Onset of eosinophilic esophagitis during a clinical trial program of oral immunotherapy for peanut allergy

Abstract

Clinical ImplicationsEosinophilic esophagitis (EoE) occurring during peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) oral immunotherapy (OIT) was responsive to standard-of-care treatments and improved or resolved after PTAH discontinuation. The risk of developing EoE during OIT with PTAH in clinical trials was approximately 1% overall without inclusion of a portion of the 5% of participants who discontinued PTAH treatment because of gastrointestinal adverse events that were not further evaluated. Eosinophilic esophagitis (EoE) occurring during peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) oral immunotherapy (OIT) was responsive to standard-of-care treatments and improved or resolved after PTAH discontinuation. The risk of developing EoE during OIT with PTAH in clinical trials was approximately 1% overall without inclusion of a portion of the 5% of participants who discontinued PTAH treatment because of gastrointestinal adverse events that were not further evaluated. Eosinophilic esophagitis (EoE) is a chronic immune-inflammatory disease triggered by food and/or environmental allergens. EoE onset has been reported in patients given oral immunotherapy (OIT) for milk, egg, and peanut allergy.1Lucendo A.J. Arias A. Tenias J.M. Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis.Ann Allergy Asthma Immunol. 2014; 113: 624-629Google Scholar Peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; previously AR101) is an approved OIT for peanut allergy. PTAH is contraindicated in patients with a history of EoE and per the product label should be discontinued if EoE develops while on treatment. Data for all participants in the PTAH clinical trial program were reviewed to identify participants with EoE as of December 15, 2018. Overall EoE incidence was calculated and outcomes were summarized along with baseline clinical characteristics, symptom presentation, and treatments received. The PTAH clinical trial program includes 2 phase 2 trials and 6 phase 3 trials in which 1217 participants (aged 4-55 years) received PTAH.2Vickery B. Vereda A. Casale T. Beyer K. du Toit G. et al.PALISADE Group of Clinical InvestigatorsAR101 oral immunotherapy for peanut allergy.N Engl J Med. 2018; 379: 1991-2001Google Scholar, 3Hourihane J.O.B. Beyer K. Abbas A. Fernandez-Rivas M. Turner P.J. Blumchen K. et al.Efficacy and safety of oral immunotherapy with AR101 in European children with a peanut allergy (ARTEMIS): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial.Lancet Child Adolesc Health. 2020; 4: 728-739Google Scholar, 4Bird J. Welch M. Spergel J. Jones S. Rachid R. Wang J. et al.Oral desensitization to peanut using AR101 peanut oral immunotherapy in a roll-over safety study ARC002.Ann Allergy Asthma Immunol. 2018; 121: 476-485.e3Google Scholar, 5Bird J.A. Spergel J.M. Jones S.M. Rachid R. Assa'ad A.H. Wang J. et al.Efficacy and safety of AR101 in oral immunotherapy for peanut allergy: results of ARC001, a randomized, double-blind, placebo-controlled phase 2 clinical trial.J Allergy Clin Immunol Pract. 2018; 6: 476-485.e3Google Scholar Of the 1217 PTAH-treated participants, 62 patients withdrew from the studies owing to gastrointestinal (GI) symptoms, 28 were referred for gastroenterology evaluation, 17 of whom underwent esophagogastroduodenoscopy (EGD), and 12 of those were diagnosed with EoE, yielding an EoE incidence of approximately 1%. The overall exposure-adjusted EoE event rate was 0.9 per 100 patient-years. The 12 EoE cases occurred in 1 woman aged 33 years and 11 participants aged 4 to 17 years, 9 of whom were male (Table I). Asthma (n = 11) was the most common comorbid atopic disease, followed by allergic rhinitis (n = 10), other food allergies (n = 9), and atopic dermatitis (n = 5). Common presenting symptoms included globus sensation, gastroesophageal reflux, regurgitation, vomiting, and postprandial abdominal pain (Table II). In 11 cases, symptom improvement or resolution occurred within 12 days to 12 months of PTAH discontinuation and standard-of-care EoE therapy initiation. The final case resolved after 12 months. Ten cases were considered related to PTAH treatment (4 had a history of chronic or recurrent GI symptoms) and 2 were considered unrelated (GI symptoms may have been present before starting PTAH). Three cases were classified as mild, 7 moderate, and 2 severe; none were considered serious. The