Introduction

Both exclusive enteral nutrition (EEN) and steroids are effective therapies to induce remission in children with Crohn’s disease (CD), but comparative data accounting for disease location are scarce.

Aims & Methods

We aimed to compare the effectiveness of EEN and steroids induction treatment in isolated ileal pediatric CD using data from two large real-world data cohorts. Children (age 2-18 years) with newly-diagnosed CD with an isolated ileal disease phenotype prospectively enrolled in the multicenter Canadian CIDsCaNN or predominantly European PIBD-SETQuality inception cohorts, who received either EEN or systemic steroids induction treatment, were eligible for this study. Demographics and extensive clinical data were collected prior to treatment and longitudinally until the last follow-up. Outcomes, including [sustained] steroid free remission ([S]SFR), normal CRP remission (NCR; defined as remission with CRP <0.5 mg/dl), and (delta) height and BMI z-scores were compared at 3 months and 1 year. Time-to-first-biologic and time-to-luminal-resection were determined by Kaplan Meier curves and compared between groups using the log-rank test.

Results

A total of 221 children (n=134 [61%] CIDsCaNN, n=87 [39%] PIBD-SETQuality) with Crohn’s disease with an isolated ileal phenotype receiving EEN (n=158 [72%]) or steroids (n=63 [28%]) as induction treatment were eligible for analysis (median follow-up 868 days [IQR 539 – 1443]). Disease phenotype, clinical and biochemical disease activity indices as well as demographics and anthropometrics, were similar between treatment groups (Table 1) and between cohorts. At 1 year, rates of SSFR (33% vs. 38%; p=0.56) and NCR (53% vs. 44%; p=0.27) were comparable between EEN and steroids-treated patients. Linear growth was borderline reduced in the steroids treated group (median height Z-score –0.42 [IQR –1.21 - 0.12]) compared to the EEN treated group (0.02 [IQR –0.94 - 0.59; p=0.050). Type of induction treatment did not affect time-to-first-biologic (p=0.84) or time-to-luminal-resection (p=0.11). At 3 months, combined rates of SFR + NCR were higher in patients who received EEN (38/111 [34%]) compared to those who received steroids (9/47 [19%]; p=0.058), largely because of differences in steroid exposure (14/121 [12%] with EEN, 19/39 [48%] with steroids; p<0.001), and normal CRP (68/108 [57%] and 18/43 [42%] respectively, p=0.084). Only in 20/220 (9%) of patients (15/157 [10%] with EEN, 5/63 [8%] with steroids; p=0.71), an additional induction therapy agent (EEN, steroids, biological, surgery) was started within 30 days after the start of induction treatment.

Conclusion

EEN and steroids induction therapy show comparable short- and long-term clinical effectiveness in children with isolated ileal CD, but EEN trended towards better linear growth outcomes at one year.

Table 1 Patient and disease characteristics at diagnosis of children with Crohn’s disease with isolated ileal disease (L1), stratified by induction therapy

Introduction

Faecal microbiota transplantation (FMT) has shown promise as treatment in inducing remission in patients with ulcerative colitis (UC), however effectiveness varies (1). Optimizing FMT protocols involving anaerobic stool processing to improve bacterial viability, dual-route administration and donor selection may improve efficacy.

Aims & Methods

Our aim was to evaluate the effectiveness of an optimized FMT protocol using anaerobically prepared stool from pre-selected donors in a randomized controlled multi-centre trial using dual-route administration in patients with mild-to-moderately active UC. A total of 85 patients were randomized to either receive donor FMT (n = 44) or autologous FMT (n = 41) via four weekly FMTs comprising two dual-route administrations, nasoduodenal administration combined with enema, and two single enemas. The study was performed at the Amsterdam University Medical Centre and University Medical Centre Groningen from June 2020 till January 2025. Follow-up time is 12 months and ongoing. Donors were selected based on their microbiota profile, informed by our previous TURN trial (2, 3). The primary outcome was steroid-free clinical remission at week 8 defined as a total adapted Mayo score of ≤2, with a stool frequency subscore of ≤1, a rectal bleeding subscore of 0, and an endoscopic subscore of ≤1. Open-label extension was offered to patients in the autologous FMT group who did not reach clinical remission.

Results

Eighty-five patients were randomized (mean age 43.6 years, 48% female), with 76 (89%) patients completing all four treatments. In the modified intention-to-treat analysis, meaning all patients that received at least one FMT treatment (n = 82), primary endpoint was reached in 10 of 44 (23%) patients receiving donor FMT and in 2 of 38 (5%) patients receiving autologous FMT, (two-sided χ², p = 0.026). A further total of 26 patients received donor FMT in open-label extension of which 21 (81%) received all four treatments with 7/26 (27%) reaching the primary endpoint. Serious adverse events occurred in 6/44 (14%) in the donor FMT group vs 4/41 (10%) the autologous group. Two events were deemed related to the FMT treatment (pneumothorax after nasoduodenal placement and overnight hospitalization for abdominal pain one-day post FMT).

