bluuebunny/crossref_metadata_2025 huggingface dataset:
OP14 Effect of mirikizumab on clinical and endoscopic outcomes after 1 anti-TNF failure in patients with moderately to severely active Ulcerative Colitis
Authors: Hart A , Martín-Arranz M D , Laharie D , Matsuoka K , Dhesi E , Redondo I , Baygani S , Zaremba-Pechmann L , Samaan K , Navabi S
Published: January 2024

Background

Mirikizumab (miri), an anti-IL-23p19 antibody, has demonstrated efficacy and safety in moderately to severely active ulcerative colitis (UC) Phase 3 trials (LUCENT-1 and -2; NCT03518086, NCT03524092) among patients who had an inadequate response, loss of response, or intolerance to conventional or advanced therapy. At the LUCENT-1 induction baseline, 41% of the population had experienced a biologic/tofacitinib failure, and 36.3% experienced at least one anti-TNF failure. Among patients with one prior anti-TNF failure only, this analysis evaluated the clinical efficacy of miri compared to placebo (PBO) in induction and maintenance therapy and the efficacy of miri in extended induction.

Methods

In LUCENT-1, UC patients were randomized to receive 3 intravenous (IV) doses of 300mg miri or PBO every four weeks (Q4W) at W0, W4, and W8 (induction population). In LUCENT 2, responders to miri induction at W12 were re-randomized to subcutaneous (SC) 200mg miri or PBO Q4W through W52 of continuous therapy (maintenance population). Patients not achieving clinical response with miri 300mg IV at W12 received extended induction treatment with open-label 300mg miri IV at W12, W16, and W20 (extended induction population). Patients responding to extended induction at W24 entered open-label maintenance and received 200mg miri Q4W SC until W52 (extended induction responders). Endpoints evaluated were clinical response, clinical remission, symptomatic remission, endoscopic remission, corticosteroid (CS)-free remission, and histologic-endoscopic mucosal remission (HEMR). Efficacy in the subgroup of patients with failure of one anti-TNF only was assessed using Cochran-Mantel-Haenszel tests at W12 (induction population) and W52 (maintenance population).

Results

At LUCENT-1 baseline, of patients who experienced anti-TNF failure, 45% of patients (n=190) had one prior anti-TNF failure only (Table 1). In the induction and maintenance populations, a significantly greater proportion of miri-treated patients achieved the following efficacy endpoints compared with PBO [miri vs. PBO, p-value]: clinical response (W12: [64.4% vs. 34.1%, p=0.001]; W52: [67.2% vs. 44.8%, p=0.03]); clinical remission (W52: [44.3% vs. 17.2%, p=0.017]); symptomatic remission (W52: [63.9% vs. 34.5%, p=0.005]) (Table 2). Among the extended induction population, 45.7% achieved clinical response at W24; 75% achieved clinical response, 30% achieved clinical remission and CS-free remission at W52 (Table 2).

Conclusion

Mirikizumab is efficacious for induction and maintenance therapy in patients with moderately to severely active UC who have failed one prior anti-TNF.
OP22 Topical Sphingosine-1-Phosphate (S1P) Receptor 1 Modulation Regulates Gut Angiogenesis in Inflammatory Bowel Diseases
Authors: Wang J , West G , Lin S , Mukherjee P , Maddux R , Wu C , Hu S , Nguyen Q T , Czarnecki D , Le H N , Mao R , Chandra J , Hu S , Gordon I , Petersen A , Harris S , Rieder F
Published: January 2024

Background

S1P receptor (S1PR)1/5 modulators have been tested successfully in clinical development programs in ulcerative colitis (UC), leading to their FDA approval. They are believed to act through lymphocyte redistribution in peripheral lymphoid tissue and reduced numbers of circulating lymphocytes, but evidence from other organs suggests potential additional mechanisms of action.

Methods

A post-hoc analysis of the phase 3 trial of the S1PR1/5 modulator Ozanimod in patients with moderately to severely active UC was performed assessing an association of absolute lymphocyte count (ALC) with efficacy. Expression levels of S1PRs were analyzed in human intestinal tissues and primary cells using qPCR and/or immunohistochemistry (IHC). Effects of S1P, S1PR1/5 modulators and S1P1 knockdown on migration, proliferation, cytokine production, downstream signaling (immunoblot), tube formation of human intestinal microvascular endothelial cells (HIMEC) was evaluated. S1P and S1PR1/5 modulators were examined in a murine matrix plug angiogenesis model and with topical and systemic S1PR1/5 modulator therapy in dextrane sodium sulfate (DSS) colitis in vivo.

Results

Baseline ALC and relative or absolute ALC reductions were neither correlated with nor predictive of clinical or endoscopic outcomes. In murine DSS colitis topical therapy with a S1PR1/5 modulator ameliorated colitis but did not alter peripheral lymphocyte numbers. S1PR1 gene and protein expression was increased in UC and Crohn’s disease (CD) patients and predominantly expressed on HIMEC. S1P promoted HIMEC migration, proliferation, tube formation, IL-8 secretion, indicative of pro-angiogenic responses in vitro. Modulation of S1PR1/5 and knockdown of S1PR1 markedly inhibited these pro-angiogenic functions in the presence of high concentrations of S1P, but enhanced angiogenesis when low S1P concentrations were present. S1PR5 had no effect on angiogenesis. In the murine plug assay, S1PR1 induced angiogenesis. In acute DSS colitis, treatment of S1PR modulator by enema reduced blood vessels, but left lymphatics unaffected.

