Shinji Noda, MD, PhD, James G

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The translational revolution and use of biologics in patients with inflammatory skin diseases Shinji Noda, MD, PhD, James G. Krueger, MD, PhD, Emma Guttman-Yassky, MD, PhD Journal of Allergy and Clinical Immunology Volume 135, Issue 2, Pages 324-336 (February 2015) DOI: 10.1016/j.jaci.2014.11.015 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Histologic features of psoriasis and AD. A-C, Histologic differences between psoriatic (Fig 1, A), AD (Fig 1, B), and normal (Fig 1, C) skin by immunostaining with hematoxylin and eosin (H&E), K16, CD3+ T cells, and CD11c+ DCs. Although more evident in patients with psoriasis, both diseases result in acanthosis with marked T-cell and DC infiltrates in superficial dermis. D, Epidermal thickness, K16 mRNA expression determined by means of RT-PCR, and CD3 and CD11c cell counts. Data are modified from Guttman-Yassky et al,2 Khattri et al,3 and Guttman-Yassky et al.4 Journal of Allergy and Clinical Immunology 2015 135, 324-336DOI: (10.1016/j.jaci.2014.11.015) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Early psoriasis and AD models. A, Fixed pathogenic models. In patients with psoriasis, epidermal hyperplasia results from autocrine growth factors released by keratinocytes and fibroblasts. Earlier models emphasized possible vascular pathogenesis. In patients with AD, epidermal hyperplasia is due to keratinocyte/barrier defects. In both types of patients, the immune infiltrate is a bystander reaction. EGFR, Epidermal growth factor receptor. B, Reversible disease phenotypes. Both psoriasis and AD are characterized by abnormal cornification, a reduced granular layer, K16 overexpression, and an increase in Ki67+ keratinocytes (activation of epidermal proliferation). Parakeratosis is mostly a characteristic feature of patients with psoriasis. These phenotypes are reversible with treatment, including narrow-band UVB and cyclosporine. C and D, Early immune models based on the TH1/TH2 paradigm. Fig 2, C, In patients with psoriasis, the TH1 axis was considered a key driver. IL-12 activates TH1 cells to secrete IFN-γ, inducing TH1-related genes, with secondary inflammation and epidermal abnormalities. MX1, Myxovirus resistance 1; STAT1, signal transducer and activator of transcription 1. Fig 2, D, In patients with AD, TH2 skewing was considered the main driver. Inherent defects in the epithelial barrier lead to penetration by epicutaneous antigens, which encounter Langerhans cells (LCs) and induce TH2 cells to produce IL-4 and IL-13 cytokines, which suppress differentiation and disrupt barrier function. CCL17 and CCL22 attract T cells to lesional AD skin. Journal of Allergy and Clinical Immunology 2015 135, 324-336DOI: (10.1016/j.jaci.2014.11.015) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 TH1-, TH2-, TH17-, and TH22-related markers in skin from patients with psoriasis (PSO), skin from patients with AD, and normal skin by using RT-PCR. A, Whereas psoriasis deviates toward TH17 and TH1 responses, AD polarizes toward a TH2 response. B, Although the downstream TH17 mediators human β-defensin 2 (HBD2; in Fig 3, A) and CXCL1 are highly upregulated in patients with psoriasis, the TH2 chemokines CCL17 and CCL22 (in Fig 3, A) are overexpressed in patients with AD. The TH1 axis (CXCL9) shows relatively higher activation in patients with psoriasis. IL-22 is similarly activated in patients with psoriasis and AD. Data are modified from Guttman-Yassky et al,9 Guttman-Yassky et al,2 Khattri et al,3 and Guttman-Yassky et al.4 Journal of Allergy and Clinical Immunology 2015 135, 324-336DOI: (10.1016/j.jaci.2014.11.015) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Multiple TH subset models in patients with psoriasis and AD. A, Psoriasis (chronic stage). The IL-23/TH17 axis is the key driver in psoriasis. TNF and inducible nitric oxide synthase–producing DCs (TIP-DCs) become activated to produce IL-23. This drives production of IL-17 from TH17 cells and IL-22 from TH22 cells. IL-17 activates keratinocytes to produce CCL20 and AMPs. IL-17 also induces synthesis of CXCL1, CXCL2, CXCL3, and CXCL8, which attract neutrophils. IL-22 induces epidermal hyperplasia and K16 and signal transducer and activator of transcription (STAT) 3 expression. It also synergizes with IL-17 to increase production of S100s. IL-12 drives IFN-γ production, which induces TH1-related products. IL-29 produced from TH17 cells also induces TH1 mediators. LCN2, Lipocalin 2; MX1, myxovirus resistance 1. B, AD (nonlesional, acute, and chronic stages). Barrier defects lead to penetration of epicutaneous antigens and keratinocyte production of IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). Langerhans cells (LCs) and DCs are activated and induce IL-4 and IL-13 production from TH2 cells. These cytokines suppress terminal differentiation and lipid production, disrupting barrier function. TH2 cells also secrete an itch-inducing cytokine, IL-31, leading to itch-scratch cycles and lichenification. Barrier damage causes TSLP induction and amplifies TH2 cytokine production. IL-22 induces epidermal hyperplasia and barrier inhibition. IL-17 synergizes with IL-22 to induce S100 family proteins and also has a role in promoting TH2 differentiation. The TH1 axis is moderately activated in patients with AD. FFA, Free fatty acid. Journal of Allergy and Clinical Immunology 2015 135, 324-336DOI: (10.1016/j.jaci.2014.11.015) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Clinical therapeutic responses in patients with AD and those with psoriasis. A, Psoriasis is characterized by well-demarcated reddish plaques with thick, silvery-white scales. Significant responses to a single dose of 300 mg of guselkumab are shown. B, AD lesions are characterized by widely distributed erythema and excoriation. Clinical symptoms are remarkably relieved by cyclosporine treatment. Data are modified from Khattri et al3 and Sofen et al.65 Journal of Allergy and Clinical Immunology 2015 135, 324-336DOI: (10.1016/j.jaci.2014.11.015) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions