de Bruin-Weller, Marjolein

de Graaf, Marlies

Hilbrands, Michelle

Knulst, André C.

Le, Thuy-My

van der Rijst, Lisa

Zuithoff, Peter

Utrecht University Repository

Received: 21 March 2024 - Revised: 17 June 2024 - Accepted: 27 June 2024DOI: 10.1002/clt2.12381L E T T E RDupilumab induces a significant decrease of food specificimmunoglobulin E levels in pediatric atopic dermatitispatientsLisa P. van der Rijst1,2 | Michelle S. Hilbrands2 | Nicolaas P. A. Zuithoff3 |Marjolein S. de Bruin‐Weller2 | André C. Knulst2 | Thuy‐My Le2 | Marlies de Graaf1,21Department of Dermatology and Allergology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands2Department of Dermatology and Allergology, National Expertise Center for Atopic Dermatitis, University Medical Center Utrecht, Utrecht, The Netherlands3Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The NetherlandsCorrespondenceMarlies de Graaf, Heidelberglaan 100, Utrecht 3584CX, The Netherlands.Email: M.deGraaf-10@umcutrecht.nlK E YWORD Satopic dermatitis, children, dupilumab, food allergy, pediatric, specific immunoglobulin ETo the Editor,Atopic dermatitis (AD) and food allergy (FA) are common chronicdiseases that have a major impact on quality of life and socio‐economic burden.1,2 AD is strongly associated with the develop-ment of immunoglobulin E (IgE)‐mediated FA.3–5 The associated im-mune response involves allergen specific T helper type 2 cellsinducing a pro‐inflammatory cytokine release, including interleukin(IL)‐4 and IL‐13, thereby causing initiation of B cell immunoglobulinclass switching to specific IgE (sIgE).4 Dupilumab, a human mono-clonal antibody that is approved for treatment of (moderate to) se-vere AD in children from the age of 6 months, blocks the IL‐4 and IL‐13 signaling pathway.6 Spekhorst et al. showed that dupilumab in-duces a profound decrease in sIgE levels of several food allergens inadult AD patients with comorbid FA, highlighting the positive effectof blocking IL‐4 and IL‐13 signaling on sIgE levels.5 As FA often de-velops at a young age, and the effect of dupilumab on food sIgE levelsin pediatric patients remains unclear, it is of particular interest toevaluate the effect of dupilumab in this young patient population.Therefore, the aim of this study was to investigate the effect ofdupilumab on food sIgE levels of 10 common allergens in food allergicpediatric patients with moderate to severe AD.Pediatric AD patients (aged 4–17 years) treated with dupilumabwith a suggestive clinical history of FA for peanut, hazelnut, cashewnut, pistachio, almond, walnut, hen's egg, cow's milk, kiwi, and/orapple with a corresponding positive sIgE (≥0.35 kU/L) at the start oftreatment (baseline), were included. Patients who were neverexposed to specific food allergens, due to severe IgE‐mediated re-actions to other food allergens (e.g., hazelnut, leading to avoidance ofother nuts) or to parental anxiety (e.g., due to severe parental FA),with a corresponding positive sIgE, were also included. sIgE levelswere measured at baseline and at least once during 1 year of follow‐up. Data were extracted from the prospective BioDay registry be-tween August 2019 and July 2023. A covariance pattern model wasused to analyze the development of (s)IgE values over time. All an-alyses were performed for each food separately using a covariancepattern model (detailed explanation of methods is described inSupporting Information S1).A total of 36 pediatric patients with a mean age of 12.5 (standarddeviation �3.6) years were included (Table 1). A total of 120 FAs,with 1008 corresponding sIgE samples, were identified (Table S1).Peanut (18.3%) and hazelnut (16.7%) were the most common foodsto which patients were sensitized. Results of baseline food sIgE levelsstratified by severity of FA are shown in Table S2. Two (5.6%) pa-tients discontinued dupilumab treatment at a mean treatmentduration of 16.5 weeks.A significant percentage decrease was observed for all food al-lergens during 1 year of treatment, with the most profound decreasein the first 16 weeks of treatment (Figure 1). In all food allergensThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro-vided the original work is properly cited.