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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.)

Background: Inhalable biologics represent a promising approach to improve the efficacy and safety of asthma treatment. Although several mAbs targeting IL-4 receptor α chain (IL-4Rα) have been approved or are undergoing clinical trials, the development of inhalable mAbs targeting IL-4Rα presents significant challenges., Objective: Capitalizing on the distinctive advantages of nanobodies (Nbs) in maintaining efficacy during storage and administration, we sought to develop a novel inhalable IL-4Rα Nb for effectively treating asthma., Methods: Three IL-4Rα immunized Nb libraries were used to generate specific and functional IL-4Rα Nbs. LQ036, a bivalent Nb comprising 2 HuNb103 units, was constructed with a high affinity and specificity for human IL-4Rα. The efficacy, pharmacokinetics, and safety of inhaled LQ036 were evaluated in B-hIL4/hIL4RA humanized mice., Results: LQ036 inhibited secreted embryonic alkaline phosphatase reporter activity, inhibited TF-1 cell proliferation, and suppressed phosphorylated signal transducer and activator of transduction 6 in T cells from patients with asthma. Crystal structure analysis revealed a binding region similar to dupilumab but with higher affinity, leading to better efficacy in blocking the signaling pathway. HuNb103 competed with IL-4 and IL-13 for IL-4Rα binding. Additionally, LQ036 significantly inhibited ovalbumin-specific IgE levels in serum, CCL17 levels in bronchoalveolar lavage fluid, bronchial mucous cell hyperplasia, and airway goblet cell hyperplasia in B-hIL4/hIL4RA humanized mice. Inhaled LQ036 exhibited favorable pharmacokinetics, safety, and tissue distribution, with higher concentrations observed in the lungs and bronchi., Conclusions: These findings from preclinical studies establish the safety and efficacy of inhaled LQ036, underscoring its potential as a pioneering inhalable biologic therapy for asthma., Competing Interests: Disclosure statement This work was funded by grants from the Shanghai Pudong New Area Science and Technology Development Fund Industry-University-Research Special Project (PKX2022-S04), the National Key Research Program (2021YFA0805200), the National Natural Science Foundation of China (32070939, 82030106, and 82270026), the Shanghai Top-Priority Clinical Key Disciplines Construction Project (2017ZZ02013), the Shanghai Municipal Key Clinical Specialty (shslczdzk02201), and the Academic Mentorship for Scientific Research Cadre Project (AMSCP-22-05). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Aspirin-exacerbated respiratory disease (AERD) is a severe disease involving dysregulated type 2 inflammation. However, the role other inflammatory pathways play in AERD is poorly understood., Objective: We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation., Methods: Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro., Results: Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family-related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts., Conclusion: In addition to type 2 inflammation, innate and IL-6-related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab's therapeutic efficacy in AERD., Competing Interests: Disclosure statement Supported by the National Institutes of Health (grants U19AI095219 and K23AI139352), by the Immune Tolerance Network (AI109565-07), and by generous contributions from the Vinik and Kaye families. Disclosure of potential conflict of interest: T. Laidlaw has served on scientific advisory boards for GlaxoSmithKline, AstraZeneca, Sanofi-Genzyme, Regeneron, and Eli Lilly. K. Buchheit has served on scientific advisory boards for AstraZeneca, Sanofi-Genzyme, Regeneron, and GlaxoSmithKline; and has received personal consulting fees from Genentech. D. Dwyer receives research funding from Blueprint Medicines and has received personal consulting fees from Celldex Therapeutics. J. Boyce serves on the scientific advisory boards of Siolta Therapeutics, Third Harmonic Bio, and Jasper Therapeutics. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. 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.)

