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Liu D, Patel D, Lau M, Largen J, Hu BD, He H, Guttman-Yassky E. A translational approach to improve therapeutics in atopic dermatitis and beyond. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf049. [PMID: 40373271 DOI: 10.1093/jimmun/vkaf049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 03/03/2025] [Indexed: 05/17/2025]
Abstract
Atopic dermatitis (AD) and alopecia areata are highly prevalent inflammatory skin/hair conditions. While previously not fully understood and limited in treatment options, AD is currently undergoing a therapeutic revolution. Our increased understanding of the underlying immunologic and barrier dysregulations and disease heterogeneity across its spectrum is facilitating hypothesis-driven therapeutic development. Early transcriptomic analyses in AD skin and blood have identified disease-specific biomarkers and uncovered immune and barrier abnormalities that may contribute to disease pathogenesis. From these findings, various therapeutic targets were then proposed and investigated in clinical trials, leading to the Food and Drug Administration approval of several biologics and small molecule drugs that are now widely used in the clinical setting. Molecular phenotyping of patient samples before and after treatment has further elucidated the specific immunomodulatory effect of each therapeutic, as well as the relative contributions of various immune pathways to disease pathogenesis. This bench-to-bedside cyclical approach has rapidly broadened our understanding of AD and enabled the rapid expansion of the AD therapeutic pipeline. In this brief review, we detail how molecular and blood profiling studies in AD laid the foundation for a therapeutic revolution, discuss currently approved and potential therapeutics for AD resulting from this bench-to-bedside approach, and highlight how this translational approach is being applied to advancing the therapeutic pipeline of alopecia areata.
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Affiliation(s)
- Daniel Liu
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Dev Patel
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Megan Lau
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Joseph Largen
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Benjamin D Hu
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Helen He
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Emma Guttman-Yassky
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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2
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Dezoteux F, Marcant P, Dendooven A, Delaunay É, Esnault S, Trauet J, Lefèvre G, Staumont-Sallé D. Enhanced Siglec-8 and HLA-DR and reduced CRTH2 surface expression highlight a distinct phenotypic signature of circulating eosinophils in atopic dermatitis. J Leukoc Biol 2025; 117:qiaf023. [PMID: 39998842 DOI: 10.1093/jleuko/qiaf023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/27/2024] [Accepted: 02/24/2025] [Indexed: 02/27/2025] Open
Abstract
Atopic dermatitis and other type 2 immune response diseases are often linked to elevated eosinophil levels in the blood. Although the role of eosinophils in atopic dermatitis pathophysiology is suspected, it remains unclear. The development of new treatments targeting the type 2 response, particularly cytokines involved in eosinophil activation and chemotaxis, makes it necessary to identify potential eosinophil profiles in atopic dermatitis that may respond to these treatments. A prospective study was conducted comparing blood eosinophil phenotypes in patients with moderate to severe atopic dermatitis (n = 19) without recent systemic treatment to healthy individuals (n = 19). The primary outcome was the membranous phenotypic signature of eosinophils, assessed by flow cytometry. Most patients with atopic dermatitis (84%) had early onset in childhood, a severe disease (mean SCORing Atopic Dermatitis of 57.5), and elevated blood eosinophil counts (310 per µL in atopic dermatitis vs 120 in healthy individuals, P < 0.0001). Patients with atopic dermatitis exhibited lower CRTH2 on eosinophils but higher levels of human leukocyte antigen-DR isotype and Siglec-8 compared to healthy individuals. Other surface proteins showed no significant differences. Clustering analysis confirmed increased Siglec-8 in patients with atopic dermatitis. Additionally, patients with atopic dermatitis had higher serum levels of type 2 immune response markers such as eotaxin-2, IL-5, IL-3, and TARC. Circulating eosinophils in patients with atopic dermatitis show a distinct phenotypic profile, suggesting a role in atopic dermatitis pathophysiology and potential involvement in differential treatment responses.
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Affiliation(s)
- Frédéric Dezoteux
- CHU Lille, Univ. Lille, Service de Dermatologie, Rue Michel Polonowski, F-59000 Lille, France
- U1286-Infinite-Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, 1, Place Verdun, F-59000 Lille, France
- Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Rue Michel Polonowki, F-59000 Lille, France
| | - Pierre Marcant
- CHU Lille, Univ. Lille, Service de Dermatologie, Rue Michel Polonowski, F-59000 Lille, France
| | - Arnaud Dendooven
- U1286-Infinite-Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, 1, Place Verdun, F-59000 Lille, France
| | - Émeline Delaunay
- U1286-Infinite-Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, 1, Place Verdun, F-59000 Lille, France
| | - Stéphane Esnault
- U1286-Infinite-Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, 1, Place Verdun, F-59000 Lille, France
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, 5158 Medical Foundation Centennial Building, 1685 Highland Ave, Madison, WI 53705, United States
| | - Jacques Trauet
- Institut d'Immunologie, CHU Lille, Boulevard du Pr Jules Leclercq, F-59000 Lille, France
| | - Guillaume Lefèvre
- U1286-Infinite-Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, 1, Place Verdun, F-59000 Lille, France
- Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Rue Michel Polonowki, F-59000 Lille, France
- Institut d'Immunologie, CHU Lille, Boulevard du Pr Jules Leclercq, F-59000 Lille, France
- Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), CHU Lille, Rue Michel Polonowski, F-59000 Lille, France
| | - Delphine Staumont-Sallé
- CHU Lille, Univ. Lille, Service de Dermatologie, Rue Michel Polonowski, F-59000 Lille, France
- U1286-Infinite-Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, 1, Place Verdun, F-59000 Lille, France
- Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Rue Michel Polonowki, F-59000 Lille, France
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3
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Luo YF, Deng Y, Yang F, Meiduosiji, Xiong X, Yuan YL, Ao SH. The role of ILC2s in asthma combined with atopic dermatitis: bridging the gap from research to clinical practice. Front Immunol 2025; 16:1567817. [PMID: 40236701 PMCID: PMC11996653 DOI: 10.3389/fimmu.2025.1567817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 03/11/2025] [Indexed: 04/17/2025] Open
Abstract
Asthma, a complex and heterogeneous respiratory disease, is often accompanied by various comorbidities, notably atopic dermatitis (AD). AD characterized by recurrent eczematous lesions and severe itching, can trigger or exacerbate asthma. Individuals with AD are 2.16 times more likely to develop asthma compared to the reference population. Furthermore, asthmatics with AD experience more severe and frequent emergency department visits and hospital admissions compared to patients with asthma alone. The close connection between asthma and AD indicates there are overlap pathophysiologic mechanisms. It is well-known that dysregulated type 2 (T2) immune inflammation is pivotal in the development of both AD and asthma, traditionally attributed to CD4+ type 2 helper T (Th2) cells. Over the past decade, group 2 innate lymphoid cells (ILC2s), as potent innate immune cells, have been demonstrated to be the key drivers of T2 inflammation, playing a crucial role in the pathogenesis of both asthma and AD. ILC2s not only trigger T2 immune-inflammation but also coordinate the recruitment and activation of innate and adaptive immune cells, thereby intensifying the inflammatory response. They are rapidly activated by epithelium alarmins producing copious amounts of T2 cytokines such as interleukin (IL) -5 and IL-13 that mediate the airway inflammation, hyperresponsiveness, and cutaneous inflammation in asthma and AD, respectively. The promising efficiency of targeted ILC2s in asthma and AD has further proven their essential roles in the pathogenesis of both conditions. However, to the best of our knowledge, there is currently no review article specifically exploring the role of ILC2s in asthma combined with AD and their potential as future therapeutic targets. Hence, we hypothesize that ILC2s may play a role in the pathogenesis of asthma combined with AD, and targeting ILC2s could be a promising therapeutic approach for this complex condition in the future. In this review, we discuss recent insights in ILC2s biology, focus on the current knowledge of ILC2s in asthma, AD, particularly in asthma combined with AD, and suggest how this knowledge might be used for improved treatments of asthma combined with AD.
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Affiliation(s)
- Yan-fang Luo
- Department of Respirology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Yu Deng
- Department of Respirology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Feng Yang
- Department of Respirology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Meiduosiji
- Department of Respirology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Xia Xiong
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
- Department of Dermatology, The First Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yu-lai Yuan
- Department of Respirology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Su-hua Ao
- Department of Respirology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
- College of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan, China
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Baker MG, Ford LS, Campbell DE, Sampson HA. Just scratching the surface: A review of pediatric skin allergies. Pediatr Allergy Immunol 2025; 36:e70038. [PMID: 39953855 DOI: 10.1111/pai.70038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 11/16/2024] [Accepted: 01/23/2025] [Indexed: 02/17/2025]
Abstract
The skin is a large and sophisticated organ populated by innate and adaptive immune effector cells. These immune cells provide a critical first line of defense against pathogens, but genetic and environmental factors can lead to inappropriate signaling that may manifest as hypersensitivity. The most common cutaneous allergic disorders in children include atopic dermatitis, urticaria/angioedema, and contact dermatitis. In this review, we will briefly review these conditions, with a focus on recent developments in our understanding of the diagnosis and management of these disorders.
