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Treatment Trends for Eosinophilic Esophagitis and the Other Eosinophilic Gastrointestinal Diseases: Systematic Review of Clinical Trials

      Abstract

      Background

      Eosinophilic gastrointestinal diseases (EGIDs) are chronic inflammatory disorders of the gut, including eosinophilic esophagitis (EoE), gastritis (EoG), duodenitis (EoD), gastroenteritis (EoGE), and colitis (EoC). Available treatments may be ineffective in some patients, and several clinical trials are investigating alternative treatments.

      Aim

      We performed a systematic review of clinical trials to illustrate EGIDs treatment research trends.

      Methods

      We searched clinicaltrials.gov to identify studies investigating EGIDs treatment. For each trial we analysed relevant data, including therapeutic intervention, method of administration, study outcomes, and temporal trends.

      Results

      For EoE, 66 studies were eligible: 26 testing topical corticosteroids (39.4%), 17 (25.8%) monoclonal antibodies, eight (12.1%) dietary measures, five (7.6%) immunomodulators, one (1.5%) esophageal dilation, and nine (13.6%) other medical treatment strategies. With regard to EoG, EoD, and EoGE, 10 studies were testing monoclonal antibodies (71.5%), one immunomodulators (7.1%), one dietary measures (7.1%), and two other treatments (14.3%). There were no trials for EoC. Ongoing studies on corticosteroids are focused on novel delivery systems, including viscous suspensions, orally disintegrating tablets, or capsules. Increased research on monoclonal antibodies was seen from 2018, with interleukin (IL)-4 receptor-α, IL-5 receptor-α, IL-5, IL-13, IL-15, and Siglec-8 as the targets.

      Conclusion

      Clinical trials on EGIDs are predominantly investigating corticosteroids or monoclonal antibodies. EGIDs therapeutic landscape will be trasnformed imminently.

      Keywords

      Abbreviations:

      EoE (Eosinophilic Esophagitis), EGID (Eosinophilic Gastrointestinal Diseases), EoG (Eosinophilic Gastritis), EoD (Eosinophilic Duodenitis), EoGE (Eosinophilic Gastroenteritis), EoC (Eosinophilic Colitis)

      1. Introduction

      Eosinophils are pleiotropic leukocytes that exert a homeostatic role in the gastrointestinal tract, providing immune protection against parasites and bacteria [
      • Jung Y.
      • Rothenberg M.E.
      Roles and regulation of gastrointestinal eosinophils in immunity and disease.
      ]. Although a certain degree of gut eosinophilia is physiological in gastrointestinal locations below the esophagus [
      • Sciumé G.D.
      • et al.
      Eosinophilic esophagitis: novel concepts regarding pathogenesis and clinical manifestations.
      ], an excessive number of activated eosinophils can cause tissue damage and promote disease pathology [
      • Travers J.
      • Rothenberg M.E.
      Eosinophils in mucosal immune responses.
      ,
      • Walker M.M.
      • Potter M.
      • Talley N.J.
      Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus.
      . In this regard, elevated tissue eosinophilia in combination with persistent gastrointestinal symptoms constitutes a group of chronic inflammatory disorders known as primary eosinophilic gastrointestinal diseases (EGIDs) [
      • Walker M.M.
      • Potter M.
      • Talley N.J.
      Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus.
      ,
      • Lucendo A.J.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      . Primary EGIDs are classified based on the region of the eosinophilic infiltrate, which can occur in any location from the esophagus to the colon, and include eosinophilic esophagitis (EoE), gastritis (EoG), duodenitis (EoD), gastroenteritis (EoGE), and colitis (EoC).
      EoE is the most frequent and best characterized EGID [
      • Visaggi P.
      • et al.
      Eosinophilic esophagitis: clinical, endoscopic, histologic and therapeutic differences and similarities between children and adults.
      ], with available international guidelines [
      • Lucendo A.J.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      ,
      • de Bortoli N.
      • et al.
      Eosinophilic esophagitis: update in diagnosis and management. Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE).
      ,
      • Hirano I.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis.
      . Incidence rates are currently close to 20 per 100,000 people per year, and prevalence is more than 1 in 1000 people in Western Countries [
      • Visaggi P.
      • et al.
      Eosinophilic esophagitis: clinical, endoscopic, histologic and therapeutic differences and similarities between children and adults.
      ,
      • Arias Á.
      • Lucendo A.J.
      Epidemiology and risk factors for eosinophilic esophagitis: lessons for clinicians.
      . Prevalence estimates of 20 diagnoses every 100,000 esophago-gastroduodenoscopies (EGDs) have been reported in Asia [
      • Kinoshita Y.
      • et al.
      Systematic review: eosinophilic esophagitis in Asian countries.
      ]. The epidemiology of EoE is still evolving, as incidence and prevalence are rising at a rate that outpaces increased recognition [
      • Dellon E.S.
      • Hirano I.
      Epidemiology and Natural History of Eosinophilic Esophagitis.
      ]. Additionally, EoE is already associated with annual healthcare-related costs that greatly exceed the cost of care of inflammatory bowel diseases and celiac disease [
      • Mukkada V.
      • et al.
      Health-Related Quality of Life and Costs Associated With Eosinophilic Esophagitis: a Systematic Review.
      ,
      • Anderson J.
      • et al.
      Cost of chronic inflammatory disease: the impact of eosinophilic esophagitis in Nevada.
      . EoE characteristically presents with symptoms of esophageal dysfunction (i.e., dysphagia, chest pain, and food bolus impaction), although vague symptoms are frequent in childhood [
      • Visaggi P.
      • et al.
      Eosinophilic esophagitis: clinical, endoscopic, histologic and therapeutic differences and similarities between children and adults.
      ]. Recommended treatment strategies for EoE include proton pump inhibitors (PPIs), topical corticosteroids, dietary measures, or esophageal dilation, when strictures are present [
      • Lucendo A.J.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      ,
      • de Bortoli N.
      • et al.
      Eosinophilic esophagitis: update in diagnosis and management. Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE).
      ,
      • Hirano I.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis.
      . However, most therapeutic approaches are recommended based on low quality evidence [
      • Lucendo A.J.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      ,
      • de Bortoli N.
      • et al.
      Eosinophilic esophagitis: update in diagnosis and management. Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE).
      ,
      • Hirano I.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis.
      , have suboptimal efficacy [
      • Visaggi P.
      • et al.
      Eosinophilic esophagitis: clinical, endoscopic, histologic and therapeutic differences and similarities between children and adults.
      ], are used off-label or, when approved, are not widely commercially available yet.
      EGIDs affecting the gastrointestinal tract below the esophagus are far less well characterized. Although histological diagnostic thresholds for each condition have been proposed (Supplementary Table 1), standardized clinical guidelines on these diseases are still lacking.
      A recent meta-analysis found that the prevalence of non-EoE EGIDs could be as high as 2.4% among patients experiencing gastrointestinal symptoms [
      • Licari A.
      • et al.
      Epidemiology of Nonesophageal Eosinophilic Gastrointestinal Diseases in Symptomatic Patients: a Systematic Review and Meta-Analysis.
      ]. Epidemiology studies conducted using electronic health records of individuals from the United States (US) found that the overall prevalence of EoGE and EoC were 5.1 per 100,000 and 2.1 per 100,000 individuals, respectively. The prevalence of non-EoE EGIDs was higher in Caucasians than Asians or African-Americans, while EoGE was more prevalent in childhood, and EoC in adulthood [
      • Mansoor E.
      • Saleh M.A.
      • Cooper G.S.
      Prevalence of Eosinophilic Gastroenteritis and Colitis in a Population-Based Study, From 2012 to 2017.
      ]. In another study of more than 75 million individuals, the standardized estimated prevalence of EoG, EoGE, and EoC were 6.3 per 100,000, 8.4 per 100,000, and 3.3 per 100.000 individuals, respectively [
      • Jensen E.T.
      • et al.
      Prevalence of Eosinophilic Gastritis, Gastroenteritis, and Colitis: estimates From a National Administrative Database.
      ]. Lastly, data from the ENIGMA trial, showed that more than 50% of subjects with moderate-to-severe gastrointestinal symptoms could have EoG or EoD, when an extended histological sampling protocol was applied [
      • Dellon E.S.
      • et al.
      Determination of Biopsy Yield That Optimally Detects Eosinophilic Gastritis and/or Duodenitis in a Randomized Trial of Lirentelimab.
      ]. Clinically, EGIDs other than EoE are often characterized by persistent and non-specific gastrointestinal symptoms, including abdominal pain, nausea, vomiting, failure to thrive, diarrhea, and weight loss [
      • Visaggi P.
      • et al.
      Eosinophilic esophagitis: clinical, endoscopic, histologic and therapeutic differences and similarities between children and adults.
      ,
      • Mansoor E.
      • Saleh M.A.
      • Cooper G.S.
      Prevalence of Eosinophilic Gastroenteritis and Colitis in a Population-Based Study, From 2012 to 2017.
      . In some instances, EGIDs may commence with more severe presentations including ascites, volvulus, intussusception, perforation, or obstruction [
      • Walker M.M.
      • Potter M.
      • Talley N.J.
      Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus.
      ]. Accepted treatment strategies for EGIDs other than EoE include dietary measures and systemic corticosteroids, although most evidence is weak and comes from small uncontrolled studies [
      • Walker M.M.
      • Potter M.
      • Talley N.J.
      Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus.
      ].
      The lack of approved effective therapeutic strategies represents a substantial unmet clinical need in EGIDs. However, although accepted management options are limited, several clinical trials are currently focusing on the investigation of novel treatments, including monoclonal antibodies, immunomodulators, topically delivered corticosteroids, dietary measures, and others. On this basis, it is predictable that novel treatments for EGIDs will be available in the coming years. Therefore, we performed a systematic review of clinical trials registered on clinicaltrials.gov to provide a snapshot of where research on EGIDs is heading, as well as to anticipate future treatments that will be available.