Conclusion

In this multi-centre randomized controlled trial, anaerobically processed, donor-selected, dual-route FMT demonstrated a higher likelihood of inducing clinical remission with donor FMT compared to autologous FMT at 8 weeks. The protocol proved feasible and generally safe. Larger trials are warranted to confirm efficacy and to optimize donor and patient selection strategies. ClinicalTrial.gov. Number: NCT05998213

References

1. Imdad A, Pandit NG, Zaman M, Minkoff NZ, Tanner-Smith EE, Gomez-Duarte OG, et al. Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database Syst Rev. 2023;4(4):Cd012774.
2. Fuentes S, Rossen NG, van der Spek MJ, Hartman JH, Huuskonen L, Korpela K, et al. Microbial shifts and signatures of long-term remission in ulcerative colitis after faecal microbiota transplantation. Isme j. 2017;11(8):1877-89.
3. Rossen NG, Fuentes S, van der Spek MJ, Tijssen JG, Hartman JH, Duflou A, et al. Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis. Gastroenterology. 2015;149(1):110-8.e4.

Disclosure

The authors report no COI with regard to this study

Introduction

Chronic low-grade inflammation, known as inflammageing, has been implicated in the pathogenesis of various digestive diseases. However, large-scale systematic evaluations of the association between inflammageing biomarker profiles and digestive system disorders remain scarce. Understanding these associations may have important implications for early detection and intervention strategies.

Aims & Methods

Leveraging the multidimensional data from the UK Biobank, this study aimed to investigate the longitudinal relationships between circulating inflammatory markers and major digestive diseases. A total of 45,475 participants were included, with inflammageing levels calculated as the average of standardized values of four circulating inflammatory markers: TNF, IL1RN, IL18, and IL6.
Digestive disease outcomes were identified from hospital records (HES) and death registries, covering 25 major diagnoses, including gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), and non-alcoholic fatty liver disease (NAFLD). Cox proportional hazards models were used to estimate hazard ratios (HRs), adjusting for age, sex, BMI, smoking, and other potential confounders.
In addition, Mendelian randomization (MR) analysis was conducted using GWAS data derived from inflammageing scores to evaluate potential causal effects on digestive outcomes. Mediation and subgroup analyses were performed to explore possible mediating factors.

Results

In the Cox regression analysis, 22 out of 25 digestive outcomes showed significant associations with baseline inflammageing levels (Bonferroni-corrected P < 0.05), with HRs ranging from 1.2 to 2.4.
Mediation analysis identified neutrophil counts and LDL-C as important mediators in these associations, suggesting potential biological pathways linking inflammageing to digestive disease development.

Conclusion

Elevated baseline inflammageing levels were significantly associated with a wide spectrum of digestive system diseases. The findings highlight a potential mechanistic role of systemic inflammation in digestive disease pathogenesis. The use of inflammageing-related biomarkers may aid in early identification of high-risk individuals, offering opportunities for early prevention and targeted interventions.

Introduction

Fistulizing perianal Crohn’s disease (CD) remains a significant therapeutic challenge, with limited randomized controlled trials to date, restricted so far to infliximab and, more recently, filgotinib. The USTAP (NCT04496063) trial aimed to evaluate the efficacy and safety of UST in patients with actively draining perianal fistulas through a multicenter randomized controlled design.

Aims & Methods

This double-blind, placebo-controlled, multicenter trial enrolled adult patients with active draining fistulizing perianal CD. Between April 2020 and June 2024, eligible patients with persistent fistula drainage were randomized 1:1, after seton placement when necessary, to receive either UST (6 mg/kg IV at baseline followed by 90 mg SC at week 8, then every 8 weeks) or placebo. Steroids were allowed at baseline with a standardized steroid taper. Seton removal was planned at week 6. The primary endpoint was combined clinical remission (absence of drainage from all external fistula openings) and radiological remission (defined as the absence of abscesses >2 cm confirmed by blinded central pelvic MRI) at week 12. Secondary endpoints included clinical remission, radiological remission, changes in disease activity (CDAI, PDAI), IBD-DI, and safety. Endpoints were independently reviewed by a blinded adjudication committee. Randomization was stratified by prior anti-TNF exposure and study center. The intended sample size was 73 patients per group to detect a 20% difference in remission rates (power 80%, alpha 5%). Due to slow recruitment, the study was discontinued in June 2024 after randomizing 32 patients, without unblinding the study data. Patients were subsequently followed until week 48.

