Narrowing the focus on fibrostenotic eosinophilic esophagitis
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EDITORIAL Narrowing the focus on fibrostenotic eosinophilic esophagitis Eosinophilic esophagitis (EoE) was a largely unrecog- nized condition until the early 1980s, around the same time that endoscopy came into widespread use. Various studies have demonstrated that the prevalence of EoE has increased considerably since 1990, 1,2 with some sug- gestion that, at least in the pediatric population, EoE may now be as prevalent as inflammatory bowel disease. As such, the public health significance of this condition has grown considerably and will likely continue to grow over the near future. It is well recognized that EoE in children tends to present with abdominal pain, vomiting, failure to thrive, and reflux, whereas adults with EoE tend to have dysphagia as the predominant symptom. Although we have come to recognize that there are varied presenta- tions of EoE, both clinically and endoscopically, data about the natural history of this disease are scarce. In the current issue of Gastrointestinal Endoscopy, Dellon et al 3 present the results of a retrospective analysis of a cohort of 379 patients with newly diagnosed eosino- philic esophagitis. On the basis of observations that EoE has varied endoscopic presentations, the authors sought to determine whether there are demographic, clinical, and pathologic differences between EoE phenotypes. They defined a priori 3 distinct endoscopic phenotypes: fi- brostenotic (rings, narrowing, or strictures), inflammatory (furrows, plaques, or normal esophagus), and mixed (fea- tures of both). They found that patients with an inflamma- tory phenotype were more representative of the pediatric EoE population: mean age 13, and more likely to have abdominal pain, vomiting, and failure to thrive. The fibros- tenotic phenotype, by contrast, was more typical of the adult EoE patient, with a mean age of 39, who was more likely to present with dysphagia and food impaction. The mixed phenotype fell somewhere in between, but overall it resembled more closely the fibrostenotic phenotype. The duration of symptoms before diagnosis of EoE for the mixed and fibrostenotic phenotypes (8 years for each group) was significantly greater than for the inflammatory phenotype (5 years). On the basis of the observation that the fibrostenotic phenotype was independently associated with both older age and longer duration of symptoms, the authors hypothesized that the development of fibrosteno- sis may be a phenomenon related to disease duration. Although the design of the current study does not permit direct assessment of the natural history of EoE, other recent studies lend credence to the view of EoE as a chronic, progressive disease in which fibrosis can develop over time. Eventually, symptoms of pediatric EoE may progress to a more dysphagia-predominant pro- file, 4 and relatively few children with EoE appear to expe- rience tolerance to offending foods. 5 A retrospective analysis from Switzerland also reported that longer delay in diagnosis was associated with an increased prevalence of fibrotic features. 6 There are also some histologic data to suggest that unchecked inflammation from EoE could result in the development of esophageal fibrosis. Straumann et al 7 studied 30 EoE patients who were not medically treated and were followed up for a mean of 7.2 years. Esophageal biopsy specimens from 7 of the 30 patients contained adequate subepithelial tissue for analysis, and the au- thors noted a marked increase in the amount of subepi- thelial fibrosis in comparison with baseline. For the current study by Dellon et al, 3 it would have been enlightening to know whether the fibrostenotic pheno- type correlated with a histologic assessment of fibrosis and whether there was less subepithelial fibrosis in the inflammatory group. A review of the data on the cellular and molecular mechanisms related to EoE also sheds some light on the relationship between esophageal inflammation and fibrosis. A number of Th-2 derived cytokines, some of which have profibrotic properties, have been shown to play an important role in EoE. The most important of these fibroblast stimulating mediators may be transforming growth factor- b1, which is involved in airway remodeling in asthma, and is upregulated in the esophagi of pediatric EoE patients. Aceves et al 8 demonstrated that transforming Although the design of the current study does not permit direct assessment of the natural history of eosinophilic esophagitis, other recent studies lend credence to the view of eosinophilic esophagitis as a chronic, progressive disease in which fibrosis can develop over time. Copyright ª 2014 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2013.12.008 586 GASTROINTESTINAL ENDOSCOPY Volume 79, No. 4 : 2014 www.giejournal.org
Transcript of Narrowing the focus on fibrostenotic eosinophilic esophagitis
EDITORIAL
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Narrowing the focus on fibrostenotic eosinophilic esophagitis
Although the design of the current studydoes not permit direct assessment of thenatural history of eosinophilic esophagitis,other recent studies lend credence to theview of eosinophilic esophagitis as a chronic,progressive disease in which fibrosis candevelop over time.
