Monitoring Treatment Response in Eosinophilic Esophagitis
Monitoring Treatment Response in Eosinophilic Esophagitis
Background Monitoring of the treatment response in eosinophilic oesophagitis (EoE) requires structured endoscopical and histological examination of the oesophagus. Less invasive methods would be highly desirable.
Aim To evaluate the utility of several EoE-associated blood and serum markers in order to non-invasively monitor the response to treatment with swallowed topical corticosteroids in adult EoE patients.
Methods In a randomised, controlled double-blind trial blood samples of EoE patients (n = 69) were collected at baseline and after 14 days of treatment with budesonide (n = 51) or placebo (n = 18) respectively. Absolute blood eosinophil count (AEC) as well as serum levels of CCL-17, CCL-18, CCL-26, eosinophil-cationic-protein (ECP) and mast cell tryptase (MCT) were determined and correlated with oesophageal eosinophil density and with symptom and endoscopy scores.
Results Histological remission, defined as mean number of <16 eos/mm hpf at end-of-treatment, was achieved in 98% of the budesonide and 0% of the placebo recipients. AEC [380.2 vs. 214.7/mm (P = 0.0001)], serum-CCL-17 [294.3 vs. 257.9 pg/mL (P = 0.0019)], -CCL-26 [26.7 vs. 16.2 pg/mL (P = 0.0058)], -ECP [45.5 ± 44.7 vs. 27.5 ± 25.0 μg/L (P = 0.0016)] and -MCT [5.3 ± 2.9 vs. 4.5 ± 2.6 μg/L (P = 0.0019)] significantly decreased under budesonide but not under placebo. AEC significantly correlated with oesophageal eosinophil density before (r = 0.28, P = 0.0236) and after (r = 0.42, P = 0.0004) budesonide treatment. In ROC-AUC analyses post-treatment values of AEC were significantly associated with histological remission (ROC-AUC 0.754; 95% CI: 0.617–0.891; P = 0.0003).
Conclusions The budesonide-induced treatment response in EoE is mirrored by several blood and serum markers, and the absolute blood eosinophil count is the most valuable as it shows correlation with the oesophageal eosinophil density.
Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated oesophageal disease characterised clinically by symptoms related to oesophageal dysfunction and histologically by a relevant, eosinophil-predominant inflammation. Treatment options of EoE include drug therapy, dietary allergen avoidance and dilation of oesophageal strictures. Among medical therapy, swallowed topical corticosteroids such as fluticasone or budesonide have proven efficacy with remission rates of 50 up to 87 percent and a good safety profile. These compounds are therefore positioned as first line medication. Monitoring of treatment response still requires repeated invasive upper endoscopy with biopsy sampling for histopathological determination of oesophageal inflammation, as clinical symptoms alone are insufficient to permit a critical assessment of the efficacy of therapy. In order to avoid serial endoscopic procedures, non-invasive biomarkers reflecting reliably the inflammatory activity would be of high clinical and economic interest, but until today no ideal marker is available.
The aim of this study was to search for biomarkers reflecting changes of the inflammatory activity of the oesophageal mucosa induced by treatment with a topical acting corticosteroid. For this purpose we evaluated absolute eosinophil count (AEC), serum-CCL-17, -CCL-18, -CCL-26, -ECP and -MCT in adult EoE patients before and after 14 days treatment with budesonide. We chose these markers because EoE is thought to be a TH2-mediated disease, in which the associated cytokines CCL-17 and CCL-18 might play an important role. Moreover, activated Th2-cells trigger oesophageal epithelial cells to produce eotaxin-3 (CCL-26), which in turn recruits eosinophils into the oesophageal tissue. Eosinophils contain cytoplasmic granules that release cationic toxic proteins such as ECP upon stimulation. Mast cells are also involved in the complex pathogenesis of EoE and secret MCT upon stimulation (see Figure 1).
(Enlarge Image)
Figure 1.
EoE is believed to be triggered by aero- and food allergens which cause a Th2-induced immune response, in which the associated cytokines CCL-17 and CCL-18 might play an important role. Activated Th2-cells trigger oesophageal epitheal cells (activated by IL-13) to produce eotaxin-3 (CCL-26), which in turn recruits eosinophils into the oesophageal tissue. Eosinophils (activated by IL-5) contain cytoplasmic granules that release cationic toxic proteins such as ECP upon stimulation. Mast cells (activated by IL-9) are also involved in the inflammatory process and secret MCT upon stimulation.
