PPIs are the first-line treatment option for patients with EoE and may be combined with elimination diets and topical steroids. The mechanisms of PPI efficacy extend beyond gastric acid suppression to include anti-inflammatory effects, such as downregulation of eotaxin-3, a chemokine central to eosinophil recruitment, enhancement of esophageal barrier integrity, and maintenance of epithelial homeostasis [3]. Interestingly, acid reflux condition may coexist or can contribute to EoE, while EoE may contribute to reflux symptoms by impairing clearance of the acid from the esophagus. Gastroesophageal reflux disease (GERD) may coexist with or exacerbate EoE, whereas EoE can impair esophageal acid clearance, contributing to reflux symptoms. Standard initial therapy consists of daily or twice-daily PPI administration before meals for a minimum of eight weeks, followed by reassessment of clinical symptoms and upper endoscopy to evaluate both endoscopic and histologic response [3]. In case of good response to therapy, PPIs should be continued at the lowest effective dose to control symptoms, whereas non-responders should be considered for topical corticosteroids. Comparative data between PPIs, topical corticosteroids, and elimination diets remain limited. In a randomized trial of 30 adults, esomeprazole 40 mg daily for eight weeks achieved reductions in esophageal eosinophil counts comparable to fluticasone 440 mcg twice daily, without significant improvement in dysphagia [24]. Another study of 42 adults demonstrated that esomeprazole 40 mg daily did not significantly reduce eosinophil counts, though 33% of patients achieved fewer than seven eos/hpf [25]. A meta-analysis encompassing 33 studies and 619 pediatric and adult patients reported clinical and histologic response rates of 61% and 51%, respectively [26]. Similarly, a multicenter observational cohort of 630 patients demonstrated clinical response and histologic remission rates of 71% and 49%, with significantly lower efficacy in patients with esophageal strictures [27]. The presence of GERD does not reliably predict response to PPI therapy, although patients with documented pathologic acid exposure may exhibit enhanced benefit. Across studies, variations in PPI type, dose, frequency, and duration preclude recommendations regarding a preferred agent or regimen. Patient education emphasizing the anti-inflammatory benefits of PPIs and strict adherence is critical to optimize therapeutic outcomes.

Potassium-competitive acid blockers (PCABs), such as vonoprazan, approved for erosive esophagitis and GERD, have been investigated as potential therapies for EoE. In a retrospective cohort of 118 patients, vonoprazan demonstrated efficacy comparable to rabeprazole (10–20 mg) and esomeprazole (20 mg), achieving complete symptomatic response in 75.7% versus 54–72% for PPIs, a 2-point reduction in eosinophilic esophagitis endoscopic reference score (EREFS), and complete histologic remission (0–1 eos/hpf) in 39.4% of patients [28]. A subsequent study of 236 histologically confirmed EoE patients reported no statistically significant differences between PCAB and PPI therapy in symptomatic response (84% vs. 80%), endoscopic response (90% vs. 86%), or histologic response (79% vs. 74%) after eight weeks of treatment [29]. Complete normalization of symptoms, endoscopic findings, and histology was achieved with vonoprazan in 25%, 50%, and 36% of patients, respectively. While preliminary data are promising, further prospective studies are required to confirm the efficacy and safety of PCABs in EoE.

Budesonide and fluticasone represent the mainstay of pharmacologic therapy for EoE. The majority of patients demonstrate both symptomatic improvement and histologic reduction in eosinophil counts with these agents [30]. However, symptom and histologic recurrence are common following treatment discontinuation. Oral budesonide suspension is generally preferred over fluticasone due to its more consistent esophageal drug delivery [31]. Fluticasone, while effective, is used off-label and has limitations related to variable esophageal deposition, higher cost, and availability [32]. Randomized controlled trials have consistently revealed that topical glucocorticoids were effective in achieving clinical and histological improvement in patients with EoE. Most studies excluded patients who responded well to PPI therapy. A large meta-analysis of 6 trials comprising 583 adults and pediatric patients with EoE revealed that topical therapy was associated with significantly greater symptomatic improvement compared to placebo after 2 to 12 weeks of treatment (RR 1.74) [33]. In a sub-analysis of 12 trials encompassing 978 patients, topical glucocorticoid therapy was associated with significant histologic remission (RR 11.94). Reported histologic response rates for both budesonide and fluticasone generally range between 60–70%. Predictors of treatment response to topical therapy remain poorly understood. Individuals presenting with abdominal pain had a good response to topical steroids, while those with esophageal stenosis had a much lower response to the therapy. Current recommendations suggest reassessment with upper endoscopy and biopsy within 8–12 weeks of initiating steroid therapy to evaluate for endoscopic and histologic improvement.

