3% for late-onset CRC).

Conclusion

This study showed that the frequency of lymph node metastasis of T1 CRC decreased according to the increase of age at diagnosis, suggesting that EO-CRC may have a greater biological malignant potential compared to late-onset CRC. As far as we know, this is also the first study to report that “protruded type” would be one of the features of EO-CRC. Although no difference was observed as for DFS between two groups, it was plausible considering that only T1 stage CRC was enrolled in this study. Further studies are warranted to evaluate the clinicopathological features characterizing early stage EO-CRC.

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