2014-04-24 19:01:53 UTC

The EOE Roller Coaster - Do not Dilate Your Patients with Eosinophilic Esophagitis

May 1, 2014

NAME

Ikuo Hirano, MD

Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL

Eosinophilic esophagitis (EoE) is a “chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.”1 The rapid rise in prevalence of EoE over the past two decades is not only the result of increased recognition, but also likely a reflection of the rise in atopic disease in general. While no therapies have yet been approved by the U.S. Food and Drug Administration, a number of medical and diet therapies have demonstrated clinical effectiveness in prospective and randomized controlled trials. My opponent, a leading authority in the field of esophagology, champions esophageal dilation as the most appropriate, primary therapy for EoE. While I have the utmost respect for Dr. Richter, I believe that he should put down his “weapon of massive dilation” in favor of an evening of refined dining with an elimination diet.

Therapy of EoE: a novel treatment paradigm for a novel disease

Since the 16th century, esophageal dilation has been the primary means of therapy for dysphagia associated with esophageal strictures. Over the years, this strategy has been a highly effective means of dealing with achalasia, Schatzki ring, cervical webs, peptic strictures and radiation strictures. In the new millennium, EoE has rapidly emerged as a leading cause of dysphagia amongst adults.2 There is little doubt that esophageal dilation is a highly effective means to deal with the fibrostenotic manifestations of EoE. EoE, however, is a novel disorder with an immune pathogenesis that is distinct from the previously mentioned esophageal disorders. The notion that dysphagia might respond to medications or elimination of dietary antigens is an innovative and foreign concept. The primarily food-antigen stimulated, Th2 inflammatory response in EoE induces remodeling effects that are mediated by IL-5, IL-13 and TGFß1.3 The resultant transmural, structural alterations are evidenced by histologic identification of esophageal subepithelial fibrosis and ultrasonographic detection of marked expansion of the mucosa, submucosa and muscularis mucosa.

In clinical practice, the remodeling can be macroscopically apparent in the form of esophageal strictures and narrow caliber. Esophageal distensibility measurements using the functional luminal imaging probe provides detailed quantification of esophageal remodeling in EoE.4 Reduced distensibility in EoE has been associated with the outcome of food impaction risk.5 Furthermore, recent studies have demonstrated that the duration of untreated EoE is a major risk factor for the development of esophageal stricture, with the prevalence of stricture doubling with each decade of untreated disease.6 It stands to reason that the primary treatment of EoE should be directed at arresting this inflammation to prevent future stricture development and not just focus on existing strictures.

Decades of experience, and Dr. Richter’s own pivotal clinical trial in GERD, have demonstrated that healing of erosive esophagitis is associated with reduced dysphagia and reduced need for esophageal dilation in the management of esophageal peptic strictures.7 Why should the management of strictures in EoE, also the result of chronic esophageal inflammation, be viewed any differently? Furthermore, fibrosis is not the only determinant of reduced luminal caliber in EoE. Mucosal/submucosal inflammatory infiltration or “edema” is evident endoscopically, histologically and endosonographically. Motility effects of esophageal eosinophilia have also been characterized as direct or indirect consequences of remodeling.

Don’t forget the kids!

The argument that esophageal dilation is appropriate therapy for patients with EoE does not apply to children. Children with EoE present with symptoms of pain, food aversion, nausea and vomiting that often mimics a pediatric presentation of GERD.8 Dysphagia, food impaction and esophageal strictures are unusual manifestations in children.9 Similarly, not every adult with EoE has evidence of esophageal stricture. Tissue inflammation is likely an important determinant of symptoms in these particular cohorts, with downstream remodeling consequences.

