technical review on the management of …...1 1 technical review on the management of eosinophilic...

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Technical Review on the Management of Eosinophilic Esophagitis: A report from 1 the American Gastroenterological Association Institute and the Joint Task Force 2 on Allergy-Immunology Practice Parameters 3 4 Matthew A. Rank MD1 * 5 Ravi N. Sharaf MD, MS2 * 6 Glenn T. Furuta MD3 7 Seema A. Aceves, MD, PhD4 8 Matthew Greenhawt, MD, MSc, MBA5 9 Jonathan M. Spergel, MD, PhD6 10 Yngve T. Falck-Ytter, MD7 * 11 Evan S. Dellon MD MPH8 * 12 13 Collaborators: Bernstein JA9, Dinakar C10 , Golden DBK11, Khan DA12, Lieberman J13, 14 Oppenheimer J14, Shaker M15, Stukus DR16, Wallace DV17, Wang J18 15 16 *These authors have contributed equally to this report. 17 1Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic, Scottsdale, AZ; 18 2Division of Gastroenterology, Donald and Barbara Zucker School of Medicine at 19 Hofstra/Northwell, Manhasset, NY; 3 Digestive Health Institute, Children’s Hospital 20 Colorado, Gastrointestinal Eosinophilic Diseases Program and University of Colorado 21 School of Medicine, Aurora, CO;4Division of Allergy Immunology Center for Immunity, 22 Infection, and Inflammation, University of California, San Diego Rady Children's 23 Hospital, San Diego, CA; 5 Section of Allergy/Immunology, Children’s Hospital Colorado, 24 University of Colorado School of Medicine, Aurora, CO; 6 Division of Allergy-25 Immunology, Children’s Hospital of Philadelphia, Perelman School of Medicine at 26 University of Pennsylvania, Philadelphia, PA; 7Division of Gastroenterology and 27 Hepatology, Cleveland VA Medical Center and University Hospitals, Case Western 28 Reserve University School of Medicine, Cleveland, OH; 8 Center for Esophageal 29 Diseases and Swallowing, Division of Gastroenterology and Hepatology, University of 30 North Carolina School of Medicine, Chapel Hill, NC 9 Department of Internal Medicine, 31 University of Cincinnati College of Medicine, Cincinnati, OH; 10 Division of Allergy and 32 Asthma, Stanford University School of Medicine, Palo Alto, CA; 11 Department of Medicine, 33 Johns Hopkins University, Baltimore, MD; 12 Division of Allergy & Immunology, Department 34 of Medicine, University of Texas Southwestern Medical Center, Dallas, TX; 13 Division of 35 Allergy and Immunology, The University of Tennessee Health Science Center, LeBonheur 36 Children’s Hospital, Memphis, TN; 14 Department of Internal Medicine, New Jersey Medical 37 School, Morristown, NJ; 15 Section of Allergy and Immunology, Dartmouth-Hitchcock Medical 38 Center and Dartmouth Geisel School of Medicine, Lebanon and Hanover, NH; 16Division of 39 Allergy and Immunology, Nationwide Children's Hospital and The Ohio State University 40 College of Medicine, Columbus, OH 17 Department of Medicine, Nova Southeastern University, 41 Davie, FL; 18 Division of Allergy and Immunology, Department of Pediatrics, The Elliot and 42

Formatted: Numbering: Continuous

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Roslyn Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, Kravis Children’s 43 Hospital, New York NY.44 45 46 47 Addresses for Correspondence: 48 Chair, Clinical Guidelines Committee, 49 American Gastroenterological Association 50 National Office, 4930 Del Ray Avenue, 51 Bethesda, Maryland 20814. 52 E-mail: ***gastro.org 53 Telephone: (301) 941-2618. 54 55 Joint Task Force on Allergy-Immunology Practice Parameters 56 555 E Wells Street , Suite 1100 57 Milwaukee, WI 53212 58 Email: [email protected] 59 60 61 Manuscript Word Count: 62 References: 116 63 Tables and Figures: 64 eTables and eFigures (in the supplement): 4 and 2 65 66 Keywords: Technical Review; eosinophilic esophagitis; proton pump inhibitor; 67 swallowed corticosteroids; corticosteroids; dietary therapy; elimination diet; elemental 68 diet; targeted elimination diet; biologic therapy; esophageal dilation 69 70 Disclosures and Conflicts of Interest: Conflict of interest disclosure: All members 71 were required to complete disclosure statement. These statements are maintained at 72 the American Gastroenterological Association Institute (AGA) headquarters in 73 Bethesda, Maryland and the Joint Task Force for Allergy-Immunology Practice 74 Parameters in Milwaukee, WI and pertinent disclosure are published with the report. 75 76 Dr. Rank is supported by the Robert E. and Patricia D. Kern Center for the Science of 77 Healthcare Delivery at Mayo Clinic and the Levin Family Foundation. Dr. Sharaf is 78 supported by the National Cancer Institute NCI 1K07CA216326-01A1 and NCI R01 79 1R01CA211723-01A1. Dr. Furuta is supported by the LaCache Chair from Children’s 80 Hospital Colorado 1K24DK100303 (FurutaGT) and Consortium for Gastrointestinal 81 Eosinophilic Researchers (CEGIR). CEGIR (U54 AI117804) is part of the Rare 82 Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare 83 Diseases Research (ORDR), NCATS, and is funded through collaboration between 84 NIAID, NIDDK, and NCATS and APFED, CURED and EFC. Dr. Aceves is supported by 85 R01, K24 AI, NIAID, and Consortium for Gastrointestinal Eosinophilic Researchers 86 (CEGIR). CEGIR (U54 AI117804) is part of the Rare Diseases Clinical Research 87 Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), 88

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NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS and 89 APFED, CURED and EFC. Dr. Greenhawt is supported by grant #5K08HS024599-02 90 from the Agency for Healthcare Quality and Research. Dr. Spergel is supported by the 91 Consortium for Gastrointestinal Eosinophilic Researchers (CEGIR). CEGIR (U54 92 AI117804) is part of the Rare Diseases Clinical Research Network (RDCRN), an 93 initiative of the Office of Rare Diseases Research (ORDR), NCATS, and is funded 94 through collaboration between NIAID, NIDDK, and NCATS and APFED, CURED and 95 EFC and Stuart Starr Chair of Pediatrics. Dr. Dellon is supported by National Institutes 96 of Health grant R01DK101856. 97 98 Acknowledgements: We sincerely thank Kellee Kaulbeck, HBA, MISt for assistance 99 with the medical information search and Stephanie Stanford of the American 100 Gastroenterology Association and Natalie Aumann of the Joint Task Force for Allergy-101 Immunology Practice Parameters for administrative support. We sincerely thank the 102 following investigators for sharing unpublished data from their studies: Jeff Alexander 103 and Fred Clayton. 104 105 Abbreviations used in this paper: APT, atopy patch test; CI, confidence interval; 106 CRD, component-resolved diagnostic; EGD, esophagogastroduodenoscopy; EoE, 107 eosinophilic esophagitis; GERD, gastroesophageal reflux disease; GRADE, Grading of 108 Recommendations Assessment, Development, and Evaluation; HPF, high-powered 109 field; ITT, intention-to-treat; LR, likelihood ratio; OR, odds ratio; PICO, population, 110 intervention, comparator, and outcome; PPI, proton pump inhibitor; RCT, randomized 111 control trial; RR, risk ratio; sIgE, specific IgE testing in serum; SPT, skin prick testing 112 113 ABSTRACT 114 115 Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. 116 Many new studies have been reported recently that describe EoE management. An 117 expert panel was convened by the American Gastroenterological Association Institute 118 and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a 119 technical report to be used as the basis for an updated clinical guideline. This technical 120 review was developed using the Grading of Recommendations Assessment, 121 Development, and Evaluation (GRADE) framework. Eighteen focused EoE 122 management questions were considered, with 15 answered using the GRADE 123 framework and 3 with a narrative summary. There is moderate certainty in the evidence 124 that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to 125 <15/hpf over a short-term treatment period of 4-12 weeks, but very low certainty about 126 the effects of using topical glucocorticosteroids as maintenance therapy. Multiple 127 dietary strategies may be effective in reducing esophageal eosinophil counts to <15/hpf 128 over a short-term treatment period, with moderate certainty for elemental diets, low 129 certainty for empiric 2,4 and 6 food elimination diets, and very low certainty that allergy-130 based testing dietary eliminations have a higher failure rate compared to empiric diet 131 elimination. There is very low certainty for the effect of PPIs in patients with esophageal 132 eosinophilia. Although esophageal dilation appears to be relatively safe there is no 133 evidence that it reduces esophageal eosinophil counts. There is very low certainty in 134

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the effects of multiple other medical treatments for EoE: anti-IL-5 therapy, anti-IL-13 135 therapy, anti-IgE therapy, montelukast, cromolyn, and anti-TNF therapy. 136 137 INTRODUCTION 138 139 Eosinophilic esophagitis (EoE) is a chronic rare inflammatory condition of the 140 esophagus that is estimated to affect 1 in every 2000 people.(1) The incidence of EoE 141 is increasing. EoE can occur in children and adults and is more common in Whites, 142 males, and is associated with other atopic diseases. EoE negatively impacts the quality 143 of life for patients and their families. Medical resource utilization costs in EoE may be 144 significant for some. (2, 3) 145 146 EoE can be characterized by the associated symptoms, visual esophageal endoscopic 147 findings, and histopathology. In adolescents and adults, symptoms often include 148 dysphagia and food impaction, but can be less specific in children, and can include 149 failure to thrive, feeding problems, vomiting, heartburn, and abdominal discomfort. 150 Direct visual inspection of the esophagus in many but not all EoE patients can reveal 151 rings, linear furrows, white plaques or exudates, edema or decreased vascularity, 152 strictures, or luminal narrowing. Histopathology will reveal eosinophils in the 153 esophageal epithelium, which can be defined as a threshold of >15 eosinophils per high 154 power field (hpf). EoE has traditionally been distinguished from gastroesophageal reflux 155 disease (GERD) by the failure of proton pump inhibitor (PPI) treatment to reduce 156 esophageal eosinophilia below a pre-specified threshold. Over the past 10 years, the 157 diagnosis of EoE has been made in a patient who has symptoms of swallowing 158 dysfunction and esophageal eosinophilia that persists despite PPI treatment, and this is 159 the definition that is used as entry criteria for most of the studies presented in this 160 technical report based on previous guidelines. (4-6) However, discerning EoE from 161 GERD remains an area of controversy and active investigation, and the most recent 162 diagnostic criteria for EoE leave the criterion of PPI failure to the clinician (7, 8) since 163 PPI-responsive esophageal eosinophilia now is considered as part of the spectrum of 164 EoE. As such, PPIs are increasingly considered as a treatment rather than as a 165 diagnostic test for EoE as described in a recent consensus document. This 166 recommendation is supported by clinical observations that PPIs resolved EoE-related 167 symptoms and histopathological abnormalities in over 50% of children and adults 168 thought to have EoE. In addition, the biological impact of PPIs to reduce expression of 169 key EoE-related cytokines including eotaxin-3 in vitro and normalize the EoE 170 transcriptome, and the multiple similarities between patients with suspected EoE who 171 do and do not respond to a PPI, together underscore that PPI- responsive esophageal 172 eosinophilia and EoE are potentially disorders in the same pathogenic spectrum. . 173 174 The most common management approaches for EoE are topical glucocorticosteroids, 175 dietary elimination, and esophageal dilation. Many new studies have been published 176 recently. Therefore, the American Gastroenterology Association Institute and the Joint 177 Task Force on Allergy-Immunology Practice Parameters (jointly sponsored by the 178 American College of Allergy, Asthma, and Immunology and the American Academy of 179 Allergy, Asthma, and Immunology) formed a team to provide up-to-date guidance for 180

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EoE management. This technical review addresses focused clinical questions 181 regarding different therapeutic strategies for managing children and adults with EoE. 182 The results of this technical review were used to inform the development of an 183 accompanying clinical guideline for EoE. 184 185 186 METHODS 187 188 System for Rating the Quality of Evidence 189 190 This technical review and the accompanying guideline were developed using the 191 Grading of Recommendations Assessment, Development, and Evaluation (GRADE) 192 framework.(9) The members of the technical review panel were selected by the AGA 193 Clinical Guidelines Committee and the Joint Task Force on Allergy-Immunology 194 Practice Parameters based on their clinical content and guidelines methodological 195 expertise. Each member underwent a thorough vetting process for potential conflicts of 196 interest. Through an iterative process, and in conjunction with the guideline panel, the 197 participants developed focused clinical questions on the role of specific interventions in 198 the management of EoE. After the focused questions were approved by the 199 organization’s respective leadership groups, the technical review team identified 200 relevant patient-important outcomes, systematically reviewed and summarized the 201 evidence for each outcome across studies, and then rated the quality of the evidence 202 across all outcomes for each clinical question using the GRADE framework. 203 204 Development of Focused Questions 205 206 Using the PICO format, which frames a clinical question by defining a specific 207 Population (P), Intervention (I), Comparator (C), and Outcomes (O), the team developed 208 clinically relevant questions. The PICOs focused on the use of therapeutics in patients 209 with symptomatic EoE. Each of the selected PICO questions was addressed in this 210 review using the GRADE framework except for 2 PICO questions which were 211 addressed using a narrative review format. Studies with children and adults were 212 included. When possible, the interventions were compared to placebo. When only 213 trials compared to another intervention were available, the intervention was presented 214 relative to another intervention (comparator). Appendix Table 1 is a summary display 215 of the 17 PICO questions in this technical report. 216 217 Outcomes 218 219 Potentially relevant patient-important outcomes were considered and rated in terms of 220 importance, as summarized in Appendix Table 2. Through consensus of the expert 221 panel, with no voting necessary during the face-to-face review, and based on precedent 222 literature, failing to achieve histologic remission of < 15 eosinophils/high power field 223 (hpf) was considered critical for decision-making.(10, 11) It was recognized that 224 untreated inflammation can potentially lead to fibro-stenotic disease, (12-15) but also 225 that symptoms do not always correspond with histology. (16-18). Symptoms, changes 226

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in peak tissue eosinophil levels, and adverse effects were considered important for 227 decision-making. If data on certain outcomes were not available, the a priori plan was 228 to use indirect evidence to guide decision making if additional data were not provided 229 after contacting the investigators. 230 231 Outcomes that are reported in the evidence profiles are those that were found in the 232 literature. Several outcomes that were rated as important by the expert panel are not 233 reported in the evidence profiles because they were not assessed in the included 234 literature. Symptoms were reported using many different scales. Validated EoE 235 symptom questionnaires were not available when most of the studies were performed. 236 Therefore, symptom severity was an outcome that could not be synthesized in a 237 summary estimate due to this heterogeneity in reporting. Similarly, not all studies 238 utilized a validated endoscopy score, and endoscopic outcomes could not be 239 synthesized. Finally, a key decision in forming the estimate of the effect for 240 observational studies lacking a contemporaneous control group was to use the placebo 241 control arm rate for failing to achieve histologic remission from topical corticosteroid 242 studies. The expert panel was in consensus, with no voting needed, that the 86.7% 243 estimate for failing to achieve histologic remission (> 15 eosinophils/hpf) in the placebo 244 arm during a study period of 8 weeks was reasonable based on the overall information 245 available in the literature. (Alexander 2012,(19) Butz 2014,(20) Dellon 2017,(21) Dohil 246 2010,(22) Gupta 2015,(23) Konikoff 2006,(24) Miehlke 2016,(25) Straumann 2010(26)) 247 248 Systematic Review Process 249 250 A common approach to study selection was used for each question. For all PICOs, we 251 first considered high quality systematic reviews for evidence synthesis, particularly 252 those that synthesized data from RCTs. If systematic reviews of RCTs were not 253 available, we then looked to individual RCTs and generated summary estimates as 254 needed. Systematic reviews of observational studies, and in particular, single arm 255 cohort/observational studies, were considered as the least-preferred option to inform the 256 evidence, with rates pooled when possible. Case series with < 5 cases and case reports 257 were excluded, unless no other evidence for the question was available. Systematic 258 reviews that were missing recent trial data were updated and re-analyzed rather than 259 creating a de novo systematic review. When well-done systematic reviews were 260 unavailable, we searched for primary articles using a preliminary search strategy. Next, 261 preliminary evidence profiles were constructed using GRADEPRO 262 (https://gradepro.org/), and were reviewed iteratively with the clinical experts (SAA, 263 GTF, MG, JMS, and ESD), where feedback was provided about missing studies, 264 missing data, and preliminary evidence ratings. 265 266 An additional, final systematic literature search was performed after the preliminary 267 evidence profiles were constructed and reviewed with the expert panel to ensure 268 completeness. Details of the search strategy are reported in the Appendix Table 3. 269 We conducted an electronic search using MEDLINE, EMBASE, and the Cochrane 270 Library until May 13, 2018. A research librarian (KK) developed a single search strategy 271 for MEDLINE and then adapted to EMBASE and Cochrane. The search strategy was 272

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iteratively refined to maximize sensitivity, working directly with the clinical experts. The 273 search excluded letters, commentaries, editorials, notes, conference abstracts, and 274 non-human studies. We only searched for clinical trials in the electronic literature 275 search for all PICO questions except for the dietary interventions where observational 276 studies were considered, a decision made by the expert panel after considering the 277 preliminary evidence profiles. We searched the WHO clinical trial registry to identify 278 additional studies (http://apps.who.int/trialsearch/). Titles and abstracts were reviewed in 279 duplicate by two authors (MR and RS). One methodologist (RS or MR) extracted data 280 from eligible reports and a second methodologist (RS or MR) evaluated the accuracy of 281 the data extraction. We contacted authors when key data were missing, first by 282 attempting to reach the corresponding author by email and then by trying a 2nd author 283 from the article if no response. Disagreements were resolved by discussion with a third 284 methodologist (YFY). 285 286 Statistical Analysis 287 288 Pooled risk ratios with 95% confidence intervals (CI) were calculated when possible, 289 using RevMan v5.3 (Cochrane Collaboration, Copenhagen, Denmark), or Open 290 Meta[analyst] (Brown University, Providence, RI), particularly when single arm rates 291 were pooled. In RevMan, analyses were performed using a random-effects model. In 292 OpenMeta[analyst], we used binary random effects using the DerSimonian Laird 293 method. Statistical heterogeneity was assessed using the I2 statistic. Publication bias 294 was assessed using funnel plots when possible. GRADEpro software was used to 295 construct the evidence profiles and calculate the absolute effects. When historical 296 controls were used, risk ratios (RRs) were presented and the resulting absolute effects 297 were informed by applying the baseline risk from the untreated control arms from steroid 298 RCTs to the RR. It is important to note that RR refers, in this technical report, to the risk 299 of not achieving histologic remission in the treatment versus a comparator. 300 301 302 RESULTS 303 304 305 #1 Should proton pump inhibitors be used in patients with esophageal 306 eosinophilia? 307 308 Evidence Summary: We identified 23 observational studies which reported that 58.3% 309 (unweighted) of subjects on PPI failed to achieve histopathologic remission (eosinophils 310 <15/hpf) compared to 86.7% (unweighted) of a placebo comparison group. 311 312 Quality of Evidence: The certainty in the effect estimate was very low. The certainty in 313 the estimate was downgraded for inconsistency. 314 315 Discussion: This question is related to patients with esophageal eosinophilia, who, 316 depending on the study and inclusion criteria, may be different than patients with EoE. 317 It is important to note that this is an indirect comparison because participants in the 318

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topical corticosteroid studies had failed PPI treatment. Understanding PPI response in 319 EoE remains an active area of investigation. The inconsistency seen in the point 320 estimates for histologic response was not clearly explained by any specific criteria (e.g. 321 pediatrics versus adult or inclusion/exclusion criteria). There were 2 RCTs identified 322 that compared PPI to topical corticosteroid, and found similar rates of histologic 323 remission (see Appendix Table 4). 324 325

PPI compared to placebo for eosinophilic esophagitis

Bibliography: Garrean 2009,(27) Peterson 2010,(28) Molina-Infante 2011,(29) Abe 2011,(30) Fujiwara 2012,(31) Francis 2012,(32) Vazquez-Elizondo 2013,(33) Moawad 2013,(34) Lee 2013(35) Dellon 2013,(36) Mangla 2014(37), Molina 2014,(38) van Rhijn 2014,(39) Gomez-Torrijos 2016,(40) Jiao 2016,(41) Savarino 2017,(42) Philpott 2016,(43) Sayej 2009,(44) Dranove 2010,(45) Schroeder 2013,(46) Rea 2013,(47) Dhaliwal 2014,(48) Gutierrez-Junquera 2016(49)

