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Background: A preference for type 2 immunity plays a central role in the pathogenesis of atopic dermatitis (AD). Dupilumab, an mAb targeting the IL-4 receptor α (IL-4Rα) subunit, inhibits IL-4 and IL-13 signaling. These cytokines contribute significantly to IgE class switch recombination in B cells, critical in atopic diseases. Recent studies indicate IgG + CD23 hi IL-4Rα + type 2 memory B cells (MBC2s) as IgE-producing B-cell precursors, linked to total IgE serum levels in atopic patients. Total IgE serum levels decreased during dupilumab treatment in previous studies., Objective: We sought to assess the effects of dupilumab treatment in comparison with alternative therapies on the frequency of MBC2s and the correlation to total IgE levels in pediatric patients with AD., Methods: Pediatric patients with AD, participating in an ongoing trial, underwent randomization into 3 treatment groups: dupilumab (n = 12), cyclosporine (n = 12), and topical treatment (n = 12). Plasma samples and PBMCs were collected at baseline (T0) and at 6 months after starting therapy (T6). Flow cytometry was used for PBMC phenotyping, and ELISA was used to assess total IgE levels in plasma., Results: Our findings revealed a significant reduction in MBC2 frequency and total IgE levels among patients treated with dupilumab. In addition, a significant correlation was observed between MBC2s and total IgE levels., Conclusions: Systemic blocking of the IL-4Rα subunit leads to a decrease in circulating MBC2 cells and total IgE levels in pediatric patients with AD. Our findings unveiled a novel mechanism through which dupilumab exerts its influence on the atopic signature., Competing Interests: Disclosure statement This work was supported by a grant from ZonMw (grant no. 848101005 to S.P.), with the Netherlands Organisation for Health Research and Development as the collaborating sponsor; a grant from the Promedica Stiftung Chur, Switzerland (grant no. 1515/M to W.V.); and a research fellowship from the European Academy of Allergy & Clinical Immunology (to M.S.). The funding sources of this research had no involvement in the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the article for publication. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis (AD) is still a demanding challenge in clinical practice. Type 2 inflammation is the most common inflammatory pathway in children and adolescents with AD. Anti-inflammatory drugs, mainly corticosteroids (CS) and immunomodulant agents are the primary therapeutic approach to dampening type 2 inflammation. However, AD patients may require long-term high CS doses or drug combinations with possibly significant adverse effects to achieve and maintain disease control. In this regard, the advent of biologics constituted a breakthrough in managing this condition. Dupilumab is a monoclonal antibody directed against the IL-4 receptor α-subunit (IL-4Rα), antagonizing both IL-4 and IL-13 and is approved for pediatric severe AD. This review presents and discusses the most recent published studies on dupilumab in children and adolescents with AD. There is convincing evidence that dupilumab is safe and effective in managing AD. It can reduce skin lesions and associated itching, reduce the need for additional medications, and improve disease control and quality of life. However, a thorough diagnostic pathway is mandatory, especially considering the different AD phenotypes. The ideal eligible candidate is a child or adolescent with AD requiring systemic treatment because of severe clinical manifestations and impaired quality of life., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Introduction: Dupilumab is a treatment option newly licensed for adolescents with moderate to severe atopic dermatitis (AD). It reduces type 2 inflammation by blocking the shared receptor subunit for IL-4/-13. Dupilumab affects three disease mechanisms in atopic dermatitis: the skin barrier, the Th2-cell differentiation and the class switch to IgE. This report is based on a systematic literature search of the PubMed Database., Areas Covered: Dupilumab showed promising results in improving AD signs, symptoms and quality of life in adolescents with moderate to severe AD. The safety profile of dupilumab in adolescents with moderate to severe AD closely resembled the known safety profile of dupilumab in adults with moderate to severe AD. Injection-site reactions and conjunctivitis were the relevant side-effects. Skin infections were less frequently observed compared to placebo., Expert Commentary: Dupilumab was approved by the Food and Drug Administration in March 2019 and by the European Medicines Agency in August 2019 for the treatment of adolescents with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical therapies or when those therapies are not advisable. Since it is the first licensed drug it will likely become the reference drug for adolescents with moderate to severe AD.

