Introduction

Until now, there have only been conflicting reports regarding whether adenomas located proximal to the splenic flexure have increased association with metachronous colorectal cancer (CRC) compared to distal adenomas, and whether adenoma location should affect surveillance practice.

Aims & Methods

To address this knowledge gap, we aimed to compare metachronous colorectal cancer (CRC) and advanced adenoma (AA) risk in patients with baseline proximal vs. distal adenomas, including consideration of metachronous CRC location, baseline proximal adenomas only vs. both proximal and distal adenomas, and baseline proximal non-advanced adenoma vs. AA.
We systematically searched Pubmed, EMBASE, and Cochrane for cohort studies and clinical trials describing CRC or AA incidence at surveillance stratified according to baseline adenoma’s location. Proximal adenomas were defined as those located from the cecum to the splenic flexure. We performed a meta-analysis by calculating pooled incidence rate ratios (IRR) and corresponding 95% confidence intervals (CI) for CRC and AA using a random-effects model. Heterogeneity was assessed with the I2 statistic.

Results

The literature search yielded 5,907 studies of which 13 were included, with a total of 205,207 patients (mean age 62.3 years, 63.8% males) and a mean duration of follow-up of 8.5 years. Compared with patients with only distal adenomas, patients with any proximal adenoma and only proximal adenomas had a significantly higher risk of metachronous CRC [1.70 (95%CI: 1.17-2.46; I2=73%), and 1.97 (95%CI: 1.41-2.75; I2=0%)], respectively. Patients with any proximal AA had also a higher risk of CRC compared to those with only distal AA [2.77 (95%CI 1.77-4.34; I²=38%)]. Also, patients with any proximal adenoma had an even higher risk of proximal CRC compared to patients with baseline only distal lesions [3.65 (95%CI 1.57-8.47; I2=86%)]. Finally, patients with any baseline proximal adenoma had also a higher risk of metachronous AA [1.82 (95%CI: 1.41-2.34; I2=59%)].

Conclusion

Our findings suggest that baseline adenoma proximal location is associated with future detection of CRC and AA. Better understanding of the reasons behind this increased CRC risk, and particularly whether these can be overcome with improved colonoscopic technique or technical innovations, will inform whether baseline adenoma location should be considered in future guidelines as an independent factor to tailor surveillance recommendations.

Introduction

Crohn’s Disease (CD), a subtype of Inflammatory Bowel Disease (IBD), is believed to arise from complex interactions between gut microbes, environment, and genetics. A significant proportion of patients develop fistulae, but unclear aetiopathogenesis impacts treatment outcomes, quality of life, and healthcare costs. Chronic granulomatous disease (CGD) is a monogenic condition caused by pathogenic variants in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complexes which can present as CD-like colitis, abscesses, and immunodeficiency. Given CD’s genetic and phenotypic similarities with CGD, we hypothesised that NADPH oxidases may contribute to CD phenotypes, specifically in relation to fistulating disease behaviour.

Aims & Methods

This study explores the role of genetic variation in NADPH oxidases in CD patients (Southampton IBD cohort) using a per-patient, per-gene deleteriousness score (GenePy) to determine whether CD fistulating disease behaviour can be predicted and establish any potential epistatic interactions between genetic variation of subunits of the NAPDH oxidase complexes relevant to CD. Key NADPH oxidase protein-coding genes involved in CD were identified via literature review. Protein-protein interaction databases were used to collate a comprehensive network of potentially implicated genes. To determine subgroups of patients with differing genetic variation in the NAPDH oxidase genes we employed a principal component analysis (PCA), followed by hierarchical clustering of patients using GenePy scores, with optimal cluster numbers determined by silhouette scores. Cluster enrichment for fistulating disease was explored using Fisher’s exact test. To identify genes driving separation between CD patients we assessed differences in GenePy scores for the top PCA gene drivers between fistulating and non-fistulating subgroups using a Mann-Whitney U-test. Mutational profile characterisation include potential gene-gene interactions were evaluated via Spearman correlations. Multiple test correction was applied.

