Eosinophilic Esophagitis: What Can We Learn from Crohn's Disease?

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Review Article United European Gastroenterology Journal 2017, Vol. 5(6) 762–772 ! Author(s) 2016 Eosinophilic esophagitis: What can Reprints and permissions: sagepub.co.uk/journalsPermissions.nav we learn from Crohn’s disease? DOI: 10.1177/2050640616672953 journals.sagepub.com/home/ueg

Javier Molina-Infante1, Alain M Schoepfer2, Alfredo J. Lucendo3 and Evan S Dellon4

Abstract Eosinophilic esophagitis (EoE) is an emerging esophageal inflammatory disorder affecting children and young adults. As a relatively new disease, EoE is still burdened by frequent diagnostic and therapeutic pitfalls in clinical practice. This manuscript posits a number of similarities with Crohn’s disease, which may help optimize EoE patient management. Commonalities include epidemiologic trends (Westernized diseases, rising incidence, early-life risk factors), diagnostic considerations (symptoms are poor predictors of disease activity, difficulties in disease activity assessment) and therapeutic issues (similar natural history and therapeutic goals, induction and maintenance phases, combination of drug and endoscopic treatment, potential drug interchangeability, long-term unsolved issues). Physicians devoted to EoE should learn from the extraordinary achievements fulfilled in Crohn’s disease: increased disease awareness, multidisciplinary specialized clinics, structured childhood and transition programs, and an ongoing roadmap for personalized treatments, including genetic susceptibility, risk factors for progression, genotype-phenotype correlation, drug monitoring and microbial data.

Keywords Eosinophilic esophagitis, Crohn’s disease, inflammatory bowel disease

Received: 3 August 2016; accepted: 14 September 2016

Introduction on-demand treatment intended to control symptoms. Only since 2007 has EoE been recognized as a distinct Eosinophilic esophagitis (EoE) is a chronic, immune/ new condition with the publication of updated guide- antigen-mediated esophageal disease characterized lines for diagnosis and management.6–8 Mounting clinically by symptoms related to esophageal dysfunc- knowledge over the past decade has contributed to tion and histologically by eosinophil (eos)-predominant situating EoE as a distinct chronic and progressive inflammation.1 In the early 1990s, two groups of inves- inflammatory condition affecting pediatric and young tigators independently reported a series of young adult adult patients, with familial aggregation.9,10 Symptom patients, mostly male, with dysphagia, typical endo- pattern usually consists of intermittent flare-ups, scopic findings and marked esophageal eosinophilia, with symptoms of esophageal dysfunction and acute in the absence of clinical evidence of gastro-esophageal reflux disease (GERD).2,3 Nevertheless, the disorder 1 was largely neglected during the 1990s and early years Department of Gastroenterology, Hospital San Pedro de Alcantara, Caceres, of the 21st century, mostly because previous studies Spain 2Division of Gastroenterology and Hepatology, Centre Hospitalier from the 1970s and 1980s equated the presence of Universitaire Vaudois et Universite´ de Lausanne, Lausanne, Switzerland 4 esophageal eosinophils (eos) and GERD. A prime 3Department of Gastroenterology, Hospital General de Tomelloso, example is a series of 19 patients with dysphagia/food Tomelloso, Spain 4 impaction, ringed narrowed esophagus and dense Center for Esophageal Diseases and Swallowing, Division of eosinophilia requiring esophageal dilation, reported as Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA GERD patients in 2001.5 Like in GERD, the most Corresponding author: common esophageal disease, many pediatric and adult Javier Molina-Infante, Department of Gastroenterology, Hospital San Pedro EoE patients are still treated in clinical practice for de Alcantara, C/ Pablo Naranjo s/n, 10003 Caceres, Spain. four to eight weeks, followed by repeat courses of Email: [email protected] Molina-Infante et al. 763 episodes of food impaction, followed by remission Needless to say, functional status in EoE patients periods.8 Symptom severity and dietary restriction is much better than that for patients with CD, in negatively affect the quality of life of patients, especially which anemia, malnutrition, infections, surgical pro- children and young adults.11,12 Furthermore, untreated cedures and drug toxicity might be common. EoE inflammation usually leads to long-term fibrostenotic and CD are also different in terms of extension complications, like narrow-caliber esophagus and through the gastrointestinal tract, gender predomin- esophageal strictures.13,14 Disease management is ance, extraintestinal manifestations, noninvasive increasingly complex, with different therapeutic assets monitoring, therapy principles, and long-term compli- such as proton pump inhibitor (PPI) therapy, swal- cations. The main differences between EoE and CD lowed topical steroids, dietary therapy, endoscopic dila- are exhibited in Table 1. A recent population-based tion and even biologic agents.15 study has suggested an increased risk of multiple This manuscript aims to discuss a relevant number of autoimmune diseases in EoE patients, including CD potential similarities between EoE and Crohn’s disease and ulcerative colitis,22 but these findings should be (CD), particularly emphasizing epidemiologic trends, further replicated. symptom pattern, impaired quality of life, natural history, disease activity assessment and therapeutic approach. Potential commonalities between EoE and CD

