Introduction

There is a small but recognised risk of malignant transformation in ileal-pouch anal anastomosis (IPAA). The risk of pouch dysplasia and pouch cancer increases over time and the reported incidence is approximately 5% after 20 years.[1] For this reason, current guidelines suggest patients to undergo pouchoscopy surveillance. However, the frequency of surveillance is still widely debated.

Aims & Methods

The primary aim of this study is to investigate the incidence of high-grade dysplasia and cancers in patients with IPAA for UC in the long-term.
All patients within 8 hospitals, under a single health board, with IPAA for UC, created between 1980 and 2019 and undergoing pouchoscopy surveillance, were reviewed.
Data collected included patient demographics, such as sex, age at diagnosis of UC, age at pouch creation and those with any identifiable risk factors. It also included specific pouch data such as date of IPAA creation, mean number of days between UC diagnosis, IPAA creation and first pouchoscopy. Surveillance data included the indication for pouchoscopy as well as pouchoscopy findings.

Results

187 patients (107 male) were under surveillance. The median age of IPAA creation was 38 years old (range 11-63).
The median duration of patient follow up was 192.2 months (range 13.1-464.9 months), with 106 patients (56.7%) having >15 years of follow up. The median interval between pouchoscopies was 27.3 months (IQR: 21.4-39.2).
A total of 574 pouchoscopies were performed on the 187 patients, by a total of 115 endoscopists. The median number of pouchoscopies per endoscopist was 2. 1 endoscopist performed 147 of the 574 pouchoscopies (25.6%). Patients averaged 3.07 scopes per person. The indication for scopes were surveillance (305, 53.1%), symptoms (248, 43.2%) and positive bowel screening (19, 3.3%).
There were no high-grade dysplasia. One cancer (0.005%) was found in the rectal cuff at 330.6 months. 18 patients (9.6%) were considered “high-risk” according to the BSG guidelines; 9 with Primary Sclerosing Cholangitis (PSC), 2 with PSC/autoimmune hepatitis overlap syndrome, 5 with a long rectal cuff, 1 with a previous colorectal malignancy and 1 with PSC and a previous colorectal malignancy. None of them developed high-grade dysplasia nor cancer. These high-risk patients had a median follow up of 158.4 months (range 64.4-405.7 month).
Other findings included pouchitis (151, 26.3%), chronic pouchitis (84, 14.6%), non-specific inflammation (144, 25.1%) and stenosis (82, 14.3%). 10 patients had their IPAA excised.

Conclusion

The incidence of high-grade dysplasia or cancer in IPAA is extremely low and may not warrant the intense surveillance.
Further protocols are needed to ensure that patients with IPAA are not undergoing national bowel screening and are having unnecessary pouchoscopies for false positive results.

References

Pouw RE, Bisschops R, Gecse KB, de Hertogh G, Iacucci M, Rutter M, Barret M, Biermann K, Czakó L, Hucl T, Jansen M, Savarino E, Spaander MCW, Schmidt PT, Dinis-Ribeiro M, Vieth M, van Hooft JE. Endoscopic tissue sampling - Part 2: Lower gastrointestinal tract. European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2021 Dec;53(12):1261-1273.

Introduction

While ileocecal resection (ICR) is the most common surgical procedure in Crohn's disease (CD), non-ICR surgeries account for only 20% of cases and remain underrepresented in the literature. This study aimed to identify specific clinical risk factors for surgical recurrence in CD patients undergoing small bowel or colonic resections without involving the ileocecal valve.

Aims & Methods

This multicenter retrospective cohort study included 257 patients with CD (124 small bowel resections, 133 colonic resections) across 13 Italian centers from 1978 to 2023. Univariate and multivariate logistic regression and Cox proportional hazards analyses were performed to identify clinical risk factors associated with surgical recurrence.