The intestinal nematode parasite Trichuris muris dwells in the caecum and proximal colon driving an acute resolving intestinal inflammation dominated by the presence of macrophages. Notably, these macrophages are characterised by their expression of RELMα during the resolution phase of the infection. The RELMα+ macrophage phenotype associates with the presence of alternatively activated macrophages and work in other model systems has demonstrated that the balance of classically and alternatively activated macrophages is critically important in enabling the resolution of inflammation. Moreover, in the context of type 2 immunity, RELMα+ alternatively activated macrophages are associated with the activation of macrophages via the IL4Rα. Despite a breadth of inflammatory pathologies associated with the large intestine, including those that accompany parasitic infection, it is not known how colonic macrophages are activated towards an alternatively activated phenotype. Here, we address this important knowledge gap by using Trichuris muris infection, in combination with transgenic mice (IL4Rαfl/fl.CX3CR1Cre) and IL4Rα-deficient/wild-type mixed bone marrow chimaeras. We make the unexpected finding that education of colonic macrophages towards a RELMα+, alternatively activated macrophage phenotype during T. muris infection does not require IL4Rα expression on macrophages. Further, this independence is maintained even when the mice are treated with an anti-IFNγ antibody during infection to create a strongly polarised Th2 environment. In contrast to RELMα, PD-L2 expression on macrophages post infection was dependent on IL4Rα signalling in the macrophages. These novel data sets are important, revealing a surprising cell-intrinsic IL4R alpha independence of the colonic RELMα+ alternatively activated macrophage during Trichuris muris infection., Competing Interests: The authors have declared that no competing interests exist.

Mucus secretion is an important feature of asthma that highly correlates with morbidity. Current therapies, including administration of mucolytics and anti-inflammatory drugs, show limited effectiveness and durability, underscoring the need for novel effective and longer lasting therapeutic approaches. Here we show that mucus production in the lungs is regulated by the TNF superfamily member 15 (TL1A) acting through the mucus-inducing cytokine IL-13. TL1A induces IL13 expression by innate lymphoid cells leading to mucus production, in addition to promoting airway inflammation and fibrosis. Reciprocally, neutralization of IL13 signaling through its receptor (IL4Rα), completely reverses TL1A-induced mucus secretion, while maintaining airway inflammation and fibrosis. Importance of TL1A is further demonstrated using a preclinical asthma model induced by chronic house dust mite exposure where TL1A neutralization by genetic deletion or antagonistic blockade of its receptor DR3 protected against mucus production and fibrosis. Thus, TL1A presents a promising therapeutic target that out benefits IL13 in reversing mucus production, airway inflammation and fibrosis, cardinal features of severe asthma in humans., Competing Interests: Authors KS, AM, and RS were employed by Kyowa Kirin Pharmaceutical Research, Inc. The authors declare that this study received funding from Kyowa Kirin Pharmaceutical Research, Inc. Authors KS, AM, and RS of Kyowa Kirin Pharmaceutical Research, Inc participated in discussing results and editing the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Steele, Sachen, McKnight, Soloff and Herro.)

Background: B cells play an important role in allergies through secretion of IgE. IL-4 receptor α (IL-4Rα) is key in allergic asthma and regulates type 2 cytokine production, IgE secretion, and airway hyperresponsiveness. IL-4 activation of B cells is essential for class switching and contributes to the induction of B effector 2 (Be2) cells. The role of Be2 cells and signaling via IL-4Rα in B cells is not clearly defined., Objective: We sought to find out whether IL-4Rα-responsive B cells or Be2 function was essential in experimental allergic asthma., Methods: Mice lacking IL-4Rα on B cells (mb1 cre IL-4Rα -/lox ) or littermate controls (IL-4Rα -/lox ) and mice lacking IL-4 or IL-4/IL-13 on B cells were sensitized and challenged with high-dose house dust mite (>10 μg) or with low-dose house dust mite (<3 μg). We also adoptively transferred naive IL-4Rα -/lox or IL-4Rα -/- B cells into μMT -/- mice a day before sensitization or a day before challenge. We analyzed lung inflammation, cellular infiltrate, and airway hyperresponsiveness., Results: We found that IL-4Rα signaling on B cells was important for optimal T H 2 allergic immune responses mainly when the load of antigen is limited. IL-4Rα signaling on B cells was essential for germinal centers and in the effector phase of allergic responses. Be2 cells were essential in airway hyperresponsiveness, but not in other parameters., Conclusions: IL-4Rα signaling on B cells is deleterious in allergic asthma because it is required for optimal T H 2 responses, Be2 function, germinal center formation, and T follicular helper cells, especially when the load of the antigen is limiting., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Asthma is a chronic disease with major public health ramifications owing to its high morbidity and mortality rates, especially in severe and recurrent cases. Conventional therapeutic options could partially alleviate the burden of asthma, yet a novel approach is needed to completely control this condition. To do so, a comprehensive understanding of the molecular mechanism underlying asthma is essential to recognize and treat the major pathways that drive its pathophysiology. In this review, we will discuss the molecular mechanism of asthma, in particular focusing on the type of inflammatory responses it elicits, namely type 2 and non-type 2 asthma. Furthermore, we will discuss the novel therapeutic options that target the aberrant molecules found in asthma pathophysiology. We will specifically focus on the role of novel monoclonal antibody therapies recently developed, such as the anti-IgE, IL-5, IL-5Rα, and IL-4Rα antibodies, drugs that have been extensively studied preclinically and clinically., Competing Interests: Conflict of Interest Tatsuya Nagano has received research funding from Astrazeneca The other authors declare there are no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