Differences between EoE and CD The main similarities shared by both disorders are sketched in Table 2. From an etiologic and pathophysiologic standpoint, EoE and CD clearly are different diseases. EoE is an Genetic predisposition and risk of inheritance antigen-mediated allergic disease, thought to be predominantly but not exclusively triggered by food anti- A genetic predisposition to EoE and CD is supported gens.6–8 Elimination diets (mainly involving cow’s milk, by evidence of familial clustering and twin studies. wheat and eggs) are effective in achieving clinical and Regarding EoE, family history has been reported in histological remission in a relevant proportion of 2%–7% of patients9,10 and susceptibility has been patients.16 In genetically predisposed individuals, envir- associated with genetic variants at 5q22 (TSLP) and onmental antigens stimulate an anomalous Th2 inflam- 2p23 (CAPN14).17 Likewise, first-degree relatives of matory response, which promotes trafficking of eos patients with CD have a greater increased risk of limited to the esophageal mucosa. Activated eos secrete developing either CD and ulcerative colitis. Genetic proinflammatory and profibrotic mediators, cause local studies have identified so far 163 susceptibility loci tissue damage, and recruit additional inflammatory for IBD, mostly shared between CD and ulcerative cells (mast cells and fibroblasts), perpetuating the colitis.23 inflammatory response and resulting in esophageal 17 remodeling. In contrast, the ultimate etiology of CD Epidemiologic trends remains unknown. One possibility is that environmental factors in genetically predisposed individuals trigger The first case series of EoE as a distinct new condition a Th1/Th17 inflammatory response resulting in a dis- were published in 1993 and 1994.2,3 Since then, EoE has turbed innate and adaptive immune response toward a rapidly become a common global disease with a steadily diminished diversity of commensal microbiota.18 An rising incidence in multiple, mostly industrialized, loca- interesting hypothesis in CD is that food-triggered tions. A first systematic review with meta-analysis changes of the intestinal microbiome might cause a exhibited a current pooled EoE incidence rate of 7.2/ proinflammatory state preceding the development of 100,000 people/year and prevalence rate of 26.3 cases/ inflammatory bowel disease (IBD). Indeed, an intact 100,000 people both in children and adults.24 However, intestinal epithelial barrier ensuring a normal bacterial this could be an underestimate. In Switzerland (Canton clearance of the intestinal surface is crucial to guarantee of Vaud), the prevalence rate in 2013 was 24.1/100,000 intestinal homeostasis. Exclusive enteral nutrition is an people,25 but the annual EoE incidence was 10.6 times extensively studied, well-established, and valid higher in the period from 2010 to 2013 when compared approach to the remission of pediatric CD.19 to that in the period from 1993 to 2009. Recent adult Interestingly, a fermentable carbohydrate restriction, data in Spain (Castilla La Mancha) have shown preva- namely the low fermentable oligosaccharides, disacchar- lence rates of 44.6 cases/100,000 people.26 Finally, ides, monosaccharides and polyols (FODMAP) diet, has prevalence rates in the United States have been been shown lately to be effective in controlling functional reported to be 56.7 cases/100,000 people, peaking in gastrointestinal symptoms, but not the underlying men 35–39 years old with a rate of 114.6/100,000 inflammation, in patients with IBD.20,21 people.27 764 United European Gastroenterology Journal 5(6)

Table 1. Main differences between eosinophilic esophagitis and Crohn’s disease.

First description as a 1993 1932 distinct entity Etiology Antigen-induced (mainly food) Uncertain Pathophysiology Anomalous Th2 response Anomalous Th1/Th17 response Extension Limited to the esophagus Entire GI tract Functional status Better Worse (usually without anemia, malnutrition, sys- (anemia, malnutrition, systemic manifest- temic manifestations, infectious complica- ations, infectious complication, surgical tion, surgeries, or drug toxicity) procedures, and drug toxicity may be common) Gender Male predominance (2–4:1) Slight female predominance Noninvasive markers of activity None yet Imaging studies/stool markers Extraintestinal manifestations To be defined Mainly musculoskeletal and dermatologic, less common hepatobiliary, ocular, renal and pulmonary. Therapy principles Locally acting anti-inflammatory drugs Systemically active immunomodulatory drugs Esophageal dilation for fibrostenotic findings (Æ combination with topical therapies) Surgery in case of complications Efficacy of dietary therapy Empiric elimination diet (mainly involving milk, Exclusive enteral nutrition can lead to disease wheat and eggs) can lead to disease remission in pediatric patients remission A low FODMAP diet may improve functional gastrointestinal symptoms Long-term clinical complications Esophageal strictures Intestinal strictures and fistulizing disease As of yet no increased risk for esophageal Increased risk for colorectal cancer and cancer demonstrated small bowel cancer Long-term drug-related Unknown yet for PPI and topical steroids Increased risk for lymphoproliferative disorders complications with thiopurines Increased melanoma and other skin cancer risk for patients under TNF-antagonists Increased risk for infectious diseases Side effects of systemic steroids

GI: gastrointestinal; FODMAP: fermentable oligosaccharides, disaccharides, monosaccharides and polyols; PPI: proton pump inhibitors; TNF: tumor necrosis factor.

Overall, incidence rates for EoE are coming steadily CD. EoE is becoming a global disease affecting children closer to that recently reported for CD in North and young adults who will suffer this chronic condition America,28 Europe,29 Spain30 and Switzerland31 (inci- for several decades, without reported complications or dence rates 9–20 cases per 100,000 people/year). Since mortality. Hence, similar and even higher prevalence CD was first described in 1932,32 prevalence rates rates to that of CD are likely expected for EoE in the (100–320 cases per 100,000 people) still remain higher next 10–20 years if current epidemiologic trends persist. compared to those in EoE.30,31 These epidemiological data are summarized in Table 3. Environmental risk factors Large numbers of EoE cases have been reported in North America, Western and Eastern Europe, and It is intriguing to speculate about why the incidence of Australia. Fewer cases have been reported in South EoE and, to a lesser extent CD, is increasing so rapidly America, Asia and the Middle East; cases from in Western countries, although these types of changes Northern Africa have recently been reported,33 and, usually indicate an environmental rather than a genetic as of yet, none in Sub-Saharan Africa or India.34 In cause. The hygiene hypothesis has been largely sug- contrast, CD has been reported worldwide, but the inci- gested as a potential cause of rising allergic and auto- dence and prevalence appear to be lower in Asia and immune disorders in industrialized countries.35 the Middle East.28 Collectively, we do believe that epi- Improved domestic hygiene and sanitation and smaller demiological figures of EoE will soon catch up with families with less-crowded living conditions might Molina-Infante et al. 765

Table 2. Potential similarities between eosinophilic esophagitis and Crohn’s disease.

