Dellon, Evan S.

Abstract Eosinophilic esophagitis (EoE), gastritis (EG), and/or duodenitis (EoD) are associated with accumulation and activation of eosinophils and mast cells in the esophagus, stomach, and/or duodenum, respectively. Lirentelimab (AK002), an antibody against siglec-8, depletes eosinophils and inhibits mast cells. We performed an open-label extension (OLE) study of subjects who completed ENIGMA (a randomized, double-blind, placebo-controlled phase 2 study of lirentelimab in adults with symptomatic, biopsy-confirmed EG and/or EoD, with or without EoE) to evaluate long-term responses. Methods Subjects who received 4 monthly infusions of lirentelimab or placebo during ENIGMA (n = 59) were eligible for the OLE; they received monthly, escalating doses of lirentelimab (0.3 or 1 mg/kg escalating to 3 mg/kg). Symptoms were assessed weekly using an electronic daily patient-reported outcome questionnaire and total symptom scores (TSS) were calculated. Patients underwent upper endoscopy with biopsy at screening and at the end of ENIGMA (day 99, week 16, blinded); in the OLE, endoscopies were performed on day 323 (30 weeks after the first dose in the OLE). Histopathology was assessed by a single pathologist. Results Fifty-eight subjects entered the OLE; 45 completed ≥52 weeks lirentelimab (including exposure during ENIGMA) and 29 completed 70 weeks. Mean TSS improved through week 70 (Figure 1). Subjects receiving 70 weeks lirentelimab (ENIGMA+OLE) had further improvements in TSS from baseline (mean reductions: 68% at weeks 29–30, 70% at weeks 51–52, 75% at weeks 69–70). Symptom scores (abdominal pain, nausea, vomiting, early satiety, appetite loss, abdominal cramping, bloating, diarrhea) decreased significantly from baseline. Treatment response was not associated with concomitant EoE. The most common adverse event was mild to moderate infusion-related reactions, usually with the first infusion. Conclusion In the OLE of the ENIGMA study, patients with EG and or EoD (with or without concomitant EoE) who received lirentelimab had sustained tissue eosinophil depletion and significant long-term symptom improvement. Symptoms continued to improve with duration of treatment. Lirentelimab appears to be a promising targeted treatment for EG and/or EoD.

Abstract Although the prevalence of eosinophilic gastrointestinal disorders (EGIDs) is increasing, there is evidence that eosinophilic gastritis and/or duodenitis (EG/EoD) are underdiagnosed. Patients with EG/EoD often present with chronic, non-specific gastrointestinal (GI) symptoms, similar to patients with functional GI disorders. We hypothesized that systematic evaluation, including multiple esophageal, gastric and duodenal biopsies, of patients with chronic GI symptoms might reveal a high rate of gastroduodenal eosinophila, with or without eosinophilic esophagitis (EoE). Methods We performed a prospective multi-center study of patients with non-specific GI symptoms for ≥6 months, from 20 sites. Patients completed a questionnaire assessing abdominal pain, abdominal cramping, early satiety, bloating, nausea, vomiting, diarrhea, and loss of appetite. Those with daily average symptom severity scores ≥3/10 for any single symptom underwent esophagogastroduodenoscopy (EGD) with collection of 4 esophageal (EoE), 8 gastric, and 4 duodenal biopsies, analyzed by central pathologists. Histologic criteria for EoE was ≥15eos/hpf in ≥1 esophageal site and for EG/EoD was peak eosinophil counts ≥30/hpf in ≥5 gastric hpfs and/or 3 duodenal hpfs—criteria used in randomized trials. Results Of 556 patients screened, 405 (73%) met symptom criteria and underwent EGD; 181 patients (45%, mean age 45, 73% female) who underwent EGD met the histologic criteria for EG/EoD, and of these, 7% also had EoE diagnosed. Overall 2% met histologic criteria for EoE alone. Of patients who met the histologic criteria for EG/EoD, 93% were previously diagnosed with gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), or functional dyspepsia (FD) (Figure 1). The average duration of GI symptoms in the screened population as well as those that met histologic criteria for EG/EoD was 11 years. Conclusion Forty-five percent of patients with moderate-to-severe GI symptoms who underwent EGD met histologic criteria for EG/EoD. Over 90% of these patients had previously been diagnosed with GERD, IBS, and/or FD, and had minimal overlap with EoE. EGD with systematic gastroduodenal biopsies, and intentional evaluation for tissue eosinophilia, should be performed in patients with chronic GI symptoms. Accurate diagnosis of EG/EoD is required for appropriate, targeted treatment and improved outcomes of patients with moderate-to-severe GI symptoms.