MAbTope is a docking-based method for the determination of epitopes. It has been used to successfully determine the epitopes of antibodies with known 3D structures. However, during the antibody discovery process, this structural information is rarely available. Although we already have evidence that homology models of antibodies could be used instead of their 3D structure, the choice of the template, the methodology for homology modeling and the resulting performance still have to be clarified. Here, we show that MAbTope has the same performance when working with homology models of the antibodies as compared to crystallographic structures. Moreover, we show that even low-quality models can be used. We applied MAbTope to determine the epitope of dupilumab, an anti- interleukin 4 receptor alpha subunit therapeutic antibody of unknown 3D structure, that we validated experimentally. Finally, we show how the MAbTope-determined epitopes for a series of antibodies targeting the same protein can be used to predict competitions, and demonstrate the accuracy with an experimentally validated example.3D: three-dimensionalRMSD: root mean square deviationCDR: complementary-determining regionCPU: central processing unitsVH: heavy chain variable regionVL: light chain variable regionscFv: single-chain variable fragmentsVHH: single-chain antibody variable regionIL4Rα: Interleukin 4 receptor alpha chainSPR: surface plasmon resonancePDB: protein data bankHEK293: Human embryonic kidney 293 cellsEDTA: Ethylenediaminetetraacetic acidFBS: Fetal bovine serumANOVA: Analysis of varianceEGFR: Epidermal growth factor receptorPE: PhycoerythrinAPC: AllophycocyaninFSC: forward scatterSSC: side scatterWT: wild typeKeywords: MAbTope, Epitope Mapping, Molecular docking, Antibody modeling, Antibody-antigen docking.

Inducing humoral, cellular and mucosal immunity is likely to improve the effectiveness of HIV-1 vaccine strategies. Here, we tested a vaccine regimen in pigtail macaques using an intranasal (i.n.) recombinant Fowl Pox Virus (FPV)-gag pol env-IL-4R antagonist prime, intramuscular (i.m.) recombinant Modified Vaccinia Ankara Virus (MVA)-gag pol-IL-4R antagonist boost followed by an i.m SOSIP-gp140 boost. The viral vector-expressed IL-4R antagonist transiently inhibited IL-4/IL-13 signalling at the vaccination site. The SOSIP booster not only induced gp140-specific IgG, ADCC (antibody-dependent cellular cytotoxicity) and some neutralisation activity, but also bolstered the HIV-specific cellular and humoral responses. Specifically, superior sustained systemic and mucosal HIV Gag-specific poly-functional/cytotoxic CD4 + and CD8 + T cells were detected with the IL-4R antagonist adjuvanted strategy compared to the unadjuvanted control. In the systemic compartment elevated Granzyme K expression was linked to CD4 + T cells, whilst Granzyme B/TIA-1 to CD8 + T cells. In contrast, the cytotoxic marker expression by mucosal CD4 + and CD8 + T cells differed according to the mucosal compartment. This vector-based mucosal IL-4R antagonist/SOSIP booster strategy, which promotes cytotoxic mucosal CD4 + T cells at the first line of defence, and cytotoxic CD4 + and CD8 + T cells plus functional antibodies in the blood, may prove valuable in combating mucosal infection with HIV-1 and warrants further investigation.