Genetic basis and Susceptibility loci identified inheritance risk Family history Environmental risk factors Lack or non-exclusive use of breastfeeding Early exposure to repeat antibiotic therapy Westernized diet Epidemiology Rising incidence, more common in Western/Northern countries Affects predominantly pediatric and young adults Natural history Chronic disease, typically with intermittent relapsing symptoms Progression from inflammation to fibrostenotic remodeling Quality of life Impaired with symptom severity and dietary restrictions Improved with therapeutic interventions Depth of inflammation Transmural Phenotypes Inflammatory/fibrostenotic Disease activity assessment Clinical manifestations poorly predict biological activity Diagnosis Symptoms, endoscopic findings and histology Therapeutic management Induction and maintenance of remission Therapeutic goals Clinic, endoscopic and histologic remission (deep remission), but still lacking validated definitions in both entities. Resolution of fibrostenotic features Therapeutic modalities Medical/dietary therapy plus endoscopic dilation if required Therapeutic agents targeting Modest results, lack of response in all patients. selective interleukins in the inflammatory cascade Unsolved issues Predictors of treatment response Predictors of disease progression Monotherapy vs. combination therapy Do all patients need maintenance treatment? Maintenance therapy discontinuation: who and when? Challenges perceived by patients Lack of disease awareness and their relatives Lack of childhood and transition experts Lack of specialized multidisciplinary units Limited access to quality endoscopy Personalized treatments

Table 3. Incidence and prevalence rates of Crohn’s disease and eosinophilic esophagitis (EoE) in North America and Europe, including Switzerland and Spain.

Incidence Prevalence

Crohn’s disease EoE Crohn’s disease EoE

North America27,28 Up to 20/100,000 year Up to 11/100,000 year 200/100,000 56.7/100,000 Europe29 14/100,000 year – 322/100,000 – Castilla La Mancha, Spain26,30 8.9/100,000 year 6.37/100,000 year 137/100,000 44.6/100,000 Canton of Vaud, Switzerland25,31 Not determined 6.3/100,000 year 100.7/100,000 24.1/100,000 account for a lower exposure to infectious agents could theoretically affect the early-life microbiome have important for the development of immunoregulatory been associated both with EoE and CD. Lack or non- mechanisms. In this regard, an inverse association exclusive breastfeeding10,37–39 and early antibiotic between H. pylori infection and EoE has been sug- exposure40,41 have been consistently associated with gested.36 Interestingly, several early-life exposures that both diseases. As for EoE, cesarean delivery has also 766 United European Gastroenterology Journal 5(6) been identified as an early-life risk factor.40 Therefore, children do not suffer from dysphagia and food impac- markers of early altered esophageal/intestinal micro- tion, which nearly universally appears in adolescents biome may modulate the risk of EoE and CD later in and adults. Furthermore, dysphagia may depend not life. It is important to note that these interesting find- only on the existence of esophageal caliber abnormal- ings have not been replicated in some studies.41,42 All of ities or active mucosal inflammation, but also on the these concepts have paved the way for the development consistency of the ingested food and behavioral adap- of fecal microbiota transplantation as an effective tations, such as food avoidance, food modification, or therapy for a subset of patients with CD.43 Several dif- an altered eating pace. In spite of these considerations, ferences in the composition of the esophageal micro- most physicians still feel symptoms are strong pre- biome have been demonstrated in EoE as compared dictors of disease activity.49 In 2014, an international to healthy controls, and its pathogenic role is currently group of experts developed and validated the EoE being evaluated.44 activity index (EEsAI), a patient-reported outcome This incidence rise of both diseases in Western coun- (PRO) instrument to be used in adult patients that tries has been steadily followed in developing countries quantifies not only the difficulties foreseen by patients paralleling the increase of Westernized diets, character- in eating eight different food consistencies, but also ized by high protein and fat as well as excessive sugar dietary or behavioral modifications for the same food intake, with fewer vegetables and less fiber. The con- consistencies.50 Two years later, this instrument was sumption of caloric sweeteners in beverages, intake of evaluated in a multicenter multinational cohort of 269 fast food (pizza, hamburgers, snacks, beverages) adult EoE patients and compared to endoscopic and and wheat-containing foods (pasta, bread, cakes) has histologic assessment.51 Esophageal symptoms alone increased enormously over the past two decades and showed a quite modest predictive capacity for estimat- continues to grow, since away-from-home-foods and ing the presence of either histological or endoscopic snacks account for almost 50% of daily consumed remission in adult patients with EoE. Therefore, clin- food and energy.45 Noteworthy, this concept linking icians should not make assumptions about the bio- Western lifestyle and CD led to the application of the logical activity of EoE based exclusively on low FODMAP diet to CD.45 A recent meta-analysis symptoms, and endoscopy