Introduction

The Phase 3 QUASAR induction study evaluated efficacy and safety of guselkumab (GUS), an IL-23 p19 subunit antagonist, in patients (pts) with moderately to severely active UC with inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, and/or advanced therapies (ie, tumor necrosis factor-alpha antagonists, integrin receptor antagonists, and/or Janus kinase inhibitors). Here we present results for effects of GUS induction on histologic and combined histologic and endoscopic outcomes at Week (Wk) 12.

Aims & Methods

Pts with a modified Mayo score of 5-9 and a centrally reviewed Mayo endoscopy subscore ≥2 at induction baseline were randomized 3:2 to receive either GUS 200mg IV or placebo (PBO) IV at Wks 0, 4, and 8. Colonic biopsies were collected during endoscopy at baseline and Wk12 to evaluate treatment effect on histology measured by using three methods: Geboes, Robarts Histopathology Index (RHI), and Nancy Histological Index (NHI). Histologic improvement (Geboes histologic score ≤3.1), histologic remission (Geboes histologic score ≤2 B.0), the combination of histologic improvement and endoscopic improvement (Geboes histologic score ≤3.1 and Mayo endoscopy subscore of 0 or 1 with no friability; histo-endoscopic mucosal improvement; HEMI), and the combination of histologic remission and endoscopic normalization (Geboes histologic score ≤2 B.0 and Mayo endoscopy subscore of 0) were evaluated at Wk12.

Results

Of the 701 pts randomized (mean age, 40.5yrs; female, 43.1%; mean UC disease duration, 7.52yrs; mean modified Mayo score, 6.9; Mayo endoscopy subscore of 3, 67.9%), 421 were treated with GUS, and 280 were treated with PBO. Baseline demographics and disease characteristics were similar across treatment groups. Histologic activity at baseline was similar across the GUS and PBO cohorts: mean Geboes total score (11.8 vs 11.9, respectively), mean RHI (16.6 vs 16.6), and mean NHI (2.7 vs 2.8). The proportion of pts with histologic improvement at Wk12 was 44.9% among GUS-treated pts and 21.4% among those treated with PBO (adjusted Δ: 23.7%; nominal p<0.001; Table). Histologic remission at Wk12 was achieved by 39.9% and 18.6% of pts receiving GUS and PBO, respectively (adjusted Δ: 21.5%; nominal p<0.001). Identical results were seen across two additional definitions of histologic remission (ie, RHI and NHI; Table). The proportion of GUS-treated pts who achieved HEMI at Wk12 was greater than PBO-treated pts and highly significant (23.5% vs 7.5%, respectively; adjusted Δ: 16.2%; p<0.001). Lastly, histologic remission and endoscopic normalization at Wk12 was achieved by a greater proportion in the GUS group than PBO group (13.5% vs 3.9%, respectively; adjusted Δ: 9.8%; nominal p<0.001).

Conclusion

In this phase 3 induction study, pts with moderately to severely active UC treated with GUS 200mg IV induction experienced clinically meaningful improvements in histologic and combined histologic and endoscopic outcomes at Wk12.

Disclosure

Julián Panés reports consultancy fees/honorarium from Janssen; reports payment for lectures including service on speaker bureau from Janssen; and reports payment for development of educational presentations from Janssen.
Bruce E. Sands reports grants, consulting and speaking fees and other support from Janssen.
Laurent Peyrin-Biroulet reports personal fees from Janssen.
Shadi Yarandi, Kuan-Hsiang G. Huang, Matthew Germinaro, Sunandini Sridhar, Patrick Branigan, Ye Miao, and Hongyan Zhang are employees of Johnson & Johnson and own company stock/stock options.
Xavier Hébuterne reports clinical research funding from Janssen; serving on advisory boards for Janssen; and participating in lectures and educational activities for Janssen.
Tibor Gyokeres reports consulting fees from Janssen; lecture fees from Janssen; and support for attending meetings and/or travel from Janssen.
Fumihito Hirai served as a clinical investigator and consultant for Janssen.
Tadakazu Hisamatsu received consulting fees from Janssen Research & Development, LLC.
David T. Rubin has served as a consultant to Janssen Pharmaceuticals.
Brian G. Feaganreceived consulting fees from Janssen; a member of the speakers bureau for Janssen; support for attending meetings and/or travel from Janssen; participation on a Data Safety Monitoring Board or Advisory Board from Janssen.

Introduction

Post-operative recurrence (POR) affects a substantial proportion of Crohn's disease (CD) patients following intestinal resection. While ileocolonoscopy remains the gold standard for detecting recurrence, its invasive nature and patient burden have spurred interest in non-invasive monitoring approaches. This study evaluates the performance of faecal calprotectin (FC) and cross-sectional imaging at different timepoints in predicting endoscopic recurrence in postoperative CD patients.

Aims & Methods

In this multicenter retrospective cohort of 895 CD patients who underwent ileocecal resection, we analyzed the diagnostic accuracy of FC measurements at 3, 6-12, and 18-24 months postoperatively for predicting endoscopic recurrence (Rutgeerts score ≥i2 or SES-CD ≥3). Additionally, we assessed the concordance between intestinal ultrasound (IUS) and magnetic resonance imagings (MRI) and endoscopic findings at both 6-12- and 18-24-months using kappa statistics.

