Key Points
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Refractory eosinophilic oesophagitis (EoE) can be defined as persistent eosinophilia with incomplete symptom resolution, and persistent endoscopic findings after a PPI trial and after topical steroid treatment or dietary elimination
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Depending on the treatment modality, non-response to topical steroid or dietary elimination in EoE can be in the range of 20–50%
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Following non-response, it is important to systematically assess for explanations (for example, non-adherence; incorrect dosing, formulation or administration; ongoing allergen or food trigger exposure; inadequate dietary elimination; and validity of original diagnosis)
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Few clinical predictors of non-response have been identified to date
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Topical steroid or dietary elimination treatments should be maximized before switching between treatment modalities
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Second-line treatment options include systemic corticosteroids, elemental formula, leukotriene antagonists, immunomodulators and experimental agents in clinical trials
Abstract
The goal of this Review is to discuss the clinical approach to patients who do not respond to treatment for eosinophilic oesophagitis (EoE). Refractory EoE is challenging to manage as there are limited data to guide decision-making. In this Review, refractory EoE is defined as persistent eosinophilia in the setting of incomplete resolution of the primary presenting symptoms and incomplete resolution of endoscopic findings following a PPI trial, and after treatment with either topical steroids or dietary elimination. However, this definition is controversial. This Review will examine these controversies, explore how frequently non-response is observed, and highlight potential explanations and predictors of non-response. Non-response is common and affects a large proportion of patients with EoE. It is important to systematically assess multiple possible causes of non-response, as well as consider treatment complications and an incorrect diagnosis of EoE. If non-response is confirmed, second-line treatments are required. Although the overall response rate for second-line therapy is disappointing, with only half of patients eventually responding, there are several promising agents that are currently under investigation, and the future is bright for new treatment modalities for refractory EoE.
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References
Furuta, G. T. et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 133, 1342–1363 (2007).
Dobbins, J. W., Sheahan, D. G. & Behar, J. Eosinophilic gastroenteritis with esophageal involvement. Gastroenterology 72, 1312–1316 (1977).
Landres, R. T., Kuster, G. G. & Strum, W. B. Eosinophilic esophagitis in a patient with vigorous achalasia. Gastroenterology 74, 1298–1301 (1978).
Attwood, S. E., Smyrk, T. C., Demeester, T. R. & Jones, J. B. Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome. Dig. Dis. Sci. 38, 109–116 (1993).
Straumann, A., Spichtin, H. P., Bernoulli, R., Loosli, J. & Vogtlin, J. Idiopathic eosinophilic esophagitis: a frequently overlooked disease with typical clinical aspects and discrete endoscopic findings. Schweiz. Med. Wochenschr. 124, 1419–1429 (in German) (1994).
Kelly, K. J. et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology 109, 1503–1512 (1995).
Dellon, E. S. Epidemiology of eosinophilic esophagitis. Gastroenterol. Clin. North Am. 43, 201–218 (2014).
Dellon, E. S. et al. The increasing incidence and prevalence of eosinophilic oesophagitis outpaces changes in endoscopic and biopsy practice: national population-based estimates from Denmark. Aliment. Pharmacol. Ther. 41, 662–670 (2015).
Dellon, E. S., Jensen, E. T., Martin, C. F., Shaheen, N. J. & Kappelman, M. D. Prevalence of eosinophilic esophagitis in the United States. Clin. Gastroenterol. Hepatol. 12, 589–596.e1 (2014).
Arias, A., Perez-Martinez, I., Tenias, J. M. & Lucendo, A. J. Systematic review with meta-analysis: the incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies. Aliment. Pharmacol. Ther. 43, 3–15 (2016).
Kidambi, T., Toto, E., Ho, N., Taft, T. & Hirano, I. Temporal trends in the relative prevalence of dysphagia etiologies from 1999–2009. World J. Gastroenterol. 18, 4335–4341 (2012).
Desai, T. K. et al. Association of eosinophilic inflammation with esophageal food impaction in adults. Gastrointest. Endosc. 61, 795–801 (2005).
Sperry, S. L., Crockett, S. D., Miller, C. B., Shaheen, N. J. & Dellon, E. S. Esophageal foreign-body impactions: epidemiology, time trends, and the impact of the increasing prevalence of eosinophilic esophagitis. Gastrointest. Endosc. 74, 985–991 (2011).