and biopsy for diagnosis has shown that high dietary intakes of polyunsatur- and monitoring of the disease continue to be neces- ated/omega-6 fatty acids and meat were associated sary.52 Regarding CD, commonly used activity scores with an increased risk of CD, whereas high fiber and are the Crohn’s Disease Activity Index (CDAI) and the fruit intakes were associated with decreased CD risk.46 Harvey-Bradshaw Index. The CDAI was developed in Exclusive enteral nutrition and a low FODMAP diet the 1970s to assess the degree of illness in individuals have recently been shown to be effective dietary inter- with CD and has since been used widely in clinical trials ventions for CD.19–21 Since oligosaccharides contained of the condition. The Harvey-Bradshaw Index is a sim- in fruits, cereals and vegetables exert a prebiotic effect plification of the CDAI, designed to make data collec- on the gastrointestinal microbiota, it seems conceivable tion and computation easier.53 Both have been that the effects of microbiota and diet are directly inter- extensively criticized for heavy weighting on subjective related in CD.47,48 As for EoE, it remains unknown clinical symptoms, besides not being specific to discrim- what has actually changed in cow’s milk, wheat and inate reliably functional symptoms related to specific eggs, which have been staple foods in Western countries irritable bowel syndrome, which may be common in for millennia. Changes in food sources, addition of patients with CD in remission.54 Conversely, it was antibiotics/fertilizers, genetic modifications to plant recently shown that half of the patients under and animal foodstuffs, drastic accelerated processing azathioprine and/or infliximab in clinical remission, of food supplies and plastic or synthetic food packaging according to CDAI score, had endoscopic and/or have all been proposed as potential causes.34 C-reactive protein evidence of residual active CD.55 The authors concluded that clinical symptoms scored Disease activity assessment by CDAI are not a reliable measure of the underlying biological activity of CD. As such, additional modalities By definition, EoE is a clinicopathological disease. Both such as biomarkers, endoscopy, or imaging should be clinical and pathologic information should be taken implemented to understand the full image of biological into consideration and neither of these parameters disease activity at baseline and during follow-up.56,57 should be interpreted in isolation.1 The development and validation of a symptom assessment instrument Quality of life for pediatric and adult EoE patients is a challenge for a number of reasons. Children may not be able to fully IBD is a chronic debilitating illness with a significant describe their symptoms and toddlers and small impact on the health status of children and young Molina-Infante et al. 767 adults. Intestinal and extra-intestinal disease activity, Therapeutic endpoints surgical interventions, drug-induced side effects and related psychosocial factors all adversely affect several The ideal treatment endpoints both for EoE and CD patient outcomes including quality of life, psycho- would be complete resolution of symptoms, endoscopic logical functioning and treatment adherence.58 findings, and histologic inflammation in order to pre- Patients also show diminished ability to undertake vent remodeling and related complications.18,66,67 household and social activities; furthermore, recent stu- Lately, mucosal healing (endoscopic remission) and dies suggest that 9% to 19% of patients with CD suffer deep remission (clinical, biologic, endoscopic and histo- from short-term absences from work and 19% to 22% logic remission) have been associated with improved are on long-term disability.59 Enormous efforts have outcomes in CD, and consequently, are currently rec- been made over the past decade to overcome the most ommended as therapeutic targets.68 The lack of vali- common challenges perceived by patients and their dated definitions, however, for symptom, endoscopic relatives: lack of awareness of the disease, lack of multi- and histologic remission both in EoE and CD consti- disciplinary and specialized clinics, lack of experts on tutes a major challenge. A panel of experts recently childhood-onset IBD and transition from pediatric to defined clinical remission in CD as resolution of adult care, difficulties in bathroom access, limited abdominal pain and diarrhea/altered bowel habit, access to skilled psychologists, dietitians and IBD whereas endoscopic remission was defined as resolution experts, as well as open discussions of personalized of ulceration at ileocolonoscopy or finding of inflam- treatments.60,61 mation on cross-sectional imaging.69 No consensus is As for EoE, evolving evidence has lately highlighted available on histologic remission yet.70 Regarding EoE, that symptom severity, biological disease activity and the precise clinical (resolution of dysphagia?, what dietary therapy negatively influence patient quality of score to use?, what about other symptoms?) and histo- life, which is improved during the course of evaluation logic (no eosinophilic inflammation?, < 5 eos/high- and treatment.11,12,62 Therefore, reducing symptoms, power field (HPF)?, < 15 eos/HPF?) targets for EoE esophageal inflammation, optimizing dietary restric- should also be a matter of debate. tions, and close monitoring of patients might be key for improvement of quality of life. Therapeutic management

