Introduction

Despite the increasing incidence of Crohn’s disease (CD), its early immune disturbances have not been described yet. The preclinical period provides an opportunity to gain insight into the initial processes involved in the pathogenesis of the disease.

Aims & Methods

The main aim of our study was to describe how the subclinical inflammatory process is modifying the individual’s immunologic environment while the patient is still on preclinical period. We analysed scRNASeq data from peripheral blood mononuclear cells (PBMC) of patients with incidentally-diagnosed CD according to ECCO criteria during the colorectal cancer screening programme, after histologic confirmation. Their gene expression profile was compared to healthy individuals acquired from publicly available datasets. The analytical pipeline included merging of the datasets followed by batch correction concerning integration from different studies, quality control and filtering, and finally cell-type annotation and differential gene expression analysis.

Results

Two patients with CD (mean age 53,5 years) and 2 healthy controls were included. We observed distinct transcriptomic profile in preclinical patients compared to controls, with small intragroup differences. The cell-type annotation identified B cells (B), CD4+ and CD8+ T-cells (CD4T, CD8T), dendritic cells (DC), monocytes (Mono) and natural killer cells (NK). The analytical pipeline included 17,021 cells (B:3,274, CD4T:5,798, CD8T:3,476, DC:315, 2, Mono:928, NK:3,230) and 3000 quantified genes. Considering each cell type individually, we identified 49 differentially expressed genes (DEG) between CD patients and controls (B:39, CD4T:37, CD8T:41, DC:42, Mono:37, NK:37), from which 30 were DEGs in all cell types.
Building on the list of 49 detected DEGs, we report three insights into the preclinical period of the disease.
First, pathway analysis revealed significant enrichment of the pathway that is related to immunoregulatory interactions between lymphoid and non-lymphoid cells, and functional annotation analysis identified gene products that are related to immunological defense. Second, we identified significant transcriptomic alterations in genes that have previously been related to the symptomatic phase of IBD, or reported as potential biomarkers. Third, after performing principal component analysis we observed greater separation between the patients groups in the CD8T cells compared to the other cell-types.

Conclusion

This study reveals the initial transcriptomic profiles and the main pathways that precede the onset of symptomatic inflammatory bowel disease. Our findings may help in identifying potential targets for early disease intervention.

Introduction

Ileocolonoscopy and Rutgeerts endoscopic score (RS) remains the gold standard to evaluate post-operative recurrence (POR) in Crohn's disease (CD). Intestinal ultrasound (IUS) is proposed as a non-invasive alternative for the diagnosis of POR, with a sensitivity of 89%, specificity of 86% and area under curve (AUC) of 0.93 (1). Bowel wall thickness (BWT) alone has a high accuracy in the diagnosis of POR and it is proposed that the association of other parameters such as hyperemia, loss of bowel wall stratification, involvement of mesenteric fat (i-fat) or ultrasound scores, increases sensitivity and specificity in the diagnosis of POR (2).

Aims & Methods

The aim of this study is to assess whether IUS parameters and ultrasound scores correlate with endoscopy in the diagnosis of POR. A unicentric retrospective study was performed. There were included patients with CD with both an ileocolonoscopy and intestinal ultrasound performed for the detection of POR, the time between tests was less than 6 months or there was no therapeutic change between tests.
Endoscopic POR was evaluated with Rutgeers score (RS), RS i0 and i1 was considered no POR and RS ≥i2a was POR. The IUS parameters were: BWT, Limberg Score, bowel wall stratification, inflammation of mesenteric fat, Simple US Score, SUS-CD and IBUS-SAS score.

Results

129 patients were included, baseline characteristics are in Table 1. In 108 patients (83.7%) the time between test was <6 months and in 21 (16.3%) >6 months without therapeutic changes. 38 (29.7%) were classified as endoscopic POR (RS i0 – i1) and 90 (69.8%) as POR: 28 (21.2%) i2a, 17 (13.3%) i2b and 45 (35.1%) severe (RS i3 – i4). With IUS, 42 patients (32.6%) were classified as no POR and 87 (67.4%) as POR. The mean BWT by IUS in patients without endoscopic POR was 2.6 mm (SD +/- 1.2) versus 4.8 (SD +/- 1.6) in patients with RS ≥i2a (p 0.001). BWT ≥3 had a sensitivity of 86.6%, specificity 78.9% and AUC of 0.83 in the diagnosis of POR. Hyperemia (Limberg ≥1) was present in 75 patients (84.3%) with RS ≥i2a versus in 8 patients (21.1%) without endoscopic POR (p 0.001). 21 patients (23.9%) of patients with RS ≥i2a presented loss of bowel wall stratification versus 0 (0%) with i0-i1 (p 0.001). I-fat was present in 16 patients (12.4%), all of them RS ≥i2a (p 0.02).
The mean results of IUS scores were: Simple Us score 5.6 (SD +/- 2.9), SUS-CD 2.1 (SD +/- 1.8) and IBUS-SAS 31.6 (SD +/- 23.3). In patients without endoscopic POR the mean result of Simple US Score was 3.0 (SD +/- 2.0) versus 6.7 (SD +/- 2.4) in RS ≥i2a (p>0.05). The mean result of SUS-CD without POR was 0.5 (SD +/ 1.0) versus 2.8 (SD +/- 1.5) in POR (p>0.05). In IBUS-SAS the mean result in RS i0-i1 was 13.4 (SD +/- 10.8) versus 39.2 (SD +/- 22.9) in RS ≥i2a (p>0.05). Simple US Score showed an AUC of 0.85 in the diagnosis of POR (95% CI 0.78 – 0.92), SUS-CD of 0.87 (95% CI 0.81 – 0.93) and IBUS-SAS of 0.85 (95% CI 0.77 – 0.92).