Dellon, E. S. et al. Clinical and endoscopic characteristics do not reliably differentiate PPI-responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study. Am. J. Gastroenterol. 108, 1854–1860 (2013).
Prasad, G. A. et al. Prevalence and predictive factors of eosinophilic esophagitis in patients presenting with dysphagia: a prospective study. Am. J. Gastroenterol. 102, 2627–2632 (2007).
Mackenzie, S. H. et al. Prospective analysis of eosinophilic esophagitis in patients presenting with dysphagia [abstract A18]. Am. J. Gastroenterol. 101, S47 (2006).
Veerappan, G. R. et al. Prevalence of eosinophilic esophagitis in an adult population undergoing upper endoscopy: a prospective study. Clin. Gastroenterol. Hepatol. 7, 420–426 (2009).
Jensen, E. T., Kappelman, M. D., Martin, C. F. & Dellon, E. S. Health-care utilization, costs, and the burden of disease related to eosinophilic esophagitis in the United States. Am. J. Gastroenterol. 110, 626–632 (2015).
Liacouras, C. A. et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J. Allergy Clin. Immunol. 128, 3–20.e6 (2011).
Dellon, E. S. et al. ACG Clinical Guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis. Am. J. Gastroenterol. 108, 679–692 (2013).
Papadopoulou, A. et al. Management guidelines of eosinophilic esophagitis in childhood. J. Pediatr. Gastroenterol. Nutr. 58, 107–118 (2014).
Dellon, E. S. & Liacouras, C. A. Advances in clinical management of eosinophilic esophagitis. Gastroenterology 147, 1238–1254 (2014).
Molina-Infante, J. et al. Esophageal eosinophilic infiltration responds to proton pump inhibition in most adults. Clin. Gastroenterol. Hepatol. 9, 110–117 (2011).
Dranove, J. E., Horn, D. S., Davis, M. A., Kernek, K. M. & Gupta, S. K. Predictors of response to proton pump inhibitor therapy among children with significant esophageal eosinophilia. J. Pediatr. 154, 96–100 (2009).
Wen, T. et al. Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation. J. Allergy Clin. Immunol. 135, 187–197 (2015).
Sodikoff, J. & Hirano, I. Proton pump inhibitor-responsive esophageal eosinophilia does not preclude food-responsive eosinophilic esophagitis. J. Allergy Clin. Immunol. 137, 631–633 (2016).
Lucendo, A. J., Arias, A., Gonzalez-Cervera, J., Olalla, J. M. & Molina-Infante, J. Dual response to dietary/topical steroid and proton pump inhibitor therapy in adult patients with eosinophilic esophagitis. J. Allergy Clin. Immunol. 137, 931–934.e2 (2016).
Lucendo, A. J., Arias, A. & Molina-Infante, J. Efficacy of proton pump inhibitor drugs for inducing clinical and histologic remission in patients with symptomatic esophageal eosinophilia: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 14, 13–22.e1 (2016).
Cheng, E. et al. Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD. Gut 62, 824–832 (2013).
Zhang, X. et al. Omeprazole blocks STAT6 binding to the eotaxin-3 promoter in eosinophilic esophagitis cells. PLoS ONE 7, e50037 (2012).
Molina-Infante, J. et al. Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut 65, 524–531 (2016).
Wolf, W. A. et al. Predictors of response to steroid therapy for eosinophilic esophagitis and treatment of steroid-refractory patients. Clin. Gastroenterol. Hepatol. 13, 452–458 (2015).
Leung, J. et al. Longitudinal perspective on managing refractory eosinophilic esophagitis. J. Allergy Clin. Immunol. Pract. 3, 951–956 (2015).
Mukkada, V. A. & Furuta, G. T. Management of refractory eosinophilic esophagitis. Dig. Dis. 32, 134–138 (2014).
Sodikoff, J. & Hirano, I. Therapeutic strategies in eosinophilic esophagitis: induction, maintenance and refractory disease. Best Pract. Res. Clin. Gastroenterol. 29, 829–839 (2015).
Hirano, I. Therapeutic end points in eosinophilic esophagitis: is elimination of esophageal eosinophils enough? Clin. Gastroenterol. Hepatol. 10, 750–752 (2012).
Franciosi, J. P. et al. Development of a validated patient-reported symptom metric for pediatric eosinophilic esophagitis: qualitative methods. BMC Gastroenterol. 11, 126 (2011).