Natural history The choice of therapy both for EoE and CD will vary depending on the anatomic location of disease (only for EoE and CD both are chronic and progressive diseases, CD), the severity of the disease, phenotype, comorbid- and in some patients persistent transmural inflamma- ities, individual characteristics of the drug and patient, tion with subsequent tissue remodeling results in fibros- local expertise, costs and the ultimate goal of therapy tenotic stricturing. In EoE, untreated symptoms and (i.e. induction or maintenance of remission).18,66,67 inflammation can remain over years because of diag- Both diseases have an induction phase, in which the nostic delay,63 and there is a high likelihood of recur- condition is brought under control, and a maintenance rence after discontinuing any modality of treatment.1 phase, in which the main goals are preventing flares by Two recent studies nicely showed that the prevalence of keeping patients in remission, thereby restoring their esophageal strictures correlates with the duration of quality of life. The therapeutic armamentarium for untreated disease.13,14 Furthermore, subepithelial both diseases includes dietary, pharmacologic and fibrous remodeling significantly increases with age.64 endoscopic interventions. Drugs and dietary changes As for CD, approximately 80% of patients have small target the inflammation associated with the disease bowel involvement (30% distal ileitis, 50% ileocolitis), pathogenesis, whereas endoscopic dilation treats 20% have disease limited to the colon and 5% predom- fibrous remodeling and complications, but has no inant involvement of the upper gastrointestinal tract. effect on underlying inflammation.66,67 The typical course in patients with CD involving the A further frustrating commonality between EoE and small and/or large intestine is one of intermittent CD is the lack of response in all patients when attempt- exacerbation of symptoms followed by periods of ing to target specific interleukins (IL) within the inflam- remission. Almost 20% of patients progress to a more matory cascade with biologic therapies. Despite aggressive phenotype at 90 days of diagnosis and 50% potentially sound theoretical mechanisms of action will eventually develop a stricturing or fistulizing com- and initially promising data, many biologic drugs tar- plication 20 years after initial diagnosis, especially when geting ILs have failed both in EoE (IL-5, IL-13)15 and ileal and perianal disease were present at the time of CD (IL-10).71 Possibly, the lack of a final common diagnosis.18 More specifically, strictures may occur in inflammatory pathway likely inhibits yielding complete one of three patients within 10 years of diagnosis.65 response. Both conditions encompass a heterogeneous 768 United European Gastroenterology Journal 5(6) group of patients with variable disease courses. A road- synergistically enhance an anti-inflammatory map for personalized disease treatment, based on gen- response,78 or if sustained histologic remission may etic susceptibility, genotype-phenotype concordance, alter the natural history of the disease. Like in CD, biomarkers, drug monitoring and microbial data, is switching drug classes or from medications to diet currently under development for CD,72,73 and so might also be feasible, as lately shown by two series should be in the foreseeable future for EoE. of patients with esophageal symptoms and eosinophilia that responded not only to PPI therapy, but also to Induction therapy. This treatment phase aims to achieve diet/topical steroid therapy, and vice versa.79,80 symptoms and endoscopic remission (CD) and symp- Maintenance therapy and its unsolved issues in EoE tom and histologic remission (EoE). In the majority of have correlates in CD. Medical therapies are intended EoE patients, a PPI should still be considered first, with to modify the underlying disease process, in the hope of dietary therapy or swallowed topical corticosteroids achieving biologic remission and preventing harmful used if there is no PPI response.66,67 Patients with complications. Mainly since 2013,81 endoscopic muco- severe fibrostenotic EoE or malnutrition at onset sal healing has been incorporated as a primary or sec- might be better treated with potent anti-inflammatory ondary long-term endpoint in therapeutic algorithms. drugs (i.e. swallowed topical corticosteroids).1,66,67 A A recent meta-analysis has shown that mucosal healing follow-up endoscopy after an initial six- to eight-week predicts long-term clinical remission and fewer hospi- course of therapy should be carried out to document talizations and surgeries.82 On the other hand, super- histologic response.66 Regarding CD, a fast-acting iority of combination therapies with thiopurines and short-term agent (i.e. steroids or anti-tumor necrosis TNF blockers for improved symptom control and factor (TNF)) is used to achieve rapid symptom mucosal healing should be balanced with the increased relief.18 Monitoring of treatment efficacy is usually risk of infectious and malignant complications. assessed by means of changes in symptom scores, non- A recent systematic review showed that more than invasive biomarkers (serum reactive C protein and fecal 50% of patients with IBD who discontinued an immu- calprotectin), endoscopy and imaging techniques (e.g. nomodulator after combination therapy had a disease magnetic resonance enterography).57,74,75 relapse.83 Therefore, accurate identification of subgroups of patients who are good candidates for discon- Maintenance therapy. The choice of a long-term interven- tinuation of treatment is required. Switching drug tion for maintenance therapy should aim to balance classes or agents is common in CD for a number of efficacy with side effects and complications within a reasons like primary non-response, loss of response, given individual. For instance, dietary therapy in EoE insufficient efficacy (i.e. absence of mucosal healing), may not be a good choice in patients with a pre-existing and intolerance or unacceptable side effects.18 The opti- restrictive diet because of multiple food allergies or with mal duration of maintenance therapy is unclear yet, predictable poor compliance, but it can be evaluated in and studies are needed to identify subgroups of patients patients unwilling to take long-term medications. in whom treatment can be discontinued. Likewise, methotrexate in CD might be a poor choice for a patient of childbearing age or with pre-existing Treatment of stricturing disease. Endoscopic dilation can liver disease, but can be an excellent option for a offer symptomatic response in case of stricturing EoE patient with CD and arthropathy. and CD. However, repeated dilations are often needed, Maintenance therapy in EoE must be considered for and long-term outcomes of endoscopic balloon dilation all