Results

Thirty-three patients consented to participate with 32 patients (women: 41%; median age: 42) ultimately randomized (UST: 16; placebo: 16) across 10 French centers. Seventy percent had prior anti-TNF exposure (50% in UST arm, 50% in placebo arm), and 23% had previously failed two or more anti-TNF therapies. At baseline, 84% had one draining fistula, 16% had two, and 25% had associated abscesses. At week 12, combined remission was achieved in 62% in the UST group versus 25% in the placebo group (Table). Clinical remission was observed in 69% in the UST group vs. 31% in the placebo group, while radiological remission rates were 87.5% in the UST group and 75% in the placebo group. In the UST arm, mean change in CDAI, PDAI and IBD-DI from baseline to week 12 was -56.3, -2.2 and -4.9, (vs. -9.8, -1.6 and +4.9, in the placebo arm, respectively). Adverse events (AE) and serious adverse events (SAE) were similar in both treatment groups: 23 AE (62%) occurred in the placebo group, and 14 AE (38%) in the UST group. Six SAEs were reported overall, including two gastrointestinal events, one renal disorder, and one anal abscess. Two patients in the placebo group discontinued study by week 6 due to SAEs (an anal abscess and a peri-ileal abscess).

Conclusion

In this trial, where the majority of patients had prior anti-TNF exposure, the observed short-term clinical benefit of UST supports its use in fistulizing perianal CD.

Disclosure

This work was supported by a grant from Johnson & Johnson
Pauline Wils : Johnson & johnson, Takeda, Amgen, Abbvie, Celltrion, Ferring
S Nancey: Abbvie, Johnson and Johnson, Fresenius Kabi, Biogen, Takeda, Medac, Celltrion, MSD, Pfizer, Sandoz, Lilly,Ferring, Amgen
E. Messmer: No conflict of interest for this study
A Bourreille: Johnson and Johnson
A Buisson: Consulting fees from: Abbvie, Amgen, Arena, Biocon, Biogen, Celltrion Healthcare, CTMA, Ferring, Galapagos/AlfaSigma, GutyCare/Resilience Janssen, Lilly, MSD, Nexbiome, Pileje, Pfizer, Roche, Sandoz, Takeda et Tillotts. Lecture fees from: Abbvie, Amgen, Biogen, Celltrion Healthcare Galapagos/AlfaSigma, Ferring, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants/fundings from: Abbvie, Celltrion Healthcare, Janssen, Lessaffre, Lilly, Pfizer, Sandoz and Takeda
L Caillo: No conflict of interest for this study
L Vuitton: abbvie amgen J&J Pfizer Takeda Lilly MSD Mayoli Ferring Dr Falk Alpha Sigma
R Altwegg: Abbvie, Johnson ans Johnson, Takeda, Pfizer, Lilly, Alphasigma, Celltrion, Amgen, Biogen, Sandoz, Ferring
X Hébuterne reports clinical research funding from Abbvie, Abivax, Amgen, Celltrion, Lilly, Fresenius-Kabi, J&J, InDex Pharmaceuticals, Pfizer, Prometheus, MSD, Roche, Takeda, serving on advisory boards for Abbvie, Biogen, Celltrion, Lilly, J&J, and participating in lectures and educational activities for Abbvie, Amgen, Celltrion, Lilly, Fresenius-Kabi, Galapagos, J&J, MSD, Nestlé Health Sciences, Nutricia, Pfizer, Tillots, Takeda.
O Ernst: No conflict of interest for this study
P Meunier: No conflict of interest for this study
V Laurent: No conflict of interest for this study
D Laharie: received board and lecture fees from: Abbvie, Alfasigma, Amgen, Biogen, Celltrion, Ferring, Fresenius-Kabi, Janssen, Lilly, MSD, Pfizer, Roche, Sandoz, Takeda
E Vicaut: No conflict of interest for this study
L Peyrin-Biroulet: Consulting : Abbvie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, BMS, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, Ysopia ; lecture : Abbvie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Janssen, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots, Viatris

Introduction

​​​​​Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that potently blocks interleukin 23 (IL-23) and binds to CD64, a receptor on cells that produce IL-23¹. In patients with moderately to severely active Crohn’s disease (CD), the GALAXI-2 and GALAXI-3 Phase 3 studies established short- and long-term efficacy of GUS compared to placebo, and statistical superiority to ustekinumab (UST) in prespecified analyses of pooled data at Week (WK)48². We subsequently developed an endoscopic clustering method using Simple Endoscopic Score for Crohn's Disease (SES-CD) segmental scores in patients from GALAXI 2/3 which revealed higher endoscopic remission rates with GUS compared with UST at WK12 and WK48 in pts characterized by ileal disease and strictured right colon³. Here we report molecular differentiation of GUS compared with UST in isolated ileal disease based on serum pharmacodynamic (PD) markers and tissue transcriptomics in CD using pooled samples from the GALAXI studies.