Martin, L. J. et al. Pediatric Eosinophilic Esophagitis Symptom Scores (PEESS v2.0) identify histologic and molecular correlates of the key clinical features of disease. J. Allergy Clin. Immunol. 135, 1519–1528.e8 (2015).
Dellon, E. S., Irani, A. M., Hill, M. R. & Hirano, I. Development and field testing of a novel patient-reported outcome measure of dysphagia in patients with eosinophilic esophagitis. Aliment. Pharmacol. Ther. 38, 634–642 (2013).
Schoepfer, A. M. et al. Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis. Gastroenterology 147, 1255–1266.e21 (2014).
Franciosi, J. P. et al. PedsQL eosinophilic esophagitis module: feasibility, reliability, and validity. J. Pediatr. Gastroenterol. Nutr. 57, 57–66 (2013).
Taft, T. H. et al. The adult eosinophilic oesophagitis quality of life questionnaire: a new measure of health-related quality of life. Aliment. Pharmacol. Ther. 34, 790–798 (2011).
Hirano, I. et al. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system. Gut 62, 489–495 (2013).
Wolf, W. A. et al. Evaluation of histologic cutpoints for treatment response in eosinophilic esophagitis. J. Gastroenterol. Hepatol. Res. 4, 1780–1787 (2015).
Wolf, W. A. et al. Evaluation of an optimal histologic threshold for treatment response in a prospective cohort of eosinophilic esophagitis patients [abstract Mo1181]. Gastroenterology 150 (Suppl. 1), S661 (2016).
Runge, T. M., Eluri, S., Woosley, J. T., Shaheen, N. J. & Dellon, E. S. Control of inflammation with topical steroids decreases subsequent esophageal dilation in patients with eosinophilic esophagitis [abstrasct Mo1187]. Gastroenterology 150 (Suppl. 1), S664 (2016).
Dellon, E. S., Aderoju, A., Woosley, J. T., Sandler, R. S. & Shaheen, N. J. Variability in diagnostic criteria for eosinophilic esophagitis: a systematic review. Am. J. Gastroenterol. 102, 2300–2313 (2007).
Schoepfer, A. M. et al. Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner. Gastroenterology 145, 1230–1236.e2 (2013).
Dellon, E. S. et al. A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease. Gastrointest. Endosc. 79, 577–585.e4 (2014).
Lipka, S., Kumar, A. & Richter, J. E. Impact of diagnostic delay and other risk factors on eosinophilic esophagitis phenotype and esophageal diameter. J. Clin. Gastroenterol. 50, 134–140 (2016).
Konikoff, M. R. et al. A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology 131, 1381–1391 (2006).
Schaefer, E. T. et al. Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children. Clin. Gastroenterol. Hepatol. 6, 165–173 (2008).
Dohil, R., Newbury, R., Fox, L., Bastian, J. & Aceves, S. Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial. Gastroenterology 139, 418–429 (2010).
Straumann, A. et al. Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis. Gastroenterology 139, 1526–1537.e1 (2010).
Dellon, E. S. et al. Viscous topical is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis. Gastroenterology 143, |321–324.e1 (2012).
Alexander, J. A. et al. Swallowed fluticasone improves histologic but not symptomatic responses of adults with eosinophilic esophagitis. Clin. Gastroenterol. Hepatol. 10, 742–749.e1 (2012).
Butz, B. K. et al. Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis. Gastroenterology 147, 324–333.e5 (2014).
Gupta, S. K., Vitanza, J. M. & Collins, M. H. Efficacy and safety of oral budesonide suspension in pediatric patients with eosinophilic esophagitis. Clin. Gastroenterol. Hepatol. 13, 66–76.e3 (2015).
Miehlke, S. et al. A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis. Gut 65, 390–399 (2016).
Dellon, E. S. et al. Budesonide oral suspension improves symptomatic, endoscopic, and histologic parameters compared with placebo in patients with eosinophilic esophagitis. Gastroenterology 152, 776–786.e5 (2017).
Moawad, F. J. et al. Randomized controlled trial comparing aerosolized swallowed fluticasone to esomeprazole for esophageal eosinophilia. Am. J. Gastroenterol. 108, 366–372 (2013).
Peterson, K. A. et al. Comparison of esomeprazole to aerosolized, swallowed fluticasone for eosinophilic esophagitis. Dig. Dis. Sci. 55, 1313–1319 (2010).
Moawad, F. et al. Predictors of non-response to topical steroids treatment in eosinophilic esophagitis [abstract 37]. Am. J. Gastroenterol. 108 (Suppl. 1), S14 (2013).