Conclusion

We present a novel mechanism of action of S1PR1 modulators in IBD intestinal tissue, potentially explaining a disconnect between ALC and efficacy observed in a post-hoc analysis of the phase 3 Ozanimod UC trial. The data presented suggest that S1P induced angiogenesis is attenuated by S1PR1 modulation in HIMEC from IBD patients when S1P levels comparable to blood were present. In the presence of S1P at concentrations consistent with lymph fluid angiogenesis was increased. Together with reduced numbers of circulating lymphocytes, this may contribute to efficacy of S1PR1 modulators in IBD patients.
OP31 Single-cell analyses identify immune and stromal signatures of perianal fistulizing Crohn's Disease
Authors: Cao S , Nguyen K , Colonna M , Deepak P
Published: January 2024

Background

Perianal fistulas occur in ~30-40% of Crohn’s disease (CD) patients associated with high morbidity and an impaired quality of life. The management of perianal fistulizing CD is a major clinical challenge, where its underlying etiology remains poorly understood.

Methods

We recruited patients with 1) CD with perianal fistulas (PCD; n = 12); 2) CD without perianal involvement (NPCD; n = 10); 3) idiopathic perianal fistulas (IPF; n = 21). Biopsies were taken from the fistula tracts, external opening of the fistulas, and rectal mucosa during examination under anesthesia or colonoscopy. Mucosal immune cells were analyzed using mass cytometry (or CyTOF), while all cells from PCD and IPF fistula tracts (n = 5 or 6) were characterized using single-cell RNA-sequencing.

Results

CyTOF revealed a skewed mucosal immune landscape in PCD. E.g., PCD fistula tracts harbored elevated CD45RO+ T cells including Tregs with increased expression of TIGIT and CD226 compared to IPF. PCD also expanded Th17 cells in the fistula tracts and IL-17-producing CD8 T cells (Tc17) in the rectum. Altered exhaustion markers CD39 and CD127 were present in both CD4 and CD8 T cells from PCD fistula tracts, external fistula openings, and rectum compared to IPF and NPCD. Regulatory B cells (Bregs), with immunomodulatory function in the gut, were dramatically diminished in PCD compared to IPF. In addition, PCD fistula tracts, fistula opening, and rectum all exhibited substantially higher CD172+TREM1+ macrophages, which were previously found to promote luminal CD (Figure 1; only fistula tract data are shown). Using scRNA-seq, we unraveled immune and stromal cell compartments in PCD and IPF fistula tracts (Figure 2). We also identified a small mast cell population, which was diminished in PCD. Mast cells are involved in tissue repair and remodeling in other diseases, although their presence in perianal fistulas was previously unknown. Three fibroblast populations (cluster 4, 6, 7 in figure 2D), with elevated activities in interferon signaling, IL-6-JAK-STAT3 pathway, TNF signaling, as well as TGF-B and epithelial-mesenchymal transition, were dramatically increased in PCD compared to IPF. Ongoing studies are focusing on spatial transcriptomics and functional analysis of fistula-associated immune cells and fibroblasts.

Conclusion

Using single cell analysis of the fistula tracts and nearby tissues from an extensive patient population, we revealed previously unknown immune and stromal cell landscapes of PCD. Our findings highlight the pathogenic roles of IL-17 signaling, T cell exhaustion, pathogenic macrophages, and pro-inflammatory/remodeling fibroblasts in the pathogenesis of PCD. This study may open new avenues for disease-specific therapies for this challenging condition.
DOP08 A novel multiomic approach to unravel the mechanisms of action of biologics and tofacitinib in Inflammatory Bowel Disease
Authors: Baldan-Martin M , Azkargorta M , Aransay A M , Gil-Redondo R , Moreno-Indias I , Iloro I , Soleto I , Orejudo M , Ramírez C , Lucendo A J , Rodríguez Gutiérrez C , Gutiérrez A , Martín Arranz E , Bujanda L , Rodríguez-Lago I , Riestra S , Iglesias-Flores E , Bermejo F , Van Domselaar M , García M J , Fernández Salazar L , De Prado Á , Calvet X , Torrealba L , Bastón Rey I , Pallarés H , Ber Y , Carnerero E L , Casanova M J , Millet Ó , Elortza F , Mato J M , Tinahones F J , Chaparro M , Gisbert J P
Published: January 2024

Background

Inflammatory bowel diseases (IBD), which includes Crohn´s disease (CD) and ulcerative colitis (UC), are complex and heterogeneous diseases characterized by a multifactorial etiology. IBD prevalence is increasing worldwide. The availability of diverse treatments with different mechanisms of action have revolutionized the ability to achieve clinical remission and endoscopic healing. The aim of this study was to achieve a deeper understanding of the mechanism of action and response to different IBD treatments using a multiomic approach.

Methods

We analysed the metabolome of serum and urine, metagenome of stool samples and transcriptome and proteome of mucosal biopsies from 53 patients with moderate-to-severe CD and 50 UC patients initiating biologic therapy (anti-TNF, ustekinumab or vedolizumab) or tofacitinib. Patients were assessed at 14 weeks for endoscopic remission and were categorized into responders or non-responders. The methodologies employed in this study were RNA-seq analysis, liquid chromatography-mass spectrometry, nuclear magnetic resonance, and 16S rRNA gene sequencing.

Results

The multiomic analyses revealed substantial alterations in the transcriptome, proteome, metabolome and metagenome of both responders and non-responders IBD patients before and after treatment (14 weeks) to different biologics and tofacitinib (Table 1). Gene enrichment analysis showed notewhorthy differences in all study comparisons, except for patients with CD and UC who did respond to anti-TNF and tofacitinib. Functional enrichment analysis of differentially expressed proteins indicated several processes that could be potentially involved in the mechanisms of action of different treatments. More differences were observed in lipoproteins than in serum and urine metabolites in the different study comparisons. Finally, metagenomic findings indicated changes in the composition of gut bacteria communities among CD patients treated with ustekinumab and UC patients treated with tofacitinib (responders vs non-responders at 14 weeks) (Figure 1).