Aims & Methods

Patients (pts) in GALAXI-2 (n=508) and GALAXI-3 (n=513) were randomized 2:2:2:1 to receive GUS 200mg IV q4w x3 → GUS 200mg SC q4w, GUS 200mg IV q4w x3→ GUS 100mg SC q8w, UST ⁓6mg/kg IV x1 → UST 90mg SC q8w or placebo IV q4w x3 (PBO). Serum biomarkers were measured in a subset of (n=50) pts per group at WK0, WK4 and WK12 using a proinflammatory panel and a high sensitivity IL-22 assay. Matched ileal and rectal biopsies were evaluated at WK0, WK12 and WK48 in a subset of 344 pts representative of the full study population. Transcriptional profiling was performed with bulk RNA sequencing (RNAseq) using transcriptional modules. Analysis of treatment effects was performed using molecularly inflamed samples (biopsy molecular inflammation score [bMIS]⁴ >0) from segments with SES-CD >0 at baseline. Serum proteins and transcriptional modules were evaluated for differential expression stratified by isolated ileal, isolated colonic and ileocolonic disease defined during screening.

Results

In pts with isolated ileal disease, GUS decreased serum protein levels of IL-22, IL-17A and IFNγ at WK12 while UST only reduced IFNγ. In ileal tissue, GUS significantly altered inflammatory modules at WK12 and WK48 including reductions in neutrophil, inflamed epithelium, IL-23/Th17 and inflammatory fibroblast biology compared with minimal changes observed with UST, which only significantly reduced neutrophil, plasma cell and macrophage modules at WK48. In contrast, in pts with isolated colonic or ileocolonic disease, both GUS and UST decreased IL-23-dependent serum proteins towards normal levels compared with an independent cohort of healthy control sera. In rectal tissue, both GUS and UST significantly altered key inflammatory transcriptional modules in rectal biopsies at WK12 and WK48. Overall, greater effects of GUS vs UST were observed in ileal tissue at WK12 and at WK48 in transcriptional modules associated with decreasing disease-related features and restoring epithelial health than UST.

Conclusion

GUS decreased IL-23-dependent serum proteins and improved tissue transcriptional profiles in pts with isolated ileal disease while UST only reduced serum IFNγ and had a minimal impact on IL-23-dependent transcriptional modules. These data suggest potential differences in IL-23 and IL-12 pathway enrichment in isolated ileal disease where inhibition of IL-23p19 subunit with GUS achieved greater molecular treatment effects early which were maintained through WK48 and associated with differential clinical outcomes in patients with isolated ileal disease.

References

1. Sachen K, Hammaker D, Sarabia I, et al. Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling. Frontiers in Immunology. 2025; doi:10.3389/fimmu.2025.1532852
2. Panaccione R, Danese S, Feagan BE, et al. Efficacy and safety of guselkumab therapy in patients with moderately to severely active Crohn’s disease: results of the GALAXI 2 & 3 phase 3 studies. Gastroenterology. 2024; 5 (Supplement): p1057b
3. Richards D, Seridi L, Sohn, K, et al. Guselkumab shows higher endoscopic remission rates than ustekinumab in patients characterized by isolated ileal and srtictured right colon Crohn’s disease: Post-hos analysis of GALAXI 2/3 Ph3 trials. DDW 2025 Abs #4253526; poster.
4. Argmann C, Hou R, Ungaro, R, et al. A biopsy and blood-based molecular biomarker of inflammation in inflammatory bowel disease. Gut. 2022; 0:1-17.

Disclosure

DR, KS, MZ, RP, BM, NAT, MV, DC and PB are current or former employees of Janssen and may hold stock in Johnson & Johnson.
WR has served as a speaker for AbbVie, Celltrion, Ferring, Janssen, Galapagos Medice, MSD, Roche, Pfizer, Sobi, Takeda, as a consultant for AbbVie, Amgen, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead, Index Pharma, Janssen, Medahead, Microbiotica, Pfizer, Takeda; as an advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Janssen, Pfizer, and has received research funding from AbbVie, Janssen, Sandoz, Sanofi, Takeda.