Introduction

Accurate assessment of disease activity and prediction of treatment response and prognosis are challenges in the management of chronic inflammatory bowel disease (IBD). Due to the invasiveness of colonoscopy, non-invasive methods are of high clinical relevance. Bowel ultrasonography (B-US) is establishing itself as a non-invasive, cost-effective method in daily clinical practice.

Aims & Methods

The aim of this study is to evaluate the correlation between B-US and endoscopy in relation to inflammatory activity and severity of IBD. Patients were retrospectively selected for comparison between B-US and endoscopy. A total of 473 patients were included, of whom (n=274) had Crohn's disease (CD) and (n=199) had ulcerative colitis (UC). The examination results were divided into four sections (terminal ileum, proximal colon, distal colon and rectum) and systematically analyzed. Inflammatory activity was classified according to intestinal wall thickness in mm: none (0): 0-2.9, mild (1): 3.0-4.9, moderate (2): 5.0-7.9, severe (3): >8.0. Endoscopic evaluation was performed according to simplified Mayo and SES-CD criteria.

Results

Based on endoscopy, patients were divided into groups with inflammatory activity (274 CD, 175 UC) and remission (34 CD, 24 UC). Comparison of B-US and endoscopy showed a significant correlation regarding inflammatory activity (r=0.44, p<0.001). The correlation was more significant in UC (r=0.5548, p<0.001) than in CD (r=0.3665), except in the ileum in UC (r=-0.1050, p<0.4822). The best correlation in MC was found in the ileum (r=0.4783, p<0.001) and in the distal colonic segments (r=0.5217, p<0.001), while in UC the best correlation was found in the proximal (r=0.5586, p<0.001) and in the distal colonic segments (r=0.6250, p<0.001). Localization of rectal inflammation was associated with lower diagnostic accuracy. Compared to endoscopy, B-US showed a sensitivity of 82.2%, a specificity of 51.7% and a positive predictive value of 92.4%.

Conclusion

B-US shows reliable diagnostic accuracy compared to endoscopy in assessing inflammatory activity in IBD patients and can be considered as a complementary non-invasive diagnostic tool.

Disclosure

AL recieved research funding from the European Regional Development Fund (Project ID: ZS/2018/11/95324) and the German Federal Ministry of Education and Research (BMBF) (FKZ 01GM2204A). AL has received speaker fees from Janssen, Ferring and Luvos.

Introduction

The incidental finding of terminal ileal inflammation during routine colonoscopy is not uncommon and is of unclear significance. It has been reported among asymptomatic persons undergoing non-diagnostic colonoscopy. There is limited data on long term follow-up and outcomes of such findings.(1)

Aims & Methods

This is a monocentric retrospective observational study spanning from 2018 to 2023, comparing two periods: the first period (P1) before the impact of the Covid-19 pandemic in 2020, and the second period (P2) starting 2020 reflecting the impact the pandemic left on colonoscopies. For each patient, variables were collected from medical records.

Results

Our initial database included 11200 colonoscopies, from which we randomly selected 2394 patients proportionally to the annual activity (mean of 1686/year before 2020 and 1189/year after 2020). Among indications of colonoscopy were screening and follow-up, change in bowel habits, anemia and bleeding. We excluded 287 patients (known history of inflammatory bowel disease and no ileum intubation). Then the sample was divided into P1 (681 patients) and P2 (1483 patients). Characteristics and findings are shown in Table 1. We noted better bowel preparation (77.1 vs 91.7%) and a higher ileum intubation in P2 (79.7 in P1 vs 93.8% in P2).
​

N=2164			P1 (N1=681)	P2 (N2= 1483)	p
Age (years)			57.5	56.9	NS
Overall endoscopic findings n(%)	Endoscopic aspect of ileitis		0 (0)	71 (5.8)	<0.001
	Abnormal ileal findings on histology		23 (3.4)	169 (11.4)	<0.001
	Diagnosis of Crohn's disease		0 (0)	19 (0.9)	<0.001
Overall histological findings n(%)	Active ileitis		19 (2.8)	147 (9.9)	<0.001
	Focal ileitis		10 (1.5)	89 (6)	<0.001
	Ulcerative ileitis		11 (1.6)	48 (3.2)	0.031
	Erosive ileitis		3 (0.4)	31 (2.1)	0.004
	Architectural distortion		1 (0.1)	16 (1.1)	0.023

