AR101 Oral Immunotherapy for Peanut Allergy Vickery, Brian P; Vereda, Andrea; Casale, Thomas B ...
New England journal of medicine/The New England journal of medicine,
11/2018, Volume:
379, Issue:
21
Journal Article
Peer reviewed
Open access
Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions.
In a phase 3 trial, we ...screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms.
Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older.
In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).
Eosinophilic esophagitis (EoE) is a chronic disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil‐predominant inflammation. EoE is frequently ...associated with concomitant atopic diseases and immunoglobulin E (IgE) sensitization to food allergens in children as well as to aeroallergens and cross‐reactive plant allergen components in adults. Patients with EoE respond well to elemental and empirical food elimination diets. Recent research has, however, indicated that the pathogenesis of EoE is distinct from IgE‐mediated food allergy. In this review, we discuss the individual roles of epithelial barrier defects, dysregulated innate and adaptive immune responses, and of microbiota in the pathogenesis of EoE. Although food has been recognized as a trigger factor of EoE, the mechanism by which it initiates or facilitates eosinophilic inflammation appears to be largely independent of IgE and needs to be further investigated. Understanding the pathogenic role of food in EoE is a prerequisite for the development of specific diagnostic tools and targeted therapeutic procedures.
Background
In the Learning Early About Peanut Allergy (LEAP) study, early peanut introduction in high‐risk 4‐ to 11‐month‐olds was associated with a significantly decreased risk of developing peanut ...allergy. However, the influences of key baseline high‐risk factors on peanut tolerance are poorly understood.
Methods
Secondary analysis was conducted on the publically available LEAP dataset, exploring relationships between peanut tolerance, baseline peanut/egg sensitization, eczema severity/duration, age of introduction, gender, and race.
Results
A multiple logistic regression model predicting odds of successful oral food challenge (OFC) at 60 months noted higher odds with early introduction (OR 9.2, P < 0.001, 95% CI 4.2–20.3), white race (OR 2.1, P = 0.04, 95% CI 1.1–3.9), and advancing age (OR 4.8, P = 0.04, 95% CI 1.1–20.8). Odds of peanut tolerance were lower with increasing peanut wheal size (OR 0.58, P < 0.001, 95% CI 0.46–0.74), increased baseline SCORAD score (OR 0.98, P = 0.04, 95% CI 0.97–1), and increased kUA/l of egg serum IgE (sIgE) (OR 0.99, P = 0.04, 95% CI 0.98–1). The probability of peanut tolerance in the early introduction group was 83% vs 43% in the avoidance group with SPT wheal of <4 mm. The probability of a successful OFC was significantly higher with peanut introduction between 6 and 11 months than at 4–6 months. Increasing eczema severity had limited impact on the probability of peanut tolerance in the early introduction arm.
Conclusion
Increasing peanut wheal size predicted peanut tolerance only in the avoidance arm. Peanut introduction between 6 and 11 months of age was associated with the highest rates of peanut tolerance, questioning the ‘urgency’ of introduction before 6 months.
Summary
Background
Eosinophilic oesophagitis (EoE) is a chronic inflammatory condition affecting both children and adults. Little is known about the natural history of EoE in the transition from ...childhood into adulthood.
Aim
To determine the prevalence of EoE symptoms and impact of EoE on quality of life among adults diagnosed with EoE during childhood.
Methods
This is a cross‐sectional study of EoE patients from the Children's Hospital of Philadelphia EoE registry. Patients ≥18 years diagnosed with EoE during childhood were administered validated dysphagia Mayo Dysphagia Questionnaire (MDQ)‐30 and Quality of Life (PAGI‐QOL) questionnaires. Ongoing EoE treatments were ascertained.
Results
A total of 140 EoE patients ≥18 years were identified; 53 completed all questions. Only 6 (11%) subjects had positive (n = 2) or indeterminate (n = 4) dysphagia scores. However, of 47 patients with negative scores, 18 (37%) reported ongoing difficulty swallowing. The mean PAGI‐QOL score was 4.58/5. The dietary dimension score was 3.73/5. Current pharmacological EoE treatments were topical steroids (3/53) and interleukin‐5 antagonists (3/53). Additionally, 26/53 (49%) were on PPI therapy and 40/53 (76%) were following allergy directed diets.
Conclusions
The majority of young adults diagnosed with EoE during childhood continue to require pharmacological treatment and/or dietary modification for EoE. A substantial proportion of this population experiences ongoing swallowing difficulties that a standard dysphagia questionnaire fails to capture. Dietary quality of life, but not total quality of life, appears to be adversely affected. These data suggest that EoE diagnosed during childhood remains a significant medical issue during early adulthood, and that better EoE symptom measurement instruments are needed.
Background
Early peanut introduction (EPI) in the first year of life is associated with reduced risk of developing peanut allergy in children with either severe eczema and/or egg allergy. However, ...EPI recommendations differ among countries with formal guidelines.
Methods
Using simulation and Markov modeling over a 20‐year horizon to attempt to explore optimal EPI strategies applied to the US population, we compared high‐risk infant‐specific IgE peanut screening (US/Canadian) with the Australiasian Society for Clinical Immunology and Allergy (Australia/New Zealand) (ASCIA) and the United Kingdom Department of Health (UKDOH)‐published EPI approaches.