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Affiliation(s)
- Mary Grace Baker
- Division of Pediatric Allergy & Immunology, Department of Pediatrics, Elliot and Roslyn Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, Kravis Children's Hospital, New York, New York, USA
| | - Lara S Ford
- Department of Allergy & Immunology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia
| | - Dianne E Campbell
- Department of Allergy & Immunology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia
- DBV Technologies, Montrouge, France
| | - Hugh A Sampson
- Division of Pediatric Allergy & Immunology, Department of Pediatrics, Elliot and Roslyn Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, Kravis Children's Hospital, New York, New York, USA
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5
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Arnold IC, Munitz A. Spatial adaptation of eosinophils and their emerging roles in homeostasis, infection and disease. Nat Rev Immunol 2024; 24:858-877. [PMID: 38982311 DOI: 10.1038/s41577-024-01048-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2024] [Indexed: 07/11/2024]
Abstract
Eosinophils are bone marrow-derived granulocytes that are traditionally associated with type 2 immune responses, such as those that occur during parasite infections and allergy. Emerging evidence demonstrates the remarkable functional plasticity of this elusive cell type and its pleiotropic functions in diverse settings. Eosinophils broadly contribute to tissue homeostasis, host defence and immune regulation, predominantly at mucosal sites. The scope of their activities primarily reflects the breadth of their portfolio of secreted mediators, which range from cytotoxic cationic proteins and reactive oxygen species to multiple cytokines, chemokines and lipid mediators. Here, we comprehensively review basic eosinophil biology that is directly related to their activities in homeostasis, protective immunity, regeneration and cancer. We examine how dysregulation of these functions contributes to the physiopathology of a broad range of inflammatory diseases. Furthermore, we discuss recent findings regarding the tissue compartmentalization and adaptation of eosinophils, shedding light on the factors that likely drive their functional diversification within tissues.
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Affiliation(s)
- Isabelle C Arnold
- Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
| | - Ariel Munitz
- Department of Clinical Microbiology and Immunology, Faculty of Medical and Health Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
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Thibaut de Ménonville C, Barakat L, Laborier F, Le Brun M, Dupin C, Neukirch C, Taillé C. [Efficacy of biologics for severe asthma on allergic comorbidities]. Rev Mal Respir 2024; 41:669-679. [PMID: 39368873 DOI: 10.1016/j.rmr.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 08/30/2024] [Indexed: 10/07/2024]
Abstract
Identification of therapeutic targets other than asthma can guide the choice of biologics in cases of severe asthma. Some of the allergic diseases (atopic dermatitis, food allergies, allergic rhinoconjunctivitis) that may be associated with asthma can be treated with biologics. In this review, we aim to assess the effectiveness of these biologic therapies on the allergic comorbidities of asthma. In the treatment of atopic dermatitis, only Dupilumab, an anti-IL4Rα, has proven its effectiveness and has received reimbursement authorization for this indication. In patients presenting with allergic rhinoconjunctivitis, Omalizumab has shown effectiveness, but has not been approved for this indication. Data from post-hoc analyses of studies on severe asthma likewise suggest the effectiveness of Dupilumab regarding allergic rhinitis. While these two biologic therapies have shown positive signals, inducing oral food tolerance, the relevant data are not robust. Biologic therapies targeting IL-5 or its receptor (Mepolizumab, Benralizumab) have seldom been evaluated in allergic comorbidities, excepting atopic dermatitis, for which their effectiveness has not been proven. Lastly, there are interesting data on the combination of biologic therapy and allergen immunotherapy in cases of allergic rhinitis and food allergies, but they need to be confirmed by randomized studies.
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Affiliation(s)
- C Thibaut de Ménonville
- Service de pneumologie et centre de référence des maladies pulmonaires rares, AP-HP Nord, hôpital Bichat, 75018 Paris, France; Service de pneumo-allergologie, hôpital Paris Saint-Joseph, 185 rue Raymond-Losserand, 75674 Paris cedex 14, France.
| | - L Barakat
- Service de pneumologie et centre de référence des maladies pulmonaires rares, AP-HP Nord, hôpital Bichat, 75018 Paris, France
| | - F Laborier
- Service de pneumologie et centre de référence des maladies pulmonaires rares, AP-HP Nord, hôpital Bichat, 75018 Paris, France
| | - M Le Brun
- Service de pneumologie et centre de référence des maladies pulmonaires rares, AP-HP Nord, hôpital Bichat, 75018 Paris, France
| | - C Dupin
- Service de pneumologie et centre de référence des maladies pulmonaires rares, AP-HP Nord, hôpital Bichat, 75018 Paris, France; Inserm UMR1152, université Paris Cité, Paris, France
| | - C Neukirch
- Service de pneumologie et centre de référence des maladies pulmonaires rares, AP-HP Nord, hôpital Bichat, 75018 Paris, France; Inserm UMR1152, université Paris Cité, Paris, France
| | - C Taillé
- Service de pneumologie et centre de référence des maladies pulmonaires rares, AP-HP Nord, hôpital Bichat, 75018 Paris, France; Inserm UMR1152, université Paris Cité, Paris, France
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7
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Antosz K, Batko J, Błażejewska M, Gawor A, Sleziak J, Gomułka K. Insight into IL-5 as a Potential Target for the Treatment of Allergic Diseases. Biomedicines 2024; 12:1531. [PMID: 39062104 PMCID: PMC11275030 DOI: 10.3390/biomedicines12071531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/01/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
Interleukin-5 functions as a B-cell differentiation factor, but more importantly, in the context of this review, it plays a variety of roles in eosinophil biology, including eosinophil differentiation and maturation in the bone marrow, and facilitates eosinophil migration to tissue sites, usually in the context of an allergic reaction. Given the availability of selective anti-IL-5 drugs such as mepolizumab and reslizumab, as well as the IL-5 receptor antagonist benralizumab, it is worth investigating whether they could be used in some cases of allergic disease. Asthma has a well-documented involvement of IL-5 in its pathophysiology and has clear benefits in the case of anti-IL-5 therapy; therefore, current knowledge is presented to provide a reference point for the study of less-described diseases such as atopic dermatitis, chronic rhinosinusitis, chronic spontaneous urticaria, and its association with both IL-5 and anti-IL-5 treatment options. We then review the current literature on these diseases, explain where appropriate potential reasons why anti-IL-5 treatments are ineffective, and then point out possible future directions for further research.
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Affiliation(s)
- Katarzyna Antosz
- Student Research Group of Internal Medicine and Allergology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland; (K.A.); (J.B.); (M.B.); (A.G.); (J.S.)
| | - Joanna Batko
- Student Research Group of Internal Medicine and Allergology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland; (K.A.); (J.B.); (M.B.); (A.G.); (J.S.)
| | - Marta Błażejewska
- Student Research Group of Internal Medicine and Allergology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland; (K.A.); (J.B.); (M.B.); (A.G.); (J.S.)
| | - Antoni Gawor
- Student Research Group of Internal Medicine and Allergology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland; (K.A.); (J.B.); (M.B.); (A.G.); (J.S.)
| | - Jakub Sleziak
- Student Research Group of Internal Medicine and Allergology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland; (K.A.); (J.B.); (M.B.); (A.G.); (J.S.)
| | - Krzysztof Gomułka
- Department of Internal Medicine, Pneumology and Allergology, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland
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Park CO, Kim SM, Lee KH, Bieber T. Biomarkers for phenotype-endotype relationship in atopic dermatitis: a critical review. EBioMedicine 2024; 103:105121. [PMID: 38614010 PMCID: PMC11021839 DOI: 10.1016/j.ebiom.2024.105121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 03/27/2024] [Accepted: 04/02/2024] [Indexed: 04/15/2024] Open
Abstract
Atopic dermatitis (AD) is the most common form of chronic skin inflammation with diverse clinical variants. Historically, various AD phenotypes have been grouped together without considering their heterogeneity. This approach has resulted in a lack of phenotype- and endotype-adapted therapeutic strategies. Comprehensive insights into AD pathogenesis have enabled precise medicinal approach for AD. These efforts aimed to redefine the endophenotype of AD and develop various biomarkers for diverse purposes. Among these endeavours, efforts are underway to elucidate the mechanisms (and related biomarkers) that lead to the emergence and progression of atopic diseases originating from AD (e.g., atopic march). This review focuses on diverse AD phenotypes and calls for a definition of endophenotypes. While awaiting scientific validation, these biomarkers ensure predicting disease onset and trajectory and tailoring therapeutic strategies for the future.
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Affiliation(s)
- Chang Ook Park
- Department of Dermatology & Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
| | - Su Min Kim
- Department of Dermatology & Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Kwang Hoon Lee
- Department of Dermatology & Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Thomas Bieber
- Christine Kühne-Center of Allergy Research and Education, Medicine Campus, Davos, Switzerland
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Pareek A, Kumari L, Pareek A, Chaudhary S, Ratan Y, Janmeda P, Chuturgoon S, Chuturgoon A. Unraveling Atopic Dermatitis: Insights into Pathophysiology, Therapeutic Advances, and Future Perspectives. Cells 2024; 13:425. [PMID: 38474389 PMCID: PMC10931328 DOI: 10.3390/cells13050425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 02/24/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
Atopic dermatitis (AD) is an inflammatory skin condition that frequently develops before the onset of allergic rhinitis or asthma. More than 10% of children are affected by this serious skin condition, which is painful for the sufferers. Recent research has connected the environment, genetics, the skin barrier, drugs, psychological factors, and the immune system to the onset and severity of AD. The causes and consequences of AD and its cellular and molecular origins are reviewed in this paper. The exploration of interleukins and their influence on the immunological pathway in AD has been facilitated by using relevant biomarkers in clinical trials. This approach enables the identification of novel therapeutic modalities, fostering the potential for targeted translational research within the realm of personalized medicine. This review focuses on AD's pathophysiology and the ever-changing therapeutic landscape. Beyond the plethora of biologic medications in various stages of approval or development, a range of non-biologic targeted therapies, specifically small molecules, have emerged. These include Janus kinase (JAK) inhibitors like Baricitinib, Upadacitinib, and Abrocitinib, thus expanding the spectrum of therapeutic options. This review also addresses the latest clinical efficacy data and elucidates the scientific rationale behind each targeted treatment for atopic dermatitis.