Impaired tolerance to innocuous particles during allergic asthma has been linked to increased plasticity of FoxP3+ regulatory T cells (Tregs) reprogramming into pathogenic effector cells, thus exacerbating airway disease. However, failure of tolerance mechanisms is driven by Th2 inflammatory signals. Therefore, the in vivo role of canonical IL-4 receptor α (IL-4Rα) signaling, an essential driver of Th2-type airway responses to allergens, on the regulatory function of FoxP3+ Tregs in allergic asthma was explored. Here, we used transgenic Foxp3cre IL-4Rα-/lox and littermate control mice to investigate the role of IL-4 and IL-13 signaling via Tregs in house dust mite-induced (HDM-induced) allergic airway disease. We sensitized mice intratracheally on day 0, challenged them on days 6-10, and analyzed airway hyperresponsiveness (AHR), airway inflammation, mucus production, and cellular profile on day 14. In the absence of IL-4Rα responsiveness on FoxP3+ Tregs, exacerbated AHR and airway inflammation were shown in HDM-sensitized mice. Interestingly, reduced induction of FoxP3+ Tregs accompanied increased IL-33 alarmin production and type 2 innate lymphoid cell activation in the lung, exacerbating airway hyperreactivity and lung eosinophilia. Taken together, our findings indicate that IL-4Rα-unresponsive FoxP3+ Tregs result in exaggerated innate Th2-type, IL-33-dependent airway inflammation and a break in tolerance during allergic asthma.

Asthma is a common respiratory immune disease in children and adults, and interleukin-4 (IL-4) is one of the key factors for the onset of asthma. Therefore, targeting human IL-4 and IL-4 receptor alpha (IL-4RA) has become one of the strategies for targeted therapy of cytokines. Herein, we established an animal model of asthmatic airway inflammation using double humanized IL-4/IL-4RA (hIL-4/hIL-4RA) mice, where human IL-4 and IL-4RA replaced their murine counterparts, respectively. We successfully identified the phenotype by Southern blotting, ELISA, and flow cytometry. The hIL-4/hIL-4RA mice induced by ovalbumin (OVA) exhibited several important features of asthma, such as inflammatory cell infiltration, IgE release, goblet cell hyperplasia, and Th2 cytokine secretion. Furthermore, treatment of these humanized mice with anti-human IL-4RA antibodies significantly inhibited level of these pathological indicators. Thus, hIL-4/hIL-4RA mice provide a validated preclinical mouse model to interrogate new therapeutic agents targeting this specific cytokine pathway in asthma., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Dupilumab is a fully human monoclonal antibody directed against the interleukin (IL)-4 receptor α subunit (IL-4Rα) of IL-4 heterodimeric type I and type II receptors that mediate IL-4/IL-13 signaling through this pathway. Blockade of these receptors broadly suppresses type 2 inflammation associated with atopic/allergic diseases, including atopic dermatitis and asthma. Six phase 1 studies investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of dupilumab in healthy subjects. Two randomized, double-blind, placebo-controlled, sequential studies assessed safety and tolerability of single escalating dupilumab doses administered intravenously or subcutaneously (one included various racial groups, and one included exclusively Japanese subjects); 3 randomized, parallel-group, single-dose studies compared the pharmacokinetic profiles of different dupilumab products and formulations after single subcutaneous doses; and one study assessed dupilumab administered as fast versus slow subcutaneous injections. Dupilumab concentrations in serum were measured in all studies, and total immunoglobulin E (IgE) and thymus- and activation-regulated chemokine (TARC) concentrations were measured in 2 studies as pharmacodynamic markers. Across the phase 1 studies, dupilumab exhibited target-mediated pharmacokinetics consisting of parallel linear and nonlinear elimination, with the target-mediated phase highly dominated by nonlinearity at lower drug concentrations. Systemic exposure and tolerability of dupilumab were consistent irrespective of differences in product, formulation, or racial background. Dupilumab reduced circulating concentrations of total IgE and TARC, indicating blockade of IL-4Rα-mediated signaling. Dupilumab had a favorable safety profile across the wide range of doses administered. Together, these findings support the continued development and use of dupilumab in treatment of type 2 diseases., (© 2020 Regeneron Pharmaceuticals, Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

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.