Results
Screening peanut skin testing of all children with early‐onset eczema and/or egg allergy before in‐office peanut introduction was dominated by a no screening approach, in terms of number of cases of peanut allergy prevented, quality‐adjusted life years (QALY), and healthcare costs, although screening resulted in a slightly lower rate of allergic reactions to peanut per patient in high‐risk children. Considering costs of peanut allergy in high‐risk children, the per‐patient cost of early introduction without screening over the model horizon was $6556.69 (95%CI, $6512.76‐$6600.62), compared with a cost of $7576.32 (95%CI, $7531.38‐$7621.26) for skin test screening prior to introduction. From a US societal perspective, screening prior to introduction cost $654 115 322 and resulted in 3208 additional peanut allergy diagnoses. Both screening and nonscreening approaches dominated deliberately delayed peanut introduction.
Conclusions
A no‐screening approach for EPI has superior health and economic benefits in terms of number of peanut allergy cases prevented, QALY, and total healthcare costs compared to screening and in‐office peanut introduction.
Background: Eosinophilic esophagitis is a disease entity in which patients have (1) elevated eosinophils on esophageal biopsy and (2) symptoms of gastroesophageal reflux. The symptoms do not improve ...on aggressive acid blockade but do improve on elimination diet or corticosteroid treatment, which tentatively links food allergies to this disorder. Objective: The purpose of this study was to identify potential food antigens in eosinophilic esophagitis. Methods: Patients with eosinophilic esophagitis were identified by biopsy. Potential food antigens were identified prospectively by skin prick testing and patch testing, which were performed through use of standard methods. Atopic tendencies, demographics, and potential food allergies were identified. Repeat esophageal biopsies were reviewed when possible. Results: A total of 26 patients (22 male, 4 female) with a biopsied-confirmed diagnosis of eosinophilic esophagitis underwent both skin prick testing and patch testing to identify potential causative foods. Milk and egg were the most common positive foods with skin prick testing. Wheat was the most common positive food with patch testing. The patients were advised to avoid positive foods as identified by skin prick testing and patch testing. In all, 18 patients had resolution of their symptoms, 6 patients had partial improvement, and 2 were lost to follow-up. Overall, after intervention, esophageal eosinophil counts improved from 55.8 to 8.4 eosinophils per high-power field. The foods most commonly identified by patients as causing symptoms were milk and egg. Conclusion: The combination of skin prick testing and patch testing can identify potential causative foods that might contribute to the pathogenesis of eosinophilic esophagitis. (J Allergy Clin Immunol 2002;109:363-8.)
The prevalence of allergic conditions has continuously increased in the last few decades in Westernized countries. A dysbiotic gut microbiome may play an important role in the development of allergic ...diseases. Genetic, environmental, and dietary factors may alter the commensal microbiota leading to inflammatory dysregulation of homeostasis. Murine and human studies have begun to elucidate the role of the microbiota in the pathogenesis of atopic diseases including asthma, atopic dermatitis, and food allergies. However, the role of the microbiome in most eosinophilic gastrointestinal diseases (EGIDs) is not yet known. This review provides an overview of what is currently known about the development of tolerance from both molecular and clinical standpoints. We also look at the gut‐specific microbiome and its role in atopic conditions with the hope of applying this knowledge to the understanding, prevention, and treatment of EGIDs, particularly EoE.
Advanced ACTPol is a polarization-sensitive upgrade for the 6 m aperture Atacama Cosmology Telescope, adding new frequencies and increasing sensitivity over the previous ACTPol receiver. In 2016, ...Advanced ACTPol will begin to map approximately half the sky in five frequency bands (28-230 GHz). Its maps of primary and secondary cosmic microwave background anisotropies-imaged in intensity and polarization at few arcminute-scale resolution-will enable precision cosmological constraints and also awide array of cross-correlation science that probes the expansion history of the universe and the growth of structure via gravitational collapse. To accomplish these scientific goals, the AdvancedACTPol receiver will be a significant upgrade to the ACTPol receiver, including four new multichroic arrays of cryogenic, feedhorn-coupled AlMn transition edge sensor polarimeters (fabricated on 150 mm diameter wafers); a system of continuously rotating meta-material silicon half-wave plates; and a new multiplexing readout architecture which uses superconducting quantum interference devices and time division to achieve a 64-row multiplexing factor. Here we present the status and scientific goals of the Advanced ACTPol instrument, emphasizing the design and implementation of the AdvancedACTPol cryogenic detector arrays.
Food protein–induced enterocolitis (FPIES) is a non-IgE cell- mediated food allergy that can be severe and lead to shock. Despite the potential seriousness of reactions, awareness of FPIES is low; ...high-quality studies providing insight into the pathophysiology, diagnosis, and management are lacking; and clinical outcomes are poorly established. This consensus document is the result of work done by an international workgroup convened through the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology and the International FPIES Association advocacy group. These are the first international evidence-based guidelines to improve the diagnosis and management of patients with FPIES. Research on prevalence, pathophysiology, diagnostic markers, and future treatments is necessary to improve the care of patients with FPIES. These guidelines will be updated periodically as more evidence becomes available.
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