Philpott, H., Nandurkar, S., Royce, S. G., Thien, F. & Gibson, P. R. A prospective open clinical trial of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis. Aliment. Pharmacol. Ther. 43, 985–993 (2016).
Boldorini, R., Mercalli, F. & Oderda, G. Eosinophilic oesophagitis in children: responders and non-responders to swallowed fluticasone. J. Clin. Pathol. 66, 399–402 (2013).
Henderson, C. J. et al. Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis. J. Allergy Clin. Immunol. 129, 1570–1578 (2012).
Spergel, J. M. et al. 14 years of eosinophilic esophagitis: clinical features and prognosis. J. Pediatr. Gastroenterol. Nutr. 48, 30–36 (2009).
Spergel, J. M. et al. Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet. J. Allergy Clin. Immunol. 130, 461–467.e5 (2012).
Kagalwalla, A. F. et al. Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clin. Gastroenterol. Hepatol. 4, 1097–1102 (2006).
Kagalwalla, A. F. et al. Identification of specific foods responsible for inflammation in children with eosinophilic esophagitis successfully treated with empiric elimination diet. J. Pediatr. Gastroenterol. Nutr. 53, 145–149 (2011).
Gonsalves, N. et al. Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology 142, 1451–1459.e1 (2012).
Lucendo, A. J. et al. Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: a prospective study on the food cause of the disease. J. Allergy Clin. Immunol. 131, 797–804 (2013).
Molina-Infante, J. et al. Four-food group elimination diet for adult eosinophilic esophagitis: a prospective multicenter study. J. Allergy Clin. Immunol. 134, 1093–1099.e1 (2014).
Wolf, W. A., Jerath, M. R., Sperry, S. L., Shaheen, N. J. & Dellon, E. S. Dietary elimination therapy is an effective option for adults with eosinophilic esophagitis. Clin. Gastroenterol. Hepatol. 12, 1272–1279 (2014).
Liacouras, C. A. et al. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin. Gastroenterol. Hepatol. 3, 1198–1206 (2005).
Markowitz, J. E., Spergel, J. M., Ruchelli, E. & Liacouras, C. A. Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am. J. Gastroenterol. 98, 777–782 (2003).
Peterson, K. A. et al. Elemental diet induces histologic response in adult eosinophilic esophagitis. Am. J. Gastroenterol. 108, 759–766 (2013).
Warners, M. J. et al. Amino acid-based diet effectively decreases eosinophilic inflammation and improves symptoms in adult eosinophilic esophagitis patients [abstract 70]. Gastroenterology 150 (Suppl. 1), S18 (2016).
Arias, A., Gonzalez-Cervera, J., Tenias, J. M. & Lucendo, A. J. Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis. Gastroenterology 146, 1639–1648 (2014).
Hirano, I. & Aceves, S. S. Clinical implications and pathogenesis of esophageal remodeling in eosinophilic esophagitis. Gastroenterol. Clin. North Am. 43, 297–316 (2014).
Dellon, E. S. et al. Accuracy of the Eosinophilic Esophagitis Endoscopic Reference Score in diagnosis and determining response to treatment. Clin. Gastroenterol. Hepatol. 14, 31–39 (2016).
Safroneeva, E. et al. Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis. Gastroenterology 150, 581–590.e4 (2016).
Hefner, J. N. et al. A randomized controlled comparison of esophageal clearance times of oral budesonide preparations. Dig. Dis. Sci. 61, 1582–1590 (2016).
Lindberg, G. M., Van Eldik, R. & Saboorian, M. H. A case of herpes esophagitis after fluticasone propionate for eosinophilic esophagitis. Nat. Clin. Pract. Gastroenterol. Hepatol. 5, 527–530 (2008).
Zimmermann, D. et al. Acute herpes simplex viral esophagitis occurring in 5 immunocompetent individuals with eosinophilic esophagitis. ACG Case Rep. J. 3, 165–168 (2016).
Noel, R. J. et al. Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis. Clin. Gastroenterol. Hepatol. 2, 568–575 (2004).
Wolf, W. A. et al. The six-food elimination diet for eosinophilic esophagitis increases grocery shopping cost and complexity. Dysphagia 31, 765–770 (2016).
Doerfler, B., Bryce, P., Hirano, I. & Gonsalves, N. Practical approach to implementing dietary therapy in adults with eosinophilic esophagitis: the Chicago experience. Dis. Esophagus 28, 42–58 (2015).
