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• W2012764570 abstract "In the past, this title would likely have meant that with the emerging interest and rising prevalence of eosinophilic esophagitis (EoE), this was a disease that would remain prominent in our literature and in clinical practice. Unfortunately, this phrase now takes on a new meaning in EoE and refers to the assuredly relapsing and chronic nature of the disease that begs the question whether patients with EoE should be treated with long-term maintenance therapy, as suggested by the important study by Straumann et al1Straumann A. Conus S. Degen L. et al.Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2011; 9: 400-409Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar that is published in this issue. Let us explore the data behind this reasoning. A genetic basis has been postulated for many allergic diseases including food allergies, asthma, and atopic dermatitis.2Hourihane J.O. Dean T.P. Warner J.O. Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges.BMJ. 1996; 313: 518-521Crossref PubMed Scopus (286) Google Scholar, 3Hong X. Tsai H.-J. Wang X. Genetics of food allergy.Curr Opin Pediatr. 2009; 21: 770-776Crossref PubMed Scopus (80) Google Scholar, 4Moffatt M.F. Kabesch M. Liang L. et al.Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.Nature. 2007; 448: 470-473Crossref PubMed Scopus (1270) Google Scholar, 5Murphy A. Weiss S.T. Lange C. Screening and replication using the same data set: testing strategies for family-based studies in which all probands are affected.PLoS Genet. 2008; 4: e1000197Crossref PubMed Scopus (25) Google Scholar Although many allergic diseases likely involve an interaction of genetic predisposition, epigenetic changes, and environmental exposure, once the allergic phenotype emerges, chronicity can generally be expected. Similarly, EoE appears to have a genetic basis and chronic symptoms. EoE has a markedly elevated sibling recurrence risk ratio and has been clearly linked to genetic abnormalities in eotaxin-3 and 5q22.6Esparza-Gordillo J. Weidinger S. Folster-Holst R. et al.A common variant on chromosome 11q13 is associated with atopic dermatitis.Nat Genet. 2009; 41: 596-601Crossref PubMed Scopus (259) Google Scholar, 7Blanchard C. Wang N. Stringer K.F. et al.Eotaxin-3 and a uniquely conserved gene expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Crossref PubMed Scopus (724) Google Scholar, 8Rothenberg M.E. Spergel J.M. Sherrill J.D. et al.Common variants at 5q22 associate with pediatric eosinophilic esophagitis.Nat Genet. 2010; 42: 28-30Crossref Scopus (358) Google Scholar, 9Blanchard C. Wang N. Rothenberg M.E. Eosinophilic esophagitis: pathogenesis, genetics, and therapy.J Allergy Clin Immunol. 2006; 118: 1054-1059Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar Moreover, clinical and histologic characterization of EoE also predicts chronic if not lifelong disease. For example, there is a long antecedent history of symptoms in patients with EoE often extending back decades before diagnosis. Although natural history studies are few, what data we have point to persistent disease both symptomatically and histologically in up to 14 years of follow-up.10Helou E.F. Simonson J. Arora A.S. 3-yr follow-up of topical corticosteroid treatment for eosinophilic esophagitis.Am J Gastroenterol. 2008; 103: 2194-2199Crossref PubMed Scopus (126) Google Scholar, 11Spergel J.M. Brown-Whitehorn T.F. Beausoleil J.L. et al.14 years of eosinophilic esophagitis: clinical features and prognosis.J Pediatr Gastroenterol Nutr. 2010; 48: 30-36Crossref Scopus (375) Google Scholar, 12Straumann A. Spichtin H.P. Grize L. et al.Natural history of primary EoE: a follow-up of 30 adult patients for up to 11.5 years.Gastroenterology. 2003; 125: 1660-1669Abstract Full Text Full Text PDF PubMed Scopus (650) Google Scholar It is also clear from these and other studies13Schaeffer E.T. Fitzgerald J.F. Molleston J.P. et al.Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children.Clin Gastroenterol Hepatol. 2008; 6: 165-173Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar, 14Liacouras C.A. Wenner W.J. Brown K. et al.Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids.J Pediatr Gastroenterol Nutr. 1998; 26: 380-385Crossref PubMed Scopus (453) Google Scholar that when we examine the follow-up of clinical studies that evaluate symptomatic and histologic response to an initial pharmacologic treatment, relapse is common if not certain. There are important reasons for which we might want to maintain remission in EoE. First, symptomatic recurrence after a course of topical steroid therapy, as mentioned above, is almost universal, with half of the patients having recurrence within 9 months.10Helou E.F. Simonson J. Arora A.S. 3-yr follow-up of topical corticosteroid treatment for eosinophilic esophagitis.Am J Gastroenterol. 