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

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

The cause of Crohn’s Disease (CD) remains unclear; however evidence suggests that dietary factors play a key role. With a rising incidence and no definitive cure, identifying modifiable risk factors is critical in preventing CD development. We aimed to study the association between fermentable dietary fibre intake and the future development of CD in an at-risk population.

Aims & Methods

Participants were recruited as part of the Crohn’s and Colitis Canada GEM study, a prospective cohort study of healthy first-degree relatives of patients with CD. At enrolment, a validated food frequency questionnaire was administered. Pectin, β-glucan, inulin, fructooligosaccharides (FOS), and arabinoxylan intake were quantified, and values energy-adjusted. Survival analysis was used to test the association between intake of fibre subtypes and risk of CD development. Generalized estimating equation tested the association between fibre intake and baseline impaired intestinal permeability (fractional urinary excretion of lactulose to mannitol ratio (LMR) >0.025); subclinical gut inflammation (faecal calprotectin (FCP) >250 μg/g); and faecal microbiome composition via 16s rRNA sequencing.

Results

76 of the 2,659 participants developed CD with a median follow-up of 8.9 years (IQR=5.7-12.3). Median age at recruitment was 17 years (IQR=12-25). 47% were male. Higher intake of inulin (HR = 0.78; 95% CI=0.61–0.99; p=0.04) and β-glucan (HR = 0.78; 95% CI=0.61–0.99; p=0.04) were associated with a reduced risk of CD development. No fibre subtype was associated with a higher risk of CD development. Lower intake of pectin, inulin, FOS and β-glucan was associated with impaired intestinal permeability (0.005<p<0.04). Lower inulin intake was associated with high FCP levels (p = 0.046). Higher pectin intake was associated with increased alpha diversity of faecal microbiome (p = 0.028). Higher inulin, FOS and pectin intake was associated with a shift in microbial taxa previously shown to be protective against CD onset in the GEM cohort; a reduction in Ruminococcus torques and an increase in NK4A214 group (phylum Firmicutes) presence (3.25×10⁻¹⁰<q<0.04).

Conclusion

This study demonstrates that dietary intake of fermentable fibre subtypes is associated with a reduced risk of CD development as well as with pleiotropic changes in CD risk biomarkers including microbiome, intestinal permeability, and subclinical inflammation. This suggests that the potential benefit of fermentable fibres on CD risk may involve changes in barrier function, and microbiome composition and function. Targeted interventions based on these findings could prove effective in preventing the onset of CD.