Introduction

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic and progressive inflammatory bowel diseases (IBD), frequently associated with bowel damage and extraintestinal manifestations, and present a significant burden for patients.

Aims & Methods

The IBD-PODCAST was a descriptive non-interventional, cross-sectional study, which aimed to estimate the proportion of patients with CD and UC with Suboptimal Disease Control (SDC) in a real-world setting, across 103 sites in 10 countries. Criteria for SDC were largely based on STRIDE-II¹ and modified by an expert panel. The original cohort consisted of 2185 IBD patients. We previously reported that treatment modification opportunities were possible in 49% of CD and 61% of UC patients on advanced therapy². The aim of this analysis was to evaluate treatment patterns and potential treatment modifications in patients on standard or escalated maintenance therapy with biologics according to summary of product characteristics (SmPC), at index date. Patients who were receiving induction phase regimen or concomitant multiple advanced therapies or were treated with lower dosages according to the label were excluded from this analysis. Patients whose therapy was escalated beyond SmPC indications (i.e., with shorter intervals of administration) were classified as “further escalated”.

Results

A total of 796 CD and 549 UC patients treated with biologics (infliximab, adalimumab, ustekinumab and vedolizumab) were analyzed. Results are summarized in Table 1. Overall, 52% CD and 47% UC patients were in SDC. Among patients treated with adalimumab standard biweekly dose, 50% CD and 37% UC patients had the potential to modify therapy, while 70% CD and 50% UC patients were still in SDC despite dose escalation; concerning patients further escalated with adalimumab, 60% CD and 75% UC were in SDC. Nearly half of the infliximab-treated-patients were still in SDC. In ustekinumab-treated group, 58% of CD patients treated every 12 weeks had SDC and were eligible for treatment modifications, while SDC was observed in 57% CD and 49% UC patients treated every 8 weeks and in 56% of CD and 82% of UC patients furtherly escalated. Among vedolizumab-treated patients, 42% CD and 39% UC patients with intravenous (IV) maintenance every 8 weeks were in SDC and candidates for treatment modification; SDC was observed also in 65% CD and 35% UC patients treated every 4 weeks with IV Vedolizumab. Table 1: treatment patterns in patients affected by UC and CD (total n = 1345)

Conclusion

This descriptive analysis showed suboptimally-controlled disease in nearly half of 1345 IBD patients treated with biologics. Moreover, almost half of patients whose therapy had already been escalated may still require treatment modification. These results further enhance the need for a targeted management strategy and additional therapeutic alternatives in IBD.

References

1. Turner D, et al.; International Organization for the Study of IBD. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology. 2021 Apr;160(5):1570-1583
2. D’Amico F , et al. Proportion of IBD patients with suboptimal control in daily clinical practice – Real-world evidence from the IBD-Podcast study. United European Gastroenterol J. 2024 (article in press).

Disclosure

This study was funded by AbbVie. No honoraria or payments were made for authorship. Fortrea, funded by AbbVie, oversaw data management, biostatistics, clinical study report, and medical writing. AbbVie reviewed and approved the publication. All authors had access to all relevant data and participated in data interpretation, writing, review, and approval of this abstract.
Ferdinando D’Amico served as a speaker for Sandoz, Takeda, Jannsen, Omega Pharma, and Galapagos and served as an advisory board member for Abbvie, Ferring, Galapagos, Jannsen, and Nestlé.
Fernando Gomollón has received honoraria as speaker from Janssen, AbbVie, Takeda, and MSD; and participated in advisory panels for Faes-Farma and AbbVie
Giorgos Bamias has received honoraria as an Advisor/Lecturer and/or research grants and/or clinical trial participant from Janssen, Pfizer, Takeda, Abbvie, MSD, Mylan, Genesis Pharma, Adacyte Therapeutics, Amgen, Ferring, Cooper, BMS, and Aenorasis.
Tobias Heatta-Speicher, Valentina Tornatore, Ricardo Prata and Lorenzo Gemignani are employees of AbbVie and may own stock/options.
Axel Dignass reports received fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis and end point committees from Abivax, AbbVie, Bristol Myers Squibb, Dr Falk Foundation, Galapagos, Gilead, Janssen, and Pfizer; consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Roche, Sandoz,; Stada, Takeda, Tillotts, and Vifor Pharma; payment for lectures including service on speakers bureaus from AbbVie, Biogen, CED Service GmbH, Celltrion, Falk Foundation, Ferring, Galapagos, Gilead, High5MD, Janssen, Materia Prima, MedToday, MSD, Pfizer, Sandoz, Takeda, Tillotts, and Vifor Pharma; payment for manuscript preparation from Abbvie, Falk Foundation, Janssen, Takeda, Thieme, and UniMed Verlag