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Affiliation(s)
- Ashutosh Pareek
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, India; (A.P.); (S.C.); (Y.R.)
| | - Lipika Kumari
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Banasthali 304022, India; (L.K.)
| | - Aaushi Pareek
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, India; (A.P.); (S.C.); (Y.R.)
| | - Simran Chaudhary
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, India; (A.P.); (S.C.); (Y.R.)
| | - Yashumati Ratan
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, India; (A.P.); (S.C.); (Y.R.)
| | - Pracheta Janmeda
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Banasthali 304022, India; (L.K.)
| | - Sanam Chuturgoon
- Northdale Hospital, Department of Health, Pietermaritzburg 3200, South Africa
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4041, South Africa
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10
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Tamari M, Del Bel KL, Ver Heul AM, Zamidar L, Orimo K, Hoshi M, Trier AM, Yano H, Yang TL, Biggs CM, Motomura K, Shibuya R, Yu CD, Xie Z, Iriki H, Wang Z, Auyeung K, Damle G, Demircioglu D, Gregory JK, Hasson D, Dai J, Chang RB, Morita H, Matsumoto K, Jain S, Van Dyken S, Milner JD, Bogunovic D, Hu H, Artis D, Turvey SE, Kim BS. Sensory neurons promote immune homeostasis in the lung. Cell 2024; 187:44-61.e17. [PMID: 38134932 PMCID: PMC10811756 DOI: 10.1016/j.cell.2023.11.027] [Citation(s) in RCA: 38] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 07/13/2023] [Accepted: 11/24/2023] [Indexed: 12/24/2023]
Abstract
Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.
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Affiliation(s)
- Masato Tamari
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Jikei University School of Medicine, Minato-ku, Tokyo 1058471, Japan; Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo 1578535, Japan
| | - Kate L Del Bel
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada
| | - Aaron M Ver Heul
- Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Lydia Zamidar
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Keisuke Orimo
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo 1578535, Japan
| | - Masato Hoshi
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Anna M Trier
- Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Hiroshi Yano
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Ting-Lin Yang
- Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Catherine M Biggs
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada
| | - Kenichiro Motomura
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo 1578535, Japan
| | - Rintaro Shibuya
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Chuyue D Yu
- Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Zili Xie
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Hisato Iriki
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Zhen Wang
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Kelsey Auyeung
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Gargi Damle
- Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Skin Biology and Disease Resource-based Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Deniz Demircioglu
- Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Skin Biology and Disease Resource-based Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jill K Gregory
- Digital and Technology Partners, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Dan Hasson
- Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Skin Biology and Disease Resource-based Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jinye Dai
- Department of Pharmacological Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Rui B Chang
- Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA; Allen Discovery Center for Neuroimmune Interactions, New York, NY 10029, USA
| | - Hideaki Morita
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo 1578535, Japan; Allergy Center, National Center for Child Health and Development, Setagaya-ku, Tokyo 1578535, Japan
| | - Kenji Matsumoto
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo 1578535, Japan
| | - Sanjay Jain
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Steven Van Dyken
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Joshua D Milner
- Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Dusan Bogunovic
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Hongzhen Hu
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - David Artis
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Allen Discovery Center for Neuroimmune Interactions, New York, NY 10029, USA; Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Stuart E Turvey
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada
| | - Brian S Kim
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Allen Discovery Center for Neuroimmune Interactions, New York, NY 10029, USA.
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11
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Iwadate Y, Arinuma Y, Matsueda Y, Tanaka T, Wada T, Tanaka S, Oku K, Yamaoka K. A case of dupilumab combination therapy for exacerbation of atopic dermatitis in a patient with eosinophilic granulomatosis with polyangiitis treated with mepolizumab. Mod Rheumatol Case Rep 2023; 8:159-162. [PMID: 37804249 DOI: 10.1093/mrcr/rxad059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 09/20/2023] [Accepted: 09/28/2023] [Indexed: 10/09/2023]
Abstract
We report a 60-year-old male with eosinophilic granulomatosis with polyangiitis (EGPA) complicated with atopic dermatitis (AD). The patient was initially treated with prednisolone, cyclosporine A, and mepolizumab (MEPO). Due to worsening skin symptoms after prednisolone tapering, dupilumab (DUP) was added as an adjunctive therapy for AD confirmed by skin biopsy. The combination therapy of MEPO and DUP resulted in rapid improvement of skin symptoms, suggesting it may be an effective therapeutic option for patients with EGPA and AD. This case report emphasises the importance of a multidisciplinary approach in treating complex diseases such as EGPA and AD.
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Affiliation(s)
- Yosuke Iwadate
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
| | - Yoshiyuki Arinuma
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
| | - Yu Matsueda
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
| | - Tomoki Tanaka
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
| | - Tatuhiko Wada
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
| | - Sumiaki Tanaka
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
| | - Kenji Oku
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
| | - Kunihiro Yamaoka
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
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12
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Chu AWL, Wong MM, Rayner DG, Guyatt GH, Díaz Martinez JP, Ceccacci R, Zhao IX, McMullen E, Srivastava A, Wang J, Wen A, Wang FC, Brignardello-Petersen R, Izcovich A, Oykhman P, Wheeler KE, Wang J, Spergel JM, Singh JA, Silverberg JI, Ong PY, O'Brien M, Martin SA, Lio PA, Lind ML, LeBovidge J, Kim E, Huynh J, Greenhawt M, Gardner DD, Frazier WT, Ellison K, Chen L, Capozza K, De Benedetto A, Boguniewicz M, Smith Begolka W, Asiniwasis RN, Schneider LC, Chu DK. Systemic treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials. J Allergy Clin Immunol 2023; 152:1470-1492. [PMID: 37678577 DOI: 10.1016/j.jaci.2023.08.029] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/06/2023] [Accepted: 08/15/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. OBJECTIVE We sought to systematically synthesize the benefits and harms of AD systemic treatments. METHODS For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna). RESULTS The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain. CONCLUSIONS Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.
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Key Words
- Atopic dermatitis (eczema)
- Janus kinase (JAK) inhibitors (upadacitinib, abrocitinib, baricitinib), patient-important outcomes and adverse events or adverse reactions, disease severity, itch, sleep, itch and sleep disturbance quality of life
- network meta-analysis (comparative effectiveness, multiple treatment comparison)
- systemic treatments and phototherapy (light therapy, immunosuppressants, immunomodulators, DMARDs, cyclosporine, methotrexate, azathioprine, mycophenolate, cortiosteroids, narrow-band UVB), biologics (dupilumab, lebrikizumab, tralokinumab, nemolizumab)
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Affiliation(s)
- Alexandro W L Chu
- Department of Medicine, McMaster University, Hamilton, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Canada
| | - Melanie M Wong
- Department of Medicine, McMaster University, Hamilton, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Canada
| | - Daniel G Rayner
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Gordon H Guyatt
- Department of Medicine, McMaster University, Hamilton, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Juan Pablo Díaz Martinez
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Renata Ceccacci
- Department of Medicine, McMaster University, Hamilton, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Canada
| | - Irene X Zhao
- Department of Medicine, McMaster University, Hamilton, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Canada
| | - Eric McMullen
- Department of Medicine, McMaster University, Hamilton, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Canada
| | - Archita Srivastava
- Evidence in Allergy Group, McMaster University, Hamilton, Canada; Department of Internal Medicine, Western University, London, Canada
| | - Jason Wang
- Department of Medicine, McMaster University, Hamilton, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Canada
| | - Aaron Wen
- Department of Medicine, McMaster University, Hamilton, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Canada
| | - Fang Chi Wang
- Evidence in Allergy Group, McMaster University, Hamilton, Canada; Schulich School of Medicine & Dentistry, Western University, London, Canada
| | | | - Ariel Izcovich
- Servicio de Clínica Médica, Hospital Aleman, Buenos Aires, Argentina
| | - Paul Oykhman
- Department of Medicine, McMaster University, Hamilton, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Canada
| | | | - Julie Wang
- Division of Pediatric Allergy and Immunology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jonathan M Spergel
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa
| | - Jasvinder A Singh
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Ala
| | - Jonathan I Silverberg
- Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Peck Y Ong
- Division of Clinical Immunology and Allergy, Children's Hospital Los Angeles, Los Angeles, Calif; Department of Pediatrics, Keck School of Medicine of USC, Los Angeles, Calif
| | | | | | - Peter A Lio
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Mary Laura Lind
- School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, Ariz
| | - Jennifer LeBovidge
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Harvard Medical School, Boston, Mass
| | | | - Joey Huynh
- Sepulveda VA Medical Center, North Hills, Calif
| | - Matthew Greenhawt
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colo; Section of Allergy and Immunology, Children's Hospital Colorado, Aurora, Colo
| | | | | | | | - Lina Chen
- Evidence in Allergy Group, McMaster University, Hamilton, Canada; Department of Pediatrics, McMaster University, Hamilton, Canada
| | - Korey Capozza
- Global Parents for Eczema Research, Santa Barbara, Calif
| | - Anna De Benedetto
- Department of Dermatology, University of Rochester Medical Center, Rochester, NY
| | - Mark Boguniewicz
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colo; Division of Pediatric Allergy and Clinical Immunology, National Jewish Health, Denver, Colo
| | | | - Rachel N Asiniwasis
- Department of Dermatology, University of Saskatchewan, Regina, Saskatchewan, Canada
| | | | - Derek K Chu
- Department of Medicine, McMaster University, Hamilton, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada; The Research Institute of St. Joe's Hamilton, Hamilton, Canada.