      2. Methods

      2.1 Search strategy

      We searched clinicaltrials.gov (https://clinicaltrials.gov), from inception to 5th December 2021 to identify interventional studies investigating treatments for EGIDs, including EoE, EoG, EoD, EoGE, and EoC. We conducted a literature search using relevant terms (a detailed search strategy is reported in the Supplementary Materials). There were no language restrictions, as all studies registered on clinicaltrials.gov are published in English. For each retrieved study, the title, study description, and brief summary were screened for potential suitability. All studies that appeared relevant to the aim of this systematic review were analysed in more detail subsequently.

      2.2 Study selection

      The eligibility assessment was performed independently by two investigators (PV, MG) using pre-designed eligibility forms. We included interventional studies investigating both medical and non-medical treatments for the management of EGIDs. We excluded studies focusing exclusively on epidemiology, pathogenesis, or treatment monitoring or follow-up strategies, observational studies, and studies that were withdrawn or whose status was unknown. Disagreements were resolved by consensus opinion among reviewers, and the degree of agreement was measured with a kappa statistic. Ethical approval was not required for this evidence synthesis exercise.

      2.3 Data extraction and analysis

      Data were extracted independently by two authors (PV, MG) onto a Microsoft Excel spreadsheet (XP professional edition; Microsoft, Redmond, WA, USA). The following data were extracted for each study: number of clinical trial (NCT) and start date; geographical region; intervention(s); method of administration; primary study outcome(s); phase of the study; state of recruitment (ongoing/completed/not yet recruiting/terminated); patient population (age range and sex); design of the study (single-/multi-center), enrolment (target/actual). Microsoft Excel spreadsheets were used for the statistical analysis of the dataset and data plotting.

      3. Results

      3.1 Literature search

      The systematic literature review retrieved 832 study records. After duplicate removal, 177 were retrieved for evaluation. Of these, 81 studies were excluded, and 96 were included for full assessment. A total of 17 studies did not meet predefined eligibility criteria and were excluded. Thus, 79 studies were included in the qualitative synthesis. For EoE, 66 studies were eligible for inclusion, 26 on topical corticosteroids (39.4%), 17 (25.8%) on monoclonal antibodies, eight (12.1%) on dietary measures, five (7.6%) on immunomodulators, one (1.5%) on esophageal dilation, and nine (13.6%) on other medical treatment strategies. With regard to EGIDs, 14 studies were eligible for inclusion (with one of them including treatment of both EoE and EoGE), 10 on monoclonal antibodies (71.5%), one on immunomodulators (7.1%), one on dietary measures (7.1%), and two on other treatments (14.3%). There were no registered trials on EoC. Agreement between investigators for assessment of study eligibility was excellent (kappa statistic = 0.87). Fig. 1 shows the literature research process.
      Fig. 1
      Fig. 1Diagram of Assessment of Studies Identified for this Systematic Review.
      Abbreviations: EoE, eosinophilic oesophagitis; EoG, eosinophilic gastritis; EoD, eosinophilic duodenitis; EoGE, eosinophilic gastroenteritis. *Trial NCT01814059 included both EoE and EoGE patients.

      3.2 Study characteristics and population

      Table 1 and Table 2 report the characteristics of all included studies. Fig. 2 shows the geographical distribution of registered clinical trials on EGIDs.
      Table 1Interventional Trials Investigating Treatment of Eosinophilic Esophagitis.
      NCT/start dateGeographical region(s)Intervention(s) armComparatorMethod of administrationPrimary study outcome(s)StudyphaseEnrolment (target/actual)Design of the studyState of recruitmentPatient population and sex
      MONOCLONAL ANTIBODIES
      NCT00123630/2005AmericaOmalizumab

      (anti-IgE mAb)
      PlaceboIntravenous infusion1.Histologic responsePhase 230MonocentricCompleted-Child, Adult (12–60 years)

      -All sexes
      NCT00274703/2005EuropeMepolizumab

      (anti-IL5 mAb)
      PlaceboIntravenous infusion1.Histologic response

      2.Safety and tolerability
      Phase 210MonocentricCompleted- Adult, Older Adult (18 years and older)

      -All sexes
      NCT00358449/2006America, EuropeMepolizumab

      (anti-IL5 mAb)
      Mepolizumab (different doses)Intravenous infusion1.Incidence of AEs

      2. Abnormal blood biochemistry, hematology, ECG, blood pressure, heart rate, temperature

      3.Presence of anti-drug antibodies

      4.Volume of distribution and plasma clearance of mepolizumab
      Phase 284MulticentreCompleted-Child (2–17 years)

      -All sexes
      NCT00523354/2007EuropeInfliximab

      (anti-TNF-α mAb)
      NoneIntravenous infusion1.Histologic responsePhase 2, OLN/AMonocentricCompleted-Adult, Older Adult (18–70 years)

      -All sexes
      NCT00538434/2008AmericaReslizumab

      (anti-IL5 mAb)
      PlaceboIntravenous infusion1.Histologic response

      2. Change in physician's EoE global assessment
      Phase 2/3227MulticentreCompleted-Child, Adult (5–18 years)

      -All sexes
      NCT00635089/2008AmericaReslizumab

      (anti-IL5 mAb)
      NoneIntravenous infusion1.Number of participants with treatment-emergent AEs, serious AEs, or discontinuation due to AEs

      2.EoE predominant symptom over time

      3.Physician's EoE global assessment over time

      4.Mean change in CHQ

      5.Change in diet

      6.Reslizumab serum concentrations

      7.Presence of anti-drug antibodies
      Phase 3, OLE190MulticentreCompleted-Child, Adult, Older Adult (5 years and older)

      -All sexes
      NCT01022970/2009AmericaDectrekumab

      (anti-IL13 mAb)
      PlaceboIntravenous infusion1.Histologic responsePhase 225MulticentreCompleted-Adult (18–50 years)

      -All sexes
      NCT02098473/2014America, EuropeCendakimab

      (anti-IL13 mAb)
      PlaceboSubcutaneous injection1.Histologic responsePhase 2100MulticentreCompleted-Adult, Older Adult (18–65 years)