median (range) PTAH dose at EoE diagnosis was 160 mg (12-950 mg).Table IBaseline characteristics of participants with diagnosed eosinophilic esophagitis across all PTAH studiesStudyCase no.Age (y)/sex/raceCountryComorbid allergic diseasesBaseline peanut-specific IgE (kUA/L)ARC001 (NCT01987817)14/M/WhiteUnited StatesAtopic dermatitis, asthma, allergic rhinitis>100ARC002 (ARC001 follow-on; NCT02198664)28/M/WhiteUnited StatesAllergic rhinitis, other food allergies5.3ARC003 (PALISADE; NCT02635776)310/M/WhiteUnited StatesAllergic rhinitis, asthma, atopic dermatitis, other food allergies351.5ARC004 (PALISADE follow-on; NCT02993107)413/F/Other∗Not reported.United StatesAllergic rhinitis, atopic dermatitis, asthma, other food allergies268533/F/WhiteUnited StatesAllergic rhinitis, asthma19.569/M/WhiteUnited StatesAsthma, other food allergies294.5ARC007 (RAMSES; NCT03126227)79/M/WhiteUnited StatesAsthma, other food allergies277817/M/WhiteCanadaAllergic rhinitis, asthma, other food allergies17.1ARC008 (NCT03292484)914/M/WhiteUnited StatesAllergic rhinitis, atopic dermatitis, asthma, other food allergies304.51017/M/WhiteCanadaAllergic rhinitis, atopic dermatitis, asthma, other food allergies70.31113/F/WhiteUnited StatesAllergic rhinitis, asthma, other food allergies62.21215/M/Other∗Not reported.United StatesAsthma, allergic rhinitis, allergic conjunctivitis81.3F, Female; M, male; PTAH, peanut (Arachis hypogaea) allergen powder-dnfp.∗ Not reported. Open table in a new tab Table IIClinical characteristics of eosinophilic esophagitis cases across all PTAH studiesCase no.Relevant medical historyPTAH dose at EoE diagnosis (mg)Total exposure to PTAH (d)SymptomsSeverity∗As determined by the investigator.Initial esophageal biopsy resultsRepeat esophageal biopsy results†Based on ongoing follow-up.TreatmentRelatedness to PTAH∗As determined by the investigator.At first GI symptom onsetAt EoE diagnosis1125858Intermittent vomiting, abdominal pain, sore throatMildEoE with peak eosinophil count of 92 eos/hpfBiopsy performed—results NA‡EGD was performed at an outside facility; report not received by the study site at the time of follow-up.Esomeprazole for vomiting; swallowed fluticasone after EoE diagnosis, elimination dietRelated2Gastroesophageal reflux during infancy and chronic regurgitation950§The open-label ARC002 study allowed for updosing up to a maximum of 2000 mg daily.58428Frequent regurgitating/spitting up, gastric refluxModerateThe peak eosinophil count was 32 eos/hpf in the distal esophagus, 7 eos/hpf in the mid-esophagus, and up to 61 eos/hpf in the proximal esophagusNRRanitidine, omeprazole, lansoprazoleRelated3Gastroesophageal reflux; recurrent nausea and cough20030176Gastroesophageal reflux, recurrent nausea and cough, globus sensationMildEoE; esophageal mucosa with intraepithelial eosinophilic infiltrates, degranulation, and plaques with bacteria; basal zone hyperplasia; fibrotic lamina propriaImproved with 22 eos/hpfOmeprazole, elimination dietRelated4GI symptoms including abdominal pain12Occurred on placebo in the parent study49Stomach painSevereEosinophil count of 195/hpf distally and 140/hpf in the mid-esophagusNo evidence of eosinophil infiltration in the esophageal squamous mucosaLansoprazoleNot related5Dysphagia200‖Dose was reduced to 200 mg 2 weeks before developing EoE.2544Esophageal dysphagiaSevereProximal and distal biopsies showed fragments of squamous mucosa with basal cell hyperplasia, intercellular edema, marked reactive changes, and markedly increased numbers of intraepithelial eosinophils and lymphocytesMild active esophagitis with rare eosinophilsBudesonide, prednisone, fluticasone, ranitidineRelated63001372Abdominal painModerateProximal esophagus squamous mucosa with mild chronic inflammation and eosinophilic infiltrate up to 50 eos/hpf; distal and mid-esophagus squamous mucosa without abnormalityNRCalcium carbonate, omeprazoleRelated7401138Emesis; globus sensationModerateSquamous mucosa with increased intraepithelial eosinophils up to 68 eos/hpf in the proximal esophagus and up to 62 eos/hpf in the distal esophagusFirst follow-up with submucosal fibrosis and squamous mucosa with increased intraepithelial eosinophils with up to 18 eos/hpf in the proximal esophagus and up to 25 eos/hpf in the distal; consistent with partially treated EoESecond follow-up 2-3 eos/hpf in proximal esophagus and 22 eos/hpf in the distal; no lymphocytes or submucal fibrosisOmeprazoleRelated8Postprandial abdominal pain, dysphagia804579Postprandial