Introduction

Although anti-TNF therapy is a cornerstone treatment for moderate to severe ulcerative colitis (UC)¹, up to 40% of patients are primary non-responders². The molecular basis for non-response in colonic mucosa remains poorly understood.

Aims & Methods

We aimed to identify compartment-specific molecular signatures in colonic epithelium and lamina propria that distinguish anti-TNF non-responders from responders with similar disease activity before treatment. UC patients with unambiguous endoscopic response (n = 6) or non-response (n = 6) after 6 months anti-TNF therapy were included. Pre-treatment inflamed and uninflamed colonic histological biopsies were laser microdissected into epithelial and lamina propria samples for total RNA sequencing. We analysed differentially expressed genes (DEGs), gene enrichment and weighted gene co-expression networks (WGCNA). Cellular deconvolution and pseudobulk validation were performed using a publicly available single-cell atlas³, and findings were further validated by immunohistochemistry.

Results

Inflammation elicited mucosal compartment-specific transcriptional changes, with more alteration in the epithelium (2,654 DEGs, log2 fold change (FC) > 0.3, padj < 0.05) enriched for interferon signaling and antigen presentation, compared to heightened cell-cycle and adaptive immune responses in the lamina propria (1,525 DEGs). We found no underlying differences in treatment response in either uninflamed or inflamed epithelium, nor in gene expression of TNF and its receptors in any compartment. The main difference between non-responders and responders was in uninflamed lamina propria where we identified distinct inflammatory signatures more overlapping with inflamed tissue (395 DEGs vs 1,112 in responders) and with high expression of cell cycle genes (e.g. TOP2A, MKI67, CDC20, CDKN1A, FZR1). A co-expression gene network enriched for humoral activity (log2 FC > 0.3, padj < 0.01) correlated strongly with non-response (r = 0.6, padj = 0.06) and contained numerous immunoglobulin genes (IGHA2, JCHAIN), including antigen-binding variable segments of heavy (IGHV4-34, IGHV3-7, IGHV3-73) and light chains (IGKV1-6, IGKV1D-17, IGLV2-11, IGLV2-14), in addition to other B cell-associated genes (BMI1, POU2AF1, TPD52). The cell cycle and humoral genes were systematically expressed higher in uninflamed lamina propria of non-responders compared to responders, with the differences disappearing in inflamed lamina propria. Cellular deconvolution³, showed that the humoral gene network was expressed in plasma cell populations (mainly IgA), which were confirmed increased in non-responder uninflamed lamina propria through tissue staining and gene expression. Pseudobulk analyses of uninflamed lamina propria samples from UC non-responders (n = 6) and responders (n = 3) filtered form the independent single-cell dataset³, validated the association of both cell cycle (14 of 18) and humoral (50 of 61) genes with uninflamed lamina propria in non-responders. Also, DEGs in uninflamed lamina propria IgA plasma cells from non-responders compared to responders in the validation dataset, were confirmed (15 of 18) in our data.

Conclusion

Our findings suggest that anti-TNF non-response in UC involves pre-existing humoral immune activation in macroscopically uninflamed colon mucosa. This spatially resolved signature offers a potential biomarker for treatment stratification and highlights the need for personalized therapeutic approaches in UC.

