Medical treatment of eosinophilic esophagitis

**Background:** Eosinophilic esophagitis (EoE) is a chronic antigen-mediated eosinophilic inflammatory disease of the esophagus, diagnosed by clinical symptoms of esophageal dysfunction and histologic findings of at least 15 eosinophils per high-powered field (eos/hpf). There is no cure, and long-term treatment is necessary. Standard modalities include dietary modifications, esophageal dilation, and pharmacologic therapy (corticosteroids, biologics, proton pump inhibitors). This Cochrane review updates a 2010 version that included only 3 RCTs, aiming to evaluate the efficacy and safety of medical interventions for EoE.

**Methods:** The authors searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and WHO ICTRP up to 3 March 2023. They included randomized controlled trials (RCTs) comparing any medical intervention or food elimination diet for EoE, alone or in combination, to any other intervention (including placebo). Pairs of review authors independently selected studies, extracted data, and assessed risk of bias. Outcomes were expressed as risk ratios (RR) or mean/standardized mean differences (MD/SMD) with 95% confidence intervals (CI). Certainty of evidence was assessed using GRADE. Primary outcomes were clinical, histological, and endoscopic improvement, and withdrawals due to adverse events. Secondary outcomes were serious and total adverse events, and quality of life.

**Key Results:** 41 RCTs with 3253 participants were included. Eleven studies included pediatric patients; the rest recruited both children and adults. Four studies were in patients with inactive disease. 19 intervention comparisons were identified. The main results for the two key comparisons are:

*Corticosteroids vs placebo for induction of remission (14 studies):* Corticosteroids may lead to slightly better clinical improvement (dichotomous: RR 1.74, 95% CI 1.08 to 2.80; NNTB=4; low certainty; continuous: SMD 0.51, 95% CI 0.17 to 0.85; low certainty). Corticosteroids lead to a large histological improvement (dichotomous: RR 11.94, 95% CI 6.56 to 21.75; NNTB=3; high certainty; continuous: SMD 1.42, 95% CI 1.02 to 1.82; low certainty). Corticosteroids may lead to little to no endoscopic improvement (dichotomous: RR 2.60, 95% CI 0.82 to 8.19; low certainty; continuous: SMD 1.33, 95% CI 0.59 to 2.08; low certainty). Corticosteroids may lead to slightly fewer withdrawals due to adverse events (RR 0.64, 95% CI 0.43 to 0.96; low certainty).

*Biologics vs placebo for induction of remission (9 studies):* Biologics may result in little to no difference in clinical improvement (dichotomous: RR 1.14, 95% CI 0.85 to 1.52; low certainty) but may result in better clinical improvement (continuous: SMD 0.50, 95% CI 0.22 to 0.78; moderate certainty). Biologics result in better histological improvement (dichotomous: RR 6.73, 95% CI 2.58 to 17.52; NNTB=2; moderate certainty; continuous: SMD 1.01, 95% CI 0.36 to 1.66; very low certainty). Biologics may result in little to no difference in endoscopic improvement (dichotomous: effect not estimable; low certainty; continuous: SMD 2.79, 95% CI 0.36 to 5.22; very low certainty). There may be no difference in withdrawals due to adverse events (RR 1.55, 95% CI 0.88 to 2.74; low certainty).

*Other comparisons:* Evidence for dietary interventions, cromolyn sodium, PGD2R antagonist, and head-to-head comparisons (e.g., fluticasone vs prednisone, budesonide vs fluticasone, esomeprazole vs fluticasone) was generally of very low certainty, precluding firm conclusions.

**Clinical Implications:** Corticosteroids (topical) are confirmed as effective first-line pharmacotherapy for induction of remission in EoE, with high-certainty evidence for histological improvement and low-certainty evidence for clinical benefit. Biologics, particularly anti-IL-13/anti-IL-4R agents, represent an emerging effective therapy, especially for histologic response, though clinical benefit is less consistent. The evidence for dietary elimination and other comparators is limited by very low certainty. The review highlights the need for standardized, validated outcome measures across trials, especially for clinical symptoms and quality of life, and for more pediatric-specific data.