Results

Twenty-nine protein-coding genes were analysed. Clustering patients by GenePy scores for these genes after PCA resulted in distinct clusters, but no significant association between fistulating phenotype and cluster assignments was observed. However, significant differences between the GenePy scores of the top 5% of fistulating and non-fistulating groups were found for NOX3 (p = 0.016) and DUOX2 (p = 0.001), with fistulating patients having lower GenePy score for these genes, indicating these genes may drive a proportion of inflammatory CD behaviour.
Four gene pairs were significantly correlated (Table 1), indicating potential epistasis within NADPH oxidase complexes for patients with CD. High deleteriousness scores in multiple genes within a complex may indicate oligogenic contribution to a disease phenotype within individuals.

Conclusion

NADPH oxidase genes, and epistatic interactions between them, may modify the risk of fistulating CD and drive disease phenotype in a proportion of patients.

Disclosure

JJA is a scientific advisory board member for Orchard Therapeutics

Introduction

Resolution of pain, fatigue and other symptoms are key treatment goals for many patients (pts) with Crohn’s disease (CD);^1,2 however, time to symptomatic improvement in pts treated with vedolizumab (VDZ) has not been formally evaluated.

Aims & Methods

VOICE (NCT06249555) is a prospective, observational study in pts with CD aged ≥18 years initiating VDZ or anti-IL-23 antagonist treatment (tx) per product labelling as part of standard of care, with the main objective to explore the time course of response to VDZ as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) domain Short Form (SF) scores. Inclusion criteria include baseline PROMIS Pain Interference (PI)-SF T-score ≥55 (0.5 SD above general population). We enrolled pts via Takeda pt support program in Canada, with additional pts enrolled at US and Canada sites. Planned sample size is 300 pts (VDZ, 200; anti-IL-23 antagonist [reference group not for formal comparison], 100); planned follow-up is 52 weeks (wks), with PROMIS PI data reported weekly for the first 14 wks. The primary endpoint is time to the first meaningful clinical improvement in PROMIS PI-SF T-score, defined as ≥2-point decrease in PROMIS PI-SF T-score from baseline. We also collect data on improvement in 7 PROMIS domains with clinical improvement defined as 5-point (0.5 SD)³ change in T-score from baseline, Short Inflammatory Bowel Disease Questionnaire (SIBDQ; including SIBDQ improvement [≥9 point increase from baseline] and SIBDQ remission [score of ≥60]) and safety. Here, we report the results from pts with ≥1 VDZ dose and ≥1 post-baseline PI assessment included in the interim analysis (IA; prespecified to occur after 50 pts from VDZ group completed or discontinued before the wk 14 assessment to provide an early evaluation of tx response and safety).

Results

Overall, 64 pts with ≥1 VDZ dose and ≥1 post-baseline PROMIS PI assessment (mean±SD age, 43.1±17.0 years, 35.9% male, 92.2% White) were included in the IA. Disease duration (mean±SD) was 6.4±12.1 years; 84.4% of pts were anti-TNF-naïve. Data collection is ongoing for 57 pts (49 with and 8 without completed wk 14 PROMIS PI questionnaire); 7 pts discontinued from the study. The median time to achieve the first ≥2_-point decrease in PROMIS PI-SF T-score (in n=56 pts) was 12 days (95% CI, 6-13). Baseline PROMIS domain scores indicated notable impairment; by wk 14, improvements in mean PROMIS scores from baseline were observed in all 7 measured domains, with ≥5-point improvements in 4/7 domains (Table). At wk 14, 37.5% (24/64) and 7.8% (5/64) pts achieved SIBDQ improvement and remission, respectively. One pt had serious adverse events of appendicitis and diverticulitis, and another pt had a fatal event; none of these were related to VDZ tx.

Table. Summary of PROMIS domain T-scores

Conclusion

The IA results through wk 14 show an early improvement across multiple symptom domains and quality of life in pts with CD starting VDZ tx. Time to first ≥2-point decrease in PROMIS PI-SF T-score was short, with a benefit observed after 12 days from VDZ initiation. Study recruitment and data collection are ongoing.

References

1. Keefer L, et al. Gastroenterology. 2022;162(5):1439-1451.
2. Kitchen H, et al. Crohns Colitis 360. 2020;2(2):otaa033
3. Cella D, et al. Value Health. 2019;22(5):537-544.
4. Shaw BE, et al. Cancer. 2018;124(4):841-849.