Conclusion

In our experience, IUS parameters such as BWT, Limberg score, loss of wall stratification, i-fat and IUS scores (IBUS-SAS, SUS-CD and Simple US Score), have a high accuracy in the diagnosis of POR.

References

1. Barchi, Alberto et al. “Recent advances in the use of ultrasound in Crohn's disease.” Expert review of medical devices vol. 20,12 (2023): 1119-1129. doi:10.1080/17434440.2023.2283166
2. Yung, Diana E et al. “Capsule Endoscopy, Magnetic Resonance Enterography, and Small Bowel Ultrasound for Evaluation of Postoperative Recurrence in Crohn's Disease: Systematic Review and Meta-Analysis.” Inflammatory bowel diseases vol. 24,1 (2017): 93-100. doi:10.1093/ibd/izx027

Introduction

Background
Lymphocyte trafficking to the inflamed gut is one of the hallmarks of Inflammatory Bowel Disease (IBD) pathology. Integrin a4b7 and its ligand MADCAM1 play an important role in targeting immune cells in the bloodstream to mucosal tissues and blocking this pathway using the anti-a4b7 monoclonal antibody Vedolizumab (VDZ) proved to be an effective treatment in IBD. However, VDZ is most efficient in treatment of Ulcerative Colitis (UC) and of colonic rather than ileal Crohn’s Disease (CD), for which the reasons have not been completely understood.

Aims & Methods

Aim:
To compare the expression of ITGA4, ITGB7 and MADCAM1 in gut tissue biopsies from small and large bowel with respect to the underlying severity of tissue inflammation.

Methods:
Differential gene expression analysis was conducted using bulk RNA Sequencing data generated from gut tissue biopsies of the large and small intestine of 611 CD and 315 UC patients enrolled in a multicentred longitudinal Study of a Prospective Adult Research Cohort with IBD (SPARC IBD) obtained from the IBD Plexus program of the Crohn’s and Colitis Foundation. Gene expression levels of ITGA4, ITGB7 and MADCAM1 were compared across ileal, colonic and rectal segments of the intestine and data were then linked to available measures of local inflammation.

Results

Results:
ITGA4, ITGB7 and MADCAM1 were expressed at comparable levels in large vs small bowel biopsies. Expression of MADCAM1 was significantly increased in both ileal and colonic biopsies from patients with moderate to severe CD based on segmental or composite endoscopy score (SES-CD) across all bowel segments. Expression of both ITGA4 and ITGB7 was similarly increased in colonic biopsies of moderate/severe CD patients, whereas only minor changes were observed for both genes in ileal biopsies. Similar findings were obtained from UC patients, where expression of MADCAM1 was significantly increased in inflamed or ulcerated biopsies from both sigmoid colon and cecum as compared to normal appearing biopsies. Expression of ITGA4 and ITGB7 was only increased in inflamed/ulcerated biopsies of the sigmoid colon but not the cecum and correlated with the modified Mayo endoscopic score (MMES).

Conclusion

Conclusion:
Our analysis suggests that influx of leukocytes to inflamed tissue via ITGA4/ITGB7 and MADCAM1 interactions is more common in the distal colon compared to proximal colon or ileum. This provides a possible mechanistic explanation as to why VDZ is most effective in patients with colonic IBD. Further work is needed to understand the differential regulation of cell trafficking to different regions of the gut.

Introduction

Autoimmune atrophic gastritis (AAG) leads to significant changes in the gastric mucosa, including hypo-achlorhydria and increased gastrin (G) levels, providing proliferative stimuli on the gastric mucosa (1-5).

Aims & Methods

The aim of our study is to evaluate the occurrence and characteristics of gastric polyps in AAG patients across six tertiary centers in Italy. We conducted a multicentric, cross-sectional study from January to June 2023, prospectively enrolling consecutive patients diagnosed with AAG, from January 2000 to June 2023, who underwent at least one endoscopy. Data on demographics, clinical history, biochemical profiles, serological data, and endoscopic and histopathological findings were collected.

