Introduction

Genetic variants associated to a higher risk of developing eosinophilic esophagitis (EoE) and other atopic conditions have been described. However, no study has investigated how these genetic variants influence clinical features of EoE or the atopic concomitances that usually accompanied this disease.

Aims & Methods

This study aims to assess whether single nucleotide polymorphisms (SNPs) in genes related to EoE and atopies associate with disease features and atopic concomitances in a large, representative cohort. Patients diagnosed of EoE according to clinical guidelines were recruited from 4 Spanish referral hospitals and demographical and clinical data were obtained both retrospectively and prospectively. The concomitant atopies analyzed were rhinitis, conjunctivitis, asthma, dermatitis and any food allergy. The recruited cohort was randomly divided into discovery (DC) and validation cohorts (VC) (70% and 30%, respectively). Genotyping was performed using an Open Array platform with 60 SNPs on DNA obtained from peripheral blood. Chi-square or Fisher’s exact test were used for statistical comparisons.

Results

Overall, 647 patients (74.7% male, 32.4±15.2 mean age) were included; 81% of them with an inflammatory phenotype. Rhinitis was the most common atopy (55.8%), while dermatitis was the least frequent (17.5%). Food allergy was documented in 28% of patients.
In relation to EoE characteristics, four SNPs were initially associated with endoscopic findings (measured by EREFS score) and with peak eosinophil counts in esophageal biopsies within the discovery cohort. However, only rs77569859 in the CAPN14 gene remained statistically significant in the validation cohort. TC and CC genotypes of this variant, present in 23.7% of the cohort, were associated with lower EREFS score under a dominant model (3.30±1.60 vs 2.92±1.66, p=0.011 DC/0.002 VC). Additionally, rs76562819, also in CAPN14 gene, showed a trend toward a lower peak eosinophil count per high power field (47.7±24.4 vs 66.6±48.3, p=0.005 DC/0.116VC) under a recessive model (AG and GG genotypes in 11.3% of our patients).
Regarding atopic comorbidities, rs1800925-TT in IL13 (found in 5.7% of our patients) was associated a higher prevalence of conjunctivitis (60% vs 39% in the overall cohort, p=0.020 DC/0.057 VC) and showed a trend toward increased asthma prevalence (54% vs 35%, p=0.056 DC/0.155 VC). A weaker association with asthma was observed for STAT6 rs324015, with an increased prevalence in patients with AG and GG genotypes (41% vs 32%, p=0.079 DC/0.162 VC; present in 34.9 % of the cohort). For dermatitis, a protective effect was seen in patients with the TT genotype of rs2032582 in ABCB1 gene (found in 16.1% of our patients), as the prevalence decreased from 19% to 8% (p=0.033 DC/0.157 VC). No consistent associations were found for rhinitis or food allergy with any SNP across both cohorts.

Conclusion

We have identified significant associations between genetic variants and both clinical features and atopic comorbidities in Spanish patients with EoE, highlighting the potential of genetic profiling to improve clinical characterization and patient management.

Introduction

Post-operative recurrence (POR) affects a substantial proportion of Crohn's disease (CD) patients following intestinal resection. While ileocolonoscopy remains the gold standard for detecting recurrence, its invasive nature and patient burden have spurred interest in non-invasive monitoring approaches. This study evaluates the performance of faecal calprotectin (FC) and cross-sectional imaging at different timepoints in predicting endoscopic recurrence in postoperative CD patients.

Aims & Methods

In this multicenter retrospective cohort of 895 CD patients who underwent ileocecal resection, we analyzed the diagnostic accuracy of FC measurements at 3, 6-12, and 18-24 months postoperatively for predicting endoscopic recurrence (Rutgeerts score ≥i2 or SES-CD ≥3). Additionally, we assessed the concordance between intestinal ultrasound (IUS) and magnetic resonance imagings (MRI) and endoscopic findings at both 6-12- and 18-24-months using kappa statistics.