Eosinophilic esophagitis (EoE) was a largely unrecog-nized condition until the early 1980s, around the sametime that endoscopy came into widespread use. Variousstudies have demonstrated that the prevalence of EoEhas increased considerably since 1990,1,2 with some sug-gestion that, at least in the pediatric population, EoE maynow be as prevalent as inflammatory bowel disease. Assuch, the public health significance of this condition hasgrown considerably and will likely continue to grow overthe near future. It is well recognized that EoE in childrentends to present with abdominal pain, vomiting, failureto thrive, and reflux, whereas adults with EoE tend tohave dysphagia as the predominant symptom. Althoughwe have come to recognize that there are varied presenta-tions of EoE, both clinically and endoscopically, data aboutthe natural history of this disease are scarce.
In the current issue of Gastrointestinal Endoscopy,Dellon et al3 present the results of a retrospective analysisof a cohort of 379 patients with newly diagnosed eosino-philic esophagitis. On the basis of observations that EoEhas varied endoscopic presentations, the authors soughtto determine whether there are demographic, clinical,and pathologic differences between EoE phenotypes.They defined a priori 3 distinct endoscopic phenotypes: fi-brostenotic (rings, narrowing, or strictures), inflammatory(furrows, plaques, or normal esophagus), and mixed (fea-tures of both). They found that patients with an inflamma-tory phenotype were more representative of the pediatricEoE population: mean age 13, and more likely to haveabdominal pain, vomiting, and failure to thrive. The fibros-tenotic phenotype, by contrast, was more typical of theadult EoE patient, with a mean age of 39, who was morelikely to present with dysphagia and food impaction. Themixed phenotype fell somewhere in between, but overallit resembled more closely the fibrostenotic phenotype.The duration of symptoms before diagnosis of EoE forthe mixed and fibrostenotic phenotypes (8 years for eachgroup) was significantly greater than for the inflammatoryphenotype (5 years). On the basis of the observation thatthe fibrostenotic phenotype was independently associatedwith both older age and longer duration of symptoms, theauthors hypothesized that the development of fibrosteno-sis may be a phenomenon related to disease duration.
right ª 2014 by the American Society for Gastrointestinal Endoscopy-5107/$36.00//dx.doi.org/10.1016/j.gie.2013.12.008
GASTROINTESTINAL ENDOSCOPY Volume 79, No. 4 : 2014
Although the design of the current study does notpermit direct assessment of the natural history of EoE,other recent studies lend credence to the view of EoEas a chronic, progressive disease in which fibrosis candevelop over time. Eventually, symptoms of pediatricEoE may progress to a more dysphagia-predominant pro-file,4 and relatively few children with EoE appear to expe-rience tolerance to offending foods.5 A retrospectiveanalysis from Switzerland also reported that longer delayin diagnosis was associated with an increased prevalenceof fibrotic features.6
There are also some histologic data to suggest thatunchecked inflammation from EoE could result in the
development of esophageal fibrosis. Straumann et al7
studied 30 EoE patients who were not medically treatedand were followed up for a mean of 7.2 years. Esophagealbiopsy specimens from 7 of the 30 patients containedadequate subepithelial tissue for analysis, and the au-thors noted a marked increase in the amount of subepi-thelial fibrosis in comparison with baseline. For thecurrent study by Dellon et al,3 it would have beenenlightening to know whether the fibrostenotic pheno-type correlated with a histologic assessment of fibrosisand whether there was less subepithelial fibrosis in theinflammatory group.