Conclusion

The present study provides novel insights into the mechanisms of action of different IBD treatments from a multiomic approach. Nonetheless, multiomic data integration and validation studies are needed to confirm these findings within a more extensive and independent cohort of patients.
DOP10 Risankizumab Versus Ustekinumab for the Achievement of Endoscopic Outcomes in Patients With Moderate-to-Severe Crohn’s Disease: Results From the Phase 3b SEQUENCE Trial
Authors: Peyrin-Biroulet L , Bossuyt P , Regueiro M , Schreiber S , Gecse K , Irving P , D’Haens G , Cao Q , Neimark E , Huang X , Anschutz T , Kligys K , O’Brien D , Panaccione R
Published: January 2024

Background

The SEQUENCE study compared the efficacy and safety of risankizumab (RZB) and ustekinumab (UST) in patients (pts) with moderate-to-severe Crohn's disease (CD) who previously failed ≥1 anti-tumour necrosis factor (TNF)a therapies. The second primary endpoint of SEQUENCE, week (wk) 48 endoscopic remission, demonstrated superiority of RZB versus (vs) UST.1 Here, additional endoscopic and clinical/endoscopic composite outcomes are reported.

Methods

SEQUENCE (NCT04524611) was an open-label, multicenter, randomised, efficacy assessment-blinded study. Pts had a baseline (BL) CD Activity Index (CDAI) of 220-450, average (avg) daily stool frequency ≥4 and/or avg daily abdominal pain score ≥2, and Simple Endoscopic Score for CD (SES-CD) ≥6 (≥4 for isolated ileal disease). Pts in the primary efficacy analysis set were randomised 1:1 to receive RZB (intravenous [IV] 600mg induction at BL, wk4 and wk8, then 360mg subcutaneous [SC] maintenance doses every 8 wks [Q8w], starting at wk12) or UST (single weight-based IV induction followed by a 90mg Q8w SC maintenance treatment starting at wk8) up to wk48. Randomisation was stratified by BL steroid use and number of failed anti-TNFa therapies. A mandatory steroid taper began at wk2. Here, we assessed at wks 24 and 48 endoscopic remission (SES-CD ≤4 and at least a 2-point reduction versus BL and no subscore >1 in any individual variable, as scored by a central reader), mucosal healing (SES-CD ulcerated surface subscore of 0 in pts with SES-CD ulcerated surface subscore ≥1 at BL, as scored by a central reader), and deep remission (endoscopic remission + clinical remission [CDAI<150]); all were prespecified, non-ranked endpoints, except for wk48 endoscopic remission (second primary endpoint). Treatment differences were adjusted for the randomisation stratification factors. Missing data were handled using non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19 and/or geopolitical conflict. P values were reported as nominal, except for wk48 endoscopic remission.

Results

With RZB vs UST, a greater proportion of pts achieved endoscopic remission (wk24: 29.4% vs 17.4%, P= 0.001; wk48: 31.8% vs 16.2%, P<0.0001), mucosal healing (wk24: 25.1% vs 14.4%, P<0.01; wk48: 30.2% vs 12.1%, P<0.0001), and the composite endpoint of deep remission (wk24: 22.0% vs 10.2%, P< 0.001; wk48: 22.7% vs 10.9%, P<0.001) at wk24 and wk48 (Figure). The safety profiles of RZB and UST were consistent with published results.1

Conclusion

Exploration of endoscopic outcomes demonstrated that pts with moderate-to-severe CD and prior anti-TNFa failure showed greater achievement of endoscopic remission, mucosal healing, and deep remission with RZB compared to UST.

1doi.org/10.1002/ueg2.12474
DOP13 Effect of 8 weeks of combined aerobic and resistance exercise on quality of life, muscle strength, aerobic capacity, and disease activity in patients with Inflammatory Bowel Disease; a parallel group randomized clinical trial
Authors: Mirmoosavi S , Alborzi Avanaki F , Javaherian M , Tabatabaei B
Published: January 2024

Background

Sarcopenia is prevalent in patients with IBD (inflammatory bowel disease). This study aimed to assess the effects of an 8-weeks combined aerobic and resistance training program on the quality of life, disease activity, muscle strength, and aerobic capacity in patients with IBD. (Registration ID: NCT05455762)

Methods

This study was a single-blind parallel-group randomized clinical trial. Inclusion criteria were patients 18 to 65 years old with a confirmed diagnosis of IBD. Exclusion criteria: active malignancy, consumption of systemic corticosteroids, and patients with moderate to severe physical activity more than 150 minutes/week. Patients were allocated to each group by block randomization with a 1:1 ratio. The intervention consisted of walking sessions on even days and six resistance exercises on odd days. The primary outcome was the patients' quality of life, measured by the Persian version of the ibdq-9 questionnaire. secondary outcomes included disease severity, muscle strength, 6-minute walk test, and 30-second sit-to-stand test. We measured muscle strength by a handheld dynamometer.

