Introduction

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), are chronic gastrointestinal disorders accompanied by psychiatric comorbidities, particularly anxiety and depression. The link between IBD and anxiety and depression remains unclear, but it appears that, among others, it may be explained by altered tryptophan metabolism. Tryptophan, an essential amino acid, is crucial for maintaining mental health and regulating mood through its metabolic processes. It serves as a precursor for several biologically significant compounds, including serotonin, melatonin, and kynurenine metabolites. The interplay between inflammation, tryptophan metabolism, and mental health in IBD remains insufficiently explored.

Aims & Methods

This study aimed to assess the association between metabolites of the tryptophan-kynurenine pathway and depressive symptoms in IBD regarding the disease activity and phenotype. A cohort of 214 patients with IBD (70 with CD and 144 with UC) was included. Disease activity was determined using the Mayo score for UC and SES-CD for CD. Peripheral blood samples were analyzed for selected biomarkers, including metabolites of tryptophan-kynurenine pathway as well as indicators of oxidative stress and inflammation. Depressive symptoms were evaluated using the Beck Depression Inventory (BDI). Statistical analyses included correlation and regression models to explore the relationship between biomarkers and BDI scores, adjusting for clinical and demographic covariates.

Results

The BDI score in the study group ranged from 0 to 52. 31 individuals met the criteria for depression by scoring over 10 points. 137 patients with active disease exhibited significantly higher levels of hsCRP and nitrotyrosine and lower kynurenic acid levels compared to 77 with inactive disease. Kynurenic acid levels were negatively correlated with BDI scores (r = -0.220, p = 0.042), suggesting an association between tryptophan metabolism and depressive symptoms. Additionally, CD patients showed higher serotonin and anthranilic acid levels compared to UC patients (16.67 ± 26.23 vs 6.29 ± 12.55 and 0.35 ± 0.26 vs 0.17 ± 0.17, respectively), though no significant differences in BDI scores were observed between the groups. Biological treatment was more frequent in the active disease group and associated with higher BDI scores, even after adjusting for covariates.

Table 1. Comparison of selected metabolite levels between individuals with active disease and with inactive disease

	Active disease	Inactive disease	p
Chlorotyrosine, nM	0.35 ± 0.41	0.26 ± 0.45	0.222
Nitrotyrosine, nM	0.38 ± 0.20	0.26 ± 0.17	0.043
Bromotyrosine, nM	0.05 ± 0.06	0.03 ± 0.03	0.553
L-tryptophan, M	54.67 ± 15.79	60.98 ± 15.34	0.117
L-kynurenine, M	3.53 ± 1.22	3.48 ± 1.01	0.680
5-hydroxy-L-trypthophan, M	0.20 ± 0.15	0.23 ± 0.13	0.233
3-indolepropionic acid, M	0.33 ± 0.57	0.20 ± 0.21	0.723
3-indoleacyrylic acid, M	2.31 ± 0.66	2.46 ± 0.54	0.322
Kynurenic acid, M	0.06 ± 0.04	0.08 ± 0.03	0.035

Data expressed as n (%) or mean ± SD.
Significant between-group differences (p < 0.05) are marked in bold.

Conclusion

The study revealed significant differences in the tryptophan-kynurenine metabolic pathway among patients with inflammatory bowel disease, which vary based on disease activity. Additionally, variations in the concentrations of certain metabolites are correlated with the severity of depression.

References

1. Kuźnicki, P., Kempiński, R., & Neubauer, K. (2021). The emerging role of mood disorders in inflammatory bowel diseases. In Advances in Clinical and Experimental Medicine. https://doi.org/10.17219/ACEM/127676
2. Mikocka-Walus, A., Pittet, V., Rossel, J.-B., von Känel, R., Anderegg, C., Bauerfeind, P., Beglinger, C., Begré, S., Belli, D., Bengoa, J. M., Biedermann, L., Bigler, B., Binek, J., Blattmann, M., Boehm, S., Borovicka, J., Braegger, C. P., Brunner, N., Bühr, P., … Zimmermann, D. (2016). Symptoms of Depression and Anxiety Are Independently Associated With Clinical Recurrence of Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology, 14(6), 829-835.e1. https://doi.org/10.1016/j.cgh.2015.12.045
3. Brown, S. J., Huang, X.-F., & Newell, K. A. (2021). The kynurenine pathway in major depression: What we know and where to next. Neuroscience & Biobehavioral Reviews, 127, 917–927. https://doi.org/10.1016/j.neubiorev.2021.05.018
4. Correia, A. S., & Vale, N. (2022). Tryptophan Metabolism in Depression: A Narrative Review with a Focus on Serotonin and Kynurenine Pathways. International Journal of Molecular Sciences, 23(15), 8493. https://doi.org/10.3390/ijms23158493

