LAUSR

Eosinophilic oesophagitis (EoE) is an immunemediated disease of uncertain aetiology. The diagnosis of EoE relies on the epithelial infiltration of eosinophils (peak eosinophil count of ≥15 per highpower field (HPF)) and on the presence of symptoms. Consequently, a combined clinical–histological endpoint has been devised to assess response to treatments in clinical trials. Recent guidelines drafted by the British Society of Gastroenterology have confirmed the pivotal role of swallowed topical steroid and, for the first time, explicitly considered the use of biological therapy in case of a coexisting severe allergic condition. These guidelines have appraised the results of pivotal trials leading to the approval of orodispersible budesonide and dupilumab, a monoclonal antibody targeting interleukin (IL)14 and IL13, since they both met the aforementioned coprimary endpoint. 3 Additionally, dupilumab also proved to enhance distensibility of the oesophagus wall. These results, along with the proved efficacy of IL13 neutralisation through cendakimab, have confirmed the paramount role of Th2 cells in EoE, as already suggested by the efficacy of allergenfree diets. Among other factors contributing to these trials, we highlight the adoption of validated tools assessing disease activity and patientreported outcomes, such as the Dysphagia Symptom Questionnaire, the EoE Symptom Activity Index, the Straumann Dysphagia Index and the EoE Quality of Life. Notably, despite their undoubted effectiveness in tackling tissue eosinophilia, monoclonal antibodies primarily targeting eosinophils failed to reach clinical endpoints. Indeed, IL5 is a critical cytokine for eosinophils, and the first therapeutic trials in EoE focused on this cytokine (table 1). First, the antiIL5 mepolizumab was evaluated in two studies. 5 Thereafter, another antiIL5 antibody, reslizumab, was studied in a trial enrolling children and adolescents. For both drugs, a reduction in peak tissue eosinophil count was found, but improvement of clinical outcomes was negligible. To note, significant methodological biases may have hampered the recognition of beneficial effects. Among these, the small sample size, the brief treatment duration, the unclear definition of ‘refractoriness to medical therapy’ and the lack of validated outcome measures are worth mentioning. Subsequently, another trial (NCT03656380) of mepolizumab was announced in 2018, but its status is ‘active but not yet recruiting’. Consequently, the results of the phase III MESSINA (a study of Benralizumab in Patients with Eosinophilic Esophagitis) trial assessing benralizumab, which targets the IL5 receptor, were eagerly awaited. Surprisingly, this trial was prematurely stopped since the interim analysis failed to achieve the composite endpoint, again due to the lack of clinical efficacy. Still, eosinophilic inflammation may exert a prominent role only in the initial phase of the disease, while symptoms are due to fibrosis in later stages. It can be hypothesised that different intrinsic endotypes (inflammatory and fibrostenotic), which are variably susceptible to this treatment, exist. All the same, the ‘eosinophilocentric’ view of EoE pathogenesis needs to be revisited. Indeed, eosinophils are not merely bystanders, being one among the mediators of tissue damage, but also mediators in tissue remodelling. Yet, according to the available evidence, they act in concert and secondarily to Th2 cells and, possibly, to other cellular types, such as mast cells, type II innate lymphoid cells, epithelial cells, which are overlooked as potential therapeutic targets. Hence, the proved efficacy of dupilumab in EoE underlies the main role of the Th2 immune branch while toning down the importance of targeting tissue eosinophils alone. To conclude, recent trials have greatly contributed to shed light into the pathogenesis of EoE by strengthening the theory that type II inflammation, and Th2 cells are the main drivers of EoE. Clinical variables, such as disease duration/phenotype, the use of endotyping and the choice of functional outcome measures, such as the oesophagus distensibility, should be prioritised in future clinical trials.