Overall ileoscopy findings showed an increased aspect of ileitis on endoscopy (0% in P1 and 5.8% in P2, with p<0.001), correlating with a significant increase in the incidence of histological findings on ileal biopsies (3.4% in P1 vs 11.4% in P2; p<0.001). These histological findings included active, focal and ulcerative ileitis, with more architectural distortion. However, these results corresponded to a less severe ileitis (0.3 vs 2.3%; p=0.001). Nineteen of these patients with positive results of ileitis were diagnosed with Crohn’s disease.

Conclusion

This study showed an increase in endoscopic and histologic ileitis on colonoscopy following the Covid-19 era. This could be the result of the direct virologic effect that the virus has on intestinal inflammation, its indirect effect on immunity triggering the onset of enteritis, or the consequence of the mass vaccination campaign held to protect from the virus. Furthermore, histology showed granulomatous inflammation similar to Crohn’s disease, which may lead to misdiagnosis and probably overtreatment.

References

1. Agrawal M, Miranda MB, Walsh S, Narula N, Colombel JF, Ungaro RC. Prevalence and Progression of Incidental Terminal Ileitis on Non-diagnostic Colonoscopy: A Systematic Review and Meta-analysis. J Crohns Colitis. 2021 Feb 14;15(9):1455–63.

Introduction

GLPG3970, a potent and selective salt-inducible kinase (SIK) 2/3 inhibitor, exerts a dual mechanism combining anti-inflammatory and immunoregulatory activity.¹ In chronic inflammatory diseases, such as inflammatory bowel disease (IBD), GLPG3970 has the potential to restore immune balance and homeostasis.^2,3 In a 6-week signal-detection phase 2a study in patients with ulcerative colitis (UC),⁴ GLPG3970 showed positive effects in histology, endoscopy and faecal calprotectin versus placebo, despite no differentiation from placebo on change from baseline on total Mayo Clinic Score at week 6.^4,5

Aims & Methods

We investigated the dual mechanism of GLPG3970 in severely inflamed ex vivo treated IBD tissue biopsies. Inflamed intestinal biopsies (most affected segment; n = 9 per patient) were obtained from patients with UC (n = 10) and Crohn’s disease (CD; n = 10) with active endoscopic disease (UC: Mayo endoscopic subscore ≥ 2; CD: SES-CD of ≥ 4). Patients were biologic-naive (UC: n = 5; CD: n = 5) or biologic-experienced (UC: n = 5; CD: n = 5). Three individual biopsies per condition were exposed ex vivo for 24 hours to vehicle control (DMSO), tofacitinib (10 µM, positive control) or GLPG3970 (60 µM). Protein secretion in supernatant was analysed by V-PLEX Human Biomarker 54-Plex (two-way ANOVA, Dunnett’s multiple comparison). RNA sequencing of biopsies was performed on Illumina NovaSeq 6000. Gene expression was quantified using Salmon (v1.5.2) and differential expression analysis was performed with DESeq2 (v1.28.0; criteria: |log2FC|> 0.58, FDR < 0.05, baseMean > 32).

Results

High levels of inflammatory cytokines and chemokines were observed in the supernatant after ex vivo culturing. Exposure to GLPG3970 resulted in a significant decrease of pro-inflammatory cytokines (e.g. TNFα, GM-CSF, IFN-γ, IL-2) and chemokines (e.g. MCP-1, MIP1α, MIP1β) in both UC and CD biopsies, relative to vehicle control. GLPG3970 activity was statistically stronger than tofacitinib for most evaluated proteins (p value), except for IL-1RA, IL-3, IL-9, IL-22, IL-23, among others. RNAseq analysis showed a clear signature of differentially expressed genes (DEGs) for GLPG3970 versus vehicle control (UC: 549 DEGs, with 288 downregulated, including pro-inflammatory genes CSF2, MMP9 and CCL4; CD: 673 DEGs, with 238 downregulated, including CSF​2, CXCL10 and CXCL11). Tofacitinib versus vehicle resulted in 582 (UC) and 681 (CD) DEGs including JAK/STAT dependent genes, such as MX1, SOCS3 and IFITM1. Direct comparison of GLPG3970 versus tofacitinib highlighted the impact of GLPG3970 on pathways involved in ‘TGF-β signalling’, indicative of enhancing immunoregulatory mechanisms, ‘TNFα signalling via NF-κB’ and ‘glycolysis’, whereas tofacitinib mainly affected ‘IFN-α response’ and ‘IFN-γ response’ in both UC and CD biopsies. In addition, GLPG3970 exposure to ex vivo biopsies resulted in a partial reversion of UC and CD transcriptome signatures (Spearman correlation: -0.25 [UC], -0.22 [CD]).⁶