Abstract and Introduction
Abstract
Background Monitoring of the treatment response in eosinophilic oesophagitis (EoE) requires structured endoscopical and histological examination of the oesophagus. Less invasive methods would be highly desirable.
Aim To evaluate the utility of several EoE-associated blood and serum markers in order to non-invasively monitor the response to treatment with swallowed topical corticosteroids in adult EoE patients.
Methods In a randomised, controlled double-blind trial blood samples of EoE patients (n = 69) were collected at baseline and after 14 days of treatment with budesonide (n = 51) or placebo (n = 18) respectively. Absolute blood eosinophil count (AEC) as well as serum levels of CCL-17, CCL-18, CCL-26, eosinophil-cationic-protein (ECP) and mast cell tryptase (MCT) were determined and correlated with oesophageal eosinophil density and with symptom and endoscopy scores.
Results Histological remission, defined as mean number of <16 eos/mm hpf at end-of-treatment, was achieved in 98% of the budesonide and 0% of the placebo recipients. AEC [380.2 vs. 214.7/mm (P = 0.0001)], serum-CCL-17 [294.3 vs. 257.9 pg/mL (P = 0.0019)], -CCL-26 [26.7 vs. 16.2 pg/mL (P = 0.0058)], -ECP [45.5 ± 44.7 vs. 27.5 ± 25.0 μg/L (P = 0.0016)] and -MCT [5.3 ± 2.9 vs. 4.5 ± 2.6 μg/L (P = 0.0019)] significantly decreased under budesonide but not under placebo. AEC significantly correlated with oesophageal eosinophil density before (r = 0.28, P = 0.0236) and after (r = 0.42, P = 0.0004) budesonide treatment. In ROC-AUC analyses post-treatment values of AEC were significantly associated with histological remission (ROC-AUC 0.754; 95% CI: 0.617–0.891; P = 0.0003).
Conclusions The budesonide-induced treatment response in EoE is mirrored by several blood and serum markers, and the absolute blood eosinophil count is the most valuable as it shows correlation with the oesophageal eosinophil density.
Introduction
Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated oesophageal disease characterised clinically by symptoms related to oesophageal dysfunction and histologically by a relevant, eosinophil-predominant inflammation. Treatment options of EoE include drug therapy, dietary allergen avoidance and dilation of oesophageal strictures. Among medical therapy, swallowed topical corticosteroids such as fluticasone or budesonide have proven efficacy with remission rates of 50 up to 87 percent and a good safety profile. These compounds are therefore positioned as first line medication. Monitoring of treatment response still requires repeated invasive upper endoscopy with biopsy sampling for histopathological determination of oesophageal inflammation, as clinical symptoms alone are insufficient to permit a critical assessment of the efficacy of therapy. In order to avoid serial endoscopic procedures, non-invasive biomarkers reflecting reliably the inflammatory activity would be of high clinical and economic interest, but until today no ideal marker is available.
The aim of this study was to search for biomarkers reflecting changes of the inflammatory activity of the oesophageal mucosa induced by treatment with a topical acting corticosteroid. For this purpose we evaluated absolute eosinophil count (AEC), serum-CCL-17, -CCL-18, -CCL-26, -ECP and -MCT in adult EoE patients before and after 14 days treatment with budesonide. We chose these markers because EoE is thought to be a TH2-mediated disease, in which the associated cytokines CCL-17 and CCL-18 might play an important role. Moreover, activated Th2-cells trigger oesophageal epithelial cells to produce eotaxin-3 (CCL-26), which in turn recruits eosinophils into the oesophageal tissue. Eosinophils contain cytoplasmic granules that release cationic toxic proteins such as ECP upon stimulation. Mast cells are also involved in the complex pathogenesis of EoE and secret MCT upon stimulation (see Figure 1).
(Enlarge Image)
Figure 1.
EoE is believed to be triggered by aero- and food allergens which cause a Th2-induced immune response, in which the associated cytokines CCL-17 and CCL-18 might play an important role. Activated Th2-cells trigger oesophageal epitheal cells (activated by IL-13) to produce eotaxin-3 (CCL-26), which in turn recruits eosinophils into the oesophageal tissue. Eosinophils (activated by IL-5) contain cytoplasmic granules that release cationic toxic proteins such as ECP upon stimulation. Mast cells (activated by IL-9) are also involved in the inflammatory process and secret MCT upon stimulation.