Localized skin lesions are characteristic of cutaneous leishmaniasis (CL); however, Leishmania ( Viannia ) species, which are responsible for most CL cases in the Americas, can spread systemically, sometimes resulting in mucosal disease. Detection of Leishmania has been documented in healthy mucosal tissues (conjunctiva, tonsils, and nasal mucosa) and healthy skin of CL patients and in individuals with asymptomatic infection in areas of endemicity of L ( V ) panamensis and L ( V ) braziliensis transmission. However, the conditions and mechanisms that favor parasite persistence in healthy mucosal tissues are unknown. In this descriptive study, we compared the cell populations of the nasal mucosa (NM) of healthy donors and patients with active CL and explored the immune gene expression signatures related to molecular detection of Leishmania in this tissue in the absence of clinical signs or symptoms of mucosal disease. The cellular composition and gene expression profiles of NM samples from active CL patients were similar to those of healthy volunteers, with a predominance of epithelial over immune cells, and within the CD45 + cell population, a higher frequency of CD66b + followed by CD14 + and CD3 + cells. In CL patients with molecular evidence of Leishmania persistence in the NM, genes characteristic of an anti-inflammatory and tissue repair responses ( IL4R , IL5RA , POSTN , and SATB1 ) were overexpressed relative to NM samples from CL patients in which Leishmania was not detected. Here, we report the first immunological description of subclinically infected NM tissues of CL patients and provide evidence of a local anti-inflammatory environment favoring parasite persistence in the NM., (Copyright © 2020 American Society for Microbiology.)

Background & Aims: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE., Methods: We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety., Results: The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P = .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group)., Conclusions: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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.)

Bullous pemphigoid, mucous membrane pemphigoid, and pemphigus vulgaris are different cutaneous autoimmune blistering diseases, with complex pathogenic mechanisms. In all of them, a type-2 response is thought to have a central role. Interleukin 4 and Interleukin 13 are crucial cytokines in type-2 response. Treatment of these conditions is often challenging. Dupilumab, a recombinant fully human IgG4 monoclonal antibody with binding specificity to human interleukin-4 receptor IL-4Rα, has the potential to inhibit both IL-4 and IL-13. We propose IL-4Rα as a theoretical drug target for cutaneous autoimmune bullous diseases., (© 2019 The Authors. Dermatologic Therapy published by Wiley Periodicals, Inc.)

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.)

Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood. Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1α (hypoxia-inducible factor-1α)-mediated neutrophil adaptation, resulting in resolution of lung injury. Methods: Neutrophil activation of IL4Ra (IL-4 receptor α) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4. Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α-dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo , IL-4Ra-deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis. Conclusions: We describe an important interaction whereby IL4Rα-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury.

Asthma is characterized by airway hyperresponsiveness and inflammation, as well as underlying structural changes to the airways. Interleukin-4 (IL-4) is a key T-helper type 2 (Th2) cytokine that plays important roles in the pathogenesis of atopic and eosinophilic asthma. We developed a novel humanized anti-IL-4Rα antibody that can potently inhibit IL-4/IL-13-mediated TF-1 cell proliferation. Using monocytes isolated from human peripheral blood mononuclear cells (PBMCs), we revealed a critical role of CD32 in modulating the immune responses of monocytes in response to blockade of IL-4Rα signaling pathway. We, therefore, devised a new strategy to increase the efficacy of the anti-IL-4Rα monoclonal antibody for the treatment of asthma and other atopic diseases by co-engaging CD32 and IL-4Rα on monocytic cells by choosing IgG classes or Fc mutations with higher affinities for CD32. The antibody with selectively enhanced affinity for CD32A displayed superior suppression of IL-4-induced monocytes' activities, including the down-regulation of CD23 expression. Intriguingly, further analysis demonstrated that both CD32A and CD32B contributed to the enhancement of antibody-mediated suppression of CD23 expression from monocytes in response to blockade of IL-4Rα signaling. Furthermore, inhibition of IgE secretion from human PBMC by the antibody variants further suggests that the complex allergic inflammation mediated by IL-4/IL-4Rα signaling might result from a global network where multiple cell types that express multiple FcγRs are all involved, of which CD32, especially CD32A, is a key mediator. In this respect, our study provides new insights into designing therapeutic antibodies for targeting Th2 cytokine-mediated allergic pathogenesis.