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13
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Zhou G, Huang Y, Chu M. Clinical trials of antibody drugs in the treatments of atopic dermatitis. Front Med (Lausanne) 2023; 10:1229539. [PMID: 37727760 PMCID: PMC10506412 DOI: 10.3389/fmed.2023.1229539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/21/2023] [Indexed: 09/21/2023] Open
Abstract
Atopic dermatitis (AD) is one of the most common, relapsing, chronic inflammatory skin disease, being regarded as a global health issue. Recent studies have shown that Th2 cell-mediated type 2 immunity plays a central role in AD. The type 2 inflammatory cytokines such as IL-4, IL-13, IL-22, IL-31, IL-17 and IL-5 mediate the pathogenesis of AD. A variety of antibody drugs targeting these cytokines have been developed to treat AD in clinics. Notably, several antibody drugs have exhibited high efficacy in treating atopic dermatitis in previous studies, demonstrating that they could be therapeutic methods for AD patients. Herein, we reviewed the clinical trials of antibody drugs in the treatment of AD, which provides a useful guideline for clinicians to treat patients with AD in clinics.
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Affiliation(s)
| | | | - Ming Chu
- Department of Immunology, School of Basic Medical Sciences, National Health Commission (NHC) Key Laboratory of Medical Immunology, Peking University, Beijing, China
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14
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O'Sullivan JA, Youngblood BA, Schleimer RP, Bochner BS. Siglecs as potential targets of therapy in human mast cell- and/or eosinophil-associated diseases. Semin Immunol 2023; 69:101799. [PMID: 37413923 PMCID: PMC10528103 DOI: 10.1016/j.smim.2023.101799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/08/2023]
Abstract
Siglecs (sialic acid-binding immunoglobulin-like lectins) are a family of vertebrate glycan-binding cell-surface proteins. The majority mediate cellular inhibitory activity once engaged by specific ligands or ligand-mimicking molecules. As a result, Siglec engagement is now of interest as a strategy to therapeutically dampen unwanted cellular responses. When considering allergic inflammation, human eosinophils and mast cells express overlapping but distinct patterns of Siglecs. For example, Siglec-6 is selectively and prominently expressed on mast cells while Siglec-8 is highly specific for both eosinophils and mast cells. This review will focus on a subset of Siglecs and their various endogenous or synthetic sialoside ligands that regulate eosinophil and mast cell function and survival. It will also summarize how certain Siglecs have become the focus of novel therapies for allergic and other eosinophil- and mast cell-related diseases.
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Affiliation(s)
- Jeremy A O'Sullivan
- Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | - Robert P Schleimer
- Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Bruce S Bochner
- Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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15
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Caffarelli C, Giannetti A, Giannì G, Ricci G. Anti-inflammatory and biologic drugs for atopic dermatitis: a therapeutic approach in children and adolescents. Front Med (Lausanne) 2023; 10:1214963. [PMID: 37654660 PMCID: PMC10466416 DOI: 10.3389/fmed.2023.1214963] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 07/27/2023] [Indexed: 09/02/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory disease with a heterogeneous pathogenesis correlated with dysregulation of the immune system and a prevalence of the T2-mediated immune pathway. Recent understanding of the pathogenesis of AD has allowed the development of new drugs targeting different mechanisms and cytokines that have changed the treatment approach. The aim of this review is to update knowledge on the standard of care and recent advancements in the control of skin inflammation. In light of recent guidelines, we report on the clinical efficacy of novel treatments, with special attention to situations where biologics and small molecules are involved.
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Affiliation(s)
- Carlo Caffarelli
- Clinica Pediatrica, Azienda Ospedaliero-Universitaria, Department of Medicine and Surgery, Università di Parma, Parma, Italy
| | - Arianna Giannetti
- Paediatrics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giuliana Giannì
- Clinica Pediatrica, Azienda Ospedaliero-Universitaria, Department of Medicine and Surgery, Università di Parma, Parma, Italy
| | - Giampaolo Ricci
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
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16
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Gatmaitan JG, Lee JH. Challenges and Future Trends in Atopic Dermatitis. Int J Mol Sci 2023; 24:11380. [PMID: 37511138 PMCID: PMC10380015 DOI: 10.3390/ijms241411380] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/06/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Atopic dermatitis represents a complex and multidimensional interaction that represents potential fields of preventive and therapeutic management. In addition to the treatment armamentarium available for atopic dermatitis, novel drugs targeting significant molecular pathways in atopic dermatitis biologics and small molecules are also being developed given the condition's complex pathophysiology. While most of the patients are expecting better efficacy and long-term control, the response to these drugs would still depend on numerous factors such as complex genotype, diverse environmental triggers and microbiome-derived signals, and, most importantly, dynamic immune responses. This review article highlights the challenges and the recently developed pharmacological agents in atopic dermatitis based on the molecular pathogenesis of this condition, creating a specific therapeutic approach toward a more personalized medicine.
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Affiliation(s)
- Julius Garcia Gatmaitan
- Department of Dermatology, Seoul St. Mary's Hospital, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
- Gatmaitan Medical and Skin Center, Baliuag 3006, Bulacan, Philippines
- Skines Aesthetic and Laser Center, Quezon City 1104, Metro Manila, Philippines
| | - Ji Hyun Lee
- Department of Dermatology, Seoul St. Mary's Hospital, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
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17
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Facheris P, Jeffery J, Del Duca E, Guttman-Yassky E. The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment. Cell Mol Immunol 2023; 20:448-474. [PMID: 36928371 PMCID: PMC10203371 DOI: 10.1038/s41423-023-00992-4] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/21/2023] [Indexed: 03/18/2023] Open
Abstract
Atopic dermatitis (AD) is the most common inflammatory skin disease, and it is considered a complex and heterogeneous condition. Different phenotypes of AD, defined according to the patient age at onset, race, and ethnic background; disease duration; and other disease characteristics, have been recently described, underlying the need for a personalized treatment approach. Recent advancements in understanding AD pathogenesis resulted in a real translational revolution and led to the exponential expansion of the therapeutic pipeline. The study of biomarkers in clinical studies of emerging treatments is helping clarify the role of each cytokine and immune pathway in AD and will allow addressing the unique immune fingerprints of each AD subset. Personalized medicine will be the ultimate goal of this targeted translational research. In this review, we discuss the changes in the concepts of both the pathogenesis of and treatment approach to AD, highlight the scientific rationale behind each targeted treatment and report the most recent clinical efficacy data.
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Affiliation(s)
- Paola Facheris
- Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Humanitas Clinical and Research Center, Department of Dermatology, Rozzano, Milano, Italy
| | - Jane Jeffery
- Duke University School of Medicine, Durham, NC, USA
| | - Ester Del Duca
- Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Emma Guttman-Yassky
- Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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18
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Targeting cytokines and signaling molecules related to immune pathways in atopic dermatitis: therapeutic implications and challenges. Arch Pharm Res 2022; 45:894-908. [DOI: 10.1007/s12272-022-01421-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022]
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Haddad EB, Cyr SL, Arima K, McDonald RA, Levit NA, Nestle FO. Current and Emerging Strategies to Inhibit Type 2 Inflammation in Atopic Dermatitis. Dermatol Ther (Heidelb) 2022; 12:1501-1533. [PMID: 35596901 PMCID: PMC9276864 DOI: 10.1007/s13555-022-00737-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Indexed: 12/30/2022] Open
Abstract
Type 2 immunity evolved to combat helminth infections by orchestrating a combined protective response of innate and adaptive immune cells and promotion of parasitic worm destruction or expulsion, wound repair, and barrier function. Aberrant type 2 immune responses are associated with allergic conditions characterized by chronic tissue inflammation, including atopic dermatitis (AD) and asthma. Signature cytokines of type 2 immunity include interleukin (IL)-4, IL-5, IL-9, IL-13, and IL-31, mainly secreted from immune cells, as well as IL-25, IL-33, and thymic stromal lymphopoietin, mainly secreted from tissue cells, particularly epithelial cells. IL-4 and IL-13 are key players mediating the prototypical type 2 response; IL-4 initiates and promotes differentiation and proliferation of naïve T-helper (Th) cells toward a Th2 cell phenotype, whereas IL-13 has a pleiotropic effect on type 2 inflammation, including, together with IL-4, decreased barrier function. Both cytokines are implicated in B-cell isotype class switching to generate immunoglobulin E, tissue fibrosis, and pruritus. IL-5, a key regulator of eosinophils, is responsible for eosinophil growth, differentiation, survival, and mobilization. In AD, IL-4, IL-13, and IL-31 are associated with sensory nerve sensitization and itch, leading to scratching that further exacerbates inflammation and barrier dysfunction. Various strategies have emerged to suppress type 2 inflammation, including biologics targeting cytokines or their receptors, and Janus kinase inhibitors that block intracellular cytokine signaling pathways. Here we review type 2 inflammation, its role in inflammatory diseases, and current and future therapies targeting type 2 pathways, with a focus on AD. INFOGRAPHIC.
