Introduction

There is an increasing diversification in the treatment landscape for Crohn’s disease (CD) driven by heterogeneity of individual phenotypes, disease courses and previous treatments. This complexity makes universal evidence-based algorithms challenging. A “treat-to-target approach” with tight inflammation monitoring after starting biologics or small molecules therapy is recommended. Intestinal ultrasound (IUS) has proven effective in monitoring treatment response in large CD cohorts. Transmural healing (TH) is a robust but puzzling endpoint that can be achieved in about one-fourth of patients treated with biological therapy and few prognostic indicators to predict it were analyzed.

Aims & Methods

We aimed to describe treatment patterns and effective therapeutic sequences to achieve TH. Secondary aim was to identify prognostic factors to predict TH. This retrospective analysis included CD patients treated with biological and small molecules therapies according to the ECCO recommendations. Patients received biological and small molecules therapies across up to four treatment lines. Biological and small molecules treatment pathways prior to achieve TH were visualized using a Sankey diagram. IUS outcomes were evaluated one year after each biological and small molecules therapy. Logistic regression analysis was performed to identify clinical predictive factors of TH, that was defined as bowel wall thickness <3 mm and no vascularization at IUS.

Results

Among 139 patients treated with biological and small molecules therapies, TH was achieved in 25.9% (n = 36). Infliximab was used as the first-line agent in 55 patients (39.6 %), adalimumab in 69 (49.6%), vedolizumab in 6 (4.4%), certolizumab pegol in 1 (0.7%), Ustekinumab in 8 (5.7%). Twenty-five patients (20%) achieved TH after the first-line therapy (n=10 with infliximab; n=9 with adalimumab; n=3 with vedolizumab; n=3 with ustekinumab). TH rates declined with each additional line of therapy. The median time to achieve TH was 25.6 months (range 12–60). Treatment sequencing analysis revealed a progressive shift toward ustekinumab in later lines, with anti-TNFs remaining the most frequent first-line agents. Multivariate analysis showed that colonic lesion and early treatment (within 2 years from diagnosis) were associated with a higher likelihood of achieving TH [OR = 7.76, p<0.001; OR 6.705, p<0.001, respectively], while perianal disease was associated with a lower likelihood of TH [OR 0.151, p=0.02].

Conclusion

This study highlights a progressive decline in TH rates with successive lines of biological and small molecule therapies in CD patients and identifies several clinical factors that influence this outcome. Long-term follow-up and prospective studies specifically designed to evaluate sequencing in patients exposed to anti-TNFs are needed to guide challenging decisions.

Introduction

Intestinal ultrasound (IUS) is increasingly used as a point-of-care tool for patients with ulcerative colitis (UC). Non-invasive monitoring is essential for managing disease progression and therapeutic intervention in pediatric UC patients. The Milan Ultrasound criteria (MUC), ulcerative colitis intestinal ultrasound score (UC-IUS), and Civitelli score show promise as real-time disease activity assessment tools, potentially reducing the need for invasive procedures like endoscopy.

Aims & Methods

A prospective cohort of 34 pediatric UC patients underwent IUS and colonoscopy to assess disease activity using MUC, UCIUS, and Civitelli scores. Assessments were conducted within a 7-day interval, with no therapeutic changes between procedures. Diagnostic accuracy was determined using receiver operating characteristic (ROC) curves, with endoscopy as the reference
standard, and histological parameters assessed in a subset of patients using the Nancy Index.

Results

The study included 34 pediatric UC patients (median age: 14.7 years; 65% male) with varied disease severities and durations (median duration: 12.6 months; median PUCAI: 30; median fecal calprotectin: 1041 μg/g). Bowel wall thickness (BWT) correlated significantly with all IUS scores; however, no correlation was observed between BWT and baseline Mayo endoscopic disease activity. The area under the curve (AUC) was 0.528 (CI:0.348–0.704) for MUC, 0.602 (CI: 0.418–0.768) for UC-IUS, and 0.572 (CI: 0.388–0.742) for the Civitelli score, indicating moderate diagnostic accuracy. While differences among scores were not statistically significant, UC-IUS demonstrated the highest accuracy. In 16 patients with available Nancy Index data, the AUC values were 0.500 for MUC, 0.579 for Civitelli, and 0.563 for UC-IUS, further supporting moderate accuracy (Table 1).