Results

FC demonstrated modest discriminatory ability at 3 months (AUC 0.642, 95% CI: 0.530-0.753) and 6-12 months (AUC 0.653, 95% CI: 0.593-0.713), with improved performance at 18-24 months (AUC 0.676, 95% CI: 0.608-0.744). The optimal cutoff values for FC (47.5 μg/g at 3 and 6-12 months; 80.0 μg/g at 18-24 months) were substantially lower than standard thresholds (150-250 μg/g) used in non-operated patients.
At 6-12 months, radiological and endoscopic assessments showed moderate agreement (κ=0.426, p<0.001) with 63.2% concordance. At 18-24 months, IUS demonstrated superior agreement with endoscopic findings (κ=0.531, p<0.001; sensitivity 83.8%, specificity 72.7%) compared to MRI (κ=0.324, p<0.001). Notably, radiological remission at 18-24 months was identified as a significant protective factor against surgical recurrence (OR 0.356, 95% CI: 0.179-0.705, p=0.003).

Table I: Concordance between endoscopic and radiologic findings (IUS and MRI) for inflammation and remission at 18–24 months post-ileocecal resection. Abbreviations: IUS: Intestinal ultrasound, MRI: Magnetic resonance imaging.

Conclusion

Non-invasive monitoring with FC shows promise in postoperative CD surveillance, though diagnostic thresholds differ substantially from those established for non-operated patients. IUS demonstrates superior concordance with endoscopic findings compared to MRI, particularly at later timepoints. The protective role of radiological remission against surgical recurrence highlights the importance of transmural healing. Combining FC with radiological assessment, especially IUS, may provide a comprehensive, patient-friendly approach to monitoring postoperative CD, potentially reducing the need for invasive procedures in selected patients but further studies are needed in this direction.

Introduction

Cholestatic pruritus is common, debilitating and undertreated in patients with primary biliary cholangitis (PBC). Here, we describe the results of GLISTEN (NCT04950127), a Phase 3 study investigating the efficacy and safety of the ileal bile acid transporter inhibitor linerixibat for pruritus in PBC.

Aims & Methods

In this double-blind, randomised, placebo-controlled study, patients with PBC and moderate-to-severe pruritus received oral linerixibat 40 mg or placebo twice daily. Pruritus severity and pruritus-related sleep interference were assessed using a 0–10 numerical rating scale. The primary endpoint was change from baseline in worst itch over 24 weeks. Secondary endpoints included: at Week 2, change in worst itch; over 24 weeks, change in sleep interference; at Week 24, proportion of responders (≥ 2-, ≥ 3-, ≥ 4-point reduction in worst itch) and analysis of responses to 2 patient global impression items (itch severity and change). Safety endpoints included adverse event (AE) reporting.

Results

238 patients were randomised; 95% were female, itch severity was mean (standard deviation [SD]) 7.34 (1.54), 52% had alkaline phosphatase < 1.67 times upper limit of normal, and 47% were receiving stable therapy for pruritus. Pruritus improvement over 24 weeks was significantly greater with linerixibat than placebo: least-squares (LS) mean change -2.86 versus -2.15, adjusted mean difference -0.72; p = 0.001. At Week 24, the observed mean (SD) difference from baseline in pruritus was -3.66 (2.50) with linerixibat and -2.82 (2.32) with placebo. The effect of linerixibat was rapid and superior to placebo at Week 2: LS mean change -1.78 versus -1.07, adjusted mean difference -0.71; p < 0.001. Linerixibat also significantly improved pruritus-related sleep interference over 24 weeks versus placebo: LS mean change ‑2.77 versus -2.24, adjusted mean difference -0.53; p = 0.024. At Week 24, more patients on linerixibat than placebo achieved a ≥ 2-point (68% vs 64%), ≥ 3-point (56% vs 43%) or ≥ 4-point (41% vs 29%) reduction in pruritus and a higher proportion of linerixibat than placebo-treated patients reported their pruritus was very much improved (55% vs 37%) or absent (21% vs 9%). AEs reported more frequently with linerixibat than placebo were predominantly gastrointestinal (GI), including diarrhoea (61% vs 18% of patients) and abdominal pain (18% vs 3% of patients); 4% of patients in the linerixibat group discontinued treatment due to diarrhoea.

Conclusion

In patients with PBC and moderate-to-severe pruritus, linerixibat rapidly and significantly improved pruritus and pruritus-related sleep interference versus placebo. While GI AEs were more common with linerixibat than placebo, they rarely led to treatment discontinuation.

Disclosure

Funded by GSK. Various authors declare conflicts of interest as consultants, employee, recipients of grants and stockholders. These will be reported in full during the presentation.