Introduction

In Crohn’s disease (CD), an exposure-response relationship is suggested for ustekinumab, with higher serum levels associated with better outcomes. Pharmacokinetic data are scarce, with suggested target maintenance trough level associated with remission at 0.8-1.4 µg/mL. ^{1, 2} The REScUE study (NCT04245215) investigated the effect of two different re-induction regimens with ustekinumab in patients with CD. No significant difference was observed on clinical, endoscopic and biological outcomes.³ Here we present the pharmacokinetic and pharmacodynamics results of the REScUE study.

Aims & Methods

This Belgian multicentre prospective double-blind randomized placebo-controlled trial included adult patients with CD treated with ustekinumab who presented with secondary loss of response to ustekinumab after documented primary response. All patients received a single IV re-induction with ustekinumab (≈6mg/kg) and were then randomized 1:1 to blinded maintenance ustekinumab 90 mg SC Q4W (intervention) or 90 mg SC Q8W (control) for 48 weeks. PK samples were obtained at baseline, week 4-8-12-20-28-36-48.

Results

In total, 108 patients were included: 67% female, median [IQR] age 41 [32-54] year, median disease duration 14 [7-22] years. Prior anti-TNF exposure was reported in 92% of the patients. Baseline ustekinumab trough levels at moment of loss of response were similar in both groups and at the suggested target level of 0.8-1.4 µg/mL ¹: median (IQR) q4 week 1.39 (0.84-2.74) µg/mL and q8 week 1.31 (0.91-2.34) µg/mL (p>0.9). Eight weeks after induction, there was a statistically significant difference in ustekinumab trough levels between both groups 10.8 (8.0-15.9) µg/mL versus 8.2 (4.9-11.1) µg/mL for q4weeks vs q8weeks respectively (p=0.002). After 48 weeks of treatment the statistically significant difference persisted with 6.0 (4.8-9.6) µg/mL versus 2.1 (1.6-2.9) µg/mL (p<0.001). No significant association between baseline/week 8/week 48 ustekinumab trough levels and (steroid free) clinical remisison [PRO2 (AP ≤ 1 AND SF ≤ 3) and FCP <250µg/g and no steroids for 90 days prior to week 48] or endoscopic remission [SES-CD <3 at week 48] was seen. However, there was a significant association between baseline/week 8/week 48 ustekinumab trough levels and biomarker remission [CRP <5 mg/L and FCP <250 µg/g at week 48]; OR (95% CI) 2.98 (1.85, 5.23), 1.12 (1.06, 1.19) and 1.35 (1.13, 1.66) (all p<0.01) respectively. As per quartile analysis of the ustekinumab trough levels at week 48, the lowest quartile (ustekinumab <0.9 µg/mL) had the lowest steroid free clinical remission in each treatment group.

Conclusion

In patients with CD experiencing secondary loss of response to ustekinumab, baseline ustekinumab levels are low. Dose optimization with a single IV re-induction followed by intensified maintenance dosing (90 mg SC q4W) leads to higher ustekinumab levels compared to IV re-induction followed by conventional maintenance dosing (90 mg SC q8W). No association was found between ustekinumab levels and different outcomes except for biomarker remission. This suggests that treatment with ustekinumab should be personalized on a patient level, guided by drug-clearance rather than guided by target trough levels.

References

¹ Adedokun O. et al Gastroenterology 2018;154:1660–1671
² Schreiber S. et al ECCO 2023 Copenhagen; P436
³ Bossuyt P. et al ECCO 2025 Berlin; OP35

Disclosure

PB: Financial support for research: AbbVie, EG. •Lecture fees: AbbVie, AMC ICP, Amgen, Bristol Myers Squibb, Celltrion, Dr Falk Benelux, EG, Galapagos, Globalport, Lilly, Medtalks, Materia Prima, Pentax, Springer Media. •Advisory board: AbbVie, Bristol Meyers Squibb, CIRC, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, Tetrameros.