Results

Of 72 patients screened 64 were eligible for the study. During the follow-up period, 13 patients, 8 from the exercise group and 5 from the control group, were excluded from the study. 51 patients, 28 females and 23 males, with a mean age of 34.9 ± 10.57 were analyzed. Two groups were matched in demographic and IBD-related characteristics. Unlike the control group, the exercise group showed a significant increase in overall quality of life (40.29 to 47.75, p=0.005), particularly in intestinal and systemic symptoms domains (p=0.01 and p=0.004). the inter-group analysis found no significantly higher mean difference in QOL scores between the exercise and control groups (p=0.053). The Partial Mayo score in patients with ulcerative colitis (UC) significantly decreased in the intervention group but not in the control group. The Harvey-Bradshaw index in Crohn patients didn’t change in either group. There were no exercise-related serious complications. The 6-minute walk test distance significantly increased in the exercise group but not in the control group. The 30-second sit-to-stand test didn’t significantly change in either group. Of muscles examined (hand grip, shoulder abductor, hip flexor, knee extensor, and elbow flexor) only knee extension strength increased in both groups.

Conclusion

Combined resistance and aerobic exercise in patients with IBD is safe and can significantly improve the quality of life and aerobic capacity. This regimen also improved clinical severity in patients with UC but not in Crohn’s. Muscle strength did not significantly improve when comparing the two groups, possibly due to the short duration of the intervention.
DOP23 The role of histology for the prediction of clinical relapse in Crohn’s Disease: A substudy of the STORI cohort
Authors: Reenaers Dr C , Enea D , Nachury M , Laharie D , Bouhnik Y , Fumery M , Gornet J M , Amiot A , Altwegg R , de Vos M , Marteau P , Bourreille A , Nancey S , Viennot S , Louis E , svrcek M
Published: January 2024

Background

Deep remission has become the target in the management of Crohn’s disease (CD). The role of histology in the management of CD has not yet been established. The aim of this work was to study the impact of histological inflammation on the risk of clinical relapse in patients with CD in clinical and endoscopic remission and to study the correlation between histology and endoscopic scores and biomarkers.

Methods

All patients included in STORI (1) were eligible for inclusion. Fecal calproptectin and colonoscopy with CDEIS calculation were performed at inclusion. Two biopsies, taken either from the most inflammed macroscopic area or from an area with previous inflammation in case of mucosal healing (MH) were prospectively performed. MH was defined by the absence of ulcers. Different histological scores were calculated by 2 independent pathologists: Robart, Geboes, modified Geboes, Nancy, and DCA-IBD scores. Histological remission was defined by Nancy=0 ; Geboes ≤2 ; modified Geboes of grade 0 ; Robarts ≤3, IBD-DCA of C≤1 and A=0. Clinical relapse was prospectively evaluated in the STORI trial as CDAI>250 or CDAI between 150 and 250 with an increase of 70 points during 2 successive weeks compared to the inclusion visit.

(1) Louis E et al .Gastroenterology 2012

Results

Eighty biopsies (22 ileal and 58 colonic) were available from 76/115 patients included in STORI. Among the 45 patients with MH, 30 had colonic biopsies, 11 had ileal biopsies and 4 had biopsies in both locations. Among colonic biopsies 68% had histological remission according to Nancy and modified Geboes scores, 65% according to DCA-IBD and Geboes scores and 71% according to Robarts score. Among ileal biopsies 53% had histological remission according to Nancy score, 47% according to Modified Geboes, Geboes and DCA-IBD scores, and 67% according to the Robarts score. Thirty-five patients (46%) experienced a clinical relapse during the follow-up including 16/45 (36%) and 19/31 (61%) in the group with MH and without MH respectively. Histological characteristics and histological scores were not predictive of clinical relapse. In the total cohort (n=76), the CDEIS score was correlated to Nancy (p<0,001, r=0,43), Geboes (p<0,001, r=0,47) and Robarts (p<0,001, r=0,45) scores. Fecal calprotectin was correlated to Nancy (p<0,001, r=0,48), Geboes (p<0,001, r=0,45) and Robarts (p<0,001, r=0,46) scores. The histological scores of Nancy, Robarts and Geboes were highly correlated (p<0,0001 ; r > 0,9).

Conclusion

Although correlated with endoscopy and biomarkers, histology was not predictive of clinical relapse in CD patients in clinical and endoscopic remission. These findings do not support the use of histology to predict clinical relapse in CD in clinical practice.
DOP27 Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn's Disease and chronic fatigue syndrome
Authors: Bourgonje A R , Hörstke N V , Fehringer M , Innocenti G , Vogl T
Published: January 2024

Background

Patients with Crohn’s disease (CD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) exhibit elevated antibody responses against gut microbiota flagellins. However, flagellin-specific antibody repertoires and functional roles in the diseases remain incompletely understood. Bacterial flagellins can be categorized into three types depending on their interaction with toll-like receptor 5 (TLR5): (1) "stimulator" and (2) "silent" flagellins, binding TLR5 through a conserved N-terminal motif, with only stimulators activating TLR5 due to a specific C-terminal domain; (3) "evader" flagellins of pathogens, which circumvent TLR5 activation via mutated N-terminal TLR5 binding motifs. Here we studied the characteristics, epitope binding, and sequence (dis)similarity of anti-flagellin antibody responses in CD and ME/CFS.

Methods

Since conventional antibody profiling methods like enzyme-linked immunosorbent assays [ELISAs] do not allow for large-scale measurements of antibody repertoires, we leveraged phage-display immunoprecipitation sequencing (PhIP-Seq) to characterize 344,000 rationally selected peptide antigens in 256 patients with CD, 40 patients with ME/CFS and in two equally sized groups of age- and sex-matched healthy controls from population-based cohorts in the Netherlands and U.K., respectively. Different sequence alignment strategies were employed to compare flagellin peptide structures with observed antibody-bound flagellin peptide reactivity.

