Determination of a treatment response threshold for the Eosinophilic Esophagitis Endoscopic Reference Score

Abstract

Background Endoscopic features of eosinophilic esophagitis (EoE) are measured using the validated EoE Endoscopic Reference Score (EREFS); however, a threshold for treatment response has not been defined. We aimed to determine a cut-point for endoscopic response as measured by EREFS.

Methods We performed a secondary analysis of a randomized clinical trial comparing budesonide slurry with swallowed fluticasone multidose inhaler for initial treatment of EoE. In the parent trial, EREFS was determined before and after treatment (score range 0–9), as were histologic findings and dysphagia symptoms. We performed tabular, flexible trend, and dependent mixture analyses of measures of treatment response to select the best clinical EREFS threshold.

Results In the 111 included patients (mean age 39 years; 67 % male; 96 % white), an EREFS threshold of ≤ 2 was 80 % sensitive (95 % confidence interval [CI] 69 % to 88 %) and 83 % specific (95 %CI 67 % to 94 %) for histologic response (peak of < 15 eosinophils per high-power field). Flexible trend analysis and dependent mixture modeling similarly suggested that a threshold of ≤ 2 best captured the correlation of EREFS with histologic and symptomatic measures. Dependent mixture modeling found near-total membership in the response class at EREFS of 0 or 1 and > 75 % at EREFS of 2 or 3.

Conclusions An EREFS of ≤ 2 was the best clinical threshold for endoscopic response to topical steroid treatment, and was consistent with clinical and histologic response. Therefore, future studies can report a binary outcome of endoscopic response when EREFS is 2 or less.