Budesonide has been approved in the United States by the FDA as an oral suspension, consumed 2 mg twice daily for a total of 12 weeks [34]. Medication should be taken over 5 to 10 minutes, with the avoidance of food or liquid intake for 30 minutes. The oral suspension provides consistent drug delivery. In Europe, budesonide is also available as a 1-mg orodispersible tablet administered twice daily [35]. Treatment with budesonide is typically well-tolerated, and symptomatic improvement can be seen within several days. Adverse effects of budesonide include adrenal suppression, headache, candidiasis, throat irritation, and respiratory tract infection. In a randomized controlled trial comprising 318 patients with EoE, oral suspension of budesonide at a dose of 2 mg twice daily was associated with higher rates of symptomatic improvement (52% vs. 39%), and higher rates of histologic remission (53% vs. 1%) after 12 weeks of therapy compared to placebo [36]. Another randomized, placebo-controlled trial of 93 adolescents and young adults with EoE and dysphagia demonstrated significant improvements in dysphagia symptom scores (15 vs. 21.5), endoscopic severity scores (–3.8 vs. 0.4), and histologic response rates (39% vs. 3%) relative to placebo [37]. In the randomized, double-blind, double-dummy clinical trial of 129 adults, comparison was made between oral budesonide suspension (1 mg twice daily) versus swallowed fluticasone provided by metered-dose inhaler (MDI) (880 mcg twice daily) given for 8 weeks. Both agents produced comparable improvements in dysphagia symptom scores (5 vs. 4), endoscopic severity scores (EREFS 2 vs. 3), and histologic remission rates (71% vs. 64%), indicating no clear superiority of one topical steroid over the other [38]. Budesonide suspension preparation off-label can be formulated by compounding pharmacies by prescription in the USA. However, the concentration of budesonide may vary in the suspension, which may affect the effectiveness of the medication [39].

Fluticasone propionate is administered via MDI without a spacer, with the spray swallowed. For adults ≥ 18 years, the recommended induction dose is 220 mcg twice daily for 4–8 weeks. An orally disintegrating tablet formulation is in phase 3 trials. In the phase 2b FLUTE trial of 106 adults, fluticasone tablets significantly reduced dysphagia at 12 weeks versus placebo, with sustained benefit at 52 weeks [40]. Histologic response rates were 86% with 1.5 mg BID and 67% with 3 mg daily dosing [40]. Symptomatic improvement may occur within days to 1 week, but relapse is frequent (14–90%) after discontinuation [41]. In a study of 21 adults, all reported symptom improvement with 220 mcg BID, though this did not correlate with eosinophil counts [42]. Reported adverse effects include esophageal candidiasis, herpes esophagitis, and dry mouth [43]. Although adrenal insufficiency is rare with induction therapy, a meta-analysis reported a 15.8% rate across steroid trials [44]. Patients with a narrow caliber esophagus or requiring dilations demonstrate lower response rates [45]. There are no established guidelines for maintenance therapy, though it is often considered in patients with severe dysphagia, food impactions, high-grade stenosis, or rapid relapse. A lower maintenance dose (often half of induction) is suggested, though higher doses may prolong remission [46]. In a randomized trial of 204 adults in remission, budesonide oral dispersible tablets (0.5–1 mg BID for 48 weeks) maintained remission in 75% compared with 4% on placebo [47]. A smaller study of 28 adults showed budesonide 0.25 mg BID maintained remission in 64% versus 36% with placebo at 50 weeks, with improvement in esophageal remodeling [48]. Meta-analyses report pooled histologic responses of 77% for budesonide and 68% for fluticasone [49, 50]. Both agents are considered reasonable first-line options. Other topical glucocorticoids evaluated in EoE, mainly in pediatrics, include ciclesonide and mometasone furoate [51, 52]. In a retrospective series of 34 children, mometasone induced histologic improvement in 76% and remission in 68% after 1 month [52]. A novel mometasone delivery system (impregnated membrane) is under investigation (NCT04849390).

Systemic glucocorticoids have a limited role in EoE and should be reserved for patients with severe disease when dietary and topical steroid therapies are not feasible or have failed. Due to frequent relapse and chronic disease course requiring repeat therapy, oral steroids should generally be avoided. Prednisone is typically administered at 1–2 mg/kg/day (maximum 60 mg/day) in divided doses. While oral prednisone has demonstrated greater efficacy than topical fluticasone, it carries a significantly higher risk of adverse effects [53]. For refractory cases, dupilumab is now preferred over systemic corticosteroids.