Vashi, R. & Hirano, I. Diet therapy for eosinophilic esophagitis: when, why and how. Curr. Opin. Gastroenterol. 29, 407–415 (2013).
Venter, C. & Fleischer, D. M. Diets for diagnosis and management of food allergy: the role of the dietitian in eosinophilic esophagitis in adults and children. Ann. Allergy Asthma Immunol. 117, 468–471 (2016).
Aceves, S. S. Food allergy testing in eosinophilic esophagitis: what the gastroenterologist needs to know. Clin. Gastroenterol. Hepatol. 12, 1216–1223 (2014).
Philpott, H., Nandurkar, S., Royce, S. G., Thien, F. & Gibson, P. R. Allergy tests do not predict food triggers in adult patients with eosinophilic oesophagitis. A comprehensive prospective study using five modalities. Aliment. Pharmacol. Ther. 44, 223–233 (2016).
Hu, Y. et al. Increased acid responsiveness in vagal sensory neurons in a guinea pig model of eosinophilic esophagitis. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G149–G157 (2014).
Walker, M. M. et al. Duodenal eosinophilia and early satiety in functional dyspepsia: confirmation of a positive association in an Australian cohort. J. Gastroenterol. Hepatol. 29, 474–479 (2014).
Dellon, E. S. et al. Markers of tyrosine kinase activity in eosinophilic esophagitis: a pilot study of the FIP1L1–PDGFRα fusion gene, pERK 1/2, and pSTAT5. Dis. Esophagus 25, 166–174 (2012).
Aceves, S. S. et al. Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids. Allergy 65, 109–116 (2010).
Eluri, S. et al. The extremely narrow-caliber esophagus is a treatment-resistant subphenotype of eosinophilic esophagitis. Gastrointest. Endosc. 83, 1142–1148 (2016).
Chen, J. W. et al. Severity of endoscopically identified esophageal rings correlates with reduced esophageal distensibility in eosinophilic esophagitis. Endoscopy 48, 794–801 (2016).
Rieder, F. et al. T-Helper 2 cytokines, transforming growth factor β1, and eosinophil products induce fibrogenesis and alter muscle motility in patients with eosinophilic esophagitis. Gastroenterology 146, 1266–1277.e9 (2014).
Albert, D. et al. Comparisons of fluticasone to budesonide in the treatment of eosinophilic esophagitis. Dig. Dis. Sci. 61, 1996–2001 (2016).
Faubion, W. A. Jr et al. Treatment of eosinophilic esophagitis with inhaled corticosteroids. J. Pediatr. Gastroenterol. Nutr. 27, 90–93 (1998).
Bergquist, H., Larsson, H., Johansson, L. & Bove, M. Dysphagia and quality of life may improve with mometasone treatment in patients with eosinophilic esophagitis: a pilot study. Otolaryngol. Head Neck Surg. 145, 551–556 (2011).
Schroeder, S. et al. Successful treatment of eosinophilic esophagitis with ciclesonide. J. Allergy Clin. Immunol. 129, 1419–1421 (2012).
Lee, J. J. et al. Topical inhaled ciclesonide for treatment of eosinophilic esophagitis. J. Allergy Clin. Immunol. 130, 1011 (2012).
Aceves, S. S., Dohil, R., Newbury, R. O. & Bastian, J. F. Topical viscous budesonide suspension for treatment of eosinophilic esophagitis. J. Allergy Clin. Immunol. 116, 705–706 (2005).
Aceves, S. S., Bastian, J. F., Newbury, R. O. & Dohil, R. Oral viscous budesonide: a potential new therapy for eosinophilic esophagitis in children. Am. J. Gastroenterol. 102, 2271–2279 (2007).
Lee, J. et al. Oral viscous budesonide can be successfully delivered through a variety of vehicles to treat eosinophilic esophagitis in children. J. Allergy Clin. Immunol. Pract. 4, 767–768 (2016).
Kia, L. et al. Oral fluticasone powder improves histopathology in adults with eosinophilic esophagitis [abstract 1706]. Am. J. Gastroenterol. 110 (Suppl. 1), S724–S725 (2015).
Liacouras, C. A., Wenner, W. J., Brown, K. & Ruchelli, E. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J. Pediatr. Gastroenterol. Nutr. 26, 380–385 (1998).
