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

A reduction of bowel wall thickness (BWT) on intestinal ultrasound (IUS) is an early predictor of endoscopic response in ulcerative colitis (UC).¹ Shear-wave elastography (SWE) may offer additional prognostic information.

Aims & Methods

We aimed to identify early IUS parameters predicting treatment response to filgotinib, a selective JAK-1 inhibitor. This prospective observational study included UC patients with endoscopically active disease starting on filgotinib 200 mg daily. IUS parameters, including SWE, were assessed at baseline (T0), week 4 (T1) and at second endoscopy (T2). The endoscopic Mayo score (EMS) was assessed at T0 and at T2 in both the most-affected segment and the sigmoid. Endoscopic response was defined as a decrease in EMS of at least 1 point.

Results

A total of 23 patients were included. 10 patients were female (10/23, 44%), the mean disease duration was 14.4 years (SD±10.4), and 14 patients (14/23, 61%) had failed 2 or more biologics. Endoscopic response was observed in 6 of the 21 patients (29%) who underwent a second endoscopy after a median of 14 weeks (IQR 12-17). The submucosal thickness in the sigmoid decreased significantly more between T0 and T1 in endoscopic responders compared to non-responders (-40±23.9% vs -11.5±24.5%, p=0.022). At T1, a BWT decrease of ≥1.33 mm or ≥24.7% (OR 32.5 [2.38-443.15], p=0.009 and OR: 13.8 [1.21-156.6], p=0.035) and a submucosal thickness decrease of ≥20.8% (OR: 13.8 [1.21-156.6], p=0.035) predicted endoscopic response at T2. Additionally, improvement in Colour Doppler Signal (CDS) at T1 predicted endoscopic response (OR: 20.0 [1.66-241.7], p=0.018). SWE values in the sigmoid at T0, T1 and T2 were not significantly different between endoscopic responders and non-responders in the sigmoid. While the change in SWE values at T2 compared to baseline was significantly different between the two groups (9.9± 11.5 kPa vs. -8.1 ± 11.4 kPa, p=0.002), the difference at T1 was not significant and did not predict endoscopic response in the sigmoid (OR: 1.07 [0.99-1.16], p=0.088).

Conclusion

On IUS, BWT, submucosal thickness and CDS predict endoscopic response after four weeks of filgotinib treatment. SWE values in the sigmoid changed differently among endoscopic responders and non-responders, but did not predict treatment response.

References

1. de Voogd FA et al. Early Intestinal Ultrasound Predicts Clinical and Endoscopic Treatment Response and Demonstrates Drug-Specific Kinetics in Moderate-to-Severe Ulcerative Colitis. Inflamm Bowel Dis 2023. DOI: 10.1093/ibd/izad274.

Disclosure

MP: none;
CT: none;
FV: received speaker’s fees from AbbVie, Pfizer and Takeda;
RJ: none,
ML: Consultancy/lecture fees from Abbvie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, Tillotts. Grants received from Alfasigma, NFU transformation deal, ZonMW and TKI.
RG: received speakers free from Janssen-Cilag BV and Pfizer Inc.
GD: has served as advisor for AbbVie, Abivax, Alimentiv,, Astrazeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, , GlaxoSmithKline, Johnson and Johnson, Merck Sharp Dome, Pfizer, Polpharm, Sanofi, Takeda, Tillotts, and received speaker fees from AbbVie, Eli Lilly, Johnson and Johnson, Merck Sharp Dome, , Pfizer, Takeda, Tillotts,.
KG: KB Gecse has received grants from AbbVie, Pfizer Inc, Celltrion and Galapagos; consultancy fees from AbbVie, Arena Pharmaceuticals, ImmunicTherapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc., and Takeda and speaker’s honoraria from Abbvie, Celltrion, Eli Lilly, Ferring, Janssen Pharmaceuticals, Pfizer Inc, Takeda and Tillotts.

Introduction

The BIOSTOP Trial is a prospective, multicenter, randomized, controlled, open-label study conducted in Norway to evaluate the two-year outcomes of tumor necrosis factor-alpha (anti-TNF) antibody withdrawal in patients with ulcerative colitis (UC) in sustained clinical and endoscopic remission. Prior non-randomized studies have suggested that approximately half of such patients maintain remission after anti-TNF discontinuation and that reintroduction of anti-TNF therapy is generally effective and safe in the event of relapse.

Aims & Methods

A total of 174 UC patients in confirmed clinical and endoscopic remission were enrolled across 19 gastroenterology centers between June 2017 and December 2020 and randomized 1:1 to either continue or discontinue anti-TNF therapy. Eligibility criteria included at least 12 months of first-line anti-TNF maintenance treatment, clinical remission, fecal calprotectin <200 µg/g, and endoscopic remission (Mayo endoscopic score 0 or 1). Two-year follow-up data were available for 172 patients (86 in each group). In 156 of the patients endoscopies were available for central reading (77 in the withdrawal group and 79 in the maintenance group). The primary endpoint was sustained endoscopic remission at two years.

Results

At two years, central reading of follow-up colonoscopies confirmed endoscopic remission in 64 of 77 patients (83%, 95% CI 71.8 – 93.1) in the anti-TNF withdrawal group, compared to 77 of 79 patients (96 %, 95 % CI 92.1 – 100.8) in the anti-TNF maintenance group. The non-inferiority primary endpoint of the study was thus not met. During the study period, 48% of patients in the withdrawal group and 88% in the maintenance group remained in sustained clinical and endoscopic remission without relapse. Among the 45 patients in the withdrawal group who experienced endoscopic confirmed relapse, 28 (62%) resumed anti-TNF therapy, with 26 achieving both clinical and endoscopic remission. Additionally, 10 of 13 patients with mild relapses achieved endoscopic remission with optimized non-biologic therapy. There were no difference in serious adverse events between the groups.

Conclusion

After two years, 83% of patients in the anti-TNF withdrawal group and 96% in the maintenance group were in clinical and endoscopic remission, including those who experienced flares and achieved new remission after reintroduction of anti-TNF or optimized non-biologic therapy. Nearly half of the patients maintained remission without anti-TNF, and the majority of relapses were effectively managed. These findings suggest that anti-TNF withdrawal is a safe option for selected UC patients in confirmed remission, provided they are monitored closely.
Trial Registration: ClinicalTrials.gov Identifier: NCT03011268; EudraCT Number: 2016-001409-18. Trial completion date: 31 January 2025.

Disclosure

No disclosures