© 2024 The Author(s). Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.Clin Transl Allergy. 2024;e12381. wileyonlinelibrary.com/journal/clt2 - 1 of 4https://doi.org/10.1002/clt2.12381(sIgE extracts and components), a decrease ranging from 70.5% (95%CI: 37.1–86.1, for apple) to 82.5% (95% CI: 75.0–87.7, for cashewnut) was observed. Figure S1 shows the significant decrease in esti-mated median sIgE levels over time for all food allergens, rangingfrom 3.1 kU/L (95% CI: 2.2–4.2, for almond) to 33.7 kU/L (95% CI:20.3–55.8, for hazelnut) at baseline and 0.8 kU/L (95% CI: 0.5–1.2,for almond) to 9.8 kU/L (95% CI: 6.0–15.9, for hazelnut) after 1 yearof treatment. Higher baseline sIgE levels did not correspond to fasteror slower decrease than lower baseline sIgE levels. In addition, sub-group analyses revealed no significant differences in the percentagedecrease in sIgE levels between patients sensitized to one food andthose sensitized to multiple foods (data not shown). However, theseresults were based on a small sample size.Total IgE levels decreased with 86.7% (95% CI: 70.2–94.1) after1 year of treatment (Figure S2). Calculated ratios of sIgE to total IgEfor various food allergens did not show significant changes over time,except for hen's egg (data not shown). However, ratios were based onlimited statistical power and debated prognostic value.This study shows a larger percentage decrease of sIgE levelscompared to what was previously reported in food allergic adult ADpatients treated with dupilumab.5 Spekhorst et al. reported an overallpercentage decrease in food sIgE levels of 53.0%–62.9% after 1 yearand 85.3%–86.9% after 3 years of dupilumab treatment.5 This differ-ence may be age‐related and/or may be a result of the higher baselinefood sIgE levels in children compared to adult AD patients.Several studies indicate that decreasing sIgE‐levels could be asurrogate marker for the probability of developing clinical foodtolerance.7–9 Nevertheless, it remains unclear whether the reductionof sIgE below a certain threshold leads to tolerance. Dupilumab,blocking the IL‐4/IL‐13 pathway, may play a key role in preventingIgE class switching, resulting in lower sIgE levels and potentiallydiminished severity of FA. Only one case report describes thedevelopment of food tolerance during dupilumab treatment forcanned corn and pistachio in an adult AD patient, confirmed by anoral food challenge.7 Prospective studies including OFCs before,during and after treatment are needed to objectify whether dupilu-mab treatment leads to a higher threshold and/or less severe FAsymptoms, the possible relation with sIgE levels, and whether thiseffect persists after treatment discontinuation. Furthermore, futureTAB L E 1 Baseline characteristics.CharacteristicTotal, n 36Gender (F), n (%) 21 (58.3)Age (years), mean (SD) 12.5 � 3.6BMI, mean (SD) 19.5 � 4.2Age AD onset (years), mean (SD) 0.8 � 2.0AD severity at inclusionEASI score, mean (SD) 21.8 � 12.5IGA score, mean (SD) 3.4 � 0.7Number of food allergies, n (%)1 11 (30.6)≥2 25 (69.4)Food allergies, total, n 120Peanut, n (%) 22 (18.3)Hazelnut, n (%) 20 (16.7)Cashew nut, n (%) 14 (11.7)Almond, n (%) 11 (9.2)Walnut, n (%) 12 (10.0)Pistachio, n (%) 9 (7.5)Hen's egg, n (%) 9 (7.5)Cow's milk, n (%) 7 (5.8)Kiwi, n (%) 9 (7.5)Apple, n (%) 7 (5.8)Atopic comorbidityAllergic asthma, n (%) 21 (58.3)Allergic rhinitis, n (%) 33 (91.7)Allergic conjunctivitis, n (%) 19 (52.8)Positive family history for atopic diseases, ≥1,n (%)34 (94.4)Atopic dermatitis, n (%) 30 (83.3)Allergic asthma, n (%) 18 (50.0)Allergic rhinitis, n (%) 25 (69.4)Food allergy, n (%) 6 (16.7)Total IgE (kU/L), median (IQR) 3786.0 (1344.0–5001.0)Missing, n (%) 7 (19.4)Serum TARC levels (pg/mL), median (IQR) 1950.0 (820.0–7260.0)Missing, n (%) 1 (2.8)Eosinophil levels (�109/L), median (IQR) 0.6 (0.4–0.9)Inhalant allergy screening, positive, n (%) 29 (80.6)House dust mite (n = 26) 24 (92.3)Birch pollen (n = 25) 24 (96.0)T A B L E 1 (Continued)CharacteristicTimothy grass pollen (n = 26) 25 (96.2)Mugwort (n = 17) 13 (76.5)Aspergillus fumigatus (n = 17) 14 (82.4)Cat (n = 24) 21 (87.5)Dog (n = 24) 24 (100.0)Missing, n (%) 7 (19.4)Abbreviations: AD, atopic dermatitis; BMI, body mass index; EASI,eczema area and severity index; IGA, Investigator's Global Assessment;IgE, immunoglobulin E; IQR, interquartile range; SD, standard deviation;TARC, thymus and activation regulated chemokine.2 of 4 - van der RIJST ET AL. 20457022, 2024, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clt2.12381 by Utrecht University, Wiley Online Library on [18/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensestudies will need to evaluate the effect of dupilumab treatment at ayounger age (>6 months of age). Potentially, treatment at young agemay influence the development of FA, by early improvement ofepidermal barrier dysfunction and reduction of transepidermal waterloss, and prevention of pro‐inflammatory cytokine release causing Bcell immunoglobulin class switching to sIgE.4F I GUR E 1 Estimated percentage decrease of median sIgE levels during 1 year of dupilumab treatment in pediatric patients withmoderate to severe AD for peanut, hazelnut, cashew nut, almond, walnut, pistachio, hen's egg, cow's milk, kiwi, and apple. Error bars indicatethe 95% confidence interval. AD, atopic dermatitis; sIgE, specific immunoglobulin E.van der RIJST ET AL. - 3 of 4 20457022, 2024, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clt2.12381 by Utrecht University, Wiley Online Library on [18/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseIn conclusion, this is the first study showing a profound decreaseof sIgE levels in 10 common food allergens in food allergic pediatricpatients with moderate to severe AD, ranging from 70.5% to 82.5%after 1 year of dupilumab treatment. These findings endorse anadditional positive effect of dupilumab on multiple FAs in pediatricAD patients with comorbid FA. To elucidate the role of dupilumab inthe treatment of FA, further understanding of the clinical andimmunological effects of dupilumab in pediatric patients is needed.AUTHOR CONTRIBUTIONSLisa P. van der Rijst: Conceptualization; data curation; formal analysis;investigation; methodology; visualization; writing ‐ original draft;writing ‐ review & editing.Michelle S. Hilbrands: Data curation; formalanalysis; investigation; methodology; writing ‐ original draft. NicolaasP. A. Zuithoff: Methodology; writing ‐ review & editing; software;validation. Marjolein S. de Bruin‐Weller: Conceptualization; projectadministration; resources; supervision; writing ‐ review & editing;funding acquisition. André C. Knulst: Writing ‐ review & editing; su-pervision. Thuy‐My Le: Conceptualization; methodology; supervision;validation; visualization; writing ‐ review & editing; writing ‐ originaldraft. Marlies de Graaf: Conceptualization; data curation; investiga-tion; methodology; resources; writing ‐ original draft; writing ‐ review& editing; supervision; visualization; funding acquisition.ACKNOWLEDGMENTSWe would like to acknowledge all the patients and their parents whoparticipated in the BioDay registry. Patients included in this manu-script participated in the BioDay registry sponsored by RegeneronPharmaceuticals and Sanofi. Data collection, analysis, and publicationof this article were not funded.CONFLICT OF INTEREST STATEMENTLisa P. van der Rijst has been a speaker for AbbVie and Novartis;Michelle S. Hilbrands has nothing to disclose; Nicolaas P. A.Zuithoff has nothing to disclose; Marjolein S. de