Attwood, S. E. et al. Eosinophilic oesophagitis: a novel treatment using Montelukast. Gut 52, 181–185 (2003).
Stumphy, J., Al-Zubeidi, D., Guerin, L., Mitros, F. & Rahhal, R. Observations on use of montelukast in pediatric eosinophilic esophagitis: insights for the future. Dis. Esophagus 24, 229–234 (2011).
Lucendo, A. J. et al. Montelukast was inefficient in maintaining steroid-induced remission in adult eosinophilic esophagitis. Dig. Dis. Sci. 56, 3551–3558 (2011).
Alexander, J. A. et al. Montelukast does not maintain symptom remission after topical steroid therapy for eosinophilic esophagitis. Clin. Gastroenterol. Hepatol. 15, 214–221.e2 (2017).
Abonia, J. P. et al. Involvement of mast cells in eosinophilic esophagitis. J. Allergy Clin. Immunol. 126, 140–149 (2010).
Aceves, S. S. et al. Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction. J. Allergy Clin. Immunol. 126, 1198–1204.e4 (2010).
Lucendo, A. J. et al. Immunophenotypic characterization and quantification of the epithelial inflammatory infiltrate in eosinophilic esophagitis through stereology: an analysis of the cellular mechanisms of the disease and the immunologic capacity of the esophagus. Am. J. Surg. Pathol. 31, 598–606 (2007).
Straumann, A., Bauer, M., Fischer, B., Blaser, K. & Simon, H. U. Idiopathic eosinophilic esophagitis is associated with a TH2-type allergic inflammatory response. J. Allergy Clin. Immunol. 108, 954–961 (2001).
Dellon, E. S. et al. Tryptase staining of mast cells may differentiate eosinophilic esophagitis from gastroesophageal reflux disease. Am. J. Gastroenterol. 106, 264–271 (2011).
Dellon, E. S. et al. Markers of eosinophilic inflammation for diagnosis of eosinophilic esophagitis and proton pump inhibitor-responsive esophageal eosinophilia: a prospective study. Clin. Gastroenterol. Hepatol. 12, 2015–2022 (2014).
Netzer, P. et al. Corticosteroid-dependent eosinophilic oesophagitis: azathioprine and 6-mercaptopurine can induce and maintain long-term remission. Eur. J. Gastroenterol. Hepatol. 19, 865–869 (2007).
Straumann, A., Bussmann, C., Conus, S., Beglinger, C. & Simon, H. U. Anti-TNF-α (infliximab) therapy for severe adult eosinophilic esophagitis. J. Allergy Clin. Immunol. 122, 425–427 (2008).
Clayton, F. et al. Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE. Gastroenterology 147, 602–609 (2014).
Rothenberg, M. E. Molecular, genetic, and cellular bases for treating eosinophilic esophagitis. Gastroenterology 148, 1143–1157 (2015).
Straumann, A. et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut 59, 21–30 (2010).
Assa'ad, A. H. et al. An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology 141, 1593–1604 (2011).
Spergel, J. M. et al. Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. J. Allergy Clin. Immunol. 129, 456–463.e3 (2012).
Blanchard, C. et al. IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids. J. Allergy Clin. Immunol. 120, 1292–1300 (2007).
Rothenberg, M. E. et al. Intravenous anti-IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis. J. Allergy Clin. Immunol. 135, 500–507 (2015).
Hirano, I. et al. A randomized, double-blind, placebo-controlled trial of a novel recombinant, humanized, anti-interleukin-13 monoclonal antibody (RPC4046) in patients with active eosinophilic esophagitis: results of the HEROES study [abstract]. United European Gastroenterol. J. 4 (Suppl. 5), OP325 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02379052 (2017).
Simpson, E. L. et al. Dupilumab therapy provides clinically meaningful improvement in patient-reported outcomes (PROs): a phase IIb, randomized, placebo-controlled, clinical trial in adult patients with moderate to severe atopic dermatitis (AD). J. Am. Acad. Dermatol. 75, 506–515 (2016).
Wenzel, S. et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 388, 31–44 (2016).
Straumann, A. et al. Anti-eosinophil activity and clinical efficacy of the CRTH2 antagonist OC000459 in eosinophilic esophagitis. Allergy 68, 375–385 (2013).
Ishimura, N., Ishihara, S. & Kinoshita, Y. Sustained acid suppression by potassium-competitive acid blocker (P-CAB) may be an attractive treatment candidate for patients with eosinophilic esophagitis. Am. J. Gastroenterol. 111, 1203–1204 (2016).