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Affiliation(s)
| | - Sonya L Cyr
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
| | | | | | - Noah A Levit
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
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Pavord ID, Bel EH, Bourdin A, Chan R, Han JK, Keene ON, Liu MC, Martin N, Papi A, Roufosse F, Steinfeld J, Wechsler ME, Yancey SW. From DREAM to REALITI-A and beyond: Mepolizumab for the treatment of eosinophil-driven diseases. Allergy 2022; 77:778-797. [PMID: 34402066 PMCID: PMC9293125 DOI: 10.1111/all.15056] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/13/2021] [Indexed: 12/11/2022]
Abstract
Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil‐reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin‐5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add‐on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real‐world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI‐A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases.
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Affiliation(s)
- Ian D. Pavord
- Nuffield Department of Medicine and Oxford Respiratory NIHR BRC University of Oxford Oxford UK
| | - Elisabeth H. Bel
- Department of Respiratory Medicine Amsterdam UMC University of Amsterdam Amsterdam The Netherlands
| | - Arnaud Bourdin
- INSERM 12 F‐CRIN Clinical Research Initiative In Severe Asthma: a Lever for Innovation & Science (CRISALIS) France
- Service de Pneumologie and INSERM CNRS CHU Montpellier Université de Montpellier Montpellier France
| | | | - Joseph K. Han
- Department of Otolaryngology, Head & Neck Surgery Eastern Virginia Medical School Norfolk Virginia USA
| | | | - Mark C. Liu
- Divisions of Allergy and Clinical Immunology, Pulmonary and Critical Care Medicine Johns Hopkins Asthma and Allergy Center Baltimore MD USA
| | - Neil Martin
- Global Medical Affairs GSK Brentford UK
- Institute for Lung Health University of Leicester Leicester UK
| | - Alberto Papi
- Research Center on Asthma and COPD University of Ferrara Ferrara Italy
| | - Florence Roufosse
- Department of Internal Medicine Hôpital Erasme Université Libre de Bruxelles Brussels Belgium
| | | | - Michael E. Wechsler
- Department of Medicine National Jewish Health Cohen Family Asthma Institute Denver CO USA
| | - Steven W. Yancey
- Respiratory Therapeutic Area Unit GSK Research Triangle Park NC USA
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21
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Fölster-Holst R, Torrelo A, Das K, Murrell DF, Patil A, Rahmat Pour Rokni G, Grabbe S, Staubach P, Sohn A, Goldust M. Biological medication in atopic dermatitis. Expert Opin Biol Ther 2022; 22:643-649. [PMID: 34991429 DOI: 10.1080/14712598.2022.2026920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Atopic dermatitis (AD) is a chronic inflammatory skin disorder associated with intense itch/pruritus and skin lesions. Several modalities of treatment including topical therapy, systemic agents, and biologics are available for the treatment of disease. Despite this, management poses challenge due to chronic nature and recurrent episodes in many patients. Biologics represent an important option of treatment for patients who do not respond to the traditional treatment. AREAS COVERED In this article, we focused on efficacy and safety of biologics in the treatment of atopic dermatitis. Other therapies are out of the scope of this review. Articles from PubMed and Google scholar and cross references of retrieved articles were used to write the narrative review. EXPERT OPINION Biologics play an important role in the treatment of atopic dermatitis. Every biologic has its own place in the treatment considering pharmacological profile, efficacy, and safety. Several biologics have been studied in the treatment of moderate-to-severe cases who failed to provide adequate response to traditional treatment. Dupilumab, is approved for the treatment of moderate-to-severe atopic dermatitis. Tralokinumab and nemolizumab have shown promising results in patients with atopic dermatitis.
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Affiliation(s)
- Regina Fölster-Holst
- Department of Dermatology, University Hospital Schleswig-Holstein, Dermatology, Campus Kiel, Kiel, Germany
| | - Antonio Torrelo
- Department of Dermatology, University Children's Hospital Niño Jesús, Madrid, Spain
| | - Kinnor Das
- Department of Dermatology Venereology and Leprosy, Silchar Medical College, Silchar, India
| | - Dedee F Murrell
- Department of Dermatology, St George Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Anant Patil
- Department of Pharmacology, Dr. Dy Patil Medical College, Navi Mumbai, India
| | | | - Stephan Grabbe
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Petra Staubach
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Anna Sohn
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Mohamad Goldust
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
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22
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Wu Y, Wang GJ, He HQ, Qin HH, Shen WT, Yu Y, Zhang X, Zhou ML, Fei JB. Low-dose intralesional injection of 5-fluorouracil and triamcinolone reduces tissue resident memory T cells in chronic eczema. World J Clin Cases 2022; 10:166-176. [PMID: 35071516 PMCID: PMC8727240 DOI: 10.12998/wjcc.v10.i1.166] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 10/29/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Tissue resident memory T (TRM) cells have been reported to play a significant role in the pathogenesis and relapse of chronic eczema.
AIM To compare the efficacy and safety of the intralesional injection of 5-fluorouracil (5-FU) and triamcinolone (TA) with those associated with TA alone for the treatment of chronic eczema.
METHODS A total of 168 patients were randomized to 5-FU+TA or TA groups and received a one-time intralesional injection of 5-FU+TA or TA only. Biopsies were collected before and 2 wk after treatment for evaluation of histopathological changes. All patients were followed up monthly for up to 1 year.
RESULTS No serious adverse event was observed in either group. Although the mean atopic dermatitis severity index scores and effective rates were comparable between the two groups after 2 wk of treatment, the relapse rate was significantly lower in the 5-FU+TA group than in the TA group. Histological examination showed significantly fewer CD8+ and CD103+ T cells but not CD4+ T cells in the 5-FU+TA group.
CONCLUSION One-time intralesional injection of 5-FU+TA is effective and safe for chronic eczema treatment and can further reduce the retention of TRM cells in the lesional skin and the relapse rate of chronic eczema.
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Affiliation(s)
- Yun Wu
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Guo-Jiang Wang
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Hui-Qiong He
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Hai-Hong Qin
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Wen-Tong Shen
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Yue Yu
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Xun Zhang
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Mao-Lin Zhou
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Jian-Biao Fei
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
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Kołkowski K, Trzeciak M, Sokołowska-Wojdyło M. Safety and Danger Considerations of Novel Treatments for Atopic Dermatitis in Context of Primary Cutaneous Lymphomas. Int J Mol Sci 2021; 22:13388. [PMID: 34948183 PMCID: PMC8703592 DOI: 10.3390/ijms222413388] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/05/2021] [Accepted: 12/06/2021] [Indexed: 12/24/2022] Open
Abstract
The impact of new and emerging therapies on the microenvironment of primary cutaneous lymphomas (PCLs) has been recently raised in the literature. Concomitantly, novel treatments are already used or registered (dupilumab, upadacitinib) and others seem to be added to the armamentarium against atopic dermatitis. Our aim was to review the literature on interleukins 4, 13, 22, and 31, and JAK/STAT pathways in PCLs to elucidate the safety of using biologics (dupilumab, tralokinumab, fezakinumab, nemolizumab) and small molecule inhibitors (upadacitinib, baricitinib, abrocitinib, ruxolitinib, tofacitinib) in the treatment of atopic dermatitis. We summarized the current state of knowledge on this topic based on the search of the PubMed database and related references published before 21 October 2021. Our analysis suggests that some of the mentioned agents (dupilumab, ruxolitinib) and others may have a direct impact on the progression of cutaneous lymphomas. This issue requires further study and meticulous monitoring of patients receiving these drugs to ensure their safety, especially in light of the FDA warning on tofacitinib. In conclusion, in the case of the rapid progression of atopic dermatitis/eczema, especially in patients older than 40 years old, there is a necessity to perform a biopsy followed by a very careful pathological examination.
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Affiliation(s)
- Karol Kołkowski
- Dermatological Students Scientific Association, Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, 80-214 Gdansk, Poland
| | - Magdalena Trzeciak
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, 80-214 Gdansk, Poland; (M.T.); (M.S.-W.)
| | - Małgorzata Sokołowska-Wojdyło
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, 80-214 Gdansk, Poland; (M.T.); (M.S.-W.)