Disclosure

This study was sponsored by Alimentiv, Inc.
V. Jairath reports consulting/advisory board fees from AbbVie, Alimentiv, Anaptyis Bio, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ensho, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, MRM Health, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Spyre, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion; speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, Tillotts and Fresenius Kabi.
M. Long reports consulting fees from AbbVie, Alimentiv, Bristol Myers Squibb, Intercept, Janssen, Lilly, Pfizer, Prometheus, Roivant, Syneos Health and Takeda; and research support from Lilly, Pfizer and Takeda.
M.D. Kappelman reports being a consultant to Eli Lilly and Takeda.
G. Radulescu and N. Li are employees of Alimentiv.
J.J. Wu, I. Romo Bautista, A. Insogna and C. Agboton are employees of Takeda and hold stock and/or share options in Takeda.
N. Narula has received advisory board/consulting honoraria from Abbvie, Amgen, Eli Lilly and Company, Ferring, Fresinius Kabi, Innomar Strategies, Iterative Health, Janssen, Novartis, Organon, Pfizer, Sandoz and Takeda.

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

Vedolizumab (VDZ) is approved for moderate-to-severe inflammatory bowel disease (IBD; ulcerative colitis [UC] & Crohn’s disease [CD]).^1,2 While the subcutaneous (SC) formulation of VDZ is effective as maintenance treatment (mTx) in patients (pts) responding to intravenous (IV) VDZ induction treatment (Tx),^1,3 real-world data on Tx patterns of pts switching mTx from VDZ IV to SC or initiating mTx VDZ SC after IV induction are limited.

Aims & Methods

This prospective, non-interventional, multicentre (NCT05384080) study (conducted under the umbrella VARIETY protocol) enrolled adults with UC or CD initiating/undergoing induction with VDZ IV or continuing VDZ IV mTx, with the option to switch to VDZ SC mTx. The primary endpoint was real-world Tx patterns with VDZ, including Tx persistence. Additional endpoints assessed pt characteristics, pt-reported outcomes, and safety (adverse events [AEs]). Data were descriptively analysed.

Results

Overall, 162 enrolled pts (August 2022–June 2023; UC, n=103; CD, n=59) were included in the interim analysis. At enrolment, 127 (78.4%) received VDZ mTx (UC, n=78; CD, n=49) and 35 (21.6%), VDZ induction (UC, n=25; CD, n=10). The mean (SD) age was 38.2 (12.3) yrs, and time since IBD diagnosis was 10.7 (11.1) yrs. Majority of pts were male (96 [59.3%]), currently employed (124 [76.5%]), had never smoked (109 [67.3%]), and reported previous biologic therapy (95 [58.6%]). Demographic and IBD Tx history data were consistent across cohorts. At baseline, in pts with UC, the mean (SD) partial Mayo score was 1.8 (2.7); in pts with CD, the mean (SD) Crohn’s Disease Activity Index (CDAI) score was 90.6 (70.1). During the 1-yr study period, 20.0% (n=7; UC, n=2; CD, n=5) of pts in the induction and 51.2% (n=65; UC, n=40; CD, n=25) in the mTx cohort switched to VDZ SC. At week (W) 52, Tx persistence was 40.0% (n=14; UC, n=11; CD, n=3) and 77.2% (n=98; UC, n=61; CD, n=37) in the induction and mTx cohorts, respectively, and highest overall in mTx pts who switched to VDZ SC (86.2%; n=56; Table). The most common reason for Tx discontinuation was investigator decision (64.7%; n=33). For VDZ IV and SC, the mean (SD) number of doses per pt was 10.5 (7.6) and 23.8 (15.0), respectively. The median time from VDZ Tx initiation to SC Tx was 383 days (induction: 98 days; mTx: 434 days). In the induction cohort, the mean (SD) Work Productivity & Activity Impairment (WPAI) scores improved from 32.7 (24.1) at baseline (n=21) to 21.5 (31.2) at W52 (n=11), and the Short IBD Questionnaire (SIBDQ) scores improved from 44.1 (10.0) at baseline (n=34) to 51.0 (12.9) at W52 (n=15). In the mTx cohort, WPAI and SIBDQ results remained consistent over time. Fifty-three AEs were reported, including 4 serious AEs (malignancy, IBD flare requiring hospitalization, abdominal abscess, and unconsciousness). One AE of special interest (hypersensitivity reaction) was considered VDZ-related.