Results

Both patients with CD and ME/CFS exhibited elevated antibody responses against distinct regions of flagellin peptides compared to healthy individuals (P<0.001). N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling ‘stimulator’ and ‘silent’ flagellins more than evaders. However, C-terminal antibody-bound flagellins showed higher resemblance to stimulator than to silent flagellins in CD, but not in ME/CFS. This group of antibody-bound flagellins was exclusively identified in a subset (10-20%) of patients with CD and characterized by its strong overrepresentation (exceeding 20-fold), underscoring its potential significance in distinguishing pathophysiologic subtypes of CD.

Conclusion

Antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between diseases. Our results highlight the diagnostic potential of these antibody responses and their impact on innate/adaptive immunity balance.
DOP32 CD226+TIGITneg expression identifies pathogenic inflammatory CD4+ memory T cells in severe Crohn’s Disease patients, opening up opportunities for patient-tailored treatment strategies
Authors: Barendregt D , Heredia M , Tindemans I , Klomberg R C W , Calado B , Hulleman-van Haaften D H , Tuk B , van Berkel L A , Escher J C , de Ridder L , Samsom J N
Published: January 2024

Background

CD4+ memory T cells (Tmem) drive chronicity of inflammation in Crohn’s disease (CD) and ulcerative colitis (UC). Treatments specifically targeting T cells effectively induce disease remission. However, due to disease heterogeneity and possibly variation in the Tmem response, not all patients achieve or maintain remission. As such, strategies are needed to identify and monitor the therapeutic target, i.e. the inflammatory Tmem response, in individual patients. Monitoring has been hampered by the large variety in both protective regulatory and pathogenic inflammatory Tmem phenotypes, thus, common denominators need to be identified to distinguish all inflammatory from all regulatory intestinal Tmem populations in individual patients. We have shown that the coinhibitory receptor T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a common denominator identifying regulatory gut-homing Tmem. TIGIT shares its ligands with the costimulatory receptor CD226. While TIGIT ligation inhibits Tmem responses, CD226 engagement enhances Tmem activity. We hypothesize that TIGIT and CD226 differentiate the protective regulatory from the pathogenic inflammatory intestinal Tmem in individual IBD patients.

Methods

We studied CD38+CD62Lneg gut-homing Tmem in blood of therapy-naive pediatric IBD patients (CD n=59; UC n=32; IBD negative controls (IBDneg) n=24).

Results

In a subgroup of CD, but not UC patients, frequencies of regulatory TIGIT+ gut-homing Tmem at diagnosis were strongly reduced compared to IBDneg. Of these CD patients with low TIGIT frequencies, a significantly higher proportion had severe disease, defined as failing to achieve remission after 6 months or having a disease relapse within 1 year, compared to CD with normal TIGIT frequencies. As TIGIT is a common denominator for regulatory cells, we hypothesized that gut-homing Tmem without TIGIT (TIGITneg) contained inflammatory Tmem. Indeed, in CD, the TIGITneg Tmem population contained increased frequencies of pathogenic IFNg+IL-17+-double-producing cells compared to IBDneg. As TIGIT and CD226 frequencies inversely correlated (R=-0.78, p=4.8e-05) in CD patients, we assessed whether additional monitoring of CD226 could be used to more precisely identify and monitor inflammatory Tmem in CD. As anticipated, TIGITnegCD226+ gut-homing Tmem frequencies significantly increased in CD patients compared to UC patients and IBDneg. TIGITnegCD226+ Tmem were more proliferative and more activated compared to IBDneg, indicating increased inflammatory function.

Conclusion

These data establish that TIGIT and CD226 can be used to enumerate and differentiate the protective regulatory from the pathogenic inflammatory gut-homing Tmem in individual IBD patients, and to identify patients with severe disease.
DOP49 Guselkumab improves health-related quality of life as measured by PROMIS-29 in patients with moderately to severely active Ulcerative Colitis: Phase 3 QUASAR induction study
Authors: Panés J , Dignass A , Lichtenstein G , Huang K H , Germinaro M , Houck N , Han C , Miao Y , Zhang H , Abu Farsakh N , Patel B , Owczarek D , Hisamatsu T , Sands B , Bressler B
Published: January 2024

Background

Patients (pts) with ulcerative colitis (UC) suffer from symptoms that impair health-related quality of life (HRQoL). The Phase 3 QUASAR induction study (NCT04033445) evaluated the efficacy and safety of guselkumab (GUS), an IL-23 p19 subunit antagonist, in pts with moderately to severely active UC who had demonstrated inadequate response, loss of response, or intolerance to conventional and/or advanced therapies (ie, tumor necrosis factor-alpha antagonists, integrin receptor antagonists, and/or Janus kinase inhibitors). Here we report the effect of GUS IV induction on HRQoL at Week (Wk) 12 as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS)-29.

Methods

Pts were randomized 3:2 to receive GUS 200 mg IV or placebo (PBO) IV at Wks 0/4/8. PROMIS-29 consists of 7 domains (anxiety, depression, fatigue, pain interference, sleep disturbance, physical function, and social participation) and a pain intensity numeric rating scale (NRS, range 0-10). The raw score of each domain was converted into a standardized T-score based on a general population mean of 50 and standard deviation (SD) of 10. Higher scores indicate better outcomes for physical function and social participation and worse outcomes for all other domains. The physical component summary (PCS) and mental component summary (MCS) scores were calculated based on the domain T-scores for physical and mental HRQoL, with higher scores representing better outcomes. Minimum clinically meaningful improvement was defined as a ≥3-point improvement in the pain intensity NRS score, a ≥5-point (one-half SD of the population) improvement in each domain, and a ≥5-point improvement in the PCS/MCS scores. More stringent thresholds (eg, ≥7- or ≥9-point improvements) were also examined and will be presented.