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McCormick JP, Lee JT. Insights into the Implications of Coexisting Type 2 Inflammatory Diseases. J Inflamm Res 2021; 14:4259-4266. [PMID: 34511966 PMCID: PMC8416183 DOI: 10.2147/jir.s311640] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/13/2021] [Indexed: 11/23/2022] Open
Abstract
The role of type 2 inflammation in the pathogenesis of certain human diseases is an area of active investigation. Certain asthma, atopic dermatitis, eosinophilic esophagitis, and chronic rhinosinusitis phenotypes are characterized by a Th2 predominant inflammatory pathway and are frequently associated with comorbid conditions in patients. The purpose of this article is to review the evidence behind concurrent Th2-mediated diseases and explore how the presence of these comorbid conditions affect patient and disease outcomes.
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Affiliation(s)
- Justin P McCormick
- Department of Head and Neck Surgery, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA
| | - Jivianne T Lee
- Department of Head and Neck Surgery, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA
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25
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Rodrigo-Muñoz JM, Gil-Martínez M, Sastre B, del Pozo V. Emerging Evidence for Pleiotropism of Eosinophils. Int J Mol Sci 2021; 22:ijms22137075. [PMID: 34209213 PMCID: PMC8269185 DOI: 10.3390/ijms22137075] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/25/2021] [Accepted: 06/27/2021] [Indexed: 02/08/2023] Open
Abstract
Eosinophils are complex granulocytes with the capacity to react upon diverse stimuli due to their numerous and variable surface receptors, which allows them to respond in very different manners. Traditionally believed to be only part of parasitic and allergic/asthmatic immune responses, as scientific studies arise, the paradigm about these cells is continuously changing, adding layers of complexity to their roles in homeostasis and disease. Developing principally in the bone marrow by the action of IL-5 and granulocyte macrophage colony-stimulating factor GM-CSF, eosinophils migrate from the blood to very different organs, performing multiple functions in tissue homeostasis as in the gastrointestinal tract, thymus, uterus, mammary glands, liver, and skeletal muscle. In organs such as the lungs and gastrointestinal tract, eosinophils are able to act as immune regulatory cells and also to perform direct actions against parasites, and bacteria, where novel mechanisms of immune defense as extracellular DNA traps are key factors. Besides, eosinophils, are of importance in an effective response against viral pathogens by their nuclease enzymatic activity and have been lately described as involved in severe acute respiratory syndrome coronavirus SARS-CoV-2 immunity. The pleiotropic role of eosinophils is sustained because eosinophils can be also detrimental to human physiology, for example, in diseases like allergies, asthma, and eosinophilic esophagitis, where exosomes can be significant pathophysiologic units. These eosinophilic pathologies, require specific treatments by eosinophils control, such as new monoclonal antibodies like mepolizumab, reslizumab, and benralizumab. In this review, we describe the roles of eosinophils as effectors and regulatory cells and their involvement in pathological disorders and treatment.
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Affiliation(s)
- José M. Rodrigo-Muñoz
- Immunoallergy Laboratory, Immunology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Avenida Reyes Católicos, 28040 Madrid, Spain; (J.M.R.-M.); (M.G.-M.)
- CIBER de Enfermedades Respiratorias (CIBERES), Av. de Monforte de Lemos, 28029 Madrid, Spain
| | - Marta Gil-Martínez
- Immunoallergy Laboratory, Immunology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Avenida Reyes Católicos, 28040 Madrid, Spain; (J.M.R.-M.); (M.G.-M.)
| | - Beatriz Sastre
- Immunoallergy Laboratory, Immunology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Avenida Reyes Católicos, 28040 Madrid, Spain; (J.M.R.-M.); (M.G.-M.)
- CIBER de Enfermedades Respiratorias (CIBERES), Av. de Monforte de Lemos, 28029 Madrid, Spain
- Correspondence: (B.S.); (V.d.P.)
| | - Victoria del Pozo
- Immunoallergy Laboratory, Immunology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Avenida Reyes Católicos, 28040 Madrid, Spain; (J.M.R.-M.); (M.G.-M.)
- CIBER de Enfermedades Respiratorias (CIBERES), Av. de Monforte de Lemos, 28029 Madrid, Spain
- Medicine Department, Universidad Autónoma de Madrid, 28029 Madrid, Spain
- Correspondence: (B.S.); (V.d.P.)
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26
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Radonjic-Hoesli S, Brüggen MC, Feldmeyer L, Simon HU, Simon D. Eosinophils in skin diseases. Semin Immunopathol 2021; 43:393-409. [PMID: 34097126 PMCID: PMC8241748 DOI: 10.1007/s00281-021-00868-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/06/2021] [Indexed: 02/06/2023]
Abstract
Eosinophil infiltration is a common finding in a broad spectrum of skin diseases, despite the fact that the skin is devoid of eosinophils under physiologic conditions. Although cutaneous eosinophilia is reactive, cytokine-mediated in most cases, diseases with an intrinsic mutation-mediated clonal expansion of eosinophils can also manifest on the skin. As eosinophils are involved in host defense, regulate immune responses, generate pruritus, induce remodeling and fibrosis, and can cause tissue damage, they have the capacity to actively contribute to the pathogenesis of diseases. Recent research provided deeper insights in the mechanisms, e.g., bacterial and viral clearance, blister formation, recruitment of cytotoxic T cells, and generation of pruritus, by which eosinophils might come into action. This review aims at providing an overview on the clinical presentations of eosinophil-associated dermatoses and the current understanding of their pathogenic role in these diseases. Further, we discuss the effects of therapies targeting eosinophils.
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Affiliation(s)
- Susanne Radonjic-Hoesli
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marie-Charlotte Brüggen
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
- Department of Dermatology, Hochgebirgsklinik Davos, Davos, Switzerland
| | - Laurence Feldmeyer
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
- Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia
- Laboratory of Molecular Immunology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Dagmar Simon
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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27
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Renz H, Bachert C, Berek C, Hamelmann E, Levi‐Schaffer F, Raap U, Simon H, Ploetz S, Taube C, Valent P, Voehringer D, Werfel T, Zhang N, Ring J. Physiology and pathology of eosinophils: Recent developments: Summary of the Focus Workshop Organized by DGAKI. Scand J Immunol 2021; 93:e13032. [PMID: 33624312 PMCID: PMC11475402 DOI: 10.1111/sji.13032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 02/10/2021] [Accepted: 02/21/2021] [Indexed: 12/15/2022]
Abstract
Over the last century, eosinophils have been regarded ambiguously either as 'friends' or 'foes'. Recent developments have greatly enhanced our understanding of the role and function of eosinophils in health and disease. Pathogenic eosinophilic inflammation can lead to severe diseases in various organs, such as the gastrointestinal tract, airways, heart and skin. In a 2-day focus workshop of the German Society for Allergology and Clinical Immunology (DGAKI), the state of the art was discussed and practical recommendations for diagnosis and treatment of eosinophilic diseases, with a particular focus on new biologics, such as anti-interleukin 5 and anti-interleukin 5R, were derived.
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Affiliation(s)
- Harald Renz
- Institute of Laboratory MedicineUniversities of Giessen and Marburg Lung Center (UGMLC)German Center for Lung Research (DZL)Philipps Universität MarburgMarburgGermany
| | - Claus Bachert
- Upper Airways Research Laboratory and Department of Oto‐Rhino‐LaryngologyGhent University and Ghent University HospitalGhentBelgium
- Division of ENT DiseasesCLINTECKarolinska InstituteUniversity of StockholmStockholmSweden
| | - Claudia Berek
- Deutsches Rheuma ForschungszentrumEin Institut der LeibnizgemeinschaftBerlinGermany
| | - Eckard Hamelmann
- Klinik für Kinder‐ und JugendmedizinEvangelisches Klinikum BethelBielefeldGermany
- Allergy Center of the Ruhr UniversityBochumGermany
| | - Francesca Levi‐Schaffer
- School of PharmacyFaculty of MedicineThe Institute for Drug ResearchThe Hebrew University of JerusalemIsrael
| | - Ulrike Raap
- Clinics of Dermatology and AllergyFaculty of Medical Health and SciencesUniversity of OldenburgGermany
| | - Hans‐Uwe Simon
- Institute of PharmacologyUniversity of BernBernSwitzerland
| | | | - Christian Taube
- Department of Pulmonary MedicineUniversity Hospital Essen—RuhrlandklinikEssenGermany
| | - Peter Valent
- Department of Internal Medicine IDivision of Hematology and Hemostaseology, and Ludwig Boltzmann Institute for Hematology & OncologyMedical University of ViennaViennaAustria
| | - David Voehringer
- Department of Infection BiologyUniversity Hospital Erlangen and Friedrich‐Alexander University Erlangen‐NurembergErlangenGermany
| | - Thomas Werfel
- Klinik für DermatologieAllergologie und VenerologieMedizinische Hochschule HannoverHannoverGermany
| | - Nan Zhang
- Upper Airways Research Laboratory and Department of Oto‐Rhino‐LaryngologyGhent University and Ghent University HospitalGhentBelgium
| | - Johannes Ring
- Deptment of Dermatology and Allergology BiedersteinTechnical University Munich (TUM)MunichGermany
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28
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Qi HJ, Li LF. New Biologics for the Treatment of Atopic Dermatitis: Analysis of Efficacy, Safety, and Paradoxical Atopic Dermatitis Acceleration. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5528372. [PMID: 34195265 PMCID: PMC8181104 DOI: 10.1155/2021/5528372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 05/21/2021] [Indexed: 01/18/2023]
Abstract
Atopic dermatitis (AD) is a chronic, inflammatory skin disease with an eczematous rash and itching. Due to undesired adverse effects of traditional systemic treatment, there is still an unmet need for safe and effective long-term therapy for refractory AD. As our understanding of the pathogenesis underlying AD grows, novel treatments targeting specific molecules have been developed. Here, we discuss the efficacy and safety profiles of these drugs in recent clinical trials. Among their adverse effects, of particular note is AD acceleration. Although there is still debate about whether certain adverse reactions can be said to be paradoxical adverse events (PAEs), a wide range of PAEs have been reported during biological treatment for chronic immune-mediated diseases. Close surveillance of novel biologics is crucial to detect new undescribed paradoxical reactions and to shed light on the convoluted pathogenesis of AD.