patients, but particularly in those with severe dys- remain to be investigated.84,85 Topical steroids and diet- phagia or food impaction, high-grade esophageal stric- ary therapy in EoE have shown their ability to reverse ture, and rapid symptomatic/histologic relapse subepithelial fibrosis.64,86,87 Whether medical/dietary following initial therapy.1,66,67 However, there is con- therapy can be effective coadjuvant treatments for dila- troversy about whether treatments should be continued tion or after dilation in EoE is yet to be determined. indefinitely, particularly in light of the potential side Likewise, the role of medical therapy in stricturing CD effects and limited long-term data. In contrast to CD, is controversial. Differentiating inflammatory from a trend toward tapering maintenance doses for PPI and fibrotic strictures remains challenging. Medical therapy topical steroids is evident in EoE.76,77 Whether drug with biologics may play a role in CD stricture with an doses for EoE may be used like in CD, not changing inflammatory component and/or concurrent inflamma- what works for a patient from induction to mainten- tion adjacent to the stricture area. Although biological ance, should be clarified. It also remains unclear when therapy may reduce the risk for the formation of stric- long-term endoscopic monitoring of disease activity tures from mucosal inflammation, rapid mucosal heal- should be performed (every year, three or five years), ing from potent biological agents may predispose whether combination therapy may potentially and patients to the development of new strictures or Molina-Infante et al. 769 worsening of existing strictures.85 Additionally, there is 7. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic no clear evidence about the efficacy of postdilation esophagitis: Updated consensus recommendations for medical therapy to prevent recurrence of strictures.85 children and adults. J Allergy Clin Immunol 2011; 128: 3–20. 8. Dellon ES, Gonsalves N, Hirano I, et al. ACG Conclusions and research agenda clinical guideline: Evidence based approach to the diagnosis and management of esophageal eosinophilia and Through a relevant number of comparisons between eosinophilic esophagitis. Am J Gastroenterol 2013; 108: EoE and CD, this review paper underscores salient fea- 679–692. tures, and unmet diagnostic and therapeutic needs, that 9. Collins MH, Blanchard C, Abonia JP, et al. Clinical, may be common for both disorders. Like in CD, the pathologic, and molecular characterization of familial upcoming research agenda for EoE should be oriented eosinophilic esophagitis compared with sporadic cases. to fill diagnostic gaps, mainly measuring disease activity Clin Gastroenterol Hepatol 2008; 6: 621–629. and deep remission, and pursue personalized treat- 10. Alexander ES, Martin LJ, Collins MH, et al. Twin and ments reversing the progressive natural history of the family studies reveal strong environmental and weaker disease, by means of increasing our knowledge of risk genetic cues explaining heritability of eosinophilic factors for progression, adequate identification of esophagitis. J Allergy Clin Immunol 2014; 134: 1084–1092.e1. phenotypes, genotype-phenotype concordance, drug 11. Franciosi JP, Hommel KA, Bendo CB, et al. PedsQL doses and monitoring, and esophageal microbiome eosinophilic esophagitis module: Feasibility, reliability, data. All these data will allow us to better predict out- and validity. J Pediatr Gastroenterol Nutr 2013; 57: comes for individual patients and to precisely tailor 57–66. therapy. 12. Safroneeva E, Coslovsky M, Kuehni CE, et al. Eosinophilic oesophagitis: Relationship of quality of life with clinical, endoscopic and histological activity. Declaration of conflicting interests Aliment Pharmacol Ther 2015; 42: 1000–1010. The authors declared no potential conflicts of interest with 13. Schoepfer AM, Safroneeva E, Bussmann C, et al. Delay respect to the research, authorship, and/or publication of this in diagnosis of eosinophilic esophagitis increases risk for article. stricture formation in a time-dependent manner. Gastroenterology 2013; 145: 1230–1236. 14. Dellon ES, Kim HP, Sperry SL, et al. A phenotypic ana- Funding lysis shows that eosinophilic esophagitis is a progressive The authors received no financial support for the research, fibrostenotic disease. Gastrointest Endosc 2014; 79: authorship, and/or publication of this article. 577–585. 15. Lucendo AJ and Molina-Infante J. Emerging therapeutic strategies for eosinophilic esophagitis. Curr Treat Options References Gastroenterol 2014; 12: 1–17. 1. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic 16. Arias A, Gonza´lez-Cervera J, Tenias JM, et al. Efficacy esophagitis: Updated consensus recommendations for of dietary interventions for inducing histologic remission children and adults. J Allerg Clin Immunol 2011; 128: in patients with eosinophilic esophagitis: A systematic 3–10. review and meta-analysis. Gastroenterology 2014; 146: 2. Attwood SE, Smyrk TC, Demeester TR, et al. Esophageal 1639–1648. eosinophilia with dysphagia. A distinct clinicopathologic 17. Rothenberg ME. Molecular, genetic, and cellular bases syndrome. Dig Dis Sci 1993; 38: 109–116. for treating eosinophilic esophagitis. Gastroenterology 3. Straumann A, Spichtin HP, Bernoulli R, et al. Idiopathic 2015; 148: 1143–1157. eosinophilic esophagitis: A frequently overlooked disease 18. Baumgart DC and Sandborn WJ. Crohn’s disease. Lancet with typical clinical aspects and discrete endoscopic find- 2012; 380: 1590–1605. ings [article in German]. Schweiz Med Wochenschr 1994; 19. Penagini F, Dilillo D, Borsani B, et al. Nutrition in pedi- 124: 1419–1429. atric inflammatory bowel disease: From etiology to treat- 4. Spechler SJ, Genta RM and Souza RF. Thoughts on the ment. A systematic review. Nutrients 2016; 8: 6. complex relationship between gastroesophageal reflux dis- 20. Gearry RB, Irving PM, Barrett JS, et al. Reduction of ease and eosinophilic esophagitis. Am J Gastroenterol dietary poorly absorbed short-chain carbohydrates 2007; 102: 1301–1306. (FODMAPs) improves abdominal symptoms in patients 5. Morrow JB, Vargo JJ, Goldblum JR, et al. The ringed with inflammatory bowel disease—a pilot study. J Crohns esophagus: Histological features of GERD. Am J Colitis 2009; 3: 8–14. Gastroenterol 2001; 96: 984–989. 21. Prince AC, Myers CE, Joyce T, et al. Fermentable 6. Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic carbohydrate restriction (low FODMAP diet) in clinical esophagitis in children and adults: A systematic review and practice improves functional gastrointestinal symptoms consensus recommendations for diagnosis and treatment. in patients with inflammatory bowel disease. Inflamm Gastroenterology 2007; 133: 1342–1363. Bowel Dis 2016; 22: 1129–1136. 770 United European Gastroenterology Journal 5(6)