Complications of esophageal dilation: “Richter-scale” rifts in the esophagus

Esophageal dilation is not without risk. Early reports of esophageal perforations occurring from dilation, endoscopic extraction of food impaction and even diagnostic endoscopy raised substantial concern regarding the safety of dilation in EoE. While subsequent, larger series have reported greater safety in the performance of dilation, complications still occur.10 Deep, intramural crevices extending for several centimeters are common following dilation in EoE. A large series from Mayo Clinic identified three perforations and one episode of major hemorrhage as a result of dilation in 161 patients.11 In the largest reported series, our group in conjunction with Drs. Schoepfer and Straumann reported no perforations in 474 dilations in 207 patients.12 Severe, post-procedural chest pain, however, is common with several reported cases that have required inpatient evaluation. Based on a patient questionnaire, 74 percent reported chest pain after dilation.10 In Dr. Richter’s early study with Dr. Morrow, 19 patients with a ringed esophageal and esophageal eosinophilia were treated with dilation and “several patients” required narcotic analgesics for chest pain.13 Moreover, the reported safety of dilation is based on reports from specialized centers for esophageal disorders. The increased safety of dilation reported in recent years likely reflects the experience of clinicians who have adopted a more conservative approach to dilation in EoE.7, 10

Can medical and diet therapy reverse or prevent existing esophageal strictures in EoE?

Numerous studies have demonstrated the clinical effectiveness of medical and diet therapies in the absence of esophageal dilation. Both forms of therapy result in convincing reduction and in many cases complete histologic normalization of eosinophilic inflammation. Evidence also points to reductions in esophageal remodeling. Significant improvement in esophageal diameter, albeit modest, has been demonstrated in a prospective trial with caliber quantified by means of barium esophagram.14 Symptom improvement in dysphagia has generally tracked with a reduction in eosinophilic inflammation in several, but not all, prospective trials using both elimination diet and topical steroids.15–19 In a randomized placebo-controlled trial, Dr. Straumann demonstrated that budesonide decreased dysphagia severity, esophageal eosinophilia, subepithelial fibrosis as well as TGFß1 expression after only 15 days of therapy.17 Furthermore, his one-year, follow-up maintenance trial of low-dose budesonide led to a significant decrease in mucosal thickness measured by endoscopic ultrasonography.20 Lucendo and colleagues demonstrated a reduction, albeit non-significant, in subepithelial fibrosis and significant reduction in fibrosis mediators following a year of topical fluticasone in adults with EoE.19 Studies in pediatric EoE have demonstrated a reduction in subepithelial fibrosis in patients treated with both topical steroids and elimination diet.21 Together, these studies provide evidence that medical therapy can at least partially reverse existing remodeling effects in EoE.


Dilation should only be done with discretion and viewed as adjunctive therapy, targeting aspects of esophageal remodeling that are not amenable to medical and diet therapies.


Clinical guidelines for dilation: what are the evidence and consensus recommendations?

Consensus statements for EoE endorsed by three major medical societies have recommended “careful” esophageal dilation for patients failing medical or diet therapies or those with severe stenosis. Dilation was not recommended as primary therapy to be used in isolation.1, 22, 23 My opponent, Dr. Richter, was in fact a co-author on these guidelines, and has thereby endorsed this approach. Retrospective data have demonstrated that medical therapy for EoE can reduce the utilization of esophageal dilation in EoE. Furthermore, a recently completed randomized controlled trial completed by Dr. Vaezi and colleagues compared esophageal dilation combined with medical therapy to medical therapy alone in adults with EoE (personnel communication). No difference in the primary outcome of dysphagia was demonstrated, again highlighting the effectiveness of medical therapy in EoE. Clearly, more work is needed to fully understand the role of medical and diet therapies in reversing the remodeling effects in EoE. Remodeling is a fundamental determinant of both the clinical symptoms and major complications of EoE.24 While esophageal dilation is effective and generally safe, it does nothing to arrest the chronic inflammatory process that leads to strictures.12 Dilation should not be utilized for children and adults with an inflammatory phenotype that lacks the symptoms or signs of fibrostenosis. Medical and diet therapies, therefore, remain fundamental to the appropriate management of EoE to eliminate active inflammation and prevent the progression of esophageal fibrostenosis.