Conclusion

Acute exposure of GLPG3970 to ex vivo inflamed tissue biopsies from patients with UC and CD showed a strong reduction in the release of pro-inflammatory mediators. Transcriptomic analysis further confirmed GLPG3970’s robust activity in reducing inflammatory NF-κB-mediated pathways while modulating TGF-β-related immunoregulatory pathways versus tofacitinib. Our findings support the dual mechanism of GLPG3970 in relevant pathogenic pathways in IBD and confirm the therapeutic potential of SIK2/SIK3 inhibition in treating patients with either UC or CD.

References

1. Peixoto C et al. J Med Chem 2024;67:5233–58.
2. Pereira-Fernandes A et al. [abstract] United European Gastroenterol J 2021;9:S8.
3. Lavazais S et al. [abstract] United European Gastroenterol J 2021;9:S8.
4. ClinicalTrials.gov. A Study Evaluating the Effects of GLPG3970 Given as an Oral Treatment for 6 Weeks in Adults With Ulcerative Colitis (SEA TURTLE). 2020. Available from: https://clinicaltrials.gov/study/NCT04577794 (Accessed 8 April 2024).
5. Galapagos. Galapagos demonstrates early clinical activity with SIK2/3 inhibition in inflammation. 2021. Available from: https://www.glpg.com/press-releases/galapagos-demonstrates-early-clinical-activity-with-sik2-3-inhibition-in-inflammation/ (Accessed 8 April 2024).
6. Massimo L et al. Nat Comput Sci 2021;1:511–15.

Disclosure

This study was funded by Galapagos NV (Mechelen, Belgium).
Editorial and publications management support was provided by PharmaGenesis London, London, UK, and was funded by Galapagos NV.
LG and KA are joint first authors.
LG, KA and EV report no disclosures.
MC and SDV are employees of Galapagos.
BV reports research support from AbbVie, Biora Therapeutics (formerly Progenity), Landos Biopharma, Pfizer, Sosei Heptares and Takeda; speaker fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring Pharmaceuticals, Galapagos, Janssen Pharmaceuticals, Lily, MSD, Pfizer, R-Biopharm, Sandoz, Takeda, Tillots Pharma, Truvion Healthcare and Viatris; consultancy fees from Abbvie, Alfasigma, Alimentiv, Applied Strategic, AstraZeneca, Atheneum, BenevolentAI, Biora Therapeutics (formerly Progenity), Boxer Capital, Bristol Myers Squibb, Galapagos, Guidepont, Landos, Lily, Mylan, Inotrem, Ipsos, Janssen Pharmaceuticals, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris; and stock options from Vagustim.
SV reports speaker and/or consultancy fees from AbbVie, Abivax, AbolerIS Pharma, AgomAb Therapeutics, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Biora Therapeutics (formerly Progenity), Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead Sciences, GSK, Hospira, IMIDomics, Janssen Pharmaceuticals, Johnson & Johnson, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic Therapeutic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Prometheus Biosciences, Robarts Clinical Trials, Surrozen, Takeda, Theravance Biopharma, Tillotts Pharma, VectivBio, Ventyx Biosciences and Zealand Pharma; grants from AbbVie, Galapagos, Johnson & Johnson, Pfizer and Takeda; and participation on a data safety monitoring board for Sanofi.

Introduction

Crohn’s disease (CD) may manifest as perianal disease (PD) in up to 36% of cases. In the majority, PD occurs simultaneously or after the diagnosis of small bowel CD. Diagnosing CD in patients with isolated PD can be challenging. Small bowel capsule endoscopy (SBCE) has been shown to have a higher diagnostic yield for small bowel findings compatible with CD than other modalities.