A review of the data on the cellular and molecularmechanisms related to EoE also sheds some light onthe relationship between esophageal inflammation andfibrosis. A number of Th-2 derived cytokines, some ofwhich have profibrotic properties, have been shown toplay an important role in EoE. The most important of thesefibroblast stimulating mediators may be transforminggrowth factor- b1, which is involved in airway remodelingin asthma, and is upregulated in the esophagi of pediatricEoE patients. Aceves et al8 demonstrated that transforming
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Lagana & Abrams Editorial
growth factor-b1 upregulation is seen mostly in theeosinophils themselves, whereas a downstream effectormolecule, phospho-SMAD2/3, is overexpressed in basalepithelial cells and by cells of the lamina propria. Thisgroup also noted an increased number of lamina propriablood vessels and increased expression of vascular celladhesion molecule 1, a marker of endothelial activation.Thus, we can see that esophageal remodeling in EoE isa complex process that involves input from epithelialcells, lymphocytes, eosinophils, fibroblasts, endothelia,and other associated cells.
The concept that chronic esophageal inflammation canlead to fibrosis is certainly consistent with observationsfrom other conditions such as Crohn’s disease and chronichepatitis. However, certain entities stand out as beingparticularly analogous to EoE and its associated fibrosis.Collagenous colitis shows similar histopathologic findingsto those of EoE-associated fibrosis, insofar as there is adense band of collagen immediately under the surfaceepithelia. Fibrosis can also be seen in eosinophilic gastro-enteritis, typically in the muscle-based variety. Indeed,some of these patients present with gastric outlet obstruc-tion or duodenal obstruction, and we have occasionallyperformed surgical resections for this indication in ourinstitution. However, fibrosis does not develop in allpatients with chronic luminal or hepatic inflammation,and one focus of future EoE research should be to identifyEoE patients at highest risk for the development offibrostenosis.
The authors of the current study chose to use durationof symptoms as a surrogate for duration of disease, areasonable assumption to make. A recent article bySchoepfer et al6 also used symptom duration as a meansof estimating disease onset in EoE. In the study by Dellonet al,3 the mean duration of symptoms for the inflamma-tory group was only 3 years less than for the fibrostenoticgroup, which suggests a relatively rapid “transition” tofibrostenosis. Alternatively, there may be a period of sub-clinical esophageal inflammation that predates the onsetof symptoms. Another possible consideration is that theremay be “slow” and “rapid” EoE progressors. Owing to thelimitations of a retrospective analysis without longitudinaldata, we are unable to answer these and other importantquestions.
The patients included in the analysis met strict criteriafor EoE, including “esophageal dysfunction” symptomsthat did not respond to proton pump inhibitors. However,it was interesting to note that among the fibrostenoticpatients in this cohort, there was a marked prevalenceof coexisting endoscopic signs of GERD, inasmuch as13% had a hiatal hernia and 35% had erosive esophagitis.In a recent clinical trial of esomeprazole versus flutica-sone in patients with esophageal eosinophilia anddysphagia, food impaction, or heartburn, patients in theesomeprazole arm surprisingly had superior improve-ment in dysphagia symptom scores.9 Furthermore, this
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treatment effect was found in both GERD-positive andGERD-negative patients. Thus, it is conceivable that con-current gastroesophageal reflux (symptomatic or silent)may be an important cofactor that contributes to thedevelopment of EoE phenotypes.