Conclusion

In this Polish real-world study, high Tx persistence was reported, especially in pts who switched to VDZ SC. No new safety signals were noted. Overall, the results were consistent with those from other VARIETY cohorts,⁴ although lower persistence was observed during induction. The small size of the induction cohort was a limitation of this study.

References

1. Sandborn WJ, et al. Gastroenterology. 2020;158:562–72.e12.
2. Loftus EV Jr, et al. Aliment Pharmacol Ther. 2020;52:1353–65.
3. Vermeire S, et al. J Crohns Colitis. 2022;16:27–38.
4. Novacek G, et al. J Crohns Colitis. 2024;18(suppl 1):i1506–7

Disclosure

Conflicts of interest: Agata Michalak received lectures fees and/or travel grants from AbbVie, Bayer, Biocodex and Takeda. Katarzyna Karłowicz received lecture fees, consultancy fees or travel educational grants from Bristol Myers Squibb, AbbVie, Polpharma, Takeda and Pfizer. Renata Talar-Wojnarowska received lecture fees and/or travel grants from AbbVie, Astellas, Ferring, Janssen and Takeda. Adam Fabisiak received fees and/or travel grants from Bristol Myers Squibb, Pro. Med. CS, Pfizer and Polpharma. Magdalena Achtenberg received lecture fees from Ferring. Piotr Eder received lecture fees and/or travel grants from Takeda, Ferring, Astellas, Pfizer and Janssen. Maria Kłopocka received payment for lectures from Janssen, Takeda, Ferring, Alfasigma and Pharmabest and travel/accommodation/meeting expenses from Ferring, Janssen, Takeda, Alfasigma and Pharmabest. Maciej Gonciarz received compensation and/or research/educational grants from Pfizer, Polfarma, Abbvie, BMS, Ewoppharma, Ferring, Astellas, Takeda, Jansen-Cilag, Celtrion, Johnson & Johnson, and Sanofi. Grażyna Rydzewska received speaker and consultant fees from AbbVie, AlfaSigma, AstraZeneca, Bayer, Biocodex, Bristol Myers Squibb, Ferring, Janssen, Lilly, Pro. Med. Pl., Recordati, Sanprobi, SOBI and Takeda and travel/accommodation meeting expenses from AbbVie, Ferring and Takeda. Eliza Majewska is a permanent employee of Takeda Pharma Sp. z o.o. Maria Kopertowska-Majchrzak, Tomasz Romańczyk, Halina Cichoż-Lach, Małgorzata Zwolińska-Wcisło, and Elżbieta Poniewierka declare no conflicts of interest.
Funding: The study was funded by Takeda Pharma Sp. z o.o.
Acknowledgements: Medical writing support was provided by Michelle Rebello, PhD, of Cactus Life Sciences (part of Cactus Communications) and funded by Takeda Pharma Sp. z o.o.

Introduction

Recurrent bile duct stones (RBDS) develop in up to 20% of patients after successful endoscopic clearance of initial stones. While anatomical and procedural risk factors are well recognized, the role of bile acid composition and bile microbiota in RBDS has gained attention. Bile acids, critical for cholesterol solubilization and intestinal homeostasis, may undergo deconjugation or biotransformation when exposed to intestinal flora via duodenobiliary reflux, altering their physicochemical properties and promoting lithogenicity.

Aims & Methods

We aimed to investigate whether alterations in bile acid composition and microbial colonization are associated with stone recurrence. A total of 184 patients who underwent biliary drainage at Konyang University Hospital (2019–2022) were enrolled. Patients were categorized into First Diagnosis Group (n=155) and Recurrence Group (n=29). Bile was aspirated after ERCP or PTBD, and 15 bile acids (5 unconjugated, 10 conjugated) were quantified using HPLC-MS/MS. Bile cultures were analyzed for microbial composition. Statistical comparisons were made using independent t-tests and chi-square analysis.