22. Peterson K, Firszt R, Fang J, et al. Risk of autoimmunity 38. Guo AY, Stevens BW, Wilson RG, et al. Early life envir- in EoE and families: A population-based cohort study. onment and natural history of inflammatory bowel dis- Am J Gastroenterol 2016; 111: 926–932. eases. BMC Gastroenterol 2014; 14: 216. 23. Jostins L, Ripke S, Weersma RK, et al. Host-microbe 39. Ng SC, Tang W, Leong RW, et al. Environmental risk interactions have shaped the genetic architecture factors in inflammatory bowel disease: A population- of inflammatory bowel disease. Nature 2012; 491: based case-control study in Asia-Pacific. Gut 2015; 64: 119–124. 1063–1071. 24. AriasA´,Pe´rez-Martıńez I, Tenıás JM, et al. Systematic 40. Jensen ET, Kappelman MD, Kim HP, et al. Early life review with meta-analysis: The incidence and prevalence exposures as risk factors for pediatric eosinophilic of eosinophilic oesophagitis in children and adults in esophagitis. J Pediatr Gastroenterol Nutr 2013; 57: 67–71. population-based studies. Aliment Pharmacol Ther 2016; 41. Ungaro R, Bernstein CN, Gearry R, et al. Antibiotics 43: 3–15. associated with increased risk of new-onset Crohn’s dis- 25. Giriens B, Yan P, Safroneeva E, et al. Escalating inci- ease but not ulcerative colitis: A meta-analysis. Am dence of eosinophilic esophagitis in Canton of Vaud, J Gastroenterol 2014; 109: 1728–1738. Switzerland, 1993–2013: A population-based study. 42. Slae M, Persad R, Leung AJ, et al. Role of environmental Allergy 2015; 70: 1633–1639. factors in the development of pediatric eosinophilic 26. Arias A and Lucendo AJ. Prevalence of eosinophilic esophagitis. Dig Dis Sci 2015; 60: 3364–3372. oesophagitis in adult patients in a central region of 43. Colman RJ and Rubin DT. Fecal microbiota transplant- Spain. Eur J Gastroenterol Hepatol 2013; 25: 208–212. ation as therapy for inflammatory bowel disease: A sys- 27. Dellon ES, Jensen ET, Martin CF, et al. Prevalence of tematic review and meta-analysis. J Crohns Colitis 2014; eosinophilic esophagitis in the United States. Clin 8: 1569–1581. Gastroenterol Hepatol 2014; 12: 589–596.e1. 44. Dellon ES. The esophageal microbiome in eosinophilic 28. Molodecky NA, Soon IS, Rabi DM, et al. Increasing esophagitis. Gastroenterology 2016; 151: 364–365. incidence and prevalence of the inflammatory bowel dis- 45. Gibson PR and Shepherd SJ. Personal view: Food for eases with time, based on systematic review. thought—western lifestyle and susceptibility to Crohn’s disease. The FODMAP hypothesis. Aliment Pharmacol Gastroenterology 2012; 142: 46–54. Ther 2005; 21: 1399–1409. 29. Vegh Z, Burisch J, Pedersen N, et al. Incidence and initial 46. Hou JK, Abraham B and El-Serag H. Dietary intake and disease course of inflammatory bowel diseases in 2011 in risk of developing inflammatory bowel disease: A system- Europe and Australia: Results of the 2011 ECCO- atic review of the literature. Am J Gastroenterol 2011; EpiCom inception cohort. J Crohns Colitis 2014; 8: 106: 563–573. 1506–1515. 47. Gibson PR, Varney J, Malakar S, et al. Food compo- 30. Lucendo AJ, Hervıás D, RonceroO´, et al. Epidemiology nents and irritable bowel syndrome. Gastroenterology and temporal trends (2000–2012) of inflammatory bowel 2015; 148: 1158–1174. disease in adult patients in a central region of Spain. Eur 48. Serban DE. Microbiota in inflammatory bowel disease J Gastroenterol Hepatol 2014; 26: 1399–1407. pathogenesis and therapy: Is it all about diet? Nutr Clin 31. Juillerat P, Pittet V, Bulliard JL, et al. Prevalence of Pract 2015; 30: 760–779. inflammatory bowel disease in the Canton of Vaud 49. Schoepfer AM, Panczak R, Zwahlen M, et al. How do (Switzerland): A population-based cohort study. gastroenterologists assess overall activity of eosinophilic J Crohns Colitis 2008; 2: 131–141. esophagitis in adult patients? Am J Gastroenterol 2015; 32. Crohn BB, Ginzburg L and Oppeheimer GD. Regional 110: 402–414. ileitis: A pathologic and clinical entity. 1932. Mt Sinai 50. Schoepfer AM, Straumann A, Panczak R, et al. J Med 2000; 67: 263–268. Development and validation of a symptom-based activity 33. Hunter SS, Helmy DO, Zayedl NA, et al. Eosinophilic index for adults with eosinophilic esophagitis. esophagitis in Egyptian adult patients presenting with Gastroenterology 2014; 147: 1255–1266. upper gastrointestinal symptoms. Open J Gastroenterol 51. Safroneeva E, Straumann A, Coslovsky M, et al. 2014; 4: 88–95. Symptoms have modest accuracy in detecting endoscopic 34. Dellon ES. Epidemiology of eosinophilic esophagitis. and histologic remission in adults with eosinophilic Gastroenterol Clin North Am 2014; 43: 201–218. esophagitis. Gastroenterology 2016; 150: 581–590. 35. Bach JF. The effect of infections on susceptibility to auto- 52. Lucendo AJ and Molina-Infante J. Limitation of symp- immune and allergic diseases. N Engl J Med 2002; 347: toms as predictors of remission in eosinophilic esopha- 911–920. gitis: The need to go beyond endoscopy and histology. 36. Dellon ES, Peery AF, Shaheen NJ, et al. Inverse associ- Gastroenterology 2016; 150: 547–549. ation of esophageal eosinophilia with Helicobacter pylori 53. Best WR. Predicting the Crohn’s disease activity index based on analysis of a US pathology database. from the Harvey-Bradshaw Index. Inflamm Bowel Dis Gastroenterology 2011; 141: 1586–1592. 2006; 12: 304–310. 37. Barclay AR, Russell RK, Wilson ML, et al. Systematic 54. Teruel C, Garrido E and Mesonero F. Diagnosis and review: The role of breastfeeding in the development of management of functional symptoms in inflammatory pediatric inflammatory bowel disease. J Pediatr 2009; bowel disease in remission. World J Gastrointest 155: 421–426. Pharmacol Ther 2016; 7: 78–90. Molina-Infante et al. 771