• References

• 1 Dellon ES, Rusin S, Gebhart JH. et al. A clinical prediction tool identifies cases of eosinophilic esophagitis without endoscopic biopsy: a prospective study. Am J Gastroenterol 2015; 110: 1347-1354
• 2 Sperry SL, Shaheen NJ, Dellon ES. Toward uniformity in the diagnosis of eosinophilic esophagitis (EoE): the effect of guidelines on variability of diagnostic criteria for EoE. Am J Gastroenterol 2011; 106: 824-832
• 3 Kim HP, Vance RB, Shaheen NJ. et al. The prevalence and diagnostic utility of endoscopic features of eosinophilic esophagitis: a meta-analysis. Clin Gastroenterol Hepatol 2012; 10: 988-996
• 4 Dellon ES, Liacouras CA, Molina-Infante J. et al. Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE Conference. Gastroenterology 2018; 155: 1022-1033
• 5 Straumann A, Katzka DA. Diagnosis and treatment of eosinophilic esophagitis. Gastroenterology 2018; 154: 346-359
• 6 Croese J, Fairley SK, Masson JW. et al. Clinical and endoscopic features of eosinophilic esophagitis in adults. Gastrointest Endosc 2003; 58: 516-522
• 7 Muir AB, Merves J, Liacouras CA. Role of endoscopy in diagnosis and management of pediatric eosinophilic esophagitis. Gastrointest Endosc Clin N Am 2016; 26: 187-200
• 8 Dellon ES, Gupta SK. A conceptual approach to understanding treatment response in eosinophilic esophagitis. Clin Gastroenterol Hepatol 2019; 17: 2149-2160
• 9 Dellon ES, Liacouras CA. Advances in clinical management of eosinophilic esophagitis. Gastroenterology 2014; 147: 1238-1254
• 10 Eluri S, Corder SR, Kim E. et al. Clinical features and time trends associated with an endoscopically normal esophagus in active eosinophilic esophagitis. Endoscopy 2021; 53: 886-892
• 11 Hirano I, Moy N, Heckman MG. et al. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system. Gut 2013; 62: 489-495
• 12 van Rhijn BD, Warners MJ, Curvers WL. et al. Evaluating the endoscopic reference score for eosinophilic esophagitis: moderate to substantial intra- and interobserver reliability. Endoscopy 2014; 46: 1049-1055
• 13 Wechsler JB, Bolton SM, Amsden K. et al. Eosinophilic Esophagitis Reference Score accurately identifies disease activity and treatment effects in children. Clin Gastroenterol Hepatol 2018; 16: 1056-1063
• 14 Dellon ES, Katzka DA, Collins MH. et al. Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis. Gastroenterology 2017; 152: 776-786
• 15 Dellon ES, Katzka DA, Collins MH. et al. Safety and efficacy of budesonide oral suspension maintenance therapy in patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2019; 17: 666-673
• 16 Hirano I, Dellon ES, Hamilton JD. et al. Efficacy of dupilumab in a Phase 2 randomized trial of adults with active eosinophilic esophagitis. Gastroenterology 2020; 158: 111-122
• 17 Hirano I, Collins MH, Assouline-Dayan Y. et al. RPC4046, a monoclonal antibody against IL13, reduces histologic and endoscopic activity in patients with eosinophilic esophagitis. Gastroenterology 2019; 156: 592-603
• 18 Dellon ES, Collins MH, Rothenberg ME. et al. Long-term efficacy and tolerability of RPC4046 in an open-label extension trial of patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2021; 19: 473-483
• 19 van Rhijn BD, Verheij J, Smout AJ. et al. The Endoscopic Reference Score shows modest accuracy to predict histologic remission in adult patients with eosinophilic esophagitis. Neurogastroenterol Motil 2016; 28: 1714-1722
• 20 Dellon ES, Cotton CC, Gebhart JH. et al. Accuracy of the Eosinophilic Esophagitis Endoscopic Reference Score in diagnosis and determining response to treatment. Clin Gastroenterol Hepatol 2016; 14: 31-39
• 21 Rodriguez-Sanchez J, Barrio-Andres J, Nantes Castillejo O. et al. The Endoscopic Reference Score shows modest accuracy to predict either clinical or histological activity in adult patients with eosinophilic oesophagitis. Aliment Pharmacol Ther 2017; 45: 300-309
• 22 Schoepfer AM, Hirano I, Coslovsky M. et al. Variation in endoscopic activity assessment and endoscopy score validation in adults with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2019; 17: 1477-1488
• 23 Dellon ES, Woosley JT, Arrington A. et al. Efficacy of budesonide vs fluticasone for initial treatment of eosinophilic esophagitis in a randomized controlled trial. Gastroenterology 2019; 157: 65-73
• 24 Dellon ES, Woosley JT, Arrington A. et al. Rapid recurrence of eosinophilic esophagitis activity after successful treatment in the observation phase of a randomized, double-blind, double-dummy trial. Clin Gastroenterol Hepatol 2020; 18: 1483-1492
• 25 Safroneeva E, Cotton CC, Schoepfer AM. et al. Dilation modifies association between symptoms and esophageal eosinophilia in adult patients with eosinophilic esophagitis. Am J Gastroenterol 2020; 115: 2098-2102
• 26 Dellon ES, Woosley JT, McGee SJ. et al. Utility of major basic protein, eotaxin-3, and mast cell tryptase staining for prediction of response to topical steroid treatment in eosinophilic esophagitis: analysis of a randomized, double-blind, double dummy clinical trial. Dis Esophagus 2020; 33: doaa003
• 27 Dellon ES, Gonsalves N, Hirano I. et al. ACG clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol 2013; 108: 679-692
• 28 Dellon ES, Irani AM, Hill MR. et al. Development and field testing of a novel patient-reported outcome measure of dysphagia in patients with eosinophilic esophagitis. Aliment Pharmacol Ther 2013; 38: 634-642
• 29 Wolf WA, Cotton CC, Green DJ. et al. Evaluation of histologic cutpoints for treatment response in eosinophilic esophagitis. J Gastroenterol Hepatol Res 2015; 4: 1780-1787
• 30 Reed CC, Wolf WA, Cotton CC. et al. Optimal histologic cutpoints for treatment response in patients with eosinophilic esophagitis: analysis of data from a prospective cohort study. Clin Gastroenterol Hepatol 2018; 16: 226-233
• 31 Schoepfer AM, Straumann A, Panczak R. et al. Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis. Gastroenterology 2014; 147: 1255-1266
• 32 Visser I, Speekenbrink M. depmixS4: An R Package for Hidden Markov Models. J Stat Softw 2010; 36: 1-21
• 33 Dellon ES. Optimizing the endoscopic examination in eosinophilic esophagitis. Clin Gastroenterol Hepatol 2021;
• 34 Hirano I, Schoepfer AM, Comer GM. et al. A randomized, double-blind, placebo-controlled trial of a fluticasone propionate orally disintegrating tablet in adult and adolescent patients with eosinophilic esophagitis: a Phase 1/2a safety and tolerability study. Gastroenterology 2017; 152: S195-S195
• 35 Lucendo AJ, Miehlke S, Schlag C. et al. Efficacy of budesonide orodispersible tablets as induction therapy for eosinophilic esophagitis in a randomized placebo-controlled trial. Gastroenterology 2019; 157: 74-86
• 36 Straumann A, Lucendo AJ, Miehlke S. et al. Budesonide orodispersible tablets maintain remission in a randomized, placebo-controlled trial of patients with eosinophilic esophagitis. Gastroenterology 2020; 159: 1672-1685