July 2024
EoE True Culprits: Beyond Eosinophils - Back to the Drawing Board
Article: Eosinophil Depletion with Benralizumab for Eosinophilic Esophagitis
Rothenberg ME, Dellon ES, Collins MH,et al
New England Journal of Medicine. 2024 June
Reviewed by Mario Ynga-Durand, MD, PhD, Cincinnati Children's Hospital Medical Center, Ohio, United States
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated esophageal disease characterized by eosinophil accumulation, causing inflammation and difficulty swallowing. The recent MESSINA trial investigated benralizumab, an eosinophil-depleting anti-interleukin-5 receptor α monoclonal antibody, for treating EoE. Read more
This phase 3 trial included active EoE patients randomly assigned to receive either subcutaneous benralizumab or placebo. The primary goals were to observe histologic response (eosinophil reduction) and symptom relief measured by the Dysphagia Symptom Questionnaire (DSQ). Results were striking: 87.4% of the benralizumab group achieved near complete eosinophil depletion compared to only 6.5% in the placebo group (P<0.001). However, this success in reducing eosinophil counts did not translate into significant symptom relief, with DSQ scores showing no meaningful difference between the two groups. Importantly, few changes in the expression of genes associated with EoE were observed relative to baseline in the benralizumab group as compared with placebo, including CLC and CCR3, both highly expressed by eosinophils.
The MESSINA trial reveals a critical insight: eosinophils, traditionally blamed as the primary culprits in EoE might not be the main drivers of the disease. While benralizumab effectively reduces eosinophil counts the lack of symptom improvement suggests a more complex underlying pathophysiology. This discrepancy indicates that other cells and mechanisms are likely involved in EoE's progression and symptoms. This work should prompt us to rethink our definition and concept of EoE. What truly is the role of eosinophils? Should we redefine the disease itself based on transcriptional and clinical changes akin to atopic dermatitis? Should we refocus on the overarching nature of the dysregulation of esophageal immunity, including neuroimmune cross-talk and epithelial responses to cytokines? Furthermore, could eosinophils have a beneficial effect as remodelers or damage-controlling cells? Understanding the true drivers of EoE, and potentially redefining eosinophils' role within the broader context of immune regulation will be key to developing more effective treatments and ultimately improving the quality of life for those affected by this complex disease. This disease may also give us a glimpse into the real nature of allergy extending beyond traditional type 2 responses and pushing us back to the drawing board.
Mario Ynga-Durand, MD, PhD, is a Research Associate in the Rothenberg CURED Lab at Cincinnati Children's Hospital Medical Center and a Pew Charitable Trust Latin American Fellow in the Biomedical Sciences. He is a member of the Outreach & Diversity Committee of the International Eosinophil Society. After training as a pediatric immunologist in Mexico, he was engaged in the clinical care of patients with allergies before transitioning into biomedical research. Following his doctoral studies in viral immunology at the Helmholtz Center for Infection Research in Germany, Mario has focused his primary interest on understanding the immunologic determinants of the pathogenesis of eosinophilic esophagitis. Ultimately, his research aims to bring advanced research closer to clinical applications.