Bruin‐Weller hasbeen a consultant, advisory board member, and/or speaker forAbbVie, Almirall, Amgen, Aslan, Eli Lilly, Galderma, Janssen, LeoPharma, Pfizer, Regeneron Pharmaceuticals, and Sanofi; André C.Knulst has been a consultant, advisory board member, and/orspeaker for ALK, Thermofisher, Nutricia/Danone, EUROIIMUN,DBV, and Novartis; Thuy‐My Le has been an advisory boardmember or speaker for Thermo Fisher Scientific, Novartis andAbbvie; Marlies de Graaf has been a consultant, advisor and/orspeaker for AbbVie, Almirall, Eli Lilly, Janssen, Leo Pharma,Novartis, Pfizer, Regeneron Pharmaceuticals, and Sanofi.DATA AVAILABILITY STATEMENTThe data that support the findings of this study are available onrequest from the corresponding author, MdG. The data are notpublicly available due to privacy restrictions.CONSENT FOR PUBLICATIONNot applicable.ORCIDLisa P. van der Rijst https://orcid.org/0000-0002-5865-8986Marlies de Graaf https://orcid.org/0000-0001-9004-5111REFERENCES1. Shaker MS, Schwartz J, Ferguson M. An update on the impact of foodallergy on anxiety and quality of life. Curr Opin Pediatr. 2017;29(4):497‐502. https://doi.org/10.1097/mop.00000000000005092. Achten R, Van der Rijst L, Piena M, et al. Economic and humanisticburden in paediatric patients with atopic dermatitis. Acta DermVenereol. 2023;103:adv00881. https://doi.org/10.2340/actadv.v103.48423. Papapostolou N, Xepapadaki P, Gregoriou S, Makris M. Atopicdermatitis and food allergy: a complex interplay what we know andwhat we would like to learn. J Clin Med. 2022;11(14):4232. https://doi.org/10.3390/jcm111442324. Brough HA, Nadeau KC, Sindher SB, et al. Epicutaneous sensitizationin the development of food allergy: what is the evidence and howcan this be prevented? Allergy. 2020;75(9):2185‐2205. https://doi.org/10.1111/all.143045. Spekhorst LS, van der Rijst LP, de Graaf M, et al. Dupilumab has aprofound effect on specific‐IgE levels of several food allergens inatopic dermatitis patients. Allergy. 2022;78(3):875‐878. https://doi.org/10.1111/all.155916. Paller AS, Simpson EL, Siegfried EC, et al. Dupilumab in children aged6 months to younger than 6 years with uncontrolled atopicdermatitis: a randomised, double‐blind, placebo‐controlled, phase 3trial. Lancet. 2022;400(10356):908‐919. https://doi.org/10.1016/s0140‐6736(22)01539‐27. Rial MJ, Barroso B, Sastre J. Dupilumab for treatment of food al-lergy. J Allergy Clin Immunol Pract. 2019;7(2):673‐674. https://doi.org/10.1016/j.jaip.2018.07.0278. Gradman J, Mortz CG, Eller E, Bindslev‐Jensen C. Relationship be-tween specific IgE to egg components and natural history of eggallergy in Danish children. Pediatr Allergy Immunol. 2016;27(8):825‐830. https://doi.org/10.1111/pai.126449. Kim JD, Kim SY, Kwak EJ, et al. Reduction rate of specific IgE level asa predictor of persistent egg allergy in children. Allergy AsthmaImmunol Res. 2019;11(4):498‐507. https://doi.org/10.4168/aair.2019.11.4.498SUPPORTING INFORMATIONAdditional supporting information can be found online in the Sup-porting Information section at the end of this article.How to cite this article: van der Rijst LP, Hilbrands MS,Zuithoff NPA, et al. Dupilumab induces a significant decreaseof food specific immunoglobulin E levels in pediatric atopicdermatitis patients. Clin Transl Allergy. 2024;e12381. https://doi.org/10.1002/clt2.123814 of 4 - van der RIJST ET AL. 20457022, 2024, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/clt2.12381 by Utrecht University, Wiley Online Library on [18/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Dupilumab induces a significant decrease of food specific immunoglobulin E levels in pediatric atopic dermatitis patients

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Dupilumab induces a significant decrease of food specific immunoglobulin E levels in pediatric atopic dermatitis patients

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