Outcomes and Follow-up

№ of participants (studies)

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with placebo

Risk difference with PPI

Not achieving histologic remission (<15 eos/hpf); follow up: mean 8 weeks

1051 (23 observational studies) a

⨁◯◯◯ VERY LOW b,c

RR 0.66 (0.61 to 0.72) d

867 per 1,000

295 fewer per 1,000 (338 fewer to 243 fewer)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio

Explanations 326

a. Included 2 RCTs of PPI vs topical steroids 327 b. I-squared = 81%; very inconsistent results in absolute terms 328 c. Patients are different than for other interventions where PPI responders were 329 excluded 330 d. Used historical control cohort of placebo arm of topical steroid studies 331 332 333

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#2 Should topical glucocorticosteroids be used in patients with EoE? 334 335 Evidence Summary: Eight double-blind placebo-controlled RCTs were identified. 336 Summary estimates indicate that 35.1% of patients treated with glucocorticosteroids 337 failed to achieve histologic remission compared to 86.7% of patients treated with 338 placebo, leading to a RR of 0.39, (95% CI 0.26-0.58). Adverse events were experienced 339 by 43% of patients in the topical glucocorticosteroid group compared to 36% of those 340 exposed to placebo, with a risk ratio of 1 (95% CI 0.85-1.19). 341 342 Quality of Evidence: The certainty in the effect estimates was moderate for the outcome 343 of histologic response. We downgraded for inconsistency due to heterogeneity 344 (I2=77%). The certainty in the effect estimates was low for the outcome of adverse 345 events. We rated down for indirectness given heterogeneity in how adverse events 346 were defined and for imprecision given that the risk ratio crossed 1. 347 348 Discussion: RCTs were excluded if they did not have an explicit glucocorticosteroid vs 349 placebo comparison,(28, 50-53) and if they did not include budesonide or fluticasone in 350 the treatment group (54). Six meta-analyses were reviewed and excluded because they 351 did not include the most recent RCTs published in the field, or included studies in 352 addition to a placebo/glucocorticosteroid comparison. 353 354 After discussion amongst the expert panel, the following decisions were made regarding 355 how to pool the data: a single pooled estimate is presented despite differences in type 356 of glucocorticosteroid, delivery mechanism, dosages, patient population 357 (adult/pediatric), and manner of outcome reporting (peak vs mean counts). Notably, 358 sensitivity analyses isolating these individual groups did not alter findings significantly, 359 lending credence to the decision to pool topical glucocorticosteroid data. Most trials 360 required a failed PPI treatment trial prior to enrolling subjects, or excluded patients with 361 GERD. 362 363 Similar categories of data were reported across the 8 included RCTs on 3 outcomes: 364 Histologic response (defined as any eosinophils <15/hpf), symptomatic response, and 365 adverse events. For histologic response: a) data are presented as failure to achieve 366 histologic response, so a RR of <1 means that patients in a given arm are less likely to 367 fail to achieve histologic response, and b) We approximated intention-to-treat (ITT) 368 estimates if not reported, by examining the CONSORT diagram and accounting for 369 dropout. All participants who dropped out in any study arm were categorized as failing 370 to achieve histologic remission. 371 372 For adverse events, there was a variable definition of adverse events (ranging from 373 general (fever/fatigue) to skin/respiratory/GI/endocrine disorders/infections, to those that 374 needed drug-discontinuation). Numbers for adverse events were taken from per 375 protocol analyses (when possible). Potential adverse events have been summarized by 376 Philpott et al. and include local infections-candida and viral, adrenal suppression, 377 diminished growth and fractures.(55) 378 379

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380 381 Topical Glucocortiosteroids compared to placebo for eosinophilic esophagitis

Bibliography: Alexander 2012,(19) Butz 2014,(20) Dellon 2017,(21) Dohil 2010,(22) Gupta 2015,(23) Konikoff 2006,(24) Miehlke 2016,(25) Straumann 2010(26)






Risk with placebo

Risk difference with Topical Steroids


437 (8 RCTs) a

⨁⨁⨁◯ MODERATE b,c,d,e

RR 0.39 (0.26 to 0.58)

880 per 1,000

537 fewer per 1,000 (from 369 fewer to 651 fewer)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio

Explanations 382

a. There was variability in whether histologic response was reported as Mean vs Peak 383 Eosinophil levels. All included trials reported Peaks with the exception of: a) Straumann 384 2010, which reported mean counts, b) Alexander 2012, which reported mean peaks 385 (personal communication), and c) Miehlke reported eosinophil density which we 386 correlated to eosinophil counts. Removing these individual trials in a sensitivity analysis 387 did not significantly alter the summary estimates (0.59 [0.46, 0.76]. 388 b. Few studies reported ITT analyses and dropout was not adequately accounted for. 389 We accounted for this by looking at the CONSORT diagram and reporting ITT results, 390 assuming that outcomes would favor the control. 391 c. I2= 77%. 392

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d. Dellon 2017 might have had a more severe baseline patient population, accounting 393 for decreased response to glucocorticosteroids when compared to other studies. We did 394 not however rate down for indirectness 395 e. Despite the fact that there are < 300 events (which can indicate suboptimal 396 information size), we did not rate down for imprecision. We also felt that because 397 inconsistency and imprecision are related concepts, a single down-grade for 398 inconsistency was sufficient. We assessed clinical behavior at the extremes of the 399 confidence interval, and judged that behavior would not change. 400 401 402 #3 Should systemic glucocorticosteroids be used in patients with EoE? 403 404 Evidence Summary: We identified 1 RCT that compared prednisone to fluticasone in 405 the treatment of EoE in children. We reported outcomes of “lack of histologic response” 406 defined as failure to achieve <15 eosinophils per hpf, and adverse events, a composite 407 endpoint defined in the footnotes. 11/40 (28%) patients in the prednisone arm vs 14/40 408 (35%) patients in the fluticasone arm failed to achieve histologic response, for a RR 409 0.79 (95% CI 0.41 to 1.52). 16/40 (40%) patients in the prednisone arm compared to 410 6/40 (15%) in the fluticasone arm experienced adverse events for a RR of 2.67 (1.16 to 411 6.11). 412 413 Quality of Evidence: The certainty in the estimates was moderate. Both outcomes were 414 rated down for imprecision; the RR for clinical response had a confidence interval which 415 crossed 1 and adverse events had few events. 416 417 Discussion: A single RCT comparing systemic and topical glucocorticosteroids 418 suggests similar efficacy but a higher rate of adverse events for patients receiving 419 systemic glucocorticosteroid. Systemic adverse events were reported as a composite 420 endpoint, defined in the study as hyperphagia, weight gain, and/or cushingoid features. 421 Other potential adverse effects that have a longer potential time frame to develop such 422 as effects on bone health, immunity, cataract formation, glucose levels, and blood 423 pressure were not measured. In the prednisone group, 16/40 (40%) experienced 424 systemic adverse events; 3 of these 16 exited the study before week 4 and were 425 transitioned to the fluticasone group (outside the protocol). In the fluticasone group, 6/40 426 (15%) patients experienced esophageal candida overgrowth, though none did in the 427 prednisone arm; all of these candida esophageal patients were free of the presenting 428 symptoms by week 4. This single study was conducted in children and may not be 429 applicable to adults. 430 431 432 433

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Systemic glucocorticosteroid compared to topical glucocorticosteroid for eosinophilic esophagitis

Bibliography: Schaefer 2008(51)






Risk with topical steroid

Risk difference with systemic steroid


80 (1 RCT)

⨁⨁⨁◯ MODERATE a,b,c

RR 0.79 (0.41 to 1.52)

350 per 1,000 d

73 fewer per 1,000 (207 fewer to 182 more)


a. Despite a lack of blinding, the study was not downgraded for risk of bias. 434 b. We did not rate down for indirectness despite the fact that this trial consists of a 435 pediatric population. 436 c. Risk Ratio crosses 1 437 d. In order to estimate an ITT analysis, we changed the denominator to the number of 438 subjects who were originally randomized to each group (40 per group). The numerator 439 denotes the number of individuals who achieved at “mild’ or normal histologic grade (per 440 Schaefer paper) at 4 weeks, which correlates to a cutoff of <15Eos/hpf. 441 442 443 444 #4 Should an elemental diet be used in patients with EoE? 445 446 Evidence Summary: We identified 6 observational studies which reported that 6.4% of 447 subjects on elemental diet failed to achieve histopathologic remission (eosinophils 448 <15/hpf) compared to 86.7% in a placebo comparison group (taken as a historical 449

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comparison group from swallowed topical steroid data) for a RR of 0.07, (95% CI 0.05-450 0.12). 451 452 Quality of Evidence: The certainty in the effect estimate was moderate. The certainty in 453 the estimate was rated up for anticipated large effect. 454 455 Discussion: There were differences in the effect estimates when grouping children and 456 adult studies, with adult studies having a lower proportion of study participants 457 achieving histologic remission. This comparison is limited by use of a historical 458 comparison group comprised of placebo treated patients in topical steroid studies, 459 which is an indirect but permissible method under GRADE to handle such situations 460 where only single arm observational studies exist. Symptom response was reported for 461 4 studies but could not be synthesized due to considerable differences in the way 462 symptoms were reported. Of the 6 studies used for the efficacy assessment, 3 463 specifically measured nutritional status and 1 measured overall quality of life. Difficulty 464 adhering to an elemental diet was raised as an important consideration for this 465 intervention. Potential harms of this intervention were raised by the expert panel and 466 include the interruption of developmental progress of eating for children, the potential 467 need for gastrostomy tube placement, and the risks associated with repeated 468 endoscopies needed when food is ultimately re-introduced. Risk of developing IgE-469 mediated food allergy following a period of food elimination has not been described in 470 EoE, but has been described in case reports of children with atopic dermatitis (56). 471 Risk of prolonged peanut avoidance versus early introduction of peanut in the first year 472 of life has been shown as a factor influencing peanut allergy development in children 473 with either severe eczema and/or known egg allergy,(57) but has not been described in 474 EoE and it is unclear how such data would therefore apply. Consultation with an 475 allergist would be recommended in this situation to manage potential competing risks 476 and harms with avoidance diets that would prolong introduction of foods such as peanut 477 (and possibly egg) in children in their first year of life, and potentially place them at risk 478 for developing IgE mediated food allergy. Finally, the expert panel noted that the 479 consideration of an elemental diet would be made in the context of other management 480 options, including other dietary management options such as empiric food elimination 481 (e.g. six food elimination diet) or testing-based elimination diet and with careful 482 consideration for the age of the patient, potential detrimental effects of widespread food 483 elimination, and patient preferences. 484 485

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Elemental Diets compared to placebo for the management of Eosinophilic Esophagitis

Bibliography: Kelly 1995a,(58) Licarous 2005b,(59) Henderson 2012,(60) Peterson 2013C,(61) Leung 2015,(62) Warners 2017(63) Outcomes and Follow-up





Risk with placebo

Risk difference with Elemental Diets

Not achieving histologic remission (eos<15/hpf) follow up: mean 8 weeks

431 (6 observational studies)

⨁⨁⨁◯ MODERATE d

RR 0.07 (0.05 to 0.12)

880 per 1,000



Explanations 486

a. 5 subjects excluded for noncompliance to diet; 2 subjects excluded for not getting 487 follow-up endoscopy 488 b. 8 subjects excluded for noncompliance 489 c. Histologic remission defined as < 10 eos/hpf; 11 who started diet dropped out 490 d. Upgraded for very large effect size 491 492 #5 Should an empiric food elimination diet be used in patients with EoE? 493 494

A. Should an empiric 6 food elimination diet be used in patients with EoE? 495 496 Evidence Summary: We identified 10 single armed observational studies which 497 reported that 32.1% (unweighted) of subjects on an empiric elimination diet failed to 498 achieve histopathologic remission (eosinophils <15/hpf) compared to 86.7% of a 499

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placebo comparison group (taken as a historical comparison group from swallowed 500 topical steroid data), for a RR=0.38, (95% CI 0.32-0.43). 501 502 Quality of Evidence: The certainty in the effect estimate was low due to non-503 comparative single arm study designs. 504 505 Discussion: Symptom response was reported for 3 studies but could not be 506 synthesized due to considerable differences in the way symptoms were reported. Of 507 the 10 studies used for the efficacy assessment, 2 specifically measured nutritional 508 status and 1 formally measured overall quality of life. Difficulty adhering to an empiric 509 diet where 6 foods were eliminated was raised as an important consideration for this 510 intervention. Empiric diet approaches with fewer foods may improve adherence to 511 dietary avoidance and be associated with fewer endoscopies required to identify food 512 triggers. Potential harms of this intervention were raised by the expert panel and 513 include the effect on nutrition and the risks associated with repeated endoscopies 514 needed when food is ultimately re-introduced. Finally, the expert panel noted that the 515 consideration of an empiric diet would be made in the context of other management 516 options, including other dietary management options such as elemental or testing-based 517 elimination diets. 518 519 520 SFED compared to placebo for the management of Eosinophilic Esophagitis

Bibliography: Kagalwalla 2006a,(64) Gonsalves 2012b,(65) Henderson 2012c,(66) Lucendo 2013d,(67) Colson 2014e,(68) Rodriguez-Sanchez 2014f,(69) Philpott 2016g,(70) Molina-Infante 2018h,(71) Reed 2017i,(72) Homan 2015(73) Outcomes № of

participants (studies) Follow-up




Risk with placebo

Risk difference with SFED

Failure to achieve histologic remission (Proportion) assessed with: Esophageal eosinphils < 15/hpf follow up: mean 6 weeks


⨁⨁◯◯ LOW j

RR 0.38 (0.32 to 0.43)

880 per 1000

550 fewer per 1000 (600 fewer to 500 fewer)

16

SFED compared to placebo for the management of Eosinophilic Esophagitis

Bibliography: Kagalwalla 2006a,(64) Gonsalves 2012b,(65) Henderson 2012c,(66) Lucendo 2013d,(67) Colson 2014e,(68) Rodriguez-Sanchez 2014f,(69) Philpott 2016g,(70) Molina-Infante 2018h,(71) Reed 2017i,(72) Homan 2015(73) Outcomes № of

participants (studies) Follow-up




Risk with placebo

Risk difference with SFED


Explanations 521

a. Used < 10 eos/hpf for definition of remission. Studies with a cutoff of < 15 eos/hpf 522 will likely underestimate the response rate within the pooled results and therefore 523 strengthen the assumed estimate of effect. 524 b. Measured SF-36 525 c. 15/26 subjects did SFED + foods with + SPT/APT 526 d. Also eliminated rice + corn 527 e. Also eliminated foods with + SPT/APT 528 f. Excluded subjects with + IgE tests prior to enrollment. The response rate is lower 529 and therefore likely underestimates the effect estimate in the pooled results. 530 g. Only subjects with < 5 eos/hpf (“complete” remission) 531 h. Combined clinical and histopathological remission; estimated for SFED based on 2-532 4-6 FED step-up protocol 533 i. Did not include Wolf 2014 in analysis to avoid duplicate subjects 534 j. When compared to historical controls, a very large effect estimate is likely. 535 However, the evidence certainty was not rated up due to concerns of possible residual 536 confounding and/or indirectness. 537 538 539

B. Should an empiric 4 food elimination diet be used in patients with EoE? 540 541 Evidence Summary: We identified 3 single armed studies which reported that 43.1% 542 (unweighted) of subjects on an empiric elimination diet failed to achieve histopathologic 543 remission (eosinophils <15/hpf) compared to 86.7% (unweighted) of a placebo 544

17

comparison group (taken as a historical comparison group from swallowed topical 545 steroid data), for a RR=0.46, (95% CI 0.42-0.57). 546 547 Quality of Evidence: The certainty in the effect estimate was low due to non-548 comparative single arm study designs. 549 550 Discussion: The 6 food elimination diet estimate for not achieving histologic remission 551 was slightly lower but similar (32% compared to 43%) than for 4 food elimination diet. 552 Similar to the 6 food elimination diet, potential harms of this intervention were raised by 553 the expert panel and include the effect on nutrition and the risks associated with 554 repeated endoscopies needed when food is ultimately re-introduced. 555 556

557 4 Food empiric elimination diet compared to placebo for eosinophilic esophagitis

Bibliography: Molina-Infante 2014,(38) Kagalwalla 2017,(74) Molina-Infante 2017a (71)






Risk with placebo

Risk difference with 4 Food empiric elimination diet

Not achieving histologic remission (No remission ) assessed with: eos < 15/ hpf follow up: 6 weeks


⨁⨁◯◯ LOW

RR 0.49 (0.42 to 0.57)

880 per 1,000b



18

Explanations 558

a. Pediatric study 559 b. Placebo group responses from topical steroid trials 560

561 C. Should an empiric 2 food elimination diet be used in patients with EoE? 562

563 Evidence Summary: We identified 2 single armed studies which reported that 57.9% 564 (unweighted) of subjects on an empiric elimination diet failed to achieve histopathologic 565 remission (eosinophils <15/hpf) compared to 86.7% (unweighted) of a placebo 566 comparison group (taken as a historical comparison group from swallowed topical 567 steroid data) for a RR=0.66, (95% CI 0.57-0.77). 568 569 Quality of Evidence: The certainty in the effect estimate was very low due to non-570 comparative single arm study designs and was further rated down for imprecision due to 571 low information size. 572 573 Discussion: The 6 and 4 food elimination diet estimates for not achieving histologic 574 remission were slightly lower than for 2 food elimination (32% and 43% compared to 575 58%). In the Molina-Infante study, the 2 foods eliminated were milk and wheat. In the 576 Reed study, the 2 foods were milk and soy, and the participants had previously been 577 treated with a combination of topical steroids and 2-food elimination in the prior 3 578 months. Potential harms of this intervention were raised by the expert panel and 579 include the effect on nutrition and the risks associated with repeated endoscopies 580 needed when food is ultimately re-introduced although fewer for an empiric 2 food 581 elimination diet than a 4 or 6 food elimination diet. Finally, the expert panel noted that 582 the consideration of an empiric diet would be made in the context of other management 583 options, including other dietary management options such as elemental, other empiric 584 elimination strategies, and testing-based dietary elimination. 585 586

19

2 food elimination diet compared to placebo for eosinophilic esophagitis

Bibliography: Molina-Infante 2017a,(71) Reed 2018b (75)






Risk with placebo

Risk difference with 2 food elimination diet

Not achieving histologic remission (Remission) assessed with: Eos < 15/hpf follow up: 6 weeks


⨁◯◯◯ VERY LOW

RR 0.66 (0.57 to 0.77)

880 per 1,000c



a. 2FED=milk + wheat 587 b. 2FED=milk + soy 588 c. Placebo group is from topical steroid trials 589

590 D. Should an empiric single food elimination diet be used in patients with 591

EoE? 592 593 Evidence Summary: We identified 2 single armed studies which reported that 45.9% 594 (unweighted) of subjects on a single food empiric elimination diet failed to achieve 595 histopathologic remission (eosinophils <15/hpf) compared to 86.7% (unweighted) of a 596 placebo comparison group (taken as a historical comparison group from swallowed 597 topical steroid data). 598 599 Quality of Evidence: The certainty in the effect estimate was very low due to non-600 comparative single arm study designs and was further rated down for imprecision due to 601 low information size. 602

20

603 Discussion: The 6 and 4 food elimination diet estimates for not achieving histologic 604 remission were slightly lower than for single food elimination for 2 food elimination (32% 605 and 43% compared to 46%) but was lower than for 2 food elimination (58%). The 606 higher rates of remission with single food (milk) compared to 2-food (both of which 607 included milk) are not easily explained based on study design or patient characteristics 608 and are very uncertain based on the assessment of quality of the evidence. While the 609 risks with a single food elimination strategy are lower compared to 2,4, or 6 food 610 elimination, similar potential harms of this intervention were raised by the expert panel 611 which include the effect on nutrition and the risk associated with endoscopy (though 612 only 1 follow endoscopy because only 1 food eliminated) Finally, the expert panel 613 noted that the consideration of an empiric diet would be made in the context of other 614 management options, including other dietary management options such as elemental, 615 other empiric elimination strategies, and testing-based dietary elimination. 616 617 Single food elimination compared to placebo for eosinophilic esophagitis

Bibliography: Kagalwalla 2012a,(76) Kruszewski 2016b (77)

Outcomes № of participants (studies) Follow-up




Risk with placebo

Risk difference with Single food elimination

Not achieving histologic remission (Remission) assessed with: eos < 15/hpf follow up: 6 weeks


⨁◯◯◯ VERY LOWc

RR 0.52 (0.37 to 0.74)

880 per 1,000d



Explanations 618

21

a. Milk 619 b. Milk, 6 dropped out and were considered treatment failures for this analysis 620 c. Low information size 621 d. Placebo data are from topical steroid studies 622