Results

Among the primary analysis population, baseline mean PROMIS-29 domain scores were similar between treatment groups, with functional domain scores <50 and symptom domain scores >50, indicating impaired HRQoL (Table). GUS-treated pts achieved a greater mean change from baseline at Wk 12 in each domain T-score, the pain intensity NRS score, and the PCS/MCS than PBO-treated pts. Additionally, the percentage of pts achieving minimum clinically meaningful improvement at Wk 12 was greater for GUS vs PBO in each domain, the pain intensity NRS score, and the PCS/MCS scores (Figure).

Conclusion

Pts with moderately to severely active UC treated with GUS IV induction experienced broad and clinically meaningful improvements in HRQoL as measured by the PROMIS-29 at Wk 12.
DOP50 PINPOINT: The epidemiology of paediatric-onset Inflammatory Bowel Disease in the United Kingdom – a prospective, national, cohort study
Authors: Henderson P , Dobson L
Published: January 2024

Background

Paediatric inflammatory bowel disease (PIBD) incidence and prevalence is increasing worldwide. Robust epidemiology can inform new aetiological hypothesis, inform healthcare provision and improve patient outcomes. The last prospective United Kingdom (UK) PIBD incidence study was performed in 1999 (5.2/100,000/yr); we aimed to update this incidence data and to provide a robust prevalence figure for PIBD prospectively across the UK.

Methods

Robust site selection identified all units in the UK providing endoscopy services for paediatric patients. Patients were included if they were diagnosed with Crohn’s disease (CD), ulcerative colitis (UC) or IBD-unclassified (IBD-U) less than 16yrs of age while a permanent UK resident. A custom-built spreadsheet was used to record basic demographics prospectively from June 2021 – December 2022 (18 months). A point prevalence study on 28th February 2023 was also performed capturing all patients under 16yrs of age living in the UK. A subset of patients was approached to provide consent for future clinical note review, data linkage and future contact (the PINPOINT cohort). Multiple data points were triangulated to avoid duplicate records. Data was securely collated electronically by the IBD Registry (www.ibdregistry.org.uk) and basic descriptive statistics performed in R v4.1.3. Publicly available population data was used to calculate rates.

Results

All 34 selected sites prospectively recorded cases; all were diagnosed by ileocolonoscopy. During the study 2,243 new diagnoses were recorded (1,050 patients [47%] also consented to join the PINPOINT cohort). UK PIBD incidence was 12.1/100,000/yr (England/Wales 11.7/100,000/yr, Northern Ireland 12.7/100,000/yr, Scotland 17.2/1000,000/yr). CD (56%) was more prevalent than UC (33%) and IBDU (11%). Median age at diagnosis was 12.9yrs (IQR 10.6-14.5). There was a male preponderance (62%) with CD, IBDU and UC having male to female ratios of 1.8, 1.7 and 1.4 respectively. With regard to ethnicity 72% of patients identified as white; those of other ethnicities were diagnosed younger (12.1yrs vs 13.0yrs; p<0.001) and had a higher incidence of UC (38.5% vs 30.3%; p=0.003). Regarding prevalence, 6,116 patients aged less than 16 years were identified as living with IBD on 28th February 2023 giving a UK prevalence of 49.6/100,000 (England/Wales 48.7/100,000, Northern Ireland 53.3/100,000, Scotland 58.6/1000,000).

Conclusion

There has been over a two-fold rise in PIBD incidence across all regions of the UK since 1999 with the first accurate prevalence figure mirroring this rise. Further detailed analysis of epidemiological trends using these data and the PINPOINT cohort are merited to drive improved care for this growing group of patients with high healthcare needs.
DOP54 Guselkumab and golimumab combination induction therapy in Ulcerative Colitis results in early local tissue healing that is sustained through guselkumab maintenance therapy
Authors: Richards D , Vetter M , Germinaro M , Verstockt B , Atreya R , Panes J , Sands B E , Feagan B , McRae B , Cua D , Branigan P , Freeman T C
Published: January 2024

Background

Combination induction therapy with guselkumab (GUS), an interleukin (IL)-23p19 subunit antagonist, and golimumab (GOL), a tumor necrosis factor (TNFα) antagonist, induced higher rates of clinical remission, endoscopic, and histologic outcomes than either monotherapy at Week (WK)12 in patients (pts) with ulcerative colitis (VEGA NCT03662542). Data through WK38 suggested the continued benefit of combination induction even after a transition to GUS monotherapy at WK12. We explored early molecular changes in colon tissue in a subset of pts at WK4 to define mechanistic contributions of each monotherapy and combination; these parameters were evaluated again at WK38 to assess potential carry-over of efficacy.

Methods

Colon biopsies were obtained at baseline (n=195), WK4 (n=42 substudy), and WK38 (n=172). Transcriptional profiles were generated with RNA sequencing (RNAseq). Gene correlation network analysis was applied in conjunction with publicly available single cell RNAseq data to define biologically relevant bulk and cell type-specific transcriptional modules associated with molecular features of disease. Gene set variation analysis (GSVA) was used to quantitatively assess changes in biologic modules with treatment.

Results

At WK4, combination induction (n=10) showed significant (p<0.05) decreases in molecular features compared to GUS (n=19) and GOL (n=13), including transcriptomic modules representing the IL-23 pathway, interferon response, and inflammatory epithelial and myeloid transcriptional states associated with endoscopic improvement at WK4 (Mayo endoscopy subscore of 0 or 1) (combination 5/11, GOL 1/13; GUS 2/19). Reduction (p<0.05) in inflammatory modules persisted through WK38 with combination vs monotherapy induction. Module changes between treatments at WK4 indicated a stronger correlation between GUS and combination (R=0.8; p=2.2e-16) than GOL and combination (R=0.52; p=4.1e-12), with processes associated with epithelial and stromal biology, and mucosal inflammation. In contrast, the combination effect on specific neutrophil/myeloid biology at WK4 was more similar to GOL than GUS, supporting the early role of GOL in targeting innate inflammation.

Conclusion

Combination induction with GUS and GOL showed significant reductions in major inflammatory features of disease as early as WK4 which persisted through WK38 with GUS maintenance. Correlative analysis supports the role of GUS as the primary driver of tissue healing, with GOL further contributing to innate inflammatory activity, which demonstrate differential and complementary mechanisms of action of TNFα and IL-23p19 subunit blockade.
DOP56 Fibrosis-related transcriptome unveils a distinctive matrix remodelling pattern in penetrating but not in stricturing ileal Crohn's Disease
Authors: Tavares de Sousa H , Ferreira M , Gullo I , Rocha A M , Oliveira C , Carneiro F , Magro F
Published: January 2024

Background

Fibrosis underlies most of CD complications requiring surgery, such as intestinal strictures and penetrating events. We previously demonstrated there were no histopathological differences on transmural fibrosis and fibromuscular changesbetween penetrating and stricturing ileal CD. This study aimed to investigate and compare the fibrosis-related transcriptomic profiles of penetrating and stricturing ileal CD.

Methods

Using Nanostring technology and comparative bioinformatics, we analysed the expression of 787 genes covering the core pathways and processes involved in fibrosis, in 34 ileal surgical specimens, 11 B2 and 23 B3, the latter encompassing 12 with associated stricture(s) (B3s) and 11 without (B3o). Each patients’ tissue was retrieved from three FFPE 20mm-sections. Quality control of extracted RNA was performed according to Nanostring parameters and principal component analysis (PCA) graph for the distribution analysis. For the selection of the differentially expressed genes (DEGs) we adopted a P-adjusted <0.05 and a Fold Change ≤-1.5 or ≥ 1.5. Statistical analysis adopted level of significance at 5%.

Results

We included 34 patients, in a well-balanced sample for age (at diagnosis and at surgery), gender, CD localization, perianal disease and therapy. Inflammation and fibrosis histopathological scoring were similar (median of 3 and 1, respectively), in the three groups. No DEGs differentiated B3s and B3o subgroups, which were grouped as B3. The B2 and B3 groups showed a very good clustering on the gene heatmap, which uncovered 30 DEGs between the 2 groups, all being upregulated in B3 and, conversely, downregulated in B2 patients – Figure. More than half of the upregulated genes have been established or partially involved in CD fibrogenesis (yellow-box and line, respectively), while 8 DEGs have been implicated in fibrosis in other organs (brown-line box) and 3 others having an anti-fibrotic role in other tissues (green-line box). Importantly, the vast majority of the most significantly active biologic processes and pathways in the B3 group were related to response to TGF b and matrix organization, production and degradation, unveiling a continuous process of tissue healing and destruction distinctive of this aggressive phenotype.

Conclusion

Despite the histopathological similarities of fibrosis between stricturing and penetrating ileal CD, their fibrosis-related transcriptomic profiles are distinct. Penetrating CD was remarkable for the activation of all the unveiled DEGs and of biologic pathways concerning permanent matrix production and degradation. Hence, although fibrosis underlies both penetrating and stricturing CD, therapeutic targets may differ even in end-of-stage disease.
P004 Functional interrogation of the stem cell graft reveals heterogeneity that may determine clinical outcomes after hematopoietic stem cell transplant for refractory Crohn's Disease
Authors: Guisado D , Talware S , Singh S , Fozilov E , Colombel J F , Cho J , Cohen L
Published: January 2024

Background

For the treatment of refractory Crohn’s disease (CD) autologous stem cell transplant (auto-SCT) is unparalleled in its ability to induce clinical and endoscopic remission. Auto-SCT is unique as a cellular therapy aimed to reset immune pathophysiology to a pre-disease state using hematopoietic stem cells (HSC). To date no studies in any cohort have defined the mucosal and peripheral immune response to auto-SCT or analyzed HSC functions.

Methods

Patients with CD were enrolled in a Phase IIa study of auto-SCT (NCT03219359) with 16 patients transplanted (2018-2023). Patients underwent a standard mobilization regimen with cyclophosphamide and G-CSF. Mononuclear cells from the mobilized stem cells of 9 patients were isolated and then analyzed for phenotyping using flow cytometry. For xenograft studies, CD34+ selected stem cells from 6 patients were injected into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice to assess engraftment and differentiation potential by flow cytometry of cells from bone marrow at multiple time points.

Results

At 6 months from auto-SCT, 15/16 patients had an endoscopic response (Total SES-CD decrease ≥ 50%) and 11/16 were in endoscopic remission (total SES-CD ≤ 4, no sub-score >1). Phenotyping of the stem cell graft demonstrated variability between patients but overall there was predominance in short-term HSCs and lineage committed progenitors rather than long-term HSCs (LT-HSC). There was variable engraftment of the CD34+ cells that were transplanted in NSG mice and 2 of the patients who had inadequate engraftment also were noted to have suboptimal clinical results, 1 with disease relapse and 1 without clinical response after auto-SCT. Of those with engraftment, we found a predominance of myeloid populations emerging early and sustaining and emergence of B cells at 8 weeks.