Results

The cohort comprised two distinct groups: small bowel resections (n=124), characterized by male predominance (63.71%), a high prevalence of stricturing disease (60.48%), and a median follow-up of 75.5 months; and colonic resections (n=133), featuring a more balanced gender distribution (47.37% male), higher rates of penetrating disease (47.37%), and a median follow-up of 88.0 months. Penetrating disease behaviour emerged as the only significant predictor of recurrence in logistic regression analysis (OR 2.16, 95% CI 1.03-4.52, p=0.041), while factors typically predictive in ICR, such as smoking (OR 0.90, p=0.843) and prior resections (OR 0.96, p=0.913), were non-significant. Cox regression identified prior biologic exposure as a significant predictor of earlier recurrence (HR 2.52, 95% CI 1.22-5.18, p=0.012), with TNF experience specifically associated with increased risk (HR 2.28, 95% CI 1.12-4.67, p=0.024). The cumulative number of risk factors (HR 1.35, 95% CI 1.01-1.82, p=0.046) and postoperative intra-abdominal septic complications (HR 2.75, 95% CI 1.18-6.44, p=0.020) also contributed to recurrence risk. Disease phenotypes significantly differed between resection types (p<0.001), with stricturing disease most prevalent in small bowel resections (60.48% vs. 36.09% in colonic) and penetrating disease more common in colonic resections (47.37% vs. 36.29% in small bowel). Results are summarized in Table 1.

Table 1: Univariate logistic regression analysis of predictors for postoperative surgical recurrence in patients undergoing small bowel or colonic resections. Abbreviations: CI: Confidence Interval; CD: Crohn’s Disease; IBD: Inflammatory Bowel Disease; POR: Postoperative recurrence; TNF: Tumour Necrosis Factors.

Conclusion

This study reveals distinct risk factors for surgical recurrence after non-ICR surgeries in CD. Unlike ICR where smoking, perianal disease, and prior resections predominate, non-ICR recurrence is primarily associated with penetrating disease phenotype and prior biologic exposure. These findings demonstrate that risk stratification models developed for ICR are not applicable to non-ICR surgeries, highlighting the need for procedure-specific approaches to postoperative management. Tailored prophylactic strategies should address the unique recurrence dynamics of small bowel and colonic resection surgeries.

Introduction

Infiltration of neutrophils into the intestinal tissue is a crucial component of the inflammatory response in Crohn‘s disease (CD). CPa9-HNE, a calprotectin fragment released by human neutrophil elastase during NETosis, has been shown to strongly correlate with endoscopic disease activity in inflammatory bowel disease (IBD) and serves as an indicator for pharmacodynamic response. Furthermore, emerging data suggests that neutrophil extracellular traps (NETs) significantly contribute to the pathogenesis of fibrosis.

Aims & Methods

For the first time, we investigated the association of CPa9-HNE with histological grading of both inflammation and fibrosis. The cohort included 62 patients with stenotic Crohn‘s disease. Inclusion criterion was the presence of stenotic disease requiring bowel resection, as confirmed by radiographic assessment. Upon surgery, the resected specimens were collected and histologically graded according to transmural fibrosis burden, and inflammation (D'Haens score). Serum was drawn at baseline (before resection). CPa9-HNE was measured, reflecting a human neutrophil elastase-derived fragment of calprotectin. Spearman’s rank correlation was applied.

Results

CPa9-HNE showed an overall positive correlation to the D'Haens score (ρ=0.279, p<0.005). Significant positive correlation was observed between CPa9-HNE and the presence of neutrophils, both in the epithelium and the lamina propria (ρ=0.309, ρ=0.349, p<0.005 both), as well as with epithelial damage (ρ=0.262, p<0.005). We also observed a positive correlation between CPa9-HNE and transmural fibrosis burden, specifically fibrosis in the submucosa (ρ=0.294, p<0.005)

Conclusion

This study showed that CPa9-HNE, a biomarker of neutrophil activity, correlated with the presence of neutrophils in the intestinal tissue, as well as epithelial damage. Interestingly, CPa9-HNE also showed association to submucosal fibrosis, emphasizing the importance of considering neutrophil activity when targeting the fibro-inflammatory axis. These findings highlight the potential use of CPa9-HNE as a complementary tool for histological grading of inflammation and fibrosis burden, and could be used to further explore the role of neutrophil extracellular traps in intestinal fibrosis.