Dupilumab, an IL-4 receptor alpha antagonist, blocks signaling of IL-4 and IL-13 and reduces Th2-mediated inflammation [54]. Initially approved for moderate-to-severe asthma and atopic dermatitis, dupilumab is now approved for both pediatric and adult EoE in the U.S., administered as 300 mg subcutaneously once weekly. In a phase 2 randomized trial of adults with active EoE, 12 weeks of dupilumab therapy led to reductions in dysphagia, histologic activity (68.3% response), improved endoscopic appearance (EREFS), and increased esophageal distensibility [55]. In a phase 3, three-part trial involving 321 PPI-nonresponsive patients (≥ 12 years), dupilumab 300 mg weekly or every 2 weeks for 24 weeks achieved histologic remission (< 6 eos/hpf) in 60% vs. 6% for placebo (P < 0.001) [54]. Weekly dosing produced significant improvement in dysphagia symptom questionnaire (DSQ) score and endoscopic severity (EREFS). The 52-week extension confirmed sustained histologic, symptomatic, and endoscopic benefits, particularly with weekly dosing [56]. In a pediatric trial of 102 patients with PPI-refractory EoE, both lower and higher dupilumab doses for 16 weeks induced histologic remission in 58–68% vs. 3% for placebo [57], with benefits maintained through 36 weeks. A retrospective study of 46 patients with fibrostenotic, refractory EoE showed histologic remission (< 15 eos/hpf) in 80%, < 6 eos/hpf in 57%, and symptomatic improvement in 91% after a median of 6 months [58]. Common adverse effects include injection site reactions, upper respiratory infections, arthralgia, and herpes viral infections; rare cytokine-mediated complications such as seronegative arthritis, iridocyclitis, and psoriasis have been reported. While long-term safety beyond one year remains to be established in EoE, safety data from other atopic conditions are reassuring [59]. A systematic review of five retrospective studies (209 subjects) demonstrated symptom improvement in 89.2% and significant reductions in endoscopic and histologic scores after an average of 5.6 months of therapy [60]. According to ACG guidelines, dupilumab is recommended for PPI-nonresponders and may be best suited for refractory EoE, contraindications to steroid therapy, or patients with concomitant atopic diseases such as asthma or eczema. Although dupilumab is costly, future studies are needed to define its long-term efficacy in preventing fibrosis or strictures and to assess cost-effectiveness as a potential first-line therapy. Table 2 provides an overview of medications currently utilized in the management of EoE in adults.

Cendakimab (RPC-4046) is a humanized monoclonal antibody directed against soluble IL-13, thereby attenuating IL-13 receptor-mediated signaling. In a phase 2 randomized controlled trial including 99 adults with EoE, weekly subcutaneous administration of cendakimab at 180 mg or 360 mg demonstrated significant reductions in mean eosinophil counts, histologic remission (< 6 eos/hpf), and improved endoscopic features (EREFS) compared with placebo at week 16. The 360 mg dose additionally improved dysphagia in steroid-refractory patients. The most common adverse events were headache and upper respiratory tract infections [62, 63]. A phase 3 study is currently in progress.

Dectrekumab (QAX576) is a human monoclonal antibody targeting IL-13. In a randomized trial of 23 adults with EoE receiving monthly intravenous infusions of 6 mg/kg, the predefined primary endpoint (> 75% reduction in peak eosinophil count) was not met. However, treatment was associated with a mean 60% reduction in esophageal eosinophil counts compared with a 23% increase in the placebo group, as well as a non-significant improvement in dysphagia severity and frequency [64].

IL-5 is a key eosinophil-specific cytokine produced by Th2 lymphocytes, mast cells, and eosinophils, regulating proliferation, differentiation, and apoptosis. Benralizumab, an anti-IL-5 receptor monoclonal antibody that induces near-complete eosinophil depletion through antibody-dependent cellular cytotoxicity, has been evaluated in phase 2 and 3 clinical studies. In a cohort of 211 adults and children with EoE receiving benralizumab 30 mg subcutaneously every 4 weeks for 24 weeks, histologic remission was achieved in 87.4% compared with 6.5% in the placebo group, although improvements in DSQ score and endoscopic (EREFS) scores were not statistically significant [65, 66].

Mepolizumab and reslizumab are monoclonal antibodies targeting soluble IL-5, thereby inhibiting eosinophil maturation and activation. In adults with chronic EoE and fibrostenotic disease, monthly intravenous mepolizumab (750 mg) led to significant reductions in eosinophil counts but did not achieve complete histologic remission (< 5 eos/hpf) [67, 68]. Subcutaneous mepolizumab similarly reduced tissue eosinophilia without corresponding improvement in symptom scores [69]. Across studies, anti-IL-5 agents have consistently demonstrated histologic responses superior to placebo but with limited symptomatic benefit [66, 70, 71].

TSLP is an epithelial-derived cytokine that initiates and amplifies type 2 inflammation via dendritic and mast cell activation. Tezepelumab, a human monoclonal antibody inhibiting TSLP, is being evaluated in the phase 3 randomized, double-blind, placebo-controlled CROSSING trial assessing efficacy and safety in adults and adolescents with EoE over 52 weeks [72]. Tezepelumab is currently approved for severe asthma. Solrikitug, a next-generation anti-TSLP antibody that prevents TSLP-receptor binding with higher potency than tezepelumab, is being studied in the phase 2 ALAMARE trial—a 24-week study with a 28-week extension evaluating histologic and symptomatic responses across three dosing regimens [73].