55. Peyrin-Biroulet L, Reinisch W, Colombel JF, et al. 70. Bryant RV, Winer S, Travis SP, et al. Systematic review: Clinical disease activity, C-reactive protein normalisation Histological remission in inflammatory bowel disease. Is and mucosal healing in Crohn’s disease in the SONIC ‘complete’ remission the new treatment paradigm? An trial. Gut 2014; 63: 88–95. IOIBD initiative. J Crohns Colitis 2014; 8: 1582–1597. 56. Van Assche G, Dignass A, Panes J, et al. The second 71. Buruiana FE, Sola` I and Alonso-Coello P. Recombinant European evidence-based consensus on the diagnosis human interleukin 10 for induction of remission in and management of Crohn’s disease: Definitions and Crohn’s disease. Cochrane Database Syst Rev 2010; 11: diagnosis. J Crohns Colitis 2010; 4: 7–27. CD005109. 57. Pane´s J, Bouzas R, Chaparro M, et al. Systematic review: 72. Cleynen I, Boucher G, Jostins L, et al. Inherited deter- The use of ultrasonography, computed tomography and minants of Crohn’s disease and ulcerative colitis pheno- magnetic resonance imaging for the diagnosis, assessment types: A genetic association study. Lancet 2016; 387: of activity and abdominal complications of Crohn’s dis- 156–167. ease. Aliment Pharmacol Ther 2011; 34: 125–145. 73. Kingsley MJ and Abreu MT. A personalized approach to 58. Taft TH and Keefer L. A systematic review of disease- managing inflammatory bowel disease. Gastroenterol related stigmatization in patients living with inflamma- Hepatol (N Y) 2016; 12: 308–315. tory bowel disease. Clin Exp Gastroenterol 2016; 9: 49–58. 74. D’Haens G, Ferrante M, Vermeire S, et al. Fecal calpro- 59. Bu¨sch K, Sonnenberg A and Bansback N. Impact of tectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease on disability. Curr inflammatory bowel disease. Inflamm Bowel Dis 2012; Gastroenterol Rep 2014; 16: 414. 18: 2218–2224. 60. Bray J, Fernandes A, Nguyen GC, et al. The challenges 75. Church PC, Turner D, Feldman BM, et al. Systematic of living with inflammatory bowel disease: Summary of a review with meta-analysis: Magnetic resonance entero- summit on patient and healthcare provider perspectives. graphy signs for the detection of inflammation and intes- Can J Gastroenterol Hepatol 2016; 2016: 9430942. tinal damage in Crohn’s disease. Aliment Pharmacol Ther 61. Varni JW, Franciosi JP, Shulman RJ, et al. PedsQL 2015; 41: 153–166. gastrointestinal symptoms scales and gastrointestinal 76. Straumann A, Conus S, Degen L, et al. Long-term bude- worry scales in pediatric patients with inflammatory sonide maintenance treatment is partially effective for bowel disease in comparison with healthy controls. patients with eosinophilic esophagitis. Clin Gastroenterol Inflamm Bowel Dis 2015; 21: 1115–1124. Hepatol 2011; 9: 400–409. 62. Klinnert MD, Silveira L, Harris R, et al. Health-related 77. Molina-Infante J, Rodriguez-Sanchez J, Martinek J, et al. quality of life over time in children with eosinophilic Long-term loss of response in proton pump inhibitor- esophagitis and their families. J Pediatr Gastroenterol responsive esophageal eosinophilia is uncommon and Nutr 2014; 59: 308–316. influenced by CYP2C19 genotype and rhinoconjunctivi- 63. Straumann A, Spichtin HP, Grize L, et al. Natural his- tis. Am J Gastroenterol 2015; 110: 1567–1575. tory of primary eosinophilic esophagitis: A follow-up of 78. Zhang X, Huo X, Yu C, et al. Omeprazole and flutica- 30 adult patients for up to 11.5 years. Gastroenterology sone inhibit IL-13-stimulated eotaxin-3 expression by 2003; 125: 1660–1669. 64. Lucendo AJ, Arias A, De Rezende LC, et al. esophageal epithelial cells through different mechanisms Subepithelial collagen deposition, profibrogenic cytokine and with additive effects: Rationale for combining PPIs gene expression, and changes after prolonged fluticasone with topical steroids for EoE patients. Gastroenterology propionate treatment in adult eosinophilic esophagitis: A 2015; 148(Suppl 1): S–51. prospective study. J Allergy Clin Immunol 2011; 128: 79. Sodikoff J and Hirano I. Proton pump inhibitor-respon- 1037–1046. sive esophageal eosinophilia does not preclude food- 65. Cosnes J, Cattan S, Blain A, et al. Long-term evolution of responsive eosinophilic esophagitis. J Allergy Clin disease behavior of Crohn’s disease. Inflamm Bowel Dis Immunol 2016; 137: 631–633. 2002; 8: 244–250. 80. Lucendo AJ, Arias A, Gonzalez-Cervera J, et al. Dual 66. Molina-Infante J and Lucendo AJ. Eosinophilic esopha- response to dietary/topical steroid and PPI therapy in gitis: A practical approach to diagnosis and management. adult patients with eosinophilic esophagitis. J Allergy Expert Rev Gastroenterol Hepatol 2014; 8: 925–934. Clin Immunol 2016; 137: 931–934. 67. Dellon ES and Liacouras CA. Advances in clinical man- 81. Ferrante M, Colombel JFF, Sandborn WJ, et al. agement of eosinophilic esophagitis. Gastroenterology Validation of endoscopic activity scores in patients with 2014; 147: 1238–1254. Crohn’s disease based on a post hoc analysis of data from 68. Pineton de Chambrun G, Blanc P and Peyrin-Biroulet L. SONIC. Gastroenterology 2013; 145: 978–986.e5. Current evidence supporting mucosal healing and deep 82. Reinink AR, Lee TC and Higgins PD. Endoscopic muco- remission as important treatment goals for inflammatory sal healing predicts favorable clinical outcomes in inflam- bowel disease. Expert Rev Gastroenterol Hepatol 2016; 10: matory bowel disease: A meta-analysis. Inflamm Bowel 915–927. Dis 2016; 22: 1859–1869. 69. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. 83. Torres J, Boyapati RK, Kennedy NA, et al. Systematic Selecting Therapeutic Targets in Inflammatory Bowel review of effects of withdrawal of immunomodulators or Disease (STRIDE): Determining therapeutic goals for biologic agents from patients with inflammatory bowel treat-to-target. Am J Gastroenterol 2015; 110: 1324–1338. disease. Gastroenterology 2015; 149: 1716–1730. 772 United European Gastroenterology Journal 5(6)

84. Runge TM, Eluri S, Cotton CC, et al. Outcomes of 86. Kagalwalla AF, Akhtar N, Woodruff SA, et al. Eosinophilic esophageal dilation in eosinophilic esophagitis: Safety, esophagitis: Epithelial mesenchymal transition contributes efficacy, and persistence of the fibrostenotic phenotype. to esophageal remodeling and reverses with treatment. J Am J Gastroenterol 2016; 111: 206–213. Allergy Clin Immunol 2012; 129: 1387–1396. 85. Bharadwaj S, Fleshner P and Shen B. Therapeutic arma- 87. Lieberman JA, Morotti RA, Konstantinou GN, et al. mentarium for stricturing Crohn’s disease: Medical Dietary therapy can reverse esophageal subepithelial versus endoscopic versus surgical approaches. Inflamm fibrosis in patients with eosinophilic esophagitis: A his- Bowel Dis 2015; 21: 2194–2213. torical cohort. Allergy 2012; 67: 1299–1307.