Conclusion

Both MUC, Civitelli, and UC-IUS scores provide moderate diagnostic accuracy in assessing pediatric UC, though potentially less effective than in adult populations. UC-IUS, with its emphasis on vascularization, haustration and wall thickness, may offer enhanced sensitivity in pediatric patients. Lowering the cut-off for bowel wall thickness may improve accuracy in children, given their thinner, yet highly vascularized bowel walls, particularly in early disease stages.

References

1. van Wassenaer EA, van Rijn RR, Zwetsloot SLM, et al. Intestinal Ultrasound to Assess Ulcerative Colitis Disease Activity in Children: External Validation and Comparison of 2 Intestinal Ultrasound Activity Indices. Inflamm Bowel Dis. 2023;29:1217-1222.
2. Allocca M, Dell'Avalle C, Craviotto V, et al. Predictive value of Milan ultrasound criteria in ulcerative colitis: A prospective observational cohort study. United European Gastroenterol J. 2022;10:190-197

Introduction

Tyrosine kinase 2 (TYK2) inhibitors block signaling downstream of multiple pro-inflammatory cytokines involved in immune-mediated inflammatory diseases, including inflammatory bowel disease, and may have an improved safety profile relative to Janus kinase inhibitors. Phase 2 studies of the highly selective and potent TYK2 inhibitor zasocitinib in Crohn’s disease (CD; NCT06233461) and ulcerative colitis (UC; NCT06254950) are ongoing.^1,2 Here, we describe the design of a combined open-label extension trial (NCT06764615), which will include patients from both parent trials who are responsive to treatment.

Aims & Methods

Patients are eligible for the phase 2 parent studies in CD and UC if they are aged 18–75 years with moderately to severely active disease, and have inadequate or loss of response to, or intolerance of, ≥ 1 standard or advanced therapy. Patients who have failed treatment with ≥ 3 classes of advanced therapy are excluded. Patients are randomized to one of three (CD) or two (UC) doses of zasocitinib, or placebo, for a 12-week double-blind induction phase followed by a 40-week sponsor-open (CD) or open-label (UC) maintenance period. At the end of the parent trials, patients will be eligible for the combined open-label extension if they are clinical (CD) or symptomatic (UC) responders at Week 52, defined as: (1) CD: a ≥ 30% decrease in average daily very soft or liquid stools and/or a ≥ 30% decrease in average daily abdominal pain from baseline; and (2) UC: a ≥ 1-point and ≥ 30% decrease from baseline in partial modified Mayo score, and a ≥ 1-point decrease from baseline in rectal bleeding (RB) subscore or achievement of an absolute RB subscore of ≤ 1. All enrolled patients will receive the same dose of open-label, oral, once-daily zasocitinib for a maximum of 108 weeks, with study visits every 12 weeks, followed by a 4-week safety follow-up period. Data analysis will be descriptive, with no formal statistical comparisons performed.

Results

The primary objective of the study is to determine long-term safety and tolerability, assessed through the incidence of treatment-emergent adverse events or adverse events of special interest. Secondary endpoints will assess the long-term efficacy of zasocitinib, including clinical, symptomatic, or endoscopic response or remission by visit or at Weeks 48 and 108, according to indication, and effects on patient-reported outcomes, including fatigue, bowel urgency, abdominal pain, and disease-specific health-related quality of life.

Conclusion

This open-label extension trial will provide data on the long-term safety of zasocitinib, as well as durability of treatment response among patients with CD or UC who experience treatment benefit in the phase 2 parent studies.

References

1. Jairath V et al. UEG Journal 2024;12(S8):1033.
2. Peyrin-Biroulet L et al. UEG Journal 2024;12(S8):1041.

Disclosure

GP reports receiving personal payments, honoraria, or speaker fees from AbbVie, Allergan, BMS, Celltrion, Ferring, Galapagos, Janssen, Pfizer, Sorriso, Takeda, and Tillotts, travel grants or fellowships from AbbVie, Celltrion, Ferring, Janssen, Takeda, and Tillotts, and is a Director and shareholder in Ampersand Health. SGR, LZ, VAN, LA, FN, TF, LS, and NS are employees and shareholders of Takeda.

Introduction

Mitochondrial dynamics refers to coordinated cycles of mitochondrial fission and fusion that allow mitochondrial networks to re-model their shape, distribution and size. These transient processes are involved in multiple cellular functions and the perturbation of mitochondrial dynamics is reported in models of Inflammatory Bowel Diseases (IBD). The role of Dynamin-related protein 1 (Drp1), a critical GTPase for mitochondrial fission, remains understudied in an intestinal disease context.