Development of antagonistic antibody (Ab) against interleukin-4 receptor alpha (IL-4Rα) subunit of IL-4/IL-13 receptors is a promising therapeutic strategy for T helper 2 (T H 2)-mediated allergic diseases such as asthma and atopic dermatitis. Here we isolated anti-human IL-4Rα antagonistic Abs from a large yeast surface-displayed human Ab library and further engineered their complementarity-determining regions to improve the affinity using yeast display technology, finally generating a candidate Ab, 4R34.1.19. When reformatted as human IgG1 form, 4R34.1.19 specifically bound to IL-4Rα with a high affinity (K D ≈ 178 pM) and effectively blocked IL-4- and IL-13-dependent signaling in a reporter cell system at a comparable level to that of the clinically approved anti-IL-4Rα dupilumab Ab analogue. Epitope mapping by alanine scanning mutagenesis revealed that 4R34.1.19 mainly bound to IL-4 binding sites on IL-4Rα with different epitopes from those of dupilumab analogue. Further, 4R34.1.19 efficiently inhibited IL-4-dependent proliferation of T cells among human peripheral blood mononuclear cells and suppressed the differentiation of naïve CD4 + T cells from healthy donors and asthmatic patients into T H 2 cells, the activities of which were comparable to those of dupilumab analogue. Our work demonstrates that both affinity and epitope are critical factors for the efficacy of anti-IL-4Rα antagonistic Abs.

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: The purpose of this study was to analyze the involvement of signaling via Interleukin-4-Receptor α (IL4Rα) and Toll like receptor (TLR) 4 at the fetomaternal interface in the process of early pregnancy., Patients and Methods: Placenta specimens of 46 patients in early pregnancy were analyzed (normal pregnancy (n = 15), spontaneous (n = 15) and habitual abortion (n = 16)). TLR4 and IL4Rα were analyzed by immunohistochemistry, immunofluorescence and real time PCR. Statistical analysis was carried out using SPSS 23 and Microsoft Excel., Results: IL4Rα could be detected in trophoblast cells of all groups. It was significantly downregulated in the syncytiotrophoblast of spontaneous and recurrent abortions (p = 0.001), and in decidual tissue of spontaneous abortions (p = 0.001). Expression of TLR4 was decreased in the intermediate villous trophoblast (IVT) and decidua of spontaneous abortions (p = 0.04 & 0.003, respectively). On mRNA level expression of IL4Rα and TLR4 was significantly decreased in the group of recurrent miscarriages (IL4Rα p = 0.002, TLR4 p = 0.004)., Conclusion: This study contributes new findings to the understanding of the complex molecular interplay at the fetomaternal interface in normal pregnancy and miscarriages. For the first time signaling via IL4Rα being involved at the very beginning of the generation of new life could demonstrated. Moreover, new evidence was provided regarding TLR4 playing a pivotal role in early pregnancy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: In a pivotal, phase 2b study (NCT01854047) in patients with uncontrolled persistent asthma, despite using medium-to-high-dose inhaled corticosteroids plus long-acting β2 agonists, dupilumab improved lung function, reduced severe exacerbations, and showed an acceptable safety profile., Objective: To assess the impact of dupilumab on asthma control, symptoms, quality of life (QoL), and productivity., Methods: Data are shown for the intention-to-treat population receiving dupilumab 200/300 mg every 2 weeks (doses being assessed in phase 3; NCT02414854), or placebo. Predefined analyses of total scores were conducted at week 24 for the 5-item Asthma Control Questionnaire (ACQ-5), patient-reported morning/evening (AM/PM) asthma symptoms, Asthma Quality of Life Questionnaire (AQLQ), and asthma-related productivity loss. Responder rate analyses for these measures, subgroup analyses by baseline characteristics, and asthma-related productivity loss analyses were conducted post hoc., Results: Data from 465 patients were analyzed (158 placebo; 307 dupilumab). Both dupilumab doses significantly improved scores through week 24 (all outcomes, overall population). The proportion of patients meeting or exceeding the minimal clinically important difference for the overall population were significantly greater vs placebo (P < .05) for ACQ-5 (range, 72.6%-76.7% vs 61.4%), for AM/PM asthma symptoms score (48.7%-54.1% vs 34.2% and 52.7%-53.5% vs 34.2%, respectively) and for AQLQ (64.0%-65.0% vs 51.3%). The effect of dupilumab was consistent across most subgroups. Productivity loss was significantly higher in placebo- vs dupilumab-treated patients (P < .0001)., Conclusion: Dupilumab produced significant, clinically meaningful improvements in asthma control, symptoms, QoL, and productivity., Registration: ClinicalTrials.gov Identifier: NCT01854047., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint blockade (ICB) is a promising novel therapy for multiple cancer types; however, most patients show limited or no clinical response. Accumulating