Introduction

Bowel urgency is one of the most bothersome symptoms of ulcerative colitis (UC) and have a great impact on quality of life and psychosocial function. The Urgency Numerical Rating Scale (U-NRS) is desinged to ojectify this subjective symptom. It measures the degree of faecal urgency experienced over the past 24 hours by patients with UC on a scale of 0-10. We assumed that the scale has a large variance, as patients evaluate their own symptoms differently, the urge may be different quality for two patients with the same score.

Aims & Methods

The objective of our study was to investigate the possible components of urgency and refine the assessment of urgency. Patients with UC older than 18 years treated at our departments for at least 3 months and having complaints were enrolled in our study. The patients filled out our non-validated questionnaire with questions about fecal urgency (U-NRS), pain level, speed of urge, incontinence and lifestyle characteristics associated with incontinence. Statistical analysis was performed using STATA 18 program.

Results

263 patients were enrolled, median age was 39.5 years, the mean of disease duration was 11.7±9.2 years. The mean U-NRS score was 3.2±3.2, 32% (84/263) had 0 score and 3% (9/263) has 10 score. 12% of the patients (n=31) felt most difficult to hold mucus, 37% (n=97) stool and 29% (n=76) other secretions. 8% (n=22) had urge with every stool in the last 24 hours, 36% (n=95) had less than half of defecations. The speed of urge defined more the level of urgency than the pain level (R2=0.798 p<0.001, β=0.894 vs R²=0.805, p<0.001, β=0.117). The duration of faeces holding in the last 7 days had significant connection to U-NRS (R²=0.211, p<0.001, β=-0.46). Patients using public restroom at least once during the last week had significantly higher score on U-NRS than other patients (4.6±3.1 vs 2.4±3 p<0.001). 12% (31/263) used diaper. The usage of diapers was also significantly more often in patients with higher U-RNS score (5.2±3.2 vs 2.9±3.1,p<0.0001). Faecal leakage both during the day and night was significiantly higher with higher U-NRS score (p<0.001 for both). Patient reported outcome (PRO2) had a weak correlation with U-NRS (R²=0.14). However if we examine bloody stool, the stool number and difficulty of faecas holding seperately we got a significant and better correlation with urgency (R²=0.43). Patients with moderately severe-severe disease (PRO2 > 5) had a higher chance to have urgency (AUC=0.9). The possibility was higher to have urgency among patients with painful defecation (R²=0.41). The level of urgency, duration of faeces holding and the frequency of faeces holding problems had the strongest correlation with U-NRS (R²=0.83). Patients defined urgency with these parameters according to this result. We created score with them, level of urgency points + half of duration points + frequency, which showed a good model to refine the definition of urgency (R²=0.83).

Conclusion

Bowel urgency affects UC patients' lives and is associated with more severe disability. Bowel urgency is common in UC affecting about two-third of patients and associates with more severe activity of UC. Fecal urgency can characterize with the level of urgency, duration of faeces holding and the frequence of stool more accurately than a single, subjective numeric scale. A new scoring system is needed to more accurately assess patients' complaints in this area and to objectify severity.

Disclosure

The authors have no potential conflict of interest to disclose

Introduction

The European Society of Gastrointestinal Endoscopy (ESGE) recommends colorectal cancer (CRC) screening for individuals at average risk, aged 50-75 years. However, recent trends indicate an increasing incidence of colorectal neoplasms among younger individuals.

Aims & Methods

The primary aim of this cross-sectional study is to record the prevalence of polyps, adenomas, and advanced neoplasia (high-grade dysplasia and CRC) in individuals up to 49 years old, and secondarily to identify predictors of neoplasia and high-grade dysplasia. The data were collected retrospectively through the hospital’s electronic database. All serial colonoscopies, with cecum intubation, from 1/1/2018 until 31/12/2024 were included. Endoscopies in patients with diagnosed familial polyposis syndromes, inflammatory bowel disease and those with poor bowel preparation were excluded. Patients’ demographics, CRC family history and the recorded polyps' size, location, Paris classification, and pathology reports were collected. SPSS 23 (IBM, Armonk, NY, USA) was used for the statistical analysis.