Aims & Methods

This study aimed to assess the impact of SBCE as a diagnostic tool for CD in patients with isolated PD.
Retrospective cohort study spanning 2008 to 2023. Adult patients with isolated PD (recurrent fissures, trans-/supra-/extra-sphincteric fistula or abscess) and negative conventional workup for CD (ileocolonoscopy and cross-sectional imaging) who underwent SBCE (Pillcam, Given®) were included. Patients using nonsteroidal anti-inflammatory drugs or with a CD history were excluded. Demographics, biomarkers, SBCE findings and subsequent management were recorded and analyzed.

Results

Forty patients (mean age 40.2 years, 67.5% females) were included. SBCE identified findings compatible with small bowel CD (aphthous ulcerations, linear/circumferential ulcers and stenosis) in 32.5% (13 patients), enabling diagnosis and subsequent treatment in all of them, based on disease severity. In this group, mean previous fecal calprotectin (FC) was 722.2µg/g, but FC was inferior to 200µg/g in 46.2% (6 patients). In 4 patients (10%) with negative SBCE, isolated perianal CD was assumed and immunosuppressors were started. There was no statistically difference in FC of the patients with positive and negative SBCE. Laboratory findings (C-reactive protein, albumin), tobacco use and family history of CD/ulcerative colitis did not show significant associations with SBCE findings.

Conclusion

For patients with PD and a negative conventional CD workup, SBCE demonstrated a 32.5% incremental diagnostic yield, leading to therapy initiation based on severity.

Introduction

Recent research finds 25%-30% of IBD patients experience chronic post-traumatic stress due to their disease (IBD-PTS) and IBD-PTS is associated with poorer outcomes. Post-traumatic growth (PTG) is defined as “positive psychological changes that occur as a result of one’s struggle to cope with trauma or a major life crisis.” PTG can reduce the negative impacts of IBD-PTS, which may be moderated by disease activity in IBD.

Aims & Methods

We aim to examine the relationship between remission status, patient expectations regarding if they can achieve and sustain remission, and PTG among patients with IBD. Adults (18+) with IBD were recruited via social media IBD support groups, and flyers posted in gastroenterology clinics and community bathrooms with additional snowball sampling methods. Surveys were completed online via Qualtrics and included demographics, Patient Simple Clinical Colitis Activity Index (P-SCCAI), Post-Traumatic Growth Inventory (PTGI), and PTSD Checklist for DSM-5 (PCL-5). Participants reported if they were in remission or experiencing a flare of symptoms, and their expectations of experiencing a flare in the next 2 months on a 4-Point Likert scale.

Results

313 adults with IBD: UC (n=140, 44.7%), CD (n=173, 55.3%). Age 18-70 years (M=33, SD=11), 75.1% female. Scores for PTGI, P-SCCAI, and PCL-5 are in Table 1. Participants tended to have active disease and high levels of IBD-PTS. No significant correlation existed between P-SCCAI score and PTG (r= -.09 p=.127). Those in a current IBD flare (n=133,42.4%) reported lower confidence in the longevity of their remission over the next 2 months compared to participants who were in remission (Χ2=114.01,p<.001), with no difference in PTG levels between groups (p=.310). However, participants who demonstrated optimism about sustained remission had higher levels of PTG (F(3,309)=4.688,p=.003). Participants who endorsed “I am positive I will experience a flare up in the next two months” had much lower levels of PTG (M=65.91,SD=25.33) than participants who endorsed “I am positive I will not experience another flare up in the next two months” (M=81.52,SD=25.58;p=.004). Those who endorsed “I am at least 50% positive I will experience another flare up” had lower rates of PTG (M=69.99, SD=22.95) than those who endorsed “I am positive I will not experience another flare up in the next 2 months” (M=65.91,SD=25.33;p=.026). A linear regression found the extent of the differences in the levels of confidence in maintaining remission influenced levels of PTG (F(3,309)=4.688 p=.003). Participants who were the least confident in their remission scored 15.61 points lower for PTG than for participants who were the most confident. Participants who were at least 50% sure they would experience another flare in the next two months scored 11.53 points lower for PTG than participants who were the most confident in their remission.