2008; 103: 2194-2199Crossref PubMed Scopus (126) Google Scholar, 12Straumann A. Spichtin H.P. Grize L. et al.Natural history of primary EoE: a follow-up of 30 adult patients for up to 11.5 years.Gastroenterology. 2003; 125: 1660-1669Abstract Full Text Full Text PDF PubMed Scopus (650) Google Scholar Second, submucosal fibrosis and stricture formation with EoE is also extremely common.12Straumann A. Spichtin H.P. Grize L. et al.Natural history of primary EoE: a follow-up of 30 adult patients for up to 11.5 years.Gastroenterology. 2003; 125: 1660-1669Abstract Full Text Full Text PDF PubMed Scopus (650) Google Scholar, 15Jung K.W. Gundersen N. Kopacova J. et al.Complications after endoscopic dilation in eosinophilic esophagitis and associated risk factors.Gastrointest Endosc. 2011; 73: 15-21Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 16Aceves S.S. Newbury R.O. Dohil R. et al.Esophageal remodelling in pediatric esosinophilic esophagitis.J Allergy Clin Immunol. 2007; 119: 206-212Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar, 17Kwiatek M.A. Hirano I. Kahrilas P.J. et al.Mechanical properties of the esophagus in eosinophilic esophagitis.Gastroenterology. 2011; 140: 82-90Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar There are encouraging data that effective steroid treatment inhibits some of the key tissue constituents and signaling pathways that contribute to fibrosis such as transforming growth factor β1, pSmad2/3, and tenascin C.18Aceves S.S. Newbury R.O. Chen D. et al.Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids.Allergy. 2010; 65: 109-116Crossref PubMed Scopus (247) Google Scholar, 19Straumann A. Conus S. Degen L. et al.Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.Gastroenterology. 2010; 139: 1526-1537Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar Furthermore, this seems to correspond with data demonstrating a reduction in lamina propria fibrosis with steroid treatment18Aceves S.S. Newbury R.O. Chen D. et al.Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids.Allergy. 2010; 65: 109-116Crossref PubMed Scopus (247) Google Scholar, 19Straumann A. Conus S. Degen L. et al.Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis.Gastroenterology. 2010; 139: 1526-1537Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar and even endoscopic reversibility of esophageal rings and strictures in some studies.20Lucendo A.J. Pascual-Turrion J.M. Navarro M. et al.Endoscopic, bioptic, and manometric findings in eosinophilic esophagitis before and after steroid therapy: a case series.Endoscopy. 2007; 39: 765-771Crossref PubMed Scopus (102) Google Scholar These facts make a strong case to place patients with EoE on continuous maintenance treatment for not only prevention or progression of disease but perhaps normalization or at least improvement in fibrotic change and symptoms. As a result, the article by Straumann et al1Straumann A. Conus S. Degen L. et al.Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2011; 9: 400-409Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar is timely. In this superbly performed randomized, double-blind, placebo-controlled 50-week trial of 28 adolescent or adult patients who used 0.25 mg of inhaled budesonide twice daily, there are several favorable results. First, there is less of an increase in eosinophil and mast cell counts in the treatment groups when compared with placebo. Second, complete histologic remission defined by normalization of eosinophil count was maintained with budesonide in 35.7% of patients compared with 0% in the placebo group. Third, with the use of maintenance budesonide, there is less of an increase in tissue levels of transforming growth factor β1 and tenascin C–expressing epithelial cell clusters as important mediators of tissue remodeling and fibrosis. This beneficial effect is corroborated by a similar reduction in increase of lamina propria fibrosis score and an overall reduction in mucosal thickness on endoscopic ultrasound. Unfortunately, many important treatment parameters did not respond. For example, there was no significant effect of maintenance budesonide on tumor necrosis factor-α or measures of epithelial apoptosis. Furthermore, although several significant differences emerged from this study, there was a blunting of progression of disease as opposed to an improvement. There were no significant differences in symptom scores, maintenance of symptomatic remission, or time to relapse when comparing patients on budesonide with those on placebo. As the authors suggested, it is possible that a higher dose of steroid might have had a greater effect. This article also demonstrates that in this early stage of determining