Disclosure

MSA, TKA, MP, MAK, ACBJ and JHM are employees of Nordic Bioscience. MAK, ACBJ and JHM are shareholders of Nordic Bioscience.

Introduction

The indication for the use of immune checkpoint inhibitors (CPIs) in the anti-cancer armamentarium has increased exponentially in recent years. So too has the incidence of ICI-induced colitis, and the need for aggressive management of same. Severe cases can require treatment escalation to biologic therapies, and can often be refractory to first-line treatments.

Aims & Methods

This study aims to describe the long term outcome of a cohort of patients that required biologic therapy for induction of remission of ICI colitis.
A single-centre retrospective analysis at a tertiary referral centre in Ireland (University Hospital Galway). All inpatient sigmoidoscopies performed over two years (January 2023 to December 2024) were reviewed and cross-referenced with electronic patient records and pathology reports to identify cases of ICI colitis. Clinical data including drug treatment and follow up was obtained from electronic patient records.

Results

25 cases of ICI colitis were identified. CPIs included Pembrolizumab, Ipilimumab, Nivolumab or a combination of these (n=23), bevacizumab (n=1), and atezolimab (n=1). Two patients (8%) responded to anti-diarrhoeal therapy alone. The remaining 23 (92%) were treated with steroid therapy. 10 responded to IV methylprednisolone and 5 to oral prednisolone. 8 (32%) failed to respond to IV MTP and required escalation to biologic therapy. Of these:

• 4 (50%) were managed with infliximab alone (median 2.5 doses)
• 2 (25%) required escalated dosing regimens of both Infliximab and Vedolizumab over a short period, and have continued on maintenance therapy (1=IFX and 1=Vedo). Both patients had remote history of UC prior to cancer diagnosis.
• 2 (25%) proved refractory to both IFX and Vedo and required escalation to Jak inhibitor therapy. Both responded to Upadatcitinib. One with severe enteritis and colitis developed cancer progression following 6/12 of maintenance therapy and died 2 months later. The second developed severe bilateral aspergillis endophthalmitis after 4 weeks of Jak inhibition (Tofa x 2/52, UPA x 2/52).
• CPIs were discontinued in 19 patients (76%). No patient that required a biologic was re-challenged with a CPI.

Conclusion

Almost one third (32%) of our patient cohort with ICI colitis required escalation to biologic treatment. Those treated with a combination of CPIs were more likely to require a biologic agent. Infliximab remains the first line agent but Upadatcitinib has shown efficacy in refractory cases. However, significant immunosuppression increases the risk of adverse events, emphasising the need for consideration of treatment withdrawal once remission has been achieved.

Introduction

PD-1 downregulates activated T cells and dysregulation of its signaling impacts critical T cell responses in inflammatory and autoimmune diseases, including ulcerative colitis (UC). In UC lamina propria, multiple T cell subtypes express PD-1, including peripheral helper T cells (Tph) and effector memory T cells, and the reduction of PD-1+ Tph cells is correlated with remission.¹ While PD-1 is being evaluated in UC, it has been clinically validated as a target in two Ph2 studies in RA.^2,3 Rosnilimab, an investigational antibody, aims to leverage immune homeostatic mechanisms to regulate T cell activity by depleting PD-1^high T cells and reducing the activity of remaining PD-1+ T cells.⁴ Rosnilimab, when compared to isotype control, reduced inflammation of the colon, reduced infiltration of CD4 T cells and maintained body weight of mice in a murine model of colitis induced by the transfer of CD4+CD45Rb+ T cells from human PD-1 transgenic mice.⁵ Additionally, pathway genes indicative of fibrosis and impaired barrier function in human UC were normalized in rosnilimab-treated animals while dysregulated in the control group.⁶ Myeloid cells also contribute to inflammation in human UC, and reduction of their elevated numbers are associated with disease remission.⁷ An inflammatory myeloid cell gene signature was derived from human UC and used to assess inflammatory myeloid cells and the therapeutic impact of rosnilimab in this murine model of colitis.