623 #6 Should allergy-based testing be used for the purpose of identifying food 624 triggers in patients with EoE? 625 626 Evidence Summary: We identified 12 single armed studies which reported that 49.2% 627 (unweighted) of subjects on a testing-based elimination diet failed to achieve 628 histopathologic remission (eosinophils <15/hpf) compared to 86.7% (unweighted) of a 629 placebo comparison group (taken as a historical comparison group from swallowed 630 topical steroid data). 631 632 Quality of Evidence: The certainty in the effect estimate was very low due to non-633 comparative single arm study designs. 634 635 Discussion: Inconsistency was noted and thought to be most likely related to the 636 different testing approaches that were used to inform the dietary elimination. Different 637 studies used different testing techniques, or combinations of techniques, including skin 638 prick testing, serum IgE testing, or patch testing. Some studies used all 3 methods to 639 select the dietary intervention. We performed a sensitivity analysis that found 41% 640 (95% CI: 18% to 64%) failed to achieve remission in studies in which patch testing was 641 used and 61% (95% CI: 38%-83%) in studies not using patch testing. Thus, there were 642 more favorable outcomes in studies in which patch testing was performed, but the 643 outcomes weren’t clearly better (considerable CI overlap) and there is very low certainty 644 in this comparative effect estimate. Symptom response was reported for 4 studies but 645 could not be synthesized due to considerable differences in the way symptoms were 646 reported. Of the 10 studies used for the efficacy assessment, 1 specifically measured 647 nutritional status and none formally measured overall quality of life. Difficulty adhering 648 to an elimination diet was raised as an important consideration for this intervention. 649 Potential harms of this intervention were raised by the expert panel and include the 650 effect on nutrition and the risks associated with repeated endoscopies needed when 651 food is ultimately re-introduced. The expert panel noted that the consideration of a 652 testing based diet would be made in the context of other management options, including 653 other dietary management options such as elemental or empiric dietary elimination. 654 Finally, the expert panel discussed the potential role of aeroallergen testing and 655 treatment in EoE. There is emerging evidence that aeroallergens may be important 656 triggers for EoE. There are currently only very small case series reporting aeroallergen 657 immunotherapy in patients with EoE. 658 659 660 661

22

Allergy-Based Elimination Diets compared to placebo for management of EoE

Bibliography: Licarous 2005a,(59) Qaugletta 2007b,(78) Rizo Pascual 2011b,(79) Henderson 2012,(66) Molina-Infante 2012c,(80) Spergel 2012,(81) Al-Hussaini 2013,(82) Rodriguez-Sanchez 2014,(69) Homan 2015,(73) Syrigou 2015d,(83) Van Rhijn 2015e,(84) Constatine 2017,(85) Reed 2017(72) Outcomes and Follow-up





Risk with placebo

Risk difference with Allergy-Based Elimination Diets

Not achieving histologic response assessed with: < 15 eos/hpf

Follow up: 8 weeks


⨁◯◯◯ VERY LOW f

RR 0.57 (0.33 to 0.73)

880 per 1,000g



Explanations 662 663 a. Skin prick test (SPT) + atopy patch test (APT), some had previously failed 664 pharmacologic therapy 665 b. Remission defined as < 10 eos/hpf 666 c. SPT + APT + PPT 667 d. SPT + specific IgE testing (sIgE) + APT 668 e. Component-resolved diagnostics (CRD) 669 f. Very inconsistent results 670 g. Placebo group responses from topical steroid trials 671 672 #7 Should maintenance therapy be recommended in patients with EoE? 673 674

23

Evidence Summary: There is 1 RCT of continuing therapy compared to placebo for 675 patients who had achieved clinical and histologic remission. The risk ratio was 0.70 676 (95% CI 0.38-1.30) for failing to maintain histologic remission, defined for that study as 677 eosinophils < 20/hpf. 678 679 Quality of Evidence: The certainty in the effect estimate was very low. The certainty in 680 the estimate was rated down for indirectness as the intervention used a delivery 681 mechanism and dose of topical corticosteroid that is different than most previously 682 reported corticosteroid studies. The certainty was also downgraded twice for very 683 serious imprecision due to very low information size. 684 685 Discussion: A single very small RCT of low dose topical glucocorticosteroid (0.25 mg 686 budesonide twice daily) failed to show or to exclude a beneficial effect on maintaining 687 remission in patient who had previously achieved it, using an absolute threshold of <20 688 eos/hpf. However, no patient in the placebo group met the definition of complete 689 response at one year (<5 eos) compared to 36% of the active arm, which was a strong 690 trend (p=0.06). Similarly, the absolute eosinophil counts were significantly lower in the 691 treatment arm compared to placebo (32 eos/hpf vs 65 eos/hpf; p=0.02). Quality of life 692 was not described and no significant harms were identified. There are observational 693 cohort studies of topical glucocorticosteroids and other maintenance treatment options 694 which provide some additional evidence. 695 696 We found 6 single-armed observational cohorts for topical glucocorticosteroids. Butz et 697 al 2014(20) reported that 11 out of 15 were able to maintain remission on a lower dose 698 of topical glucocorticosteroid (fluticasone 0.88 mg) over 3 months. Andreae et al 2016 699 (86) reported on 54 pediatric patients treated long term with swallowed fluticasone and 700 with mean follow-up of 20 months found 63% remained in histologic remission. Dellon 701 et al 2016 (87) reported in an abstract that 42% of their cohort were able to maintain 702 remission on budesonide 2 mg/day. Greuter et al 2017(88) reported that out of 33 703 people who had achieved clinical and histological remission for 6 months, 27 704 experienced relapse with an average time-to-relapse of 22 weeks after stopping topical 705 glucocortiocsteroids. Eluri et al 2017 (89) reported that 20 out of 33 adults who were 706 using topical glucocorticosteroids experienced a relapse when followed over a 12 month 707 period. Rubenstein et al 2018 ***reported that 7 of 8 children who attempted to reduce 708 budesonide to a 3-times-per-week dosing schedule from a daily schedule experienced a 709 relapse. 710 711 Alexander et al 2017 (90) was profiled earlier in this technical report, and is listed here 712 because the subjects were in remission when they were randomized to montelukast or 713 placebo. 714 715 We identified 3 long term PPI studies that reported remission/relapse rates over 716 extended time periods. Molina-Infante 2015(91) reported that 55 of 75 remained in 717 remission on PPI with a mean follow-up length of 26 months. Gomez-Torrijos 2016(40) 718 reported that 31 of 38 remained in remission when dose of PPI reduced to once daily, 719 and 15 of 18 remained in remission when daily high dose PPI was reduced to regular 720

24

dose PPI. Gutierrez-Junquera 2016(49) reported that 17 of 57 failed to maintain 721 remission over a 1 year period on 1 mg/kg per dose twice daily of PPI. 722 723 We identified 3 single-armed cohorts of long term dietary treatment. Lucendo 2013 724 (92) reported that 25 of 42 who had initially achieved remission with dietary therapy 725 remained in remission 52 weeks later, with many patients dropping out of the study. 726 Philpott 2015 (93) reported that 10 of 10 who maintained dietary therapy remained in 727 remission with a mean follow-up length of 36 weeks. Reed 2017 (72) reported that 10 728 of 10 who maintained dietary therapy remained in remission over a mean follow-up 729 length of 25 weeks. 730 731 Overall, it appears clear from the placebo arms of randomized trials, natural history 732 studies, and cohort studies that if treatments in EoE are stopped, then disease activity 733 (including symptomatic, endoscopic, and histologic) has a high chance of recurring. 734 The difficulty is that there are few data to guide either treatment or surveillance of long 735 term treatment in EoE. A general approach is to repeat an endoscopy for monitoring 736 after treatment changes, which is discussed in a later question in this document. For 737 dietary treatment, continuing to avoid confirmed food triggers should be effective but 738 may have significant nutritional and/or quality of life deficits depending on the nature 739 and duration of prolonged avoidance. However, the details of dosing, treatment 740 intensity, and endoscopic surveillance frequency remain areas that need to be studied. 741 742 Maintenance Therapy compared to placebo for eosinophilic esophagitis

Bibliography: Straumann 2011a (50)

Outcomes and Follow up





Risk with placebo

Risk difference with Maintenance Therapy

Not achieving histologic remission (Eos < 20/hpf) (Hist remission) assessed with: Eos < 20/hpf follow up: mean 50 weeks

28 (1 RCT)

⨁◯◯◯ VERY LOWb,c

RR 0.70 (0.38 to 1.30)

714 per 1,000


25

Maintenance Therapy compared to placebo for eosinophilic esophagitis

Bibliography: Straumann 2011a (50)

Outcomes and Follow up





Risk with placebo

Risk difference with Maintenance Therapy


Explanations 743 744 a. To be eligible had to be in remission eos < 5 /hpf on high dose budesonide 2 mg/day 745 and low symptom score (< 2 on their scale); budesonide given via TIA nebulizer (does 746 not exist in US) at dose 0.5 mg (low); partial remission < 20 rather than < 15 which is 747 used for most other intervention outcomes; not all patients completed 50 weeks---if 748 clinical symptoms and relapse confirmed they stopped (9 completed 50 weeks in BUD 749 group and 5 in PLAC) 750 b. Used low dose of budesonide delivered through a device not available in the US 751 c. Very low information size and CI crosses 1. 752 753 #8 Should esophageal dilation be used in patients with EoE? 754 755 Evidence Summary: Histologic remission was not assessed for this intervention. 756 Estimates were taken from the Dougherty 2017 meta-analysis(94) that investigated the 757 use of dilation in patients with EoE. Data for outcomes of interest were extracted and 758 pooled from studies included in the Dougherty meta-analysis that explicitly noted that 759 they were performed with greater than 5 participants. We summarized outcomes on 760 clinical improvement as well as adverse events (mortality, perforation, hospitalization, 761 and hemorrhage). Rates for each outcome are presented. The assumption was that no 762 clinical improvement nor adverse events would reasonably occur if dilation was not 763 performed. 87% of patients experienced clinical improvement with esophageal dilation 764 in symptoms (but not esophageal eosinophil counts). There was no mortality associated 765 with dilation. The pooled perforation rate was 0.4%, hospitalization was reported after 766 1.2% of dilations, and significant GI hemorrhage was reported in 0.1% of dilations. 767

26

768 Quality of Evidence: The certainty in the effect estimate was very low across all 769 outcomes. We rated down for risk of bias given that there was no control group. This, 770 combined with the fact that we started with a majority of observational data, yielded very 771 low certainty in the effect. It is also important to note that the assessment of clinical 772 improvement does not account for concomitant use of medication or diet. We did not 773 rate down for indirectness though it was noted that patients who need dilation have 774 fibro-stenotic disease. Though this population may be distinct from those included in 775 studies where therapeutic management with medications was investigated, for “clinical 776 improvement”, we did not rate down for inconsistency despite heterogeneity of the 777 pooled estimate (I2); our assumption was that dilation does indeed result symptomatic 778 improvement. 779 780 Discussion: There are 3 meta-analyses from 2017 that investigated the use of dilation in 781 patients with EoE (94-96). We compared them, found the Dougherty to be the most 782 inclusive after discussion with the expert panel, and used that study as the basis for our 783 evidence profile. Use of dilation in this patient population was not associated with any 784 noted safety risks. Clinicians should recognize that dilation is not a treatment for the 785 inflammation associated with EoE per se, but rather a treatment directed at the 786 dysphagia symptoms associated with EoE. Histologic outcomes are not routinely 787 reported in dilation studies nor are biopsies taken during dilation, and this measure is 788 not being discussed in the context of a management strategy that would decrease 789 esophageal eosinophilia. We recognized that there was significant variability in how 790 several outcomes were measured in the constituent studies. Rates and absolute effects 791 were presented because the majority of the included studies had no control group. 792 793 794

27

Esophageal dilation compared to no dilatation for Eosinophilic Esophagitis

Bibliography: Dougherty 2017(94)





Risk with no dilatation

Risk difference with Esophageal dilation

Clinical Improvement (not defined) a,b

1928 dilations (14 observational studies) c

⨁◯◯◯ VERY LOW d,e,f

not estimable

0 per 100 g

0 fewer per 100 (0 fewer to 0 fewer)

Mortality h 2772 dilations (20 observational studies) i

⨁◯◯◯ VERY LOW d,f

not estimable

-- per -- g -- per -- (-- to --)

Perforation h 2772 dilations (20 observational studies) i


not estimable

0 per 1,000 g


Hospitalization h 2466 dilations (12 observational studies) j


not estimable

0 per 1,000 g


28

Esophageal dilation compared to no dilatation for Eosinophilic Esophagitis

Bibliography: Dougherty 2017(94)





Risk with no dilatation

Risk difference with Esophageal dilation

Hemorrhage h,k 2588 dilations (12 observational studies)


not estimable

0 per 1,000 g



Explanations 795

a. Follow up Median of 12 months and a range from 1 week to 36 months 796 b. Clinical improvement expressed per patient. Heterogeneous definition of "clinical 797 improvement". 798 c. 37 studies were included in meta-analysis, though only 14 studies were included for 799 this outcome. There was one randomized trial (Kavitt) and there rest were observational 800 studies with greater than 5 participants. Some studies did not specify the number of 801 participants, and as such, were excluded. The included case-control (Cohen et al) study 802 in the Dougherty meta-analysis was also excluded in this analysis. 803 d. Absolute rate calculated from data provided in Dougherty et al meta-analysis, pooling 804 data from cohort/RCT studies where "n" was available for outcome of interest. Case-805 control and observational studies will <5 patients were excluded. Only absolute rates 806 provided because there was no control group. 807 e. Despite heterogeneity of pooled estimate, assumption is that dilation does cause 808 symptomatic improvement. 809

29

f. It was noted that patients who need dilation have fibrostenotic disease. Though this 810 population may be distinct from those included in studies where therapeutic 811 management with medications was investigated, we did not rate down for indirectness. 812 g. Assumption was that no clinical improvement nor adverse events could occur if 813 dilation not performed. 814 h. Expressed as number per dilation 815 i. 37 studies were included in meta-analysis, though only 20 studies were included for 816 this outcome. There was one randomized trial (Kavitt) and there rest were observational 817 studies with greater than 5 participants. Some studies did not specify the number of 818 participants, and as such, were excluded. The included case-control (Cohen et al) study 819 in the Dougherty meta-analysis was also excluded in this analysis. 820 j. 37 studies were included in meta-analysis, though only 12 studies were included for 821 this outcome. There was one randomized trial (Kavitt) and there rest were observational 822 studies with greater than 5 participants. Some studies did not specify the number of 823 participants, and as such, were excluded. The included case-control (Cohen et al) study 824 in the Dougherty meta analysis was also excluded in this analysis. 825 k. Significant GI bleeds were those defined as needing additional clinical intervention, 826 usually re-endoscopy, and did not include mucosal tears seen immediately after dilation. 827 828 #9 Should anti-IL-5 therapy be used in patients with EoE? 829 830 Evidence Summary: There are 3 RCTs of anti-IL-5 therapy compared to placebo. Anti-831 IL-5 treatment had little or no effect, with 94.4% of patients assigned to anti-IL-5 832 therapy failed to achieve histologic remission compared to 93.9% of the placebo group, 833 for a RR of 0.92, 0.84, 1.00. 834 835 Quality of Evidence: The certainty in the effect estimate was low. The certainty in the 836 estimate was downgraded for indirectness because the participants in this study were 837 different than other interventions in that many had failed the other interventions prior to 838 entering the trials. The certainty was also downgraded for imprecision because the 839 confidence interval included 1. 840 841 Discussion: Very few individuals in the intervention or placebo arms achieved the pre-842 specified histologic remission rate of < 15 eosinophils/hpf. We grouped 2 different 843 drugs with similar mechanisms of action-mepolizumab and reslizumab-for the effect size 844 estimate. One of the studies (Assa’ad 2011) did not have a true placebo group but 845 instead used a low dose of mepolizumab as a comparator. The participants in these 846 studies frequently failed other treatments and had higher levels of esophageal 847 eosinophilia upon entry into the study than in studies for other interventions. Symptom 848 outcomes were reported differently in the 3 studies and therefore were not grouped to 849 create an effect estimate. Quality of life was reported in 1 study (Spergel 2012), and 850 there were no major signals of harms reported in the 3 studies. 851 852 . 853

30

Anti-IL-5 monoclonal antibodies compared to placebo for eosinophilic esophagitis

Bibliography: Straumann 2010a,(97) Assa'ad 2011b,(98) Spergel 2012c (99)






Risk with placebo

Risk difference with Anti-IL-5 monoclonal antibodies

Not achieving histologic remission ( < 15 eos/hpf) (Remission (partial)) assessed with: < 15/hpf follow up: range 9 weeks to 16 weeks

286 (3 RCTs)

⨁⨁◯◯ LOWe,f

RR 0.92 (0.84 to 1.00)

902 per 1,000



Explanations 854 a. Mepolizumab in adults (escalating mepolizumab doses) 855 b. Mepolizumab in children, used very low dose mepolizumab as placebo or 856 “comparator” group as suggested by authors in the methods section; grouped other 2 857 doses of mepolizumab together (no obvious dose response); missing description of 858 blinding and allocation concealment 859 c. Reslizumab in children; grouped 3 doses of reslizumab together in intervention 860 group (no obvious dose response) 861 d. Participant selection for these studies are different than for other interventions—862 have failed many other interventions prior to enrolling in this study 863 e. CI crosses 1 864 f. CI touches 1 (upper boundary of CI is 1.0—no effect—which could lead to a 865 different recommendation and therefore represents imprecision. 866

31

867 #10 Should anti-IL-13 therapy be used in patients with EoE? 868 869 Evidence Summary: There is 1 published RCT of anti-IL-13 therapy compared to 870 placebo. The RR was 1.08 (95% CI 0.81-1.40) for participants in the anti-IL-13 arm 871 failing to achieve histologic remission compared to placebo. 872 873 Quality of Evidence: The certainty in the effect estimate was low. The certainty in the 874 estimate was downgraded for imprecision due to very low information size and for 875 indirectness as patients who entered the study were more likely to have failed other 876 treatments and have very high baseline esophageal eosinophilia. 877 878 Discussion: A single small RCT failed to show or exclude an effect of anti-IL-13 in EoE. 879 Quality of life was not described and no significant harms were reported. The expert 880 panel identified 2 additional RCTs which are reported as abstracts but not yet published 881 as full manuscripts. These 2 studies each included interventions that are somewhat 882 different than in Rothenberg et al. In Hirano et al, dupilumab, an IL-13/IL-4 receptor 883 blocker, was compared with placebo. In the dupilumab arm, 4 of 23 failed to achieve 884 histologic remission < 15/hpf compared to 24 out of 24 in the placebo arm (risk 885 ratio=0.17, 0.07-0.42). In Dellon et al, two doses of an anti-IL-13Ra1/Ra2 blocker, was 886 compared to placebo in 99 subjects. The mean eosinophil counts were significant 887 reduced from baseline for both doses levels compared to placebo (-99.9 eos/hpf for 888 high dose, -94.8 eos/hpf for low dose, and -4.4 eos/hpf for placebo; all comparisons 889 p<0.0001). 890 891

a. 892 QAX-576 compared to placebo for eosinophilic esophagitis

Bibliography: Rothenberg 2015 (100)

Outcomes and Follow-up № of participants (studies)




Risk with placebo

Risk difference with QAX-576

Not achieving histologic remission < 15 eos/hpf (hist remission) assessed with: < 15 eos/hpf follow up: mean 12 weeks

25 (1 RCT)

⨁⨁◯◯ LOWa,b

RR 0.94 (0.67 to 1.30)

875 per 1,000


32

QAX-576 compared to placebo for eosinophilic esophagitis

Bibliography: Rothenberg 2015 (100)





Risk with placebo

Risk difference with QAX-576


Explanation 893 a. Very low information size 894 b. Patients with higher baseline esophageal eosinophilia and more likely to have 895

failed other treatments 896 897 #11 Should anti-IgE therapy be used in patients with EoE? 898 899 Evidence Summary: There is 1 RCT of anti-IgE therapy compared to placebo. The RR 900 was not estimable because no subjects in either trial arm achieved histologic remission. 901 902 Quality of Evidence: The certainty in the effect estimate was very low. The certainty in 903 the estimate was downgraded for imprecision due to very low information size and for 904 indirectness because subjects were selected who failed topical steroid. 905 906 Discussion: A single very small RCT showed no effect of omalizumab in EoE. We 907 identified an observational cohort (Loizou 2015) (101) but elected to only consider the 908 RCT given the stronger study design and larger overall number of subjects. Quality of 909 life or harms were not described in the RCT. 910 911 912