Results

FC demonstrated modest discriminatory ability at 3 months (AUC 0.642, 95% CI: 0.530-0.753) and 6-12 months (AUC 0.653, 95% CI: 0.593-0.713), with improved performance at 18-24 months (AUC 0.676, 95% CI: 0.608-0.744). The optimal cutoff values for FC (47.5 μg/g at 3 and 6-12 months; 80.0 μg/g at 18-24 months) were substantially lower than standard thresholds (150-250 μg/g) used in non-operated patients.
At 6-12 months, radiological and endoscopic assessments showed moderate agreement (κ=0.426, p<0.001) with 63.2% concordance. At 18-24 months, IUS demonstrated superior agreement with endoscopic findings (κ=0.531, p<0.001; sensitivity 83.8%, specificity 72.7%) compared to MRI (κ=0.324, p<0.001). Notably, radiological remission at 18-24 months was identified as a significant protective factor against surgical recurrence (OR 0.356, 95% CI: 0.179-0.705, p=0.003).

Table I: Concordance between endoscopic and radiologic findings (IUS and MRI) for inflammation and remission at 18–24 months post-ileocecal resection. Abbreviations: IUS: Intestinal ultrasound, MRI: Magnetic resonance imaging.

Conclusion

Non-invasive monitoring with FC shows promise in postoperative CD surveillance, though diagnostic thresholds differ substantially from those established for non-operated patients. IUS demonstrates superior concordance with endoscopic findings compared to MRI, particularly at later timepoints. The protective role of radiological remission against surgical recurrence highlights the importance of transmural healing. Combining FC with radiological assessment, especially IUS, may provide a comprehensive, patient-friendly approach to monitoring postoperative CD, potentially reducing the need for invasive procedures in selected patients but further studies are needed in this direction.

Introduction

The role of the gut microbiota in inflammatory bowel disease (IBD) pathogenesis is widely acknowledged, with numerous bacteria identified as contributing factors. Little however is known about the part viruses play – a likely major component in the structuring and functioning of the gut microbiota. Understanding how viruses interact with the gut microbiota and host cells in the context of IBD could facilitate innovative treatment approaches and personalized interventions.

Aims & Methods

We explore the colonic and upper intestinal virome in patients with IBD compared with general population (GP) controls. Faecal (colonic) and effluent (upper intestinal) derived shotgun metaviromes of 100 IBD individuals (UC = 50, CD = 50) and 50 IBD individuals with an ileostomy, respectively were compared to faecal derived metaviromes of 50 GP individuals. Metaviromes were generated using a combination of shotgun methods and viral particle enrichment, allowing for identification of both eukaryotic and prokaryotic, dsDNA, ssDNA and RNA viruses. Viral diversity, composition and prevalence were compared by calculating Shannon diversity, Bray-Curtis distances and performing logistic regression analyses. P-values were adjusted using false discovery rate (FDR) to correct for multiple testing, where relevant; FDR<0.05 was considered significant.

Results

Similar to bacterial diversity in IBD versus GP samples, we see a significantly lower viral diversity in CD and UC colonic samples compared with the GP, and an even lower diversity when comparing upper intestinal samples to colonic samples (FDR<0.05). Comparing viral populations between groups, we observe that, whilst there is evident interindividual variability within groups, distinct clustering between colonic and upper intestinal samples can be seen, with colonic IBD samples clustering slightly more towards upper intestinal samples. When comparing viral group prevalences between GP and IBD colonic samples, 83 out of 260 viral groups present in IBD-UC samples are absent in the GP samples and 125 out of 302 viral groups present in the GP were absent in IBD-UC. For IBD-CD samples these numbers are 79 out of 248 and 133 out of 302, respectively. The top 3 viral groups that positively associated with IBD-UC samples are: one unknown phage group (predicted bacterial host: Parasutterella spp.), a group containing Lactobacillus phages (bacterial host: Lactobacillus spp.) and a group containing Lactococcus phages (bacterial host: primarily Lactococcus spp). The top 3 viral groups that positively associated with IBD-CD samples are: the same unknown phage group as for IBD-UC, and two other unknown phage groups (predicted bacterial hosts: primarily Enterocloster & Bacteroides spp, respectively).

Conclusion

This first comprehensive description of the gut virome across multiple gastrointestinal sites shows specific alterations in IBD. Many viral groups differentially present in the IBD intestine infect bacteria often associated with gut health and significantly reduced in IBD patients. Dysregulated bile acid signaling has also been implicated in the pathogenesis of IBD, with bacterial dysbiosis being linked to its cause. In IBD populations, we observe phages with the host E.bolteae – a bacteria increased in dysbiosis due to their potential to metabolise bile acids. We speculate that alterations in the gut virome composition are key events that disrupt the equilibrium between gut microbiota and host, promoting a pro-inflammatory state and driving IBD pathogenesis. The next steps will be to investigate the mechanisms underlying these complex interactions.

Disclosure

RKW unrestricted grants: Takeda, Johnson and Johnson, Tramedico, Ferring. Consultant: Takeda