Results

Table. Polyps, adenomas and advanced adenomas by age groups
	<25 (n=36)	25-29 (n=31)	30-34 (n=61)	35-39 (n=76)	40-44 (n=146)	45-49 (n=218)	Total (n=568)	P
Polyps, n (%)	0 (0)	2 (6.5)	6 (9.8)	20 (26.3)	52 (35.6)	86 (39.4)	166 (29.2)	<0.001
Adenoma, n (%)	0 (0)	1 (3.2)	2 (3.3)	9 (11.8)	21 (14.4)	36 (16.5)	68 (12.1)	0.006
Advanced adenoma, n (%)	0 (0)	1 (3.2)	0 (0)	3 (3.9)	4 (2.8)	12 (5.6)	20 (3.5)	0.266

A total of 568 colonoscopies were included, involving 306 male patients (53.8%), with a median age of 42 years (IQR: 36-46). Of these, 71 patients (12.5%) had a family history of CRC. At least one polyp was identified in 166 patients (29.2%), with adenomas observed in 68 patients (12.1%) and advanced neoplasia in 20 patients (3.5%), including 3 patients (0.5%) diagnosed with CRC (Table). Advanced adenomas were more frequently detected in colonoscopies performed due to visible blood in stools (8.5%) and as follow-up after diverticulitis (7.1%). In multivariate analysis, in which age, family history of CRC, and bowel preparation quality were included as variables, the presence of adenomas and advanced adenomas was significantly associated with age (adenoma OR = 1.08; 95% CI: 1.04-1.13 and advanced adenoma OR = 1.08; 95% CI: 1.00-1.18).
In total 271 polyps were identified. Ninety-four were adenomas of which 74 had low-grade dysplasia and 20 high-grade dysplasia or cancer. Sixteen of 177 not-adenomatous polyps were found to be serrated and 2 of those had low-grade dysplasia. “Large” polyps [≥10mm] had a higher probability of being adenomas (71.4%) compared to “small” [5-9mm] (26.2%) and “diminutive” [<5mm] (24.4%), Chi square P<0.001. Regarding the Paris classification Ip and Isp presented a higher probability to be adenomas (87.5% and 86.4% respectively) in contrast to Is and 0-IIa (35.6% and 12.2% respectively), Chi square P<0.001.
The resected adenomas were also categorized according to the type of reported dysplasia to identify predictors of high-grade dysplasia. High-grade dysplasia was present in 42.5% of large polyps compared to 4.5% of small and 6.2% of diminutive (Chi square P<0.001). High-grade dysplasia was also present in a higher frequency in polyps resected from the “left” colon (26.2%) compared to the “right” (10.3%) and in 0-IIa (66.7%) and Ip (38.1%) compared to Isp (21.1%) and Is (12.5%) polyps according to the Paris classification, but not in a statistically significant degree (Chi square P<0.010).

Conclusion

Despite the relatively small sample size of our study, initiation of screening at a younger age should be considered to be lowered, since adenoma and advanced adenoma were identified in 15% and 4.3% of individuals aged 35-49.

Disclosure

GB: Advisor/lecturer for Janssen, Pfizer, Takeda, Abbvie, MSD, Mylan, Genesis Pharma, Adacyte Therapeutics, Amgen, Ferring, Cooper; Funding (Grants/Honoraria): Pfizer, Takeda, Abbvie, Aenorasis; Research/Clinical Trials: Abbvie, Takeda.

Introduction

The BIOSTOP trial is a Norwegian, multicenter study with a prospective, randomized, controlled, and open-label design. The trial was initiated to evaluate the two-year outcomes following the withdrawal of tumor necrosis factor-alpha (anti-TNF) antibodies in patients with ulcerative colitis (UC) who are in sustained clinical and endoscopic remission.

Aims & Methods

The main aim was to identify transcriptomic differences in colon biopsies associated with increased risk of relapse with anti-TNF withdrawal. We also wanted to increase our understanding of the underlying pathological mechanisms of relapse after anti-TNF withdrawal and treatment failure during continued treatment.
Between June 2017 and December 2020, 174 ulcerative colitis patients in confirmed clinical and endoscopic remission were enrolled and randomized, with 86 assigned to continue anti-TNF therapy (control group) and 86 to discontinue treatment (intervention group). Mucosal biopsies were collected at baseline, two-year follow-up, and at point of relaps
Bulk mRNA-sequencing was performed on RNA extracted from rectal biopsies. For patients in remission, samples from baseline and two-year follow-up were analyzed. For those who relapsed or experienced treatment failure, samples from baseline and point of relapse were analyzed. Differential gene expression was performed using DESeq2, and pathway enrichment analysis was assessed with clusterProfiler.