33

Omalizumab compared to placebo for eosinophilic esophagitis

Bibliography: Clayton 2014 (102)






Risk with placebo

Risk difference with Omalizumab

Change in peak eosinophil counts/hpf (Peak eosinophils) assessed with: eos/hpf follow up: mean 16 weeks

30 (1 RCT)

⨁◯◯◯ VERY LOWa,b

- The mean change in peak eosinophil counts/hpf was 0 eos/hpfc

MD 6 eos/hpf more (4 fewer to 16 more)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; MD: Mean difference

a. Selected subjects who failed topical steroid; some had trialed PPI before and 913 some were on PPI during trial, outcome is change in mean eosinophils which may be a 914 less direct outcome to consider. 915 b. Very low information size 916 c. Personal communication with Dr. Fred Clayton that no subject in either arm 917 achieved histologic remission < 15 eos/hpf. 918 919 #12 Should montelukast be used in patients with EoE? 920 921 Evidence Summary: There is 1 RCT that compares montelukast with placebo for 922 maintenance therapy after subjects had achieved symptomatic and histologic 923 remission(90), and 4 observational studies that report outcomes after montelukast use 924 [Atwood 2003 (n=8)(103); Vanderhoof 2003 (n=8)(104); Lucendo 2011 (n=11)(105); 925 Stumphy 2011 (n=8)(106)]. Based on the RCT, the RR for the recurrence of solid food 926 dysphagia was 0.79 (95% CI 0.51 to 1.21). Failing to achieve histologic remission of < 927 15 eosinophils/high power field was not measured in this trial. 928 929

34

Quality of Evidence: The certainty in the effect estimate was very low. The certainty 930 was downgraded for serious indirectness because subjects in the study had already 931 achieved remission with topical glucocorticosteroid and for very serious imprecision due 932 to very low information size. The observational data were not summarized in an 933 evidence profile. 934 935 Discussion: The findings from the RCT are most relevant to patients who had already 936 achieved remission after taking topical glucocorticosteroids. However, the certainty 937 about the efficacy of montelukast for EoE after patients achieved remission with topical 938 glucocorticosteroid is very low. The findings are not informative for the outcome of 939 histological remission because this outcome was not measured in the single clinical trial 940 of montelukast for EoE. The trial was performed in adults and therefore the data may 941 not be applicable to children. The findings are not directly relevant for patients who are 942 newly diagnosed with EoE and have not started any previous treatments. 943 944 945 Montelukast compared to placebo for management of Eosinophilic esophagitis

Bibliography: Alexander 2017 (90)






Risk with placebo

Risk difference with montelukast

Solid food dysphagia (improvement) (Telephone symptom questionnairre)a follow up: 26 weeks

41 (1 RCT)

⨁◯◯◯ VERY LOW b,c,

RR 0.79 (0.51 to 1.21)

760 per 1000

160 fewer per 1000 (370 fewer to 160 more)


35

Explanations 946

a. The abridged dysphagia questionnaire used the questions on dysphagia frequency, 947 severity, and food impaction from the Mayo Dysphagia Questionnaire, 2-week version 948 b. All patients had first achieved remission with topical glucocorticosteroid treatment. 949 Therefore, this is indirect to our PICO question of should we use montelukast for EoE as 950 the question is very specific to should we use montelukast to maintain remission. 951 c. Large confidence interval that crosses 1; estimate based on a single RCT 952 953 954 #13 Should cromolyn be used in patients with EoE? 955 956 Evidence Summary: There is 1 RCT of cromolyn compared to placebo. Based on the 957 trial, 89% of subjects (8 out of 9) treated with cromolyn failed to achieve histologic 958 remission compared to 100% (7 out of 7) in the placebo arm. 959 960 Quality of Evidence: The certainty in the effect estimate was low. The certainty in the 961 estimate was downgraded twice for very serious imprecision given the very low number 962 of study participants and because the 95% confidence interval crosses 1. 963 964 Discussion: Mast cells are implicated in EoE pathogenesis. Therefore, targeting mast 965 cells with cromolyn has biological plausibility. The single, small study performed with 966 cromolyn does not exclude the possibility of a benefit for cromolyn in patients with EoE. 967 An observational study of 14 children with EoE treated with cromolyn found that none of 968 the children had improvement in histology or symptoms. (59) 969 970 971 Cromolyn compared to placebo for eosinophilic esophagitis

Bibliography: Lieberman 2018(107)





Risk with placebo

Risk difference with cromolyn

Not achieving histologic remission (Histologic remission) assessed with: Eos < 5/hpf follow up: mean 8 weeks

16 (1 RCT)

⨁⨁◯◯ LOWa

RR 0.89 (0.71 to 1.12)

1,000 per 1,000


36

Cromolyn compared to placebo for eosinophilic esophagitis

Bibliography: Lieberman 2018(107)





Risk with placebo

Risk difference with cromolyn


Explanation 972 a. Very serious imprecision 973

974 #14 Should anti-TNFs be used in pts with EoE? 975 976 Evidence Summary: There is one observational study, a case-series described as an 977 open-label, nonrandomized pilot T1 translational trial, that investigated the use of 978 infliximab as acute therapy in 3 adults with EoE who were steroid-resistant and included 979 patients had active EoE.(108) Three outcomes were measured: Response (as inferred 980 by study report of esophageal eosinophilic infiltration), Response (as inferred by 981 symptom score (Straumann's Criteria), and endoscopic alterations (Straumann's 982 Criteria). Results are described narratively because quantitative summary estimates 983 were not presented in the included study. 984 985 Quality of Evidence: The overall certainty in the effects was very low. The certainty was 986 rated down due to risk of bias (no control population, the possibility of selection bias. 987 and that fact outcome measures may not be well-validated). We could not assess 988 publication bias, effect size, or confounding. It is a relevant patient population, though 989 one that is refractory to standard therapy. We did rate down for indirectness given that it 990 was a population that was refractory to standard therapy. 991 992 Discussion: Active EoE was defined clinically as dysphagia (when not on anti-993 inflammatory therapy) and histologically by a peak cell density of greater than 24 994 eosinophils/ high-power field (is this also on anti-inflammatory therapy?). Included 995 patients had “inadequate response to prior treatment”. This was explained by the 996 authors as Patients 1 and 3 were almost free of symptoms during maintenance therapy 997

37

with topical fluticasone, but immediately after cessation of the medication, symptoms 998 reappeared. Patient 2 had been receiving systemic corticosteroid treatment for the past 999 8 years and needed at least 10 mg of prednisone per day for symptom control. Patients 1000 2 and 3 had previously undergone repeated dilations for the treatment of strictures. No 1001 adverse events were reported. 1002 1003 1004 #15 Should immunomodulators be used in the treatment of EoE? 1005 1006 Evidence Summary: Two observational studies were included identified that 1007 investigated the use of immunomodulators in EoE. The outcome listed in the evidence 1008 profile was response though it was variably defined in the included studies as 1009 “symptomatic remission” or “clinical remission”. Results are described narratively 1010 because quantitative summary estimates were not presented in the included study. 1011 1012 Quality of the Evidence: The certainty in the effect estimate was very low. The quality of 1013 the evidence was rated down for the lack of control populations, suspected selection 1014 bias, possible confounding, and outcomes that were not well-defined. There was also 1015 concern regarding indirectness of the included patient population, as a more severe 1016 disease phenotype, given that included patients were steroid-dependent. We did rate 1017 down for indirectness given that it was a population that was refractory to standard 1018 therapy. 1019 1020 1021 1022 Discussion: The evidence was derived from 2 papers with a total included population of 1023 4 people; therefore the evidence base for immunodulator treatment in patients with EoE 1024 is very small.(109, 110) In these case series, it is not clear if the histologic changes 1025 were related to starting the immunomodulator or other factors, such as the attempts with 1026 withdraw systemic steroid. Therefore it is difficult to draw any conclusions about how 1027 immunomodulators work for EoE. 1028 1029 1030 Narrative Summaries 1031 1032 The following 2 PICO questions are addressed as narrative summaries based on the 1033 consensus of the expert panel that data in format amenable to GRADE analysis was not 1034 available. 1035 #16 Should repeat EGD be used to assess patients with EoE after a change in 1036 treatment? 1037 1038 The role of performing upper endoscopy and biopsy for monitoring EoE biologic disease 1039 activity (endoscopic severity assessed visually with the EREFS classification and 1040 esophageal eosinophilia assessed histologically) has not been formally studied in higher 1041 quality trials. However, there are numerous studies that support performing endoscopy 1042

38

to survey disease activity. This is based on several concepts. The first is an 1043 understanding that for many patients, the natural history of untreated esophageal 1044 eosinophilia is a progression from an inflammatory to a fibrostenotic phenotype(1). 1045 Cohort studies of untreated patients and placebo groups of RCTs repeatedly 1046 demonstrate that esophageal eosinophilia does not resolve over time and that patients 1047 with EoE do not “grow out of it”(111). Further, a set of four studies from different 1048 centers in the U.S. and Europe independently show that the longer the duration of 1049 disease prior to diagnosis (as a proxy for time prior to treatment), the higher the 1050 proportion of patients who have a stricture or fibrostenotic phenotype at the time of 1051 diagnosis (12-15). For example, in one study, more than 80% of patients had strictures 1052 if the diagnostic delay was >20 years. Other studies document progression in distinct 1053 patients (112). Therefore, because there is a consequence to persistent eosinophilic 1054 inflammation in the esophagus (fibrosis leading to strictures), it is important to survey to 1055 confirm that esophageal eosinophilia has been corrected. Second, symptoms only 1056 modestly correlate with disease activity. Numerous studies have shown discordance 1057 between symptoms of esophageal dysfunction and endoscopic and histologic disease 1058 activity (18, 75, 113). There are several reasons for this. Patients can avoid foods that 1059 cause dysphagia or other symptoms, or modify the way they eat (chewing carefully, 1060 eating slowly, lubricating foods, drinking copious fluids) to minimize symptom regardless 1061 of the level of biologic disease activity. Additionally, symptoms and biologic activity do 1062 not have a linear relationship, and symptoms may remain quite mild until a certain 1063 threshold of endoscopic severity is reached. If patients have previously had an 1064 esophageal stricture and have undergone esophageal dilation, then symptoms of 1065 dysphagia will be improved regardless of underlying biologic activity. The third concept 1066 is specific for PPIs. Reflux and EoE can have a complicated relationship. In particular, 1067 the two conditions may overlap, and EoE may predispose to secondary reflux or less 1068 effective clearance of physiologic reflux (due to decreased esophageal compliance 1069 and/or the mild dysmotility)(114). In this situation, PPIs may help to treat reflux and thus 1070 improve some symptoms, but might not be effective for the underlying EoE. In sum, the 1071 chronic nature of EoE where esophageal eosinophilia can lead to progressive fibrosis, 1072 the potential discordance between symptoms and underlying biologic disease activity of 1073 EoE, and a possible non-EoE-related mechanism of potential symptom response to 1074 PPI, all suggests that endoscopy for surveillance may be effective, even in patients who 1075 have a symptom response to PPI. Reasons for not performing follow up endoscopies 1076 include potential risks of sedation impacting development in younger children, risks of 1077 repeated endoscopy, financial and time burden. These considerations need to be 1078 accounted for when balancing the risks and benefits of performing surveillance 1079 endoscopies especially in children. 1080 1081 1082 1083 #17 What is the management of patients who become asymptomatic after initial 1084 PPI treatment? 1085 1086 1087

39

The significance of esophageal eosinophilia is not a pathognomonic finding and has to 1088 be carefully considered within the appropriate clinical context. For instance, if an 1089 otherwise healthy atopic adult patient undergoes endoscopy for food impaction or 1090 dysphagia and is found to have esophageal eosinophilia, both the literature and clinical 1091 experience support a probable diagnosis of eosinophilic esophagitis and high likelihood 1092 of some response to PPIs (See Question 1). If a young child with chronic vomiting, 1093 abdominal pain and weight loss is found to have esophageal eosinophilia, a diagnosis 1094 of gastroesophageal reflux is more probable and similarly will have a high likelihood of 1095 response to PPI. Endoscopic features and associated histological findings beyond 1096 eosinophil counts should be considered supplementary to helping establish diagnostic 1097 clarity. A friable mucosa is an unusual finding in EoE, whereas extensive eosinophilic 1098 degranulation would be a much more common finding. 1099 1100 In either situation, an argument can be made for the value of a post PPI treatment 1101 follow-up endoscopy. For either diagnostic situation detailed above, resolution of 1102 eosinophilia would need to be documented to ensure healing has occurred that may 1103 potentially alter the long-term outcome. Historically, children with EoE have 1104 demonstrated a poor correlation between symptoms and inflammation. Recent data 1105 from Aceves et al has recently showed that proximal eosinophilia associates with self-1106 reported symptoms in a sample of children from CeGIR consortium centers, which may 1107 hold potential promise as a marker to monitor disease progression.(115) 1108 1109 The long term management of children and adults with esophageal eosinophilia who are 1110 treated with PPIs remains an evolving concept. If a patient is thought to have EoE, long 1111 term treatment would be indicated with appropriate follow up as described above and in 1112 Question #16. Clinical observation for side effects of PPIs is warranted. While a degree 1113 of overlap exists between EoE and GERD (116, 117), performance of a fundoplication 1114 for PPI responsive EoE is not currently recommended because of the potential anti-1115 inflammatory properties of PPIs, the theoretical concern for retention of offending food 1116 antigens in the esophagus, and worsening dysmotility due to a tight gastro-esophageal 1117 junction. 1118 1119 There are multiple unresolved additional issues, including establishing the optimal 1120 minimal duration of PPI treatment prior to repeat endoscopy, optimal dose and duration 1121 of PPI use as a primary EoE treatment, optimal duration of long-term PPI treatment if a 1122 PPI response is observed, and determining the next best treatment if inflammation 1123 persists despite PPI therapy. 1124 1125 1126 1127 SUMMARY AND CONCLUSIONS 1128 1129 In evaluating the efficacy of multiple treatments for EoE to achieve a primary outcome of 1130 reducing esophageal eosinophil counts to <15 eos/hpf, few treatments have moderate 1131 certainty of evidence for such an effect, and most have low to very low certainty of 1132 evidence for such an effect. There is moderate certainty in the evidence that topical 1133

40

glucocorticosteroids effectively reduce esophageal eosinophil counts to <15/hpf over a 1134 short-term treatment period of 4-12 weeks, but very low certainty about the effects of 1135 using topical glucocortiocsteroids as maintenance therapy given the lack of studies on 1136 this topic. Moderately certain evidence suggests that systemic glucocorticosteroids 1137 have similar efficacy rates as topical glucocorticosteroids, but at a cost of higher rates of 1138 adverse effects. Multiple dietary strategies may be effective in reducing esophageal 1139 eosinophil counts to <15/hpf over a short-term treatment period, with moderate certainty 1140 for elemental diets, low certainty for empiric 4 and 6 food elimination diets, and very low 1141 certainty for allergy-based testing dietary eliminations and empiric 1 and 2 food 1142 elimination diets. We report very low certainty for the effect of PPIs in patients with 1143 esophageal eosinophilia and for the effects of esophageal dilation in patients with EoE, 1144 although it appears to be relatively safe. We found low or very low certainty in the 1145 effects of multiple other medical treatments for EoE: anti-IL-5 therapy, anti-IL-13 1146 therapy, anti-IgE therapy montelukast, cromolyn, and anti-TNF therapy, many of which 1147 failed to exclude or confirm a benefit. Current research should focus on directly 1148 comparing available treatments with more reliable study designs, testing new 1149 treatments, using validated symptom questionnaires, and consistently measuring quality 1150 of life and nutritional status. 1151 1152 APPENDIX 1153 1154 Table of Contents: 1155 Table 1. PICO Questions 1156 Table 2. Summary of EoE outcomes considered 1157 Table 3. Electronic Search Strategies 1158 Table 4. Additional Evidence Profiles 1159 Figure 1. PRISMA Flow diagram for identifying articles 1160 Figure 2. Forest Plots for each PICO Question 1161 1162 1163 Appendix Table 1. PICO Questions 1164 1165

# Question PICO Question Method Population Intervent

ion(s) Comparator

Outcome

1 Should PPIs be used in patients with symptomatic esophageal eosinophilia?

Esophageal eosinophilia, not necessarily meeting EoE criteria

PPI

Placebo -Failing to achieve histologic remission (eosinophils<15/hpf) -Symptoms -Adverse events

GRADE

41

2 Should topical glucocortiocsteroids be used in patients with EoE?

Patients with EoE

Topical Steroids


GRADE

3 Should systemic glucocorticosteroids be used in patients with EoE?

Patients with EoE

Systemic steroids

Placebo or topical steroids

-Failing to achieve histologic remission (eosinophils<15/hpf) -Symptoms -Adverse events

GRADE

4 Should an elemental diet be used in patients with EoE?

Patients with EoE

Elemental diet

No diet change


GRADE

5 Should an empiric elimination diet be used in patients with EoE?

Patients with EoE

-6 food elimination diet -4 food elimination diet -2 food elimination diet -Single food elimination diet

No elimination diet


GRADE

42

6 Should allergy-based testing be used for the purpose of identifying food triggers in patients with EoE?

Patients with EoE

-SPT, sIGE, APT, and/or CRD to direct an elimination diet

No elimination diet


GRADE

7 Is maintenance therapy recommended in patients with EoE?

Patients with EoE who are in clinical and histologic remission

Maintaining therapy

Discontinuing therapy


GRADE

8 Should esophageal dilation be used in patients with EoE?

Patients with EoE

Dilation No dilation -Adverse events

GRADE

9 Should anti-IL-5 therapy be used in patients with EoE?

Patients with EoE

Anti-IL-5 therapy


GRADE

10

Should anti-IL-13 therapy be used in patients with EoE?

Patients with EoE

Anti-IL-13 therapy


GRADE

43

11

Should anti-IgE therapy be used in patients with EoE?

Patients with EoE

Anti-IgE therapy


GRADE

12

Should montelukast be used in patients with EoE?

Patients with EoE

Montelukast


GRADE

13

Should cromolyn be used in patients with EoE?

Patients with EoE

Cromolyn Placebo -Failing to achieve histologic remission (eosinophils<15/hpf) -Symptoms -Adverse events

GRADE

14

Should anti-TNFs be used in patients with EoE?

Patients with EoE

Anti-TNF Placebo -Failing to achieve histologic remission (eosinophils<15/hpf) -Symptoms -Adverse events

GRADE

15

Should Immunomodulators be used in patients with EoE?

Patients with EoE

Azathioprine or 6-MP


GRADE

44

16

Should repeat EGD be used to assess patients with EoE after a change in treatment?

Patients with EoE

EGD with Esophageal biopsy

N/A N/A Narrative

17

Management of patients who become asymptomatic on initial PPI treatment

Patients with esophageal eosinophilia and/or EoE

Repeat EGD, followed by additional therapy if eosinophils still elevated

No EGD, no change in treatment


Narrative

1166 1167 1168 1169 Appendix Table 2. Summary of EoE outcomes considered 1170 1171

Name of Outcome Definition Minimally Important Difference

Rating (1-9)

Critical vs Important vs Non-important

Histology eosinophil counts <15/hpf in esophagus

Not known 8 Critical

Symptoms DSQ, MDQ, EEsAI, PEES

Response: 30-50% improvement Remission: Absence of symptoms. For EEsAI, score <30 may indicate inactive disease/remission

6 Important

Endoscopic Findings (EREFS) Response: 30-50% improvement

6 Important

45

Remission: normalization

Complications of EoE Stricture Food impaction Malnutrition psychiatric

N/A 8 Critical

Quality of Life Peds EoE QL Adult Eoe QL

Response: 30-50% improvement as response Remission: Baseline for healthy people

6 Important

Biomarkers Peripheral Eos Progenitor Eos Gene Expression Cytosponge EST readout Tissue cytokines eosinophil granules

N/A 4 Non-important

Adverse Events of Medication Treatment

Allergy Weight gain Anaphylaxis Infections

N/A 6 Important

Complications of endoscopy

Perforation Anesthesia complications

N/A 8 Critical

Costs N/A 6 Important 1172 Appendix Table 3. Electronic Search Strategies 1173 1174 Search Strategy 1175 EoE – Final Search 1176 1177 Search date: May 13, 2018 1178 Databases searched: Ovid MEDLINE: Epub Ahead of Print, In-Process & Other Non-1179 Indexed Citations, Ovid MEDLINE® Daily and Ovid MEDLINE® 1946-Present, Embase 1180 Classic+Embase 1947 to 2018 May 11; Wiley Cochrane. Individual systematic review 1181

46

searches were not registered in Prospero, as this technical report represents an 1182 umbrella evidence review. 1183 1184 Ovid MEDLINE(R), Embase 1185

# Searches Results

1 exp Eosinophilic Esophagitis/ 5991

2 (eosinophilic adj2 (esophagitis or oesophagitis)).ti,ab. 6556

3 1 or 2 7480

4 exp EOSINOPHILIA/ 62171

5 exp ESOPHAGITIS/ 45445

6 exp ESOPHAGUS/ 133201

7 4 and (5 or 6) 2855

8 eoe.ti,ab. 3588

9 3 and (7 or 8) 4580

10 exp Adrenal Cortex Hormones/ use ppez 376133

11 exp corticosteroid/ use emczd 935731

12 (corticosteroid* or steroid* or prednisone or budesonide or fluticasone).ti,ab. 786701

13 exp Leukotriene Antagonists/ use ppez 2974

14 exp leukotriene receptor blocking agent/ use emczd 18407

15 exp montelukast/ use emczd 8443

16 (montelukast or singulair).mp. 10840

17 exp Proton Pump Inhibitors/ use ppez 16773

18 exp proton pump inhibitor/ use emczd 68622

19 (proton pump inhibitor* or PPI* or omeprazole or Prilosec or Yosprala or lansoprazole or Prevacid or dexlansoprazole or Dexilent or rabeprazole or Aciphex or pantoprazole or Protonix or esomeprazole or Nexium or Vimovo or Zegerid).ti,ab.