Abstract Background Dysphagia is the main symptom of adult eosinophilic esophagitis (EoE). We describe a novel syndrome, referred to as “food‐induced immediate response of the esophagus” (FIRE), observed in EoE patients. Methods Food‐induced immediate response of the esophagus is an unpleasant/painful sensation, unrelated to dysphagia, occurring immediately after esophageal contact with specific foods. Eosinophilic esophagitis experts were surveyed to estimate the prevalence of FIRE, characterize symptoms, and identify food triggers. We also surveyed a large group of EoE patients enrolled in the Swiss EoE Cohort Study for FIRE. Results Response rates were 82% (47/57) for the expert and 65% (239/368) for the patient survey, respectively. Almost, 90% of EoE experts had observed the FIRE symptom complex in their patients. Forty percent of EoE patients reported experiencing FIRE, more commonly in patients who developed EoE symptoms at a younger age (mean age of 46.4 years vs 54.1 years without FIRE; P < .01) and in those with high allergic comorbidity. Food‐induced immediate response of the esophagus symptoms included narrowing, burning, choking, and pressure in the esophagus appearing within 5 minutes of ingesting a provoking food that lasted less than 2 hours. Symptom severity rated a median 7 points on a visual analogue scale from 1 to 10. Fresh fruits/vegetables and wine were the most frequent triggers. Endoscopic food removal was significantly more commonly reported in male patients with vs without FIRE (44.3% vs 27.6%; P = .03). Conclusions Food‐induced immediate response of the esophagus is a novel syndrome frequently reported in EoE patients, characterized by an intense, unpleasant/painful sensation occurring rapidly and reproducibly in 40% of surveyed EoE patients after esophageal contact with specific foods.

ABSTRACT Objectives: Clinical features of eosinophilic esophagitis (EoE) have been well‐described in the literature, however, characterization of features experienced by patients with other eosinophilic gastrointestinal diseases (EGIDs) is lacking. Using data collected from a patient contact registry, we sought to characterize and contrast patient‐reported gastrointestinal and extragastrointestinal symptoms and comorbidities in non‐EoE EGIDs, including eosinophilic gastritis, gastroenteritis and colitis, relative to EoE. Methods: We conducted a cross‐sectional study of contact registry data collected from 2015 to 2018. Statistical comparisons were made using chi‐square (categorical measures) and the Mann‐Whitney U test (continuous measures). Multivariable analyses were used to evaluate associations between treatment and feelings of isolation. Results: Of the 715 reporting an EGID diagnosis (n = 525 EoE; n = 190 non‐EoE EGID), a higher proportion of those with a non‐EoE EGID reported more frequent specific and nonspecific gastrointestinal symptoms, including nausea, abdominal pain, diarrhea, constipation, and bloating ( P < 0.01 for all). Participants with a non‐EoE EGID were more likely to report higher frequency of fatigue, isolation, and deep muscle or joint pain ( P < 0.01 for all). Specific food elimination and elemental formula treatments were associated with increased odds of more frequent (at least weekly) feelings of isolation for participants with EoE (adjusted odds rtaio [aOR]: 2.4; 95% confidence interval [CI]: 1.5‐‐4.1 for specific food elimination and adjusted OR: 1.9; 95% CI: 1.2‐‐3.3 for elemental formula). Conclusions: Significant differences exist in the symptoms and comorbidities experienced between those with EoE versus non‐EoE EGIDs. Additional investigation is needed to elucidate the factors that may contribute to the high disease burden of these poorly understood conditions.

OBJECTIVES: Dietary elimination for treatment of eosinophilic esophagitis (EoE) is limited by lack of accuracy in current allergy tests. We aimed to develop an immunologic approach to identify dietary triggers and prospectively test allergen-specific immune signature-guided dietary elimination therapy. METHODS: In the first phase, we developed and assessed 2 methods for determining selected food triggers using samples from 24 adults with EoE: a CD4+ T-cell proliferation assay in peripheral blood and food-specific tissue IgG4 levels in esophageal biopsies. In the second phase, we clinically tested elimination diets created from these methods in a prospective cohort treated for 6 weeks (NCT02722148). Outcomes included peak eosinophil counts (eos/hpf), endoscopic findings (measured by the EoE Endoscopic Reference Score), and symptoms (measured by the EoE Symptom Activity Index). RESULTS: Parameters were optimized with a positive test on either assay, yielding agreements of 60%, 75%, 53%, 58%, and 53% between predicted and known triggers of peanut, egg, soy, wheat, and milk, respectively. In clinical testing, the mean number of foods eliminated based on the assays was 3.4, and 19 of 22 subjects were compliant with treatment. After treatment, median peak eosinophil counts decreased from 75 to 35 ( P = 0.007); there were 4 histologic responders (21%). The EoE Endoscopic Reference Score and EoE Symptom Activity Index score also decreased after treatment (4.6 vs 3.0; P = 0.002; and 32.5 vs 25.0; P = 0.06, respectively). DISCUSSION: We successfully developed a new testing approach using CD4 + T-cell proliferation and esophageal food-specific IgG4 levels, with promising accuracy rates. In clinical testing, this led to improvement in eosinophil counts, endoscopic severity, and symptoms of dysphagia, but a smaller than expected number of patients achieved histologic remission.