      -All sexes
      NCT02379052/2015AmericaDupilumab

      (anti-IL4 receptor α mAb)
      PlaceboSubcutaneous injection1.Change in SDIPhase 247MulticentreCompleted-Adult, Older Adult (18–65 years)

      -All sexes
      NCT03633617/2018America, Europe, OceaniaDupilumab

      (anti-IL4 receptor α mAb)
      PlaceboSubcutaneous injection1.Histologic response

      2.Change in DSQ
      Phase 3321MulticentreActive, not recruiting-Child, Adult, Older Adult (12 years and older)

      -All sexes
      NCT03656380/2019AmericaMepolizumab

      (anti-IL5 mAb)
      PlaceboSubcutaneous injection1.Change in EEsAIPhase 272MulticentreOngoing-Child, Adult, Older Adult (16–75 years)

      -All sexes
      NCT04322708/2020

      America, Europe, OceaniaLirentelimab

      (anti-Siglec-8 mAb)
      PlaceboIntravenous infusion1.Histologic response

      2.Change in DSQ
      Phase 2/3277MulticentreActive, not recruiting-Child, Adult, Older Adult (12–80 years)

      -All sexes
      NCT04394351/2020AmericaDupilumab

      (anti-IL4 receptor α mAb)
      PlaceboSubcutaneous injection1.Histologic responsePhase 390MulticentreActive, not recruiting-Child (1–11 years)

      -All sexes
      NCT04593251/2020EuropeCALY-002

      (anti-IL15 mAb)
      PlaceboIntravenous infusion1.Incidence of AEsPhase 195MulticentreOngoing-Adult, Older Adult (18 years and older)

      -All sexes
      NCT04543409/

      2020

      America, Asia, EuropeBenralizumab (anti-IL5 receptor α mAb)PlaceboSubcutaneous injection1.Histologic response

      2.Change in DSQ
      Phase 3170MulticentreOngoing-Child, Adult, Older Adult (12–65 years)

      -All sexes
      NCT04991935/ 2021America, Asia, EuropeCendakimab

      (anti-IL13 mAb)
      NoneSubcutaneous injection1.Incidence of AEsPhase 3, OLE259MulticentreOngoing-Child, Adult, Older Adult (12–75 years)

      -All sexes
      NCT04753697/2021America, Asia, Europe, OceaniaCendakimab

      (anti-IL13 mAb)
      PlaceboSubcutaneous injection1.Dysphagia days

      2.Histologic response
      Phase 3399MulticentreOngoing-Child, Adult, Older Adult (12–75 years)

      -All sexes
      IMMUNOMODULATORS
      NCT01056783/2010EuropeOC000459

      (selective DP2 antagonist)
      PlaceboOral

      (tablets)
      1.Histologic responsePhase 226MonocentricCompleted-Adult, Older Adult (18–75 years)

      -All sexes
      NCT01814059/2013AmericaSirolimus

      (inhibitor of Th2 cells proliferation)
      NoneOral

      (Tablets)
      1. SafetyPhase 14MonocentricTerminated-Adult, Older Adult

      −18 Years to 65 Years
      NCT04682639/ 2021America, Europe, OceaniaEtrasimod

      (S1P-receptor modulator)
      PlaceboOral

      (tablets)
      1.Histologic responsePhase 296MulticentreOngoing- Adult, Older Adult (18–65 years)

      -All sexes
      NCT05084963/2021AmericaIRL201104

      (Immunomodulator peptide)
      PlaceboIntravenous infusion1.Histologic responsePhase 236MulticentreOngoing

      -Adult, Older Adult (18–75 years)

      -All sexes

      NCT04835168/2022N/ABT-11

      (LANCL2 modulator)
      PlaceboOral

      (tablets)
      1.Incidence and severity of AEsPhase 136N/ANot yet recruiting-Adult, Older Adult (18–65 years)

      -All sexes
      CORTICOSTEROIDS
      NCT00266578/2002AmericaFluticasone propionatePlaceboOral

      (inhaled/swallowed)
      1.Histologic responsePhase 330MonocentricCompleted-Child, Adult (3–30 years)

      -All sexes
      NCT00275561/2005AmericaFluticasonePlaceboOral

      (inhaled/swallowed)
      1.Dysphagia responsePhase 242MonocentricCompleted-Adult (18–60 years)

      -All sexes
      NCT00271349/2005EuropeBudesonidePlaceboOral

      (inhaled/swallowed)
      1.Histologic responsePhase 228MonocentricCompleted-Child, Adult, Older Adult (14–70 years)

      -All sexes
      NCT00426283/2007AmericaFluticasone proprionatePlaceboOral

      (inhaled/swallowed)
      1.Histologic responsePhase 242MulticentreCompleted-Child, Adult (3–30 years)

      -All sexes
      NCT00638456/2008AmericaBudesonide + LansoprazolePlacebo + LansoprazoleOral

      (viscous)
      1.Histologic responsePhase 232MonocentricCompleted-Child, Adult, Older Adult (1 year and older)

      -All sexes
      NCT00895817/2008AmericaFluticasoneEsomeprazoleOral1.Histologic responseNot applicable42MonocentricCompleted-Adult, Older Adult (18 years and older)

      -All sexes
      NCT00762073/2009AmericaBudesonidePlaceboOral

      (suspension)
      1.Histologic response

      2.Clinical symptom score response
      Phase 282MulticentreCompleted-Child, Adult (2–18 years)

      -All sexes
      NCT00961233/2009AmericaBudesonide

      (inhaled/swallowed)
      Budesonide

      (viscous/swallowed)
      Oral1.Histologic responseNot applicable25MonocentricCompleted-Adult, Older Adult (18 years and older)

      -All sexes
      NCT01016223/2010AmericaBeclomethasone dipropionatePlaceboOral

      (inhaled/swallowed)
      1.Clinical responsePhase 120MonocentricCompleted-Adult, Older Adult (18–65 years)

      -All sexes
      NCT02280616/2011EuropeBudesonidePlaceboOral

      (tablet and suspension)
      1.Histologic response

      Phase 276MonocentricCompleted-Adult, Older Adult (18–75 years)

      -All sexes
      NCT01386112/2011AmericaEUR-1100

      (fluticasone propionate)
      PlaceboOral1.Safety and tolerabilityPhase 1/224MulticentreCompleted-Child, Adult (12–55 years)

      -All sexes
      NCT01642212/2012AmericaBudesonidePlaceboOral

      (suspension)
      1.Histologic response

      2.Change in DSQ
      Phase 293MulticentreCompleted-Child, Adult (11–40 years)

      -All sexes
      NCT02113267/2014EuropeMometasone furoatePlaceboOral

      (inhaled/swallowed)
      1.Dysphagia scorePhase 240MonocentricTerminated-Adult, Older Adult (18 years and older)

      -All sexes
      NCT02019758/2015America-Budesonide

      (viscous/swallowed)

      -Fluticasone (inhaled/swallowed)
      -Placebo

      (slurry)

      -Placebo (inhaled)
      Oral1.Histologic response

      2.Dysphagia score
      Phase 4129MonocentricCompleted-Child, Adult, Older Adult (16–80 years)

      -All sexes
      NCT02434029/2015EuropeBudesonidePlaceboOral

      (ODT)
      1.Histologic response

      2.Clinical response
      Phase 388MonocentricCompleted-Adult, Older Adult (18–75 years)

      -All sexes
      NCT02605837/2015AmericaBudesonidePlaceboOral

      (suspension)
      1.Histologic response

      2.Dysphagia response
      Phase 3318MulticentreCompleted-Child, Adult (11–55 years)

      -All sexes
      NCT02736409/2016

      AmericaBudesonidePlaceboOral

      (suspension)
      1.Relapse during treatmentPhase 3219MulticentreCompleted-Child, Adult (11–55 years)

      -All sexes
      NCT02493335/2016

      EuropeBudesonidePlaceboOral

      (ODT)
      1.Rate of treatment failurePhase 3204MonocentricCompleted-Adult, Older Adult (18–75 years)