Aims & Methods

This research aims to examine how mitochondrial networks are altered in mouse and cell culture-based models of intestinal injury and IBD. Cell culture-based assays were performed with the MODE-K intestinal epithelial cell line to explore the role of mitochondrial dynamics in vitro. A Drp1-specific knockout (Drp1 KO MODE-K) was generated using CRISPR-based approaches . Mitochondrial fission was also targeted pharmacologically using P110 and Mdivi-1 fission inhibitors. Intestinal tissue from IBD-related mouse models including TNF^ΔARE (ileitis), Il10^-/- (colitis), Hsp60 ^Δ/ΔIEC (metabolic injury) and Hsp60 ^Δ/ΔIEC;Il10^-/- (metabolic injury/colitis) mice were used for histological analyses and ex vivo organoid cultures. TOM20 was used to stain mitochondrial networks. A novel IBD mouse model with a Drp1 intestinal epithelial cell specific knockout Drp1 ^Δ/ΔIEC;Il10^-/- was generated to assess the role of Drp1-mediated mitochondrial fission in vivo.

Results

TOM20 immunofluorescence staining of mouse tissue sections show that mitochondrial morphology, localisation and mass are diverse under different inflammation and injury-based conditions. The colitis susceptible Il10^-/- mice typically show more fragmented, rounder mitochondria with a decrease in mitochondrial mass compared to Il10^+/+ controls. Hsp60^Δ/ΔIEC mice have a conditional deletion of the Heat shock protein 60 (Hsp60) in the epithelium which results in metabolic injury, a transient tissue injury with irregular tissue architecture and altered mitochondrial metabolism. This Hsp60 loss further accelerates Il10^-/- pathology in Hsp60 ^Δ/ΔIEC;Il10^-/- mice. At day 4 (D4) post tamoxifen treatment, before the onset of crypt loss, Hsp60 ^Δ/ΔIEC;Il10^-/- mice show an increase in a phosphorylated form of Drp1 (pDrp1^Ser616) indicating increased mitochondrial fission. At day 8 (D8), during peak metabolic injury, both Hsp60 ^Δ/ΔIEC;Il10^+/+ and Hsp60 ^Δ/ΔIEC;Il10^-/- mice show a significant increase in mitochondrial mass compared to controls. Furthermore, co-stimulation of ex vivo wild-type organoids with the inflammatory cytokine Tnf and the Drp1-specific inhibitor P110 increases mitochondrial unfolded protein response (UPR) markers at the mRNA level, highlighting the interplay between mitochondrial dynamics and stress responses in injury-based inflammatory conditions. Drp1 KO MODE-K cells also show a noticeable increase in dense, peri-nuclear TOM20 staining when compared to control cells. In extension, the novel Drp1 ^Δ/ΔIEC;Il10^-/- model has proved viable and preliminary data indicates that Drp1 ^Δ/ΔIEC;Il10^+/+ mice have reduced body weights compared to Drp1 ^flox/flox;Il10^+/+ mice. Further characterisation will provide insight into the interplay between Drp1, mitochondrial dynamics and intestinal disease development.

Conclusion

Mitochondrial networks are altered in response to different types of inflammation or injury in models of IBD. Regulated mitochondrial fission and fusion is important for intestinal epithelial cell homeostasis and Drp1 loss or inhibition affects intestinal epithelial cell responses.

Introduction

IIn Crohn’s disease, chronic inflammation drives fibroblast activation, excessive collagen deposition, and creeping fat expansion, all contributing to fibrostenotic strictures. We examined serum markers related to collagen formation, macrophage and neutrophil activation, and NETosis, exploring their associations with stricturing Crohn’s disease in a treatment-naïve IBD inception cohort.

Aims & Methods

142 Serum samples from CD patients were analysed (IBSEN III population matched baseline and 1-year follow-up). The Montreal classification (luminal, fibrostenotic strictures, fistula) was applied to assess disease complications at the time of serum sampling, e.g. baseline biomarkers measurements were paired with baseline Montreal B assessment, and one-year followup biomarkers measurements were paired with one-year followup Montreal B assessment. The biomarkers C4M, C6M, C7M, PRO-C3, PRO-C4, PRO-C5, PRO-C6, PRO-C11, PRO-C16, PRO-C22, VICM, CTX-III, CPa9-HNE were measured in the serum samples at baseline (total n=142; luminal n=114; fibrostenotic n=23, fistula n=5) and 1-year follow-up (total n=142; luminal n=111; fibrostenotic n=24, fistula n=7). One-way-ANOVA with LSD correction was applied for statistical analysis.

