Allergy REVIEW ARTICLE EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders O. Boyman1, C. Kaegi1, M. Akdis2,3, S. Bavbek4, A. Bossios5, A. Chatzipetrou6, T. Eiwegger7, D. Firinu8, T. Harr9, E. Knol10, A. Matucci11, O. Palomares12, C. Schmidt-Weber13, H.-U. Simon14, U. C. Steiner15, A. Vultaggio11, C. A. Akdis2,3 & F. Spertini16 1Department of Immunology, University Hospital Zurich, University of Zurich, Zurich; 2Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos; 3Christine Kuhne-Center€ for Allergy Research and Education (CK-CARE), Davos, Switzerland; 4Division of Immunology and Allergy, Department of Pulmonary Disease, School of Medicine, Ankara University, Ankara, Turkey; 5Krefting Research Centre, Department of Internal Medicine and Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 6Allergy Unit ‘D. Kalogeromitros’, 2nd Department of Dermatology and Venereology, ‘Attikon’ University Hospital, Medical School, University of Athens, Athens, Greece; 7Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria; 8Unit of Internal Medicine, Allergy and Clinical Immunology, Department of Medical Sciences ‘M. Aresu’, University of Cagliari, Monserrato, Italy; 9Service d’Immunologie et d’Allergologie, Specialit es de Medecine, Hopitaux^ Universitaires de Geneve, Geneva, Switzerland; 10Departments of Immunology and Dermatology/Allergology, University Medical Center Utrecht, Utrecht, The Netherlands; 11Immunoallergology Unit, Department of Biomedicine, Azienda Ospedaliero Universitaria Careggi, Florence, Italy; 12Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of Madrid, Madrid, Spain; 13Center of Allergy and Environment (ZAUM), Technische Universitat€ and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Germany; 14Institute of Pharmacology, University of Bern, Bern; 15Division of Allergology and Clinical Immunology, Spitalnetz Bern Tiefenau Ziegler, Bern; 16Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland To cite this article: Boyman O, Kaegi C, Akdis M, Bavbek S, Bossios A, Chatzipetrou A, Eiwegger T, Firinu D, Harr T, Knol E, Matucci A, Palomares O, Schmidt-Weber C, Simon H-U, Steiner UC, Vultaggio A, Akdis CA, Spertini F. EAACI IG biologicals task force paper on the use of biologic agents in allergic disorders. Allergy 2015; 70: 727–754. Keywords Abstract allergic rhinitis; asthma; atopic dermatitis; Biologic agents (also termed biologicals or biologics) are therapeutics that are synthe- eosinophilic disorders; food allergy; hymenoptera allergy; urticaria. sized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have rev- Correspondence olutionized the treatment of several immune-mediated disorders. Biologicals have Onur Boyman, MD, Department of also been tested in allergic disorders. These include agents targeting IgE; T helper 2 Immunology, University Hospital Zurich, (Th2)-type and Th2-promoting cytokines, including interleukin-4 (IL-4), IL-5, IL-9, University of Zurich, Raemistrasse 100, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP); pro-inflammatory cyto- CH-8091 Zurich, Switzerland. kines, such as IL-1b, IL-12, IL-17A, IL-17F, IL-23, and tumor necrosis factor Tel.: +41 44 255 2069 Fax: +41 44 255 1400 (TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, E-mail: [email protected] including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Accepted for publication 22 March 2015 Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on DOI:10.1111/all.12616 their state of development, area of use, adverse events, and future research directions. Edited by: Thomas Bieber Abbreviations ABPA, allergic bronchopulmonary aspergillosis; ACQ-5/ACQ-6/ACQ-7, 5-item/6-item/7-item ACQ; ACQ, asthma control questionnaire; ADA, antidrug antibody; AD, atopic dermatitis; AE, adverse event; BHR, bronchial hyper-responsiveness; CAU, chronic autoimmune urticaria; CindU, chronic inducible urticaria; CSU, chronic spontaneous urticaria; DC, dendritic cell; EGPA, eosinophilic granulomatosis with polyangiitis; EoE, eosinophilic esophagitis; FeNO, exhaled nitric oxide; FEV1, forced expiratory volume in one second; HES, hypereosinophilic syndromes; ICS, inhaled corticosteroid; ILC, innate lymphoid cell; IL, interleukin; IM, intramuscular; IV, intravenous; LABA, long-acting beta-agonist; mAb, monoclonal antibody; NKT, natural killer T cell; NP, nasal polyposis; OIT, oral immunotherapy; PEF, peak expiratory flow; QoL, quality of life; RCT, randomized controlled trial; RIT, rush immunotherapy; SAE, serious