Aims & Methods

A UC myeloid gene signature was derived via secondary analyses of single-cell RNA sequencing data from a published atlas of human UC tissue⁷ to identify 1,652 genes that were upregulated in inflamed myeloid cells compared to non-inflamed cells. These genes were then compared with 3,859 genes upregulated in a murine model of colitis. The resultant overlap of 625 genes was used to define the mouse colitis myeloid gene signature. Overlapping genes were analyzed for regulation in the murine model of colitis following rosnilimab treatment. Myeloid cell gene transcription in colonic tissue from mice treated with rosnilimab or isotype control was assessed via spatial transcriptomics.

Results

In a murine model of colitis, rosnilimab treatment resulted in the downregulation of 399 (64%) of the mouse colitis myeloid signature genes, suggesting an ability to impact a large proportion of the overlapping genes that are similarly dysregulated in human UC. These included mediators of immune cell recruitment (Ccl3, Ccr1) and detection of bacterial components (Cd14, Tlr2 and Tlr4). Additionally, genes involved in immune activation and amplification mediated by myeloid cells were reduced by rosnilimab (Il6, Cd80, Cd86, Myd88, Trem1, and Stat4). Spatial transcriptomic analyses of colonic tissue showed that rosnilimab reduced myeloid cell numbers, including M1 and M2 macrophage subtypes, compared to isotype control treated mice.

Conclusion

In addition to reducing pathogenic T cell numbers in this murine model of colitis, rosnilimab treatment also reduced pathogenic macrophages and the inflammatory myeloid gene signature in the colon. These data support previous preclinical findings demonstrating the potential therapeutic benefits of selectively targeting activated PD-1+ T cells and depleting PD-1^high T cells in reducing inflammation and improving UC outcomes in a murine model of colitis. These results, together with existing rosnilimab safety data in humans, support the scientific rationale for evaluating rosnilimab in an ongoing Phase 2 study in UC (NCT06127043).

References

1. Long Y, et al. Immunol Letters 2021;233:2-10.
2. AnaptysBio press release February 12, 2025. Ir.anaptsbio.com/news-release-details.
3. Tuttle J, et al. N Engl J Med 2023;388:1853-62.
4. Luu K, et al. J Crohn’s Colitis 2024;18(S1):i225 (Abstract DOP81).
5. Parmley S, et al. United Eur Gastroenterol J 2024;12:482 (Abstract MP448).
6. Linggi B, et al. J Crohn’s Colitis 2025;19(S1):i475 (Abstract P0101).
7. Thomas T, et al. Nature Immunol 2024;25:2152-65.

Disclosure

All authors are employees and shareholders of AnaptysBio

Introduction

Inflammatory Bowel Diseases (IBD) are chronic immune-mediated disorders of the gastrointestinal tract. Fibrosis is a frequent manifestation in IBD driven by inflammatory cytokines. During fibrosis, extracellular matrix proteins accumulate in the tissue, causing the disruption of the epithelial barrier and stenosis, ultimately causing malabsorption and intestinal motility issues. This can eventually lead to further serious complications, strictures, fistulas, or ileus. No drugs are available targeting fibrosis, in these cases, only surgical intervention can be used. A defined primary in vitro cell culture model is not available for intestinal fibrosis modeling.

Aims & Methods

Therefore, we aimed to establish and characterize human primary fibroblast cell culture from intestinal biopsies of control and IBD patients.
Human primary fibroblast cell cultures were generated from colonic biopsy of patients with IBD (N=4) and control (N=4). All downstream analyses were applied in passage number 3. For the phenotype observation, immunofluorescent staining was used. Targeted proteins were COL1A1, TGF-ß1, PAI-1, α-SMA, and PHH3. Proteome Profiler Human Cytokine Array Kit was used for the secreted cytokine pattern observation. For the gene expression analysis, RNA was isolated, and the qRT-PCR technique was utilized for the following target genes: COL1A1, ACTA2, TGF-ß1, FN1, PAI-1, H3C4. Scratch assay was used to examine wound closure, we monitored the closing for 48 hours taking photographs throughout. We evaluated the collected data and performed statistical analysis.

