From Pages to Practice
Published January 4, 2023
Eosinophils are granulocytes theorized to have developed in humans to guard against parasitic infections, including nematodes that reside in human intestines. As a result, eosinophils appear to be normal constituents of gastrointestinal tissue, with an increasing gradient from the esophagus to the colon. Normally, <5, 5–10, 10–25, and >50 eosinophils per high-powered field (hpf) are found in the esophagus, stomach, duodenum, and cecum, respectively. An excess number of eosinophils in these organs can lead to tissue inflammation, damage, and ultimately fibrosis. Eosinophilic esophagitis (EoE) is one disease resulting from this process that has been increasingly well-characterized in the past decade.
Patients with EoE, especially children, present with nonspecific symptoms that result in a median delayed diagnosis of 6 years. Young children are more likely to present with vomiting and failure-to-thrive, and older children with abdominal pain. Adolescents and adults experience chest discomfort, food impaction, and dysphagia. In fact, nearly half of all adults with food impaction and 7% of those with dysphagia meet histological criteria for EoE.
Standard management of EoE has evolved with improved understanding of the disease. Initially, a subset of EoE was thought to be related to gastroesophageal reflux, but acid-directed therapies lead to remission in only 50% of patients. Food allergens may recruit an excess of eosinophils in an allergic response, and six-food elimination diets can lead to remission in up to 75% of children, but adherence is difficult. Swallowed budesonide has been used with varying success, ranging from histological response rates nearing 50% to minimal symptom improvement, particularly in adults. Additionally, despite a theoretical local effect, adrenal suppression from topical corticosteroids has been documented. All of these off-label treatments have paved the way for the trial by Dellon et al. in the December 22 issue of NEJM.
Dupilumab is a monoclonal antibody that blocks interleukin (IL)-4Rα, attenuating IL-4 and IL-13-induced inflammatory responses, which ultimately recruit eosinophils. In two separate phase 3 trials, researchers randomized 81 and 240 patients aged 12 years and older to receive weekly or biweekly subcutaneous dupilumab or placebo injections. After 24 weeks, more patients in the dupilumab group in both trials achieved the co-primary endpoint of ≤6 eosinophils/hpf on histology and improvement in a dysphagia questionnaire score. More injection-site reactions were reported in the dupilumab groups, and one patient treated with dupilumab developed systemic inflammatory response syndrome (SIRS). These results led to FDA approval of dupilumab for EoE in May 2022, making it the first approved drug for EoE.
Application of these results to patients with EoE requires important considerations. Because the patient population consisted largely of white men with atopic disease (e.g., allergic rhinitis or asthma), EoE that was refractory to topical steroids, and high-peak esophageal eosinophil concentrations of 87–89/hpf, the efficacy of dupilumab in women, nonwhite patients, children, and patients without histories of corticosteroid or PPI therapy remains unclear. Further, whether patients with milder disease, atypical symptoms (e.g., abdominal pain or vomiting), or without coexisting atopy will derive as much benefit from dupilumab is uncertain. Finally, the short follow-up of only 24 weeks after treatment initiation begs the question of whether dupilumab can prevent long-term complications of EoE, such as esophageal stricturing or perforation.
Notwithstanding these shortcomings, dupilumab appears to be effective in patients with EoE with a strong allergic component. EoE can now be added to the list of eosinophil-related allergic conditions (including asthma and eczema) for which dupilumab efficacy has been demonstrated. Data on the long-term efficacy of the drug, along with its efficacy in children and other populations not captured in these trials, are crucial to advancing the care of patients with EoE.