      -All sexes
      NCT03191864/2017

      America, EuropeAPT-1011

      (fluticasone proprionate)
      PlaceboOral

      (ODT)
      1.Histologic responsePhase 2106MulticentreCompleted-Adult, Older Adult (18–75 years)

      -All sexes
      NCT03245840/2017AmericaBudesonideNoneOral

      (suspension)
      1.Safety and tolerabilityPhase 3, OL133MulticentreActive, not recruiting-Child, Adult (11–55 years)

      -All sexes
      NCT03781596/2018AmericaFluticasone (inhaled/swallowed) + OmeprazoleFluticasone (inhaled/swallowed) + PlaceboOral

      (inhaled/swallowed)
      1.Histologic responsePhase 4100MonocentricOngoing-Child, Adult (6–60 years)

      -All sexes
      NCT04281108/2020

      America, Europe, OceaniaAPT-1011

      (fluticasone proprionate)
      PlaceboOral

      (ODT)
      1.Histologic response

      2.Change in number of dysphagia episodes
      Phase 3143MulticentreActive, not recruiting-Adult, Older Adult (18 years and older)

      -All sexes
      NCT04849390/2021EuropeESO-101

      (mometasone)
      PlaceboOral

      (capsule)
      1.Histologic responsePhase 242MulticentreOngoing-Adult, Older Adult (18–70 years)

      -All sexes
      NCT05083312/2021America, OceaniaAPT-1011

      (fluticasone proprionate)
      PlaceboOral

      (ODT)
      1.Histologic response

      2.Change in number of dysphagia episodes
      Phase 330MulticentreOngoing-Child (12–18 years)

      -All sexes
      NCT02873468/2021AmericaFluticasone propionatePlaceboOral

      (suspension)
      1.Histologic responsePhase 2116MonocentricOngoing-Adult, Older Adult (18 years and older)

      -All sexes
      NCT05095116/2021N/AAPT-1011

      (fluticasone proprionate)
      None

      Oral

      (ODT)
      1. Patients may participate up until APT-1011 is commercially available in the relevant regions or the protocol is terminated by the SponsorEAP, OLN/AN/AAvailable-Child, Adult, Older Adult (12 years and older)

      -All sexes
      OTHER MEDICAL TREATMENTS
      NCT00511316/2007AmericaMontelukast

      (leukotriene receptor antagonist)
      PlaceboOral

      (tablet)
      1.Effectiveness*Phase 141MonocentricCompleted-Adult, Older Adult (18–100 years)

      -All sexes
      NCT01458418/2011AmericaMontelukast

      (leukotriene receptor antagonist)
      PlaceboOral

      (tablet)
      1.Histologic responseNot applicable4MonocentricTerminated

      (Inability to complete enrolment)
      -Child (2–17 years)

      -All sexes
      NCT01808196/2013AmericaLosartan potassiumNoneOral

      (tablet)
      1.Histologic responsePhase 26MonocentricCompleted-Child, Adult (5–21 years)

      -All sexes
      NCT02371941/2014AmericaCromolyn sodiumPlaceboOral

      (viscous)
      1.Histologic responsePhase 416MonocentricCompleted-Child, Adult (2–18 years)

      -All sexes
      NCT02058537/2014AmericaBethanecholNoneOral

      (tablet)
      1.Change in HRIMPhase 22MonocentricTerminated

      (Initial PI left)
      -Adult, Older Adult (18–75 years)

      -All sexes
      NCT02353078/2015AmericaSucralfateNoneOral

      (slurry)
      1.Histologic responseEarly phase 13MonocentricCompleted-Adult, Older Adult (18–80 years)

      -All sexes
      NCT03029091/2017AmericaLosartan potassiumNoneOral

      (tablet)
      1.Histologic response

      2.Incidence of AEs
      Phase 215MulticentreCompleted-Child, Adult (5–25 years)

      -All sexes
      NCT04248712/2020AmericaFamotidine + LoratadinePlaceboOral

      (tablet)
      1.Incidence of AEs

      2.Histologic response
      Phase 250MonocentricOngoing-Adult, Older Adult (18 years and older)

      -All sexes
      NCT04149470/2020AmericaOmeprazoleNoneOral

      (tablet)
      1.Histologic responsePhase 490MonocentricOngoing-Child, Adult (8–22 years)

      -All sexes
      ESOPHAGEAL DILATION
      NCT00880906/2008AmericaEsophageal dilation + Dexlansoprazole + FluticasoneDexlansoprazole + FluticasoneEndoscopic procedure + Oral

      (tablet)
      1.Change in DSQNot applicable50MonocentricCompleted-Adult, Older Adult (18–75 years)

      -All sexes
      DIETARY MEASURES
      NCT01846962/2012Europe6FED-Budesonide (inhaled/swallowed)

      -Budesonide

      (viscous/swallowed)

      -Fluticasone

      (inhaled/swallowed)
      Oral1.Clinical severity score responsePhase 464MonocentricCompleted-Child, Adult (6 months-18 years)

      -All sexes
      NCT01821898/2013AmericaAllergy test-based EDBudesonideOral1.Histologic responsePhase 23MonocentricTerminated-Child (3–17 years)

      -All sexes
      NCT02227836/2014AmericaAllergy test-based EDNoneOral1.Sensitivity of APTNot applicable8MonocentricCompleted-Adult, Older Adult (18–90 years)

      -All sexes
      NCT02722148/2016AmericaAllergy test-based EDNoneOral1.Histologic responseNot applicable24MonocentricCompleted-Child, Adult, Older Adult (16–80 years)

      -All sexes
      NCT02610816/2016America1FED4FEDOral1.Change from baseline in PEESS

      2.Withnin groups comparisons of PEESS
      Phase 2/363MonocentricCompleted-Child (6–17 years)

      -All sexes
      NCT02778867/2016America1FED6FEDOral1.Histologic responsePhase 2/3129MulticentreCompleted-Adult (18–60 years)

      -All sexes
      NCT03657771/2018AmericaDEDFREEOral1.Histologic responseNot applicable72MulticentreOngoing-Child, Adult (2–18 years)

      -All sexes
      NCT02881372/2018AmericaOFDNoneOral1.Histologic responseNot applicable5MonocentricOngoing-Child (3–17 years)

      -All sexes
      Abbreviations: AEs, adverse events; APT, atopy patch-test; CHQ, child health questionnaire; DED, dairy elimination diet; DP2, D prostanoid receptor 2; DSQ, dysphagia symptom questionnaire; EAP, Expanded access protocol; ECG, electrocardiogram; EEsAI, eosinophilic esophagitis symptom activity index; EoE, eosinophilic esophagitis; FREE, dairy elimination plus food additive elimination; Ig, immunoglobulin; IL, interleukin; LANCL2, Lanthionine Synthetase C-Like 2; mAb, monoclonal antibody; N/A, not available; NCT, number of clinical trial; ODT, orally disintegrating tablet; OFD, oral food desensitization; OL, open label; OLE, open label extension; PEESS, pediatric eosinophilic esophagitis symptom score; PI, principal investigator; SDI, Straumann dysphagia instrument; S1P, sphingosine 1 phosphate; Th2, T-helper type 2; TNF, tumor necrosis factor; 6FED, six-food elimination diet; ED, elimination diet; HRIM, high-resolution impedance manometry; 1FED, one-food elimination diet; 4FED, four-food elimination diet; *not specified further.
      Table 2Interventional Trials Investigating Treatment of Eosinophilic Gastritis, Duodenitis, and Gastroenteritis.
      NCT/start datesubtype of EGIDGeographical region(s)Intervention(s) armComparatorMethod of administrationPrimary study outcome(s)StudyphaseEnrolment (Target/Actual)Design of the studyState of recruitmentPatient population and gender
      MONOCLONAL ANTIBODIES
      NCT00017862/2001EoGE*AmericaSCH 55,700