The Th2 cytokines interleukin 4 (IL-4) and IL-13 and the heterodimeric IL-4 receptor (IL-4R) complexes that they interact with play a key role in the pathogenesis of allergic disorders. Dupilumab is a humanized IgG4 monoclonal antibody that targets the IL-4 receptor alpha chain (IL-4Rα), common to both IL-4R complexes: type 1 (IL-4Rα/γc; IL-4 specific) and type 2 (IL-4Rα/IL-13Rα1; IL-4 and IL-13 specific). In this review, we detail the current state of knowledge of the different signalling pathways coupled to the IL-4R complexes and examine the possible mechanisms of Dupilumab action and survey its clinical efficacy in different allergic disorders. The development of Dupilumab and the widening spectrum of its clinical applications is relevant to the current emphasis on precision medicine approaches to the blockade of pathways involved in allergic diseases., (© 2019 John Wiley & Sons Ltd.)

Despite sharing interleukin-4 receptor α (IL-4Rα) in their signaling cascades, IL-4 and IL-13 have different functions in atopic inflammation. IL-13 preferentially participates in the peripheral tissues because tissue-resident group 2 innate lymphoid cells produce IL-13 but not IL-4. In contrast, lymph node T follicular helper cells express IL-4 but not IL-13 to regulate B-cell immunity. The dominant microenvironment of IL-13 is evident in the lesional skin of atopic dermatitis (AD). The IL-13-rich local milieu causes barrier dysfunction by down-regulating the OVOL1-filaggrin (FLG) axis and up-regulating the periostin-IL-24 axis. Genome-wide association studies also point to the crucial involvement of the IL-13, OVOL1 and FLG genes in the pathogenesis of AD. Biologics targeting IL-13, such as the anti-IL-4Rα antibody dupilumab and the anti-IL-13 antibody tralokinumab, successfully improve AD lesions and further highlight the importance of IL-13 in the pathogenesis of AD., (© 2019 John Wiley & Sons Ltd.)

Background: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo., Objectives: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials., Methods: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47)., Results: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis., Conclusions: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD., (© 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Systemic treatment options for chronic hand eczema are limited. Dupilumab is used in atopic dermatitis (AD) but is not licensed for (isolated) hand eczema. In this observational prospective study we aimed to determine the response of hand eczema to dupilumab in patients with AD. Adult patients with hand eczema and AD received dupilumab s.c. at a 600 mg loading dose, followed by 300 mg every 2 weeks. Primary outcome was a minimum improvement of 75% on the Hand Eczema Severity Index after 16 weeks (HECSI-75). Secondary outcomes were severity, measured using the Photographic guide; quality of life improvement as patient-reported outcome, measured using the Dermatology Life Quality Index (DLQI); and AD severity, measured using the Eczema Area and Severity Index (EASI). Forty-seven patients were included (32 males; mean age, 45 years). HECSI-75 was achieved by 28 (60%). Mean HECSI score reduction was 49.2 points (range, 0-164; 95% within-subject confidence interval, 46.4-52.0), which was already significantly decreased after 4 weeks (P < 0.001). DLQI score mean improvement was 8.8 points (standard deviation [SD], 6.0) or 70.0% decrease (SD, 26.4) (P < 0.001). Eighteen patients (38%) were classified as responders on the Photographic guide. There was no difference in response between chronic fissured and recurrent vesicular clinical subtypes. Similar percentages of patients achieving EASI-75 and HECSI-75 were seen after 16 weeks. In conclusion, this study shows a favorable response of hand eczema to dupilumab in patients with AD. This raises the question whether a response will also be seen in isolated hand eczema., (© 2019 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Introduction: For many years, oral immunosuppressive drugs such as cyclosporine A, azathioprine, mycophenolic acid, and methotrexate were the only treatment options, in addition to topical treatment, in patients with severe atopic dermatitis (AD). Dupilumab, a monoclonal antibody targeting the IL-4 receptor alpha, is the first antibody-based treatment commercially available for the treatment of AD. In the near future, more antibody-based treatments and small molecules will become available in the treatment of severe AD., Areas Covered: This review gives an overview of current and future therapies for severe AD, outlines options to optimize treatment with oral immunosuppressive drugs and gives an insight into the future of personalized treatment in AD., Expert Opinion: Due to the heterogeneous character of AD, it is unlikely that all patients will respond equally to these newly tested drugs. We believe that biomarkers will lead to better identification of patients that will benefit from these highly specific, but expensive new treatments. In addition to a role for biomarkers in new treatments, the use of pharmacogenomic biomarkers can improve the efficacy of currently used oral immunosuppressive drugs in AD, which will still be needed for the treatment of moderate to severe AD in the coming years.

