Proton-Pump Inhibitors in Eosinophilic Esophagitis: A Review Focused on the Role of Pharmacogenetics.

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.

Fibrous Remodeling in Eosinophilic Esophagitis: Clinical Facts and Pathophysiological Uncertainties.

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.

Impact of HLA-DQA1∗05 Genotype in Immunogenicity and Failure to Treatment with Tumor Necrosis Factor-alpha Antagonists in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: HLA-DQA1*05 carriage has been associated with an increased risk of immunogenicity in patients with immune-mediated inflammatory diseases treated with tumor 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 optimization and association with immunomodulatory drugs. AIMS: To define the association of HLA-DQA1*05 on anti-drug antibody development and loss of response (LOR) to anti-TNF-a in IBD. METHODS: 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. RESULTS: Twenty-four studies comprising 12 papers, 11 abstracts and 1 research letter, with a total of 5,727 IBD patients, were included. In a meta-analysis of 10 studies (2,984 patients; 41.9% with HLA-DQA1*05 genotype), HLA-DQA1*05 carriers had higher risk of immunogenicity compared to non-carriers (risk ratio, 1.54; 95%CI, 1.23-1.94; I2=62%) (low certainty evidence). Lack of therapeutic drug monitoring (TDM) increased immunogenicity in the presence of risk HLA (risk ratio 1.97; 95%CI, 1.35-2.88; I2=66%), while proactive TDM revoked this association (very low certainty of evidence). A meta-analysis of 6 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. CONCLUSION: HLA-DQA1*05 carriage may be associated with an increased risk of immunogenicity and secondary LOR in IBD patients treated with TNF-a antagonists.