      (anti IL-5 mAb)
      NoneIntravenous infusion1.reducing peripheral blood eosinophiliaPhase 210MonocentricCompleted-Adult, Older Adult

      (18 years and older)

      -All sexes
      NCT00266565/2001EoGE*AmericaMepolizumab

      (anti-IL5 mAb)
      NoneIntravenous infusion1. Assess toxicity of anti IL5Phase 1/224MonocentricCompleted-Adult, Older Adult

      (18–65 years)

      -All sexes
      NCT00084097/2004EoGEAmericaOmalizumab

      (anti-IgE mAb)
      NoneSubcutaneous injection1.safety

      2. reducing peripheral blood eosinophilia
      Phase 230MonocentricCompleted-Child, Adult, Older Adult

      (12–76 years)

      -All sexes
      NCT03473977/2018EoG or EoGEAmericaBenralizumab

      (anti-IL5 receptor α mAb)
      PlaceboSubcutaneous injection1.Histologic responsePhase 2/326MonocentricActive, not recruiting-Child, Adult

      (12–60 years)

      –All sexes
      NCT03496571/2018EoG or EoGEAmericaLirentelimab

      (anti-Siglec-8 mAb)
      PlaceboIntravenous infusion1. Histologic response

      2. Change in PRO Questionnaire
      Phase 265MulticentreCompleted-Adult, Older Adult (18–80 years)

      -All sexes
      NCT03664960/2018EoG or EoD or EoGEAmericaLirentelimab

      (anti-Siglec-8 mAb)
      NoneIntravenous infusion1. Safety and tolerability

      2. Change in PRO Questionnaire

      3. Histologic response
      Phase 2, OLE58MulticentreActive, not recruiting-Adult, Older Adult (18–80 years)

      -All sexes
      NCT04322604/ 2020EoG or EoDAmericaLirentelimab

      (anti-Siglec-8 mAb)
      PlaceboIntravenous infusion1. safety and tolerability

      2. Change in PRO Questionnaire

      3. Histologic response
      Phase 3180MulticentreActive, not recruiting-Adult, Older Adult (18–80 years)

      -All sexes
      NCT04620811/2020EoG or EoDAmericaLirentelimab

      (anti-Siglec-8 mAb)
      NoneIntravenous infusion1. Safety and tolerability

      2. Change in PRO Questionnaire

      3. Histologic response
      Phase 3170MulticentreEnrolling by invitation-Adult, Older Adult (18–80 years)

      -All sexes
      NCT04856891/2021EoD or EoGEAmericaLirentelimab

      (anti-Siglec-8 mAb)
      PlaceboIntravenous infusion1. Histologic response

      2. Change in PRO
      Phase 380MulticentreOngoing-Adult, Older Adult (18–80 years)

      -All sexes
      NCT03678545/2021EoG or EoGEAmericaDupilumab

      (anti-IL4 receptor α mAb)
      PlaceboSubcutaneous injection1. Histologic response

      2. Change in PRO
      Phase 240MulticentreOngoing-Child, Adult, Older Adult

      (12–70 years)

      -All sexes
      IMMUNOMODULATORS
      NCT01814059/2013EoGEAmericaSirolimus

      (inhibitor of Th2 cells proliferation)
      NoneOral

      (Tablets)
      1. SafetyPhase 14MonocentricTerminated
      Not specified further.
      -Adult, Older Adult (18–65 years)

      -All sexes
      OTHER MEDICAL TREATMENTS
      NCT00124501/2004EoDAmericaBiofeedback-assisted Relaxation Training + SMTSMTNot applicable1.Feasibility of the methodNot applicable20MonocentricCompleted-Child

      (8–17 years)

      -All sexes
      NCT00148603/2005EoGEAmericaMontelukast

      (leukotriene receptor antagonist)
      NoneOral1.eosinophil density

      2.eosinophil activation

      3.mast cell density

      4.Serum eosinophils

      5. Eosinophil cationic protein
      Not applicable24MonocentricCompleted-Child

      (8–17 years)

      -All sexes
      DIETARY MEASURES
      NCT03320369/2017EoGEAmericaElemental DietNoneOral1. Histologic responseNot applicable18MonocentricCompleted-Adult, Older Adult (18–65 years)

      -All sexes
      Abbreviations: EGID, eosinophilic gastrointestinal disease; EoGE, eosinophilic gastroenteritis; Ig, immunoglobulin; SMT, standard medical treatment; *this trial also enrolled patients with hyper eosinophilic syndrome.
      § Not specified further.
      Fig. 2
      Fig. 2Geographical distribution of clinical trials on eosinophilic gastrointestinal diseases.
      With regard to EoE, 34 studies (51.5%) had a monocentric design, 30 (45.5%) were multicentre, and in two cases (3.0%) the design was not available. Most of the studies (53/66, 80.3%) were located in a single geographical region, while five were located in three (7.6%) or two (7.6%) geographical regions, one study (1.5%) was located in four geographical regions. The location was not available for two studies (3.0%). All studies included both sexes, 12 studies (18.2%) included a population of children, adults, and older adults, 17 (25.8%) included children and adults, 26 (39.4%) adults and older adults, seven (10.6%) children only, and four (6.0%) adults only.
      With regard to non-EoE EGIDs, eight studies (57.1%) had a monocentric design and six (42.9%) were multicentre. All studies were located in America and included both sexes. Two studies included a population of children, adults, and older adults, one included children and adults, nine adults and older adults, and two children only.

      3.3 Recruitment status and study phases

      For EoE, at the time of the literature research, most of the studies had completed recruitment (39/66, 59.1%), a considerable number were actively recruiting (15/66, 22.7%), five (7.6%) had terminated recruitment because of recruitment problems, insufficient funds, or because the principal investigator had left, and seven were in other recruitment phases (Table 1). Of the included studies, the majority were in phase 2 (27/66, 40.9%) and a substantial proportion were in phase 3 (14/66, 21.2%). Twenty-five studies were in other study phases (Table 1).
      As for EGIDS, half of clinical trials had completed recruitment (7/14, 50%), two were actively recruiting (14.3%), and five were in other recruitment phases (Table 2). The majority of trials on non-EoE EGIDS were in phase 2 (5/14, 35.7%) or phase 3 (3/14, 21.4%) (Table 2).