adverse event; SAR, seasonal allergic rhinitis; SC, subcutaneous; SIT, specific immunotherapy; Th, T helper; TNF, tumor necrosis factor (also known as TNF--a); TSLP, thymic stromal lymphopoietin; VIT, venom-specific immunotherapy. Allergy 70 (2015) 727–754 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 727 Biologicals in allergic disorders Boyman et al. Allergen Pathogens Epithelium IL-25 IL-13R IL-33 ILC2 TNF TSLP IL-13 Periostin IL-1β APC IL-5 IL-13 MHC-II Plasma Differentiation cell IgE Afferent lymphatic CD20 B cell BCR Th2 Efferent lymphatics IL-12 CD25 IL-4 IL-2 Th2 IL-5 CD2 Th2 IL-13 Th2 APC LFA-3 IL-4 TCR Th0 Differentiation CD80 CD86 CD28 Lymph node Figure 1 The sensitization phase of an allergic reaction. An allergic interaction of major histocompatibility complex (MHC) class II/aller- reaction requires the priming (or sensitization) of an individual to an gen fragmentÀT-cell receptor (TCR), CD80/CD86ÀCD28, and lym- allergen. Allergens enter via microlesions of a body surface (such phocyte function-associated antigen 3 (LFA-3)ÀCD2, as well as as the skin or the lungs), and their entry might be accompanied by cytokines, including IL-12. Under the influence of these interac- a concomitant exposure to pathogens. The allergen is phagocy- tions and stimuli, Th0 cells differentiate to Th2 cells, producing the tosed by antigen-presenting cells (APC), which subsequently Th2-type cytokines IL-4 and IL-13 and further expanding via auto- mature, aided by stimulation with different cytokines produced by and paracrine actions of IL-2 binding to CD25 along with IL-2 activated epithelial cells, such as tumor necrosis factor (TNF), receptor bc. In parallel, allergen-specific B cells become activated IL-1b, IL-33, and thymic stromal lymphopoietin (TSLP), as well as via their B-cell receptor (BCR) by the allergen, leading to their dif- contact with microbial products. Early on, also type-2 innate lym- ferentiation and, under the influence of Th2-type cytokines, isotype phoid cells (ILC2) become activated by IL-25 among other factors, class switching to IgE-producing plasma cells. During this process, and produce IL-5 and IL-13, the latter of which can act on epithelial B cells lose their surface CD20 expression. The molecules high- cells. Mature APCs migrate to the local draining lymph nodes lighted in yellow indicate the targets of biologicals for allergic where they stimulate undifferentiated CD4+ T helper (Th0) cells via disorders. 728 Allergy 70 (2015) 727–754 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Boyman et al. Biologicals in allergic disorders Allergen Epithelium Mucus Goblet Epithelial cells cell IL-13 IL-4 IL-22 IgE Histamine etc. CCL5 FcεR Mast cell CCL17 CCL22 IL-9 CCR4 Th2 OX40L IL-9 IL-5 IL-17 IL-17 IL-22 Th17 TNFR Eosinophil IL-5R FcεR Th17 IgE Th2 Basophil Neutrophil Blood vessel Figure 2 The re-exposure and chronic relapsing phase of an aller- such as CCR4 by chemokines produced in these tissues, includ- gic reaction. In an individual sensitized to an allergen (see Fig. 1), ing CCL5, CCL17, and CCL22 in the skin. Th2 cells, upon activa- the allergen-specific IgE molecules produced by B cells and tion by their T-cell receptor or cytokines, secrete Th2-type plasma cells have bound, via Fce receptors FceRI and FceRII, to cytokines, including IL-4, IL-5, IL-9, and IL-13, which synergize mast cells and basophils. Upon re-exposure to the same allergen, with other sources of these cytokines to stimulate immune, epi- allergen molecules bind to these IgE molecules, thereby cross- thelial, and airway goblet cells (the latter producing mucus in the linking and activating FceRs on mast cells and basophils and lead- airways). Chronification of certain allergic disorders is paralleled by ing to the release within minutes of various mediators, such as a recruitment of Th17 cells, able to produce IL-17 and IL-22, histamine, leukotrienes, prostaglandins, tryptase, heparin, seroto- which stimulate neutrophils and epithelial cells, respectively. Neu- nin, and proteases. Similar to the arming of mast cells by IgE fol- trophils can also be stimulated by various other cytokines, includ- lowing sensitization, also T helper 2 (Th2) cells become recruited ing TNF. The molecules highlighted in yellow indicate the targets to peripheral sites via activation of specific chemokine receptors of biologicals for allergic disorders. Allergy 70 (2015) 727–754 © 2015 John Wiley & Sons A/S. Published by John Wiley &