INTRODUCTION: Patients with eosinophilic gastritis and/or gastroenteritis (EG/EGE) experience significantly reduced health-related quality of life related to the symptoms and signs of their disease. There is a need to develop a PRO questionnaire for clinical research in EG/EGE. The objectives of this study were to develop a symptom questionnaire (drafted using literature and clinician input to determine preliminary measurement concepts) and then (1) identify, describe, and substantiate signs, symptoms, and impacts of EG/EGE from the perspective of adults with the condition via concept elicitation methods; and (2) evaluate the properties of the questionnaire and make modifications via cognitive debriefing methods. METHODS: Interviews were conducted, transcribed, coded, and analyzed. Eligible adults with EG/EGE first participated in a concept elicitation segment where they described their experiences with EG/EGE, continuing until saturation was achieved, adding symptoms to the draft symptom questionnaire as needed. This was followed by a cognitive debrief to assess the appropriateness of the draft symptom questionnaire, where patients assessed readability, comprehensibility, relevance, and comprehensiveness. The questionnaire was modified based on patient feedback, then re-evaluated to confirm its appropriateness. RESULTS: In total, 16 interviews were conducted and 24 signs and symptoms were reported during concept elicitation. The most frequently reported (Figure 1) were abdominal pain, nausea, diarrhea, vomiting, and abdominal cramping; while abdominal pain, nausea, and diarrhea were the most bothersome to patients. Saturation was achieved after 12 interviews. In the cognitive debriefing, revisions included the addition of a vomiting frequency item and revision of the early satiety item for clarity. Response options were modified to instruct the participants to assess each symptom “at its worst”. For the final version of the EG/EGE-SQ©, participants were able to read, comprehend, and provide appropriate responses, and reported that the resulting questionnaire was comprehensive for their condition. CONCLUSION: The results of this research support the content validity, including comprehensiveness and interpretability, of the EG/EGE-SQ© which offers the potential for use in clinical research to assess symptoms in patients with EG/EGE. Future research is needed to assess its psychometric properties including reliability and validity, responsiveness, and potential for use in pediatric populations.

INTRODUCTION: Eosinophilic gastrointestinal diseases (EGIDs) are a set of inflammatory diseases subclassified according to the site(s) of abnormal accumulation of eosinophils (eos) in the gastrointestinal (GI) tract such as eosinophilic esophagitis (EoE), gastroenteritis (EGE), and colitis. These conditions often decrease quality of life due to debilitating symptoms. While the pathogenesis of EGIDs is primarily thought to be driven by eos, there is increasing evidence for the involvement of mast cells (MCs). AIM: To characterize symptomatic patients (pts) with suspected EG/EGE who did not meet histopathologic entry criteria for mucosal eosinophilia for a Phase 2 randomized, double-blind, placebo-controlled study of AK002, an anti-Siglec-8 antibody. METHODS: To undergo screening endoscopy for this study, pts were required to report an average symptom score ≥3 (0 to 10 scale) for abdominal pain, nausea, and/or diarrhea on a daily patient-reported outcome questionnaire for ≥2 weeks and have no other known cause for GI symptoms. During the screening endoscopy, biopsies were systematically obtained from the stomach and duodenum, and read by a single pathologist. Eos counts (eos/hpf; hpf area = 0.237 mm 2 ) were assessed on H&E slides. To quantify MCs, immunohistochemistry for tryptase was performed. We quantified eos and MCs in the stomach and duodenum. Histopathologic entry criteria for the randomized study was ≥30 eos/hpf in 5 hpfs in the stomach (EG) and/or ≥30 eos/hpf in 3 hpfs in the duodenum (EGE). A literature review was conducted to determine normal MC counts in the GI tract. RESULTS: Eighty-eight pts underwent screening endoscopy based upon suspected EG/EGE and active symptoms, and 72 pts met histopathologic eos criteria. All pts whose eos did not meet entry criteria (n = 16) were found to have elevated MC counts (Figure 1; reported normal range = 12-19 MCs/hpf). In these pts, the mean gastric eos count was 6 eos/hpf in 5 hpfs and mean duodenal eos count was 15 eos/hpf in 3 hpfs. In contrast, these pts exhibited a mean gastric MC count of 47 MC/hpf in 5 hpfs and a mean duodenal MC count of 49 MC/hpf in 3 hpfs. Almost all symptomatic pts screened (87/88; 99%) had elevated MC counts. CONCLUSION: Data from this large randomized EG/EGE study showed that symptomatic pts with suspected EG/EGE had increased mucosal MCs with or without mucosal eosinophilia. These data suggest that MCs may play a role in pts with suspected EG/EGE and raise the possibility of a unique clinical presentation driven by MCs.