Conclusion

Here we report the first ever study of the stem cell graft using a xenograft model to understand therapeutic mechanisms of auto-SCT for refractory CD. These results show tremendous functional variation in mobilized stem cell populations from patients with CD and a complete lack of LT-HSCs, which have greater self-renewing potential. This suggests that the efficacy of auto-SCT for refractory CD may be due in part to the HSCs transplanted and not just the conditioning regimen (i.e. chemotherapy). These studies suggest the response to stem cell transplant may depend on the presence of functional HSC populations and perhaps the lack of long-term response is due to the lack of LT-HSC in all patients.
P011 Altered Expression and Enzymatic Activity of Xanthine Oxidase in Inflammatory Bowel Disease
Authors: Di Petrillo A , Onali S , Era B , Raho N , Murtas D , Maxia C , Favale A , Eleonora G , Pinto S , Fais A , Fantini M C
Published: January 2024

Background

Xanthine oxidase (XO) is involved in the last steps of purine metabolism; indeed, it catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid (UA) with the production of superoxide anion. The accumulation of UA has been shown to initiate the inflammatory process through NLRP3 inflammasome and the production of reactive oxygen species (ROS) contributes to inflammation-related tissue damage. In murine models of colitis, XO inhibitors, allopurinol or febuxostat, reduced the expression of proinflammatory cytokines supporting the involvement of XO in the intestinal inflammatory process. This study aims to conduct a thorough investigation of the role XO plays in IBD pathogenesis and to explore the potential of XO inhibition as a therapeutic strategy.

Methods

Biopsies from the colon of patients with ulcerative colitis (UC) and Crohn’s disease (CD) were collected at University Hospital of Cagliari. Disease activity was assessed using Mayo and SES-CD scores. XO expression levels were evaluated using Real-Time PCR, validated by GEO database (GSE11223, GSE117993). XO enzymatic activity was quantified spectrophotometrically in protein extracts from the biopsies. XO and NLRP3 inflammasome activation pathway, including NLRP3, ASC, and CASPASE1, was investigated using immunohistochemistry (IHC). In vitro, Caco2, HT29, SW480 cells were treated with xanthine, XO inhibitors (allopurinol, febuxostat) to assess XO inhibition on NLRP3 activation, analyzed by immunocytochemistry (ICC).

Results

Biopsies from the sigmoid colon of 15 HC, 20 UC, and 15 CD patients, as well as from the ileum of 10 HC and 10 CD, were analyzed. Increased XO expression was found in UC and CD sigmoid mucosa (Relative Quantification [RQ]: 1.93 vs. 0.99, p=0.004), and CD ileum (RQ: 2.72 vs. 1.26, p=0.004), confirmed by GEO data. XO activity was higher in UC and CD sigmoid (3.86 nmol UA/min/mg in UC, 4.82 in CD vs. 1.03 in HC, p<0.001) and CD ileum (8.41 vs. 1.83 in HC, p<0.001). IHC confirmed that XO and the NLRP3 inflammasome pathway are more highly expressed in IBD patients than HC, predominantly within epithelial cells. In vitro studies on Caco2, HT29, and SW480 cells demonstrated that suppressing XO activity with XO inhibitors leads to the inhibition of the NLRP3 pathway.

Conclusion

XO expression was higher in IBD pts than in HC individuals. Alongside this increase in XO activity, there was a concurrent hyperactivation of the NLRP3 inflammasome. The inhibition of XO activity in cell lines resulted in reduced activation of the NLRP3 inflammasome pathway. These findings support the hypothesis that XO plays a critical role in the pathogenesis of IBD and highlight its potential as a therapeutic target.
P017 An activity-based chemiluminescence assay targeting granzyme A for the detection of Inflammatory Bowel Diseases
Authors: Scott J , Thompson E , Cheng Z , David M , Gordon D , Medive-Tapia L , Jones G R , Hall R , Chuah S , Drury B , Rossi A , Shabat D , Ho G T , Vendrell M
Published: January 2024

Background

Inflammatory Bowel Diseases (IBD) represent a pressing global health concern lacking precise diagnostic tools for accurate patient stratification. Conventional methods, such as colonoscopy are extremely invasive whilst generic inflammatory markers (such as CRP or Calprotectin), are not specific enough and pose limitations in assessing disease activity, urging the need for novel, non-invasive diagnostic approaches which can rapidly inform clinicians on the inflammatory status of a patients bowels.

Methods

Our study focused on developing a non-invasive chemiluminescence assay targeting active granzyme A (GzmA) in stool supernatants. Employing a multifaceted approach encompassing functional, chemical, and imaging assays on human cells and gut tissue biopsies, we discerned elevated GzmA levels predominantly secreted by CD8+ T cells in inflamed gut tissues.

Results

The design of GzmA-INH, a specific inhibitor for GzmA, underscored the prevalence of active extracellular GzmA and it’s role in driving inflammation in the guts - revealing promising potential as a novel IBD biomarker. Further, we synthesized GzmA-CL, a highly reactive and selective chemiluminescent reporter for GzmA. Integrating GzmA-CL into a robust antibody-coated 96-well plate assay (Figure 1a), we analyzed 30 IBD biosamples along with healthy controls. Notably, substantially higher GzmA levels were observed in IBD patients, with discernible distinctions between ulcerative colitis (UC) and Crohn’s disease (CD) (Figure 1b). These levels correlated positively with established biomarkers, including faecal calprotectin and immune cell counts.

Conclusion

Our investigation highlighted active extracellular GzmA as a noteworthy biomarker in gut inflammation. The rapid, selective, and sensitive nature of our chemiluminescence assay presents promising prospects for precise IBD diagnosis and advancements in personalized medicine.