Results

Among 612 AAG patients (73.9% female, median age 66) followed up for a median of 4 (IQR 2-7.5) years, 222 (36.3%) had at least one gastric polyp. Non-endocrine polyps (214) were found in 162 patients, including 151 (70.5%) inflammatory, 29 (13.6%) adenomatous, 18 (8.4%) fundic gland polyps, 13 (6.1%) adenocarcinomas, and one MALT lymphoma. Additionally, 108 patients (48.6% of the population with polyps and 17.6% of the overall AAG patients) presented with gastric neuroendocrine neoplasms (gNENs), 48 of whom also had non-endocrine polyps. The median polyp size was 4 (IQR 2-7) mm. Older age, smoking prevalence, and higher levels of G and chromogranin A (CgA) were associated with polyp presence. No significant differences in OLGA/OLGIM stages or H. pylori status were noted between patients with and without polyps.

Conclusion

This study represents the largest multicentric cohort of AAG patients, highlighting the significant presence of gastric polyps, including gNENs and various non-endocrine types including a not negligible proportion of patients who showed gastric adenocarcinoma. These results emphasize the importance of proactive endoscopic monitoring and comprehensive histopathological evaluation in patients with AAG, to effectively identify and manage these different gastric lesions.

References

1. Zhang H, Jin Z, Cui R, Ding S, Huang Y, Zhou L. Autoimmune metaplastic atrophic gastritis in chinese: a study of 320 patients at a large tertiary medical center. Scand J Gastroenterol. 2017;52(2):150-6.
2. Krasinskas AM, Abraham SC, Metz DC, Furth EE. Oxyntic mucosa pseudopolyps: a presentation of atrophic autoimmune gastritis. Am J Surg Pathol. 2003;27(2):236-41.
3. Kishino M, Nonaka K. Endoscopic Features of Autoimmune Gastritis: Focus on Typical Images and Early Images. J Clin Med. 2022;11(12).
4. Park JY, Cornish TC, Lam-Himlin D, Shi C, Montgomery E. Gastric lesions in patients with autoimmune metaplastic atrophic gastritis (AMAG) in a tertiary care setting. Am J Surg Pathol. 2010;34(11):1591-8.
5. Massironi S, Elvevi A, Gallo C, Laffusa A, Tortorella A, Invernizzi P. Exploring the spectrum of incidental gastric polyps in autoimmune gastritis. Dig Liver Dis. 2023.

Introduction

Crohn’s disease (CD) is characterized by discontinuous inflammation. Failure to identify skipping lesions of the terminal ileum (TI) or transmural changes can lead to incorrect management.

Aims & Methods

Eligible adult patients with CD undergoing ileo-colonoscopy and computed tomography enterography (CTE) or magnetic resonance enterography (MRE) within six months. We determined the prevalence of endoscopic skipping (normal ileum on colonoscopy but proximal small bowel inflammation on cross-sectional imaging), skip lesions (discontinuous inflammation along the gastrointestinal tract identified on cross-sectional imaging), and penetrating complications.

Results

Among 202 patients, 45 (22.3%) had endoscopic skipping proximal to TI intubation. Fifty patients (24.5%) had small bowel skip lesions, primarily in the ileum. Strictures were identified in 34 patients (16.8%) through both imaging and ileo-colonoscopy, in 21 patients (10.4%) solely through cross-sectional imaging, and in 3 patients (1.5%) solely through ileo-colonoscopy. Approximately 63.8% of stricturing cases would be missed without cross-sectional imaging. Penetrating complications, including abscesses (2.5%) and various fistula types (4.9%), were detected in 15 (7.4%) patients.

Table. Comparison between patients who had active Crohn’s disease with and without abnormal TI on colonoscopy

Conclusion

Ileo-colonoscopy missed detection of active CD in approximately one-fifth of cases due to more proximal disease location. Stricturing disease would be missed in more than half of cases if cross-sectional imaging was not performed.

Disclosure

Virginia Solitano no conflict of interests.
Sudheer Kumar Vuyyuru has received consultancy fees from Alimentiv Inc.
Achuthan Aruljothy no conflict of interests.
Maan Alkhattabi has received consulting fees from Janssen. Speaker’s fees from Janssen, Takeda & Pfizer.
Melanie Beaton has received advisory board fees from AbbVie, Astra Zeneca, Gilead,
Janssen, Novo Nordisk, Lupin, Pfizer and Takeda.
Jamie Gregor has no conflict of interests.
Zahra Kassam has received Bayer Pharmaceuticals speaker honorarium and research grant, Fusion MD speaker fees, Alimentiv Inc consulting fees.
Rocio Sedano has received consultancy fees from Alimentiv Inc.
Harry Marshall has no conflict of interests,
Darryl Ramsewak has no conflict of interests.
Michael Sey has received consultant fees from Medtronic; Research grants and speaker fees from Pendopharm; Educational grant from Cook Medical.
Vipul Jairath has received consultancy/advisory board fees from AbbVie, Alimentiv Inc., Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Topivert, Ventyx, and Vividion; and speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi.

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.