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Affiliation(s)
- Hong-jiao Qi
- Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lin-Feng Li
- Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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29
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Catherine J, Roufosse F. What does elevated TARC/CCL17 expression tell us about eosinophilic disorders? Semin Immunopathol 2021; 43:439-458. [PMID: 34009399 PMCID: PMC8132044 DOI: 10.1007/s00281-021-00857-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/14/2021] [Indexed: 12/19/2022]
Abstract
Eosinophilic disorders encompass a large spectrum of heterogeneous diseases sharing the presence of elevated numbers of eosinophils in blood and/or tissues. Among these disorders, the role of eosinophils can vary widely, ranging from a modest participation in the disease process to the predominant perpetrator of tissue damage. In many cases, eosinophilic expansion is polyclonal, driven by enhanced production of interleukin-5, mainly by type 2 helper cells (Th2 cells) with a possible contribution of type 2 innate lymphoid cells (ILC2s). Among the key steps implicated in the establishment of type 2 immune responses, leukocyte recruitment toward inflamed tissues is particularly relevant. Herein, the contribution of the chemo-attractant molecule thymus and activation-regulated chemokine (TARC/CCL17) to type 2 immunity will be reviewed. The clinical relevance of this chemokine and its target, C-C chemokine receptor 4 (CCR4), will be illustrated in the setting of various eosinophilic disorders. Special emphasis will be put on the potential diagnostic, prognostic, and therapeutic implications related to activation of the TARC/CCL17-CCR4 axis.
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Affiliation(s)
- Julien Catherine
- Department of Internal Medicine, Hôpital Erasme, 808 Route de Lennik, 1070, Brussels, Belgium. .,Institute for Medical Immunology, Université Libre de Bruxelles, 6041 Gosselies, Brussels, Belgium.
| | - Florence Roufosse
- Department of Internal Medicine, Hôpital Erasme, 808 Route de Lennik, 1070, Brussels, Belgium.,Institute for Medical Immunology, Université Libre de Bruxelles, 6041 Gosselies, Brussels, Belgium
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Jacobsen EA, Jackson DJ, Heffler E, Mathur SK, Bredenoord AJ, Pavord ID, Akuthota P, Roufosse F, Rothenberg ME. Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies. Annu Rev Immunol 2021; 39:719-757. [PMID: 33646859 PMCID: PMC8317994 DOI: 10.1146/annurev-immunol-093019-125918] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The enigmatic eosinophil has emerged as an exciting component of the immune system, involved in a plethora of homeostatic and inflammatory responses. Substantial progress has been achieved through experimental systems manipulating eosinophils in vivo, initially in mice and more recently in humans. Researchers using eosinophil knockout mice have identified a contributory role for eosinophils in basal and inflammatory processes and protective immunity. Primarily fueled by the purported proinflammatory role of eosinophils in eosinophil-associated diseases, a series of anti-eosinophil therapeutics have emerged as a new class of drugs. These agents, which dramatically deplete eosinophils, provide a valuable opportunity to characterize the consequences of eosinophil knockout humans. Herein, we comparatively describe mouse and human eosinophil knockouts. We put forth the view that human eosinophils negatively contribute to a variety of diseases and, unlike mouse eosinophils, do not yet have an identified role in physiological health; thus, clarifying all roles of eosinophils remains an ongoing pursuit.
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Affiliation(s)
- Elizabeth A Jacobsen
- Division of Allergy, Asthma and Clinical Immunology, Mayo Clinic, Scottsdale, Arizona 85259, USA;
| | - David J Jackson
- Guy's and St Thomas' Hospitals, London WC2R 2LS, United Kingdom;
- Department of Immunobiology, King's College London, London WC2R 2LS, United Kingdom
| | - Enrico Heffler
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy
- Personalized Medicine, Asthma and Allergy Unit, Humanitas Clinical and Research Center IRCCS, 20089 Milan, Italy;
| | - Sameer K Mathur
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin 53792, USA;
| | - Albert J Bredenoord
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Ian D Pavord
- Respiratory Medicine Unit, Oxford Respiratory NIHR BRC, Nuffield Department of Medicine, Oxford OX3 9DU, United Kingdom;
| | - Praveen Akuthota
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA;
| | - Florence Roufosse
- Médecine Interne, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium;
| | - Marc E Rothenberg
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA;
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Lessons learned from targeting eosinophils in human disease. Semin Immunopathol 2021; 43:459-475. [PMID: 33891135 DOI: 10.1007/s00281-021-00849-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/02/2021] [Indexed: 02/08/2023]
Abstract
Eosinophils are a minor subset of the granulocyte lineage distinguished by their unique morphology, phenotype, cytoplasmic contents, and function. Evolutionarily, these are ancient cells whose existence has been conserved within vertebrates for millions of years, suggesting that their contribution to innate immunity and other pathologic and homeostatic responses are important to the host. Knowledge regarding the role of eosinophils in health and disease took a leap forward in 2004 with the creation of mouse strains deficient in eosinophils. This advance was paralleled in humans using pharmacology, namely, with the development of drugs capable of selectively reducing and sometimes even eliminating human eosinophils in those receiving these agents. As a result, a more definitive picture of what eosinophils do, and do not do, is emerging. This review will summarize recent advances in our understanding of the role of eosinophils in human disease by focusing mainly on data from clinical studies with anti-eosinophil therapies, even though the first of such agents, mepolizumab, was only approved in the USA in November 2015. Information regarding both efficacy and safety will be highlighted, and where relevant, intriguing data from animal models will also be mentioned, especially if there are conflicting effects seen in humans.
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De Bruyn Carlier T, Badloe FMS, Ring J, Gutermuth J, Kortekaas Krohn I. Autoreactive T cells and their role in atopic dermatitis. J Autoimmun 2021; 120:102634. [PMID: 33892348 DOI: 10.1016/j.jaut.2021.102634] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023]
Abstract
Atopic dermatitis (AD) is an itchy, non-contagious relapsing and chronic inflammatory skin disease that usually develops in early childhood. This pathology is associated with food allergy, allergic asthma, allergic rhinitis and anaphylaxis which may persist in adulthood. The underlying mechanisms of AD (endotypes) are just beginning to be discovered and show a complex interaction of various pathways including skin barrier function and immune deviation. Immune reactions to self-proteins (autoantigens) of the skin have been identified in patients with inflammatory skin diseases, such as chronic spontaneous urticaria, connective tissue disease, pemphigus vulgaris and bullous pemphigoid. IgE antibodies and T cells directed against epitopes of the skin were observed in adult patients with severe and chronic AD as well. This was associated with disease severity and suggests a progression from allergic inflammation to severe autoimmune processes against the skin. IgE-mediated autoimmunity and self-reactive T cells might accelerate the ongoing skin inflammation or might contribute to the relapsing course of the disease. However, to date, the exact mechanisms of IgE-mediated autoimmunity and self-reactive T cells in the pathophysiology of AD are still unclear. The aim of this review is to evaluate the development of (autoreactive) T cells and their response to (auto)antigens, as well as the role of the peripheral tolerance in autoimmunity in the pathophysiology of AD, including the unmet needs and gaps.
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Affiliation(s)
- Tina De Bruyn Carlier
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium.
| | - Fariza Mishaal Saiema Badloe
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
| | - Johannes Ring
- Department of Dermatology and Allergology Biederstein, Technical University Munich, München, Germany.
| | - Jan Gutermuth
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
| | - Inge Kortekaas Krohn
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
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Liu J, Ting JP, Al-Azzam S, Ding Y, Afshar S. Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases. Int J Mol Sci 2021; 22:ijms22062805. [PMID: 33802091 PMCID: PMC8001105 DOI: 10.3390/ijms22062805] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/02/2021] [Accepted: 03/06/2021] [Indexed: 02/08/2023] Open
Abstract
Since 2015, 170 small molecules, 60 antibody-based entities, 12 peptides, and 15 gene- or cell-therapies have been approved by FDA for diverse disease indications. Recent advancement in medicine is facilitated by identification of new targets and mechanisms of actions, advancement in discovery and development platforms, and the emergence of novel technologies. Early disease detection, precision intervention, and personalized treatments have revolutionized patient care in the last decade. In this review, we provide a comprehensive overview of current and emerging therapeutic modalities developed in the recent years. We focus on nine diseases in three major therapeutics areas, diabetes, autoimmune, and neurological disorders. The pathogenesis of each disease at physiological and molecular levels is discussed and recently approved drugs as well as drugs in the clinic are presented.