The classification of patients into endoscopic pheno-types may ultimately influence choice of medical therapies,given that some data suggest that patients with dysphagia-predominant symptoms respond less well to steroids. In arandomized trial by Alexander et al,10 36 adult EoE patientswith symptomatic dysphagia were treated with swallowedfluticasone 880 mg or placebo twice daily. Patients in thefluticasone arm had significantly greater eosinophil reduc-tion than did those in the placebo group, but there was nosignificant difference in dysphagia improvement betweenthe 2 groups. Steroids, however, were effective in a sepa-rate randomized placebo-controlled trial of 24 childrenwith EoE and varied clinical presentations (includingabdominal pain, vomiting, and regurgitation). In this study,budesonide was superior to placebo in terms of symptomimprovement.11
The results of the study by Dellon et al3 demonstratethat EoE has varied presentations; perhaps more impor-tantly, one can infer from these findings that EoE mayin fact represent a chronic progressive disease in manypatients. Recent clinical trial data suggest that medical ther-apy may have reduced efficacy in patients with fibroste-notic EoE. This highlights the need for efforts aimed atearly recognition and diagnosis of EoE and the develop-ment of therapies specifically aimed at prevention of andreversal of esophageal fibrosis. Although there are severalongoing trials of short-term steroids as well as novel ther-apeutic agents, there is still a need for studies with long-term follow-up to assess the prevention of stenosis. Giventhe rising prevalence of EoE, gastroenterologists for adultsshould expect a marked increase in patients “graduating”from their pediatric gastroenterologists in the comingyears. However, there still remain many unanswered ques-tions that need to be addressed before we can optimizemanagement for these patients.
DISCLOSURE
All authors disclosed no financial relationships rele-vant to this publication.
Stephen M. Lagana, MDDepartment of Pathology
Columbia University Medical CenterNew York, NY
Julian A. Abrams, MD, MSDivision of Digestive and Liver Diseases
Columbia University Medical CenterNew York, NY
Volume 79, No. 4 : 2014 GASTROINTESTINAL ENDOSCOPY 587
Editorial Lagana & Abrams
REFERENCES
1. Hruz P, Straumann A, Bussmann C, et al. Escalating incidence of eosin-ophilic esophagitis: a 20-year prospective, population-based studyin Olten County, Switzerland. J Allergy Clin Immunol 2011;128:1349-50.e5.
2. Prasad GA, Alexander JA, Schleck CD, et al. Epidemiology of eosino-philic esophagitis over three decades in Olmsted County, Minnesota.Clin Gastroenterol Hepatol 2009;7:1055-61.
3. Dellon ES, Kim HP, Sperry SL, et al. A phenotypic analysis shows eosin-ophilic esophagitis is a progressive fibrostenotic disease. GastrointestEndosc 2014;79:577-85.
4. DeBrosse CW, Collins MH, Buckmeier Butz BK, et al. Identification,epidemiology, and chronicity of pediatric esophageal eosinophilia,1982-1999. J Allergy Clin Immunol 2010;126:112-9.
5. Menard-Katcher P, Marks KL, Liacouras CA, et al. The natural history ofeosinophilic oesophagitis in the transition from childhood to adult-hood. Aliment Pharmacol Ther 2013;37:114-21.
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6. Schoepfer AM, Safroneeva E, Bussmann C, et al. Delay in diagnosis ofeosinophilic esophagitis increases risk for stricture formation in a time-dependent manner. Gastroenterology 2013;145:1230-6.e2.
7. Straumann A, Spichtin HP, Grize L, et al. Natural history of primaryeosinophilic esophagitis: a follow-up of 30 adult patients for up to11.5 years. Gastroenterology 2003;125:1660-9.
8. Aceves SS, Newbury RO, Dohil R, et al. Esophageal remodeling inpediatric eosinophilic esophagitis. J Allergy Clin Immunol 2007;119:206-12.
9. Moawad FJ, Veerappan GR, Dias JA, et al. Randomized controlled trialcomparing aerosolized swallowed fluticasone to esomeprazole foresophageal eosinophilia. Am J Gastroenterol 2013;108:366-72.
10. Alexander JA, Jung KW, Arora AS, et al. Swallowed fluticasone im-proves histologic but not symptomatic response of adults with eosin-ophilic esophagitis. Clin Gastroenterol Hepatol 2012;10:742-9.e1.
11. Dohil R, Newbury R, Fox L, et al. Oral viscous budesonide is effective inchildren with eosinophilic esophagitis in a randomized, placebo-controlled trial. Gastroenterology 2010;139:418-29.
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