Results

The PRO-C6 (p<0.001) and CPa9-HNE (p<0.05) biomarkers were significantly elevated in CD patients with fibrostenotic strictures compared to luminal CD patients at baseline, and PRO-C6 was continually elevated in serum after 1 year of follow-up in patients with fibrostenotic strictures (p<0.01). At baseline, C7M was demonstrated to be elevated in fistulizing CD patients compared to luminal and fibrostenotic CD patients (P<0.01). PRO-C5 (p<0.001) and PRO-C16 (p<0.01) were significantly elevated at 1-year follow-up in the CD patients with fibrostenotic strictures compared with luminal CD patients. None of the remaining biomarkers were associated with stenotic or fistulizing CD.

Conclusion

These encouraging biomarker data from the IBSEN III, especially PRO-C6, seem to be a promising biomarker for intestinal fibrosis, as PRO-C6 was demonstrated to be elevated at baseline and after 1 year follow-up. CPa9-HNE levels were highest in the fibrostenotic group, suggesting neutrophil activity and NETosis involvement in intestinal fibrogenesis. Elevated levels of C7M were associated with fistula in CD patients, suggesting that C7M is reflective of transmural inflammation. The biomarkers PRO-C5 and PRO-C16 are also relevant biomarkers of established intestinal fibrosis, as these were elevated after 1 year of follow-up. Collectively, these biomarker data highlight the importance of quantifying collagen protein fragments in serum as tools for assessing intestinal fibrosis in Crohn’s disease.

Disclosure

Full time employee at Nordic Bioscience A/S

Introduction

Vedolizumab (VDZ) is a monoclonal antibody therapy approved in China in 2020 for the treatment of patients with inflammatory bowel disease (IBD; Crohn's disease [CD] and ulcerative colitis [UC])² who were intolerant to conventional therapies.¹ VDZ has a unique, gut-selective, anti-lymphocyte trafficking (GSALT) mechanism of action.³ However, data on the efficacy and safety of VDZ in Chinese patients with IBD in the real-world setting are limited.⁴ This study evaluated the safety of VDZ in adult patients with IBD.

Aims & Methods

VALUE (NCT04872491) was a multicenter, single-arm, prospective, observational study to evaluate the safety of VDZ in adult Chinese patients with IBD (N=500) over a maximum observation period of 72 weeks. Incidence of adverse events (AEs), serious AEs (SAEs), treatment-related adverse drug reactions (ADRs), and AEs of special interest (AESIs) was evaluated. This was the final analysis of the VALUE study conducted in patients with IBD.

Results

A total of 500 patients (UC: n=409; CD: n=91) received VDZ 300 mg. Mean (±standard deviation) age of patients was 44.3 (±15.2) years, and 61.4% (n=307) were male. The mean duration for VDZ exposure was 414 days (UC: 416 days; CD:407 days). A total of 500 patients developed 674 AEs (Table), and the most frequent AEs were infections and infestations (I&I; UC: 115 [28.1%]; CD: 24 [26.4%]), followed by gastrointestinal disorders (GIDS; UC: 87 [21.3%]; CD: 18 [19.8%]). Incidence rates of AEs (/patient-years) were 1.2 and 1.0 in patients with UC and CD, respectively. Overall, 13 (3.2%) patients with UC and 10 (11.0%) with CD had AEs leading to study discontinuation. SAEs were observed in 78 patients with UC and 18 with CD (Table). A total of 19 AESIs were reported by patients with UC and 9 AESIs by those with CD, with the most common AESIs being I&I (UC: 13 [3.2%]; CD: 4 [4.4%]) and malignancy (UC: 3 [0.7%], CD: 2 [2.2%]). The most common I&I disorders reported by patients with UC and CD were Clostridium difficileinfection (4 [1.0%]) and pneumonia (1 [1.1%]), respectively. Overall, 17 (4.2%) patients with UC and 7 (7.7%) with CD had at least 1 AESI. A total of 91 and 15 treatment-related ADRs were observed in patients with UC and CD, respectively; I&I were the most frequently documented ADRs to VDZ treatment (Table). A total of 10 (UC: 5 [1.2%]; CD: 5 [5.5%]) patients treated under concomitant IBD advanced therapy (CIBDAT) experienced a total of 16 AEs (UC: 9; CD: 7), with the most common AEs being I&I (UC: 1 [20.0%]; CD: 2 [40.0%]) and GIDS (UC: 3 [60.0%]; CD: 1 [20.0%]) with CIBDAT. No deaths were reported during the study.