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Affiliation(s)
- Jinsha Liu
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Joey Paolo Ting
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Shams Al-Azzam
- Professional Scientific Services, Eurofins Lancaster Laboratories, Lancaster, PA 17605, USA;
| | - Yun Ding
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Sepideh Afshar
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
- Correspondence:
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Ahn J, Choi Y, Simpson EL. Therapeutic New Era for Atopic Dermatitis: Part 1. Biologics. Ann Dermatol 2020; 33:1-10. [PMID: 33911806 PMCID: PMC7875213 DOI: 10.5021/ad.2021.33.1.1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/18/2020] [Accepted: 09/23/2020] [Indexed: 12/11/2022] Open
Abstract
Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disease driven by immune dysregulation and skin barrier dysfunction. We are currently experiencing a new era of understanding of the pathogenesis of AD and, as a consequence, a new era of innovation in therapeutics, including small molecules and biologic therapy. Recently, advances in translational research have challenged the traditional AD pathogenesis paradigm of AD being solely a Th2-dominant disease. Other immune pathways seem to play a role in the complex AD pathophysiology, although the clinical relevance of these additional immune pathway abnormalities is unclear. Type 1, type 22, and type 17 pathway activation (with related cytokines/chemokines) have been demonstrated in the skin and blood of AD patients. Type 2 (interleukin [IL]-4, IL-13), IL-31, and type 22 (IL-22) pathway cytokines are increased in AD acute lesions. IL-22 induces both an epidermal hyperplasia at the onset of acute AD and a marked increase in the terminal differentiation S100 genes. This understanding of pathogenesis corresponds to a historic increase in therapeutic development in AD. The extreme clinical heterogeneity and the chronic progression of AD establish the need for newer, safer, and more effective treatments, control the disease, and improve the quality of life of affected patients.
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Affiliation(s)
- Jiyoung Ahn
- Department of Dermatology, National Medical Center, Seoul, Korea
| | - Yusung Choi
- Department of Dermatology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Eric Lawrence Simpson
- Department of Dermatology, Oregon Health & Science University, Portland, OR, United States
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Kucuksezer UC, Ozdemir C, Cevhertas L, Ogulur I, Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy and allergen tolerance. Allergol Int 2020; 69:549-560. [PMID: 32900655 DOI: 10.1016/j.alit.2020.08.002] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 08/10/2020] [Indexed: 12/28/2022] Open
Abstract
Allergen-specific immunotherapy (AIT) is the mainstay treatment for the cure of allergic disorders, with depicted efficacy and safety by several trials and meta-analysis. AIT impressively contributes to the management of allergic rhinitis, asthma and venom allergies. Food allergy is a new arena for AIT with promising results, especially via novel administration routes. Cell subsets with regulatory capacities are induced during AIT. IL-10 and transforming growth factor (TGF)-β are the main suppressor cytokines, in addition to surface molecules such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) within the micro milieu. Modified T- and B-cell responses and antibody isotypes, increased activity thresholds for eosinophils, basophils and mast cells and consequent limitation of inflammatory cascades altogether induce and maintain a state of sustained allergen-specific unresponsiveness. Established tolerance is reflected into the clinical perspectives as improvement of allergy symptoms together with reduced medication requirements and evolved disease severity. Long treatment durations, costs, reduced patient compliance and risk of severe, even life-threatening adverse reactions during treatment stand as major limiting factors for AIT. By development of purified non-allergenic, highly-immunogenic modified allergen extracts, and combinational usage of them with novel adjuvant molecules via new routes may shorten treatment durations and possibly reduce these drawbacks. AIT is the best model for custom-tailored therapy of allergic disorders. Better characterization of disease endotypes, definition of specific biomarkers for diagnosis and therapy follow-up, as well as precision medicine approaches may further contribute to success of AIT in management of allergic disorders.
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Abstract
Atopic dermatitis (AD) is a common chronic inflammatory skin disease that has become a global health problem. The pathophysiology of AD includes both skin barrier and immune abnormalities, with type 2 immune deviation central to several clinical phenotypes and underlying endotypes. Recognition of the persistent nature and systemic aspects of AD provides a rationale for treatment with a biologic. Dupilumab has been approved for patients 6 years of age and older with moderate to severe AD. Monoclonal antibodies are in phase 3 trials and may become part of a precision medicine approach to AD.
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MESH Headings
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Biological Products/pharmacology
- Biological Products/therapeutic use
- Clinical Trials as Topic
- Dermatitis, Atopic/diagnosis
- Dermatitis, Atopic/drug therapy
- Dermatitis, Atopic/immunology
- Dermatitis, Atopic/pathology
- Drug Approval
- Humans
- Immunoglobulin E/metabolism
- Interleukin-13/antagonists & inhibitors
- Interleukin-13/metabolism
- Interleukin-4/metabolism
- Interleukin-4 Receptor alpha Subunit/antagonists & inhibitors
- Interleukin-4 Receptor alpha Subunit/metabolism
- Off-Label Use
- Omalizumab/pharmacology
- Omalizumab/therapeutic use
- Receptors, Interleukin/antagonists & inhibitors
- Receptors, Interleukin/metabolism
- Severity of Illness Index
- Signal Transduction/drug effects
- Signal Transduction/immunology
- Skin/drug effects
- Skin/immunology
- Skin/pathology
- Treatment Outcome
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Affiliation(s)
- Mark Boguniewicz
- Division of Allergy-Immunology, Department of Pediatrics, National Jewish Health and University of Colorado School of Medicine, 1400 Jackson Street, J310, Denver, CO 80206, USA.
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Matsuda‐Hirose H, Takeo N, Ando M, Kizu Y, Hatano Y. Dupilumab treatment of a case of asthma, chronic rhinosinusitis, and atopic dermatitis after initial benralizumab administration. JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY 2020. [DOI: 10.1002/cia2.12115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Affiliation(s)
| | - Naoko Takeo
- Department of Dermatology Oita University Yufu Oita Japan
| | - Masaru Ando
- Departments of Respiratory Medicine and Infectious Diseases Oita University Yufu Oita Japan
| | - Yumi Kizu
- Department of Otolaryngology Head and Neck Surgery Faculty of Medicine Oita University Yufu Oita Japan
| | - Yutaka Hatano
- Department of Dermatology Oita University Yufu Oita Japan
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Abstract
PURPOSE OF REVIEW Atopic dermatitis (AD), chronic spontaneous urticaria (CSU), and allergic contact dermatitis (ACD) represent three important allergic dermatoses with many unmet therapeutic needs. The development of biologic agents has opened the door to both new treatment options and improved understanding of the underlying pathophysiology, both shared and unique for these entities. With several FDA-approved medications available and many more in development, the biologic revolution has begun for allergic dermatoses. RECENT FINDINGS This is a narrative review on the current state of pathomechanisms and appropriately targeted biologic agents for these three common allergic skin conditions. The importance of Th2 inflammation and the effect of inflammatory cytokines on the skin barrier may help explain the impressive efficacy of biologic agents, while maintaining relative safety. While some of the biologic agents show efficacy across multiple allergic dermatoses, more often it seems these more targeted pathways show accordingly precise efficacy. However, in each disease, multiple agents hold promise, and may be differentiated by safety and adverse effect profile rather than simply by efficacy. New understanding of the pathogenesis of the allergic dermatoses has ushered in a new era of biologic therapies. Competing mechanisms and molecules will continue to be developed and vetted in trials with hopes of continuously refined precision therapies with optimized safety and efficacy profiles.
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Affiliation(s)
- Sara N Bilimoria
- Northwestern University Feinberg School of Medicine, 363 W. Erie Street, Suite 350, Chicago, IL, 60616, USA
| | - Peter A Lio
- Northwestern University Feinberg School of Medicine, 363 W. Erie Street, Suite 350, Chicago, IL, 60616, USA.
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Wu J, Guttman-Yassky E. Efficacy of biologics in atopic dermatitis. Expert Opin Biol Ther 2020; 20:525-538. [PMID: 32003247 DOI: 10.1080/14712598.2020.1722998] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 01/25/2020] [Indexed: 12/22/2022]
Abstract
Introduction: Atopic dermatitis (AD) is a heterogeneous disease. Recent advancements in understanding AD pathogenesis resulted in the exponential expansion of its therapeutic pipeline, particularly following the success and FDA-approval of dupilumab. Different phenotypes of AD by age and ethnicity have also recently been described and clinical studies of emerging treatments will further clarify the role of each cytokine pathway in AD.Areas covered: We review the impressive repertoire of biologics for treatment of moderate-to-severe AD, including those targeting Th2, Th22, Th17/IL-23 and IgE. We highlight the scientific rationale behind each approach and provide a discussion of the most recent clinical efficacy and safety data.Expert opinion: AD is a complex disease and recent research has identified numerous endotypes, reinforcing the rationale for developing targeted therapeutics to antagonize these factors. Dupilumab has revolutionized AD treatment and its mechanistic studies also offer crucial insight into AD pathogenesis. Nevertheless, this biologic does not work for everyone, highlighting the need for a more precise approach to address the unique immune fingerprints of each AD subset. Ultimately targeted therapeutics will complement our understanding of the AD molecular map and help push AD management into an era of personalized medicine.
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Affiliation(s)
- Jianni Wu
- Department of Dermatology, Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, USA
- College of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA
| | - Emma Guttman-Yassky
- Department of Dermatology, Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, USA
- Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA
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