References

1 Raine, T. et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohn's Colitis 16, 2-17 (2021). https://doi.org/10.1093/ecco-jcc/jjab178
2 Ben-Horin, S., Kopylov, U. & Chowers, Y. Optimizing anti-TNF treatments in inflammatory bowel disease. Autoimmunity Reviews 13, 24-30 (2014). https://doi.org/https://doi.org/10.1016/j.autrev.2013.06.002
3 Thomas, T. et al. A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease. Nature Immunology 25, 1-14 (2024). https://doi.org/10.1038/s41590-024-01994-8

Introduction

In patients with ulcerative colitis (UC), total proctocolectomy with restorative ileal pouch-anal anastomosis (IPAA) is a definitive surgical treatment for refractory disease or colorectal dysplasia. A short rectal cuff is typically retained and anastomosed to the pouch, and may become inflamed over time, a condition referred to as cuffitis. The clinical relevance of cuffitis remain unexplored. In this study, we aimed to characterize the long-term disease course associated with histologic cuffitis.

Aims & Methods

Patients with UC who underwent total proctocolectomy and IPAA were prospectively followed in a comprehensive pouch clinic at a tertiary referral center for patients with inflammatory bowel diseases (IBD). We included all patients who underwent at least one pouch endoscopy with paired pouch and cuff biopsies between 2017 and 2024. Cuffitis was defined as a NANCY Index histologic score of 3-4, and pouchitis was defined as histologic subscore of PDAI³2. Outcomes assessed included documented inflammatory pouch flares, defined by clinical evaluation; antibiotics used due to pouch inflammation; and initiation of biologics. Associations were evaluated using Poisson regression to estimate incidence rate ratios (IRRs) and Fisher’s exact test for categorical comparisons.

Results

A total of 116 patients underwent 250 pouch endoscopies during the study period. Average age of the cohort was 50.4 (±14.9) and 59% were females. Histologic pouchitis was detected in 80 (68.9%), and cuffitis in 76 (65.5%) patients. Most patients had extensive disease prior to IPAA (n=105, 90.5%) and indication for surgery was refractory UC (n=94, 81.0%). Concurrent pouchitis and cuffitis were identified in 54 (46.5%) patients. Patients with histologic-proven cuffitis had a significantly higher incidence rate of subsequent disease flares(IRR 4.39, 95% CI: 2.26-9.86, p<0.001) and required more antibiotic courses (IRR 1.94, 95% CI: 1.11-3.62, p=0.027) compared to those who never developed cuffitis. These associations remained significant after adjusting for the presence of histologic pouchitis. No significant difference was observed in the initiation of biologics (p=0.81). Among patients with at least two endoscopies during follow-up and isolated cuffitis at baseline (n=61), 6 patients with isolated cuffitis further developed new-onset pouchitis, while 15 patients with isolated pouchitis subsequently developed cuffitis. The remaining 40 patients (65.5%) maintained the same inflammatory pattern over time.

Conclusion

Histologic-proven cuffitis is independently associated with adverse long-term outcomes in patients post-IPAA, including flares and repeated antibiotic use, even in the absence of pouchitis. The persistence of inflammation in the retained rectal cuff, representing a remnant of the previously diseased colonic mucosa, raises mechanistic questions about its potential role in modulating inflammatory activity of the pouch. These findings emphasize the clinical importance of evaluating the rectal cuff in patients post-IPAA. Routine histologic assessment of the cuff should be incorporated into post IPAA surveillance, and interventional studies are warranted to determine whether targeted treatment of cuffitis can mitigate pouch related morbidity.

Disclosure

Jacob E Ollech: Has received grant support from Pfizer, consulting fees from Takeda, and
speaker fees from Abbvie, Janssen, Pfizer, Takeda, Novartis, and Bristol Myers Squibb.
Iris Dotan: consultation fee or honorarium from: Abbott, Abbvie, Athos, Arena, Altman
Research, Cambridge Healthcare, Celltrion, Celgene/BMS, Eli-Lilly, Ferring, Falk Pharma, Food
Industries Organization, Gilead, Galapagos, Iterative Scopes, Integra Holdings, Janssen,
Neopharm, Pfizer, Rafa laboratories, Roche/Genentech, Sangamo, Sublimity, Sandoz, Takeda,
Wildbio. Grants: Altman Research, BMS, Pfizer