Spechler, S. J., Genta, R. M. & Souza, R. F. Thoughts on the complex relationship between gastroesophageal reflux disease and eosinophilic esophagitis. Am. J. Gastroenterol. 102, 1301–1306 (2007).
Molina-Infante, J. et al. Long-term loss of response in proton pump inhibitor-responsive esophageal eosinophilia is uncommon and influenced by CYP2C19 genotype and rhinoconjunctivitis. Am. J. Gastroenterol. 110, 1567–1575 (2015).
Gentile, N. et al. Oesophageal narrowing is common and frequently under-appreciated at endoscopy in patients with oesophageal eosinophilia. Aliment. Pharmacol. Ther. 40, 1333–1340 (2014).
Menard-Katcher, C., Swerdlow, M. P., Mehta, P., Furuta, G. T. & Fenton, L. Z. Contribution of esophagram to the evaluation of complicated pediatric eosinophilic esophagitis. J. Pediatr. Gastroenterol. Nutr. 61, 541–546 (2015).
Madanick, R. D., Shaheen, N. J. & Dellon, E. S. A novel balloon pull-through technique for esophageal dilation in eosinophilic esophagitis (with video). Gastrointest. Endosc. 73, 138–142 (2011).
Bohm, M. E. & Richter, J. E. Review article: oesophageal dilation in adults with eosinophilic oesophagitis. Aliment. Pharmacol. Ther. 33, 748–757 (2011).
Saligram, S. & McGrath, K. The safety of a strict wire-guided dilation protocol for eosinophilic esophagitis. Eur. J. Gastroenterol. Hepatol. 26, 699–703 (2014).
Cohen, M. S. et al. An audit of endoscopic complications in adult eosinophilic esophagitis. Clin. Gastroenterol. Hepatol. 5, 1149–1153 (2007).
Kaplan, M. et al. Endoscopy in eosinophilic esophagitis: “feline” esophagus and perforation risk. Clin. Gastroenterol. Hepatol. 1, 433–437 (2003).
Straumann, A. et al. Eosinophilic esophagitis: analysis of food impaction and perforation in 251 adolescent and adult patients. Clin. Gastroenterol. Hepatol. 6, 598–600 (2008).
Dellon, E. S. et al. Esophageal dilation in eosinophilic esophagitis: safety and predictors of clinical response and complications. Gastrointest. Endosc. 71, 706–712 (2010).
Schoepfer, A. M. et al. Esophageal dilation in eosinophilic esophagitis: effectiveness, safety, and impact on the underlying inflammation. Am. J. Gastroenterol. 105, 1062–1070 (2010).
Jung, K. W. et al. Occurrence of and risk factors for complications after endoscopic dilation in eosinophilic esophagitis. Gastrointest. Endosc. 73, 15–21 (2011).
Jacobs, J. W. Jr & Spechler, S. J. A systematic review of the risk of perforation during esophageal dilation for patients with eosinophilic esophagitis. Dig. Dis. Sci. 55, 1512–1515 (2010).
Runge, T. M. et al. Outcomes of esophageal dilation in eosinophilic esophagitis: safety, efficacy, and persistence of the fibrostenotic phenotype. Am. J. Gastroenterol. 111, 206–213 (2016).
Richter, J. E. Eosinophilic esophagitis dilation in the community — try it — you will like it — but start low and go slow. Am. J. Gastroenterol. 111, 214–216 (2016).
Acknowledgements
E.S.D. is supported, in part, by the US National Institutes of Health (NIH; grant R01 DK101856), as well as the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR; grant U54AI117804), which is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Disease Research (ORDR), the US National Center for Advancing Translational Sciences (NCATS), and is funded through collaboration between the US National Institute of Allergy and Infectious Diseases (NIAID), the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and NCATS.
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E.S.D. is a consultant for Adare, Alivio, Banner, GlaxoSmithKline, Receptos, Regeneron and Shire. He has received research funding from Meritage, Miraca Life Sciences, Nutricia, Receptos, Regeneron and Shire, and an educational grant from Banner.
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Dellon, E. Management of refractory eosinophilic oesophagitis. Nat Rev Gastroenterol Hepatol 14, 479–490 (2017). https://doi.org/10.1038/nrgastro.2017.56
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DOI: https://doi.org/10.1038/nrgastro.2017.56
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