好酸球性消化管疾患

INTRODUCTION: Eosinophilic gastritis (EoG) is a rare disease characterized by eosinophilic infiltration of the gastric wall. The endoscopic findings of EoG are diverse. CASE PRESENTATION: We report a rare case of EoG in a 60-year-old woman presenting with a solitary deep-penetrating gastric ulcer accompanied by fold convergence. The lesion was resistant to potassium-competitive acid blocker therapy. Histopathological examination revealed dense eosinophilic infiltration (approximately 300 cells/high-power field) confined exclusively to the ulcer margin, with the surrounding gastric mucosa and other gastrointestinal sites showing no significant eosinophilic infiltration. EoG was diagnosed after excluding other possible causes. Corticosteroid therapy resulted in ulcer healing and an improvement in eosinophil infiltration. CONCLUSION: This case represents a rare instance of EoG presenting as a solitary gastric ulcer. EoG should be considered among the differential diagnoses for refractory gastric ulcer, even in the absence of diffuse mucosal eosinophilic infiltration.

BACKGROUND: Eosinophilic colitis (EC) is a rare eosinophilic gastrointestinal disorder with increasing frequency in recent years. Although normal eosinophil density varies substantially by colonic segment, several proposed eosinophil thresholds have been used in the literature to support the diagnosis in the appropriate clinical context. However, some patients with clinical features suggestive of eosinophilic colitis (EC) do not demonstrate increased tissue eosinophil counts on histopathologic examination. OBJECTIVE: To compare eosinophil-derived cell-free granules based on expression of their surface markers between two groups of patients with symptoms consistent with EC: those with increased tissue eosinophils and those without tissue eosinophilia. METHODS: This study included 10 pediatric patients with histologically confirmed EC and 13 patients with clinical suspicion of EC. Eosinophil-derived cell-free granules were evaluated in colonic tissue samples using immunohistochemistry (IHC), with antibodies against MBP and CCR3. RESULTS: Eosinophil-derived cell-free granules were detected in all specimens from patients with suspected EC and in the majority of specimens from patients with confirmed EC. Degranulating eosinophils were identified in all specimens from both groups, although the proportion of degranulating eosinophils varied among patients. Furthermore, the abundance of granules was significantly associated with the percentage of degranulating eosinophils. CONCLUSION: Our findings indicate that IHC can be used to detect eosinophil-derived granules in colonic tissue. The presence of cell-free eosinophil granules with varying abundance, along with evidence of eosinophil degranulation in all specimens from patients with suspected EC, may provide supportive histopathological features that contribute to improving the diagnostic assessment of EC.