      3.4 Interventions, comparators, and method of administration

      Fig. 3a reports the number of clinical trials for each therapeutic intervention for EoE. Table 1 and Table 2 report the details of interventions, comparators, and method of administration used in each trial.
      Fig. 3
      Fig. 3(a) Number of Registered Trials for EoE Treatment; (b) Number of Registered Trials for Eosinophilic Gastritis, Duodenitis, and Gastroenteritis Treatment.
      Abbreviations: EoE, eosinophilic oesophagitis; MAB, monoclonal antibodies.
      Of the 17 studies on monoclonal antibodies for the treatment of EoE, five studies investigated an anti-interleukin (IL)−5 (mepolizumab or reslizumab), four an anti-IL-13 (dectrekumab or cendakimab), three an anti-IL-4 receptor-α (dupilumab), and one an anti-IL5 receptor-α (benralizumab), anti-IL15 (CALY-002), anti-IgE (omalizumab), anti-Siglec-8 (lirentelimab), or anti-TNF-α (infliximab). Among these, the majority compared monoclonal antibodies with placebo (13/17, 76.5%) (Table 1). Among monoclonal antibodies, nine were administered via intravenous infusion, and eight via subcutaneous injection.
      There were five trials on immunomodulators, investigating etrasimod, sirolimus, BT-11, IRL201104, or OC000459. In four trials the comparator was placebo, and there was no comparator in one study. Four treatments were administered orally, and one intravenously.
      Twenty-six clinical trials investigated EoE treatment with topical corticosteroids (one of these investigated two different corticosteroids). The majority used fluticasone (11/26, 42.3%) or budesonide (11/26, 42.3%), and compared active treatment with placebo (20/26, 76.9%) (Table 1). In all 26 trials the treatment was administered orally, and in three studies there were two drug chemical formulations. Topical corticosteroids were administered via either orally disintegrating a tablet (n = 6), a viscous suspension (n = 10), a capsule (n = 1), a tablet (n = 1), inhaled or swallowed (n = 9). In two cases the method of administration was reported as oral, without further details.
      Eight trials investigated dietary measures for the treatment of EoE. Most trials were on elimination diets and one on oral food desensitization. Comparators used in dietary measures trials were variegated and are reported in Table 1.
      Of the nine studies investigating other medical treatments for EoE, two used montelukast, two losartan potassium, one omeprazole, one famotidine plus loratadine, one sucralfate, one bethanechol (a muscarinic agonist), and one cromolyn sodium. Of these, four studies compared active treatment with placebo, while five did not use a comparator arm.
      Finally, one study investigated the use of a combination of esophageal dilation, dexlansoprazole, and fluticasone compared with oral medical treatment alone (Table 1).
      Fig. 3b reports the number of clinical trials for each therapeutic intervention for non-EoE EGIDs. Five were on anti-Siglec-8 (lirentelimab; EoG n = 4, EoD n = 4, EoGE n = 3), two studies were on anti-IL5 for EoGE (mepolizumab, SCH55700), and one was on either anti-IL-5 receptor-α, anti-IL4 receptor-α, or anti-IgE (benralizumab for EoG or EoGE, dupilumab for EoG or EoGE, omalizumab for EoGE). Among these trials, in five cases the comparator was placebo, while there was no comparator in five studies. Seven monoclonal antibodies were administered intravenously, and three via subcutaneous injection.
      One trial investigated an immunomodulator (sirolimus) administered orally in the context of EoGE without a comparator treatment. One trial investigated oral montelukast for EoGE with no comparator, and one study investigated biofeedback-assisted relaxation training in combination with standard medical treatment compared with standard medical treatment alone for the treatment of EoD. Finally, one study investigated an elemental diet for EoGE with no comparator arm.

      3.5 Primary study outcomes

      As regard primary outcomes, 44 clinical trials on EoE (66.7%) investigated histologic response, 19 (28.8%) clinical response, and 11 (16.7%) evaluated the incidence of adverse events, safety, and tolerability. Other single studies investigated changes in high-resolution impedance manometry, the sensitivity of atopy patch-test for guiding elemental diet, the rate of treatment failure or relapse during treatment, changes in physician's global assessment, the presence of anti-drug antibodies, or the volume of distribution of the investigational drug.
      In trials conducted in non-EoE EGIDs, the primary outcome was histologic response in nine studies (64.3%), clinical response in six studies (42.8%), safety, tolerability, or toxicity in six studies (42.8%), reduction of peripheral eosinophilia in two studies (14.3%), and feasibility of biofeedback-assisted relaxation training, eosinophil activation, mast cell density, serum eosinophils, and eosinophil cationic protein in one study (7.1%).

      3.6 Temporal trends

      Fig. 4a shows the temporal trend of interventional studies on the treatment of EoE. The first registered clinical trial on EoE commenced in 2002 and investigated the use of topical corticosteroids. Twenty-five more studies focusing on corticosteroid treatment for EoE were commenced in the following years, with a relevant increase after 2019, making topical corticosteroids the most investigated drugs in clinical trials for EoE to date. Monoclonal antibodies currently represent the second most studied treatment in clinical trials for EoE. The first trials investigating a monoclonal antibody for the treatment of EoE started in 2005, and a gradual increase was seen afterwards. However, a sharp increase in studies on monoclonal antibodies for EoE was recorded subsequently, with six studies commencing in the past 2 years. With regard to immunomodulators for EoE, although only two studies had started in the period 2010–2020, two more studies were commenced in 2021 and one is due to start in 2022. The first registered clinical trial for the dietary treatment of EoE was commenced in 2012. Although an initial increase was observed subsequently, with five more studies started in the following four years, the two most recent studies on dietary regimens for EoE date back to 2018. From 2007 to 2020, 10 clinical trials investigating other treatments for EoE were commenced.
      Fig. 4
      Fig. 4a) Temporal Trend of Clinical Trials Investigating Treatments for EoE b) Temporal Trend of Clinical Trials Investigating Treatments For Eosinophilic Gastritis, Duodenitis, and Gastroenteritis.
      Abbreviations: EoE, eosinophilic oesophagitis; EGIDs, eosinophilic gastrointestinal diseasess; mAb, monoclonal antibodies.
      Fig. 4b shows the temporal trend of interventional studies on the treatment of EoG, EoD, and EoGE. Monoclonal antibodies are by far the most investigated treatments for non-EoE EGIDs. The first registered trials on monoclonal antibodies for EGIDs started in 2001. Although only one study on monoclonal antibodies was commenced over the following 17 years, seven studies were commenced over the past 3 years. From 2004 to 2017, single studies on other treatments, including biofeedback, montelukast, immunomodulators, and elemental diet were commenced.