Conclusion

Our findings suggest IBD patients who expect to achieve disease remission are more likely to have higher levels of PTG than those who are more pessimistic about their disease course, independent of current symptom activity. However, those in an IBD flare are less likely to believe they can attain remission. Due to the unpredictable nature of IBD, patients are chronically exposed to risks for medically traumatic experiences. Patients with confidence in their remission longevity may conceptualize remission as an “end” to the threat of IBD-PTS, thus allowing PTG to occur. Conversely, if remission is seen as a temporary reprieve before the next inevitable flare, it may limit patients’ abilities to cultivate PTG. Providers can help patients move towards a PTG mindset by assessing patients’ expectations of remission, modeling optimism in a patient’s prognosis, and providing evidence for ongoing hope.

References

Fuss, A., & Lease, S. (2023). Moderating the Relationship Between Ulcerative Colitis and Crohn’s Disease and Symptoms of PTSD: The Role of Remission. Journal of Clinical Gastroenterology, 57(8), 816-823.

Purc-Stephenson, R. J. (2014). The posttraumatic growth inventory: Factor structure andinvariance among persons with chronic diseases. Rehabilitation Psychology, 59, 10–18.https://doi.org/10.1037/a0035353

Disclosure

The authors have no disclosures

Introduction

Intestinal ultrasound (IUS) has proven to be a valuable tool for accurately detecting intestinal damage and characterizing disease behavior in Crohn’s disease (CD). IUS scoring systems for CD activity have been developed, however all the studies had methodological flaws. Therefore, studies comparing and validating the existing IUS scores in CD patients are required.

Aims & Methods

In this study, we aimed to compare two main existing scores, Bowel Ultrasound Score (BUSS) and International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) in patients with ileal CD using the simplified endoscopic activity score for CD (SES-CD).
An observational cross-sectional study was performed to evaluate the disease activity in adult CD patients with ileal involvement between November 2019 and February 2024. All patients had undergone ileocolonoscopy and IUS, the time interval between the two procedures was lower than 10 days. Receiver operating characteristic (ROC) curve analyses was performed for BUSS and IBUS-SAS to predict SES-CD ≤2 for CD.

Results

Total 56 adult patients with ileal CD were included in the study, 38 patients (67.9%) were male, the median age was 40.5 (IQR 26-46.75) years and the median duration of the disease was 8.4 (IQR, 4.93-10.29) years. In the endoscopically remission (SES-CD ≤2) group; the median BUSS was 2.63 (IQR 2.12-3.45) and the median IBUS-SAS was 14 (IQR, 11.3-18.4), while in the endoscopically active (SES-CD >2) group; the median BUSS was 5.67 (IQR, 3.47-7.76) and the median IBUS-SAS was 49.7 (IQR, 23.3-72.65). The median BUSS and median IBUS-SAS in the endoscopically remission group were significantly lower than those of the endoscopically active group (p< 0.001, for both). The cut-off value for BUSS to determine endoscopic remission (SES-CD ≤2) was 3.9 (AUC: 0.839, 95% CI: 0.737-0.941, sensitivity: 92%, specificity: 73%, p < 0.001), while the cut-off value for IBUS-SAS to establish endoscopic remission (SES-CD ≤2) was 24.4 (AUC: 0.871, 95% CI: 0.780-0.962, sensitivity: 100%, specificity: 73%, p < 0.001).
There was a very high positive correlation between BUSS and IBUS-SAS (r=0.914, p<0.001), a high positive correlation between BUSS and SES-CD (r=0.659, p<0.001), a moderate positive correlation between BUSS and CRP (r=0.577, p<0.001). There was a high positive correlation between IBUS-SAS and SES-CD as well as IBUS-SAS and CRP (r=0.728, p<0.001 and r=0.657, p<0.001 respectively).

Conclusion

In this study, we found that the most accurate cut-off value for BUSS was 3.9 and the most accurate cut-off value for IBUS-SAS was 24.4 in CD patients with endoscopic remission (SES-CD ≤2) group. Also, we have confirmed that both BUSS and IBUS-SAS significantly correlate with endoscopic activity in a real-world cohort.