maintenance treatment of EoE, there is still a devil in the details. First, who needs maintenance therapy? Certainly, those patients with frequent recurrent symptoms do. What about those with less frequent symptoms and a normal or mildly narrowed caliber esophagus? Do patients with EoE with a normal or mildly narrow caliber esophagus follow an inexorable course to severe stricture formation if left untreated and therefore require chronic preventative treatment? If this were so, why do we not see more patients with a small caliber esophagus? Is as needed intermittent therapy appropriate for some patients? Second, important questions remain in treatment such as what is the desired end point of treatment: improvement of histology, symptoms, or both? Is normalization of the esophageal mucosa the only acceptable histologic end point of treatment, and how likely are we to achieve this? Third, will this be safe therapy long term? Will there be evidence of adrenal insufficiency or osteoporosis after decades of use? One might also ask whether there are alternatives to chronic steroid therapy that we could consider. For example, are there predictable environmentally induced exacerbations that are better served by anticipated as needed rather than chronic therapy? Indeed, in the animal model of EoE, airway exposure is one of the putative first steps in causing eosinophilic infiltration.21Mishra A. Hogan S.P. Brandt E.B. et al.An etiological role for aeroallergens and eosinophils in experimental esophagitis.J Clin Invest. 2001; 107: 83-90Crossref PubMed Scopus (536) Google Scholar Furthermore, clinical studies have demonstrated both an exacerbation of esophageal disease during flares of seasonal allergies11Spergel J.M. Brown-Whitehorn T.F. Beausoleil J.L. et al.14 years of eosinophilic esophagitis: clinical features and prognosis.J Pediatr Gastroenterol Nutr. 2010; 48: 30-36Crossref Scopus (375) Google Scholar and that airway allergies precede esophageal disease by 10 years on average.22Simon D. Marti H. Heer P. et al.EoE is frequently associated with IgE-mediated allergic airway diseases.J Allergy Clin Immunol. 2005; 115: 1090-1092Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar As a result, could we prophylactically treat patients during times of seasonal allergy flares? Although this might be an attractive means of expectantly treating patients with EoE, unfortunately, it is difficult to apply these principles to specific patients. Another pharmacologic approach to long-term maintenance therapy might be the use of proton pump inhibitors (PPIs). Several studies have shown both symptomatic and histologic response to PPIs in patients with EoE. One recent study demonstrated that patients with the typical phenotype of EoE have a 50% response rate to PPIs that is not predicted by abnormal acid exposure as demonstrated on ambulatory pH monitoring.23Molina-Infante J. Ferrando-Lamana L. Ripoll C. et al.Esophageal eosinophilic infiltration responds to proton pump inhibitors in most adults.Clin Gastroenterol Hepatol. 2011; 9: 110-117Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar Whether this response to PPIs indicates that these patients do not have EoE and acid reflux is causing their disease or that the disease is multifactorial is open to debate. There are also preliminary basic science data suggesting that the beneficial effect of PPIs on EoE might be independent of acid suppression and work through direct effects on blocking secretion of inflammatory cytokines.24Zhang X. Cheng E. Huo X. et al.In esophageal squamous epithelial cell lines from patients with eosinophilic esophagitis (EoE), omeprazole blocks the stimulated secretion of eotaxin-3: a potential anti-inflammatory effect of omeprazole in EoE that is independent of acid inhibition.Gastroenterology. 2010; 138: S122Google Scholar Whether PPIs become a maintenance therapy for EoE on the basis of these data remains to be determined. Use of diet therapy would be ideal for long-term remission. With the knowledge that an elemental diet, that is, avoidance of culpable food allergens, leads to complete histologic remission of esophageal disease in children11Spergel J.M. Brown-Whitehorn T.F. Beausoleil J.L. et al.14 years of eosinophilic esophagitis: clinical features and prognosis.J Pediatr Gastroenterol Nutr. 2010; 48: 30-36Crossref Scopus (375) Google Scholar and perhaps adults, a diet that excludes these food antigens would be safe and relatively inexpensive. Furthermore, data in children suggest that after use of an elemental diet, esophageal tolerance might develop to previously antigenic foods, although in a low percentage of patients.11Spergel J.M. Brown-Whitehorn T.F. Beausoleil J.L. et al.14 years of eosinophilic esophagitis: clinical features and prognosis.J Pediatr