      4. Discussion

      This systematic review provided a snapshot of ongoing research on the treatment of EGIDs to assess the state of current research and possibly forecast future developments in the field. EGIDs are chronic gastrointestinal diseases whose epidemiology is rapidly changing as a consequence of a combination of increased recognition and incidence rates [
      • Dellon E.S.
      • Hirano I.
      Epidemiology and Natural History of Eosinophilic Esophagitis.
      ]. Concerning EoE, currently recommended management strategies include corticosteroids, dietary measures, PPIs, and possible dilation of stenoses, while oral corticosteroids and dietary interventions are suggested for non-EoE EGIDs [
      • Walker M.M.
      • Potter M.
      • Talley N.J.
      Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus.
      ,
      • Lucendo A.J.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      ,
      • de Bortoli N.
      • et al.
      Eosinophilic esophagitis: update in diagnosis and management. Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE).
      ,
      • Hirano I.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis.
      . However, most treatments are currently not approved by the United States Food and Drug Administration and European Medicines Agency, have very low to moderate levels of evidence, and possible novel strategies, such as monoclonal antibodies, currently lack any recommendations because of knowledge gaps [
      • Walker M.M.
      • Potter M.
      • Talley N.J.
      Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus.
      ,
      • Lucendo A.J.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      ,
      • Hirano I.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis.
      . However, there is a considerable number of active clinical trials aiming to fill these unmet needs, and it is predicted that novel treatments for EGIDs will be available imminently. We screened 832 clinical trials, of which 79 were eligible for inclusion. Sixty-five investigated treatments for EoE, one for EoE and EoGE, and 13 investigated treatments for EoG, EoD and/or EoGE. There were no trials on EoC.
      As regard EoE, off-label inhaled/swallowed topical corticosteroids have demonstrated effectiveness on histology and symptoms in patients with EoE in previous meta-analyses [
      • Sawas T.
      • et al.
      Systematic review with meta-analysis: pharmacological interventions for eosinophilic oesophagitis.
      ,
      • Tan N.D.
      • Xiao Y.L.
      • Chen M.H.
      Steroids therapy for eosinophilic esophagitis: systematic review and meta-analysis.
      . Accordingly, in the past 20 years, 26 clinical trials on the use of topical corticosteroids for EoE were commenced. Analysis of temporal trends of studies on corticosteroids showed a gradual increase until 2020, when a sharp rise occurred. It appears that research on corticosteroids is heading towards the development of ad-hoc topical corticosteroids for the treatment of EoE. Although some studies are aimed at assessing the efficacy of inhaled or swallowed topical corticosteroids, the latest studies focused consistently on novel delivery systems that could improve the administration of the drug, including viscous suspensions, orally disintegrating tablets, or capsules. In contrast, although patients with lower EGIDs are commonly and effectively treated with systemic corticosteroids [
      • Walker M.M.
      • Potter M.
      • Talley N.J.
      Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus.
      ], there were no registered trials investigating corticosteroid drugs in EoG, EoD, or EoGE. Although systemic corticosteroids are well known anti-inflammatory drugs, their effectiveness and safety in the context of non-EoE EGIDs still needs to be assessed in registered clinical trials.
      Current guidelines, which have been published in 2017 and 2020 [
      • Lucendo A.J.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      ,
      • Hirano I.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis.
      , are generally against, or provide no recommendation on, the use of monoclonal antibodies for the treatment of EoE. Meta-analyses on a very limited number of studies on monoclonal antibodies for EoE were published only recently [
      • Rokkas T.
      • Niv Y.
      • Malfertheiner P.
      A Network Meta-Analysis of Randomized Controlled Trials on the Treatment of Eosinophilic Esophagitis in Adults and Children.
      ,
      • Tomizawa Y.
      • et al.
      Efficacy of Pharmacologic Therapy for Eosinophilic Esophagitis: a Systematic Review and Network Meta-Analysis.
      . However, an increase in research on monoclonal antibodies was seen after 2018, in parallel with the discovery of new potential targets (i.e., IL-4, Il-5, IL-13, IL-15, and Siglec-8), and several studies will be completed in the coming years. Consistently, we found that most studies on monoclonal antibodies were in advanced phases or had already completed recruitment at the time of this systematic review. Additionally, from 2018 onwards, there has been a shift towards a subcutaneous, rather than intravenous, route of administration of monoclonal antibodies, and this may result in self, rather than in-hospital, administration of novel molecules. Similarly, trials on monoclonal antibodies for other EGIDs have gradually increased since 2001, have had considerable growth from 2018, and now represent the most investigated drug for EoG, EoD, and EoGE. Based on the status of current research on monoclonal antibodies for EGIDs, it is predictable that several monoclonal antibodies will be available and possibly be recommended by clinical guidelines soon. However, we observed a lack of interest in evaluating these novel drugs in EoC, which will likely remain without labelled therapeutic options in the longer term.
      PPIs are currently considered as one of the possible first line treatments for EoE [
      • Lucendo A.J.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      ,
      • de Bortoli N.
      • et al.
      Eosinophilic esophagitis: update in diagnosis and management. Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE).
      ,
      • Hirano I.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis.
      because they are effective in controlling esophageal inflammation and symptoms [
      • Gutierrez-Junquera C.
      • et al.
      Long-term Treatment With Proton Pump Inhibitors Is Effective in Children With Eosinophilic Esophagitis.
      ,
      • Lucendo A.J.
      • Arias A.
      • Molina-Infante J.
      Efficacy of Proton Pump Inhibitor Drugs for Inducing Clinical and Histologic Remission in Patients With Symptomatic Esophageal Eosinophilia: a Systematic Review and Meta-Analysis.
      . However, since 2008, only five trials registered on clinicaltrials.gov investigated treatment with PPIs, either as monotherapy or in combination with other treatments. Although two of these studies commenced in the past 3 years and are currently recruiting, it is likely that PPIs will continue to be used off-label for the foreseeable future. Studies on immunomodulators for EGIDs are in their early phases or are not yet recruiting. Therefore, it is likely that the availability of these drugs will take longer, compared with other medical treatments. Elimination diets are a recognized treatment for EGIDs [
      • Lucendo A.J.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      ,
      • de Bortoli N.
      • et al.
      Eosinophilic esophagitis: update in diagnosis and management. Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE).
      ,
      • Hirano I.
      • et al.
      AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis.
      , and represent a long-term, drug-free, and effective treatment for EoE, comparable to topical corticosteroids and PPIs [
      • Visaggi P.
      • et al.
      Dietary Management of Eosinophilic Esophagitis: tailoring the Approach.
      ]. Until 2016, most clinical trials on elimination diets for EoE focused on allergy test-based or multiple food elimination regimens. Since 2018, there has been a tendency to move towards simpler and more tolerable one-food elimination strategies. A possible explanation for this shift is that almost 50% of patients can achieve remission with a two-food elimination diet, and that up to 70% of responders to this diet have only one food trigger [
      • Molina-Infante J.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      ]. Additionally, less restrictive dietary regimens are more tolerable for patients and may be more easily applicable to clinical practice outside clinical trials [
      • Visaggi P.
      • et al.
      Dietary Management of Eosinophilic Esophagitis: tailoring the Approach.
      ]. As for EoGE, a unique trial on therapeutic dietary restrictions (elemental diet) was retrieved. Overall, elimination diets are still being investigated in the EoE setting, while they seem rather under-investigated in other EGIDs.
      Primary study endpoints of included trials were mostly histology-centered (66.7% of studies on EoE and 64.3% of studies on EGIDs). Although esophageal inflammation seems to be the main determinant of disease progression [
      • Dellon E.S.
      • Hirano I.
      Epidemiology and Natural History of Eosinophilic Esophagitis.
      ], EoE is a complex disease with histological, clinical, and endoscopic markers of disease activity whose response to treatment may be inconsistent [
      • Visaggi P.
      • et al.
      Dietary Management of Eosinophilic Esophagitis: tailoring the Approach.
      ]. Accordingly, to fill major gaps in knowledge related to measuring treatment response, it would be desirable to include standardized definitions of symptoms and endoscopy findings among primary treatment outcomes. In this regard, in 2018, a systematic review individuated significant heterogeneity in outcome measurement and outcome definitions used for histology, endoscopy, and patient-reported endpoints in clinical trials on EoE [
      • Ma C.
      • et al.
      Heterogeneity in Clinical, Endoscopic, and Histologic Outcome Measures and Placebo Response Rates in Clinical Trials of Eosinophilic Esophagitis: a Systematic Review.
      ], which makes the management of patients more challenging. In addition, as hypervigilance, anxiety, and esophageal motor disorders have been demonstrated to be involved in refractoriness of symptoms [
      • Taft T.H.
      • et al.
      Esophageal Hypervigilance and Symptom-Specific Anxiety in Patients with Eosinophilic Esophagitis.
      ,
      • Visaggi P.
      • et al.
      Systematic Review: esophageal motility patterns in patients with eosinophilic esophagitis.
      , the standardized and concomitant assessment of these factors in the setting of clinical trials may help to further elucidate the efficacy of treatments.
      This study has some limitations. First, clinicaltrials.gov was the only database searched for eligible studies and unregistered trials have not been included. However, clinicaltrials.gov currently covers around 400,000 research studies in 220 countries and represents the largest clinical trial registry worldwide. Second, the results of clinical trials were not included in this study. In this regard, meta-analytic studies investigating efficacy estimates of treatments for EoE [
      • Sawas T.
      • et al.
      Systematic review with meta-analysis: pharmacological interventions for eosinophilic oesophagitis.
      ,
      • Tan N.D.
      • Xiao Y.L.
      • Chen M.H.
      Steroids therapy for eosinophilic esophagitis: systematic review and meta-analysis.
      ,
      • Rokkas T.
      • Niv Y.
      • Malfertheiner P.
      A Network Meta-Analysis of Randomized Controlled Trials on the Treatment of Eosinophilic Esophagitis in Adults and Children.
      ,
      • Tomizawa Y.
      • et al.
      Efficacy of Pharmacologic Therapy for Eosinophilic Esophagitis: a Systematic Review and Network Meta-Analysis.
      ,
      • Lucendo A.J.
      • Arias A.
      • Molina-Infante J.
      Efficacy of Proton Pump Inhibitor Drugs for Inducing Clinical and Histologic Remission in Patients With Symptomatic Esophageal Eosinophilia: a Systematic Review and Meta-Analysis.
      ,
      • Moawad F.J.
      • et al.
      Systematic review with meta-analysis: endoscopic dilation is highly effective and safe in children and adults with eosinophilic oesophagitis.
      ,
      • Arias A.
      • et al.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      already showed that a considerable proportion of patients do not achieve disease remission while con currently available treatments. Accordingly, treatment efficacy outcomes were beyond the scope of this systematic review, which aimed at providing an overview of treatment trials in EGIDs registered in clinicaltrials.gov to provide a summary of current research trends. Reasons why research on EGIDS is heading towards the development of therapeutic alternatives include the suboptimal efficacy of current treatments, the recognition of novel key inflammatory molecular targets, and the development of new pharmacologic techniques.
      In conclusion, numerous clinical trials are investigating possible treatments for EoE, EoG, EoD, and EoGE, with corticosteroids and monoclonal antibodies making up the majority of these and overall research showing increasing trends. It seems likely that the therapeutic landscape of EGIDs will widen imminently.