88470

20 exp monoclonal antibody/ use emczd 480638

21 exp Antibodies, Monoclonal, Humanized/ use ppez 39896

22 exp Interleukin-5/ai [Antagonists & Inhibitors] 293

23 exp Receptors, Interleukin-5/ai [Antagonists & Inhibitors] 31

47

24 exp interleukin 5/ use emczd 25332

25 (anti-il-5* or Interleukin-5 or Mepolizumab or nucala or Reslizumab or Cinqair or Benralizumab or fasenra).ti,ab.

6850


27 interleukin 13/ use emczd 20432


29 exp interleukin 4/ use emczd 71100

30 (Dupilumab or Dupixent or anti-il-13* or anti-il-4* or Interleukin-13 or Interleukin-4).ti,ab.

26804

31 exp Immunoglobulin E/ai [Antagonists & Inhibitors] 20

32 immunoglobulin e/ use emczd or immunoglobulin e antibody/ use emczd 80681

33 (anti-IGE or Omalizumab or Xolair).mp. 14248

34 exp Dilatation/ use ppez 10447

35 exp esophagus dilatation/ use emczd 3265

36 (dilation or dilatation).ti,ab. 210743

37 exp Immunologic Factors/ use ppez 1274605

38 exp immunomodulating agent/ use emczd 1045440

39 immunomodulator*.ti,ab. 93101

40 exp Mercaptopurine/ 46362

41 (6-Mercaptopurine or 6-MP or Purinethol or Purixan or azothioprine or Azathioprine or Azasan or Imuran).ti,ab.

46642

42 exp Tumor Necrosis Factor-alpha/ai [Antagonists & Inhibitors] 14168

43 tumor necrosis factor inhibitor/ use emczd 10354

44 (Infliximab or remicade or adalimumab or humira or golimumab or simponi or vedolizumab or entyvio or tofacitinib or Xeljanz or Jakvinus).ti,ab.

45437

45 exp Cromolyn Sodium/ use ppez 4044

46 exp cromoglycate disodium/ use emczd 15471

47 cromolyn.ti,ab. 2968

48 Food Hypersensitivity/di [Diagnosis] 6271

49 exp Protein Array Analysis/ use ppez 7467

48

50 exp IMMUNOASSAY/ use ppez 475054

51 exp allergy test/ use emczd or exp food allergy/ use emczd 35286

52 (Component Resolved Diagnostic Testing or crd).ti,ab. 6533

53 (test* adj2 (allerg* or hypersensitivit*)).ti,ab. 17189

54 or/10-53 4631827

55 9 and 54 2875

56 (Randomized Controlled Trial or Pragmatic Clinical Trial or meta-analysis).pt. 550035

57 exp Randomized Controlled Trials as Topic/ 263799

58 "Randomized Controlled Trial (topic)"/ 145282

59 Randomized Controlled Trial/ or Randomization/ or Random Allocation/ or Double-Blind Method/ or Double Blind Procedure/ or Double-Blind Studies/ or Single-Blind Method/ or Single Blind Procedure/ or Single-Blind Studies/ or Placebos/ or Placebo/

1420748

60 meta-analysis/ or systematic review/ or meta-analysis as topic/ or "meta analysis (topic)"/ or "systematic review (topic)"/ or exp technology assessment, biomedical/

416180

61 (random* or sham or placebo*).ti,ab,hw,kf,kw. 3100357

62 ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf,kw. 491550

63 ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf,kw. 1696

64 ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab,kf,kw.

303565

65 ((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or overview*))).ti,ab,kf,kw.

19173

66 ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab,kf,kw.

49299

67 (data synthes* or data extraction* or data abstraction* or handsearch* or hand search or mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square* or met analy* or metanaly* or technology assessment* or HTA or HTAs or technology overview* or technology appraisal* or meta regression* or metaregression* or outcomes research or relative effectiveness).ti,ab,kf,kw.

151747

68 (cochrane or (health adj2 technology assessment) or evidence report).jw. 44072

69 (meta-analy* or metaanaly* or systematic review* or biomedical technology assessment* or bio-medical technology assessment*).mp,hw.

594805

49

70 (medline or cochrane or pubmed or medlars or embase or cinahl).ti,ab,hw. 387579

71 (meta-analysis or systematic review).md. 0

72 (comparative adj3 (efficacy or effectiveness)).ti,ab,kf,kw. 27349

73 ((indirect or indirect treatment or mixed-treatment) adj comparison*).ti,ab,kf,kw.

4938

74 or/56-73 3749981

75 55 and 74 420

76 exp diet therapy/ 380595

77 (diet* adj2 (6 food or six food or elimination or elemental)).ti,ab. 5676

78 76 or 77 385128

79 9 and 78 875

80 75 or 79 1166

81 animals/ not (humans/ and animals/) 5768520

82 80 not 81 1163

83 limit 82 to (case reports or comment or editorial or letter or conference abstract or note) [Limit not valid in Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher,Embase; records were retained]

418

84 case report/ 4211687

85 82 not (83 or 84) 722

86 remove duplicates from 85 496 1186 Wiley Cochrane 1187 ID Search Hits 1188 #1 MeSH descriptor: [Eosinophilic Esophagitis] explode all trees 26 1189 #2 (eosinophilic near/2 (esophagitis or oesophagitis)):ti,ab 126 1190 #3 #1 or #2 128 1191 #4 MeSH descriptor: [Eosinophilia] explode all trees 240 1192 #5 MeSH descriptor: [Esophagitis] explode all trees 680 1193 #6 MeSH descriptor: [Esophagus] explode all trees 1282 1194 #7 #4 and (#5 or #6) 36 1195 #8 eoe:ti,ab 86 1196 #9 #3 or #7 or #8 131 1197 #10 MeSH descriptor: [Adrenal Cortex Hormones] explode all trees 13563 1198

50

#11 (corticosteroid* or steroid* or prednisone or budesonide or 1199 fluticasone):ti,ab 35079 1200 #12 MeSH descriptor: [Leukotriene Antagonists] explode all trees 439 1201 #13 (montelukast or singulair):ti,ab 1269 1202 #14 MeSH descriptor: [Proton Pump Inhibitors] explode all trees 1302 1203 #15 (proton pump inhibitor* or PPI* or omeprazole or Prilosec or Yosprala or 1204 lansoprazole or Prevacid or dexlansoprazole or Dexilent or rabeprazole or Aciphex or 1205 pantoprazole or Protonix or esomeprazole or Nexium or Vimovo or Zegerid):ti,ab 1206 6841 1207 #16 MeSH descriptor: [Antibodies, Monoclonal, Humanized] explode all trees 1208 3971 1209 #17 MeSH descriptor: [Interleukin-5] explode all trees 159 1210 #18 MeSH descriptor: [Receptors, Interleukin-5] explode all trees 9 1211 #19 (anti-il-5* or Interleukin-5 or Mepolizumab or nucala or Reslizumab or 1212 Cinqair or Benralizumab or fasenra):ti,ab 806 1213 #20 MeSH descriptor: [Interleukin-13] explode all trees 81 1214 #21 MeSH descriptor: [Interleukin-4] explode all trees 332 1215 #22 (Dupilumab or Dupixent or anti-il-13* or anti-il-4* or Interleukin-13 or 1216 Interleukin-4):ti,ab 873 1217 #23 MeSH descriptor: [Immunoglobulin E] explode all trees 1287 1218 #24 (anti-IGE or Omalizumab or Xolair):ti,ab 704 1219 #25 MeSH descriptor: [Dilatation] explode all trees 420 1220 #26 (dilation or dilatation):ti,ab 6065 1221 #27 MeSH descriptor: [Immunologic Factors] explode all trees 8197 1222 #28 immunomodulator*:ti,ab 2491 1223 #29 MeSH descriptor: [Mercaptopurine] explode all trees 1304 1224 #30 (6-Mercaptopurine or 6-MP or Purinethol or Purixan or azothioprine or 1225 Azathioprine or Azasan or Imuran):ti,ab 2101 1226 #31 MeSH descriptor: [Tumor Necrosis Factor-alpha] explode all trees 1227 3094 1228 #32 (Infliximab or remicade or adalimumab or humira or golimumab or simponi 1229 or vedolizumab or entyvio or tofacitinib or Xeljanz or Jakvinus):ti,ab 3531 1230 #33 MeSH descriptor: [Cromolyn Sodium] explode all trees 705 1231 #34 cromolyn:ti,ab 332 1232 #35 MeSH descriptor: [Food Hypersensitivity] explode all trees 731 1233 #36 MeSH descriptor: [Protein Array Analysis] explode all trees 34 1234 #37 MeSH descriptor: [Immunoassay] explode all trees 4804 1235 #38 (Component Resolved Diagnostic Testing or crd):ti,ab 166 1236 #39 (test* near/2 (allerg* or hypersensitivit*)):ti,ab 756 1237 #40 MeSH descriptor: [Diet Therapy] explode all trees 5354 1238 #41 (diet* near/2 (6 food or six food or elimination or elemental)):ti,ab 306 1239 #42 #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 1240 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or 1241 #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 86910 1242 #43 #9 and #42 103 1243 1244

51

. 1245 1246 1247 1248 1249 1250

1251

52

Appendix Table 4. Additional Evidence Profile 1252 1253 Bibliography: Peterson 2010, Moawad 2013 1254

Certainty assessment № of patients Effect

Certainty

Importance

№ of studie

s

Study design

Risk of

bias

Inconsistency

Indirectness

Imprecision

Other consideratio

ns

Topical

Steroids

PPI

Relative

(95% CI)

Absolute

(95% CI)

Failure to achieve histologic response (assessed with: < 15 Eos/hpf)

2 randomised trials

not serious

not serious serious a serious b none 53/88 (60.2%

)

55/88 (62.5%)

RR 0.96 (0.76

to 1.22)

25 fewer per

1,000 (from 137

more to 150

fewer)

⨁⨁◯◯

LOW

CRITICAL

CI: Confidence interval; RR: Risk ratio 1255

Explanations 1256 a. No PPI trial before steroids (so GERD is possible confounder) 1257 b. Clinical management would vary at ends of CI 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283

53

Figure 1. PRISMA Flow Diagram 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324

Records identified through database searching

(n = 453 )

Additional records identified through other sources (expert input and systematic reviews)

(n = 47)* All studies that were identified before the search (and not specifically searched for)

Records after duplicates removed (n =500)

Records screened (n =500 )

Records excluded (n =373 )

Full-text articles assessed for eligibility

(n =127 )

Full-text articles excluded, with reasons

(n =40 ) Most excluded because

systematic reviews, others failed to meet

inclusion/exclusion

Studies included in qualitative/quantitative

synthesis (n = 87 )

54

Figure 2. Forest Plots for each PICO question 1325 1326 #1 Should proton pump inhibitors be used in patients with esophageal 1327 eosinophilia? 1328 1329

1330 1331 1332 1333 1334 #2 Should topical glucocorticosteroids be used in patients with EoE? 1335 1336 1337

1338 1339 1340 1341

55

Adverse events in topical steroids compared to placebo 1342 1343

1344 1345 1346 #3 Should systemic glucocorticosteroids be used in patients with EoE? 1347 1348 Forest plot not shown (only 1 study) 1349 1350 1351 #4 Should an elemental diet be used in patients with EoE? 1352 1353

1354 1355 #5 Should an empiric food elimination diet be used in patients with EoE? 1356 1357 6 food elimination 1358

1359

56

1360 4 food elimination 1361

1362 2 food elimination 1363

1364 Single food elimination 1365

1366 1367 1368 #6 Should allergy-based testing be used for the purpose of identifying food 1369 triggers in patients with EoE? 1370

1371 1372

57

Studies including patch testing 1373

1374 Studies not using patch testing 1375

1376 1377 #7 Should maintenance therapy be recommended in patients with EoE? 1378 1379 Forest Plot not shown (only 1 study) 1380 1381 #8 Should esophageal dilation be used in patients with EoE? 1382 1383 1384 1385 Clinical Improvement: 1386 1387

1388 1389

58

1390 1391 1392 Mortality 1393 1394

1395 1396 1397 Perforation 1398 1399

1400 1401 1402 Hospitalizations 1403

59

1404 1405 1406

60

1407 1408 Hemorrhage 1409

1410 1411 1412 1413 #9 Should anti-IL-5 therapy be used in patients with EoE? 1414 1415

1416 1417 1418 #10 Should anti-IL-13 therapy be used in patients with EoE? 1419 1420 Forest plot not shown (only 1 study) 1421 1422 #11 Should anti-IgE therapy be used in patients with EoE? 1423 1424 Forest plot not shown (only 1 study) 1425 1426 #12 Should montelukast be used in patients with EoE? 1427 1428 Forest plot not shown (only 1 study) 1429 1430 #13 Should cromolyn be used in patients with EoE? 1431 1432 Forest plot not shown (only 1 study) 1433 1434 #14 Should anti-TNFs be used in pts with EoE? 1435 1436 Forest plot not shown (only 1 study) 1437

61

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inhibitor-responsive oesophageal eosinophilia is a GERD-related phenomenon. Aliment 1588 Pharmacol Ther. 2016;44(5):522-30. 1589 43. Philpott H, Nandurkar S, Royce S, Thien F, Gibson P. A prospective open clinical trial of 1590 a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis. 1591 Alimentary pharmacology & therapeutics [Internet]. 2016; 43(9):[985-93 pp.]. Available from: 1592 http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/852/CN-01140852/frame.html. 1593 44. Sayej WN, Patel R, Baker RD, Tron E, Baker SS. Treatment with high-dose proton pump 1594 inhibitors helps distinguish eosinophilic esophagitis from noneosinophilic esophagitis. J Pediatr 1595 Gastroenterol Nutr. 2009;49(4):393-9. 1596 45. Dranove JE, Horn DS, Davis MA, Kernek KM, Gupta SK. Predictors of response to 1597 proton pump inhibitor therapy among children with significant esophageal eosinophilia. The 1598 Journal of pediatrics. 2009;154(1):96-100. 1599 46. Schroeder S, Capocelli KE, Masterson JC, Harris R, Protheroe C, Lee JJ, et al. Effect of 1600 proton pump inhibitor on esophageal eosinophilia. J Pediatr Gastroenterol Nutr. 2013;56(2):166-1601 72. 1602 47. Rea F, Caldaro T, Tambucci R, Romeo EF, Caloisi C, Torroni F, et al. Eosinophilic 1603 esophagitis: Is it also a surgical disease? Journal of Pediatric Surgery. 2013;48(2):304-8. 1604 48. Dhaliwal J, Tobias V, Sugo E, Varjavandi V, Lemberg D, Day A, et al. Eosinophilic 1605 esophagitis in children with esophageal atresia. Dis Esophagus. 2014;27(4):340-7. 1606 49. Gutierrez-Junquera C, Fernandez-Fernandez S, Cilleruelo ML, Rayo A, Echeverria L, 1607 Quevedo S, et al. High Prevalence of Response to Proton-pump Inhibitor Treatment in Children 1608 With Esophageal Eosinophilia. J Pediatr Gastroenterol Nutr. 2016;62(5):704-10. 1609 50. Straumann A, Conus S, Degen L, Frei C, Bussmann C, Beglinger C, et al. Long-Term 1610 Budesonide Maintenance Treatment Is Partially Effective for Patients With Eosinophilic 1611 Esophagitis. Clinical Gastroenterology and Hepatology. 2011;9(5):400-9.e1. 1612 51. Schaefer E, Fitzgerald J, Molleston J, Croffie J, Pfefferkorn M, Corkins M, et al. 1613 Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic 1614 esophagitis: a randomized trial in children. Clinical gastroenterology and hepatology [Internet]. 1615 2008; 6(2):[165-73 pp.]. Available from: http://cochranelibrary-1616 wiley.com/o/cochrane/clcentral/articles/409/CN-00622409/frame.html. 1617 52. Moawad FJ, Veerappan GR, Dias JA, Baker TP, Maydonovitch CL, Wong RKH. 1618 Randomized controlled trial comparing aerosolized swallowed fluticasone to esomeprazole for 1619 esophageal eosinophilia. American Journal of Gastroenterology. 2013;108(3):366-72. 1620 53. Dellon E, Sheikh A, Speck O, Woodward K, Whitlow A, Hores J, et al. Viscous topical is 1621 more effective than nebulized steroid therapy for patients with eosinophilic esophagitis. 1622 Gastroenterology [Internet]. 2012; 143(2):[321-4.e1 pp.]. Available from: http://cochranelibrary-1623 wiley.com/o/cochrane/clcentral/articles/750/CN-00832750/frame.html. 1624 54. Bhardwaj N, Ishmael F, Lehman E, Bethards D, Ruggiero F, Ghaffari G. Effect of topical 1625 beclomethasone on inflammatory markers in adults with eosinophilic esophagitis: A pilot study. 1626 Allergy & Rhinology. 2017;8(2):85-94. 1627 55. Philpott H, Dougherty MK, Reed CC, Caldwell M, Kirk D, Torpy DJ, et al. Systematic 1628 review: adrenal insufficiency secondary to swallowed topical corticosteroids in eosinophilic 1629 oesophagitis. Aliment Pharmacol Ther. 2018;47(8):1071-8. 1630 56. Chang A, Robison R, Cai M, Singh AM. Natural History of Food-Triggered Atopic 1631 Dermatitis and Development of Immediate Reactions in Children. The journal of allergy and 1632 clinical immunology In practice. 2016;4(2):229-36.e1. 1633 57. Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. 1634 Randomized trial of peanut consumption in infants at risk for peanut allergy. The New England 1635 journal of medicine. 2015;372(9):803-13. 1636