Should we dilate? Yes, but dilation should only be done with discretion and viewed as adjunctive therapy, targeting aspects of esophageal remodeling that are not amenable to medical and diet therapies.

Dr. Hirano has no conflicts to disclose.

References

1. Liacouras, C.A., et al., Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol, 2011. 128(1): p. 3-20 e6; quiz 21-2.

2. Kidambi, T., et al., Temporal trends in the relative prevalence of dysphagia etiologies from 1999-2009. World J Gastroenterol, 2012. 18(32): p. 4335-41.

3. Aceves, S.S. and S.J. Ackerman, Relationships between eosinophilic inflammation, tissue remodeling, and fibrosis in eosinophilic esophagitis. Immunol Allergy Clin North Am, 2009. 29(1): p. 197-211, xiii-xiv.

4. Kwiatek, M.A., et al., Mechanical properties of the esophagus in eosinophilic esophagitis. Gastroenterology, 2011. 140(1): p. 82-90.

5. Nicodeme, F., et al., Esophageal distensibility as a measure of disease severity in patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol, 2013. 11(9): p. 1101-1107 e1.

6. Schoepfer, A.M., et al., Delay in Diagnosis of Eosinophilic Esophagitis Increases Risk for Stricture Formation, in a Time-Dependent Manner. Gastroenterology, 2013.

7. Marks, R.D., et al., Omeprazole versus H2-receptor antagonists in treating patients with peptic stricture and esophagitis. Gastroenterology, 1994. 106(4): p. 907-15.

8. Spergel, J.M., et al., 14 years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr, 2009. 48(1): p. 30-6.

9. Straumann, A. and A.M. Schoepfer, Therapeutic concepts in adult and paediatric eosinophilic oesophagitis. Nat Rev Gastroenterol Hepatol, 2012. 9(12): p. 697-704.

10. Hirano, I., Dilation in eosinophilic esophagitis: to do or not to do? Gastrointest Endosc, 2010. 71(4): p. 713-4.

11. Jung, K.W., et al., Occurrence of and risk factors for complications after endoscopic dilation in eosinophilic esophagitis. Gastrointest Endosc, 2011. 73(1): p. 15-21.

12. Schoepfer, A.M., et al., Esophageal dilation in eosinophilic esophagitis: effectiveness, safety, and impact on the underlying inflammation. Am J Gastroenterol, 2010. 105(5): p. 1062-70.

13. Morrow, J.B., et al., The ringed esophagus: histological features of GERD. Am J Gastroenterol, 2001. 96(4): p. 984-9.

14. Lee, J., et al., Esophageal diameter is decreased in some patients with eosinophilic esophagitis and might increase with topical corticosteroid therapy. Clin Gastroenterol Hepatol, 2012. 10(5): p. 481-6.

15. Gonsalves, N., et al., Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology, 2012. 142(7): p. 1451-9 e1; quiz e14-5.

16. Dohil, R., et al., Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial. Gastroenterology, 2010. 139(2): p. 418-29.

17. Straumann, A., et al., Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis. Gastroenterology, 2010. 139(5): p. 1526-37, 1537 e1.

18. Remedios, M., et al., Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointest Endosc, 2006. 63(1): p. 3-12.

19. Hirano, I., Therapeutic end points in eosinophilic esophagitis: is elimination of esophageal eosinophils enough? Clin Gastroenterol Hepatol, 2012. 10(7): p. 750-2.

20. Straumann, A., et al., Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol, 2011. 9(5): p. 400-9 e1.

21. Aceves, S.S., et al., Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids. Allergy, 2010. 65(1): p. 109-16.

22. Furuta, G.T., et al., Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology, 2007. 133(4): p. 1342-63.

23. Dellon, E.S., 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(5): p. 679-92; quiz 693.

24. Hirano, I. and S. Aceves, Clinical Implications and Pathogenesis of Esophageal Remodeling in Eosinophilic Esophagitis Gastroenterology Clinics of North America, 2014.

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