      Declaration of Competing Interest

      Pierfrancesco Visaggi: none. Matteo Ghisa: none. Brigida Barberio: none. Daria Maniero: none. Eliana Greco: none. Vincenzo Savarino: none. Christopher J Black: None. Alexander C Ford: None. Nicola de Bortoli: has received lecture or consultancy fees from Malesci and Reckitt Benckiser, outside the submitted work. Edoardo Savarino: has received lecture or consultancy fees from Abbvie, Alfasigma, Amgen, Aurora Pharma, Bristol-Myers Squibb, EG Stada Group, Fresenius Kabi, Grifols, Janssen, Johnson&Johnson, Innovamedica, Malesci, Medtronic, Merck & Co, Reckitt Benckiser, Sandoz, Shire, SILA, Sofar, Takeda, Unifarco, outside the submitted work.

      Guarantor of the article

      Prof Edoardo Savarino

      Acknowledgments

      None

      Author contributions

      PV, MG, NdB, EVS conceived and drafted the study. PV and MG collected and interpreted all data. PV, MG, BB, DM, EG, VS, CJB, ACF, NdB, EVS drafted the manuscript. All authors commented on drafts of the paper. All authors have approved the final draft of the manuscript.

      Funding

      None.

      Ethics committee approval

      Not required because this study retrieved and synthesised data from already published studies.

      Data sharing statement

      No additional data available.
      All authors approved the final version of the manuscript

      Appendix. Supplementary materials

      References

        • Jung Y.
        • Rothenberg M.E.
        Roles and regulation of gastrointestinal eosinophils in immunity and disease.
        J Immunol. 2014; 193: 999-1005
        • Sciumé G.D.
        • et al.
        Eosinophilic esophagitis: novel concepts regarding pathogenesis and clinical manifestations.
        Minerva Gastroenterol (Torino). 2022; 68: 23-39
        • Travers J.
        • Rothenberg M.E.
        Eosinophils in mucosal immune responses.
        Mucosal Immunol. 2015; 8: 464-475
        • Walker M.M.
        • Potter M.
        • Talley N.J.
        Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus.
        Lancet Gastroenterol Hepatol. 2018; 3: 271-280
        • Lucendo A.J.
        • et al.
        Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
        United European Gastroenterol J. 2017; 5: 335-358
        • Visaggi P.
        • et al.
        Eosinophilic esophagitis: clinical, endoscopic, histologic and therapeutic differences and similarities between children and adults.
        Therap Adv Gastroenterol. 2021; 141756284820980860
        • de Bortoli N.
        • et al.
        Eosinophilic esophagitis: update in diagnosis and management. Position paper by the Italian Society of Gastroenterology and Gastrointestinal Endoscopy (SIGE).
        Dig Liver Dis. 2017; 49: 254-260
        • Hirano I.
        • et al.
        AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis.
        Gastroenterology. 2020; 158: 1776-1786
        • Arias Á.
        • Lucendo A.J.
        Epidemiology and risk factors for eosinophilic esophagitis: lessons for clinicians.
        Expert Rev Gastroenterol Hepatol. 2020; 14: 1069-1082
        • Kinoshita Y.
        • et al.
        Systematic review: eosinophilic esophagitis in Asian countries.
        World J Gastroenterol. 2015; 21: 8433-8440
        • Dellon E.S.
        • Hirano I.
        Epidemiology and Natural History of Eosinophilic Esophagitis.
        Gastroenterology. 2018; 154 (e3): 319-332
        • Mukkada V.
        • et al.
        Health-Related Quality of Life and Costs Associated With Eosinophilic Esophagitis: a Systematic Review.
        Clinical Gastroenterol Hepatol. 2018; 16 (e8): 495-503
        • Anderson J.
        • et al.
        Cost of chronic inflammatory disease: the impact of eosinophilic esophagitis in Nevada.
        J Dig Dis. 2020; 21: 12-19
        • Licari A.
        • et al.
        Epidemiology of Nonesophageal Eosinophilic Gastrointestinal Diseases in Symptomatic Patients: a Systematic Review and Meta-Analysis.
        J Allergy Clin Immunol Pract. 2020; 8 (e2): 1994-2003
        • Mansoor E.
        • Saleh M.A.
        • Cooper G.S.
        Prevalence of Eosinophilic Gastroenteritis and Colitis in a Population-Based Study, From 2012 to 2017.
        Clin Gastroenterol Hepatol. 2017; 15: 1733-1741
        • Jensen E.T.
        • et al.
        Prevalence of Eosinophilic Gastritis, Gastroenteritis, and Colitis: estimates From a National Administrative Database.
        J Pediatr Gastroenterol Nutr. 2016; 62: 36-42
        • Dellon E.S.
        • et al.
        Determination of Biopsy Yield That Optimally Detects Eosinophilic Gastritis and/or Duodenitis in a Randomized Trial of Lirentelimab.
        Clin Gastroenterol Hepatol. 2022; 20 (.e15): 535-545
        • Sawas T.
        • et al.
        Systematic review with meta-analysis: pharmacological interventions for eosinophilic oesophagitis.
        Aliment Pharmacol Ther. 2015; 41: 797-806
        • Tan N.D.
        • Xiao Y.L.
        • Chen M.H.
        Steroids therapy for eosinophilic esophagitis: systematic review and meta-analysis.
        J Dig Dis. 2015; 16: 431-442
        • Rokkas T.
        • Niv Y.
        • Malfertheiner P.
        A Network Meta-Analysis of Randomized Controlled Trials on the Treatment of Eosinophilic Esophagitis in Adults and Children.
        J Clin Gastroenterol. 2021; 55: 400-410
        • Tomizawa Y.
        • et al.
        Efficacy of Pharmacologic Therapy for Eosinophilic Esophagitis: a Systematic Review and Network Meta-Analysis.
        J Clin Gastroenterol. 2018; 52: 596-606
        • Gutierrez-Junquera C.
        • et al.
        Long-term Treatment With Proton Pump Inhibitors Is Effective in Children With Eosinophilic Esophagitis.
        J Pediatr Gastroenterol Nutr. 2018; 67: 210-216
        • Lucendo A.J.
        • Arias A.
        • Molina-Infante J.
        Efficacy of Proton Pump Inhibitor Drugs for Inducing Clinical and Histologic Remission in Patients With Symptomatic Esophageal Eosinophilia: a Systematic Review and Meta-Analysis.
        Clin Gastroenterol Hepatol. 2016; 14 (e1): 13-22
        • Visaggi P.
        • et al.
        Dietary Management of Eosinophilic Esophagitis: tailoring the Approach.
        Nutrients. 2021; 13
        • Molina-Infante J.
        • et al.
        Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
        J Allergy Clin Immunol. 2018; 141: 1365-1372
        • Ma C.
        • et al.
        Heterogeneity in Clinical, Endoscopic, and Histologic Outcome Measures and Placebo Response Rates in Clinical Trials of Eosinophilic Esophagitis: a Systematic Review.
        Clin Gastroenterol Hepatol. 2018; 16 (e3): 1714-1729
        • Taft T.H.
        • et al.
        Esophageal Hypervigilance and Symptom-Specific Anxiety in Patients with Eosinophilic Esophagitis.
        Gastroenterology. 2021; 161: 1133-1144
        • Visaggi P.
        • et al.
        Systematic Review: esophageal motility patterns in patients with eosinophilic esophagitis.
        Digestive Liver Disease. 2022;
        • Moawad F.J.
        • et al.
        Systematic review with meta-analysis: endoscopic dilation is highly effective and safe in children and adults with eosinophilic oesophagitis.
        Aliment Pharmacol Ther. 2017; 46: 96-105
        • Arias A.
        • et al.
        Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
        Gastroenterology. 2014; 146: 1639-1648