BACKGROUND: Eosinophilic gastritis currently has no approved treatments and is postulated to be driven by type 2 inflammation. Dupilumab blocks type 2 cytokines IL-4 and IL-13 and has efficacy in multiple diseases characterised by type 2 inflammation, including eosinophilic oesophagitis. We aimed to assess the efficacy and safety of dupilumab in patients with eosinophilic gastritis. METHODS: DEGAS was a proof-of-concept, phase 2, multicentre, randomised controlled trial consisting of a 12-week, double-blind, placebo-controlled period, followed by a 24-week open-label extension period. Patients aged 12-70 years from 11 hospitals in the USA with histologically active eosinophilic gastritis (≥30 eosinophils per high-power field [HPF] in at least five HPFs in the gastric antrum and/or body) and moderate-to-severe symptoms occurring at least 2 days per week in the 2 weeks before screening were recruited. Patients with current or recent use of any biologic or current use of systemic steroids at a dose of more than 10 mg/day (prednisone) were excluded. Eligible patients were individually randomised (1:1) to parallel groups and received six injections over 12 weeks: subcutaneous dupilumab (600 mg once followed by 300 mg every 2 weeks) or subcutaneous placebo. Randomisation was performed using a central variable block (block sizes permuted between 2 and 4), with stratification by age (12-17 years or ≥18 years) and use (yes or no) of either systemic corticosteroids, swallowed corticosteroids for eosinophilic gastritis, or non-steroidal systemic immunosuppression therapy. Throughout the duration of the study, patients were expected to maintain their treatments or diets for eosinophilic gastritis. All patients who completed the double-blind period could enter the open-label extension at week 12, during which both groups received dupilumab until week 34. The primary endpoint of relative change from baseline in mean gastric eosinophil count from the five most eosinophil-dense HPFs in the gastric antrum and/or body was analysed at week 12 using linear regression. Secondary endpoints included absolute changes from baseline in Eosinophilic Gastritis Histologic Scoring System (EoS-HSS) total score, mean gastric eosinophil count from the five most eosinophil-dense HPFs, and Eosinophilic Gastritis Endoscopic Reference System (EoG-REFS) total score. All randomly assigned patients who received at least one dose of study drug were included in the safety analysis and efficacy analyses were done in all randomly assigned patients who received at least one dose of study drug and had outcome data available at week 12 (complete case). This study is registered with ClinicalTrials.gov (NCT03678545) and is now complete. FINDINGS: Between May 14, 2021, and Nov 10, 2023, we randomly assigned 41 patients, of whom 21 (51%) received dupilumab and 20 (49%) received placebo during the double-blind period and were included in the safety analysis. Patients were aged 12-59 years (mean 30·5 years [SD 13·2]; seven [17%] aged <18 years), 37 (90%) were White, one (2%) was Asian, one (2%) was Black or African American, two (5%) were of multiple races, 25 (61%) were female, and 16 (39%) were male. One patient from the placebo group withdrew before week 12; the remaining 21 patients treated with dupilumab and 19 patients treated with placebo had available data and were assessed for the primary endpoint. At week 12, the relative reduction in the primary endpoint was greater with dupilumab (estimated mean change -50% [95% CI -66 to -34]) than with placebo (-4% [-20 to 13]; difference -47 percentage points [-70 to -24]; p<0·0001). Significant differences between groups were noted for the secondary endpoints of absolute change from baseline in EoS-HSS total score (difference -0·10 [95% CI -0·18 to -0·03]; p=0·0055), absolute change from baseline in mean gastric eosinophil count (-38·8 [-75·6 to -17·8]; p=0·0008), and absolute change from baseline in EoG-REFS total score (-3·42 [-6·18 to -0·65]; p=0·016). At week 12, the incidence of treatment-emergent adverse events was similar between dupilumab (17 [81%]) and placebo (17 [85%]). The most common adverse event was blood eosinophilia, with similar incidence in the dupilumab (six [29%]) and placebo (six [30%]) groups. No serious adverse events or treatment-related deaths were reported. INTERPRETATION: The improvement of histological outcomes of eosinophilic gastritis with dupilumab in this proof-of-concept study shows type 2 inflammatory involvement in the disease and the potential value of dupilumab for the treatment of eosinophilic gastritis. FUNDING: National Institutes of Health, USA; Regeneron Pharmaceuticals Inc; and Sanofi.

Increased sensory nerve density has been described in type 2 inflammatory conditions and is linked to eosinophil and mast cell infiltration and neuropathic pain. To examine these relationships in eosinophilic gastrointestinal diseases, we developed a protocol using Ce3D (clearing-enhanced 3D) tissue clearing to evaluate mucosal gastrointestinal (GI) nerve remodeling and interactions with eosinophils and mast cells in whole-mount GI biopsies. Human gastric and esophageal biopsies were processed for 3-dimensional imaging. Tissues were fixed, permeabilized, and immunolabeled for mucosal nerves (Protein Gene Product 9.5), sensory neurons (substance P), eosinophils (eosinophil peroxidase), mast cells (tryptase), and epithelial cells (pan-cytokeratin). Vacuum-microwave-assisted staining was employed to enhance antibody penetration and protocol efficiency. Samples were cleared with Ce3D and imaged using confocal microscopy. Machine learning-enhanced quantitative analysis and modeling of nerve morphology and cellular interactions, including nerve length, branching, and spatial relationships between eosinophils, mast cells, and sensory neurons were performed. We established a 3-dimensional imaging method for whole-mount GI biopsies to characterize nerve architecture and eosinophil and mast cell interactions in the human esophagus and stomach. This approach enables high resolution and volumetric analyses and can be modified to assess other spatial neuroimmune interactions in human GI mucosal biopsies.

Crohn's disease (CD) and eosinophilic gastrointestinal diseases (EGIDs) are distinct inflammatory entities, but eosinophilic disease may emerge as a paradoxical immune complication of anti-tumor necrosis factor therapy. We report a 12-year-old boy with terminal ileal CD who developed severe eosinophilic gastritis and ileitis, peripheral eosinophilia, and psoriasiform dermatitis during prolonged anti-TNF treatment, despite CD remission. Corticosteroids, dietary modification, and sequential biologic therapy resulted in incomplete or transient responses. Following anti-TNF withdrawal, eosinophilic disease persisted, prompting compassionate off-label treatment with benralizumab, an interleukin-5 (IL-5) receptor α-antagonist, alongside vedolizumab for CD maintenance. Benralizumab led to rapid normalization of peripheral eosinophil counts, resolution of gastrointestinal symptoms, improved food tolerance, and histologic remission at 6 months. This case illustrates persistent anti-TNF-associated immune deviation and supports targeted IL-5 receptor blockade as an effective strategy for refractory eosinophilic gastrointestinal disease while maintaining CD remission.