Results

We can successfully generate and maintain human colon primary fibroblast cell cultures from colonic biopsies of healthy and Crohn’s disease (CD) origins. Morphological differences were observed between control and diseased patient samples. In the protein examinations, the fluorescent intensity of fibrotic markers (COL1A1, TGF-ß1, PAI-1) and the mitosis marker PHH3 were significantly higher in the CD samples, indicating that the cells maintained fibrotic phenotype and the diseased fibroblasts had a higher proliferation rate. The myofibroblast marker, α-SMA, didn’t show a significant difference. In the cytokine pattern analysis, 22 cytokines showed a twofold increase or decreased by half between the two groups. HGF and DPPIV showed higher quantities in the CD-originated fibroblast. These cytokines are connected to the induction of fibrosis. However, the ANG, BDNF, PTX-3, VEGF, and VCAM-1 were higher in the control samples. Interestingly, no significant differences were noted between the two groups in the targeted genes examined by qRT-PCR measurements. We observed the closure of the artificial wound was faster and more effective in the Crohn’s disease culture compared to the control.

Conclusion

In conclusion, we can generate primary human intestinal fibroblast cell cultures and maintain them to passage number 3, approximately a month long. Fibrotic markers, secreted cytokines and morphological differences distinguish the diseased cultures from the healthy subjects; therefore, it could be useful for in vitro fibrosis modeling in the future. On the other hand, the gene expression analysis doesn’t discriminate between the two groups at passage number 3. To continue with our work, we will observe the fibrotic properties in earlier passage numbers.

Introduction

Corticosteroids are a common treatment for patients with moderate to severe active ulcerative colitis (UC), but their effects can vary among individuals, including resistance, response, and dependence. While patient responses to corticosteroid therapy are generally swift, clinical remission may not be immediate for some. This suggests that corticosteroid treatment should be continued for a period of time to differentiate between corticosteroid-resistant and corticosteroid-sensitive patients with moderate to severe disease activity. Consequently, identifying factors that can predict whether steroid use should be maintained or if a switch to a different treatment is necessary is an important consideration.

Aims & Methods

We compared the clinical characteristics of steroid responders and non-responders in patients with UC and retrospectively evaluated for biomarkers that could predict the efficacy of corticosteroid therapy prior to treatment in patients with moderate to severe active UC. Additionally, we compared the changes in various parameters before and after corticosteroid administration between steroid responders and non-responders. We enrolled 102 UC patients from Nippon Medical School Hospital who had a history of corticosteroid treatment prior to June 2024. The patients were divided into two groups: steroid responders and steroid non-responders. Their clinical characteristics were determined based on medical records.

Results

A total 102 UC patients with moderate to severe disease activity were included in this study. The clinical characteristics at baseline were as follows: the median age, 43 years (average 44.76± 17.79); with 61 males and 41 females. The most common distribution of disease type was total colitis (65%), followed by left-sided colitis (32%), and proctitis (2%). 42.6% of patients had severe disease activity. After remission induction therapy, 16% of patients were steroid non-responders, while 84% were steroid responders. The average Mayo Endoscopic Score was significantly lower, and eosinophil counts were higher in the steroid responder group compared to the steroid non-responder group (P=0.023, 0.016). We also compared changes in various parameters at baseline and 4 weeks after steroid treatment between the two groups. After 4 weeks, inflammation markers including CRP and platelet counts decreased significantly in both groups. Hemoglobin and albumin levels increased significantly, and eosinophil counts decreased in the steroid responder group, but these changes were not observed in the steroid non-responder group.
Histological examination revealed no significant difference in the number of eosinophils infiltrating the colorectal mucosa on biopsy before steroid therapy between the two groups. However, 4 weeks after treatment, the number of infiltrating eosinophils was significantly decreased in the steroid responder group (P<0.001, Wilcoxon signed-rank test), while no change was observed in the steroid non-responder group.

Conclusion

Eosinophil count in the blood could serve as a potential biomarker for steroid responsiveness prior to administration. Additionally, steroid use decreases inflammatory markers such as CRP and platelet count, regardless of patient response. However, eosinophil counts were reduced only in the responder group, suggesting that changes in eosinophil count may also be a predictor of efficacy in the long term.