Barzolvolimab is a mast cell–depleting anti-tyrosine protein kinase (KIT) monoclonal antibody under investigation in the phase 2 “EvolvE” trial. In this randomized, double-blind, placebo-controlled study, 151 adults with EoE received barzolvolimab 300 mg every 4 weeks for 8 weeks. The primary endpoint—a reduction in peak esophageal mast cell count—was achieved, with concomitant decreases in eosinophil infiltration and improvement in DSQ score, suggesting potential therapeutic efficacy [74].

CALY-002, an anti-IL-15 monoclonal antibody, is being investigated in patients with EoE and celiac disease. IL-15, expressed by dendritic cells, macrophages, and fibroblasts, is upregulated in basal epithelial layers in EoE. The ongoing trial (ClinicalTrials.gov Identifier: NCT04593251) aims to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with EoE [75].

Lirentelimab (AK002) is a humanized IgG1 monoclonal antibody targeting sialic acid-binding Ig-like lectin 8 (SIGLEC-8), a receptor selectively expressed on mast cells and eosinophils. The antibody inhibits mast cell activation and induces eosinophil apoptosis through antibody-dependent cytotoxicity. In the KRYPTOS trial, both high- and low-dose lirentelimab achieved complete histologic remission in 88% and 92% of patients, respectively, compared with 11% in the placebo group; however, the primary endpoint of symptomatic improvement (by DSQ) was not met [76]. A meta-analysis of 17 randomized trials, including topical steroids, PPIs, dupilumab, and lirentelimab, demonstrated that monthly lirentelimab (1 mg/kg) achieved the highest rates of histologic remission, though without consistent endoscopic or symptomatic improvement [77].

The prostaglandin D₂ receptor antagonist OC000459, evaluated in a randomized controlled trial of 26 adults with steroid-dependent or steroid-refractory EoE, resulted in significant reductions in eosinophil counts and symptomatic improvement over 8 weeks compared with baseline [78]. A meta-analysis of six randomized controlled trials (533 patients) demonstrated that monoclonal antibodies significantly reduced both peak and mean esophageal eosinophil counts compared with placebo. Agents targeting IL-13 (dupilumab, dectrekumab, cendakimab) were associated with the most consistent improvements in histologic (EoE-HSS), endoscopic (EREFS), and DSQ score. The incidence of serious adverse events was comparable to placebo across studies [79]. Several investigational therapies targeting key inflammatory pathways are under evaluation in phase 2 and 3 clinical trials, as outlined in Table 3.

Montelukast, a leukotriene receptor antagonist, has been evaluated in EoE with inconsistent outcomes, and its therapeutic role remains uncertain [80, 81]. Omalizumab, an anti-IgE monoclonal antibody, did not demonstrate meaningful histologic or clinical improvement, with a response observed in only 33% of patients, further supporting that EoE is not primarily an IgE-mediated disorder [82, 83]. Likewise, infliximab, an anti-TNFα IgG1 antibody, failed to show a significant benefit in EoE [84]. Accordingly, recent ACG guidelines do not recommend the use of these agents in EoE management [3].

There are no standardized recommendations for long-term monitoring in EoE. Follow-up endoscopic evaluation should be individualized based on symptom trajectory, esophageal pathology, need for therapeutic adjustment, and patient preference. Endoscopy is particularly warranted in patients with worsening dysphagia, therapeutic modification, or when dilation is anticipated. The reliance on serial endoscopic assessments remains a major limitation in EoE care. Although several noninvasive biomarkers have been investigated for diagnostic and monitoring purposes, heterogeneity among candidate markers and methodologies limits their clinical utility [85]. Endoscopy with biopsy remains the gold standard for both diagnosis and surveillance. Nonetheless, the development of validated noninvasive biomarkers could substantially reduce procedural burden and improve cost-effectiveness in the future.

Disease progression may lead to a fibrostenotic phenotype, characterized by persistent dysphagia and the need for repeated dilations. Esophageal dilation is typically reserved for patients refractory to medical therapy or those with high-grade strictures. Given the increased risk of deep mucosal tears or perforation, dilation should be performed gradually, with luminal expansion not exceeding 3 mm per session [86, 87]. Earlier reports suggested a perforation rate of 5–7%, whereas more recent evidence demonstrates a markedly lower risk. In a meta-analysis of 37 studies encompassing 977 patients and 2,034 dilations, the perforation rate was only 0.03%, with hospitalization required in 0.7% of cases [88, 89].

A stepwise approach to the management of EoE in adults is outlined in Figure 1.