Elena Grueso-Navarro

Eosinophilic esophagitis (EoE) has transitioned from an isolated gastrointestinal disorder to a recognized type 2 immune-mediated allergic disease, most likely representing a late manifestation of the atopic march. This comprehensive review examines the complex inflammatory pathogenesis linking EoE and food allergy, and critically discusses the mechanisms of disease induction, dietary treatments, and emerging clinical challenges. While genome-wide association studies identify shared susceptibility loci with classic atopy, EoE exhibits distinct tissue-specific pathways, particularly dominated by the local interleukin (IL)-13 axis and highly esophagus-selective proteases like Calpain-14. This unique immunological interplay is clinically epitomized by food oral immunotherapy (OIT)-induced EoE. During OIT, systemic immune reprogramming successfully drives immune tolerance—marked by a robust increase in plasma food-specific IgG4—but fails at the local level, due to the persistence of pathogenic Th2 cells and aberrant mucosal IgG4 immune complex deposition within the esophageal lamina propria. Regarding therapeutic management, conventional skin and serum allergy testing remain highly inaccurate in identifying dietary triggers, rendering test-guided diets ineffective. Conversely, empiric elimination diets achieve robust histological remission, ranging from standardized six-food restrictions to pragmatic single-food approaches targeting cow’s milk. Furthermore, novel insights into industrial milk processing (such as UHT sterilization and homogenization) and specific beta-casein genetic variants (A1 vs A2) highlight how altered protein structures generate neoantigens that accelerate esophageal immunogenicity. In conclusion, decoding the divergent immunological mechanisms operating in the refractory esophagus is essential to move beyond trial-and-error dietary interventions towards non-invasive monitoring tools, precision medicine, and optimized biological therapies in EoE management.

Background: Endoscopy with histopathological assessment of esophageal biopsies is the cornerstone for the diagnosis and phenotypic characterization of eosinophilic esophagitis (EoE). Objective: To evaluate temporal trends in endoscopic assessment and biopsy sampling practices for EoE in a large European cohort and their association with temporal trends in diagnostic delay (DD). Methods: A cross‐sectional analysis was conducted using multicenter data from the EoE CONNECT registry. Endoscopic findings and biopsy data at diagnosis were analyzed. Temporal trends in biopsy strategies, EREFS implementation, and DD were assessed. Diagnostic sensitivity of individual esophageal segments and their combinations was evaluated in patients undergoing multi‐segment sampling. Associations between guideline publication and biopsy practices were analyzed using logistic regression models. Results: A total of 3298 patients were included. Biopsies were obtained from one esophageal segment in 12.6% of patients, two segments in 63.6%, and three segments in 23.8%. Adherence to guideline‐recommended biopsy strategies improved over time, with reduced single‐segment sampling and increased use of ≥ 2 segments. Distal esophageal biopsies provided the highest diagnostic sensitivity, and sampling that included the distal segment achieved sensitivity above 97%, particularly when combined with middle esophageal biopsies. EREFS reporting increased from 88–90% to over 98% in recent years. DD decreased significantly over time (approximately 0.7 years per calendar year), accompanied by a shift from mixed/stricturing to inflammatory phenotypes. Conclusion: Increased alignment with international guidelines, reflected by standardized endoscopic reporting and multi‐segment biopsy protocols, was associated with improved diagnostic sensitivity, reduced DD, and fewer fibrostricturing presentations.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver comorbidity in patients with inflammatory bowel disease (IBD). This paper outlines common pathophysiological aspects related to MASLD and IBD; describes the epidemiological clues associated with both diseases; analyzes risk factors contributing to MASLD appearance and progression in IBD patients; reviews data on clinical consequences for this population; and provides advice on the management of patients with both conditions. IBD itself, especially Crohns' disease, is a risk factor for MASLD and its progression to liver cirrhosis, independent of other cardiometabolic risk factors. Intestine-dependent mechanisms which contribute to MASLD in IBD and interplay with classic metabolic factors include sarcopenia, disease phenotype, duration and activity. Changes in microbiota also contribute to deregulating the gut-liver-axis in these conditions. By contrast, IBD therapies do not seem to play a relevant role in the risk of developing MASLD; and the potential of biologics and novel small molecules on liver changes requires further investigation. MASLD increases comorbidities, impairs clinical outcomes and increases mortality in IBD patients; therefore, early detection of MASLD is a priority in IBD populations. Individualized and integrative management of both MASLD and IBD is required to improve results.

Eosinophilic esophagitis (EoE) is a chronic inflammatory esophageal disorder. The lack of non-invasive biomarkers currently results in dependency on endoscopy with biopsies for its diagnosis and monitoring. We aimed to identify potential non-invasive biomarkers using microRNAs (miRNAs) in plasma-derived extracellular vesicles (pEVs). This was a prospective single-center observational study of a discovery cohort of EoE patients (n = 26) with active disease (EoE.Basal) and after anti-inflammatory treatment (EoE.Post.tx) and control subjects (n = 16). Small-RNA-seq was performed to identify differentially regulated small RNAs (sRNAs). Candidate miRNAs were validated in an independent cohort (EoE patients, n = 33; controls, n = 14). The pEVs-sRNA cargo differed among conditions. Compared with controls, Ser_Comb_22, Leu_Comb_5, miR-10b-5p, and miR-125a-5p were upregulated in EoE.Basal, and miR-224-5p, miR-221-3p, let-7d-5p, and miR-191-5p were downregulated. The combination of miR-221-3p and miR-10b-5p showed the best diagnostic performance. Comparing paired EoE samples, miR-374a-5p and miR-30a-3p were upregulated in EoE.Basal, while miR-15a-5p and let-7d-5p were downregulated. Combined miR-30a-3p and miR-15a-5p showed the best AUC values, and miR-30a-3p alone was best as a monitoring biomarker (p = 0.001). In conclusion, pEVs-sRNA changed upon inflammation in EoE patients, and miR-30a-3p was proposed as a potential biomarker for monitoring the treatment. This study was the first to explore the use of pEVs as a non-invasive biomarker for EoE.

Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to a double dosage of PPI. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In order to avoid endoscopy with biopsies—the only accurate method of assessing PPI response—efforts have been made to identify PPI responder patients. The clinical or endoscopic features and biomarkers evaluated so far, however, have not proven to be sufficient in predicting PPI response. Although new approaches based on omics technologies have uncovered promising biomarkers, the specialized and complex procedures required are difficult to implement in clinical settings. Alternatively, PPI pharmacogenetics based on identifying variations in CYP2C19 and STAT6 genes have shown promising results in EoE, and could easily be performed in most laboratories. Other genetic variations have also been associated with PPI response and may explain those cases not related to CYP2C19 or STAT6. Here, we provide an overview of PPI treatment in EoE and evidence of how genetic variations in CYP2C19 and other genes could affect PPI effectiveness, and also discuss studies evaluating the role of pharmacogenetics in predicting PPI response in patients with EoE.

Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to PPI at double dosage. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In order to avoid endoscopy with biopsies − the only accurate method of assessing PPI response − efforts have been made to identify PPI responder patients. Clinical or endoscopic features and biomarkers evaluated so far however, have not proved good enough in predicting PPI response. Although new approaches based on omics technologies have uncovered promising biomarkers, the specialized and complex procedures required are difficult to implement in clinical settings. Alternatively, PPI pharmacogenetics based on identifying variations in CYP2C19 and STAT6 genes have shown promising results in EoE, and could easily be performed in most laboratories. Other genetic variations have also been associated with PPI response and may explain those cases not related to CYP2C19 or STAT6. Here, we give an overview of PPI treatment in EoE and evidence of how genetic variations in CYP2C19 and other genes could affect PPI effectiveness, and also discuss studies evaluating the role of pharmacogenetics in predicting PPI response in patients with EoE.

HLA-DQA1*05 carriage has been associated with an increased risk of immunogenicity in patients with immune-mediated inflammatory diseases treated with tumour necrosis factor-alpha [TNF-a] antagonists. Results have shown an inconsistent association with a loss of response [LOR] in patients with inflammatory bowel disease [IBD], which could be modified when using proactive optimisation and association with immunomodulatory drugs. To define the association of HLA-DQA1*05 on anti-drug antibody development and loss of response [LOR] to anti-TNF-a in IBD. We searched MEDLINE, EMBASE, and SCOPUS, for the period up to August 2023, to identify studies reporting the risk of immunogenicity and/or LOR in IBD patients with HLA-DQA1*05 genotype. A total of 24 studies comprising 12 papers, 11 abstracts and one research letter, with a total of 5727 IBD patients, were included. In a meta-analysis of 10 studies [2984 patients; 41.9% with HLA-DQA1*05 genotype], HLA-DQA1*05 carriers had higher risk of immunogenicity compared with non-carriers (risk ratio, 1.54; 95% confidence interval [CI], 1.23 − 1.94; I² = 62%) [low certainty evidence]. Lack of therapeutic drug monitoring [TDM] increased immunogenicity in the presence of risk human leukocyte antigen [HLA] [risk ratio 1.97; 95% CI, 1.35 − 2.88; I² = 66%], whereas proactive TDM revoked this association [very low certainty of evidence]. A meta-analysis of six studies [765 patients] found that risk for secondary LOR was higher among HLA-DQA1*05 carriers [hazard ratio 2.21; 95% CI, 1.69 − 2.88; I² = 0%] [very low certainty evidence], although definition and time to assessment varied widely among studies. HLA-DQA1*05 carriage may be associated with an increased risk of immunogenicity and secondary LOR in IBD patients treated with TNF-a antagonists.

Eosinophilic esophagitis (EoE) is a chronic, progressive, type 2 inflammatory disease with increasing global prevalence. An eosinophil-predominant inflammation that permeates the epithelium and deeper esophageal layers characterizes the disease. Several cytokines, mainly derived from inflammatory T-helper 2 (Th2) cells and epithelial cells, are involved in perpetuating inflammatory responses by increasing surface permeability and promoting tissue remodeling characterized by epithelial–mesenchymal transition (EMT) and collagen deposition. This leads to esophageal strictures and narrow caliber esophagi, which are proportional a patient’s age and untreated disease length. Pathophysiological mechanisms leading to EoE have been described in recent years, and transforming growth factor beta (TGF)-beta have been involved in fibrotic phenomena in EoE. However, evidence on the dependence of these phenomena on TGF-beta is scarce and contradictory. This review provides state-of-the art knowledge on intimate mechanisms of esophageal fibrosis in EoE and its clinical consequences.

INPLASY202320076 Influence of HLA-DQA1*05 allele in the response to anti-TNFα drugs in inflammatory bowel diseases Keywords: Tumor Necrosis Factor Inhibitors; infliximab; adalimumab; HLA-DQ alpha-c…