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58. Kelly KJ, Lazenby AJ, Rowe PC, Yardley JH, Perman JA, Sampson HA. Eosinophilic 1637 esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based 1638 formula. Gastroenterology. 1995;109(5):1503-12. 1639 59. Liacouras CA, Spergel JM, Ruchelli E, Verma R, Mascarenhas M, Semeao E, et al. 1640 Eosinophilic esophagitis: A 10-year experience in 381 children. Clinical Gastroenterology and 1641 Hepatology. 2005;3(12):1198-206. 1642 60. Henderson CJ, Abonia JP, King EC, Putnam PE, Collins MH, Franciosi JP, et al. 1643 Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis. 1644 The Journal of allergy and clinical immunology. 2012;129(6):1570-8. 1645 61. Peterson KA, Byrne KR, Vinson LA, Ying J, Boynton KK, Fang JC, et al. Elemental diet 1646 induces histologic response in adult eosinophilic esophagitis. American Journal of 1647 Gastroenterology. 2013;108(5):759-66. 1648 62. Leung J, Mehrzad R, Hundal NV, Alejos A, Hesterberg PE, Katz AJ, et al. Longitudinal 1649 Perspective on Managing Refractory Eosinophilic Esophagitis. The journal of allergy and clinical 1650 immunology In practice. 2015;3(6):951-6. 1651 63. Warners MJ, Vlieg-Boerstra BJ, Verheij J, van Rhijn BD, Van Ampting MTJ, Harthoorn 1652 LF, et al. Elemental diet decreases inflammation and improves symptoms in adult eosinophilic 1653 oesophagitis patients. Alimentary Pharmacology and Therapeutics. 2017;45(6):777-87. 1654 64. Kagalwalla AF, Sentongo TA, Ritz S, Hess T, Nelson SP, Emerick KM, et al. Effect of 1655 six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clinical 1656 Gastroenterology & Hepatology. 2006;4(9):1097-102. 1657 65. Gonsalves N, Yang GY, Doerfler B, Ritz S, Ditto AM, Hirano I. Elimination diet effectively 1658 treats eosinophilic esophagitis in adults; Food reintroduction identifies causative factors. 1659 Gastroenterology. 2012;142(7):1451-9.e1. 1660 66. Henderson CJ, Abonia JP, King EC, Putnam PE, Collins MH, Franciosi JP, et al. 1661 Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis. 1662 Journal of Allergy & Clinical Immunology. 2012;129(6):1570-8. 1663 67. Lucendo A, Arias Á, González-Cervera J, Yagüe-Compadre J, Guagnozzi D, Angueira 1664 T, et al. Empiric 6-food elimination diet induced and maintained prolonged remission in patients 1665 with adult eosinophilic esophagitis: a prospective study on the food cause of the disease. 1666 Journal of allergy and clinical immunology [Internet]. 2013; 131(3):[797-804 pp.]. Available from: 1667 http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/622/CN-00965622/frame.html. 1668 68. Colson D, Kalach N, Soulaines P, Vannerom Y, Campeotto F, Talbotec C, et al. The 1669 Impact of Dietary Therapy on Clinical and Biologic Parameters of Pediatric Patients with 1670 Eosinophilic Esophagitis. Journal of Allergy and Clinical Immunology: In Practice. 1671 2014;2(5):587-93. 1672 69. Rodriguez-Sanchez J, Gomez Torrijos E, Lopez Viedma B, De La Santa Belda E, Martin 1673 Davila F, Garcia Rodriguez C, et al. Efficacy of IgE-targeted vs empiric six-food elimination diets 1674 for adult eosinophilic oesophagitis. Allergy: European Journal of Allergy and Clinical 1675 Immunology. 2014;69(7):936-42. 1676 70. Philpott H, Nandurkar S, Royce SG, Thien F, Gibson PR. A prospective open clinical trial 1677 of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis. 1678 Alimentary Pharmacology and Therapeutics. 2016;43(9):985-93. 1679 71. Molina-Infante J, Arias A, Alcedo J, Garcia-Romero R, Casabona-Frances S, Prieto-1680 Garcia A, et al. Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: 1681 The 2-4-6 study. Journal of Allergy and Clinical Immunology. 2018;141(4):1365-72. 1682 72. Reed CC, Fan C, Koutlas NT, Shaheen NJ, Dellon ES. Food elimination diets are 1683 effective for long-term treatment of adults with eosinophilic oesophagitis. Alimentary 1684 Pharmacology and Therapeutics. 2017;46(9):836-44. 1685

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73. Homan M, Blagus R, Koren Jeverica A, Orel R. Pediatric eosinophilic esophagitis in 1686 Slovenia: Data from a retrospective 2005-2012 epidemiological study. Journal of Pediatric 1687 Gastroenterology and Nutrition. 2015;61(3):313-8. 1688 74. Kagalwalla AF, Wechsler JB, Amsden K, Schwartz S, Makhija M, Olive A, et al. Efficacy 1689 of a 4-Food Elimination Diet for Children With Eosinophilic Esophagitis. Clinical 1690 Gastroenterology and Hepatology. 2017;15(11):1698-707.e7. 1691 75. Reed CC, Safta AM, Qasem S, Angie Almond M, Dellon ES, Jensen ET. Combined and 1692 Alternating Topical Steroids and Food Elimination Diet for the Treatment of Eosinophilic 1693 Esophagitis. Digestive Diseases and Sciences. 2018:1-8. 1694 76. Kagalwalla AF, Amsden K, Shah A, Ritz S, Manuel-Rubio M, Dunne K, et al. Cow's milk 1695 elimination: a novel dietary approach to treat eosinophilic esophagitis. J Pediatr Gastroenterol 1696 Nutr. 2012;55(6):711-6. 1697 77. Kruszewski PG, Russo JM, Franciosi JP, Varni JW, Platts-Mills TAE, Erwin EA. 1698 Prospective, comparative effectiveness trial of cow's milk elimination and swallowed fluticasone 1699 for pediatric eosinophilic esophagitis. Diseases of the Esophagus. 2016;29(4):377-84. 1700 78. Quaglietta L, Coccorullo P, Miele E, Pascarella F, Troncone R, Staiano A. Eosinophilic 1701 oesophagitis and coeliac disease: is there an association? Aliment Pharmacol Ther. 1702 2007;26(3):487-93. 1703 79. Rizo Pascual JM, De La Hoz Caballer B, Redondo Verge C, Terrados Cepeda S, Roy 1704 Arino G, Riesco Lopez JM, et al. Allergy assessment in children with eosinophilic esophagitis. 1705 Journal of Investigational Allergology & Clinical Immunology. 2011;21(1):59-65. 1706 80. Molina-Infante J, Martin-Noguerol E, Alvarado-Arenas M, Porcel-Carreno SL, Jimenez-1707 Timon S, Hernandez-Arbeiza FJ. Selective elimination diet based on skin testing has suboptimal 1708 efficacy for adult eosinophilic esophagitis. The Journal of allergy and clinical immunology. 1709 2012;130(5):1200-2. 1710 81. Spergel JM, Brown-Whitehorn TF, Cianferoni A, Shuker M, Wang ML, Verma R, et al. 1711 Identification of causative foods in children with eosinophilic esophagitis treated with an 1712 elimination diet. Journal of Allergy and Clinical Immunology. 2012;130(2):461-7.e5. 1713 82. Al-Hussaini A, Al-Idressi E, Al-Zahrani M. The role of allergy evaluation in children with 1714 eosinophilic esophagitis. Journal of Gastroenterology. 2013;48(11):1205-12. 1715 83. Syrigou E, Angelakopoulou A, Zande M, Panagiotou I, Roma E, Pitsios C. Allergy-test-1716 driven elimination diet is useful in children with eosinophilic esophagitis, regardless of the 1717 severity of symptoms. Pediatric Allergy and Immunology. 2015;26(4):323-9. 1718 84. Van Rhijn BD, Verheij J, Van Den Bergh Weerman MA, Verseijden C, Van Den 1719 Wijngaard RMJGJ, De Jonge WJ, et al. Histological Response to Fluticasone Propionate in 1720 Patients with Eosinophilic Esophagitis is Associated with Improved Functional Esophageal 1721 Mucosal Integrity. American Journal of Gastroenterology. 2015;110(9):1289-97. 1722 85. Constantine G, Seth N, Chokshi N, Minard CG, Guffey D, Olive AP, et al. Combination 1723 Steroid and Test-based Food Elimination for Eosinophilic Esophagitis: A Retrospective Analysis. 1724 Journal of Pediatric Gastroenterology and Nutrition. 2017;64(6):933-8. 1725 86. Andreae DA, Hanna MG, Magid MS, Malerba S, Andreae MH, Bagiella E, et al. 1726 Swallowed Fluticasone Propionate Is an Effective Long-Term Maintenance Therapy for Children 1727 With Eosinophilic Esophagitis. The American journal of gastroenterology. 2016;111(8):1187-97. 1728 87. Dellon ESKD CM, Hamdi M, et al. . Safety and efficacy of oral budesonide suspension 1729 for maintenance therapy in eosinophilic 1730 esophagitis: results from a prospective open-label study 1731 of adolescents and adults. . Gastroenterology 2016;150(Suppl 1732 1):S188 (Ab 953). 1733 88. Greuter T, Bussmann C, Safroneeva E, Schoepfer AM, Biedermann L, Vavricka SR, et 1734 al. Long-Term Treatment of Eosinophilic Esophagitis With Swallowed Topical Corticosteroids: 1735

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Development and Evaluation of a Therapeutic Concept. The American journal of 1736 gastroenterology. 2017;112(10):1527-35. 1737 89. Eluri S, Runge TM, Hansen J, Kochar B, Reed CC, Robey BS, et al. Diminishing 1738 Effectiveness of Long-Term Maintenance Topical Steroid Therapy in PPI Non-Responsive 1739 Eosinophilic Esophagitis. Clin Transl Gastroenterol. 2017;8(6):e97. 1740 90. Alexander J, Ravi K, Enders F, Geno D, Kryzer L, Mara K, et al. Montelukast Does not 1741 Maintain Symptom Remission After Topical Steroid Therapy for Eosinophilic Esophagitis. 1742 Clinical gastroenterology and hepatology [Internet]. 2017; 15(2):[214-21.e2 pp.]. Available from: 1743 http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/040/CN-01333040/frame.html. 1744 91. Molina-Infante J, Rodriguez-Sanchez J, Martinek J, van Rhijn BD, Krajciova J, Rivas 1745 MD, et al. Long-Term Loss of Response in Proton Pump Inhibitor-Responsive Esophageal 1746 Eosinophilia Is Uncommon and Influenced by CYP2C19 Genotype and Rhinoconjunctivitis. The 1747 American journal of gastroenterology. 2015;110(11):1567-75. 1748 92. Lucendo AJ, Arias A, Gonzalez-Cervera J, Yague-Compadre JL, Guagnozzi D, Angueira 1749 T, et al. Empiric 6-food elimination diet induced and maintained prolonged remission in patients 1750 with adult eosinophilic esophagitis: A prospective study on the food cause of the disease. 1751 Journal of Allergy and Clinical Immunology. 2013;131(3):797-804. 1752 93. Philpott H, Nandurkar S, Royce SG, Thien F, Gibson PR. A prospective open clinical trial 1753 of a proton pump inhibitor, elimination diet and/or budesonide for eosinophilic oesophagitis. 1754 Aliment Pharmacol Ther. 2016;43(9):985-93. 1755 94. Dougherty M, Runge TM, Eluri S, Dellon ES. Esophageal dilation with either bougie or 1756 balloon technique as a treatment for eosinophilic esophagitis: a systematic review and meta-1757 analysis. Gastrointestinal Endoscopy. 2017;86(4):581-91.e3. 1758 95. Moole H, Jacob K, Duvvuri A, Moole V, Dharmapuri S, Boddireddy R, et al. Role of 1759 endoscopic esophageal dilation in managing eosinophilic esophagitis. Medicine (United States). 1760 2017;96 (14) (no pagination)(e5877). 1761 96. Moawad FJ, Molina-Infante J, Lucendo AJ, Cantrell SE, Tmanova L, Douglas KM. 1762 Systematic review with meta-analysis: endoscopic dilation is highly effective and safe in children 1763 and adults with eosinophilic oesophagitis. Alimentary Pharmacology and Therapeutics. 1764 2017;46(2):96-105. 1765 97. Straumann A, Conus S, Grzonka P, Kita H, Kephart G, Bussmann C, et al. Anti-1766 interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a 1767 randomised, placebo-controlled, double-blind trial. Gut [Internet]. 2010; 59(1):[21-30 pp.]. 1768 Available from: http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/524/CN-1769 00730524/frame.html. 1770 98. Assa'ad AH, Gupta SK, Collins MH, Thomson M, Heath AT, Smith DA, et al. An antibody 1771 against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with 1772 eosinophilic esophagitis. Gastroenterology. 2011;141(5):1593-604. 1773 99. Spergel JM, Rothenberg ME, Collins MH, Furuta GT, Markowitz JE, Fuchs G, 3rd, et al. 1774 Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, 1775 randomized, placebo-controlled trial. Journal of Allergy & Clinical Immunology. 2012;129(2):456-1776 63, 63.e1-3. 1777 100. Rothenberg M, Wen T, Greenberg A, Alpan O, Enav B, Hirano I, et al. Intravenous anti-1778 IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis. Journal of allergy and clinical 1779 immunology [Internet]. 2014; 135(2):[500-7 pp.]. Available from: http://cochranelibrary-1780 wiley.com/o/cochrane/clcentral/articles/719/CN-01072719/frame.html. 1781 101. Loizou D, Enav B, Komlodi-Pasztor E, Hider P, Kim-Chang J, Noonan L, et al. A pilot 1782 study of omalizumab in eosinophilic esophagitis. PLoS ONE. 2015;10 (3) (no 1783 pagination)(e0113483). 1784

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102. Clayton F, Fang JC, Gleich GJ, Lucendo AJ, Olalla JM, Vinson LA, et al. Eosinophilic 1785 esophagitis in adults is associated with IgG4 and not mediated by IgE. Gastroenterology. 1786 2014;147(3):602-9. 1787 103. Attwood SE, Lewis CJ, Bronder CS, Morris CD, Armstrong GR, Whittam J. Eosinophilic 1788 oesophagitis: a novel treatment using Montelukast. Gut. 2003;52(2):181-5. 1789 104. Vanderhoof JA, Young RJ, Hanner TL, Kettlehut B. Montelukast: use in pediatric 1790 patients with eosinophilic gastrointestinal disease. J Pediatr Gastroenterol Nutr. 2003;36(2):293-1791 4. 1792 105. Lucendo AJ, De Rezende LC, Jimenez-Contreras S, Yague-Compadre JL, Gonzalez-1793 Cervera J, Mota-Huertas T, et al. Montelukast was inefficient in maintaining steroid-induced 1794 remission in adult eosinophilic esophagitis. Dig Dis Sci. 2011;56(12):3551-8. 1795 106. Stumphy J, Al-Zubeidi D, Guerin L, Mitros F, Rahhal R. Observations on use of 1796 montelukast in pediatric eosinophilic esophagitis: insights for the future. Dis Esophagus. 1797 2011;24(4):229-34. 1798 107. Lieberman JA, Zhang J, Whitworth J, Cavender C. A randomized, double-blinded, 1799 placebo-controlled study of the use of viscous oral cromolyn sodium for the treatment of 1800 eosinophilic esophagitis. Annals of Allergy, Asthma and Immunology. 2018;120(5):527-31. 1801 108. Straumann A, Bussmann C, Conus S, Beglinger C, Simon HU. Anti-TNF-alpha 1802 (infliximab) therapy for severe adult eosinophilic esophagitis. The Journal of allergy and clinical 1803 immunology. 2008;122(2):425-7. 1804 109. Louis-Auguste JR, Hoare J. A hard act to swallow: modern management of eosinophilic 1805 oesophagitis. Frontline gastroenterology. 2013;4(2):91-5. 1806 110. Netzer P, Gschossmann JM, Straumann A, Sendensky A, Weimann R, Schoepfer AM. 1807 Corticosteroid-dependent eosinophilic oesophagitis: azathioprine and 6-mercaptopurine can 1808 induce and maintain long-term remission. Eur J Gastroenterol Hepatol. 2007;19(10):865-9. 1809 111. Philpott H, Dellon ES. The role of maintenance therapy in eosinophilic esophagitis: who, 1810 why, and how? Journal of Gastroenterology. 2018;53(2):165-71. 1811 112. Koutlas NT, Dellon ES. Progression from an Inflammatory to a Fibrostenotic Phenotype 1812 in Eosinophilic Esophagitis. Case reports in gastroenterology. 2017;11(2):382-8. 1813 113. Safroneeva E, Coslovsky M, Kuehni CE, Zwahlen M, Haas NA, Panczak R, et al. 1814 Eosinophilic oesophagitis: Relationship of quality of life with clinical, endoscopic and histological 1815 activity. Alimentary Pharmacology and Therapeutics. 2015;42(8):1000-10. 1816 114. Spechler SJ, Genta RM, Souza RF. Thoughts on the complex relationship between 1817 gastroesophageal reflux disease and eosinophilic esophagitis. The American journal of 1818 gastroenterology. 2007;102(6):1301-6. 1819 115. Aceves SS, King E, Collins MH, Yang GY, Capocelli KE, Abonia JP, et al. Alignment of 1820 parent- and child-reported outcomes and histology in eosinophilic esophagitis across multiple 1821 CEGIR sites. The Journal of allergy and clinical immunology. 2018;142(1):130-8.e1. 1822 116. Ishimura N, Sumi S, Okada M, Mikami H, Okimoto E, Nagano N, et al. Is asymptomatic 1823 esophageal eosinophilia the same disease entity as eosinophilic esophagitis? Clin 1824 Gastroenterol Hepatol. 2018. 1825 117. Molina-Infante J, Bredenoord AJ, Cheng E, Dellon ES, Furuta GT, Gupta SK, et al. 1826 Proton pump inhibitor-responsive oesophageal eosinophilia: An entity challenging current 1827 diagnostic criteria for eosinophilic oesophagitis. Gut. 2016;65(3):521-31. 1828 1829

1

American Gastroenterological Institute and the Joint Task Force on 1

Allergy-Immunology Practice Parameters Clinical Guidelines for the 2

Management of Eosinophilic Esophagitis 3

Hirano I1, Chan ES2, Rank M3, Sharaf R4, Stollman N5, Stukus D6, Wang K7 , Greenhawt M,8 Falck-4 Ytter Y9 5 6 Collaborators: Bernstein JA10, Dinakar C11 , Golden DBK12, Khan DA13, Lieberman J, Oppenheimer J15, 7 Shaker M16, Wallace DV17, Wang J18 8 9 1 Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 10 Chicago, Illinois; 2 Division of Allergy and Immunology, Department of Pediatrics, British Columbia Children’s 11 Hospital, University of British Columbia, Vancouver, BC, Canada 3 Division of Allergy, Asthma, and Clinical 12 Immunology, Mayo Clinic, Scottsdale, AZ and Division of Pulmonology Phoenix Children’s Hospital 13 Phoenix, AZ; 4Division of Gastroenterology, Department of Medicine and Department of 14 Healthcare Research and Policy. Weill Cornell Medicine; 5Division of Gastroenterology, Alta Bates 15 Summit Medical Center, Oakland, California;; 6Division of Allergy and Immunology, Nationwide 16 Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio, United States; 17 7Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 18 8 Section of Allergy/Immunology, Children’s Hospital Colorado, University of Colorado School of 19 Medicine, Aurora, CO; 9 Division of Gastroenterology and Hepatology, Cleveland VA Medical Center 20 and University Hospitals, Case Western Reserve University School of Medicine, Cleveland, OH, 10 21 Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH; 11 22 Division of Allergy and Asthma, Stanford University School of Medicine, Palo Alto, CA; 12 Department 23 of Medicine, Johns Hopkins University, Baltimore, MD; 13 Division of Allergy & Immunology, 24 Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX; 14 Division of 25 Allergy and Immunology, The University of Tennessee Health Science Center, LeBonheur Children’s 26 Hospital, Memphis, TN; 15 Department of Internal Medicine, New Jersey Medical School, Morristown, 27 NJ; 16 Section of Allergy and Immunology, Dartmouth-Hitchcock Medical Center and Dartmouth Geisel 28 School of Medicine, Lebanon and Hanover, NH; 17 Department of Medicine, Nova Southeastern 29 University, Davie, FL; 18 Division of Allergy and Immunology, Department of Pediatrics, The Elliot and 30 Roslyn Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, Kravis Children’s 31 Hospital, New York NY.32

33

Acknowledgements: Clinical Guidelines Committee included: 34

35

This document presents the official recommendations of the American Gastroenterological Association 36

(AGA) and the Joint Task Force on Allergy-Immunology Practice Parameters on the Management of 37

Formatted: Numbering: Continuous

2

Eosinophilic Esophagitis. The guideline was jointly developed by the AGA’s Clinical Practice Guideline 38

Committee and the Joint Task Force on Allergy Practice Parameters with approval of both the boards of 39

the American Academy of Allergy, Asthma, and Immunology and the American College of Allergy, 40

Asthma, and Immunology; and approved by both the AGA Governing Board and JTF Governing 41

Boards. Development of this guideline and its accompanying technical review was fully funded by both 42

the AGA Institute and the JTF, with no additional outside funding. 43

44

1. Disclose conflicts of interest: 45

Conflict of interest disclosure: All members were required to complete disclosure statement. By mutual 46

agreement with the JTF ,these statements are maintained at the American Gastroenterological 47

Association Institute (AGA) headquarters in Bethesda, Maryland and pertinent disclosure are published 48

with the report. 49

50

Dr. Hirano is supported by NIH grants U54AI117804 and 1P01DK117824 and has received consulting 51

fees and research support from Adare, Allakos, Celgene, Regeneron, Shire Pharmaceuticals. Dr. Chan 52

has received research support from DBV Technologies, has been a member of advisory boards for Pfizer 53

and Aralez Pharmaceuticals, is a member of the scientific advisory board for Food Allergy Canada, and 54

was an expert panel and coordinating committee member of the National Institute of Allergy and 55

Infectious Diseases (NIAID)-sponsored Guidelines for Peanut Allergy Prevention. Dr. Sharaf receives 56

salary support from NCI 1K07CA216326 - 01A1, NCI 5 R01 CA211723 02, and a PCORI Improving 57