Conclusion

The VALUE study indicated that VDZ was well tolerated in Chinese patients with IBD, with no new safety concerns.

References

1. Scribano ML. World J Gastroenterol. 2018; 24: 2457-2467.
2. Yamamoto S et al., Cureus. 2024;16: e59691.
3. Soler D et al. J Pharmacol Exp Ther. 2009; 330: 864-875.
4. Baili C et al. Am J Gastroenterol. 2023; 118: S213-S214.

Disclosure

This study was funded by Takeda (China) International Trading Co. Ltd. Li Li, Haiyan Zhang, Chengxia Liu, and Xiaomei Sun have no conflicts of interest. Xiaoyu Qian and Fang Zhou are Takeda employees and hold Takeda stock options. Minhu Chen received speaker honorariums from Takeda China, AstraZeneca China, Xian Janssen, and Eisai China.
Medical writing support for the development of this abstract under the direction of the authors was provided by Vibhuti Singh, Ph.D., of Cactus Life Sciences (part of Cactus Communications), funded by Takeda (China) International Trading Co., Ltd.

Introduction

Recurrence of Crohn’s disease (CD) lesions after surgery remains high. Identifying patients at high risk of recurrence who may benefit from prophylactic therapy would be relevant. However, data on specific preoperative risk factors remain scarce, while onset and severity of Post Operative Recurrence (POR) are assessed with the Rutgeerts score (RS)(1). Still, the value of early endoscopic lesions, and RSi2, to predict the later course of the disease and the risk of late (from 1 to 10 years) POR in any individual patient is unclear. Non-invasive Small Intestine Contrast Ultrasonography (SICUS) assesses intramural extension of CD lesions, their progression, and is as effective as RS in detecting early POR lesions (2).

Aims & Methods

1. To develop a risk score based on pre-operative clinical predictors to estimate POR likelihood;
2. to identify predictors of severity of mucosal lesion according to RS;
3. to assess the overtime progression of transmural lesion.
Prospective cohort study (1998-2022). CD patients were evaluated at ileo-colonic surgery and every 6-12 months thereafter. Sex, age at diagnosis/surgery, active smoking, CD behaviour (B)/location (L), perianal disease (PD), length of resected bowel, steroids, immunosuppressants/biologics therapy use, and CD duration before surgery were analysed using multivariable proportional hazards regression. Cumulative POR rates and risk score were calculated with Poisson models, taking for each predictor the integer part of the Poisson model parameter.

Results

Over a median follow-up of 7.6 years (IQR 4.1–12), 78 patients (32 F; median age 30 years; 60% smokers) were analysed. CD characteristics: B1 8%; B2 67%; B3 25%; L1 63%; L3 36%; PD 22%; immunosuppressive/biologics 17%; median CD duration pre-surgery 4.7 years; median resected bowel length 28 cm. Cumulative POR rates were 51.8% (IQR,41%-63.4%), 65.2% (54.4%-75.7%), 69% (58.6%-79%), 75.9% (65.8% -84.8%), 78.9% (69.0%-87.3%), at 1, 2, 3, 4, and 5 years. POR risk factors included active smoking, age ≥35 years at surgery, and marginally B1 (Table). Predictors of RS were PD (HR=3.39; 95% CI 1.12-10.26; p=0.03 and CD duration ≥5 years pre-surgery (3.45; 1.15–10.32; p=0.03). The estimated cumulative probability of POR increased with higher risk scores (from 1 to 3) being 22%, 58%, 83% and, respectively, 43%, 80% and 100% at 1 and 4 years. Lesion length at POR varied by RS (median, IQR): RSi1 (32%): 0.5 cm (0.5-0.5), RSi2 (35%): 4 cm (0.5-7), RSi3 (15%): 15 cm (8.5-21.5), RSi4 (5%): 16 cm (9.5-23.5). Lesions remained stable in patients with RSi1 and RSi3 (45%) but fluctuated in those with RSi2 and RSi4 (31% increased, 24% decreased).

Conclusion

The present score based on preoperative factors predicts the risk of postoperative recurrence. Patients with preoperative higher risk scores or RSi2 at recurrence would require early and close monitoring due to significant transmural lesion progression.

References

1.Rutgeerts R et al. 1990; 2. Pallotta N et al. 2010.

Disclosure

Nothing to disclosure