abdominal pain; dysphagiaMildIntraepithelial eosinophils with a peak of approximately 25 eos/hpf and basal cell hyperplasia and ridge elongation in the proximal esophagus; focal mild basal cell hyperplasia in the distal esophagusFollow-up EGD not performedLansoprazole, topical budesonideNot related9Dysphagia1601788DysphagiaModerateProximal and mid-esophagus with moderate esophagitis with abundant eosinophils; distal esophagus with mild esophagitis with abundant eosinophils (up to 215 eos/hpf)Multiple repeat EGDs with eventual decreasing degree of eosinophiliaEsomeprazole, budesonideRelated102401640Abdominal pain, dysphagia, nausea, vomiting, gagging, reflux, decreased appetiteModerateInvestigator report that biopsy consistent with EoE diagnosis, but pathology report not availableMultiple repeat EGDs with improvement with most recent biopsy showing up to 6 eos/hpf in the distal esophagus and up to 2 eos/hpf in the mid-esophagusPantoprazole, rabeprazole, fluticasone, budesonideRelated111601225Dysphagia, throat irritation and tightness, abdominal pain, heartburnModerateSuperficial esophageal squamous mucosa with histological chances compatible with EoE with up to 144 eos/hpf in the proximal esophagus and up to 113 eos/hpf in the distalSecond EGD with proximal and distal biopsies with superficial squamous mucosa with >100 eos/hpf; third EGD with normal biopsies per investigator reportSwallowed fluticasoneRelated1240¶Last dose before treatment discontinuation. EoE was diagnosed 52 days after treatment discontinuation.3188Emesis, GI upset unspecifiedModerateDistal and mid-esophageal biopsies favored EoE with up to 12 eos/hpf distally and up to 15 eos/hpf in the mid-esophagusFollow-up EGD not performedOmeprazoleRelatedEGD, Esophagogastroduodenoscopy; EoE, eosinophilic esophagitis; eos, eosinophils; GI, gastrointestinal; hpf, high-power field; NA, not available; NR, not reported; PTAH, peanut (Arachis hypogaea) allergen powder-dnfp.Treatments were not all necessarily given at the same time and may have been given in sequence.∗ As determined by the investigator.† Based on ongoing follow-up.‡ EGD was performed at an outside facility; report not received by the study site at the time of follow-up.§ The open-label ARC002 study allowed for updosing up to a maximum of 2000 mg daily.‖ Dose was reduced to 200 mg 2 weeks before developing EoE.¶ Last dose before treatment discontinuation. EoE was diagnosed 52 days after treatment discontinuation. Open table in a new tab F, Female; M, male; PTAH, peanut (Arachis hypogaea) allergen powder-dnfp. EGD, Esophagogastroduodenoscopy; EoE, eosinophilic esophagitis; eos, eosinophils; GI, gastrointestinal; hpf, high-power field; NA, not available; NR, not reported; PTAH, peanut (Arachis hypogaea) allergen powder-dnfp. Treatments were not all necessarily given at the same time and may have been given in sequence. All 12 patients received medications for their symptoms; most (83.3%; n = 10) were treated with a proton pump inhibitor (PPI) with or without a topical corticosteroid (fluticasone and/or budesonide, n = 4). All but 1 participant discontinued treatment with PTAH after EoE diagnosis. In 7 participants with available follow-up biopsy results provided by investigators, 5 had endoscopic findings consistent with resolved EoE (4 of 5 received PPI) and 2 had improved but not fully resolved EoE (both received PPI). Of the 2 with improved EoE, symptoms were not resolved in 1 participant >1 year after stopping PTAH, and follow-up biopsy data were unavailable for 1 participant; both were thought to be symptoms suggestive of EoE before study entry. In this analysis of the PTAH clinical trial program, the overall incidence of EoE was approximately 1%, which is lower than previously reported rates of EoE with OIT for food allergies (2.7% in a meta-analysis and 5.1% in a recent retrospective review).1Lucendo A.J. Arias A. Tenias J.M. Relation between eosinophilic esophagitis and oral immunotherapy for food allergy: a systematic review with meta-analysis.Ann Allergy Asthma Immunol. 2014; 113: 624-629Google Scholar,6Petroni D. Spergel J.M. Eosinophilic esophagitis and symptoms possibly related to eosinophilic esophagitis in oral immunotherapy.Ann Allergy Asthma Immunol. 