Atopic dermatitis (AD) is caused by complex interactions between a variety of genetic and environmental factors that contribute to the maintenance of the chronic inflammatory skin condition. Most conventional treatments have been designed for the so-called 'average patient'. In recent years however, many previously unknown details pertaining to the mechanisms of the pathogenesis of AD have been elucidated, and novel treatments based on these pathological mechanisms or on subgroup classifications have been developed. Herein, how future treatment strategies for AD can be developed is described.

Purpose of Review: An update on new therapies currently approved or potentially useful in the future for the management of patients suffering moderate-to-severe atopic dermatitis., Recent Findings: New pathogenic mechanisms involved in atopic dermatitis have permitted to propose novel therapeutic approaches devised to control the inflammatory process observed in involved cutaneous tissues by neutralizing mediators, cytokines, and their receptors. Recent research findings have disclosed important and previously unrecognized pathogenic mechanisms that have resulted in innovative targeted therapies, such as dupilumab, and potentially other biologicals and small molecules. Further studies should permit the sub-classification of patients according to the relevance of different mediators and inflammatory cells. It can be concluded that the treatment of atopic dermatitis has entered into the era of personalized/precision medicine.

Background: Dupilumab, a fully human monoclonal antibody against interleukin-4 receptor alpha, inhibits the signals of interleukin-4 and interleukin-13, and has also shown significant efficacy in patients with moderate-to-severe atopic dermatitis (AD), while the effect of it on adverse events remains controversial., Objective: To assess the influence of dupilumab on adverse events in adults with moderate-to-severe AD., Method: Randomised controlled trials (RCTs) that compared dupilumab with a placebo for patients with moderate-to-severe AD were searched in the MEDLINE, EMBASE, Web of Science and Cochrane databases. The outcome of the study was the incidence of adverse events during the observation period., Results: Eight RCTs were analysed in this study. Meta-analysis showed that patients treated with dupilumab had a lower risk of skin infection (risk ratio [RR] 0.54; 95% confidence interval [CI] 0.42-0.69) and exacerbation of AD (RR 0.44, 95% CI 0.34-0.59), but had a higher risk of injection-site reaction (RR 2.24, 95% CI 1.68-2.99), headache (RR 1.47, 95% CI 1.05-2.06), and conjunctivitis (RR 2.64, 95% CI 1.79-3.89) than did patients treated with a placebo. Nasopharyngitis, urinary tract infection, upper respiratory tract infection, and herpes virus infection were found balanced in dupilumab groups and placebo groups., Conclusion: Dupilumab moderately reduced the risk of skin infection and the exacerbation of AD, slightly increased the risk of headache, and moderately increased the risk of injection-site reaction and conjunctivitis, but had little effect on other infections in adults with moderate-to-severe AD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Atopic dermatitis (AD) is one of the most common skin disorders with a prevalence of about 20% in children and affecting adults in significant numbers. Moderate to severe AD significantly impairs a patient's quality of life with severe pruritus as a major issue that impairs sleep and contributes to major psychological disturbances. Detailed studies of its pathogenesis have revealed that immune mechanisms are involved including activation of T helper type 2 cells (Th2). Dupilumab is a fully human Ig4 monoclonal antibody directed against the interleukin-4 receptor subunit α (IL-4Rα) of IL-4 and IL-13 receptors. In clinical studies it has been demonstrated to significantly reduce the molecular signature in the skin of patients with AD and to significantly reduce the clinical manifestations of moderate to severe AD. It also very importantly significantly reduces the pruritus of moderate to severe AD thus improving the patients' quality of life. Dupilumab is administered by subcutaneous injection every other week. It was approved by the FDA in March 2017 for the treatment of moderate to severe AD., (Copyright 2017 Clarivate Analytics.)

Atopic dermatitis (AD) is among the most common inflammatory skin diseases in children and adults in industrialized countries. Up to one-third of adults (probably a smaller proportion in childhood) suffer from moderate-to-severe AD, whose recommended treatment is usually based on systemic therapies. The currently available therapeutics are limited, and AD management becomes challenging in most cases. Over the last few years, new advances in the understanding of AD pathogenic mechanisms and inflammatory pathways have led to the identification of specific therapeutic targets and new molecules have been tested. Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor α subunit that is able to block the signaling of both IL-4 and IL-13 and achieve rapid and significant improvements in adults with moderate-to-severe AD. Dupilumab is ready to inaugurate a long and promising biological target treatment option for Th2 cell-mediated atopic immune response that characterizes AD., Competing Interests: Disclosure The authors declare no affiliation or significant financial involvement in any organizations or entity with a direct financial interest in the subject matter or materials discussed in the present manuscript. The authors report no conflicts of interest in this work.