Results

Patients with RBDS were significantly older (77.8 vs. 69.0 years, P=0.005). Total bile acid concentration was lower in the Recurrence Group (4734 vs. 5902 ppm, P=0.083). Conjugated bile acids—including T-CA, T-DCA, G-CA, G-DCA, and G-LCA—were significantly reduced (P<0.05). Taurine-conjugated bile acids showed a marked decline (1326 vs. 1876 ppm, P=0.041). Primary bile acids were lower in the Recurrence Group (3272 vs. 4339 ppm, P=0.035), while the primary-to-secondary bile acid ratio was significantly decreased (3.29 vs. 7.35, P=0.001), indicating a shift toward hydrophobic bile.
Microbiologically, Enterococcus spp. were significantly more prevalent in the Recurrence Group (76% vs. 30%, P<0.001), particularly E. faecalis, E. casseliflavus, and E. gallinarum. Notably, E. faecalis possesses bile salt hydrolase (BSH) activity that can deconjugate bile acids, promoting accumulation of hydrophobic, poorly soluble forms. This aligns with the observed increase in unconjugated LCA and DCA.

Conclusion

Recurrent bile duct stone patients exhibit reduced levels of conjugated and primary bile acids and increased prevalence of bile-resident Enterococcus spp., known for bile salt hydrolase activity. These changes may lead to deconjugation, increased hydrophobicity, and impaired micelle formation, contributing to bile lithogenicity. These findings support the potential utility of bile acid profiling and bile microbiota analysis as predictive and preventive tools in RBDS management.

References

1. Hofmann AF, Mysels KJ. Bile acids as biological surfactants. Colloids Surf. 1987;30(1):145–173.
2. Begley M, Hill C, Gahan CG. Bile salt hydrolase activity in probiotics. Appl Environ Microbiol. 2006;72(3):1729–1738.
3. Choe JW, Lee JM, Hyun JJ, Lee HS. Analysis on microbial profiles and components of bile in patients with recurrent CBD stones after endoscopic removal: a preliminary study. J Clin Med. 2021;10(15):3303.
4. Ryu KH. Gut Microbiota and Pancreatobiliary System. Korean J Gastroenterol. 2020;75(5):231–239. (Korean)
5. Di Ciaula A, Garruti G, Baccetto RL, Molina-Molina E, Bonfrate L, Portincasa P. Bile acid physiology. Ann Hepatol. 2018;16(1):4–14.
6. Wang DQ, Cohen DE, Carey MC. Biliary lipids and cholesterol gallstone disease. J Lipid Res. 2009;50 Suppl:S406–S411.

Introduction

Crohn’s disease (CD) is a chronic condition characterized by a relapsing-remitting course, often requiring intestinal resection. Postoperative management primarily aims to maintain clinical remission. The advent of biologic therapies has undoubtedly improved disease prognosis following initial surgery. However, access to this therapeutic class remains limited in lower-middle income countries such as Tunisia, necessitating the use of alternative agents, notably azathioprine (AZA), which has been widely used for this indication, albeit with controversial results.

Aims & Methods

This study aimed to evaluate the effectiveness of AZA in maintaining remission after a first intestinal resection in patients with ileal or ileocolonic Crohn’s disease, and to identify factors associated with treatment failure.
​We conducted a retrospective, descriptive, and analytical study in the gastroenterology department of Sahloul University Hospital in Sousse (Tunisia) over a 4-year period (2020–2024). We included all patients with ileal or right ileocolonic CD who underwent intestinal resection and received AZA in the postoperative period.

Results

A total of 66 patients were included, with a mean age at diagnosis of 31.50 ± 12.24 years and a male-to-female ratio of 1.06. The median interval between diagnosis and surgery was 21.5 months. During follow-up, AZA failure occurred in 63.6% of patients (n=42), with a mean time from surgery to failure of 44.71 ± 37.74 months. In univariate analysis, ileocolonic disease location (p=0.042), the total number of flares (p=0.007), and the number of severe flares (p<0.001) prior to surgery were significantly associated with AZA failure. Failure rates were also significantly higher in patients who underwent emergency surgery (p=0.007). Inflammatory resection margins (p<0.001) and severe inflammatory activity (p=0.007) were also significantly associated with treatment failure. In multivariate analysis, three independent risk factors were identified: the number of severe flares before surgery (p=0.031), preoperative inflammatory syndrome (p=0.008), and histopathological evidence of disease at the resection margins (p=0.004).

Conclusion

Our findings suggest that thiopurines remain a valuable therapeutic option in the management of Crohn’s disease, particularly in our setting, where access to alternative therapies is limited and associated with high costs.