Gastroenterol Nutr. 2010; 48: 30-36Crossref Scopus (375) Google Scholar Unfortunately, we still lack, particularly in adults, an accurate means of identifying these antigens, and from a more practical point of view, the multitude of food antigens commonly identified in patients makes avoidance difficult if not impossible. One must also ask whether dilation alone would be adequate for maintenance of clinical remission. Although in the early days of dilation of esophageal strictures in patients with EoE the complications of the procedure were predicted to occur at a high rate and to be potentially devastating, several recent studies of relatively large numbers of patients have demonstrated efficacy and safety of dilation in these patients.15Jung K.W. Gundersen N. Kopacova J. et al.Complications after endoscopic dilation in eosinophilic esophagitis and associated risk factors.Gastrointest Endosc. 2011; 73: 15-21Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 25Schoepfer A.M. Gonsalves N. Bussman C. et al.Esophageal dilation in eosinophilic esophagitis: effectiveness, safety, and impact on the underlying inflammation.Am J Gastroenterol. 2010; 105: 1062-1070Crossref PubMed Scopus (255) Google Scholar Furthermore, these studies demonstrate relief of symptoms up to almost 2 years on average. Although we are obviously not treating the biology of the disease with dilation, without concern over neoplastic predisposition at this point or other serious sequelae of chronic inflammation, dilation becomes an interesting alternative. After all, EoE, as far as we know, is not a life-threatening disease and is not one with high morbidity, but for the risks of presenting with food impaction requiring endoscopic intervention and the decrease in social quality of life. How vigilant must we be in controlling ongoing esophageal inflammation? Finally, one must ask if EoE is found incidentally without symptoms when endoscopy is performed for a non-esophageal indication, does treatment need to be initiated? The frequency with which this occurs is not well known, but such cases exist, particularly with large population screening studies. This scenario similarly begs the question about what is the natural history of this disease and whether treatment at this point will prevent future complications. For truly asymptomatic patients (ie, patients devoid of subtle signs of dysphagia such as chronic slow eating, careful chewing, and food avoidance), treatment benefits are not clear. We should not view this study as a negative study. This study is landmark in that it is an attempt to address the important question of maintenance therapy. It also demonstrates beneficial effects, albeit perhaps not as robust as we might have liked. It gives support to performing future studies to attempt to find effective pharmacologic maintenance therapy of EoE. There is clear optimism from this study that there will be a dose of a topical esophageal steroid preparation that will prevent and perhaps reverse progression of EoE. Whether the benefits of this dose of medication will outweigh the long-term risks will need to be determined. Is it acceptable to place all current patients on budesonide 1 mg daily, as suggested in the study by Straumann et al?1Straumann A. Conus S. Degen L. et al.Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2011; 9: 400-409Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar This will depend on whether you view the study results as a glass half empty or half full. Certainly, there is no consensus yet that this specific therapy is generally applicable for chronic use in EoE. Our understanding of and care for patients with EoE have come a long way. Much of the pathophysiology has been elucidated, and we have therapies that are effective in treating the esophageal inflammatory response and hopefully avoiding the mechanical complications that accompany years of disease. Unfortunately, the battle has just begun as we move into the next phase of treatment, that is, maintenance of remission in a disease that is chronic and likely to be lifelong after onset. With this study by Straumann et al, we make the first important strike. Long-Term Budesonide Maintenance Treatment Is Partially Effective for Patients With Eosinophilic EsophagitisClinical Gastroenterology and HepatologyVol. 9Issue 5PreviewTopical corticosteroids are effective in inducing clinical and histologic remission in patients with eosinophilic esophagitis (EoE). However, the best long-term management strategy for this chronic inflammatory disease has not been determined. Full-Text PDF" @default.
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• W2012764570 title "Eosinophilic Esophagitis: It Is Here to Stay" @default.
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