2018; 120: 237-240.e4Google Scholar The etiology of EoE pathogenesis in the cases reported in the PTAH clinical trial program is not definitively known, but may include EoE present and not diagnosed before OIT, EoE pre-existing but subclinical and exacerbated by OIT, or EoE triggered de novo by OIT. A recent cohort study showed that 1 in 20 participants with IgE-mediated food allergy had EoE at baseline irrespective of exposure to OIT.7Hill D.A. Dudley J.W. Spergel J.M. The prevalence of eosinophilic esophagitis in pediatric patients with IgE-mediated food allergy.J Allergy Clin Immunol Pract. 2017; 5: 369-375Google Scholar Individuals with IgE-mediated food allergy, including peanut allergy, are at increased risk of developing EoE, and the risk increases with additional IgE-mediated food allergies. Our population had increased baseline risk, with 9 of the 12 patients (75%) also having additional food allergies. It is unknown whether there was a subset of cases that would have had transient esophageal eosinophilia or developed EoE but did not undergo EGD. In a recent longitudinal placebo-controlled study examining serial endoscopic biopsies during peanut OIT, all the peanut-allergic participants had signs of epithelial barrier dysfunction at baseline and in some cases esophageal eosinophilia.8Wright B.L. Fernandez-Becker N.Q. Kambham N. Purington N. Cao S. Tupa D. et al.Gastrointestinal eosinophil responses in a longitudinal, randomized trial of peanut oral immunotherapy.Clin Gastroenterol Hepatol. 2021; 19: 1151-1159.e14Google Scholar The study demonstrated that most OIT-associated esophageal eosinophilia resolves during maintenance OIT and is not associated with clinical symptoms. Because the majority of participants in the PTAH clinical trials stopped the study drug around the time of EoE diagnosis, it is not known whether the eosinophilic infiltrate would have resolved with continued dosing. The majority of EoE cases resolved and, in all cases, improved with discontinuation of PTAH and standard-of-care treatment. It has previously been noted that EoE reported during OIT can respond to removal of the allergen and standard-of-care medications similarly to spontaneously occurring EoE.9Gómez-Aldana A. Jaramillo-Santos M. Delgado A. Jaramillo C. Lúquez-Mindiola A. Eosinophilic esophagitis: current concepts in diagnosis and treatment.World J Gastroenterol. 2019; 25: 4598-4613Google Scholar This analysis is limited in that it includes cases from multiple clinical trials and cannot provide the same quality of evidence as a true longitudinal incidence study of EoE, in which baseline and follow-up EGDs would be performed irrespective of whether symptoms emerged with PTAH. In addition, the low rate of EoE in our analysis may have been influenced by exclusion criteria in the clinical trials program. Owing to the need for esophageal biopsy to diagnose EoE, the incidence of EoE may be underestimated, and analysis is limited by the absence of baseline EGD with biopsy. We are unable to confirm whether a portion of the 62 (5%) participants who discontinued PTAH treatment because of GI adverse events may have had undiagnosed EoE. The long-term effects of asymptomatic eosinophilia are not established, but progression to structural disease that will ultimately cause symptomatic disease is possible. In clinical practice, GI symptoms suggestive of possible EoE may resolve after discontinuation of PTAH; however, if patients have GI symptoms that persist, then evaluation by a gastroenterologist is recommended. Further, referral to a gastroenterologist is recommended for patients receiving OIT who develop persistent GI symptoms concerning for EoE with those found to have EoE comanaged by allergy and gastroenterology. The importance of ruling out EoE in those with persistent GI symptoms is also highlighted by these data: 5 of 17 (30%) subjects who had symptoms suggestive of EoE leading to endoscopy did not have EoE. In conclusion, the rate of developing EoE with PTAH in this clinical trial program was approximately 1%, not including the 5% of participants who discontinued PTAH treatment because of GI adverse events that were not further evaluated. EoE occurring during PTAH OIT was responsive to standard-of-care treatments and improved or resolved after per protocol-recommended PTAH discontinuation. The authors would like to thank Andrea Vereda for her comments and careful reading of the manuscript. The authors would like to thank study participants and their families, the principal investigators, subinvestigators, trial coordinators, nurses, dietitians, and other personnel at all the trial sites. Editorial assistance and medical writing support were provided by The Curry Rockefeller Group , LLC (Tarrytown, NY).