Results

There were no significant differences found at baseline between patients that relapsed (n=45) vs those that stayed in remission (n=41) after anti-TNF withdrawal. In patients that relapsed, the comparison from baseline to point of relapse showed upregulation of key inflammatory genes, including IL1B, STAT3, OSMR, TNF and CXCL10. Pathway enrichment analysis showed that the upregulated genes were associated with an inflammatory response, including TNF-signaling. At two-year follow-up patients who remained in remission also showed upregulation of proinflammatory genes, including genes associated with TNF-signaling. However, the expression levels were lower than in the relapse group. Patients in the control group who experienced treatment failure (n=10) showed a gene expression signature that strongly overlapped with those that relapsed in the intervention group.

Conclusion

We did not detect any transcriptional differences between the relapse and remission group at baseline and after anti-TNF withdrawal the expression of proinflammatory genes including genes involved in TNF-signaling increased in both groups. However, a more pronounced increase was observed in the relapse group, suggesting that those that relapse exhibited reduced immunoregulatory capacity.

Introduction

Vedolizumab, a α4β7 integrin monoclonal antibody represents an effective and well-tolerated therapeutic option for patients with moderate to severe Crohn's disease (CD)¹. Its use as a first-line biologic therapy is authorized in some European countries, particularly Belgium, providing an opportunity to assess its performance when introduced early in the treatment algorithm. Real-world data on long-term treatment persistence, particularly beyond three years, remain limited. This retrospective monocentric study aims to assess Vedolizumab persistence over five years in patients with CD, as well as evaluating the ability to predict treatment persistence based on the CDST (Crohn’s Disease Subtype Tool) score.

Aims & Methods

This is a retrospective monocentric study including 60 patients with CD, followed at a central university hospital in Brussels. All patients were treated with Vedolizumab administered intravenously, between 2015 and 2024. We evaluated treatment persistence defined as the continuation of Vedolizumab without interruption assessed at 6,12,24,36,and 60 months. Patients who had not yet reached the pre-set follow-up time points at the time of inclusion were excluded from the analysis at that specific time point, without being considered as treatment discontinuation. Persistence was described cross-sectionally at each time point. A CDST score was retrospectively calculated for all patients based on the available data before treatment initiation.

Results

A total of 60 patients with CD treated with Vedolizumab were included. Follow-up duration ranged between 1 and 107 months. The cohort consisted of 52% males with a mean age of 45.4 ± 14.5 years. 58 patients had completed at least 6 months of follow-up. Treatment persistence with Vedolizumab was 93% at 6 months (54/58), 87% at 12 months (47/54), 76.5% at 24 months (39/51), 67.4% at 36 months (31/46), and 56.1% at 60 months (23/41). 62% of patients were bio-naïve. The mean CDST score for all patients was 20.6 ± 2.6. The distribution of patients according to their predicted response to Vedolizumab was as follows: low probability of response (CDST ≤ 13): 1 patient (2%); intermediate probability (13 < CDST ≤ 19): 12 patients (20%); high probability of response (CDST > 19): 47 patients (78%). A comparative analysis of the CDST scores between patients who discontinued treatment and those with treatment persistence was performed at each follow-up time point. At 6 months, the mean CDST score was 20.47 in the treatment discontinuation group versus 21.2 in the persistence group (p = 0.713). At 12 months, the means were 21.6 and 21.0, respectively (p = 0.713). Similar trends were observed at 24 months (19.2 vs 20.9; p = 0.304), at 36 months (18.23 vs 20.9; p = 0.136), and at 60 months (19.7 vs 20.6; p = 0.523). These results suggest a trend toward higher CDST scores in patients with treatment persistence, although these differences did not reach statistical significance. Of the patients who completed five years of vedolizumab treatment, 9 out of 23 (39%) were biologic-naïve, while 14 out of 23 (61%) had prior exposure to biologic therapies.

Conclusion

This real-world retrospective study provides valuable insights into the long-term use of Vedolizumab in patients with CD, with a follow-up period extending up to five years. Treatment persistence over time was favorable in both biologic-naïve and exposed patients, particularly among those with a high CDST score. The extended follow-up period reinforces the durability and safety of Vedolizumab as a long-term therapeutic option in clinical practice. Prospective studies are needed to confirm these findings and identify predictors of sustained response.

References

Sandborn, W. J., Feagan, B. G., Fedorak, R. N., & et al. (2013). Vedolizumab as induction and maintenance therapy for ulcerative colitis. New England Journal of Medicine, 369(8), 699-710.