evidence indicates that myeloid-derived suppressor cells (MDSCs) are a major factor responsible for immunosuppression in patients with cancer. Therefore, identifying effective therapies that deplete or modulate MDSCs is essential. In this study, we focus on the anticonvulsant drug valproic acid (VPA), which has additional activities including anticancer and immunoregulation by inhibition of histone deacetylases. We showed that VPA decreased the proportion of polymorphonuclear (PMN)-MDSCs in vitro and showed for the first time that VPA greatly attenuated the immunosuppressive function of MDSCs in a dose-dependent manner. Moreover, we demonstrated that in vitro differentiated VPA-conditioned MDSCs exhibited impaired ability to stimulate tumor progression in vivo. We also showed the possible involvement of several mechanisms in the VPA-induced attenuation of the immunosuppressive function of MDSCs, including the interleukin-4 receptor-α (IL-4Rα)/arginase axis, programmed cell death 1 ligand 1 (PD-L1) and toll-like receptor 4 (TLR4) signaling pathways, and retinoblastoma 1 (Rb1) derepression. This research highlights the potential of combining VPA with ICB in cancer treatment., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Barrier tissue dysfunction is a fundamental feature of chronic human inflammatory diseases 1 . Specialized subsets of epithelial cells-including secretory and ciliated cells-differentiate from basal stem cells to collectively protect the upper airway 2-4 . Allergic inflammation can develop from persistent activation 5 of type 2 immunity 6 in the upper airway, resulting in chronic rhinosinusitis, which ranges in severity from rhinitis to severe nasal polyps 7 . Basal cell hyperplasia is a hallmark of severe disease 7-9 , but it is not known how these progenitor cells 2,10,11 contribute to clinical presentation and barrier tissue dysfunction in humans. Here we profile primary human surgical chronic rhinosinusitis samples (18,036 cells, n = 12) that span the disease spectrum using Seq-Well for massively parallel single-cell RNA sequencing 12 , report transcriptomes for human respiratory epithelial, immune and stromal cell types and subsets from a type 2 inflammatory disease, and map key mediators. By comparison with nasal scrapings (18,704 cells, n = 9), we define signatures of core, healthy, inflamed and polyp secretory cells. We reveal marked differences between the epithelial compartments of the non-polyp and polyp cellular ecosystems, identifying and validating a global reduction in cellular diversity of polyps characterized by basal cell hyperplasia, concomitant decreases in glandular cells, and phenotypic shifts in secretory cell antimicrobial expression. We detect an aberrant basal progenitor differentiation trajectory in polyps, and propose cell-intrinsic 13 , epigenetic 14,15 and extrinsic factors 11,16,17 that lock polyp basal cells into this uncommitted state. Finally, we functionally demonstrate that ex vivo cultured basal cells retain intrinsic memory of IL-4/IL-13 exposure, and test the potential for clinical blockade of the IL-4 receptor α-subunit to modify basal and secretory cell states in vivo. Overall, we find that reduced epithelial diversity stemming from functional shifts in basal cells is a key characteristic of type 2 immune-mediated barrier tissue dysfunction. Our results demonstrate that epithelial stem cells may contribute to the persistence of human disease by serving as repositories for allergic memories.

Interleukin (IL)-4 and IL-13 are related cytokines that regulate many aspects of allergic inflammation. They play important roles in regulating the responses of lymphocytes, myeloid cells, and non-hematopoietic cells. In T-cells, IL-4 induces the differentiation of naïve CD4 T cells into Th2 cells, in B cells, IL-4 drives the immunoglobulin (Ig) class switch to IgG1 and IgE, and in macrophages, IL-4 and IL-13 induce alternative macrophage activation. This review gives a short insight into the functional formation of these cytokine receptors. I will discuss both the binding kinetics of ligand/receptor interactions and the expression of the receptor chains for these cytokines in various cell types; both of which are crucial factors in explaining the efficiency by which these cytokines induce intracellular signaling and gene expression. Work initiated in part by William (Bill) E. Paul on IL-4 some 30 years ago has now grown into a major building block of our current understanding of basic immunology and the immune response. This knowledge on IL-4 has growing clinical importance, as therapeutic approaches targeting the cytokine and its signal transduction are becoming a part of the clinical practice in treating allergic diseases. Just by reading the reference list of this short review, one can appreciate the enormous input Bill has had on shaping our understanding of the pathophysiology of allergic inflammation and in particular the role of IL-4 in this process.

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.)