Health Systems Award. He is a paid consultant for the non-profit Institute for Clinical and Economic 58

Review. Dr. Stukus received consulting fees from Aimmune Therapeutics, Inc. and Before Brands to 59

deliver unbranded educational symposia. Dr. Greenhawt is supported by grant #5K08HS024599-02 60

from the Agency for Healthcare Quality and Research, is an expert panel and coordinating committee 61

3

member of the NIAID-sponsored Guidelines for Peanut Allergy Prevention; has served as a consultant 62

for the Canadian Transportation Agency, Thermo Fisher, Intrommune, and Aimmune Therapeutics; is a 63

member of physician/medical advisory boards for Aimmune Therapeutics, DBV Technologies, 64

Sanofi/Genzyme, Genentech, Nutricia, Kaleo Pharmaceutical, Nestle, Aquestive, Allergy Therapeutics, 65

and Monsanto; is a member of the scientific advisory council for the National Peanut Board; has 66

received honorarium for lectures from Thermo Fisher, Aimmune, DBV, Before Brands, multiple state 67

allergy societies, the ACAAI, the EAACI; is an associate editor for the Annals of Allergy, Asthma, and 68

Immunology; and is a member of the Joint Taskforce on Allergy Practice Parameters. These 69

relationships are unrelated to the work on this guideline and pose no conflict of interest. The 70

recommendations involving medications undergoing clinical trials were written by members of the 71

guideline committee without conflict of interest. 72

73

74

75

4

Eosinophilic esophagitis (EoE) was first characterized as a distinct clinical entity by Attwood 76

and Straumann in the early 1990s. A dramatic rise in the recognition of EoE in the United States, first in 77

pediatrics and subsequently in adults, was paralleled by an increase in publications on EoE.1 The past 25 78

years has witnessed the emergence of the field from small case series and observational studies to larger, 79

international, multi-center, randomized controlled trials (RCTs) of both medical and dietary therapies.2 80

This guideline provides evidence-based recommendations focusing on the clinical management of EoE 81

for both pediatric and adult allergists and gastroenterologists. Unless specified, the recommendations are 82

applicable to the short-term treatment of EoE, as the current evidence-base is primarily comprised of 83

trials extending from 2 to 16 weeks. The majority of recommendations are based on the failure to 84

achieve histologic remission of < 15 eosinophils/high power field (eos/hpf) as the definition of treatment 85

effect.2 Additional relevant outcome metrics, including symptoms and endoscopic features, could not be 86

synthesized due to the use of varying and largely unvalidated instruments, variable study methodology, 87

and a large degree of heterogeneity in reporting of outcomes. In forming the estimate of the effect for 88

observational studies lacking a contemporaneous control group, the 8-week, placebo control arm rate for 89

failing to achieve histologic remission from topical glucocorticosteroid studies (86.7%) was used to 90

allow comparison. In recommendations that this historical control group was used, the quality and 91

strength of evidence was downgraded for using this indirect comparator. For these recommendations, 92

risk ratios (RRs) are presented by applying the baseline risk from the untreated control arms from steroid 93

RCTs to the RR. As was reviewed in the technical report use of this comparator should not be viewed 94

the same as a direct control group comparison, but as an approximated measure that is permissible under 95

GRADE methodology. 96

97

The guideline was developed utilizing a process outlined elsewhere.3 Briefly, both the AGA and 98

the JTF process for developing clinical practice guidelines incorporates GRADE methodology3 and best 99

5

practices as outlined by the Institute of Medicine.4 GRADE methodology was utilized to prepare the 100

background information for the guideline and the technical review which accompanies it.2 GRADE uses 101

the PICO format, which frames a clinical question by defining a specific Population (P), Intervention (I), 102

Comparator (C), and Outcomes (O). The PICOs focused on the use of therapeutics in patients with EoE. 103

Each of the selected PICO questions was addressed in this review using the GRADE framework except 104

for last two PICO questions which were addressed using a narrative review format. Optimal 105

understanding of this guideline will be enhanced by reading applicable portions of the technical review. 106

A unique aspect of this guideline and the corresponding technical review was the development in a joint 107

manner through a collaboration between AGA and Joint Task Force for Allergy-Immunology Practice 108

Parameters (JTF) that is comprised of the American Academy of Allergy, Asthma & Immunology 109

(AAAAI), American College of Allergy, Asthma and Immunology (ACAAI). In addition, representatives 110

of both pediatric and adult medicine were included as well as a patient with EoE. This collaborative 111

guideline reflects the interdisciplinary nature of EoE that integrates clinical and investigative efforts of 112

multiple domains and builds upon prior consensus recommendations published in both the allergy and 113

gastroenterology literature.5,6 114

115

116 Table 1. GRADE Definitions on Strength of Recommendation 117

For the Patient For the Clinician

Strong Most individuals in this situation would want the recommended course of action and only a small proportion would not.

Most individuals should receive the recommended course of action Formal decision aids are not likely to help individuals make decisions consistent with their values and preferences.

Conditional The majority of individuals in this situation would want the suggested course of action, but many would not.

Different choices will be appropriate for different patients. Decision aids may be useful in helping individuals in making decisions consistent with their values and preferences. Clinicians should expect to spend more time with patients when working towards a decision.

118

6

119

Table 2. GRADE Definitions on Quality of Evidence 120

High We are very confident that the true effect lies close to that of the estimate of the effect. Moderate We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the

effect, but there is a possibility that it is substantially different. Low Our confidence in the effect estimate is limited. The true effect may be substantially different from the

estimate of the effect. Very Low

We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect

121

Table 3: AGA-JTF Guideline Recommendations on the Management of Eosinophilic Esophagitis (EoE) 122

Recommendation Strength of Recommendation Quality of Evidence

1. Recommendation: In patients with symptomatic esophageal eosinophilia, the AGA/JTF suggests using proton pump inhibition over no treatment

Conditional Very low quality

2. In patients with EoE, the AGA/JTF recommends topical glucocorticosteroids over no treatment Strong Moderate

3. In patients with EoE, the AGA/JTF suggests topical glucocorticosteroids rather than oral glucocorticosteroids Conditional Moderate

4. In patients with EoE, the AGA/JTF suggests using elemental diet over no treatment Comment: Patients who put a higher value on avoiding the challenges of adherence to an elemental diet and the prolonged process of dietary reintroduction may reasonably decline this treatment option.

Conditional Moderate

5. In patients with EoE, the AGA/JTF suggests using an empiric, six-food elimination diet over no treatment Comment: Patients who put a higher value on avoiding the challenges of adherence to diet involving elimination of multiple common food staples and the prolonged process of dietary reintroduction may reasonably decline this treatment option.

Conditional Low

6. In patients with EoE, the AGA/JTF suggests using an allergy testing-based elimination diet over no treatment Comment: Due to the potential limited accuracy of currently available, allergy-based testing for the identification of specific food triggers for EoE, patients may prefer alternative medical or dietary therapies to an exclusively testing-based elimination diet.


7. Recommendation: In patient with EoE in remission following short-term use of topical glucocorticosteroids, the AGA/JTF suggests continuation of topical glucocorticosteroids over discontinuation of treatment


7

Comments: Patients who put a high value on the avoidance of long-term topical steroid use and its possible associated adverse effects, and/or place a lower value on the prevention of potential long-term undesirable outcomes (i.e. recurrent dysphagia, food impaction, and esophageal stricture), could reasonably prefer cessation of treatment after initial remission is achieved, provided clinical follow-up is maintained. 8. Recommendation: In adult patients with dysphagia from a stricture associated with EoE, the AGA/JTF suggests endoscopic dilation over no dilation


9. Recommendation: In patients with EoE, the AGA/JTF recommends using anti-IL-5 therapy for EoE only in the context of a clinical trial No recommendation Knowledge gap

10. Recommendation: In patients with EoE, the AGA/JTF recommends using anti-IL-13 or anti-IL-4 receptor alpha therapy for EoE only in the context of a clinical trial No recommendation Knowledge gap

11. Recommendation: In patients with EoE, the AGA/JTF suggests against the use of anti-IgE therapy for EoE Conditional Very low quality

12-15. Recommendation: In patients with EoE the AGA/JTF suggest using montelukast, cromolyn sodium, immunomodulators, and anti-TNF for EoE only in the context of a clinical trial

No recommendation Knowledge gap

123

124

RECOMMENDATIONS 125

Question 1. Should proton pump inhibitors be used in patients with esophageal eosinophilia? 126

127

In patients with symptomatic esophageal eosinophilia, the AGA/JTF suggests using proton pump inhibition over no treatment (conditional recommendation, very low-quality evidence).

8

Twenty-three observational studies that evaluated the histologic response to proton pump 128

inhibitors (PPI) reported an overall, unweighted histologic response rate of 42%. PPIs failed to induce 129

histologic remission in approximately 2/3 of treated patients, compared with >85% of patients treated 130

with placebo, for a RR of 0.66, (95% CI 0.61-0.72). A high degree of inconsistency makes it difficult to 131

provide a precise estimate of an absolute effect size and raises important concerns regarding variation in 132

the criteria for patient selection, study design, as well as proton pump inhibitor (PPI) duration, dosing 133

and formulation. Furthermore, most studies were non-comparative, single-arm, retrospective studies. 134

Based on these factors, the strength of the recommendation was lowered. Nevertheless, a clinical 135

benefit to the use of PPI monotherapy may be evident for certain patients. It is important to note that a 136

European and an International consensus recommendation have recently removed the PPI trial from the 137

diagnostic criteria of EoE.7,8 Following the exclusion of secondary causes of esophageal eosinophilia, 138

symptomatic esophageal eosinophilia is now viewed as synonymous with EoE. PPIs are positioned as an 139

effective, primary therapeutic option for certain patients with EoE. Based on their long-standing safety 140

profile and ease of administration, patients may prefer to start with this form of therapy prior to trials of 141

glucocorticosteroids or elimination diets. It should be emphasized that direct comparison of the efficacy 142

of PPI and other medical or dietary EoE therapies is limited since, up to this time, most trials in EoE 143

have excluded patients with esophageal eosinophilia that responded to a PPI (formerly denoted as PPI-144

responsive esophageal eosinophilia or PPIREE). 145

146

Question 2. Should topical glucocorticosteroids be used in patients with EoE? 147

148

In patients with EoE, the AGA/JTF recommends topical glucocorticosteroids over no treatment (Strong recommendation, moderate quality evidence)

9

Eight double blind placebo-controlled studies enrolling 437 patients followed for a mean of eight 149

weeks compared treatment with topical budesonide or topical fluticasone to placebo.2 It is of note that 150

most of these studies required patients first fail a PPI trial or excluded patients with known GERD, 151

which may not reflect routine clinical practice or the most current consensus-driven recommendations. 152

Two of the trials used formulations of topical steroids specifically developed for esophageal delivery 153

(tablet or liquid) whereas the remainder utilized ingested formulations designed for the treatment of 154

asthma. As the result of a review process described in the technical guidelines, a single pooled estimate 155

is presented herein, despite many methodologic differences between these studies including the relative 156

potency and bioavailability of the agents used, method of administration, definition of response, dose, 157

and differences that may occur in pediatric versus adult patients. All such factors may limit 158

generalizability of this recommendation. Topical glucocorticosteroids failed to induce histologic 159

remission in approximately 1/3 of treated patients, compared with >85% of patients treated with 160

placebo, for a RR of 0.39, (95% CI 0.26-0.58).2 The certainty of this estimate is moderate; it was 161

downgraded for inconsistency due to heterogeneity of the studies. In short-term studies of three months 162

or less, there was no increased risk of adverse events in patients treated with steroids compared with 163

placebo (risk ratio of 1 (95% CI 0.85-1.19), although local viral and fungal infections and very limited 164

description of adrenal suppression have been described in certain populations. Longer-term studies 165

prospectively assessing the safety of topical glucocorticosteroid use are ongoing. It is relevant to 166

consider that the same inhaled steroid agents are considered very safe for use in children and adults with 167

asthma and are routinely used in the primary management of this disease. While no medications have 168

been yet approved for treatment of EoE by the Food and Drug Administration, the European Medicines 169

Agency approved a budesonide tablet formulation for EoE in 2018. 170

171

10

Question 3. Should systemic glucocorticosteroids be used in patients with EoE? 172

173

There has only been a single randomized trial of topical versus systemic glucocorticosteroids in 174

80 children with EoE.2 Prednisone was given at a dose of 1 mg/kg twice a day while fluticasone was 175

given at a dose of 2 puffs four time a day (110 ug/puff for those < 10 years of age and 220 ug/puff for 176

those 11-18 years) for 4 weeks followed by tapered dosing over 8 weeks. The primary endpoint was the 177

histological response which was based on a score consisting of the percentage of basal cell hyperplasia 178

and eosinophil density (eos/hpf). Both groups had similar histological improvement defined as a 1-point 179

drop in this score. However, this score showed statistically greater improvement in the prednisone 180

treated group compared to the fluticasone treated group at 4 weeks. The clinical significance of this 181

difference, however, is unclear given that symptomatic improvement was similar in both groups with 182

72% response rates in the prednisone arm versus 65% in the fluticasone arm. Relapse rates were also 183

similar at 45% in both groups at week 24. Systemic complications were increased at 40% in the 184

prednisone group, including weight gain and Cushingoid appearance compared with a 15% rate of oral 185

Candidiasis in the fluticasone group. Based on the similar effectiveness and well-characterized side 186

effects of systemic glucocorticosteroids, topical glucocorticosteroids are preferred over prednisone for 187

treatment of children with EoE. Similarities in disease pathogenesis and clinical manifestations in 188

children and adults with EoE support the extension of the recommendation to adult populations. The 189

potential benefits of systemic glucocorticosteroids in EoE patients that are refractory to topical 190

glucocorticosteroids are currently unknown. 191

192

In patients with EoE, the AGA/JTF suggests topical glucocorticosteroids rather than oral glucocorticosteroids (Conditional recommendation, moderate quality evidence)

11

Question 4. Should an elemental diet be used in patients with EoE? 193

194

The relevant data on efficacy of elemental diets (amino acid-based formulas) for treatment of 195

EoE are derived from 6 single arm, observational studies without control group comparators, which 196

indicate that very few (6.4%) of these subjects on elemental diet failed to achieve histologic remission 197

(defined as <15 eosinophils/hpf).2 This contrasts with failure to achieve histologic remission in 86.7% 198

of a historical placebo comparison group glucocorticosteroid, resulting in an estimated RR of 0.07 (95% 199

CI 0.05-0.12).2 Adult studies had a lower proportion of participants achieving histologic remission than 200

pediatric studies.2 201

Difficulty adhering to elemental diets for reasons such as taste, nutritional concerns, practical 202

implementation within the context of overall dietary alternatives, and breadth of avoidance in this style 203

of diet, and cost are of concern. Harms include interference with development of oral motor skills in 204

children, social isolation created by dining restrictions, the potential need for gastrostomy tube, costs of 205

elemental formula, and burden of repeated endoscopies during gradual food re-introduction. From a 206

food allergy perspective, there may be some risk of developing de novo IgE-mediated food allergy in 207

previously tolerant patients on elimination diets for EoE, as has been noted in isolated case reports in 208

EoE as well as in atopic dermatitis.9 10 There is insufficient literature beyond a handful of case reports 209

describing such events to determine if such risk exists and further studies are needed to evaluate this 210

concern. Hence, elimination diets of any type should be used in discretion and for as short a period that 211

In patients with EoE, the AGA/JTF suggests using elemental diet over no treatment (conditional recommendation, moderate quality evidence).

Comment: Patients who put a higher value on avoiding the challenges of adherence to an elemental diet and the prolonged process of dietary reintroduction may reasonably decline this treatment option.

12

is suitable to treat the underlying EoE. Consultation with a board-certified allergist who is skilled in the 212

management of IgE-mediated food allergy should be a strong consideration. 213

Therefore, although the evidence for efficacy of elemental diets is of moderate quality due to 214

possible large effects, we suggest a conditional recommendation for elemental diet. Clinicians should 215

consider patient age and preferences for alternative medical and dietary management therapeutic options 216

when considering elemental diets. 217

218

Question 5. Should an empiric food elimination diet be used in patients with EoE? 219

220

Ten studies reported the effectiveness of an empiric, six-food elimination diet (SFED) with an 221

overall, unweighted histologic response rate of 68%, though these also suffered from the same 222

limitations of elemental diet studies in that all were single arm, observational studies.2 The RR for 223

failure to achieve histologic remission relative to placebo based on historical controls was 0.38 (0.32 to 224

0.43).2 While uniformly beneficial from these observational studies, certainty in the effect estimate was 225

rated down as none of the studies were controlled trials. Although these studies were reported as “six-226

food” elimination diets, the inclusion of both tree nuts and peanuts as well as finned fish and shellfish 227

could be considered as 8 separate food groups. Furthermore, this approach entails a higher number of 228

actual foods on account of the multiple different types of tree nuts, fin fish and shellfish. In addition, two 229

In patient with EoE the AGA/JTF suggests using an empiric six-food elimination diet over no treatment (conditional recommendation, low quality evidence).

Comment: Patients who put a higher value on avoiding the challenges of adherence to diet involving elimination of multiple common food staples and the prolonged process of dietary reintroduction may reasonably decline this treatment option.

13

studies eliminated foods to which patients had abnormal skin testing and one also eliminated corn, rice 230

and legumes. 231

Several practical concerns limit the utilization of empiric elimination diets in EoE. Heterogeneity 232

in response rates could reflect selection bias and potential for exclusion of patients with limited 233

adherence to the diet. Incomplete or inconsistent diet reintroduction may reflect the challenges in 234

adherence and activity assessment defining disease relapse (symptoms vs. pathology) during the 235

reintroduction process. As is common to any form of elimination diet, the time, risk, and financial 236

burden of repeated endoscopies are also potential implementation barriers, as is long-term adherence 237

following the identification of specific food trigger(s) in the re-introduction process and the possible 238

development of de-novo IgE-mediated food allergy upon re-introduction.11 239

Several trials were reviewed utilizing empiric elimination diets that limited the number of 240

avoided foods to 1, 2 or 4 given data by Kagalwalla et al suggestive that peanut/tree nut and 241

finfish/shellfish reintroduction after SFED was associated with low rates of disease recurrence, and that 242

not all major allergens needed to be removed initially.2 While this approach potentially reduces the 243

burden of repeated endoscopies during the reintroduction process and may improve lifestyle and 244

adherence, the effectiveness appears to be lower.2 Less invasive procedures such as transnasal 245

endoscopy (which does not require sedation) as well as non-endoscopic, office-based methods to assess 246

disease activity through assessment of surrogate markers are under development and could obviate the 247

need for repeated biopsy sampling during the reintroduction process, thereby increasing the practical 248

application of elimination diet for EoE.12 249

250

14

Question 6. Should allergy-based testing be used for the purpose of identifying food triggers in 251

patients with EoE? 252

253

Like elemental and empiric elimination diets, the evidence-base for using allergy-based testing to 254

identify food triggers in patients with EoE is limited to single-armed, observational studies that have 255

non-comparative study designs. Testing based diets involve the scientific rational of identifying a 256

potential immune-mediated mechanism of food allergy involving either food-specific IgE or cell-257

mediated pathways, as opposed to empiric diets which simply presume importance of common allergens 258

as trigger without identifying their direct role in the pathogenesis of the disease process. Twelve single 259

armed studies reported that 49.2% of subjects on an allergy-testing based elimination diet failed to 260

achieve histologic remission (defined as <15 eosinophils/hpf). The estimated RR for failure to achieve 261

histologic remission relative to placebo based on historical controls was 0.57 (0.33 to 0.73).2 An 262

important limitation in pooling these studies involves the degree of inconsistency due to different testing 263

techniques (e.g., skin prick testing, serum specific IgE testing, patch testing, or combinations of these) 264

used in different studies. A sensitivity analysis failed to show any statistically significant difference 265

between studies that used patch testing and those that did not; however, a sensitivity analysis excluding 266

studies using serum specific IgE was not performed. There may be a potential role for aeroallergen 267

testing and treatment in EoE, which is presently being evaluated. Similar to potential risks for other 268

dietary elimination strategies, there may be challenges with long-term adherence to dietary elimination 269

6. In patients with EoE, the AGA/JTF suggests allergy testing-based elimination diet over no treatment (Conditional recommendation, very low quality evidence)

Comment: Due to the potential limited accuracy of currently available, allergy-based testing for the identification of specific food triggers, patients may prefer alternative medical or dietary therapies to an exclusively testing-based elimination diet

15

and a potential risk of de-novo IgE-mediated food allergy upon re-introduction. 270

271

Question 7: Should maintenance therapy be recommended in patients with EoE? 272

273

The chronicity and potential for disease progression provide the rationale for maintenance 274

therapy of EoE. Retrospective natural history studies, placebo data from randomized controlled trials, 275

and observational cohort studies support the likely chronic nature of symptoms and histopathology of 276

EoE if it either is untreated, or if treatment is discontinued. Spontaneous disease remission has been 277

reported but is uncommon in either pediatric or adult series, with limited description in the literature. 278

Moreover, the available data in adults, albeit retrospective and subject to certain biases, have 279

demonstrated the potential for long-term progression from inflammation to esophageal strictures in a 280

proportion of EoE patients with untreated disease. 1,19 281

At this time, there are a paucity of studies, and therefore very limited evidence, to define what 282

constitutes effective maintenance therapy in EoE.2 Only one very small trial randomized patients to a 283

year of low dose budesonide (0.25 mg bid) or placebo. While a significant reduction in eosinophil 284

density was noted with active drug compared to placebo, only 36% of patients maintained an eosinophil 285

Recommendation: In patient with EoE in remission following short-term use of topical glucocorticosteroids, the AGA/JTF suggests continuation of topical glucocorticosteroids over discontinuation of treatment (Conditional recommendation, very low quality evidence)

Comments: Patients who put a high value on the avoidance of long-term topical steroid use and its possible associated adverse effects, and/or place a lower value on the prevention of potential long-term undesirable outcomes (i.e. recurrent dysphagia, food impaction, and esophageal stricture), could reasonably prefer cessation of treatment after initial remission is achieved, provided clinical follow-up is maintained.

16

density < 5 eos/hpf at one year, and no dose finding study supported the choice of the 0.25mg BID as 286

appropriate or sufficient versus other amounts. The use of a low maintenance dose of budesonide 287

compared to the induction dose of 1 mg BID likely reduced the efficacy, although development of 288

steroid-tolerance or selection of steroid-refractory patients is plausible. Additional single-armed 289

observational studies of topical steroids also reported a high proportion of patients with histologic 290

recurrence but most also utilized dosing lower than administered during induction. In contrast, three, 291

single-armed observational studies of PPIs noted sustained histologic response in the majority of adults 292

despite dose reduction. Very limited data are available on the long-term effectiveness of elimination 293

diets. 294

Until more data are available, the continued use of either PPI, topical glucocorticosteroids or 295

elimination diets are reasonable options, and this is a very preference-sensitive area of management. As 296

there was limited evidence on PPI or diet therapies, the guideline recommendation was written to only 297

include topical glucocorticosteroids. The limited data, as well as uncertainties in the natural history of 298

EoE, provide very low confidence in the estimated benefits of long-term therapy for EoE, but must also 299

be balanced with the risks of potential disease recurrence in individual patients when treatment is 300

discontinued. 301

302

Question 8. Should esophageal dilation be used in patients with EoE? 303

304

A recent meta-analysis of 1607 patients in 39 publications who underwent esophageal dilatation 305

found symptom relief in 85% in patients with dysphagia and EoE, although this evidence was 306

considered low quality due to the retrospective, single arm design of these reports and the lack of a 307

In adult patients with dysphagia from a stricture associated with eosinophilic esophagitis, the AGA/JTF suggests endoscopic dilation over no dilation (Conditional recommendation, very low-quality evidence.)

17

standard definition for what constitutes clinical improvement.2,13 There is no associated benefit in terms 308

of histological improvement in eosinophilia with dilation, and dilation is considered a point of care 309

option for the endoscopist. Of importance, despite the initial case reports of increased complications 310

from dilation in EoE, large series using a more conservative dilatation approach in experienced centers 311

found that complications were not increased over rates expected from dilation of non-EoE, benign 312

esophageal strictures.2 313

A systematic review and meta-analysis of 977 patients who underwent 2034 dilatations for EoE 314

found that the rate of perforation was 0.033% (95% CI 0-0.226%) with none of the perforations 315

requiring surgical intervention nor related to subsequent patient mortality.2,14 Most of the perforations 316

were prior to 2009 with subsequent improvement in perforation rate after this time period which was 317

speculated to be the result of more conservative techniques. The use of balloon or bougies did not 318

significantly increase rate of perforation though numerically balloons had a perforation rate of 0.06% 319

(95% CI 0 – 0.37%) versus 0.02% (95% CI 0-0.34%) with bougies. Larger dilators (>17 mm diameter) 320

were associated with an increased rate of perforation though this was not statistically significant since 321

only 9 perforations were reported in these studies. The most common adverse event reported was chest 322

discomfort in 24% (95% CI 5.9-41%) and GI hemorrhage occurring in 0.03% (95% CI 0-0.217%). 323

For individual patients that place a higher value on the avoidance of the uncommon 324

complications of dilation, it may be reasonable to use medical or dietary therapy prior to using dilation. 325

Though fibrostenotic disease may be present in many of these patients, it has not been demonstrated that 326

these patients will respond better to dilation as opposed to alternative medical or diet therapies. 327

Retrospective case series have identified a lower utilization of esophageal dilation among patients 328

effectively treated with medical therapy. Esophageal dilatation alone as a treatment modality for patients 329

with EoE and daily dysphagia has only been reported in a small retrospective series and required 330

maintenance dilatation on average every two years.15 The limited, available data support the use of 331

18

medical/diet therapy in combination with periodic dilation as necessary for adults with EoE and 332

esophageal stricture. 333

Question 9. Should anti-IL-5 therapy be used in patients with EoE? 334

335

Given the role of IL-5 in the maturation and release of eosinophils, there is a biologically 336

plausible mechanism to support the use of anti-IL-5 therapy in patients with EoE. Three RCTs have 337

been conducted, 2 using mepolizumab (1 involving adults and 1 in children) and 1 using reslizumab 338

(children).2 Participants in each study had higher baseline levels of esophageal eosinophilia and had 339

frequently failed clinical management with other therapies. The results from the mepolizumab and 340

reslizumab studies were combined for the purpose of GRADE analysis despite difference in ages of 341

enrollees of these trials and similar mechanisms of action of these therapies though formal non-342

inferiority between the drugs has not been studied. While a reduction in tissue eosinophilia was 343

observed, very few participants achieved prespecified histologic remission with < 15 eosinophils/hpf. 344

Greater than 90% of patients in treatment groups failed to achieve histologic remission, for a RR of 0.92 345

(0.84-1.00). Symptomatic improvement was evaluated differently in each study and not grouped for 346

GRADE analysis; however, a significant improvement in symptoms compared with placebo was not 347

observed. No significant safety issues occurred in any of the trials. 348

349

Anti-IL-5 therapies are currently approved for use in moderate-to-severe persistent eosinophilic 350

asthma. Initial studies in asthmatics demonstrated a reduction in tissue eosinophilia but lack of clinical 351

improvement. Follow-up studies that focused treatment on a more specific patient population with 352

steroid resistant refractory eosinophilic asthma were needed to better understand potential clinical 353

In patients with EoE the AGA/JTF recommends using anti-IL-5 therapy only in the context of a clinical trial (no recommendation; knowledge gap).

19

benefit. In a similar fashion, additional studies in patients with EoE are needed before use in clinical 354

practice can be recommended. 355

356

Question 10. Should anti-IL-13 therapy be used in patients with EoE? 357

358

The IL-4 and IL-13 pathway is known to be involved in Th-2 inflammatory conditions by 359

directing eosinophil production, prolonged survival, and trafficking into tissues. Anti-IL-4 and anti-IL-360

13 therapy has shown benefit in Th-2 associated conditions such as atopic dermatitis and asthma, thus 361

there is a biologically plausible pathway for use in EoE. IL-13 is overexpressed in the esophageal 362

mucosa and induces a gene expression profile that closely resembles the EoE transcriptome. 363

Three clinical trials have evaluated the efficacy of biologic therapy directed at the IL-13 pathway 364

in EoE. One RCT involving 25 adult participants evaluated the use of anti-IL-13 therapy with QAX576 365

in EoE.2 This study did not meet its primary endpoint of > 75% decrease in peak eosinophil counts 12 366

weeks after starting therapy. Mean esophageal eosinophil counts decreased compared with placebo, but 367

no significant difference was observed in symptoms. Two additional RCTs that utilized monoclonal 368

antibodies targeting the IL-13 pathway were not included as the full manuscripts were not available at 369

the time of this systematic review, both of which showed promise. The first was a phase 2 study using 370

RPC4046, a monoclonal antibody against IL-13, that demonstrated histologic and endoscopic efficacy 371

compared to placebo in 99 adults with EoE.16 The second study using dupilumab, a monoclonal 372

antibody against the IL-4α receptor inhibiting the signaling of both IL-13 and IL-4, demonstrated 373

symptom, histologic and endoscopic efficacy compared to placebo in 47 adults with EoE.3 While these 374

In patients with EoE the AGA/JTF recommends using anti-IL-13 or anti-IL4 receptor alpha therapy for EoE only in the context of a clinical trial (no recommendation; knowledge gap).

20

newer preliminary results appear favorable, the use of anti-IL-13 therapy in EoE is not recommended for 375

clinical use outside of a clinical trial at this time. 376

Question 11. Should anti-IgE therapy be used in patients with EoE? 377

IgE is involved in anti-helminthic responses and mediates type 1 hypersensitivity reactions. 378

However, IgE is not known to be directly involved in the development or recruitment of eosinophils. 379

Anti-IgE therapy is currently approved for use in patients with moderate-to-severe persistent atopic 380

asthma and in patients with chronic urticaria who are refractory to first-line therapy. 381

There has been 1 RCT involving 30 adult participants evaluating use of anti-IgE therapy in EoE.2 382

This study did not demonstrate any change in esophageal eosinophilia or reduction in symptoms. Based 383

upon limited evidence and lack of a biologically plausible mechanism, use of anti-IgE therapy in EoE is 384

not recommended for clinical use. A conditional recommendation against use was made for anti-IgE 385

therapy because of the quality of the RCT and the inclusion of the primary endpoint evaluated in this 386

guideline (eosinophils < 15/hpf). Other interventions, such as montelukast (did not include 387

eosinophils/hpf) and cromolyn sodium (very low sample size), had very major limitations and therefore 388

insufficient evidence to recommend against and therefore no recommendation was made about their use. 389

Questions 12-15. Should montelukast, cromolyn, immunomodulators, or anti-TNF therapy be 390

used in patients with EoE? 391

In patients with EoE the AGA/JTF suggests against the use of anti-IgE therapy for EoE (conditional recommendation; very low-quality evidence)

In patients with EoE, the AGA/JTF recommends topical steroids over no treatment (strong recommendation, moderate quality evidence).

In patients with EoE the AGA/JTF suggest using montelukast, cromolyn sodium, immunomodulators, and anti-TNF only in the context of a clinical trial (no recommendation; knowledge gap).

21

392

Given the few studies and low quality of evidence, use of montelukast, cromolyn, 393

immunomodulators, and anti-TNF therapies are not recommended for clinical use.2 These therapeutic 394

agents have been grouped together for the purposes of this guideline based upon limited evidence for a 395

mechanistic role of their biological markers in the development of EoE and limited studies surrounding 396

each therapy. 397

Montelukast is a leukotriene receptor antagonist approved for use in the treatment of persistent 398

asthma and exercise-induced bronchospasm. There is 1 RCT with adult participants (n=41) comparing 399

montelukast with placebo for maintenance therapy after histologic remission was already achieved and 400

did not show any difference in symptoms. A histologic outcome was not included in the study design. 401

Cromolyn is a mast cell stabilizer that can prevent the release of inflammatory mediators in 402

patients with allergic rhinitis and asthma. Mast cell and mast cell mediators have been implicated in 403

EoE pathogenesis. There has been 1 RCT of cromolyn compared to placebo (n=16), which demonstrated 404

that only 1 patient treated with cromolyn achieved histologic remission. 405

Two immunomodulators (azathioprine and 6-mercaptopurine) have been retrospectively reported 406

in a total of 4 patients with EoE but without any use of control subjects. All patients had EoE refractory 407

to other therapies and multiple confounders that make it difficult to discern the impact of 408

immunomodulatory therapy.2 409

TNF-related apoptosis-inducing ligand has been shown to promote inflammation in EoE. One 410

observational case-series described open-label use of anti-TNF in a clinical trial in 3 adult patients with 411

EoE, all of whom had inadequate response to prior therapy.2 The 3 case reports all reported different 412

outcomes including symptom scores, esophageal eosinophilia and endoscopic changes. While interval 413

22

improvement was observed, the differences in patient presentation, outcome measures and lack of 414

control subjects limit extrapolation of these findings. 415

416

Question 16. Should repeat EGD be used to assess patients with EoE after a change in treatment? 417

418

Numerous randomized, placebo-controlled trials of medical therapies for EoE included in this 419

guideline and accompanying technical review have demonstrated significant improvement in symptom, 420

endoscopic, and histologic endpoints using validated instruments.2 Generally, the improvement in 421

objective parameters of endoscopy and pathology have been more robust and consistent than the 422

subjective improvement in symptom outcomes. Moreover, symptom and pathology outcomes are often 423

discordant with one another, although disease remission currently remains anchored in histologic 424

criteria. Evidence that the assessment of biologic activity with endoscopic and histologic parameters 425

following treatment will reduce long-term disease complications is limited.17 On the other hand, the use 426

of symptom-based therapeutic assessment without EGD and biopsy is limited and often misleading due 427

to the ability of patients to modify dietary intake (i.e. avoidance of hard texture foods, excessive 428

mastication, prolonged meal times) to overcome objective histologic and endoscopic disease 429

manifestations.2,18 Dissociation between biologic activity and symptoms in adults is further compounded 430

by the presence of strictures related to fibrostenosis that do not reflect mucosal inflammatory activity. 431

This concept is evident in the symptom relief provided by esophageal dilation in the absence of 432

improvement in esophageal inflammation. 433

The importance of the documentation of adequate suppression of mucosal inflammation after 434

therapeutic intervention is indirectly supported by several retrospective studies that have associated 435

prolonged, untreated disease with the increased prevalence of esophageal strictures.1 In addition, 436

23

retrospective case series have reported a reduction in frequency of esophageal dilation as well as food 437

impactions with improvement in pathology with topical glucocorticosteroids. Nevertheless, the 438

supposition that reduction in esophageal eosinophilia will prevent progressive disease remodeling 439

consequences requires confirmation in prospective, long-term studies. Similarly, although the use of 440

endoscopic outcomes in GERD and inflammatory bowel disease serve as precedents, their application to 441

EoE needs further study to demonstrate their relevance to long-term disease outcomes. 442

While not a formal recommendation of this guideline, the use of repeat EGD with biopsy to 443

assess disease activity after a change in therapy is reasonable. The criteria for histologic and endoscopic 444

improvement following therapy are being actively investigated to identify core outcome metrics for both 445

clinical trials and clinical practice.2 Until such metrics are established, a threshold of < 15 eos/hpf to 446

define an adequate therapeutic response serves as a response criterion until a better measure is 447

established.3,19 The recommended frequency for EGD with biopsy during clinical follow-up is identified 448

as a knowledge gap and may vary depending upon the severity of initial clinical presentation. 449

450

Question 17. What is the management of patients who become asymptomatic after initial PPI 451

treatment? 452

The recently published European and International consensus statements have removed the PPI 453

trial from the diagnostic criteria for EoE.7,8 Based on this revised definition of EoE, the use of repeat 454

EGD with biopsy after PPI therapy would follow the same rationale as recommendation 16. 455

456

Conclusions 457

24

Over the past 2 decades, EoE has emerged as a dominant cause of dysphagia worldwide. In 458

concert with the rise in disease prevalence, an increasingly robust evidence base has provided insights 459

into effective management strategies that are summarized in this guideline. While swallowed, topical 460

glucocorticosteroids were the only therapy to receive a strong recommendation, the evidence supported 461

conditional recommendations for proton pump inhibition and diet therapy as well as esophageal dilation. 462

The use of novel, targeted biologic therapies for EoE are being actively evaluated. A common theme 463

apparent in both the guideline and the accompanying technical review includes the need for uniform 464

endpoints in clinical trials to facilitate meaningful comparisons between therapies. Furthermore, a 465

deeper understanding of the natural history of EoE in both children and adults is needed to inform 466

clinical decisions regarding the optimal use of disease monitoring and long-term, maintenance therapy. 467

In the dawn of this new disease, much light has been shed and the future is bright. 468

469

470

471

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REFERENCES 472

1. Dellon ES, Hirano I. Epidemiology and Natural History of Eosinophilic Esophagitis. Gastroenterology. 473 2018;154(2):319-332 e313. 474

2. Rank MA, Sharaf RN, Furuta GT, et al. Technical Review on the Management of Eosinophilic Esophagitis: 475 A report from the American Gastroenterological Association Institute and the Joint Task Force on 476 Allergy-Immunology Practice Parameters Gastroenterology. 2018. 477

3. Sultan S, Falck-Ytter Y, Inadomi JM. The AGA institute process for developing clinical practice guidelines 478 part one: grading the evidence. Clin Gastroenterol Hepatol. 2013;11(4):329-332. 479

4. Clinical Practice Guidelines We Can Trust. National Academies Press (US); 2011. 480 5. Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a systematic 481

review and consensus recommendations for diagnosis and treatment. Gastroenterology. 482 2007;133(4):1342-1363. 483

6. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations 484 for children and adults. J Allergy Clin Immunol. 2011;128(1):3-20 e26; quiz 21-22. 485

7. Molina-Infante J, Bredenoord AJ, Cheng E, et al. Proton pump inhibitor-responsive oesophageal 486 eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut. 487 2016;65(3):524-531. 488

8. Dellon ES, Liacouras CA, Molina-Infante J, et al. Updated International Consensus Diagnostic Criteria for 489 Eosinophilic Esophagitis: Proceedings of the AGREE Conference. Gastroenterology. 2018;155(4):1022-490 1033 e1010. 491

9. Chang A, Robison R, Cai M, Singh AM. Natural History of Food-Triggered Atopic Dermatitis and 492 Development of Immediate Reactions in Children. J Allergy Clin Immunol Pract. 2016;4(2):229-236 e221. 493

10. Ho HE, Chehade M. Development of IgE-mediated immediate hypersensitivity to a previously tolerated 494 food following its avoidance for eosinophilic gastrointestinal diseases. J Allergy Clin Immunol Pract. 495 2018;6(2):649-650. 496

11. Wang R, Hirano I, Doerfler B, Zalewski A, Gonsalves N, Taft T. Assessing Adherence and Barriers to Long-497 Term Elimination Diet Therapy in Adults with Eosinophilic Esophagitis. Dig Dis Sci. 2018;63(7):1756-1762. 498

12. Hiremath G, Gupta SK. Promising Modalities to Identify and Monitor Eosinophilic Esophagitis. Clin 499 Gastroenterol Hepatol. 2017;15(11):1655-1664. 500

13. Moole H, Jacob K, Duvvuri A, et al. Role of endoscopic esophageal dilation in managing eosinophilic 501 esophagitis: A systematic review and meta-analysis. Medicine (Baltimore). 2017;96(14):e5877. 502

14. Dougherty M, Runge TM, Eluri S, Dellon ES. Esophageal dilation with either bougie or balloon technique 503 as a treatment for eosinophilic esophagitis: a systematic review and meta-analysis. Gastrointest Endosc. 504 2017;86(4):581-591 e583. 505

15. Lipka S, Keshishian J, Boyce HW, Estores D, Richter JE. The natural history of steroid-naive eosinophilic 506 esophagitis in adults treated with endoscopic dilation and proton pump inhibitor therapy over a mean 507 duration of nearly 14 years. Gastrointest Endosc. 2014;80(4):592-598. 508

16. Hirano I, Collins MH, Assouline-Dayan Y, et al. RPC4046, a Monoclonal Antibody Against IL13, Reduces 509 Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis. Gastroenterology. 2018. 510

17. Hirano I, Aceves SS. Clinical implications and pathogenesis of esophageal remodeling in eosinophilic 511 esophagitis. Gastroenterol Clin North Am. 2014;43(2):297-316. 512

18. Safroneeva E, Straumann A, Coslovsky M, et al. Symptoms Have Modest Accuracy in Detecting 513 Endoscopic and Histologic Remission in Adults With Eosinophilic Esophagitis. Gastroenterology. 514 2016;150(3):581-590 e584. 515

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19. Reed CC, Wolf WA, Cotton CC, et al. Optimal Histologic Cutpoints for Treatment Response in Patients 516 With Eosinophilic Esophagitis: Analysis of Data From a Prospective Cohort Study. Clin Gastroenterol 517 Hepatol. 2018;16(2):226-233 e222. 518

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